JP4961562B2 - 19−ノルビタミンd誘導体 - Google Patents
19−ノルビタミンd誘導体 Download PDFInfo
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- JP4961562B2 JP4961562B2 JP2007506036A JP2007506036A JP4961562B2 JP 4961562 B2 JP4961562 B2 JP 4961562B2 JP 2007506036 A JP2007506036 A JP 2007506036A JP 2007506036 A JP2007506036 A JP 2007506036A JP 4961562 B2 JP4961562 B2 JP 4961562B2
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- PKFBWEUIKKCWEW-WEZTXPJVSA-N (1r,3r)-5-[(2e)-2-[(1r,3as,7ar)-1-[(2r)-6-hydroxy-6-methylheptan-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]cyclohexane-1,3-diol Chemical class C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1C[C@@H](O)C[C@H](O)C1 PKFBWEUIKKCWEW-WEZTXPJVSA-N 0.000 title claims description 27
- 239000003814 drug Substances 0.000 claims description 23
- 229940124597 therapeutic agent Drugs 0.000 claims description 22
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- -1 hydroxyethoxy group Chemical group 0.000 claims description 10
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical compound P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 claims description 10
- 238000005859 coupling reaction Methods 0.000 claims description 9
- 239000002246 antineoplastic agent Substances 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000004434 sulfur atom Chemical group 0.000 claims description 6
- 208000023275 Autoimmune disease Diseases 0.000 claims description 5
- 208000001132 Osteoporosis Diseases 0.000 claims description 5
- 208000005368 osteomalacia Diseases 0.000 claims description 5
- 208000007442 rickets Diseases 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 2
- 239000000463 material Substances 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 586
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 411
- 239000000243 solution Substances 0.000 description 258
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 237
- 150000001875 compounds Chemical class 0.000 description 229
- 239000000203 mixture Substances 0.000 description 188
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 140
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 102
- 238000010898 silica gel chromatography Methods 0.000 description 96
- 239000012044 organic layer Substances 0.000 description 92
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 91
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 88
- 238000005481 NMR spectroscopy Methods 0.000 description 75
- 238000003756 stirring Methods 0.000 description 58
- 239000011541 reaction mixture Substances 0.000 description 57
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 53
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 52
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 49
- 239000005457 ice water Substances 0.000 description 49
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 49
- 238000005160 1H NMR spectroscopy Methods 0.000 description 47
- 150000003710 vitamin D derivatives Chemical class 0.000 description 47
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 45
- 239000002904 solvent Substances 0.000 description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
- 238000006243 chemical reaction Methods 0.000 description 35
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 33
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 31
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 29
- 238000000034 method Methods 0.000 description 27
- 230000000694 effects Effects 0.000 description 26
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 26
- 235000017557 sodium bicarbonate Nutrition 0.000 description 26
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 26
- 230000015572 biosynthetic process Effects 0.000 description 24
