NO178064B - Process for Preparation of 5-Amino-1- (hydroxymethyl) cyclopentane-1,2,3,4-tetraol - Google Patents
Process for Preparation of 5-Amino-1- (hydroxymethyl) cyclopentane-1,2,3,4-tetraol Download PDFInfo
- Publication number
- NO178064B NO178064B NO923593A NO923593A NO178064B NO 178064 B NO178064 B NO 178064B NO 923593 A NO923593 A NO 923593A NO 923593 A NO923593 A NO 923593A NO 178064 B NO178064 B NO 178064B
- Authority
- NO
- Norway
- Prior art keywords
- acid
- hydroxymethyl
- amino
- tetraol
- cyclopentane
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 20
- 238000002360 preparation method Methods 0.000 title description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 28
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- 229910001868 water Inorganic materials 0.000 claims description 18
- 238000006460 hydrolysis reaction Methods 0.000 claims description 16
- BZVATLSLUPKXJY-UHFFFAOYSA-N 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydrocyclopenta[d][1,3]oxazole-4,5,6-triol Chemical compound OC1C(O)C(CO)(O)C2C1OC(N)=N2 BZVATLSLUPKXJY-UHFFFAOYSA-N 0.000 claims description 15
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Landscapes
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- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
Den foreliggende oppfinnelse vedrører en fremgangsmåte til fremstilling av 5-amino-l-(hydroksymetyl)syklopentan-1,2,3,4-tetraol. The present invention relates to a method for the production of 5-amino-1-(hydroxymethyl)cyclopentane-1,2,3,4-tetraol.
Forbindelsen fremstilt ifølge oppfinnelsen har formelen (I) som er angitt nedenfor. Fremgangsmåten kjenne-tegnes ved at den utføres ved hydrolyse i nærvær av vann av trehazolin som har de nedenfor viste formler (III) og (Illa): The compound produced according to the invention has the formula (I) which is indicated below. The method is characterized by the fact that it is carried out by hydrolysis in the presence of water of trehazoline which has the formulas (III) and (Illa) shown below:
Det antas at trehazolin kan være den samme forbindelse som den som er benevnt "trehalostatin" i PCT publikasjon WO 90/10010. It is believed that trehazoline may be the same compound as that named "trehalostatin" in PCT publication WO 90/10010.
Forbindelsen fremstilt ifølge den foreliggende oppfinnelse har evnen til å inhibere aktiviteten til forskjellige sukkerhydrolaser, særlig p-glukosidase og sukrase. The compound produced according to the present invention has the ability to inhibit the activity of various sugar hydrolases, particularly p-glucosidase and sucrase.
Det er blitt rapportert at forbindelser som har en sterk inhiberende aktivitet mot p-glukosidase, så som kastano-spermin og deoksynojirimycin, er anvendelige som anti-neoplastiske midler og som midler mot AIDS (Acquired Immune Deficiency Syndrome) (R.A. Gruters et al., Nature, Vol 330, 1987, p. 74-77 og M.J. Humphries et al., Cancer Res., Vol 46, 1986, p. 5215-5222). Det forventes derfor at forbindelser som har evnen til å inhibere aktiviteten til p-glukosidase vil være anvendelige som anti-neoplastiske midler eller midler mot It has been reported that compounds having a strong inhibitory activity against β-glucosidase, such as castano-spermine and deoxynojirimycin, are useful as anti-neoplastic agents and as agents against AIDS (Acquired Immune Deficiency Syndrome) (R.A. Gruters et al., Nature, Vol 330, 1987, p. 74-77 and M.J. Humphries et al., Cancer Res., Vol 46, 1986, p. 5215-5222). It is therefore expected that compounds which have the ability to inhibit the activity of β-glucosidase will be useful as anti-neoplastic agents or agents against
AIDS. AIDS.
Det er også blitt rapportert at forbindelser som har en sterkt inhiberende aktivitet mot sukrase, så som AO-128 og Acarbose, er anvendelige som anti-diabetiske midler og midler mot fettsyke (Satoshi Horii et al., Journal of Medicinal Chemistry, Vol 29, 1986, p. 1038-1046 og T. Aida et al., Journal of Japanese Society of Food and Nutrition, Vol 34, (2), 1981, p. 134-139). Det forventes derfor at forbindelser som har evnen til å inhibere aktiviteten til sukrase vil være anvendelige til behandlingen og forebyggingen av sukkersyke og fettsyke. It has also been reported that compounds having a strong inhibitory activity against sucrase, such as AO-128 and Acarbose, are useful as anti-diabetic and anti-obesity agents (Satoshi Horii et al., Journal of Medicinal Chemistry, Vol 29, 1986, pp. 1038-1046 and T. Aida et al., Journal of Japanese Society of Food and Nutrition, Vol 34, (2), 1981, pp. 134-139). It is therefore expected that compounds which have the ability to inhibit the activity of sucrase will be useful for the treatment and prevention of diabetes and obesity.
