DK156726B - 3-hydroxy-24,24-difluor-25-hydroxy-cholestan-5,7-dien - Google Patents
3-hydroxy-24,24-difluor-25-hydroxy-cholestan-5,7-dien Download PDFInfo
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- DK156726B DK156726B DK425183AA DK425183A DK156726B DK 156726 B DK156726 B DK 156726B DK 425183A A DK425183A A DK 425183AA DK 425183 A DK425183 A DK 425183A DK 156726 B DK156726 B DK 156726B
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- 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 title claims description 5
- 241000700159 Rattus Species 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- 239000011575 calcium Substances 0.000 description 19
- 150000003722 vitamin derivatives Chemical class 0.000 description 17
- 229940088594 vitamin Drugs 0.000 description 16
- 239000011782 vitamin Substances 0.000 description 16
- 229910052791 calcium Inorganic materials 0.000 description 15
- 229930003231 vitamin Natural products 0.000 description 15
- 235000013343 vitamin Nutrition 0.000 description 15
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 150000001875 compounds Chemical class 0.000 description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 235000005911 diet Nutrition 0.000 description 6
- 230000037213 diet Effects 0.000 description 6
- 239000011574 phosphorus Substances 0.000 description 6
- 229910052698 phosphorus Inorganic materials 0.000 description 6
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 5
- 210000000988 bone and bone Anatomy 0.000 description 5
- 230000000968 intestinal effect Effects 0.000 description 5
- 210000002966 serum Anatomy 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
- 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 description 4
- 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
- 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
- 210000001198 duodenum Anatomy 0.000 description 3
- 238000000034 method Methods 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
- 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 2
- 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
- 239000004380 Cholic acid Substances 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 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
- 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 2
- 229960002471 cholic acid Drugs 0.000 description 2
- 235000019416 cholic acid Nutrition 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 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 2
- 238000001727 in vivo Methods 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000006467 substitution reaction Methods 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
- 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
- DYSJMQABFPKAQM-UHFFFAOYSA-N 1-benzothiophene-2-carboxylic acid Chemical compound C1=CC=C2SC(C(=O)O)=CC2=C1 DYSJMQABFPKAQM-UHFFFAOYSA-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
- HUHXLHLWASNVDB-UHFFFAOYSA-N 2-(oxan-2-yloxy)oxane Chemical compound O1CCCCC1OC1OCCCC1 HUHXLHLWASNVDB-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- YEYKMVJDLWJFOA-UHFFFAOYSA-N 2-propoxyethanol Chemical compound CCCOCCO YEYKMVJDLWJFOA-UHFFFAOYSA-N 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
- 239000003872 25-hydroxy-cholecalciferol Substances 0.000 description 1
- KJKIIUAXZGLUND-ICCVIKJNSA-N 25-hydroxyvitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](\C=C\[C@H](C)C(C)(C)O)C)=C\C=C1\C[C@@H](O)CCC1=C KJKIIUAXZGLUND-ICCVIKJNSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 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
- IXYOGYACUGRKQY-UHFFFAOYSA-M [Na+].[Cl-].OC(=O)CF Chemical compound [Na+].[Cl-].OC(=O)CF IXYOGYACUGRKQY-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000003556 assay Methods 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
- 238000006731 degradation reaction Methods 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
- 210000002745 epiphysis Anatomy 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000010438 heat treatment 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
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000031891 intestinal absorption Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000004460 liquid liquid chromatography Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000005259 measurement Methods 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
- 239000003960 organic solvent 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
- 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
- 238000010992 reflux Methods 0.000 description 1
- 208000007442 rickets Diseases 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000007920 subcutaneous administration 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
-
- 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 156726 B
Opfindelsen angâr den hidtil ukendte 3-hydroxy-24,24-di-fluor-25-hydroxycholestan-5,7-dien, der er mellemprodukt ved fremstilling af det hidtil ukendte 24,24-difluor-25-hydroxycholecalciferol.
5 Vitamin er et velkendt middel til at kontrollere cal cium- og phosphorhomeostase. Hos normale dyr eller menne-sker vides denne forbindelse ogsâ at stimulere tarmcal-ciumtransporten og knogle-calciummobiliseringen, og den er i stand til at forebygge rakitis.
