NO763667L - - Google Patents
Info
- Publication number
- NO763667L NO763667L NO763667A NO763667A NO763667L NO 763667 L NO763667 L NO 763667L NO 763667 A NO763667 A NO 763667A NO 763667 A NO763667 A NO 763667A NO 763667 L NO763667 L NO 763667L
- Authority
- NO
- Norway
- Prior art keywords
- cyclosporin
- methanol
- cyclosporine
- chloroform
- dihydro
- Prior art date
Links
- 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 claims description 11
- 108010036949 Cyclosporine Proteins 0.000 claims description 11
- 229960001265 ciclosporin Drugs 0.000 claims description 11
- 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 claims description 8
- 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 claims description 8
- 229930182912 cyclosporin Natural products 0.000 claims description 8
- 108010019248 cyclosporin C Proteins 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 6
- 108010040786 dihydrocyclosporin C Proteins 0.000 claims description 5
- 241000123975 Trichoderma polysporum Species 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 241000875119 Cylindrocarpon lucidum Species 0.000 claims description 2
- 230000002538 fungal effect Effects 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 25
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- 229930105110 Cyclosporin A Natural products 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 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 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 2
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- TYFOVYYNQGNDKH-KCLVVAEESA-N (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-30-ethyl-33-[(1r)-1-hydroxy-2-methylhexyl]-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-undecazacyclotritriacontane-2,5,8,11,14,17,20,23,26, Chemical compound CCCCC(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](CC)NC1=O TYFOVYYNQGNDKH-KCLVVAEESA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241000228245 Aspergillus niger Species 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241000364057 Peoria Species 0.000 description 1
- -1 aliphatic alcohols Chemical class 0.000 description 1
- 230000002456 anti-arthritic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000000287 crude extract Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000005192 partition Methods 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
- 229910052697 platinum Inorganic materials 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/14—Fungi; Culture media therefor
- C12N1/145—Fungal isolates
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
- C12R2001/00—Microorganisms ; Processes using microorganisms
- C12R2001/645—Fungi ; Processes using fungi
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
- C12R2001/00—Microorganisms ; Processes using microorganisms
- C12R2001/645—Fungi ; Processes using fungi
- C12R2001/885—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
- Y10S930/27—Cyclic peptide or cyclic protein
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Immunology (AREA)
- Mycology (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Botany (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Tropical Medicine & Parasitology (AREA)
- Virology (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Microbiology (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biophysics (AREA)
- General Engineering & Computer Science (AREA)
- Transplantation (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (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)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Fremgangsmåte for fremstilling av dihydro-cyklosporin.
Foreliggende oppfinnelse vedrører en fremgangsmåte for fremstilling av dihydro-cyklosporin C (formelI) Det særegne ved fremgangsmåten i henhold til oppfinnelsen er at cyklosporin C (formel II)
hydrogeneres.
Dihydro-cyklosporin C har følgende egenskaper: Smeltepunkt 160 - 162°C (omorft), svakt hydroskopisk.
20
Qx] = 242° ( c 0,5 i CHC10)
D 3
174,5° ( c = 0,5 i CH30H)
I UV-spektrum (metanol) viser forbindelsen ende-absorpsjon. IR-spektrum i C^Clg er vist i fig. 1, NMR-spektrum i CDCl^, 90 MHz, med tetrametylsilan som intern standard, er vist i fig. 2 (signalene ved 7,23 ppm og ved 7,33 ppm stammer fra meget små mengder av CHCl^henhv. CgHg).
Bruttoformen:
Dihydro-cyklosporin C er ved romtemperatur lettløselig i benzen, diklormetan, kloroform, etylacetat, aceton, etanol, metanol og meget llngtløsel ig i vann.
R^-verdiene av dihydro-cyklosporin C i tynnskiktkromatogram fremgår av følgende tabell:
DG-ferdigplate "Merck", kiselgel 60 F-254.
