JP2018035142A - Asgpr標的化剤としての置換6,8−ジオキサビシクロ[3.2.1]オクタン−2,3−ジオール化合物 - Google Patents
Asgpr標的化剤としての置換6,8−ジオキサビシクロ[3.2.1]オクタン−2,3−ジオール化合物 Download PDFInfo
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- JP2018035142A JP2018035142A JP2017154022A JP2017154022A JP2018035142A JP 2018035142 A JP2018035142 A JP 2018035142A JP 2017154022 A JP2017154022 A JP 2017154022A JP 2017154022 A JP2017154022 A JP 2017154022A JP 2018035142 A JP2018035142 A JP 2018035142A
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- mmol
- methanol
- nmr
- dioxabicyclo
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- -1 Substituted-6,8-dioxabicyclo[3.2.1]octane-2,3-diol compounds Chemical class 0.000 title abstract description 213
- 230000008685 targeting Effects 0.000 title abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 289
- 108091033409 CRISPR Proteins 0.000 claims abstract description 30
- 102000004389 Ribonucleoproteins Human genes 0.000 claims abstract description 9
- 108010081734 Ribonucleoproteins Proteins 0.000 claims abstract description 9
- 239000013612 plasmid Substances 0.000 claims abstract description 5
- 125000005647 linker group Chemical group 0.000 claims description 45
- 125000000217 alkyl group Chemical group 0.000 claims description 38
- 125000005842 heteroatom Chemical group 0.000 claims description 36
- 125000004432 carbon atom Chemical group C* 0.000 claims description 22
- 125000003118 aryl group Chemical group 0.000 claims description 19
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 16
- 150000003536 tetrazoles Chemical class 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 150000003852 triazoles Chemical class 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 7
- 125000004450 alkenylene group Chemical group 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- 125000004419 alkynylene group Chemical group 0.000 claims description 6
- 125000004429 atom Chemical group 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 125000006743 (C1-C60) alkyl group Chemical group 0.000 claims description 2
- 125000006651 (C3-C20) cycloalkyl group Chemical group 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 abstract description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 14
- 102000005427 Asialoglycoprotein Receptor Human genes 0.000 abstract description 13
- 108010006523 asialoglycoprotein receptor Proteins 0.000 abstract description 13
- 238000012377 drug delivery Methods 0.000 abstract description 11
- 201000010099 disease Diseases 0.000 abstract description 10
- 210000004185 liver Anatomy 0.000 abstract description 4
- 208000019423 liver disease Diseases 0.000 abstract description 3
- 229940124447 delivery agent Drugs 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 467
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 398
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 366
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 269
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 178
- 238000006243 chemical reaction Methods 0.000 description 166
