DK159652B - Cholecalciferolderivater, disse derivater til brug som terapeutisk aktive substanser, fremgangsmaade til fremstilling deraf samt farmaceutisk praeparat baseret paa disse cholecalciferolderivater - Google Patents
Cholecalciferolderivater, disse derivater til brug som terapeutisk aktive substanser, fremgangsmaade til fremstilling deraf samt farmaceutisk praeparat baseret paa disse cholecalciferolderivater Download PDFInfo
- Publication number
- DK159652B DK159652B DK524585A DK524585A DK159652B DK 159652 B DK159652 B DK 159652B DK 524585 A DK524585 A DK 524585A DK 524585 A DK524585 A DK 524585A DK 159652 B DK159652 B DK 159652B
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- DK
- Denmark
- Prior art keywords
- methyl
- derivatives
- cholecalciferold
- octahydro
- trifluoromethyl
- Prior art date
Links
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- 239000013543 active substance Substances 0.000 title claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 title 1
- 230000001225 therapeutic effect Effects 0.000 title 1
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- 229940046008 vitamin d Drugs 0.000 claims description 2
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- 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 claims 1
- FNIATMYXUPOJRW-UHFFFAOYSA-N cyclohexylidene Chemical group [C]1CCCCC1 FNIATMYXUPOJRW-UHFFFAOYSA-N 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
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- 150000001875 compounds Chemical class 0.000 description 23
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- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
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- 229910052786 argon Inorganic materials 0.000 description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
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- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 4
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- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 3
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- 229910052736 halogen Inorganic materials 0.000 description 2
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- MJGFBOZCAJSGQW-UHFFFAOYSA-N mercury sodium Chemical compound [Na].[Hg] MJGFBOZCAJSGQW-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
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- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
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- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
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- 125000004432 carbon atom Chemical group C* 0.000 description 1
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- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- VLCINIKIVYNLPT-UHFFFAOYSA-J dicalcium;hydrogen phosphate Chemical compound [Ca+2].[Ca+2].OP(O)([O-])=O.[O-]P([O-])([O-])=O VLCINIKIVYNLPT-UHFFFAOYSA-J 0.000 description 1
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- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
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- 238000009472 formulation Methods 0.000 description 1
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- 238000010438 heat treatment Methods 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- SNWQUNCRDLUDEX-UHFFFAOYSA-N inden-1-one Chemical class C1=CC=C2C(=O)C=CC2=C1 SNWQUNCRDLUDEX-UHFFFAOYSA-N 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
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- 238000002347 injection Methods 0.000 description 1
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- 239000000463 material Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
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- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 229940074439 potassium sodium tartrate Drugs 0.000 description 1
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- 239000003755 preservative agent Substances 0.000 description 1
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- 208000007442 rickets Diseases 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
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- MZSDGDXXBZSFTG-UHFFFAOYSA-M sodium;benzenesulfonate Chemical compound [Na+].[O-]S(=O)(=O)C1=CC=CC=C1 MZSDGDXXBZSFTG-UHFFFAOYSA-M 0.000 description 1
- SRJQTHAZUNRMPR-UYQKXTDMSA-N spinosyn A Chemical compound O([C@H]1CCC[C@@H](OC(=O)C[C@H]2[C@@H]3C=C[C@@H]4C[C@H](C[C@H]4[C@@H]3C=C2C(=O)[C@@H]1C)O[C@H]1[C@@H]([C@H](OC)[C@@H](OC)[C@H](C)O1)OC)CC)[C@H]1CC[C@H](N(C)C)[C@@H](C)O1 SRJQTHAZUNRMPR-UYQKXTDMSA-N 0.000 description 1
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- 150000003431 steroids Chemical class 0.000 description 1
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- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C7/00—Purification; Separation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
- C07C49/743—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups having unsaturation outside the rings, e.g. humulones, lupulones
-
- 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
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Description
t DK 159652 B
Den foreliggende opfindelse angår de hidtil ukendte cholecalciferol-derivater Δ^- og Δ^^-26,26,26,27,27,27-hexafluor-la,25-dihydroxycho-lecalciferol, disse derivater til brug som terapeutisk aktive substanser, især med vitamin D-aktivitet, farmaceutiske præparater 5 baseret på disse, samt en fremgangsmåde til fremstilling af disse. Fremgangsmåden ifølge opfindelsen er ejendommelig ved det i krav 4's kendetegnende del angivne.
22 23
Cholecalciferolderivaterne ifølge opfindelsen er Δ - eller Δ - 26,26,26,27,27,27-hexafluor-la,25-dihydroxycholecalciferol, i det 22 23 10 følgende betegnet henholdsvis Δ - og Δ -forbindelsen. Ved fremgangsmåden ifølge opfindelsen fremstilles disse forbindelser ved, at [IR- [ί,β(R*) ,3aa,4/?, 7a/3] ] -octahydro-1- [6,6,6-trifluor-5-trimethylsi-lyloxy- 5 - tr if luorme thyl -1 -methyl - 2 -hexenyl ] - 7a-me thyl - IH- inden-4- on eller [IR- [i/?(R*) , 3aa,4/J,7a/?] ] -octahydro-1- [6,6,6-trifluor-5-trime-15 thylsilyloxy- 5-trifluormethyl-l-methyl-3-hexenyl]-7a-methyl-lH-in-den-4-on behandles med [3S-(3a,5/9,Z) ]-2-[2-methylen-3,5-bis[ (1,1-dimethylethyl)dimethylsilyloxy]cyclohexyliden]ethyldiphenylphosphino-xid, og silylbeskyttelsesgrupperne fraspaltes.