- 238000003786 synthesis reaction Methods 0.000 description 24
- 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 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 22
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 20
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 18
- 102000009310 vitamin D receptors Human genes 0.000 description 18
- 108050000156 vitamin D receptors Proteins 0.000 description 18
- 0 C[C@](*)C(C1(C)CCC2)=CCC1C2=CC=C1C=C(C)C(*)=CC1 Chemical compound C[C@](*)C(C1(C)CCC2)=CCC1C2=CC=C1C=C(C)C(*)=CC1 0.000 description 17
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 16
- 238000011156 evaluation Methods 0.000 description 16
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 14
- 230000004069 differentiation Effects 0.000 description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 12
- 235000019270 ammonium chloride Nutrition 0.000 description 11
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 11
- 229920006395 saturated elastomer Polymers 0.000 description 11
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 239000003446 ligand Substances 0.000 description 10
- 210000002997 osteoclast Anatomy 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 9
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 9
- MVXAKOGJWVQPKC-UHFFFAOYSA-N 5-(3-ethynyl-5-fluorophenyl)-2-pyridin-2-yl-4,6,7,8-tetrahydro-[1,3]oxazolo[4,5-c]azepine Chemical compound FC1=CC(C#C)=CC(N2CC=3N=C(OC=3CCC2)C=2N=CC=CC=2)=C1 MVXAKOGJWVQPKC-UHFFFAOYSA-N 0.000 description 8
- 150000001299 aldehydes Chemical class 0.000 description 8
- 230000027455 binding Effects 0.000 description 8
- QBZXOWQOWPHHRA-UHFFFAOYSA-N lithium;ethane Chemical compound [Li+].[CH2-]C QBZXOWQOWPHHRA-UHFFFAOYSA-N 0.000 description 8
- JYRWUSXRTGACLY-UHFFFAOYSA-N tert-butyl 4-[[3-(4-methylsulfonylphenyl)-[1,2]oxazolo[4,5-d]pyrimidin-7-yl]oxy]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1OC1=NC=NC2=C1ON=C2C1=CC=C(S(C)(=O)=O)C=C1 JYRWUSXRTGACLY-UHFFFAOYSA-N 0.000 description 8
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 7
- 230000004071 biological effect Effects 0.000 description 7
- 229940061627 chloromethyl methyl ether Drugs 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 230000001939 inductive effect Effects 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 210000004443 dendritic cell Anatomy 0.000 description 6
- 230000029279 positive regulation of transcription, DNA-dependent Effects 0.000 description 6
- LPWKFUVWWQYLOD-UHFFFAOYSA-N 9-(dimethylamino)-3-(4-methylphenyl)pyrido[2,3]thieno[2,4-d]pyrimidin-4-one Chemical compound C1=2C(N(C)C)=CN=CC=2SC(C2=O)=C1N=CN2C1=CC=C(C)C=C1 LPWKFUVWWQYLOD-UHFFFAOYSA-N 0.000 description 5
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 5
- 150000002576 ketones Chemical class 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 description 5
- 239000012279 sodium borohydride Substances 0.000 description 5
- 230000002194 synthesizing effect Effects 0.000 description 5
- LENAVORGWBTPJR-UHFFFAOYSA-N (5-pyridin-3-ylfuran-2-yl)methanamine Chemical compound O1C(CN)=CC=C1C1=CC=CN=C1 LENAVORGWBTPJR-UHFFFAOYSA-N 0.000 description 4
- JHLIGYPHPBLDDL-UHFFFAOYSA-N (5-pyridin-3-ylthiophen-2-yl)methanamine Chemical compound S1C(CN)=CC=C1C1=CC=CN=C1 JHLIGYPHPBLDDL-UHFFFAOYSA-N 0.000 description 4
- LFOIDLOIBZFWDO-UHFFFAOYSA-N 2-methoxy-6-[6-methoxy-4-[(3-phenylmethoxyphenyl)methoxy]-1-benzofuran-2-yl]imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=C2SC(OC)=NN2C=C1C(OC1=CC(OC)=C2)=CC1=C2OCC(C=1)=CC=CC=1OCC1=CC=CC=C1 LFOIDLOIBZFWDO-UHFFFAOYSA-N 0.000 description 4
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 229930003316 Vitamin D Natural products 0.000 description 4
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 4
