NO139563B - PROCEDURES FOR THE PREPARATION OF 1-N- (L - (-) - ALFA-HYDROXY-GAMMA-AMINOBUTYRYL) -XK-62-2 - Google Patents
PROCEDURES FOR THE PREPARATION OF 1-N- (L - (-) - ALFA-HYDROXY-GAMMA-AMINOBUTYRYL) -XK-62-2 Download PDFInfo
- Publication number
- NO139563B NO139563B NO74744448A NO744448A NO139563B NO 139563 B NO139563 B NO 139563B NO 74744448 A NO74744448 A NO 74744448A NO 744448 A NO744448 A NO 744448A NO 139563 B NO139563 B NO 139563B
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- Norway
- Prior art keywords
- compound
- hydroxy
- acid
- haba
- formula
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- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical group CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
Classifications
-
- 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
- C07H15/226—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings
- C07H15/234—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2
- C07H15/236—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2 a saccharide radical being substituted by an alkylamino radical in position 3 and by two substituents different from hydrogen in position 4, e.g. gentamicin complex, sisomicin, verdamycin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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
Description
Foreliggende oppfinnelse vedrører en fremgangsmåte The present invention relates to a method
til fremstilling av det hittil ukjente 1-N-/L-(-)-a-hydroksy-y-aminobutyryl7XK-62-2, et halvsyntetisk derivat av antibioti- for the production of the hitherto unknown 1-N-/L-(-)-a-hydroxy-y-aminobutyryl7XK-62-2, a semi-synthetic derivative of the antibiotic
kumet XK-62-2, eller syreaddisjonssalter derav. kumet XK-62-2, or acid addition salts thereof.
Fremgangsmåten til fremstilling av og de fysikalsk-kjemiske egenskaper til antibiotikumet XK-62-2, som anvendes som utgangs-materiale ved fremgangsmåten ifølge oppfinnelsen, er beskrevet i detalj i U.S. patent nr. 4.045.298 The method for producing and the physico-chemical properties of the antibiotic XK-62-2, which is used as starting material in the method according to the invention, is described in detail in U.S. patent No. 4,045,298
Kort fortalt fremstilles XK-62-2 lett ved dyrking av aktinomyceter, slik som Micromonospora sagamiensis, Micromonospora echinospora og Micromonospora purpurea ved metoder som vanligvis benyttes til dyrking av aktinomyceter. Nærmere bestemt innpodes stammer av de ovennevnte microorganismer i et flytende medium inneholdende en karbonkilde som mikroorganismen kan utnytte, slik som sukkerstoffer, hydrokarboner, alkoholer, organiske syrer osv.; uorganiske eller organiske nitrogenkilder og dessuten uorganiske salter og vekstfremmende faktorer, og dyrkes ved 25_iJ0oC i 2-12 Briefly, XK-62-2 is easily produced by culturing actinomycetes, such as Micromonospora sagamiensis, Micromonospora echinospora and Micromonospora purpurea by methods usually used for culturing actinomycetes. More specifically, strains of the above-mentioned microorganisms are inoculated into a liquid medium containing a carbon source that the microorganism can utilize, such as sugars, hydrocarbons, alcohols, organic acids, etc.; inorganic or organic nitrogen sources and also inorganic salts and growth-promoting factors, and grown at 25_iJ0oC for 2-12
dager. Isoleringen og rensing av XK-62-2 utføres ved en passende kombinasjon av adsorpsjon og desorpsjon fra ioneutvekslerharpikser og aktivkull og søylekromatografi under anvendelse av cellulose, "Sephadex" og silisiumdioksydgel. På denne måte kan XK-62-2 days. The isolation and purification of XK-62-2 is carried out by a suitable combination of adsorption and desorption from ion exchange resins and activated carbon and column chromatography using cellulose, "Sephadex" and silica gel. In this way, the XK-62-2
oppnås i form av sulfatet eller i den frie form. obtained in the form of the sulphate or in the free form.
XK-62-2 er et basisk stoff og oppnås som et hvitt pulver. XK-62-2 har molekylformelen C^H^Nt-O,-, og molekylvekten 463. XK-62-2 is a basic substance and is obtained as a white powder. XK-62-2 has the molecular formula C^H^Nt-O,-, and the molecular weight 463.
Stoffet er lett oppløselig i vann og metanol, tungt oppløselig i The substance is easily soluble in water and methanol, poorly soluble in
etanol og aceton og uoppløselig i kloroform, benzen, etylacetat og n-heksan. ethanol and acetone and insoluble in chloroform, benzene, ethyl acetate and n-hexane.
Foreliggende oppfinnelse angår fremstilling av et The present invention relates to the production of a
hittil ukjent antibiotikum ved kjemisk modifisering av antibio- hitherto unknown antibiotic by chemical modification of antibio-
tikum XK-62-2 med formelen: tikum XK-62-2 with the formula:
Fremgangsmåten ifølge oppfinnelsen er kjennetegnet ved The method according to the invention is characterized by
det i kravets kjennetegnende del anførte. that stated in the distinguishing part of the claim.
Beskyttelsen'av aminogruppen bundet til karbonatomet i 2'-stilling kan utføres med et acyleringsmiddel med formelen: The protection of the amino group attached to the carbon atom in the 2' position can be carried out with an acylating agent of the formula:
hvor R<1> og R kan være like eller forskjellige og er H, OH, N02, Cl, Br, I, alkyl med 1-5 karbonatomer eller alkoksy med 1-5 karbonatomer, R^ er Cl, Br eller I, og R er H, Cl, Br eller I, med en aminobeskyttende reagens med formelen: , hvor R har den ovenfor angitte betydning, for dannelse av en forbindelse med formelen: 1 2 hvor Y er hydrogen, og Y er: 12 4 i hvor 2R , R og R har den ovenfor angitte betydning, eller Y og Y danner en ftaloylgruppe. where R<1> and R can be the same or different and are H, OH, NO2, Cl, Br, I, alkyl of 1-5 carbon atoms or alkoxy of 1-5 carbon atoms, R^ is Cl, Br or I, and R is H, Cl, Br or I, with an amino-protecting reagent of the formula: , where R is as defined above, to form a compound of the formula: 1 2 where Y is hydrogen, and Y is: 12 4 i where 2R , R and R have the meaning given above, or Y and Y form a phthaloyl group.
Den resulterende forbindelse acyleres deretter med et acyleringsmiddel med formelen: The resulting compound is then acylated with an acylating agent of the formula:
3 4 hvor Y er hydrogen, og Y er: 12 4 .. 3 hvor R , R og R har den ovenfor angitte betydning, eller Y og Y 11 danner en ftaloylgruppe, og Z er for dannelse av en forbindelse med formelen: i 2 "5 4 hvor Y-1-, Y , Y og Y har den ovenfor angitte betydning, hvor-12 3 4 etter de beskyttende grupper Y , Y , Y og Y fjernes på kjent måte for dannelse av en forbindelse med formelen: 3 4 where Y is hydrogen, and Y is: 12 4 .. 3 where R , R and R have the meaning given above, or Y and Y 11 form a phthaloyl group, and Z is for the formation of a compound of the formula: i 2 "5 4 where Y-1-, Y , Y and Y have the above meaning, where-12 3 4 after the protective groups Y , Y , Y and Y are removed in a known manner to form a compound with the formula:
om ønsket, denne forbindelse ytterligere overføres til et farmasøytisk akseptabelt, ikke-toksisk syreaddisjonssalt på kjent måte. if desired, this compound is further converted to a pharmaceutically acceptable, non-toxic acid addition salt in known manner.
Det ved fremgangsmåten ifølge oppfinnelsen fremstilte derivat av XK-62-2 har en sterk antibakteriell aktivitet overfor en rekke gram-positive og gram-negative bakterier og har spesielt en særlig sterk antibakteriell aktivitet overfor de bakterier som er resistente overfor de kjente aminoglykosid-antibiotika. The derivative of XK-62-2 produced by the method according to the invention has a strong antibacterial activity against a number of gram-positive and gram-negative bacteria and in particular has a particularly strong antibacterial activity against those bacteria which are resistant to the known aminoglycoside antibiotics.
Som en følge av dette er det ifølge oppfinnelsen fremstilte antibiotikum nyttig for rensing og sterilisering av laboratorie-glassutstyr og kirurgiske instrumenter og kan også anvendes i kombinasjon med forskjellige såper til hygieneformål og til rensing og sterilisering av hospitalrom og områder, som benyttes til fremstilling av matvarer. Videre forventes derivatet å være effektivt ved behandling av forskjellige infeksjoner slik som urinveisinfeksjoner og luftveisinfeksjoner fremkalt av forskjellige flogogene bakterier. As a consequence of this, the antibiotic produced according to the invention is useful for cleaning and sterilizing laboratory glassware and surgical instruments and can also be used in combination with various soaps for hygiene purposes and for cleaning and sterilizing hospital rooms and areas used for the production of foodstuffs . Furthermore, the derivative is expected to be effective in the treatment of various infections such as urinary tract infections and respiratory tract infections caused by various phlogogenic bacteria.
