CA2235584A1 - 24-homo-26,27-hexafluoro-cholecalciferols - Google Patents
24-homo-26,27-hexafluoro-cholecalciferols Download PDFInfo
- Publication number
- CA2235584A1 CA2235584A1 CA002235584A CA2235584A CA2235584A1 CA 2235584 A1 CA2235584 A1 CA 2235584A1 CA 002235584 A CA002235584 A CA 002235584A CA 2235584 A CA2235584 A CA 2235584A CA 2235584 A1 CA2235584 A1 CA 2235584A1
- Authority
- CA
- Canada
- 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.)
- Abandoned
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 106
- 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
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
- 208000032839 leukemia Diseases 0.000 claims abstract description 7
- 230000035755 proliferation Effects 0.000 claims abstract description 7
- 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 16
- 229940021056 vitamin d3 Drugs 0.000 claims description 16
- 239000000543 intermediate Substances 0.000 claims description 7
- 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 3
- 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 32
- 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
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 17
- 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
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 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
- 235000019441 ethanol Nutrition 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 12
- 238000003818 flash chromatography Methods 0.000 description 11
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
- 229940126062 Compound A Drugs 0.000 description 9
- 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 9
- -1 alkyl lithium Chemical compound 0.000 description 9
- 239000000284 extract Substances 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 8
- 101150041968 CDC13 gene Proteins 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
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 125000000217 alkyl group Chemical group 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
- 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
- 238000005160 1H NMR spectroscopy Methods 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
- 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
- 239000002775 capsule Substances 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
- 239000008273 gelatin Substances 0.000 description 4
- 229920000159 gelatin Polymers 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
- 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
- 210000003491 skin Anatomy 0.000 description 4
- 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
- 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 229920001214 Polysorbate 60 Polymers 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 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
- 239000002585 base Substances 0.000 description 3
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 3
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000012894 fetal calf serum Substances 0.000 description 3
- 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
- 230000003780 keratinization Effects 0.000 description 3
- 239000006210 lotion Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 3
- 239000006186 oral dosage form Substances 0.000 description 3
- 239000011736 potassium bicarbonate Substances 0.000 description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 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
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 2
- 241000167854 Bourreria succulenta Species 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 101150065749 Churc1 gene Proteins 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- YFPJFKYCVYXDJK-UHFFFAOYSA-N Diphenylphosphine oxide Chemical compound C=1C=CC=CC=1[P+](=O)C1=CC=CC=C1 YFPJFKYCVYXDJK-UHFFFAOYSA-N 0.000 description 2
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
- 229930182816 L-glutamine Natural products 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- YKFRUJSEPGHZFJ-UHFFFAOYSA-N N-trimethylsilylimidazole Chemical compound C[Si](C)(C)N1C=CN=C1 YKFRUJSEPGHZFJ-UHFFFAOYSA-N 0.000 description 2
- ZMCZBSAOZUPGQD-UHFFFAOYSA-J O[Cr](Cl)(=O)=O.O[Cr](Cl)(=O)=O.C1=CC=NC(C2=CC=CC=N2)=C1 Chemical compound O[Cr](Cl)(=O)=O.O[Cr](Cl)(=O)=O.C1=CC=NC(C2=CC=CC=N2)=C1 ZMCZBSAOZUPGQD-UHFFFAOYSA-J 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 102100038239 Protein Churchill Human genes 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 239000012979 RPMI medium Substances 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 229960000541 cetyl alcohol Drugs 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 235000019693 cherries Nutrition 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229940124274 edetate disodium Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- VBZWSGALLODQNC-UHFFFAOYSA-N hexafluoroacetone Chemical compound FC(F)(F)C(=O)C(F)(F)F VBZWSGALLODQNC-UHFFFAOYSA-N 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- VLQPTWRGZFDXMO-UHFFFAOYSA-N inden-4-one Chemical compound O=C1C=CC=C2C=CC=C12 VLQPTWRGZFDXMO-UHFFFAOYSA-N 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 210000002510 keratinocyte Anatomy 0.000 description 2
- 239000011981 lindlar catalyst Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 235000010241 potassium sorbate Nutrition 0.000 description 2
- 239000004302 potassium sorbate Substances 0.000 description 2
- 229940069338 potassium sorbate Drugs 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229910001961 silver nitrate Inorganic materials 0.000 description 2
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 235000010199 sorbic acid Nutrition 0.000 description 2
- 229940075582 sorbic acid Drugs 0.000 description 2
- 239000004334 sorbic acid Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- LADGBHLMCUINGV-UHFFFAOYSA-N tricaprin Chemical compound CCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCC)COC(=O)CCCCCCCCC LADGBHLMCUINGV-UHFFFAOYSA-N 0.000 description 2
- PBSHVEOONSKWJF-UHFFFAOYSA-M triphenyl(3-trimethylsilylprop-2-ynyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CC#C[Si](C)(C)C)C1=CC=CC=C1 PBSHVEOONSKWJF-UHFFFAOYSA-M 0.000 description 2
- 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 2
- OXIKLRTYAYRAOE-CMDGGOBGSA-N (e)-3-(1-benzyl-3-pyridin-3-ylpyrazol-4-yl)prop-2-enoic acid Chemical compound N1=C(C=2C=NC=CC=2)C(/C=C/C(=O)O)=CN1CC1=CC=CC=C1 OXIKLRTYAYRAOE-CMDGGOBGSA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical class CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- TZEIAPXWECOJGT-UHFFFAOYSA-N 1h-inden-4-ol Chemical compound OC1=CC=CC2=C1C=CC2 TZEIAPXWECOJGT-UHFFFAOYSA-N 0.000 description 1
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 1
- 238000010600 3H thymidine incorporation assay Methods 0.000 description 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical class CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical group OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 102000009016 Cholera Toxin Human genes 0.000 description 1
- 108010049048 Cholera Toxin Proteins 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 229910018557 Si O Inorganic materials 0.000 description 1
- 229910007161 Si(CH3)3 Inorganic materials 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 1
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- 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 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- HVUMOYIDDBPOLL-XGKPLOKHSA-N [2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XGKPLOKHSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000000538 analytical sample Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 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
- 239000011612 calcitriol Substances 0.000 description 1
- 229960005084 calcitriol Drugs 0.000 description 1
- 235000020964 calcitriol Nutrition 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 230000004094 calcium homeostasis Effects 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229940096529 carboxypolymethylene Drugs 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000007958 cherry flavor Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- FNIATMYXUPOJRW-UHFFFAOYSA-N cyclohexylidene Chemical group [C]1CCCCC1 FNIATMYXUPOJRW-UHFFFAOYSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 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
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 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
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 150000002221 fluorine Chemical class 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 229940100242 glycol stearate Drugs 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 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
- 229940039717 lanolin Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 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
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 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
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
- 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
- 235000019271 petrolatum Nutrition 0.000 description 1
- 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
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 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
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 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
- LIVNPJMFVYWSIS-UHFFFAOYSA-N silicon monoxide Inorganic materials [Si-]#[O+] LIVNPJMFVYWSIS-UHFFFAOYSA-N 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
- 238000010998 test method Methods 0.000 description 1
- 229940104230 thymidine Drugs 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a compound of formula (I) wherein A is a carbon double bond having the stereochemical configuration E or Z, i.e. of formula (a) or (b), respectively, R is hydroxy and R1 is hydrogen or =CH2 or R is hydrogen or fluoro and R1 is =CH2. 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.
Description
CA 0223~84 1998-04-22 24-Homo-26.27-hexafluoro-cholecalciferols The invention relates to a compound of the formula '-"~/~ A--C--OH
~ /
3 ~ I
J~, HO R
wherein A is a carbon double bond having the stereochemical configuration E or Z, i.e. of the formula:
/c= c\ or /c= C\
H H H
~0 respectively, R is hydroxy and Rl is hydrogen or =CH2 or R is hydrogen or fluoro and Rl is =CH2-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 leul~emia.
As used herein, the term "lower alkyl" denotes a straight or branched-chain al~yl group containing 1 to 4 carbon atoms, for CA 0223~84 l998-04-22 WO 97/16423 PCT/EP~G~ )2 example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like.
The term "ar-lower alkyl" are p-tolyl, benzyl, phenylethyl, phenylpropyl, and the like. The term "aryl" denotes a group derived from an aromatic hydrocarbon which may be unsubstituted or 5 substituted by one or more lower alkyl groups. Exemplary of "aryl"
are phenyl and p-methyl phenyl. The term "halogen" denotes the halogens, that is, bromine, chlorine, fluorine, or iodine.
The invention relates to a composition comprising a compound o 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.
In a preferred embodiment of the compounds of formula I, R is 20 hydroxy and Rl is =CH2. In another compound of formula I, Rl is hydrogen .
Most preferred compounds of formula I are:
1,25-dihydroxy-22E,24Z-diene-24-homo-26,27-hexafluoro-cholecalciferol;
1,25 -dihydroxy-22E,24E-diene-24-homo-26,27-hexafluoro-cholecalciferol;
1,25-dihydroxy-22E,24Z-diene-24-homo- 19-nor-26,27-hexafluorocholecalciferol;
1,25-dihydroxy-22E,24E-diene-24-homo- 19-nor-26,27-hexafluorocholecalciferol;
1 (x-fluoro-25-hydroxy-22E,24Z-diene-24-homo-26,27-hexafluorocholecalciferol; and 1 a-fluoro-25-hydroxy-22E,24E-diene-24-homo-26,27-hexafluorocholecalciferol .
-WO 971~6423 PCT/EP96/0459Z
The compounds of formula I are prepared as hereafter described, with particular reference to Formula Schemes I-III and the Examples below, by removing the protecting groups of formula -Si(R4,R5,R6) from correspondingly protected compounds..
FORlV~Ul,A SCED3ME I
fF3 R4 ~ A-- f o si--R5 ~> CF3 R6 CF3 ~4 CF3 ~4 CF3 R4 A--C--o-~i-R5 1 l CF3 R6 ~ ~ A--C--O-~:~ R5 ~"",~A--f o-- i- R5 CF3 R6 [~ CF3 R6 R5 Si, o~ R4 ~ R4 ,~ F
I~a R6 R6 IVb R6 IVc CF3 ~ A-- C--OH ~ A I --OH
""'[~ HO "'& HO F
Ia Ib Ic -CA 0223~84 1998-04-22 wherein R1 and A are as described above and R4 and R6 are independently lower alkyl and R5 is independently lower alkyl, aryl, or ar-lower alkyl.
In the above Formula Scheme I, the compound of formula II is ~ converted to a compound of formula IVa, IVb, or IVc by reaction with the corresponding compound of formula Ph2P=O
R5--Si-O""' ~R7 m ~0 where Ph is phenyl; and Rl, R4, R5 and R6 are as described above; R7 is hydrogen, fluorine or Rl4 O--Si--R5 wherein R4, R5 and R6 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 20 preferably dry tetrahydrofuran, in the presence of a strong base such as an alkyl lithium like butyl lithium.
Compounds of formula III are known or can be prepared in accordance with known methods.
2s 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 WO 97/16423 PCT/E~9G,'~ 1~;92 preferably tetrahydrofuran to yield a corresponding compound of formula Ia, Ib or Ic.
The intermediates of formula II as described above are s prepared as hereinafter described with particular reference to Formula Scheme II below.
FORMULA SCHEME II
~,~ CF3 ~ ~ CF3 HO H HO
V VI
CF3 R4 ~ CF3 ~A f--O--Si--R5 " ~A f--OH
ç~ CF3 R6 Ç~ CF3 ~ H O
I O II VII
wherein R4, R5 and R6 are as described above.
In the above Formula Scheme II, when the compounds of formula I, wherein A is /c=c~ are prepared, the compound of H H
5 formula V is reduced to a corresponding compound of formula VI by reaction with hydrogen and Lindlar catalyst in an organic solvent, such as, a combination of ethyl acetate, hexane and ethanol.
CA 0223~84 1998-04-22 WO 97/164Z3 PCT~EP~G~ ;9Z
In the above Formula Scheme II, when the compound of \ _ ~
formula I, wherein A is /c c\ are prepared, the compound of formula V is partially hydrogenated to obtain the corresponding s 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, o cooled to about 0~C, and worked up by conventional means.
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 5 room temperature, in an aprotic solvent such as dry tetrahydrofuran, or more preferably, dry methylene chloride.
The compound of formula VII is converted to a compound of formula II, by reaction with, for example, a (trialkylsilyl)imidazole 20 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.
25The compound of formula V is prepared as hereafter described with particular reference to formula Scheme III below.
-WO 97/16423 pcT/Er~6lo 1 ~s2 FORMULA SCHEME III
CHO
OH ~
t-Bu(CH3)2SiO H t-Bu(CH3)2SiO H
V~ ~
Si(CH3)3 Ç~' ~
H
t-Bu(CH3)2SiO H t-Bu(C~3)2S10 XI X
/~ OH CF3 CF3 ~'~OcHF3 t-Bu(CH3)2SiO HO
V O
In the above Formula Scheme III, 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 CA 0223~S84 1998-04-22 W O 97/16423 PCTrEP~ 9Z
_ 9 _ 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.
