NO301488B1 - Polyhydroxycyclopentane derivatives, process for their preparation, and biologically pure strains of microorganisms useful in the process - Google Patents
Polyhydroxycyclopentane derivatives, process for their preparation, and biologically pure strains of microorganisms useful in the process Download PDFInfo
- Publication number
- NO301488B1 NO301488B1 NO923592A NO923592A NO301488B1 NO 301488 B1 NO301488 B1 NO 301488B1 NO 923592 A NO923592 A NO 923592A NO 923592 A NO923592 A NO 923592A NO 301488 B1 NO301488 B1 NO 301488B1
- Authority
- NO
- Norway
- Prior art keywords
- sank
- amino
- triol
- hydroxymethyl
- oxazole
- Prior art date
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Landscapes
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Description
Den foreliggende oppfinnelse vedrører et polyhydrok-sycyklopentanderivat som har visse verdifulle biologiske virkninger. Oppfinnelsen vedrører også en fremgangsmåte til fremstilling av derivatet, samt biologisk rene stammer av mikroorganismer som er anvendelige i fremgangsmåten. The present invention relates to a polyhydroxycyclopentane derivative which has certain valuable biological effects. The invention also relates to a method for producing the derivative, as well as biologically pure strains of microorganisms that can be used in the method.
Forbindelsen ifølge oppfinnelsen er 2-amino-4-(hydroksymetyl)-3a,5,6,6a-tetrahydro-4H-cyklopent[d]oksazol-4,5,6-triol, hvis formel (II) er angitt nedenfor. Denne forbindelsen kan fremstilles ved fermentering. Men 2-amino-4-(hydroksymetyl)-3a,5,6,6a-tetrahydro-4H-cyklopent[d]oksazol-4,5,6-triol gjennomgår tautomeri, og kan derfor også angis med den nedenfor viste formel (Ila): The compound according to the invention is 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopent[d]oxazole-4,5,6-triol, whose formula (II) is given below. This compound can be produced by fermentation. But 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopent[d]oxazole-4,5,6-triol undergoes tautomerism, and can therefore also be represented by the formula shown below ( Ila):
Forbindelsen ifølge den foreliggende oppfinnelse har evnen til å inhibere aktiviteten til forskjellige sukkerhydrolaser, særlig p-glukosidase og sukrase. The compound according to the present invention has the ability to inhibit the activity of various sugar hydrolases, in particular β-glucosidase and sucrase.
Det er blitt rapportert at forbindelser som har en sterk inhiberende aktivitet mot p-glukosidase, såsom 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, pp. 74-77 and M.J. Humphries et al., Cancer Res., Vol 46, 1986, pp. 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, såsom 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 agents 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 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 of the present invention are: the mannostatins described inter alia by T. Aoyagi et al in The Journal of Antibiotics, Vol. XLII, No. 6, 1989, p. 883, which are said to have the ability to inhibit the activity of α-D-mannosidase,
(IS,2R,3S,4R,5R)-metyl[2,3,4-trihydroksy-5-(hydroksy-metyl )cyklopen tyl] amin, som er blant annet beskrevet avR.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-(hydroxy-methyl)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. Kaya- kifunensin, which, among others, is described by H. Kaya-
kiri 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. kiri 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 forbindelse som har inhiberende aktivitet mot visse sukkerhydrolaser. It is an object of the present invention to produce a new compound which has inhibitory activity against certain sugar hydrolases.
Det er et annet formål med oppfinnelsen å frembringe en forbindelse som har slik aktivitet og som derfor forventes å være anvendelig i behandlingen og forebyggingen av neoplas-maer, AIDS, fettsyke og sukkersyke. It is another object of the invention to produce a compound which has such activity and which is therefore expected to be applicable in the treatment and prevention of neoplasms, AIDS, obesity and diabetes.
Den kjemiske forbindelse ifølge oppfinnelsen er kjennetegnet ved at den er 2-amino-4-(hydroksymetyl)-3a,5,6,6a-tetrahydro-4H-cyklopent[d]-oksazol-4,5,6-triol, samt farmasøytisk akseptable salter derav, som har den ovenfor angitte formelen (II). The chemical compound according to the invention is characterized by the fact that it is 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopent[d]-oxazole-4,5,6-triol, as well as pharmaceutical acceptable salts thereof, which have the above formula (II).
Ifølge oppfinnelsen fremstilles 2-amino-4-,5, 6-triol ved en fremgangsmåte som er kjennetegnet ved dyrking av mikroorganismen Micromonospora sp. SANK 62390, FERM BP-3521 eller mutanter derav med vesentlig de samme morfologiske og biokjemiske egenskaper, eller mikroorganismen Amycolatopsis sp. SANK 60791, FERM BP-3513 eller mutanter derav med vesentlig de samme morfologiske og biokjemiske egenskaper, som er i stand til å danne 2-amino-4-(hydroksymetyl)-3a,5,6,6a-tetrahydro-4H-cyklopent[d]oksazol-4,5,6-triolen, og fraskilling av 2-amino-4-(hydroksymetyl)-3a,5,6,6a-tetra-hydro-4H-cyklopent[d]-oksazol-4,5,6-triolen fra dyrkingsmediet. According to the invention, 2-amino-4-,5,6-triol is produced by a method which is characterized by cultivation of the microorganism Micromonospora sp. SANK 62390, FERM BP-3521 or mutants thereof with substantially the same morphological and biochemical characteristics, or the microorganism Amycolatopsis sp. SANK 60791, FERM BP-3513 or mutants thereof with substantially the same morphological and biochemical characteristics, capable of forming 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopent[ d]oxazole-4,5,6-triol, and separation of 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetra-hydro-4H-cyclopent[d]-oxazole-4,5, The 6-triol from the culture medium.
Ifølge oppfinnelsen er det således også tilveiebrakt en biologisk ren stamme av en mikroorganisme av slekten Micromonospora, Micromonospora sp. SANK 62390. Denne mikroorganisme ble først deponert på deponeringsstedet til Fermentation Research Institute, Agency of Industrial Science and Technology, Tsukuba-shi, Ibaraki-ken, Japan den 26. juli 1990 under aksesjonsnummeret FERM P-11631, og ble deretter deponert i overensstemmelse med Budapestkonvensjonen hos Fermentation Research Institute, Agency of Industrial Science and Technology den 21. august 1991 med aksesjonsnummeret FERM BP-3521. According to the invention, a biologically pure strain of a microorganism of the genus Micromonospora, Micromonospora sp, has thus also been provided. SANK 62390. This microorganism was first deposited at the depository of the Fermentation Research Institute, Agency of Industrial Science and Technology, Tsukuba-shi, Ibaraki-ken, Japan on July 26, 1990 under the accession number FERM P-11631, and was subsequently deposited in accordance with Budapest Convention at the Fermentation Research Institute, Agency of Industrial Science and Technology on 21 August 1991 with accession number FERM BP-3521.
Ifølge oppfinnelsen er det videre tilveiebrakt en biologisk ren stamme av en mikroorganisme av slekten Amycolatopsis, Amycolatopsis sp. SANK 60791, som ble deponert i overensstemmelse med Budapestkonvensjonen hos Fermentation Research Institute, Agency of Industrial Science and Technology, Tsukuba-shi, Ibaraki-ken, Japan den 14. august 1991 med aksesjonsnummeret FERM BP-3513. According to the invention, a biologically pure strain of a microorganism of the genus Amycolatopsis, Amycolatopsis sp., has also been provided. SANK 60791, which was deposited in accordance with the Budapest Convention at the Fermentation Research Institute, Agency of Industrial Science and Technology, Tsukuba-shi, Ibaraki-ken, Japan on August 14, 1991 under accession number FERM BP-3513.