Forbindelser som har en viss strukturell likhet med forbindelsen fremstilt ifølge den foreliggende oppfinnelse er: mannostatinene som blant annet er beskrevet av T. Aoyagi et al i The Journal of Antibiotics, Vol. XLII, nr. 6, 1989, p. 883, som sies å ha evnen til å inhibere aktiviteten til a-D-mannosidase, Compounds that have some structural similarity to the compound prepared according to the present invention are: the mannostatins described, among others, by T. Aoyagi et al in The Journal of Antibiotics, Vol. XLII, No. 6, 1989, p. 883, which says having the ability to inhibit the activity of α-D-mannosidase,
(IS,2R,3S,4R,5R)-metyl[2,3,4-trihydroksy-5-(hydroksymetyl)syklopentyl]amin, som er blant annet beskrevet av R.A. Farr et al. i Tetrahedron Letters, Vol 31, 1990, p. 7109, som også sies å ha evnen til å inhibere aktiviteten til a-mannosidase, (IS,2R,3S,4R,5R)-methyl[2,3,4-trihydroxy-5-(hydroxymethyl)cyclopentyl]amine, which is described among others by R.A. Farr et al. in Tetrahedron Letters, Vol 31, 1990, p. 7109, which is also said to have the ability to inhibit the activity of α-mannosidase,
allosamidin, som er beskrevet blant annet av S. Sakuda et al. i Tetrahedron Letters, Vol 27, 1986, p. 2475, som sies å ha evnen til å inhibere aktiviteten til insekt-chitinase, samt allosamidine, which is described among others by S. Sakuda et al. in Tetrahedron Letters, Vol 27, 1986, p. 2475, which is said to have the ability to inhibit the activity of insect chitinase, as well as
kifunensin, som blant annet er beskrevet av H. Kayakiri et al. i J. Org. Chem., Vol 54, 1989, p. 4015, som sies å være en immunmodulator med evnen til å inhibere aktiviteten til a-mannosidase. kifunensin, which, among other things, has been described by H. Kayakiri et al. in J. Org. Chem., Vol 54, 1989, p. 4015, which is said to be an immunomodulator with the ability to inhibit the activity of α-mannosidase.
Det er et formål med den foreliggende oppfinnelse å frembringe en ny fremgangsmåte for fremstilling av en forbindelse som har inhiberende aktivitet mot visse sukkerhydrolaser, og som derfor forventes å være anvendelig i behandlingen og forebyggingen av neoplasmaer, AIDS, fettsyke og sukkersyke. It is an object of the present invention to produce a new method for producing a compound which has inhibitory activity against certain sugar hydrolases, and which is therefore expected to be applicable in the treatment and prevention of neoplasms, AIDS, obesity and diabetes.
Forbindelsen fremstilt ifølge oppfinnelsen er 5-amino-1-(hydroksymetyl)syklopentan-l,2,3, 4-tetraol, som har den ovenfor angitte formelen (I). The compound produced according to the invention is 5-amino-1-(hydroxymethyl)cyclopentane-1,2,3,4-tetraol, which has the above-mentioned formula (I).
5-amino-l-(hydroksymetyl)syklopentan-l,2,3,4-tetraol kan fremstilles ved hydrolyse av trehazolin eller av 2-amino-4-(hydroksymetyl)-3a,5,6,6a-tetrahydro-4H-syklopent[d]oksazol-4,5,6-triol som har den ovenfor angitte formel (II), noe som vil bli beskrevet mer detaljert i det etterfølgende. 2-amino-4-(hydroksymetyl)-3a,5,6,6a-tetrahydro-4H-syklopent[d]oksazol-4,5,6-triol kan fremstilles ved hydrolyse av trehazolin eller ved fermentering under anvendelse av en mikroorganisme av slekten Micromonospora eller Amycolatopsis. 5-amino-1-(hydroxymethyl)cyclopentane-1,2,3,4-tetraol can be prepared by hydrolysis of trehazoline or of 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H- cyclopent[d]oxazole-4,5,6-triol having the above formula (II), which will be described in more detail hereinafter. 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopent[d]oxazole-4,5,6-triol can be prepared by hydrolysis of trehazoline or by fermentation using a microorganism of the genus Micromonospora or Amycolatopsis.
Trehazolin, som kan anvendes som utgangsmateriale ved fremgangsmåten ifølge den foreliggende oppfinnelse, kan fremstilles ved dyrking av en trehazolin-produserende mikroorganisme av slekten Micromonospora eller Amycolatopsis, fortrinnsvis en trehazolin-produserende mikroorganisme av slekten Micromonospora. Trehazolin, which can be used as starting material in the method according to the present invention, can be produced by cultivating a trehazolin-producing microorganism of the genus Micromonospora or Amycolatopsis, preferably a trehazolin-producing microorganism of the genus Micromonospora.
Etter fullføring av dyrkingen kan det ønskede trehazolin og/eller 2-amino-4-(hydroksymetyl)-3a,5, 6,6a-tetrahydro-4H-syklopent[d]oksazol-4,5,6-triol, som foreligger i dyrkings-mediets væskefase, fraksjoneres ved avfiltrering av myceliet og andre faste stoffer, fortrinnsvis under anvendelse av di-atomé jord som filtreringshjelpemiddel, eller ved sentrifuger-ing. Disse forbindelser, som deretter foreligger i filtratet eller i supernatanten, kan utvinnes ved ekstrahering og kan deretter renses på vanlig måte under utnyttelse av deres fysikalsk-kjemiske egenskaper. After completion of cultivation, the desired trehazoline and/or 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopent[d]oxazole-4,5,6-triol, which is present in the culture medium's liquid phase is fractionated by filtering off the mycelium and other solids, preferably using diatomaceous earth as a filtration aid, or by centrifugation. These compounds, which are then present in the filtrate or in the supernatant, can be recovered by extraction and can then be purified in the usual way using their physico-chemical properties.
