JP5255994B2 - 核内受容体リガンド - Google Patents
核内受容体リガンド Download PDFInfo
- Publication number
- JP5255994B2 JP5255994B2 JP2008282792A JP2008282792A JP5255994B2 JP 5255994 B2 JP5255994 B2 JP 5255994B2 JP 2008282792 A JP2008282792 A JP 2008282792A JP 2008282792 A JP2008282792 A JP 2008282792A JP 5255994 B2 JP5255994 B2 JP 5255994B2
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- JP
- Japan
- Prior art keywords
- ethyl acetate
- mmol
- hexane
- mixture
- reaction
- 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.)
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- 108020005497 Nuclear hormone receptor Proteins 0.000 title description 18
- 102000006255 nuclear receptors Human genes 0.000 title description 18
- 108020004017 nuclear receptors Proteins 0.000 title description 18
- 239000003446 ligand Substances 0.000 title description 12
- 150000001875 compounds Chemical class 0.000 claims description 141
- 102000034527 Retinoid X Receptors Human genes 0.000 claims description 50
- 108010038912 Retinoid X Receptors Proteins 0.000 claims description 50
- 125000000217 alkyl group Chemical group 0.000 claims description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 16
- 239000004480 active ingredient Substances 0.000 claims description 15
- 230000002103 transcriptional effect Effects 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 3
- 125000003262 carboxylic acid ester group Chemical class [H]C([H])([*:2])OC(=O)C([H])([H])[*:1] 0.000 claims 1
- 125000006501 nitrophenyl group Chemical group 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 474
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 228
- 239000000543 intermediate Substances 0.000 description 185
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 92
- 239000000203 mixture Substances 0.000 description 84
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 81
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 78
- 239000002904 solvent Substances 0.000 description 78
- 238000006243 chemical reaction Methods 0.000 description 76
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 75
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
- 238000005481 NMR spectroscopy Methods 0.000 description 68
- 230000015572 biosynthetic process Effects 0.000 description 66
- 238000003786 synthesis reaction Methods 0.000 description 66
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 58
- 239000012044 organic layer Substances 0.000 description 56
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 50
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 47
- -1 alkali metal salts Chemical class 0.000 description 47
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 46
- 239000000243 solution Substances 0.000 description 45
- 239000013078 crystal Substances 0.000 description 43
