JP5100641B2 - 2−アミノブタノール化合物及びその医薬用途 - Google Patents
2−アミノブタノール化合物及びその医薬用途 Download PDFInfo
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- JP5100641B2 JP5100641B2 JP2008513283A JP2008513283A JP5100641B2 JP 5100641 B2 JP5100641 B2 JP 5100641B2 JP 2008513283 A JP2008513283 A JP 2008513283A JP 2008513283 A JP2008513283 A JP 2008513283A JP 5100641 B2 JP5100641 B2 JP 5100641B2
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- -1 2-Aminobutanol compound Chemical class 0.000 title claims description 151
- 150000001875 compounds Chemical class 0.000 claims description 189
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 110
- 125000005843 halogen group Chemical group 0.000 claims description 74
- 125000004432 carbon atom Chemical group C* 0.000 claims description 52
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 47
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 42
- 125000000217 alkyl group Chemical group 0.000 claims description 39
- 125000006239 protecting group Chemical group 0.000 claims description 36
- 239000002253 acid Substances 0.000 claims description 34
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 29
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 22
- 125000002252 acyl group Chemical group 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 20
- 239000012453 solvate Substances 0.000 claims description 18
- 125000000732 arylene group Chemical group 0.000 claims description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims description 17
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 230000002265 prevention Effects 0.000 claims description 15
- VYFZAYULNQOSQP-UHFFFAOYSA-N 2-amino-2-[2-[4-[2-fluoro-4-(4-methylphenyl)sulfanylphenyl]phenyl]ethyl]propane-1,3-diol Chemical compound C1=CC(C)=CC=C1SC1=CC=C(C=2C=CC(CCC(N)(CO)CO)=CC=2)C(F)=C1 VYFZAYULNQOSQP-UHFFFAOYSA-N 0.000 claims description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 125000004434 sulfur atom Chemical group 0.000 claims description 11
- 125000005549 heteroarylene group Chemical group 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 8
- 125000003107 substituted aryl group Chemical group 0.000 claims description 8
- 238000010511 deprotection reaction Methods 0.000 claims description 7
- 150000004677 hydrates Chemical class 0.000 claims description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 238000009833 condensation Methods 0.000 claims description 6
- 230000005494 condensation Effects 0.000 claims description 6
- 210000000056 organ Anatomy 0.000 claims description 6
- 238000002054 transplantation Methods 0.000 claims description 6
- 208000023275 Autoimmune disease Diseases 0.000 claims description 5
- 230000001154 acute effect Effects 0.000 claims description 5
- 208000026935 allergic disease Diseases 0.000 claims description 5
- 238000010322 bone marrow transplantation Methods 0.000 claims description 5
- 230000001684 chronic effect Effects 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 230000001629 suppression Effects 0.000 claims description 4
- 210000001519 tissue Anatomy 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 297
- 239000000203 mixture Substances 0.000 description 154
- 239000002904 solvent Substances 0.000 description 148
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 140
- 238000006243 chemical reaction Methods 0.000 description 129
- 239000000243 solution Substances 0.000 description 124
- 239000013078 crystal Substances 0.000 description 118
- 230000002829 reductive effect Effects 0.000 description 110
- 238000005160 1H NMR spectroscopy Methods 0.000 description 95
- 239000011541 reaction mixture Substances 0.000 description 95
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 92
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 81
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 72
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 72
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 71
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 69
- 238000010898 silica gel chromatography Methods 0.000 description 64
- 238000003786 synthesis reaction Methods 0.000 description 59
- 230000015572 biosynthetic process Effects 0.000 description 58
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 57
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- 238000010992 reflux Methods 0.000 description 47
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 46
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 42
- 238000001914 filtration Methods 0.000 description 42
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 39
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 37
- 239000000047 product Substances 0.000 description 37
- LNAMMBFJMYMQTO-FNEBRGMMSA-N chloroform;(1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].ClC(Cl)Cl.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 LNAMMBFJMYMQTO-FNEBRGMMSA-N 0.000 description 36
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 34
- 238000000034 method Methods 0.000 description 31
- 238000001816 cooling Methods 0.000 description 29
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 28
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 27
- 238000000605 extraction Methods 0.000 description 27
- 239000012299 nitrogen atmosphere Substances 0.000 description 25
- 239000012044 organic layer Substances 0.000 description 23
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 23