F.eks. kan disse forbindelser utvinnes fra filtratet eller supernatanten ved å lede det eller den gjennom en kolonne som inneholder et adsorbsjonsmiddel, så som en ione-bytterharpiks, f.eks. "Amberlite" IRC-50 eller CG-50, eller "Dowex" 50WX4 eller SBR-P, slik at enten urenhetene holdes tilbake av harpiksen og derved utvinnes, eller den ønskede forbindelse holdes tilbake og deretter utvinnes ved eluering, f.eks. med vandig ammoniakk. Eksempler på andre adorbsjonsmid-ler omfatter aktivt trekull eller andre adsorberende harpik-ser, så som "Amberlite" XAD-2 eller XAD-4, eller "Diaion" HP-10, HP-20, CHP-20 eller HP-50. En løsning som inneholder trehazolinet og/eller 2-amino-4-(hydroksymetyl)-3a,5,6,6a-tetra-hydro-4H-syklopent[d]oksazol-4,5,6-triolen ledes gjennom et adsorberende lag som inneholder en av disse andre adsorbsjons-midler, som er beskrevet ovenfor, slik at enten urenhetene holdes tilbake av adsorbsjonsmidlet og derved utvinnes, eller den ønskede forbindelse holdes tilbake og deretter utvinnes ved eluering, f.eks. med vandig metanol, vandig aceton eller lignende. E.g. these compounds can be recovered from the filtrate or supernatant by passing it through a column containing an adsorbent, such as an ion-exchange resin, e.g. "Amberlite" IRC-50 or CG-50, or "Dowex" 50WX4 or SBR-P, so that either the impurities are retained by the resin and thereby recovered, or the desired compound is retained and then recovered by elution, e.g. with aqueous ammonia. Examples of other adsorbents include activated charcoal or other adsorbent resins, such as "Amberlite" XAD-2 or XAD-4, or "Diaion" HP-10, HP-20, CHP-20 or HP-50. A solution containing the trehazoline and/or 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopent[d]oxazole-4,5,6-triol is passed through an adsorbent layer which contains one of these other adsorbents, which are described above, so that either the impurities are retained by the adsorbent and thereby recovered, or the desired compound is retained and then recovered by elution, e.g. with aqueous methanol, aqueous acetone or the like.
Trehazolinet eller 2-amino-4-(hydroksymetyl)-3a,5,6,6a-tetrahydro-4H-syklopent[d]oksazol-4,5,6-triolen som derved oppnås kan renses ytterligere ved forskjellige kjente metoder, f.eks. absorpsjonskolonnekromatografi under anvendelse av en bærer, så som silikagel eller "Florisil", fordel-ingskolonnekromatografi under anvendelse av "Avicel" eller "Sephadex" LH-20, eller høytrykksvæskekromatografi under anvendelse av en normal, omvendt fase eller ionebytterkolonne. The trehazoline or 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopent[d]oxazole-4,5,6-triol that is thereby obtained can be further purified by various known methods, e.g. e.g. absorption column chromatography using a support such as silica gel or "Florisil", distribution column chromatography using "Avicel" or "Sephadex" LH-20, or high pressure liquid chromatography using a normal, reverse phase or ion exchange column.
5-amino-l-(hydroksymetyl)syklopentan-l,2,3,4-tetra-olen, forbindelsen med formelen (I) fremstilt ved fremgangsmåten ifølge oppfinnelsen, og 2-amino-4-(hydroksymetyl)-3a,5,6,6a-tetrahydro-4H-syklopent[d]oksazol-4, 5,6-triolen, forbindelsen med formelen (II) som kan anvendes som utgangs- 5-amino-1-(hydroxymethyl)cyclopentane-1,2,3,4-tetra-ol, the compound with the formula (I) produced by the method according to the invention, and 2-amino-4-(hydroxymethyl)-3a,5, 6,6a-tetrahydro-4H-cyclopent[d]oxazole-4, 5,6-triol, the compound with the formula (II) which can be used as starting
forbindelse ved fremgangsmåten ifølge oppfinnelsen, kan fremstilles ved hydrolyse av trehazolinet som er fremstilt slik som beskrevet ovenfor. compound by the method according to the invention, can be prepared by hydrolysis of the treazoline which has been prepared as described above.
Denne reaksjon utføres fortrinnsvis i nærvær av en syre og må utføres i nærvær av vann. Det er ingen spesiell begrensning på naturen til syren som anvendes, og enhver syre som det er vanlig å anvende for konvensjonelle hydrolysereak-sjoner kan like gjerne anvendes her. Eksempler omfatter slike uorganiske syrer som saltsyre eller svovelsyre og slike organiske syrer som eddiksyre eller propionsyre, i en vandig løs-ning. En foretrukket syre er saltsyre. This reaction is preferably carried out in the presence of an acid and must be carried out in the presence of water. There is no particular limitation on the nature of the acid used, and any acid which is commonly used for conventional hydrolysis reactions may equally well be used here. Examples include such inorganic acids as hydrochloric acid or sulfuric acid and such organic acids as acetic acid or propionic acid, in an aqueous solution. A preferred acid is hydrochloric acid.
Reaksjonen kan foregå over et vidt temperaturområde, og den nøyaktige reaksjons temperatur er ikke kritisk for oppfinnelsen. Vanligvis vil det være hensiktsmessig å utføre reaksjonen ved en temperatur på fra romtemperatur til 120 °C, mer foretrukket fra 90 °C til 100 °C. Reaksjonstiden kan også variere sterk, avhengig av mange faktorer, særlig reaksjons-temperaturen og reaktantene og løsningsmidlet som anvendes, samt av, slik som forklart nedenfor, det ønskede produkt. The reaction can take place over a wide temperature range, and the exact reaction temperature is not critical for the invention. Usually, it will be appropriate to carry out the reaction at a temperature of from room temperature to 120 °C, more preferably from 90 °C to 100 °C. The reaction time can also vary greatly, depending on many factors, in particular the reaction temperature and the reactants and solvent used, as well as, as explained below, the desired product.
