DK156635B - Analogifremgangsmaade til fremstilling af 24,24-difluor-25-hydroxycholecalciferol - Google Patents
Analogifremgangsmaade til fremstilling af 24,24-difluor-25-hydroxycholecalciferol Download PDFInfo
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- DK156635B DK156635B DK467780AA DK467780A DK156635B DK 156635 B DK156635 B DK 156635B DK 467780A A DK467780A A DK 467780AA DK 467780 A DK467780 A DK 467780A DK 156635 B DK156635 B DK 156635B
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- 238000000034 method Methods 0.000 title claims description 8
- 239000003872 25-hydroxy-cholecalciferol Substances 0.000 title description 2
- 238000002360 preparation method Methods 0.000 claims description 3
- LRNVEDCUBISUTC-OWRPZGOZSA-N 24,24-difluoro-25-hydroxyvitamin D3 Chemical compound C1(/[C@@H]2CCC([C@]2(CCC1)C)[C@@H](CCC(F)(F)C(C)(C)O)C)=C\C=C1\C[C@H](O)CCC1=C LRNVEDCUBISUTC-OWRPZGOZSA-N 0.000 claims description 2
- 241000700159 Rattus Species 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- 229940088594 vitamin Drugs 0.000 description 20
- 239000011782 vitamin Substances 0.000 description 20
- 229930003231 vitamin Natural products 0.000 description 19
- 235000013343 vitamin Nutrition 0.000 description 19
- 239000011575 calcium Substances 0.000 description 18
- 150000003722 vitamin derivatives Chemical class 0.000 description 18
- 229910052791 calcium Inorganic materials 0.000 description 14
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 6
- 230000000968 intestinal effect Effects 0.000 description 6
- 239000011574 phosphorus Substances 0.000 description 6
- 229910052698 phosphorus Inorganic materials 0.000 description 6
- 210000002966 serum Anatomy 0.000 description 6
- 230000037213 diet Effects 0.000 description 5
- 235000005911 diet Nutrition 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 210000000988 bone and bone Anatomy 0.000 description 4
- IYRWEQXVUNLMAY-UHFFFAOYSA-N carbonyl fluoride Chemical compound FC(F)=O IYRWEQXVUNLMAY-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000021736 acetylation Effects 0.000 description 3
- 238000006640 acetylation reaction Methods 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 210000000689 upper leg Anatomy 0.000 description 3
- 150000003710 vitamin D derivatives Chemical class 0.000 description 3
- GPCDGGKVBPVZCT-UHFFFAOYSA-N 1,1-difluorocyclopropane Chemical compound FC1(F)CC1 GPCDGGKVBPVZCT-UHFFFAOYSA-N 0.000 description 2
- JWUBBDSIWDLEOM-UHFFFAOYSA-N 25-Hydroxycholecalciferol Natural products C1CCC2(C)C(C(CCCC(C)(C)O)C)CCC2C1=CC=C1CC(O)CCC1=C JWUBBDSIWDLEOM-UHFFFAOYSA-N 0.000 description 2
- 235000021318 Calcifediol Nutrition 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229930003316 Vitamin D Natural products 0.000 description 2
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 2
- RTEXIPZMMDUXMR-UHFFFAOYSA-N benzene;ethyl acetate Chemical compound CCOC(C)=O.C1=CC=CC=C1 RTEXIPZMMDUXMR-UHFFFAOYSA-N 0.000 description 2
- MDHYEMXUFSJLGV-UHFFFAOYSA-N beta-phenethyl acetate Natural products CC(=O)OCCC1=CC=CC=C1 MDHYEMXUFSJLGV-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 150000001993 dienes Chemical class 0.000 description 2
- 210000001198 duodenum Anatomy 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 235000019166 vitamin D Nutrition 0.000 description 2
- 239000011710 vitamin D Substances 0.000 description 2
- 229940046008 vitamin d Drugs 0.000 description 2
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 1