Denne reaktion kan udføres ved lav temperatur, fx under -50eC, for-20 trinsvis ved ca. -78°C, under en inert atmosfære, fx under argon, i et inert opløsningsmiddel såsom en cyclisk ether, fortrinsvis tetra-hydrofuran (THF). Hensigtsmæssigt omdannes phosphinoxidet først og fremmest til den tilsvarende carbanion. Dette kan udføres ved, at phosphinoxidet til at begynde med behandles med et alkyllithium, fx 25 n-butyllithium, i et inert opløsningsmiddel såsom en lavere alkan, fx hexan, ved nedsat temperatur. Det resulterende produkt kan fx oprenses på chromatografi på silicagel.
Inden for opfindelsens rammer betegner udtrykket "lavere alkyl" li-gekædede eller forgrenede alkylgrupper med 1-8 carbonatomer, fx me-30 thyl, ethyl, n-propyl, i-propyl og tert.butyl. "Aryl" betegner phenyl, eventuelt substitueret med alkyl, halogen, nitro, cyan eller trifluormethyl. Eksempler på aralkylgrupper er benzyl og phenethyl.
De ved ovenstående fremgangsmåde anvendte indenonudgangsforbindelser kan fremstilles på følgende måde: 2
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[ 1R- [ 1/J, [<*S*, £S* ], 3 aa, 4a/3,7a/S ] ] - oc tahydro-β,Ί&- dime thyl -4-[(l,l-di-methylethyl)dimethylsilyloxy]-a-ethenyl-lH-inden-l-ethanol kan ved behandling med thionylchlorid efterfulgt af pyridin omdannes til [1R-[1^(R*>,3aa,4£»7a^]]-1-(4-chlor-1-methyl-2-buteny1)octahydro-4- , 5 [(l,l-dimethylethyl)-dimethylsilyloxyJ-7a-methyl-lH-inden. Det resulterende allyliske chlorid omsættes derefter med et arylsulfinsyre-salt, fx benzensulfinsyrenatriumsalt, til den tilsvarende 4-apylsul-fonylforbindelsé, fx [IR- ,3aa,4£, 7a/J] ] -1- [ (4-phenylsulfonyl) - 1-methyl-2-butenyl]octahydro-4-[(1,1-dimethylethyl)dimethylsilyloxy]-10 7a- methyl-IH-inden. Til fuldendelse af sidekæden i en vunden sulfo- nylforbindelse kan sidstnævnte omsættes med n-butyllithium eller li-thiumdiisopropylamid og den opståede carbanion omsættes med hexa-fluoracetone.
I den vundne forbindelse med den almene formel I
15 f°2X
^OH
CF3 ' S2-Si-0 13 R*5 hvor X er aryl, og R^·, R^ og R^ er lavere alkyl, aryl eller aralkyl, 20 er X fortrinsvis phenyl, R^- og R^ methyl og R^ tert.butyl.
Forbindelsen med den almene formel I kan først og fremmest omsættes med et di-alkalimetalphosphat, fx dikaliumhydrogenphosphat, hensigtsmæssigt tinder stuebetingelser og derefter omsættes med et alkalimeta-lamalgam, fx natriumamalgam, hensigtsmæssigt ved en temperatur under 25 0eC, fx ved ca. -20eC. Reaktionen kan udføres i et inert opløsningsmiddel såsom en lavere alkanol, fx methanol, en cyclisk ether, fx 3
DK 159652 B
THF, fortrinsvis i blandinger deraf. Reaktionsprodukterne [1R-[1/?(R*) ,3aa,40,7a/?] ] -octahydro-1- [ 6,6,6-trifluor-5-hydroxy-5-tri-fluormethyl-l-methyl-2-hexenyl]-7a-methyl-lH-inden-4-ol eller [1R-[1/?(R*),3aa,4/?,7a/?]]-octahydro-1-[6,6,6-trifluor-5-hydroxy-5-triflu-5 ormethyl-1-methyl-3-hexenyl]-7a-methyl-lH-inden-4-ol kan fås i renset og opspaltet form ved en første chromatografering på en silicagelsøj-le efterfulgt af behandling med en katioribytterharpiks og til slut ved selektiv chromatografi på en silicagelsøjle.
I næste trin kan et vundet indenolderivat (forbindelse II) behandles 10 med et basisk organisk aminchromatsalt, fx pyridiniumhalogenchromat, især pyridiniumchlorchromat. Reaktionen udføres hensigtsmæssigt under stuebetingelser i et inert opløsningsmiddel såsom en halogeneret alkan, fx en chloralkan, fortrinsvis methylenchlorid.