10 Det er ogsê velkendt, at vitamin for at være virksomt ma omdannes in vivo til dets hydroxylerede former. F.eks. hydroxyleres vitaminet forst i leveren til dannelse af 25-hydroxy-vitamin D-j, og hydroxyleres yderligere i nyrer-ne, hvorved der dannes la,25-dihydroxy vitamin eller 15 24,25-dihydroxy-vitamin D^· Den Ια-hydroxylerede form af vitaminet antages sædvanlig at være den fysiologisk akti-ve eller. hormonale form af vitaminet og at være ansvarlig for, hvad der betegnes som den vitamin D^-lignende virkning, som f.eks. foroget tarmabsorption af calcium og phosphat, 20 mobilisering af knoglemineral og tilbageholdelse af cal cium i nyrerne.
Der findes forskellige omtaler af vitamin D-deriva-ter indenfor patent- og anden litteratur herunder USA
patentskriftet nr> 3 553 924, der omhandler 25-hydroxychole-25 calciferol.
Et hidtil ukendt dérivât af vitamin har nu vist sig at udvise en udmærket vitamin D-lignende aktivitet og kan derfor tjene som erstatning for vitamin inden for dettes forskellige anvendelsesomrâder, og det vil være værdi-30 fuldt ved behandlingen af forskellige sygdomme som oste- malacia, osteodystrofi og hypoparathyroidisme.
DK 156726B
2
Derivatet er blevet identificeret som 24,24-difluor-25-hydroxycholecalciferol (24,24-difluor-25-hydroxy-vitamin D3 eller 24 F2,25-0H D3).
Tilstedeværelsen af 2 fluoratomer i det ovennævnte deri-5 vat bevirker, at forbindelsen bliver i besiddelse af forbedrede biologiske egenskaber, der ikke findes hos de tilsvarende usubstituerede forbindelser. Specielt bevirker en 24,24-difluorsubstitution ved C-24-stillin-gen, at forbindelsen ikke kan hydrolyseres ved C-24-stil-10 lingen in vivo, der normalt er en hovedomsætningsreak- tion for 25-hydroxyvitamin D^'s begyndende nedbrydning i organismen. 24,24-difluorsubstitutionen bevirker sâ-ledes en forbedret biologisk aktivitet.
Mellemproduktet ved fremstillingen af dette vitamin 15 D^-derivat er den omhandlede 3-hydroxy-24,24-difluor- 25-hydroxycholestan-5,7-dien. Reaktionsskemaet er vist nedenfor.
DK 156726 B
3 O Ofic.
yAyCÛOH \^ν\ Ύ\Λ.
Z*xaJ
^ A 3 N(r FF oAc jciS^dS0^^
é> 5 H
Ho ,
DK 156726B
4 EKSEMPEL 1
Cholensyre (I) behandles med dihydropyran i et passende organisk oplesningsmiddel (CI^C]^) ved 0 °C i nærværelse af p-toluensulfonsyre og herefter med IN NaOH i éthanol 5 ved 20 °C, hvorved der dannes cholensyretetrahydropyrany1- ether (beskyttelse af hydroxylgruppen i A ringen). Denne forbindelse behandles herefter med overskud af CH^Li i te-trahydrofuran (THF)-ethylether ved o °C i 4 timer, hvor-efter den beskyttende tetrahydropyranylgruppe fjernedes 10 ved behandling med p-TsOH i CH^Cl^-nnethanol i 24 timer ved 20 °C. Efterfolgende acetylering (Ac2Û-pyridin-C^C^, 20 °C, 24 timer) gav methylketonen (2) (smeltepunkt 148-151°, £ 22,12 (3H,s,C-25), m/e 354 (M-60) (udbytte = 6% ialt ud fra 1)).
15 Methylketonen (2) kogtes under tilbagesvaling i 7 timer i eddikesyreanhydrid i nærværelse af p-Ts0H(enolacetyle-ring), hvorved man fik diacetatet (3) (smp. 109-110 °C,S
5,02 (lH,m,C-23), 1,90 (3H,s,C-25) m/e 396 (M-60)). Oiace-tatet omdannedes herefter til difluorcyclopropanen (4) 20 ved opvarmning med natriumchloridfluoracetatet i diglym ved 170 °C i 0,5 timer. Udbytte 34%; smeltepunkt 112-115°; 5,38 (1H,m,C-6 ), 4,60 (lH,m,C-3), 2,05 (3H,s,24-0Ac), 2,02 (3H,s,3-OAc), 1,60 (3H,m,C-26), m/e 446 (M-60)).