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 147
- 230000002829 reductive effect Effects 0.000 description 146
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 132
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 129
- 239000013058 crude material Substances 0.000 description 125
- 239000000243 solution Substances 0.000 description 125
- 238000000034 method Methods 0.000 description 117
- 229910052739 hydrogen Inorganic materials 0.000 description 115
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 105
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 103
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 98
- 239000000741 silica gel Substances 0.000 description 92
- 229910002027 silica gel Inorganic materials 0.000 description 92
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 87
- 239000000203 mixture Substances 0.000 description 78
- 239000011541 reaction mixture Substances 0.000 description 68
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 66
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 66
- 239000012071 phase Substances 0.000 description 66
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 65
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 62
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 60
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 58
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 54
- 239000002904 solvent Substances 0.000 description 51
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 47
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 47
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 46
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 44
- 239000003643 water by type Substances 0.000 description 43
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 42
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 41
- 239000012044 organic layer Substances 0.000 description 41
- 239000012267 brine Substances 0.000 description 39
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 39
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 37
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 36
- 229910052737 gold Inorganic materials 0.000 description 36
- 239000010931 gold Substances 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 35
- 238000000746 purification Methods 0.000 description 35
- 239000003921 oil Substances 0.000 description 34
- 239000000047 product Substances 0.000 description 34
- 239000000543 intermediate Substances 0.000 description 31
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 31
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 239000011734 sodium Substances 0.000 description 30
- 239000007787 solid Substances 0.000 description 30
- 235000011054 acetic acid Nutrition 0.000 description 29
- 229960000583 acetic acid Drugs 0.000 description 29
- 229910052757 nitrogen Inorganic materials 0.000 description 28
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 26
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 25
- 235000019341 magnesium sulphate Nutrition 0.000 description 25