- 235000017557 sodium bicarbonate Nutrition 0.000 description 23
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 20
- 239000003921 oil Substances 0.000 description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 238000001953 recrystallisation Methods 0.000 description 18
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 18
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 17
- KSMXJBMNDAXDEN-UHFFFAOYSA-N n-[5-[2-[4-(4-bromo-2-fluorophenyl)phenyl]ethyl]-2,2-dimethyl-1,3-dioxan-5-yl]acetamide Chemical compound C=1C=C(C=2C(=CC(Br)=CC=2)F)C=CC=1CCC1(NC(=O)C)COC(C)(C)OC1 KSMXJBMNDAXDEN-UHFFFAOYSA-N 0.000 description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 239000012046 mixed solvent Substances 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- 238000005406 washing Methods 0.000 description 16
- 238000001035 drying Methods 0.000 description 15
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 238000002953 preparative HPLC Methods 0.000 description 14
- 125000003277 amino group Chemical group 0.000 description 13
- 239000012267 brine Substances 0.000 description 13
- 239000003054 catalyst Substances 0.000 description 13
- 239000003153 chemical reaction reagent Substances 0.000 description 13
- 239000011259 mixed solution Substances 0.000 description 13
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 13
- 125000001424 substituent group Chemical group 0.000 description 13
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 239000012230 colorless oil Substances 0.000 description 12
- 210000002216 heart Anatomy 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 229910052731 fluorine Inorganic materials 0.000 description 10
- 125000001153 fluoro group Chemical group F* 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 239000002798 polar solvent Substances 0.000 description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 9
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 9
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
- MYIFLDFUXIHOCJ-UHFFFAOYSA-N 2-amino-2-[2-[2-chloro-4-(3-phenylmethoxyphenyl)sulfanylphenyl]ethyl]propane-1,3-diol;hydrochloride Chemical compound Cl.C1=C(Cl)C(CCC(CO)(CO)N)=CC=C1SC1=CC=CC(OCC=2C=CC=CC=2)=C1 MYIFLDFUXIHOCJ-UHFFFAOYSA-N 0.000 description 8
- WLHCBQAPPJAULW-UHFFFAOYSA-N 4-methylbenzenethiol Chemical compound CC1=CC=C(S)C=C1 WLHCBQAPPJAULW-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 8
- 241000700159 Rattus Species 0.000 description 7
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 7
- 230000003213 activating effect Effects 0.000 description 7
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- 235000011056 potassium acetate Nutrition 0.000 description 7
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- 238000000926 separation method Methods 0.000 description 7
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- NDQXKKFRNOPRDW-UHFFFAOYSA-N 1,1,1-triethoxyethane Chemical compound CCOC(C)(OCC)OCC NDQXKKFRNOPRDW-UHFFFAOYSA-N 0.000 description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- 239000004215 Carbon black (E152) Substances 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 6
- 230000001476 alcoholic effect Effects 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 229930195733 hydrocarbon Natural products 0.000 description 6
- 150000002430 hydrocarbons Chemical class 0.000 description 6
- 150000007529 inorganic bases Chemical class 0.000 description 6
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- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 6
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 6
- 150000008300 phosphoramidites Chemical class 0.000 description 6
- 230000000865 phosphorylative effect Effects 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
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- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 6
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 5
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 5
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 5
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 5
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- 238000006482 condensation reaction Methods 0.000 description 5
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- SWZTYAVBMYWFGS-UHFFFAOYSA-N fingolimod hydrochloride Chemical compound Cl.CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1 SWZTYAVBMYWFGS-UHFFFAOYSA-N 0.000 description 5
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 5
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- SQKQPJOTLBXORD-UHFFFAOYSA-N 2-amino-2-[2-[4-[2-fluoro-4-(4-methylphenoxy)phenyl]phenyl]ethyl]propane-1,3-diol Chemical compound C1=CC(C)=CC=C1OC1=CC=C(C=2C=CC(CCC(N)(CO)CO)=CC=2)C(F)=C1 SQKQPJOTLBXORD-UHFFFAOYSA-N 0.000 description 4
- BGLMJIVDFVKYIU-UHFFFAOYSA-N 2-amino-2-[2-[4-[5-(3-methylphenyl)sulfanylnaphthalen-1-yl]phenyl]ethyl]propane-1,3-diol Chemical compound CC1=CC=CC(SC=2C3=CC=CC(=C3C=CC=2)C=2C=CC(CCC(N)(CO)CO)=CC=2)=C1 BGLMJIVDFVKYIU-UHFFFAOYSA-N 0.000 description 4
- DJBXQJLGOGLGOO-UHFFFAOYSA-N 2-amino-2-[2-[4-[5-(4-methylphenyl)sulfanylnaphthalen-1-yl]phenyl]ethyl]propane-1,3-diol;hydrochloride Chemical compound Cl.C1=CC(C)=CC=C1SC1=CC=CC2=C(C=3C=CC(CCC(N)(CO)CO)=CC=3)C=CC=C12 DJBXQJLGOGLGOO-UHFFFAOYSA-N 0.000 description 4