Behandling af (4) med LiOH i THF-methanol-vand ved 20 °C 25 i 2 timer efterfulgt af acetylering (Ac20-pyridin-CH2Cl25 20 °C, 24 timer) gav efter chromatografi pâ silicagel di-fluorketonen (5) (9,3% udbytte, smp. 135-136,5 °C,4*2,26 (3H,t,Jj_jp = 1 HZ,C-26), m/e 404 (M-60)). Difluorketonen opnâedes i en blanding med den 23(E)- og den 23(Z)-konju-30 gerede keton, idet difluorketonen fraskiltes ved chroma- tografi pâ silicagel.
Difluorketonen (5) omsattes med et overskud af CH^Mgl i 5
DK 156726 B
ethylether ved 0 °C i 15 minutter, hvorefter der acylere-des (Ac20-pyridin-CH2Cl^, 20 °C, 20 timer), hvorved man fik 25-carbinolen (6) i 85% udbytte (smp. 163-164,5 °C, cTl, 28 (6H,8,C-26,27), m/e 420 (M-60))· Carbinolen (6) 5 allylbromeredes ved at omsætte den med N-bromsuccinimid i CCl^ under tilbagesvaling i 25 minutter. Den bromerede forbindelse dehydrobromeredes herefter ved behandling med s-collidin i xylen under tilbagesvaling i 15 minutter, hvorved man fik en blanding af 4,6-dienen og 5,7-dienen 10 (7), 5,7-dienen (% 263, 272, 282 og 292 nm, m/e 419 (M — 59) isoleredes i 28% udbytte ved behandling med p-TsOH i acetone ved 20 °C i 15 timer efterfulgt af præpa-rativ tyndtlagschromatografi (benzen-ethylacetat (15:1), 3 gan-ge). Den udvundne 5,7-dien hydrolyseredes ved behandling 15 med 5% KOH-methanol ved 20 °C i 15 timer til opnâelse af det omhandlede mellemprodukt 3-hydroxy-24,24-difluor-25-hydroxy-cholestan-5,7-dien, hvorefter der bestrâ-ledes (Hanovia hojtryks-kvarts-kviksolvdamplampe, model "654A36"; 200 W) i en blanding af éthanol og benzen 20 i 2,5 minutter ved 0 °C, hvorved man fik prævitaminet (8) i oplosning. Herefter kogtes den bestrâlede oplosning under tilbagesvaling i 1 time, og der fraktioneredes ved hjælp af tyndtlagschromatografi (silicagel, benzen-ethylacetat, (5:1), 3 gange) og hojtryks-væske-chromatografi 25 (Zorbax "SIL", 25 cm x 2,1 mm indre diameter, forhandlet af DuPont Co., Wilmington, Delaware) C^C^) hvorved man fik 24,24-difluor-25-hydroxy-vitamin D^, 9, (?tmax 264 nm, ^nin 228 nm, m/e 436 (M+) 421, 418, 403, 377, 271, 253, 136, 118).
30 Eventuelt kan man ogsâ udvinde prævitaminet (8) ved af- dampning af oplesningsmidlet ved 5 °C og efterfolgende chromatografi pâ silicagel og herefter omdanne til vita- minet.
DK 156726 Ô 6
Bioloqisk virkninq Dën biologiske virkning unders0gtes ved, at frâvænnede hanrotter, der var anbragt i hængende netbure, fodredes ad libitum med en lav-calcium, vitamin D-fri diæt beskre-5 ved af Suda et al. (J. Nutr. 100, 1049 (1970)) i 3 uger inden de anvendtes til forsogene.
Tarmcaleiumtransport
Grupper pâ fem eller seks rotter fodret son angivet oven-for indgaves intrajugulært en enkelt dosis (650 p-mol) af 10 enten 24,24-difluor-25-hydroxy-vitamin (24 F2,25-GH D^) eller 25-hydroxy-vitamin (25-OHD^) oplast i 0,05 ml 95/0 éthanol henholdsvis 8, 23 eller 30 timer, inden de aflivedes. Rotterne i kontrolgruppen indgaves kun ethanol-bærestoffet. Rotterne aflivedes ved décapitation efter de 15 angivne tider, og deres duodénum anvendtes til at mâle tarmcalcium-transportaktivitetén i overensstemmelse med metoderne beskrevet af Martin og DeLuca (Am. J. Physiolo-gy 216, 1351 (1969)). Resultaterne er angivet i tabel 1 nedenfor.