På tegningen viser The drawing shows
fig. 1 det infrarøde absorpsjonsspektrum for den ifølge oppfinnelsen fremstilte forbindelse; og fig. 1 the infrared absorption spectrum for the compound produced according to the invention; and
fig. 2 det magnetiske kjerneresonans-spektrum for den ifølge oppfinnelsen fremstilte forbindelse. fig. 2 the nuclear magnetic resonance spectrum for the compound produced according to the invention.
Ved fremgangsmåten ifølge oppfinnelsen fremstilles 1-N-/L-(-)-a-hydroksy-Y-aminobutyryl7-XK-62-2 ved blant de tre frie aminogrupper i XK-62-2 selektivt å acylere den frie aminogruppe bundet til karbonatomet i 1-stillingen med en a-hydroksy-y-amino-butyrylgruppe. In the method according to the invention, 1-N-/L-(-)-a-hydroxy-Y-aminobutyryl7-XK-62-2 is produced by selectively acylating the free amino group bound to the carbon atom among the three free amino groups in XK-62-2 in the 1-position with an α-hydroxy-γ-amino-butyryl group.
Som nevnt ovenfor beskyttes først den frie aminogruppe bundet til karbonatomet i 2'-stillingen som er den mest reaktive blant de tre frie aminogrupper i XK-62-2, ved utnytt-else av forskjellen i reaktivitet mellom disse frie aminogrupper. As mentioned above, the free amino group bound to the carbon atom in the 2' position, which is the most reactive among the three free amino groups in XK-62-2, is first protected by exploiting the difference in reactivity between these free amino groups.
Beskyttelsen av aminogruppen utføres på vanlig måte. Por imidlertid selektivt å beskytte aminogruppen bundet til karbonatomet i 2'-stilling, er det ønskelig å benytte 0,5-1,5 The protection of the amino group is carried out in the usual way. However, in order to selectively protect the amino group bound to the carbon atom in the 2' position, it is desirable to use 0.5-1.5
mol, fortrinnsvis 0,7-1,2 mol, beskyttende stoff pr. mol XK- mol, preferably 0.7-1.2 mol, protective substance per mol XK-
62-2. Reaksjonstemperaturen er mellom -50 og +50°C, fortrinnsvis mellom -20 og +20°C, i fra 15 minutter til 24 timer, fortrinnsvis 5-15 timer. Hvis det benyttes en forøket mengde, f.eks. 3 mol, av det beskyttende stoff, eller reaksjonen utføres ved en for høy temperatur, f.eks. 100°C, kan reaksjonen foregå, men selektiviteten av den stilling hvori den beskyttende gruppe innføres, nedsettes sterkt. Som en følge av dette, forminskes dannelsesforholdet av forbindelse II i reaksjonsblandingen. 62-2. The reaction temperature is between -50 and +50°C, preferably between -20 and +20°C, for from 15 minutes to 24 hours, preferably 5-15 hours. If an increased amount is used, e.g. 3 mol, of the protective substance, or the reaction is carried out at too high a temperature, e.g. 100°C, the reaction can take place, but the selectivity of the position in which the protecting group is introduced is greatly reduced. As a result, the formation ratio of compound II in the reaction mixture decreases.
Oppløsningsmidlet for reaksjonen'kan være minst ett oppløsningsmiddel valgt blant tetrahydrofuran, dimetylacetamid, dimetylformamid, lavere alkoholer, dioksan, etylenglykol-dimetyleter, pyridin og vann. The solvent for the reaction may be at least one solvent selected from tetrahydrofuran, dimethylacetamide, dimethylformamide, lower alcohols, dioxane, ethylene glycol dimethyl ether, pyridine and water.
Den således fremstilte forbindelse (II) acyleres deretter med et. acyleringsmiddel med formelen: hvor Y 3 , Y 4og Z har den ovenfor angitte betydning, eller en forbindelse som er funksjonelt ekvivalent med nevnte acyleringsmiddel, for dannelse av en forbindelse med formelen: The thus prepared compound (II) is then acylated with et. acylating agent of the formula: where Y 3 , Y 4 and Z have the above meaning, or a compound functionally equivalent to said acylating agent, to form a compound of the formula:
hvor Y 1, Y 2 , Y 3 og Y 4har den ovenfor angitte betydning. where Y 1, Y 2 , Y 3 and Y 4 have the meaning stated above.
Ovennevnte acyleringsreaksjon utføres fortrinnsvis ved anvendelse av et acyleringsmiddel med formelen: The above-mentioned acylation reaction is preferably carried out using an acylating agent with the formula:
i et oppløsningsmiddel valgt blant tetrahydrofuran, dimetylacetamid, dimetylformamid, lavere alkoholer, dioksan, etylenglykol-dimetyleter, pyridin, vann og blandinger derav, fortrinnsvis i en blanding av etanol og vann i volumforholdet 2:1 ved en temperatur mellom -50 og +50°C, fortrinnsvis mellom -20 og 20°C, i fra 15 minutter til 24 timer, fortrinnsvis 5~15 timer. in a solvent selected from tetrahydrofuran, dimethylacetamide, dimethylformamide, lower alcohols, dioxane, ethylene glycol dimethyl ether, pyridine, water and mixtures thereof, preferably in a mixture of ethanol and water in the volume ratio 2:1 at a temperature between -50 and +50° C, preferably between -20 and 20°C, for from 15 minutes to 24 hours, preferably 5~15 hours.
I dette tilfellet er det ønskelig å benytte 0,5_1,5 mol, fortrinnsvis 0,7-ls2 mol, acyleringsmiddel pr. mol av forbindelsen (II). Hvis det benyttes en forøket mengde, f.eks. 3 mol, av acyleringsmidlet, eller hvis reaksjonen utføres ved en forhøyet temperatur, f.eks. ved 100°C, kan reaksjonen foregå, men selektiviteten av den stilling hvori den acylerende gruppe innføres, nedsettes sterkt, eller så nedbrytes acyleringsmidlet. Som en følge av dette forminskes dannelsesforholdet av forbindelsen (III) i reaksjonsblandingen. In this case, it is desirable to use 0.5-1.5 mol, preferably 0.7-12 mol, of acylating agent per moles of the compound (II). If an increased amount is used, e.g. 3 mol, of the acylating agent, or if the reaction is carried out at an elevated temperature, e.g. at 100°C, the reaction can take place, but the selectivity of the position in which the acylating group is introduced is greatly reduced, or the acylating agent is degraded. As a result of this, the formation ratio of the compound (III) in the reaction mixture is reduced.
De beskyttende grupper på forbindelsen (III) fjernes deretter på kjent måte for dannelse av en forbindelse med formelen: The protecting groups on the compound (III) are then removed in a known manner to form a compound of the formula:
Fjerningen utføres ved konvensjonelle metoder. Hvis The removal is carried out by conventional methods. If
f.eks. de beskyttende grupper danner en ftaloylgruppe, utføres fjerningen med hydrazin; hvis de beskyttende grupper er metoksykarbonyl-grupper eller etoksykarbonylgrupper utføres fjerningen med barium-hydroksyd; hvis de beskyttende grupper er tertiær-butoksykarbonyl-grupper, utføres fjerningen med maursyre eller trifluoreddiksyre; e.g. the protecting groups form a phthaloyl group, the removal is carried out with hydrazine; if the protecting groups are methoxycarbonyl groups or ethoxycarbonyl groups, the removal is carried out with barium hydroxide; if the protecting groups are tertiary butoxycarbonyl groups, the removal is carried out with formic acid or trifluoroacetic acid;
hvis de beskyttende grupper er tritylgrupper, utføres fjerningen med eddiksyre eller trifluoreddiksyre; hvis de beskyttende grupper er o-nitrofenylsulfenylgrupper, utføres fjerningen med eddiksyre eller saltsyre; og hvis de beskyttende grupper er kloracetylgrupper utføres fjerningen med 3-nitropyridin-2-tion (rapportert av K. Undheim et al: Journal of the Chemical Society, Parkin Transactions, Part I, side 829 (1973)). if the protecting groups are trityl groups, the removal is carried out with acetic acid or trifluoroacetic acid; if the protecting groups are o-nitrophenylsulfenyl groups, the removal is carried out with acetic acid or hydrochloric acid; and if the protecting groups are chloroacetyl groups, the removal is carried out with 3-nitropyridine-2-thione (reported by K. Undheim et al: Journal of the Chemical Society, Parkin Transactions, Part I, page 829 (1973)).
