DK147300B - 24,24-difluor-25-hydroxy-6-alkoxy-3,5-cyclovitamin d3 forbindelser - Google Patents
24,24-difluor-25-hydroxy-6-alkoxy-3,5-cyclovitamin d3 forbindelser Download PDFInfo
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- DK147300B DK147300B DK505080AA DK505080A DK147300B DK 147300 B DK147300 B DK 147300B DK 505080A A DK505080A A DK 505080AA DK 505080 A DK505080 A DK 505080A DK 147300 B DK147300 B DK 147300B
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- vitamin
- difluoro
- dihydroxy
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- 150000001875 compounds Chemical class 0.000 title description 21
- 229940088594 vitamin Drugs 0.000 description 27
- 239000011782 vitamin Substances 0.000 description 27
- 229930003231 vitamin Natural products 0.000 description 25
- 235000013343 vitamin Nutrition 0.000 description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- 150000003722 vitamin derivatives Chemical class 0.000 description 22
- 239000011575 calcium Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 229910052791 calcium Inorganic materials 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 8
- 239000011710 vitamin D Substances 0.000 description 8
- 229940046008 vitamin d Drugs 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 210000000988 bone and bone Anatomy 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 150000003710 vitamin D derivatives Chemical class 0.000 description 5
- 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
- 238000000605 extraction Methods 0.000 description 4
- 238000005805 hydroxylation reaction Methods 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 235000019166 vitamin D Nutrition 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000011612 calcitriol Substances 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 230000003054 hormonal effect Effects 0.000 description 2
- 230000033444 hydroxylation Effects 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000027425 release of sequestered calcium ion into cytosol Effects 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 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 2
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 1
- GMRQFYUYWCNGIN-UHFFFAOYSA-N 1,25-Dihydroxy-vitamin D3' Natural products C1CCC2(C)C(C(CCCC(C)(C)O)C)CCC2C1=CC=C1CC(O)CC(O)C1=C GMRQFYUYWCNGIN-UHFFFAOYSA-N 0.000 description 1
- GMRQFYUYWCNGIN-ZVUFCXRFSA-N 1,25-dihydroxy vitamin D3 Chemical compound C1([C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=CC=C1C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-ZVUFCXRFSA-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
- 239000003872 25-hydroxy-cholecalciferol Substances 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol 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)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 description 1
- 235000020964 calcitriol Nutrition 0.000 description 1
- 229940043430 calcium compound Drugs 0.000 description 1
- 150000001674 calcium compounds Chemical class 0.000 description 1
- 230000003913 calcium metabolism Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 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
- HKXBNHCUPKIYDM-CGMHZMFXSA-N doxercalciferol 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)C[C@H](O)C1=C HKXBNHCUPKIYDM-CGMHZMFXSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 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
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000031891 intestinal absorption Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 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
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 208000007442 rickets Diseases 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 150000003431 steroids Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C35/48—Halogenated derivatives
- C07C35/52—Alcohols with a condensed ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/24—All rings being cycloaliphatic the ring system containing nine carbon atoms, e.g. perhydroindane
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- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (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)
- Information Retrieval, Db Structures And Fs Structures Therefor (AREA)
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Description
147300 i
Opfindelsen angår hidtil ukendte 24,24-difluor-25-hydroxy-6-alkoxy-3,5-cyclovitamin forbindelser med formlen
P F
JL I OH
zo < J
et.
Ri hvori Z betegner en carbonhydridgruppe med 1-4 carbonato-mer, der er mellemprodukter ved fremstillingen af det hid-3 til ukendte 24,24-difluor-loi, 25-dihydroxy-vitamin D^.
Vitamin er et velkendt middel til at kontrollere kalcium- og phosphorhomeostase. Hos normale dyr eller mennesker vides denne forbindelse også at stimulere tarmkalci-umtransporten og knoglekalciummobiliseringen, og den er i 10 stand til at forebygge rakitis.