- JWUBBDSIWDLEOM-XHQRYOPUSA-N (3e)-3-[(2e)-2-[1-(6-hydroxy-6-methylheptan-2-yl)-7a-methyl-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexan-1-ol Chemical compound C1CCC2(C)C(C(CCCC(C)(C)O)C)CCC2\C1=C\C=C1/CC(O)CCC1=C JWUBBDSIWDLEOM-XHQRYOPUSA-N 0.000 description 1
- NEDKJIMKPXKCNZ-PWHJGDGMSA-N (9S,10R,13R,14R,17R)-17-[(2R)-5,5-difluoro-6-hydroxy-6-methylheptan-2-yl]-10,13-dimethyl-2,3,4,9,11,12,14,15,16,17-decahydro-1H-cyclopenta[a]phenanthren-3-ol Chemical compound C[C@H](CCC(F)(F)C(C)(C)O)[C@H]1CC[C@H]2C3=CC=C4CC(O)CC[C@]4(C)[C@H]3CC[C@]12C NEDKJIMKPXKCNZ-PWHJGDGMSA-N 0.000 description 1
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- FCKJYANJHNLEEP-OIMXRAFZSA-N 24,25-Dihydroxyvitamin D Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCC(O)C(C)(C)O)C)=C\C=C1\C[C@H](O)CCC1=C FCKJYANJHNLEEP-OIMXRAFZSA-N 0.000 description 1
- JWUBBDSIWDLEOM-DCHLRESJSA-N 25-Hydroxyvitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C/C=C1\C[C@@H](O)CCC1=C JWUBBDSIWDLEOM-DCHLRESJSA-N 0.000 description 1
- JWUBBDSIWDLEOM-NQZHSCJISA-N 25-hydroxy-3 epi cholecalciferol Chemical compound C1([C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=CC=C1C[C@H](O)CCC1=C JWUBBDSIWDLEOM-NQZHSCJISA-N 0.000 description 1
- 241001249699 Capitata Species 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 208000000038 Hypoparathyroidism Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 206010031240 Osteodystrophy Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000536399 Tina Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- JWUBBDSIWDLEOM-DTOXIADCSA-N calcidiol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)CCC1=C JWUBBDSIWDLEOM-DTOXIADCSA-N 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 229960002471 cholic acid Drugs 0.000 description 1
- 235000019416 cholic acid Nutrition 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 1
- DAKIDYQCFJQMDF-UHFFFAOYSA-N dichloromethane;pyridine Chemical compound ClCCl.C1=CC=NC=C1 DAKIDYQCFJQMDF-UHFFFAOYSA-N 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- CCNWZGXOWHXIJE-UHFFFAOYSA-N ethoxyethane;oxane Chemical compound CCOCC.C1CCOCC1 CCNWZGXOWHXIJE-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 210000004349 growth plate Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000031891 intestinal absorption Effects 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- SPAKMVQVTSVXES-UHFFFAOYSA-N methanol;oxolane;hydrate Chemical compound O.OC.C1CCOC1 SPAKMVQVTSVXES-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 208000005368 osteomalacia Diseases 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- CASUWPDYGGAUQV-UHFFFAOYSA-M potassium;methanol;hydroxide Chemical compound [OH-].[K+].OC CASUWPDYGGAUQV-UHFFFAOYSA-M 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 208000007442 rickets Diseases 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- MRTAVLDNYYEJHK-UHFFFAOYSA-M sodium;2-chloro-2,2-difluoroacetate Chemical compound [Na+].[O-]C(=O)C(F)(F)Cl MRTAVLDNYYEJHK-UHFFFAOYSA-M 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Obesity (AREA)
- Pharmacology & Pharmacy (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Nutrition Science (AREA)
- Endocrinology (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Steroid Compounds (AREA)
Description
, DK 156635 B
Opfindelsen angâr en analogifremgangsmâde til frem-stilling af den hidtil ukendte 24,24-difluor-25-hydroxy-cholecalciferol, et dérivât af vitamin med vita-min D lignende virkning.
5 Vitamin er et velkendt middel til at kontrollere calcium- og phosphorhomeostase. Hos normale dyr el-ler mennesker vides denne forbindelse ogsâ at stimu-lere tarmcalciumtransporten og knogle-calciummobili-setènifém, feg deft èr i stand til at forebygge rakitis.