I en foretrukken utførelsesform er Y1 og Y^ hydrogen, In a preferred embodiment, Y1 and Y^ are hydrogen,
2 4 2 4
og Y og Y er benzyloksykarbonylgrupper, og fjerningen utføres ved hydrogenolyse i nærvær av en metallkatalysator valgt blant palladium, platina, rhodium og Raney-nikkel, fortrinnsvis palladium på en bærer av aktivkull, i minst ett oppløsningsmiddel valgt blant vann, tetrahydrofuran, dimetylacetamid, dimetylformamid, lavere alkoholer, dioksan og etylenglykol-dimetyleter, fortrinnsvis i en blanding av vann og metanol i volumforholdet 1:1, i nærvær av en liten mengde saltsyre, hydrogenbromidsyre, hydrogenjodidsyre eller fortrinnsvis eddiksyre; ved romtemperatur og atmosfæretrykk. and Y and Y are benzyloxycarbonyl groups, and the removal is carried out by hydrogenolysis in the presence of a metal catalyst selected from palladium, platinum, rhodium and Raney nickel, preferably palladium on a support of activated carbon, in at least one solvent selected from water, tetrahydrofuran, dimethylacetamide, dimethylformamide , lower alcohols, dioxane and ethylene glycol dimethyl ether, preferably in a mixture of water and methanol in the volume ratio 1:1, in the presence of a small amount of hydrochloric acid, hydrobromic acid, hydroiodic acid or preferably acetic acid; at room temperature and atmospheric pressure.
Om ønsket kan den ovenfor fremstilte forbindelse (IV) overføres til farmasøytisk akseptable, ikke-toksiske syreaddisjonssalter (mono-, di-, tri-, tetra- eller penta-salter). Ikke-toksiske syrer er f.eks. uorganiske syrer slik som saltsyre, hydrogenbromidsyre, hydrogenjodidsyre, svovelsyre, fosforsyre, karbonsyre osv., og organiske syrer slik som eddiksyre, fumarsyre, eplesyre, sitron-syre, rnandelsyre, vinsyre, askorbinsyre osv. Fremgangsmåtene til fremstilling av syreaddisjonssaltene er velkjente innen teknikken. If desired, the compound (IV) prepared above can be transferred to pharmaceutically acceptable, non-toxic acid addition salts (mono-, di-, tri-, tetra- or penta-salts). Non-toxic acids are e.g. inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, carbonic acid, etc., and organic acids such as acetic acid, fumaric acid, malic acid, citric acid, randelic acid, tartaric acid, ascorbic acid, etc. The methods for preparing the acid addition salts are well known in the art.
Det halvsyntetiske derivat (IV) av XK-62-2 som fremstilles ved fremgangsmåten ifølge oppfinnelsen har en utmerket antibakteriell aktivitet. Det er spesielt bemerkelsesverdig at derivatet har en sterk antibakteriell aktivitet overfor stammer av Escherichia coli med en R-faktor som viser resistens overfor kjente aminoglykosid-antibiotika. The semi-synthetic derivative (IV) of XK-62-2 which is produced by the method according to the invention has an excellent antibacterial activity. It is particularly noteworthy that the derivative has a strong antibacterial activity against strains of Escherichia coli with an R factor showing resistance to known aminoglycoside antibiotics.
Tabell 1 viser det antibakterielle spektrum av kanamycin A, gentamicin C, la. XK-62-2 og forbindelsen (IV) overfor forskjellige gram-positive og gram-negative bakterier målt ved agar-fortynningsmetoden ved pH 8,0. Table 1 shows the antibacterial spectrum of kanamycin A, gentamicin C, la. XK-62-2 and the compound (IV) against various Gram-positive and Gram-negative bacteria measured by the agar dilution method at pH 8.0.
Ut fra en sammenligning av den i tabell 1 anførte minimale inhiberende konsentrasjon er det klart at forbindelsen (IV) har en sterk antibakteriell aktivitet. Karakteristisk utviser forbindelsen en særlig sterk antibakteriell aktivitet overfor Escherichia coli KY 8327 og 8348. From a comparison of the minimal inhibitory concentration listed in Table 1, it is clear that the compound (IV) has a strong antibacterial activity. Characteristically, the compound exhibits a particularly strong antibacterial activity against Escherichia coli KY 8327 and 8348.
I den ovenfor angitte tabell produserer Escherichia coli KY 8327 og KY 8348 henholdsvis gentamicin-adenyltransferase og gentamicin-acetyltransferase type I intracellulært. Den førstnevnte bakterie inaktiverer kanamycin og gentamiciner ved adenylering, og den sistnevnte inaktiverer gentamiciner ved acetylering. In the above table, Escherichia coli KY 8327 and KY 8348 produce gentamicin adenyltransferase and gentamicin acetyltransferase type I intracellularly, respectively. The former bacterium inactivates kanamycin and gentamicins by adenylation, and the latter inactivates gentamicins by acetylation.
Videre vises det antibakterielle spektrum av l-N-/L-(-)-a-hydroksy-y-aminobutyryl7-XK-62-2 (forbindelse IV) sammenlignet med kanamycin A, gentamicin-kompleks (C^, C^ a og C^) og XK-62-2 målt ved agar-fortynningsmetoden ved pH 7, 2 i nedenstående tabell 2. Furthermore, the antibacterial spectrum of l-N-/L-(-)-α-hydroxy-γ-aminobutyryl7-XK-62-2 (compound IV) compared to kanamycin A, gentamicin complex (C^, C^ a and C^ ) and XK-62-2 measured by the agar dilution method at pH 7.2 in Table 2 below.
1: produserer gentamicin-adenyltransferase 1: produces gentamicin adenyltransferase
2: produserer gentamicin-adenyltransferase og neomycin-kanamycin-fosfotransferase type II 2: produces gentamicin adenyltransferase and neomycin-kanamycin phosphotransferase type II
3: produserer gentamicin-acetyltransferase type I 3: produces gentamicin acetyltransferase type I
4: produserer neomycin-kanamycin-fosfotransferase type I 4: produces neomycin-kanamycin phosphotransferase type I
5: produserer kanamycin-acetyltransferase 5: produces kanamycin acetyltransferase
6: produserer gentamicin-acetyltransferase type I og neomycin-kanamycin-fosfotransferase type I 6: produces gentamicin acetyltransferase type I and neomycin-kanamycin phosphotransferase type I
7: produserer neomycin-kanamycin-fosfotransferase type I og type II 7: produces neomycin-kanamycin phosphotransferase type I and type II
og streptomycin-fosfotransferase and streptomycin phosphotransferase
8: produserer muligens kanamycin-acetyltransferase 9: produserer gentamicin-acetyltransferase type II 8: possibly produces kanamycin acetyltransferase 9: produces gentamicin acetyltransferase type II
Fra ovenstående tabell 2 er det klart at den ved fremgangsmåten ifølge oppfinnelsen fremstilte forbindelse (IV), 1-N-(L-(-)-a-hydroksy-Y-aminobutyryl)-XK-62-2 har en meget sterk antibakteriell aktivitet overfor forskjellige bakterier med resistens overfor minst ett av gentamicin-antibiotika og XK-62-2, som produserer gentamicin-adenyltransferase og/eller gentamicin-acetyltransf erase type I og type II intracellulært og derved inaktiverer gentamicin-antibiotika og XK-62-2. From the above table 2, it is clear that the compound (IV) produced by the method according to the invention, 1-N-(L-(-)-α-hydroxy-Y-aminobutyryl)-XK-62-2 has a very strong antibacterial activity against various bacteria with resistance to at least one of gentamicin antibiotics and XK-62-2, which produce gentamicin adenyltransferase and/or gentamicin acetyltransferase type I and type II intracellularly and thereby inactivate gentamicin antibiotics and XK-62-2.
Videre er det ved forskjellige forsøk med hensyn til beskyttelsen mot infeksjoner fremkalt av stammer av de førstnevnte resistente bakterier påvist at den ved fremgangsmåten ifølge oppfinnelsen fremstilte forbindelse bevarer a-hydroksy-y-aminobutyryl-gruppen in vivo og derfor utviser meget høyere antibakteriell aktivitet enn genetamicin-antibiotika og XK-62-2. Furthermore, in various experiments with regard to the protection against infections caused by strains of the first-mentioned resistant bacteria, it has been demonstrated that the compound produced by the method according to the invention preserves the α-hydroxy-γ-aminobutyryl group in vivo and therefore exhibits much higher antibacterial activity than genetamicin -antibiotics and XK-62-2.
