JP5309591B2 - キャビコール類縁体化合物、キャビコール類縁体化合物の製造方法、およびmapキナーゼシグナル伝達阻害剤 - Google Patents
キャビコール類縁体化合物、キャビコール類縁体化合物の製造方法、およびmapキナーゼシグナル伝達阻害剤 Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 59
- 108091054455 MAP kinase family Chemical group 0.000 title claims abstract description 26
- 102000043136 MAP kinase family Human genes 0.000 title claims abstract description 26
- 239000003112 inhibitor Substances 0.000 title claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 title abstract description 9
- 230000019491 signal transduction Effects 0.000 title description 11
- -1 chavicol analog compound Chemical class 0.000 claims abstract description 40
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 17
- 230000011664 signaling Effects 0.000 claims abstract description 9
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 229920006395 saturated elastomer Polymers 0.000 claims description 9
- 125000004417 unsaturated alkyl group Chemical group 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- KQNPFQTWMSNSAP-UHFFFAOYSA-N alpha-isobutyric acid Natural products CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 claims 1
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims 1
- 150000001721 carbon Chemical class 0.000 claims 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 8
- 201000011510 cancer Diseases 0.000 abstract description 8
- 125000004423 acyloxy group Chemical group 0.000 abstract description 7
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 abstract description 7
- 239000001257 hydrogen Substances 0.000 abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 7
- 230000000903 blocking effect Effects 0.000 abstract description 6
- 208000027866 inflammatory disease Diseases 0.000 abstract description 6
- 201000010099 disease Diseases 0.000 abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 4
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- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract 1
- 230000001575 pathological effect Effects 0.000 abstract 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 39
- 230000015572 biosynthetic process Effects 0.000 description 29
- 238000003786 synthesis reaction Methods 0.000 description 29
- GPPYYOFCUVXNNH-UHFFFAOYSA-N methyl hydrogen carbonate;hydrochloride Chemical compound Cl.COC(O)=O GPPYYOFCUVXNNH-UHFFFAOYSA-N 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000005917 acylation reaction Methods 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- 238000002329 infrared spectrum Methods 0.000 description 11
- NPFYZDNDJHZQKY-UHFFFAOYSA-N 4-Hydroxybenzophenone Chemical compound C1=CC(O)=CC=C1C(=O)C1=CC=CC=C1 NPFYZDNDJHZQKY-UHFFFAOYSA-N 0.000 description 10
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 9
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 238000007083 alkoxycarbonylation reaction Methods 0.000 description 8
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- 238000000034 method Methods 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 6
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- 125000006239 protecting group Chemical group 0.000 description 6
- RXNYJUSEXLAVNQ-UHFFFAOYSA-N 4,4'-Dihydroxybenzophenone Chemical compound C1=CC(O)=CC=C1C(=O)C1=CC=C(O)C=C1 RXNYJUSEXLAVNQ-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
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- 150000002431 hydrogen Chemical class 0.000 description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 5
- 102000004631 Calcineurin Human genes 0.000 description 4
- 108010042955 Calcineurin Proteins 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
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- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
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- 125000001979 organolithium group Chemical group 0.000 description 4
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 4
- 238000006884 silylation reaction Methods 0.000 description 4
- 239000007818 Grignard reagent Substances 0.000 description 3
- WXMRTXLVRIIFAG-UHFFFAOYSA-N [4-(hydroxymethyl)phenyl]-phenylmethanol Chemical compound C1=CC(CO)=CC=C1C(O)C1=CC=CC=C1 WXMRTXLVRIIFAG-UHFFFAOYSA-N 0.000 description 3
