JP5399249B2 - 3環系アミン化合物 - Google Patents
3環系アミン化合物 Download PDFInfo
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- JP5399249B2 JP5399249B2 JP2009528147A JP2009528147A JP5399249B2 JP 5399249 B2 JP5399249 B2 JP 5399249B2 JP 2009528147 A JP2009528147 A JP 2009528147A JP 2009528147 A JP2009528147 A JP 2009528147A JP 5399249 B2 JP5399249 B2 JP 5399249B2
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- -1 amine compounds Chemical class 0.000 title claims description 71
- 150000001875 compounds Chemical class 0.000 claims description 96
- 230000009471 action Effects 0.000 claims description 32
- 150000003839 salts Chemical class 0.000 claims description 24
- 150000004492 retinoid derivatives Chemical class 0.000 claims description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 9
- 239000004480 active ingredient Substances 0.000 claims description 7
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 3
- 239000003623 enhancer Substances 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 142
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 108
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 99
- 239000000203 mixture Substances 0.000 description 92
- 239000000243 solution Substances 0.000 description 86
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 81
- 239000011541 reaction mixture Substances 0.000 description 81
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 78
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 76
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 73
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 71
- 239000012044 organic layer Substances 0.000 description 71
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 71
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 65
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 62
- 238000005160 1H NMR spectroscopy Methods 0.000 description 59
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 45
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 40
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 38
- 239000000725 suspension Substances 0.000 description 38
- 239000002904 solvent Substances 0.000 description 36
- 238000010898 silica gel chromatography Methods 0.000 description 31
- 238000002844 melting Methods 0.000 description 28
- 230000008018 melting Effects 0.000 description 28
- 229920006395 saturated elastomer Polymers 0.000 description 27
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 24
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 21
- 235000019270 ammonium chloride Nutrition 0.000 description 20
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 19
- 239000012312 sodium hydride Substances 0.000 description 19
- 229910000104 sodium hydride Inorganic materials 0.000 description 19
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 18
- 239000003814 drug Substances 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 238000001816 cooling Methods 0.000 description 14
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 14
- 125000001424 substituent group Chemical group 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 13
- 238000010992 reflux Methods 0.000 description 13
- 239000005711 Benzoic acid Substances 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- MJBWDEQAUQTVKK-IAGOWNOFSA-N aflatoxin M1 Chemical compound C=1([C@]2(O)C=CO[C@@H]2OC=1C=C(C1=2)OC)C=2OC(=O)C2=C1CCC2=O MJBWDEQAUQTVKK-IAGOWNOFSA-N 0.000 description 12
- 235000010233 benzoic acid Nutrition 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 230000002708 enhancing effect Effects 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 102000034527 Retinoid X Receptors Human genes 0.000 description 9
- 108010038912 Retinoid X Receptors Proteins 0.000 description 9
- 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 9
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 9