Fra DE-OS 2.234.315 er det kjent en fremgangsmåte for innføring av L-(-)-a-hydroksy-y-aminobutyrylgruppen (i det følg-ende betegnet "HABA") på aminogruppen i 1-stillingen av kanamycin A eller kanamycin B (i det følgende betegnet henholdsvis "KMA" og "KMB") for dannelse av henholdsvis 1-N-HABA-KMA og 1-N-HABA-KMB. From DE-OS 2,234,315, a method is known for introducing the L-(-)-α-hydroxy-γ-aminobutyryl group (hereinafter referred to as "HABA") onto the amino group in the 1-position of kanamycin A or kanamycin B (hereinafter referred to as "KMA" and "KMB") to form 1-N-HABA-KMA and 1-N-HABA-KMB, respectively.
I nedenstående tabell 3 er det angitt data for sammenligning av det antibakterielle spektrum overfor 63 mikroorganisme-stammer for den ifølge oppfinnelsen fremstilte forbindelse (i det følgende betegnet l-N-HABA-XK-62-2) og den kjente forbindelse 1-N-HABA-KMA. Den minimale inhiberende konsentrasjon (i det følgende betegnet "MIC") er målt ved samme metode som angitt i forbindelse med tabell 2 ovenfor. Table 3 below shows data for comparison of the antibacterial spectrum against 63 microorganism strains for the compound produced according to the invention (hereinafter referred to as 1-N-HABA-XK-62-2) and the known compound 1-N-HABA- KMA. The minimal inhibitory concentration (hereinafter referred to as "MIC") is measured by the same method as indicated in connection with Table 2 above.
Fra tabell 3 fremgår det at l-N-HABA-XK-62-2 er vesentlig bedre enn 1-N-HABA-KMA fordi det er mer effektivt overfor 30 stammer og ekvivalent med 1-N-HABA-KMA overfor de andre stammer. Ved bedømmelsen av antibakteriell aktivitet ansees en forskjell på én størrelsesorden (2- eller 1/2-ganger) i MIC, for å være usignifikant og en forskjell på mer enn to størrelses-ordner (4- eller 1/4-ganger) i MIC, ansees for å være signifikant. From table 3 it appears that 1-N-HABA-XK-62-2 is significantly better than 1-N-HABA-KMA because it is more effective against 30 strains and equivalent to 1-N-HABA-KMA against the other strains. When assessing antibacterial activity, a difference of one order of magnitude (2- or 1/2-fold) in MIC is considered insignificant and a difference of more than two orders of magnitude (4- or 1/4-fold) in MIC , is considered to be significant.
Videre har l-N-HABA-XK-62-2 følgende spesielle trekk. Furthermore, l-N-HABA-XK-62-2 has the following special features.
Det er kjent at et aminoglykosid-antibiotikum, som har en primær aminogruppe i 6<1->stillingen, inaktiveres av en mikroorganisme som inneholder acetyltransferase. 1-N-HABA-KMA og 1-N-HABA-KMB har en primær aminogruppe i 6'-stillingen. Det antas derfor at disse antibiotika inaktiveres av en mikroorganisme som inneholder acetyltransferase og at de er ineffektive overfor en slik mikroorganisme. På den annen side, siden aminogruppen i 6'-stillingen av l-N-HABA-XK-62-2 er beskyttet av en metylgruppe, inaktiveres dette antibiotikum ikke av en mikroorganisme som inneholder acetyltransferase, og den er derfor effektiv overfor en en slik mikroorganisme. Dette bevises av at l-N-HABA-XK-62-2 It is known that an aminoglycoside antibiotic, having a primary amino group in the 6<1-> position, is inactivated by a microorganism containing acetyltransferase. 1-N-HABA-KMA and 1-N-HABA-KMB have a primary amino group in the 6' position. It is therefore assumed that these antibiotics are inactivated by a microorganism containing acetyltransferase and that they are ineffective against such a microorganism. On the other hand, since the amino group in the 6' position of 1-N-HABA-XK-62-2 is protected by a methyl group, this antibiotic is not inactivated by a microorganism containing acetyltransferase and is therefore effective against such a microorganism. This is proven by the fact that l-N-HABA-XK-62-2
har en høyere antibakteriell aktivitet enn 1-N-HABA-KMA overfor en mikroorganisme som inneholder kanamycinacetyltransferase. has a higher antibacterial activity than 1-N-HABA-KMA against a microorganism containing kanamycin acetyltransferase.
I tabell 3 er Escherichia coli KY Z-3^3, Pseudomonas aeruginosa KY 8510, Pseudomonas aeruginosa KY 8516 og Serratia marcescens POE IO65 mikroorganismer som inneholder kanamycin-acetyltransf erase . Fra de i tabell 3 angitte data for MIC fremgår det at l-N-HABA-XK-62-2 er mer effektive enn 1-N-HABA-KMA overfor disse fire mikroorganismer. In Table 3, Escherichia coli KY Z-3^3, Pseudomonas aeruginosa KY 8510, Pseudomonas aeruginosa KY 8516 and Serratia marcescens POE IO65 are microorganisms that contain kanamycin acetyltransferase. From the data for MIC shown in Table 3, it appears that 1-N-HABA-XK-62-2 is more effective than 1-N-HABA-KMA against these four microorganisms.
Selv om det ikke er noen forsøksdata i tilfelle av 1-N-HABA-KMB, må det naturligvis forventes at 1-N-HABA-KMB med en primær aminogruppe i 6'-stillingen er mindre effektiv enn l-N-HABA-XK-62-2 overfor de fire ovennevnte mikroorganismer. Although there are no experimental data in the case of 1-N-HABA-KMB, it is naturally to be expected that 1-N-HABA-KMB with a primary amino group in the 6' position is less effective than 1-N-HABA-XK-62 -2 against the four above-mentioned microorganisms.
Det er også kjent at et aminoglykosid-antibiotikum It is also known that an aminoglycoside antibiotic
som har en hydroksygruppe i 3'-stillingen, inaktiveres av en mikroorganisme som inneholder fosfotransferase. KMA, KMB, 1-N-HABA-KMA og 1-N-HABA-KMB har en hydroksygruppe i 3'-stillingen. Det antas derfor at disse antibiotika fosforeres av en mikroorganisme som inneholder fosfotransferase og at de er ineffektive overfor en slik mikroorganisme. Det angis faktisk i tabell IV i US-patent nr. 3-781.268 at MIC for KMA og BBK-26 (1-N-HABA-KMB) overfor Pseudomonas aeruginosa D113, som inneholder fosforylase, er henholdsvis >50 og 50. De høye MIC-verdier viser at KMA og 1-N-HABA-KMB er ineffektive overfor Ps. aeruginosa D113. which has a hydroxy group in the 3' position, is inactivated by a microorganism containing phosphotransferase. KMA, KMB, 1-N-HABA-KMA and 1-N-HABA-KMB have a hydroxy group in the 3' position. It is therefore assumed that these antibiotics are phosphorylated by a microorganism containing phosphotransferase and that they are ineffective against such a microorganism. Indeed, it is stated in Table IV of US Patent No. 3-781,268 that the MICs of KMA and BBK-26 (1-N-HABA-KMB) against Pseudomonas aeruginosa D113, which contain phosphorylase, are >50 and 50, respectively. The high MIC values show that KMA and 1-N-HABA-KMB are ineffective against Ps. aeruginosa D113.
På den annen side antas det at et aminoglykosid-antibiotikum uten en hydroksygruppe i 3'-stillingen, slik som XK-62-2 og l-N-HABA-XK-62-2, ikke fosforeres av en mikroorganisme som inneholder fosforylase og at antibiotikumet er effektivt overfor en slik mikroorganisme. For eksempel er Escherichia coli On the other hand, it is believed that an aminoglycoside antibiotic without a hydroxy group in the 3' position, such as XK-62-2 and 1-N-HABA-XK-62-2, is not phosphorylated by a microorganism containing phosphorylase and that the antibiotic is effective against such a microorganism. An example is Escherichia coli
KY 8349 og Pseudomonas aeruginosa KY 8512 i tabell 2 mikroorga- KY 8349 and Pseudomonas aeruginosa KY 8512 in Table 2 microorganism
nismer som inneholder noemycin-kanamycin-fosfotransforase type I. nisms containing noemycin-kanamycin-phosphotransferase type I.