Det vil forstås av både 5-amino-l-(hydroksymetyl)-syklopentan-1,2,3,4-tetraolen og 2-amino-4-(hydroksymetyl)-3a, 5, 6, 6a-tetrahydro-4H-syklopent[d]oksazol-4,5,6-triolen fremstilles fra samme utgangsmateriale under anvendelse av samme hydrolysereaksjon. Følgelig vil produktet generelt inne-holde en blanding av de to forbindelser. Men det er mulig å favorisere fremstillingen av den ene av disse forbindelser i forhold til den annen ved hensiktsmessig valg av reaksjons-betingelser. Således vil generelt mildere betingelser favorisere fremstillingen av 2-amino-4-(hydroksymetyl)-3a,5,6,6a-tetrahydro-4H-syklopent[d]oksazol-4, 5, 6-triol, mens mer strenge betingelser vil favorisere fremstillingen av 5-amino-1- (hydroksymetyl)syklopentan-1,2,3,4-tetraol. It will be understood by both 5-amino-1-(hydroxymethyl)-cyclopentane-1,2,3,4-tetraol and 2-amino-4-(hydroxymethyl)-3a, 5, 6, 6a-tetrahydro-4H-cyclopent The [d]oxazole-4,5,6-triol is prepared from the same starting material using the same hydrolysis reaction. Consequently, the product will generally contain a mixture of the two compounds. But it is possible to favor the production of one of these compounds in relation to the other by appropriate choice of reaction conditions. Thus, in general, milder conditions will favor the production of 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopent[d]oxazole-4, 5, 6-triol, while more stringent conditions will favor the preparation of 5-amino-1-(hydroxymethyl)cyclopentane-1,2,3,4-tetraol.
Følgelig foretrekkes det til fremstilling av 2-amino-4-(hydroksymetyl)-3a,5,6,6a-tetrahydro-4H-syklopent[d]oksazol-4, 5,6-triol å anvende en forholdsvis mildere sur reagens, f.eks. en 0,2 N vandig saltsyre, og reaksjonen får fortsette i et tidsrom på fra 1 time til 2 dager, mer foretrukket fra 5 til 6 timer. Consequently, for the preparation of 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopent[d]oxazole-4,5,6-triol, it is preferred to use a relatively milder acidic reagent, e.g. .ex. a 0.2 N aqueous hydrochloric acid, and the reaction is allowed to continue for a period of from 1 hour to 2 days, more preferably from 5 to 6 hours.
På den annen side foretrekkes for å oppmuntre reaksjonen til å gå helt frem til dannelse av 5-amino-l-(hydroksymetyl )syklopentan-l,2,3,4-tetraol en sterkere syre, så som 4 N vandig saltsyre, og reaksjonen får fortrinnsvis fortsette i et tidsrom fra 1 time til 2 dager, mer foretrukket fra 20 timer On the other hand, to encourage the reaction to proceed completely to the formation of 5-amino-1-(hydroxymethyl)cyclopentane-1,2,3,4-tetraol, a stronger acid, such as 4 N aqueous hydrochloric acid, is preferred, and the reaction is preferably allowed to continue for a period of from 1 hour to 2 days, more preferably from 20 hours
til 24 timer. to 24 hours.
I tillegg kan 5-amino-l-(hydroksymetyl)syklopentan-1,2,3,4-tetraol fremstilles ved hydrolyse av 2-amino-4-(hydroksymetyl)-3a,5,6,6a-tetrahydro-4H-syklopent[d]oksazol-4,5,6-triol. I dette tilfelle utføres hydrolysereaksjonen ifølge den foreliggende oppfinnelse i nærvær av en syre. Det er ingen spesiell begrensning på naturen til syren som anvendes, og enhver syre som vanligvis anvendes i hydrolysereak-sjoner kan like gjerne anvendes her. In addition, 5-amino-1-(hydroxymethyl)cyclopentane-1,2,3,4-tetraol can be prepared by hydrolysis of 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopent [d]oxazole-4,5,6-triol. In this case, the hydrolysis reaction according to the present invention is carried out in the presence of an acid. There is no particular limitation on the nature of the acid used, and any acid which is usually used in hydrolysis reactions may equally well be used here.
Eksempler på egnete syrer omfatter: uorganiske syrer, så som hydrohalogensyrene, (f.eks. saltsyre, hydrobromsyre og hydrojodsyre), svovelsyre, perklorsyre, fosforsyre og salpetersyre; organiske karboksylsyrer, så som lavere alkan-syrer (f.eks. maursyre, eddiksyre, oksalsyre eller trifluor-eddiksyre); lavere alkansulfonsyrer (f.eks. metansulfonsyre, etansulfonsyre eller trifluormetansulfonsyre); samt arylsulfonsyrer (f.eks. benzensulfonsyre eller p-toluensulfonsyre etc). De foretrukne syrer er de uorganiske syrer, særlig saltsyre. Examples of suitable acids include: inorganic acids, such as the hydrohalic acids, (eg hydrochloric acid, hydrobromic acid and hydroiodic acid), sulfuric acid, perchloric acid, phosphoric acid and nitric acid; organic carboxylic acids, such as lower alkanoic acids (eg formic acid, acetic acid, oxalic acid or trifluoroacetic acid); lower alkanesulfonic acids (eg methanesulfonic acid, ethanesulfonic acid or trifluoromethanesulfonic acid); as well as arylsulfonic acids (e.g. benzenesulfonic acid or p-toluenesulfonic acid etc). The preferred acids are the inorganic acids, especially hydrochloric acid.
Reaksjonen kan utføres i nærvær av et løsningsmiddel. Der er ingen spesiell begrensning på naturen til løsnings-midlet som anvendes under forutsetning av at det ikke har noen ugunstig virkning på reaksjonen eller på de involverte reak-tanter og at det kan løse reaktantene, i det minste til en viss grad. Eksempler på egnete løsningsmidler omfatter: alko-holer, så som metanol, etanol, propanol eller butanol; sulfok-sider, så som dimetylsulfoksid eller sulfolan; organiske syrer, særlig fettsyrer, så som eddiksyre eller propionsyre; samt vann. Foretrukne løsningsmidler omfatter vann og en blanding av vann og et løsningsmiddel. The reaction can be carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent used provided that it has no adverse effect on the reaction or on the reactants involved and that it can dissolve the reactants, at least to a certain extent. Examples of suitable solvents include: alcohols, such as methanol, ethanol, propanol or butanol; sulfokides, such as dimethyl sulfoxide or sulfolane; organic acids, especially fatty acids, such as acetic acid or propionic acid; as well as water. Preferred solvents include water and a mixture of water and a solvent.