Flekkene kan gjøres synlige på kjent måte, f.eks. med jod.
Fremgangsmåten i henhold til oppfinnelsen lar seg utføre på \ kjent må fe, f.eks. ved katalytisk hydrogenering. /
Som løsningsmiddel anvendes foretrukket etylacetat eller lavere alifatiske alkoholer som f. eks. metanol-, etanol, isopropanol. Hydrogeneringen skjer hensiktsmessig i nøytralt område ved temperaturer mellom 20 og 30°C og ved atmosfæretrykk eller litt forhøyet trykk. Som katalysator kan anvendes platina, men foretrukket palladium, f.eks. palladium på kull. Det således erholdte hydrogeneringsprodukt av cyklosporin C renses deretter på i og for seg kjent måte, f .eks. ved kromatograf ering'.
Det som utgangsprodukt anvendte cyklosporin C. k.an erholdes
ved at en cyklosporin C- produserende stamme av sopparten trichoderma-polysporum (Link ex Pers.) rifai eller cylindrocarpon lucidum Booth dyrkes og cykl.osp.orin C isoleres fra dyrkingsbuljongen. Dyrkingen skjer på i og for seg kjent måte, idet man foretrukket anvender en stamme NRRL 5760 eller en stamme NRRL 8044(se f.eks. DOS 2.455.859). Kulturer av de to stammer er deponert ved United States Department of Agriculture (Northern Research and Development Division), Peoria, 111., USA. Cyklosporin kan is.oleres på .-kromatograf isk måte som et mot aspergillus niger aktivt produkt med mer polar virkning enn cyklosporin. A og B (i DOS 2.455.859 betegnes cyklosporin A og B som henhv. S 7481/F/l og S 7481/F-2.
Dihydro-cyklosporin C u.tmerker seg ved interessante kjemo-terapeutiske og farmakologiske egenskaper og kan følgelig anvendes som medisin.
Dihydro-cyklosp.orin C er spesielt indikert som antiartritikum og for behandling av immunologisk betingede reaksjoner.
Som legemiddel kan dihydro-cyklosporin C tilføres alene eller
i passende preparatform sammen med farmakologisk indiffirente hj elpestoffer.
I det etterfølgende eksempel som skal illustrere oppfinnelsen er alle temperaturangivelser i °C.
EKSEMPEL:
420 mg palladium-kull (10 % palladium) forhåndshydrogeneres i 40 ml etanol i 75 min. Til.denne suspensjon av palladium-katalysatoren tilsettes løsningen av 8,53 g cyklosporin C
i 110 ml etanol og hydrogeneres deretter ved 20°C og et trykk på 736 mm kvikksølvsøyle til avsluttet hydrogenopptagelse. Deretter frafilteeres katalysatoren og filtratet inndampes i vakuum ved 20. til 40°C til tørrhet. Resten kromatograferes på
en kolonne med 1 kg kiselgel "Merck", kornsfcørrelse 0,06 til 0,2mm. Eluering med kloroform-metanol (97,5 : 2,5) gir etter forening
av de rene fraksjoner hvitt amorft dihydro-cyklosporin C som tørkes i høyvakuum ved 55°C i 6 timer. For bortskaffing av vannet destilleres preparatet i vakuum ved 30 - 50°C tre ganger med benzen og tørkes deretter først ved 55°C (2 timer) deretter ved 80°C (2 timer) i høyvakuum.
Det som utgangsmaterial anvendte cyklosporin C fremstilles på følgende måte:
En ved aerob neddykket dyrking av trichoderma polysporum
(link ec Pers.) rifai (NRRL 8044) erholdt dyrkingsbuljong (400 1) (se eksempel 3 i DOS 2.455.859) ble utrørt med 400 1 n-butylacetat. Etter separering i en Westfalia-separator ble den organiske fase konsentrert i vakuum og råekstrakten avfettet ved tre trinns fordeling .mellom petroleter og metanol/vann (9:1).