- ZUAQJCFFHOVOMS-UHFFFAOYSA-N 2-amino-2-ethyl-4-[4-[2-fluoro-4-(4-methylphenyl)sulfanylphenyl]phenyl]butan-1-ol Chemical compound C1=CC(CCC(N)(CO)CC)=CC=C1C(C(=C1)F)=CC=C1SC1=CC=C(C)C=C1 ZUAQJCFFHOVOMS-UHFFFAOYSA-N 0.000 description 4
- WRXOZRLZDJAYDR-UHFFFAOYSA-N 3-methylbenzenethiol Chemical compound CC1=CC=CC(S)=C1 WRXOZRLZDJAYDR-UHFFFAOYSA-N 0.000 description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 4
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 4
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- 101710155454 Sphingosine 1-phosphate receptor 1 Proteins 0.000 description 4
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- 229940127557 pharmaceutical product Drugs 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001012 protector Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 125000005551 pyridylene group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000002683 reaction inhibitor Substances 0.000 description 1
- 229940075993 receptor modulator Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 108010035597 sphingosine kinase Proteins 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229910021515 thallium hydroxide Inorganic materials 0.000 description 1
- QGYXCSSUHCHXHB-UHFFFAOYSA-M thallium(i) hydroxide Chemical compound [OH-].[Tl+] QGYXCSSUHCHXHB-UHFFFAOYSA-M 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000005557 thiazolylene group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- ARYHTUPFQTUBBG-UHFFFAOYSA-N thiophen-2-ylboronic acid Chemical compound OB(O)C1=CC=CS1 ARYHTUPFQTUBBG-UHFFFAOYSA-N 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- 229960001005 tuberculin Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000002689 xenotransplantation Methods 0.000 description 1
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Description
(1)下記一般式(I)
b.2−アミノ−4−[2’−フルオロ−4’−(4−メチルフェニルチオ)ビフェニル−4−イル]−2−(ホスホリルオキシメチル)ブタノール
(8)2−アミノ−2−{2−[2’−フルオロ−4’−(4−メチルフェニルチオ)ビフェニル−4−イル]エチル}プロパン−1,3−ジオール、又はその塩酸塩。
(12)一般式(II−1)で表される脱離基Xcを有するベンゼン化合物と一般式(II−2)で表されるベンゼンチオールとを縮合させることを特徴とする、一般式(II−3)で表される化合物の製造方法。
(13)一般式(II−1’)で表されるチオール化合物と一般式(II−2’)で表される脱離基Xcを有するベンゼン化合物とを縮合させることを特徴とする、一般式(II−3)で表される化合物の製造方法。
(1)2−アミノ−2−{2−[2’−フルオロ−4’−(4−メチルフェニルチオ)ビフェニル−4−イル]エチル}プロパン−1,3−ジオール、
(2)2−アミノ−4−[2’−フルオロ−4’−(4−メチルフェニルチオ)ビフェニル−4−イル]−2−(ホスホリルオキシメチル)ブタノール。
1)本発明化合物のうち、一般式(I)中のR1が水素原子で表されるもの(I−1)は以下のスキーム(III)により合成される。
式中のRaは水素原子又は水酸基を保護するものであれば特に限定されない。例えば、アシル(好ましくは炭素数2〜4程度のもの、具体的にはアセチルなど)、トリアルキルシリル(具体的にはトリメチルシリルなど)、ベンジル又はアセタールを形成する保護基(具体的にはメトキシメチル、テトラヒドロピラニルなど)が挙げられる。また、R8に保護された水酸基が含まれる場合、その保護基Rc(RcとしてはRaと同様のものが挙げられる)とRaが結合し、環状のアセタールを形成することもできる。式中のRbは水素原子又はアミノ基を保護するものであれば特に限定されない。例えば、アシル(好ましくは炭素数2〜4程度のもの、具体的にはアセチルなど)、カルバメート(具体的にはt−ブトキシカルボニルやベンジルオキシカルボニル)等が挙げられる。Xa、Xb、Xcで示される脱離基は、活性化基Yaの導入反応又は縮合反応時に脱離するものであれば特に限定されない。例えば、ハロゲン原子(好ましくはヨウ素原子、臭素原子など)、トリフルオロメタンスルホニルオキシ等が挙げられる。Yaで示される活性化基としてはリチウムやマグネシウム等の金属を含んだ置換基、又はケイ素やホウ素等の非金属元素を含む置換基があげられる。上記脱離基と活性化基は縮合反応の種類に応じて適切な組み合わせで用いられる。
式中のRdで示される保護基はアミノ基を保護するものであれば特に限定されない。例えば、アシル(好ましくは炭素数2〜4程度のもの、具体的にはアセチルなど)、カルバメート(具体的にはt−ブトキシカルボニルやベンジルオキシカルボニル)等が挙げられる。また化合物(I−1)のR2に水酸基が含まれる場合、その水酸基も保護基Rc(Rcは前述と同義)で保護できるが、R2がヒドロキシメチルやヒドロキシエチルの場合、以下のような環状化合物(IV−1a、IV−1b)
を形成することによって、アミノ基及びR2に含まれる水酸基を保護することもできる。式中のReで示される保護基としてはリン酸基を保護するものであれば特に限定されない。例えばアルキル(好ましくは炭素数1〜6程度のもの、具体的にはt−ブチルなど)、ベンジル、フェニル等が挙げられる。
式中のRa、Rb、Rd、Re及びXcで表される保護基及び脱離基は、スキーム(III)及びスキーム(IV)で述べたものと同じものが挙げられる。また化合物(V−1)のR2に水酸基が含まれる場合、その水酸基も保護基Rc(Rcは前述と同義)で保護できるが、R2がヒドロキシメチルやヒドロキシエチルの場合、下記のような環状化合物(V−2a、V−2b)
を形成することによって、アミノ基及びR2に含まれる水酸基を保護することもできる。
Ra、Rb、Xcの具体的な例としては、スキーム(III)で挙げたものと同様のものが挙げられる。R8の保護されていても良い水酸基の保護基Rcとしては、Raと同様のものが挙げられるが、RcとRaが結合し、環状のアセタールを形成することもできる。Aの置換されていても良いアリーレン及び置換されていても良いヘテロアリーレンの具体例としてはAr1と同様のものが挙げられる。Ar3の置換されていても良いアリール及び置換されていても良いヘテロアリールの具体例としてはAr2と同様のものが挙げられる。Ar3の「保護されていても良い水酸基で置換されたフェニル」における水酸基の保護基としては、反応中に脱離しないものであれば特に限定されないが、メトキシメチル、ベンジルオキシメチル、テトラヒドロピラニル等のアセタールを形成する保護基、トリメチルシリル等のシリルエーテル、メチル等のエーテル、アセチル、メトキシカルボニル等のアシル等が挙げられる。上記式(II−1)、(II−2)、(II−3)、(II−1’)及び(II−2’)において、R8の好ましい例としては水酸基が保護されていても良いヒドロキシメチル、より好ましい例としてはアセトキシメチル、R3の好ましい例としては水素原子、Ar3の好ましい例としては置換されていても良いアリール、より好ましい例としてはメチルフェニル、Aの好ましい例としては置換されていても良いアリーレン、より好ましい例としては
上記式(II−4)において、R2の好ましい例としてはヒドロキシメチル、R3の好ましい例としては水素原子、Ar4の好ましい例としては置換されていても良いアリール、より好ましい例としてはメチルフェニル、Aの好ましい例としては置換されていても良いアリーレン、より好ましい例としては
トリフルオロメタンスルホン酸 5−ベンジルオキシナフタレン−1−イルエステル
1H−NMR(DMSO−d6)δ(ppm):5.37(2H、s)、7.28−7.73(10H、m)、8.34(1H、d、J=8.2Hz)。
2−(4−ブロモフェニル)エチルヨージド
1H−NMR(CDCl3)δ(ppm):3.13(2H、t、J=7.7Hz)、3.32(2H、d、J=7.4Hz)、7.07(2H、d、J=8.4Hz)、7.44(2H、d、J=8.1Hz)。
2−アセタミド−2−[2−(4−ブロモフェニル)エチル]マロン酸ジエチル
1H−NMR(CDCl3)δ(ppm):1.25(6H、t、J=7.2Hz)、1.99(3H、s)、2.41−2.46(2H、m)、2.64−2.69(2H、m)、4.16−4.29(4H、m)、6.75(1H、s)、7.02(2H、d、J=8.4Hz)、7.38(2H、d、J=8.1Hz)。
N−[3−(4−ブロモフェニル)−1,1−ビス(ヒドロキシメチル)プロピル]アセタミド
1H−NMR(DMSO−d6)δ(ppm):1.81−1.87(5H、m)、2.45−2.51(2H、m)、3.46(2H、dd、J=6.9、11.1Hz)、3.56(2H、dd、J=5.7、10.8Hz)、4.81(2H、t、J=5.7Hz)、7.14(2H、d、J=8.1Hz)、7.44(2H、d、J=8.4Hz)。
N−{5−[2−(4−ブロモフェニル)エチル]−2,2−ジメチル−1,3−ジオキサン−5−イル}アセタミド
1H−NMR(CDCl3)δ(ppm):1.43(6H、s)、2.03(3H、s)、2.01−2.06(2H、m)、2.46−2.52(2H、m)、3.67(2H、d、J=11.7Hz)、3.95(2H、d、J=11.7Hz)、5.76(1H、s)、7.05(2H、d、J=8.4Hz)、7.38(2H、d、J=8.4Hz)。
N−(5−{2−[4−(5,5−ジメチル−1,3,2−ジオキサボリナン−2−イル)フェニル]エチル}−2,2−ジメチル−1,3−ジオキサン−5−イル)アセタミド
1H−NMR(CDCl3)δ(ppm):1.01(6H、s)、1.42(6H、s)、2.02(3H、s)、2.03−2.09(2H、m)、2.53−2.58(2H、m)、3.66(2H、d、J=11.7Hz)、3.76(4H、s)、3.97(2H、d、J=12.0Hz)、5.71(1H、s)、7.17(2H、d、J=8.1Hz)、7.70(2H、d、J=7.8Hz)。
N−[1,1−ビス(アセトキシメチル)−3−(4−ブロモフェニル)プロピル]アセタミド
1H−NMR(CDCl3)δ(ppm):1.99(3H、s)、2.10(6H、s)、2.16−2.22(2H、m)、2.53−2.59(2H、m)、4.33(4H、s)、5.73(1H、s)、7.06(2H、d、J=8.1Hz)、7.39(2H、d、J=8.7Hz)。