10 Detoefi'.ogsâ velkendt, at vitamin for at være virk- soihtf mâ iqmdailines ! in vivo til dets hydroxylerede for-mërtO F'i'ekàtuiiydroxyleres vitaminet forst i leveren til dannelse af 25-hydroxy-vitamin og hydroxyle-res yderligere i nyrene, hvorved dër dannes 1G&25-15 dihydroxy vitamin eller 24,25-dihydroxy-vitamin . Den lCfc-hydroxylerede form af vitaminet antages sædvanligvis at være den fysiologisk aktive eller hormonale form af vitaminet og at være ansvarlig for, hvad der betegnes som den vitamin D-lignende virk-20 ning, som f.eks. foroget tarmabsorption af calcium og phosphat, mobilisering af knoglemineral og til-bageholdelse af calcium i nyrene.
Der findes forskellige henvisninger til vitamin D-derivater indenfor patent- og anden litteratur her-25 under USA patentskriftet nr. 3 565 924, der omhandler 25-hydroxycholecalciferol.
Det hidtil ukendte dérivât af vitamin har nu vist sig at udvise en udmærket vitamin D-lignende aktivi-tet og kan derfor tjene som erstatning for vitamin 30 D3 inden for dettes forskellige anvendelsesomrâder, og det vil være værdifuldt ved behandlingen af forskel-. lige sygdomme som ostemalacia, osteodystrofi og hypo-parathyroïdisme.
2
DK 156635 B
Derivatet er blevet identificeret som 24,24-difluor-2 5-hydroxycholecalciferο1 (2 4,2 4-difluor-2 5-hydroxy-vitamin eller 24 F2/25-OH ).
Tilstedeværelsen af 2 fluoratomer i det omhandlede 5 dérivât bevirker, at forbindelsen bliver i besid- delse af: forbedrede biologiske egenskaber, der ikke findes hos de tilsvarende usubstituerede forbindelser. Specielt bevirker en 24,24-difluorsubstitution ved C-24-stillingen, at forbindelsen ikke kan hydroxyle-10 res ved C-24-stillingen in vivo, der normalt er en hovedomsætningsreaktion for 25-hydroxyvitamin D^'s begyndende nedbrydning i organismen. 24,24-difluor-forbindelse kan sâledes ikke undergâ ovennævnte ak-tivitetssvækkende hydroxylering i organismen.
15 Fremgangsmâden ifolge opfindelsen er ejendommelig ved det i kravets kendetegnende del anforte og illustreres nærmere med folgende reaktionsskema og nedenstâende eksempel.
3
DK 156635 B
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EKSEMPEL
Cholensyre .(Γ) behandles med dihydropyran i passende organisé: oplosningsmiddel (CE^C^) ved 0° C i nærværelse af p-toluensulfonsyre og herefter med IN NaOH i éthanol ved 20° C, hvorved der dannes cholensyretetrahydropy-5 ranether (beskyttelse af hydroxylgruppen i A ringen).
Denne forbindelse behandledes herefter med overskud. af CH^Li i tetrahydrofuran (THF)-ethylether ved 0° C i fire timer, hvorefter den beskyttende tetrahydropyranylgruppe fjemedes ved behandling med p-TsOH i CH^C^-methanol i 10 24 timer ved 20° C. Efterf0lgende acetylering (AcgO-pyri- din-CK^C^, 20° C 24 timer) gav methylketonen (2) (smelte-punkt 148-151°·, é2,12 (3H,s,C-25), m/e 354 (M-60)) (ud-bytte = 6% ialt ud fra 1).
Methylketonen (2) kogtes under tilbagesvaling i syv timer i 15 eddikesyreanhydrid i nærværelse af p-TsOH(enolacetylering), hvorved man fik diacetatet (3·) (smp. 109-110 °e&5,02· (lH,m,c-23), l, 90(3H,s,C25) m/e 396 (M-60)). Diacetatet omdannedes herefter til difluorcyclopropanen (4) ved opvarmning med na-triumchlordifluoracetatet i diglym ved 170° C i 0,5 timer.
20 Udbytte 34%; smeltepunkt 112-115°; 5*38 (lH,m,C-6), 4,60 (lH,m,C-3), 205(3H,s,24-OAc), 2,02(3H,s,3-0Ac), 1,60(3H, m, C-26), m/e 446 (M-60)).