- 229930002330 retinoic acid Natural products 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 239000005457 ice water Substances 0.000 description 8
- 230000001766 physiological effect Effects 0.000 description 8
- 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 8
- 125000000217 alkyl group Chemical group 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 230000002265 prevention Effects 0.000 description 7
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- 108090000064 retinoic acid receptors Proteins 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 229960001727 tretinoin Drugs 0.000 description 7
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound 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-YRZJJWOYSA-N 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 6
- AEILLAXRDHDKDY-UHFFFAOYSA-N bromomethylcyclopropane Chemical compound BrCC1CC1 AEILLAXRDHDKDY-UHFFFAOYSA-N 0.000 description 6
- OQNGCCWBHLEQFN-UHFFFAOYSA-N chloroform;hexane Chemical compound ClC(Cl)Cl.CCCCCC OQNGCCWBHLEQFN-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 125000002192 heptalenyl group Chemical group 0.000 description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000008194 pharmaceutical composition Substances 0.000 description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 6
- XUIIKFGFIJCVMT-GFCCVEGCSA-N D-thyroxine Chemical compound IC1=CC(C[C@@H](N)C(O)=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-GFCCVEGCSA-N 0.000 description 5
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- JPXMTWWFLBLUCD-UHFFFAOYSA-N nitro blue tetrazolium(2+) Chemical compound COC1=CC(C=2C=C(OC)C(=CC=2)[N+]=2N(N=C(N=2)C=2C=CC=CC=2)C=2C=CC(=CC=2)[N+]([O-])=O)=CC=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=C([N+]([O-])=O)C=C1 JPXMTWWFLBLUCD-UHFFFAOYSA-N 0.000 description 5
- 102000006255 nuclear receptors Human genes 0.000 description 5
- 108020004017 nuclear receptors Proteins 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 229940034208 thyroxine Drugs 0.000 description 5
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 5
- 208000020084 Bone disease Diseases 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 4
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- UXTMROKLAAOEQO-UHFFFAOYSA-N chloroform;ethanol Chemical compound CCO.ClC(Cl)Cl UXTMROKLAAOEQO-UHFFFAOYSA-N 0.000 description 4
- 230000004069 differentiation Effects 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 4
- 229910001948 sodium oxide Inorganic materials 0.000 description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- 102100038495 Bile acid receptor Human genes 0.000 description 3
- 208000019736 Cranial nerve disease Diseases 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 206010020649 Hyperkeratosis Diseases 0.000 description 3
- 208000001126 Keratosis Diseases 0.000 description 3
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- 239000012979 RPMI medium Substances 0.000 description 3
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- 125000003277 amino group Chemical group 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
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- 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 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- IEMKQRSOAOPKRJ-UHFFFAOYSA-N ethyl 2-chloropyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(Cl)N=C1 IEMKQRSOAOPKRJ-UHFFFAOYSA-N 0.000 description 3
- YCBJOQUNPLTBGG-UHFFFAOYSA-N ethyl 4-iodobenzoate Chemical compound CCOC(=O)C1=CC=C(I)C=C1 YCBJOQUNPLTBGG-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
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- 238000012360 testing method Methods 0.000 description 3
- 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 2