- 125000006239 protecting group Chemical group 0.000 description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- 238000003818 flash chromatography Methods 0.000 description 23
- 230000014759 maintenance of location Effects 0.000 description 23
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
- 239000010410 layer Substances 0.000 description 21
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 20
- 239000000463 material Substances 0.000 description 20
- 150000001413 amino acids Chemical group 0.000 description 19
- ALBYIUDWACNRRB-UHFFFAOYSA-N hexanamide Chemical compound CCCCCC(N)=O ALBYIUDWACNRRB-UHFFFAOYSA-N 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000003153 chemical reaction reagent Substances 0.000 description 18
- 239000000126 substance Substances 0.000 description 18
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 17
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 17
- 229910052938 sodium sulfate Inorganic materials 0.000 description 17
- 235000011152 sodium sulphate Nutrition 0.000 description 17
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 16
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 15
- 108090000623 proteins and genes Proteins 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 14
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 14
- 229920000642 polymer Polymers 0.000 description 14
- 235000018102 proteins Nutrition 0.000 description 14
- 102000004169 proteins and genes Human genes 0.000 description 14
- 238000004007 reversed phase HPLC Methods 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 13
- 239000003814 drug Substances 0.000 description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 13
- 229920001223 polyethylene glycol Polymers 0.000 description 13
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 12
- 239000000872 buffer Substances 0.000 description 12
- 239000001257 hydrogen Substances 0.000 description 12
- 238000002953 preparative HPLC Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 238000011282 treatment Methods 0.000 description 12
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 11
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 11
- 238000007792 addition Methods 0.000 description 11
- 150000001345 alkine derivatives Chemical class 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- 229940079593 drug Drugs 0.000 description 11
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 11
- 229920006395 saturated elastomer Polymers 0.000 description 11
- QDXQAOGNBCOEQX-UHFFFAOYSA-N 1-methylcyclohexa-1,4-diene Chemical compound CC1=CCC=CC1 QDXQAOGNBCOEQX-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 10
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 10
- 230000004048 modification Effects 0.000 description 10
- 238000012986 modification Methods 0.000 description 10
- 239000008194 pharmaceutical composition Substances 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- 239000012099 Alexa Fluor family Substances 0.000 description 9