N−{1,1−ビス(アセトキシメチル)−3−[4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)フェニル]プロピル}アセタミド
1H−NMR(DMSO−d6)δ(ppm):1.28(12H、s)、1.85(3H、s)、1.93−1.97(2H、m)、2.02(6H、s)、2.50−2.56(2H、m)、4.19(2H、d、J=11.0Hz)、4.28(2H、d、J=11.0Hz)、7.19(2H、d、J=7.8Hz)、7.59(2H、d、J=7.8Hz)、7.68(1H、s)。
N−{1,1−ビス(アセトキシメチル)−3−[4−(5,5−ジメチル−1,3,2−ジオキサボリナン−2−イル)フェニル]プロピル}アセタミド
1H−NMR(CDCl3)δ(ppm):1.02(6H、s)、1.95(3H、s)、2.09(6H、s)、2.17−2.23(2H、m)、2.59−2.65(2H、m)、3.76(4H、s)、4.35(4H、m)、5.65(1H、s)、7.18(2H、d、J=7.9Hz)、7.72(2H、d、J=7.8Hz)。
N−{5−[2−(4’−ブロモ−2’−フルオロビフェニル−4−イル)エチル]−2,2−ジメチル−1,3−ジオキサン−5−イル}アセタミド
1H−NMR(DMSO−d6)δ(ppm):1.35(6H、s)、1.87(3H、s)、1.98−2.04(2H、m)、2.47−2.53(2H、m)、3.71(2H、d、J=11.8Hz)、3.97(2H、d、J=11.6Hz)、7.27(2H、d、J=8.1Hz)、7.44−7.53(3H、m)、7.61−7.66(2H、m)。
4−ブロモ−2−クロロ安息香酸メチル
1H−NMR(CDCl3)δ(ppm):3.93(3H、s)、7.46(1H、dd、J=1.8、8.4Hz)、7.64(1H、d、J=1.8Hz)、7.72(1H、d、J=8.4Hz)。
4−ブロモ−2−クロロベンジルアルコール
1H−NMR(CDCl3)δ(ppm):1.87(1H、t、J=5.8Hz)、4.74(2H、d、J=5.8Hz)、7.38(1H、d、J=8.2Hz)、7.42(1H、dd、J=1.8、8.2Hz)、7.53(1H、d、J=1.8Hz)。
4−ブロモ−2−クロロベンジルブロミド
1H−NMR(CDCl3)δ(ppm):4.53(2H、s)、7.31(1H、d、J=8.2Hz)、7.39(1H、dd、J=1.8、8.2Hz)、7.56(1H、d、J=1.8Hz)。
4−ブロモ−2−クロロベンジルシアニド
1H−NMR(CDCl3)δ(ppm):3.79(2H、s)、7.40(1H、d、J=8.2Hz)、7.46(1H、dd、J=1.8、8.2Hz)、7.60(1H、d、J=1.8Hz)。
4−ブロモ−2−クロロフェニル酢酸
1H−NMR(CDCl3)δ(ppm):3.78(2H、s)、7.17(1H、d、J=8.2Hz)、7.38(1H、dd、J=1.8、8.2Hz)、7.57(1H、d、J=1.8Hz)。
4−ブロモ−2−クロロフェニル酢酸メチルエステル
1H−NMR(CDCl3)δ(ppm):3.71(3H、s)、3.73(2H、s)、7.16(1H、d、J=8.2Hz)、7.37(1H、dd、J=2.0、8.2Hz)、7.56(1H、d、J=2.0Hz)。
2−(4−ブロモ−2−クロロフェニル)エタノール
1H−NMR(CDCl3)δ(ppm):1.38(1H、brs)、2.97(2H、t、J=6.6Hz)、3.87(2H、t、J=6.6Hz)、7.16(1H、d、J=8.2Hz)、7.34(1H、dd、J=1.8、8.2Hz)、7.56(1H、d、J=1.8Hz)。
2−(4−ブロモ−2−クロロフェニル)エチルヨージド
1H−NMR(CDCl3)δ(ppm):3.22−3.28(2H、m)、3.32−3.38(2H、m)、7.12(1H、d、J=8.1Hz)、7.36(1H、dd、J=1.8、8.1Hz)、7.53(1H、d、J=2.1Hz)。
2−[2−(4−ブロモ−2−クロロフェニル)エチル]−2−[(tert−ブトキシカルボニル)アミノ]マロン酸ジエチル
1H−NMR(CDCl3)δ(ppm):1.26(6H、t、J=7.1Hz)、1.44(9H、s)、2.57(4H、s)、4.16−4.30(4H、m)、6.01(1H、s)、7.05(1H、d、J=8.1Hz)、7.30(1H、dd、J=1.8、8.4Hz)、7.49(1H、d、J=1.8Hz)。
[1,1−ビス(ヒドロキシメチル)−3−(4−ブロモ−2−クロロフェニル)プロピル]カルバミド酸tert−ブチルエステル
1H−NMR(CDCl3)δ(ppm):1.45(9H、s)、1.80−1.86(2H、m)、2.67−2.73(2H、m)、3.32(2H、brs)、3.63−3.69(2H、m)、3.87−3.93(2H、m)、5.10(1H、s)、7.11(1H、d、J=8.2Hz)、7.32(1H、dd、J=2.1、8.2Hz)、7.49(1H、d、J=1.9Hz)。
N−[1,1−ビス(アセトキシメチル)−3−(4−ブロモ−2−クロロフェニル)プロピル]アセタミド
1H−NMR(CDCl3)δ(ppm):2.00(3H、s)、2.10(6H、s)、2.12−2.16(2H、m)、2.66−2.72(2H、m)、4.36(4H、s)、5.75(1H、s)、7.10(1H、d、J=8.2Hz)、7.32(1H、dd、J=1.9、8.2Hz)、7.50(1H、d、J=1.9Hz)。
N−{1,1−ビス(アセトキシメチル)−3−[2−クロロ−4−(5,5−ジメチル−1,3,2−ジオキサボリナン−2−イル)フェニル]プロピル}アセタミド
1H−NMR(CDCl3)δ(ppm):1.01(6H、s)、1.99(3H、s)、2.09(6H、s)、2.12−2.18(2H、m)、2.71−2.77(2H、m)、3.76(4H、s)、4.38(4H、s)、5.71(1H、s)、7.21(1H、d、J=7.8Hz)、7.59(1H、d、J=7.5Hz)、7.75(1H、d、J=0.9Hz)。
N−[1,1−ビス(アセトキシメチル)−3−(4’−ブロモ−3−クロロ−2’−フルオロビフェニル−4−イル)プロピル]アセタミド
1H−NMR(CDCl3)δ(ppm):2.01(3H、s)、2.11(6H、s)、2.18−2.24(2H、m)、2.75−2.81(2H、m)、4.39(4H、s)、5.74(1H、s)、7.24−7.38(5H、m)、7.50(1H、s)。
2−[2−(4−ブロモフェニル)エチル]−2−メチルマロン酸ジエチル
MS(ESI)m/z:357、359[M+H]
1H−NMR(CDCl3)δ(ppm):1.26(6H、t、J=7.1Hz)、1.48(3H、s)、2.10−2.14(2H、m)、2.51−2.56(2H、m)、4.19(4H、q、J=7.1Hz)、7.05(2H、d、J=7.9Hz)、7.39(2H、d、J=7.9Hz)。
4−(4−ブロモフェニル)−2−エトキシカルボニル−2−メチル酪酸
1H−NMR(CDCl3)δ(ppm):1.29(3H、t、J=7.1Hz)、1.54(3H、s)、2.09−2.23(2H、m)、2.50−2.63(2H、m)、4.23(2H、q、J=6.7Hz)、7.05(2H、d、J=8.4Hz)、7.39(2H、d、J=8.4Hz)。
4−(4−ブロモフェニル)−2−メトキシカルボニルアミノ−2−メチル酪酸エチル
MS(ESI)m/z:358、360[M+H]
1H−NMR(CDCl3)δ(ppm):1.28(3H、t、J=7.1Hz)、1.59(3H、s)、2.06−2.11(1H、m)、2.30−2.38(1H、m)、2.52−2.62(2H、m)、3.65(3H、s)、4.14−4.22(2H、m)、5.68(1H、brs)、7.02(2H、d、J=8.4Hz)、7.37(2H、d、J=8.4Hz)。
2−アセタミド−4−(4−ブロモフェニル)−2−メチルブチル アセタート
MS(ESI)m/z:342、344[M+H]
1H−NMR(CDCl3)δ(ppm):1.36(3H、s)、1.89−1.96(1H、m)、1.94(3H、s)、2.09(3H、s)、2.18−2.26(1H、m)、2.51−2.58(2H、m)、4.15(1H、d、J=11.2Hz)、4.32(1H、d、J=11.2Hz)、5.36(1H、brs)、7.06(2H、d、J=8.3Hz)、7.38(2H、d、J=8.3Hz)。
2−アセタミド−4−[4−(5,5−ジメチル−1,3,2−ジオキサボリナン−2−イル)フェニル]−2−メチルブチル アセタート
1H−NMR(CDCl3)δ(ppm):1.01(6H、s)、1.37(3H、s)、1.87−1.97(1H、m)、1.91(3H、s)、2.09(3H、s)、2.16−2.26(1H、m)、2.61(2H、t、J=8.6Hz)、3.76(4H、s)、4.18(1H、d、J=11.1Hz)、4.33(1H、d、J=11.1Hz)、5.33(1H、s)、7.18(2H、d、J=7.5Hz)、7.71(2H、d、J=7.8Hz)。
2−アセタミド−4−(4’−ブロモ−2’−フルオロビフェニル−4−イル)−2−メチルブチル アセタート
1H−NMR(CDCl3)δ(ppm):1.39(3H、s)、1.92−2.03(1H、m)、1.94(3H、s)、2.10(3H、s)、2.26−2.34(1H、m)、2.65(2H、t、J=8.7Hz)、4.19(1H、d、J=11.1Hz)、4.36(1H、d、J=11.4Hz)、5.39(1H、s)、7.26−7.36(5H、m)、7.43(2H、dd、J=1.2、7.8Hz)。
4−(4−ブロモフェニル)−2−エトキシカルボニル−2−エチル酪酸
1H−NMR(CDCl3)δ(ppm):0.89(3H、t、J=7.5Hz)、1.32(3H、t、J=7.2Hz)、1.90−2.00(1H、m)、2.02−2.18(2H、m)、2.22−2.31(1H、m)、2.37−2.44(1H、m)、2.52−2.60(1H、m)、4.18−4.31(2H、m)、7.03(2H、d、J=8.4Hz)、7.39(2H、d、J=8.4Hz)。
4−(4−ブロモフェニル)−2−エチル−2−(メトキシカルボニルアミノ)酪酸エチル
MS(ESI)m/z:372、374[M+H]
1H−NMR(CDCl3)δ(ppm):0.76(3H、t、J=7.4Hz)、1.29(3H、t、J=7.3Hz)、1.71−1.80(1H、m)、2.01−2.08(1H、m)、2.24−2.39(2H、m)、2.53−2.62(1H、m)、2.64−2.73(1H、m)、3.64(3H、s)、4.09−4.25(2H、m)、5.81(1H、br.s)、7.01(2H、d、 J=8.2Hz)、7.37(2H、d、J=8.2Hz)。
2−アセタミド−2−エチル−4−(4−ブロモフェニル)ブチル アセタート
MS(ESI)m/z:356、358[M+H]
1H−NMR(CDCl3)δ(ppm):0.89(3H、t、J=7.6Hz)、1.75−1.85(2H、m)、1.91−1.99(1H、m)、1.95(3H、s)、2.07−2.15(1H、m)、2.09(3H、s)、2.48−2.54(2H、m)、4.27(1H、d、J=11.3Hz)、4.31(1H、d、J=11.3Hz)、5.23(1H、br.s)、7.05(2H、d、J=8.4Hz)、7.39(2H、d、J=8.4Hz)。
2−アセタミド−4−[4−(5,5−ジメチル−1,3,2−ジオキサボリナン−2−イル)フェニル]−2−エチルブチル アセタート
1H−NMR(CDCl3)δ(ppm):0.88(3H、t、J=7.5Hz)、1.01(6H、s)、1.70−2.18(4H、m)、1.93(3H、s)、2.08(3H、s)、2.56(2H、t、J=8.6Hz)、3.76(4H、s)、4.32(2H、s)、5.26(1H、s)、7.17(2H、d、J=7.5Hz)、7.71(2H、d、J=7.8Hz)。
2−アセタミド−4−(4’−ブロモ−2’−フルオロビフェニル−4−イル)−2−エチルブチル アセタート