Det er klart at XK-62-2 og l-N-HABA-XK-62-2 er effektive overfor It is clear that XK-62-2 and l-N-HABA-XK-62-2 are effective against
disse mikroorganismer ettersom MIC for XK-62-2 overfor disse mikroorganismer er henholdsvis 0,4 og 0,78, og MIC av l-N-HABA-XK-62-2 overfor dem er henholdsvis 0,2 og 0,78. På den annen these microorganisms as the MIC of XK-62-2 against these microorganisms is 0.4 and 0.78, respectively, and the MIC of l-N-HABA-XK-62-2 against them is 0.2 and 0.78, respectively. On the other
side er det klart at KMA er ineffektivt overfor disse mikroorganismer ettersom MIC av KMA overfor dem er henholdsvis >100 og 12,5- side, it is clear that KMA is ineffective against these microorganisms as the MIC of KMA against them is respectively >100 and 12.5-
Fra de foregående tabeller er det klart at den ved fremgangsmåten ifølge oppfinnelsen fremstilte forbindelse utviser en bemerkelsesverdig sterk antibakteriell aktivitet overfor en rekke gram-positive bakterier og gram-negative bakterier, inkludert de som er resistente overfor aminoglykosidantibiotika. Derfor forventes den å.være effektiv ved behandling av forskjellige infeksjoner hos mennesker og dyr fremkalt av slike flogogene bakterier. F.eks. forventes forbindelsen å være effektiv ved behandling av urinveisinfeksjoner og luftveisinfeksjoner fremkalt av Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa og stammer av slekten Proteus. From the preceding tables, it is clear that the compound produced by the method according to the invention exhibits a remarkably strong antibacterial activity against a number of gram-positive bacteria and gram-negative bacteria, including those resistant to aminoglycoside antibiotics. It is therefore expected to be effective in the treatment of various infections in humans and animals caused by such phlogogenic bacteria. E.g. the compound is expected to be effective in the treatment of urinary tract infections and respiratory tract infections caused by Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and strains of the genus Proteus.
Ved administrasjon av forbindelsen eller dens syreaddisjonssalter foretrekkes parenteral administrasjon med en effektiv dose på 1,6-6 mg/kg pr. dag. When administering the compound or its acid addition salts, parenteral administration is preferred with an effective dose of 1.6-6 mg/kg per day.
Den akutte toksisitet (LD^q) til 1-N-/L-(-)-a-hydroksy-y-aminobutyryl7-XK-62-2 hos mus er 250 mg/kg ved intravenøs injeksjon, mens toksisiteten av XK-62-2 og av gentamicin-komplekset (en blanding av C-^, <C>la og C2) er henholdsvis 93 mg/kg og 72 mg/kg. The acute toxicity (LD^q) of 1-N-/L-(-)-α-hydroxy-γ-aminobutyryl7-XK-62-2 in mice is 250 mg/kg by intravenous injection, while the toxicity of XK-62 -2 and of the gentamicin complex (a mixture of C-^, <C>1a and C2) are 93 mg/kg and 72 mg/kg respectively.
Fremgangsmåten ifølge oppfinnelsen illustreres nærmere The method according to the invention is illustrated in more detail
ved følgende utførelseseksempler. in the following execution examples.
Eksempel 1 Example 1
Fremstilling av 2'- N- karbobenzoksy- XK- 62- 2 ( forbindelse II) Preparation of 2'-N-carbobenzoxy-XK-62-2 (compound II)
En prøve av XK-62-2 (2,778 g, 6,0 mmol) oppløses i A sample of XK-62-2 (2.778 g, 6.0 mmol) is dissolved in
30 ml vandig 50% dimetylformamid. Til oppløsningen tilsettes dråpevis en oppløsning av N-(benzyloksykarbonyloksy)-succinimid (2,56 g, 1,03 mmol) i 25 ml dimetylformamid under omrøring, mens temperaturen holdes mellom -10 og 5°C. ^ Tilsetningen fullføres i løpet av 2 timer. Blandingen hensettes ved samme temperatur natten over. Ved silisiumdioksydgel-tynnsjiktskromatografi (utviklingsmiddel: isopropanol/ konsentrert ammoniakkvann/kloroform i volumforholdet 2:1:1; farge-middel, ninhydrin) bekreftes tilstedeværelsen av ureagert XK-62-2 foruten hovedproduktet II (Rf 0,86). Reaksjonsblandingen fortynnes deretter med 30 ml vann og føres gjennom en søyle (diameter 2,5 cm) 30 ml of aqueous 50% dimethylformamide. A solution of N-(benzyloxycarbonyloxy)-succinimide (2.56 g, 1.03 mmol) in 25 ml of dimethylformamide is added dropwise to the solution with stirring, while the temperature is kept between -10 and 5°C. ^ The addition is completed within 2 hours. The mixture is left at the same temperature overnight. By silica gel thin-layer chromatography (developing agent: isopropanol/concentrated ammonia water/chloroform in the volume ratio 2:1:1; coloring agent, ninhydrin) the presence of unreacted XK-62-2 is confirmed in addition to the main product II (Rf 0.86). The reaction mixture is then diluted with 30 ml of water and passed through a column (diameter 2.5 cm)
av en ioneutvekslerharpiks "Amberlite <®> CG-50" (ammoniumform, 150 ml). Deretter føres 200 ml vann gjennom søylen etterfulgt av 300 ml of an ion exchange resin "Amberlite <®> CG-50" (ammonium form, 150 ml). Then 200 ml of water is passed through the column followed by 300 ml
0,05 N vandig ammoniakk, 300 ml 0,10 N vandig ammoniakk og til slutt 0,15 N vandig ammoniakk. Eluatet undersøkes ved tynnsjiktskromatograf: og fraksjonene inneholdende forbindelsen II og den eneste komponent kombineres og inndampes til tørrhet under forminsket trykk. Som resultat oppnås hovedproduktet (forbindelse II) som et fargeløst amorft fast stoff (1,82 g, utbytte 47, 2%). Den således oppnådde prøve kan direkte anvendes som råmateriale for den etterfølgende reaksjon. Imidlertid er det mulig å rense produktet ytterligere ved søylekromatografi under anvendelse av den ovennevnte ioneutveksler-harpiksbehandling. 0.05 N aqueous ammonia, 300 ml 0.10 N aqueous ammonia and finally 0.15 N aqueous ammonia. The eluate is examined by thin-layer chromatography: and the fractions containing compound II and the sole component are combined and evaporated to dryness under reduced pressure. As a result, the main product (compound II) is obtained as a colorless amorphous solid (1.82 g, yield 47.2%). The sample thus obtained can be directly used as raw material for the subsequent reaction. However, it is possible to further purify the product by column chromatography using the above ion exchange resin treatment.
Analyse av produktet (forbindelse II) viser følgende: Smeltepunkt: 107-H0°C Analysis of the product (compound II) shows the following: Melting point: 107-H0°C
Optisk dreiing: (a)^<5>= +87,7° (c = 0,10, vann) Optical rotation: (a)^<5>= +87.7° (c = 0.10, water)
Infrarødt absorpsjonsspektrum (KBr) (cm<-1>): 3700-3100, 2930, Infrared absorption spectrum (KBr) (cm<-1>): 3700-3100, 2930,
1702, 1530, 1451, 1310, 1255, llMl, 1053, 1021, 960, 735, 697, 604. Magnetisk kjerneresonansspektrum (i metanol -d^) 6 (i ppm fra TMS): 1,13 (3H, singlet), 2,42 (3H, singlet), 2,60 (3H, singlet), 2,88 1702, 1530, 1451, 1310, 1255, 11Ml, 1053, 1021, 960, 735, 697, 604. Nuclear magnetic resonance spectrum (in methanol -d^) 6 (in ppm from TMS): 1.13 (3H, singlet), 2.42 (3H, singlet), 2.60 (3H, singlet), 2.88
(2H, singlet), 5,33-4,90 (multiplet overlapper signalet fra OH), (2H, singlet), 5.33-4.90 (the multiplet overlaps the signal from OH),
7,43 (5H, singlet). 7.43 (5H, singlet).
Elementæranalyse: Elemental analysis:
Beregnet for CggH^NgO. 2H20: C 53,08 - H 8,06 - N 11,06. Calculated for CggH^NgO. 2H 2 O: C 53.08 - H 8.06 - N 11.06.
Funnet: C 53,19 - H 7,91 - N 10,02. Found: C 53.19 - H 7.91 - N 10.02.
