DE2648121C2 - Dihydro-cyclosporin C, Verfahren zu dessen Herstellung und diese Verbindung enthaltende Arzneimittel - Google Patents
Dihydro-cyclosporin C, Verfahren zu dessen Herstellung und diese Verbindung enthaltende ArzneimittelInfo
- Publication number
- DE2648121C2 DE2648121C2 DE2648121A DE2648121A DE2648121C2 DE 2648121 C2 DE2648121 C2 DE 2648121C2 DE 2648121 A DE2648121 A DE 2648121A DE 2648121 A DE2648121 A DE 2648121A DE 2648121 C2 DE2648121 C2 DE 2648121C2
- Authority
- DE
- Germany
- Prior art keywords
- cyclosporin
- dihydro
- preparation
- methanol
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 108010040786 dihydrocyclosporin C Proteins 0.000 title claims description 13
- 239000003814 drug Substances 0.000 title claims description 5
- 238000000034 method Methods 0.000 title claims description 4
- 238000002360 preparation method Methods 0.000 title claims description 3
- 150000001875 compounds Chemical class 0.000 title 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 claims description 12
- 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 12
- 108010019248 cyclosporin C Proteins 0.000 claims description 12
- 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 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
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 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 6
- 108010036949 Cyclosporine Proteins 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
- 229960001265 ciclosporin Drugs 0.000 description 5
- 229930105110 Cyclosporin A Natural products 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 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 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 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
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-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
- 241001149960 Tolypocladium inflatum Species 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
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229930182912 cyclosporin Natural products 0.000 description 2
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 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
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241000228245 Aspergillus niger Species 0.000 description 1
- 241000875119 Cylindrocarpon lucidum 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
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- -1 aliphatic alcohols Chemical class 0.000 description 1
- 230000002456 anti-arthritic effect Effects 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 238000004140 cleaning Methods 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
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000001900 immune effect Effects 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
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-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
- 239000003208 petroleum Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 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
- 239000002904 solvent 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
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
Classifications
-
- 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
-
- 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
- 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
10 15 20
30 35 40
Die Erfindung betrifft die Verbindung Dihydrocyclosporin C (Formel I).
CH3
CH2
H2C
H2C
CH3
3 \
CH3
CH
CH2
CH3
CH3
HO
CH3 CH
CH3 CH
CH,
CH2
CH
CH
CH3
CH
CH-OH CH3
CH3
CH3
CH3-N-CH-CO-N-CH-C-N-CH-CO-N-CH-C-N-Ch2
I (D (L) 1 (L) I (L) Il
CO ? H ?
γ co
CH-CH2-CH(L)
CH3-N
I
O
O
i N-CH3
(D) (L) I (L) υ (L) I (L)
OC-CH-N-CO-CH-N-CO-CH-N-C-CH-N-CO-CH
CH3 H CH3 CH2 CH3 CH
CH CH3 CH3
/ \
CH3 CH3
CH3 CH3
CH2 CH
/ CH3
CH3
Erfindungsgemäß gelangt man zum Dihydro-cyclosporin C durch Hydrierung des Cyclosporin C (Formel Il).
CH3 H
45 50 55 60 65
CH3
3 \
CH CH2
CH3 CH3
CH,
H
HO
HO
CH2
CH
CH
CH
\
CH3 CH
CH3 CH
(R)
CH3
CH3
CH3
CH-OH CH3
CH3-N-CH-CO-N-CH-C-N-CH-CO-N-CH-C-N-Ch2
(L)
CH3
CO
(L) H O
(L)
CO
CH3-N
CH-CH2-CH(L) j j j
CH3' „„ J7 I II N-CH3
H OH
(D) (L) I (L) Il (L) I (L)
OC-CH-N-CO-CH-N-CO-CH-N-C-CH-N-CO-CH
CH3 H CH3 CH2 CH3 CH
CH CH3 CH3 CH3 CH3
CH2 CH
CH3
CH3
Dihydro-cyclosporin C hat folgende Charakteristika:
Ι·\ I6O-I62°C (amorph), leicht hygroskopisch.
[α]?,1 -242°C (£· = 0,5 in CHCI3)
[α]?,1 -242°C (£· = 0,5 in CHCI3)
-174,5°C (c = 0,5 in CH1OH)
Im UV-Spektrum (Methanol) zeigt die Verbindung Endabsorption. Das IR-Spektrum in CH2Cl2 ist die F i g. 1,
das NMR-Spektrum in CDCl3, 90 MHz, mit Tetramethylsilan als internem Standard, ist die Fig. 2 dargestellt
(Die Signale bei 7.23 ppm und bei 7.33 ppm rühren von sehr kleinen Mengen von CHCl3 resp. C6H6 her).