- 239000011541 reaction mixture Substances 0.000 description 34
- 238000001704 evaporation Methods 0.000 description 29
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
- 125000003545 alkoxy group Chemical group 0.000 description 25
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 24
- 238000003818 flash chromatography Methods 0.000 description 24
- 238000001953 recrystallisation Methods 0.000 description 24
- 230000009471 action Effects 0.000 description 22
- 230000000694 effects Effects 0.000 description 20
- 238000010992 reflux Methods 0.000 description 20
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 18
- 125000003342 alkenyl group Chemical group 0.000 description 18
- 125000000304 alkynyl group Chemical group 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 18
- 238000010438 heat treatment Methods 0.000 description 18
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 16
- 230000008020 evaporation Effects 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 238000001914 filtration Methods 0.000 description 14
- 239000002253 acid Substances 0.000 description 13
- 229920006395 saturated elastomer Polymers 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 12
- 238000004519 manufacturing process Methods 0.000 description 12
- QIOKXWXQMLGEJP-UHFFFAOYSA-N methyl 3-amino-4-[(3,5,5,8,8-pentamethyl-6,7-dihydronaphthalen-2-yl)amino]benzoate Chemical compound NC1=CC(C(=O)OC)=CC=C1NC1=CC(C(CCC2(C)C)(C)C)=C2C=C1C QIOKXWXQMLGEJP-UHFFFAOYSA-N 0.000 description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 239000003814 drug Substances 0.000 description 11
- 239000000843 powder Substances 0.000 description 11
- 0 CCC(C)*CCC(CCCC1)C1C(C)C1(CC)C(C)(C)CC2C1CCCC2 Chemical compound CCC(C)*CCC(CCCC1)C1C(C)C1(CC)C(C)(C)CC2C1CCCC2 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- 125000002252 acyl group Chemical group 0.000 description 10
- 125000003282 alkyl amino group Chemical group 0.000 description 10
- 125000001769 aryl amino group Chemical group 0.000 description 10
- 150000002431 hydrogen Chemical class 0.000 description 10
- 150000004492 retinoid derivatives Chemical class 0.000 description 10
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 229940121908 Retinoid X receptor agonist Drugs 0.000 description 9
- 239000000556 agonist Substances 0.000 description 9
- 238000005259 measurement Methods 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 8
- 230000001270 agonistic effect Effects 0.000 description 8
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 8
- 125000003277 amino group Chemical group 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 239000003112 inhibitor Substances 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 239000012300 argon atmosphere Substances 0.000 description 7