- NFPDOMFGPMKFGV-UHFFFAOYSA-N 2,3,3a,4,5,6-hexahydro-1h-phenalene Chemical compound C1CCC2=CC=CC3=C2C1CCC3 NFPDOMFGPMKFGV-UHFFFAOYSA-N 0.000 description 2
- XPHNRJFEXSZMSH-UHFFFAOYSA-N 2-(6,7,8,9-tetrahydro-5h-benzo[7]annulen-5-yl)acetaldehyde Chemical compound O=CCC1CCCCC2=CC=CC=C12 XPHNRJFEXSZMSH-UHFFFAOYSA-N 0.000 description 2
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- MZXDADITQOAGKS-UHFFFAOYSA-N 4-(6,7,8,9-tetrahydro-5h-benzo[7]annulen-5-yl)butanoic acid Chemical compound OC(=O)CCCC1CCCCC2=CC=CC=C12 MZXDADITQOAGKS-UHFFFAOYSA-N 0.000 description 2
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- SVVJJKODCRMZGE-UHFFFAOYSA-N ethyl 2-[(6a-methyl-4,5,6,7,8,9-hexahydrophenalen-2-yl)amino]pyrimidine-5-carboxylate Chemical compound N1=CC(C(=O)OCC)=CN=C1NC1=CC(CCCC2(C)CCC3)=C2C3=C1 SVVJJKODCRMZGE-UHFFFAOYSA-N 0.000 description 2
- NREMTRFANINULE-UHFFFAOYSA-N ethyl 4-(6,7,8,9-tetrahydro-5h-benzo[7]annulen-5-yl)butanoate Chemical compound CCOC(=O)CCCC1CCCCC2=CC=CC=C12 NREMTRFANINULE-UHFFFAOYSA-N 0.000 description 2
- SYSCTRIWNSIRKA-UHFFFAOYSA-N ethyl 4-[(6a-methyl-4,5,6,7,8,9-hexahydrophenalen-2-yl)amino]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1NC1=CC(CCCC2(C)CCC3)=C2C3=C1 SYSCTRIWNSIRKA-UHFFFAOYSA-N 0.000 description 2
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- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical group C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- IIVUJUOJERNGQX-UHFFFAOYSA-N pyrimidine-5-carboxylic acid Chemical compound OC(=O)C1=CN=CN=C1 IIVUJUOJERNGQX-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 150000003536 tetrazoles Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 150000002266 vitamin A derivatives Chemical class 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C229/60—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in meta- or para- positions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
- C07C2603/28—Phenalenes; Hydrogenated phenalenes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/30—Ortho- or ortho- and peri-condensed systems containing three rings containing seven-membered rings
- C07C2603/34—Benzoheptalenes; Hydrogenated benzoheptalenes
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nutrition Science (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
一般式(I)で表される化合物のエステルは、一般式(I)で表される化合物のプロドラッグとして使用することができ、同様に医薬の有効成分として用いることができる。
(1)2,3,3a,4,5,6-ヘキサヒドロ-1H-フェナレン
2,3,3a,4,5,6-ヘキサヒドロ-フェナレン-1-オン(2.00 g)の無水テトラヒドロフラン(7 0ml)溶液を0℃に冷却し、水素化ホウ素ナトリウム(1.62 g)および塩化アルミニウム(2.85 g)をゆっくり加えた。反応混合物を3時間加熱還流した後、0℃に冷却し、酢酸エチルで希釈した。発泡しなくなるまで氷をゆっくりと加えた後、室温にして一夜撹拌した。酢酸エチルで抽出し、有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒;n-ヘキサン)で精製し、標記化合物(1.47 g、収率80%)を得た。
1H-NMR(400MHz,CDCl3):δ1.26-1.40(2H,m),1.70-1.84(2H,m),1.85-2.00(4H,m),2.52-2.63(1H,m),2.78-2.82(4H,m),6.89(1H,d,J=7.5Hz),7.02(1H,t,J=7.5Hz)
塩化アルミニウム(0.250 g)の二硫化炭素(3 ml)懸濁液にアセチルクロリド(0.16 ml)を加えた。室温で5分撹拌後、2 mlの二硫化炭素に溶解した2,3,3a,4,5,6-ヘキサヒドロ-1H-フェナレン(0.250 g)を0℃でゆっくりと加えた。0℃で1時間、室温で1時間撹拌した後、反応混合物を氷水に注ぎ酢酸エチルで抽出した。有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒;酢酸エチル:n-ヘキサン=1:500)で精製して1-(5,6,6a,7,8,9-ヘキサヒドロ-4H-1-フェナレニル)エタノン(0.139g,収率45%)および標記化合物(0.135g,収率43%)を得た。
1H-NMR(400MHz,CDCl3):δ1.26-1.40(2H,m),1.77-2.02(6H,m),2.55(3H,s),2.56-2.60(1H,m),2.82-2.87(4H,m),7.50(2H,s)
2.5N水酸化ナトリウム水溶液(9.2 ml)を0℃に冷却し、臭素(0.30 ml)をゆっくりと加えた後、1,4-ジオキサン(1.5 ml)で希釈して黄色溶液を得た。1-(5,6,6a,7,8,9-ヘキサヒドロ-4H-2-フェナレニル)エタノン(0.380 g)の水(5 ml)および1,4-ジオキサン(10 ml)溶液を0℃に冷却し、先に調製した黄色溶液をゆっくりと加え、0℃で10分間、室温で1時間撹拌した。反応混合物を0℃に冷却し、10%亜硫酸ナトリウム水溶液を加えた後、2N塩酸水溶液で酸性にしてクロロホルムで抽出した。有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮して得られた残渣を酢酸エチル−n-ヘキサンより再結晶して標記化合物(0.338g,収率88%)を無色針状晶(融点208-209℃)として得た。
1H-NMR(400MHz,CDCl3):δ1.26-1.41(2H,m),1.73-1.86(2H,m),1.88-2.05(4H,m),2.54-2.65(1H,m),2.82-2.88(4H,m),7.64(2H,s)
