EP0874813A1 - 24-homo-26,27-hexafluoro-cholecalciferols - Google Patents
24-homo-26,27-hexafluoro-cholecalciferolsInfo
- Publication number
- EP0874813A1 EP0874813A1 EP96934788A EP96934788A EP0874813A1 EP 0874813 A1 EP0874813 A1 EP 0874813A1 EP 96934788 A EP96934788 A EP 96934788A EP 96934788 A EP96934788 A EP 96934788A EP 0874813 A1 EP0874813 A1 EP 0874813A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- formula
- accordance
- treatment
- homo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 107
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 14
- 239000001257 hydrogen Substances 0.000 claims abstract description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 11
- 230000003463 hyperproliferative effect Effects 0.000 claims abstract description 11
- 208000017520 skin disease Diseases 0.000 claims abstract description 11
- 201000004681 Psoriasis Diseases 0.000 claims abstract description 10
- 201000010099 disease Diseases 0.000 claims abstract description 10
- 230000001613 neoplastic effect Effects 0.000 claims abstract description 9
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 8
- 230000004069 differentiation Effects 0.000 claims abstract description 8
- 208000032839 leukemia Diseases 0.000 claims abstract description 8
- 230000035755 proliferation Effects 0.000 claims abstract description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 6
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 5
- 201000011510 cancer Diseases 0.000 claims abstract description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 5
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims description 24
- 239000011647 vitamin D3 Substances 0.000 claims description 17
- 229940021056 vitamin d3 Drugs 0.000 claims description 17
- 239000000543 intermediate Substances 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000001939 inductive effect Effects 0.000 claims 3
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 230000005764 inhibitory process Effects 0.000 abstract description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 239000012267 brine Substances 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 14
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 14
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 229940093499 ethyl acetate Drugs 0.000 description 13
- 235000019439 ethyl acetate Nutrition 0.000 description 13
- 229910052938 sodium sulfate Inorganic materials 0.000 description 13
- 235000011152 sodium sulphate Nutrition 0.000 description 13
- 239000012043 crude product Substances 0.000 description 12
- 238000003818 flash chromatography Methods 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 235000019441 ethanol Nutrition 0.000 description 11
- 229940126062 Compound A Drugs 0.000 description 10
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 10
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
- -1 for example Chemical group 0.000 description 10
- 239000000284 extract Substances 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 7
- 238000002953 preparative HPLC Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
- 230000000699 topical effect Effects 0.000 description 6
- 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 5
- JPXMTWWFLBLUCD-UHFFFAOYSA-N nitro blue tetrazolium(2+) Chemical compound COC1=CC(C=2C=C(OC)C(=CC=2)[N+]=2N(N=C(N=2)C=2C=CC=CC=2)C=2C=CC(=CC=2)[N+]([O-])=O)=CC=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=C([N+]([O-])=O)C=C1 JPXMTWWFLBLUCD-UHFFFAOYSA-N 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 239000006208 topical dosage form Substances 0.000 description 5
- 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 4
- 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 4
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 4
- 206010004146 Basal cell carcinoma Diseases 0.000 description 4
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 4
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- 206010020649 Hyperkeratosis Diseases 0.000 description 4
- 208000001126 Keratosis Diseases 0.000 description 4
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 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 4
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 4
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 4
- 239000011736 potassium bicarbonate Substances 0.000 description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 4
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 4
- 229910000077 silane Inorganic materials 0.000 description 4
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 4
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- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 235000005282 vitamin D3 Nutrition 0.000 description 4
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 3
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 229920001214 Polysorbate 60 Polymers 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000000010 aprotic solvent Substances 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
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- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 description 3
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- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 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
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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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- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
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- WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 description 1
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
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- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
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- 238000002474 experimental method Methods 0.000 description 1
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- 239000000796 flavoring agent Substances 0.000 description 1
- 150000002221 fluorine Chemical class 0.000 description 1
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- 239000003349 gelling agent Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
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- 229940075507 glyceryl monostearate Drugs 0.000 description 1
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- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
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- 229940125396 insulin Drugs 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
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- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
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- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
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- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
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- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- PHEDXBVPIONUQT-RGYGYFBISA-N phorbol 13-acetate 12-myristate Chemical compound C([C@]1(O)C(=O)C(C)=C[C@H]1[C@@]1(O)[C@H](C)[C@H]2OC(=O)CCCCCCCCCCCCC)C(CO)=C[C@H]1[C@H]1[C@]2(OC(C)=O)C1(C)C PHEDXBVPIONUQT-RGYGYFBISA-N 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000059 polyethylene glycol stearate Polymers 0.000 description 1
- 229940068917 polyethylene glycols Drugs 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000019254 respiratory burst Effects 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 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
- 235000013874 shellac Nutrition 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
Classifications
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- 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
Definitions
- the invention relates to a compound of the formula
- A is a carbon double bond having the stereochemical configuration E or Z, i.e. of the formula:
- Compounds of formula I induce differentiation and inhibition of proliferation in certain skin and cancer cell lines. Accordingly, the compounds of formula I are useful as agents for the treatment of hyperproliferative skin diseases such as, psoriasis. Compounds of formula I are also useful as agents for the treatment of neoplastic diseases, such as leukemia.