Karakterisering av mikroorganismer Characterization of microorganisms
Micromonospora sp. SANK 62390 Micromonospora sp. SANK 62390
Stammen Micromonospora sp. SANK 62390 har følgende mykologiske egenskaper: The strain Micromonospora sp. SANK 62390 has the following mycological properties:
1. Morfologiske karakteristika 1. Morphological characteristics
Stamme SANK 62390 vokser normalt eller litt dårlig under dyrking ved 28°C i et tidsrom på fra 7 til 14 dager på et vanlig agar dyrkingsmedium anvendt for identifisering av stammen. Substrathyfer forlenges skikkelig og forgrener seg med en lys orange, orange til mørkebrunaktig grå farge, men uten innsnittene eller de skarpe svinger som iakttas i stammer av slekten Nocardia. Luftmycelier er rudimentære og er farget hvite til brunhvite. Sporer iakttas bare på substrathyfer og dannes én etter én på en forholdsvis kort sporangiofor. Spore-formen er sfærisk og sporeoverflaten er glatt. Ingen spesielle organer, såsom sporangia, hviteknoller, snurringer eller lignende iakttas. Strain SANK 62390 grows normally or slightly poorly when cultured at 28°C for a period of 7 to 14 days on a common agar culture medium used for identification of the strain. Substrate hyphae are properly elongated and branched with a light orange, orange to dark brownish gray color, but without the incisions or sharp bends observed in stems of the genus Nocardia. Aerial mycelia are rudimentary and are colored white to brownish white. Spores are only observed on substrate hyphae and are formed one by one on a relatively short sporangiophore. The spore shape is spherical and the spore surface is smooth. No special organs, such as sporangia, white tubercles, whorls or the like are observed.
2. Vekst på forskjellige medier 2. Growth on different media
Stammen ble dyrket ved 28°C i 14 dager på forskjellige dyrkingsmedier og oppviste de egenskaper som er vist i tabell 1. Angivelse av fargetonene er indikert med fargetupp-tallet i "Guide to Color Standard" utgitt av Japan Color Research Institute. The strain was cultured at 28°C for 14 days on various culture media and exhibited the characteristics shown in Table 1. Indication of the color tones is indicated by the color tip number in the "Guide to Color Standard" published by the Japan Color Research Institute.
I tabellen benyttes følgende forkortelser: The following abbreviations are used in the table:
G: vekst, AM: luftmycelium, R: omvendt, SP: løselig pigment. G: growth, AM: aerial mycelium, R: reverse, SP: soluble pigment.
Stammen SANK 62390 ble også dyrket ved 28"C under anvendelse av Pridham-Gottlieb agar (ISP 9) som dyrkingsmedium. Assimileringen av karbonkilder som ble iakttatt etter dyrking i 14 dager er vist i tabell 3. The strain SANK 62390 was also grown at 28°C using Pridham-Gottlieb agar (ISP 9) as the culture medium. The assimilation of carbon sources observed after cultivation for 14 days is shown in Table 3.
4. Cellebestanddeler 4. Cell constituents
Celleveggene til stammen SANK 62390 ble analysert ved fremgangsmåten til B. Becker et al., Applied Microbiology, Vol 12, 1984, p. 421-423, og viste seg å inneholde meso-diamino-pimelinsyre. Dessuten ble sukkerbestanddelene i hele celleveggene til stammen SANK 62390 analysert ved fremgangsmåten til M.P. Lechevalier, Journal of Laboratory and Clinical Medicine, Vol 71, 1968, p. 934, og viste seg å inneholde arabinose og xylose, men ikke mykolinsyre. Peptidet glykan av acyltype i cellen viste seg å være av glykolyltypen. Hovedmekaninonbe-standdelene som ble påvist var MK-10(H6), MK-10(H4) samt MK-10(H8). The cell walls of strain SANK 62390 were analyzed by the method of B. Becker et al., Applied Microbiology, Vol 12, 1984, p. 421-423, and were found to contain meso-diamino-pimelic acid. In addition, the sugar constituents in the whole cell walls of the strain SANK 62390 were analyzed by the method of M.P. Lechevalier, Journal of Laboratory and Clinical Medicine, Vol 71, 1968, p. 934, and was found to contain arabinose and xylose but not mycolic acid. The acyl-type glycan peptide in the cell was found to be of the glycolyl type. The main mechaninone components detected were MK-10(H6), MK-10(H4) and MK-10(H8).
Det er derfor klart at denne mikroorganisme skal klassifiseres som en ny art som hører til slekten Micromonospora av familien Actinomycetes. På denne basis ble den betegnet som mikromonospora sp. SANK 62390. It is therefore clear that this microorganism should be classified as a new species belonging to the genus Micromonospora of the family Actinomycetes. On this basis it was designated as micromonospora sp. SANK 62390.
Amycolatopsis sp. SANK 60791 Amycolatopsis sp. SANK 60791
Stammen Amycolatopsis sp. SANK 60791 har følgende mykologiske egenskaper: The strain Amycolatopsis sp. SANK 60791 has the following mycological properties:
1.Morfologiske karakteristika 1. Morphological characteristics
Stamme SANK 60791 vokser normalt eller litt dårlig under dyrking ved 28°C i et tidsrom på fra 7 til 14 dager på et vanlig agar dyrkingsmedium anvendt for identifisering av stammen. Substrathyfer forlenges skikkelig og forgrener seg jevnt eller uregelmessig med en brunaktig hvit, lys gulaktig brun til svak gul farge. Luftmycelier er få eller rudimentære med hvit, lysegul til svakt orange farge. På senere stadier av inkuberingen delte substrathyfer og lyftmycelier seg i seksjo-ner, og det iakttas til tider luftmycelier med bacillstruktur. Hyfene forlenges uten de skarpe svinger som iakttas i stammer av slekten Nocardia. Ingen spesielle organer, såsom sporangia, hviteknoller, snurringer eller lignende iakttas. Strain SANK 60791 grows normally or slightly poorly when cultured at 28°C for a period of from 7 to 14 days on a common agar culture medium used for identification of the strain. Substrate hyphae elongate properly and branch evenly or irregularly with a brownish white, light yellowish brown to faint yellow color. Aerial mycelia are few or rudimentary with a white, light yellow to slightly orange colour. At later stages of incubation, substrate hyphae and lifting mycelia split into sections, and aerial mycelia with a bacillary structure are sometimes observed. The hyphae are elongated without the sharp bends observed in strains of the genus Nocardia. No special organs, such as sporangia, white tubercles, whorls or the like are observed.
2. Vekst på forskjellige medier 2. Growth on different media
Stammen ble dyrket ved 28°C i 14 dager på forskjellige dyrkingsmedier og oppviste de egenskaper som er vist i tabell 4. Angivelse av fargetonene er indikert med fargetupp-tallet i "Guide to Color Standard" utgitt av Japan Color Research Institute. The strain was cultured at 28°C for 14 days on various culture media and exhibited the characteristics shown in Table 4. Indication of the color tones is indicated by the color tip number in the "Guide to Color Standard" published by the Japan Color Research Institute.
I tabellen benyttes følgende forkortelser: The following abbreviations are used in the table:
G: vekst, AM: luftmycelium, R: omvendt, SP: løselig pigment. G: growth, AM: aerial mycelium, R: reverse, SP: soluble pigment.
3. Fysiologiske egenskaper 3. Physiological properties
Stammen SANK 60791 sine fysiologiske egenskaper iakttatt i tidsrommet fra dag 2 til dag 21 etter begynnelsen av dyrkingen ved 28°C er vist i tabell 52. The physiological characteristics of the strain SANK 60791 observed in the period from day 2 to day 21 after the beginning of cultivation at 28°C are shown in table 52.
Stammen SANK 60791 ble også dyrket ved 28°C under anvendelse av Pridham-Gottlieb agar (ISP 9) som dyrkingsmedium. Assimileringen av karbonkilder som ble iakttatt etter dyrking i 14 dager er vist i tabell 6. The strain SANK 60791 was also grown at 28°C using Pridham-Gottlieb agar (ISP 9) as culture medium. The assimilation of carbon sources observed after cultivation for 14 days is shown in Table 6.
4. Cellebestanddeler 4. Cell constituents
Celleveggene til stammen SANK 60791 ble analysert ved fremgangsmåten til B. Becker et al., Applied Microbiology, Vol 12, 1984, p. 421-423, og viste seg å inneholde meso-diamino-pimelinsyre. Dessuten ble sukkerbestanddelene i hele celleveggene til stammen SANK 60791 analysert ved fremgangsmåten til M.P. Lechevalier, Journal of Laboratory and Clinical Medicine, Vol 71, 1968, p. 934, og viste seg å inneholde arabinose, men ikke mykolinsyre. Peptidet glykan av acyltype i celleveggen viste seg å være av acetyltypen. Hovedmekaninonbestanddelen som ble påvist var MK-9(H4). The cell walls of strain SANK 60791 were analyzed by the method of B. Becker et al., Applied Microbiology, Vol 12, 1984, p. 421-423, and were found to contain meso-diamino-pimelic acid. In addition, the sugar constituents in the whole cell walls of the strain SANK 60791 were analyzed by the method of M.P. Lechevalier, Journal of Laboratory and Clinical Medicine, Vol 71, 1968, p 934, and was found to contain arabinose but not mycolic acid. The peptide glycan of acyl type in the cell wall turned out to be of the acetyl type. The main mechaninone component detected was MK-9(H4).