Mengden syre som anvendes er vanligvis og fortrinnsvis fra 1 til 20 mol, mer foretrukket fra 5 til 10 mol, per mol av utgangsforbindelsen. The amount of acid used is usually and preferably from 1 to 20 mol, more preferably from 5 to 10 mol, per mol of the starting compound.
Reaksjonen kan foregå i et vidt temperaturområde, og den nøyaktige reaksjonstemperatur er ikke kritisk for oppfinnelsen. Vanligvis vil det være hensiktsmessig å utføre reaksjonen ved en temperatur på fra romtemperatur til 150 °C, mer foretrukket fra 90 °C til 110 °C. Reaksjonstiden kan også variere sterkt avhengig av mange faktorer, særlig reaksjons-temperaturen og reaktantene og løsningsmidlet som anvendes. Men under forutsetning av at reaksjonen utføres under de foretrukne betingelser som er angitt ovenfor, vil et tidsrom på fra 1 time til 2 dager, mer foretrukket fra 20 timer til 30 timer, vanligvis være tilstrekkelig. The reaction can take place in a wide temperature range, and the exact reaction temperature is not critical for the invention. Usually, it will be appropriate to carry out the reaction at a temperature of from room temperature to 150 °C, more preferably from 90 °C to 110 °C. The reaction time can also vary greatly depending on many factors, in particular the reaction temperature and the reactants and solvent used. However, provided that the reaction is carried out under the preferred conditions set forth above, a period of from 1 hour to 2 days, more preferably from 20 hours to 30 hours, will usually be sufficient.
De ønskede forbindelser med formlene (I) og (II) kan utvinnes av reaksjonsblandingen på måter som det er vanlig å anvende for separering og utvinning av en organisk forbindelse, f.eks. de forskjellige kromatografimetoder, særlig søylekromatografi og preparativ tynnsjiktskromatografi. Forskjellige valg er blitt beskrevet i forbindelse med separeringen og rensingen av trehazolin og 2-amino-4-(hydroksymetyl ) -3a, 5,6,6a-tetrahydro-4H-syklopent[d]oksazol-4,5,6-triol fremstilt ved fermentering, og disse valg kan også benyttes til å separere og rense 5-amino-l-(hydroksymetyl)-syklopentan-1,2,3,4-tetraolen og 2-amino-4-(hydroksymetyl )-3a,5,6,6a-tetrahydro-4H-syklopent[d]oksazol-4,5,6-triol fremstilt slik som beskrevet ovenfor ved hydrolyse. The desired compounds with the formulas (I) and (II) can be recovered from the reaction mixture in ways which are commonly used for the separation and recovery of an organic compound, e.g. the different chromatography methods, especially column chromatography and preparative thin-layer chromatography. Various options have been described in connection with the separation and purification of trehazoline and 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopent[d]oxazole-4,5,6-triol prepared by fermentation, and these choices can also be used to separate and purify 5-amino-1-(hydroxymethyl)-cyclopentane-1,2,3,4-tetraol and 2-amino-4-(hydroxymethyl)-3a,5, 6,6a-tetrahydro-4H-cyclopent[d]oxazole-4,5,6-triol prepared as described above by hydrolysis.
Forbindelsen fremstilt ved fremgangsmåten ifølge den foreliggende oppfinnelse, 5-amino-l-(hydroksymetyl)syklopentan-1 , 2, 3, 4-tetraol, og utgangsforbindelsen 2-amino-4-(hydroksymetyl)-3a,5,6,6a-tetrahydro-4H-syklopent[d]oksazol-4,5,6-triol, inneholder begge minst ett basisk nitrogenatom og kan derved danne syreaddisjonssalter. Der er ingen spesiell begrensning på naturen til disse salter under forutsetning av at de, når de er beregnet for terapeutisk anvendelse, er farmasøytisk akseptable. Når de er beregnet for ikke-terapeut-iske anvendelser, f.eks. som mellomprodukter til fremstilling av andre, og eventuelt mer aktive, forbindelser, gjelder selv ikke denne begrensning. Eksempler på slike syreaddisjonssalter omfatter: salter med mineralsyrer, særlig hydrohalogensyrer, så som fluorsyre, hydrobromsyre, hydrojodsyre eller saltsyre, perklorsyre, salpetersyre, karbonsyre, svovelsyre eller fosforsyre; salter med lavere alkylsulfonsyrer, så som metansulfonsyre, trifluormetansulfonsyre eller etansulfonsyre; salter med arylsulfonsyrer, så som benzensulfonsyre eller p-toluensulfonsyre; salter med organiske karboksylsyrer, så som eddiksyre, fumarsyre, vinsyre, oksalsyre, maleinsyre, eplesyre, ravsyre eller sitronsyre samt salter med aminosyrer, så som glutaminsyre eller asparaginsyre. The compound produced by the method according to the present invention, 5-amino-1-(hydroxymethyl)cyclopentane-1,2,3,4-tetraol, and the starting compound 2-amino-4-(hydroxymethyl)-3a,5,6,6a- tetrahydro-4H-cyclopent[d]oxazole-4,5,6-triol, both contain at least one basic nitrogen atom and can thereby form acid addition salts. There is no particular limitation on the nature of these salts provided that, when intended for therapeutic use, they are pharmaceutically acceptable. When they are intended for non-therapeutic applications, e.g. as intermediates for the production of other, and possibly more active, compounds, even this limitation does not apply. Examples of such acid addition salts include: salts with mineral acids, especially hydrohalic acids, such as hydrofluoric acid, hydrobromic acid, hydroiodic acid or hydrochloric acid, perchloric acid, nitric acid, carbonic acid, sulfuric acid or phosphoric acid; salts with lower alkylsulfonic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid or ethanesulfonic acid; salts with arylsulfonic acids, such as benzenesulfonic acid or p-toluenesulfonic acid; salts with organic carboxylic acids, such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid or citric acid and salts with amino acids, such as glutamic acid or aspartic acid.