1H−NMR(CDCl3)δ(ppm):0.91(3H、t、J=7.5Hz)、1.70−2.25(4H、m)、1.96(3H、s)、2.10(3H、s)、2.61(2H、t、J=8.5Hz)、4.30(2H、d、J=11.4Hz)、4.36(2H、d、J=11.4Hz)、7.25−7.36(5H、m)、7.43(2H、dd、J=1.5、8.2Hz)。
2−アミノ−2−{2−[4−(5−フェニルチオナフタレン−1−イル)フェニル]エチル}プロパン−1,3−ジオール塩酸塩
(1−1)N−{1,1−ビス(アセトキシメチル)−3−[4−(5−ベンジルオキシナフタレン−1−イル)フェニル]プロピル}アセタミドの合成
MS(ESI)m/z:554[M+H]
1H−NMR(DMSO−d6)δ(ppm):1.88(3H、s)、2.05(6H、s)、2.05−2.10(2H、m)、2.62−2.66(2H、m)、4.23(2H、d、J=11.0Hz)、4.32(2H、d、J=11.0Hz)、5.34(2H、s)、7.11(1H、dd、J=2.7、5.7Hz)、7.31−7.46(10H、m)、7.54−7.58(3H、m)、7.68(1H、s)、8.26(1H、d、J=8.4Hz)。
MS(ESI)m/z:464[M+H]
1H−NMR(DMSO−d6)δ(ppm):1.88(3H、s)、2.05(6H、s)、2.05−2.09(2H、m)、2.62−2.66(2H、m)、4.23(2H、d、J=11.0Hz)、4.32(2H、d、J=11.0Hz)、6.89(1H、dd、J=1.4、6.4Hz)、7.21−7.40(7H、m)、7.46−7.50(1H、m)、7.68(1H、s)、8.17(1H、d、J=8.4Hz)、10.15(1H、brs)。
1H−NMR(DMSO−d6)δ(ppm):1.90(3H、s)、2.07(6H、s)、2.07−2.12(2H、m)、2.66−2.70(2H、m)、4.25(2H、d、J=11.0Hz)、4.34(2H、d、J=11.1Hz)、7.38(2H、d、J=8.2Hz)、7.44(2H、d、J=8.2Hz)、7.62−7.76(4H、m)、7.86(1H、dd、J=7.3、8.2Hz)、7.95(1H、d、J=8.6Hz)、8.03(1H、d、J=8.4Hz)。
MS(ESI)m/z:430[M+H]
1H−NMR(DMSO−d6)δ(ppm):1.87−1.92(2H、m)、2.70−2.74(2H、m)、3.57(4H、d、J=4.8Hz)、5.40(2H、t、J=4.8Hz)、7.20−7.53(11H、m)、7.63−7.67(1H、m)、7.73(1H、d、J=7.2Hz)、7.78(3H、brs)、7.87(1H、d、J=8.6Hz)、8.33(1H、d、J=8.5Hz)。
2−アミノ−2−(2−{4−[5−(4−メチルフェニルチオ)ナフタレン−1−イル]フェニル}エチル)プロパン−1,3−ジオール塩酸塩
(2−1)N−(1,1−ビス(アセトキシメチル)−3−{4−[5−(4−メチルフェニルチオ)ナフタレン−1−イル]フェニル}プロピル)アセタミドの合成
MS(ESI)m/z:444[M+H]
1H−NMR(DMSO−d6)δ(ppm):1.87−1.92(2H、m)、2.27(3H、s)、2.70−2.74(2H、m)、3.57(4H、d、J=4.7Hz)、5.40(2H、t、J=4.9Hz)、7.16−7.20(4H、m)、7.37−7.48(6H、m)、7.58−7.66(2H、m)、7.79−7.83(4H、m)、8.32(1H、d、J=8.6Hz)。
2−アミノ−2−{2−[2’−フルオロ−4’−(フェニルチオ)ビフェニル−4−イル]エチル}プロパン−1,3−ジオール塩酸塩
(3−1)N−(5−{2−[2’−フルオロ−4’−(フェニルチオ)ビフェニル−4−イル]エチル}−2,2−ジメチル−1,3−ジオキサン−5−イル)アセタミドの合成
1H−NMR(CDCl3)δ(ppm):1.43(6H、s)、2.02(3H、s)、2.07−2.13(2H、m)、2.55−2.61(2H、m)、3.69(2H、d、J=11.7Hz)、4.00(2H、d、J=11.7Hz)、5.79(1H、s)、7.02(1H、d、J=11.1Hz)、7.10(1H、d、J=9.6Hz)、7.23−7.47(10H、m)。
(468mg)をメタノール(6mL)に溶解させ、濃塩酸(3mL)を加え、70℃にて3.5時間攪拌した。反応液を濃縮し、残渣の粗結晶をジイソプロピルエーテルで縣濁濾取することにより、表題化合物329mgを白色結晶として得た。
MS(ESI)m/z:398[M+H]
1H−NMR(DMSO−d6)δ(ppm):1.79−1.85(2H、m)、2.63−2.69(2H、m)、3.54(4H、d、J=4.5Hz)、5.41(2H、t、J=5.0Hz)、7.13−7.17(2H、m)、7.32(2H、d、J=8.4Hz)、7.44−7.53(8H、m)、7.83(3H、brs)。
2−アミノ−2−{2−[2’−フルオロ−4’−(4−メチルフェニルチオ)ビフェニル−4−イル]エチル}プロパン−1,3−ジオール
(4−1)N−(5−{2−[2’−フルオロ−4’−(4−メチルフェニルチオ)ビフェニル−4−イル]エチル}−2,2−ジメチル−1,3−ジオキサン−5−イル)アセタミドの合成
1H−NMR(CDCl3)δ(ppm):1.43(6H、s)、2.02(3H、s)、2.05−2.12(2H、m)、2.38(3H、s)、2.55−2.60(2H、m)、3.69(2H、d、J=12.0Hz)、3.99(2H、d、J=12.0Hz)、5.74(1H、s)、6.93(1H、d、J=11.1Hz)、7.03(1H、d、J=9.9Hz)、7.18−7.42(9H、m)。
MS(ESI)m/z:412[M+H]
1H−NMR(DMSO−d6)δ(ppm):1.30(2H、brs)、1.49−1.54(2H、m)、2.35(3H、s)、2.60−2.65(2H、m)、3.19−3.29(4H、m)、4.47(2H、brs)、7.04(2H、d、J=9.9Hz)、7.29(4H、m)、7.39−7.48(5H、m)。
2−アミノ−2−{2−[2’−フルオロ−4’−(3−メチルフェニルチオ)ビフェニル−4−イル]エチル}プロパン−1,3−ジオール塩酸塩
(5−1)N−[5−{2−[2’−フルオロ−4’−(3−メチルフェニルチオ)ビフェニル−4−イル]エチル)−2,2−ジメチル−1,3−ジオキサン−5−イル}アセタミドの合成
1H−NMR(CDCl3)δ(ppm):1.43(6H、s)、2.02(3H、s)、2.07−2.13(2H、m)、2.35(3H、s)、2.55−2.61(2H、m)、3.70(2H、d、J=11.9Hz)、4.00(2H、d、J=11.9Hz)、5.78(1H、s)、7.00(1H、d、J=11.8Hz)、7.07−7.10(1H、m)、7.23−7.43(9H、m)。
MS(ESI)m/z:412[M+H]
1H−NMR(DMSO−d6)δ(ppm):1.79−1.85(2H、m)、2.33(3H、s)、2.63−2.68(2H、m)、3.53−3.54(4H、m)、5.39(2H、t、J=4.7Hz)、7.10−7.14(2H、m)、7.23−7.49(9H、m)、7.81(3H、brs)。
2−アミノ−2−{2−[4’−(4−エチルフェニルチオ)−2’−フルオロ−ビフェニル−4−イル]エチル}プロパン−1,3−ジオールの合成
MS(ESI)m/z:426[M+H]
1H−NMR(DMSO−d6)δ(ppm):1.20(3H、t、J=7.5Hz)、1.29(2H、brs)、1.49−1.54(2H、m)、2.60−2.68(4H、m)、3.21−3.29(4H、m)、4.46(2H、t、J=5.1Hz)、7.05−7.08(2H、m)、7.09−7.34(4H、m)、7.40−7.49(5H、m)。
2−アミノ−2−{2−[2’−フルオロ−4’−(3−フルオロフェニルチオ)ビフェニル−4−イル]エチル}プロパン−1,3−ジオールの合成
MS(ESI)m/z:416[M+H]
1H−NMR(DMSO−d6)δ(ppm):1.30(2H、brs)、1.50−1.56(2H、m)、2.61−2.67(2H、m)、3.19−3.30(4H、m)、4.47(2H、t、J=5.4Hz)、7.23−7.33(7H、m)、7.44−7.55(4H、m)。
2−アミノ−2−{2−[2’−フルオロ−4’−(2−フルオロ−4−メチルフェニルチオ)ビフェニル−4−イル]エチル}プロパン−1,3−ジオールの合成
MS(ESI)m/z:430[M+H]
1H−NMR(DMSO−d6)δ(ppm):1.29(2H、brs)、1.49−1.55(2H、m)、2.38(3H、s)、2.60−2.65(2H、m)、3.19−3.32(4H、m)、4.46(2H、t、J=5.1Hz)、7.01−7.08(2H、m)、7.15(1H、d、J=7.2Hz)、7.25−7.29(3H、m)、7.40−7.51(4H、m)。
2−アミノ−2−{2−[2’−フルオロ−4’−(4−フルオロフェニルチオ)ビフェニル−4−イル]エチル}プロパン−1,3−ジオールの合成
MS(ESI)m/z:416[M+H]
1H−NMR(DMSO−d6)δ(ppm):1.29(2H、brs)、1.49−1.55(2H、m)、2.60−2.66(2H、m)、3.19−3.29(4H、m)、4.46(2H、t、J=5.2Hz)、7.07−7.26(2H、m)、7.29−7.60(9H、m)。
2−アミノ−2−{2−[4’−(4−クロロフェニルチオ)−2’−フルオロビフェニル−4−イル]エチル}プロパン−1,3−ジオールの合成
MS(ESI)m/z:432[M+H]
1H−NMR(DMSO−d6)δ(ppm):1.31(2H、brs)、1.50−1.55(2H、m)、2.61−2.66(2H、m)、3.20−3.28(4H、m)、4.46(2H、brs)、7.16−7.30(4H、m)、7.43−7.55(7H、m)。
2−アミノ−2−{2−[2’−フルオロ−4’−(5−メチル−2−チエニルチオ)ビフェニル−4−イル]エチル}プロパン−1,3−ジオールの合成
MS(ESI)m/z:418[M+H]
1H−NMR(DMSO−d6)δ(ppm):1.33(2H、brs)、1.49−1.55(2H、m)、2.50(3H、s)、2.60−2.65(2H、m)、3.20−3.24(4H、m)、4.46(2H、brs)、6.94(1H、d、J=3.3Hz)、7.00−7.05(2H、m)、7.26−7.49(6H、m)。
2−アミノ−2−{2−[2’−フルオロ−4’−(4−トリフルオロメチルフェニルチオ)ビフェニル−4−イル]エチル}プロパン−1,3−ジオールの合成
MS(ESI)m/z:466[M+H]
1H−NMR(DMSO−d6)δ(ppm):1.32(2H、brs)、1.51−1.56(2H、m)、2.62−2.68(2H、m)、3.22−3.29(4H、m)、4.48(2H、brs)、7.30−7.38(3H、m)、7.44−7.52(5H、m)、7.61(1H、t、J=8.2Hz)、7.74(2H、d、J=8.4Hz)。
2−アミノ−2−{2−[4’−(2,4−ジメチルフェニルチオ)−2’−フルオロビフェニル−4−イル]エチル}プロパン−1,3−ジオール
(13−1)N−(5−{2−[4’−(2,4−ジメチルフェニルチオ)−2’−フルオロビフェニル−4−イル]エチル}−2,2−ジメチル−1,3−ジオキサン−5−イル)アセタミドの合成
1H−NMR(CDCl3)δ(ppm):1.43(6H、s)、2.01(3H、s)、2.07−2.12(2H、m)、2.35(3H、s)、2.36(3H、s)、2.54−2.60(2H、m)、3.69(2H、d、J=12.0Hz)、3.99(2H、d、J=12.0Hz)、5.79(1H、s)、6.78(1H、dd、J=1.8、11.4Hz)、6.91(1H、dd、J=1.8、8.1Hz)、7.04(1H、d、J=7.8Hz)、7.14(1H、s)、7.21−7.28(3H、m)、7.38−7.41(3H、m)。
MS(ESI)m/z:426[M+H]
1H−NMR(DMSO−d6)δ(ppm):1.40−1.82(4H、m)、2.32(3H、s)、2.33(3H、s)、2.59−2.65(2H、m)、3.21−3.29(4H、m)、4.48(2H、brs)、6.88(1H、d、J=3.7Hz)、6.92(1H、s)、7.13(1H、d、J=7.8Hz)、7.27(3H、d、J=7.4Hz)、7.39−7.49(4H、m)。