- 230000001476 alcoholic effect Effects 0.000 description 3
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 3
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
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- DGMOBVGABMBZSB-UHFFFAOYSA-N 2-methylpropanoyl chloride Chemical compound CC(C)C(Cl)=O DGMOBVGABMBZSB-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
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- 101150069639 LEU1 gene Proteins 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 241000235347 Schizosaccharomyces pombe Species 0.000 description 2
- 101100352915 Schizosaccharomyces pombe (strain 972 / ATCC 24843) ppb1 gene Proteins 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 101100181629 Thermus thermophilus leuA gene Proteins 0.000 description 2
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- 230000009401 metastasis Effects 0.000 description 2
- 229940017219 methyl propionate Drugs 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- CFFZDZCDUFSOFZ-UHFFFAOYSA-N 3,4-Dihydroxyphenylacetic acid Natural products OC(=O)CC1=CC=C(O)C(O)=C1 CFFZDZCDUFSOFZ-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- HPUSHJXRBGOUIP-UHFFFAOYSA-M C(C1=CC=CC=C1)OC=1C=C(C=CC1OCC1=CC=CC=C1)C=C[Mg]Br Chemical compound C(C1=CC=CC=C1)OC=1C=C(C=CC1OCC1=CC=CC=C1)C=C[Mg]Br HPUSHJXRBGOUIP-UHFFFAOYSA-M 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- WTXLDOMLNRXUQY-UHFFFAOYSA-N [4-(1-acetyloxy-2-phenylethyl)phenyl] acetate Chemical compound C=1C=C(OC(C)=O)C=CC=1C(OC(=O)C)CC1=CC=CC=C1 WTXLDOMLNRXUQY-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
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- 235000019270 ammonium chloride Nutrition 0.000 description 1
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- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 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
- 230000008827 biological function Effects 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
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- 230000012010 growth Effects 0.000 description 1
- 230000009390 immune abnormality Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
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- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 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 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- RMGJCSHZTFKPNO-UHFFFAOYSA-M magnesium;ethene;bromide Chemical compound [Mg+2].[Br-].[CH-]=C RMGJCSHZTFKPNO-UHFFFAOYSA-M 0.000 description 1
- UGVPKMAWLOMPRS-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].CC[CH2-] UGVPKMAWLOMPRS-UHFFFAOYSA-M 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
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- 230000008506 pathogenesis Effects 0.000 description 1
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- 102000020233 phosphotransferase Human genes 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000003938 response to stress Effects 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 150000004072 triols Chemical group 0.000 description 1
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
で表される1’S‐1’‐アセトキシキャビコールとその類縁体のMAPキナーゼシグナル遮断機構について検討を行うとともに、種々のキャビコール類縁体についてそのMAPキナーゼシグナル遮断作用を検討した結果、特定の種類のキャビコール類縁体が、強力なMAPキナーゼシグナル遮断作用を有することを見出し本発明を完成した。
(式中、R1及びR2は、それぞれ、ヒドロキシ基、アシルオキシ基、又はアルコキシカルボニルオキシ基を表し、R3は、水素、又は飽和もしくは不飽和のアルキル基を表し、nは、0又は1を表す。)で表されることを特徴とするキャビコール類縁体化合物を提供する(請求項1)。
4‐ヒドロキシベンズアルデヒドより、4‐(ヒドロキシフェニルメチル)フェニルメタノール(4-(hydroxyphenylmethyl)phenylmethanol)の合成
IR(KBr): 3402cm−1
1H−NMR(CD3OD) δ: 5.69 (1H, s), 6.74 (2H, d, J = 8.6 Hz), 7.16 (2H, d, J = 8.6 Hz), 7.20-7.36 (5H, m)
13C−NMR(CD3OD) δ: 76.6 (d), 116.0 (d), 127.5 (d), 128.0 (d), 129.1 (d x 2), 136.8 (s), 146.0 (s), 157.6 (s)
EI−MS m/z:200[M]+
4‐(メトキシカルボニルオキシフェニルメチル)フェニルメチルカーボネート(4-(methoxycarbonyloxyphenylmethyl)phenyl methyl carbonate)の合成
合成例1で得られた4‐(ヒドロキシフェニルメチル)フェニルメタノール(800mg、4mmol)と乾燥ピリジン(2mL)の混合物に、メチル炭酸クロリド(0.77mL、10.0mmol)を0℃にて加える。30分撹拌し、水を加え、酢酸エチル(30mL×3)にて抽出した。抽出液を10%塩酸、飽和重曹水、飽和食塩水で洗浄し、溶媒留去し、得られた残渣をカラムクロマトグラフィー(ヘキサン:酢酸エチル=30:1)で精製し4‐(メトキシカルボニルオキシフェニルメチル)フェニルメチルカーボネート(1.09mg、86%)を得た。
1H−NMR(CDCl3)δ: 3.79 (3H, s), 3.89 (3H, s), 6.70, (1H, s), 7.15 (2H, d, J = 8.9 Hz), 7.28.10-7.39 (7H, m).