- lower alkyl denotes a straight or branched-chain alkyl group containing 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like.
- ar-lower alkyl are p-tolyl, benzyl, phenylethyl, phenylpropyl, and the like.
- aryl denotes a group derived from an aromatic hydrocarbon which may be unsubstituted or substituted by one or more lower alkyl groups. Exemplary of "aryl” are phenyl and p-methyl phenyl.
- halogen denotes the halogens, that is, bromine, chlorine, fluorine, or iodine.
- the invention relates to a composition
- a composition comprising a compound of formula I, or a mixture of two or more compounds of formula I.
- the invention also relates to a method for treating the above ⁇ mentioned disease states by administration of a compound of formula I, or a mixture of two or more compounds of formula I.
- the invention also relates to a process for preparing compounds of formula I and intermediates of formulas X, XI, XII and V.
- Rl and A are as described above and R4 and R6 are independently lower alkyl and R-5 is independently lower alkyl, aryl, or ar-lower alkyl.
- Ph is phenyl
- Rl , R ⁇ , R5 and R'S are as described above
- R ⁇ is hydrogen, fluorine or
- R ⁇ , R-5 and R ⁇ are as described above.
- the reaction is carried out at -60°C to - 90°C, preferably -78°C, in a polar, aprotic, organic solvent, such as dry ether or more preferably dry tetrahydrofuran, in the presence of a strong base such as an alkyl lithium like butyl lithium.
- a polar, aprotic, organic solvent such as dry ether or more preferably dry tetrahydrofuran
- the protecting groups of a compound of formula IVa, IVb or IVc are removed by reaction with a fluorine salt, such as tetrabutyl- ammonium fluoride in a polar, organic solvent such as ether, or more preferably tetrahydrofuran to yield a corresponding compound of formula Ia, Ib or Ic.
- a fluorine salt such as tetrabutyl- ammonium fluoride
- a polar, organic solvent such as ether
- tetrahydrofuran to yield a corresponding compound of formula Ia, Ib or Ic.
- the compound of formula V is partially hydrogenated to obtain the corresponding compound of formula VI by reaction with a reducing agent such as lithium aluminum hydride, preferably in the presence of an alkali metal alkoxide, like sodium methoxide, in an aprotic organic solvent like dry ether, or more preferably dry tetrahydrofuran, at reflux temperature (about 80°C for tetrahydrofuran) for about 2.5 hours, cooled to about 0°C, and worked up by conventional means.
- a reducing agent such as lithium aluminum hydride
- an alkali metal alkoxide like sodium methoxide
- an aprotic organic solvent like dry ether, or more preferably dry tetrahydrofuran
- the resulting compound of formula VI is oxidized to the compound of formula VII by treatment with an oxidizing agent such as 2,2'-bipyridinium chlorochromate, or pyridinium dichromate, at room temperature, in an aprotic solvent such as dry tetrahydrofuran, or more preferably, dry methylene chloride.