Forbindelsene inneholder nødvendigvis atskillige asymmetriske karbonatomer i sine "molekyler og kan derved fore-ligge som optiske isomerer. Selv om disse her alle er angitt med én eneste molekylformel omfattes både de individuelle, isolerte isomerer og blandinger, også racemater, derav. Når det benyttes stereospesifikke syntesemetoder eller det anvendes optisk aktive forbindelser som utgangsmaterialer kan individuelle isomerer fremstilles direkte. Dersom det på den annen side fremstilles en blanding av isomerer kan de individuelle isomerer oppnås ved konvensjonelle spaltningsmetoder. The compounds necessarily contain several asymmetric carbon atoms in their molecules and can thereby exist as optical isomers. Although these are all indicated here with a single molecular formula, both the individual, isolated isomers and mixtures, including racemates, thereof are included. When stereospecific synthetic methods or optically active compounds are used as starting materials, individual isomers can be prepared directly.If, on the other hand, a mixture of isomers is prepared, the individual isomers can be obtained by conventional cleavage methods.
5-amino-l-(hydroksymetyl)syklopentan-l,2,3,4-tetraol har evnen til å inhibere aktiviteten til p-glukosidase og har lav toksisitet og kan derfor forventes å være anvendelig i behandlingen og forebyggingen av tumorer og AIDS. 5-amino-1-(hydroxymethyl)cyclopentane-1,2,3,4-tetraol has the ability to inhibit the activity of β-glucosidase and has low toxicity and can therefore be expected to be applicable in the treatment and prevention of tumors and AIDS.
Når denne forbindelsen er beregnet for terapeutisk anvendelse kan den administreres alene eller i et egnet farma-søytisk preparat som i tillegg til den aktive forbindelse inneholder ett eller flere konvensjonelle tynningsmidler, bærere eller eksipienser. When this compound is intended for therapeutic use, it can be administered alone or in a suitable pharmaceutical preparation which, in addition to the active compound, contains one or more conventional diluents, carriers or excipients.
Fremstillingen av forbindelsen ved fremgangsmåten ifølge oppfinnelsen vil bli ytterligere belyst i de etterføl-gende eksempler. The production of the compound by the method according to the invention will be further explained in the following examples.
Eksempel 1 Example 1
Fremstilling av 5- amino- l-( hydroksymetyl)- svklopentan- l, 2, 3, 4-tetraol Preparation of 5-amino-1-(hydroxymethyl)-cyclopentane-1, 2, 3, 4-tetraol
En løsning av 19,3 mg trehazolin løst i 1 ml 4 N vandig saltsyre ble anbrakt i en ampulle og hydrolysert ved oppvarming ved 100 °C i 24 timer. Ved slutten av dette tidsrom ble reaksjonsblandingen blandet med vann og deretter konsentrert til tørr tilstand ved inndampning under senket trykk. Resten ble igjen blandet med vann og konsentrert til tørr tilstand ved inndampning under senket trykk for å avdestillere saltsyren. Resten fra denne destillasjon ble løst i 20 ml vann, og løsningens pH ble regulert til en verdi på 6,0. Den resulterende løsning ble ledet gjennom en kolonne av 20 ml "Amberlite CG-50" (NH4), og kolonnen ble vasket med 60 ml avionisert vann og deretter eluert med 0,2 N vandig ammoniakk. Eluatet ble konsentrert ved inndampning under senket trykk, og resten ble lyofilisert, hvorved det ble oppnådd 5,1 g uren 5-amino-1-(hydroksymetyl)syklopentah-l,2,3, 4-tetraol som et fargeløst pulver. A solution of 19.3 mg of trehazoline dissolved in 1 ml of 4 N aqueous hydrochloric acid was placed in a vial and hydrolyzed by heating at 100°C for 24 hours. At the end of this time, the reaction mixture was mixed with water and then concentrated to dryness by evaporation under reduced pressure. The residue was again mixed with water and concentrated to dryness by evaporation under reduced pressure to distill off the hydrochloric acid. The residue from this distillation was dissolved in 20 ml of water, and the pH of the solution was adjusted to a value of 6.0. The resulting solution was passed through a column of 20 ml "Amberlite CG-50" (NH 4 ), and the column was washed with 60 ml of deionized water and then eluted with 0.2 N aqueous ammonia. The eluate was concentrated by evaporation under reduced pressure, and the residue was lyophilized to obtain 5.1 g of impure 5-amino-1-(hydroxymethyl)cyclopentah-1,2,3,4-tetraol as a colorless powder.