- AUHUDHNNFFCFJG-PSDLAXTLSA-N CC(=O)N[C@@H]1[C@@H]([C@H]([C@@]2(CO[C@H]1O2)COC(=O)C)CC(=O)O)CC(=O)O Chemical compound CC(=O)N[C@@H]1[C@@H]([C@H]([C@@]2(CO[C@H]1O2)COC(=O)C)CC(=O)O)CC(=O)O AUHUDHNNFFCFJG-PSDLAXTLSA-N 0.000 description 9
- HMTHQRMBTWVCLT-OMHSBUABSA-N OC[C@@]12[C@H]3[C@@H]([C@H]([C@@H](OC1)O2)NC(C)=O)OC(O3)(C)C Chemical compound OC[C@@]12[C@H]3[C@@H]([C@H]([C@@H](OC1)O2)NC(C)=O)OC(O3)(C)C HMTHQRMBTWVCLT-OMHSBUABSA-N 0.000 description 9
- WNFLYNFMVWRDEE-UHFFFAOYSA-N acetic acid;hexanamide Chemical compound CC(O)=O.CCCCCC(N)=O WNFLYNFMVWRDEE-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
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- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 9
- 239000000284 extract Substances 0.000 description 9
- 230000035772 mutation Effects 0.000 description 9
- 229910052763 palladium Inorganic materials 0.000 description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 9
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 9
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- DDUJWFAEMUQBQP-OVHBTUCOSA-N (1S,2R,3R,4R,5S)-4-azido-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3-diol Chemical compound N(=[N+]=[N-])[C@@H]1[C@H]([C@H]([C@@]2(CO[C@H]1O2)CO)O)O DDUJWFAEMUQBQP-OVHBTUCOSA-N 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
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- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
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- VAKXPQHQQNOUEZ-UHFFFAOYSA-N 3-[4-[[bis[[1-(3-hydroxypropyl)triazol-4-yl]methyl]amino]methyl]triazol-1-yl]propan-1-ol Chemical compound N1=NN(CCCO)C=C1CN(CC=1N=NN(CCCO)C=1)CC1=CN(CCCO)N=N1 VAKXPQHQQNOUEZ-UHFFFAOYSA-N 0.000 description 6
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- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 5
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- 125000000524 functional group Chemical group 0.000 description 5
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- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 5
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Abstract
Description
R1は、−CN、CH2−CN、−C≡CH、−CH2−N3、−CH2−NH2、−CH2−N(R4)−S(O)2−R5、−CH2−CO2H、−CO2H、−CH2−OH、−CH2−SH、−CH=CH−R5、−CH2−R5、−CH2−S−R5、−CH2−N(R4)−R5、−CH2−N(R4)−C(O)−R5、−CH2−N(R4)−C(O)−O−R5、−CH2−N(R4)−C(O)−N(R4)−R5、−CH2−O−R5、−CH2−O−C(O)−R5、−CH2−O−C(O)−N(R4)−R5、−CH2−O−C(O)−O−R5、−CH2−S(O)−R5、−CH2−S(O)2−R5、−CH2−S(O)2−N(R4)−R5、−C(O)−NH2、−C(O)−O−R5、−C(O)−N(R4)−R5、またはアリールもしくはヘテロアリールであり、アリールまたはヘテロアリールは、R5で置換されていてもよく、
またはR1は、−Z−X−Yであり、Xは、リンカーまたは薬物送達系であり、Yは、存在しないか、または低分子、アミノ酸配列、核酸配列、抗体、オリゴマー、ポリマー、遺伝学的に得た材料、リポソーム、ナノ粒子、色素、蛍光プローブ、またはこれらの組合せからなる群から選択されるリガンドであり、Zは、存在しないか、または−C≡C−、−CH=CH−、−CH2−、−CH2−O−、−C(O)−N(R4)−、−CH2−S−、−CH2−S(O)−、−CH2−S(O)2−、−CH2−S(O)2−N(R4)−、−C(O)−O−、−CH2−N(R4)−、−CH2−N(R4)−C(O)−、−CH2−N(R4)−S(O)2−、−CH2−N(R4)−C(O)−O−、−CH2−N(R4)−C(O)−N(R4)−、−CH2−O−C(O)−、−CH2−O−C(O)−N(R4)−、−CH2−O−C(O)−O−、またはアリールもしくはヘテロアリールであり、アリールまたはヘテロアリールは、R5で置換されていてもよく、
R2は、−OH、−N3、−N(R3)2、−N(R3)−C(O)−R3、−N(R3)−C(O)−N(R3)2、−N(R3)−C(O)−OR3、テトラゾール、またはトリアゾールであり、テトラゾールおよびトリアゾールは、R3で置換されていてもよく、