Det er derfor klart at denne mikroorganisme skal klassifiseres som en ny art som hører til slekten Amycolatopsis av familien Actinomycetes. På denne basis ble den betegnet som Amycolatopsis sp. SANK 60791. It is therefore clear that this microorganism should be classified as a new species belonging to the genus Amycolatopsis of the family Actinomycetes. On this basis it was designated as Amycolatopsis sp. SANK 60791.
Identifisering av stammene SANK 62390 og SANK 60791 ble gjort i overensstemmelse med standardene til ISP (The International Streptomyces Project), Bergey's Manual of Syste-matic Bacteriology, Vol 4, The Actinomycetes, Vol 2 og annen nyere litteratur vedrørende Actinomycetes. Identification of strains SANK 62390 and SANK 60791 was made in accordance with the standards of ISP (The International Streptomyces Project), Bergey's Manual of Systematic Bacteriology, Vol 4, The Actinomycetes, Vol 2 and other recent literature concerning Actinomycetes.
Det er blitt fastslått at stammene SANK 62390 og SANK 60791 danner trehazolin og 2-amino-4-(hydroksymetyl)- 3a, 5, 6,6a-tetrahydro-4H-cyklopent[d]oksazol-4,5,6-triol. Men som kjent kan egenskapene til sopp generelt og actinomycet-mikroorganismer spesielt variere betydelig, og slike sopper kan lett gjennomgå mutasjon, både på grunn av naturlige år-saker og som resultatet av anvendelse av kunstige midler, f.eks. ultrafiolett stråling, radioaktiv stråling, kjemisk behandling etc. Følgelig omfatter den foreliggende oppfinnelse anvendelsen av enhver mikroorganisme som kan klassifiseres innen slekten Micromonospora eller Amycolatopsis og som deler med stammene SANK 62390 og SANK 60791 den karakteristiske evne å danne trehazolin og 2-amino-4-(hydroksymetyl)-3a,5,6,6a-tetrahydro-4H-cyklopent[d]oksazol-4,5,6-triol. De nye mikroorganismer, stammene SANK 62390 og SANK 60791 forventes ikke å være en unntagelse, og betegnelsene "SANK 62390" og "SANK 60791" omfatter alle mutanter av disse stammer som deler med stammene SANK 62390 og SANK 60791 den karakteristiske evne å danne trehazolin og 2-amino-4-(hydroksymetyl)-3a, 5,6,6a-tetra-hydro-4H-cyklopent[d]oksazol-4,5, 6-triol. Dessuten omfatter disse mutanter alle de som oppnås ved hjelp av genetiske metoder, f.eks. rekombinering, transduksjon, transformasjon eller lignende. Det er en enkel forsøkssak å bestemme, på grunnlag av den informasjon som gis her når det gjelder egenskapene til trehazolin og 2-amino-4-(hydroksymetyl)-3a,5,6, 6a-tetrahydro-4H-cyklopent[d]oksazol-4,5,6-triol, om en vilkårlig gitt stamme danner disse forbindelser eller danner dem i tilstrekkelig mengde til å gjøre stammen av mulig kommersiell interesse. It has been determined that strains SANK 62390 and SANK 60791 form trehazoline and 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopent[d]oxazole-4,5,6-triol. But as is known, the characteristics of fungi in general and actinomycete microorganisms in particular can vary considerably, and such fungi can easily undergo mutation, both due to natural causes and as a result of the use of artificial agents, e.g. ultraviolet radiation, radioactive radiation, chemical treatment, etc. Accordingly, the present invention encompasses the use of any microorganism which can be classified within the genus Micromonospora or Amycolatopsis and which shares with the strains SANK 62390 and SANK 60791 the characteristic ability to form trehazoline and 2-amino-4- (hydroxymethyl)-3α,5,6,6α-tetrahydro-4H-cyclopent[d]oxazole-4,5,6-triol. The new microorganisms, strains SANK 62390 and SANK 60791 are not expected to be an exception, and the designations "SANK 62390" and "SANK 60791" include all mutants of these strains that share with strains SANK 62390 and SANK 60791 the characteristic ability to form trehazoline and 2-Amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopent[d]oxazole-4,5,6-triol. Moreover, these mutants include all those obtained by genetic methods, e.g. recombination, transduction, transformation or the like. It is a simple experimental matter to determine, on the basis of the information given here, regarding the properties of trehazoline and 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopent[d]oxazole -4,5,6-triol, if any given strain forms these compounds or forms them in sufficient quantity to make the strain of possible commercial interest.
Trehazolin og 2-amino-4-(hydroksymetyl)-3a,5,6,6a-tetrahydro-4H-cyklopent[d]oksazol-4, 5, 6-triol ifølge oppfinnelsen kan fremstilles ved dyrking av disse stammer av sopp i dyrkingsmedier av den type som vanligvis anvendes til fremstillingen av andre fermenteringsprodukter fra lignende mikroorganismer. Slike medier inneholder nødvendigvis mikrobiolo-gisk assimilerbare kilder for karbon og nitrogen samt uorganiske salter, slik det er velkjent for fagfolk på området. Trehazoline and 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopent[d]oxazole-4, 5, 6-triol according to the invention can be produced by growing these strains of fungi in culture media of the type usually used for the production of other fermentation products from similar microorganisms. Such media necessarily contain microbiologically assimilable sources of carbon and nitrogen as well as inorganic salts, as is well known to professionals in the field.
Foretrukne eksempler på karbonkilder omfatter: glukose, fruktose, maltose, sukrose, mannitol, glycerol, dek-strin, havre, rug, maisstivelse, potetstivelse, maismel, soya-bønnemel, bommullsfrøkake, bommullsfrøolje, melasse, sitronsyre, vinsyre og lignende. Slike forbindelser kan anvendes alene eller i enhver egnet kombinasjon. Generelt kan mengden som anvendes variere i området fra 1 til 10 vekt% av dyrkingsmediet. Preferred examples of carbon sources include: glucose, fructose, maltose, sucrose, mannitol, glycerol, dextrin, oat, rye, corn starch, potato starch, corn meal, soybean meal, cottonseed cake, cottonseed oil, molasses, citric acid, tartaric acid and the like. Such compounds may be used alone or in any suitable combination. In general, the amount used can vary in the range from 1 to 10% by weight of the culture medium.
Foretrukne nitrogenkilder er vanligvis proteinholdige materialer, såsom de som vanligvis anvendes i en fermenter-ingsprosess. Eksempler på slike nitrogenkilder omfatter: soya-bønnemel, hvetekli, peanøttmel, bommulsfrøkake, bommulsfrø-olje, bommulsfrømel, kaseinhydrolysater, farmamin, fiskemel, maisstøpevæske, pepton, kjøttekstrakt, gjær, gjærekstrakt, maltekstrakt, natriumnitrat, ammoniumnitrat, ammoniumsulfat og lignende. Disse nitrogenkilder kan anvendes alene eller i enhver kombinasjon. Vanligvis foretrekkes det å anvende dem i en konsentrasjon på mellom 0,2 og 6 vekt% av dyrkingsmediet. Preferred nitrogen sources are usually proteinaceous materials, such as those commonly used in a fermentation process. Examples of such nitrogen sources include: soybean meal, wheat bran, peanut meal, cotton seed cake, cotton seed oil, cotton seed meal, casein hydrolysates, pharmamin, fish meal, corn casting liquid, peptone, meat extract, yeast, yeast extract, malt extract, sodium nitrate, ammonium nitrate, ammonium sulfate and the like. These nitrogen sources can be used alone or in any combination. Generally, it is preferred to use them in a concentration of between 0.2 and 6% by weight of the culture medium.