All den urene, pulverformede 5-amino-l-(hydroksymetyl )-syklopentan-l, 2,3, 4-tetraol (5,1 mg) som ble oppnådd slik som beskrevet ovenfor ble løst i litt vann og renset ved preparativ tynnsjiktskromatografi på følgende måte: Løsningen ble påført på to 20 x 20 cm silikagelplater (Merck Art 5715) og fremkalt under anvendelse av en 6:1:3 volumblanding av acetonitril, eddiksyre og vann opptil en høyde på 15 cm. Båndet mellom Rf 0,36 og 0,47 ble skrapet av platen og pakket i en kolonne, som deretter ble eluert med 50 ml avionisert vann. Eluatet ble ledet gjennom 10 ml "Amberlite CG-50" (NH4), hvorved 5-amino-l-(hydroksymetyl)syklopentan-l,2,3,4-tetraolen ble adsorbert på kolonnen. Kolonnen ble deretter vasket med 50 ml avionisert vann og eluert med 50 ml 0,2 N vandig ammoniakk. Eluatet ble konsentrert ved inndampning under senket trykk og lyofilisert, hvorved det ble oppnådd 3 mg av den ønskede 5-amino-l-(hydroksymetyl)syklopentan-1,2,3,4-tetraol som et fargeløst pulver som hadde følgende egenskaper: 1) Farge og utseende: basisk fargeløst pulver. 2) Løselighet: løselig i vann, uløselig i aceton og kloroform. All of the impure powdered 5-amino-1-(hydroxymethyl )-cyclopentane-1,2,3,4-tetraol (5.1 mg) obtained as described above was dissolved in a little water and purified by preparative thin-layer chromatography on following manner: The solution was applied to two 20 x 20 cm silica gel plates (Merck Art 5715) and developed using a 6:1:3 volume mixture of acetonitrile, acetic acid and water up to a height of 15 cm. The band between Rf 0.36 and 0.47 was scraped from the plate and packed into a column, which was then eluted with 50 ml of deionized water. The eluate was passed through 10 ml of "Amberlite CG-50" (NH 4 ), whereby 5-amino-1-(hydroxymethyl)cyclopentane-1,2,3,4-tetraol was adsorbed onto the column. The column was then washed with 50 ml of deionized water and eluted with 50 ml of 0.2 N aqueous ammonia. The eluate was concentrated by evaporation under reduced pressure and lyophilized, whereby 3 mg of the desired 5-amino-1-(hydroxymethyl)cyclopentane-1,2,3,4-tetraol was obtained as a colorless powder having the following properties: 1 ) Color and appearance: basic colorless powder. 2) Solubility: soluble in water, insoluble in acetone and chloroform.
3) Fargetest: positiv i en ninhydrinreaksjon. 3) Color test: positive in a ninhydrin reaction.
4) Molekylformel: C6<H1>3<N0>5. 4) Molecular formula: C6<H1>3<N0>5.
5) Molekylvekt: 179 (bestemt ved FAB-massespektroskopi). 5) Molecular weight: 179 (determined by FAB mass spectroscopy).
6) Spesifikk dreining: [a]25<=> -<3,>7° (c=0,51, H20). 6) Specific rotation: [a]25<=> -<3.>7° (c=0.51, H20).
7) UV-spektrum: ^m^g nm (cm): UV-spektret målt i vann viste ikke noen karakteristiske absorpsjons-maksima over 210 nm. 8) IR-spektrum: vmaks cm<-1> (i KBr), 3358, 1668, 1397 og 1066. <9>) -J-H-NMR-spektrum: 6 ppm. <1>H-NMR-spektret (400 MHz) ble målt i deuteriumoksid under anvendelse av tetrametyl-silan som en ekstern standard og viste følgende signaler: 7) UV spectrum: ^m^g nm (cm): The UV spectrum measured in water did not show any characteristic absorption maxima above 210 nm. 8) IR spectrum: vmax cm<-1> (in KBr), 3358, 1668, 1397 and 1066. <9>) -J-H-NMR spectrum: 6 ppm. The <1>H-NMR spectrum (400 MHz) was measured in deuterium oxide using tetramethylsilane as an external standard and showed the following signals:
3,12 (1H, dublett, J = 7,1 Hz), 3.12 (1H, doublet, J = 7.1 Hz),
3,56 (1H, dublett, J = 11,98 Hz), 3.56 (1H, doublet, J = 11.98 Hz),
3,62 (1H, dublett, J = 12,2 Hz), 3.62 (1H, doublet, J = 12.2 Hz),
3,62 (1H, dublett, J = 6,8 Hz), 3.62 (1H, doublet, J = 6.8 Hz),
3,78 (1H, dublett av dubletter, J = 5,5 & 6,8 Hz), 3,90 (1H, dublett av dubletter, J = 5,5 & 7,1 Hz). 3.78 (1H, doublet of doublets, J = 5.5 & 6.8 Hz), 3.90 (1H, doublet of doublets, J = 5.5 & 7.1 Hz).
10) <13>C-NMR-spektrum: 6 ppm. 13C-NMR-spektret (100 MHz) ble målt i deuteriumoksid under anvendelse av tetra-metylsilan som en ekstern standard og viste følgende signaler: 57,8, 61,0, 73,6, 79,4, 81,5 og 81,7. 10) <13>C-NMR spectrum: 6 ppm. The 13 C-NMR spectrum (100 MHz) was measured in deuterium oxide using tetramethylsilane as an external standard and showed the following signals: 57.8, 61.0, 73.6, 79.4, 81.5 and 81, 7.
11) Tynnsj iktskromatografi: 11) Thin layer chromatography:
Rf-verdi: 0,39. Rf value: 0.39.
Adsorbsjonsmiddel: silikagel på glassplate (Merck Art 5715). Adsorbent: silica gel on glass plate (Merck Art 5715).
Fremkallingsløsningsmiddel: en 6:1:3 volumblanding av acetonitril, eddiksyre og vann. Development solvent: a 6:1:3 volume mixture of acetonitrile, acetic acid and water.