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. The reaction is carried out at -78~C.
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. 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 tetrahydrofuran .
The compounds of formula I as described above can be 2s ~ministered orally, for the treatment of neoplastic diseases such as leukemia, to warmblooded ~nim~l~ which need such treatment. More specifically, the compounds of formula I as described above can be ~lministered orally to an adult human in dosages that are in the range of about .05 to 50 11 g per day for the treatment of neoplastic 3 0 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 3s keratination, and keratosis, to warmblooded ~nim~l~ which need such treatment. More specifically, the compounds of formula I as described above can be ~lmini~tered orally to an adult human in dosages that are in the range of about 0.5 to 50 ,u g per day for the treatment of CA 0223~84 1998-04-22 WO 97/16423 PCT/Er~)6/015~2 hyperproliferative skin diseases such as psoriasis, basal cell carcinomas, disorders of keratinization, and keratosis. These compounds can be ~lmini~tered orally for the treatment of acne in humans at a dosage of about .05 to 50 ~lg per day; preferably 0.5 to 50 5 ,u 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 o keratinization, and keratosis, to warmblooded animals which need such treatment. More specifically, the compounds of formula I as described above can be ~-lministered topically in dosages that are in the range of about 0.5 to about 50 llg per gram of topical formulation per day, for the treatment of hyperproliferative skin diseases such as 15 psoriasis, basal cell carcinomas, disorders of keratinization, and keratosis .
The useful activity of compounds o~ formula I as agents for the treatment of neoplastic diseases can be demonstrated by the following 20 test procedures.
HL-60 Cell Differentiation The induction of differentiation of HL-60 cells was assayed by 2s measuring their oxidative burst potential via the reduction of nitrobluetetrazolium (NBT).
HL-60 cells were maintained in RPMI 1640 medium supplemented with 10% fetal calf serum (FCS), 2mM L-glutamine, 30 lmM sodium pyruvate, 1% non-essential amino acids, 50 U/ml penicillin, and 50 ,~Lg/ml streptomycin. HL-60 cells (30,000 cells in 90 ~Ll of supplemented RPMI medium) were seeded into flat-bottomed microliter wells. Immediately after seeding, 10 ~Ll of test compounds listed below in Table I diluted in supplemented RPMI medium were 3s added to the wells to yield final concentrations of between 10- 1 1 and 1 o-6 M (starting from stock solutions of 10-3 M in ethanol, stored at -20~C and protected from light). After 3 days, medium was removed from the wells with a multichannel pipette and replaced with 100 111 CA 0223~84 1998-04-22 WO 97116423 PCT/EP96~0459Z
of NBT solution (1 mg/ml in phosphate buffered saline with 200 nM
phorbol myristate acetate). Following an additional hour incubation at 37~C the NBT solution was removed and 100 ,ul of 10% sodium dodecyl sulfate in 0.01 N HC 1 was added. The amount of the reduced NBT was s quantified photometrically at 540 nm using an automated plate reader. The mean of 3 wells was calculated. S.E.M. were between 5 and 10% . Values were expressed as percent of maximal differentiation achieved with 100- 1000 nM calcitriol in the same experiment. The concentration (nM) leading to 50% of this maximal o value is determined graphically and given in Table I as ED50.
TABLE I
COMPOUND ED50 (nM) 1,25-Dihydroxy-cholecalciferol 6.0 1,25-Dihydroxy-22E,24Z-diene-24- 1.6 homo-26,27-hexafluoro-cholecalciferol 1,25-Dihydroxy-22E,24E-diene-24- 0.9 homo-26,27-hexafluoro-cholecalciferol l 5 From the above results, it can be seen that 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.
The useful activity of compounds of formula I as agents for the treatment of hyperproliferative skin disease can be demonstrated by the following.
Tnhibition of Keratinocytes Proliferation HaCaT cell line - The immortalized human cell line HaCaT was used (originally obtained from N.E. Fusenig, German Cancer Research Center, Heidelberg, Germany). 3 H-thymidine incorporation was ~ measured in exponentially growing cultures after 6 days of culture in presence of the test compound.
CA 0223~84 1998-04-22 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 UI/ml, penicillin, 5 ~O,~Lg/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.
Inhibition of 3 H-thymidine uptake - HaCaT cells (250 cells in 180 ~11 of the supplemented mixture) were seeded into 96-well culture dishes and incubated at 37~C with 5% CO2 and 95% air.
Immediately after seeding, 20 ,ul of test compounds listed below in Table II, diluted in the supplemented mixture containing 1% ethanol, 5 were added to the wells to yield final concentrations of between 10- 9 and 10-6 M (starting from 1 mM stock solutions in ethanol, stored at -20~C and protected from light). After 6 days, 3H-thymidine (5 Ci/mmol) was added to the wells at a concentration of 1 ~lCi/well.
Cells were pulse-labeled for the last 6 hours of the growth period.
20 Cells were then trypsinized for 10 minutes at 37~C under a vigorous agitation and harvested on to a 96-well filter plate using a cell harvester. After drying at 40~C under vacuum for 20-30 minutes, 20 ,ul of scintillator was added and the radioactivity bound to the filters was counted.
Values are expressed as percent of controls (samples without test compound). The concentration leading to 50% of control values is determined graphically and given as IC5 o (inhibitory concentration) in Table II.
CA 0223S~84 1998-04-22 W O 97/16423 PCTAEP~6/Oq5~Z
T~BLE II
COMPOUND IC50 (nM) 1,25 -Dihydroxy-cholecalciferol 55.0 1,25-Dihydroxy-22E,24Z-diene-24-homo- 2.1 26,27-hexafluoro-cholecalciferol 1,25-Dihydroxy-22E,24E-24-homo-diene- 5.1 26,27-hexafluoro-cholecalciferol From the above results, it can be seen that compounds of 5 formula I inhibit proliferation of keratinocytes. Accordingly, compounds of formula I are useful in the treatment of hyperproliferative skin diseases, such as psoriasis.
Calcium tolerance test in mice Profound changes in calcium homeostasis strongly affect the weight development of mice.
Mice (25-30 g body weight) received daily subcutaneous 15 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.
TABLF. III
COMPOUND HTD (llg/kg) 1,25-Dihydroxycholecalciferol 0.5 1,25-Dihydroxy-22E,24Z-24-homo-26,27- 0.4 hexafluoro-cholecalciferol 1,25-Dihydroxy-22E,24Z-24-homo-23E- 0.8 ~ diene-26,27-hexafluoro-cholecalciferol CA 0223~84 1998-04-22 From the above results, it can be seen that the compounds of formula I exhibit approximately the same HTD as 1,25-dihydroxycholecalciferol .
s The following Examples are provided to further describe the invention and are not intended to limit it in any way.
Oral dosage forms comprising compounds of formula I of the invention may be incorporated in capsules, tablets and the like with 0 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 l s 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. Various other materials may be present as coating or to otherwise modify the physical form of the dosage unit.
For instance, tablets may be coated with shellac, sugar, or both. A
syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye, and a flavoring such as cherry or orange flavor.
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, 3 5 and the like; gelatin or gums, which incorporate the active ingredient in a vehicle made up of water, alcohol, glycerin and the like.
CA 0223~584 1998-04-22 W O 97/16423 PCT~EP96104592 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 5 consistency with the use of alkalies, such as, sodium hydroxide and amines, such as, polyethylenecocoamine.
As used herein, the term " topical" denotes the use of the active ingredient, incorporated in a suitable pharmaceutical carrier, and l o applied at the site of the inflammation for the exertion of local action.
Accordingly, 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 15 applying medication to the skin obtained by admixing the compounds of formula I with known pharmaceutical topical carrier materials. In addition to application to the skin, the topical compositions of this invention can also be employed in the treatment of infl~mm~tions of mucous membranes, where such membranes are accessible to topical 20 application of medication. For example, the topical composition can be applied to the mucous lining of the mouth or lower colon.
EXAMPLE I
25 [lR-[la(S*),3a~,4a,7aa]]-4-[[1,1-Dimethylethyl) dimethylsilyl]-oxy] octahydro- ,B ,7a-dimethyl- 1 H-indene- 1 -acetaldehyde To a stirred suspension of 5.37g (25 mmole) of pyridinium chlorochromate in 50 ml of anhydrous methylene chloride under 30 argon atmosphere was added dropwise 3.26 g (10 mmole) of [lR-[ I a(S *),3a,3,4a,7aa]]-4-[[ 1,1 -dimethylethyl)dimethylsilyl]-o xy ] o c tah y dro - ,B ,7 a-dimethyl- 1 H-indene- 1 -ethanol in 15 ml anhydrous methylene chloride. The reaction mixture was stirred for one hour, then diluted with 120 ml of ether, and purified on a 100 g 35 Florosil column tO give 3.04 g (94%) of the title compound. lH-NMR
(CDC13):~0.02 (s,6H, 2CH3), 0.88 (s, 9H, 3CH3), 1.09 (d, 3H, J = 7 Hz, CH3), 4.02 (brm, lH, CH) 9.58 (d, lH, J= 3 Hz, CH).
CA 0223~84 1998-04-22 [lR-[la(lR*,2E),3a~,4a,7aa]]-(1,1-Dimethylethyl) dimethyl-t[octahydro-7a-methyl- 1 -[1 -methyl-5-(trimethylsilyl)-2-penten-4-s ynyl~- 1 H-inden-4-yl]oxy]silane To a stirred suspension of 1 g (2.2 mmole) of (3-trimethylsilyl-2-propynyl)-triphenyl-phosphonium bromide in 20 ml anhydrous tetrahydrofuran at -78~C was added 1.4 ml (2.2 mmole) of 1.6M n-o butyllithium in hexane. After addition was complete, the reactionmixture was warmed up to 40~C, stirred for 0.5 hour when it turned to a red solution. It was then cooled to -78~C and 478 mg (1.47 mmole) of [lR-[laS*), 3a,~, 4a,7aa]]-4-[[(1,1-dimethylethyl)dimethyl-silyl]oxy]octahydro-~,7a-dimethyl-lH-indene-l-acetaldehyde in 6 ml 5 anhydrous tetrahydrofuran was added, then stirred at room temperature for one hour, and quenched by addition of water. It was thoroughly extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over sodium sulfate, and evaporated to dryness. The residue was triturated with hexane and 20 the soluble part was purified by FLASH chromatography with hexane.
It gave 396 mg (64%) of the title compound. Analytical sample was purified by preparative HPLC with hexane, and was crystallized from ethanol, m.p. 81-83~C; [a]25D + 80.5~ (c 0.2) CHCl3); UV~ (hexane):
shoulder 227nm (~17,000, max 236-237 nm (~21,800), shoulder 295 2s nm (~16,600); lH-NMR (CDCl3): ~0.01 (s, 6H, 2CH3), 0.19 (s,9H, 3CH3), 0.89 (s, 9H, 3CH3), 0.93 (s, 3H, CH3), 1.02 (d, 3H, J = 6.7 Hz, CH3), 1.80 (m, lH, CH of CH2), 1.91 (dm, lH, Jgem = 12.5 Hz, CH or CH2), 2.11 (m, lH, CH), 3.99 (m, lH, CH), 5.42 (d, lH, Jtrans = 15.9 Hz, CH), 6.06 (dd, lH, Jvic = 8.8 Hz, Jtrans = 15.9 CH). The structure of this compound 30 was confirmed by an X-ray analysis; Analysis: Calcd for C2SH46osi2: C
71.70, H 11.07; Found: C 71..23; H 11.04.
CA 0223~84 1998-04-22 WO 97/16423 PCT/EF~16~ 5~12 F.X~MPLE 3 [1 R- [ l oc( l R* ,2E), 3a,B ,4a,7 aa] ] -(1,1 -Dimethylethyl) dimethyl-- [ [octahydro-7 a-methyl- 1 - [1 -methyl-2-penten-4-ynyl)- 1 H-inden-4- 5 yl] oxy] silane -To a stirred suspension of 1.5 g (3.58 mmole) of [lR-[la(lR*,2E),3a,B,4cc,7aa]]-(1,1-dimethylethyl)dimethyl-[[octahydro-7a-methyl- 1 - [1 -methyl-5-trimethylsilyl)-2-penten-4-ynyl)- 1 H-inden-4-l o yl] oxy] silane in 9 ml anhydrous tetrahydrofuran and 60 ml ethanol atroom temperature was added dropwise a solution of 3.65 g (21.4 mmole) silver nitrate in 72 ml of 3: 1 ethanol-water., A yellowish-white precipitate developed, and such a formed mixture was stirred for one hour. This was followed by addition of 4.19 g (64.4 mmole) 5 potassium cyanide in 60 ml water, when the precipitate dissolved.