Det erholdte material løses i klproform og kromatograferes på 4,5 kg kiselgel 60 "Merck", kornstørÉelse 0,2 - 0,5 mm, idet kloroform med stigende åndel av'metanol tjente som elueringsmiddel. De med kloroform + 1,5% metanol erholdte fraksjoner inneholdt overveiende.cyklosporin A og B, de senere med kloroform +3% metanol eluerte fraksjoner overveiende cyklosporin C. Deres påvisning i eluatfraksjonene skjedde ved hjelp av tynnskikt-kromatografji, idet de fremviste en vesentlig lavere RF-verdi enn de to førstnevnte substanser, f.eks. på silikagel-ferdigfolier "polygram"'med kloroform-metanol (95:5) som flytemiddel,
RF = 0,26-(RF av cyklosporin A: 0,44, og av cyklosporin B: 0,37). Etter forening og inndamping av eluatfraksjonene, som etter tynnskiktkromatografisk prøving helt eller overveiende bestod av cykiosporin C, gjentas den kromatografiske rensing. Eluatfraksjonene ble prøvd på sin sammensetning ved tynnskiktkromatogram som ovenfor og de av fraksjonene som i sin helhet bestod av cyklosporin C ble forenet og inndampet til tørrhet i vakuum ved 20 til 40°C. Resten ble etter oppløsning i den ti-dobbelte mengde alkohol behandlet med 5 vektprosent aktivt karbon, etter frafiltrering av karbonet ble filtratet inndampet ved 20 til 40°C i vakuum og resten tørket i høyvakuum ved 55°C.
Det siste renseskritt bestod deri at resten ble løst i den fem-dobbelte mengde eter og den faste substans utfelt ved langsom tilsetning av den tredve-dobbelte mengde heksan under omrysting og frafiltrering-etter avkjøling av blandingen til 0,til 5°C, vasking med koid heksan og tørking i høyvakuum ved 55°C. Fra den 2,5-dobbelte mengde aceton erholdes ved -15°C fargeløse, prismatiske nåler 'av -krystallinsk cyklosporin C.
Smeltepunkt 152 - 155°C
HD<20>= - 255 (kloroform, c= 0,5)
20
|jxj = - 182°- (metanol, c= 0,5)
D
Claims (2)
1. Fremgangsmåte for fremstilling av dihydro-cyklosporin C (formel I)
karakterisert ved at cyklosporin C,
formel II)
hydrogeneres.
2. Fremgangsmåte for fremstilling av det cyklosporin C som er angitt i krav 1,
karakterisert ved at en cyklosporin C-produserende stamme av sopparten trichoderma polysporum (Link ex Pers.) rifai eller cylindrocarpon lucidum Booth dyrkes og cyklosporin C isoleres fra dyrkingsbuljongen*
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1419575A CH614931A5 (no) | 1975-11-04 | 1975-11-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO763667L true NO763667L (no) | 1977-05-05 |
Family
ID=4398730
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO763667A NO763667L (no) | 1975-11-04 | 1976-10-27 |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US4108985A (no) |
| JP (2) | JPS5259180A (no) |
| AT (1) | AT359642B (no) |
| AU (1) | AU513538B2 (no) |
| BE (1) | BE847941A (no) |
| CA (1) | CA1087609A (no) |
| CH (2) | CH614931A5 (no) |
| DE (2) | DE2661031C2 (no) |
| DK (1) | DK148907C (no) |
| ES (1) | ES452942A1 (no) |
| FI (1) | FI60701C (no) |
| FR (2) | FR2330387A1 (no) |
| GB (2) | GB1567201A (no) |