- 239000012298 atmosphere Substances 0.000 description 7
- 230000003197 catalytic effect Effects 0.000 description 7
- 229910052763 palladium Inorganic materials 0.000 description 7
- 239000008194 pharmaceutical composition Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- MUTNCGKQJGXKEM-UHFFFAOYSA-N tamibarotene Chemical compound C=1C=C2C(C)(C)CCC(C)(C)C2=CC=1NC(=O)C1=CC=C(C(O)=O)C=C1 MUTNCGKQJGXKEM-UHFFFAOYSA-N 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 6
- DIKWEMPBWUQZIV-UHFFFAOYSA-N COC(C1=CC(=C(C=C1)NC1=CC=2C(CCC(C2C=C1)(C)C)(C)C)N)=O Chemical compound COC(C1=CC(=C(C=C1)NC1=CC=2C(CCC(C2C=C1)(C)C)(C)C)N)=O DIKWEMPBWUQZIV-UHFFFAOYSA-N 0.000 description 6
- XHRZDGBYUHRQDW-UHFFFAOYSA-N COC(C1=CC(=C(C=C1)NC1=CC=2C(CCC(C2C=C1OC)(C)C)(C)C)N)=O Chemical compound COC(C1=CC(=C(C=C1)NC1=CC=2C(CCC(C2C=C1OC)(C)C)(C)C)N)=O XHRZDGBYUHRQDW-UHFFFAOYSA-N 0.000 description 6
- 108060001084 Luciferase Proteins 0.000 description 6
- 239000005089 Luciferase Substances 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 6
- NAVMQTYZDKMPEU-UHFFFAOYSA-N Targretin Chemical compound CC1=CC(C(CCC2(C)C)(C)C)=C2C=C1C(=C)C1=CC=C(C(O)=O)C=C1 NAVMQTYZDKMPEU-UHFFFAOYSA-N 0.000 description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 6
- 239000005557 antagonist Substances 0.000 description 6
- 239000002246 antineoplastic agent Substances 0.000 description 6
- 229960002938 bexarotene Drugs 0.000 description 6
- 150000001733 carboxylic acid esters Chemical class 0.000 description 6
- 230000024245 cell differentiation Effects 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- SCMBIQRYVKITCY-UHFFFAOYSA-N methyl 4-iodo-3-nitrobenzoate Chemical compound COC(=O)C1=CC=C(I)C([N+]([O-])=O)=C1 SCMBIQRYVKITCY-UHFFFAOYSA-N 0.000 description 6
- 150000004702 methyl esters Chemical class 0.000 description 6
- 229930002330 retinoic acid Natural products 0.000 description 6
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 229950010130 tamibarotene Drugs 0.000 description 6
- 230000003042 antagnostic effect Effects 0.000 description 5
- 239000002260 anti-inflammatory agent Substances 0.000 description 5
- 229940121363 anti-inflammatory agent Drugs 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- 239000013024 dilution buffer Substances 0.000 description 5
- 239000001963 growth medium Substances 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 229960001727 tretinoin Drugs 0.000 description 5
- 229910021642 ultra pure water Inorganic materials 0.000 description 5
- 239000012498 ultrapure water Substances 0.000 description 5
- HSTAGCWQAIXJQM-UHFFFAOYSA-N 2,5-dichloro-2,5-dimethylhexane Chemical compound CC(C)(Cl)CCC(C)(C)Cl HSTAGCWQAIXJQM-UHFFFAOYSA-N 0.000 description 4