After 0.5 hour t.l.c. indicated that the reaction was complete. The mixture was diluted with SOOml of water and brine (1: 1), and extracted thoroughly with ethyl acetate. The combined extracts were washed with water and brine, dried over sodium sulfate and 20 evaporated to dryness. The crude product was purified by FLASH
chromatography with hexane, followed by preparative HPLC with hexane using a YMC column (50 mm x 50 cm). It have 1.26 g (100%) of the title compound. lH-NMR (CDCl3) ~0.00 (s, 6H, 2CH3), 0.89 (s, 9H, 3CH3), 0.94 (s, 3H, CH3), 1.02 (d, 3H, J = 7Hz, CH3), 2.13 (m, lH, 25 CH), 2.75 (d, lH, J = 2.5 Hz, CH), 3.99 (brs, lH, CH), 5.25 (dd, lH, Jvic =
2.5 Hz, Jtrans = 16 Hz, CH), 6.09 (dd, lH, Jvic = 8 Hz, Jtrans = 16 Hz, C~.
F~xAMpLE 4 [lR-[la(lR*,2E),3a~,4a,7aa]]-7-[4-[[(1,1-Dimethylethyl)-dimethyl-silyl]oxy]octahydro-7a-methyl-lH-inden-l-yl]-l,l,l-trifluoro-2(trifluoromethyl)-5 -octen-3 -yn-2-ol 3s To a stirred solution of 0.91 g (2.63 mmole) of [lR-[la(lR*,2E),3a,~,4a,7aa]]-(1,1-dimethylethyl)dimethyl[[octahydro-7a-methyl- 1 -(1 -methyl-2-penten-4-ynyl)- 1 H-inden-4-yl] oxy] silane in 15 ml anhydrous tetrahydrofuran at -78~C was added 1.65 ml 1.6M n-CA 0223~84 1998-04-22 WO 97/16423 PCT/EP96/0~592 butyllithium in hexane, and the mixture was stirred for 0.5 hour. At this point in time gaseous hexafluoroacetone was introduced by a dispersion tube for 2 minutes, and the reaction mixture was stirred for additional 1.5 hours, when t.l.c. indicated that the reaction was s complete. The reaction mixture was then diluted with 400 ml water and extracted thoroughly with hexane. The combined extracts were washed with water and brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by FLASH
chromatography with hexane-ethyl acetate 19:1 to give 1.27 (95%) of 10 the title compound. lH-NMR (CDCl3) ~0.00 (s, 6H, 2CH3), 0.88 (s, 9H, 3CH3), 1.03 (d, 3H, CH3), 2.18 (m, lH, CH), 4.00 (brs, lH, CH), 5.42 (d, lH, Jtrans = 16 Hz, CH), 6.26 (dd, lH, Jvic = 9 Hz, Jtrans = 16 Hz, CH).
[lR-[la(lR*,2E),3a~,4a,7aa]]-Octahydro-7a-methyl-1-[7,7,7-trifluoro-6-hydroxy- 1 -methyl-6-(trifluoro-methyl)-2-hepten-4-ynyl]- lH-inden-4-ol~
To a stirred solution of 1.648 g (3.21 mmole) of LlR-[1 a( l R*,2E),3a~,4a,7aa]]-7-[4-[[(1,1 -dimethylethyl)-dimethylsilyl]-oxy]octahydro-7a-methyl- 1 H-inden- 1 -yl]- 1,1,1 -trifluoro-2-(trifluoromethyl)-5-octen-3-yn-2-ol in 30 ml acetonitrile and 24 ml anhydrous tetrahydrofuran was added at room temperature 30 ml 49% hydrofluoric acid, and thus obtained reaction mixture was stirred for 3 hours. It was then diluted with 400ml water and extracted thoroughly with ethyl acetate. The combined extracts were washed with 2N potassium bicarbonate and water, and finally with brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by FLASH chromatography with hexane-ethyl acetate 2: 1 the title compound, which was crystallized from ether-petroleum ether (2:25) to give 1.087 g (85%), m.p. 108-109~C; [a~25D +
47~ (c 0.2, CHC13); UV~ (EtOH): max 224 nm (~20,060), shoulder 230-231 nm (~18,600); lH-NMR (CDCl3): ~0.96 (s, 3H, CH3), 1.05 (d, 3H, J =
6.41 Hz, CH3), 1.96 (brd, lH, Jgem = 13 Hz, CH of CH2), 2.19 (m, lH, CH), 4.10 (brs, lH, CH), 5.44 (d, lH, Jtrans = 16Hz, CH), 6.25 (dd, lH, Jvic = 8.9 Hz J trans = 16Hz, CH). Analysis: Calcd. for Cl9H24F6~2:
C57.28, H 6.07; Found: C 57.29, H 6.19.
CA 0223~84 1998-04-22 .
[lR-[la(lR*,2E,4E),3a,~,4a,7aa]]-Octahydro-7a-methyl-1-[7,7,7-5 trifluoro-6-hydroxy- 1 -methyl-6-(trifluoro-methyl)-2,4-heptadienyl]-- 1 H-inden-4-ol]
To a 100 ml three necked flask fitted with a dropping funnel, condenser and argon inlet tube was added 143 mg (3.75 mmole) of 10 lithium aluminum hydride suspended in 1.5 ml anhydrous tetrahydrofuran. The flask was cooled in an ice-bath and with stirring was added carefully first 203 mg (3.75 mmole) of solid sodium methoxide, and then dropwise the solution of 300mg (0.753 mmole) of [lR-[la(lR*,2E),3a,B,4a,7aa]]-Octahydro-7c~-methyl-1-[7,7,7-trifluoro-15 6-hydroxy- 1 -methyl-6-(trifluoromethyl)-2-hepten-4-ynyl]- 1 H-inden-4-ol in 6 ml anhydrous tetrahydrofuran. After addition was completed, the ice-bath was removed, and the reaction mixture was heated under reflux at 80~C for 2.5 hours. It was then cooled in ice-bath, quenched with 1 ml water and 1 ml 2N sodium hydroxide; 20 ml 20 of ether was added, stirred for 0.5 hr., 2.2 g of MgSO4 was added, stirred for 0.5 hr, filtered, filter was washed with ether, and the filtrates were evaporated to dryness. The crude product was purified by preparative HPLC with hexane-ethyl acetate 4: 1, to give, after recrystallization from methylene chloride-hexane mixture, 251 mg 2s (83.2%) of crystalline title compound, m.p. 146-148~C. UV ~max (EtOH): 228-229 nm (~ 32,100); 1H-NMR (CDCl3): ~0.907 (s, 3H, CH3), 1.05 (d, 3H, J = 6.5 Hz, CH3), 1.69 (m, lH, CH), 1.98 (brd, lH, Jgem = 13 Hz, CH of CH2), 2.17 (m, lH, CH), 4.09 (brs, lH, CH), 5.59 (d, lH, Jtrans =
15.4 Hz, CH), 5.79 (dd, lH, Jvic = 8.6 Hz, Jtrans = 15.3 Hz, CH), 6.05 (dd, 30 lH, Jvic = 10.5 Hz, Jtrans = 15.3 Hz, CH), 6.68 (dd, lH, Jvic = 10.6 Hz, Jtrans = 15.3 Hz, CH). Analysis: Calcd. for C1gH26F6O2: C 56.99, H
6.55; Found C 56.64, H 6.41.
CA 0223~84 1998-04-22 WO 97/16423 PCT/EP~6/0~92 [lR-[la(lR*,2E,4E),3a,B,7aa]]-Octahydro-7a-methyl-1-[7,7,7-trifluoro-6-hydroxy- 1 -methyl-6-(trifluoro-methyl)-2,4-heptadienyl]-4H- -s inden-4-one To a stirred solution of 300 mg (0.75 mmole) of [1 R-[la(lR*,2E,4E),3a,B,4a,7aa]]-octahydro-7a-methyl-1-[7,7,7-trifluoro-6-hydroxy- 1 -methyl-6-(trifluoromethyl)-2,4-heptadienyl]-4H-inden-4-o ol in 15 ml anhydrous methylene chloride was added 1.465 g (3.9mmole) pyridinium dichromate, and stirred at room temperature for 3.5 hours. After addition of 25 ml ether and stirring for 15 minutes, the mixture was filtered through a celite pad, which was washed with 3 x 25 ml ethyl acetate. The combined filtrates were washed with 2N
5 potassium bicarbonate, water and brine, dried over sodium sulfate, and evaporated to dryness. The crude product was purified by FLASH
chromatography with hexane-ethyl acetate 3: 1 to give 267 mg (89.5%) of the title compound. 1H-NMR (CDC13): ~0.66 (s, 3H, CH3), 1.08 (d, 3H, J = 6.5 Hz, CH3), 2.46 (dd, lH, J = 8 and 11 Hz, CH) 5.58 (d, lH, Jtrans =
20 15 Hz, CH), 5.77 (dd, lH, Jvic = 8.5 Hz, Jtrans = 15 Hz, CH), 6.04 (dd, lH, Jvic = 10.5 Hz, Jtrans = 15 Hz, CH), 6.68 (dd, lH, Jvic = 10.5 Hz, Jtrans =
15 Hz, CH).
F.XAMPLE 8 2s [lR-[la(lR*,2E,4E),3a,B,7aa]]-Octahydro-7a-methyl-1-[7,7,7-trifluoro-1 -methyl-6-(trifluoromethyl)-6-[(trimethylsilyl)oxy]-2,4-heptadienyl] -4H-inden-4-one To a stirred solution of 267 mg (0.67 mmole) of [lR-[1 a(1 R*,2E,4E),3a,B,7aa]]-octahydro-7a-methyl- 1 -[7,7,7-trifluoro-6-hydroxy- 1 -methyl-6-(trifluoromethyl)-2,4-heptadienyl]-4H-inden-4-one in 10 ml anhydrous methylene chloride was added 0.885ml (6.03 mmole) of 1-(trimethyl-silyl)imidazole and stirred at room temperature overnight. The reaction was then quenched by addition of water, and was extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over sodium sulfate, and evaporated to dryness. The crude product was purified by FLASH
CA 0223~S84 1998-04-22 W O 97/16423 PCT~EF96~ 92 chromatography with hexane-ethyl acetate 5: 1 to give 307 mg (97.3%) of the title compound. 1H-NMR (CDC13): ~0.20 (s, 9H, 3CH3), 0.66 (s, 3H, CH3), 1.10 (d, 3H, J = 6.5 Hz, CH3), 2.45 (dd, lH, J = 8 and 11 Hz, CH
of CH2), 5.55 (dd, lH, Jtrans = 15 Hz, CH), 5.73 (dd, lH, Jvic = 8.5 Hz, 5 Jtrans = 15 Hz, CH), 6.01 (dd, lH, Jvic = 10 Hz, Jtrans = 15 Hz, CH), 6.51 - (dd, lH, Jvic = 10 Hz, Jtrans = 15 Hz, CH).
o 1,25-Dihydroxy-22E,24E-diene-26,27-hexafluoro-24-homo-cholecalciferol To a stirred solution of 0.608 g (1.04 mmole) of [3S-(lZ,3a,5,B)]-[2-[3,5-bis[[( l, l -dimethylethyl)dimethylsilyl]oxy]-2-methylene-1S cyclohexylidene]ethyl]diphenylphosphine oxide in 10 ml anhydroustetrahydrofuran at -78~C was added 0.652 ml (1.04 mmole) of 1.6M
n-butyllithium in hexane. The solution turned red and the color persisted during the entire addition of 307 mg (0.652 mmole) of [1 R-[1 a( l R*,2E,4E),3a~,7aa]]-octahydro-7a-methyl- 1 -[7,7,7-trifluoro- 1 -20 methyl-6-(trifluoromethyl)-6-[(trimethylsilyl)oxy]-2,4-heptadienyl]-4H-inden-4-one in 8 ml anhydrous tetrahydrofuran. The reaction mixture was stirred at -78~C for 0.5 hr and then quenched with water.
It was extracted with 4 x 50 ml ethyl acetate. The combined extracts were washed with water and brine, dried over sodium sulfate and 2s evaporated to dryness. The crude product was purified by FLASH
chromatography with hexane-ethyl acetate 10: 1 to give 337 mg of trisilylated intermediate.
To the solution of 337 mg of trisilylated intermediate in 8 ml 30 anhydrous tetrahydrofuran stirred at room temperature under argon was added in portions 3 ml (3 mmole) of 1 M tetrabutyl ammonium fluoride in tetrahydrofuran. The reaction mixture was stirred overnight, then diluted with water and extracted with ethyl acetate.