- an oxidizing agent such as 2,2'-bipyridinium chlorochromate, or pyridinium dichromate
- the compound of formula VII is converted to a compound of formula II, by reaction with, for example, a (trialkylsilyl)imidazole such as (trimethylsilyl)imidazole in an aprotic, organic solvent such as dry tetrahydrofuran, or more preferably, dry methylene chloride.
- a (trialkylsilyl)imidazole such as (trimethylsilyl)imidazole in an aprotic, organic solvent such as dry tetrahydrofuran, or more preferably, dry methylene chloride.
- the compound of formula II is worked up by conventional means such as extraction followed by chromatography.
- the compound of formula VIII a known compound (Wovkulich, P.M. et al., Proceedings of the 6th Workshop of Vitamin D, 1985, p. 755-764), is converted to a compound of formula IX by treatment with an oxidizing agent, such as, 2,2'-bipyridinium chlorochromate, or pyridinium chlorochromate, in an aprotic solvent such as dry tetrahydrofuran, or more preferably, dry methylene chloride under an argon atmosphere.
- an oxidizing agent such as, 2,2'-bipyridinium chlorochromate, or pyridinium chlorochromate
- an aprotic solvent such as dry tetrahydrofuran, or more preferably, dry methylene chloride under an argon atmosphere.
- the compound of formula IX is converted to a compound of formula X by reaction with Wittig reagent, such as, (3-trimethyl-silyl- 2-propynyl)-triphenyl-phosphonium bromide, in an aprotic solvent, such as dry tetrahydrofuran or dry methylene chloride, and a base such as butylithium.
- Wittig reagent such as, (3-trimethyl-silyl- 2-propynyl)-triphenyl-phosphonium bromide
- an aprotic solvent such as dry tetrahydrofuran or dry methylene chloride
- a base such as butylithium
- the compound of formula X is converted to a compound of formula XI by reaction with silver nitrate in a alcohol solvent, such as ethanol .
- the compound of formula XI is converted to the compound of formula XII by reaction with a fluorinated acetone, such as hexafluoroacetone.
- a fluorinated acetone such as hexafluoroacetone.
- the reaction is carried out at -78° C.
- the compound of formula XII is converted to the compound of formula V by reaction with a disilylating reagent, such as hydrofluoric acid, in an organic solvent, such as a combination of acetonitrile and te trah ydrofuran .
- a disilylating reagent such as hydrofluoric acid
- the compounds of formula I as described above can be administered orally, for the treatment of neoplastic diseases such as leukemia, to warmblooded animals which need such treatment. More specifically, the compounds of formula I as described above can be administered orally to an adult human in dosages that are in the range of about .05 to 50 ⁇ g per day for the treatment of neoplastic diseases such as leukemia.
- the compounds of formula I as described above can be administered orally, for the treatment of hyperproliferative skin diseases such as psoriasis, basal cell carcinomas, disorders of keratination, and keratosis, to warmblooded animals which need such treatment. More specifically, the compounds of formula I as described above can be administered orally to an adult human in dosages that are in the range of about 0.5 to 50 ⁇ g per day for the treatment of hyperproliferative skin diseases such as psoriasis, basal cell carcinomas, disorders of keratinization, and keratosis. These compounds can be administered orally for the treatment of acne in humans at a dosage of about .05 to 50 ⁇ g per day; preferably 0.5 to 50 ⁇ g per day.
- the compounds of formula I as described above can be administered topically, for the treatment of hyperproliferative skin diseases such as psoriasis, basal cell carcinomas, disorders of keratinization, and keratosis, to warmblooded animals which need such treatment. More specifically, the compounds of formula I as described above can be administered topically in dosages that are in the range of about 0.5 to about 50 ⁇ g per gram of topical formulation per day, for the treatment of hyperproliferative skin diseases such as psoriasis, basal cell carcinomas, disorders of keratinization, and keratosis.
- the induction of differentiation of HL-60 cells was assayed by measuring their oxidative burst potential via the reduction of nitrobluetetrazolium (NBT).
- NBT nitrobluetetrazolium
- HL-60 cells were maintained in RPMI 1640 medium supplemented with 10% fetal calf serum (FCS), 2mM L-glutamine, ImM sodium pyruvate, 1 % non-essential amino acids, 50 U/ml penicillin, and 50 ⁇ g/ml streptomycin.