Det er også velkendt, at vitamin for at være virksomt må omdannes in vivo til dets hydroxylerede former. F.eks. hydroxyleres vitaminet først i leveren til dannelse af 25-hydroxy-vitamin og hydroxyleres yderligere i nyrerne, 15 hvorved der dannes la,25-dihydroxy-vitamin eller 24, 25-dihydroxy-vitamin D-j. Den Ια-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- 2 147300 ning, som f.eks. forøget tarmabsorption af calcium og phosphat, mobilisering af knoglemineral og tilbageholdelse af calcium i nyrerne.
Siden opdagelsen af biologisk aktive metabolitter (meta-5 boliseringsprodukter) af vitamin 0 har der været megen interesse for fremstilling af strukturanaloge af disse metabolitter, fordi sådanne forbindelser kan udgøre værdifulde terapeutiske midler til behandling af sygdomme, der skyldes uregelmæssigheder ved calciummetabolismen.
10 En hel række vitamin D-lignende forbindelser er blevet syntetiseret. Jfr. US patentskrifterne 3 741 996, der omhandler Ια-hydroxycholecalciferol; 3 907 843, der omhandler la^hydroxyergocalciferol; 3 786 062, der omhandler 22-dehydro-25-hydroxycholecalciferol; 3 906 014, der 15 omhandler 3-deoxy-la-hydroxycholecalciferol og 4 069 321, der omhandler fremstillingen af forskellige sidekædefluo-rerede vitamin Dj-derivater og sidekædefluorerede dihy-drotachysterolanaloge. Mange af disse forbindelser har faktisk vist sig at være i besiddelse af kraftig vitamin 20 D-lignende virkning, og nogle af disse frembyder andre praktiske fordele, som f.eks. at de er forholdsvis lette at fremstille, eller at de har delvis selektiv virkningsmåde, men ingen har endnu vist sig så aktiv in vivo som la,25-dihydroxycholecalciferol (la,25-dihydroxy-vitamin 25 Dj), der nu sædvanligvis antages at være den targetcelle- aktive hormonale form.af vitamin D.
Man har nu fremstillet et nyt derivat af vitamin D, der er i det mindste så kraftigt som la,25-dihydroxy-vitamin Dj, når man måler dets evne til at stimulere tarmcalcium-30 transporten eller dets evne til at mobilisere calcium fra knogler. Dette derivat er blevet identificeret som 24,24-difluor-la,25-dihydroxycholecalciferol (24,24-difluor-la,-25-dihydroxy-vitamin Dj eller 24-F2~l,25(0H)2Dj).
3 147300
Det omhandlede derivat kan udgøre et foretrukkent middel til mange terapeutiske formål, fordi det er blokeret for yderligere metabolisme ved carbonatomet 24. Det er velkendt, at la,23-dihydroxy-vitamin D^ kan undergå yder-5 ligere nedbrydning in vivo, hvorved der opstår la,24R,25- trihydroxy-vitamin D^· Denne 24-hydroxylerede form er i-midlertid mindre aktiv end selve la,25-dihydroxy-vitamin D^, og 24-hydroxyleringen kan faktisk repræsentere et første trin mod nedbrydning og fjernelse af denne forbin-10 delse fra organismen. I det omhandlede derivat forhindrer tilstedeværelsen af 2 fluoratomer ved carbon 24 naturligvis hydroxyleringen af dette carbonatom, og forbindelsen er derfor ikke følsom for den aktivitetsformindskende nedbrydning, der påvirker 1,25-dihydroxy-cholecalciferol.
15 Forhindring af denne sidekædemetabolisme bevirker, at det er muligt at opretholde højere celleniveauer af den analoge gennem et længere tidsrum, en faktor, der har selvfølgelige fordele til mange terapeutiske formål.
Identiteten af forbindelsen som 24,24-difluor-ΐα,25-di-20 hydroxy-vitamin D^ kan bekræftes ud fra de spektroskopi- ske egenskaber. Forbindelsen udviser den typiske vitamin D-lignende ultraviolette absorption med et maksimum ved 264 nm. Massespektret af forbindelsen indeholder en mole-kylarion ved m/e 452, således som der kræves for et 24,24-25 difluorderivat af la,25-dihydroxy-vitamin D^. Fragmentio nerne m/e 434 og 416 repræsenterer fjernelsen af 1 og 2 molekyler 1^0. Tabet af hele steroidsidekæden bevirker fragmentering af m/e 287, der ved fjernelse af 1 og 2 molekyler ^0 forårsager to toppe ved m/e 269 og 251. Her-30 udover viser spektret udtalte toppe ved m/e 152 og m/e 134 (152-^0), der repræsenterer ring A fragmenter og som er typiske for la,30-dihydroxy-vitamin D^-forbindelser.
