FI59814B - Foerfarande foer framstaellning av terapeutiskt anvaendbar cyklosporin d - Google Patents
Foerfarande foer framstaellning av terapeutiskt anvaendbar cyklosporin d Download PDFInfo
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- FI59814B FI59814B FI781348A FI781348A FI59814B FI 59814 B FI59814 B FI 59814B FI 781348 A FI781348 A FI 781348A FI 781348 A FI781348 A FI 781348A FI 59814 B FI59814 B FI 59814B
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- cyclosporin
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- 229930182912 cyclosporin Natural products 0.000 title claims description 3
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 title description 8
- 108010036949 Cyclosporine Proteins 0.000 title description 8
- 229960001265 ciclosporin Drugs 0.000 title description 8
- 230000001225 therapeutic effect Effects 0.000 title 1
- 238000002560 therapeutic procedure Methods 0.000 title 1
- ZNVBEWJRWHNZMK-SYOLRUPNSA-N (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-33-[(e,1r,2r)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21,30-tri(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17,20,2 Chemical compound C\C=C\C[C@@H](C)[C@@H](O)[C@@H]1N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C(=O)[C@H](C(C)C)NC1=O ZNVBEWJRWHNZMK-SYOLRUPNSA-N 0.000 claims description 28
- 108010019594 cyclosporin D Proteins 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 6
- 241001149960 Tolypocladium inflatum Species 0.000 claims description 4
- 230000002538 fungal effect Effects 0.000 claims description 4
- 239000001963 growth medium Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 3
- 108010036941 Cyclosporins Proteins 0.000 claims description 2
- 238000007796 conventional method Methods 0.000 claims 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 229930105110 Cyclosporin A Natural products 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 206010003246 arthritis Diseases 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 210000004698 lymphocyte Anatomy 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- JTOKYIBTLUQVQV-QRVTZXGZSA-N (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-30-[(1r)-1-hydroxyethyl]-33-[(e,1r,2r)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontan Chemical compound C\C=C\C[C@@H](C)[C@@H](O)[C@@H]1N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C(=O)[C@H]([C@@H](C)O)NC1=O JTOKYIBTLUQVQV-QRVTZXGZSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- JTOKYIBTLUQVQV-UHFFFAOYSA-N Cyclosporin C Natural products CC=CCC(C)C(O)C1N(C)C(=O)C(C(C)C)N(C)C(=O)C(CC(C)C)N(C)C(=O)C(CC(C)C)N(C)C(=O)C(C)NC(=O)C(C)NC(=O)C(CC(C)C)N(C)C(=O)C(C(C)C)NC(=O)C(CC(C)C)N(C)C(=O)CN(C)C(=O)C(C(C)O)NC1=O JTOKYIBTLUQVQV-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000003409 anti-rejection Effects 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 108010019248 cyclosporin C Proteins 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- UCOQITKXMNKTKF-MXGZYYNMSA-N (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-33-[(e,1r,2r)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28,30-decamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17,20,23 Chemical compound C\C=C\C[C@@H](C)[C@@H](O)[C@@H]1N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C(=O)[C@H](C)NC1=O UCOQITKXMNKTKF-MXGZYYNMSA-N 0.000 description 1
- 239000004254 Ammonium phosphate Substances 0.000 description 1
- 102000011632 Caseins Human genes 0.000 description 1
- 108010076119 Caseins Proteins 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 108010062580 Concanavalin A Proteins 0.000 description 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical class CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000364057 Peoria Species 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 241000123975 Trichoderma polysporum Species 0.000 description 1
- 238000005273 aeration Methods 0.000 description 1
- 229910000148 ammonium phosphate Inorganic materials 0.000 description 1
- 235000019289 ammonium phosphates Nutrition 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000002456 anti-arthritic effect Effects 0.000 description 1
- 229940124347 antiarthritic drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 239000000287 crude extract Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229940080237 sodium caseinate Drugs 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/64—Cyclic peptides containing only normal peptide links
- C07K7/645—Cyclosporins; Related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S435/00—Chemistry: molecular biology and microbiology
- Y10S435/8215—Microorganisms
- Y10S435/911—Microorganisms using fungi
- Y10S435/945—Trichoderma
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S930/00—Peptide or protein sequence
- Y10S930/01—Peptide or protein sequence
- Y10S930/19—Antibiotic
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S930/00—Peptide or protein sequence
- Y10S930/01—Peptide or protein sequence
- Y10S930/27—Cyclic peptide or cyclic protein
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- Immunology (AREA)
- General Chemical & Material Sciences (AREA)
- Biophysics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmacology & Pharmacy (AREA)
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- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
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- Veterinary Medicine (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
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- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
ν55^71 ΓβΊ m,KUULUTUSjULKAISU cc o -li.