13C−NMR(CDCl3)δ: 54.8 (q), 55.2 (q), 79.9 (q), 121.0 (d), 126.8 (d),128.10 (d), 128.14 (d), 128.4 (d), 137.4 (s), 139.2 (s), 150.7 (s), 153.9 (s), 154.9 (s).
FAB−MS m/z:316[M]+
HR−FAB−MS m/z:316.0943(C17H16O5,理論値:316.0947)
フェニルリチウムの代わりに、3‐cis‐ヘプタ‐3,6‐ジエニルマグネシウムブロマイドを用いた以外は合成例1と同様に、又、メチル炭酸クロリドの変わりに無水酢酸を用いた以外は合成例2と同様にして、酢酸4‐cis‐1‐(4‐アセトキシフェニル)オクタ‐4,7‐ジエニルを得た。
1H−NMR(CDCl3)δ: 1.79-2.22 (4H, m), 2.08 (3H, s), 2.30 (3H, s), 4.64 (2H, t, J = 6.4 Hz), 4.81-5.04 (2H, m), 5.45 (1H, m), 5.85 (2H, m), 7.06 (2H, d, J = 8.6 Hz), 7.34 (2H, d, J = 8.6 Hz).
13C−NMR(CDCl3)δ: 21.2 (q), 21.3 (q), 29.7 (t), 31.2 (t), 35.4 (t), 74.9 (d), 114.9 (t), 121.7 (d), 127.4 (d), 127.8 (d), 126.8 (d), 128.6 (d), 136.7 (t), 138.1, (s), 150.1 (s), 169.1 (s), 170.2 (s).
FAB−MS m/z:302[M]+
HR−FAB−MS m/z:302.1509(C18H22O4,理論値:302.1518)
フェニルリチウムの代わりに、アリルマグネシウムブロマイドを用いた以外は合成例1と同様に、又、メチル炭酸クロリドの変わりに無水酢酸、イソ酪酸クロリドを順次用いた以外は合成例2と同様にして、イソ酪酸1‐(4‐アセトキシフェニル)ブト‐3‐エニルを得た。
1H−NMR(CDCl3)δ: 1.16 (3H, t, J = 7.6, 7.6 Hz), 2.34 (2H, q, J = 7.6, 7.6, 7.6 Hz), 2.35-2.70 (2H, m), 5.03-5.10 (2H, m), 5.66 (1H, ddt, J = 13.8, 10.3, 6.8, 6.8 Hz), 5.80 (1H, dd, J = 7.6, 5.9 Hz), 7.06 (2H, J = 8.4 Hz), 7.34 (2H, d, J = 8.4 Hz).
13C−NMR(CDCl3)δ: 9.1 (q), 21.1 (q), 27.7 (t), 40.7 (t), 74.2 (d), 118.1 (t), 121.5 (d), 127.7 (d), 133.7 (d), 137.8 (s), 150.2 (s), 169.4 (s), 173.5 (s).
FAB−MS m/z:276[M]+
HR−FAB−MS m/z:276.1352(C16H20O4,理論値:276.1362)
フェニルリチウムの代わりに、アリルマグネシウムブロマイドを用いた以外は合成例1と同様に、又、メチル炭酸クロリドの変わりに無水酢酸、ピバリン酸クロリドを順次用いた以外は合成例2と同様にして、2,2‐ジメチルプロピオン酸1‐(4‐アセトキシフェニル)ブト‐3‐エニルを得た。
1H−NMR(CDCl3)δ: 1.20 (9H, s), 2.29 (3H, s), 2.42-2.68 (2H, m), 5.67 (1H, ddt, J = 17.0, 10.3, 6.8, 6.8 Hz), 5.78 (1H, dd, J = 7.6, 5.6 Hz), 7.05 (2H, d, J = 8.6 Hz), 7.32 (2H, d, J = 8.6 Hz).
13C−NMR(CDCl3)δ: 21.1 (q), 27.0 (q), 41.1 (s), 74.0 (d), 118.1 (t), 121.5 (d), 127.3 (d), 133.2 (d), 138.1 (d), 141.1 (s), 150.1 (s), 166.5 (s), 169.4 (s).