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 4
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- 150000002009 diols Chemical class 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 4
- SKEAGJWUKCNICJ-LSDHHAIUSA-N n-[(4-fluoro-3-methoxyphenyl)methyl]-6-[2-[[(2s,5r)-5-(hydroxymethyl)-1,4-dioxan-2-yl]methyl]tetrazol-5-yl]-2-methylpyrimidine-4-carboxamide Chemical compound C1=C(F)C(OC)=CC(CNC(=O)C=2N=C(C)N=C(C=2)C2=NN(C[C@@H]3OC[C@@H](CO)OC3)N=N2)=C1 SKEAGJWUKCNICJ-LSDHHAIUSA-N 0.000 description 4
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 235000019166 vitamin D Nutrition 0.000 description 4
- 239000011710 vitamin D Substances 0.000 description 4
- 229940046008 vitamin d Drugs 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- LAJAFFLJAJMYLK-CVOKMOJFSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[[(7s)-4-methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5h-benzo[7]annulen-3-yl]amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound N1([C@H]2CCC3=CC=C(C(=C3CC2)OC)NC=2N=C(C(=CN=2)Cl)N[C@H]2[C@H]([C@@]3([H])C[C@@]2(C=C3)[H])C(N)=O)CCOCC1 LAJAFFLJAJMYLK-CVOKMOJFSA-N 0.000 description 3
- KSOVGRCOLZZTPF-QMKUDKLTSA-N (1s,2s,3r,4r)-3-[[5-fluoro-2-[3-methyl-4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound N([C@H]1[C@H]([C@@]2([H])C[C@@]1(C=C2)[H])C(N)=O)C(C(=CN=1)F)=NC=1NC(C=C1C)=CC=C1N1CCN(C)CC1 KSOVGRCOLZZTPF-QMKUDKLTSA-N 0.000 description 3
- AEVBPXDFDKBGLT-YOUFYPILSA-N (2s,3s,4r,5r)-n-[2-[4-(diethoxyphosphorylmethyl)anilino]-2-oxoethyl]-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolane-2-carboxamide Chemical compound C1=CC(CP(=O)(OCC)OCC)=CC=C1NC(=O)CNC(=O)[C@@H]1[C@@H](O)[C@@H](O)[C@H](N2C(NC(=O)C=C2)=O)O1 AEVBPXDFDKBGLT-YOUFYPILSA-N 0.000 description 3
- YCGQPIRMLGEWMW-UHFFFAOYSA-N 1-[1-butyl-4-(3-methoxyphenyl)-2-oxo-1,8-naphthyridin-3-yl]-3-[4-[(dimethylamino)methyl]-2,6-di(propan-2-yl)phenyl]urea;hydrochloride Chemical compound Cl.CC(C)C=1C=C(CN(C)C)C=C(C(C)C)C=1NC(=O)NC=1C(=O)N(CCCC)C2=NC=CC=C2C=1C1=CC=CC(OC)=C1 YCGQPIRMLGEWMW-UHFFFAOYSA-N 0.000 description 3
- SZCBDIVMCGFVPW-UHFFFAOYSA-N 1-[4-(aminomethyl)-2,6-di(propan-2-yl)phenyl]-3-[1-butyl-4-(3-methoxyphenyl)-2-oxo-1,8-naphthyridin-3-yl]urea;hydrochloride Chemical compound Cl.CC(C)C=1C=C(CN)C=C(C(C)C)C=1NC(=O)NC=1C(=O)N(CCCC)C2=NC=CC=C2C=1C1=CC=CC(OC)=C1 SZCBDIVMCGFVPW-UHFFFAOYSA-N 0.000 description 3
- BCSHRERPHLTPEE-NRFANRHFSA-N 2-[[5-chloro-2-[[(6s)-6-[4-(2-hydroxyethyl)piperazin-1-yl]-1-methoxy-6,7,8,9-tetrahydro-5h-benzo[7]annulen-2-yl]amino]pyrimidin-4-yl]amino]-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC=C1NC1=NC(NC=2C(=C3CCC[C@@H](CC3=CC=2)N2CCN(CCO)CC2)OC)=NC=C1Cl BCSHRERPHLTPEE-NRFANRHFSA-N 0.000 description 3
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 3
- VGOALPIDEXVYQI-UHFFFAOYSA-N 3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-n-[3-imidazol-1-yl-5-(trifluoromethyl)phenyl]-4-methylbenzamide Chemical compound C1=C(C#CC=2N3N=CC=CC3=NC=2)C(C)=CC=C1C(=O)NC(C=C(C=1)C(F)(F)F)=CC=1N1C=CN=C1 VGOALPIDEXVYQI-UHFFFAOYSA-N 0.000 description 3
- UNSHMXUHOHBLIQ-UHFFFAOYSA-N 3-[4-chloro-3-(2-methylphenoxy)naphthalen-1-yl]-6-(trifluoromethyl)-1H-pyrimidine-2,4-dione Chemical compound ClC1=C(C=C(C2=CC=CC=C12)N1C(NC(=CC1=O)C(F)(F)F)=O)OC1=C(C=CC=C1)C UNSHMXUHOHBLIQ-UHFFFAOYSA-N 0.000 description 3
- TXEBWPPWSVMYOA-UHFFFAOYSA-N 4-[3-[(1-amino-2-chloroethyl)amino]propyl]-1-[[3-(2-chlorophenyl)phenyl]methyl]-5-hydroxyimidazolidin-2-one Chemical compound NC(CCl)NCCCC1NC(=O)N(Cc2cccc(c2)-c2ccccc2Cl)C1O TXEBWPPWSVMYOA-UHFFFAOYSA-N 0.000 description 3
- WCDLCPLAAKUJNY-UHFFFAOYSA-N 4-[4-[3-(1h-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl]phenyl]morpholine Chemical compound C1COCCN1C1=CC=C(C2=CN3N=CC(=C3N=C2)C2=CNN=C2)C=C1 WCDLCPLAAKUJNY-UHFFFAOYSA-N 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 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 3
- HPKJGHVHQWJOOT-ZJOUEHCJSA-N N-[(2S)-3-cyclohexyl-1-oxo-1-({(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}amino)propan-2-yl]-1H-indole-2-carboxamide Chemical compound C1C(CCCC1)C[C@H](NC(=O)C=1NC2=CC=CC=C2C=1)C(=O)N[C@@H](C[C@H]1C(=O)NCC1)C=O HPKJGHVHQWJOOT-ZJOUEHCJSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 238000004364 calculation method Methods 0.000 description 3
- AEULIVPVIDOLIN-UHFFFAOYSA-N cep-11981 Chemical compound C1=C2C3=C4CNC(=O)C4=C4C5=CN(C)N=C5CCC4=C3N(CC(C)C)C2=CC=C1NC1=NC=CC=N1 AEULIVPVIDOLIN-UHFFFAOYSA-N 0.000 description 3
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Description
本発明の19−ノルビタミンD誘導体(以下、単にビタミンD誘導体ともいう)において、一般式(1)、(2)で表されるビタミンD誘導体は、CD環シントンとA環パートをそれぞれ別途に合成し、カップリング反応により19−ノルビタミンD骨格を構築後、2位を構造修飾し製造することができる。
構造式(31a)及び(31b)で表されるCD環シントンは、ビタミンD2を出発原料として、11工程、又は、12工程により、製造することができる。
次に、合成したCD環シントンとA環ホスフィンオキシド体とのカップリング反応により22−チア−19−ノルビタミンDアナログの合成を行なう。CD環シントンの20S体(31a)とA環ホスフィンオキシド体(32)のカップリングはBaseにLiHMDSを用いて行なうことにより、19−ノル体(2位の異性体比:約3:2)(33a)が得られる。19−ノル体(33a)は、酢酸酸性条件下選択的にTMS基を除去し、2−アルコール体(34a)へ誘導する。2−アルコール体(34a)をエーテル化、続く脱保護反応に付し(20S)−2−ヒドロキシエトキシ−19−ノルビタミンD誘導体(11a)、(12a)を得る。二種の立体異性体はODS系のカラムを用いたHPLCにて分離する。同様に、CD環シントンの20R体(31b)より(20R)−2−ヒドロキシエトキシ−19−ノルビタミンD誘導体(11b)、(12b)を得る。
一般式(3)、(4)で表されるビタミンD誘導体についても同様に、CD環シントンとA環パートをそれぞれ別途に合成し、カップリング反応により19−ノルビタミンD誘導体を製造することができる。以下、製造方法の一例を具体的に説明する。
20−アルコール体の20S体(25a)、20R体(25b)から以下に示す9工程により、CD環シントンの20S体(64a)、20R体(64b)を製造した。A環ホスフィンオキシド体(40)とのカップリング反応により、(20S)−22−オキサ−19−ノルビタミンD誘導体(20a)、(20R)−22−オキサ−19−ノルビタミンD誘導体(20b)を製造する。
本発明のビタミンD誘導体は、骨粗鬆症治療薬、制癌剤、自己免疫疾患治療薬、くる病治療薬、または、骨軟化症治療薬(以下、「治療薬」ともいう)として用いることができる。
治療薬は、本発明のビタミンDを有効成分として含有する以外に、必要な添加剤を配合して、常法に従って、固形経口製剤、経口用液体製剤、又は、注射剤等の非経口製剤として調製することができる。最も好ましいのは、固形経口製剤である。
本発明のビタミンD誘導体の有効投与量は、患者の体重、年齢、性別、投与方法、体調、症状、剤型等により異なるが、成人に対する経口の場合、1日当たり0.001μg以上50μg以下、より好ましくは0.01μg以上10μg以下であり、1回又は2〜数回に分けて服用することが好ましい。
以下のスキームに従って、下記の手順で合成した。
化合物24:1H−NMR(CDCl3)δ:0.00,0.01(each 1H,s,SiMe x 2),0.87(9H,s,tBuSi),0.85(3H,s,H−18),2.09(3H,s,H−21),4.04(1H,m,H−8).
Mass m/z(%):310(M+,2),253(100),161(29),145(23),119(43),75(57).
Mass m/z(%):312(M+,1),255(19),237(100),161(38),75(72).
化合物25b:1H−NMR(CDCl3)δ:−0.003,0.01(each 1H,s,SiMe x 2),0.88(9H,s,tBuSi),0.91(3H,s,H−18),1.20(3H,d,J=6.2Hz,H−21),3.68(1H,m,H−20),4.02(1H,m,H−8).
Mass m/z(%):312(M+,1),255(5),237(100),161(45),75(94).
Mass m/z(%):294(M+,6),237(100),161(85),75(75).
Mass m/z(%):310(no M+),235(100),160(75),75(90).
Mass m/z(%):446(M+,1),389(2),292(10),235(100),161(80),75(85).
Mass m/z(%):398(M+,35),383(15),341(28),256(19),235(92),161(100),75(58).
Mass m/z(%):396(M+,35),324(32),267(37),235(73),161(100),75(80).
化合物29a’:1H−NMR(CDCl3)δ:0.03(6H,s,SiMe x 2),0.89(9H,s,tBuSi),0.87(6H,t,J=7.4Hz,H−26a,27a),1.15(3H,s,H−18),1.37(3H,d,J=7.0Hz,H−21),2.56(2H,s,H−23),3.37(1H,q,J=7.0Hz,H−20),4.08(1H,m,H−8),5.63(1H,m,H−16).
Mass m/z(%):426(M+,38),408(20),235(91),161(100),75(62).
Mass m/z(%):312(M+,1),294(6),276(16),160(73),145(100).
Mass m/z(%):310(M+,13),292(49),209(29),177(100),115(49).
Mass m/z(%):354(M+,1),292(8),252(13),176(100),117(92).
Mass m/z(%):794(M+,1),732(3),616(53),484(94),427(47),309(36),73(100).
Mass m/z(%):722(no M+),660(2),603(2),544(10),355(35),309(32),75(100).
Mass m/z(%):720(no M+),601(10),485(100),353(78).
Mass m/z(%):743(M+,1),681(2),565(60),508(79),481(60),73(100).
化合物37a(Z体):1H−NMR(CDCl3)δ:0.02,0.07,0.10,0.11(each 3H,s,Si−Me x 4),0.84,0.93(each 9H,s,Si−tBu x 2,overlapped with H−18,26a,27a),1.42(3H,d,J=7.0Hz,H−21),2.82(1H,m,H−9),3.02(1H,m,H−10),3.37(3H,s,OMe,overlapped with H−20),4.69(2H,s,OCH2O,overlapped with H−3),5.54(1H,m,H−1),5.62(1H,m,H−16),5.89(1H,d,J=11.4Hz,H−7),6.16(1H,m,C=CH),6.31(1H,d,J=11.4Hz,H−6),10.16(1H,d,J=7.7Hz,CHO).
化合物38a(Z体):1H−NMR(CDCl3)δ:0.01〜0.10(12H,Si−Me x 4),0.82,0.93(each 9H,s,Si−tBu x 2,overlapped with H−18,26a,27a),1.42(3H,d,J=7.0Hz,H−21),3.40(3H,s,OMe,overlapped with H−20),4.69(2H,s,OCH2O),4.17〜4.34(2H,m,CH2OH),4.48(1H,m,H−3),4.88(1H,m,H−1),5.61(1H,m,H−16),5.72(1H,m,C=CH),5.90(1H,d,J=11.0Hz,H−7),6.25(1H,d,J=11.0Hz,H−6).
UV λmax(EtOH):245nm(ε=31600),254nm(ε=35800),263nm(ε=24100).
化合物14a(Z体):1H−NMR(CDCl3)δ:0.85(3H,s,H−18),0.865,0.873(each 3H,t,J=7.4Hz,H−26a,27a),1.42(3H,d,J=7.0Hz,H−21),2.54,2.57(each 1H,d,J=12.9Hz,H−23),2.69(1H,dd,J=12.7,4.7Hz,H−4),2.80(1H,m,H−9),2.88(1H,dd,J=14.2,4.0Hz,H−10),3.43(1H,q,J=7.0Hz,H−20),4.16(1H,dd,J=12.5,5.7Hz,CH2OH),4.36(1H,dd,J=12.5,8.1Hz,CH2OH),4.45(1H,m,H−3),4.85(1H,m,H−1),5.63(1H,m,H−16),5.77(1H,m,C=CH),5.94(1H,d,J=11.2Hz,H−7),6.37(1H,d,J=11.2Hz,H−6).
UV λmax(EtOH):245nm,254nm,263nm.
UV λmax(EtOH):243nm(ε=28400),251nm(ε=33200),261nm(ε=22300).
化合物12a(β体):1H−NMR(CDCl3)δ:0.83(3H,s,H−18),0.856,0.866(each 3H,t,J=7.5Hz,H−26a,27a),1.42(3H,d,J=6.9Hz,H−21),2.49(1H,m,H−4),2.56,2.57(each 1H,d,J=12.9Hz,H−23),2.78(1H,m,H−9),3.09(1H,dd,J=13.5,3.4Hz,H−10),3.30(1H,dd,J=8.7,2.8Hz,H−2),3.43(1H,q,J=6.9Hz,H−20),3.65〜3.89(5H,m,H−1,OCH2CH2O),4.18(1H,m,H−3),5.63(1H,m,H−16),5.94(1H,d,J=11.3Hz,H−7),6.27(1H,d,J=11.3Hz,H−6).
UV λmax(EtOH):243nm,251nm,261nm.
以下のスキームに従って、下記の手順で合成した。
Mass m/z(%):308(M+,12),293(3),251(100),159(8),75(19).
Mass m/z(%):310(M+,5),292(9),253(17),235(51),161(100),75(49).
Mass m/z(%):446(M+,3),431(1),389(4),293(17),235(13),161(100).
Mass m/z(%):398(M+,37),383(16),341(24),292(7),235(62),161(100),75(48).
Mass m/z(%):396(M+,5),339(1),324(4),267(6),235(60),161(69),75(100).
化合物29b’:1H−NMR(CDCl3)δ:0.02,0.03(each 3H,s,SiMe x 2),0.89(9H,s,tBuSi,overlapped with H−26a,27a),1.04(3H,s,H−18),1.45(3H,d,J=6.9Hz,H−21),2.57,2.63(each 1H,d,J=12.7Hz,H−23),3.30(1H,q,J=7.0Hz,H−20),4.09(1H,m,H−8),5.55(1H,m,H−16).
Mass m/z(%):426(M+,8),408(6),235(79),161(46),75(100).
Mass m/z(%):312(M+,8),294(2),276(15),160(71),145(100).
Mass m/z(%):310(M+,16),292(24),209(29),176(100),161(63).
Mass m/z(%):354(M+,6),322(6),292(19),222(16),176(100),161(61).
Mass m/z(%):794(no M+),616(18),559(4),484(36),427(18),309(53),75(10).
Mass m/z(%):722(no M+),660(1),544(54),487(20),412(19),355(100).
Mass m/z(%):720(M+,1),601(13),542(8),485(100),353(38).
化合物36b(Z体):1H−NMR(CDCl3)δ:0.06,0.08,0.11,0.13(each 3H,s,Si−Me x 4),0.71(3H,s,H−18),0.82,0.93(each 9H,s,Si−tBu x 2),0.87(6H,t,J=7.5Hz,H−26a,27a),1.47(3H,d,J=6.9Hz,H−21),2.65(2H,s,H−23),2.79(1H,m,H−9),3.00(1H,m,H−10),3.32(1H,q,J=6.9Hz,H−20),3.41(3H,s,OMe),4.69(2H,s,OCH2O),4.59(1H,m H−3),5.04(1H,m,H−1),5.47(1H,d,J=1.9Hz,C=CH),5.58(1H,m,H−16),5.88(1H,d,J=11.2Hz,H−7),6.31(1H,d,J=11.2Hz,H−6).
Mass m/z(%):743(no M+),681(1),565(56),508(100),481(72),433(37),376(19).
化合物37b(Z体):1H−NMR(CDCl3)δ:0.02,0.08,0.10,0.11(each 3H,s,Si−Me x 4),0.72(3H,s,H−18),0.83,0.93(each 9H,s,Si−tBu x 2),0.89(6H,t,J=7.5Hz,H−26a,27a),1.47(3H,d,J=7.0Hz,H−21),2.65(2H,s,H−23),2.79(1H,m,H−9),3.00(1H,m,H−10),3.32(1H,q,J=7.0Hz,H−20),3.41(3H,s,OMe),4.69(2H,s,OCH2O,overlapped with H−3),5.54(1H,m,H−1),5.58(1H,m,H−16),5.89(1H,d,J=11.2Hz,H−7),6.16(1H,m,C=CH),6.31(1H,d,J=11.2Hz,H−6),10.16(1H,d,J=7.7Hz,CHO).
化合物38b(Z体):1H−NMR(CDCl3)δ:0.01〜0.10(12H,Si−Me x 4),0.72(3H,s,H−18),0.83,0.93(each 9H,s,Si−tBu x 2),0.87(6H,t,J=7.3Hz,H−26a,27a),1.46(3H,d,J=6.9Hz,H−21),2.65(2H,s,H−23),2.79(1H,m,H−9),3.32(1H,q,J=6.9Hz,H−20),3.41(3H,s,OMe),4.69(2H,s,OCH2O),4.17〜4.33(2H,m,CH2OH),4.48(1H,m,H−3),4.86(1H,m,H−1),5.58(1H,m,H−16),5.72(1H,m,C=CH),5.90(1H,d,J=11.1Hz,H−7),6.25(1H,d,J=11.1Hz,H−6).
UV λmax(EtOH):245nm,254nm,263nm.
化合物14b(Z体):1H−NMR(CDCl3)δ:0.74(3H,s,H−18),0.87,0.88(each 3H,t,J=7.4Hz,H−26a,27a),1.46(3H,d,J=6.9Hz,H−21),2.58,2.63(each 1H,d,J=12.8Hz,H−23),2.68(1H,dd,J=12.8,4.5Hz,H−4),2.79(1H,m,H−9),2.88(1H,m,H−10),3.35(1H,q,J=6.9Hz,H−20),4.15(1H,dd,J=12.4,5.3Hz,CH2OH),4.36(1H,dd,J=12.4,8.3Hz,CH2OH),4.44(1H,m,H−3),4.85(1H,m,H−1),5.60(1H,m,H−16),5.76(1H,m,C=CH),5.93(1H,d,J=11.1Hz,H−7),6.37(1H,d,J=11.1Hz,H−6).
UV λmax(EtOH):245nm,254nm,263nm.
UV λmax(EtOH):243nm,251nm,261nm.
化合物12b(β体)1H−NMR(CDCl3)δ:0.72(3H,s,H−18),0.87,0.88(each 3H,t,J=7.5Hz,H−26a,27a),1.46(3H,d,J=7.0Hz,H−21),2.58,2.63(each 1H,d,J=12.8Hz,H−23),2.78(1H,m,H−9),3.09(1H,dd,J=13.3,3.4Hz,H−10),3.31(1H,dd,J=8.8,2.9Hz,H−2),3.35(1H,q,J=7.0Hz,H−20),3.66〜3.90(5H,m,H−1,OCH2CH2O),4.18(1H,m,H−3),5.61(1H,m,H−16),5.93(1H,d,J=11.3Hz,H−7),6.28(1H,d,J=11.3Hz,H−6).
UV λmax(EtOH):243nm,251nm,261nm.
以下のスキームに従って、下記の手順で合成した。
13C NMR (CDCl3) δ:7.20,7.43,8.28,8.45,18.0,21.5,23.9,24.1,27.3,31.9,32.3,34.4,39.3,40.1,40.6,53.4,63.9,125.1,153.8,210.9.
Mass m/z(%):424(M+,1),395(3),338(8),292(10),263(1),201(100),177(14),115(20),75(9).
13C NMR (CDCl3) δ:−4.70,−4.62,−4.52,−4.43,7.23,7.47,8.27,8.43,17.7,18.3,18.4,21.7,23.5,26.0,28.5,29.6,31.9,32.3,35.4,36.9,39.5,40.1,43.9,46.3,49.6,59.1,68.2,68.3,78.5,116.6,121.8,125.1,134.3,140.0,155.8.
Mass m/z(%):776(M+,3),747(1),719(1),644(6),615(1),560(3),528(18),471(5),429(2),396(31),339(15),301(6),265(9),201(100),159(7),103(15),75(28),73(23).
13C NMR (CDCl3)δ:8.23,17.7,21.9,23.6,28.7,29.7,31.0,35.3,37.4,39.9,41.1,42.4,44.8,49.7,59.0,67.4,67.6,74.0,115.8,123.9,125.6,131.8,141.9,155.5.
以下のスキームに従って、下記の手順で合成した。
13C NMR (CDCl3)δ:7.2,7.5,8.3,8.4,17.8,22.1,24.3,27.4,32.1,34.7,37.9,39.3,40.7,54.0,62.9,78.4,123.9,153.5,211.0.
Mass m/z(%):776(M+,7),644(7),528(38),513(9),471(13),396(65),339(34),309(18),264(23),201(100),185(20),103(35),75(77),73(52).
13C NMR (CDCl3)δ:8.3,17.4,22.6,23.7,23.9,28.8,31.1,35.5,37.4,38.9,40.8,42.4,44.8,49.6,50.2,58.1,67.5,67.6,73.9,115.6,123.9,124.8,131.6,142.2,155.4.
Mass m/z(%):434(M+, 1),398(10),380(9),300(100),282(51),264(48),159(52),145(32),91(57),55(50).
以下のスキームに従って、下記の手順で合成した。
以下のスキームに従って、下記の手順で合成した。
Mass m/z(%):440(M+,15),422(11),293(4),235(42),161(100).
Mass m/z(%):484(M+,7),422(11),292(15),235(100),160 (86).
Mass m/z(%):368(M+,4),336(3),306(18),176(84),161(78),131(100).
Massm/z (%):720(no M+),528(19),471(5),396(30),339(17),264(13),75(100).
Mass m/z(%):448(M+,1),430(9),412(7),394(5),300(100),282(33),249 (23).
UV λmax (EtOH):244nm,252nm(ε=28,650),262nm.
以下のスキームに従って、下記の手順で合成した。
Mass m/z(%):426(M+,20),369(10),292(9),235(100),161 (86).
Mass m/z(%):454(M+,6),436(4),292(5),235(76),161(86),143(100).
Mass m/z(%):498(M+,4),436(7),292(5),235(100),161 (61).
Mass m/z(%):384(M+,2),322(2),252(21),145(100).
Mass m/z(%):382(M+,15),320(50),236(16),177(100).
Mass m/z(%):734(no M+),528(28),471(8),396(50),339(26),264(16),75(100).
Mass m/z(%):462(no M+),444(3),426(3),408(3),300(46),282(28),264(33),249(31),143(100).
UV λmax (EtOH):244nm,252nm(ε=29,660),262nm.
以下のスキームに従って、下記の手順で合成した。
Mass m/z(%):426(M+,24),369(9),292(5),235(70),161(100).
Mass m/z(%):454(M+,7),436(3),292(5),235(98),161(73),75(100).
Mass m/z(%):498(M+,4),436(9),292(4),235(74),161(73),75(100).
Mass m/z(%):384(M+,1),322(2),252(13),160(58),145(100).
Mass m/z(%):382(M+,10),320(30),236(10),177(100).
Mass m/z(%):734(no M+),528(57),471(16),396(86),339(38),264(20),75(100).
Mass m/z(%):462(M+,1),444(2),426(3),408(2),300(36),282(22),264(22),249(22),143(100).
UV λmax(EtOH):244nm,252nm(ε=28,260),262nm..
以下のスキームに従って、下記の手順で合成した。
以下のスキームに従って、下記の手順で合成した。
以下のスキームに従って、下記の手順で合成した。
Mass m/z(%):no M+,528(50),471(20),396(100),339(46),264(24).
Mass m/z(%):418(M+,5),400(3),300(100),282(42).
以下のスキームに従って、下記の手順で合成した。
[転写活性化能の評価]
上記の構造式(11a)、(12a)、(11b)、(12b)、(15a)、(15b)、(16a)、(16b)、(17a)、(17b)で表されるビタミンD誘導体及び、比較例として、1,25−(OH)2D3、2MDについて、以下の評価を行った。
構造式(11a)、(12a)、(11b)、(12b)で表されるビタミンD誘導体、対照として1,25−(OH)2D3と2MDを用い、10−12〜10−8Mの各濃度で活性を比較した。1,25−(OH)2D3と2MD(構造式(c))の結果を図3に、構造式(11a)、(12a)で表されるビタミンD誘導体の結果を図4に、構造式(11b)、(12b)で表されるビタミンD誘導体の結果を図5に示す。2MDは1,25−(OH)2D3と比較して、破骨細胞分化を約100倍強い促進活性を示した。YI−690A(12a)は2MDより強い破骨細胞分化促進活性を示した。YI−690B(11a)は2MDと同等の活性であった。YI−725A(11b),725B(12b)も1,25−(OH)2D3に比べて強い分化誘導活性を有していた。
成熟樹状細胞への分化に対する効果は、マウス骨髄由来のマクロファージを用いて、GM−CSF(顆粒球・マクロファージコロニー刺激因子)およびビタミンD誘導体存在下、LPS(リボ多糖)未刺激または刺激によるCD86の発現量を蛍光抗体で標識し、FACS(蛍光抗体法)で測定して評価した。結果を図6に示す。
ラットビタミンD受容体リガンド結合ドメインは大腸菌タンパク発現系を用いてLB培地中で大量合成した。タンパクを強発現させた菌体を集菌し、超音波処理後に超遠心分離(17,000rpm,20min,6℃)により上清部を得た。約0.025μgのラットビタミンD受容体リガンド結合ドメインを含む上清部を600μlの50mM Tris buffer[50mM Tris,100mM KCl、5mM DTT(dithiothreitol)、0.5%CHAPS、BSA(Bovine serum albumin)100μg/ml、pH7.5]に溶かし、レセプター溶液とした。この溶液570μlをカルチャーチューブに入れ、局方エタノール(15μl)に溶解した1,25−(OH)2D3(最終濃度:0.01nM〜1μM)または各サンプルを添加しボルテックス後、室温にてインキュベートした。30分後、局方エタノール(15μl)に溶解した[3H]−1,25−(OH)2D3(2,000〜3,000cpm)を各チューブに添加およびボルテックス後、4℃、遮光下でインキュベートした。20時間後、各チューブに200μlのDCC(デキストラン被覆チャコール、ヤマサ醤油株式会社より購入)を添加、ボルテックス後、室温で30分間インキュベートした。遠心分離(3,000rpm、10min、0℃)により受容体に結合した[3H]−1,25−(OH)2D3と遊離の[3H]−1,25−(OH)2D3とを分離後、各チューブから500μlを取り、液体シンチレーター(ACS−II、9.5ml)を加え、放射活性を測定した。実験は各サンプルについて2回行った。
以下の式により算出した。なお、値が大きい程活性が強いことを示す。
X=y/x
X:各サンプルのVDRへの相対的結合性(VDR親和性)
y:1,25−(OH)2D3が[3H]−1,25−(OH)2D3とVDRとの結合を50%阻害する濃度
x:各サンプルが[3H]−1,25−(OH)2D3とVDRとの結合を50%阻害する濃度
一つのサンプルについてドースリスポンスカーブ(濃度を変えて測定)を作成し、ED50値(各サンプルの最大活性の50%を示す濃度)を求める。1,25−(OH)2D3のED50値を1として、各サンプルのED50との相対値で示す。値が大きい程活性が強いことを示す。
である。
Claims (5)
- 前記一般式(1)又は(2)中のR1が、ヒドロキシエトキシ基、又は、ヒドロキシエチリデン基である請求項1記載の19−ノルビタミンD誘導体。
- 請求項1から3いずれか記載の19−ノルビタミンD誘導体を有効成分とする、骨粗鬆症治療薬、制癌剤、自己免疫疾患治療薬、くる病治療薬、又は、骨軟化症治療薬。
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JPH10231284A (ja) * | 1996-12-20 | 1998-09-02 | Chugai Pharmaceut Co Ltd | 16−エン−ビタミンd誘導体 |
JP2001515881A (ja) * | 1997-09-08 | 2001-09-25 | エフ.ホフマン−ラ ロシュ アーゲー | 1,3−ジヒドロキシ−20,20−ジアルキル−ビタミンd3類似体 |
WO2001079166A1 (fr) * | 2000-04-19 | 2001-10-25 | Chugai Seiyaku Kabushiki Kaisha | Derives de la vitamine d |
WO2001096293A1 (fr) * | 2000-06-15 | 2001-12-20 | Chugai Seiyaku Kabushiki Kaisha | Derives de vitamine d |
JP2002537222A (ja) * | 1998-08-18 | 2002-11-05 | ウィスコンシン・アルムニ・リサーチ・ファウンデーション | カルセミック活性を持つ19−ノル−ビタミンd3化合物 |
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PT947504E (pt) * | 1996-12-20 | 2003-12-31 | Chugai Pharmaceutical Co Ltd | Derivados de vitamina d 16-eno |
US5945410A (en) * | 1997-03-17 | 1999-08-31 | Wisconsin Alumni Research Foundation | 2-alkyl-19-nor-vitamin D compounds |
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JPH10231284A (ja) * | 1996-12-20 | 1998-09-02 | Chugai Pharmaceut Co Ltd | 16−エン−ビタミンd誘導体 |
JP2001515881A (ja) * | 1997-09-08 | 2001-09-25 | エフ.ホフマン−ラ ロシュ アーゲー | 1,3−ジヒドロキシ−20,20−ジアルキル−ビタミンd3類似体 |
JP2002537222A (ja) * | 1998-08-18 | 2002-11-05 | ウィスコンシン・アルムニ・リサーチ・ファウンデーション | カルセミック活性を持つ19−ノル−ビタミンd3化合物 |
WO2001079166A1 (fr) * | 2000-04-19 | 2001-10-25 | Chugai Seiyaku Kabushiki Kaisha | Derives de la vitamine d |
WO2001096293A1 (fr) * | 2000-06-15 | 2001-12-20 | Chugai Seiyaku Kabushiki Kaisha | Derives de vitamine d |
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