2−アミノ−2−{2−[2’−フルオロ−4’−(3−メトキシフェニルチオ)ビフェニル−4−イル]エチル}プロパン−1,3−ジオール
(14−1)N−(5−{2−[2’−フルオロ−4’−(3−メトキシフェニルチオ)ビフェニル−4−イル]エチル}−2,2−ジメチル−1,3−ジオキサン−5−イル)アセタミドの合成
1H−NMR(CDCl3)δ(ppm):1.43(6H、s)、2.02(3H、s)、2.08−2.13(2H、m)、2.55−2.61(2H、m)、3.70(2H、d、J=11.7Hz)、3.79(3H、s)、4.00(2H、d、J=12.0Hz)、5.76(1H、s)、6.80−6.88(1H、m)、6.98−7.14(4H、m)、7.23−7.33(4H、m)、7.42(2H、dd、J=1.5、8.1Hz)。
MS(ESI)m/z:428[M+H]
1H−NMR(DMSO−d6)δ(ppm):1.55−1.61(2H、m)、2.61−2.66(2H、m)、3.26−3.33(4H、m)、3.76(3H、s)、4.64(2H、brs)、6.92−7.08(3H、m)、7.15−7.58(8H、m)。
2−アミノ−2−{2−[2’−フルオロ−4’−(4−メトキシフェニルチオ)ビフェニル−4−イル]エチル}プロパン−1,3−ジオール塩酸塩
(15−1)N−(5−{2−[2’−フルオロ−4’−(4−メトキシフェニルチオ)ビフェニル−4−イル]エチル}−2,2−ジメチル−1,3−ジオキサン−5−イル)アセタミドの合成
1H−NMR(CDCl3)δ(ppm):1.43(6H、s)、2.02(3H、s)、2.07−2.12(2H、m)、2.54−2.60(2H、m)、3.69(2H、d、J=11.9Hz)、3.85(3H、s)、3.99(2H、d、J=11.9Hz)、5.74(1H、s)、6.80−6.86(1H、m)、6.93−6.98(3H、m)、7.21−7.26(3H、m)、7.40(2H、dd、J=1.3、8.1Hz)、7.46−7.49(2H、m)。
MS(ESI)m/z:428[M+H]
1H−NMR(DMSO−d6)δ(ppm):1.75−1.81(2H、m)、2.59−2.65(2H、m)、3.50(4H、d、J=4.3Hz)、3.80(3H、s)、5.36(2H、brs)、6.92−6.96(2H、m)、7.05(2H、d、J=6.6Hz)、7.28(2H、d、J=8.2Hz)、7.41−7.43(3H、m)、7.50(2H、d、J=8.8Hz)、7.69(3H、brs)。
2−アミノ−2−{2−[4’−(3,4−ジメチルフェニルチオ)−2’−フルオロビフェニル−4−イル]エチル}プロパン−1,3−ジオール塩酸塩
(16−1)N−(5−{2−[4’−(3,4−ジメチルフェニルチオ)−2’−フルオロビフェニル−4−イル]エチル}−2,2−ジメチル−1,3−ジオキサン−5−イル)アセタミドの合成
1H−NMR(CDCl3)δ(ppm):1.43(6H、s)、2.02(3H、s)、2.07−2.12(2H、m)、2.26(3H、s)、2.28(3H、s)、2.55−2.60(2H、m)、3.69(2H、d、J=12.0Hz)、3.99(2H、d、J=11.7Hz)、5.76(1H、s)、6.92(1H、d、J=11.1Hz)、7.02(1H、dd、J=1.8、9.9Hz)、7.05−7.29(6H、m)、7.41(2H、dd、J=1.5、8.1Hz)。
MS(ESI)m/z:426[M+H]
1H−NMR(DMSO−d6)δ(ppm):1.76−1.82(2H、m)、2.23(3H、s)、2.24(3H、s)、2.60−2.66(2H、m)、3.51(4H、d、J=4.4Hz)、5.38(2H、brs)、7.01(2H、d、J=9.9Hz)、7.24−7.33(5H、m)、7.41−7.46(3H、m)、7.77(3H、brs)。
2−アミノ−2−{2−[2’−フルオロ−4’−(4−イソプロピルフェニルチオ)ビフェニル−4−イル]エチル}プロパン−1,3−ジオール塩酸塩
(17−1)N−(5−{2−[2’−フルオロ−4’−(4−イソプロピルフェニルチオ)ビフェニル−4−イル]エチル}−2,2−ジメチル−1,3−ジオキサン−5−イル)アセタミドの合成
1H−NMR(CDCl3)δ(ppm):1.27(6H、d、J=6.9Hz)、1.43(6H、s)、2.02(3H、s)、2.07−2.13(2H、m)、2.55−2.60(2H、m)、2.93(1H、sept、J=6.9Hz)、3.69(2H、d、J=12.0Hz)、4.00(2H、d、J=12.0Hz)、5.76(1H、s)、6.96(1H、dd、J=1.8、11.1Hz)、7.05(1H、dd、J=1.8、8.1Hz)、7.22−7.32(5H、m)、7.41(4H、d、J=8.1Hz)。
MS(ESI)m/z:440[M+H]
1H−NMR(DMSO−d6)δ(ppm):1.20(6H、d、J=6.9Hz)、1.77−1.83(2H、m)、2.61−2.66(2H、m)、2.91(1H、sept、J=6.9Hz)、3.52(4H、d、J=4.6Hz)、5.39(2H、t、J=4.6Hz)、7.05−7.09(2H、m)、7.28−7.35(4H、m)、7.41−7.46(5H、m)、7.83(3H、brs)。
2−アミノ−2−{2−[3−クロロ−2’−フルオロ−4’−(4−メチルフェニルチオ)ビフェニル−4−イル]エチル}プロパン−1,3−ジオール
(18−1)N−[1,1−ビス(アセトキシメチル)−3−[3−クロロ−2’−フルオロ−4’−(4−メチルフェニルチオ)ビフェニル−4−イル]プロピル]アセタミドの合成
1H−NMR(CDCl3)δ(ppm):2.00(3H、s)、2.10(6H、s)、2.17−2.22(2H、m)、2.38(3H、s)、2.73−2.79(2H、m)、4.39(4H、s)、5.77(1H、s)、6.91(1H、dd、J=1.8、11.4Hz)、7.02(1H、dd、J=1.5、9.9Hz)、7.20−7.32(5H、m)、7.40(2H、d、J=8.1Hz)、7.48(1H、s)。
MS(ESI)m/z:446[M+H]
1H−NMR(DMSO−d6)δ(ppm):1.29(2H、brs)、1.47−1.53(2H、m)、2.35(3H、s)、2.72−2.77(2H、m)、3.21−3.30(4H、m)、4.49(2H、t、J=4.7Hz)、7.01−7.06(2H、m)、7.30(2H、d、J=8.0Hz)、7.38−7.52(6H、m)。
2−アミノ−2−{2−[2’−フルオロ−4’−(4−メチルフェノキシ)ビフェニル−4−イル]エチル}プロパン−1,3−ジオール
(19−1)N−[1,1−ビス(アセトキシメチル)−3−(2’−フルオロ−4’−ヒドロキシビフェニル−4−イル)プロピル]アセタミドの合成
1H−NMR(CDCl3)δ(ppm):2.04(3H、s)、2.11(6H、s)、2.29−2.34(2H、m)、2.61−2.67(2H、m)、4.38(4H、s)、6.06(1H、s)、6.64−6.71(2H、m)、7.10−7.27(3H、m)、7.38(2H、dd、J=1.2、8.1Hz)、8.42(1H、brs)。
1H−NMR(CDCl3)δ(ppm):1.97(3H、s)、2.09(6H、s)、2.22−2.28(2H、m)、2.35(3H、s)、2.63−2.68(2H、m)、4.37(4H、s)、5.80(1H、s)、6.72−6.79(2H、m)、6.97(2H、d、J=8.4Hz)、7.16−7.44(7H、m)。
MS(ESI)m/z:396[M+H]
1H−NMR(DMSO−d6)δ(ppm):1.72−1.78(2H、m)、2.36(3H、s)、2.67−2.72(2H、m)、3.54(2H、d、J=10.5Hz)、3.63(2H、d、J=10.8Hz)、6.72−6.83(2H、m)、6.98(2H、d、J=8.7Hz)、7.18(2H、d、J=8.4Hz)、7.25−7.28(2H、m)、7.34(1H、t、J=8.6Hz)、7.44(2H、dd、J=1.5、8.1Hz)。
(5−{4−[3−アミノ−4−ヒドロキシ−3−(ヒドロキシメチル)ブチル]フェニル}−2−チエニル)(4−メチルフェニル)ケトン
(20−1)N−(5−{2−[4−(5−ホルミル−2−チエニル)フェニル]エチル}−2,2−ジメチル−1,3−ジオキサン−5−イル)アセタミドの合成
1H−NMR(CDCl3)δ(ppm):1.44(6H、s)、2.05(3H、s)、2.08−2.12(2H、m)、2.55−2.61(2H、m)、3.70(2H、d、J=11.7Hz)、3.98(2H、d、J=11.7Hz)、5.78(1H、s)、7.25(2H、d、J=8.7Hz)、7.37(1H、d、J=3.3Hz)、7.58(2H、d、J=8.4Hz)、7.73(1H、d、J=3.9Hz)、9.88(1H、s)。
1H−NMR(CDCl3)δ(ppm):1.42(6H、s)、2.02−2.09(5H、m)、2.36(3H、s)、2.50−2.56(2H、m)、3.65−3.69(3H、m)、3.97(2H、d、J=12.0Hz)、5.74(1H、s)、6.00(1H、d、J=3.6Hz)、6.83(1H、d、J=3.6Hz)、7.08(1H、d、J=3.6Hz)、7.13−7.26(4H、m)、7.37(2H、d、J=8.1Hz)、7.44(2H、d、J=8.1Hz)。
1H−NMR(CDCl3)δ(ppm):1.44(6H、s)、2.04(3H、s)、2.06−2.12(2H、m)、2.45(3H、s)、2.55−2.60(2H、m)、3.70(2H、d、J=12.0Hz)、3.98(2H、d、J=12.0Hz)、5.83(1H、s)、7.22−7.31(5H、m)、7.57−7.60(3H、m)、7.79(2H、d、J=8.1Hz)。
MS(ESI)m/z:396[M+H]
1H−NMR(DMSO−d6)δ(ppm):1.61−1.67(2H、m)、2.42(3H、s)、2.62−2.68(2H、m)、3.32(4H、brs)、4.83(4H、brs)、7.32(2H、t、J=8.1Hz)、7.39(2H、t、J=7.8Hz)、7.63(1H、d、J=4.2Hz)、7.71−7.79(5H、m)。
2−アミノ−4−[2’−フルオロ−4’−(4−メチルフェニルチオ)ビフェニル−4−イル]−2−メチルブタノール塩酸塩
(21−1)2−アセタミド−4−[2’−フルオロ−4’−(4−メチルフェニルチオ)ビフェニル−4−イル]−2−メチルブチル アセタートの合成
1H−NMR(CDCl3)δ(ppm):1.39(3H,s)、1.92−2.04(1H、m)、1.92(3H、s)、2.10(3H、s)、2.18−2.34(1H、m)、2.38(3H、s)、2.64(2H、t、J=8.4Hz)、4.19(1H、d、J=11.1Hz)、4.35(1H、d、J=11.1Hz)、5.35(1H、s)、6.93(1H、dd、J=1.8、11.1Hz)、7.03(1H、dd、J=1.8、8.1Hz)、7.19−7.32(6H、m)、7.38−7.43(3H、m)。
MS(ESI)m/z:396[M+H]
1H−NMR(DMSO−d6)δ(ppm):1.22(3H、s)、1.76−1.91(2H、m)、2.35(3H、s)、2.65(2H、t、J=8.7Hz)、3.41−3.50(2H、m)、5.50(1H、s)、7.03−7.07(2H、m)、7.29−7.32(4H、m)、7.41−7.49(5H、m)、7.84(3H、brs)。
2−アミノ−2−エチル−4−[2’−フルオロ−4’−(4−メチルフェニルチオ)ビフェニル−4−イル]ブタノール
(22−1)2−アセタミド−2−エチル−4−[2’−フルオロ−4’−(4−メチルフェニルチオ)ビフェニル−4−イル]ブチル アセタートの合成
1H−NMR(CDCl3)δ(ppm):0.90(3H、t、J=7.5Hz)、1.74−2.14(4H、m)、1.94(3H、s)、2.10(3H、s)、2.38(3H、s)、2.60(2H、t、J=8.4Hz)、4.30(1H、d、J=11.4Hz)、4.35(1H、d、J=11.4Hz)、5.22(1H、s)、6.94(1H、d、J=11.1Hz)、7.02−7.05(1H、m)、7.19−7.43(9H、m)。
