DK156644B - 3-acetoxy-24,24-difluor-25-hydroxy-cholestan-5,7-dien - Google Patents
3-acetoxy-24,24-difluor-25-hydroxy-cholestan-5,7-dien Download PDFInfo
- Publication number
- DK156644B DK156644B DK446482A DK446482A DK156644B DK 156644 B DK156644 B DK 156644B DK 446482 A DK446482 A DK 446482A DK 446482 A DK446482 A DK 446482A DK 156644 B DK156644 B DK 156644B
- Authority
- DK
- Denmark
- Prior art keywords
- vitamin
- hours
- rats
- difluoro
- hydroxy
- Prior art date
Links
- QFJZFUWPKOFYCY-HWHNCCJPSA-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-yl] acetate Chemical compound C1C(OC(C)=O)CC[C@]2(C)[C@@H](CC[C@@]3([C@@H]([C@@H](CCC(F)(F)C(C)(C)O)C)CC[C@H]33)C)C3=CC=C21 QFJZFUWPKOFYCY-HWHNCCJPSA-N 0.000 title claims 2
- 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
- 229940088594 vitamin Drugs 0.000 description 18
- 239000011782 vitamin Substances 0.000 description 18
- 229930003231 vitamin Natural products 0.000 description 17
- 235000013343 vitamin Nutrition 0.000 description 17
- 229910052791 calcium Inorganic materials 0.000 description 15
- 150000003722 vitamin derivatives Chemical class 0.000 description 14
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 13
- 230000000694 effects Effects 0.000 description 11
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 8
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 6
- IYRWEQXVUNLMAY-UHFFFAOYSA-N carbonyl fluoride Chemical compound FC(F)=O IYRWEQXVUNLMAY-UHFFFAOYSA-N 0.000 description 6
- 230000037213 diet Effects 0.000 description 6
- 235000005911 diet Nutrition 0.000 description 6
- 239000011574 phosphorus Substances 0.000 description 6
- 229910052698 phosphorus Inorganic materials 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-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
- 150000003710 vitamin D derivatives Chemical class 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 229930003316 Vitamin D Natural products 0.000 description 4
- 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 4
- 239000002956 ash Substances 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 235000019166 vitamin D Nutrition 0.000 description 4
- 239000011710 vitamin D Substances 0.000 description 4
- 229940046008 vitamin d Drugs 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
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 210000001198 duodenum Anatomy 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 210000000689 upper leg Anatomy 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
- 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 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
- 239000003872 25-hydroxy-cholecalciferol Substances 0.000 description 2
- 239000004380 Cholic acid Substances 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 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
- 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
- 230000002354 daily effect Effects 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
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000010992 reflux 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
- WFZKUWGUJVKMHC-QPGHTDHKSA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-1-[(2r)-5,6-dihydroxy-6-methylheptan-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol 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)C[C@H](O)C1=C WFZKUWGUJVKMHC-QPGHTDHKSA-N 0.000 description 1
- QOWCBCXATJITSI-ZLNGONTQSA-N (6r)-6-[(1r,3as,4e,7ar)-4-[(2z)-2-[(5s)-5-hydroxy-2-methylidenecyclohexylidene]ethylidene]-7a-methyl-2,3,3a,5,6,7-hexahydro-1h-inden-1-yl]-2-methylheptane-1,2-diol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(O)CO)C)=C\C=C1\C[C@@H](O)CCC1=C QOWCBCXATJITSI-ZLNGONTQSA-N 0.000 description 1
- PAKKXLLOIJSLLK-DXEOSGPYSA-N (6r)-6-[(9s,10r,13r,14r,17r)-10,13-dimethyl-2,3,4,9,11,12,14,15,16,17-decahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylheptan-1-ol Chemical compound C1CCC[C@]2(C)[C@@H](CC[C@@]3([C@@H]([C@H](C)CCCC(CO)C)CC[C@H]33)C)C3=CC=C21 PAKKXLLOIJSLLK-DXEOSGPYSA-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
- 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
- FCKJYANJHNLEEP-SRLFHJKTSA-N 24,25-dihydroxycholecalciferol 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-SRLFHJKTSA-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
- 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