- AMDKYPNODLTUMY-UHFFFAOYSA-N 5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-amine Chemical compound NC1=CC=C2C(C)(C)CCC(C)(C)C2=C1 AMDKYPNODLTUMY-UHFFFAOYSA-N 0.000 description 4
- QMEFOSXIVMLWDY-UHFFFAOYSA-N COC(C1=CC(=C(C=C1)NC1=CC=2C(CCC(C2C=C1)(C)C)(C)C)NC(C)=O)=O Chemical compound COC(C1=CC(=C(C=C1)NC1=CC=2C(CCC(C2C=C1)(C)C)(C)C)NC(C)=O)=O QMEFOSXIVMLWDY-UHFFFAOYSA-N 0.000 description 4
- YTMOFZWDUFRTCE-UHFFFAOYSA-N COC(C1=CC(=C(C=C1)NC1=CC=2C(CCC(C2C=C1C)(C)C)(C)C)NC(CCC)=O)=O Chemical compound COC(C1=CC(=C(C=C1)NC1=CC=2C(CCC(C2C=C1C)(C)C)(C)C)NC(CCC)=O)=O YTMOFZWDUFRTCE-UHFFFAOYSA-N 0.000 description 4
- OAMVUQIMSSVLRC-UHFFFAOYSA-N COC(C1=CC(=C(C=C1)NC1=CC=2C(CCC(C2C=C1C)(C)C)(C)C)NC(CCCCC)=O)=O Chemical compound COC(C1=CC(=C(C=C1)NC1=CC=2C(CCC(C2C=C1C)(C)C)(C)C)NC(CCCCC)=O)=O OAMVUQIMSSVLRC-UHFFFAOYSA-N 0.000 description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 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
- 239000000043 antiallergic agent Substances 0.000 description 4
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical group C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 238000007865 diluting Methods 0.000 description 4
- FBZRWCVSAQPVIJ-UHFFFAOYSA-N ethyl 3-bromo-4-nitrobenzoate Chemical compound CCOC(=O)C1=CC=C([N+]([O-])=O)C(Br)=C1 FBZRWCVSAQPVIJ-UHFFFAOYSA-N 0.000 description 4
- NOGUJGZZMMKQOZ-UHFFFAOYSA-N ethyl 4-amino-3-bromobenzoate Chemical compound CCOC(=O)C1=CC=C(N)C(Br)=C1 NOGUJGZZMMKQOZ-UHFFFAOYSA-N 0.000 description 4
- DYUWQWMXZHDZOR-UHFFFAOYSA-N methyl 4-iodobenzoate Chemical compound COC(=O)C1=CC=C(I)C=C1 DYUWQWMXZHDZOR-UHFFFAOYSA-N 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- 230000035897 transcription Effects 0.000 description 4
- 238000013518 transcription Methods 0.000 description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 4
- AISXBZVAYNUAKB-UHFFFAOYSA-N 1,1,4,4,6-pentamethyl-2,3-dihydronaphthalene Chemical compound CC1(C)CCC(C)(C)C=2C1=CC(C)=CC=2 AISXBZVAYNUAKB-UHFFFAOYSA-N 0.000 description 3
- KUXVNYLIMHYPOE-UHFFFAOYSA-N 1,1,4,4,6-pentamethyl-7-nitro-2,3-dihydronaphthalene Chemical compound CC1(C)CCC(C)(C)C2=C1C=C([N+]([O-])=O)C(C)=C2 KUXVNYLIMHYPOE-UHFFFAOYSA-N 0.000 description 3
- CCQKWSZYTOCEIB-UHFFFAOYSA-N 1,1,4,4-tetramethyl-2,3-dihydronaphthalene Chemical compound C1=CC=C2C(C)(C)CCC(C)(C)C2=C1 CCQKWSZYTOCEIB-UHFFFAOYSA-N 0.000 description 3
- ZABFOFGWNHHHOO-UHFFFAOYSA-N 1,1,4,4-tetramethyl-6-nitro-2,3-dihydronaphthalene Chemical compound [O-][N+](=O)C1=CC=C2C(C)(C)CCC(C)(C)C2=C1 ZABFOFGWNHHHOO-UHFFFAOYSA-N 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- NDQSUCPZRPRYLX-UHFFFAOYSA-N 3,5,5,8,8-pentamethyl-6,7-dihydronaphthalen-2-amine Chemical compound CC1(C)CCC(C)(C)C2=C1C=C(N)C(C)=C2 NDQSUCPZRPRYLX-UHFFFAOYSA-N 0.000 description 3