4 147300
Fremstilling af 24,24-difluor-la,25-dihydroxy-vitamin kan udføres ved direkte C-l-hydroxylering via 3,5-cyclo-vitamin D-mellemprodukterne ifølge opfindelsen ved hjælp af almene metoder beskrevet af Paaren et al., (Proc. Nat.
Acad. Sci., U.S.A. 7V5, 2080-2081 (1978)). Syntesen er vist på det skematiske processkema nedenfor
F F F F F-s/F
rD^°H
r4 (h tt H0,.,kA ^ 'y™
9 10 U
v p F F F F
F F γΧ/
Y>ybH. ^HrtS ^0H
ΓΤ AooXXh HoXXac H0-0-0H
HO
14 12 13 15 5 147300
Behandling af en pyridinopløsning af 24,24-difluor-25-hydroxy-vitamin D-j (9) med 1-1,5 ækvivalenter p-toluen-sulfonylchlorid i 24 timer ved 3°C, giver efter tilsætning en mættet opløsning af NaHCO^, ekstraktion med ether, 5 og efterfølgende afdampning af etheren, det tilsvarende 3-monotosylerede derivat. Dette materiale opløses i vandfrit methanol og behandles herefter med 5-10 ækvivalenter NaOAc. Efter opvarmning til 55°C i 20 timer afkøles blandingen, der fortyndes med h^O og ekstraheres med ether.
10 Den ønskede forbindelse 24,24-difluor-25-hydroxy-6-methoxy- 3,5-cyclovitamin D^ (10) (Z = methyl) fås efter afdampning af etheren med et 50¾ totaludbytte. Anvendelsen af andre alkoholiske opløsningsmidler, såsom ethanol og propanol, i den ovenfor nævnte reaktion giver analoge cyclovitamin 15 D-forbindelser med den almene formel (10), hvor Z = ethyl, propyl. Disse analoge er lige så anvendelige til de efterfølgende syntetiske trin, som beskrives nedenfor. Dersom det ønskes, kan cyclovitamin D-forbindelsen renses ved hjælp af silicagel-tyndtlagschromatografi, idet man anven-20 der hexan/ethylacetat (8:2) som opløsningsmiddelsystem, men den kan også anvendes direkte i det næste trin, der indebærer behandling af cyclovitamin-mellemproduktet, opløst i et halogen-carbonopløsningsmiddel (f.eks. Ch^C^), med Se02 (0,5 ækvivalenter) og t-butylhydroperoxid (2 ækvi-25 valenter, således som beskrevet af Paaren et al. (oven for). Efter 15 minutters omsætning ved stuetemperatur til-, sættes en 10¾ NaOH-opløsning, og produktet ekstraheres med ether. Etherfasen vaskes med vandig alkali og herefter med vand, der inddampes og efter tyndtlagschromatografi af re-30 manensen (idet man anvender silicagel og hexan/ethylacetat (6:4) som opløsningsmiddel) fås det rene 24,24-difluor-la,-25-dihydroxy-6-methoxy-3,5-cyclovitamin (11) (Z = methyl) (udbytte 55¾). Behandling af denne forbindelse med iseddikesyre ved 60°C i 15 minutter efterfulgt af neutra-35 lisering af eddikesyren med vandig alkali og ekstraktion med ether giver efter afdampning af opløsningsmidlet en 147300 6 blanding af 24,24-difluor-la,25-dihydroxy-vitamin Dj-3-acetat (12) og den tilsvarende 5,6-transisomere (13) (forhold ca. 3:1). Disse forbindelser kan bekvemt adskilles enten ved søjlechromatografi eller tyndtlagschromatografi 5 (f.eks. silicagel, hexan:ethylacetatopløsningsmiddel) el ler højtryksvæskechromatografi, og det således opnåede rene 24,24-difluor-la,25-dihydroxy-vitamin Dj-3-acetat hydrolyseres ved behandling med base (f.eks. 5% NaOH/MeOH, 2 timer ved stuetemperatur), hvorefter man ved ekstrak-10 tion med ether og afdampning af etheren får den ønskede analoge 24,24-difluor-let, 25-dihydroxy-vitamin Dj (14) i ren form, der udviser samme spektrale egenskaber som en tilsvarende forbindelse, der er fremstillet enzymatisk ved hydroxylering af 24,24-difluor-25-hydroxy-vitamin Dj.