The combined extracts were washed with water and brine, dried over 35 sodium sulfate and evaporated to dryness . The crude product was purified by FLASH chromatography with hexane-ethyl acetate 1 :3, and preparative HPLC with hexane-ethyl acetate 1 :4 to give 235 mg (67.4%) of the title compound as white foam, [a]25D + 64.5~ (c0.2, CA 0223~84 1998-04-22 W O 97/16423 PCT/E~96/04592 EtOH); UV ~max (EtOH): 229 nm (~ 40,500), 262-263 nm (~ 17,600);
lH-NMR (CDC13): ~0.57 (s, 3H,CH3), 1.08 (d, 3H, J= 6.5 Hz, CH3) 2.18 (m, lH, CH), 2.32, 2.60 (AB of ABX, 2H, Jvic = 6.5 and 3 Hz, Jgem = 13 Hz, CH2), 2.83 (brdd, lH, Jgem = 12.5 Hz, CH of CH2), 4.23 (brm, lH, CH), 5 4.44 (brm, lH, CH), 5.00, 5.23 (2s, 2H, CH2), 5.60 (d, lH, Jtrans = 15.5 Hz, CH), 5.82 (dd, lH, Jvic = 9 Hz, Jtrans = 15 Hz, CH), 6.01, 6.36 (AB, 2H, Jvic = 11 Hz, CHCH), 6.05 (dd, lH, Jvic = 10.5 Hz, Jtrans = 15 Hz, CH), 6.69 (dd, lH, Jvic = 10.5 Hz, Jtrans = 15.5 Hz, CH). Analysis:
Calcd:. for C2gH36F6O3: C 62.91, H 6.79; Found C 61.83, H 7.02 E~XAMPLE 10 [lR-[la(lR*,2E,4Z),3a,B,7aa]]-Octahydro-7a-methyl-1-[7,7,7-trifluoro-6-hydroxy- 1 -methyl-6-(trifluoro-methyl)-2,4-heptadienyl] - 1 H-I ~ inden-4-ol]
The mixture of 392 mg (0.98 mmole) of [lR-tla(lR*,2E) 3a~,4a,7aa]]-octahydro-7a-methyl- 1 -[7,7,7-trifluoro-6-hydroxy- 1 -methyl-6-(trifluoromethyl)-2-hepten-4-ynyl]- 1 H-inden-4-ol], 5 ml 20 ethylacetate, 12.5 ml hexane, 0.35 ml absolute ethanol, 0.017 ml quinoline and 63 mg Lindlar catalyst (5% Pd on CaC03) was hydrogenated for 2 hrs at 1 atm. and room temperature. The reaction mixture was filtered through a celite pad and the pad was washed with hexane. The combined filtrates were washed with dilute acid, 25 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.
30 140-141~C; UV ~max (EtOH): 231-232 nm (~ 30,600); lH-NMR (CDC13):
~0.97 (s, 3H, CH3), 1.05 (d, 3H, J = 6.7 Hz, CH3) 1.98 (brd, lH, Jgem = 13 Hz, CH of CH2), 2.21 (m, lH, CH), 4.08 (brs, lH, CH), 5.25 (d, lH, Jcis =
11.5 Hz, CH), 5.75 (dd, lH, Jvic = 8.8 Hz, Jtrans = 15 Hz, CH), 6.43 (t, lH, Jvic and Jcis = 11.5 Hz, CH), 6.71 (dd, lH, Jvic = 11.5 Hz, Jtrans = 15 Hz, 3s CH). Analysis: Calcd. for ClgH26F6O2: C 56.99, H 6.55; Found: C 57.03, H 6.69 CA 0223~84 1998-04-22 WO 97/16423 PCT/EF96/'~ 15~2 F~AMPLE 11 [lR-[la(lR*,2E,4Z),3a~,7aa]]-Octahydro-7a-methyl-1-r7,7,7-trifluoro-6-hydroxy- 1 -methyl-6-(trifluoro-methyl)-2,4-heptadienyl]-4H-5 inden-4-one To the at room temperature stirred soluton of 202 mg (0.52 mmole) [lR-[la(lR*,2E,4Z),3a,B,4a,7aa]]-octahydro-7a-methyl-1-[7,7,7-trifluoro-6-hydroxy- 1 -methyl-6-(trifluoromethyl)-2,4-10 heptadienyl]-lH-inden-4-ol in 10 ml anhydrous methylene chloride was added 886 mg (2.36 mmole) pyridinium dichromate, and stirred for 0.5 hr. Then 25 ml of ether was added, stirred for 15 minutes, and filtered through a celite pad. The pad was washed with 3 x 25 ml ethyl acetate. The combined filtrates were washed with 2N potassium 5 bicarbonate, water and brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by FLASH
chromatography with methylene chloride-ethyl acetate 20: 1 to give 196 mg (96%) of the title compound. lH-NMR (CDC13): ~0.67 (s, 3H, CH3), 1.10 (d, lH, J = 6.5 Hz, CH3), 2.45 (dd, lH, J = 8 and 11 Hz, CH), 20 5.26 (d, lH, Jcis = 11.5 Hz, CH), 5.76 (dd, lH, Jvic = 8.5 Hz, Jtrans = 15 Hz, CH), 6.43 (t, lH, Jvic and Jcis = 11.5 Hz, CH), 6.73 (dd, lH, Jvic =
11.5 Hz, Jtrans = 15 Hz, CH).
F.~AMPLE 12 2s [lR-[la(lR*,2E,4Z),3a~,7aa]]-Octahydro-7a-methyl-1-[7,7,7-trifluoro-1 -methyl-6-(trifluoromethyl)-6-[(trimethylsilyl)oxy]-2,4-heptadienyl] -4H-inden-4-one To a stirred solution of 196 mg (0.49 mmole) [lR-[la(lR*,2E, 4Z),3 a~ ,7 aa] ] -octahydro-7 a-methyl- 1 - [7,7,7 -trifluoro-6-hydro xy- 1 -methyl-6-(trifluoromethyl)-2,4-heptadienyl]-4H-inden-4-one in 10 ml anhydrous methylene chloride under argon was added 0.67 ml (4.42 mmole) of l-(trimethylsilyl)-imidazole, and thus was obtained reaction mixture was stirred at room temperature overnight. It was then diluted with ethyl acetate, washed with water and brine, dried CA 0223~84 1998-04-22 over sodium sulfate and evaporated to dryness. The crude product was purified by FLASH chromatography with hexane-ethyl acetate 5:1 to give 229 mg (99%) of the title compound.
s ~XAMPLE~ 13 1 ,25-Dihydroxy-22E,24Z-diene-26,27-hexafluoro-24-homo-cholecalciferol To a stirred solution of 467 mg (0.80 mmole) of [3S-(lZ,3a,5~)]-[2-[3,5-bis[[( 1,1 -dimethylethyl)dimethylsilyl]-oxy]-2-methylene-cyclohexylidene]ethyl]diphenylphosphine oxide in 10 ml anhydrous tetrahydrofuran at -78~C was added 0.5 ml (0.80 mmole) of 1.6M n-butyllithium in hexane. The solution turned red and the color persisted during the entire addition of 229 mg (0.486 mmole) of [lR-[ 1 a( 1 R* ,2E,4Z),3a~ ,7aa]]-octahydro-7a-methyl- 1 -[7,7,7-trifluoro- 1-methyl-6-(trifluoromethyl)-6-[(trimethylsilyl)oxy]-2,4-heptadienyl]-4H-inden-4-one in 8 ml anhydrous tetrahydrofuran. The reaction mixture was stirred at -78~C for 1.5 hrs and quenched with water. It o was extracted thoroughly with ethyl acetate . The combined extracts were washed with water and brine, dried over sodium sulfate and evaporated to dryness. The crude residue was purified by FLASH
chromatography with hexane-ethyl acetate 10:1. This gave 310 mg of the trisilylated intermediate.
To the solution of 310 mg of trisilylated intermediate in 8 ml anhydrous tetrahydrofuran stirred at room temperature under argon was added in portions 4.5 ml of 1 M tetrabutyl ammonium fluoride in tetrahydrofuran. The reaction mixture was stirred for 48 hrs, then diluted with water and extracted thoroughly with ethyl acetate. The combined extracts were washed with water and brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified first by FLASH chromatography with hexane-ethyl acetate 1:3, and preparative HPLC with hexane-ethyl acetate 1:4 and then by 3 5 preparative HPLC with hexane-ethyl acetate 1:4 to give 206 mg (79.2%) of the title compound as white foam, ~o~]25D + 17.5~ (c 0.2, EtOH); UV~ (EtOH): max 232-233 nm (~ 38,700), shoulder 265 nm (~17,200); 1H-NMR (CDC13); ~0.57 (s, 3H, CH3), 1.07 (d, 3H, J = 6.5 Hz, CA 0223~84 1998-04-22 CH3), 2.22 (m, lH, CH), 2.32, 2.. 60 (AB of ABX, 2H, Jvic = 6.5 and 3.5 Hz Jgem = 13 Hz, CH2), 2.84 (dd, lH, Jvic = 4Hz, Jgem - 12.5 Hz, CH of CH2), 4.23 (brm, lH, CH), 4.43 (brm, lH, CH), 5.00, 5.33 (2s, 2H, CH2) 5.25 (d, lH, Jcis = 12 Hz, CH), 5.76 (dd, lH, Jvic = 8.5 Hz, Jtrans = 15 5 Hz, CH), 6.02, 6.38 (AB, 2H, Jvic = 11.3 Hz, CHCH), 6.43 (t, lH, ~vic and Jtrans = 12 Hz, CH), 6.71 (dd, lH, Jvic = 12 Hz, Jtrans = 15 Hz, CH).
Analysis: Calcd. for C2gH36F6O3: C 62.91, H 6.79; Found: C 61.73, H
6.74 Oral Dosage Form Soft Gelatin Capsule mg/capsule 1 ,25-dihydroxy-22E,24E-diene-24-homo-26,27-hexafluoro-cholecalciferol0.0005 - 0.050 (Compound A) Butylated Hydroxytoluene (BHT) 0.016 Butylated Hydroxyanisole (BHA) 0.016 Myglyol(~)-8 12 qs 1 6 0 1. Suspend BHT and BHA in Myglyol~)-812. Warm to about 5 0~ C, and stir until dissolved.
2. Dissolve Compound A in the solution from Step 1.
3. Fill the solution from Step 2 in a soft gelatin cap.
All steps are performed under a nitrogen atmosphere and protected from light.
F.XAMPLE 15 Oral Dosage Form Soft Gelatin Capsule mg/cap sule Compound A 0.0005 - 0.050 a-Tocopherol 0.0 16 Myglyol(~)-812 qs 160 s 1 . Suspend a-Tocopherol in Myglyol~-8 12. Warm to about 5 0~ C, and stir until dissolved.
2. Dissolve Compound A in the solution from Step 1.
0 3. Fill the solution from Step 2 in a soft gelatin cap.
All steps are performed under a nitrogen atmosphere and protected from light.
CA 0223~84 1998-04-22 WO 97116423 PCT/EP9~ 5~72 Topical Dosage Form Cream % wlw Compound A0.00005-5.0 Cetyl Alcohol 1 . 5 0 S tearyl Alcohol 2 . 5 0 Sorbitan Monostearate (Span 60) 2.00 Mineral Oil 2 . 0 0 Glyceryl Monostearate and Polyoxyethylene Glycol Stearate 4.00 Blend (Arlacel 165) Polysorbate 60 (Tween 60) 1.00 Caprylic/Capric Triglyceride 5 . 00 Sorbitol Solution 4 . 00 Edetate Disodium 0.10 Butylated Hydroxyanisole (BHA) 0.02 Sorbic Acid 0.20 Potassium Sorbate 0.1 - 0.2 Water q.s. to 100.00 5 1. Stir Compound A until dissolved.
2. Warm mixture of cetyl alcohol, stearyl alcohol, Span 60, mineral oil, Arlacel 165, Tween 60 and BHA to about 70-75~C, to form oily solution.
3. Add solution from Step 1 to solution from Step 2 while mixing.
~ /
3 ~ I
J~, HO R
wherein A is a carbon double bond having the stereochemical configuration E or Z, i.e. of the formula:
/c= c\ or /c= C\
H H H
~0 respectively, R is hydroxy and Rl is hydrogen or =CH2 or R is hydrogen or fluoro and Rl is =CH2-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 leul~emia.
As used herein, the term "lower alkyl" denotes a straight or branched-chain al~yl group containing 1 to 4 carbon atoms, for CA 0223~84 l998-04-22 WO 97/16423 PCT/EP~G~ )2 example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like.
The term "ar-lower alkyl" are p-tolyl, benzyl, phenylethyl, phenylpropyl, and the like. The term "aryl" denotes a group derived from an aromatic hydrocarbon which may be unsubstituted or 5 substituted by one or more lower alkyl groups. Exemplary of "aryl"
are phenyl and p-methyl phenyl. The term "halogen" denotes the halogens, that is, bromine, chlorine, fluorine, or iodine.
The invention relates to a composition comprising a compound o 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.
In a preferred embodiment of the compounds of formula I, R is 20 hydroxy and Rl is =CH2. In another compound of formula I, Rl is hydrogen .