Fremstilling av 1-N-/L-(-)-a-hydroksy-y-karbobenzoksy-aminobutyryl7-21lN=karbobenzokSY-XK-62-2_(forb Preparation of 1-N-/L-(-)-a-hydroxy-y-carbobenzoxy-aminobutyryl7-21lN=carbobenzoxSY-XK-62-2_(forb
2'-N-karbobenzoksy-XK-62-2-dihydrat (643 mg, 1,0 millimol) oppløses i 20 ml vandig 50$ tetrahydrofuran. Til oppløsningen tilsettes dråpevis en oppløsning av N-hydroksysuccinimidesteren av L-(-)-a-hydroksy-Y-karbobenzoksy-aminosmørsyre (fremstillingen av forbindelsen fra L-(-)-a-hydroksy-y-aminosmørsyre er beskrevet i 2'-N-Carbobenzoxy-XK-62-2-dihydrate (643 mg, 1.0 mmol) is dissolved in 20 mL of aqueous 50% tetrahydrofuran. A solution of the N-hydroxysuccinimide ester of L-(-)-α-hydroxy-Y-carbobenzoxy-aminobutyric acid is added dropwise to the solution (the preparation of the compound from L-(-)-α-hydroxy-γ-aminobutyric acid is described in
the Journal of Antibiotics, Vol. XXV, side 695-708 (1972). Fremstillingen av L-(-)-a-hydroksy-Y-aminosmørsyre er beskrevet i Tetrahedron Letters, side 2625-2628 (1971)) (385 mg, 1,1 millimol) i the Journal of Antibiotics, Vol. XXV, pages 695-708 (1972). The preparation of L-(-)-α-hydroxy-Y-aminobutyric acid is described in Tetrahedron Letters, pages 2625-2628 (1971)) (385 mg, 1.1 mmol) in
10 ml tetrahydrofuran under omrøring og avkjøling til mellom 0 og -5°C. Tilsetningen fullføres i løpet av 1 time. Blandingen hensettes deretter natten over. Ved silisiumdioksydgel-tynnsjiktskromatografi (under de samme betingelser som beskrevet ovenfor påvises tilstedeværelsen av en liten mengde biprodukter og ureagert forbindelse II foruten hovedproduktet III (Rf 0,91). Reaksjonsblandingen konsentreres under forminsket trykk, hvorved det oppnås 1,05 g av en svakt gulaktig rest. Resten inneholder N-hydroksysuccinimid og L-(-)-a-hydroksy-y-karbo-benzoksyaminosmørsyre foruten de ovennevnte komponenter. Imidlertid anvendes resten til den etterfølgende reaksjon uten rensing. Om ønsket kan forbindelsen III isoleres og renses ved ioneutveksler-kromatografi på< samme måte som beskrevet ovenfor. 10 ml of tetrahydrofuran with stirring and cooling to between 0 and -5°C. The addition is completed within 1 hour. The mixture is then allowed to stand overnight. Silica gel thin-layer chromatography (under the same conditions as described above) shows the presence of a small amount of by-products and unreacted compound II in addition to the main product III (Rf 0.91). The reaction mixture is concentrated under reduced pressure, whereby 1.05 g of a slightly yellowish residue. The residue contains N-hydroxysuccinimide and L-(-)-α-hydroxy-γ-carbo-benzoxyaminobutyric acid in addition to the above components. However, the residue is used for the subsequent reaction without purification. If desired, compound III can be isolated and purified by ion exchange chromatography in< the same way as described above.
Fremstilling av l-N-/E-(-)-a-hydroksy-Y-aminobutyryl7-XK-62-2 i£2rbindelse_IV) Preparation of 1-N-/E-(-)-α-hydroxy-Y-aminobutyryl7-XK-62-2 i£2rcompound_IV)
Det ovennevnte urene produkt inneholdende forbindelsen III som hovedkomponent, oppløses i 20 ml vandig 20% metanol. Til oppløsningen tilsettes 2 ml eddiksyre, og blandingen underkastes hydrogenolyse i nærvær av 150 mg 5% palladium-på-aktivkull ved romtemperatur og atmosfæretrykk i 6 timer. Ved silisiumdioksydgel-tynnsj iktskromatograf i (under de samme betingelser som beskrevet ovenfor) påvises tilstedeværelsen av forbindelsen IV (Rf 0,40) som hovedkomponent, en liten mengde XK-62-2 (på grunn av ureagert II) The above-mentioned impure product containing compound III as the main component is dissolved in 20 ml of aqueous 20% methanol. 2 ml of acetic acid is added to the solution, and the mixture is subjected to hydrogenolysis in the presence of 150 mg of 5% palladium-on-activated carbon at room temperature and atmospheric pressure for 6 hours. By silica gel thin-layer chromatography (under the same conditions as described above), the presence of the compound IV (Rf 0.40) as the main component is detected, a small amount of XK-62-2 (due to unreacted II)
og de stillingsisomere av forbindelsen IV. Katalysatoren fjernes ved. filtrering, og filtratet konsentreres under forminsket trykk. Resten oppløses deretter i 10 ml vann, og oppløsningen underkastes inoeutvekslerkromatografi under anvendelse av "Amberlite<®> CG-50" and the positional isomers of compound IV. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is then dissolved in 10 ml of water and the solution subjected to ion exchange chromatography using "Amberlite<®> CG-50"
(ammoniumform, 80 ml, søylens diameter: 1,5 cm) som beskrevet ovenfor. (ammonium form, 80 ml, column diameter: 1.5 cm) as described above.
Søylen vaskes deretter med 150 ml vann, og 0,2N vandig ammoniakk føres gjennom søylen for utvinning av XK-62-2 (63 mg). Elueringen utføres deretter med 0,4N vandig ammoniakk mens eluatet kontrolleres ved tynnsjiktskromatografi. Eluatet inneholdende forbindelse IV som eneste komponent, opptas som fraksjoner og inndampes til tørrhet under forminsket trykk, hvorved det oppnås et fargeløst ikke-krystallinsk fast stoff (459 mg; utbytte fra forbindelsen II: 6H%) . The column is then washed with 150 ml of water, and 0.2N aqueous ammonia is passed through the column to recover XK-62-2 (63 mg). The elution is then carried out with 0.4N aqueous ammonia while the eluate is checked by thin-layer chromatography. The eluate containing compound IV as the only component is collected as fractions and evaporated to dryness under reduced pressure, whereby a colorless non-crystalline solid is obtained (459 mg; yield from compound II: 6H%).
Analyse av produktet viser følgende: Analysis of the product shows the following:
Smeltepunkt: 120-124°C. Melting point: 120-124°C.
Optisk dreiing: (ct)p9 = +99,0° (c = 0,10, vann). Optical rotation: (ct)p9 = +99.0° (c = 0.10, water).
Infrarødt absorpsjonsspektrum (KBr, cm<-1>): 3700-3100, 2940, 1610, 1565, 1480, 1385, 1340, 1282, 1111, 1054, 1022, 973, 816, 700-600 (fig. 1). Infrared absorption spectrum (KBr, cm<-1>): 3700-3100, 2940, 1610, 1565, 1480, 1385, 1340, 1282, 1111, 1054, 1022, 973, 816, 700-600 (Fig. 1).
NMR-spektrum (i deuteriumoksyd) 6 (i ppm fra DSS): 1,20 (3H, singlet), 2,36 (3H, singlet), 2,52 (3H, singlet), 5,14 (1H, dublet, J = 4,0 Hz), 5,22 (1H, dublet, J=4,0 Hz) (fig. 2). NMR spectrum (in deuterium oxide) 6 (in ppm from DSS): 1.20 (3H, singlet), 2.36 (3H, singlet), 2.52 (3H, singlet), 5.14 (1H, doublet, J = 4.0 Hz), 5.22 (1H, doublet, J=4.0 Hz) (Fig. 2).