Et vundet indenonderivat (forbindelse III) kan derefter under en 15 inert atmosfære, fx tinder argon, behandles med et middel, der indfører en trimethylsilylbeskyttelsesgruppe på sidekædens hydroxygrup-pe, fx trimethylsilylimidazol.
De vundne forbindelser [IR-[10(R*),3aa,40,7a0]]-octahydro-1-[6,6,6-trifluor-5-trimethyls ilyloxy-5-trifluormethyl-1-methyl-2-hexenyl]-7a-20 methyl-IH-inden-4-on eller [IR-[10(R*),3ao,40,7aØ]]-octahydro-1- [6,6,6-trifluor-5-trimethylsilyloxy-5-trifluormethyl-l-methyl-3-hexenyl]-7a-methyl-lH-inden-4-on samt de yderligere ovenfor nævnte forbindelser I og III er hidtil ukendte.
22 23 Δ - og Δ -forbindelserne har vitamin D3-lignende aktivitet og udvi-25 ser antiproliferative og celledifferentieringsinducerende virkninger.
Disse virkninger på HL-60-celler in vitro kan påvises ved kendte metoder, fx som beskrevet i Progress in Cancer Research and Therapy, bind 23: "Maturation Factors and Cancer", Red. M.A.S. Moore, Raven Press, New York 1982; Nature, 270 (1977) s. 347-349 og Blood, 54 30 (1979), s. 429-439. Resultaterne er anført i nedenstående tabel: 4
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Koncentration af Δ^-forbindelse (x 10molær)
Proliferation ^ 5 HL-60-celler % Reduktion pr. ml x 10"^ i antal celler
Eksperiment 1 10 Nul (mediekontrol) 77,1±3,3
Vehikel (0,1% ethanol) 76,9±5,1 0 0,1 66,7±1,6 13 1 24,8±0,6 68 10 17,0±1,6 78 15 100 16,4±1,1 79
Eksperiment 2
Nul (mediekontrol) 92,2±7,6
Vehikel (0,1% ethanol) 94,1±3,4 0 20 0,1 97,9±6,2 0 0,3 74,310,8 21 1 47,611,3 49 3 30,911,2 67 10 28,210,6 70 25 30 25,312,0 73
Eksperiment 3
Nul (mediekontrol) 74,411,9
Vehikel (0,1% ethanol) 80,614,8 0 30 0,1 74,411,3 8 0,3 60,912,0 24 1 38,411,6 52 3 24,711,0 69 10 21,010,4 74 35 30 21,010,5 74 5
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Differentiering NBT-Reduktion Phagocytose
Formazan "+" phagocytiske celler 5 sum af talte sum af talte celler % "+" celler % "+"
Eksperiment 1
Nul (mediekontrol) 3/378 <1 10 Vehikel (0,1% ethanol) 2/359 <1 0,1 6/347 2 1 280/328 85 10 306/319 96 15 100 348/356 98
Eksperiment 2
Nul (mediekontrol) 2/346 <1 4/386 1
Vehikel (0,1% ethanol) 3/381 <1 3/336 <1 20 0,1 3/343 <1 4/359 1 0,3 45/355 13 49/376 13 1 212/317 67 229/330 69 3 290/316 92 284/303 94 10 353/360 98 311/328 95 25 30 310/316 98 339/344 98
Eksperiment 3
Nul (mediekontrol) 2/346 <1
Vehikel (0,1% ethanol) 3/374 <1 30 0,1 2/380 <1 0,3 23/338 10 1 231/332 70 3 354/367 96 10 314/332 95 35 30 312/322 96
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e
Tabel fortsat \ 23
Koncentration af ' Δ -forbindelse (x 10’9 molær)
Proliferation ^ 5 _ HL-60-celler % Reduktion pr. ml x 10"4 i antal celler
Eksperiment 1 10 _
Nul (mediekontrol) 74,0±1,0
Vehikel (0,1% ethanol) 67,8±0,5 0 0,1 64,8±1,7 4 15 0,3 58,8±3,6 13 1 42,0±2,1 38 3 22,5±1,4 67 10 16,2±0,7 76 30 14,5±0,8 79 20 100 13,6±0,9 80
Eksperiment 2
Nul (mediekontrol) 74,4±1,9
Vehikel 25 (0,1% ethanol) 80,6±4,8 0 0,1 71,4±1,2 11 0,3 64,8±7,3 20 1 55,1±0,9 32 3 47,5±3,0 41 30 10 44,0±0,9 45 30 39,7±2,2 51 7
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Tabel fortsat Differentiering NBT-Reduktion Phagocytose 5 Formazan "+" phagocytiske celler sum af talte sum af celler % "+" talte celler % "+"
Eksperiment 1 10 _
Nul (mediekontrol) 3/318 <1 11/350 3
Vehikel (0,1% ethanol) 3/316 <1 7/345 2 0,1 3/310 <1 4/448 <1 15 0,3 16/351 5 12/343 4 1 184/328 56 155/352 44 3 342/360 95 305/330 92 10 353/359 98 335/347 97 30 335/339 99 372/379 98 20 100 331/335 99
Eksperiment 2
Nul (mediekontrol) 2/343 <1
Vehikel 25 (0,1% ethanol) 3/374 <1 0,1 3/351 <1 0,3 13/327 4 1 218/347 63 3 284/324 88 30 10 318/324 98 30 346/354 98 I alle testkulturer udgjorde vehikelkoncentrationen 0,1% (volu- men/volumen) ethanol.
I alle kulturer var cellelevedygtigheden større end 95%. Begyndelseskoncentrationen i alle kulturer udgjorde 2 x 10^ HL-60-celler pr. ml.
35 8
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22 23
Dataene i tabellen viser, at Δ - og Δ -forbindelsen hæmmer prolife-rationen af menneskelige promyelocytiske tumorceller in vitro og derved ikke er celletoxiske. Endvidere kunne celler, der var blevet dyrket i lavere koncentrationer af disse forbindelser (0,3 - 10 x 10'^ 5 molær), bringes til at differentiere til en mere moden celletype, hvilket ytrede sig ved opnåelse af enzymaktivitet og cellefunktion.
22 23
Det kan forventes, at Δ - og Δ -forbindelserne kan anvendes ved behandling af sygdomme såsom neoplastiske sygdomme, der delvis er forårsaget af afvigende celleproliferation og/eller -differentiering.
22 23 10 Δ - og Δ -forbindelserne kan indgives i doser i området fra ca.
0,10 til 3,0, fortrinsvis fra 0,25 til 2,0 /ig/dag til behandling af sygdomme såsom osteoporose, osteodystrofi, steroidinduceret osteope- ni, hypoparathyroidi, hypophosphatæmisk rachitis og hypophosphatæmisk osteomalaci, der er karakteriseret ved unormalt lave niveauer af en- 22 23 15 dogent produceret la,25-dihydroxycholecalciferol. Δ - og Δ -forbindelserne kan indgives i det ovennævnte dosisområde til behandling af 22 23 proliferative sygdomme såsom leukæmi. Δ - og Δ -forbindelserne kan indgives oralt, fx i form af tabletter, kapsler eller eliksirer; eller subcutant, intramuskulært, intravenøst, intraperitonealt eller 20 topisk, fx i form af sterile opløsninger eller suspensioner. En en- 22 keltdosis kan indeholde ca. 0,10-3,0, fortrinsvis 0,25-2,0 pg af Δ -23 eller Δ -forbindelsen sammen med en farmaceutisk acceptabel vehikel, bærer, konserveringsmiddel, stabiliseringsmiddel, bindemiddel, fx traganthgummi, excipiens, fx kalciumphosphat, sprængmiddel, fx 25 majsstivelse, glittemiddel, fx magnesiumstearat, sødemiddel, fx sucrose, smagsstof, fx pebermynte. Til modificering af enkeltdoseringens udseende kan der anvendes andre materialer såsom overtræk, fx Shellac.
22 23 Δ - og Δ -forbindelserne kan også indgives i sædvanlige formulerin- 30 ger til behandling af mælkefeber hos drægtige drøvtyggere i doser i området 100-1500 /ig/dag, fortrinsvis 200-1000 /ig/dag. Fx kan der fremstilles sterile præparater til injektionsbrug og/eller topisk 22 23 indgivelse ved opløsning eller suspendering af Δ - eller Δ -forbindelsen i en vehikel, fx en 10-20%'s eller 80-95%'s ethanol-(eller 9
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propylenglycol)-vandblanding, en naturligt forekommende planteolie såsom sesamolie, eller et syntetisk fast bindemiddel såsom ethylole-22 23 at. Δ - eller Δ -forbindelsen lader sig også indgive oralt i en mængde på 100-1500 μ$ i form af fedtsyrepellets.
5 EKSEMPEL 1 a) En opløsning af 2,9 g (8,22 mmol) [IR-[10, [aS*,/9S*] , 3aa,4a/?, 7a/3] ]-octahydro-Ø,7a-dimethyl-4-[(1,1-dimethylethy1)dimethyls ilyloxy]-a-ethenyl-lH-inden-l-ethanol i 100 ml vandfri ether blev afkølet til 0°C og blev dråbevis og. under argon behandlet med 2,76 ml 10 (37,84 mmol) thionylchlorid efterfulgt af 0,276 ml pyridin. Blandin gen blev omrørt i 2 timer ved 0°C, og der blev derefter tilsat 50 ml af en 2N opløsning af natriumkaliumtartrat. Etherfasen blev skilt fra, og den vandige fase blev ekstraheret med ethylacetat. De forenede organiske faser blev vasket med IN saltsyre, vand, 2N kalium-15 hydrogencarbonat og saltvand, tørret og inddampet. Opløsningsmidlet blev dampet af i vakuum, og remanensen blev oprenset ved chromatogra-fi på silicagel ved hjælp af hexan/ethylacetat. Herved fås 2,9 g (95%'s udbytte) rent [IR- [10(R*) ,3aa,40,7a0] ]-1-(4-chlor-l-methyl-2-butenyl)octahydro-4- [(1,1-dimethylethyl)-dimethylsilyloxy]-7a-metyl-20 IH-inden i form af et lavtsmeltende fast stof.
b) En opløsning af 2,9 g (7,81 mmol) af det allyliske chlorid fra la) i 130 ml hexamethylphosphoramid blev behandlet med 10,1 g (61,52 mmol) benzensulf-insyrenatriumsalt og omrørt ved stuetemperatur under argon i 24 timer. Der blev derefter tilsat 130 ml isvand, og 25 efter omrøring i 30 minutter blev blandingen ekstraheret med ethylacetat. De forenede ekstrakter blev vasket med vand, tørret og inddampet til tørhed. Remanensen blev oprenset ved chromatografi på silicagel med hexan/ethylacetat. Herved fås 3,5 g (94%'s udbytte) [1R-[10(R*) ,3aa,40,7aØ] ] -1- [ (4-phenylsulfonyl) -1 -methyl-2-butenyl] -octa-30 hydro-4-[(l,l-dimethylethyl)dimethylsilyloxy]-7a-methyl-lH-inden i form af et lavtsmeltende fast stof.
c) En opløsning af 0,628 ml (4,48 mmol) diisopropylamin i 10 ml vandfri THF blev afkølet til 0°C og blev dråbevis under argon behandlet 10
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med 2,70 ml (4,32 mmol) af en 1,6 M opløsning af n-butyllithium i hexan. Efter omrøring i· 15 minutter ved 0°C blev den resulterende opløsning afkølet til -78°C og fortyndet med 17 ml vandfri THF. Den blev derefter behandlet dråbevis med en opløsning af 1,25 g 5 (2,62 mmol) af sulfonen fra lb) i 16 ml THF og omrørt i 30 minutter ved -78eC. Der blev boblet hexafluoracetone gennem opløsningen indtil den gule farve forsvandt. Efter omrøring i 5 minutter blev reaktionen standset ved tilsætning af 30 ml af en l:l-blanding af 2N natriumka-liumtartrat og 2N kaliumhydrogencarbonat, reaktionsblandingen fik lov 10 at varme op til stuetemperatur og blev ekstraheret med methylench-lorid. De organiske ekstrakter blev vasket med saltvand, tørret og inddampet til tørhed. Remanensen blev oprenset ved chromatografi på silicagel ved hjælp af hexan/ethylacetat. Herved fås 1,23 g (72%'s udbytte) [IR- [1/?(R*),3aa,4/S,7a/9] ] -octåhydro-1- [6,6,6-trifluor-5-15 hydroxy- 5-trifluormethyl-4-phenylsulfonyl-l-methyl-2-hexenyl]-4- [(1,1-dimethylethyl)-dimethylsilyloxy] -7a-methyl-lH-inden i form af en farveløs olie.
d) En opløsning af 1,23 g (1,91 mmol) af sulfonen fra lc) i form af en epimer blanding i 40 ml methanol og 40 ml THF blev behandlet med 20 23 g dikaliumhydrogenphosphat og, efter afkøling til -20°C, med 24 g 6% natriumamalgam. Efter omrøring af den resulterende blanding i 15 minutter blev der tilsat 60 ml saltvand. Efter opvarmning til stuetemperatur blev der ekstraheret med ethylacetat. De organiske ekstrakter blev vasket med saltvand, tørret og inddampet til tørhed.
25 Remanensen blev oprenset ved chromatografi på silicagel ved hjælp af hexan/ethylacetat. Produktet (0,815 g) blev opløst i 40 ml ethanol, omrørt i 6 dage ved stuetemperatur med 10 g af en kationbytterharpiks (AG 50W-X4, 0,074-0,037 mm, Bio-Rad Laboratories, Richmond, Californien, USA). Efter frafiltrering af harpiksen og afdampning af op-30 løsningsmidlet blev remanensen oprenset ved to på hinanden følgende chromatograferinger på silicagel, den første med hexan/ethylacetat, og den anden med methylenchlorid. Herved fås 200 mg rent [IR- [1/3-(R*) ,3ace,4)9,7a/J] ] -octahydro-1- [6,6,6-trifluor-5-hydroxy-5-trifluorme-thyl-1-methyl-2-hexenyl]-7a-methyl-lH-inden-4-ol og 50 mg [IR- [1/9-35 (R*),3aa,4^,7aj8]]-octahydro-1-[6,6,6-trifluor-5-hydroxy-5-trifluorme- thyl-1-methyl-3-hexenyl]-7a-methyl-lH-inden-4-ol.
11
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e) Til en opløsning af 182 mg (0,469 mmol) af diolen [1R-[1/J(R*) , 3aa,4/3,7a/J] ] -octahydro-1- [6,6,6- tr if luor - 5 -hydroxy - 5 -tri-fluormethyl-1-methyl-2-hexenyl]-7a-methyl-lH-inden-4-ol i 2 ml me-thylenchlorid blev sat en opslæmning af 300 mg (1,392 mmol) pyridi- 5 niumchlorchromat i 7 ml methylenchlorid. Den resulterende blanding blev omrørt i 2 1/2 time ved stuetemperatur. Blandingen blev fortyndet med 10 ml ether, omrørt i 15 minutter og filtreret. Remanensen blev revet flere gange med ether. Tritureringsekstrakterne blev forenet og filtreret. Efter inddampning til tørhed og oprensning af re-10 manensen ved chromatografi med hexan/ethylacetat opnåedes 174 mg (96%'s udbytte) [ IR- [ ίβ(R*) , 3aa, 4)9,7αβ] ] - octahydro-1 - [ 6,6,6 - trifluor- 5-hydroxy-5-trifluormethyl-1-methyl-2-hexenyl]-7a-methyl-IH-inden-4-on.
f) En opløsning af 174 mg (0,450 mmol) af ketonen fra le) i 9 ml me-15 thylenchlorid blev behandlet med 0,4 ml (2,726 mmol) trimethylsilyl- imidazol og omrørt i 6 timer ved stuetemperatur under argon. Efter tilsætning af 1 ml vand blev blandingen omrørt i 20 minutter, blev derefter fortyndet med vand og ekstraheret med ethylacetat. De organiske ekstrakter blev vasket med vand og saltopløsning, tørret og 20 inddampet til tørhed. Remanensen blev oprenset ved chromatografi ved hjælp af hexan/ethylacetat. Herved fås 177 mg (86%'s udbytte) rent [IR- [1/J(R*) ,3aa,4jØ,7a/?] ] - octahydro -1 - [ 6,6,6 - trif luor - 5 - trimethylsi-lyloxy-5-trifluormethyl-1-methyl-2-hexenyl]-7a-methyl-IH-inden-4-on.
g) En opløsning af 365 mg (0,584 mmol) [3S-(3a,5/3,Z)]-2-[2-methylen- 25 3,5-bis[(1,l-dimethylethyl)dimethylsilyloxy]cyclohexyliden] ethyl- diphenylphosphinoxid i 10 ml vandfrit THF blev afkølet til -78°C og blev dråbevis under argon behandlet med 0,358 ml (0,573 mmol) af en 1,6M opløsning af n-butyllithium i hexan. Efter omrøring i 5 minutter blev der til den orangefarvede phosphinoxy-carbanionopløsning dråbe-30 vis sat en opløsning af 177 mg (0,386 mmol) af ketonen fra lf) i 2,5 ml vandfrit THF. Den resulterende blanding blev omrørt i 1 time ved -78°C. Den blev derefter behandlet med 3 ml af en l:l-blanding (volumen/volumen) af 2N kaliumnatriumtartrat og 2N kaliumcarbonat, fortyndet med vand efter opvarmning til stuetemperatur og ekstraheret 35 med ethylacetat. De forenede organiske faser blev vasket med saltvand, tørret og inddampet til tørhed. Remanensen blev oprenset ved 12
DK 159652 B
filtrering gennem silicagel og eluering med hexan/ethylacetat, blev derefter opløst i 0,8 ml methylenchlorid og 9 ml methanol og omrørt natten over ved stuetemperatur sammen med 3,5 g af en katioribytter-harpiks (AG 50W-X4). Efter filtrering og afdampning af opløsnings-5 midlet blev remanensen opløst i 5 ml THF og behandlet med 0,650 ml af en 1M opløsning af tetrabutylammoniumfluorid i THF og omrørt i 1 time. Blandingen blev derefter behandlet med 0,5 ml vand og ekstraheret med ethylacetat. De forenede organiske faser blev vasket med vand, tørret og inddampet til tørhed. Det rå produkt blev oprenset ved 10 chromatografi på silicagel ved hjælp af hexan/ethylacetat. Herved fås 181 mg (90%'s udbytte) rent 26,26,26,27,27,27-hexafluor- la,25-dihy- 22 oe droxy-Δ -cholecalciferol som et hvidt amorft pulver, [α]β - 13,9° (c 0,2 i ethanol).
EKSEMPEL 2 15 a) Efter metoden beskrevet i eksempel le) blev 45,0 mg [1R-[1/?- (R*),3aa,^β,7αβ])-octahydro-1-[6,6,6-trifluor-5-hydroxy-5-trifluorme-thyl-l-methyl-3-hexenyl]-7a-methyl-lH-inden-4-ol omdannet til 42,0 mg [IR- [10(R*) ,3aa,4/J,7a/J] ] -octahydro-1- [6,6,6-trifluor-5-hydroxy-5-tri-f luorme thyl-1 -methyl - 3 -hexenyl ] - 7a-methyl- IH- inden-4- on.
20 b) Efter metoden beskrevet i eksempel lf) blev 42,0 mg af ketonen fra 2a) omdannet til 35,5 mg [IR- [1/?(R*) ,3aa,4/?,7a£] ]-octahydro-1-[6,6,6-trifluor-5-trimethylsilyloxy-5-trifluormethyl-1-methyl-3-hexenyl]-7a-methyl-IH-inden-4-on.
c) Efter metoden beskrevet i eksempel lg) blev 35,5 mg af ketonen fra 25 2b) omdannet til 18,8 mg 26,26,26,27,27,27-hexafluor-la,25-dihydroxy- Δ^-cholecalciferol, [a]§5 - +14,2° (c - 0,1 i ethanol).
13
DK 159652 B
EKSEMPEL A
Bestanddele mg/kapsel 22 1. Δ - eller Δ23-forbindelse 0,00010 0,00025 0,00050 5 2. Polyethylengly- col 400 200,00 200,00 200,00 3. Butyleret hy- droxyanisol 0,100 0,100 0,100 4. Ascorbylpalmitat 1,00 1,00 1,00 10 Bestanddelene 1, 3 og 4 opløses under kvælstof i bestanddel 2 og fyldes i en kapsel.