Most preferred compounds of formula I are:
1,25-dihydroxy-22E,24Z-diene-24-homo-26,27-hexafluoro-cholecalciferol;
1,25 -dihydroxy-22E,24E-diene-24-homo-26,27-hexafluoro-cholecalciferol;
1,25-dihydroxy-22E,24Z-diene-24-homo- 19-nor-26,27-hexafluorocholecalciferol;
1,25-dihydroxy-22E,24E-diene-24-homo- 19-nor-26,27-hexafluorocholecalciferol;
1 (x-fluoro-25-hydroxy-22E,24Z-diene-24-homo-26,27-hexafluorocholecalciferol; and 1 a-fluoro-25-hydroxy-22E,24E-diene-24-homo-26,27-hexafluorocholecalciferol .
-WO 971~6423 PCT/EP96/0459Z
The compounds of formula I are prepared as hereafter described, with particular reference to Formula Schemes I-III and the Examples below, by removing the protecting groups of formula -Si(R4,R5,R6) from correspondingly protected compounds..
FORlV~Ul,A SCED3ME I
fF3 R4 ~ A-- f o si--R5 ~> CF3 R6 CF3 ~4 CF3 ~4 CF3 R4 A--C--o-~i-R5 1 l CF3 R6 ~ ~ A--C--O-~:~ R5 ~"",~A--f o-- i- R5 CF3 R6 [~ CF3 R6 R5 Si, o~ R4 ~ R4 ,~ F
I~a R6 R6 IVb R6 IVc CF3 ~ A-- C--OH ~ A I --OH
""'[~ HO "'& HO F
Ia Ib Ic -CA 0223~84 1998-04-22 wherein R1 and A are as described above and R4 and R6 are independently lower alkyl and R5 is independently lower alkyl, aryl, or ar-lower alkyl.
In the above Formula Scheme I, the compound of formula II is ~ converted to a compound of formula IVa, IVb, or IVc by reaction with the corresponding compound of formula Ph2P=O
R5--Si-O""' ~R7 m ~0 where Ph is phenyl; and Rl, R4, R5 and R6 are as described above; R7 is hydrogen, fluorine or Rl4 O--Si--R5 wherein R4, R5 and R6 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 20 preferably dry tetrahydrofuran, in the presence of a strong base such as an alkyl lithium like butyl lithium.
Compounds of formula III are known or can be prepared in accordance with known methods.
2s 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 WO 97/16423 PCT/E~9G,'~ 1~;92 preferably tetrahydrofuran to yield a corresponding compound of formula Ia, Ib or Ic.
The intermediates of formula II as described above are s prepared as hereinafter described with particular reference to Formula Scheme II below.
FORMULA SCHEME II
~,~ CF3 ~ ~ CF3 HO H HO
V VI
CF3 R4 ~ CF3 ~A f--O--Si--R5 " ~A f--OH
ç~ CF3 R6 Ç~ CF3 ~ H O
I O II VII
wherein R4, R5 and R6 are as described above.
In the above Formula Scheme II, when the compounds of formula I, wherein A is /c=c~ are prepared, the compound of H H
5 formula V is reduced to a corresponding compound of formula VI by reaction with hydrogen and Lindlar catalyst in an organic solvent, such as, a combination of ethyl acetate, hexane and ethanol.
CA 0223~84 1998-04-22 WO 97/164Z3 PCT~EP~G~ ;9Z
In the above Formula Scheme II, when the compound of \ _ ~
formula I, wherein A is /c c\ are prepared, the compound of formula V is partially hydrogenated to obtain the corresponding s 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, o cooled to about 0~C, and worked up by conventional means.
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 5 room temperature, in an aprotic solvent such as dry tetrahydrofuran, or more preferably, dry methylene chloride.
The compound of formula VII is converted to a compound of formula II, by reaction with, for example, a (trialkylsilyl)imidazole 20 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.
25The compound of formula V is prepared as hereafter described with particular reference to formula Scheme III below.
-WO 97/16423 pcT/Er~6lo 1 ~s2 FORMULA SCHEME III
CHO
OH ~
t-Bu(CH3)2SiO H t-Bu(CH3)2SiO H
V~ ~
Si(CH3)3 Ç~' ~
H
t-Bu(CH3)2SiO H t-Bu(C~3)2S10 XI X
/~ OH CF3 CF3 ~'~OcHF3 t-Bu(CH3)2SiO HO
V O
In the above Formula Scheme III, 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 CA 0223~S84 1998-04-22 W O 97/16423 PCTrEP~ 9Z
_ 9 _ 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.
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. The reaction is carried out at -78~C.
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. 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 tetrahydrofuran .
The compounds of formula I as described above can be 2s ~ministered orally, for the treatment of neoplastic diseases such as leukemia, to warmblooded ~nim~l~ which need such treatment. More specifically, the compounds of formula I as described above can be ~lministered orally to an adult human in dosages that are in the range of about .05 to 50 11 g per day for the treatment of neoplastic 3 0 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 3s keratination, and keratosis, to warmblooded ~nim~l~ which need such treatment. More specifically, the compounds of formula I as described above can be ~lmini~tered orally to an adult human in dosages that are in the range of about 0.5 to 50 ,u g per day for the treatment of CA 0223~84 1998-04-22 WO 97/16423 PCT/Er~)6/015~2 hyperproliferative skin diseases such as psoriasis, basal cell carcinomas, disorders of keratinization, and keratosis. These compounds can be ~lmini~tered orally for the treatment of acne in humans at a dosage of about .05 to 50 ~lg per day; preferably 0.5 to 50 5 ,u 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 o keratinization, and keratosis, to warmblooded animals which need such treatment. More specifically, the compounds of formula I as described above can be ~-lministered topically in dosages that are in the range of about 0.5 to about 50 llg per gram of topical formulation per day, for the treatment of hyperproliferative skin diseases such as 15 psoriasis, basal cell carcinomas, disorders of keratinization, and keratosis .
The useful activity of compounds o~ formula I as agents for the treatment of neoplastic diseases can be demonstrated by the following 20 test procedures.
HL-60 Cell Differentiation The induction of differentiation of HL-60 cells was assayed by 2s measuring their oxidative burst potential via the reduction of nitrobluetetrazolium (NBT).
HL-60 cells were maintained in RPMI 1640 medium supplemented with 10% fetal calf serum (FCS), 2mM L-glutamine, 30 lmM sodium pyruvate, 1% non-essential amino acids, 50 U/ml penicillin, and 50 ,~Lg/ml streptomycin. HL-60 cells (30,000 cells in 90 ~Ll of supplemented RPMI medium) were seeded into flat-bottomed microliter wells. Immediately after seeding, 10 ~Ll of test compounds listed below in Table I diluted in supplemented RPMI medium were 3s added to the wells to yield final concentrations of between 10- 1 1 and 1 o-6 M (starting from stock solutions of 10-3 M in ethanol, stored at -20~C and protected from light). After 3 days, medium was removed from the wells with a multichannel pipette and replaced with 100 111 CA 0223~84 1998-04-22 WO 97116423 PCT/EP96~0459Z
of NBT solution (1 mg/ml in phosphate buffered saline with 200 nM
phorbol myristate acetate). Following an additional hour incubation at 37~C the NBT solution was removed and 100 ,ul of 10% sodium dodecyl sulfate in 0.01 N HC 1 was added. The amount of the reduced NBT was s quantified photometrically at 540 nm using an automated plate reader. The mean of 3 wells was calculated. S.E.M. were between 5 and 10% . Values were expressed as percent of maximal differentiation achieved with 100- 1000 nM calcitriol in the same experiment. The concentration (nM) leading to 50% of this maximal o value is determined graphically and given in Table I as ED50.
TABLE I
COMPOUND ED50 (nM) 1,25-Dihydroxy-cholecalciferol 6.0 1,25-Dihydroxy-22E,24Z-diene-24- 1.6 homo-26,27-hexafluoro-cholecalciferol 1,25-Dihydroxy-22E,24E-diene-24- 0.9 homo-26,27-hexafluoro-cholecalciferol l 5 From the above results, it can be seen that 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.
The useful activity of compounds of formula I as agents for the treatment of hyperproliferative skin disease can be demonstrated by the following.
Tnhibition of Keratinocytes Proliferation HaCaT cell line - The immortalized human cell line HaCaT was used (originally obtained from N.E. Fusenig, German Cancer Research Center, Heidelberg, Germany). 3 H-thymidine incorporation was ~ measured in exponentially growing cultures after 6 days of culture in presence of the test compound.
CA 0223~84 1998-04-22 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 UI/ml, penicillin, 5 ~O,~Lg/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.
Inhibition of 3 H-thymidine uptake - HaCaT cells (250 cells in 180 ~11 of the supplemented mixture) were seeded into 96-well culture dishes and incubated at 37~C with 5% CO2 and 95% air.
Immediately after seeding, 20 ,ul of test compounds listed below in Table II, diluted in the supplemented mixture containing 1% ethanol, 5 were added to the wells to yield final concentrations of between 10- 9 and 10-6 M (starting from 1 mM stock solutions in ethanol, stored at -20~C and protected from light). After 6 days, 3H-thymidine (5 Ci/mmol) was added to the wells at a concentration of 1 ~lCi/well.
Cells were pulse-labeled for the last 6 hours of the growth period.
20 Cells were then trypsinized for 10 minutes at 37~C under a vigorous agitation and harvested on to a 96-well filter plate using a cell harvester. After drying at 40~C under vacuum for 20-30 minutes, 20 ,ul of scintillator was added and the radioactivity bound to the filters was counted.
Values are expressed as percent of controls (samples without test compound). The concentration leading to 50% of control values is determined graphically and given as IC5 o (inhibitory concentration) in Table II.
CA 0223S~84 1998-04-22 W O 97/16423 PCTAEP~6/Oq5~Z
T~BLE II
COMPOUND IC50 (nM) 1,25 -Dihydroxy-cholecalciferol 55.0 1,25-Dihydroxy-22E,24Z-diene-24-homo- 2.1 26,27-hexafluoro-cholecalciferol 1,25-Dihydroxy-22E,24E-24-homo-diene- 5.1 26,27-hexafluoro-cholecalciferol From the above results, it can be seen that compounds of 5 formula I inhibit proliferation of keratinocytes. Accordingly, compounds of formula I are useful in the treatment of hyperproliferative skin diseases, such as psoriasis.
Calcium tolerance test in mice Profound changes in calcium homeostasis strongly affect the weight development of mice.
Mice (25-30 g body weight) received daily subcutaneous 15 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.
TABLF. III
COMPOUND HTD (llg/kg) 1,25-Dihydroxycholecalciferol 0.5 1,25-Dihydroxy-22E,24Z-24-homo-26,27- 0.4 hexafluoro-cholecalciferol 1,25-Dihydroxy-22E,24Z-24-homo-23E- 0.8 ~ diene-26,27-hexafluoro-cholecalciferol CA 0223~84 1998-04-22 From the above results, it can be seen that the compounds of formula I exhibit approximately the same HTD as 1,25-dihydroxycholecalciferol .
s The following Examples are provided to further describe the invention and are not intended to limit it in any way.
Oral dosage forms comprising compounds of formula I of the invention may be incorporated in capsules, tablets and the like with 0 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 l s 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. Various other materials may be present as coating or to otherwise modify the physical form of the dosage unit.
For instance, tablets may be coated with shellac, sugar, or both. A
syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye, and a flavoring such as cherry or orange flavor.
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, 3 5 and the like; gelatin or gums, which incorporate the active ingredient in a vehicle made up of water, alcohol, glycerin and the like.
CA 0223~584 1998-04-22 W O 97/16423 PCT~EP96104592 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 5 consistency with the use of alkalies, such as, sodium hydroxide and amines, such as, polyethylenecocoamine.
As used herein, the term " topical" denotes the use of the active ingredient, incorporated in a suitable pharmaceutical carrier, and l o applied at the site of the inflammation for the exertion of local action.
Accordingly, 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 15 applying medication to the skin obtained by admixing the compounds of formula I with known pharmaceutical topical carrier materials. In addition to application to the skin, the topical compositions of this invention can also be employed in the treatment of infl~mm~tions of mucous membranes, where such membranes are accessible to topical 20 application of medication. For example, the topical composition can be applied to the mucous lining of the mouth or lower colon.