FAB−MS m/z:290[M]+
HR−FAB−MS m/z:290.1502(C17H22O4,理論値:290.1518)
フェニルリチウムの代わりに、アリルマグネシウムブロマイドを用いた以外は合成例1と同様に、又、メチル炭酸クロリドの変わりに無水酢酸、安息香酸クロリドを順次用いた以外は合成例2と同様にして、安息香酸1‐(4‐アセトキシフェニル)ブト‐3‐エニルを得た。
1H−NMR(CDCl3)δ: 12.33 (3H, s), 2.62-2.85 (2H, m), 5.05-5.16 (2H, m), 5.77 (1H, ddt, J = 17.0, 10.3, 6.8, 6.8 Hz), 6.05 (1H, dd, J = 7.6, 5.9 Hz), 7.08 (2H, d, J = 11.1 Hz), 7.35 (7H, m), 8.05 (2H, d, J = 8.6 Hz).
13C−NMR(CDCl3)δ: 21.1 (q), 40.9 (t), 75.1 (d), 118.4 (t), 121.5 (d), 127.6 (d), 128.9 (d), 129.6 (d), 130.2 (s), 132.9 (d), 133.0 (d), 137.7 (d), 150.3 (s), 165.6 (s), 169.3 (s).
FAB−MS m/z:311[M+H]+
HR−FAB−MS m/z:311.1246(C19H19O4,理論値:311.1283)
フェニルリチウムの代わりに、n‐プロピルマグネシウムブロマイドを用いた以外は合成例1と同様に、又、メチル炭酸クロリドの変わりに無水酢酸を用いた以外は合成例2と同様にして、酢酸1‐(4‐アセトキシフェニル)ブチルを得た。
フェニルリチウムの代わりに、エチルマグネシウムブロマイドを用いた以外は合成例1と同様に、又、メチル炭酸クロリドの変わりにプロピオン酸クロリドを用いた以外は合成例2と同様にして、プロピオン酸1‐(4‐プロピオニルオキシフェニル)プロピルを得た。
フェニルリチウムの代わりに、ビニルマグネシウムブロマイドを用いた以外は合成例1と同様に、又、メチル炭酸クロリドの変わりに無水酢酸を用いた以外は合成例2と同様にして、酢酸1‐(4‐アセトキシフェニル)アリルを得た。
フェニルリチウムの代わりに、3,4‐ビス(ベンジルオキシ)フェニルビニルマグネシウムブロマイドを用いた以外は合成例1と同様に、又、メチル炭酸クロリドの変わりに無水酢酸を用いた以外は合成例2と同様にして、さらに、Pd‐C触媒存在下、エタノール中、水素雰囲気下でベンジル基を脱保護することにより、酢酸1‐(4‐アセトキシフェニル)‐3‐(3,4‐ジハイドロキシフェニル)アリルを得た。
特開2007−230949号の実施例2の方法で、4‐(メトキシカルボニルオキシフェニルメチル)フェニルメチルカーボネートを得た。
特開2007−230949号の実施例3の方法で、酢酸ビス‐(4‐アセトキシフェニル)メチルを得た。
特開2007−230949号の実施例4の方法で、酢酸1‐(4‐アセトキシフェニル)‐2‐フェニルエチルを得た。
無水酢酸の代わりに塩化プロピオニルを、メチル炭酸クロリドの代わりに塩化プロピオニルを用いた以外は、特開2007−230949号の実施例1と同様な方法によりプロピオン酸フェニル‐(4‐プロピオニルオキシフェニル)メチルを得た。
1H−NMR(CDCl3)δ: 1.17 (3H, t, J = 7.6 Hz), 1.25, (3H, t, J = 7.6 Hz), 2.44 (2H, q, J = 7.6 Hz), 2.57 (2H, t, J = 7.6 Hz), 6.89, (1H, s), 7.45 (2H, d, J = 8.6 Hz), 7.26-7.35 (7H, m).
13C−NMR(CDCl3)δ: 8.9 (q), 27.6 (t), 27.7 (t), 75.9 (d), 121.5 (d), 126.9 (d), 127.8 (d), 128.2 (d), 128.4 (d), 137.7 (s), 140.0 (d), 150.2 (s), 172.7 (s), 173.1 (s).