Bruttoformel: C62HiI3NnOiJ
Ber. C 61,0 H 9,3 N 12,6 O 17,0%
Gef. C 61,1 H 9,6 N 12,4 O 17,3%
Ber. C 61,0 H 9,3 N 12,6 O 17,0%
Gef. C 61,1 H 9,6 N 12,4 O 17,3%
Dihydro-cyclosporin C ist bei Raumtemperatur leicht löslich in Benzol, Dichlormethan, Chloroform, Äthylacetat,
Aceton, Äthanol, Methanol und sehr schwer löslich in Wasser.
Die RpWerte von Dihydro-cyclosporin C im Dünnschichtchromatogramm gehen aus folgender Tabelle hervor:
R|-Wene
Chloroform-Methanol (94 : 6) 0,40
Aceton 0,66
Aceton-Hexan (1:1) 0,38
Aceton-Chloroform (1:1) 0,42
DC-Fertigplatte »Merck«, Kieselgel 60 F-254.
Die Sichtbarmachung der Flecken kann in bekannter Weise, z. B. mit Jod, erfolgen.
Das erfindungsgemäße Verfahren läßt sich nach an sich bekannten Methoden ausführen, z. B. durch katalytische
Hydrierung.
Als Lösungsmittel kommen vorzugsweise Äthylacetat oder niedere aliphatische Alkohole, wie z. B. Methanol,
Äthanol, Isopropanol, in Frage. Die Hydrierung erfolgt zweckmäßigerweise im neutralen Bereich bei Temperaturen
zwischen 20 und 30° und bei Atmosphärendruck oder wenig erhöhtem Druck. Als Katalysator kommt Platin,
vorzugsweise Palladium, z. B. Palladium auf Kohle, in Frage. Das so erhaltene Hydrierungsprodukt von
Cyclosporin C wird hierauf in an sich bekannter Weise gereinigt, z. B. durch Chromatographie.
Das als Ausgangsprodukt benutzte Cyclosporin C kann erhalten werden, indem man einen Cyclosporin C produzierenden
Stamm der Pilzspecies Tolypocladium inflatum Garns, vormals Trichoderma polysporum (Link ex
Pers.) Rifai, oder Cylindrocarpon lucidum Booth züchtet und Cyclosporin C aus der Kulturbrühe isoliert. Die
Züchtung erfolgt auf an sich bekannter Weise, indem man vorzugsweise einen Stamm NRRL 5760 oder einen
Stamm NRRL 8044 verwendet (siehe z. B. DE-OS 24 55 859). Kulturen der beiden Stämme sind beim United
States Department of Agriculture (Northern Research and Development Division), Peoria, 111., USA deponiert.
Cyclosporin C kann auf chromatographischem Wege isoliert werden als ein gegen Aspergillus niger aktives
Produkt mit polarerer Wirkung als Cyclosporin A und B (In der DE-OS 24 55 859 werden Cyclosporin A und B
als S 7481/F-l und S 7481/F-2 bezeichnet).
Dihydro-cyclosporin C zeichnet sich durch interessante chemotherapeutische und pharmakologische Eigenschaften
aus und kann daher als Arzneimittel verwendet werden.
Dihydro-cyclosporin C ist insbesondere indiziert als Antiarthriticum und zur Behandlung immunologisch
bedingter Reaktionen.
Als Arzneimittel kann Dihydro-cyclosporin C allein oder in geeigneter Arzneiform mit pharmakologisch
indifferenten Hüfsstoffen verabreicht werden.
In dem nachfolgenden Beispiel, das die Erfindung näher erläutert, erfolgen alle Temperaturangaben in Celsiusgraden.
420 mg Palladium-Kohle (10% Palladium) werden in 40 ml Äthanol während 75 Minuten vorhydriert. Zu dieser
Suspension des Palladiumkatalysators wird die Lösung von 8,53 g Cyclosporin C in 110 ml Äthanol zugegeben
und darauf bei 20° und einem Druck von 736 mm Quecksilbersäule bis zur beendeten Wasserstoffaufnahme
hydriert. Anschließend filtriert man vom Katalysator ab und dampft das Filtrat im Vakuum bei 20-40° zur
Trockene ein. Der Rückstand wird an einer Säule von 1 kg Kieselgel »Merck«, Korngröße 0,06-0,2 mm, chromatographiert.