EXAMPLE I
25 [lR-[la(S*),3a~,4a,7aa]]-4-[[1,1-Dimethylethyl) dimethylsilyl]-oxy] octahydro- ,B ,7a-dimethyl- 1 H-indene- 1 -acetaldehyde To a stirred suspension of 5.37g (25 mmole) of pyridinium chlorochromate in 50 ml of anhydrous methylene chloride under 30 argon atmosphere was added dropwise 3.26 g (10 mmole) of [lR-[ I a(S *),3a,3,4a,7aa]]-4-[[ 1,1 -dimethylethyl)dimethylsilyl]-o xy ] o c tah y dro - ,B ,7 a-dimethyl- 1 H-indene- 1 -ethanol in 15 ml anhydrous methylene chloride. The reaction mixture was stirred for one hour, then diluted with 120 ml of ether, and purified on a 100 g 35 Florosil column tO give 3.04 g (94%) of the title compound. lH-NMR
(CDC13):~0.02 (s,6H, 2CH3), 0.88 (s, 9H, 3CH3), 1.09 (d, 3H, J = 7 Hz, CH3), 4.02 (brm, lH, CH) 9.58 (d, lH, J= 3 Hz, CH).
CA 0223~84 1998-04-22 [lR-[la(lR*,2E),3a~,4a,7aa]]-(1,1-Dimethylethyl) dimethyl-t[octahydro-7a-methyl- 1 -[1 -methyl-5-(trimethylsilyl)-2-penten-4-s ynyl~- 1 H-inden-4-yl]oxy]silane To a stirred suspension of 1 g (2.2 mmole) of (3-trimethylsilyl-2-propynyl)-triphenyl-phosphonium bromide in 20 ml anhydrous tetrahydrofuran at -78~C was added 1.4 ml (2.2 mmole) of 1.6M n-o butyllithium in hexane. After addition was complete, the reactionmixture was warmed up to 40~C, stirred for 0.5 hour when it turned to a red solution. It was then cooled to -78~C and 478 mg (1.47 mmole) of [lR-[laS*), 3a,~, 4a,7aa]]-4-[[(1,1-dimethylethyl)dimethyl-silyl]oxy]octahydro-~,7a-dimethyl-lH-indene-l-acetaldehyde in 6 ml 5 anhydrous tetrahydrofuran was added, then stirred at room temperature for one hour, and quenched by addition of water. It was thoroughly extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over sodium sulfate, and evaporated to dryness. The residue was triturated with hexane and 20 the soluble part was purified by FLASH chromatography with hexane.
It gave 396 mg (64%) of the title compound. Analytical sample was purified by preparative HPLC with hexane, and was crystallized from ethanol, m.p. 81-83~C; [a]25D + 80.5~ (c 0.2) CHCl3); UV~ (hexane):
shoulder 227nm (~17,000, max 236-237 nm (~21,800), shoulder 295 2s nm (~16,600); lH-NMR (CDCl3): ~0.01 (s, 6H, 2CH3), 0.19 (s,9H, 3CH3), 0.89 (s, 9H, 3CH3), 0.93 (s, 3H, CH3), 1.02 (d, 3H, J = 6.7 Hz, CH3), 1.80 (m, lH, CH of CH2), 1.91 (dm, lH, Jgem = 12.5 Hz, CH or CH2), 2.11 (m, lH, CH), 3.99 (m, lH, CH), 5.42 (d, lH, Jtrans = 15.9 Hz, CH), 6.06 (dd, lH, Jvic = 8.8 Hz, Jtrans = 15.9 CH). The structure of this compound 30 was confirmed by an X-ray analysis; Analysis: Calcd for C2SH46osi2: C
71.70, H 11.07; Found: C 71..23; H 11.04.
CA 0223~84 1998-04-22 WO 97/16423 PCT/EF~16~ 5~12 F.X~MPLE 3 [1 R- [ l oc( l R* ,2E), 3a,B ,4a,7 aa] ] -(1,1 -Dimethylethyl) dimethyl-- [ [octahydro-7 a-methyl- 1 - [1 -methyl-2-penten-4-ynyl)- 1 H-inden-4- 5 yl] oxy] silane -To a stirred suspension of 1.5 g (3.58 mmole) of [lR-[la(lR*,2E),3a,B,4cc,7aa]]-(1,1-dimethylethyl)dimethyl-[[octahydro-7a-methyl- 1 - [1 -methyl-5-trimethylsilyl)-2-penten-4-ynyl)- 1 H-inden-4-l o yl] oxy] silane in 9 ml anhydrous tetrahydrofuran and 60 ml ethanol atroom temperature was added dropwise a solution of 3.65 g (21.4 mmole) silver nitrate in 72 ml of 3: 1 ethanol-water., A yellowish-white precipitate developed, and such a formed mixture was stirred for one hour. This was followed by addition of 4.19 g (64.4 mmole) 5 potassium cyanide in 60 ml water, when the precipitate dissolved.
After 0.5 hour t.l.c. indicated that the reaction was complete. The mixture was diluted with SOOml of water and brine (1: 1), and extracted thoroughly with ethyl acetate. The combined extracts were washed with water and brine, dried over sodium sulfate and 20 evaporated to dryness. The crude product was purified by FLASH
chromatography with hexane, followed by preparative HPLC with hexane using a YMC column (50 mm x 50 cm). It have 1.26 g (100%) of the title compound. lH-NMR (CDCl3) ~0.00 (s, 6H, 2CH3), 0.89 (s, 9H, 3CH3), 0.94 (s, 3H, CH3), 1.02 (d, 3H, J = 7Hz, CH3), 2.13 (m, lH, 25 CH), 2.75 (d, lH, J = 2.5 Hz, CH), 3.99 (brs, lH, CH), 5.25 (dd, lH, Jvic =
2.5 Hz, Jtrans = 16 Hz, CH), 6.09 (dd, lH, Jvic = 8 Hz, Jtrans = 16 Hz, C~.
F~xAMpLE 4 [lR-[la(lR*,2E),3a~,4a,7aa]]-7-[4-[[(1,1-Dimethylethyl)-dimethyl-silyl]oxy]octahydro-7a-methyl-lH-inden-l-yl]-l,l,l-trifluoro-2(trifluoromethyl)-5 -octen-3 -yn-2-ol 3s To a stirred solution of 0.91 g (2.63 mmole) of [lR-[la(lR*,2E),3a,~,4a,7aa]]-(1,1-dimethylethyl)dimethyl[[octahydro-7a-methyl- 1 -(1 -methyl-2-penten-4-ynyl)- 1 H-inden-4-yl] oxy] silane in 15 ml anhydrous tetrahydrofuran at -78~C was added 1.65 ml 1.6M n-CA 0223~84 1998-04-22 WO 97/16423 PCT/EP96/0~592 butyllithium in hexane, and the mixture was stirred for 0.5 hour. At this point in time gaseous hexafluoroacetone was introduced by a dispersion tube for 2 minutes, and the reaction mixture was stirred for additional 1.5 hours, when t.l.c. indicated that the reaction was s complete. The reaction mixture was then diluted with 400 ml water and extracted thoroughly with hexane. The combined extracts were washed with water and brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by FLASH
chromatography with hexane-ethyl acetate 19:1 to give 1.27 (95%) of 10 the title compound. lH-NMR (CDCl3) ~0.00 (s, 6H, 2CH3), 0.88 (s, 9H, 3CH3), 1.03 (d, 3H, CH3), 2.18 (m, lH, CH), 4.00 (brs, lH, CH), 5.42 (d, lH, Jtrans = 16 Hz, CH), 6.26 (dd, lH, Jvic = 9 Hz, Jtrans = 16 Hz, CH).
[lR-[la(lR*,2E),3a~,4a,7aa]]-Octahydro-7a-methyl-1-[7,7,7-trifluoro-6-hydroxy- 1 -methyl-6-(trifluoro-methyl)-2-hepten-4-ynyl]- lH-inden-4-ol~
To a stirred solution of 1.648 g (3.21 mmole) of LlR-[1 a( l R*,2E),3a~,4a,7aa]]-7-[4-[[(1,1 -dimethylethyl)-dimethylsilyl]-oxy]octahydro-7a-methyl- 1 H-inden- 1 -yl]- 1,1,1 -trifluoro-2-(trifluoromethyl)-5-octen-3-yn-2-ol in 30 ml acetonitrile and 24 ml anhydrous tetrahydrofuran was added at room temperature 30 ml 49% hydrofluoric acid, and thus obtained reaction mixture was stirred for 3 hours. It was then diluted with 400ml water and extracted thoroughly with ethyl acetate. The combined extracts were washed with 2N potassium bicarbonate and water, and finally with brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by FLASH chromatography with hexane-ethyl acetate 2: 1 the title compound, which was crystallized from ether-petroleum ether (2:25) to give 1.087 g (85%), m.p. 108-109~C; [a~25D +
47~ (c 0.2, CHC13); UV~ (EtOH): max 224 nm (~20,060), shoulder 230-231 nm (~18,600); lH-NMR (CDCl3): ~0.96 (s, 3H, CH3), 1.05 (d, 3H, J =
6.41 Hz, CH3), 1.96 (brd, lH, Jgem = 13 Hz, CH of CH2), 2.19 (m, lH, CH), 4.10 (brs, lH, CH), 5.44 (d, lH, Jtrans = 16Hz, CH), 6.25 (dd, lH, Jvic = 8.9 Hz J trans = 16Hz, CH). Analysis: Calcd. for Cl9H24F6~2:
C57.28, H 6.07; Found: C 57.29, H 6.19.
CA 0223~84 1998-04-22 .
[lR-[la(lR*,2E,4E),3a,~,4a,7aa]]-Octahydro-7a-methyl-1-[7,7,7-5 trifluoro-6-hydroxy- 1 -methyl-6-(trifluoro-methyl)-2,4-heptadienyl]-- 1 H-inden-4-ol]
To a 100 ml three necked flask fitted with a dropping funnel, condenser and argon inlet tube was added 143 mg (3.75 mmole) of 10 lithium aluminum hydride suspended in 1.5 ml anhydrous tetrahydrofuran. The flask was cooled in an ice-bath and with stirring was added carefully first 203 mg (3.75 mmole) of solid sodium methoxide, and then dropwise the solution of 300mg (0.753 mmole) of [lR-[la(lR*,2E),3a,B,4a,7aa]]-Octahydro-7c~-methyl-1-[7,7,7-trifluoro-15 6-hydroxy- 1 -methyl-6-(trifluoromethyl)-2-hepten-4-ynyl]- 1 H-inden-4-ol in 6 ml anhydrous tetrahydrofuran. After addition was completed, the ice-bath was removed, and the reaction mixture was heated under reflux at 80~C for 2.5 hours. It was then cooled in ice-bath, quenched with 1 ml water and 1 ml 2N sodium hydroxide; 20 ml 20 of ether was added, stirred for 0.5 hr., 2.2 g of MgSO4 was added, stirred for 0.5 hr, filtered, filter was washed with ether, and the filtrates were evaporated to dryness. The crude product was purified by preparative HPLC with hexane-ethyl acetate 4: 1, to give, after recrystallization from methylene chloride-hexane mixture, 251 mg 2s (83.2%) of crystalline title compound, m.p. 146-148~C. UV ~max (EtOH): 228-229 nm (~ 32,100); 1H-NMR (CDCl3): ~0.907 (s, 3H, CH3), 1.05 (d, 3H, J = 6.5 Hz, CH3), 1.69 (m, lH, CH), 1.98 (brd, lH, Jgem = 13 Hz, CH of CH2), 2.17 (m, lH, CH), 4.09 (brs, lH, CH), 5.59 (d, lH, Jtrans =
15.4 Hz, CH), 5.79 (dd, lH, Jvic = 8.6 Hz, Jtrans = 15.3 Hz, CH), 6.05 (dd, 30 lH, Jvic = 10.5 Hz, Jtrans = 15.3 Hz, CH), 6.68 (dd, lH, Jvic = 10.6 Hz, Jtrans = 15.3 Hz, CH). Analysis: Calcd. for C1gH26F6O2: C 56.99, H
6.55; Found C 56.64, H 6.41.