20 TABEL 1 , . . ^Ca serosal/^Ca mucosal
Indgiven -- forbindelse__8 timer 23 timer 30 timer
Kontrol 2,7+0,2âa) 2,5+0,43) 2,6+0,2a) 24F2,25-0HD3 6,6+1,2b) 5,9+0,6b) 8,2+2,lb) 25 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 4 0,001 b) fra c) b) fra c) b) fra c) 30 p <0,025 ' ikke sign. p<0,05 ô Standardafvigelse pâ middelværdien 7
DK 156726 B
For at vise virkningen af smâ doser 24F2, 25-OHDj pâ tarm-calciumtransporten indgaves rotter, der var fodret med ovennævnte diæt med lavt calciumindhold, i grupper pâ fem eller seks en enkelt dosis intrajugulært af 24F2, 25-OHD^ 5 eller 25-OHD^ oplast i 0,05 ml 95¾ éthanol. Rotlerne i kontrolgruppen indgaves kun bærestoffet. Enten 20 timer eller 168 timer efter indgivelse aflivedes rotterne, og deres duodénum anvendtes til at mâle tarm-calciumtrans-portaktiviteten i overensstemmelse med den ovenfor anfar-10 te metode af Martin :og DeLuca. Resultaterne er angivet i tabel 2.
TABEL 2 _ . . „ . ^Ca serosal/^Ca mucosal
Indgiven Dosis --1---“—' forbindelse__(,p-mol/rotte )__20 timer__168 timer r/ t , .,„,03) 2,0+0,4a) 15 Kontrol 1,5+0,5 - 24F2,25-0HD3 6,5 1,9+Q,6b) 2,1+0,lb) 32,5 1,9+0,3b) 3,7+0,9c) 25-0HD, 6,5 l»8+0,4b! 2.,l+0,2b? 5 32,5 2,2+0, 6° ' 3,8+0, 7° ' 20 Significans b) fra a) b!) fra a) af forskel ikke sign. ïik'ke sign.
, c) fra a) p <0,05 d) fra a) 25 p <0,001 A Standardafvigelse af mid'delværdien
Serumcalciumkoncentration
For at undersage serum-calciumkoncentrationen opdeltes rotter, der var fodsret som angivet ovenfor, i grupper 30 med seks rotter i hver. Rotterne i den ene gruppe indgaves enkelt dosis pâ 650 pmol 24F2, 25-OHD^, i den anden gruppe 650 pmol 25-OHD^ (i begge tilfælde var vitamin D^- 8
DK 156726 B
derivatet oplost i 0,05 ml 95% éthanol), medens den tredie gruppe (kontrol) kun indgaves bærestoffet. For-bindelserne administreredes intrajugulært enten 8 eller 29 timer inden aflivningen.
5 Rotterne aflivedes ved décapitation efter de angivne ti-der, og blodet opsamledes og centrifugeredes, sâledes at man opnâede serumet. Serumet (0,1 ml) blandedes med 1,9 ml 0,1% NaCl oplosning, og calciumkoncentrationen mâltes med et atomabsorptionsspektrophotometer (Perkin-Elmer model 10 "HO-214"). Resultaterne er angivet i tabel 3 nedenfor.
TABEL 3 Sérum calcium (mq 100 ml)
Indgiven---- Ί forbindelse__8 timer__24 timer__ 15 Kontrol 7,7+0,263^ 3,9+0,1 24F2,25-0HD3 4,9+0,2b ^ 5,2+0,2b) 25-0HD3 4,7+0,3b) 5,3+0,2b)
Significans b) fra a) b) fra a) af forskel p <0,001 p< 0,001 20 A Standardafvigelse pâ middelværdien Antirakitis virkninq
Den antirakitiske virkning undersogtes pâ fravænnede han-rotter (Holtzman Co., Madison, Wisconsin)» anbragt i hæn-gende netbure, og fodredes i gr-upper pâ seks med den la-25 ve phosphordiæt beskrevet i Am. J. Physiol. 204, 833 (1963) (Guroff, DeLuca and Steenbock) og samtidigt indgaves enten 24F2, 25-0HD3 eller 25-0HD3 oplest i 0 ,1 ml éthanol/ propylenglycol (5/95, vol/vol) subcutant hver dag i 2 uger.
9
DK 156726 B
Rotterne i kontrolgruppen fodres pâ samme mâde, men de ind-gaves kun bærestoffet subcutant.
24 timer efter den sidste subcutane dosis aflivedes rot-terne ved décapitation, og deres duodénum anvendtes til 5 at mâle tarm-calciurotransporten som beskrevet ovenfor.
Deres spoleben og albueben fjernedes til mâling af for-starrede epif ysepladler, og lârbenet til bestemmelse af aske-indholdet (lârbenet tarret til konstant vægt, hworefter der foraskedes i en .muffelovn ved 650 °C i 8 timier).