Eksempel 2 Example 2
Fremstilling av 5- amino- l-( hydroksymetyl) syklopentan- l, 2, 3, 4-tetraol Preparation of 5-amino-1-(hydroxymethyl)cyclopentane-1,2,3,4-tetraol
En løsning av 16 mg pulverformet 2-amino-4-(hydroksymetyl )-3a, 5,6,6a-tetrahydro-4H-syklopent[d]oksazol-4,5,6-triol løst i 2 ml 6 N vandig saltsyre ble forseglet i en ampulle og deretter hydrolysert ved oppvarming ved 100 °C i 24 timer. Ved slutten av dette tidsrom ble vann tilsatt til hydrolysatet, og den resulterende blanding ble konsentrert til tørr tilstand ved inndampning under senket trykk. Resten ble igjen løst i vann, og den resulterende løsning ble igjen konsentrert til tørr tilstand for å fjerne saltsyren, og deretter ble den resulterende rest løst i 20 ml vann, og løsningens pH ble regulert til en verdi på 6,0 ved tilsetning av en 1 N vandig løsning av natriumhydroksid. Løsningen ble ledet gjennom 20 ml "Amberlite CG-50" (NH4) for å holde 5-amino-l-(hydroksymetyl)-syklopentan-1,2,3,4-tetraolen tilbake ved adsorpsjon, og kolonnen ble vasket med 60 ml avionisert vann og deretter eluert med en 0,2 N vandig ammoniakkløsning. Eluatet ble konsentrert ved inndampning under senket trykk, hvorved det ble oppnådd 5 ml av et konsentrat. Dette konsentrat ble anbrakt på en kolonne som var pakket med 50 ml "Dowex 1X2" (0H~), og kolonnen ble vasket med 200 ml avionisert vann og deretter eluert med 20 volumprosentig, vandig metanol. Eluatet ble fraksjonert i 5 ml porsjoner. Fraksjonene 5-23, som oppviste en inhiberende aktivitet mot p-glukosidase, ble kombinert og konsentrert ved inndampning under senket trykk. Konsentratet ble lyofilisert, hvorved det ble oppnådd 6,2 mg av 5-amino-l-(hydroksymetyl)syklopentan-1,2, 3,4-tetraol som et fargeløst pulver som hadde de egenskaper som er beskrevet ovenfor. A solution of 16 mg of powdered 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopent[d]oxazole-4,5,6-triol dissolved in 2 ml of 6 N aqueous hydrochloric acid was sealed in a vial and then hydrolyzed by heating at 100 °C for 24 h. At the end of this time, water was added to the hydrolyzate, and the resulting mixture was concentrated to dryness by evaporation under reduced pressure. The residue was again dissolved in water, and the resulting solution was again concentrated to dryness to remove the hydrochloric acid, and then the resulting residue was dissolved in 20 ml of water, and the pH of the solution was adjusted to a value of 6.0 by adding a 1 N aqueous solution of sodium hydroxide. The solution was passed through 20 ml of "Amberlite CG-50" (NH 4 ) to retain the 5-amino-1-(hydroxymethyl)-cyclopentane-1,2,3,4-tetraol by adsorption, and the column was washed with 60 ml deionized water and then eluted with a 0.2 N aqueous ammonia solution. The eluate was concentrated by evaporation under reduced pressure, whereby 5 ml of a concentrate was obtained. This concentrate was applied to a column packed with 50 ml of "Dowex 1X2" (0H~), and the column was washed with 200 ml of deionized water and then eluted with 20% by volume, aqueous methanol. The eluate was fractionated into 5 ml portions. Fractions 5-23, which showed inhibitory activity against β-glucosidase, were combined and concentrated by evaporation under reduced pressure. The concentrate was lyophilized, whereby 6.2 mg of 5-amino-1-(hydroxymethyl)cyclopentane-1,2,3,4-tetraol was obtained as a colorless powder having the properties described above.
Claims (9)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO923593A NO178064C (en) | 1991-02-15 | 1992-09-16 | Process for Preparation of 5-Amino-1- (hydroxymethyl) cyclopentane-1,2,3,4-tetraol |
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2197691 | 1991-02-15 | ||
| JP13294691 | 1991-06-04 | ||
| JP21345091 | 1991-08-26 | ||
| JP27241291 | 1991-10-21 | ||
| NO920555A NO177589C (en) | 1991-02-15 | 1992-02-13 | Polyhydroksycyklopentanderivat |
| NO923593A NO178064C (en) | 1991-02-15 | 1992-09-16 | Process for Preparation of 5-Amino-1- (hydroxymethyl) cyclopentane-1,2,3,4-tetraol |
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| Publication Number | Publication Date |
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| NO923593L NO923593L (en) | 1992-08-17 |
| NO923593D0 NO923593D0 (en) | 1992-09-16 |
| NO178064B true NO178064B (en) | 1995-10-09 |
| NO178064C NO178064C (en) | 1996-01-17 |
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| NO923593A NO178064C (en) | 1991-02-15 | 1992-09-16 | Process for Preparation of 5-Amino-1- (hydroxymethyl) cyclopentane-1,2,3,4-tetraol |
| NO923592A NO301488B1 (en) | 1991-02-15 | 1992-09-16 | Polyhydroxycyclopentane derivatives, process for their preparation, and biologically pure strains of microorganisms useful in the process |
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| NO923592A NO301488B1 (en) | 1991-02-15 | 1992-09-16 | Polyhydroxycyclopentane derivatives, process for their preparation, and biologically pure strains of microorganisms useful in the process |
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| Country | Link |
|---|---|
| NO (2) | NO178064C (en) |
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1992
- 1992-09-16 NO NO923593A patent/NO178064C/en not_active IP Right Cessation
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| NO301488B1 (en) | 1997-11-03 |
| NO923593L (en) | 1992-08-17 |
| NO923592L (en) | 1992-08-17 |
| NO178064C (en) | 1996-01-17 |
| NO923593D0 (en) | 1992-09-16 |
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