Elementanalyse: Elemental analysis:
Beregnet for C^H^gN^. 1/2H2C03: C 49,39 - H 8,29 - N 14,11Calculated for C^H^gN^. 1/2H2CO3: C 49.39 - H 8.29 - N 14.11
Funnet: C 48,96 - H 8,37 - N 13,95-Eksempel 2 Found: C 48.96 - H 8.37 - N 13.95-Example 2
Fremstilling av 1-N-/L-(-)-a-hydroksy-y-aminobutyryl7-XK-62-2 lf2i:bindelse_IV) Preparation of 1-N-/L-(-)-α-hydroxy-γ-aminobutyryl7-XK-62-2 lf2i:bond_IV)
N-hydroksysuccinimid (113 mg; 0,97 millimol) og L-(-)-a-hydroksy-y-ftalimidosmørsyre (forbindelsen er benyttet i The Journal of Antibiotics, Vol. XXV, side 741-742 (1972)) (242 mg; 0,97 millimol) oppløses i 20 ml tetrahydrofuran. Til oppløsningen tilsettes dicykloheksylkarbodiimid (200 mg; 0,97 millimol) under omrøring og isavkjøling. Etter 1 time fjernes det utfelte dicykloheksylurea ved filtrering og filtratet tilsettes til en oppløsning av 2'-N-karbobenzoksy-XK-62-2-dihydrat (482 mg; 0,75 millimol) i 10 ml vandig 50$ tetrahydrofuran. Tilsetningen fullføres i løpet av 30 minutter. Blandingen hensettes natten over. Reaksjonsblandingen konsentreres deretter under forminsket trykk og den utskilte dicykloheksylurea fjernes ved filtrering. Resten oppløses i 10 ml vandig 50% etanol og inneholdende 10% hydrazin, og oppløsningen får lov å reagere ved 60°C i 3 timer for å fjerne ftaloylgruppen. Til N-hydroxysuccinimide (113 mg; 0.97 mmol) and L-(-)-α-hydroxy-γ-phthalimidobutyric acid (the compound is used in The Journal of Antibiotics, Vol. XXV, pages 741-742 (1972)) (242 mg; 0.97 millimol) is dissolved in 20 ml of tetrahydrofuran. Dicyclohexylcarbodiimide (200 mg; 0.97 millimoles) is added to the solution with stirring and ice-cooling. After 1 hour, the precipitated dicyclohexylurea is removed by filtration and the filtrate is added to a solution of 2'-N-carbobenzoxy-XK-62-2-dihydrate (482 mg; 0.75 mmol) in 10 ml of aqueous 50% tetrahydrofuran. The addition is completed within 30 minutes. The mixture is left overnight. The reaction mixture is then concentrated under reduced pressure and the separated dicyclohexylurea is removed by filtration. The residue is dissolved in 10 ml of aqueous 50% ethanol and containing 10% hydrazine, and the solution is allowed to react at 60°C for 3 hours to remove the phthaloyl group. To
den resulterende reaksjonsblanding tilsettes 5 ml eddiksyre, 10 ml etanol og 200 mg 5% palladium-på-aktivkull, og blandingen underkastes hydrogenolyse ved romtemperatur og atmosfæretrykk for å fjerne karbobenzoksygruppen. Katalysatoren utskilles deretter ved filtrering. Filtratet behandles på samme måte som beskrevet i eksempel 3 og underkastes søylekromatografi under anvendelse av "Amberlite ® CG-50" 5 ml of acetic acid, 10 ml of ethanol and 200 mg of 5% palladium-on-activated carbon are added to the resulting reaction mixture, and the mixture is subjected to hydrogenolysis at room temperature and atmospheric pressure to remove the carbobenzoxy group. The catalyst is then separated by filtration. The filtrate is treated in the same way as described in example 3 and subjected to column chromatography using "Amberlite ® CG-50"
(ammoniumform, 200 ml, søylens diameter: 2,5 cm). Elueringen ut-føres mens eluatet kontrolleres ved silisiumdioksydgel-tynnsjiktskromatograf i . De eluerte fraksjoner inneholdende den ønskede forbindelse IV som den eneste komponent oppsamles og inndampes til tørrhet under forminsket trykk. Som resultat oppnås 226 mg av et fargeløst produkt (utbytte fra forbindelsen II: 42,1$). Produktet (ammonium form, 200 ml, column diameter: 2.5 cm). The elution is carried out while the eluate is checked by a silicon dioxide gel thin-layer chromatograph in . The eluted fractions containing the desired compound IV as the only component are collected and evaporated to dryness under reduced pressure. As a result, 226 mg of a colorless product is obtained (yield from compound II: 42.1$). The product
viser en Rf-verdi på 0,40 ved silisiumdioksyd-tynnsjiktskromatografi (under de samme betingelser som i eksempel 1). Rf-verdien stemmer overens med Rf-verdien for forbindelse IV i eksempel 1. shows an Rf value of 0.40 by silica thin layer chromatography (under the same conditions as in Example 1). The Rf value agrees with the Rf value of compound IV in Example 1.
Eksempel 3 Example 3
Fremstilling av 1-N-/L-(-)-a-hydroksy-Y-aminobutyryl7-XK-62-2 iforDiDdelse_IV) Preparation of 1-N-/L-(-)-α-hydroxy-Y-aminobutyryl7-XK-62-2 iPreparation_IV)
En prøve av XK-62-2 (2,778 g; 6,0 millimol) oppløses i A sample of XK-62-2 (2.778 g; 6.0 mmol) is dissolved in
30 ml av en blanding av vann, pyridin og trietylamin i volumforholdet 10:10:1. Til blandingen tilsettes dråpevis en oppløsning av tertiær-butyloksykarbonylazid (1,04 g, 7,2 millimol) i 10 ml vandig 50$ pyridin under omrøring, mens temperaturen holdes mellom -10 og -5°C. Tilsetningen fullføres i løpet av 2 timer. Blandingen får deretter anledning til å reagere natten over ved samme temperatur. Den resulterende reaksjonsblanding konsentreres under forminsket trykk, hvorved det oppnås en svakt gul rest inneholdende 2'-N-tertiær-butyloksykarbonyl-XK-62-2 som hovedkomponent. Resten oppløses i 30 ml vandig 50$ dimetylformamid. 30 ml of a mixture of water, pyridine and triethylamine in the volume ratio 10:10:1. To the mixture is added dropwise a solution of tertiary-butyloxycarbonyl azide (1.04 g, 7.2 millimoles) in 10 ml of aqueous 50% pyridine with stirring, while the temperature is maintained between -10 and -5°C. The addition is completed within 2 hours. The mixture is then allowed to react overnight at the same temperature. The resulting reaction mixture is concentrated under reduced pressure, whereby a faint yellow residue is obtained containing 2'-N-tertiary-butyloxycarbonyl-XK-62-2 as the main component. The residue is dissolved in 30 ml of aqueous 50% dimethylformamide.
Til oppløsningen tilsettes dråpevis en oppløsning av N-hydroksy-succinimide.steren av L- (-) -a-hydroksy-y-karbobenzoksy-aminosmørsyre (2,52 g, 7,2 millimol ) i 15 ml dimetylformamid under omrøring, mens temperaturen holdes mellom -10 og -5°C. Tilsetningen fullføres i løpet av 1 time. Blandingen får deretter anledning til å reagere natten over. Ved silisiumdioksydgel-tynnsjiktskromatografi (under de samme betingelser som i eksempel 1) påvises tilstedeværelsen av 1-N-/L-(-)-a-hydroksy-Y-karbobenzoksyaminobutyryl7-2'-N-tertiær-butyloksykarbonyl-XK-62-2 som hovedkomponent og en To the solution is added dropwise a solution of the N-hydroxy-succinimide ester of L-(-)-α-hydroxy-γ-carbobenzoxy-aminobutyric acid (2.52 g, 7.2 mmol) in 15 ml of dimethylformamide with stirring, while the temperature kept between -10 and -5°C. The addition is completed within 1 hour. The mixture is then allowed to react overnight. By silica gel thin-layer chromatography (under the same conditions as in example 1), the presence of 1-N-/L-(-)-α-hydroxy-Y-carbobenzoxyaminobutyryl7-2'-N-tertiary-butyloxycarbonyl-XK-62-2 is detected as the main component and a
liten mengde av de stillingsisomere og ureagert XK-62-2. Reaksjonsblandingen konsentreres under forminsket trykk. Resten oppløses i en blanding av 5 ml tirfluoreddiksyre og 7 ml metanol. Oppløsningen underkastes deretter hydrogenolyse i nærvær av 160 ml 5$ palladium-på-aktivkull ved romtemperatur og atmosfæretrykk i 3 timer for å fjerne tertiær-butyloksykarbonylgruppen og benzyloksykarbonylgruppen. Ved silisiumdioksydgel-tynnsjiktskromatografi (under de samme betingelser som i eksempel 1) påvises tilstedeværelsen av forbindelse IV som hovedkomponent, en liten mengde av de stillingsisomere derav og ureagert XK-62-2 (på grunn av det ureagerte XK-62-2 small amount of the positional isomers and unreacted XK-62-2. The reaction mixture is concentrated under reduced pressure. The residue is dissolved in a mixture of 5 ml of trifluoroacetic acid and 7 ml of methanol. The solution is then subjected to hydrogenolysis in the presence of 160 ml of 5$ palladium on activated carbon at room temperature and atmospheric pressure for 3 hours to remove the tertiary butyloxycarbonyl group and the benzyloxycarbonyl group. By silica gel thin-layer chromatography (under the same conditions as in example 1), the presence of compound IV as the main component, a small amount of its positional isomers and unreacted XK-62-2 is detected (due to the unreacted XK-62-2
og ureagert 2'-N-tertiær-butyloksy-karbonyl-XK-62-2). and unreacted 2'-N-tertiary-butyloxy-carbonyl-XK-62-2).