5,6,6a,7,8,9-ヘキサヒドロ-4H-2-フェナレンカルボン酸(0.320 g)の無水ベンゼン(2 ml)溶液にチオニルクロリド(3 ml)を加えて2時間加熱還流した。減圧濃縮して得られた残渣の無水テトラヒドロフラン(10 ml)溶液を0℃に冷却し、アジ化ナトリウム(0.290 g)の水(1 ml)溶液を加え、0℃で30分間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、ジエチルエーテルで抽出した。有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮して得られた残渣を酢酸(7 ml)および水(3 ml)に溶かし、一夜加熱還流した。放冷後、反応混合物に飽和炭酸水素ナトリウム水溶液を加えてアルカリ性にした後、酢酸エチルで抽出した。有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮して得られた残渣をメタノール(10 ml)に溶かし、濃塩酸(5 ml)を加えて3時間加熱還流した。放冷後、ジエチルエーテルで希釈し、2N塩酸水溶液で抽出した。水層を2N水酸化ナトリウム水溶液でアルカリ性にしてジエチルエーテルで抽出した。有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒;酢酸エチル:n-ヘキサン=1:50)で精製し、標記化合物(0.260g,収率94%)を得た。
1H-NMR(400MHz,CDCl3):δ1.22-1.34(2H,m),1.66-1.80(2H,m),1.81-1.93(4H,m),2.40-2.54(1H,m),2.69-2.74(4H,m),3.43(2H,br-s),6.29(2H,s)
1H-NMR(400MHz,CDCl3):δ1.26-1.38(2H,m),1.37(3H,t,J=7.2Hz),1.71-1.85(2H,m),1.87-1.99(4H,m),2.49-2.60(1H,m),2.76-2.80(4H,m),4.46(2H,q,J=7.2Hz),5.86(1H,br-s),6.73(2H,s),6.93(2H,d,J=9.0Hz),7.90(2H,d,J=9.0Hz)
1H-NMR(400MHz,CDCl3):δ1.26-1.40(2H,m),1.72-1.86(2H,m),1.88-2.00(4H,m),2.50-2.60(1H,m),2.77-2.81(4H,m),5.93(1H,br-s),6.76(2H,s),6.94(2H,d,J=8.7Hz),7.95(2H,d,J=8.7Hz)
(1)4-[N-メチル-(5,6,6a,7,8,9-ヘキサヒドロ-4H-2-フェナレニル)アミノ]安息香酸メチル
1H-NMR(400MHz,CDCl3):δ1.28-1.42(2H,m),1.72-1.86(2H,m),1.87-2.00(4H,m),2.52-2.63(1H,m),2.76-2.80(4H,m),3.31(3H,s),3.85(3H,s),6.72(2H,d,J=8.7Hz),6.74(2H,s),7.84(2H,d,J=8.7Hz)
1H-NMR(400MHz,CDCl3+CD3OD):δ1.29-1.42(2H,m),1.72-1.86(2H,m),1.88-2.01(4H,m),2.54-2.62(1H,m),2.75-2.80(4H,m),3.31(3H,s),6.72(2H,d,J=9.0Hz),6.75(2H,s),7.85(2H,d,J=9.0Hz)
1H-NMR(400MHz,DMSO-d6):δ1.23(2H,td,J=11.7,4.5Hz),1.62-1.74(2H,m),1.78-1.94(4H,m),2.50-2.53(1H,m),2.67-2.72(4H,m),3.21(3H,s),6.68(2H,d,J=8.7Hz),6.72(2H,s),7.69(2H,d,J=8.7Hz)
(1)4-[N-エチル-(5,6,6a,7,8,9-ヘキサヒドロ-4H-2-フェナレニル)アミノ]安息香酸エチル
1H-NMR(400MHz,CDCl3):δ1.23(3H,t,J=7.2Hz),1.35(3H,t,J=7.2Hz),1.29-1.42(2H,m),1.72-1.86(2H,m),1.87-2.01(2H,m),2.53-2.63(1H,m),2.75-2.80(4H,m),3.74(2H,q,J=7.2Hz),4.30(2H,q,J=7.2Hz),6.65(2H,d,J=8.7Hz),6.72(2H,s),7.82(2H,d,J=8.7Hz)
1H-NMR(400MHz,CDCl3):δ1.25(3H,t,J=7.2Hz),1.29-1.43(2H,m),1.76-1.86(2H,m),1.88-2.00(4H,m),2.53-2.64(1H,m),2.77-2.81(4H,m),3.75(2H,q,J=7.2Hz),6.65(2H,d,J=8.7Hz),6.73(2H,s),7.85(2H,d,J=8.7Hz)
(1)4-[N-シクロプロピルメチル-(5,6,6a,7,8,9-ヘキサヒドロ-4H-2-フェナレニル)アミノ]安息香酸エチル
1H-NMR(400MHz,CDCl3):δ0.16(2H,q,J=4.8Hz),0.46-0.53(2H,m),1.11-1.21(1H,m),1.28-1.43(2H,m),1.35(3H,t,J=7.2Hz),1.72-1.86(2H,m),1.87-2.01(4H,m),2.52-2.63(1H,m),2.75-2.79(4H,m),3.54(2H,d,J=6.6Hz),4.31(2H,q,J=7.2Hz),6.69(2H,d,J=8.7Hz),6.74(2H,s),7.82(2H,d,J=8.7Hz)
1H-NMR(400MHz,CDCl3):δ0.17(2H,q,J=5.7Hz),0.48-0.54(2H,m),1.14-1.22(2H,m),1.29-1.43(2H,m),1.75-1.86(2H,m),1.89-2.00(4H,m),2.53-2.62(2H,m),2.77-2.80(4H,m),3.55(2H,d,J=6.3Hz),6.68(2H,d,J=8.7Hz),6.75(2H,s),7.86(2H,d,J=8.7Hz)
(1)2-[(5,6,6a,7,8,9-ヘキサヒドロ-4H-2-フェナレニル)アミノ]ピリミジン-5-カルボン酸エチル
1H-NMR(400MHz,CDCl3):δ1.25-1.35(2H,m),1.38(3H,t,J=7.2 Hz),1.71-1.85(2H,m),1.87-1.99(4H,m),2.51- 2.59(1H,m),2.80-2.85(4H,m),3.86(2H,q,J=7.2 Hz),7.13(2H,s),7.83(1H,br-s),8.94(2H,s)
1H-NMR(400MHz,DMSO-d6):δ1.14-1.23(2H,m),1.63-1.71(2H,m),1.77-1.90(4H,m),2.22-2.28(1H,m),2.65-2.70(4H,m),7.17(2H,s),8.66(2H,s),9.75(1H,s)
2-[N-メチル-(5,6,6a,7,8,9-ヘキサヒドロ-4H-2-フェナレニル)アミノ]ピリミジン-5-カルボン酸
1H-NMR(400MHz,CDCl3):δ1.34-1.43(2H,m),1.72-1.86(2H,m),1.88-1.95(4H,m),2.53-2.62(1H,m),2.80- 2.84(4H,m),3.55(3H,s),6.81(2H,s),8.91(2H,s)
2-[N-エチル-(5,6,6a,7,8,9-ヘキサヒドロ-4H-2-フェナレニル)アミノ]ピリミジン-5-カルボン酸
1H-NMR(400MHz,CDCl3):δ1.26(3H,t,J=7.2Hz),1.34-1.43(2H,m),1.75-1.85(2H,m),1.89-1.98(4H,m),2.54-2.63,1H,m),2.80-2.84(4H,m),4.02(2H,q,J=7.2Hz),6.76(2H,s),8.89(2H,s)
2-[N-シクロプロピルメチル-(5,6,6a,7,8,9-ヘキサヒドロ-4H-2-フェナレニル)アミノ]ピリミジン-5-カルボン酸
1H-NMR(400MHz,CDCl3):δ0.25(2H,dd,J=10.8,4.8Hz),0.44-0.50(2H,m),1.15-1.23(1H,m),1.30-1.43(2H,m),1.75-1.85(2H,m),1.88-1.98(4H,m),2.54-2.62(1H,m)2.82(4H,br-dd,J=8.1,4.5Hz),3.86(2H,d,J=7.2Hz),6.80(2H,s),8.79(2H,s)
(1)3a-メチル-2,3,3a,4-テトラヒドロ-1H-フェナレン
3a-メチル-2,3,3a,4,5,6-ヘキサヒドロ-1-フェナレノン(2.14 g)の無水テトラヒドロフラン(70 ml)溶液を0℃に冷却し、水素化ホウ素ナトリウム(1.62 g)および塩化アルミニウム(2.85 g)をゆっくりと加えた。反応混合物を3時間加熱還流した後、0℃に冷却し、酢酸エチルで希釈した。発泡しなくなるまで氷をゆっくりと加えた後、室温にして一夜撹拌した。酢酸エチルで抽出し、有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒;n-ヘキサン)で精製し、標記化合物(1.83 g、収率97%)を得た。