R1が−CH2−OHであるとき、R2は、−N3、−N(R3)2、−N(R3)−C(O)−R3、−N(R3)−C(O)−N(R3)2、−N(R3)−C(O)−OR3、テトラゾール、またはトリアゾールであり、テトラゾールおよびトリアゾールは、R3で置換されていてもよく、
各R3は、独立に、−H、−(C1〜C5)アルキル、ハロ置換(C1〜C5)アルキル、または(C3〜C6)シクロアルキルであり、アルキルまたはシクロアルキルの−CH2−基は、−O−、−S−、および−N(R4)−から選択されるヘテロ原子基で置き換えられていてもよく、アルキルの−CH3は、−N(R4)2、−OR4、および−S(R4)から選択されるヘテロ原子基で置き換えられていてもよく、ヘテロ原子基は、少なくとも2個の炭素原子で隔てられており、
各R4は、独立に、−H、−(C1〜C20)アルキル、または(C3〜C6)シクロアルキルであり、少なくとも2個の炭素原子で隔てられた、アルキルまたはシクロアルキルの1〜6つの−CH2−基は、−O−、−S−、または−N(R4)−で置き換えられていてもよく、アルキルの−CH3は、−N(R4)2、−OR4、および−S(R4)から選択されるヘテロ原子基で置き換えられていてもよく、ヘテロ原子基は、少なくとも2個の炭素原子で隔てられており、アルキルおよびシクロアルキルは、1〜6個のハロ原子で置換されていてもよく、
各R5は、独立に、−H、−(C3〜C20)シクロアルキル、または(C1〜C20)アルキルであり、少なくとも2個の炭素原子で隔てられた、アルキルまたはシクロアルキルの1〜6つの−CH2−基は、−O−、−S−、または−N(R4)−で置き換えられていてもよく、アルキルの−CH3は、−N(R4)2、−OR4、および−S(R4)から選択されるヘテロ原子基で置き換えられていてもよく、ヘテロ原子基は、少なくとも2個の炭素原子で隔てられており、アルキルおよびシクロアルキルは、1〜6個のハロ原子で置換されていてもよい]
または薬学的に許容できるその塩を包含する。
R1は、−CN、CH2−CN、−C≡CH、−CH2−N3、−CH2−NH2、−CH2−N(R4)−S(O)2−R5、−CH2−CO2H、−CO2H、−CH2−OH、−CH2−SH、−CH=CH−R5、−CH2−R5、−CH2−S−R5、−CH2−N(R4)−R5、−CH2−N(R4)−C(O)−R5、−CH2−N(R4)−C(O)−O−R5、−CH2−N(R4)−C(O)−N(R4)−R5、−CH2−O−R5、−CH2−O−C(O)−R5、−CH2−O−C(O)−N(R4)−R5、−CH2−O−C(O)−O−R5、−CH2−S(O)−R5、−CH2−S(O)2−R5、−CH2−S(O)2−N(R4)−R5、−C(O)−NH2、−C(O)−O−R5、−C(O)−N(R4)−R5、−S(O)3H、−S(O)2Cl、S(O)2F、またはアリールもしくはヘテロアリールであり、アリールまたはヘテロアリールは、R5で置換されていてもよく、
またはR1は、−Z−X−Y、−Z−Y、−X−Y、−X、−Y、または−Z−Xであり、Xは、リンカーまたは薬物送達系であり、Yは、R6であるか、または低分子、アミノ酸配列、核酸配列、抗体、オリゴマー、ポリマー、遺伝学的に得た材料、リポソーム、ナノ粒子、色素、蛍光プローブ、またはこれらの組合せからなる群から選択されるリガンドであり、Zは、−C≡C−、−CH=CH−、−CH2−、−CH2−O−、−C(O)−N(R4)−、−CH2−S−、−CH2−S(O)−、−CH2−S(O)2−、−CH2−S(O)2−N(R4)−、−C(O)−O−、−CH2−N(R4)−、−CH2−N(R4)−C(O)−、−CH2−N(R4)−S(O)2−、−CH2−N(R4)−C(O)−O−、−CH2−N(R4)−C(O)−N(R4)−、−CH2−O−C(O)−、−CH2−O−C(O)−N(R4)−、−CH2−O−C(O)−O−、またはアリールもしくはヘテロアリールであり、アリールまたはヘテロアリールは、R5で置換されていてもよく、
R2は、−OH、−N3、−N(R3)2、−N(R3)−C(O)−R3、−N(R3)−C(O)−N(R3)2、−N(R3)−C(O)−OR3、−N(R3)−S(O)2−R3、テトラゾール、またはトリアゾールであり、テトラゾールおよびトリアゾールは、R3で置換されていてもよく、
R1が−CH2−OHであるとき、R2は、−N3、−N(R3)2、−N(R3)−C(O)−R3、−N(R3)−C(O)−N(R3)2、−N(R3)−C(O)−OR3、N(R3)−S(O)2−R3、テトラゾール、またはトリアゾールであり、テトラゾールおよびトリアゾールは、R3で置換されていてもよく、
各R3は、独立に、−H、−(C1〜C5)アルキル、ハロ置換(C1〜C5)アルキル、または(C3〜C6)シクロアルキルであり、アルキルまたはシクロアルキルの1つまたは複数の−CH2−基は、−O−、−S−、および−N(R4)−から独立に選択されるヘテロ原子基でそれぞれ置き換えられていてもよく、アルキルの−CH3は、−N(R4)2、−OR4、および−S(R4)から選択されるヘテロ原子基で置き換えられていてもよく、ヘテロ原子基は、少なくとも2個の炭素原子で隔てられており、
各R4は、独立に、−H、−(C1〜C20)アルキル、または(C3〜C6)シクロアルキルであり、少なくとも2個の炭素原子で隔てられた、アルキルまたはシクロアルキルの1〜6つの−CH2−基は、−O−、−S−、または−N(R4)−から独立に選択されるヘテロ原子でそれぞれ置き換えられていてもよく、アルキルの−CH3は、−N(R4)2、−OR4、および−S(R4)から選択されるヘテロ原子基で置き換えられていてもよく、ヘテロ原子基は、少なくとも2個の炭素原子で隔てられており、アルキルおよびシクロアルキルは、ハロ原子で置換されていてもよく、
各R5は、独立に、−H、(C3〜C20)シクロアルキル、または(C1〜C60)アルキルであり、シクロアルキルの1〜6つの−CH2−基またはアルキルの1〜20の−CH2−基は、−O−、−S−、および−N(R4)−から独立に選択されるヘテロ原子でそれぞれ置き換えられていてもよく、ヘテロ原子は、少なくとも2個の炭素原子で隔てられており、アルキルの−CH3は、−N(R4)2、−OR4、および−S(R4)から選択されるヘテロ原子基で置き換えられていてもよく、ヘテロ原子基は、少なくとも2個の炭素原子で隔てられており、アルキルおよびシクロアルキルは、ハロ原子で置換されていてもよく、
各R6は、独立に、H、−C≡CH、−C=CH2、−CH3、−N3、−N(R4)2、−OH、−S(O)−(R4)、−S(O)2−(R4)、−C(O)−OH、−S−S−アリール、−S−S−ヘテロアリール、ヘテロシクリル、アリール、またはヘテロアリールであり、各アリールまたはヘテロアリールは、R5で置換されていてもよい]
または薬学的に許容できるその塩を包含する。