CA 0223~84 1998-04-22 WO 97/16423 PCT/EP~6/0~92 [lR-[la(lR*,2E,4E),3a,B,7aa]]-Octahydro-7a-methyl-1-[7,7,7-trifluoro-6-hydroxy- 1 -methyl-6-(trifluoro-methyl)-2,4-heptadienyl]-4H- -s inden-4-one To a stirred solution of 300 mg (0.75 mmole) of [1 R-[la(lR*,2E,4E),3a,B,4a,7aa]]-octahydro-7a-methyl-1-[7,7,7-trifluoro-6-hydroxy- 1 -methyl-6-(trifluoromethyl)-2,4-heptadienyl]-4H-inden-4-o ol in 15 ml anhydrous methylene chloride was added 1.465 g (3.9mmole) pyridinium dichromate, and stirred at room temperature for 3.5 hours. After addition of 25 ml ether and stirring for 15 minutes, the mixture was filtered through a celite pad, which was washed with 3 x 25 ml ethyl acetate. The combined filtrates were washed with 2N
5 potassium bicarbonate, water and brine, dried over sodium sulfate, and evaporated to dryness. The crude product was purified by FLASH
chromatography with hexane-ethyl acetate 3: 1 to give 267 mg (89.5%) of the title compound. 1H-NMR (CDC13): ~0.66 (s, 3H, CH3), 1.08 (d, 3H, J = 6.5 Hz, CH3), 2.46 (dd, lH, J = 8 and 11 Hz, CH) 5.58 (d, lH, Jtrans =
20 15 Hz, CH), 5.77 (dd, lH, Jvic = 8.5 Hz, Jtrans = 15 Hz, CH), 6.04 (dd, lH, Jvic = 10.5 Hz, Jtrans = 15 Hz, CH), 6.68 (dd, lH, Jvic = 10.5 Hz, Jtrans =
15 Hz, CH).
F.XAMPLE 8 2s [lR-[la(lR*,2E,4E),3a,B,7aa]]-Octahydro-7a-methyl-1-[7,7,7-trifluoro-1 -methyl-6-(trifluoromethyl)-6-[(trimethylsilyl)oxy]-2,4-heptadienyl] -4H-inden-4-one To a stirred solution of 267 mg (0.67 mmole) of [lR-[1 a(1 R*,2E,4E),3a,B,7aa]]-octahydro-7a-methyl- 1 -[7,7,7-trifluoro-6-hydroxy- 1 -methyl-6-(trifluoromethyl)-2,4-heptadienyl]-4H-inden-4-one in 10 ml anhydrous methylene chloride was added 0.885ml (6.03 mmole) of 1-(trimethyl-silyl)imidazole and stirred at room temperature overnight. The reaction was then quenched by addition of water, and was extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over sodium sulfate, and evaporated to dryness. The crude product was purified by FLASH
CA 0223~S84 1998-04-22 W O 97/16423 PCT~EF96~ 92 chromatography with hexane-ethyl acetate 5: 1 to give 307 mg (97.3%) of the title compound. 1H-NMR (CDC13): ~0.20 (s, 9H, 3CH3), 0.66 (s, 3H, CH3), 1.10 (d, 3H, J = 6.5 Hz, CH3), 2.45 (dd, lH, J = 8 and 11 Hz, CH
of CH2), 5.55 (dd, lH, Jtrans = 15 Hz, CH), 5.73 (dd, lH, Jvic = 8.5 Hz, 5 Jtrans = 15 Hz, CH), 6.01 (dd, lH, Jvic = 10 Hz, Jtrans = 15 Hz, CH), 6.51 - (dd, lH, Jvic = 10 Hz, Jtrans = 15 Hz, CH).
o 1,25-Dihydroxy-22E,24E-diene-26,27-hexafluoro-24-homo-cholecalciferol To a stirred solution of 0.608 g (1.04 mmole) of [3S-(lZ,3a,5,B)]-[2-[3,5-bis[[( l, l -dimethylethyl)dimethylsilyl]oxy]-2-methylene-1S cyclohexylidene]ethyl]diphenylphosphine oxide in 10 ml anhydroustetrahydrofuran at -78~C was added 0.652 ml (1.04 mmole) of 1.6M
n-butyllithium in hexane. The solution turned red and the color persisted during the entire addition of 307 mg (0.652 mmole) of [1 R-[1 a( l R*,2E,4E),3a~,7aa]]-octahydro-7a-methyl- 1 -[7,7,7-trifluoro- 1 -20 methyl-6-(trifluoromethyl)-6-[(trimethylsilyl)oxy]-2,4-heptadienyl]-4H-inden-4-one in 8 ml anhydrous tetrahydrofuran. The reaction mixture was stirred at -78~C for 0.5 hr and then quenched with water.
It was extracted with 4 x 50 ml ethyl acetate. The combined extracts were washed with water and brine, dried over sodium sulfate and 2s evaporated to dryness. The crude product was purified by FLASH
chromatography with hexane-ethyl acetate 10: 1 to give 337 mg of trisilylated intermediate.
To the solution of 337 mg of trisilylated intermediate in 8 ml 30 anhydrous tetrahydrofuran stirred at room temperature under argon was added in portions 3 ml (3 mmole) of 1 M tetrabutyl ammonium fluoride in tetrahydrofuran. The reaction mixture was stirred overnight, then diluted with water and extracted with ethyl acetate.
The combined extracts were washed with water and brine, dried over 35 sodium sulfate and evaporated to dryness . The crude product was purified by FLASH chromatography with hexane-ethyl acetate 1 :3, and preparative HPLC with hexane-ethyl acetate 1 :4 to give 235 mg (67.4%) of the title compound as white foam, [a]25D + 64.5~ (c0.2, CA 0223~84 1998-04-22 W O 97/16423 PCT/E~96/04592 EtOH); UV ~max (EtOH): 229 nm (~ 40,500), 262-263 nm (~ 17,600);
lH-NMR (CDC13): ~0.57 (s, 3H,CH3), 1.08 (d, 3H, J= 6.5 Hz, CH3) 2.18 (m, lH, CH), 2.32, 2.60 (AB of ABX, 2H, Jvic = 6.5 and 3 Hz, Jgem = 13 Hz, CH2), 2.83 (brdd, lH, Jgem = 12.5 Hz, CH of CH2), 4.23 (brm, lH, CH), 5 4.44 (brm, lH, CH), 5.00, 5.23 (2s, 2H, CH2), 5.60 (d, lH, Jtrans = 15.5 Hz, CH), 5.82 (dd, lH, Jvic = 9 Hz, Jtrans = 15 Hz, CH), 6.01, 6.36 (AB, 2H, Jvic = 11 Hz, CHCH), 6.05 (dd, lH, Jvic = 10.5 Hz, Jtrans = 15 Hz, CH), 6.69 (dd, lH, Jvic = 10.5 Hz, Jtrans = 15.5 Hz, CH). Analysis:
Calcd:. for C2gH36F6O3: C 62.91, H 6.79; Found C 61.83, H 7.02 E~XAMPLE 10 [lR-[la(lR*,2E,4Z),3a,B,7aa]]-Octahydro-7a-methyl-1-[7,7,7-trifluoro-6-hydroxy- 1 -methyl-6-(trifluoro-methyl)-2,4-heptadienyl] - 1 H-I ~ inden-4-ol]
The mixture of 392 mg (0.98 mmole) of [lR-tla(lR*,2E) 3a~,4a,7aa]]-octahydro-7a-methyl- 1 -[7,7,7-trifluoro-6-hydroxy- 1 -methyl-6-(trifluoromethyl)-2-hepten-4-ynyl]- 1 H-inden-4-ol], 5 ml 20 ethylacetate, 12.5 ml hexane, 0.35 ml absolute ethanol, 0.017 ml quinoline and 63 mg Lindlar catalyst (5% Pd on CaC03) was hydrogenated for 2 hrs at 1 atm. and room temperature. The reaction mixture was filtered through a celite pad and the pad was washed with hexane. The combined filtrates were washed with dilute acid, 25 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.
30 140-141~C; UV ~max (EtOH): 231-232 nm (~ 30,600); lH-NMR (CDC13):
~0.97 (s, 3H, CH3), 1.05 (d, 3H, J = 6.7 Hz, CH3) 1.98 (brd, lH, Jgem = 13 Hz, CH of CH2), 2.21 (m, lH, CH), 4.08 (brs, lH, CH), 5.25 (d, lH, Jcis =
11.5 Hz, CH), 5.75 (dd, lH, Jvic = 8.8 Hz, Jtrans = 15 Hz, CH), 6.43 (t, lH, Jvic and Jcis = 11.5 Hz, CH), 6.71 (dd, lH, Jvic = 11.5 Hz, Jtrans = 15 Hz, 3s CH). Analysis: Calcd. for ClgH26F6O2: C 56.99, H 6.55; Found: C 57.03, H 6.69 CA 0223~84 1998-04-22 WO 97/16423 PCT/EF96/'~ 15~2 F~AMPLE 11 [lR-[la(lR*,2E,4Z),3a~,7aa]]-Octahydro-7a-methyl-1-r7,7,7-trifluoro-6-hydroxy- 1 -methyl-6-(trifluoro-methyl)-2,4-heptadienyl]-4H-5 inden-4-one To the at room temperature stirred soluton of 202 mg (0.52 mmole) [lR-[la(lR*,2E,4Z),3a,B,4a,7aa]]-octahydro-7a-methyl-1-[7,7,7-trifluoro-6-hydroxy- 1 -methyl-6-(trifluoromethyl)-2,4-10 heptadienyl]-lH-inden-4-ol in 10 ml anhydrous methylene chloride was added 886 mg (2.36 mmole) pyridinium dichromate, and stirred for 0.5 hr. Then 25 ml of ether was added, stirred for 15 minutes, and filtered through a celite pad. The pad was washed with 3 x 25 ml ethyl acetate. The combined filtrates were washed with 2N potassium 5 bicarbonate, water and brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by FLASH
chromatography with methylene chloride-ethyl acetate 20: 1 to give 196 mg (96%) of the title compound. lH-NMR (CDC13): ~0.67 (s, 3H, CH3), 1.10 (d, lH, J = 6.5 Hz, CH3), 2.45 (dd, lH, J = 8 and 11 Hz, CH), 20 5.26 (d, lH, Jcis = 11.5 Hz, CH), 5.76 (dd, lH, Jvic = 8.5 Hz, Jtrans = 15 Hz, CH), 6.43 (t, lH, Jvic and Jcis = 11.5 Hz, CH), 6.73 (dd, lH, Jvic =
11.5 Hz, Jtrans = 15 Hz, CH).
F.~AMPLE 12 2s [lR-[la(lR*,2E,4Z),3a~,7aa]]-Octahydro-7a-methyl-1-[7,7,7-trifluoro-1 -methyl-6-(trifluoromethyl)-6-[(trimethylsilyl)oxy]-2,4-heptadienyl] -4H-inden-4-one To a stirred solution of 196 mg (0.49 mmole) [lR-[la(lR*,2E, 4Z),3 a~ ,7 aa] ] -octahydro-7 a-methyl- 1 - [7,7,7 -trifluoro-6-hydro xy- 1 -methyl-6-(trifluoromethyl)-2,4-heptadienyl]-4H-inden-4-one in 10 ml anhydrous methylene chloride under argon was added 0.67 ml (4.42 mmole) of l-(trimethylsilyl)-imidazole, and thus was obtained reaction mixture was stirred at room temperature overnight. It was then diluted with ethyl acetate, washed with water and brine, dried CA 0223~84 1998-04-22 over sodium sulfate and evaporated to dryness. The crude product was purified by FLASH chromatography with hexane-ethyl acetate 5:1 to give 229 mg (99%) of the title compound.
s ~XAMPLE~ 13 1 ,25-Dihydroxy-22E,24Z-diene-26,27-hexafluoro-24-homo-cholecalciferol To a stirred solution of 467 mg (0.80 mmole) of [3S-(lZ,3a,5~)]-[2-[3,5-bis[[( 1,1 -dimethylethyl)dimethylsilyl]-oxy]-2-methylene-cyclohexylidene]ethyl]diphenylphosphine oxide in 10 ml anhydrous tetrahydrofuran at -78~C was added 0.5 ml (0.80 mmole) of 1.6M n-butyllithium in hexane. The solution turned red and the color persisted during the entire addition of 229 mg (0.486 mmole) of [lR-[ 1 a( 1 R* ,2E,4Z),3a~ ,7aa]]-octahydro-7a-methyl- 1 -[7,7,7-trifluoro- 1-methyl-6-(trifluoromethyl)-6-[(trimethylsilyl)oxy]-2,4-heptadienyl]-4H-inden-4-one in 8 ml anhydrous tetrahydrofuran. The reaction mixture was stirred at -78~C for 1.5 hrs and quenched with water. It o was extracted thoroughly with ethyl acetate . The combined extracts were washed with water and brine, dried over sodium sulfate and evaporated to dryness. The crude residue was purified by FLASH
chromatography with hexane-ethyl acetate 10:1. This gave 310 mg of the trisilylated intermediate.
To the solution of 310 mg of trisilylated intermediate in 8 ml anhydrous tetrahydrofuran stirred at room temperature under argon was added in portions 4.5 ml of 1 M tetrabutyl ammonium fluoride in tetrahydrofuran. The reaction mixture was stirred for 48 hrs, then diluted with water and extracted thoroughly with ethyl acetate. The combined extracts were washed with water and brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified first by FLASH chromatography with hexane-ethyl acetate 1:3, and preparative HPLC with hexane-ethyl acetate 1:4 and then by 3 5 preparative HPLC with hexane-ethyl acetate 1:4 to give 206 mg (79.2%) of the title compound as white foam, ~o~]25D + 17.5~ (c 0.2, EtOH); UV~ (EtOH): max 232-233 nm (~ 38,700), shoulder 265 nm (~17,200); 1H-NMR (CDC13); ~0.57 (s, 3H, CH3), 1.07 (d, 3H, J = 6.5 Hz, CA 0223~84 1998-04-22 CH3), 2.22 (m, lH, CH), 2.32, 2.. 60 (AB of ABX, 2H, Jvic = 6.5 and 3.5 Hz Jgem = 13 Hz, CH2), 2.84 (dd, lH, Jvic = 4Hz, Jgem - 12.5 Hz, CH of CH2), 4.23 (brm, lH, CH), 4.43 (brm, lH, CH), 5.00, 5.33 (2s, 2H, CH2) 5.25 (d, lH, Jcis = 12 Hz, CH), 5.76 (dd, lH, Jvic = 8.5 Hz, Jtrans = 15 5 Hz, CH), 6.02, 6.38 (AB, 2H, Jvic = 11.3 Hz, CHCH), 6.43 (t, lH, ~vic and Jtrans = 12 Hz, CH), 6.71 (dd, lH, Jvic = 12 Hz, Jtrans = 15 Hz, CH).