| IE (2) | IE44750B1 (no) |
| IL (1) | IL50836A (no) |
| NL (1) | NL7612026A (no) |
| NO (1) | NO763667L (no) |
| NZ (1) | NZ182496A (no) |
| PH (1) | PH14725A (no) |
| PT (1) | PT65791B (no) |
| SE (2) | SE432247B (no) |
| YU (1) | YU270076A (no) |
| ZA (1) | ZA766340B (no) |
Families Citing this family (71)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4210581A (en) * | 1975-11-04 | 1980-07-01 | Sandoz Ltd. | Organic compounds |
| DE2819094A1 (de) * | 1977-05-10 | 1978-11-23 | Sandoz Ag | Cyclosporin-derivate, ihre verwendung und herstellung |
| FR2410658A1 (fr) * | 1977-11-30 | 1979-06-29 | Science Union & Cie | Nouveau produit biologique d'origine fongique, son obtention et son application a la therapeutique |
| SE445174B (sv) * | 1978-03-07 | 1986-06-09 | Sandoz Ag | Farmaceutisk komposition innehallande en cyklosporin och en berarsubstans |
| SE448386B (sv) * | 1978-10-18 | 1987-02-16 | Sandoz Ag | Nya cyklosporinderivat, forfarande for framstellning av dem samt farmaceutisk komposition innehallande dem |
| US4201771A (en) * | 1979-03-12 | 1980-05-06 | Merck & Co., Inc. | Antibiotic A43F |
| JPS5665853A (en) * | 1979-11-01 | 1981-06-03 | Sankyo Co Ltd | Mycoplanesin derivative and its preparation |
| EP0034567B1 (en) * | 1980-02-14 | 1984-11-07 | Sandoz Ag | A method for the total synthesis of cyclosporins and novel cyclosporins |
| US4396542A (en) * | 1980-02-14 | 1983-08-02 | Sandoz Ltd. | Method for the total synthesis of cyclosporins, novel cyclosporins and novel intermediates and methods for their production |
| US4370266A (en) * | 1980-04-07 | 1983-01-25 | Sankyo Company, Limited | Mycoplanecin derivatives and their preparation |
| US4384996A (en) * | 1981-01-09 | 1983-05-24 | Sandoz Ltd. | Novel cyclosporins |
| US5639724A (en) | 1984-07-24 | 1997-06-17 | Sandoz Ltd. | Cyclosporin galenic forms |
| GB8422253D0 (en) * | 1984-09-04 | 1984-10-10 | Sandoz Ltd | Organic compounds |
| EP0198026B1 (en) | 1984-10-04 | 1993-08-04 | Sandoz Ag | Monoclonal antibodies to cyclosporings |
| US4727035A (en) * | 1984-11-14 | 1988-02-23 | Mahoney Walter C | Immunoassay for cyclosporin |
| US4764503A (en) * | 1986-11-19 | 1988-08-16 | Sandoz Ltd. | Novel cyclosporins |
| US4798823A (en) * | 1987-06-03 | 1989-01-17 | Merck & Co., Inc. | New cyclosporin analogs with modified "C-9 amino acids" |
| ATE95193T1 (de) * | 1987-06-17 | 1993-10-15 | Sandoz Ag | Cyclosporine und deren benutzung als arzneimittel. |
| EP0373260B1 (en) * | 1987-06-22 | 1994-03-09 | Merck & Co. Inc. | Cyclosporin derivatives with modified "8-amino acid" |
| GB8717299D0 (en) * | 1987-07-22 | 1987-08-26 | Nat Res Dev | Peptides |
| GB8717300D0 (en) * | 1987-07-22 | 1987-08-26 | Nat Res Dev | Cyclosporins |
| US5227467A (en) * | 1987-08-03 | 1993-07-13 | Merck & Co., Inc. | Immunosuppressive fluorinated cyclosporin analogs |
| US4839342A (en) * | 1987-09-03 | 1989-06-13 | University Of Georgia Research Foundation, Inc. | Method of increasing tear production by topical administration of cyclosporin |
| EP0391909B1 (en) * | 1987-09-03 | 1994-08-17 | The University Of Georgia Research Foundation, Inc. | Ocular cyclosporin composition |
| US4914188A (en) * | 1987-11-16 | 1990-04-03 | Merck & Co., Inc. | Novel 6-position cyclosporin analogs as non-immunosuppressive antagonists of cyclosporin binding to cyclophilin |
| US5236899A (en) * | 1987-11-16 | 1993-08-17 | Merck & Co., Inc. | 6-position cyclosporin a analogs as modifiers of cytotoxic drug resistance |
| HU203564B (en) * | 1987-12-21 | 1991-08-28 | Sandoz Ag | Process for producing new orthorombos cyclosporin without solvatation |
| US4943560A (en) * | 1988-04-06 | 1990-07-24 | Regents Of The University Of Minnesota | Solvent system for chronic vascular infusion of hydrophobic drugs |
| US5342625A (en) * | 1988-09-16 | 1994-08-30 | Sandoz Ltd. | Pharmaceutical compositions comprising cyclosporins |
| US7081445B2 (en) * | 1989-02-20 | 2006-07-25 | Novartis Ag | Cyclosporin galenic forms |
| US4996193A (en) * | 1989-03-03 | 1991-02-26 | The Regents Of The University Of California | Combined topical and systemic method of administration of cyclosporine |
| US5540931A (en) * | 1989-03-03 | 1996-07-30 | Charles W. Hewitt | Methods for inducing site-specific immunosuppression and compositions of site specific immunosuppressants |
| GB8916901D0 (en) | 1989-07-24 | 1989-09-06 | Sandoz Ltd | Improvements in or relating to organic compounds |
| US5122511A (en) * | 1990-02-27 | 1992-06-16 | Merck & Co., Inc. | Immunosuppressive cyclosporin analogs with modified amino acids at position-8 |
| DE69222150T2 (de) * | 1991-01-25 | 1998-01-15 | Fujisawa Pharmaceutical Co | Prozess zur produktion von cyclosporin-a und/oder c |
| ES2065273B1 (es) * | 1993-05-25 | 1995-09-16 | Biogal Gyogyszergyar | Procedimiento para la purificacion de ciclosporina a. |
| US5709797A (en) * | 1996-06-05 | 1998-01-20 | Poli Industria Chimica S.P.A. | Method of isolating cyclosporins |
| BR9807528A (pt) | 1997-01-30 | 2000-03-14 | Novartis Ag | Composições farmacêuticas isentas de óleo contendo ciclosporina a |
| US6346511B1 (en) | 1997-09-08 | 2002-02-12 | Panacea Biotec Limited | Pharmaceutical composition comprising cyclosporin |
| US6187747B1 (en) | 1997-09-08 | 2001-02-13 | Panacea Biotech Limited | Pharmaceutical composition comprising cyclosporin |
| IN188719B (no) * | 1997-09-08 | 2002-11-02 | Panacea Biotec Ltd | |
| US6008191A (en) * | 1997-09-08 | 1999-12-28 | Panacea Biotec Limited | Pharmaceutical compositions containing cyclosporin |
| JP4261049B2 (ja) | 1997-10-08 | 2009-04-30 | アイソテクニカ インコーポレイテッド | 重水素化シクロスポリンアナログおよび免疫調節剤としてのそれらの使用 |
| US20030220234A1 (en) * | 1998-11-02 | 2003-11-27 | Selvaraj Naicker | Deuterated cyclosporine analogs and their use as immunodulating agents |
| DE69928938T2 (de) | 1998-07-01 | 2006-08-17 | Debiopharm S.A. | Neues cyclosporin mit verbesserter wirkung |
| EP2116228A1 (en) * | 2001-10-19 | 2009-11-11 | Isotechnika Inc. | Novel cyclosporin analog microemulsion preconcentrates |
| PL210795B1 (pl) | 2001-10-19 | 2012-03-30 | Isotechnika Inc | Sposób wytwarzania mieszaniny ISATX247 wzbogaconej w izomer (E), sposób wytwarzania mieszaniny ISATX247 wzbogaconej w izomer (Z), sposób stereoselektywnej syntezy izomeru (E) ISATX247, sposób stereoselektywnej syntezy izomeru (Z) ISATX247 i sposób wytwarzania mieszaniny izomerów ISATX247 |
| US20060014677A1 (en) * | 2004-07-19 | 2006-01-19 | Isotechnika International Inc. | Method for maximizing efficacy and predicting and minimizing toxicity of calcineurin inhibitor compounds |
| EP1809656A4 (en) | 2004-09-29 | 2009-03-25 | Amr Technology Inc | CYCLOSPORINAL KINANALOGA AND ITS PHARMACEUTICAL APPLICATIONS |
| US7511013B2 (en) | 2004-09-29 | 2009-03-31 | Amr Technology, Inc. | Cyclosporin analogues and their pharmaceutical uses |
| US7361636B2 (en) | 2004-10-06 | 2008-04-22 | Amr Technology, Inc. | Cyclosporin alkynes and their utility as pharmaceutical agents |
| US11311477B2 (en) | 2006-03-07 | 2022-04-26 | Sgn Nanopharma Inc. | Ophthalmic preparations |
| US10137083B2 (en) | 2006-03-07 | 2018-11-27 | SGN Nanopharma Inc | Ophthalmic preparations |
| US7696165B2 (en) | 2006-03-28 | 2010-04-13 | Albany Molecular Research, Inc. | Use of cyclosporin alkyne analogues for preventing or treating viral-induced disorders |
| US7696166B2 (en) | 2006-03-28 | 2010-04-13 | Albany Molecular Research, Inc. | Use of cyclosporin alkyne/alkene analogues for preventing or treating viral-induced disorders |
| WO2008036244A1 (en) * | 2006-09-18 | 2008-03-27 | The Burham Institute For Medical Research | Use of cyclosporin a to sensitize resistant cancer cells to death receptor ligands |
| TW200932240A (en) | 2007-10-25 | 2009-08-01 | Astellas Pharma Inc | Pharmaceutical composition containing lipophilic substance which inhibits IL-2 production |
| CN102365094A (zh) * | 2009-01-30 | 2012-02-29 | 英安塔制药有限公司 | 用于预防或者治疗肝炎感染的环孢菌素类似物 |
| US8481483B2 (en) * | 2009-02-19 | 2013-07-09 | Enanta Pharmaceuticals, Inc. | Cyclosporin analogues |
| US8685917B2 (en) * | 2009-07-09 | 2014-04-01 | Enanta Pharmaceuticals, Inc. | Cyclosporin analogues |
| US8367053B2 (en) | 2009-07-09 | 2013-02-05 | Enanta Pharmaceuticals, Inc. | Cyclosporin analogues |
| US8349312B2 (en) * | 2009-07-09 | 2013-01-08 | Enanta Pharmaceuticals, Inc. | Proline substituted cyclosporin analogues |
| US8623814B2 (en) * | 2010-02-23 | 2014-01-07 | Enanta Pharmaceuticals, Inc. | Antiviral agents |
| US9217015B2 (en) | 2010-07-16 | 2015-12-22 | S&T Global Inc. | Cyclosporin derivatives for the treatment and prevention of a viral infection |
| US9573978B2 (en) | 2010-08-12 | 2017-02-21 | S&T Global, Inc. | Cyclosporin derivatives for the treatment and prevention of a viral infection |
| US9890198B2 (en) | 2010-12-03 | 2018-02-13 | S&T Global Inc. | Cyclosporin derivatives and uses thereof |
| DK2651965T3 (en) | 2010-12-15 | 2019-02-18 | Contravir Pharmaceuticals Inc | CYCLOSPORIN ANALOGUAL MODULES MODIFIED BY AMINO ACID 1 AND 3 |