- ABKXDOMMAKFRNB-UHFFFAOYSA-N 3-methoxy-5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-amine Chemical compound CC1(C)CCC(C)(C)C2=C1C=C(N)C(OC)=C2 ABKXDOMMAKFRNB-UHFFFAOYSA-N 0.000 description 3
- FNDPAUHMSYDDTI-UHFFFAOYSA-N 5,5,8,8-tetramethyl-3-nitro-6,7-dihydronaphthalen-2-ol Chemical compound [O-][N+](=O)C1=C(O)C=C2C(C)(C)CCC(C)(C)C2=C1 FNDPAUHMSYDDTI-UHFFFAOYSA-N 0.000 description 3
- UZHCJGSIRIFQTO-UHFFFAOYSA-N 5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-ol Chemical compound OC1=CC=C2C(C)(C)CCC(C)(C)C2=C1 UZHCJGSIRIFQTO-UHFFFAOYSA-N 0.000 description 3
- BITXZEUVMXSLCA-UHFFFAOYSA-N 6-methoxy-1,1,4,4-tetramethyl-7-nitro-2,3-dihydronaphthalene Chemical compound CC1(C)CCC(C)(C)C2=C1C=C([N+]([O-])=O)C(OC)=C2 BITXZEUVMXSLCA-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
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Description
Science, 290, pp.2140-2144, 2000 Cell, 83, pp.841-850, 1995 アムノレイク錠2mg<タミバロテン製剤>日本新薬販売添付文書(2005年6月作成) Journal of Medicinal Chemistry, 37, pp.1508-1517, 1994 The Journal of Clinical Investigation, 108, pp.1001-1013, 2001 Cancer Research, 58, pp.479-484, 1998など Cancer Letters, 201, pp.17-24, 2003 Clinical Cancer Research, 10, pp8656-8664, 2004 British Journal of Cancer, 94, pp.654-660, 2006 Nature, 386, pp.407-410, 1997
1.下記の一般式Iで表される化合物。
一般式I:
(式中、R1, R2は、各々直鎖アルキル鎖、分枝アルキル鎖、及び分枝アルキル基を有するアルコキシ基から選択され、互いに独立又は閉環しており、その位置は、R3に対し、メタ位若しくはパラ位に位置し、
R3は、水素、アルキル基、アルケニル基、アルキニル基、アルコキシ基、アシル基、アルキルアミノ基、及びアリールアミノ基から選択され、
環A及び環Bは、各々芳香環からなり、
環B及びN-Y-Xで構築される環は、5員環であり、
前記環B及びN-Y-Xで構築される環のうちX-Yは、N=N又はN=C-R5 であり、R5は、アルキル基、アルケニル基、アルキニル基、置換フェニル基、アルコキシ基及び置換アミノ基から選択され、
Zは、カルボン酸エステル、並びにカルボキシル基、ヒドロキサム酸及びそれらの塩から選択され、Xに対し、メタ位若しくはパラ位に位置する化合物。)
2.下記の一般式IIで表される化合物。
一般式II:
環B及びN-Y-Xで構築される環は、5員環であり、
前記環B及びN-Y-Xで構築される環のうちX-Yは、N=N又はN=C-R5 であり、R5は、アルキル基、アルケニル基、アルキニル基、置換フェニル基、アルコキシ基及び置換アミノ基から選択され、
Zは、カルボン酸エステル、並びにカルボキシル基、ヒドロキサム酸及びそれらの塩から選択され、Xに対し、メタ位若しくはパラ位に位置する化合物。)
3.下記の一般式IIIで表される化合物。
一般式III:
R3は、水素、アルキル基、アルケニル基、アルキニル基、アルコキシ基、アシル基、アルキルアミノ基、及びアリールアミノ基から選択され、
R4Oは、直鎖アルキル又は分枝アルキルを有するアルコキシ基であり、その位置は、R3に対し、R2とは異なるメタ位又はパラ位に位置し、
環B及びN-Y-Xで構築される環は、5員環であり、
前記環B及びN-Y-Xで構築される環のうちX-Yは、N=N又はN=C-R5 であり、R5は、アルキル基、アルケニル基、アルキニル基、置換フェニル基、アルコキシ基及び置換アミノ基から選択され、
Zは、カルボン酸エステル、並びにカルボキシル基、ヒドロキサム酸及びそれらの塩から選択され、Xに対し、メタ位若しくはパラ位に位置する化合物。)
4.下記の一般式IVで表される、前項2に記載の化合物。
一般式IV:
(式中、R3は、水素、アルキル基、アルケニル基、アルキニル基、アルコキシ基、アシル基、アルキルアミノ基、及びアリールアミノ基から選択され、
R5は、アルキル基、アルケニル基、アルキニル基、置換フェニル基、アルコキシ基及び置換アミノ基から選択される化合物。)
5.下記の一般式Vで表される前項4に記載の化合物。
一般式V:
6.前項1〜5のいずれか1に記載の化合物を有効成分として含有するRXR受容体タンパク質の転写調節剤。
一般式I:
(式中、R1, R2は、各々直鎖アルキル鎖、分枝アルキル鎖、及び分枝アルキル基を有するアルコキシ基から選択され、互いに独立又は閉環しており、その位置は、R3に対し、メタ位若しくはパラ位に位置し、
R3は、水素、アルキル基、アルケニル基、アルキニル基、アルコキシ基、アシル基、アルキルアミノ基、及びアリールアミノ基から選択され、
環A及び環Bは、各々芳香環からなり、
環B及びN-Y-Xで構築される環は、5員環であり、
前記環B及びN-Y-Xで構築される環のうちX-Yは、N=N又はN=C-R5 であり、R5は、アルキル基、アルケニル基、アルキニル基、置換フェニル基、アルコキシ基及び置換アミノ基から選択され、