FAB−MS m/z:313[M+H]+
HR−FAB−MS m/z:312.1360(C19H20O4,理論値:312.1362)
メチル炭酸クロリドの代わりにイソ酪酸クロリドを用いた以外は、特開2007−230949号の実施例1と同様な方法により、イソ酪酸(4‐アセトキシフェニル)フェニルメチルを得た。
1H−NMR(CDCl3)δ: 1.20 (3H, d, J = 7.0 Hz), 1.28, (3H, d, J = 6.8 Hz), 2.65 (1H, spt., J = 7.0 Hz), 2.77 (1H, spt., J = 6.8 Hz), 6.87, (1H, s), 7.04 (2H, d, J = 8.6 Hz), 7.22-7.35 (7H, m).
13C−NMR(CDCl3)δ: 18.8 (q), 34.0 (d), 34.1 (d), 75.8 (d), 121.4 (d), 126.8 (d), 127.9 (d), 128.1 (d), 128.4 (d), 137.7 (s), 140.1 (d), 150.3 (s), 172.7 (s), 175.3 (s), 175.7, (s).
FAB−MS m/z:340[M+H]+
HR−FAB−MS m/z:340.1687(C21H24O4,理論値:340.1675)
メチル炭酸クロリドの代わりにピバルクロリドを用いた以外は、特開2007−230949号の実施例1と同様な方法により、2,2‐ジメチルプロピオン酸(4‐アセトキシフェニル)フェニルメチルを得た。
1H−NMR(CDCl3)δ: 1.24 (9H, s), 2.25 (3H, s), 6.83 (1H, s), 7.05 (2H, d, J = 8.6 Hz), 7.23-7.35 (7H, m).
13C−NMR(CDCl3)δ: 20.9 (q), 27.0 (q), 38.8 (s), 75.9 (d), 121.5 (d), 126.8 (d), 127.8 (d),128.0, (d), 128.4 (d), 150.1 (s), 169.2(s), 177.1 (s).
EI−MS m/z:326[M]+
HR−EI−MS m/z:326.1530(C20H22O4,理論値:326.1518)
無水酢酸の代わりにメチル炭酸クロリドを用いた以外は、特開2007−230949号の実施例3と同様な方法により、ビス‐(4‐メトキシカルボニルオキシフェニルメチル)メチルカーボネートを得た。
IR(neat): 1743, 1720cm−1
1H−NMR(CDCl3)δ: 3.15 (3H, s), 3.29 (6H, s), 6.88 (1H, s), 7.06 (4H, d, J = 8.4Hz), 7.33 (4H, d, J = 8.4 Hz).
13C−NMR(CDCl3)δ: 41.1 (q), 41.2 (q), 75.6 (d), 121.6 (d), 128.3 (d), 137.4 (s), 150.3 (s), 169.3 (s), 170 (s).
FAB−MS m/z:391[M+H]+
HR−FSB−MS m/z:391.1025(C19H19O9,理論値:391.1029)
メチル炭酸クロリドの代わりに塩化プロピオニルを用いた以外は、特開2007−230949号の実施例1と同様な方法により、プロピオン酸(4‐アセトキシフェニル)フェニルメチルを得た。
1H−NMR(CDCl3)δ: 1.17 (3H, t, J = 7.6 Hz), 2.28 (3H, s), 2.44 (2H, q, J = 7.6 Hz), 6.89 (1H, s), 7.05 (2H, d, J = 8.7 Hz), 7.24-7.35 (7H, m).
13C−NMR(CDCl3)δ: 9.0, 21.1, 27.8, 76.0, 121.6, 127.0, 128.0, 128.3, 128.5, 137.9, 140.0, 150.2, 169.3, 173.3.
FAB−MS m/z:298[M+H]+
HR−FSB−MS m/z:298.1205(C18H18O4,理論値:298.1183)
モデル細胞である分裂酵母カルシニューリン遺伝子ノックアウト細胞(h+ leu1 ura4-D18 ppb1::ura4+)を用い、塩化マグネシウム含有培地での生育を判定することでMAPキナーゼシグナル伝達阻害の指標とし、MAPキナーゼシグナル伝達阻害作用を検討した。
Claims (2)
- 酢酸4‐cis‐1‐(4‐アセトキシフェニル)オクタ‐4,7‐ジエニル、イソ酪酸1‐(4‐アセトキシフェニル)ブト‐3‐エニル、2,2‐ジメチルプロピオン酸1‐(4‐アセトキシフェニル)ブト‐3‐エニル、及び安息香酸1‐(4‐アセトキシフェニル)ブト‐3‐エニルから選ばれることを特徴とするキャビコール類縁体化合物。
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