- HL-60 cells (30,000 cells in 90 ⁇ l of supplemented RPMI medium) were seeded into flat-bottomed microliter wells.
- 10 ⁇ l of test compounds listed below in Table I diluted in supplemented RPMI medium were added to the wells to yield final concentrations of between 10" ! and 10 ⁇ 6 M (starting from stock solutions of 10 * 3 M in ethanol, stored at -20°C and protected from light).
- compounds of formula I induce differentiation of HL-60 cells and thereby stop these tumor cells from growing. Accordingly, compounds of formula I are useful in the treatment of neoplastic diseases such as leukemia.
- HaCaT cell line The immortalized human cell line HaCaT was used (originally obtained from N.E. Fusenig, German Cancer Research Center, Heidelberg, Germany). ⁇ H-thymidine incorporation was measured in exponentially growing cultures after 6 days of culture in presence of the test compound.
- Cell culture - HaCaT cells were cultured in a mixture of Dulbecco's Modified Eagle Medium containing 4.5 g glucose and Nutrient Mixture Ham's F12, 3: 1 (v/v).
- This mixture was supplemented with 10% FCS, 2mM L-glutamine, 50 Ul/ml, penicillin, 50 ⁇ g/ml streptomycin, 10 ng/ml EGF, 400 ng/ml hydrocortisone, 8.5 ng/ml cholera toxin, and 5 ng/ml insulin.
- the cells were maintained in a humidified atmosphere containing 5% CO2 and 95% air and passaged every 3-4 days.
- compounds of formula I inhibit proliferation of keratinocytes. Accordingly, compounds of formula I are useful in the treatment of hyperproliferative skin diseases, such as psoriasis.
- mice 25-30 g body weight received daily subcutaneous administrations of the compound for 4 consecutive days. Body weight was registered just before and at the end of a 5 day treatment period. The "highest tolerated dose” (HTD) is the dose which results in zero weight gain during this treatment period. The results are set forth in Table III.
- Oral dosage forms comprising compounds of formula I of the invention may be incorporated in capsules, tablets and the like with pharmaceutically acceptable carrier materials.
- Illustrative of the pharmaceutically acceptable carrier materials which may be incorporated into capsules, and the like are the following: a binder such as gum tragacanth, acacia, corn starch, or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, algenic acid, and the like; a lubricant such as magnesium stearate, a sweetening agent such as sucrose, lactose, or saccharin; a flavoring agent such as peppermint, oil of wintergreen or cherry.
- a binder such as gum tragacanth, acacia, corn starch, or gelatin
- an excipient such as dicalcium phosphate
- a disintegrating agent such as corn starch, potato starch, algenic acid, and the like
- a lubricant such as magnesium stearate
- a sweetening agent such as sucrose, lactose, or saccharin
- a flavoring agent such as pepper
- Topical dosage forms comprising compounds of formula I of the invention include: ointments and creams encompassing formulations having oleaginous, adsorbable, water-soluble and emulsion-type bases such as petrolatum, lanolin, polyethylene glycols and the like.
- Lotions are liquid preparations and vary from simple solutions to aqueous or hydroalcoholic preparations containing finely divided substances.
- Lotions can contain suspending or dispersing agents, for example, cellulose derivatives such as ethyl cellulose, methyl cellulose, and the like; gelatin or gums, which incorporate the active ingredient in a vehicle made up of water, alcohol, glycerin and the like.
- Gels are semi-solid preparations made by gelling a solution or suspension of the active ingredient in a carrier vehicle.
- the vehicles which can be hydrous or anhydrous, are gelled using a gelling agent, such as, carboxy polymethylene, and neutralized to a proper gel consistency with the use of alkalies, such as, sodium hydroxide and amines, such as, polyethylenecocoamine.
- a gelling agent such as, carboxy polymethylene
- alkalies such as, sodium hydroxide and amines, such as, polyethylenecocoamine.
- topical denotes the use of the active ingredient, incorporated in a suitable pharmaceutical carrier, and applied at the site of the inflammation for the exertion of local action.
- the topical composition include those pharmaceutical forms in which the compound is applied externally by direct contact with the skin.