- 235000021318 Calcifediol Nutrition 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- 235000002918 Fraxinus excelsior Nutrition 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
- MECHNRXZTMCUDQ-UHFFFAOYSA-N Vitamin D2 Natural products C1CCC2(C)C(C(C)C=CC(C)C(C)C)CCC2C1=CC=C1CC(O)CCC1=C MECHNRXZTMCUDQ-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- OFHCOWSQAMBJIW-AVJTYSNKSA-N alfacalcidol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C OFHCOWSQAMBJIW-AVJTYSNKSA-N 0.000 description 1
- 229960002535 alfacalcidol Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 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
- 235000013351 cheese Nutrition 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
- ILYCWAKSDCYMBB-OPCMSESCSA-N dihydrotachysterol Chemical class C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1/C[C@@H](O)CC[C@@H]1C ILYCWAKSDCYMBB-OPCMSESCSA-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
- 229960002061 ergocalciferol Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000003203 everyday effect Effects 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
- 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
- 230000001418 larval effect Effects 0.000 description 1
- 210000002414 leg Anatomy 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
- 239000003960 organic solvent Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 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
- 238000011084 recovery Methods 0.000 description 1
- 208000007442 rickets Diseases 0.000 description 1
- 210000000582 semen Anatomy 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
- 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
- 239000011653 vitamin D2 Substances 0.000 description 1
- 235000001892 vitamin D2 Nutrition 0.000 description 1
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 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
Landscapes
- 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 1566446
Opfindelsen angâr det hidtil ukendte 3-acetoxy-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 calcium- 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.
j_g Det er ogsâ velkendt, at vitamin Dj for at være virksomt mâ omdannes in vivo til dets hydroxyïerede former. F.eks. hydroxyleres vitaminet ferst i leveren til dannelse af 25-hydroxy-vitamin Dj og hydroxyleres yderligere i nyrer-ne, hvorved der dannes la,25-dihydroxy vitamin eller 15 24,25-dihydroxy-vitamin . Den Ια-hydroxylerede form af vitaminet antages sædvanlig at være den fysiologisk àkti-ve eller hormonale form af vitaminet og at være ansvarlig for, hvad der betegnes som den vitamin D-lignende virkning, som f.eks. foreget tarmabsorptïôn~af calcium og phôlTphat, 20 mobilisering af knoglemineral og tilbageholdelse af calcium i nyrerne.
Der findes forskellige henvisninger til vitamin D-deriva-ter indenfor patent- og anden litteratur, jfr. f.eks. USA patentskrifterne J 365 924, der omhandler 25-hydroxychole-25 calciferol; 3 697 559, der omhandler 1,25-dihydroxy-chole-calciferol; 3 741 996, der omhandler la-hydroxycholecal-ciferol; 3 907 843, der omhandler la-hydroxyergocalcife-rol; 3 715 374, der omhandler 24,25-dihydroxycholecalci-ferol; 3 739 001, der omhandler 25,26-dihydroxycholecal-30 ciferol; 3·786 062, der omhandler 22-dèhydro-25-hydroxy-cholecalciferol; 3 847 955, der omhandler 1,24,25-trihy-droxycholecalciferol; 3 906 014, der omhandler 3-deoxy-Ια-hydroxycholecalciferol og 4 069 321, der omhandler frem-stillingen af forskellige sidekædefluorerede vitamin D^-35 derivater og sidekædefluorerede dihydrotachysterol^ ana- 2
DK 156644B
loge.
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 D-^ inden for det-5 tes forskellige anvendelsesomrâder, og det vil være værdi-fuldt ved behandlingen af forskellige sygdomme som oste-malacia, osteodystrofi og hypoparathyroidisme.
Derivatet er blevet identificeret som 24,24-difluor-25-hydroxycholecalciferol (24,24-difluor-25-hydroxy-vitamin - 10 D3 eller 24 F2,25-0H D3).
Tilstedeværelsen af 2 fluoratomer i det ovennævnte dérivât bevirker, at forbindelsen bliver i besiddelse af forbedrede biologiske egenskaber, der ikke findes ved de tilsvarende usubstituerede forbindelser. Specielt be-15 virker en 24,24-difluorsubstitution ved C-24-stillin- gen, at forbindelsen ikke kan hydrolyseres ved C-24-stil-lingen in vivo, der normalt er en hovedomsætningsreaktion for 25- hydroxyvitamin D3 s begyndende nedbrydning i orga-nismen. 24,24-difluorsubstitutionen bevirker sâledes en 20 forbedret biologisk aktivitet.
