FI60701B - Foerfarande foer framstaellning av terapeutiskt anvaendbar dihydrocyklosporin c - Google Patents
Foerfarande foer framstaellning av terapeutiskt anvaendbar dihydrocyklosporin c Download PDFInfo
- Publication number
- FI60701B FI60701B FI763049A FI763049A FI60701B FI 60701 B FI60701 B FI 60701B FI 763049 A FI763049 A FI 763049A FI 763049 A FI763049 A FI 763049A FI 60701 B FI60701 B FI 60701B
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- chj
- therapeutic
- dihydrocyclosporin
- cyclosporin
- iii
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- 108010040786 dihydrocyclosporin C Proteins 0.000 title claims description 15
- 230000001225 therapeutic effect Effects 0.000 title 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 claims description 13
- 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 13
- 108010019248 cyclosporin C Proteins 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 6
- 238000005984 hydrogenation reaction Methods 0.000 claims description 4
- QSLPNSWXUQHVLP-UHFFFAOYSA-N $l^{1}-sulfanylmethane Chemical compound [S]C QSLPNSWXUQHVLP-UHFFFAOYSA-N 0.000 claims 2
- 102100030500 Heparin cofactor 2 Human genes 0.000 claims 1
- 101710153650 Heparin cofactor 2 Proteins 0.000 claims 1
- 101100054666 Streptomyces halstedii sch3 gene Proteins 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 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 description 9
- 229930105110 Cyclosporin A Natural products 0.000 description 8
- 108010036949 Cyclosporine Proteins 0.000 description 8
- 229960001265 ciclosporin Drugs 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 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 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000004809 thin layer chromatography Methods 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
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 229930182912 cyclosporin Natural products 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 101710154606 Hemagglutinin Proteins 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 101710093908 Outer capsid protein VP4 Proteins 0.000 description 2
- 101710135467 Outer capsid protein sigma-1 Proteins 0.000 description 2
- 101710176177 Protein A56 Proteins 0.000 description 2
- 241000123975 Trichoderma polysporum Species 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000185 hemagglutinin Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 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
- 239000000047 product Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 101000765308 Aspergillus niger N-(5'-phosphoribosyl)anthranilate isomerase Proteins 0.000 description 1
- 241000875119 Cylindrocarpon lucidum Species 0.000 description 1
- 241000282560 Macaca mulatta Species 0.000 description 1
- 241000364057 Peoria Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- -1 aliphatic alcohols Chemical class 0.000 description 1
- 230000002022 anti-cellular effect Effects 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000000287 crude extract Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229960004592 isopropanol Drugs 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 150000002940 palladium Chemical class 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance 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
- 231100000816 toxic dose Toxicity 0.000 description 1
- 238000002211 ultraviolet spectrum 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
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- 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)
- Wood Science & Technology (AREA)
- Biotechnology (AREA)
- Zoology (AREA)
- Biochemistry (AREA)
- Immunology (AREA)
- Biophysics (AREA)
- Tropical Medicine & Parasitology (AREA)
- Veterinary Medicine (AREA)
- General Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Botany (AREA)
- Mycology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Virology (AREA)
- Biomedical Technology (AREA)
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- Rheumatology (AREA)
- Transplantation (AREA)
- Pain & Pain Management (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (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
Ε35^Π ΓβΊ rt-.KUULUTOejULKAUU ,λπλ,
J®Ta w (11)utläggningsskrift6U/UI
• C (45) Γ2tontti i.y inn, lly 13 03 1932
Patent medöelst * (51) Kv.ik.Vci.3 c 0? C 103/52 // C 07 D 259/00 SUOMI—FINLAND (21) p»t**ittih«k«mu*-p»t*ot*»ökntnt 76301+9 (22) H»k«ml«pllvt — AiwBknlngsdtg 26.10.76 * * (23) Alkupilvt—Glltigh«t*d*g 26.10.76 (41) Tullut (ulklMkil — Bllvlt off«ntllg γγ
Patentti· ja rekisterihallitus NStoMttpa*. j. kuuLjuitah-n p-. -
Patent· och registerstyrelsen ' ' Antöktn utl»*d och utl.*krift*n pubikarad 30.11.81 (32)(33)(31) ^yy4#«y «uelkaui—BajIrd prloriut Olt.11.75
Sveitsi-Schweiz(CH) 11+195/75 (71) Sandoz A.G., Basel, Sveitsi-Schveiz(CH) (72) Artur Ruegger, Bottmingen, Max Kuhn, Basel, Sveitsi-Schveiz(CH) (7I+) Oy Kolster Ab
(51+) Menetelmä terapeuttisesti käyttökelpoisen dihydrosyklosporiinin C valmistamiseksi - Förfarande för framställning av terapeutiskt an-vändbar dihydrocyklosporin C
Tämä keksintö koskee menetelmää terapeuttisesti käyttökelpoi-Sen dihydrosyklosporiinin C valmistamiseksi, jonka kaava on ch3x^ CHj H,c.