1H-NMR(400MHz,CDCl3):δ1.16(3H,s),1.64(1H,td,J=13.1,3.4Hz),1.74(1H,dt,J=12.8,3.4Hz),1.79-1.89(1H,m),1.92-2.04(1H,m),2.10(1H,dd,J=17.1,6.3Hz),2.27(1H,dt,J=17.1,2.7Hz),2.77-2.83(2H,m)5.89-5.95(1H,m),6.45(1H,dd,J=9.6,3.0Hz),6.85(1H,d,J=7.5Hz),6.92(1H,d,J=7.5Hz),7.03(1H,t,J=7.5Hz)
3a-メチル-2,3,3a,4-テトラヒドロ-1H-フェナレン(1.83 g)をエタノール(12 ml)に溶解させ、10% パラジウム炭素(0.183 g)を加え、水素気流下6時間撹拌した。反応混合物をセライトを通して濾過後、濾液の溶媒を減圧濃縮して得られた残渣を少量のシリカゲルを用いたシリカゲルカラムクロマトグラフィー(展開溶媒;n-ヘキサン)で精製し、標記化合物(1.74 g,収率94%)を得た。
1H-NMR(400MHz,CDCl3):δ1.17(3H,s),1.51(2H,td,J=13.1,5.1Hz),1.66(2H,dt,J=13.1,4.1Hz),1.74-1.86(2H,m),1.98-2.14(2H,m),2.79(2H,dt,J=17.1,8.6Hz),2.91(2H,ddd,J=17.1,8.1,3.5Hz),6.88(2H,dd,J=7.5,0.8Hz),7.00(1H,dd,J=8.1,6.6Hz)
塩化アルミニウム(1.62 g)の二硫化炭素(25 ml)懸濁液にアセチルクロリド(1.00 ml)を-10℃で加えた。-10℃で20分間撹拌後、15 mlの二硫化炭素に溶解した3a-メチル-2,3,3a,4,5,6-ヘキサヒドロ-1H-フェナレン(1.74 g)をゆっくりと加え、徐々に室温まで温度を上げた。室温で30分間撹拌した後、反応混合物を氷水に注ぎ酢酸エチルで抽出した。有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒;酢酸エチル:n-ヘキサン=1:500)で精製して1-(6a-メチル-5,6,6a,7,8,9-ヘキサヒドロ-4H-1-フェナレニル)エタノン(1.63 g,収率77%)および標記化合物(0.465 g,収率22%)を得た。n-ヘキサンより再結晶して無色プリズム晶(融点100-101.5℃)を得た。
1H-NMR(400MHz,CDCl3):δ1.17(3H,s),1.51(2H,td,J=13.0,4.8Hz),1.70(2H,dt,J=13.0,4.1Hz),1.78-1.89(2H,m),1.99-2.15(2H,m),2.55(3H,s),2.82(2H,dt,J=17.1,8.6Hz),2.97(2H,ddd,J=17.3,7.9,3.3Hz),7.48(2H,s)
2.5N水酸化ナトリウム水溶液(9.3 ml)を0℃に冷却し、臭素(0.30 ml)をゆっくりと加えた後、1,4-ジオキサン(10 ml)で希釈して黄色溶液を得た。1-(6a-メチル-5,6,6a,7,8,9-ヘキサヒドロ-4H-2-フェナレニル)エタノン(0.409 g)の水(5 ml)および1,4-ジオキサン(10 ml)溶液を0℃に冷却し、先に調製した黄色溶液をゆっくりと加え、0℃で30分間、室温で1時間撹拌した。反応混合物を0℃に冷却し、10%亜硫酸ナトリウム水溶液を加えた後、2N塩酸水溶液で酸性にしてクロロホルムで抽出した。有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮して得られた残渣を酢酸エチル−n-ヘキサンより再結晶して標記化合物(0.333 g,収率81%)を無色針状晶(融点213-215℃)として得た。
1H-NMR(400MHz,CDCl3):δ1.17(3H,s),1.52(2H,td,J=13.1,5.1Hz),1.70(2H,dt,J=13.1,4.1Hz),1.78-1.89(2H,m),1.99-2.15(2H,m),2.84(2H,dt,J=17.3,8.6Hz),2.97(2H,ddd,J=17.3,8.1,3.6Hz),7.62(2H,s)
6a-メチル-5,6,6a,7,8,9-ヘキサヒドロ-4H-2-フェナレンカルボン酸(0.165 g)の無水ベンゼン(3 ml)溶液にチオニルクロリド(1 ml)を加えて2時間加熱還流した。減圧濃縮して得られた残渣の無水テトラヒドロフラン(5 ml)溶液を0℃に冷却し、アジ化ナトリウム(0.140 g)の水(0.5 ml)溶液を加え、0℃で30分間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、ジエチルエーテルで抽出した。有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮して得られた残渣を酢酸(5 ml)および水(2 ml)に溶かし、一夜加熱還流した。放冷後、反応混合物に飽和炭酸水素ナトリウム水溶液を加えてアルカリ性にした後、酢酸エチルで抽出した。有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮して得られた残渣をメタノール(5 ml)に溶かし、濃塩酸(3 ml)を加えて3時間加熱還流した。放冷後、10%炭酸ナトリウム水溶液でアルカリ性にしてジエチルエーテルで抽出した。有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒;酢酸エチル:n-ヘキサン=1:50)で精製し、標記化合物(0.138g,収率96%)を得た。
1H-NMR(400MHz,CDCl3):δ1.13(3H,s),1.46(2H,td,J=12.9,5.1Hz),1.62(2H,dt,J=12.9,4.1Hz),1.71-1.82(2H,m),1.94-2.10(2H,m),2.69(2H,dt,J=17.1,8.6Hz),2.81(2H,ddd,J=17.4,8.0,3.5Hz),3.40(2H,br-s),6.27(2H,s)
1H-NMR(400MHz,CDCl3):δ1.17(3H,s),1.37(3H,t,J=7.2Hz),1.50(2H,td,J=12.9,5.1Hz),1.68(2H,dt,J=12.9,4.1Hz),1.75-1.86(2H,m),1.98-2.15(2H,m),2.75(2H,dt,J=17.3,8.6Hz),2.88(2H,ddd,J=17.3,7.8,3.3Hz),4.33(2H,q,J=7.2Hz),5.84(1H,br-s),6.72(2H,s),6.93(2H,d,J=9.0Hz),7.89(2H,d,J=9.0Hz)
1H-NMR(400MHz,CDCl3):δ1.18(3H,s),1.51(2H,td,J=12.9,4.8Hz),1.69(2H,dt,J=12.9,4.1Hz),1.76-1.87(2H,m),1.99-2.18(2H,m),2.76(2H,dt,J=17.3,8.7Hz),2.89(2H,ddd,J=17.3,7.9,3.3Hz),5.91(1H,br-s),6.74(2H,s),6.94(2H,d,J=8.6Hz),7.94(2H,d,J=8.6Hz)
(1)4-[N-メチル-(6a-メチル-5,6,6a,7,8,9-ヘキサヒドロ-4H-2-フェナレニル)アミノ]安息香酸メチル
1H-NMR(400MHz,CDCl3):δ1.19(3H,s),1.52(2H,td,J=12.9,5.1Hz),1.69(2H,dt,J=12.9,3.9Hz),1.76-1.87(2H,m),1.99-2.15(2H,m),2.75(2H,dt,J=17.3,8.7Hz),2.87(2H,ddd,J=17.1,8.0,3.5Hz),3.30(3H,s),3.85(3H,s),6.71(2H,d,J=8.7Hz),6.72(2H,s),7.84(2H,d,J=8.7Hz)
1H-NMR(400MHz,CDCl3+CD3OD):δ1.20(3H,s),1.53(2H,td,J=12.9,5.1Hz),1.70(2H,dt,J=12.9,3.9Hz),1.77-1.88(2H,m),2.00-2.16(2H,m),2.76(2H,dt,J=17.4,8.7Hz),2.89(2H,ddd,J=17.4,8.1,3.3Hz),3.31(3H,s),6.72(2H,d,J=9.0Hz),6.73(2H,s),7.85(2H,d,J=9.0Hz)