Katalysatoren utskilles ved filtrering og filtratet konsentreres under forminsket trykk. Resten oppløses i 30 ml vann og oppløsningen behandles på samme måte som i eksempel 1, dvs. oppløsningen Underkastes søylekromatografi under anvendelse av "Amberlite ^fp-)CG-50" The catalyst is separated by filtration and the filtrate is concentrated under reduced pressure. The residue is dissolved in 30 ml of water and the solution is treated in the same way as in example 1, i.e. the solution is subjected to column chromatography using "Amberlite ^fp-)CG-50"
(ammoniumform, 150 ml, søylens diameter: 2,5 cm). Elueringen ut-føres deretter mens eluatet kontrolleres ved silisiumdioksydgel-tynnsj iktskromatograf i (under de samme betingelser som i eksempel 1). Eluatet opptas som fraksjoner og fraksjonene inneholdende forbindelse IV som den eneste komponent oppsamles og konsentreres til tørrhet under forminsket trykk. Som resultat oppnås 1,95 g av et fargeløst produkt bestående av forbindelsen IV (utbytte fra forbindelse II: 45,3$). (ammonium form, 150 ml, column diameter: 2.5 cm). The elution is then carried out while the eluate is checked by silica gel thin-layer chromatography (under the same conditions as in example 1). The eluate is collected as fractions and the fractions containing compound IV as the only component are collected and concentrated to dryness under reduced pressure. As a result, 1.95 g of a colorless product consisting of compound IV is obtained (yield from compound II: 45.3$).
Det således oppnådde produkt stemmer overens med det i eksempel 1 oppnådde sluttprodukt med hensyn til smeltepunkt, den optiske dreiing, det infrarøde absorpsjonsspektrum, NMR-spekteret og elementanalysen. The product thus obtained corresponds to the final product obtained in example 1 with regard to melting point, the optical rotation, the infrared absorption spectrum, the NMR spectrum and the elemental analysis.
Eksempel 4 Example 4
Fremstilling av sulfatet av 1-N-/L-(-)-a-hydroksy-y-aminobutyryl7-XK-62-2 (forbindelse IV), hvor 1 mol forbindelse IV er kombinert m§2^_?.i§_m2l_ svovelsyre Preparation of the sulfate of 1-N-/L-(-)-α-hydroxy-γ-aminobutyryl7-XK-62-2 (compound IV), where 1 mol of compound IV is combined m§2^_?.i§_m2l_ sulfuric acid
0,1 mol forbindelse IV oppløses i 200 ml vann. Til oppløsningen tilsettes en oppløsning av 0,25 mol svovelsyre i 50 0.1 mol of compound IV is dissolved in 200 ml of water. A solution of 0.25 mol of sulfuric acid in 50 is added to the solution
ml vann under avkjøling. Etter 30 min. tilsettes etanol til opp-løsningen for dannelse av et bunnfall, inntil utfellingen er full-stendig. Bunnfallet fraskilles ved filtrering og tørkes for oppnåelse av et hvitt pulver. ml of water while cooling. After 30 min. ethanol is added to the solution to form a precipitate, until precipitation is complete. The precipitate is separated by filtration and dried to obtain a white powder.
Analyse av pulveret viser følgende: Analysis of the powder shows the following:
Smeltepunkt: 242,8°C. Melting point: 242.8°C.
Spesifikk dreiing: (ct)^5 = +95,9° (c = l,0, vann). Specific rotation: (ct)^5 = +95.9° (c = l.0, water).
Infrarødt absorpsjonsspektrum (KBr) (cm<-1>): 3400, 1625, 1122. NMR-spektrum (i deuteriumoksyd) (i ppm fra DSS): 1,33 (3H, s), Infrared absorption spectrum (KBr) (cm<-1>): 3400, 1625, 1122. NMR spectrum (in deuterium oxide) (in ppm from DSS): 1.33 (3H, s),
2,77 (3H, s), 2,93 (3H, s), 5,20 (1H, d, J=3,9 Hz), 5,93 (1H, d, J=3,9 Hz). 2.77 (3H, s), 2.93 (3H, s), 5.20 (1H, d, J=3.9 Hz), 5.93 (1H, d, J=3.9 Hz).
Elementæranalyse: Elemental analysis:
Beregnet for C^H^gNgOg • ^SO^-H^: C 34 ,95$, H 7,14$, N 10,04$, Calculated for C^H^gNgOg • ^SO^-H^: C 34 .95$, H 7.14$, N 10.04$,
S 9,40$. S 9.40$.
Funnet: C 34,82$, H 6,70$, N 10,15$, S 9,68$. Found: C $34.82, H $6.70, N $10.15, S $9.68.
Fra den ovenstående analyse identifiseres pulveret som sulfatet av forbindelse IV med molekylformelen Cg^H^gNgOg-^5280^ .H2O. From the above analysis, the powder is identified as the sulfate of compound IV with the molecular formula Cg^H^gNgOg-^5280^ .H2O.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13782873A JPS5635194B2 (en) | 1973-12-12 | 1973-12-12 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO744448L NO744448L (en) | 1975-07-07 |
| NO139563B true NO139563B (en) | 1978-12-27 |
| NO139563C NO139563C (en) | 1979-04-04 |
Family
ID=15207784
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO744448A NO139563C (en) | 1973-12-12 | 1974-12-10 | PROCEDURES FOR THE PREPARATION OF 1-N- (L - (-) - ALFA-HYDROXY-GAMMA-AMINOBUTYRYL) -XK-62-2 |
Country Status (14)
| Country | Link |
|---|---|
| JP (1) | JPS5635194B2 (en) |
| AT (1) | AT337360B (en) |
| CA (1) | CA1030531A (en) |
| DE (1) | DE2458920A1 (en) |
| DK (1) | DK644274A (en) |
| ES (1) | ES432863A1 (en) |
| FR (1) | FR2254566B1 (en) |
| GB (1) | GB1470330A (en) |
| IN (1) | IN141069B (en) |
| NL (1) | NL7416210A (en) |
| NO (1) | NO139563C (en) |
| PH (1) | PH14352A (en) |
| SE (1) | SE417826B (en) |
| ZA (1) | ZA747908B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX3676E (en) * | 1975-07-15 | 1981-04-23 | Abbott Lab | PROCEDURE FOR OBTAINING DERIVATIVES FROM ANTIBIOTIC XK-62-2 |
-
1973
- 1973-12-12 JP JP13782873A patent/JPS5635194B2/ja not_active Expired
-
1974
- 1974-12-10 NO NO744448A patent/NO139563C/en unknown
- 1974-12-11 ZA ZA00747908A patent/ZA747908B/en unknown
- 1974-12-11 PH PH16610A patent/PH14352A/en unknown
- 1974-12-11 DK DK644274A patent/DK644274A/da unknown
- 1974-12-12 AT AT991974A patent/AT337360B/en not_active IP Right Cessation
- 1974-12-12 NL NL7416210A patent/NL7416210A/en not_active Application Discontinuation
- 1974-12-12 ES ES432863A patent/ES432863A1/en not_active Expired
- 1974-12-12 SE SE7415610A patent/SE417826B/en unknown
- 1974-12-12 CA CA216,641A patent/CA1030531A/en not_active Expired
- 1974-12-12 DE DE19742458920 patent/DE2458920A1/en active Pending
- 1974-12-12 FR FR7440978A patent/FR2254566B1/fr not_active Expired
- 1974-12-12 GB GB5378174A patent/GB1470330A/en not_active Expired
- 1974-12-24 IN IN2848/CAL/1974A patent/IN141069B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ES432863A1 (en) | 1976-11-01 |
| DE2458920A1 (en) | 1975-06-26 |
| JPS5088051A (en) | 1975-07-15 |
| IN141069B (en) | 1977-01-15 |
| AT337360B (en) | 1977-06-27 |
| CA1030531A (en) | 1978-05-02 |
| NO744448L (en) | 1975-07-07 |
| ATA991974A (en) | 1976-10-15 |
| SE417826B (en) | 1981-04-13 |
| PH14352A (en) | 1981-06-03 |
| ZA747908B (en) | 1976-01-28 |
| GB1470330A (en) | 1977-04-14 |
| SE7415610L (en) | 1975-06-13 |
| DK644274A (en) | 1975-08-18 |
| FR2254566A1 (en) | 1975-07-11 |
| NO139563C (en) | 1979-04-04 |
| JPS5635194B2 (en) | 1981-08-15 |
| FR2254566B1 (en) | 1979-08-10 |
| NL7416210A (en) | 1975-06-16 |
| AU7636174A (en) | 1976-06-17 |
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