10 Resultaterne er vist i falgende tabel.
10
DK 156726 B
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DK 156726B
11
Fravænnede hanrotter bleu fodret diæten med det lave phosphor-indhold angivet oveinfor, hvorefter de opdeltes i grupper pâ fem eller seks rotter hver. Rotterne i hver gruppe ind-gaves intrajugulært henholdsvis en enkelt dosis (som vist 5 i tabellen nedenfor) af enten 24F25-OHD^ eller 25-OHD^ oplost 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 spoleben og 10 albuebenene fjernedes for at bestemme den antiraikitiske virkning i overensstemmelse med rotte-linie-forseget (U.S. Pharmacopoeia, 15th IR®v. , Mack Publishing Co., Easton.,
Pa., 1955, p. 889). Blodet' centrifugeredes umiddelbart efter opsamlingen for at udvinde sérum. Det uorganiske 15 phosphor i serumet 'biestemtes ved fremgangsmâden ibeskre- vet af Chen et al (Anal. Chem., 28, 1756, (1956)). Resul-taterne er angivet i tabel 5 nedenfor.
TABEL 5
Liimleforsegs- 20 Indgiven Dosis Uorganisk phosphor vundering : forbindelse (p mol) i sérum (mg/100 ml) (eimiheder)
Kontrol l,6+0,2â3^ 0 24F2,25-0HD3 130 3,Û+0,2b) 4,4+1,43^ 325 3,5+0,4b) 5 25 25-0HD3 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 jp<0,025 fi Standardafvigelse pâ middelværdien 30 For at bestemme den antirakitiske virkning som respons pâ en daglig dosis af 24F 25-0HD3 fodredes rotter med den ovenfor angivne diæt med lavt phosphorindhold i ca. 3 uger. Herefter indgaves de enten subcutant 24F2, 25-0HID3 eller
DK 156726B
12 25-OHD-j (i begge tilfælde 65 pmol opl0st i 0,1 ml éthanol/ propylenclycol (p/95, vol/vol)) huer dag i otte dage, medens man holdt dem pâ samme dlæt (9 rotter i huer grup-pe). Rotterne i kontrolgruppen (4 rotter) indgaves kun 5 ethanol/propylglycolbærestoffet pâ samme mâde.
24 timer efter at hâve fâet den sidste dosis aflivedes de, og deres spoleben og albueben fjernedes og anvendtes til mâling af antirakitisk virkning (rotte-linie-forsoget an-givet ovenfor), medens deres lârben fjernedes og foraske-10 des, sâledes som beskrevet ovenfor.
Resultaterne er angivet i falgende tabel.
TABEL 6
Indgiven Linieforsogsvurde- Total lârbens- Aske forbindelse ring (enhed)__aske (mq)__%_ 15 Kontrol 0 23,80±3,98ôa) 19,5+3,4a) 24F2,25-0HD3 » 5 37,03+4,94b) 26,2+l,8b) 25-0HD3 » 5 38,56+5,79^ 27,4+2,4b)
Significans b) fra a) b) fra a) af forskel p <. 0,001 p <0,005 20 ô Standardafvigelse pâ middelværdien
Det vil fremgâ af ovennævnte data at 24,24-difluor-25-hydroxy-vitamin D3 udviser udtalt vitamin D-lignende virkning, og at det viser sig at være fuldstændigt sâ 25 effektivt med hensyn til denne evne som 25-hydroxy-vitamin D3 (jfr. USA patentskrift nr. 3 565 924).
Claims (1)
- DK 156726 B Patentkrav : 3-hydroxy-24,24-difluor-25--hydroxy-cholestan-5,7-dien med formlen
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 (4)
| Publication Number | Publication Date |
|---|---|
| DK425183D0 DK425183D0 (da) | 1983-09-19 |
| DK425183A DK425183A (da) | 1983-09-19 |
| DK156726B true DK156726B (da) | 1989-09-25 |
| DK156726C DK156726C (da) | 1990-03-05 |
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 Before (2)
| 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 |
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) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6884796B2 (en) | 1998-05-13 | 2005-04-26 | Novonordisk A/S | Meiosis regulating compounds |
Families Citing this family (10)
| 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. |
| 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
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6884796B2 (en) | 1998-05-13 | 2005-04-26 | Novonordisk A/S | Meiosis regulating compounds |
| USRE39678E1 (en) * | 1998-05-13 | 2007-06-05 | Novo Nordisk A/S | Meiosis regulating compounds |
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