1H-NMR(400MHz,DMSO-d6):δ1.11(3H,s),1.40(2H,td,J=12.9,4.8Hz),1.59-1.66(2H,m),1.68-1.78(2H,m),1.89-2.04(2H,m),2.68(2H,dt,J=17.4,8.7Hz),2.82(2H,ddd,J=17.4,8.1,3.3Hz),3.21(3H,s),6.68(2H,d,J=8.7Hz),6.70(2H,s),7.69(2H,d,J=8.7Hz)
(1)4-[N-エチル-(6a-メチル-5,6,6a,7,8,9-ヘキサヒドロ-4H-2-フェナレニル)アミノ]安息香酸エチル
1H-NMR(400MHz,CDCl3):δ1.19(3H,s),1.23(3H,t,J=7.2Hz),1.34(3H, t, J=7.2 Hz),1.53(2H,td,J=12.9,5.1Hz),1.69(2H,dt,J=12.9,3.9Hz),1.76-1.87(2H,m),1.99-2.15(2H,m),2.75(2H,dt,J=17.4,8.7Hz),2.87(2H,ddd,J=17.4,8.1,3.3Hz),3.73(2H,q,J=7.2Hz),4.30(2H,q,J=7.2Hz),6.64(2H,d,J=8.7Hz),6.69(2H,s),7.82(2H,d,J=8.7Hz)
1H-NMR(400MHz,CDCl3):δ1.20(3H,s),1.24(3H,t,J=6.9Hz),1.48-1.58(2H,m),1.66-1.73(2H,m),1.76-1.88(2H,m),1.99-2.16(2H,m),2.76(2H,dt,J=17.1,8.7Hz),2.88(2H,ddd,J=17.1,8.1,3.3Hz),3.74(2H,q,J=6.9Hz),6.64(2H,d,J=8.7Hz),6.70(2H,s),7.86(2H,d,J=8.7Hz)
(1)4-[N-シクロプロピルメチル-(6a-メチル-5,6,6a,7,8,9-ヘキサヒドロ-4H-2-フェナレニル)アミノ]安息香酸エチル
1H-NMR(400MHz,CDCl3):δ0.15(2H,q,J=5.1Hz),0.46-0.52(2H,m),1.09-1.17(1H,m),1.19(3H,s),1.34(3H,t,J=7.2Hz),1.48-1.57(2H,m),1.69(2H,dt,J=12.9,3.9Hz),1.76-1.87(2H,m),1.99-2.15(2H,m),2.74(2H,dt,J=17.1,8.7Hz),2.87(2H,ddd,J=17.1,7.8,3.3Hz),3.53(2H,d,J=6.3Hz),4.30(2H,q,J=7.2Hz),6.68(2H,d,J=8.7Hz),6.72(2H,s),7.82(2H,d,J=8.7Hz)
1H-NMR(400MHz,CDCl3):δ0.16(2H,q,J=4.8Hz),0.47-0.53(2H,m),1.12-1.17(1H,m),1.19(3H,s),1.48-1.58(2H,m),1.67-1.72(2H,m),1.76-1.87(2H,m),1.99-2.16(2H,m),2.75(2H,dt,J=17.4,8.7Hz),2.83-2.92(2H,m),3.54(2H,d,J=6.3Hz),6.67(2H,d,J=8.7Hz),6.73(2H,s),7.86(2H,d,J=8.7Hz)
(1)2-[(5,6,6a,7,8,9-ヘキサヒドロ-6a-メチル-4H-2-フェナレニル)アミノ]ピリミジン-5-カルボン酸エチル
1H-NMR(400MHz,CDCl3):δ1.16(3H,s),1.49(2H,td,J=12.9,4.8Hz),1.67(2H,dt,J=12.9,4.1Hz),1.76-1.87(2H,m),1.98-2.15(2H,m),2.80(2H,dt,J=17.1,8.4Hz),2.93(2H,ddd,J=17.1,8.1,3.3Hz),4.36(2H,q,J=7.2Hz),7.12(2H,s),7.77(1H,br-s),8.94(2H,s)
1H-NMR(400MHz,DMSO-d6):δ1.06(3H,s),1.30-1.40(2H, m), 1.56-1.63(2H, m), 1.66-1.75(2H, m), 1.91-1.98(2H, m), 2.62-2.71'2H, m), 2.74-2.78(2H, m), 7.13(2H, s), 8.76(2H, s), 9.78(1H, s)
2-[N-メチル-(5,6,6a,7,8,9-ヘキサヒドロ-6a-メチル-4H-2-フェナレニル)アミノ]ピリミジン-5-カルボン酸
1H-NMR(400MHz,CDCl3):δ1.19(3H,s),1.52(2H,td,J=12.9,5.4Hz),1.67(2H,m),1.77-1.86(2H,m),1.99-2.15(2H,m),2.74-2.86(2H,m),2.91(2H,ddd,J=17.1,7.8,3.3Hz),3.54(3H,s),6.80(2H,s),8.91(2H,s)
2-[N-エチル-(5,6,6a,7,8,9-ヘキサヒドロ-6a-メチル-4H-2-フェナレニル)アミノ]ピリミジン-5-カルボン酸
1H-NMR(400MHz,CDCl3):δ1.19(3H,s),1.24(3H,t,J=7.2Hz),1.53(2H,td,J=12.9, 4.8Hz),1.63-1.70(2H,m),1.77-1.86(2H,m),2.01-2.10(2H,m),2.74-2.83(2H,m),2.86-2.95(2H,m),4.01(2H,q,J=7.2Hz),6.73(2H,s),8.89(2H,s)
2-[N-シクロプロピルメチル-(5,6,6a,7,8,9-ヘキサヒドロ-6a-メチル-4H-2-フェナレニル)アミノ]ピリミジン-5-カルボン酸
1H-NMR(400MHz,CDCl3):δ0.20-0.25(2H,m),0.43-0.49(2H,m),0.95-0.98(1H,m),1.18(3H,s),1.48-1.58(2H,m),1.63(2H,m),1.74-1.85(2H,m),1.98-2.10(2H,m),2.74-2.82(2H,m),2.83-2.95(2H,m),3.85(2H,d,J=6.9Hz),6.77(2H,s),8.87(2H,s)
(1)(6,7,8,9-テトラヒドロ-5-ベンゾシクロヘプテニリデン)酢酸エチル
水素化ナトリウム(60%,2.25 g)の無水ベンゼン(100 ml)懸濁液にジエチルホスホノアセテート(14.0g)の無水ベンゼン(20 ml)溶液を0℃でゆっくりと加え、0℃で15分間撹拌した。1-ベンゾスベロン(5.00 g)の無水ベンゼン(30 ml)溶液を加えて0℃で15分間撹拌後、一夜加熱還流した。放冷後、反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルにより抽出した。有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒;酢酸エチル:n-ヘキサン=1:200)で精製し、標記化合物を定量的に得た。
(6,7,8,9-テトラヒドロ-5-ベンゾシクロヘプテニリデン)酢酸エチル(0.550 g)の酢酸エチル(10 ml)溶液に10%パラジウム炭素(0.055 g)を加え、水素気流下3時間撹拌した。反応混合物をセライトを通して濾過後、濾液の溶媒を減圧濃縮して標記化合物(0.551g,収率99%)を得た。
1H-NMR(400MHz,CDCl3):δ1.22(3H,t,J=7.2Hz),1.47-1.64(2H,m),1.72-1.95(4H,m),2.65-2.79(2H,m),2.82-2.95(2H,m),3.43-3.52(1H,m),4.12(2H,q,J=7.2Hz),7.07-7.15(4H,m)
(6,7,8,9-テトラヒドロ-5H-5-ベンゾシクロヘプテニル)酢酸エチル(0.550 g)を無水トルエン(10 ml)に溶解させ、アルゴン気流下、水素化ジイソブチルアルミニウム(0.93M n-ヘキサン溶液,2.8 ml)を-78℃でゆっくりと加えた。反応混合物を-78℃で1時間撹拌後、メタノール(3 ml)および2N塩酸水溶液をゆっくりと加えて酢酸エチルにより抽出した。有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒;酢酸エチル:n-ヘキサン=1:300)で精製し、標記化合物(0.432 g,収率97%)を得た。
1H-NMR(400MHz,CDCl3):δ1.48-1.65(2H,m),1.73-1.90(4H,m),2.75-2.98(4H,m),3.53-3.61(1H,m),7.05-7.16(4H,m),9.80(1H,t,J=2.1Hz)