xh2
CH3 ^CH3 I
CM HO. /CH CH]
I CH3,. ^cm3 CH * xh3 I
CMj CHj CH CHj CH-OH CH3 CH3-N-CH-CO-J1-4m C N —CM CO N—CH—C N CHj h 1 ä 1 1 1 s co : ; : * I i ! !
Cm-cmj-ch l : : : I
CH3/ I I I i N-CHj chj-n : : ·.
I m 9 V
I O t I l II u I ,-rH
OC-CM-N-CO-CH—N-CO—'CH-N-C—CH-N-CO y"
I I I I I I
CHj H CHj CMj CHj CH , I c£ CHj Im /Cv. c£l ^CH3 CM3 CH3 CM3 2 60701
Dihydrosylkosporiinilla C on mielenkiintoisia kemoterapeut-tisia ja farmakologisia ominaisuuksia ja siten sitä voidaan käyttää lääkkeenä; erityisesti dihydrosylkosporiini C sopii niveltulehduksen ja immunologisten reaktioiden hoitoon.
Keksinnön mukaisesti päädytään yhdisteeseen dihydrosyklospo-riini C hydraamalla yhdistettä syklosporiini C, jonka kaava on
ch3^ /H
c
| II
*N:h2
CH3- CH3 I
CH HO /CH CH3 | ch3 CH3 CM « nch3 | CM2 CH3 CH CH3 CH-OH CHj
III I I I I
CH.-N-CH-CO-N-CH-C-N-CM-CO-N—CH-C-N —CHj
| 1 1 S 1 i 1 S I
co : : ; I
CH\ I i ! i Γ
ch-chj-ch u : ; : I
cho^ | : : j n-ch3 ch,-n : : !
I h ° H
I O L I L II L | L
OC-CH-N-CO-CH — N-CO-CH-N-C-CH-N-CO-CH
CH3 H CH3 CH2 CH3 CH CHj
i ci; cmj I
CH
CH3 ^CHs CH3 CH3
Keksinnön mukainen menetelmä on toteutettavissa tunnetuin menetelmin esim. hydraamalla katalyyttisesti.
Liuottimina tulevat kysymykseen erityisesti etyyliasetaatti tai alemmat alifaattiset alkoholit, esim. metanoli, etanoli tai iso-propanoli. Hydraus tapahtuu sopivimmin neutraalissa liuoksessa lämpötilassa 20° - 30° ja normaalipaineessa tai hieman kohotetussa paineessa. Katalyytteinä tulevat kysymykseen platina ja erityisesti palladium, esim. palladium-hiili. Syklosporiinin C näin saatua hydraustuotetta puhdistetaan tunnettuun tapaan esim. kromatografoi-malla.