Behandling af (4) med LiOH i THF-methanol-vand ved 20° C i to timer efterfulgt af acetylering ( Ac20“Pyridin-CH2Cl2, 25 20° C, 24 timer) gav efter chromatografi pâ silicagel di- fluorketonen (5) (9,3 % udbytte, smp. 135-136,5° C, $2,26 (3H,t,Jgp= 1 Hz,C-26), m/e 404 (M-60)). Difluorketonen opnâedes i en blanding med den 23(E)- og'den 23(Z)-konju-gerede keton, idet difluorketonen fraskiltes ved chroma-30 tografi pâ silicagel.
Difluorketonen (5) _omsattes med et overskud af CH^Mgl i ethyl-ether ved 0° C i 15 minutter, hvorefter der acetyleredes (Ac20-pyridin-CH2Cl2» 20° C, 20 timer), hvorved man fik 25-carbinolen (6) i 85 % udbytte (smp. 163-164,5° C, 35 £L,28(6H,s,C-26,27), m/e 420 (M-60)). Carbinolen (6) allyl- bromeredes ved at omsætte den med N-bromsuccinimid i 5
DK 156635 B
CC14 under tilbagesvaling i 25 minutter. Den bromere-de forbindelse dehydrobromeres herefter ved behand-ling med s-collidin i xylen under tilbagesvaling i 15 minutter, hvorved man fik en blanding af 4,6-5 dienen og 5,7- dienen (7). 5,7-dienen(Amax 263, 272, 282 og 292 nm, m/e 419 (M-59) isoleredes i 28% udbytte ved behandling med p-TsOH i acetone ved 20° i 15 ti-mer efterfulgt af præparativ tyndtlagschromatografi (benzen-ethylacetat (15:1), 3 gange). Den udvundne 10 5,7-dien hydrolyseredes ved behandling med 5% KOH- methanol ved 20 °C i 15 timer til opnâelse af 3-hydroxy-24,24-difluor-25-hydroxycholestan-5,7-dien, hvorefter der bestrâledes (Hanovia hojtryks-kvarts-kviksolvsdamplampe, model " 654A36" ,* 200 W) i en blan-15 ding af éthanol og benzen i 2,5-minutter ved 0 °C, hvorved man fik prævitaminet (8)-i- ©plosning. Herefter kogtes den bestrâlede oplosning under tilbagesvaling i 1 time, og der fraktioneredes ved hjælp af tyndtlagschromatografi (-silicagel ), benzen-ethyl-20 acetat, (5:1), 3 gange) og hojtryks-væskechromatogra- fi (Zorbax "SIL", 25 cm x 2,1 mm indre diameter, forhandlet af DuPont Co., Willmington, Delaware)CH2Cl2) hvorved man fik 24,24-difluor-25-hydroxy-vitamin D^, 9, (Amav 264 nm, A_-_ 228 nm, m/e 436 (M+), 421, 418,
UlaX IUj.I1 25 403, 377, 271, 253, 136, 118).
Den foreliggende opfindelse tilvejebringer sâledes en analogifremgangsmâde til fremstilling af 24,24-di-fluor-25-hydroxyvitamin D^ ved isomerisëring af 24,24-dif luor-25-hydroxy-prævitamin D^.
30 Eventuelt kan prævitaminet (8) ogsâ udvindes ved afdamp- ning af oplosningsmidlet ved 5 °C og efterfolgende chromatografi pâ silicagel og herefter omdannes til vitaminet.
DK 156635 B
6
Biologisk virkninq
Den biologiske virkning undersogtes ved, at fravænnede hanrotter, der var anbragt i hængende netbure, fodre-des ad libitum med en lav-calcium, vitamin D-fri diæt 5 beskrevet af Suda et al. (J. Nutr. 100, 1049 (1970)) tre uger inden de anvendtes til fors0gene.
Tarmcalciumtransport
Grupper pâ fem eller seks rotter fodret som angivet oven-for indgaves intrajugulsert-an·· enkelt dos-is·· (650 p-mol) af enten 24,24-difluor-25-hydroxy-vitamin 10 (24 F2>25-0H P^) eller 25-hydroxy-vitamin (25-OHD^). op- lest i 0,05 ml 95 % éthanol henholdsvis 8, 23 eller 30 timer inden de aflivedes. Rotterne i kontrolgruppen indgaves kun ethanol-bærestoffet. Rotterne aflivedes veddecapitatien--efter de angivne tider, og der es duodénum-.-anvendtes til at mâle 15 tarmcalcium-transportaktiviteten . i overensstemmelse med metoderne beskrevet af Martin og DeLuoa (Am. J. Physiology 216, 1351 (1969)). Resultaterne er angivet i tabel 1 ne-denfor.