水素化ナトリウム(60%,0.130 g)の無水ベンゼン(5 ml)懸濁液にジエチルホスホノアセテート(0.750 g)を0℃でゆっくりと加え、0℃で10分間撹拌した。(6,7,8,9-テトラヒドロ-5H-5-ベンゾシクロヘプテニル)アセトアルデヒド(0.419 g)の無水ベンゼン(5 ml)溶液を加えて0℃で5分間撹拌後、一夜加熱還流した。放冷後、反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルにより抽出した。有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒;酢酸エチル:n-ヘキサン=1:300)で精製し、標記化合物(0.544 g,収率94%)を得た。
4-(6,7,8,9-テトラヒドロ-5H-5-ベンゾシクロヘプテニル)-2-ブテン酸エチル(0.544 g)の酢酸エチル(10 ml)溶液に10%パラジウム炭素(0.054 g)を加え、水素気流下3時間撹拌した。反応混合物をセライトを通して濾過後、濾液の溶媒を減圧濃縮して標記化合物(0.534 g,収率97%)を得た。
1H-NMR(400MHz,CDCl3):δ1.25(3H,t,J=7.2Hz),1.58-1.89(10H,m),2.32(2H,t,J=7.2Hz),2.83(3H,dd,J=11.4,4.8Hz),4.12(2H,q,J=7.2Hz),7.06-7.09(2H,m),7.10-7.12(2H,m)
4-(6,7,8,9-テトラヒドロ-5H-5-ベンゾシクロヘプテニル)酪酸エチル(0.534 g)のメタノール(10 ml)溶液に2N水酸化ナトリウム水溶液(2 ml)を加え、室温で3時間撹拌した。反応混合物に2N塩酸水溶液を加えて酸性にし、クロロホルムにより抽出した。有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した後、減圧濃縮して標記化合物を定量的に得た。
1H-NMR(400MHz,CDCl3):δ1.51-1.92(10H,m),2.38(2H,t,J=7.2Hz),2.80-2.85(3H,m),7.07-7.12(4H,m)
4-(6,7,8,9-テトラヒドロ-5H-5-ベンゾシクロヘプテニル)酪酸(0.478 g)にポリリン酸(4.80 g)を加え、110℃で4時間撹拌した。反応混合物を氷水へ注ぎ、酢酸エチルで抽出した。有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒;酢酸エチル:n-ヘキサン=1:100)で精製し、標記化合物(0.326 g,収率74%)を得た。
1H-NMR(400MHz,CDCl3):δ1.45-1.54(1H,m),1.61-1.75(2H,m),1.92-1.99(7H,m),2.56-2.62(1H,m),2.81-2.97(3H,m),3.40-3.48(1H,m)7.13(1H,t,J=7.5Hz),7.20(1H,dd,J=7.5,1.5Hz),7.37(1H,dd,J=7.5,1.5Hz)
5,6,7,7a,8,9,10,11-オクタヒドロ-4-ベンゾ[ef]ヘプタレノン(0.280 g)のトリフルオロ酢酸(2 ml)溶液にトリエチルシラン(0.42 ml)を加え、60℃で一夜撹拌した。反応混合物を減圧濃縮して得られた残渣を氷水へ注ぎ、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒;n-ヘキサン)で精製し、標記化合物(0.195 g,収率74%)を得た。
1H-NMR(400MHz,CDCl3):δ1.47-1.66(6H,m),1.78-1.96(6H,m),2.81-2.86(4H,m),3.20-3.29(1H,m)6.90-6.99(3H,m)
塩化アルミニウム(0.155 g)の二硫化炭素(3 ml)懸濁液にアセチルクロリド(0.090 ml)を加え、室温で15分間撹拌した。反応混合物を0℃に冷却し、2 mlの二硫化炭素に溶解した5,6,7,7a,8,9,10,11-オクタヒドロ-4H-ベンゾ[ef]ヘプタレン(0.194 g)をゆっくりと加え、0℃で30分間、室温で一晩撹拌した。反応混合物を氷水に注ぎ酢酸エチルで抽出し、有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒;酢酸エチル:n-ヘキサン=1:300)で精製して1-(5,6,7,7a,8,9,10,11-オクタヒドロ-4H-1-ベンゾ[ef]ヘプタレニル)エタノン(0.042 g,収率18%)および標記化合物(0.180 g,収率77%)を得た。
1H-NMR(400MHz,CDCl3):δ1.47-1.70(6H,m),1.78-1.98(6H,m),2.56(3H,s),2.90(4H,t,J=5.4Hz),3.24-3.31(1H,m),7.52(2H,s)
2.5N水酸化ナトリウム水溶液(4 ml)を0℃に冷却し、臭素(0.13 ml)をゆっくりと加えた後、1,4-ジオキサン(3 ml)で希釈して黄色溶液を得た。1-(5,6,7,7a,8,9,10,11-オクタヒドロ-4H-2-ベンゾ[ef]ヘプタレニル)エタノン(0.180 g)の水(2 ml)および1,4-ジオキサン(5 ml)溶液を0℃に冷却し、先に調製した黄色溶液をゆっくりと加え、0℃で30分間、室温で3時間撹拌した。反応混合物を0℃に冷却し、10%亜硫酸ナトリウム水溶液を加えた後、2N塩酸水溶液で酸性にしてクロロホルムで抽出した。有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮して得られた残渣を酢酸エチル−n-ヘキサンより再結晶して標記化合物(0.161 g,収率88%)を無色針状晶(融点178.5-179.5℃)として得た。
1H-NMR(400MHz,CDCl3):δ1.48-1.71(6H,m),1.78-1.96(6H,m),2.91(4H,t,J=5.4Hz),3.26-3.33(1H,m),7.67(2H,s)
5,6,7,7a,8,9,10,11-オクタヒドロ-4H-2-ベンゾ[ef]ヘプタレンカルボン酸(0.250 g)の無水ベンゼン(2 ml)溶液にチオニルクロリド(1 ml)を加えて3時間加熱還流した。減圧濃縮して得られた残渣の無水テトラヒドロフラン(10 ml)溶液を0℃に冷却し、アジ化ナトリウム(0.199 g)の水(1 ml)溶液を加え、0℃で10分間、室温で1時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、ジエチルエーテルで抽出した。有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮して得られた残渣を酢酸(5 ml)および水(2 ml)に溶かし、1時間加熱還流した。放冷後、反応混合物に飽和炭酸水素ナトリウム水溶液を加えてアルカリ性にした後、酢酸エチルで抽出した。有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮して得られた残渣をメタノール(5 ml)に溶かし、濃塩酸(5 ml)を加えて3時間加熱還流した。放冷後、2N水酸化ナトリウム水溶液でアルカリ性にしてジエチルエーテルで抽出した。有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒;酢酸エチル:n-ヘキサン=1:50)で精製し、標記化合物(0.134 g,収率61%)を得た。
1H-NMR(400MHz,CDCl3):δ1.44-1.64(6H,m),1.76-1.92(6H,m),2.70-2.76(4H,m),3.09-3.16(1H,m),3.43(2H,br-s),6.31(2H,s)
1H-NMR(400MHz,CDCl3):δ1.37(3H,t,J=7.2Hz),1.51-1.69(6H,m),1.80-1.96(6H,m),2.73-2.88(4H,m),3.17-3.24(1H,m),4.33(2H,q,J=7.2Hz),5.86(1H,br-s),6.76(2H,s),6.95(2H,d,J=9.0Hz),7.90(2H,d,J=9.0Hz)
1H-NMR(400MHz,CDCl3):δ1.48-1.67(6H,m),1.80-1.96(6H,m),2.74-2.87(4H,m),3.18-3.25(1H,m),5.92(1H,br-s),6.78(2H,s),6.95(2H,d,J=8.7Hz),7.95(2H,d,J=8.7Hz)
(1)4-[N-メチル-(5,6,7,7a,8,9,10,11-オクタヒドロ-4H-2-ベンゾ[ef]ヘプタレニル)アミノ]安息香酸エチル