Mellemproduktet ved fremstillingen af dette vitamin Dj-derivat er den omhandlede 5,7-dien. Reaktionsskemaet er vist nedenfor.
DK 156644 B
3 O Oftc.
' * 3 J,
y£x!ç _T
ÂcO AcO AcO^v^
6 5 H
Y^., ^ Y>i joî^^-îw -<p 7 * jl Ηί" , 4
DK 156644B
Opfindelsen illustreres nærmere ved hjælp af det folgende eksempel.
EKSEMPEL
Cholensyre ( I) behandles med dihydropyran i et passende or-ganisk oplesningsmiddel (Ch^C^) ved 0 °C i nærvarelse af p-toluensulfonsyre og herefter med IN NaOH i éthanol ved 5 20 °C, hvorved der dannes cholensyretetràhydropyranylether (beskyttelse af hydroxylgruppen i A ringen). Denne for-bindelse behandles herefter med overskud af CH^Li i te-trabydrofuran (THF)-ethylether ved 0 °C i 4 timer, hvorefter den beskyttende tetrahydropyranylgruppe fjerne-10 des ved behandling med p-TsOH i C^C^-methanol i 24 timer ved 20 °C. Efterfolgende acetylering (Ac2Û-pyridin-CI^C^j 20 °C, 24 timer) gav methylketonen (2) (smelte-punkt 148-151°, *T2,12 (3H,s,C-25), m/e 354 (M-60)) (ud-bytte = 6515 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, 5,02 (1H,m,C-23 ), 1,90 (3H,s,C-25) m/e.396 (M-60)). Diacetatet omdannedes herefter til difluorcyclopropanen (4) 20 ved opvarmning med natriumchlordifluoracetatet i diglym ved 170 °C i 0,5 timer. Udbytte 3455; 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-CH2Cl2, 20 °C, 24 timer) gav efter chromatografi pâ silicagel di-fluorketonen (5) (9,355 udbytte, smp. 135-136,5 °C,«P2,26 (3H,t,JHp = 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 156644B
des (Ac20-pyridin-CH2Cl2» 20 °C, 20 timer), hvorved man fik 25-carbinolen (6) i 85$ udbytte (smp. 163-164,5 °C, tf 1,28 (6H,s,C-26,27 ), m/e 420 (M-60)). Carbinolen (6) al- lylbromeredes ved at omsætte den med N-bromsuccinimid i 5 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 (7). 5,7-dienen Q. 263, 272, 282 og 292 nm, m/e 419 max
10 (M-59)) isoleredes i 28% udbytte ved behandling medp-TsOH
i acetone ved 20 °C i 15 timer efterfulgt af præparativ tyndtlagschromatografi (benzen-ethylacetat (15:1), 3 gan-ge). Den udvundne 5,7-dien hydrolyseredes ved behandling med 5% KOH-methanol ved 20 °C i 15 timer, hvorefter man be-15 strâlede (Hanovia hojtryks-kvarts-kviksolvdamplampe, model "654A36"; 200 W) i en blanding af éthanol og benzen 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 20 hjælp af tyndtlagschromatografi (silicagel, benzen-ethylacetat, (5:1), 3 gange) og hojtryks-væske-chromatografi (Zorbax "SIL", 25 cm x 2,1 mm indre diameter, forhandlet af DuPont Co., Wilmington, Delau/are) CH2CI2) hvorved man fik 24,24-difluor-25-hydroxy-vitamin D,, 9, (X 264 nm, ' j max 25 X 228 nm, m/e 436 (M+), 421, 418, 403, 377, 271, 253, 136, 118).
Dersom det onskes til visse formai» kan den acetylerede 5,7-dien (7) efter udvindelsen beskrevet ovenfor hydrolyseres ved velkendte metoder (5% Κ0Η i MeOH, 20 °C, 15 timer) 50 for at omdanne acetoxygruppen i 3-stillingen til hydroxy.
Eventuelt kan man ogsâ udvinde prævitaminet (8) ved af-dampning af oplosningsmidlet ved 5 °C og efterfolgerrde chromatografi pâ silicagel og herefter omdanne til vita-minet.