Analysis: Calcd. for C2gH36F6O3: C 62.91, H 6.79; Found: C 61.73, H
6.74 Oral Dosage Form Soft Gelatin Capsule mg/capsule 1 ,25-dihydroxy-22E,24E-diene-24-homo-26,27-hexafluoro-cholecalciferol0.0005 - 0.050 (Compound A) Butylated Hydroxytoluene (BHT) 0.016 Butylated Hydroxyanisole (BHA) 0.016 Myglyol(~)-8 12 qs 1 6 0 1. Suspend BHT and BHA in Myglyol~)-812. Warm to about 5 0~ C, and stir until dissolved.
2. Dissolve Compound A in the solution from Step 1.
3. Fill the solution from Step 2 in a soft gelatin cap.
All steps are performed under a nitrogen atmosphere and protected from light.
F.XAMPLE 15 Oral Dosage Form Soft Gelatin Capsule mg/cap sule Compound A 0.0005 - 0.050 a-Tocopherol 0.0 16 Myglyol(~)-812 qs 160 s 1 . Suspend a-Tocopherol in Myglyol~-8 12. Warm to about 5 0~ C, and stir until dissolved.
2. Dissolve Compound A in the solution from Step 1.
0 3. Fill the solution from Step 2 in a soft gelatin cap.
All steps are performed under a nitrogen atmosphere and protected from light.
CA 0223~84 1998-04-22 WO 97116423 PCT/EP9~ 5~72 Topical Dosage Form Cream % wlw Compound A0.00005-5.0 Cetyl Alcohol 1 . 5 0 S tearyl Alcohol 2 . 5 0 Sorbitan Monostearate (Span 60) 2.00 Mineral Oil 2 . 0 0 Glyceryl Monostearate and Polyoxyethylene Glycol Stearate 4.00 Blend (Arlacel 165) Polysorbate 60 (Tween 60) 1.00 Caprylic/Capric Triglyceride 5 . 00 Sorbitol Solution 4 . 00 Edetate Disodium 0.10 Butylated Hydroxyanisole (BHA) 0.02 Sorbic Acid 0.20 Potassium Sorbate 0.1 - 0.2 Water q.s. to 100.00 5 1. Stir Compound A until dissolved.
2. Warm mixture of cetyl alcohol, stearyl alcohol, Span 60, mineral oil, Arlacel 165, Tween 60 and BHA to about 70-75~C, to form oily solution.
3. Add solution from Step 1 to solution from Step 2 while mixing.
4. Warm mixture of water, sorbitol solution, edetate disodium~
sorbic acid, and potassium sorbate to 70-75~C.
sorbic acid, and potassium sorbate to 70-75~C.
5. Add solution from Step 3 to solution from Step 4 while emulsifying with a high speed mixer.
5 6. Cool emulsion from Step 5 to room temperature until emulsion congeals.
CA 0223~84 l998-04-22 WO 97/16423 PCT/E~96/015~2 Topical Dosage Form Gel % w/w Compound A 0.00005 5.0 Butylated Hydroxyanisole (BHA) 0 .02 Hydroxypropyl Cellulose 3 . 00 Ethyl Alcohol, USP 45.00 Water q.s. to 100.00 5 1. Dissolve BHA in mixture of ethyl alcohol and water.
2. Dissolve Compound A in solution from Step 1.
3. Disperse hydroxypropyl cellulose in solution from Step 2.
E~XAMPLE 18 o Topical Dosage Form Solution % wlw Compound A 0.00005 - 5.0 Propylene Glycol10.00 Caprylic/Capric Tri~lyceride 30.00 Butylated Hydroxyanisole (BHA) 0.02 Ethyl Alcohol, Absolute q.s. to100 . 00 1. Dissolve Compound A in ethyl alcohol.
2. Add BHA to solution from Step 1 and dissolve.
s 3 . Add propylene glycol and caprylic/capric triglyceride to solution from Step 2 and mix until solution becomes clear.
5 6. Cool emulsion from Step 5 to room temperature until emulsion congeals.
CA 0223~84 l998-04-22 WO 97/16423 PCT/E~96/015~2 Topical Dosage Form Gel % w/w Compound A 0.00005 5.0 Butylated Hydroxyanisole (BHA) 0 .02 Hydroxypropyl Cellulose 3 . 00 Ethyl Alcohol, USP 45.00 Water q.s. to 100.00 5 1. Dissolve BHA in mixture of ethyl alcohol and water.
2. Dissolve Compound A in solution from Step 1.
3. Disperse hydroxypropyl cellulose in solution from Step 2.
E~XAMPLE 18 o Topical Dosage Form Solution % wlw Compound A 0.00005 - 5.0 Propylene Glycol10.00 Caprylic/Capric Tri~lyceride 30.00 Butylated Hydroxyanisole (BHA) 0.02 Ethyl Alcohol, Absolute q.s. to100 . 00 1. Dissolve Compound A in ethyl alcohol.
2. Add BHA to solution from Step 1 and dissolve.
s 3 . Add propylene glycol and caprylic/capric triglyceride to solution from Step 2 and mix until solution becomes clear.
Claims (22)
1. A compound of the formula wherein A is a carbon double bond having the stereochemical configuration E or Z, i.e. of the formula:
or , respectively, R is hydroxy and R1 is hydrogen or =CH2 or R is hydrogen or fluoro and R1 is =CH2.
or , respectively, R is hydroxy and R1 is hydrogen or =CH2 or R is hydrogen or fluoro and R1 is =CH2.
2. A compound in accordance with claim 1, wherein A is .
3. A compound in accordance with Claim 2, wherein R is hydroxy.
4. A compound in accordance with Claim 2, wherein R is fluoro.
5. A compound in accordance with Claim 2, wherein R1 is =CH2.
6. A compound in accordance with Claim 3, wherein R1 is hydrogen.
7. A compound in accordance with Claim 3, 1,25-dihdyroxy-22E,24E-diene-26,27-hexafluoro-24-homo-cholecalciferol.
8. A compound in accordance with Claim 6, 1,25-dihydroxy-22E,24E-diene-19-nor-26,27-hexafluoro-24-homo-cholecalciferol.
9. A compound in accordance with Claim 4, 1.alpha.-fluoro-25-hydroxy-22E,24E-diene-26,27-hexafluoro-24-homo-cholecalciferol.
10. A compound in accordance with claim 1, wherein A is .
11. A compound in accordance with Claim 10, wherein R is hydroxy.
12. A compound in accordance with Claim 10, wherein R is fluoro.
13. A compound in accordance with Claim 10, wherein R1 is =CH2.
14. A compound in accordance with Claim 11, wherein R1 is hydrogen.
15. A compound in accordance with Claim 11, 1,25-dihydroxy-22E,24Z-diene-26,27-hexafluoro-24-homo-cholecalciferol.
16. A compound in accordance with Claim 14, 1,25-dihydroxy-22E,24Z-diene-19-nor-26,27-hexafluoro-24-homo-cholecalciferol.
17. A compound in accordance with Claim 12, 1.alpha.-fluoro-25-hydroxy-22E,24Z-diene-26,27-hexafluoro-24-homo-cholecalciferol.
18. A compound of the formula or of the formula or of the formula or of the formula
19. A pharmaceutical composition, particularly for inducing differentiation and inhibiting proliferation in certain skin and cancer cell lines, specially for the treatment of hyperproliferative skin disorders, such as psoriasis, and for the treatment of neoplastic diseases such as leukemia, comprising (a) an effective amount of a compound of the formula I in claim 1, and (b) an inert carrier.
20. The compounds of claims 1 to 17 for use as agent for inducing differentiation and inhibiting proliferation in certain skin and cancer cell lines, specially for the treatment of hyperproliferative skin disorders, such as psoriasis, and for the treatment of neoplastic diseases such as leukemia.
21. The use of the compounds of claims 1 to 17 for the production of medicaments for inducing differentiation and inhibiting proliferation in certain skin and cancer cell lines, specially for the treatment of hyperproliferative skin disorders, such as psoriasis, and for the treatment of neoplastic diseases such as leukemia.
22. Novel compounds, intermediates, formulations, processes and methods substantially as described herein.
***
***
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US712595P | 1995-10-31 | 1995-10-31 | |
US60/007,125 | 1995-10-31 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2235584A1 true CA2235584A1 (en) | 1997-05-09 |
Family
ID=21724362
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002235584A Abandoned CA2235584A1 (en) | 1995-10-31 | 1996-10-23 | 24-homo-26,27-hexafluoro-cholecalciferols |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP0874813A1 (en) |
JP (1) | JPH10512297A (en) |
KR (1) | KR19990067173A (en) |
CN (1) | CN1201452A (en) |
AU (1) | AU7297496A (en) |
CA (1) | CA2235584A1 (en) |
MX (1) | MX9803345A (en) |
WO (1) | WO1997016423A1 (en) |
ZA (1) | ZA968953B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114276284A (en) * | 2021-12-30 | 2022-04-05 | 正大制药(青岛)有限公司 | Preparation method of fluocalcitol |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
ATE251133T1 (en) * | 1993-07-09 | 2003-10-15 | Theramex | NEW STRUCTURAL VITAMIN D DERIVATIVES |
-
1996
- 1996-10-23 KR KR1019980703124A patent/KR19990067173A/en not_active Application Discontinuation
- 1996-10-23 EP EP96934788A patent/EP0874813A1/en not_active Withdrawn
- 1996-10-23 AU AU72974/96A patent/AU7297496A/en not_active Abandoned
- 1996-10-23 JP JP9517038A patent/JPH10512297A/en active Pending
- 1996-10-23 CN CN96198019A patent/CN1201452A/en active Pending
- 1996-10-23 WO PCT/EP1996/004592 patent/WO1997016423A1/en not_active Application Discontinuation
- 1996-10-23 CA CA002235584A patent/CA2235584A1/en not_active Abandoned
- 1996-10-24 ZA ZA968953A patent/ZA968953B/en unknown
-
1998
- 1998-04-28 MX MX9803345A patent/MX9803345A/en unknown
Also Published As
Publication number | Publication date |
---|---|
AU7297496A (en) | 1997-05-22 |
CN1201452A (en) | 1998-12-09 |
ZA968953B (en) | 1997-07-30 |
WO1997016423A1 (en) | 1997-05-09 |
KR19990067173A (en) | 1999-08-16 |
JPH10512297A (en) | 1998-11-24 |
MX9803345A (en) | 1998-09-30 |
EP0874813A1 (en) | 1998-11-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0654467B1 (en) | Vitamin D3 analogs | |
US5451574A (en) | Vitamin D3 Flourinated Analogs | |
US7531527B2 (en) | 2-Propylidene-19-nor-vitamin D compounds | |
CA2205275C (en) | Vitamin d3 analogs | |
EP0580968B1 (en) | Vitamin D3 fluorinated analogs | |
BG60530B2 (en) | Dehydrocholecalciferoles | |
US5750517A (en) | Method of treating sebaceous gland diseases with vitamin D3 fluorinated analogs | |
JP2908566B2 (en) | Dermatological use of vitamin D derivatives | |
CA2237897C (en) | 25-hydroxy-16-ene-26,27-bishomo-cholecalciferols | |
US5969190A (en) | Cyclohexanediol derivatives | |
CA2235584A1 (en) | 24-homo-26,27-hexafluoro-cholecalciferols | |
US4929609A (en) | 25, 28-dihydroxyergocalciferol and 1,25,28-trihydroxyergocalciferol compositions thereof and their use in the treatment of hyperproliferative disease | |
EP0796843B1 (en) | 1,25-dihydroxy-16,22,23-trisdehydro-cholecalciferol derivatives | |
US5840718A (en) | 22-epimeric-1,25-dihydroxy-16,22,23-triene-cholecalciferol | |
MXPA98003345A (en) | 24-homo-26,27-hexafluoro-colecalcifero | |
Enrico et al. | Method of treating hyperproliferative skin diseases with fluorinated vitamin D 3 analogs | |
Giuseppe et al. | Method of treating sebaceous gland diseases with vitamin D 3 fluorinated analogs | |
MXPA97003774A (en) | Vitamin analogues | |
MXPA97003720A (en) | Compounds of 18-nor-vitamin |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
FZDE | Dead |