1H-NMR(400MHz,CDCl3):δ1.36(3H,t,J=7.2Hz),1.52-1.71(6H,m),1.81-1.97(6H,m),2.71-2.88(4H,m),3.20-3.27(1H,m),3.32(3H,s),4.31(2H,q,J=7.2Hz),6.74(2H,d,J=8.7Hz),6.76(2H,s),7.86(2H,d,J=8.7Hz)
1H-NMR(400MHz,CDCl3):δ1.53-1.71(6H,m),1.81-1.97(6H,m),2.73-2.89(4H,m),3.20-3.28(1H,m),3.34(3H,s),6.73(2H,d,J=8.7Hz),6.78(2H,s),7.90(2H,d,J=8.7Hz)
(1)4-[N-エチル-(5,6,7,7a,8,9,10,11-オクタヒドロ-4H-2-ベンゾ[ef]ヘプタレニル)アミノ]安息香酸エチル
1H-NMR(400MHz,CDCl3):δ1.24(3H,t,J=7.2Hz),1.35(3H,t,J=7.2Hz),1.52-1.72(6H,m),1.81-1.98(6H,m),2.71-2.88(4H,m),3.20-3.27(1H,m),3.75(2H,q,J=7.2Hz),4.31(2H,q,J=7.2Hz),6.66(2H,d,J=8.7Hz),6.74(2H,s),7.83(2H,d,J=8.7Hz)
1H-NMR(400MHz,CDCl3):δ1.25(3H,t,J=7.2Hz),1.52-1.72(6H,m),1.81-1.97(6H,m),2.73-2.89(4H,m),3.21-3.28(1H,m),3.76(2H,q,J=7.2Hz),6.65(2H,d,J=8.7Hz),6.75(2H,s),7.87(2H,d,J=8.7Hz)
(1)4-[N-シクロプロピルメチル-(5,6,7,7a,8,9,10,11-オクタヒドロ-4H-2-ベンゾ[ef]ヘプタレニル)アミノ]安息香酸エチル
1H-NMR(400MHz,CDCl3):δ0.15(2H,dd,J=10.5,5.1Hz),0.46-0.52(2H,m),1.10-1.21(1H,m),1.35(3H,t,J=7.2Hz),1.50-1.71(6H,m),1.80-1.98(6H,m),2.71-2.87(4H,m),3.21-3.28(1H,m),3.56(2H,d,J=6.6Hz),4.31(2H,q,J=7.2Hz),6.70(2H,d,J=8.7Hz),6.77(2H,s),7.83(2H,d,J=8.7Hz)
1H-NMR(400MHz,CDCl3):δ0.15(2H,dd,J=10.8,5.1Hz),0.47-0.53(2H,m),1.13-1.22(1H,m),1.52-1.71(6H,m),1.80-1.97(6H,m),2.73-2.88(4H,m),3.21-3.28(1H,m),3.56(2H,d,J=6.3Hz), 6.69(2H,d,J=9.0Hz),6.78(2H,s),7.88(2H,d,J=9.0Hz)
(1)2-[(5,6,7,7a,8,9,10,11-オクタヒドロ-4H-2-ベンゾ[ef]ヘプタレニル)アミノ]ピリミジン-5-カルボン酸エチル
1H-NMR(400MHz,CDCl3):δ1.38(3H,t,J=7.2Hz),1.52-1.69(6H,m),1.80-1.92(6H,m),2.79-2.90(4H,m),3.18-3.24(1H,m),4.37(2H,q,J=7.2Hz),7.19(2H,s),7.74(1H,s),8.95(2H,s)
1H-NMR(400MHz,DMSO-d6):δ1.38-1.55(6H,m),1.71-1.88(6H,m),2.66-2.81(4H,m),3.11-3.20(1H,m),7.26(2H,s),8.79(2H,s),9.85(1H,s)
2-[N-メチル-(5,6,7,7a,8,9,10,11-オクタヒドロ-4H-2-ベンゾ[ef]ヘプタレニル)アミノ]ピリミジン-5-カルボン酸
1H-NMR(400MHz,CDCl3):δ1.54-1.69(6H,m),1.82-1.98(6H,m),2.75-2.93(4H,m),3.20-3.28(1H,m),3.56(3H,s),6.85(2H,s),8.91(2H,s)
2-[N-エチル-(5,6,7,7a,8,9,10,11-オクタヒドロ-4H-2-ベンゾ[ef]ヘプタレニル)アミノ]ピリミジン-5-カルボン酸
1H-NMR(400MHz,CDCl3):δ1.26(3H,t,J=7.2Hz),1.54-1.69(6H,m),1.82-1.94(6H,m),2.75-2.92(4H,m),3.21-3.28(1H,m),4.12(2H,q,J=7.2Hz),6.79(2H,s),8.89(2H,s)
2-[N-シクロプロピルメチル-(5,6,7,7a,8,9,10,11-オクタヒドロ-4H-2-ベンゾ[ef]ヘプタレニル)アミノ]ピリミジン-5-カルボン酸
1H-NMR(400MHz,CDCl3):δ0.22(2H,dd,J=10.8,4.5Hz),0.43-0.50(2H,m),1.14-1.20(1H,m)1.57-1.68(6H,m),1.85-1.97(6H,m),2.75-2.91(4H,m),3.21-3.29(1H,m),3.87(2H,d,J=6.9Hz),6.83(2H,s),8.88(2H,s)
ヒト急性前骨髄球性白血病細胞株HL-60を5% FBS含有RPMI培地を用いてCO2インキュベーター内(5% CO2、37℃)で培養した。4-[(5,6,7,8-テトラヒドロ-5,5,8,8-テトラメチル-2-ナフタレニル)カルバモイル]安息香酸(Am80)が惹起するHL-60細胞に対する分化誘導作用を前骨髄球から顆粒球への分化度を指標としたニトロブルーテトラゾリウム(NBT)還元能により評価した。対数増殖期に入りコンフルエント程度に達した細胞を1000 rpmで5分間遠心し、培養上清を除去した。細胞ペレットを新たな5% FBS含有RPMI培地で8.0×104 cells/mlに調製し、次いでDMSOで溶解した被験化合物を目的濃度になるように添加し、4日間培養後に実験に供した。各サンプルについていずれもDMSO濃度が同じになるよう調製した。
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JPS6176440A (ja) | 1984-09-19 | 1986-04-18 | Koichi Shiyudo | 安息香酸誘導体 |
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US5442124A (en) | 1989-06-30 | 1995-08-15 | Firmenich Sa | Process for the preparation of novel aromatic compounds |
US5185318A (en) | 1989-06-30 | 1993-02-09 | Firmenich S.A. | Aromatic compounds, a process for preparation thereof and use of same as perfuming ingredients |
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JPN7008006925; Edward PIERS et al.: 'Synthesis of functionalized hexahydro-, octahydro-, and decahydro-1H-phenalenes via Diels-Alder reac' Canadian Journal of Chemistry Vol.71, No.9, 1993, P.1463-1483 * |
JPN7008006926; James P. DAVIDSON et al.: 'First Enantiospecific Total Synthesis of the Antitubercular Marine Natural Product Pseudopteroxazole' Journal of the American Chemical Society Vol.125, No.44, 2003, P.13486-13489 * |
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WO2009022722A1 (ja) | 2009-02-19 |
US20110288299A1 (en) | 2011-11-24 |
CA2695984A1 (en) | 2009-02-19 |
TW200927709A (en) | 2009-07-01 |
JPWO2009022722A1 (ja) | 2010-11-18 |
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