TABEL_I
Indgiven _^Ca serosal/^Ca mucosal forbindelse 8 timer P 23 timer 30 timer
Kontrol 2,7+0,2**) 2,5+0,4^ 2,6+0,2a) 24F2,25-0HD3 6,6+l,2b) 5,9±0,6b) 8,2+2,lb) 25“0HD3 5,0+0,7c) 5>5±0>8c) 5,7±1,4c)
Significans b)&c) fra b)&c) fra b)&c) fra af forskel a) a) a) p<0,001 p<0,001 p <0,001 b)fra c) b)fra c) b)fra c) P<0,025 ikke s„ign. p <0,05 & Standardafvigelse pâ middelværdien.
DK 156635 B
7
For at vise virkningen af smâ doser 24F2, 25-0HD^ pâ tarm-calciumtransporten indgaves rotter, der var fodret med ovennævn te diæt med lavt calciumindhold, i grupper pâ fem eller. seks en enkelt dosis intrajugulært af 24f2* 25-OHD- eller 5 25-OHD^ oplost i 0,05 ml 95 % éthanol. Rotterne i kon- trolgruppen indgaves kun bærestoffet. Enten 20 timer eller 168 timer efter indgivelsen aflivedes. rotterne, og deres duodénum anvendtes til at mâle tarm-calciumtransportak-tiviteten i overensstemmelse med den ovenfor anf0rte me-tode af Martin og DeLuca. Resultaterne er angivet i ta-bel 2.
TABEL_2
Indgiven Dosis ^Ca serosal/^Ca mucosal
forbindelse (p mol/rotte) 20 timer 168 time"F
** '***- ·" --- * A.wep-«B.: ' - - -
Kontrol l,5±0,.5*a^ 2,0+0,4a^ 24F2,25-OHD, 6,5 1,9+0,6¾ 2,1+0,1¾ ^ 32,5 _ 1,9+0,3D; 3,7+0,9°' 25-OHD, 6,5 1,8+0,4¾ " 2^,1+0,2¾ D 32,5 2,2+0,6°' 3,8+0,7 '
Significans b) fra a) b) fra a) af forskel ikke. sign. ikke sign.
c) fra a) P <0,05 d) fra a) p< 0,001 & Standardafvigelse af middelværdien Serumcaloiumkoncentration
For at undersoge serumr-calciumkoncentrationen opdeltes 15 rottery der var fodret som angivet ovenfor, i grupper med seks rotter i hver. Rotterne i en gruppe indgaves enkelt dosis af 650 pmol 24F2, 25-OHD^, i den anden gruppe pâ 650 pmol 25-OHD^ (i begge tilfælde var vitamin D-3" derivatet oplost i 0,05 ml 95 % éthanol), medens den tre-20 die gruppe (kontrol) kun indgaves bærestoffet. Materialer-
DK 156635 B
8 inden aflivningen.
Rotterne aflivedes ved décapitation efter de angivne tider, og blodet opsamledes og centrifugeredes, sâledes at man opnâede serumet. Serumet (0,1 ml) blandesmed 5 1,9 ml 0,1 % NaCl oplssning, og calciumkoncentrationen mâltes med et atomabsorptionsspektrophotometer (Per- kin-Elmer model "H0-2l4M). Resultaterne er angivet i tabel 3 nedenfor.