De uorganiske næringssalter som kan tilsettes til dyrkingsmediet er konvensjonelle salter som er i stand til å The inorganic nutrient salts that can be added to the culture medium are conventional salts that are able to
frembringe forskjellige ioner som er nødvendige for mikroorga-nismenes vekst, såsom natrium, ammonium, kalsium, fosfat, sul-fat, klorid og karbonat. I tillegg bør mediet inneholde mindre mengder essensielle sporelementer, såsom kalium, kalsium, produce various ions necessary for the growth of microorganisms, such as sodium, ammonium, calcium, phosphate, sulphate, chloride and carbonate. In addition, the medium should contain smaller amounts of essential trace elements, such as potassium, calcium,
kobolt, mangan, jern og magnesium. cobalt, manganese, iron and magnesium.
Når fremgangsmåten ifølge oppfinnelsen utføres ved hjelp av en metode med væskeformet kultur anvendes det fortrinnsvis et anti-skummingsmiddel, såsom en silikonolje, planteolje, eller overflateaktivt stoff, i dyrkingsmediet. pH i dyrkingsmediet til fremstilling av trehazolin eller 2-amino-4-(hydroksymetyl)-3a,5,6,6a-tetrahydro-4H-cyklopent[d]oksazol-4,5,6-triol ved dyrkingen av mikroorganismer av slektene Micromonospora og Amycolatopsis, særlig stammene SANK 62390 og SANK 60791, varierer fortrinnsvis i området fra 5,0 til 8,0, mer foretrukket fra 6,5 til 7,5. When the method according to the invention is carried out using a liquid culture method, an anti-foaming agent, such as a silicone oil, plant oil or surfactant, is preferably used in the culture medium. pH in the culture medium for the production of trehazoline or 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopent[d]oxazole-4,5,6-triol in the cultivation of microorganisms of the genus Micromonospora and Amycolatopsis, particularly strains SANK 62390 and SANK 60791, preferably varies in the range from 5.0 to 8.0, more preferably from 6.5 to 7.5.
Dyrkingen kan utføres ved enhver temperatur i området fra 15 til 38°C, selv om en temperatur på fra 22 til 38°C foretrekkes for god vekst, og en temperatur på fra 22 til 28°C foretrekkes for å optimalisere dannelsen av trehazolin og 2-amino-4-(hydroksymetyl)-3a,5,6,6a-tetrahydro-4H-cyklopent-[d]oksazol-4,5,6-triol. The cultivation can be carried out at any temperature in the range from 15 to 38°C, although a temperature of from 22 to 38°C is preferred for good growth, and a temperature of from 22 to 28°C is preferred to optimize the formation of trehazoline and 2 -amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopent-[d]oxazole-4,5,6-triol.
Disse forbindelser fremstilles under aerobiske kulturbetingelser og ved konvensjonelle aerobiske kultur-metoder, såsom fast kultur, rystet kultur og kultur med lufting og omrøring (neddykket). Ved dyrking i liten skala er rystet kultur i noen få dager ved 28°C typisk. Ved en slik kulturmetode i liten skala kan kulturen initieres med ett eller to for-formeringstrinn, hvor det fremstilles kimkulturer i f.eks. Erlenmeyer-kolber utstyrt med skilleplater som funk-sjonerer som en væskestrømsregulator. Mediet for kimkul-turtrinnene inneholder fortrinnsvis både karbon- og nitrogenkilder. I den foretrukne sekvens av operasjoner ved slik dyrking i liten skala rystes kimkulturkolbene i en inkubator med en konstant temperatur på 28°C i 7 dager inntil det er oppnådd tilstrekkelig vekst. Den vokste kimkultur overføres deretter til et andre kimmedium eller til produksjonsmediet. Når det benyttes en mellomliggende vekstfase benyttes stort sett samme fremgangsmåte for vekst, og en prøve av det resulterende mel-lomprodukt inokuleres i produksjonsmediet. Den inokulerte kolbe kan deretter inkuberes i atskillige dager under rysting, og etter fullføring av inkuberingen kan innholdet i kolben sentrifugeres eller filtreres. These compounds are produced under aerobic culture conditions and by conventional aerobic culture methods, such as solid culture, shaken culture and culture with aeration and stirring (submerged). In small-scale cultivation, shaken culture for a few days at 28°C is typical. With such a culture method on a small scale, the culture can be initiated with one or two pre-propagation steps, where germ cultures are produced in e.g. Erlenmeyer flasks equipped with separators that function as a liquid flow regulator. The medium for the germination stages preferably contains both carbon and nitrogen sources. In the preferred sequence of operations in such small-scale cultivation, the seed culture flasks are shaken in an incubator at a constant temperature of 28°C for 7 days until sufficient growth is achieved. The grown seed culture is then transferred to a second seed medium or to the production medium. When an intermediate growth phase is used, largely the same method is used for growth, and a sample of the resulting intermediate product is inoculated into the production medium. The inoculated flask can then be incubated for several days under shaking, and after completion of the incubation the contents of the flask can be centrifuged or filtered.
Ved produksjon i stor skala foretrekkes det å anvende en egnet fermentor utstyrt med en rører og et lufteapparat. I dette tilfelle kan næringsmediet fremstilles inne i fermentoren. Mediet steriliseres fortrinnsvis ved økning av temperaturen til 125°C. Etter avkjøling kan det steriliserte medium inokuleres med en forhåndsfremstilt kimkultur. Dyrkingen fort-setter deretter under omrøring og lufting ved f.eks. 28°C. Denne fremgangsmåte er egnet for oppnåelse av forbindelsen ifølge oppfinnelsen i store mengder. For large-scale production, it is preferable to use a suitable fermenter equipped with a stirrer and an aerator. In this case, the nutrient medium can be produced inside the fermenter. The medium is preferably sterilized by increasing the temperature to 125°C. After cooling, the sterilized medium can be inoculated with a pre-prepared seed culture. Cultivation then continues under stirring and aeration by e.g. 28°C. This method is suitable for obtaining the compound according to the invention in large quantities.
Fremskridelsen av dyrkingen og mengden av det ønskede 2-amino-4-(hydroksymetyl)-3a, 5, 6, 6a-tetrahydro-4H-cyklopent-[d]oksazol-4,5,6-triol som dannes etter hvert som dyrkingen skrider frem, kan bestemmes ved måling av de biologiske virkninger av forbindelsen eller ved høytrykksvæskekromatografi eller gasskromatografi/massespektrometri av en renset prøve av forbindelsen fra dyrkingsmediet, slik som beskrevet mer detal-jert nedenfor. Trehazolin har en inhiberende aktivitet mot silkeorm-trehalase, og dannelsen av det kan overvåkes ved å følge dyrkingsmediets aktivitet mot silkeorm-trehalase under anvendelse av metoder som den som er vist i det etterfølgende testeksempel 3. The progress of the cultivation and the amount of the desired 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopent-[d]oxazole-4,5,6-triol formed as the cultivation progresses progress, can be determined by measuring the biological effects of the compound or by high-pressure liquid chromatography or gas chromatography/mass spectrometry of a purified sample of the compound from the culture medium, as described in more detail below. Trehazoline has an inhibitory activity against silkworm trehalase, and its formation can be monitored by monitoring the activity of the culture medium against silkworm trehalase using methods such as that shown in the following Test Example 3.