Lähtöaineena käytetty syklosporiini C valmistetaan viljelemällä sienilajin Trichoderma polysporum (Link ex Pers.). Rifai tai Cylindrocarpon lucidum Booth syklosporiinia C tuottavaa kantaa ja 60701 eristämällä syklospor.iini C ravinnealustasta. Viljely tapahtuu tunnettuun tapaan käyttäen mieluiten kantaa NRRL 5760 tai kantaa NRRL 8044 (ks. saksalaista patenttijulkistusta 2 455 859). Molempien kantojen viljelmät on talletettu United States Department of Agriculture (Northern Research and Development Division), Peoria, 111., USA, Syklosporiini C voidaan eristää kromatografisesti Aspergillus niger.in suhteen aktiivisena tuotteena, jolla on polaarisempi vaikutus kuin syklosporiinilla A ja B (saksalaisessa patenttijulkistuksessa syklosporiinista A ja B käytetään nimityksiä S 7481/F-1 ja S 7481/F-2).
Dihydrosyklosporiinilla C on seuraavat tunnusarvot:
Sp. 160°-162°C(amorfinen); lievästi hygroskooppinen aine.
= -242° (c = 0,5 kloroformissa) ja -174,5° (c = metanol.issa). UV-spektrin mukaan (metanol.i) yhdisteellä on pääteabsorpt io. IR-spektri Cl^Cl^ssa ilmenee kuvasta 1 ja NMR-spektri. CDClgissa, 90 MHz, tetrametyylis.ilaan.i sisäisenä standardina, kuvasta 2 (signaalit 7,23 ppm ja 7,33 ppm johtuvat hyvin pienistä määristä CHCl^ ja CgHg).
Bruttokaava CgjH^gN^O^g
Laskettu; C 61,0 H 9,3 N 12,6 0 17,0 %
Saatu: C 61,1 H 9,6 N 12,4 0 17,3 %,
Huoneen lämpötilassa dihydrosyklosporiini C liukenee helposti bentseeniin, dikloorimetaani.in, kloroformiin, etyyliasetaattiin, asetoniin, etanoliin ja metanoliin. Se on erittäin niukkaliukoinen veteen.
Dihydrosyklosporiin.in C ohutkerroskromatogrammin R^-arvot ilmenevät alla olevasta taulukosta: R^-arvot kloroformi-metanol.i (94:6) 0,4 0 asetoni 0,66 asetoni-heksaani (1:1) 0,38 asetoni-kloroformi (1:1) 0,42
Ohutkerroskromatograf iavalm.islevy silikageeli 6 0 F-2 54 (valmistaja Merck), Täplät saadaan näkyviin tavalliseen tapaan esim. jodilla. Suomalaisesta kuulutusjulkaisusta 52 851 tunnetaan menetelmä syklosporiinin A ja syklosporiinin B valmistamiseksi. Keksinnön 4 60701 mukaisesti valmistettu yhdiste, dihydrosyklosporiini C, eroaa tunnetusta yhdisteestä, syklospori.in.ista A, vaikutuksessa nesteimmuni-teettiin (eli vasta-aineiden muodostumiseen). Dihydrosyklosporiini C vaikuttaa vasta-aineiden muodostumiseen vasta suurissa pitoisuuksissa (eli toksisissa pitoisuuksissa), ja vaikutus on hidas ja sangen lievä - vasta-aineiden muodostuminen ei siis ole estetty.
Kun esimerkiksi hemagglut.inaat.iokokeessa (HAT) annettiin Rhesus-apinoille 5 x 250 mg/kg dihydrosyklospori.inia C, ei voitu todeta tilastollisesti merkitsevää hemagglutini.in.iti.itterin vähenemistä.
Sama annos syklospor.iinia A aikaansai käytännöllisesti katsoen täydellisen eston. Dihydrosyklosporiinilla C on siten huomattava etu hoidettaessa kroonisia tulehduksia, koska sillä on voimakas solunvastainen, mutta vain heikko vasta-aineiden vastainen vaikutus.
Seuraava esimerkki valaisee keksintöä. Lämpötilat ovat Cels ius-asteinä.