Zは、カルボン酸エステル、並びにカルボキシル基、ヒドロキサム酸及びそれらの塩から選択され、Xに対し、メタ位若しくはパラ位に位置する化合物。)
一般式II:
環B及びN-Y-Xで構築される環は、5員環であり、
前記環B及びN-Y-Xで構築される環のうちX-Yは、N=N又はN=C-R5 であり、R5は、アルキル基、アルケニル基、アルキニル基、置換フェニル基、アルコキシ基及び置換アミノ基から選択され、
Zは、カルボン酸エステル、並びにカルボキシル基、ヒドロキサム酸及びそれらの塩から選択され、Xに対し、メタ位若しくはパラ位に位置する化合物。)
一般式III:
R3は、水素、アルキル基、アルケニル基、アルキニル基、アルコキシ基、アシル基、アルキルアミノ基、及びアリールアミノ基から選択され、
R4Oは、直鎖アルキル又は分枝アルキルを有するアルコキシ基であり、その位置は、R3に対し、R2とは異なるメタ位又はパラ位に位置し、
環B及びN-Y-Xで構築される環は、5員環であり、
前記環B及びN-Y-Xで構築される環のうちX-Yは、N=N又はN=C-R5 であり、R5は、アルキル基、アルケニル基、アルキニル基、置換フェニル基、アルコキシ基及び置換アミノ基から選択され、
Zは、カルボン酸エステル、並びにカルボキシル基、ヒドロキサム酸及びそれらの塩から選択され、Xに対し、メタ位若しくはパラ位に位置する化合物。)
一般式IV:
(式中、R3は、水素、アルキル基、アルケニル基、アルキニル基、アルコキシ基、アシル基、アルキルアミノ基、及びアリールアミノ基から選択され、
R5は、アルキル基、アルケニル基、アルキニル基、置換フェニル基、アルコキシ基及び置換アミノ基から選択される化合物。
一般式V:
塩基性付加塩としては、例えばナトリウム塩、カリウム塩等のアルカリ金属塩;例えばカルシウム塩、マグネシウム塩等のアルカリ土類金属塩;例えばアンモニウム塩;例えばトリメチルアミン塩、トリエチルアミン塩;ジシクロヘキシルアミン塩、エタノールアミン塩、ジエタノールアミン塩、トリエタノールアミン塩、ブロカイン塩等の脂肪族アミン塩;たとえばN,N−ジベンジルエチレンジアミン等のアラルキルアミン塩;例えばピリジン塩、ピコリン塩、キノリン塩、イソキノリン塩等の複素環芳香族アミン塩;例えばテトラメチルアンモニウム塩、テトラエチルアンモニウム塩、ベンジルトリメチルアンモニウム塩、ベンジルトリエチルアンモニウム塩、ベンジルトリブチルアンモニウム塩、メチルトリオクチルアンモニウム塩、テトラブチルアンモニウム塩等の第4級アンモニウム塩;アルギニン塩;リジン塩等の塩基性アミノ酸塩等が挙げられる。
本実施例における中間体5a, 5b, 5cを得るまでの製造方法のスキームを図2に示した。
16)中間体 3-Nitro-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamino)-benzoic acid methyl ester (10a) の合成
本実施例における目的化合物(25a, 25b, 25c)を得るまでの製造方法のスキームを図6に示した。
本実施例における目的化合物(27a, 27b, 27c)を得るまでの製造方法のスキームを図7に示した。
本実施例における目的化合物(29a, 29b, 29c)を得るまでの製造方法のスキームを図8に示した。
1)測定原理
核内受容体の多くは転写調節に関わる転写因子であるため、その転写活性を測定する手段としてレポーター遺伝子アッセイ(reporter gene assay)が行われる。COS-1細胞やHeLa細胞などの細胞に、RXR受容体タンパク質発現プラスミド及びレポータープラスミドを導入し、融合タンパク質(fusion protein)を過剰発現させる。そこに、RXR作動性物質(リガンド)が受容体に結合すると、転写がリガンド依存的に起こり、その下流にある融合タンパク質が生成され、下流にあるルシフェラーゼの産生が始まる。このルシフェラーゼ活性を測ることにより、RXR作動活性を測定した。
細胞の増殖培地は、ダルベッコ変法イーグルMEM培地(DMEM)を用いた。まず、1 Lの超純水(Milli-Q(R)にて生成)にDMEM粉末を9.5 g溶解し、高圧加熱滅菌(121℃、15分間)を行った後、室温に戻し、これを非働化したウシ胎児血清(FBS)を10 % (v/v)となるように加え、さらに高圧加熱滅菌した10 % NaHCO3を10 mL添加し、その後L‐グルタミン10 mLをろ過滅菌後添加して調製した。
形質転換はEffecteneTM Transection Reagent (QIAGEN社)を用いて行った。RXRの陽性コントロールにはLGD1069を用いた。これらは、DMSO溶解したものをストック溶液とし、アッセイするプレートにおいて計測した。
(1日目)60 mm培養シャーレに、増殖培地15 mLとともにCOS-1細胞を50×104 cells播種し、一晩培養した。
(2日目)EffecteneTM Transection Reagent (QIAGEN社)を用いたリポフェクション法により形質転換を行った。
(3日目)16〜18時間後、培養上清を除き、トリプシン処理により細胞を回収し、4 ℃、1000 rpm、3分間遠心分離後、増殖培地を加えて細胞を分散し、2.0×104 cells/wellとなるように96ウェルのホワイトプレートに播種した。その後、DMSO濃度が1%以下になるように各化合物を加えた。
(4日目)24時間後、上清25μLをSEAP測定に用い、残りの細胞液はルシフェラーゼ活性測定に用いた。
具体的には、以下の方法で測定した。上記4日目の上清25μLに対して希釈用緩衝液を25μL加えた後、65 ℃で30分インキュベートした。その後室温に戻し、アッセイ用緩衝液 (7μL)、10×MUP (0.3 μL)、希釈用緩衝液 (2.7 μL)を加え、暗所室温で60分インキュベートした。その後、マイクロプレートリーダー(インフィニットTM (infinite)200、TECAN社製)を用い励起波長360 nm、蛍光波長460 nmにより蛍光強度を測定した。
上記の測定結果を以下の表1〜3に示した。
Claims (4)
- 請求項1〜3のいずれか1に記載の化合物を有効成分として含有するRXR受容体タンパク質の転写調節剤。
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