På den annen side overvåkes dannelsen av 2-amino-4-(hydroksymetyl)-3a,5,6,6a-tetrahydro-4H-cyklopent[d]oksazol-4,5,6-triol best ved høytrykksvæskekromatografi eller gasskromatografi/massespektrometri. Dette kan utføres ved å bringe dyrkingsmediet i kontakt med en egnet adsorberende harpiks [f.eks. den som selges under handelsnavnet "Amberlite IRC-50" On the other hand, the formation of 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopent[d]oxazole-4,5,6-triol is best monitored by high pressure liquid chromatography or gas chromatography/mass spectrometry. This can be accomplished by contacting the culture medium with a suitable adsorbent resin [e.g. the one sold under the trade name "Amberlite IRC-50"
(NH^)] for å adsorbere 2-amino-4-(hydroksymetyl)-3a,5,6,6a-tetrahydro-4H-cyklopent[d]oksazol-4, 5, 6-triol i f.eks. en kro-matografikolonne. Dette kan etterfølges av: Vasking med vann, eluering med et egnet elueringsmiddel, f.eks. en 0,5 N vandig løsning av ammoniakk, konsentrering av eluatet, f.eks. ved inndampning under senket trykk, samt lyofilisering av resten til fremstilling av et pulver. Mengden 2-amino-4-(hydroksymetyl)-3a,5,6,6a-tetrahydro-4H-cyklopent[d]oksazol-4,5,6-triol i pulveret kan måles ved høytrykksvæskekromato-graf! . Alternativt kan forbindelsen først acetyleres, og mengden 2-amino-4-(hydroksymetyl)-3a,5,6,6a-tetrahydro-4H-cyklo-pent[d]oksazol-4,5,6-triol i pulveret kan måles ved gasskromatografi/massespektrometri. (NH^)] to adsorb 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopent[d]oxazole-4, 5, 6-triol in e.g. a chromatography column. This can be followed by: Washing with water, elution with a suitable eluent, e.g. a 0.5 N aqueous solution of ammonia, concentration of the eluate, e.g. by evaporation under reduced pressure, as well as lyophilization of the residue to produce a powder. The amount of 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopent[d]oxazole-4,5,6-triol in the powder can be measured by high-pressure liquid chromatography! . Alternatively, the compound can first be acetylated, and the amount of 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclo-pent[d]oxazole-4,5,6-triol in the powder can be measured by gas chromatography/mass spectrometry.
Vanligvis når mengden trehazolin et maksimum mellom 72 og 150 timer etter startingen av fermenteringen, mens mengden 2-amino-4-(hydroksymetyl)-3a,5,6,6a-tetrahydro-4H-cyklo-pent[d]oksazol-4,5,6-triol når et maksimum mellom 96 og 168 timer etter startingen av fermenteringen. Men det nøyaktige tidspunkt vil variere avhengig av temperaturen og andre fermenteringsbetingelser, og det nøyaktige optimale tidspunkt for ethvert sett betingelser kan lettvint bestemmes ved å følge dannelsen av den ønskede forbindelse, slik som antydet ovenfor. Generally, the amount of trehazoline reaches a maximum between 72 and 150 hours after the start of fermentation, while the amount of 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclo-pent[d]oxazole-4, 5,6-triol reaches a maximum between 96 and 168 hours after the start of fermentation. But the exact time will vary depending on the temperature and other fermentation conditions, and the exact optimal time for any set of conditions can be easily determined by following the formation of the desired compound, as indicated above.
Når det anvendes en stamme av slekten Micromonospora dannes det normalt både trehazolin og 2-amino-4-(hydroksy-metyl )-3a, 5,6,6a-tetrahydro-4H-cyklopent[d]oksazol-4,5,6-triol, og disse kan separeres på vanlig måte under utvin-ningen, slik som beskrevet nedenfor. Stammer av slekten Amycolatopsis danner vanligvis bare 2-amino-4-(hydroksymetyl )-3a,5,6,6a-tetrahydro-4H-cyklopent[d]oksazol-4,5,6-triol. Begge forbindelser frigjøres i væskefasen, selv om de begge også foreligger i myceliet. De utvinnes meget lettvint fra væskefasen. When a strain of the genus Micromonospora is used, both trehazoline and 2-amino-4-(hydroxy-methyl)-3a, 5,6,6a-tetrahydro-4H-cyclopent[d]oxazole-4,5,6- triol, and these can be separated in the usual way during the extraction, as described below. Strains of the genus Amycolatopsis usually form only 2-amino-4-(hydroxymethyl )-3a,5,6,6a-tetrahydro-4H-cyclopent[d]oxazole-4,5,6-triol. Both compounds are released in the liquid phase, although they are both also present in the mycelium. They are very easily recovered from the liquid phase.
Etter fullføring av dyrkingen kan det ønskede 2-amino-4-(hydroksymetyl)-3a,5,6,6a-tetrahydro-4H-cyklo-pent[d]oksazol-4,5,6-triol, som foreligger i dyrkingsmediets væskefase, fraksjoneres ved avfiltrering av myceliet og andre faste stoffer, fortrinnsvis under anvendelse av diatomejord som filtreringshjelpemiddel, eller ved sentrifugering. Denne forbindelsen, 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 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclo-pent[d]oxazole-4,5,6-triol, which is present in the liquid phase of the culture medium , is fractionated by filtering off the mycelium and other solids, preferably using diatomaceous earth as a filtration aid, or by centrifugation. This compound, which is then present in the filtrate or in the supernatant, can be recovered by extraction and can then be purified in the usual way, making use of their physico-chemical properties.
F.eks kan denne forbindelsen utvinnes fra filtratet eller supernatanten ved å lede den gjennom en kolonne som inneholder et adsorbsjonsmiddel, såsom en ionebytterharpiks, f.eks. "Amberlite" IRC-50 eller CG-50, eller "Dowex" 50WX4 eller SBR-P, slik at enten urenhetene holdes tilbake av har-piksen og derved utvinnes, eller den ønskede forbindelse holdes tilbake og deretter utvinnes ved eluering, f.eks. med vandig ammoniakk. Eksempler på andre adorbsjonsmidler omfatter aktivt trekull eller andre adsorberende harpikser, såsom "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-tetrahydro-4H-cyklopent[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. For example, this compound 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 pix 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 containing one of these other adsorbents, which is 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.
2-amino-4-(hydroksymetyl)-3a,5,6,6a-tetrahydro-4H-cyklopent[d]oksazol-4,5,6-triolen som derved oppnås kan renses ytterligere ved forskjellige kjente metoder, f.eks. absorp-sjonskolonnekromatografi under anvendelse av en bærer, såsom silikagel eller "Florisil", fordelingskolonnekromatografi under anvendelse av "Avicel" eller "Sephadex" LH-20, eller høytrykksvæskekromatografi under anvendelse av en normal, omvendt fase eller ionebytterkolonne. The 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopent[d]oxazole-4,5,6-triol thus obtained can be further purified by various known methods, 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.
Forbindelsen ifølge den foreliggende oppfinnelse, 2-amino-4-(hydroksymetyl)-3a,5,6,6a-tetrahydro-4H-cyklopent[d]- oksazol-4,5,6-triol, inneholder minst et basisk nitrogenatom og kan derved danne syreaddisjonssalter. Der er ingen spesiell begrensning på naturen til disse salter under forutsetning av at de er farmasøytisk akseptable. Eksempler på slike syreaddisjonssalter omfatter: salter med mineralsyrer, særlig hydro-halogensyrer, såsom fluorsyre, hydrobromsyre, hydrojodsyre eller saltsyre, perklorsyre, salpetersyre, karbonsyre, svovel-syre eller fosforsyre; salter med lavere alkylsulfonsyrer, såsom metansulfonsyre, trifluormetansulfonsyre eller etansul-fonsyre; salter med arylsulfonsyrer, såsom benzensulfonsyre eller p-toluensulfonsyre; salter med organiske karboksylsyrer, såsom eddiksyre, fumarsyre, vinsyre, oksalsyre, maleinsyre, eplesyre, ravsyre eller sitronsyre samt salter med aminosyrer, såsom glutaminsyre eller aspartinsyre. The compound of the present invention, 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopent[d]-oxazole-4,5,6-triol, contains at least one basic nitrogen atom and can thereby forming acid addition salts. There is no particular limitation on the nature of these salts provided they are pharmaceutically acceptable. 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.
Forbindelsen ifølge den foreliggende oppfinnelse inneholder flere asymmetriske karbonatomer i molekylet og kan derved danne optiske isomerer. Selv om disse her alle er angitt med én eneste molekylformel omfatter oppfinnelsen 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 spaltningsme-toder. The compound according to the present invention contains several asymmetric carbon atoms in the molecule and can thereby form optical isomers. Although these are all indicated here with a single molecular formula, the invention encompasses both the individual, isolated isomers and mixtures, including racemates, thereof. When stereospecific synthesis methods are used 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 produced, the individual isomers can be obtained by conventional cleavage methods.