DK 156644B
6
Bioloqisk virkninq
Den biologiske virkning undersegtes ved, at fravænnede hanrotter, der var anbragt i hængende netbure, fodredes ad libitum med en lav-calcium, vitamin D-fri diæt beskre-5 vet af Suda et al. (J. Nutr. 100, 1049 (1970)) i 3 uger inden de anvendtes til forsagene.
Tarmeaieiumtransport
Grupper pâ fem eller seks rotter fodret som angivet oven-for indgaves intrajugulært en enkelt dosis (650 p-mol) af 10 enten 24,24-difluor-25-hydroxy-vitamin (24 F2>25-0H D^) eller 25-hydroxy-vitamin (25-OHD^) oplast i 0,05 ml 95% 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-transportaktiviteten 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 45 /45 T , . Ca serosal/ Ca mucosal
Indgiven ---- forbindelse__8 timer 23 timer 30 timer
Kontrol 2,7+0,2&a) 2,5+0,4a) 2,6+0,23^ 24F2,25-0HD3 6,6+l,2b) 5,9+0,6b) 8,.2+2,.lb) 25 25-OHDj 5,0+0,7c) 5,5+0,8c) 5,7+l,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) 30 p <0,025 ikke sign. p< 0,05 A Standardafvigelse pâ middelværdien Ί DK 156644Β
For at vise virkningen af smâ doser. 24F2, 25-OHD^ 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-j 5 eller 25-OHD^ oplest i 0,05 ml 95% éthanol. Rotterne 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 anfor-10 te metode af Martin og DeLuca. Resultaterne er angivet i tabel 2.
TABEL 2 T , . ' ^Ca serosal/^Ca mucosal
Indgiven Dosis --S--- forbindelse__(p mol/rotte)__20 timer__168 timer 15 Kontrol l,5+0,5Ôa) 2,0+0,4 24F2,25-0HD3 6,5 l,9+0,6b) 2,l+0,lb) 32,5 1,9+0, 3 b ^ 3,7+0,9C^ 25-OHD, 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. ikke sign.
c) fra a) p <0,05 d) fra a) 25 p '<0,001 A Standardafvigelse af middelværdien
Serumcalciumkoncentration
For at undersoge serum-calciumkoncentrationen opdeltes rotter, der var fodret sont angivet ovenfor, i grupper 30 med seks rotter i hver. Rotterne i den ene gruppe indgaves enkelt dosis pâ 650p mol 24F2 , 25-OHD^, i den anden gruppe 650 p mol 25-OHD-j (1 begge tilfslde var vitamin D^-deri-
DK 156644B
8 vatet aplest i 0,05 ml 95¾ éthanol), medens den tredie gruppe (kontrol) kun indgaves bærestoffet. Forbindelserne administreredes intrajugulært enten 8 eller 29 timer in-— den 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 0,1¾ NaCl oplesning, og calciumkoncentrationen mâltes med et atomabsorptionsspektrophotometer (Perkin-Elmer model 10 "HO-214"). Resultaterne er angivet i tabel 3 nedenfor.
TABEL 3 T_j . __ Sérum calcium (mq 100 ml) indgiven ---3- forbindelse__8 timer__24 timer__
Kontrol 7,7+0,2ôa) 3,9+0,la) 15 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 A Standardafvigelse pâ middelværdien 20 Antirakitis virkninq
Den antirakitiske virkning undersegtes pâ fravænnede han-rotter (Holtzman Co., Madison, Wisconsin), anbragt i hæn-gende netbure, og fodredes i grupper pâ seks med den lave phosphordiæt beskrevet i Am. 3. Physiol. 204, 833 (1963) 25 (Guroff, DeLuca and Steenbock) og samtidigt indgaves enten 24F2, 25-0HD3 eller 25-0HD3 oplast i 0,1 ml éthanol/ propylenglycol (5/95, vol/vol) subcutant hver dag i 2 uger. Rotterne i kontrolgruppen fodres pâ samme mâde, men de indgaves kun bærestoffet subcutant.
9
DK 156644 B
24 tiirier 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-5 sterrede epifyseplader, og lârbenet til bestemmelse af askeindholdet (lârbenet torret til konstant vægt, hvor-efter der foraskedes i en muffelovn ved 650 °C i 8 timer).