Die Elution mit Chloroform-Methanol (97,5 : 2,5) liefert nach Vereinigung der reinen Fraktionen
weißes, amorphes Dihydro-cyclosporin C, das im Hochvakuum bei 55° während 6 Stunden getrocknet wird. Zur
Befreiung von Wasser wird das Präparat im Vakuum bei 30-50° dreimal mit Benzol hochgezogen und anschlie-Bend
zuerst bei 55° (2 Stunden), dann bei 80° (2 Stunden) im Hochvakuum getrocknet. Das als Ausgangsmaterial verwendete Cyclosporin C wird wie folgt hergestellt:
Eine durch aerobe Submerszüchtung von Tolypocladium inflatum Garns, vormals Trichoderma polysporum
(Link ex Pers.) Rifai (NRRL 8044) erhaltene Kulturbrühe (400 L) [siehe Beispiel 3 von DE-OS 24 55 859] wurde
mit 400 L n-Butylacetat ausgerührt. Nach Auftrennung in einem Westfalia-Separator wurde die organische
Phase im Vakuum konzentriert, und der Rohextrakt durch 3stufige Verteilung zwischen Petroläther und
Methanol/Wasser (9:1) entfettet. Das anfallende Material löste man in Chloroform und chromatographierte an
s 4,5 kg Kieselgel 60 »Merck«, Korngröße 0,2-0,5 mm), wobei Chloroform mit steigenden Anteilen Methanol als
Elutionsmittel diente. Die mit Chloroform +1,5% Methanol erhaltenen Fraktionen enthielten vorwiegend
Cyclosporin A und B, die späteren, mit Chloroform +3% Methanol eluierten Anteile vorwiegend Cyclosporin C.
Ihr Nachweis in den Eluatfraktionen erfolgt mit Hilfe der Dünnschichtchromatographie, wobei sie einen
wesentlich niedrigeren Rr-Wert aufweist als die beiden erstgenannten Substanzen, z. B. auf Silicagel-Fertigfolien
ίο »Polygram« mit Chloroform-Methanol (95 :5) als Fließmittel, Rf = 0,26 (Rf von Cyclosporin A: 0,44, von Cyclosporin
B: 0,37). Nach Vereinigung und Eindampfen der Eluatfraktionen, die nach der dünnschichtchromatographischen
Prüfung ganz oder vorwiegend aus Cyclosporin C bestehen, wird die chromatographische Reinigung
wiederholt. Die Eluatfraktionen werden wie oben im Dünnschichtchromatogramm auf ihre Zusammensetzung
geprüft und diejenigen von ihnen, die ganz aus Cyclosporin C bestehen, vereinigt und im Vakuum bei 20-40°
zur Trockene verdampft. Den Rückstand behandelt man nach Lösen in der lOfachen Menge Alkohol mit
5 Gewichtsprozent Aktivkohle, dampft nach dem Abfiltrieren der Kohle das Filtrat bei 20-40° im Vakuum ein
und trocknet den Rückstand im Hochvakuum bei 55°.
Der letzte Reinigungsschritt besteht darin, daß man den Rückstand in der 5fachen Menge Äther löst und
durch langsames Zufügen der 30fachen Menge Hexan unter Schütteln die feste Substanz ausfällt und sie nach
Abkühlen des Gemisches auf 0 bis 5° abfiltriert, mit kaltem Hexan wäscht und im Hochvakuum bei 55° trocknet.
Aus der 2,5fachen Menge Aceton werden bei -15° farblose, prismatische Nadeln von kristallinem Cyclosporin
C erhalten.
F. 152-155°
la]h° -255° (Chloroform, c = 0,5)
[aß? -182° (Methanol, c = 0,5)
Hierzu 2 Blatt Zeichnungen
Claims (2)
1. Dihydro-cyclosporin C (Formel I).
Patentansprüche:
CH3
CH3
CH3
3 \
CH3
CH
CH2
CH3
CH2
H2C
H2C
CH2
HO CH
\ /(R) \ CH3 CH CH3
(R)
CH3
CH3
CH1
CH-OH CH3
CH3
CH3-N-CH-CO-N-CH-C-N-CH-CO-N-CH-C-N-Ch2
I (L) (L) I (L) I (L) H
O HO
i CO
CH-CH2-CHa)
CH3
CH3-N
i N-CH3 H OH
(D) (L) I (L) I (L) I (L)
OC-CH-N-CO-CH-N-CO-CH-N-C-CH-N-CO-CH
III III I
CH3 H CH3 CH2 CH3 CH CH2
I / \ I
CH CH3 CH3 CH
CH3
CH3
2. Verfahren zur Herstellung von Dihydro-cyclosporin C, dadurch gekennzeichnet, daß man Cyclosporin C
(Formel II)
CH3
3
\
\
Il
c
CH3
3 \
/ CH
CH2
CH3
CH3
CH3
CH,
H
HO
HO
CH2
CH
CH3 CH CH3
(R)
CH3
CH-OH CH3
CH
CH3-N-CH-CO-N-CH-C-N-CH-CO-N-CH-C-N-Ch2
(L) (L) Il (L) I (L) υ
O HO
I j i co
CO
CH-CH2-CH(L)
CH3
CH3-N
N-CH3
H O
(D) (L) I (L) II (L) I (L)
OC-CH-N-CO-CH-N-CO-CH-N-C-CH-N-CO-CH
CH3 H CH3 CH2 CH3 CH CH2
I / \ I
CH CH3 CH3 CH
CH3 CH3
CH3 CH3
(Π)
in an sich bekannter Weise hydriert.
3. Arzneimittel, enthaltend Dihydro-cyclosporin C gemäß Anspruch 1.
3. Arzneimittel, enthaltend Dihydro-cyclosporin C gemäß Anspruch 1.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1419575A CH614931A5 (de) | 1975-11-04 | 1975-11-04 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE2648121A1 DE2648121A1 (de) | 1977-05-12 |
| DE2648121C2 true DE2648121C2 (de) | 1986-05-28 |
Family
ID=4398730
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE2648121A Expired DE2648121C2 (de) | 1975-11-04 | 1976-10-23 | Dihydro-cyclosporin C, Verfahren zu dessen Herstellung und diese Verbindung enthaltende Arzneimittel |
| DE2661031A Expired DE2661031C2 (de) | 1975-11-04 | 1976-10-23 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE2661031A Expired DE2661031C2 (de) | 1975-11-04 | 1976-10-23 |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US4108985A (de) |
| JP (2) | JPS5259180A (de) |
| AT (1) | AT359642B (de) |
| AU (1) | AU513538B2 (de) |
| BE (1) | BE847941A (de) |
| CA (1) | CA1087609A (de) |
| CH (2) | CH614931A5 (de) |
| DE (2) | DE2648121C2 (de) |
| DK (1) | DK148907C (de) |
| ES (1) | ES452942A1 (de) |
| FI (1) | FI60701C (de) |
| FR (2) | FR2330387A1 (de) |
| GB (2) | GB1567202A (de) |
| IE (2) | IE44750B1 (de) |
| IL (1) | IL50836A (de) |
| NL (1) | NL7612026A (de) |
| NO (1) | NO763667L (de) |
| NZ (1) | NZ182496A (de) |
| PH (1) | PH14725A (de) |
| PT (1) | PT65791B (de) |
| SE (2) | SE432247B (de) |
| YU (1) | YU270076A (de) |
| ZA (1) | ZA766340B (de) |
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| US4370266A (en) * | 1980-04-07 | 1983-01-25 | Sankyo Company, Limited | Mycoplanecin derivatives and their preparation |
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| US4727035A (en) * | 1984-11-14 | 1988-02-23 | Mahoney Walter C | Immunoassay for cyclosporin |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2455859A1 (de) | 1973-12-06 | 1975-06-12 | Sandoz Ag | Verfahren zur herstellung neuer antibiotika |
-
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 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 AU AU19262/76A patent/AU513538B2/en not_active Ceased
- 1976-11-02 GB GB19922/79A patent/GB1567202A/en not_active Expired
- 1976-11-02 IE IE2379/81A patent/IE44750B1/en unknown
- 1976-11-02 PH PH19079A patent/PH14725A/en unknown
- 1976-11-02 IE IE2439/76A patent/IE44749B1/en unknown
- 1976-11-02 JP JP51131314A patent/JPS5259180A/ja active Granted
- 1976-11-02 GB GB45485/76A patent/GB1567201A/en not_active Expired
- 1976-11-02 NZ NZ182496A patent/NZ182496A/xx unknown
- 1976-11-02 CA CA264,703A patent/CA1087609A/en not_active Expired
- 1976-11-03 IL IL50836A patent/IL50836A/xx unknown
- 1976-11-03 AT AT812276A patent/AT359642B/de not_active IP Right Cessation
- 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
- 1976-11-03 PT PT65791A patent/PT65791B/pt unknown
- 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
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2455859A1 (de) | 1973-12-06 | 1975-06-12 | Sandoz Ag | Verfahren zur herstellung neuer antibiotika |
Non-Patent Citations (1)
| Title |
|---|
| NICHTS-ERMITTELT |
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