2-amino-4-(hydroksymetyl)-3a, 5,6, 6a-tetrahydro-4H-cyklopent[d]oksazol-4,5, 6-triol har evnen til å inhibere aktiviteten til sukrase og har lav toksisitet og kan derfor forventes å være anvendelig i behandlingen og forebyggingen av sukkersyke og fettsyre. 2-amino-4-(hydroxymethyl)-3a, 5,6, 6a-tetrahydro-4H-cyclopent[d]oxazole-4,5, 6-triol has the ability to inhibit the activity of sucrase and has low toxicity and can therefore is expected to be applicable in the treatment and prevention of diabetes and fatty acidosis.
Når denne forbindelsen er beregnet for terapeutisk anvendelse, kan den administreres alene eller i et egnet far-masøytisk preparat som i tillegg til den aktive forbindelse inneholder ett eller flere konvensjonelle tynningsmidler, bærere eller eksipienser. Naturen til preparatet vil selvføl-gelig avhenge av den tiltenkte administreringsmåte. Men for oral administrering vil forbindelsen fortrinnsvis formuleres som pulver, granulat, tablett eller kapsel. For parenteral administrering formuleres det fortrinnsvis som en injeksjon. Disse preparater kan fremstilles på kjent måte ved tilsetning av slike tilsetningsmidler som vehikler, bindemidler, oppsmul-dringsmidler, smøremidler, stabilisatorer og korregentia. Selv om doseringen kan variere avhengig av symptomene og alderen til pasienten, sykdommens eller forstyrrelsens natur og hvor alvorlig den er, samt administreringsveien og -måten, kan forbindelsene ifølge oppfinnelsen ved oral administrering til et voksent menneske som pasient vanligvis administreres i en dag-lig dose på fra 1 til 1000 mg. Forbindelsene kan administreres i én eneste dose eller i delte doser, f.eks. to eller tre ganger per dag. 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. The nature of the preparation will of course depend on the intended method of administration. However, for oral administration, the compound will preferably be formulated as a powder, granule, tablet or capsule. For parenteral administration, it is preferably formulated as an injection. These preparations can be prepared in a known manner by adding such additives as vehicles, binders, disintegrants, lubricants, stabilizers and corregents. Although the dosage may vary depending on the symptoms and age of the patient, the nature and severity of the disease or disorder, as well as the route and method of administration, the compounds of the invention when administered orally to an adult human patient can usually be administered in a daily dose of from 1 to 1000 mg. The compounds may be administered in a single dose or in divided doses, e.g. two or three times per day.
Fremstillingen av forbindelsen ifølge oppfinnelsen vil bli ytterligere belyst i de etterfølgende eksempler. The preparation of the compound according to the invention will be further explained in the following examples.
Eksempel 1 Example 1
Fremstilling av 2- amino- 4-( hydroksymetyl)- 3a, 5, 6, 6a-tetrahydro- 4H- cyklopentTdloksazol- 4, 5, 6- triol Preparation of 2-amino- 4-(hydroxymethyl)-3a, 5, 6, 6a-tetrahydro- 4H-cyclopentTdloxazole- 4, 5, 6-triol
( A) Dyrking (A) Cultivation
En prøve tatt fra skråsubstrat av Amycolatopsis sp. SANK 60791 ble anvendt til å inokulere hver av to 500 ml Erlenmeyer-kolber som hver var utstyrt med skilleplater og som hver inneholdt 80 ml Medium 1 (som hadde den sammensetning som er angitt ovenfor i eksempel 1), og de inokulerte kolber ble inkubert ved 28°C i 96 timer på en roterende ristemaskin som roterte med en hastighet på 210 omdr./min, hvorved det ble oppnådd et kimdyrkingsmedium. A sample taken from inclined substrate of Amycolatopsis sp. SANK 60791 was used to inoculate each of two 500 ml Erlenmeyer flasks each equipped with separator plates and each containing 80 ml of Medium 1 (having the composition indicated above in Example 1), and the inoculated flasks were incubated at 28°C for 96 hours on a rotary shaker rotating at a speed of 210 rpm, whereby a seed culture medium was obtained.
To 30 liter krukkefermentorer som hver inneholdt 15 liter Medium 2 (som hadde den sammensetning som er angitt i eksempel 1) ble sterilisert ved 120°C i 30 minutter. De ble deretter avkjølt til 28<6>C, og 75 ml av kimdyrkingsmediet ble inokulert i hver krukkefermentor. Krukkefermentorene ble deretter omrørt ved 28°C med en hastighet som ble regulert i området fra 100 til 400 omdr./min. (for å opprettholde 2 ppm løst oksygen) i 144 timer og med lufting ved en luftstrøm på 7,5 liter per minutt. Two 30 liter jar fermenters each containing 15 liters of Medium 2 (which had the composition stated in Example 1) were sterilized at 120°C for 30 minutes. They were then cooled to 28<6>C, and 75 ml of the seed culture medium was inoculated into each jar fermenter. The jar fermenters were then stirred at 28°C with a speed that was regulated in the range from 100 to 400 rpm. (to maintain 2 ppm dissolved oxygen) for 144 hours and with aeration at an air flow of 7.5 liters per minute.
( B) Utvinning (B) Extraction
1,5 kg "Celite 545" filterhjelpemiddel ble tilsatt til 25 liter av hele mediet [oppnådd slik som beskrevet under 1.5 kg of "Celite 545" filter aid was added to 25 liters of the entire medium [obtained as described under
(A)] ovenfor, og blandingen ble filtrert, hvorved det ble oppnådd 23 liter filtrat. Filtratets pH ble regulert til en verdi (A)] above and the mixture was filtered to obtain 23 liters of filtrate. The pH of the filtrate was adjusted to a value
på 6,0 ved tilsetning av vandig saltsyre, og løsningen ble ledet gjennom en kolonne som var pakket med 3 liter "Amberlite IRC-50" (NH4) for å adsorbere 2-amino-4-(hydroksymetyl )-3a, 5,6,6a-tetrahydro-4H-cyklopent[d]oksazol-4,5,6-triolen. Kolonnen ble vasket med 15 liter avionisert vann og deretter eluert med 0,5 N vandig ammoniakk. Etter at eluatet var blitt alkalisk ble 4,5 liter av eluatet oppsamlet og konsentrert ved inndampning under senket trykk til et volum på 200 ml. Konsentratet ble ledet gjennom en kolonne pakket med 450 ml "Dowex 1X2" (0H~), og kolonnen ble eluert med avionisert vann. De første 800 ml av eluatet ble fjernet, og det etterfølgende eluat ble fraksjonert i 20 ml porsjoner. Det ble bestemt ved kvantitativ analyse, enten under anvendelse av høytrykks-væskekromatografi, slik som beskrevet nedenfor, eller gasskromatografi/massespektrometri, at fraksjonene 60-90 inneholdt den ønskede 2-amino-4-(hydroksymetyl)-3a, 5, 6, 6a-tetrahydro-4H-cyklopent[d]oksazol-4,5,6-triol, og derfor ble disse fraksjoner kombinert og konsentrert ved inndampning under senket trykk. Konsentratet ble lyofilisert, hvorved det ble oppnådd 16,6 mg 2-amino-4-(hydroksymetyl)-3a,5, 6, 6a-tetrahydro-4H-cyklopent[d]oksazol-4,5,6-triol som et fargeløst pulver som hadde de egenskaper som er beskrevet nedenfor. of 6.0 by addition of aqueous hydrochloric acid, and the solution was passed through a column packed with 3 liters of "Amberlite IRC-50" (NH4) to adsorb 2-amino-4-(hydroxymethyl )-3a, 5.6 ,6α-tetrahydro-4H-cyclopent[d]oxazole-4,5,6-triol. The column was washed with 15 liters of deionized water and then eluted with 0.5 N aqueous ammonia. After the eluate had become alkaline, 4.5 liters of the eluate were collected and concentrated by evaporation under reduced pressure to a volume of 200 ml. The concentrate was passed through a column packed with 450 ml "Dowex 1X2" (0H~), and the column was eluted with deionized water. The first 800 ml of the eluate was removed and the subsequent eluate was fractionated into 20 ml portions. It was determined by quantitative analysis, either using high pressure liquid chromatography, as described below, or gas chromatography/mass spectrometry, that fractions 60-90 contained the desired 2-amino-4-(hydroxymethyl)-3a, 5, 6, 6a -tetrahydro-4H-cyclopent[d]oxazole-4,5,6-triol, and therefore these fractions were combined and concentrated by evaporation under reduced pressure. The concentrate was lyophilized, whereby 16.6 mg of 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopent[d]oxazole-4,5,6-triol was obtained as a colorless powder which had the properties described below.