Resultaterne er vist i folgende tabel.
DK 156644B
ίο
i—I i—i Γ-* CD CO lA
~ “ - -H CV4 ο CM j—I i—I N CM roocoo^-o +1 +1 +1 +1 +1 ^ - K ~ oa -
fA 0\ 1Λ r-' <f <1- O *P O _ O
°° ~ “ V v h v Γ- O 00 -100 ^ V ^ „
(U CM tA ΓΑ IA IA -Q Q. Ό CL
-* ^--
CO CO
CO <^\
(0 CO -Q O OU CO
C—' VÛCMiAiHCM P
ωσοοοίΠΓΛΓ^ —v —-> <+-
JJ Ë » ·> ~ C0 lA CO lA rH
P '~s ΙΑ ΓΛ IA MD MD O CM—'O
°co +f +1 +1 +1 +1 co o co o <u o _l r-H -( IA lA fA V0 P - P - co n o\ oo vo k. o 4. o ·» o -P·'·'·'·'·' v/ v v O On l'-.CM On ΓΑ —v TT —s _ 1— CM ΙΑ ΙΑ ΙΑ ΙΑ Λ 11 Ό “ ü Q.
/-s
E
E
v_' 1---V
CO
eu -< TJ CO o
CO P O
Cl·- (H —X —V —N \ —i —S —V U— M
co a co jqo χ ω co ca co ia o (U IA CM i—1 IA CM a CM '—- . , eu co ·> ~ ~ cooœocu^ TJ > O O O O CD P *· P ~ Q.
tj e*- +1 +|+| +1+1 Cl- o 0- o oü CD -H CM LA LA IA NO v v
^ Q IN ·« tN «\ #N /*S r <*N
ffl 11 ΙΛ rMO —I O -O ^ TJ O
—s o
N
E h ^
D'-' <ü C
•h —' ω u -p co —* —^ > «a —i -h —ι ρ <6 jo ο τι ω o tj CDD ΙΛ CM Μ IA O O t-i a a ~ ~ ~ *< - T3 - a* I CO O —1 CM O CM ~ ^ O 3«
E C +| +| +1 +| +| -N CO v, -H
PCD i—I Γ' CM st CO Ü ω
10 h ·.·.·> « *. *> CO Q. TJ
I— -P CM LA rH LA O —^ P TI
*H '—I X Cw Ή
E
-——“—————— - oC0 /—v Q_
rH ΙΑ ΙΑ ΙΑ tA
CQ O ·» ·» ·ν Q) H E VO VO NO VO ' C0 CO Ή ο α· ω q ^ en
•H
----3>
Ct-
IA CO
ω CD CO Ό
CD X C rH P
—i o co ω co c 0 i υ tj
<t CD TJ Ή LA fA -H CO C
> c o cm a u- f-, co
_1 ·Η ·Η P ·> X ·Η O -P
LU DUO -P CM O C t|_ co co Ό p c u. i en ce C Ο O «cf iA *rt ti_ h- HH tp iÉ CM CM tn co «ce 11
DK 156644 B
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 intrajugulært henholdsvis en enkelt dosis (som vist 5 i tabellen nedenfor) af enten 24F2, 25-OHD^ eller 25-OHD^ oplost i 0,05 ml 35% 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 antirakitiske virkning i overensstemmelse med rotte-linie-forseget (U.S. Pharmacopoeia, 15ende Rev., Mack Publishing Cb ., Easton.,
Pa., 1955, p. 889). Blodet centrifugeredes umiddelbart efter opsamlingen for at udvinde sérum. Det uorganiske 15 phosphor i serumet bestemtes ved fremgangsmâden beskre- vet af Chen et al (Anal. Chem., 28, 1756, (1956)). Resul-taterne er angivet i tabel 5 nedenfor.