TABEL_3
Indgiven -........- _Sérum caleium-fog/lOO^TBil-) - - ^------- - forbindelse 8 timer j 24 timer
Kontrol 7,7+0,2Aa^ 3,9+0,la^ 24F2,25-0HDj 4,9+0,2b^ 5,2+0,2b^ 25-OHP,__4,7+0,3b) 5,3+0,2b)
Significans b) fra a) b)fra a) -af forskel p <10,001 p ^0,001 A Standardafvigelse pà middelværdien 10 Antirakitis virkning
Den antirakitiske virkning undersogtes ved at fravænnede hanrotter (Holtzman Co., Madison, Wisconsin), anbragt i hængende netbure, fodredes i grupper pâ séks med den lave phosphordiæt beskrevet i A®, J. Physiol. 204, 833 (1963) 15 (Guroff, DeLuca and Steenbock) og samtidigt indgaves en-ten 24F2, 25-OHD^ oplost i 0,1 ml ethanol/propylenglycol (5/95, vol/vol) subcutant hver dag i to uger. Rotterne i kontrolgruppen fodres pâ samme mâde, men de indgaves kun bærestoffet subcutant.
20 24 timer efter den sidste subcutane dosis aflivedes rot terne ved décapitation, og deres duodénum anvendtes til at mâle tarm-calciumtransporten som beskrevet ovenfor.
Deres spoleben og albueben fjernedes til mâling af for-
DK 156635 B
9 starrede epôfyseplader, og lârbenet til bestemmelse af askeindholdet (lârbenet t0rret til konstant vœgt, hvor- efter der foraskedes i en muf£elovn ved 650° C i &'tinaer). Resultaterne er vist i f0lgende tabel 4··
10 DK 156635 B
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•H H d ·> W HO to W3A -P CM O d+l + Ό d d fc ι δ, w do O <f LA H+l H+l W CM CM CQCd
DK 156635 B
11
Fravænnede hanrotter fodres diæten med det lave phosphor-indhold angivet ovenfor, hvorefter de opdeltes i grupper pâ fem eller seks rotter hver. Rotterne i hver gruppe ind-gaves intrajugulsert henholdsvis en enkelt dosis (som vist 5 i tabellen nedenfor) af enten 24F2, 25-OHD^ eller 25-OHD^ oplest i 0,05 ml 95 % éthanol. Rotterne i kontrolgruppen indgaves kun ethanolbærestoffet. 168 timer efter at hâve fâet de angivne doser aflivedes rotterne ved décapitation, og man opsamlede blodet fra hver gruppe, og spolebene og 10 albuebenene fjernedes for at bestemme den antirakitiske virkning i overensstemmelse med rotte-linje-forseget (U.S. Pharmacopoeia, 15th Rev., Mack Pub'lishing Co., Easton.,
Pa., 1955, p. 889). Blodet centrifugeredes umiddelbart efter opsamlingen for at udvinde sérum. Det uorganiske 15 phosphor i serumet bestemtes ved fremgangsmâden beskrevet af Chen et al.(Anal„ Chem., 28, 1756, (1956)),. Resulta-terne er angivet i tabelv5. nedenfor.
TABEL_5
Indgiven Dosis Uorganisk phosphor linie forsegs- forbindelse (p mol) i sérum (mg/lOOml) vurdering (enheder'
Kontrol l,6+0,2&a^ 0 24F2,25-0HD3 130 3,0+0,2b) 4,4+l,4a) 325 3,5±0,4b) 5 25-OHDj 130 3,3±0,lb) 2,6+0,6b) 325 3,6+0,4b) ;3,5±0,6
Significans b) fra a) b) fra a) af forskel p-<0,001 jx.0,025 & Standardafvigelse pâ middelvserdien
For at bestemme den antirakitiske virkning som respons pâ 20 en daglig dosis af 24F2, 25-OHD^ fodredes rotter med den ovenfor angivne diæt med lavt phosphorindhold i ca. tre uger. Herefter indgaves de enten subcutant 24F2, 25-OHD^ eller 25-OHD^ (i begge tilfælde 65 pmol oplest i 0,1 ml éthanol/ propylenglycol (5/95, vol/vol)) hver dag i otte dage, medens 12
DK 156635 B
terne i kontrolgruppen (4 rotter) indgaves kun éthanol/ propylenglycolbærestoffet pâ samme mâde.
24 timer efter at hâve fâet den sidste dosls aflivedes de, og deres spoleben og albüeben fjernedes og anvendtes til 5 mâling af antirakitisk virkning (rotte-linie-forsoget an-givet ovenfor), medens deres lârben fjernedes og foraske-des, sâledes som beskrevet ovenfor.
Resultaterne er angivet i folgende tabel.