•^ΙΠ? ^ ^ UTLÄGGNINGSSKRIFT 5 581 4 c (4¾ Pat;·;.:. Li I Ly 12 lU 1 .· J1 ' ^ ' (51) Kv.ik.^/int.ci.3 G 12 P 17/10, C 07 D 259/00.
C O? C 103/52 SUOMI — FINLAND (21) P»tanttlhakemut — Patentanseknlng 7813^8 (22) Hakemiaptlvl — Ansöknlngsdag 02.05.78 (23) AlkupSlvi—Glklghatsdag 02.05.78 (41) Tullut Julkiseksi — Bllvlt offentlig 11.11.78
Patentti· ja rekisterihallitut .... .............______ . . .....
· , (+4) Nlhtivlkslpanen Ja kuuLjulkalaun pvm. — n.
Patent- och registerstyrelsen Ansökan utlagd oeh utl.skrlften publicerad 30. 00. Ö1 (32)(33)(31) Pyydetty etuoikeus—Begird priorltet 10.05*77 10.05*77, i7.O6.77 Sveitsi-Schveiz(CH) 5822/77, 5823/77, 71*57/77 (71) Sandoz A. G. , CH-1*002 Basel, Sveitsi-Schveiz(CH) 1 (72) Rene P. Trater, Basel, Max Kuhn, Basel, Hans Hofmann, Ettingen,
Eugen Harri, Therwil, Sveitsi-Schweiz(CH) (7l*) Oy Kolster Ah
(5*0 Menetelmä terapeuttisesti käytettävän syklosporiini D:n valmistamiseksi - Förfarande för framställning av terapeutiskt användbar cyklosporin D
Tämän keksinnön kohteena on menetelmä terapeuttisesti käytettävän syklosporiini D:n valmistamiseksi, jolla on kaava
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I CK3^ ^CH3 ch Ncn3 CH
CHj ch3 ch CHj I j CH3 CHj-M-CH-CO-N--Ιη -C-Nl-CH-CO-N-CH-C-f!)-CH,
I «- L II l I L II
I O HO
CO
CH3^ j CO
CH-CHj-CH t.
CH3 I N-CH,
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I H 0 m I t I e II u I i
OC-CH-N-CO-CH-N-CO-CH-N-C-CH-N-CO-C M
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CH3 ·Η CH] CH2 CH] CH CH]
I C H] SCH] I
CM CH
/ \ / \ CH] CH] CH] CH] 2 59814
Keksinnön mukaan syklosporiini D:tä saadaan siten, että viljellään viljelyväli-aineessa tunnettua sienilajin Tolypocladium inflatum Gams kantaa NRRL 80I+U ja syklosporiini D eristetään sinänsä tunnetuin menetelmin 'viljelyväliaineesta, joka sisältää syklosporiini D:n lisäksi tunnettuja polaarisempia syklosporiineja A, B ja C.
Menetelmän mukainen viljely voidaan suorittaa analogisten kantojen viljelystä sinänsä tunnetuin menetelmin, esim. siten kuin on kuvattu esimerkissä 1.
Edullinen syklosporiini D:tä tuottava kanta on vapaasti saatavana oleva sienilajin Tolypocladium inflatum Gams kantaa NRRL 8oUU. Tämän kannan viljelmä on talletettu laitoksessa United States Department of Agriculture (Northern Research and Development Division), Peoria, 111., USA. Tämä kanta on aikaisemmin määritelty kuuluvaksi sienilajiin Trichoderma polysporum (Link ex. Pers.), ja se on kuvattu esimerkiksi FI-patenttijulkaisussa 5^ 6θ6.
Syklosporiini D voidaan eristää sinänsä tunnetulla tavalla, esim. siten kuin esimerkissä on kuvattu. Tällöin syklosporiini D voidaan erottaa suurina määrinä esiintyvistä luonnon tuotteista, esim. jonkin verran polaarisemmasta syklosporiini A:sta (tunnetaan myös nimellä S 7^81/F-1), polaarisemmasta syklosporiini B:stä (tunnetaan myös nimellä S 7^81/f-2) ja vielä polaarisemmasta syklosporiini C:stä.
Syklosporiini D:llä on mielenkiintoisia kemoterapeuttisia ja farmakologisia ominaisuuksia, ja erityisesti se sopii käytettäväksi lääkeaineena niveltulehduksen vastaisen' aktiviteettinsa vuoksi.
Syklosporiini D:n edullinen vaikutus niveltulehdukseen todettiin käyttämällä Freund-adjuvantilla keinotekoisesti aikaansaatua niveltulehdusta. Kokeissa saatiin syklosporiini D:n ED^-annoksen arvoksi mg/kg p.o. Vertailuyhdisteenä käytetyllä syklosporiini A: 11a (FI-patenttijulkaisun 52 851 yhdiste S 7*+8l/F-l) vastaava ED^Q oli 25 mg/kg p.o. Erityisen mielenkiintoinen on kuitenkin syklosporiini D:n erittäin heikko hylkimisreaktiota vastustava vaikutus, joka ominaisuus viittaa sen erityisen hyvin sopivan niveltulehdusten vastaiseksi lääkeaineeksi, koska sitä käytettäessä lymfosyytit eivät vaurioidu. Syklosporiini D:n ja syklosporiini A:n hylkimisreaktion vastaista vaikutusta verrattiin Janossy'n ja Greaves’in ^Clin. exp. Immunol.
9., U83 (1971) ja £0, 525 (1972)7 esittämässä lymfosyyttistimulaatiokokeessa in vitro käyttäen koemateriaalina konkan avaliini A:11a stimuloituja hiiren pernan lymfosyyttejä. Syklosporiini D:llä saatiin 50-$:inen proliferaation estovaikutus konsentraatiolla 200 ng/ml, kun se vastaavasti syklosporiini A:11a oli 30 ng/ml.
Marsuilla suoritetuissa tuberkkelikokeissa (PPD-koe) /.G.L. Floersheim, Z. Naturviss. med. Grundlagenforsch. 2, 307 (1905)7 koe-eläinten nahan paksuuden lisäkasvu annettaessa syklosporiini D:tä 50 mg/kg i.p. samanaikaisesti PPD:n kanssa pysyi samana kuin käsittelemättömillä kontrollieläimillä (syklosporiini A:11a 3 59814 saatu arvo oli TO % pienempi).
Syklosporiini D:tä voidaan käyttää lääkkeenä joko sellaisenaan tai sopivana lääkemuotona sekoitettuna farmakologisesti vaikuttamattomien apuaineiden kanssa.
Seuraavissa esimerkeissä kaikki lämpötilatiedot ovat Celsius-asteina.
Esimerkki:
Syklosporiini D
500 litraan ravintoliuosta, joka litraa kohti sisältää U0 g glukoosia, 2,0 g natriumkaseinaattia, 2,5 g ammoniumfosfaattia, 5 g MgSO^. THgO, 2 g KH^PO^, 3 g NaNO^, 0,5 g KC1, 0,01 g FeSO^ ja demineralisoitua vettä, ympätään 50 litraa Toly-pocladium inflatum Gams kannan NRRL 80l*U esiviljelmää ja inkuboidaan teräsferment-torissa sekoittaen (1TO rpm) ja ilmastaen (1 litra ilmaa/min/1 ravintoliuosta) 13 vrk 2T°:ssa (ks. FI-patenttijulkaisu 5^ 6θ6).
Viljelyliemeen lisätään yhtä suuri tilavuusmäärä n-butyyliasetaattia, orgaaninen faasi erotetaan ja väkevöidään tyhjössä, sitten raakauutteesta poistetaan rasva 3-vaiheisella jakouutolla metanolivedellä (9**l) ja petrolieetterillä. Metanolifaasi erotetaan, haihdutetaan tyhjössä, ja raakatuote saostetaan lisäämällä vettä. Suodattamalla saatu materiaali kromatografoidaan silikageelillä käyttäen eluointiin hek-saani-asetonia (2:1), jolloin ensiksi eluoituneet fraktiot sisältävät pääasiassa syklosporiini A:ta ja syklosporiini D:tä, myöhemmin eluoituneet fraktiot pääasiassa syklosporiini C:tä. Puhdistusta jatketaan kiteyttämällä syklosporiini A:ta ja syklosporiini D:tä sisältävät fraktiot 2-2,5-kertaisestä määrästä asetonia -15°C:ssa, ja kromatografoimalla kaksi kertaa saatu kiteytetty tuote silikageelillä, jolloin vedellä kyllästetyllä etyyliasetaatilla ensin eluoituneet fraktiot sisältävät syklosporiini D:tä vahvasti rikastuneena. Nämä liuotetaan kaksinkertaiseen määrään asetonia ja kiteytetään -15°:ssa. Saatu kiteinen syklosporiini D puhdistetaan edelleen liuottamalla 10-kertaiseen asetonimäärään, lisäämällä liuokseen 2 paino-5 aktiivihiiltä ja kuumentamalla liuosta 5 min 6o°:ssa. Suodattamalla talkkikerroksen lävitse saadaan kirkas, lähes väritön suodos, joka haihdutetaan 1/3 tilavuuteen ja jätetään sitten huoneen lämpötilaan jäähtymään, jolloin siitä kiteytyy itsestään syklosporiini D:tä. Seisottamalla -1T°:ssa kiteytyminen saadaan täydellisemmäksi. Suodattamalla erotetut kiteet pestään pienellä määrällä jääkylmää asetonia ja kuivataan sitten suurtyhjössä 80°:ssa 2 tuntia.
Syklosporiini D:n ominaisuudet: Värittömiä, prismamaisia kiteitä, sp. lU8-151° 20 o /Si/» = -2U5 (c = 0,52 kloroformissa) _ _2n° (c = 0,51 metanolissaj.
Claims (1)
11 5981 4 Pat ent t i vaat imus: Menetelmä terapeuttisesti käytettävän syklosporiini D:n valmistamiseksi, c II H CH3v* CH3 Ir ch, .ch, > CH CH HO^R/Cm 3n/ 3 I CH3^ ^CH, ch CHj ch ch2 ch, ch ch, I I chj I ! i I I II CH,—N-CH-CO-N-CH C-N-CH-CO-N-CH-C N-CH, I L «.Il L I L II I O HO CO ch3^ j CO CH-CH,-CH t. / l CHj j N-CH3 CH,-N I H OH I O. L | L II U | (. OC-CH-N-CO-CH — N-CO-CH-N-C-CH-N-CO-CH II! Ill I CH, H CH, CH, CH, CH CH, I CH3 CHj I Ch CH / \ / N Chj CHj Chj CHj tunnettu siitä, että viljellään viljely-väliaineessa tunnettua sienilajin Tolypocladium inflatum Gams kantaa NRRL 8oUU ja syklosporiini D eristetään tavanomaisin menetelmin viljelyväliaineesta, joka sisältää syklosporiini D:n lisäksi tunnettuja polaarisempia sylllosporiineja A, B ja C.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FI801682A FI63562C (fi) | 1977-05-10 | 1980-05-26 | Foerfarande foer framstaellning av terapeutiskt anvaendbar isocyklosporin d |
| FI801681A FI63561C (fi) | 1977-05-10 | 1980-05-26 | Foerfarande foer framstaellning av terapeutiskt anvaendbar dihydrocyklosporin d |
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH582377A CH628023A5 (en) | 1977-05-10 | 1977-05-10 | Process for the preparation of an antibiotic derivative |
| CH582377 | 1977-05-10 | ||
| CH582277 | 1977-05-10 | ||
| CH582277A CH628022A5 (en) | 1977-05-10 | 1977-05-10 | Process for the preparation of an antibiotic derivative |
| CH745777 | 1977-06-17 | ||
| CH745777A CH632010A5 (en) | 1977-06-17 | 1977-06-17 | Process for the preparation of a novel antibiotic |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| FI781348A7 FI781348A7 (fi) | 1978-11-11 |
| FI59814B true FI59814B (fi) | 1981-06-30 |
| FI59814C FI59814C (fi) | 1981-10-12 |
Family
ID=27175344
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI781348A FI59814C (fi) | 1977-05-10 | 1978-05-02 | Foerfarande foer framstaellning av terapeutiskt anvaendbar cyklosporin d |
Country Status (17)
| Country | Link |
|---|---|
| US (2) | US4220641A (fi) |
| JP (1) | JPS53139789A (fi) |
| AU (1) | AU526582B2 (fi) |
| CA (1) | CA1117046A (fi) |
| DE (1) | DE2819094A1 (fi) |
| DK (1) | DK148751C (fi) |
| ES (1) | ES469567A1 (fi) |
| FI (1) | FI59814C (fi) |
| FR (1) | FR2390420A1 (fi) |
| GB (1) | GB1591934A (fi) |
| IE (1) | IE46883B1 (fi) |
| IL (1) | IL54666A (fi) |
| IT (1) | IT1104195B (fi) |
| NL (1) | NL7804846A (fi) |
| PH (1) | PH13973A (fi) |
| PT (1) | PT68013B (fi) |
| SE (3) | SE438860B (fi) |
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Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS4838877B1 (fi) * | 1970-06-30 | 1973-11-20 | Toyo Jozo Kk | |
| CH614931A5 (fi) * | 1975-11-04 | 1979-12-28 | Sandoz Ag | |
| US4215199A (en) * | 1978-06-05 | 1980-07-29 | Sandoz Ltd. | Antibiotic production |
-
1978
- 1978-04-29 DE DE19782819094 patent/DE2819094A1/de active Granted
- 1978-05-01 DK DK188778A patent/DK148751C/da not_active IP Right Cessation
- 1978-05-02 SE SE7805055A patent/SE438860B/sv not_active IP Right Cessation
- 1978-05-02 FI FI781348A patent/FI59814C/fi not_active IP Right Cessation
- 1978-05-04 US US05/902,794 patent/US4220641A/en not_active Expired - Lifetime
- 1978-05-05 IT IT49208/78A patent/IT1104195B/it active
- 1978-05-05 NL NL7804846A patent/NL7804846A/xx not_active Application Discontinuation
- 1978-05-08 PH PH21111A patent/PH13973A/en unknown
- 1978-05-08 ES ES469567A patent/ES469567A1/es not_active Expired
- 1978-05-08 GB GB6316/80A patent/GB1591934A/en not_active Expired
- 1978-05-08 IL IL54666A patent/IL54666A/xx unknown
- 1978-05-08 PT PT68013A patent/PT68013B/pt unknown
- 1978-05-08 IE IE932/78A patent/IE46883B1/en unknown
- 1978-05-09 CA CA000302914A patent/CA1117046A/en not_active Expired
- 1978-05-09 JP JP5412578A patent/JPS53139789A/ja active Granted
- 1978-05-09 FR FR7813625A patent/FR2390420A1/fr active Granted
- 1978-05-09 AU AU35947/78A patent/AU526582B2/en not_active Expired
-
1980
- 1980-03-03 US US06/126,215 patent/US4289851A/en not_active Expired - Lifetime
-
1984
- 1984-03-01 SE SE8401135A patent/SE8401135D0/xx not_active Application Discontinuation
- 1984-03-01 SE SE8401134A patent/SE8401134D0/xx not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| ES469567A1 (es) | 1980-01-01 |
| IL54666A0 (en) | 1978-07-31 |
| JPS6252760B2 (fi) | 1987-11-06 |
| JPS53139789A (en) | 1978-12-06 |
| NL7804846A (nl) | 1978-11-14 |
| DK148751C (da) | 1986-02-24 |
| AU526582B2 (en) | 1983-01-20 |
| AU3594778A (en) | 1979-11-15 |
| FR2390420B1 (fi) | 1980-10-31 |
| SE438860B (sv) | 1985-05-13 |
| FR2390420A1 (fr) | 1978-12-08 |
| CA1117046A (en) | 1982-01-26 |
| PT68013A (fr) | 1978-06-01 |
| FI781348A7 (fi) | 1978-11-11 |
| DE2819094A1 (de) | 1978-11-23 |
| SE7805055L (sv) | 1978-11-11 |
| IT7849208A0 (it) | 1978-05-05 |
| IE46883B1 (en) | 1983-10-19 |
| SE8401134L (sv) | 1984-03-01 |
| SE8401135L (sv) | 1984-03-01 |
| US4289851A (en) | 1981-09-15 |
| IT1104195B (it) | 1985-10-21 |
| FI59814C (fi) | 1981-10-12 |
| DE2819094C2 (fi) | 1988-11-03 |
| DK188778A (da) | 1978-11-11 |
| US4220641A (en) | 1980-09-02 |
| SE8401134D0 (sv) | 1984-03-01 |
| GB1591934A (en) | 1981-07-01 |
| SE8401135D0 (sv) | 1984-03-01 |
| IL54666A (en) | 1980-12-31 |
| IE780932L (en) | 1978-11-10 |
| PT68013B (fr) | 1980-03-05 |
| DK148751B (da) | 1985-09-16 |
| PH13973A (en) | 1980-11-20 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM | Patent lapsed |
Owner name: SANDOZ AG |