EKSEMPEL B
Bestanddele 22 23 1. Δ - eller Δ -forbindelse 0,10 mg 0,50 mg 15 2. 95% ethanol/5% vand 2,00 ml 3,00 ml.
Bestanddel 1 opløses under kvælstof i bestanddel 2 og injiceres in-tramuskulært.
Claims (4)
1. A^- eller ~26,26,26,27,27,27-hexafluor-la, 25-dihydroxychole-calciferol.
2. Δ^- eller Δ^-26,26,26,27,27,27-hexafluor-la,25-dihydroxychole- 5 calciferol til brug som terapeutisk aktiv substans, især med vitamin D-aktivitet. 22 23
3. Farmaceutisk præparat baseret på Δ - eller Δ -26,26,26,27,27,27-hexafluor-le,25-dihydroxycholecalciferol. 22 23
4. Fremgangsmåde til fremstilling af Δ - eller Δ - 10 26,26,26,27,27,27-hexafluor-la,25-dihydroxycholecalciferol, kendetegnet ved, at [IR- [1£(R*) , 3aa,4/?,7a/?] ]-octahydro-1-[6,6,6-trifluor-5-trimethylsilyloxy-5-trifluormethyl-l-methyl-2-hex-enyl] -7a-methyl-lH-inden-4-on eller [IR- [1j3(R*) ,3aa,4/?,7a/?] ] -octahy-dro-1-[6,6,6-trifluor-5-trimethyls ilyloxy-5-trifluormethyl-1-methyl-15 3- hexenyl]-7a-methyl-lH-inden-4-on behandles med [3S-(3a,5/J,Z)]-2- [2-methylen-3,5-bis[(1,1-dimethylethyl)-dimethylsilyloxy]cyclohexyli-den]ethyldiphenylphosphinoxid, og silylbeskyttelsesgruppeme fraspaltes.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US67205984 | 1984-11-16 | ||
| US06/672,059 US4613594A (en) | 1984-11-16 | 1984-11-16 | Fluorinated vitamin D3 compounds |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| DK524585D0 DK524585D0 (da) | 1985-11-13 |
| DK524585A DK524585A (da) | 1986-05-17 |
| DK159652B true DK159652B (da) | 1990-11-12 |
| DK159652C DK159652C (da) | 1991-04-08 |
Family
ID=24696990
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK524585A DK159652C (da) | 1984-11-16 | 1985-11-13 | Cholecalciferolderivater, disse derivater til brug som terapeutisk aktive substanser, fremgangsmaade til fremstilling deraf samt farmaceutisk praeparat baseret paa disse cholecalciferolderivater |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US4613594A (da) |
| EP (1) | EP0182298B1 (da) |
| JP (1) | JPS61122237A (da) |
| KR (1) | KR930007993B1 (da) |
| AR (1) | AR242767A1 (da) |
| AT (1) | ATE48412T1 (da) |
| AU (1) | AU588012B2 (da) |
| CA (1) | CA1286693C (da) |
| DE (1) | DE3574587D1 (da) |
| DK (1) | DK159652C (da) |
| ES (1) | ES8801198A1 (da) |
| FI (1) | FI84599C (da) |
| HU (1) | HU194162B (da) |
| IE (1) | IE58851B1 (da) |
| IL (1) | IL77052A (da) |
| MC (1) | MC1709A1 (da) |
| NO (1) | NO162906C (da) |
| NZ (1) | NZ214175A (da) |
| PH (1) | PH21540A (da) |
| PT (1) | PT81502B (da) |
| ZA (1) | ZA858151B (da) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63196556A (ja) * | 1987-02-10 | 1988-08-15 | Taisho Pharmaceut Co Ltd | 含フツ素ビタミンｄ誘導体 |
| AU5185790A (en) * | 1989-02-16 | 1990-09-05 | University Of Georgia Research Foundation, Inc., The | Treatment of tibial dyschondroplasia |
| US5316770A (en) * | 1989-02-16 | 1994-05-31 | University Of Georgia Research Foundation, Inc. | Vitamin D derivative feed compositions and methods of use |
| US5366736A (en) * | 1989-02-16 | 1994-11-22 | University Of Georgia Research Foundation, Inc. | Vitamin D derivative feed compositions and methods of use |
| JP2525478B2 (ja) * | 1989-03-01 | 1996-08-21 | 帝人株式会社 | 安定性の改良された活性型ビタミンｄ▲下３▼類固型製剤 |
| AU650751B2 (en) * | 1991-05-28 | 1994-06-30 | Wisconsin Alumni Research Foundation | Novel synthesis of 19-nor vitamin D compounds |
| US5278155A (en) * | 1991-06-05 | 1994-01-11 | Daikin Industries, Ltd. | Fluorine-containing vitamin D3 analogues and cell differentiation-inducing agent containing the same |
| US5206230A (en) * | 1991-06-05 | 1993-04-27 | Daikin Industries, Ltd. | Fluorine-containing vitamin D3 analogues and pharmaceutical composition containing the same |