15 5,6-Trans-24,24-difluor-la,25-dihydroxy-vitamin Dj-3- acetat (13) isomeren, der fås i ren form efter chromato-grafien beskrevet ovenfor, hydrolyseres i fortyndet base (5/ό NaOH/MeOH, 2 timer ved stuetemperatur), hvorved man efter etherekstraktion og afdampning af etheren får det 20 rene 5,6-trans-24,24-difluor-la,25-dihydroxy-vitamin Dj (15). Denne forbindelse viser et massespektrum, der er meget lig med den tilsvarende 5,6-cis-isomere, men den udviser et ultraviolet spektrum med et maksimum ved 270 nm, hvilket er karakteristisk for den 5,6-trans-vitamin 25 D-chromofore.
5,6-Trans-24,24-difluor-la,25-dihydroxy-vitamin Dj-for-bindelsen kan natuligvis omdannes til 24,24-difluor-la,-25-d.ihydroxy-vitamin Dj ved den velkendte fotokemiske isomerisering af 5,6-dobbeltbindingen, idet man anvender 30 fremgangsmåden, f.eks. beskrevet af Inhoffen et al., (Chem. Ber. 9J3, 2544 (1957)). Alternativt kan 5,6-trans-3-acetat-mellemproduktet (13) opnået ved solvolysen af cyclovitaminforbindelse, således som beskrevet ovenfor, isomeriseres med bestråling ved ultraviolet lys, hvorved
t473OO
7 man får 5,6-cis-3-acetatet (12), og omdannelsen af dette materiale til den ønskede 24,24-difluor-la, 25-dihydroxy-vitamin D^-analoge kan herefter opnås ved hydrolyse i mild base, således som allerede beskrevet.
5 Biologisk aktivitet
Den biologiske effektivitet af den omhandlede analoge er bekræftet ved forsøg in vivo over for rotter.
Fravænnede hanrotter fodres med lav-calcium, vitamin D-fri diæt, beskrevet af Suda et al. (J. Nutr. 100, 1049-10 1052 (1970)) i 3,5 uger. De opdeltes i tre grupper med 5-6 dyr i hver. Dyrene fra den ene gruppe (kontrolgruppen) fik 0,05 ml ethanol intrajugulært. Den anden og tredje gruppe fik en kendt mængde af henholdsvis 24,24-difluor-la, 25-dihydroxy-vitamin D^ (24,24-F2-l>25-(0H)2D^) 15 og la,25-dihydroxy-vitamin D^ (la,25-(OH)2^3) som opløs ninger i 0,05 ml ethanol intrajugulært. Med passende mellemrum undersøgtes virkningen af forsøgsforbindelserne på tarmcalciumtransporten og på serumcalciumniveauerne (et mal for knoglecalciummobilisering) yed standardmetoder 20 (Martin og DeLuca, Am. J. Phys. 216, 1351-1359 (1969) og
Tanaka et al., Biochemistry _14, 3293-3296 (1975)) med følgende resultater: 147300 8
Biologisk aktivitet af 24,24-F2~l, 25-(OH)2D^ T arm-Ca-
Timer transport Serum
Indgiven Dosis efter ,45p ς , Calcium forbindelse (pmol) dosis ^ 5 mg/100 ml) 5 _ ua mucos)_
EtOh 1,9± 0,4a 3,2Ϊ0,13 24,24-F2 65 6 4,6± 0,8b 4,3^0,213 1,25-(0H)2D;5 24 4,7- 0,9C 4,1^0,313 1,2_5-(0H)2D3 65 6 4,8± 0,7d 4,2io,3b
10 24 5,1- 0,7e 4,li0,4C
Signifikans b,c,d,e fra a b fra a af forskel P< 0,001; P< 0,001; c fra e c fra a ikke signi- P< 0,005; 15 fikant
De ovenstående data viser, at 24,24-F2~l,25-(OH)2D^ er virksom både i tarmen og i knoglerne, og at forbindelsen er mindst lige så virksom som 1,25-(OH)2D^, det mest aktive, hidtil kendte vitamin D-derivat.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK582283A DK147525C (da) | 1979-03-28 | 1983-12-16 | 24,24-difluor-25-hydroxy-6-alkoxy-3,5-cyclovitamin d3 forbindelser |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/024,848 US4201881A (en) | 1979-03-28 | 1979-03-28 | 24,24-Difluoro-1α,25-dihydroxycholecalciferol |