Esimerkki
Esihydratti.in 7 5 minuuttia 4 20 mg palladium-hiiltä (10 % palladiumia) 4 0 ml:ssa etanolia. Tähän pallad.iumkatalyytt isuspensioon lisättiin liuos, jossa oli 8,53 g syklosporiinia C 110 ml:ssa etanolia ja hydrattiin lämpötilassa 20°C ja paineessa 736 mm Hg, kunnes vedynsitoutuminen päättyi, Sitten katalyytti poistettiin suodattamalla ja suodos haihdutettiin kuiviin vakuumissa ja lämpötilassa 20°-40°C. Jäännös kromatograf oiti.in kolonnissa, jossa oli 1 kg silikageeliä (valmistaja Merck, raekoko 0,06-0,2 mm). Eluoitiin kloroformi-metanolilla (97,5:2,5), ja yhdistettiin puhtaat fraktiot, jolloin saatiin valkoista, amorfista dihydrosyklosporiinia C, joka kuivattiin 6 tuntia korkeavakuum.issa lämpötilassa 30°-50°C. Veden poistamiseksi valmistetta käsiteltiin kolmasti bentseenillä ja haihdutettiin korkeavakuum.issa lämpötilassa 30°-50°C, Sitten kuivattiin 2 tuntia 55°C:ssa ja 2 tuntia korkeavakuumissa 80°C:ssa.
Lähtöaineena käytetty syklosporiini C valmistettiin seuraavasti :
Sekoitettiin 400 1 Trichoderma polysporumin (Link ex Pers.) Rifai (NRRL 8044) aerobista, pinnanalaista viljelmää (ks. saksalaisen patenttijulkistuksen 2 455 859 esimerkkiä 3) ja 400 1 n-butyyli-asetaattia, Erotettiin Westfalia-erottimessa orgaaninen faasi ja se konsentroitiin vakuumissa, ja rasva poistettiin epäpuhtaasta uutteesta 5 60701 antamalla kolmivaiheisesta jakaantua petrolieetteriin ja metanoli-veteen (9:1), Sakka liuotettiin kloroformiin ja kromatografoitiin 4,5 kg:11a silikageeliä "60", (valmistaja Merck, hiukkaskoko 0,2-0,5 mm), jolloin eluointiaineena käytettiin kasvavaa määrää metanol.ia sisältävää kloroformia. Fraktiot, jotka saatiin kloroformilla ja 1,5-% metanol.illa, sisälsivät pääasiallisesti syklosporiinia A ja B, ja niiden jälkeen kloroformilla ja 3-% metanolilla eluoitavat fraktiot sisälsivät pääasiallisesti syklosporiinia C. Toteaminen eluaat-tifraktioissa tapahtui ohutkerroskromatograaf isest.i , jolloi n iälk.im-mäisillä fraktioilla oli huomattavasti pienempi R^-arvo kuin ensiksi mainituilla fraktioilla es.im, silikageelivalmiskalvoilla "Polygram", kloroformi-metanoli (95:5) eluointiaineena (R^ syklospori.ini C = 0,26, syklosporiin.i A = 0,44 ja syklospori.ini B = 0,37), Yhdistettiin eluaattifraktiot ja haihdutettiin ne kuiviin; fraktiot olivat ohutkerroskromatografiän mukaan kokonaan tai pääasiallisesti syklo-sporiinista C. Kromatografinen puhdistus toistettiin, tutkittiin eluaattifraktioiden koostumus ohutkerroskromatografisesti, yhdistettiin pelkästä syklospor.iinista C muodostuvat fraktiot ja haihdutettiin kuiviin vakuumissa lämpötilassa 20°-40°C. Jäännös liuotettiin kymmenkertaiseen määrään alkoholia, käsiteltiin 5 paino-%:lla aktiivihiiltä, hiili poistettiin 20°-40°C:ssa ja jäännös kuivattiin korkeavakuumissa lämpötilassa 55°C,
Viimeisessä puhdistusvaiheessa jäännös liuotettiin viisinkertaiseen määrään eetteriä, saostettiin kiintoaine lisäämällä hitaasti kolmikymmenkertainen määrä heksaania ravistellen, eristettiin suodattamalla seoksen 0°-5°C:een jäähdyttämisen jälkeen, pestiin kylmällä heksaan.illa ja kuivattiin korkeavakuumissa lämpötilassa 55°C, Kiteytettiin 2 1/2-kertaisesta määrästä asetonia, jolloin saatiin -15°C;ssa kiteisen syklospor.i.in.in C värittömiä, prismamai-sia neulasia,
Sp, 1 52-1 5 5°C
= ~2 5 5° (kloroformi, c = 0,5) γλ( 720 o *- •'d = "182° (metanoli, c = 0,5),
Claims (1)
- 6 60701 Patenttivaatimus Menetelmä terapeuttisesti käyttökelpoisen dihydrosyklosporiinin C valmistamiseksi, jonka kaava on ch3s CHj HJcv I XH2 CH3v ^CH3 | CH HO /CH CH I CH3\ /c”3 CM R ^CH3 I CH2 CHj CH CH3 £ CH-OH CH3 I I I I l| CHj-N-CH-CO-N-CH-C-N-CH-CO-N—CH-C N-CH, Il l II «. I l II I O HO co : : : CH\ I i i I co ch-chj-ch l : : : CB>/ I 1 il N —CM, CHj-N : ::3 I H OH I “ L I «· Il L I L OC-CH-N-CO-CH — N-CO-CH-N-C-CH-N-CO-CH I 1 1 III I ch3 H CH3 CHj CHj CH CHj I / \ I I CHj CH3 I CH ja CH / S / \ CH3 CH3 CHj CHj tunnettu siitä, että hydrataan syklosporiini C, jonka kaava on CH3S /H C II Ν:η2 11 CH3^ ^,CH3 I CH HO /CH CHj | CH3^ /CHj ^CH « ^CH3 I CH2 CH3 CH CH3 CH-OH CHj CH,-N-CH-CO-N-A H-C-N-CH-CO-N —CH-C-il-CH, Il l II l I t II | O HO co I : ch\ l ! i i f ch-chj-ch l : : : e***'' ( : : : n-chj chj-n : : : | I H OH I O L I L (I L I L I OC-CH-N CO-CH — N CO CH-N C CH N-CO CH III lii l CH3 H CH3 CHj CHj CH CHj l CH3 CHj I CH CH / \ / \ CHj CHj CHj CHj 7 60701 Förfarande för framställning av dihydrocyklosporin C, som har formeln CHjs CH j • h2c I CH3^ ^CH3 I CH HO >CH CH3 | CH\ CH R SCH3 | CH2 CH3 CH CH3 CH-OH CH3 i i l i I ii CH-,- N — CH — CO —N-CH-C-N-CH-CO-N —CH-C-N-CH, I L L l| L I L II I O HO C° : : : ch3 : : : co ch-ch,-ch l : : : / I : : i CH3 I : : : n-ch, ch3-n : : : H OH I ° L | L II C l c OC-CH-N-CO-CH — N-CO-CH-N-C-CH-N-CO-CM III III I CH3 H CH3 CH, CH, CM CH, I / N | I CH3 CH] I CH CH / \ / s ch3 ch3 ch3 ch3 kännetecknat därav, att man hydrerar cyklosporin C, som har formeln CH3S /H C I II VsCH2 CH3 CH] | CH HO /CH c„ | CH3^ /CH] ^CH R ^CH3 | CH2 CH] CH CH] CH-OH CH3 CH-,-N — CH-CO-N-1h-C-il-CM-CO-N —CH-C-il-CH, | L L l| L I L II I O HO CO : : : CH\ I I i I co CH-CHj-CH U : ; ; ch3 J : : i n-cH] ch,-n : i : | I H OH I O «- | L |j L | L I OC-CH-N CO-CH — N CO CH-N C CH N-CO CH III III I CH] H CH3 CHj CH] CH CH] I CH3 ^CH] I CH CH / \ / V- ch3 ch3 ch3 ch3
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FI802084A FI60718C (fi) | 1975-11-04 | 1980-06-30 | En ny ringpeptid cyklosporin c anvaendbar som mellanprodukt vid framstaellning av dihydrocyklosporin c och ett foerfarande foer dess framstaellning |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1419575 | 1975-11-04 | ||
| CH1419575A CH614931A5 (fi) | 1975-11-04 | 1975-11-04 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| FI763049A7 FI763049A7 (fi) | 1977-05-05 |
| FI60701B true FI60701B (fi) | 1981-11-30 |
| FI60701C FI60701C (fi) | 1982-03-10 |
Family
ID=4398730
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI763049A FI60701C (fi) | 1975-11-04 | 1976-10-26 | Foerfarande foer framstaellning av terapeutiskt anvaendbar dihydrocyklosporin c |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US4108985A (fi) |
| JP (2) | JPS5259180A (fi) |
| AT (1) | AT359642B (fi) |
| AU (1) | AU513538B2 (fi) |
| BE (1) | BE847941A (fi) |
| CA (1) | CA1087609A (fi) |
| CH (2) | CH614931A5 (fi) |
| DE (2) | DE2648121C2 (fi) |
| DK (1) | DK148907C (fi) |
| ES (1) | ES452942A1 (fi) |
| FI (1) | FI60701C (fi) |
| FR (2) | FR2330387A1 (fi) |
| GB (2) | GB1567202A (fi) |
| IE (2) | IE44750B1 (fi) |
| IL (1) | IL50836A (fi) |
| NL (1) | NL7612026A (fi) |
| NO (1) | NO763667L (fi) |
| NZ (1) | NZ182496A (fi) |
| PH (1) | PH14725A (fi) |
| PT (1) | PT65791B (fi) |
| SE (2) | SE432247B (fi) |
| YU (1) | YU270076A (fi) |
| ZA (1) | ZA766340B (fi) |
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| IE54936B1 (en) * | 1980-02-14 | 1990-03-28 | Sandoz Ltd | A method for the total synthesis of cyclosporins, novel cyclosporins and novel intermediates and methods for their production |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2455859C2 (de) * | 1973-12-06 | 1983-12-15 | Sandoz-Patent-GmbH, 7850 Lörrach | Das Antibiotikum Cyclosporin A (S 7481/F-1), seine Herstellung und Verwendung |
-
1975
- 1975-11-04 CH CH1419575A patent/CH614931A5/xx not_active IP Right Cessation
-
1976
- 1976-10-23 DE DE2648121A patent/DE2648121C2/de not_active Expired
- 1976-10-23 DE DE2661031A patent/DE2661031C2/de not_active Expired
- 1976-10-25 ZA ZA00766340A patent/ZA766340B/xx unknown
- 1976-10-26 DK DK483176A patent/DK148907C/da not_active IP Right Cessation
- 1976-10-26 FI FI763049A patent/FI60701C/fi not_active IP Right Cessation
- 1976-10-27 US US05/736,106 patent/US4108985A/en not_active Expired - Lifetime
- 1976-10-27 SE SE7611906A patent/SE432247B/xx unknown
- 1976-10-27 NO NO763667A patent/NO763667L/no unknown
- 1976-10-29 NL NL7612026A patent/NL7612026A/xx not_active Application Discontinuation
- 1976-11-02 GB GB19922/79A patent/GB1567202A/en not_active Expired
- 1976-11-02 JP JP51131314A patent/JPS5259180A/ja active Granted
- 1976-11-02 PH PH19079A patent/PH14725A/en unknown
- 1976-11-02 NZ NZ182496A patent/NZ182496A/xx unknown
- 1976-11-02 IE IE2379/81A patent/IE44750B1/en unknown
- 1976-11-02 GB GB45485/76A patent/GB1567201A/en not_active Expired
- 1976-11-02 CA CA264,703A patent/CA1087609A/en not_active Expired
- 1976-11-02 AU AU19262/76A patent/AU513538B2/en not_active Ceased
- 1976-11-02 IE IE2439/76A patent/IE44749B1/en unknown
- 1976-11-03 PT PT65791A patent/PT65791B/pt unknown
- 1976-11-03 AT AT812276A patent/AT359642B/de not_active IP Right Cessation
- 1976-11-03 ES ES452942A patent/ES452942A1/es not_active Expired
- 1976-11-03 YU YU02700/76A patent/YU270076A/xx unknown
- 1976-11-03 IL IL50836A patent/IL50836A/xx unknown
- 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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