TABEL 5
Linieforsogs-
Indgiven Dosis Uorganisk phosphor vurdering 20 forbindelse (p mol) i sérum (mg/100 ml) (enheder)
Kontrol l,6+0,2Aa) 0 24F2,25-0HD3 130 3,0+0,2b) 4,4+l,4a) 325 3,5+0,4b) 5 25-0HD3 130 3,3+0,lb) 2,6+0,6b) 25 325 3,6+0,4b) 3,5+0,6
Significans b) fra a) b) fra a) af forskel p<0,001 p<0,025 A Standardafvigelse pâ middelværdien
For at bestemme den antirakitiske virkning som respons pâ 30 en daglig dosis af 24F2, 25-0HD3 fodredes rotter med den ovenfor angivne diæt med lavt phosphorindhold i ca. 3 uger. Herefter indgaves de enten subcutant 24F2, 25-0HD3 eller 25-OHD3 (i begge tilfælde 65 pmol oplost i 0,1 ml éthanol/
DK 156644 B
12 propylenglycol (5/95, vol/vol)) hver dag i otte dage, medens man holdt dem pâ samme diæt (9 rotter i hver grup-pe). Rotterne i kontrolgruppen (4 rotter) indgaves kun ethanol/propylenglycolbærestoffet pâ samme mâde.
5 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-des, sâledes som beskrevet ovenfor.
10 Resultaterne er angivet i falgende tabel.
TABEL 6
Indgiven Linieforsogsvurde- Total lârbens- Aske forbindelse ring (enhed)__aske (mq)__5o_
Kontrol 0 23,80+3,98ôa) 19,5+3,4a) 15 24F2,23-0HD3 » 5 37,03+4,94b) 26,2+l,8b) 25-OHDj » 5 38,5 6+5, 7 9 b ^ 27,4+2,4b)
Significans b) fra a) b) fra a) af forskel p<0,001 p<0,005 û Standardafvigelse pâ middelværdien 20 Det vil fremgâ af ovennævnte data at 24,24-difluor-25- hydroxy-vitamin udviser udtalt vitamin D-ligende virkning, og at det viser sig at være fuldstændigt sa effek-tivt med hensyn til denne evne som 25-hydroxy-vitamin (jfr. USA patentskrift nr. 3 565 924).
Claims (1)
13 DK 1S6644B Patentkrav : 3-acetoxy-24,24-difluor-25-hydroxy-cholestan-5,7-dien med formlen p p A c 0
Applications Claiming Priority (2)
| 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 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK446482A DK446482A (da) | 1982-10-08 |
| DK156644B true DK156644B (da) | 1989-09-18 |
| DK156644C DK156644C (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 Before (1)
| 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 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| 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) |
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 |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4358406A (en) | 26,26,26,27,27,27-Hexafluoro-1α,25-dihydroxycholecalciferol and process for preparing same | |
| DK156644B (da) | 3-acetoxy-24,24-difluor-25-hydroxy-cholestan-5,7-dien | |
| NL8920414A (nl) | Verbindingen met celdifferentiatieopwekkende werking. | |
| NL7920012A (nl) | Werkwijze ter bereiding van 1-gefluoreerde vitamine d verbindingen. | |
| EP1888614A2 (en) | Process for preparing 3alpha(beta)-7alpha(beta)-dihydroxy-6alpha(beta)-alkyl-5beta-cholanic acid | |
| IE50815B1 (en) | 25-hydroxy-26,26,26,27,27,27-hexafluorocholecalciferol | |
| EP0171990B1 (en) | Vitamin d3 derivatives | |
| DK147300B (da) | 24,24-difluor-25-hydroxy-6-alkoxy-3,5-cyclovitamin d3 forbindelser | |
| NL8420327A (nl) | Isomeren van hydroxyvitamine d2. | |
| US4832875A (en) | Vitamin D3 derivative | |
| US5036061A (en) | Process for the preparation of 1 alpha,25-dihydroxylated vitamin D2 and related compounds | |
| CA1159850A (en) | 24,24-difluoro-25-hydroxycholecalciferol | |
| ES2693259T3 (es) | Síntesis de ent-progesterona e intermedios de la misma | |
| NZ207413A (en) | Steroid intermediates in the preparation of 24,24-difluoro-25-hydroxy-vitamin d3 | |
| NL8520021A (nl) | 1alpha-hydroxyvitamine d2 analoga en werkwijze voor het bereiden daarvan. | |
| JPS59500864A (ja) | ２６，２６．２６，２７．２７，２７―ヘキサフルオロ―１α，２５―ジヒドロキシコレステロール化合物及びその製造方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |