JP2009256361A - 24−ヒドロキシビタミンd誘導体 - Google Patents
24−ヒドロキシビタミンd誘導体 Download PDFInfo
- Publication number
- JP2009256361A JP2009256361A JP2009148244A JP2009148244A JP2009256361A JP 2009256361 A JP2009256361 A JP 2009256361A JP 2009148244 A JP2009148244 A JP 2009148244A JP 2009148244 A JP2009148244 A JP 2009148244A JP 2009256361 A JP2009256361 A JP 2009256361A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- methyl
- group
- octahydro
- general formula
- 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.)
- Granted
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- 125000006239 protecting group Chemical group 0.000 claims abstract description 40
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 29
- 150000003710 vitamin D derivatives Chemical class 0.000 claims abstract description 27
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 87
- 238000000034 method Methods 0.000 abstract description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 84
- -1 steroid compound Chemical class 0.000 description 74
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 67
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 63
- 239000000243 solution Substances 0.000 description 46
- 230000015572 biosynthetic process Effects 0.000 description 41
- 238000003786 synthesis reaction Methods 0.000 description 41
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 35
- 230000002829 reductive effect Effects 0.000 description 29
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 26
- 239000000203 mixture Substances 0.000 description 25
- 239000002904 solvent Substances 0.000 description 25
- 239000012230 colorless oil Substances 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- 238000005481 NMR spectroscopy Methods 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 19
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 16
- 235000019341 magnesium sulphate Nutrition 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000011612 calcitriol Substances 0.000 description 12
- 238000003818 flash chromatography Methods 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 125000001137 3-hydroxypropoxy group Chemical group [H]OC([H])([H])C([H])([H])C([H])([H])O* 0.000 description 11
- NOIDOYJLIPVSOK-XNWIYYODSA-N C1CCCC2[C@H](C)CCC21 Chemical compound C1CCCC2[C@H](C)CCC21 NOIDOYJLIPVSOK-XNWIYYODSA-N 0.000 description 11
- 229910052739 hydrogen Inorganic materials 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 10
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000005859 coupling reaction Methods 0.000 description 9
- 230000002194 synthesizing effect Effects 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000012300 argon atmosphere Substances 0.000 description 8
- 238000012746 preparative thin layer chromatography Methods 0.000 description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 102000009310 vitamin D receptors Human genes 0.000 description 8
- 108050000156 vitamin D receptors Proteins 0.000 description 8
- 230000001766 physiological effect Effects 0.000 description 7
- XRFAFHWDKTZOKV-CBMCFHRWSA-N (1S,7aR)-7a-methyl-1,2,3,3a,4,5,6,7-octahydroinden-1-ol Chemical compound C1CCCC2CC[C@H](O)[C@@]21C XRFAFHWDKTZOKV-CBMCFHRWSA-N 0.000 description 6
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 6
- 0 BC=C(CCC1)[C@](CC2)[C@@]1(C)C2(*C)[C@](C)CC[C@](C)(*)C(C)(C)O* Chemical compound BC=C(CCC1)[C@](CC2)[C@@]1(C)C2(*C)[C@](C)CC[C@](C)(*)C(C)(C)O* 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 239000008194 pharmaceutical composition Substances 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 5
- IRCBNGIADAIKGQ-AFPNSQJFSA-N C[C@H](CC1)C(CCC2)C1C2=O Chemical compound C[C@H](CC1)C(CCC2)C1C2=O IRCBNGIADAIKGQ-AFPNSQJFSA-N 0.000 description 5
- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 4
- 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
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 101100189356 Mus musculus Papolb gene Proteins 0.000 description 4
- WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 235000020964 calcitriol Nutrition 0.000 description 4
- 230000003913 calcium metabolism Effects 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- BNRNAKTVFSZAFA-UHFFFAOYSA-N hydrindane Chemical compound C1CCCC2CCCC21 BNRNAKTVFSZAFA-UHFFFAOYSA-N 0.000 description 4
- 239000012280 lithium aluminium hydride Substances 0.000 description 4
- 239000002808 molecular sieve Substances 0.000 description 4
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 4
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 3
- ULALARGFGSDNST-UHFFFAOYSA-N 3-[2-(2,2-dimethylpropanoyloxy)-1-(oxiran-2-yl)but-3-enoxy]propyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCCOC(C(OC(=O)C(C)(C)C)C=C)C1CO1 ULALARGFGSDNST-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- XXICBPSJGZAFBO-UHFFFAOYSA-N [6-(bromomethylidene)cyclohexa-2,4-dien-1-yl]-diphenylphosphanium;bromide Chemical compound [Br-].BrC=C1C=CC=CC1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 XXICBPSJGZAFBO-UHFFFAOYSA-N 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 125000003710 aryl alkyl group Chemical group 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 239000002207 metabolite Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- OKDQKPLMQBXTNH-UHFFFAOYSA-N n,n-dimethyl-2h-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N p-toluenesulfonic acid Substances CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 3
- 235000019345 sodium thiosulphate Nutrition 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 150000003704 vitamin D3 derivatives Chemical class 0.000 description 3
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 2
- LJIOTBMDLVHTBO-CUYJMHBOSA-N (2s)-2-amino-n-[(1r,2r)-1-cyano-2-[4-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]cyclopropyl]butanamide Chemical compound CC[C@H](N)C(=O)N[C@]1(C#N)C[C@@H]1C1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)N2CCN(C)CC2)C=C1 LJIOTBMDLVHTBO-CUYJMHBOSA-N 0.000 description 2
- GQQUMQKFDJXACY-UNWFITJNSA-N (3E,3aR)-3-(bromomethylidene)-3a-methyl-2,4,5,6,7,7a-hexahydro-1H-indene Chemical compound C1CCCC2CC\C(=C/Br)[C@@]21C GQQUMQKFDJXACY-UNWFITJNSA-N 0.000 description 2
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 description 2
- FRJJJAKBRKABFA-TYFAACHXSA-N (4r,6s)-6-[(e)-2-[6-chloro-4-(4-fluorophenyl)-2-propan-2-ylquinolin-3-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C(\[C@H]1OC(=O)C[C@H](O)C1)=C/C=1C(C(C)C)=NC2=CC=C(Cl)C=C2C=1C1=CC=C(F)C=C1 FRJJJAKBRKABFA-TYFAACHXSA-N 0.000 description 2
- DPRJPRMZJGWLHY-HNGSOEQISA-N (e,3r,5s)-7-[5-(4-fluorophenyl)-3-propan-2-yl-1-pyrazin-2-ylpyrazol-4-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound OC(=O)C[C@H](O)C[C@H](O)/C=C/C=1C(C(C)C)=NN(C=2N=CC=NC=2)C=1C1=CC=C(F)C=C1 DPRJPRMZJGWLHY-HNGSOEQISA-N 0.000 description 2
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 2
- IRCBNGIADAIKGQ-UHFFFAOYSA-N 1-methyl-1,2,3,3a,5,6,7,7a-octahydroinden-4-one Chemical compound C1CCC(=O)C2C1C(C)CC2 IRCBNGIADAIKGQ-UHFFFAOYSA-N 0.000 description 2
- NOIDOYJLIPVSOK-UHFFFAOYSA-N 1-methyl-2,3,3a,4,5,6,7,7a-octahydro-1h-indene Chemical compound C1CCCC2C(C)CCC21 NOIDOYJLIPVSOK-UHFFFAOYSA-N 0.000 description 2
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 2
- MSSQOQPKGAMUSY-LEAFIULHSA-N 2-[1-[2-[(4r,6s)-8-chloro-6-(2,3-dimethoxyphenyl)-4,6-dihydropyrrolo[1,2-a][4,1]benzoxazepin-4-yl]acetyl]piperidin-4-yl]acetic acid Chemical compound COC1=CC=CC([C@@H]2C3=CC(Cl)=CC=C3N3C=CC=C3[C@@H](CC(=O)N3CCC(CC(O)=O)CC3)O2)=C1OC MSSQOQPKGAMUSY-LEAFIULHSA-N 0.000 description 2
- OJXOCHUHYYCJPV-UHFFFAOYSA-N 3-[3,5-bis[[tert-butyl(dimethyl)silyl]oxy]oct-1-en-7-yn-4-yloxy]propoxy-tert-butyl-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OCCCOC(C(CC#C)O[Si](C)(C)C(C)(C)C)C(O[Si](C)(C)C(C)(C)C)C=C OJXOCHUHYYCJPV-UHFFFAOYSA-N 0.000 description 2
- TZKBVRDEOITLRB-UHFFFAOYSA-N 4-methyl-n-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[2-(1h-pyrazolo[3,4-b]pyridin-5-yl)ethynyl]benzamide Chemical compound C1CN(C)CCN1CC(C(=C1)C(F)(F)F)=CC=C1NC(=O)C1=CC=C(C)C(C#CC=2C=C3C=NNC3=NC=2)=C1 TZKBVRDEOITLRB-UHFFFAOYSA-N 0.000 description 2
- KUZSBKJSGSKPJH-VXGBXAGGSA-N 5-[(9R)-6-[(3R)-3-methylmorpholin-4-yl]-11-oxa-1,3,5-triazatricyclo[7.4.0.02,7]trideca-2,4,6-trien-4-yl]pyrazin-2-amine Chemical compound C[C@@H]1COCCN1c1nc(nc2N3CCOC[C@H]3Cc12)-c1cnc(N)cn1 KUZSBKJSGSKPJH-VXGBXAGGSA-N 0.000 description 2
- LDIOUQIXNSSOGU-UHFFFAOYSA-N 8-(3-pentylamino)-2-methyl-3-(2-chloro-4-methoxyphenyl)-6,7-dihydro-5h-cyclopenta[d]pyrazolo[1,5-a]pyrimidine Chemical compound CC1=NN2C(NC(CC)CC)=C3CCCC3=NC2=C1C1=CC=C(OC)C=C1Cl LDIOUQIXNSSOGU-UHFFFAOYSA-N 0.000 description 2
- MITGKKFYIJJQGL-UHFFFAOYSA-N 9-(4-chlorobenzoyl)-6-methylsulfonyl-2,3-dihydro-1H-carbazol-4-one Chemical compound ClC1=CC=C(C(=O)N2C3=CC=C(C=C3C=3C(CCCC2=3)=O)S(=O)(=O)C)C=C1 MITGKKFYIJJQGL-UHFFFAOYSA-N 0.000 description 2
- QUMCIHKVKQYNPA-RUZDIDTESA-N C1(CCCCC1)CN1[C@@H](C=2N(C=3C=NC(=NC1=3)NC1=C(C=C(C(=O)NC3CCN(CC3)C)C=C1)OC)C(=NN=2)C)CC Chemical compound C1(CCCCC1)CN1[C@@H](C=2N(C=3C=NC(=NC1=3)NC1=C(C=C(C(=O)NC3CCN(CC3)C)C=C1)OC)C(=NN=2)C)CC QUMCIHKVKQYNPA-RUZDIDTESA-N 0.000 description 2
- GTGFEMLBUOZMFR-DTIOYNMSSA-N C[C@@]1(C(CC2)CCCC1)C2=C Chemical compound C[C@@]1(C(CC2)CCCC1)C2=C GTGFEMLBUOZMFR-DTIOYNMSSA-N 0.000 description 2
- XRFAFHWDKTZOKV-UDNWOFFPSA-N C[C@@]1(C(CC2)CCCC1)C2O Chemical compound C[C@@]1(C(CC2)CCCC1)C2O XRFAFHWDKTZOKV-UDNWOFFPSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 208000001132 Osteoporosis Diseases 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C33/40—Halogenated unsaturated alcohols
- C07C33/44—Halogenated unsaturated alcohols containing rings other than six-membered aromatic rings
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- 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
- C07C35/22—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 polycyclic, at least one hydroxy group bound to a condensed ring system
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- C07C35/32—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 polycyclic, at least one hydroxy group bound to a condensed ring system with hydroxy on a condensed ring system having two rings the condensed ring system being a (4.3.0) system, e.g. indenols
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- 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 System
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Abstract
Description
を有するビタミンD誘導体が提供される。
本発明の第2の側面によれば、一般式(2):
を有する化合物、一般式(3):
を有する化合物、並びに一般式(4):
を有する化合物が提供される。これらの化合物は一般式(1)の化合物の合成に有用な中間体化合物である。
を有する化合物が提供される。この化合物は一般式(1)の化合物の合成に有用な中間体である。
を有するビタミンD誘導体の製造方法であって、一般式(4):
を有する化合物を、一般式(5):
を有する化合物と反応させることを含む方法が提供される。
を有するビタミンD誘導体の製造方法であって、一般式(7):
を有する化合物を、一般式(5):
を有する化合物と反応させることを含む方法が提供される。
を有するビタミンD誘導体を含む、医薬組成物が提供される。
(II)RbOCO−で表されるアルコキシカルボニル基(式中、RbはC1−C6アルキル基、C1−C6アルケニル基、C7−C9アラルキル基、アリール基を表す);例えば、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、アリルオキシカルボニル、ベンジルオキシカルボニル、フェノキシカルボニル基など;
(III)下記式
(IV)下記式
(V)下記式
(VI)ベンジル基などのアラルキル基:
あるいは、本発明においてR1 とR5 は一緒になって、ビシナル−ジオールの保護基を形成していてもよい。
氷冷下、[3a(R)]−4(S)−ヒドロキシ−7a(R)−メチル−1(R)−[1(S)−メチル−2−フェニルスルホニルエチル]−オクタヒドロ−1H−インデン(化合物4;334mg,994μmol)、ピリジン(200μl)およびN,N−ジメチルアミノピリジン(DMAP)(18mg)のジクロロメタン(20ml)溶液に、無水酢酸(188μl,1.99mmol)を添加し、アルゴン雰囲気下、室温で16時間撹拌した。反応混合物を希塩酸に注ぎ、ジクロロメタンで抽出し、飽和炭酸水素ナトリウム(NaHCO3 )溶液で洗浄した。有機層を硫酸マグネシウム(MgSO4 )で乾燥後、溶媒を減圧留去して得られる残渣をフラッシュカラムクロマトグラフィー(40%酢酸エチル/ヘキサン)で精製し、無色油状の標題化合物(368mg,98%)を得た。
IR(neat)cm−1:2945,1735,1310,1250,1150;
MS(m/z):336(M+−AC),135(100%);
UV λ max nm:270,263,257,217。
アルゴン雰囲気下、−20℃で[3a(R)]−4(S)−アセチルオキシ−7a(R)−メチル−1(R)−[1(S)−メチル−2−フェニルスルホニルエチル]−オクタヒドロ−1H−インデン(実施例1で得たもの、160mg,423μmol)および2(R),3−ジヒドロキシ−3−メチル−1−パラトルエンスルホニルオキシブタン(R.DumontおよびH.Pfander,Helvetica Chimica Acta,66,814(1983)並びにその中の引用文献に記載)(232mg,847μmol)のTHE(15ml)溶液に、n−ブチルリチウム(1.63M,2.3ml,3.75mmol)を滴下し、同温度で2時間撹拌した。反応混合物を飽和塩化アンモニウム水溶液に注ぎ、酢酸エチルで2回抽出し、飽和食塩水で洗浄した。有機層を硫酸マグネシウムで乾燥した後、溶媒を減圧留去して得られる残渣をフラッシュカラムクロマトグラフィー(エタノール:ジクロロメタン=0.3:5)で精製し、無色泡状の標題化合物(131mg,71%)を得た。
IR(neat)cm−1:3500(br),2935,1300,1280,1135;
MS(m/z):439(M++1),71(100%);
UV λ max nm:271,263,257,216。
[3a(R)]−4(S)−ヒドロキシ−7a(R)−メチル−1(R)−[1(S)−メチル−2−フェニルスルホニルエチル]−オクタヒドロ−1H−インデン(化合物4;305mg,908μmol)、2(S),3−ジヒドロキシ−3−メチル−1−パラトルエンスルホニルオキシブタン(R.DumontおよびH.Pfander,Helvetica Chimica Acta,66,814(1983)並びにその中の引用文献に記載)(化合物6b;249mg,909μmol)、THE(20ml)およびn−ブチルリチウム(1.69M,4.3ml,7.27mmol)を使用し、実施例2の合成と同様の操作を行った(カラムクロマトグラフィーの溶媒のみ酢酸エチル:ヘキサン=4:1)。無色油状の標題化合物(110mg,28%)を得た。
IR(neat)cm−1:3460(br),2925,1280,1135,1075;
MS(m/z):439(M++1),60(100%)
実施例4:[3a(R)]−1(R)−[4(R),5−ジヒドロキシ−1(S),5−ジメチルヘキシル]−4(S)−ヒドロキシ−7a(R)−メチル−オクタヒドロ−1H−インデン(化合物8a)の合成
実施例2で得た[3a(R)]−1(R)−[4(R),5−ジヒドロキシ−1(S),5−ジメチル−2−フェニルスルホニルヘキシル]−4(S)−ヒドロキシ−7a(R)−メチル−オクタヒドロ−1H−インデン(化合物7a;104mg,237μmol)のTHE(5.5ml)およびメタノール(3.5ml)溶液に、ナトリウムアマルガム(5%,5.01g,10.9mmol)を加え、室温で15時間撹拌した。反応液にメタノール(5.4ml)および水(5.4ml)を加え、さらに30分間撹拌した。アマルガムをデカンテーションにより除去後、反応液を飽和塩化アンモニウム水溶液に注ぎ、酢酸エチルで2回抽出し、飽和食塩水で洗浄した。有機層を硫酸マグネシウムで乾燥後、溶媒を減圧留去して得られる残渣をフラッシュカラムクロマトグラフィー(エタノール:ジクロロメタン=0.3:5)で精製し、無色泡状の標題化合物(68mg,96%)を得た。
IR(neat)cm−1:3400(br),2930;
MS(m/z):298(M+),135(100%)
実施例5:[3a(R)]−1(R)−[4(S),5−ジヒドロキシ−1(S),5−ジメチルヘキシル]−4(S)−ヒドロキシ−7a(R)−メチル−オクタヒドロ−1H−インデン(化合物8b)の合成
実施例3で得た[3a(R)]−1(R)−[4(S),5−ジヒドロキシ−1(S),5−ジメチル−2−フェニルスルホニルヘキシル]−4(S)−ヒドロキシ−7a(R)−メチル−オクタヒドロ−1H−インデン(化合物7b;216mg,493μmol)、THF(12ml)、メタノール(7.5ml)およびナトリウムアマルガム(5%,12.4g,27.0mmol)を使用し、実施例4の合成と同様の操作を行った。無色油状の標題化合物(100mg,68%)を得た。
IR(neat)cm−1:3400(br),2930;
MS(m/z):280(M+−H2 O),60(100%)。
実施例4で得た[3a(R)]−1(R)−[4(R),5−ジヒドロキシ−1(S),5−ジメチルヘキシル]−4(S)−ヒドロキシ−7a(R)−メチル−オクタヒドロ−1H−インデン(化合物8a;86mg,289μmol)および2,2−ジメトキシプロパン(DMP,2.93g,28.1mmol)のアセトン(19.5ml)溶液にp−トルエンスルホン酸(TsOH)(6.5mg,34.2μmol)を添加し、アルゴン雰囲気下、室温で15時間撹拌した。反応混合物に炭酸水素ナトリウム(10mg)を添加し、減圧濃縮後、ジクロロメタンで2回抽出した。有機層を硫酸マグネシウムで乾燥後、溶媒を減圧留去して得られる残渣をフラッシュカラムクロマトグラフィー(エタノール:ジクロロメタン=0.2:5)で精製し、無色プリズム晶の粗製の標題化合物(107mg)を得、これをこれ以上精製することなく次の工程に用いた。
IR(KBr)cm−1:3485(br),2920;
MS(m/z):338(M+),323(100%)
実施例7:[3a(R)]−4(S)−ヒドロキシ−7a(R)−メチル−1(R)−[1(S)−メチル−3−[2,2,4,4−テトラメチル−1,3−ジオキソラン−2(S)−イル]プロピル]−オクタヒドロ−1H−インデン(化合物9b)の合成
実施例5で得た[3a(R)]−1(R)−[4(S),5−ジヒドロキシ−1(S),5−ジメチルヘキシル]−4(S)−ヒドロキシ−7a(R)−メチル−オクタヒドロ−1H−インデン(化合物8b;100mg,289μmol)、2,2−ジメトキシプロパン(3.8g,36.5mmol)、アセトン(23ml),TsOH(15mg,78.9μmol)および炭酸水素ナトリウム(20mg)を使用し、実施例6の合成と同様の操作を行った。無色油状の標題化合物(76mg,67%)を得た。
IR(neat)cm−1:3520(br),2930;
MS(m/z):323(M+−Me,100%)
実施例8:[3a(R)]−4(S)−アセチルオキシ−1(R)−[1(S)−メチル−3−[2,2,4,4−テトラメチル−1,3−ジオキソラン−2(R)−イル]プロピル]−7a(R)−メチル−オクタヒドロ−1H−インデン(化合物10a)の合成
実施例6で得た粗製の[3a(R)]−4(S)−ヒドロキシ−7a(R)−メチル−1(R)−[1(S)−メチル−3−[2,2,4,4−テトラメチル−1,3−ジオキソラン−2(R)−イル]プロピル]−オクタヒドロ−1H−インデン(化合物9a;107mg)、ピリジン(128μl)およびDMAP(7mg)のジクロロメタン(10ml)溶液に、無水酢酸(120μl,1.27mmol)を添加し、アルゴン雰囲気下、室温で4時間撹拌した。反応混合物を希塩酸に注ぎ、ジクロロメタンで抽出し、飽和炭酸ナトリウム溶液で洗浄した。有機層を硫酸マグネシウムで乾燥後、溶媒を減圧留去して得られる残渣をフラッシュカラムクロマトグラフィー(15% 酢酸エチル/ヘキサン)で精製し、無色油状の標題化合物(91mg,[3a(R)]−1(R)−[4(R),5−ジヒドロキシ−1(S),5−ジメチルヘキシル]−4(S)−ヒドロキシ−7a(R)−メチル−オクタヒドロ−1H−インデンからみて83%)を得た。
IR(neat)cm−1:2940,1735:
MS(m/z):365(M+−Me,100%)。
実施例7で得た[3a(R)]−4(S)−ヒドロキシ−7a(R)−メチル−1(R)−[1(S)−メチル−3−[2,2,4,4−テトラメチル−1,3−ジオキソラン−2(S)−イル]プロピル]−オクタヒドロ−1H−インデン(化合物9b;76mg,225μmol)、ピリジン(500μl)、DMAP(3mg)、ジクロロメタン(3ml)および無水酢酸(250μl,2.64mmol)を使用し、実施例8の合成と同様の操作を行った。淡黄色油状の標題化合物(82mg,96%)を得た。
IR(neat)cm−1:2930,1735;
MS(m/z):365(M+−Me,100%)。
実施例8で得た[3a(R)]−4(S)−アセチルオキシ−1(R)−[1(S)−メチル−3−[2,2,4,4−テトラメチル−1,3−ジオキソラン−2(R)−イル]プロピル]−7a(R)−メチル−オクタヒドロ−1H−インデン(化合物10a;46mg,121μmol)に1%ヨウ素/メタノール(2ml)を加え、4.5時間加熱還流した。反応混合物を10%チオ硫酸ナトリウム(Na2 S2 O3 )溶液に注ぎ、減圧濃縮後、酢酸エチルで抽出し、2回水洗した。有機層を硫酸マグネシウムで乾燥した後、溶媒を減圧留去して得られる残渣をフラッシュカラムクロマトグラフィー(40% 酢酸エチル/ヘキサン)で精製し、無色油状の標題化合物(25mg,61%)を得た。
IR(neat)cm−1:3455(br),2930,1735;
MS(m/z):280(M+−Ac−H2 O),59(100%)。
実施例9で得た[3a(R)]−4(S)−アセチルオキシ−1(R)−[1(S)−メチル−3−[2,2,4,4−テトラメチル−1,3−ジオキソラン−2(S)−イル]プロピル]−7a(R)−メチル−オクタヒドロ−1H−インデン(化合物10b;34mg,89.5μmol)、酢酸(240μl)、水(1.99ml)およびエタノール(2.6ml)の混合物を70℃で5日間撹拌した。反応混合物を飽和炭酸水素ナトリウム溶液に注ぎ、酢酸エチルで2回抽出し、飽和食塩水で洗浄した。有機層を硫酸マグネシウムで乾燥後、溶媒を減圧留去して得られる残渣をフラッシュカラムクロマトグラフィー(40% 酢酸エチル/ヘキサン)で精製し、無色油状の標題化合物(25mg,83%)を得た。
IR(neat)cm−1:3460(br),2935,1730:
MS(m/z):340(M+),135(100%)。
氷冷下、実施例10で得た[3a(R)]−4(S)−アセチルオキシ−1(R)−[4(R),5−ジヒドロキシ−1(S),5−ジメチルヘキシル]−7a(R)−メチル−オクタヒドロ−1H−インデン(化合物11a;46mg,135μmol)および2,6−ルチジン(355μl,3.03mmol)のジクロロメタン(10ml)溶液にt−ブチルジメチルシリルトリフルオロメタンスルホネート(TBSOTf)(466μl,2.03mmol)を添加し、室温で1.5時間撹拌した。反応混合物を氷冷した1N塩酸に注ぎ、ジクロロメタンで抽出し、飽和炭酸ナトリウム溶液で洗浄した。有機層を硫酸マグネシウムで乾燥後、溶媒を減圧留去して得られる残渣をフラッシュカラムクロマトグラフィー(6% 酢酸エチル/ヘキサン)で精製し、無色油状の標題化合物(71mg,92%)を得た。
IR(neat)cm−1:2945,1745:
MS(m/z):553(M+−Me),173(100%)。
実施例11で得た[3a(R)]−4(S)−アセチルオキシ−1(R)−[4(S),5−ジヒドロキシ−1(S),5−ジメチルヘキシル]−7a(R)−メチル−オクタヒドロ−1H−インデン(化合物11b;31mg,91.2μmol)、2,6−ルチジン(64μl,550μmol)、ジクロロメタン(2ml)およびTBSOTf(84μl,366mmol)を使用し、実施例12の合成と同様の操作を行った。無色油状の標題化合物(47mg,91%)を得た。
IR(neat)cm−1:2945,1735:
MS(m/z):553(M+−Me),173(100%)。
氷冷下、水素化リチウムアルミニウム(LiAlH4 )(20mg,528μmol)のTHE(1ml)懸濁液に、実施例12で得た[3a(R)]−4(S)−アセチルオキシ−1(R)−[4(R),5−ビス(t−ブチルジメチルシリルオキシ)−1(S),5−ジメチルヘキシル]−7a(R)−メチル−オクタヒドロ−1H−インデン(化合物12a;71mg,125μmol)のTHF(2ml)溶液を滴下し、アルゴン雰囲気下、同温度で1.5時間撹拌した。反応混合物に1Nの水酸化ナトリウム(NaOH)(5滴)を滴下し、さらにロッシェル塩水溶液を加えて酢酸エチルで2回抽出し、飽和食塩水で洗浄した。
IR(neat)cm−1:3425(br),2925;
MS(m/z):511(M+−Me),173(100%)。
LiAlH4 (6.3mg,166μmol)、THF(3ml)および実施例13で得た[3a(R)]−4(S)−アセチルオキシ−1(R)−[4(S),5−ビス(t−ブチルジメチルシリルオキシ)−1(S),5−ジメチルヘキシル]−7a(R)−メチル−オクタヒドロ−1H−インデン(化合物12b;47mg,82.7μmol)を使用し、実施例14の合成と同様の操作を行った。無色油状の標題化合物(44mg,100%)を得た。
IR(neat)cm−1:3430(br),2920;
MS(m/z):511(M+−Me),173(100%)。
実施例14で得た[3a(R)]−1(R)−[4(R),5−ビス(t−ブチルジメチルシリルオキシ)−1(S),5−ジメチルヘキシル]−4(S)−ヒドロキシ−7a(R)−メチル−オクタヒドロ−1H−インデン(化合物3a;16.4mg,31.2μmol)、4−メチルモルホリンN−オキシド(NMO)(5.5mg,46.9μmol)およびモレキュラーシーブス4A(6mg)のジクロロメタン(1.3ml)懸濁液に、テトラn−プロピルアンモニウムパールテネート(TPAP,0.6mg,1.71μmol)を添加し、アルゴン雰囲気下、室温で1時間撹拌した。皮応混合物を10%Na2 S2 O3 溶液に注ぎ、ジクロロメタンで2回抽出し、飽和食塩水で洗浄した。有機層を硫酸マグネシウムで乾燥した後、溶媒を減圧留去して得られる残渣をフラッシュカラムクロマトグラフィー(7% 酢酸エチル/ヘキサン)で精製し、無色油状の標題化合物(14mg,86%)を得た。
IR(neat)cm−1:2950,1715;
MS(m/z):524(M+),173(100%)。
アルゴン雰囲気下、−80℃で、2−[3’,5’−ビス(t−ブチルジメチルシリルオキシ)−2’−メチレンシクロヘキシリデン]−1−ジフェニルホスホリルエタン(化合物13、S.Hatakeyama他,The Journal of Organic Chemistry,54,3515(1989)に記載)(45mg,77.3μmol)のTHE(0.5ml)溶液にn−ブチルリチウム(1.47mol/l,88μl,129μmol)を滴下し、同温度で5分間撹拌後、実施例16で得た[3a(R)]−1(R)−[4(R),5−ビス(t−ブチルジメチルシリルオキシ)−1(S),5−ジメチルヘキシル]−7a(R)−メチル−オクタヒドロ−1H−インデン−4−オン(化
合物2a;8.7mg,16.6μmol)のTHF(300μl)溶液を滴下し、同温度で1時間撹拌した後、室温で10分間撹拌した。反応混合物を飽和食塩水に注ぎ、酢酸エチルで2回抽出した。有機層を硫酸マグネシウムで乾燥後、溶媒を減圧留去して得られる残渣をプレパラティブ薄層クロマトグラフィー(TLC)(3%酢酸エチル/ヘキサン)で精製し、無色油状の標題化合物(7mg,48%)を得た。
IR(neat)cm−1:2940;
MS(m/z):888(M+),173(100%);
UV λ max nm:264,min nm:227。
参考例1で得た1(S),3(R),24(R),25−テトラキス(t−ブチルジメチルシリルオキシ)−9,10−セココレスタ−5,7,10(19)−トリエン(化合物15a;7mg,7.88μmol)の1,3−ジメチル−2−イミダゾリジノン(DMI)(3ml)溶液にテトラn−ブチルアンモニウムフルオリド(TBAF)(1mol/l,300μl,300μmol)を添加し、アルゴン雰囲気下、105℃で2時間撹拌した。反応混合物を水に注ぎ、酢酸エチルで2回抽出し、2回水洗した。有機層を硫酸マグネシウムで乾燥後、溶媒を減圧留去して得られる残渣をプレパラティブTLC(エタノール:ヘキサン=3:25)で精製し、白色粉末状の標題化合物(2.7mg,79%)を得た。
IR(KBr)cm−1:3380(br),2925;
MS(m/z):432(M+),134(100%);
UV λ max nm:264,min nm:227。
IR(neat)1716,1467,1252cm−1;
1H NMR(300MHz,CDCl3 )δ 3.18(dd,1H,J=2.4Hz,7.5Hz),2.43(dd,1H,J=7.5Hz,11.1Hz),1.20−2.28(m,16H),1.19(s,3H),1.10(s,3H),0.94(d,3H,J=6.3Hz),0.88(s,9H),0.85(s,9H),0.63(s,3H),0.08(s,3H),0.07(s,3H),0.06(s,3H),0.04(s,3H);
13C NMR(75MHz,CDCl3 )δ 212.2,81.2,76.4,62.1,56.8,50.0,41.1,39.1,36.2,34.1,29.7,29.0,27.8,26.2,26.0,24.2,23.2,19.2,18.8,18.3,18.2,12.5,−1.8,−1.9,−3.1,−3.7。
HRMS(EI)C29 H57 O3 Si2 の計算値 509.3846;実測値 C29 H57 O3 Si2 509.3852。
IR(neat)1716,1460,1252cm−1;
1H NMR(300MHz,CDCl3 )δ 3.18−3.24(m,1H),2.45(dd,1H,J=7.5Hz,11.1Hz),1.20−2.34(m,16H),1.18(s,3H),1.11(s,3H),0.94(d,3H,J=5.7Hz),0.89(s,9H),0.85(s,9H),0.63(s,3H),0.08(s,3H),0.07(s,3H),0.06(s,3H),0.04(s,3H);
13C NMR(75MHz,CDCl3 )δ 212.2,81.0,76.4,62.1,56.7,50.0,41.1,39.1,36.3,33.8,29.6,29.0,27.6,26.2,25.9,24.2,23.6,19.2,18.9,18.3,18.2,12.6,−1.8,−1.9,−3.1,−3.9。
HRMS(EI)C29 H57 O3 Si2 の計算値 509.3846;実測値 C29 H57 O3 Si2 509.3845。
.37mmol)のTHF(0.9ml)溶液に−60℃で、ナトリウムビス(
トリメチルシリル)アミド(THF中1M,355μl,0.36mmol)を
加え、アルゴン気流中1時間撹拌し、さらに実施例17で得た[3a(R)]−
1(R)−[4(S),5−ビス(t−ブチルジメチルシリルオキシ)−1(S
),5−ジメチルヘキシル]−7a(R)−メチル−オクタヒドロ−1H−イン
デン−4−オン(23.9mg,0.046mmol)のTHF溶液(0.3m
l)を加え、すぐに反応温度を室温にした。1時間後、n−ヘキサンで希釈し、
シリカゲルでろ過し、ろ液を減圧下濃縮した。残渣をプレパラティブTLC(n
−ヘキサン)で精製し、標題化合物(15.6mg,57%)を黄色油状物とし
て得た。
IR(neat)1466,1252cm−1;
1H NMR(300MHz,CDCl3 )δ 5.64(s,1H),3.18(dd,1H,J=2.1Hz,7.5Hz),2.82−2.91(m,1H),1.00−2.16(m,16H),1.19(s,3H),1.10(s,3H),0.92(d,3H,J=6.0Hz),0.88(s,9H),0.85(s,9H),0.56(s,3H),0.08(s,3H),0.07(s,3H),0.06(s,3H),0.04(s,3H);
13C NMR(75MHz,CDCl3 )δ 145.3,97.4,81.2,76.4,56.0,55.9,45.6,40.0,36.7,34.2,31.2,29.7,29.0,27.9,26.2,25.9,23.2,22.7,22.1,18.9,18.3,18.2,11.9,−1.8,−1.9,−3.1,−3.7。
HRMS(EI)C27 H52 O2 Si2 Brの計算値 543.2689;測定値 C27 H52 O2 Si2 Br543.2692。
IR(neat)1467,1253cm−1;
1H NMR(300MHz,CDCl3 )δ 5.64(s,1H),3.18−3.24(m,1H),2.82−2.91(m,1H),1.20−2.04(m,16H),1.18(s,3H),1.11(s,3H),0.92(d,3H,J=6.0Hz),0.89(s,9H),0.85(s,9H),0.56(s,3H),0.08(s,3H),0.07(s,3H),0.06(s,3H),0.04(s,3H);
13C NMR(75MHz,CDCl3 )δ 145.3,97.4,81.1,76.4,56.0,55.9,45.6,40.0,36.8,33.9,31.2,29.6,29.1,27.7,26.2,26.0,23.6,22.7,22.2,19.0,18.3,18.2,−1.8,−1.9,−3.1,−3.9.
MS(EI)m/z 73,585(M+−CH3 ),543(M+−57),
HRMS(EI) C30 H58 O2 Si2 Brの計算値 585.3150;実測値 C30 H58 O2 Si2 Br585.3134。
[α]D25+15.4°(c0.52,CHCl3 );
IR(neat)3314,1468,1254cm−1;
1H NMR(300MHz,CDCl3 )δ 5.89(ddd,1H,J=6.0Hz,10.5Hz,17.4Hz),5.26(dt,1H,J=1.5Hz,17.1Hz),5.14(dt,1H,J=1.5Hz,10.5Hz),4.18(t,1H,J=6.3Hz),3.98(ddd,1H,J=1.8Hz,4.8Hz,7.2Hz),3.60−3.82(m,4H),3.27(dd,1H,J=2.1Hz,6.6Hz),2.46(ddd,1H,J=3.0Hz,5.1Hz,17.1Hz),1.92(t,1H,2.7Hz),1.78(quint.2H,J=6.0Hz),0.89−0.90(m,2H),0.10(s,3H),0.08(s,3H),0.06(s,3H),0.04(s,6H),0.03(s,3H);
13C NMR(75MHz,CDCl3 )δ 138.5,116.0,86.9,83.2,74.4,72.1,69.5,60.5,33.7,26.1,26.0,23.3,18.5,18.4,−4.3,−4.4,−4.5,−5.2。
[α]D25−2.3°(c0.80,CHCl3 );
IR(neat)3314,1468,1254cm−1;
1H NMR(300MHz,CDCl3 )δ 5.88(ddd,1H,J=6.0Hz,10.2Hz,17.4Hz),5.26(dt,1H,J=1.5Hz,17.1Hz),5.14(dt,1H,J=1.5Hz,10.5Hz),4.27(dd,1H,J=4.5Hz,6.0Hz),3.85(dt,1H,J=4.2Hz,5.7Hz),3.74(ddd,2H,J=3.0Hz,6.3Hz,12.9Hz),3.67(t,2H,J=6.3Hz),3.36(dd,1H,J=4.5Hz,5.7Hz),2.53(ddd,1H,J=2.7Hz,5.7Hz,17.4Hz),1.93(t,1H,J=2.7Hz),1.74(quint.2H,J=6.3Hz),0.91(s,9H),0.90(s,9H),0.88(s,9H),0.03−0.12(m,18H);
13C NMR(75MHz,CDCl3 )δ 138.2,116.1,85.7,82.3,74.4,71.0,69.8,69.7,60.3,33.7,26.1,26.0,23.3,18.5,18.2,18.2,−4.2,−4.3,−4.4,−4.7,−5.2。
IR(neat)1467,1252cm−1;
1H NMR(300MHz,CDCl3 )δ 6.22(d,1H,J=10.5Hz),6.00(d,1H,J=10.8Hz),5.26(br s,1H),4.98(br s,1H),4.16−4.26(m,2H),3.58−3.76(m,4H),3.16−3.24(m,2H),2.81(br d,1H,J=13.5Hz),2.46(br dd,1H,J=11.6Hz,8.1Hz),2.22(br dd,1H,J=12.6Hz,3.8Hz),1.20−2.05(m,18H),1.19(s,3H),1.11(s,3H),0.82−0.94(m,48H),0.52(s,3H),0.02−0.10(m,30H)。
[α]D23+25.8°(c0.28,CHCl3 );
IR(neat)1467,1252cm−1;
1H NMR(300MHz,CDCl3 )δ 6.22(d,1H,J=10.5Hz),6.00(d,1H,J=10.8Hz),5.26(br s,1H),4.98(br s,1H),4.16−4.26(m,2H),3.58−3.76(m,4H),3.22(m,2H),2.81(br d,1H,J=12.3Hz),2.46(br dd,1H,J=12.9Hz,7.8Hz),2.23(br dd,1H,J=12.6Hz,3.3Hz),1.20−2.05(m,18H),1.18(s,3H),1.11(s,3H),0.82−0.94(m,48H),0.52(s,3H),0.02−0.10(m,30H)。
アルゴン雰囲気下、(5Z,7E)−(1R,2R,3R,24S)−1,3,24,25−テトラキス(t−ブチルジメチルシリルオキシ)−2−(3−t−ブチルジメチルシリルオキシプロポキシ)−9,10−セココレスタ−5,7,10(19)−トリエン(化合物20a;5.1mg,4.73μmol)のトルエン(0.5ml)溶液に1M−TBAF−THF溶液(237μl,237μmol)を加え、外温105℃で2時間加熱撹拌した。反応溶液を室温に戻し、酢酸エチルで希釈し、水(2回)及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残渣をプレパラティブTLC(シリカゲル厚0.25mm、ジクロロメタン;エタノール=5:1)により精製し、無色油状の標題化合物(化合物1a;1.45mg,60%)を得た。
1H NMR(270MHz,CDCl3 )δ 0.55(s,3H),0.95(d,J=6.3Hz,3H),1.16(s,3H),1.22(s,3H),2.42(brd,J=13.9Hz,1H),2.55(dd,J=14.5,4.5Hz,1H),2.75−2.87(m,1H),3.20−3.37(m,2H),3.68−3.78(m,1H),3.80−3.99(m,3H),4.20−4.36(m,2H),5.08(brs,1H),5.50(brs,1H),6.04(d,J=11.2Hz,1H),6.36(d,J=11.2Hz,1H);
IR(neat,cm−1)3400,2947,2929,2873,1378,1107,1072;
UV(EtOH)λmax 264nm。
(5Z,7E)−(1R,2R,3R,24R)−1,3,24,25−テトラキス(t−ブチルジメチルシリルオキシ)−2−(3−t−ブチルジメチルシリルオキシプロポキシ)−9,10−セココレスタ−5,7,10(19)−トリエン(化合物20b;3.3mg,3.06μmol)、トルエン(0.5ml)、1M−TBAF−THF溶液(153μl,237μmol)を用い、実施例24と同様の操作を行い、無色油状の標題化合物(化合物1b;1.02mg,66%)を得た。
[α]24D −23°(c0.07,EtOH);
1H NMR(270MHz,CDCl3 )δ 0.56(s,3H),0.94(d,J=5.9Hz,3H),1.16(s,3H),1.22(s,3H),2.42(brd,J=14.5Hz,1H),2.55(dd,J=14.5,4.0Hz,1H),2.76−2.87(m,1H),3.27(dd,J=8.8,2.8Hz,1H),3.30−3.37(m,1H),3.68−3.78(m,1H),3.80−4.00(m,3H),4.21−4.36(m,2H),5.08(brs,1H),5.50(brs,1H),6.04(d,J=11.2Hz,1H),6.36(d,J=11.2Hz,1H);
IR(neat,cm−1)3400,2947,2927,2871,1377,1105,1070;
UV(EtOH)λmax 264nm。
[3a(R)]−4(S)−アセチルオキシ−1(R)−[1(S),5−ジメチル−5−ヒトロキシヘキシル]−7a(R)−メチル−オクタヒドロ−1H−インデン(化合物1、Hatakeyama,S.他、The Journal of Organic Chemistry,56,461(1991)から公知、1.38g、4.25mmol)、2,6−ルチジン(0.79ml,6.80mmol)のジクロロメタン(10ml)溶液に、トリエチルシリルトリフルオロスタンスルホネート(TESOTf)(1.3ml,5.53mmol)を加えて30分間攪拌した。反応溶液をジクロロメタンで希釈し、氷冷0.5N塩酸、飽和炭酸水素ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去した後、シリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=19:1)により精製し、無色油状の標題化合物(1.66g,89%)を得た。
参考例3で得た[3a(R)]−4(S)−アセチルオキシ−1(R)−[1(S),5−ジメチル−5−トリエチルシリルオキシヘキシル]−7a(R)−メチル−オクタヒドロ−1H−インデン(化合物2、1.65g,3.76mmol)のTHF(15ml)溶液を0℃に冷却し、LiAlH4 (214mg,5.64mmol)をゆっくり加えた後、反応溶液を室温で30分間攪拌した。
IR(neat)1462,1235cm−1;
1H NMR(200MHz,CDCl3 )δ 5.64(br t,1H,J=1.6Hz),2.86(br dd,1H,J=9.2,4.0Hz),1.20−2.10(m,18H),1.18(s,6H),0.94(t,9H,J=7.9Hz),0.90(s,3H),0.56(s,3H),0.56(q,6H,J=7.9Hz)。
本発明化合物である化合物1aおよび化合物1bについて、ニワトリ小腸由来ビタミンDレセプターに対する結合能をradio receptor assay(RRA)法を用いて試験した。
Claims (1)
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WO2012057068A1 (ja) * | 2010-10-25 | 2012-05-03 | 帝人ファーマ株式会社 | 23-イン-ビタミンd3誘導体 |
WO2013162047A1 (ja) * | 2012-04-24 | 2013-10-31 | 帝人ファーマ株式会社 | 二次性副甲状腺機能亢進症治療剤 |
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WO1999043641A1 (fr) * | 1998-02-27 | 1999-09-02 | Chugai Seiyaku Kabushiki Kaisha | Composes intermediaires entrant dans la synthese de la fraction cyclique de derives 2-substitues de la vitamine d |
EP1812011A1 (en) | 2004-11-12 | 2007-08-01 | Bioxell S.p.a. | Combined use of vitamin d derivatives and anti-proliferative agents for treating bladder cancer |
WO2008062871A1 (fr) | 2006-11-22 | 2008-05-29 | Shiseido Company Ltd. | Procédé de production d'une poudre de fines particules d'oxyde de zinc et de cosmétiques contenant la poudre |
WO2010007039A1 (de) | 2008-07-18 | 2010-01-21 | Basf Se | Modifizierte zinkoxid-teilchen |
MX2021013876A (es) * | 2019-05-13 | 2022-02-22 | Faes Farma Sa | Procedimiento y productos intermedios para la preparación de eldecalcitol. |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS61267549A (ja) * | 1984-12-05 | 1986-11-27 | Chugai Pharmaceut Co Ltd | 2位に置換基を有するビタミンd▲下3▼誘導体 |
JPS63107929A (ja) * | 1986-06-05 | 1988-05-12 | Chugai Pharmaceut Co Ltd | 新規ビタミンd↓3誘導体を有効成分とする医薬 |
JPH11130711A (ja) * | 1997-10-24 | 1999-05-18 | Teijin Ltd | 1α,24,25−トリヒドロキシビタミンD3類の合成中間体およびその製造法 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS51108048A (en) * | 1975-03-17 | 1976-09-25 | Teijin Ltd | 1 arufua * 24 * s * *255 torihidokishikorekarushifuerooruno seizoho |
JPS5846507B2 (ja) * | 1978-12-26 | 1983-10-17 | 帝人株式会社 | 1α,24(R),25↓−トリヒドロキシコレカルシフエロ−ルの製造法 |
JPS58208223A (ja) * | 1982-05-28 | 1983-12-03 | Kureha Chem Ind Co Ltd | 抗腫瘍剤 |
DK0972762T3 (da) * | 1993-07-09 | 2004-02-09 | Theramex | Hidtil ukendte strukturelle analoger af vitamin D |
JP3712077B2 (ja) * | 1995-05-12 | 2005-11-02 | 株式会社クラレ | ヒドロインダン−4−オール誘導体およびその製造方法 |
WO1999043641A1 (fr) * | 1998-02-27 | 1999-09-02 | Chugai Seiyaku Kabushiki Kaisha | Composes intermediaires entrant dans la synthese de la fraction cyclique de derives 2-substitues de la vitamine d |
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- 1999-02-23 DE DE69939106T patent/DE69939106D1/de not_active Expired - Lifetime
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS61267549A (ja) * | 1984-12-05 | 1986-11-27 | Chugai Pharmaceut Co Ltd | 2位に置換基を有するビタミンd▲下3▼誘導体 |
JPS63107929A (ja) * | 1986-06-05 | 1988-05-12 | Chugai Pharmaceut Co Ltd | 新規ビタミンd↓3誘導体を有効成分とする医薬 |
JPH11130711A (ja) * | 1997-10-24 | 1999-05-18 | Teijin Ltd | 1α,24,25−トリヒドロキシビタミンD3類の合成中間体およびその製造法 |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2012057068A1 (ja) * | 2010-10-25 | 2012-05-03 | 帝人ファーマ株式会社 | 23-イン-ビタミンd3誘導体 |
US9006220B2 (en) | 2010-10-25 | 2015-04-14 | Teijin Pharma Limited | 23-yne-vitamin D3 derivative |
JP5738307B2 (ja) * | 2010-10-25 | 2015-06-24 | 帝人ファーマ株式会社 | 23−イン−ビタミンd3誘導体 |
US9079843B2 (en) | 2010-10-25 | 2015-07-14 | Teijin Pharma Limited | 23-yne-vitamin D3 derivative |
KR101853518B1 (ko) * | 2010-10-25 | 2018-04-30 | 데이진 화-마 가부시키가이샤 | 23-인-비타민 d3 유도체 |
WO2013162047A1 (ja) * | 2012-04-24 | 2013-10-31 | 帝人ファーマ株式会社 | 二次性副甲状腺機能亢進症治療剤 |
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DE69939106D1 (de) | 2008-08-28 |
EP1061070A1 (en) | 2000-12-20 |
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JP4357114B2 (ja) | 2009-11-04 |
ATE401303T1 (de) | 2008-08-15 |
EP1061070A4 (en) | 2005-03-30 |
WO1999043645A1 (fr) | 1999-09-02 |
AU2549099A (en) | 1999-09-15 |
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