- the topical dosage forms comprise gels, creams, lotions, ointments, powders, aerosols and other conventional forms for applying medication to the skin obtained by admixing the compounds of formula I with known pharmaceutical topical carrier materials.
- the topical compositions of this invention can also be employed in the treatment of inflammations of mucous membranes, where such membranes are accessible to topical application of medication.
- the topical composition can be applied to the mucous lining of the mouth or lower colon.
- the reaction mixture was filtered through a celite pad and the pad was washed with hexane.
- the combined filtrates were washed with dilute acid, brine, 2N potassium bicarbonate and water, dried over sodium sulfate and evaporated to dryness.
- the crude product was recrystallized from hexane.
- the first crop and mother liquors were separately purified by preparative HPLC with hexane-ethyl acetate 3: 1. Ultimately 220 mg (56% of the title compound was obtained, mm.p.
- BHT Butylated Hydroxytoluene
- Polysorbate 60 (Tween 60) 1 .00
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Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US712595P | 1995-10-31 | 1995-10-31 | |
US7125P | 1995-10-31 | ||
PCT/EP1996/004592 WO1997016423A1 (en) | 1995-10-31 | 1996-10-23 | 24-homo-26,27-hexafluoro-cholecalciferols |
Publications (1)
Publication Number | Publication Date |
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EP0874813A1 true EP0874813A1 (en) | 1998-11-04 |
Family
ID=21724362
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP96934788A Withdrawn EP0874813A1 (en) | 1995-10-31 | 1996-10-23 | 24-homo-26,27-hexafluoro-cholecalciferols |
Country Status (9)
Country | Link |
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EP (1) | EP0874813A1 (ko) |
JP (1) | JPH10512297A (ko) |
KR (1) | KR19990067173A (ko) |
CN (1) | CN1201452A (ko) |
AU (1) | AU7297496A (ko) |
CA (1) | CA2235584A1 (ko) |
MX (1) | MX9803345A (ko) |
WO (1) | WO1997016423A1 (ko) |
ZA (1) | ZA968953B (ko) |
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CN114276284A (zh) * | 2021-12-30 | 2022-04-05 | 正大制药(青岛)有限公司 | 一种氟骨化醇的制备方法 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
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GB8915770D0 (en) * | 1989-07-10 | 1989-08-31 | Leo Pharm Prod Ltd | Chemical compounds |
US5206230A (en) * | 1991-06-05 | 1993-04-27 | Daikin Industries, Ltd. | Fluorine-containing vitamin D3 analogues and pharmaceutical composition containing the same |
EP0972762B1 (en) * | 1993-07-09 | 2003-10-01 | Laboratoire Theramex | Novel structural analogues of vitamin D |
-
1996
- 1996-10-23 JP JP9517038A patent/JPH10512297A/ja active Pending
- 1996-10-23 EP EP96934788A patent/EP0874813A1/en not_active Withdrawn
- 1996-10-23 CA CA002235584A patent/CA2235584A1/en not_active Abandoned
- 1996-10-23 KR KR1019980703124A patent/KR19990067173A/ko not_active Application Discontinuation
- 1996-10-23 AU AU72974/96A patent/AU7297496A/en not_active Abandoned
- 1996-10-23 CN CN96198019A patent/CN1201452A/zh active Pending
- 1996-10-23 WO PCT/EP1996/004592 patent/WO1997016423A1/en not_active Application Discontinuation
- 1996-10-24 ZA ZA968953A patent/ZA968953B/xx unknown
-
1998
- 1998-04-28 MX MX9803345A patent/MX9803345A/es unknown
Non-Patent Citations (1)
Title |
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See references of WO9716423A1 * |
Also Published As
Publication number | Publication date |
---|---|
WO1997016423A1 (en) | 1997-05-09 |
ZA968953B (en) | 1997-07-30 |
KR19990067173A (ko) | 1999-08-16 |
JPH10512297A (ja) | 1998-11-24 |
MX9803345A (es) | 1998-09-30 |
CN1201452A (zh) | 1998-12-09 |
AU7297496A (en) | 1997-05-22 |
CA2235584A1 (en) | 1997-05-09 |
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