Kvantitativ analyse under anvendelse av høytrykksvæskekromato-qrafi: Kolonne for separering: Asahi pak ES-502C (Asahi Chemical Industry Co., Ltd.). Quantitative analysis using high pressure liquid chromatography: Column for separation: Asahi pak ES-502C (Asahi Chemical Industry Co., Ltd.).
Mobil fase: 20 mM ammoniumacetat (pH 8,5) 0 50 mM saltlake. Strømningshastighet: 1 ml/min. Mobile phase: 20 mM ammonium acetate (pH 8.5) 0 50 mM saline. Flow rate: 1 ml/min.
Bølgelengde for bestemmelse: 210 nm. Wavelength for determination: 210 nm.
Temperatur: 25°C. Temperature: 25°C.
Oppholdstid: 8,39 minutter. Dwell time: 8.39 minutes.
Kvantitativ analyse av 2- amino- 4-( hydroksymetyl)- 3a, 5, 6, 6a-tetrahydro- 4H- cyklopentTdloksazol- 4, 5, 6- triol under anvendelse av qasskromatografi/ massespektrometri Quantitative analysis of 2- amino- 4-( hydroxymethyl)- 3a, 5, 6, 6a- tetrahydro- 4H- cyclopentaTdloxazole- 4, 5, 6- triol using gas chromatography/mass spectrometry
Den kvantitative analyse som det er referert til The quantitative analysis referred to
ovenfor ble utført på følgende måte: above was carried out in the following way:
En prøve ble løst i et løsningsmiddel (vann) med kjent væskevolum. 10 pl av den resulterende løsning ble anbrakt i en prøveflaske og inndampet til tørr tilstand for ace-tylering. 30 ul eddiksyreanhydrid og 50 ul pyridin ble tilsatt til resten, og den resulterende blanding ble oppvarmet ved 60°C i 40 minutter. Eventuelt overskudd av reaktanten ble fjernet ved at en strøm av nitrogengass ble blåst gjennom reaksjonsblandingen. Resten ble blandet med en kjent mengde av en intern standard (pentaacetyl-l-amino-l-deoksy-p-D-glukose), og blandingen ble løst i 100 ul etylacetat for å fremstille en prøve for gasskromatografi-/massespektrometrianalyse. Analysen ble utført under anvendelse av en kapillær kolonne med smeltet silika (et produkt fra J & W Scientific Co., DB-5, 15 meter) som gasskromatografikolonne. En prøve, 2 pl, ble innført, og kolonnens temperatur ble økt fra 60°C til 280°C med en hastighet på 25°C/min. Negative ioner ble påvist ved en kjemisk ioniseringsmetode under anvendelse av metangass med et quadru-pole massespektrometer Trio-1 (et produkt fra VG). Topper for negative ioner ved m/z 388 (som svarte til den interne standard pentacetylforbindelsen) og ved m/z 413 [som svarte til pentaacetatet av 2-amino-4-(hydroksymetyl)-3a,5,6,6a-tetra-hydro-4H-cyklopent[d]oksazol-4, 5,6-triol] ble anvendt til kvantitativ analyse. Innholdet av 2-amino-4-(hydroksymetyl)-3a,5,6,6a-tetrahydro-4H-cyklopent[d]oksazol-4,5,6-triolen ble beregnet ved hjelp av en intern standardmetode. A sample was dissolved in a solvent (water) of known liquid volume. 10 µl of the resulting solution was placed in a test bottle and evaporated to dryness for acetylation. 30 µl of acetic anhydride and 50 µl of pyridine were added to the residue, and the resulting mixture was heated at 60°C for 40 minutes. Any excess of the reactant was removed by blowing a stream of nitrogen gas through the reaction mixture. The residue was mixed with a known amount of an internal standard (pentaacetyl-1-amino-1-deoxy-β-D-glucose), and the mixture was dissolved in 100 µl ethyl acetate to prepare a sample for gas chromatography/mass spectrometry analysis. The analysis was performed using a fused silica capillary column (a product of J & W Scientific Co., DB-5, 15 meters) as a gas chromatography column. A sample, 2 µl, was introduced and the temperature of the column was increased from 60°C to 280°C at a rate of 25°C/min. Negative ions were detected by a chemical ionization method using methane gas with a quadrupole mass spectrometer Trio-1 (a product from VG). Negative ion peaks at m/z 388 (corresponding to the internal standard pentacetyl compound) and at m/z 413 [corresponding to the pentaacetate of 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetra- hydro-4H-cyclopent[d]oxazole-4, 5,6-triol] was used for quantitative analysis. The content of 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopent[d]oxazole-4,5,6-triol was calculated using an internal standard method.
Eksempel 2 Example 2
Fremstilling av 2- amino- 4-( hydroksymetyl)- 3a, 5. 6. 6a-tetrahydro- 4H- cyklopent Tdloksazol- 4, 5, 6- triol Preparation of 2-amino-4-(hydroxymethyl)-3a,5.6.6a-tetrahydro-4H-cyclopenta Tdloxazole-4,5,6-triol
( A) Dyrking (A) Cultivation
Et skråsubstrat av Micromonospora sp. SANK 62390 ble homogenisert i 10 ml fysiologisk saltløsning, hvorved det ble dannet en suspensjon. 1 ml av suspensjonen ble inokulert i hver av to 2 liter Erlenmeyer-kolber, som hver var utstyrt med skilleplater og som hver inneholdt 500 ml Medium 3 (som hadde den sammensetning som er angitt nedenfor), og de inokulerte kolber ble inkubert ved 28°C i 96 timer på en roterende ristemaskin som roterte med en hastighet på 210 omdr./min., hvorved det ble fremstilt et første kimdyrkingsmedium. A slant substrate of Micromonospora sp. SANK 62390 was homogenized in 10 ml of physiological saline, whereby a suspension was formed. 1 ml of the suspension was inoculated into each of two 2 liter Erlenmeyer flasks, each fitted with separatory plates and each containing 500 ml of Medium 3 (having the composition indicated below), and the inoculated flasks incubated at 28° C for 96 hours on a rotary shaker rotating at a speed of 210 rpm, whereby a first seed culture medium was prepared.
Medium 3: Medium 3:
Prosentandelene er etter vekt, regnet av mediets endelige volum. 30 liter av Medium 3 ble anbrakt i en 60 liter krukkefermentor og sterilisert ved 120°C i 30 minutter. Det ble deretter avkjølt til 28°C, og 600 ml av det første kimdyrkingsmedium ble inokulert i det. Fermentoren ble omrørt med en hastighet på 165 omdr./min. ved 28"C i 48 timer med lufting ved en luftstrøm på 15 liter per minutt for å fremstille et andre kimdyrkingsmedium. The percentages are by weight, calculated from the final volume of the medium. 30 liters of Medium 3 were placed in a 60 liter jar fermenter and sterilized at 120°C for 30 minutes. It was then cooled to 28°C, and 600 ml of the first seed culture medium was inoculated into it. The fermenter was stirred at a speed of 165 rpm. at 28°C for 48 hours with aeration at an air flow of 15 liters per minute to prepare a second seed culture medium.
En 600 liter beholder som inneholdt 300 liter av Medium 4, med den nedenfor angitte sammensetning, ble sterilisert ved 120°C i 35 minutter. Det ble deretter avkjølt til 28°C, og 15 liter av det andre kimdyrkingsmedium ble inokulert i det. Beholderen ble deretter omrørt ved 28°C med en hastighet som var regulert i området fra 82 til 142 omdr./min. (for å opprettholde 2 ppm løst oksygen) i 144 timer med lufting ved en luftstrøm på 150 liter per minutt og et indre trykk på 0,5 kg/cm"6. A 600 liter container containing 300 liters of Medium 4, with the composition indicated below, was sterilized at 120°C for 35 minutes. It was then cooled to 28°C, and 15 liters of the second seed culture medium was inoculated into it. The container was then stirred at 28°C at a speed that was regulated in the range from 82 to 142 rpm. (to maintain 2 ppm dissolved oxygen) for 144 hours of aeration at an air flow of 150 liters per minute and an internal pressure of 0.5 kg/cm"6.