| WO2012145427A1 (en) | 2011-04-18 | 2012-10-26 | The Trustees Of Columbia University In The City Of New York | Methods to treat cancer using cyclosporine and cyclosporine derivatives |
| US8906853B2 (en) | 2012-11-28 | 2014-12-09 | Enanta Pharmaceuticals, Inc. | [N-Me-4-hydroxyleucine]-9-cyclosporin analogues for treatment and prevention of hepatitis C infection |
| RU2016110247A (ru) | 2013-08-26 | 2017-10-02 | Энанта Фармасьютикалс, Инк. | Аналоги циклоспорина для предупреждения или лечения гепатита с |
| US9669095B2 (en) | 2014-11-03 | 2017-06-06 | Enanta Pharmaceuticals, Inc. | Cyclosporin analogues for preventing or treating hepatitis C infection |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2463138C2 (de) * | 1973-12-06 | 1984-07-05 | Sandoz-Patent-GmbH, 7850 Lörrach | Das Antibiotikum Cyclosporin B (S 7481/F-2), seine Herstellung und Verwendung |
-
1975
- 1975-11-04 CH CH1419575A patent/CH614931A5/xx not_active IP Right Cessation
-
1976
- 1976-10-23 DE DE2661031A patent/DE2661031C2/de not_active Expired
- 1976-10-23 DE DE2648121A patent/DE2648121C2/de not_active Expired
- 1976-10-25 ZA ZA00766340A patent/ZA766340B/xx unknown
- 1976-10-26 FI FI763049A patent/FI60701C/fi not_active IP Right Cessation
- 1976-10-26 DK DK483176A patent/DK148907C/da not_active IP Right Cessation
- 1976-10-27 NO NO763667A patent/NO763667L/no unknown
- 1976-10-27 SE SE7611906A patent/SE432247B/xx unknown
- 1976-10-27 US US05/736,106 patent/US4108985A/en not_active Expired - Lifetime
- 1976-10-29 NL NL7612026A patent/NL7612026A/xx not_active Application Discontinuation
- 1976-11-02 JP JP51131314A patent/JPS5259180A/ja active Granted
- 1976-11-02 CA CA264,703A patent/CA1087609A/en not_active Expired
- 1976-11-02 NZ NZ182496A patent/NZ182496A/xx unknown
- 1976-11-02 GB GB45485/76A patent/GB1567201A/en not_active Expired
- 1976-11-02 AU AU19262/76A patent/AU513538B2/en not_active Ceased
- 1976-11-02 IE IE2379/81A patent/IE44750B1/en unknown
- 1976-11-02 GB GB19922/79A patent/GB1567202A/en not_active Expired
- 1976-11-02 IE IE2439/76A patent/IE44749B1/en unknown
- 1976-11-02 PH PH19079A patent/PH14725A/en unknown
- 1976-11-03 AT AT812276A patent/AT359642B/de not_active IP Right Cessation
- 1976-11-03 IL IL50836A patent/IL50836A/xx unknown
- 1976-11-03 PT PT65791A patent/PT65791B/pt unknown
- 1976-11-03 YU YU02700/76A patent/YU270076A/xx unknown
- 1976-11-03 ES ES452942A patent/ES452942A1/es not_active Expired
- 1976-11-03 BE BE172045A patent/BE847941A/xx not_active IP Right Cessation
- 1976-11-04 FR FR7633231A patent/FR2330387A1/fr active Granted
-
1977
- 1977-04-21 FR FR7711993A patent/FR2338251A1/fr active Granted
-
1979
- 1979-06-11 CH CH543479A patent/CH619735A5/de not_active IP Right Cessation
-
1982
- 1982-03-30 SE SE8202039A patent/SE8202039L/sv not_active Application Discontinuation
-
1986
- 1986-09-11 JP JP61215602A patent/JPS6277399A/ja active Granted
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