MS(ESI)m/z:410[M+H]
1H−NMR(DMSO−d6)δ(ppm):0.82(3H、t、J=7.5Hz)、1.21(2H、brs)、1.34(2H、q、J=7.5Hz)、1.50(2H、t、J=8.6Hz)、2.35(3H、s)、2.55−2.62(2H、m)、3.19(2H、d、J=4.5Hz)、4.47(1H、t、J=4.5Hz)、7.03−7.06(2H、m)、7.26−7.30(4H、m)、7.40−7.48(5H、m)。
2−アミノ−4−[2’−フルオロ−4’−(フェニルチオ)ビフェニル−4−イル]−2−(ホスホリルオキシメチル)ブタノール
(23−1)2−アミノ−2−[2−(4’−ブロモ−2’−フルオロビフェニル−4−イル)エチル]プロパン−1,3−ジオールの合成
1H−NMR(DMSO−d6)δ(ppm):1.28(2H、s)、1.50−1.55(2H、m)、2.61−2.67(2H、m)、3.25(4H、dd、J=10.8、15.4Hz)、4.49(2H、brs)、7.30(2H、d、J=8.1Hz)、7.43−7.52(4H、m)、7.64(1H、d、J=11.0Hz)。
1H−NMR(CDCl3)δ(ppm):1.49(18H、s)、1.87−2.02(2H、m)、2.04(3H、s)、2.70(2H、t、J=8.6Hz)、3.86−4.02(3H、m)、4.36(1H、d、J=8.9Hz)、7.26−7.44(7H、m)。
1H−NMR(CDCl3)δ(ppm):1.49(18H、s)、1.58−1.95(2H、m)、2.02(3H、s)、2.69(2H、t、J=8.6Hz)、3.87−4.03(3H、m)、4.36(1H、d、J=8.7Hz)、7.04−7.12(2H、m)、7.24−7.47(10H、m)。
MS(ESI)m/z:478[M+H]
1H−NMR(CD3OD)δ(ppm):1.94−2.05(2H、m)、2.68−2.80(2H、m)、3.73(2H、s)、3.93−4.08(2H、m)、7.03−7.06(1H、m)、7.13(1H、d、J=8.4Hz)、7.34−7.49(10H、m)。
2−アミノ−4−[2’−フルオロ−4’−(4−メチルフェニルチオ)ビフェニル−4−イル]−2−(ホスホリルオキシメチル)ブタノール
(24−1)4−{2−[2’−フルオロ−4’−(4−メチルフェニルチオ)ビフェニル−4−イル]エチル}−4−ジ(tert−ブチル)ホスホリルオキシメチル−2−メチル−2−オキサゾリンの合成
1H−NMR(CDCl3)δ(ppm):1.48(18H、s)、1.77−2.10(2H、m)、2.01(3H、s)、2.38(3H、s)、2.69(2H、t、J=8.7Hz)、3.89(1H、dd、J=4.8、10.2Hz)、3.97(1H、dd、J=5.1、9.9Hz)、4.01(1H、d、J=8.7Hz)、4.35(1H、d、J=8.7Hz)、6.93(1H、d、J=12.6Hz)、7.03(1H、d、J=9.6Hz)、7.18−7.32(5H、m)、7.38−7.43(4H、m)。
MS(ESI)m/z:492[M+H]
1H−NMR(CD3OD)δ(ppm):1.98−2.08(2H、m)、2.38(3H、s)、2.68−2.82(2H、m)、3.72(2H、s)、3.94−4.10(2H、m)、6.91(1H、d、J=11.4Hz)、7.05(1H、d、J=8.1Hz)、7.24−7.45(9H、m)。
2−アミノ−4−[2’−フルオロ−4’−(3−メチルフェニルチオ)ビフェニル−4−イル]−2−(ホスホリルオキシメチル)ブタノール
(25−1)4−{2−[2’−フルオロ−4’−(3−メチルフェニルチオ)ビフェニル−4−イル]エチル}−4−ジ(tert−ブチル)ホスホリルオキシメチル−2−メチル−2−オキサゾリンの合成
1H−NMR(CDCl3)δ(ppm):1.49(18H、s)、1.64−2.10(5H、m)、2.35(3H、s)、2.69(2H、t、J=8.7Hz)、3.89(1H、dd、J=4.5、9.9Hz)、3.98(1H、dd、J=5.1、9.9Hz)、4.01(1H、d、J=8.7Hz)、4.36(1H、d、J=9.0Hz)、7.00(1H、d、J=12.9Hz)、7.09(1H、d、J=8.1Hz)、7.14−7.35(7H、m)、7.43(2H、dd、J=1.5、7.8Hz)。
MS(ESI)m/z:492[M+H]
1H−NMR(CD3OD)δ(ppm):1.97−2.05(2H、m)、2.34(3H、s)、2.68−2.82(2H、m)、3.72(2H、s)、3.92−4.10(2H、m)、6.97(1H、d、J=11.4Hz)、7.09(1H、d、J=9.9Hz)、7.18−7.47(9H、m)。
2−アミノ−4−[2’−フルオロ−4’−(4−メチルフェノキシ)ビフェニル−4−イル]−2−(ホスホリルオキシメチル)ブタノール
(26−1)4−{2−[2’−フルオロ−4’−(4−メチルフェノキシ)ビフェニル−4−イル]エチル}−4−ジ(tert−ブチル)ホスホリルオキシメチル−2−メチル−2−オキサゾリンの合成
1H−NMR(CDCl3)δ(ppm):1.49(18H、s)、1.80−2.10(2H、m)、2.02(3H、s)、2.36(3H、s)、2.69(2H、t、J=8.6Hz)、3.90(1H、dd、J=4.5、9.9Hz)、3.98(1H、dd、J=4.8、9.9Hz)、4.02(1H、d、J=8.4Hz)、4.36(1H、d、J=8.7Hz)、6.72−6.82(2H、m)、6.96−6.99(2H、m)、7.17−7.44(7H、m)。
MS(ESI)m/z:476[M+H]
1H−NMR(CD3OD)δ(ppm):1.96−2.08(2H、m)、2.35(3H、s)、2.64−2.80(2H、m)、3.72(2H、s)、3.95−4.08(2H、m)、6.71−6.83(2H、m)、6.96(2H、d、J=8.4Hz)、7.22(2H、d、J=8.4Hz)、7.31−7.45(5H、m)。
2−アミノ−4−[3−クロロ−2’−フルオロ−4’−(4−メチルフェニルチオ)ビフェニル−4−イル]−2−(ホスホリルオキシメチル)ブタノール
(27−1)2−アミノ−2−[2−(4’−ブロモ−3−クロロ−2’−フルオロビフェニル−4−イル)エチル]プロパン−1,3−ジオール塩酸塩の合成
1H−NMR(DMSO−d6)δ(ppm):1.80−1.85(2H、m)、2.77−2.83(2H、m)、3.57(4H、d、J=4.7Hz)、5.42(2H、t、J=4.8Hz)、7.48−7.53(4H、m)、7.60(1H、s)、7.68(1H、d、J=10.1Hz)7.91(3H、brs)。
1H−NMR(CDCl3)δ(ppm):1.49(18H、s)、1.85−1.95(2H、m)、2.03(3H、s)、2.73−2.85(2H、m)、3.92(1H、dd、J=4.8、9.9Hz)、3.99(1H、dd、J=4.8、9.9Hz)、4.11(1H、d、J=9.0Hz)、4.38(1H、d、J=8.7Hz)、7.24−7.37(5H、m)、7.49(1H、s)。
1H−NMR(CDCl3)δ(ppm):1.49(18H、s)、1.85−1.95(2H、m)、2.03(3H、s)、2.39(3H、s)、2.72−2.83(2H、m)、3.92(1H、dd、J=4.8、9.9Hz)、3.99(1H、dd、J=4.8、9.9Hz)、4.12(1H、d、J=8.7Hz)、4.39(1H、d、J=8.9Hz)、6.93(1H、d、J=12.7Hz)、7.04(1H、d、J=8.2Hz)、7.20−7.42(7H、m)、7.49(1H、s)。
MS(ESI)m/z:526[M+H]
1H−NMR(CD3OD)δ(ppm):1.93−2.02(2H、m)、2.39(3H、s)、2.85−2.91(2H、m)、3.68−3.82(2H、m)、3.95−4.10(2H、m)、6.91(1H、d、J=11.1Hz)、7.04(1H、d、J=8.4Hz)、7.27(2H、d、J=7.8Hz)、7.35−7.42(5H、m)、7.53(1H、s)。
2−アミノ−2−(2−{4−[5−(3−メチルフェニルチオ)ナフタレン−1−イル]フェニル}エチル)プロパン−1,3−ジオール
(28−1)N−(1,1−ビス(アセトキシメチル)−3−{4−[5−(3−メチルフェニルチオ)ナフタレン−1−イル]フェニル}プロピル)アセタミドの合成
の合成
MS(ESI)m/z:444[M+H]
1H−NMR(DMSO−d6)δ(ppm):1.63−1.68(2H、m)、2.25(3H、s)、2.68−2.72(2H、m)、3.30−3.37(4H、m)、4.64(2H、brs)、6.96(1H、d、J=7.8Hz)、7.06(1H、d、J=7.6Hz)、7.15(1H、s)、7.20(1H、t、J=7.7Hz)、7.36(2H、d、J=8.2Hz)、7.39(2H、d、J=8.2Hz)、7.47−7.51(2H、m)、7.64(1H、dd、J=7.3、8.4Hz)、7.68(1H、d、J=7.1Hz)、7.86(1H、d、J=7.1Hz)、8.32(1H、d、J=8.3Hz)。
2−アミノ−2−{2−[2’−フルオロ−4’−(4−メチルフェニルカルボニル)ビフェニル−4−イル]エチル}プロパン−1,3−ジオール塩酸塩
MS(ESI)m/z:408[M+H]
1H−NMR(DMSO−d6)δ(ppm):1.82−1.88(2H、m)、2.43(3H、s)、2.66−2.72(2H、m)、3.55(4H、d、J=4.8Hz)、5.43(2H、t、J=4.8Hz)、7.38(2H、d、J=8.1Hz)、7.41(2H、d、J=7.8Hz)、7.57−7.63(4H、m)、7.69−7.73(3H、m)、7.90(3H、brs)。
2−アミノ−4−[2’−フルオロ−4’−(4−メチルフェニルカルボニル)ビフェニル−4−イル]−2−(ホスホリルオキシメチル)ブタノール
(30−1)4−{2−[2’−フルオロ−4’−(4−メチルフェニルカルボニル)ビフェニル−4−イル]エチル}−4−ジ(tert−ブチル)ホスホリルオキシメチル−2−メチル−2−オキサゾリンの合成
1H−NMR(CDCl3)δ(ppm):1.49(18H、s)、1.70−1.90(2H、m)、2.03(3H、s)、2.46(3H、s)、2.72(2H、t、J=9.0Hz)、3.87−4.00(2H、m)、4.03(1H、d、J=8.4Hz)、4.37(1H、d、J=8.4Hz)、7.27−7.32(4H、m)、7.51−7.64(5H、m)、7.75(2H、d、J=7.8Hz)。
MS(ESI)m/z:488[M+H]
1H−NMR(CD3OD)δ(ppm):2.01−2.06(2H、m)、2.46(3H、s)、2.44−2.81(2H、m)、3.74(2H、s)、3.92−4.12(2H、m)、7.37−7.42(4H、m)、7.56−7.68(5H、m)、7.73(2H、d、J=8.4Hz)。
2−アミノ−2−{2−[4−(3−ベンジルオキシフェニルチオ)−2−クロロフェニル]エチル}プロパン−1,3−ジオール塩酸塩の合成
(1−1)N−{1,1−ビス(アセトキシメチル)−3−[2−クロロ−4−(3−ヒドロキシフェニルチオ)フェニル]プロピル}アセタミドの合成
1H−NMR(DMSO−d6)δ(ppm):1.84(3H、s)、1.92−1.97(2H、m)、2.02(6H、s)、2.62−2.66(2H、m)、4.20(2H、d、J=11.0Hz)、4.28(2H、d、J=11.1Hz)、6.70−6.78(3H、m)、7.18−7.32(4H、m)、7.68(1H、s)、9.76(1H、brs)。
MS(ESI)m/z:444[M+H]
1H−NMR(DMSO−d6)δ(ppm):1.77−1.81(2H、m)、2.72−2.76(2H、m)、3.56(4H、s)、5.10(2H、s)、5.40(2H、brs)、6.90−7.01(3H、m)、7.25(1H、dd、J=J=1.5、8.0Hz)、7.30−7.41(8H、m)、7.91(3H、brs)。