Medium 4: Medium 4:
( B) Utvinning (B) Extraction
15 kg "Celite 545" filterhjelpemiddel ble tilsatt til 300 liter av hele mediet som ble fremstilt slik som beskrevet ovenfor, og blandingen ble filtrert, hvorved det ble oppnådd 290 liter av et filtrat. pH i 20 liter av filtratet ble regulert til en verdi på 6,0 ved tilsetning av vandig saltsyre. Den resulterende løsning ble ledet gjennom en kolonne pakket med 3 liter "Amberlite IRC-50" (NH4), og den ønskede 2-amino-4-(hydroksymetyl)-3a,5,6,6a-tetrahydro-4H-cyklopent[d]oksazol-4,5,6-triol ble holdt tilbake i kolonnen ved adsorpsjon. Kolonnen ble vasket med 15 liter avionisert vann og eluert med 0,5 N vandig ammoniakk. Etter at eluatet var blitt alkalisk ble 4,5 liter av eluatet oppsamlet og konsentrert ved inndampning under senket trykk til et volum på 150 ml. Konsentratet ble ledet gjennom en kolonne som var pakket med 500 ml "Dowex 1X2" (0H~) og eluert med avionisert vann. Den første hele liter ble fjernet og det etterfølgende eluat ble fraksjonert i 20 ml porsjoner. Hver fraksjon ble undersøkt ved den kvantitative analyse som er beskrevet i eksempel 1. Fraksjonene 58-80 viste seg å inneholde den aktive forbindelse, og disse fraksjoner ble kombinert og konsentrert ved inndampning under senket trykk. Resten ble lyofilisert, hvorved det ble oppnådd 9,6 mg av 2-amino-4-(hydroksymetyl)-3a, 5,6,6a-tetrahydro-4H-cyklopent[d]oksazol-4,5,6-triol som et råpulver. Pulveret ble renset igjen ved kolonnekromatografi under anvendelse av en kolonne som var pakket med 100 ml "Dowex 1X2" (0H~) eluert med avionisert vann, hvorved det ble oppnådd 4,8 mg av 2-amino-4-(hydroksymetyl)-3a,5,6,6a-tetrahydro-4H-cyklopent[d]oksazol-4,5,6-triol som et fargeløst pulver som hadde de egenskaper som er beskrevet ovenfor. 15 kg of "Celite 545" filter aid was added to 300 liters of the entire medium prepared as described above, and the mixture was filtered, whereby 290 liters of a filtrate was obtained. The pH in 20 liters of the filtrate was adjusted to a value of 6.0 by the addition of aqueous hydrochloric acid. The resulting solution was passed through a column packed with 3 liters of "Amberlite IRC-50" (NH4), and the desired 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopent[d ]oxazole-4,5,6-triol was retained in the column by adsorption. The column was washed with 15 liters of deionized water and eluted with 0.5 N aqueous ammonia. After the eluate had become alkaline, 4.5 liters of the eluate were collected and concentrated by evaporation under reduced pressure to a volume of 150 ml. The concentrate was passed through a column packed with 500 ml "Dowex 1X2" (0H~) and eluted with deionized water. The first full liter was removed and the subsequent eluate was fractionated into 20 ml portions. Each fraction was examined by the quantitative analysis described in Example 1. Fractions 58-80 were found to contain the active compound, and these fractions were combined and concentrated by evaporation under reduced pressure. The residue was lyophilized, whereby 9.6 mg of 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopent[d]oxazole-4,5,6-triol was obtained as a raw powder. The powder was purified again by column chromatography using a column packed with 100 ml of "Dowex 1X2" (0H~) eluted with deionized water to give 4.8 mg of 2-amino-4-(hydroxymethyl)-3a ,5,6,6α-tetrahydro-4H-cyclopent[d]oxazole-4,5,6-triol as a colorless powder which had the properties described above.
FORSØKSEKSEMPEL TEST EXAMPLE
BIOLOGISK AKTIVITET BIOLOGICAL ACTIVITY
Inhiberende aktivitet av 2- amino- 4-( hydroksymetyl)- 3a, 5, 6, 6a-tetrahydro- 4H- cyklopentTdloksazol- 4, 5, 6- triol rforbindelse ( 11) 1 mot rottesukrase Inhibitory activity of 2- amino- 4-( hydroxymethyl)- 3a, 5, 6, 6a-tetrahydro- 4H- cyclopentTdloxazol- 4, 5, 6- triol compound ( 11) 1 against rat sucrase
Ved fremgangsmåten til M. Kessler et al. (Biochimica et Biophysica Acta, Vol 506, 1978, p. 136-154) ble det fremstilt en børstegrense-membranenzymløsning av en rottetynntarm fra tynntarmene fra tre hannrotter av Wistar-stammen og suspendert i 3 ml fysiologisk saltløsning. By the method of M. Kessler et al. (Biochimica et Biophysica Acta, Vol 506, 1978, p. 136-154) a brush border membrane enzyme solution of a rat small intestine was prepared from the small intestines of three male Wistar rats and suspended in 3 ml of physiological saline.
En prøve av 4-aminoantipyrin (A 4383) ble levert av Sigma Chemical Co., og prøver av peroksidase (kvalitet I) og glukoseoksidase (kvalitet I) ble levert av Boehringer Mannheim Co. En buffer løsning (pH 6,2) som inneholdt 20 mM sitronsyre og 40 mM dinatriumfosfat ble anvendt som tynningsmiddel i det etterfølgende forsøk. A sample of 4-aminoantipyrine (A 4383) was provided by Sigma Chemical Co., and samples of peroxidase (grade I) and glucose oxidase (grade I) were provided by Boehringer Mannheim Co. A buffer solution (pH 6.2) containing 20 mM citric acid and 40 mM disodium phosphate was used as diluent in the subsequent experiment.
Hver brønn i en mikro-titerplate med 96 brønner (et produkt fra Falcon Co.) ble fylt med 130 ul totalt av en blanding som inneholdt 0,2 mg bovinserumalbumin (Sigma, Each well of a 96-well microtiter plate (a product of Falcon Co.) was filled with a total of 130 µl of a mixture containing 0.2 mg of bovine serum albumin (Sigma,
A 7906), 3 enheter glukoseoksidase, 0,132 enheter peroksidase, 20 mg 4-aminoantipyrin, 40 ug fenol, 3 umol sukrose og 1 testforbindelse. Til brønnen ble det tilsatt 20 ul av en 100 ganger tynnet løsning av en børstegrense-membranenzymløsning fra rottetynntarm. Blandingen fikk reagere ved 37 "C og mengden glukose som ble frigjort ble overvåket ved absorbsjon ved 492 nm. A 7906), 3 units glucose oxidase, 0.132 units peroxidase, 20 mg 4-aminoantipyrine, 40 µg phenol, 3 µmol sucrose and 1 test compound. To the well was added 20 µl of a 100-fold diluted solution of a brush border membrane enzyme solution from rat small intestine. The mixture was allowed to react at 37°C and the amount of glucose released was monitored by absorbance at 492 nm.
Når enzymreaksjonene ble utført uten tilsetning av en testforbindelse og uten tilsetning av en enzymløsning ble kon-sentrasjonen av glukose antatt å være henholdsvis 0% og 100% inhibering. Den konsentrasjon av forbindelsen med formelen (II) som var nødvendig for å inhibere aktiviteten til rottesukrase med 50% (IC^q) viste seg å være 18 ug/m. When the enzyme reactions were carried out without the addition of a test compound and without the addition of an enzyme solution, the concentration of glucose was assumed to be 0% and 100% inhibition, respectively. The concentration of the compound of formula (II) required to inhibit the activity of rat sucrase by 50% (IC^q) was found to be 18 µg/m.
Claims (6)
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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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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 |
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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NO923592L NO923592L (en) | 1992-08-17 |
NO923592D0 NO923592D0 (en) | 1992-09-16 |
NO301488B1 true NO301488B1 (en) | 1997-11-03 |
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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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1992
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NO923593D0 (en) | 1992-09-16 |
NO178064B (en) | 1995-10-09 |
NO923592L (en) | 1992-08-17 |
NO178064C (en) | 1996-01-17 |
NO923592D0 (en) | 1992-09-16 |
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