TABEL_§
Indgiven Linieforsogsvurde- Total lârbens- Aske forbindelse ring (enhed) aske (mg) %
Kontrol 0 23,80+3,98*a^19,5±3,4a^ 24F2,25-0HD5 »5 37,03±4,94 26,2+l,8b^ 25-0HD3 >>5 38,56+5,79 b) 27,4±2,4b)
Significans b) fra a) b) fra a) af forskel ·. ρ <0,001 ψ<0,005 Λ Standardafvigelse pâ middelværdien 10 Det vil fremgâ af ovennævnte data at 24,24-difluor-25- hydroxy-vitamin udviser udtalt vitamin D-lignende virkning, og at det viser sig at være fuldstændigt sâ effektivt med hensyn til denne egenskab som 25-hydroxy-vitamin D3, (jfr. USA patentskrift nr.. 3 565 924).
Claims (1)
- DK 156635 B Patentkrav : Analogifremgangsmâde til fremstilling af 24,24-difluor-25-hydroxycholecalciferol F F HO kendetegnet ved, at man isomeriserer 24,24-5 difluor-25-hydroxy-prævitamin med formlen F*' F ' ^NlJk I^OH
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/017,168 US4196133A (en) | 1979-03-05 | 1979-03-05 | 24,24-Difluoro-25-hydroxycholecalciferol |
| US1716879 | 1979-03-05 | ||
| US7900898 | 1979-10-15 | ||
| PCT/US1979/000898 WO1980001915A1 (en) | 1979-03-05 | 1979-10-15 | 24,24-difluoro-25-hydroxycholecalciferol |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK467780A DK467780A (da) | 1980-11-04 |
| DK156635B true DK156635B (da) | 1989-09-18 |
| DK156635C DK156635C (da) | 1990-02-12 |
Family
ID=21781101
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK467780A DK156635C (da) | 1979-03-05 | 1980-11-04 | Analogifremgangsmaade til fremstilling af 24,24-difluor-25-hydroxycholecalciferol |
| DK446482A DK156644C (da) | 1979-03-05 | 1982-10-08 | 3-acetoxy-24,24-difluor-25-hydroxy-cholestan-5,7-dien |
| DK425183A DK156726C (da) | 1979-03-05 | 1983-09-19 | 3-hydroxy-24,24-difluor-25-hydroxy-cholestan-5,7-dien |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK446482A DK156644C (da) | 1979-03-05 | 1982-10-08 | 3-acetoxy-24,24-difluor-25-hydroxy-cholestan-5,7-dien |
| DK425183A DK156726C (da) | 1979-03-05 | 1983-09-19 | 3-hydroxy-24,24-difluor-25-hydroxy-cholestan-5,7-dien |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US4196133A (da) |
| JP (2) | JPS6310946B2 (da) |
| AU (1) | AU532388B2 (da) |
| BE (1) | BE882036A (da) |
| CA (1) | CA1157049A (da) |
| CH (2) | CH653018A5 (da) |
| DK (3) | DK156635C (da) |
| FR (2) | FR2450814B1 (da) |
| GB (1) | GB2044770B (da) |
| IE (1) | IE49532B1 (da) |
| IL (1) | IL58525A (da) |
| IT (1) | IT1151077B (da) |
| NL (1) | NL7920160A (da) |
| NZ (1) | NZ191899A (da) |
| SE (1) | SE8007427L (da) |
| WO (1) | WO1980001915A1 (da) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4284577A (en) * | 1979-02-16 | 1981-08-18 | Sachiko Yamada | Novel vitamin D3 derivative and process for preparing the same |
| US4248791A (en) * | 1980-02-04 | 1981-02-03 | Wisconsin Alumni Research Foundation | 25-Hydroxy-26,26,26,27,27,27-hexafluorocholecalciferol |
| US4254045A (en) * | 1980-04-21 | 1981-03-03 | Wisconsin Alumni Research Foundation | 1α-Hydroxy-2β-fluorocholecalciferol |
| US4307025A (en) * | 1981-02-17 | 1981-12-22 | Wisconsin Alumni Research Foundation | 1α, 25-dihydroxy-2β-fluorovitamin D3 |
| US4428946A (en) * | 1982-07-26 | 1984-01-31 | Wisconsin Alumni Research Foundation | Method of preventing milk fever in dairy cattle |
| US4500460A (en) * | 1983-08-18 | 1985-02-19 | Wisconsin Alumni Research Foundation | 23,23-Difluoro-25-hydroxy-vitamin D3 and process for preparing same |
| US4564474A (en) * | 1983-08-18 | 1986-01-14 | Wisconsin Alumni Research Foundation | 23,23-Difluoro-25-hydroxy-vitamin D3 and process for preparing same |
| GB2145091B (en) * | 1983-08-18 | 1987-08-12 | Wisconsin Alumni Res Found | Vitamin d3 derivatives |
| ATE45347T1 (de) * | 1985-05-30 | 1989-08-15 | Taisho Pharmaceutical Co Ltd | Vitamin d3-derivate. |
| IL139241A0 (en) * | 1998-05-13 | 2001-11-25 | Novo Nordisk As | Meiosis regulating compounds |
| JP3485097B2 (ja) | 2001-03-13 | 2004-01-13 | 日本電気株式会社 | 移動無線通信における適応再送要求制御方式、及び適応再送要求制御装置 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3993675A (en) * | 1975-02-24 | 1976-11-23 | Hoffmann-La Roche Inc. | Process for the preparation of 1α,25-dihydroxycholecalciferol |
| US4069321A (en) * | 1975-10-14 | 1978-01-17 | Merck & Co., Inc. | Blocked cholecalciferol and dihydrotachysterol 3 derivatives |
| US4028349A (en) * | 1976-03-08 | 1977-06-07 | Hoffmann-La Roche Inc. | Syntheses of 24R,25- and 24S,25-dihydroxycholesterol 24,25-ketals and alkanoyl derivatives thereof |
| JPS595432B2 (ja) * | 1976-11-09 | 1984-02-04 | 凸版印刷株式会社 | 容器の製造方法 |
| US4188345A (en) * | 1978-07-26 | 1980-02-12 | Wisconsin Alumni Research Foundation | Fluorovitamin D compounds and processes for their preparation |
| US4284577A (en) * | 1979-02-16 | 1981-08-18 | Sachiko Yamada | Novel vitamin D3 derivative and process for preparing the same |
-
1979
- 1979-03-05 US US06/017,168 patent/US4196133A/en not_active Expired - Lifetime
- 1979-10-15 NL NL7920160A patent/NL7920160A/xx unknown
- 1979-10-15 CH CH8306/80A patent/CH653018A5/de not_active IP Right Cessation
- 1979-10-15 WO PCT/US1979/000898 patent/WO1980001915A1/en not_active Ceased
- 1979-10-15 JP JP55500008A patent/JPS6310946B2/ja not_active Expired
- 1979-10-15 CH CH1133/85A patent/CH654015A5/de not_active IP Right Cessation
- 1979-10-22 IL IL58525A patent/IL58525A/xx unknown
- 1979-10-23 NZ NZ191899A patent/NZ191899A/en unknown
-
1980
- 1980-02-22 AU AU55809/80A patent/AU532388B2/en not_active Ceased
- 1980-02-28 CA CA000346646A patent/CA1157049A/en not_active Expired
- 1980-03-03 BE BE0/199639A patent/BE882036A/fr not_active IP Right Cessation
- 1980-03-03 IE IE420/80A patent/IE49532B1/en unknown
- 1980-03-03 GB GB8007118A patent/GB2044770B/en not_active Expired
- 1980-03-03 IT IT20326/80A patent/IT1151077B/it active
- 1980-03-04 FR FR8004852A patent/FR2450814B1/fr not_active Expired
- 1980-09-02 FR FR8018944A patent/FR2455609A1/fr active Granted
- 1980-10-22 SE SE8007427A patent/SE8007427L/xx unknown
- 1980-11-04 DK DK467780A patent/DK156635C/da not_active IP Right Cessation
-
1982
- 1982-10-08 DK DK446482A patent/DK156644C/da not_active IP Right Cessation
-
1983
- 1983-09-19 DK DK425183A patent/DK156726C/da not_active IP Right Cessation
-
1987
- 1987-09-16 JP JP62229954A patent/JPS63183559A/ja active Granted
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