本発明化合物を20%シクロデキストリン(日本食品化工社製)に溶解又は懸濁させて、0.001〜10mg/kg体重の用量で、7〜10週齢の雄性BALB/cAnNCrjマウス(日本チャールス・リバー)に腹腔内投与した。本発明化合物の投与24時間後、エーテル麻酔下にマウスの後大静脈から、ヘパリンナトリウム(ノボ・ノルディスク社製)で処理したツベルクリン用シリンジ(テルモ社製)を用いて、末梢血を約0.3ml採取した。0.1mlの血液を自動溶血処理装置(TQ−Prep、ベックマン・コールター社製)を用いて溶血した後、フローサイトメーター(CYTOMICS FC 500、ベックマン・コールター社製)を用い、既知数の標準粒子であるFlow−CountTMFluorospheres(ベックマン・コールター社製)を内部標準として、レーザー光の前方及び側方散乱を指標としたゲーティング法でリンパ球数を測定した。ビークル群のリンパ球数を100%としたときに、それを50%低下させる用量を算出し、ED50値(mg/kg体重)とした。
雄性Sprague−Dawley(IGS)ラットにネンブタール(大日本製薬社製)を腹腔内投与することで麻酔した後、テレメトリー送信器(TL11M2−C50−PTX、データサイエンスインターナショナル社製)に接続している圧センサーを腹部大動脈内に挿入し、送信器を腹部皮下に留置した。血圧・心拍数のデータは受信器(RPC−1、データサイエンスインターナショナル社製)を介して解析ソフト(Dataquest A.R.T.、データサイエンス社)により記録した。術後10日から2週間経過後に心拍数のサーカデイアンリズムが回復したことを確認し、実験に供した。本発明化合物は、0.5%ヒドロキシプロピルメチルセルロース(信越化学工業製)に懸濁させて、経口投与した。心拍数は投与前24時間から投与後72時間まで測定した。実施例4で得られた化合物は、投与量10mg/kg体重までラットの心拍数に影響を与えなかった。
雄性Sprague−Dawley(IGS)ラットにネンブタール(大日本製薬社製)を腹腔内投与することで麻酔した後、背位に固定する。四肢に電極を装着し、心電図アンプ(AC−601G、日本光電社製)を用いて標準四肢第II誘導法にて心電図を計測する。心電図波をトリガーとして瞬時心拍計ユニット(AT−601G、日本光電社製)より心拍数を計数する。被験化合物は、20%シクロデキストリン(日本食品化工社製)に溶解させて、0.001〜10mg/kg体重の用量で、30秒間かけて静脈内投与する。心拍数は、投与前、投与後1、2、3、4、5、10及び15分に測定する。
本出願は、日本で出願された特願2006−126102を基礎としており、その内容は本明細書にすべて包含されるものである。
Claims (13)
- 下記一般式(I)
- Xが硫黄原子である請求項1に記載の2−アミノブタノール化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
- R3が水素原子又はハロゲン原子である請求項1又は2に記載の2−アミノブタノール化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
- Ar1が置換されていても良いアリーレンである請求項1〜3のいずれか1項に記載の2−アミノブタノール化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
- Ar2が置換されていても良いアリールである請求項1〜4のいずれか1項に記載の2−アミノブタノール化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
- 一般式(I)の化合物が以下のa、bのいずれかである請求項1〜6のいずれか1項に記載の化合物、若しくはその製薬上許容しうる酸付加塩、又はそれらの水和物、若しくは溶媒和物。
a.2−アミノ−2−{2−[2’−フルオロ−4’−(4−メチルフェニルチオ)ビフェニル−4−イル]エチル}プロパン−1,3−ジオール
b.2−アミノ−4−[2’−フルオロ−4’−(4−メチルフェニルチオ)ビフェニル−4−イル]−2−(ホスホリルオキシメチル)ブタノール - 2−アミノ−2−{2−[2’−フルオロ−4’−(4−メチルフェニルチオ)ビフェニル−4−イル]エチル}プロパン−1,3−ジオール、又はその塩酸塩。
- 請求項1〜8のいずれか1項に記載の化合物及び製薬上許容しうる担体を含有する医薬組成物。
- 自己免疫疾患の治療又は予防;器官又は組織の移植に対する急性拒絶反応又は慢性拒絶反応の予防又は抑制;骨髄移植による移植片対宿主(GvH)病の治療又は予防;アレルギー性疾患の治療又は予防のために用いられる請求項9に記載の医薬組成物。
- 一般式(II−4)で表される化合物の製造方法であって、一般式(II−1)で表される脱離基Xcを有するベンゼン化合物と一般式(II−2)で表される化合物とを縮合させ、又は一般式(II−1’)で表されるチオール化合物と一般式(II−2’)で表される脱離基Xcを有する化合物とを縮合させて、一般式(II−3)で表される化合物を得た後、脱保護を行うことを特徴とする製造方法。
- 一般式(II−1)で表される脱離基Xcを有するベンゼン化合物と一般式(II−2)で表される化合物とを縮合させることを特徴とする、一般式(II−3)で表される化合物の製造方法。
- 一般式(II−1’)で表されるチオール化合物と一般式(II−2’)で表される脱離基Xcを有する化合物とを縮合させることを特徴とする、一般式(II−3)で表される化合物の製造方法。
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PCT/JP2007/059150 WO2007126042A1 (ja) | 2006-04-28 | 2007-04-27 | 2-アミノブタノール化合物及びその医薬用途 |
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JP (1) | JP5100641B2 (ja) |
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SI2058317T1 (sl) | 2006-08-08 | 2014-01-31 | Kyorin Pharmaceutical Co., Ltd. | Derivat estra aminofosforjeve kisline in S1P receptorski modulator, ki ga vsebuje kot učinkovino |
AU2007282556B2 (en) | 2006-08-08 | 2012-03-08 | Kyorin Pharmaceutical Co., Ltd. | Aminoalcohol derivative and immunosuppressant containing the same as active ingredient |
US8476305B2 (en) | 2008-02-07 | 2013-07-02 | Kyorin Pharmaceutical Co., Ltd. | Therapeutic agent or prophylactic agent for inflammatory bowel disease comprising amino alcohol derivative as active ingredient |
US9493410B2 (en) * | 2008-03-24 | 2016-11-15 | Kyorin Pharmaceutical Co., Ltd. | Method for crystallization of 2-amino-2-[2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-ethyl]-1,3-propanediol hydrochloride |
KR20140048874A (ko) * | 2011-04-14 | 2014-04-24 | 알러간, 인코포레이티드 | 스핑고신-1 포스페이트 수용체 조절제로서의 페닐 이환식 메틸 아민 유도체 |
CA2868277A1 (en) | 2012-03-26 | 2013-10-03 | Rolf E. Swenson | Novel sphingosine 1-phosphate receptor antagonists |
JP6194306B2 (ja) * | 2012-04-23 | 2017-09-06 | 田辺三菱製薬株式会社 | アミン化合物及びその医薬用途 |
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WO2003029205A1 (fr) * | 2001-09-27 | 2003-04-10 | Kyorin Pharmaceutical Co., Ltd. | Derive de sulfure de diaryle, son sel d'addition et immunosuppresseur |
JP2005527612A (ja) * | 2002-05-27 | 2005-09-15 | ノバルティス アクチエンゲゼルシャフト | ビス芳香族アルカノール類 |
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EP0627406B1 (en) | 1992-10-21 | 1998-10-28 | Yoshitomi Pharmaceutical Industries, Ltd. | 2-amino-1,3-propanediol compound and immunosuppressant |
ATE211726T1 (de) | 1994-08-22 | 2002-01-15 | Welfide Corp | Benzolderivate und deren medizinische verwendung |
GB9707307D0 (en) | 1997-04-10 | 1997-05-28 | Ciba Geigy Ag | Polypeptide markers |
EP1431275B1 (en) | 2001-09-27 | 2010-04-07 | Kyorin Pharmaceutical Co., Ltd. | Diaryl ether derivative, addition salt thereof, and immunosuppressant |
JP2004307440A (ja) | 2003-04-10 | 2004-11-04 | Kyorin Pharmaceut Co Ltd | 2−アミノ‐1,3‐プロパンジオール誘導体とその付加塩 |
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WO2003029205A1 (fr) * | 2001-09-27 | 2003-04-10 | Kyorin Pharmaceutical Co., Ltd. | Derive de sulfure de diaryle, son sel d'addition et immunosuppresseur |
JP2005527612A (ja) * | 2002-05-27 | 2005-09-15 | ノバルティス アクチエンゲゼルシャフト | ビス芳香族アルカノール類 |
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US8114902B2 (en) | 2012-02-14 |
ES2491224T3 (es) | 2014-09-05 |
EP2017257A4 (en) | 2010-04-14 |
EP2017257B1 (en) | 2014-08-06 |
TW200811083A (en) | 2008-03-01 |
JPWO2007126042A1 (ja) | 2009-09-10 |
WO2007126042A1 (ja) | 2007-11-08 |
US20090082311A1 (en) | 2009-03-26 |
EP2017257A1 (en) | 2009-01-21 |
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