| US2484879 | 1979-03-28 | ||
| US7900899 | 1979-10-15 | ||
| PCT/US1979/000899 WO1980002028A1 (en) | 1979-03-28 | 1979-10-15 | 24,24-difluoro-1alpha,25-dihydroxycholecalciferol |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK505080A DK505080A (da) | 1980-11-27 |
| DK147300B true DK147300B (da) | 1984-06-12 |
| DK147300C DK147300C (da) | 1984-12-24 |
Family
ID=21822707
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK505080A DK147300C (da) | 1979-03-28 | 1980-11-27 | 24,24-difluor-25-hydroxy-6-alkoxy-3,5-cyclovitamin d3 forbindelser |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US4201881A (da) |
| JP (2) | JPS6342618B2 (da) |
| AU (1) | AU530015B2 (da) |
| BE (1) | BE882143A (da) |
| CH (1) | CH650240A5 (da) |
| DK (1) | DK147300C (da) |
| FR (1) | FR2452481A1 (da) |
| GB (2) | GB2067567B (da) |
| IE (1) | IE49753B1 (da) |
| IL (1) | IL58526A (da) |
| IT (1) | IT1140776B (da) |
| NL (1) | NL7920190A (da) |
| NZ (1) | NZ191900A (da) |
| SE (1) | SE8008339L (da) |
| WO (1) | WO1980002028A1 (da) |
Families Citing this family (15)
| 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 |
| ZA826210B (en) * | 1981-08-28 | 1983-07-27 | Hoffmann La Roche | Cholecalciferol derivatives |
| US4456689A (en) * | 1982-05-17 | 1984-06-26 | Becton Dickinson And Company | Competitive protein binding assay using an organosilane-silica gel separation medium |
| DE3317562A1 (de) * | 1982-05-17 | 1983-11-17 | F. Hoffmann-La Roche & Co AG, 4002 Basel | Verwendung eines cholecalciferolderivates |
| US4428946A (en) * | 1982-07-26 | 1984-01-31 | Wisconsin Alumni Research Foundation | Method of preventing milk fever in dairy cattle |
| ATE45347T1 (de) * | 1985-05-30 | 1989-08-15 | Taisho Pharmaceutical Co Ltd | Vitamin d3-derivate. |
| WO1987003282A1 (fr) * | 1985-11-21 | 1987-06-04 | Taisho Pharmaceutical Co., Ltd. | Derive de la vitamine d3 |
| US4853378A (en) * | 1986-10-20 | 1989-08-01 | Sumitomo Chemical Company, Limited | Fluorine derivatives of vitamin D3 and process for producing the same |
| US5316770A (en) * | 1989-02-16 | 1994-05-31 | University Of Georgia Research Foundation, Inc. | Vitamin D derivative feed compositions and methods of use |
| WO1990009179A1 (en) * | 1989-02-16 | 1990-08-23 | University Of Georgia Research Foundation, Inc. | Treatment of tibial dyschondroplasia |
| US5366736A (en) * | 1989-02-16 | 1994-11-22 | University Of Georgia Research Foundation, Inc. | Vitamin D derivative feed compositions and methods of use |
| US5063234A (en) * | 1990-05-25 | 1991-11-05 | Eli Lilly And Company | Method of inhibiting demineralization of bone |
| MX2010007266A (es) * | 2007-12-28 | 2010-11-30 | Wisconsin Alumni Res Found | Análogos de vitamina d, (20s)-23, 23-difluoro-2-metilen-19-nor-bis homopregnacalciferol. |