| DK0521550T3 (da) * | 1991-07-05 | 1996-11-04 | Duphar Int Res | Vitamin D forbindelse, fremgangsmåde til fremstilling af denne forbindelse og mellemprodukt derfor |
| US5753638A (en) * | 1992-10-07 | 1998-05-19 | Hoffmann-La Roche Inc. | Method of treating hyperproliferative skin disease with Vitamin D3 fluorinated analogs |
| CA2096105A1 (en) * | 1992-10-07 | 1994-04-08 | Enrico Giuseppe Baggiolini (Deceased) | Vitamin d3 fluorinated analogs |
| US5547947A (en) * | 1993-03-11 | 1996-08-20 | Hoffmann-La Roche Inc. | Methods of treatment |
| US5552392A (en) * | 1993-11-03 | 1996-09-03 | Wisconsin Alumni Research Foundation | Method of treating hypoparathyroidism with (20S) vitamin D compounds |
| US5428029A (en) * | 1993-11-24 | 1995-06-27 | Hoffmann-La Roche Inc. | Vitamin D3 fluorinated analogs |
| US5872113A (en) * | 1997-05-16 | 1999-02-16 | Syntex (U.S.A.) Inc. | Fluorinated vitamin D3 analogs |
| US20080293647A1 (en) | 2004-11-12 | 2008-11-27 | Luciano Adorini | Combined Use Of Vitamin D Derivatives And Anti-Proliferative Agents For Treating Bladder Cancer |
| CN117088798A (zh) * | 2023-09-04 | 2023-11-21 | 正大制药（青岛）有限公司 | 一种氟骨化醇22,23-双键杂质的制备方法 |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4248791A (en) * | 1980-02-04 | 1981-02-03 | Wisconsin Alumni Research Foundation | 25-Hydroxy-26,26,26,27,27,27-hexafluorocholecalciferol |
| JPS57149224A (en) * | 1981-03-13 | 1982-09-14 | Chugai Pharmaceut Co Ltd | Tumor-suppressing agent |
| US4358406A (en) * | 1981-07-27 | 1982-11-09 | Wisconsin Alumni Research Foundation | 26,26,26,27,27,27-Hexafluoro-1α,25-dihydroxycholecalciferol and process for preparing same |
| US4411833A (en) * | 1982-05-26 | 1983-10-25 | Wisconsin Alumni Research Foundation | Method for preparing 26,26,26,27,27,27-hexafluoro-1α,25-dihydroxycholesterol |
| DE3471928D1 (en) * | 1983-01-28 | 1988-07-14 | Hoffmann La Roche | Process for the preparation of cholecalciferol derivatives |
| US4508651A (en) * | 1983-03-21 | 1985-04-02 | Hoffmann-La Roche Inc. | Synthesis of 1α,25-dihydroxyergocalciferol |
| US4505906A (en) * | 1984-01-30 | 1985-03-19 | Wisconsin Alumni Research Foundation | Hydroxyvitamin D2 isomers |
| US4521410A (en) * | 1984-05-03 | 1985-06-04 | The General Hospital Corporation | Vitamin D glycosyl orthoesters |
-
1984
- 1984-11-16 US US06/672,059 patent/US4613594A/en not_active Expired - Fee Related
-
1985
- 1985-10-23 ZA ZA858151A patent/ZA858151B/xx unknown
- 1985-11-13 CA CA000495246A patent/CA1286693C/en not_active Expired - Fee Related
- 1985-11-13 NZ NZ214175A patent/NZ214175A/xx unknown
- 1985-11-13 DK DK524585A patent/DK159652C/da not_active IP Right Cessation
- 1985-11-14 AR AR85302272A patent/AR242767A1/es active
- 1985-11-14 EP EP85114493A patent/EP0182298B1/de not_active Expired
- 1985-11-14 FI FI854492A patent/FI84599C/fi not_active IP Right Cessation
- 1985-11-14 DE DE8585114493T patent/DE3574587D1/de not_active Expired - Lifetime
- 1985-11-14 AT AT85114493T patent/ATE48412T1/de not_active IP Right Cessation
- 1985-11-14 MC MC851803A patent/MC1709A1/fr unknown
- 1985-11-14 IL IL77052A patent/IL77052A/xx not_active IP Right Cessation
- 1985-11-15 NO NO854576A patent/NO162906C/no unknown
- 1985-11-15 PH PH33060A patent/PH21540A/en unknown
- 1985-11-15 KR KR1019850008546A patent/KR930007993B1/ko not_active Expired - Fee Related
- 1985-11-15 IE IE287585A patent/IE58851B1/en not_active IP Right Cessation
- 1985-11-15 JP JP60255154A patent/JPS61122237A/ja active Granted
- 1985-11-15 ES ES548910A patent/ES8801198A1/es not_active Expired
- 1985-11-15 PT PT81502A patent/PT81502B/pt not_active IP Right Cessation
- 1985-11-15 HU HU854361A patent/HU194162B/hu not_active IP Right Cessation
- 1985-12-09 AU AU50898/85A patent/AU588012B2/en not_active Ceased
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