| JP5504898B2 (ja) * | 2010-01-08 | 2014-05-28 | セントラル硝子株式会社 | ジフルオロシクロプロパン化合物の製造方法 |
| GB202016614D0 (en) | 2020-10-20 | 2020-12-02 | King S College London | Compounds |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3741996A (en) * | 1971-12-02 | 1973-06-26 | Wisconsin Alumni Res Found | 1{60 -hydroxycholecalciferol |
| US3969700A (en) * | 1974-04-10 | 1976-07-13 | International Business Machines Corporation | Regional context maximum likelihood error correction for OCR, keyboard, and the like |
| FR2267590B1 (da) * | 1974-04-10 | 1977-05-20 | Ibm | |
| JPS5729745B2 (da) * | 1974-09-25 | 1982-06-24 | ||
| 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 |
| US4284577A (en) * | 1979-02-16 | 1981-08-18 | Sachiko Yamada | Novel vitamin D3 derivative and process for preparing the same |
-
1979
- 1979-03-28 US US06/024,848 patent/US4201881A/en not_active Expired - Lifetime
- 1979-10-15 NL NL7920190A patent/NL7920190A/nl unknown
- 1979-10-15 JP JP55500243A patent/JPS6342618B2/ja not_active Expired
- 1979-10-15 WO PCT/US1979/000899 patent/WO1980002028A1/en not_active Ceased
- 1979-10-15 CH CH8817/80A patent/CH650240A5/de not_active IP Right Cessation
- 1979-10-22 IL IL58526A patent/IL58526A/xx unknown
-
1980
- 1980-02-08 NZ NZ191900A patent/NZ191900A/xx unknown
- 1980-02-22 AU AU55810/80A patent/AU530015B2/en not_active Ceased
- 1980-03-07 BE BE0/199728A patent/BE882143A/fr not_active IP Right Cessation
- 1980-03-11 IT IT20508/80A patent/IT1140776B/it active
- 1980-03-13 GB GB8035585A patent/GB2067567B/en not_active Expired
- 1980-03-13 GB GB8008488A patent/GB2045765B/en not_active Expired
- 1980-03-17 FR FR8005935A patent/FR2452481A1/fr active Granted
- 1980-03-26 IE IE619/80A patent/IE49753B1/en unknown
- 1980-11-27 DK DK505080A patent/DK147300C/da not_active IP Right Cessation
- 1980-11-27 SE SE8008339A patent/SE8008339L/xx unknown
-
1987
- 1987-09-16 JP JP62229955A patent/JPS63179855A/ja active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| IE49753B1 (en) | 1985-12-11 |
| GB2067567B (en) | 1983-03-02 |
| JPS6342618B2 (da) | 1988-08-24 |
| SE8008339L (sv) | 1980-11-27 |
| IT8020508A0 (it) | 1980-03-11 |
| FR2452481B1 (da) | 1984-10-19 |
| GB2045765B (en) | 1983-06-15 |
| WO1980002028A1 (en) | 1980-10-02 |
| JPS63179855A (ja) | 1988-07-23 |
| GB2045765A (en) | 1980-11-05 |
| IT1140776B (it) | 1986-10-10 |
| IL58526A (en) | 1983-05-15 |
| IL58526A0 (en) | 1980-01-31 |
| AU530015B2 (en) | 1983-06-30 |
| CH650240A5 (de) | 1985-07-15 |
| US4201881A (en) | 1980-05-06 |
| DK147300C (da) | 1984-12-24 |
| GB2067567A (en) | 1981-07-30 |
| NZ191900A (en) | 1984-11-09 |
| IE800619L (en) | 1980-09-28 |
| BE882143A (fr) | 1980-07-01 |
| FR2452481A1 (fr) | 1980-10-24 |
| AU5581080A (en) | 1980-10-02 |
| DK505080A (da) | 1980-11-27 |
| JPH0146504B2 (da) | 1989-10-09 |
| JPS56500296A (da) | 1981-03-12 |
| NL7920190A (nl) | 1981-01-30 |
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| Date | Code | Title | Description |
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| PBP | Patent lapsed |