各Qは、独立に、存在しないか、またはC(O)、C(O)−NR4、NR4−C(O)、O−C(O)−NR4、NR4−C(O)−O、−CH2−、ヘテロアリール、もしくはO、S、S−S、S(O)、S(O)2、およびNR4から選択されるヘテロ原子基であり、少なくとも2個の炭素原子が、ヘテロ原子基O、S、S−S、S(O)、S(O)2、およびNR4を、他のいずれかのヘテロ原子基と隔てており、
各R4は、独立に、−H、−(C1〜C20)アルキル、または(C3〜C6)シクロアルキルであり、少なくとも2個の炭素原子で隔てられた、アルキルまたはシクロアルキルの1〜6つの−CH2−基は、−O−、−S−、または−N(R4)−で置き換えられていてもよく、アルキルの−CH3は、−N(R4)2、−OR4、および−S(R4)から選択されるヘテロ原子基で置き換えられていてもよく、ヘテロ原子基は、少なくとも2個の炭素原子で隔てられており、アルキルおよびシクロアルキルは、ハロ原子で置換されていてもよく、
各nは、独立に、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、または40である。nが1より大きい場合、各(T−Q−T−Q)の各Tおよび各Qは、独立に選択される。
nces in Heterocyclic Chemistry、9、165(1968);S.J.Wittenberger、Organic Preparations and Procedures International、26、499(1994);M.G.Finnら、Angewandte Chemie International Edition、48、9879(2009)において要約されている)条件下で適切な試薬および合成中間体を用い、さらに官能基化し、反応させて、本発明の請求項に係る、追加の5および6員環(たとえば、イソオキサゾール、イソチアゾール、ピラゾール、オキサゾール、チアゾール、イミダゾール、1,2,4−オキサジアゾール、1,2,4−チアジアゾール、1,2,4−トリアゾール、1,3,4−オキサジアゾール、1,3,4−チアジアゾール、テトラゾール、1,2,3−トリアゾール)連結型のXY含有化合物を生成することができる。(III−e−6)や(IV−e−4)などのアルキン、またはこうしたアルキンのヘテロ置換類似体(すなわち、(III−e−6)/(IV−e−4)におけるアルキン水素をOR4、N(R4)2、SR4で置き換えることによるもの;こうした化合物は、当業者に公知の条件および試薬を使用して取得することができる)から、当業者に公知の芳香環化反応(benzannulation reaction)(ダンハイザー式またはデッツ式の芳香環化など)によって、本発明の請求項に係る、アリール環連結型のXY含有化合物を取得することもできる。
NMRスペクトルは、プロトンについて、Varian Unity(商標)400(Varian Inc.、Palo Alto、CAから入手可能)で室温にて400MHzで記録した。化学シフトは、内部基準としての残留溶媒に対する百万分率(デルタ)で表示する。ピーク形状は、次のように表記する:s、一重線;d、二重線;dd、二重二重線;t、三重線;q、四重線;m、多重線;bsまたはbr.s.、ブロード一重線;2s、2本の一重線;br.d.、ブロード二重線。場合によっては、代表的な1H NMRピークのみが示される。カラムクロマトグラフィーは、ガラスカラム中またはFlash 40 Biotage(商標)カラム(ISC,Inc.、Shelton、CT)中のBaker(商標)シリカゲル(40マイクロメートル;J.T.Baker、Phillipsburg、NJ)またはSilica Gel 50(EM Sciences(商標)、Gibbstown、NJ)のいずれかを用いて行った。MPLC(中圧液体クロマトグラフィー)は、Biotage(商標)SP精製システム、またはTeledyne(商標)Isco(商標)から入手したCombiflash(登録商標)Companion(登録商標)を使用して行った;低窒素圧下のBiotage(商標)SNAPカートリッジKPsilまたはRedisep Rfシリカ(Teledyne(商標)Isco(商標)から入手)を使用した。別段の断りがない限り、すべての反応は、無水溶媒を使用して窒素ガスの不活性雰囲気下で行った。また、別段の断りがない限り、すべての反応は室温(約23℃)で行った。TLC(薄層クロマトグラフィー)を行うとき、Rfは、化合物が移動した距離を溶離液が移動した距離で割った比として定義される。Rt(保持時間)。H−Cube(登録商標)連続フロー式水素化反応装置:連続フローの微量化学と内生的なオンデマンド水素生成および使い捨て触媒カートリッジシステムとを組み合わせた卓上独立型水素化反応装置。
LC/MS TOF(ESI):すべてのデータは、エレクトロスプレーイオン化源とともに動作しているMSD TOF(AgilentモデルG1969A)質量スペクトル検出器を備えたAgilent 1100 LC上に集められた。LC機器は、試料提出に外部試行(external try)を用いるオートサンプラー(AgilentモデルG1313A)に取り付けた400barの圧力上限を有するバイナリポンプ(AgilentモデルG1312A)、およびダイオードアレイ(AgilentモデルG1315A)に取り付けたカラムコンパートメント(AgilentモデルG1316A)を含む。機器取得およびデータ取扱いは、Agilent MassHunter TOF/Q−TOF B.02(B11285)パッチ1.2.3を用いて行った。溶出条件:カラム:カラムは使用しなかった。フロー注入:注入容量:1.0マイクロL;流速:0.5mL/分。実行時間:1.0分;溶媒:メタノール(0.1%ギ酸および0.05%ギ酸アンモニウム)。TOF条件:イオン化源:ポジティブモードのエレクトロスプレーイオン化源;ガス温度:325℃;乾燥ガス:6L/分;ネブライザー:50psg;VCap:3500V;質量範囲110〜100m/z;取得速度:0.99スペクトル/秒:取得時間;1012.8ms/スペクトル。すべての溶媒は、Sigma Aldrich(St.Louis、Missouri)から入手したHPLC Chromasolvグレードのものであった。化学物質および緩衝剤の大部分をSigma Aldrichから購入し、すべて純度97%以上であった。
方法C 1.5分間実行LRMS(低分解能質量分析):Waters Acqity HSS T3、2.1mm×50mm、C18、1.7μm;移動相:A:水中0.1%ギ酸(v/v);移動相B:アセトニトリル中0.1%ギ酸(v/v);流速−1.25ml/分;初期条件:A−95%:B−5%;0.0〜0.1分は初期に保持;0.1〜1.0分にかけてA−5%:B−95%に直線ランプ;1.0〜1.1分はA−5%:B−95%に保持;1.1〜1.5分で初期条件に戻した。
方法C 3.0分間実行LRMS(低分解能質量分析):Waters Acqity HSS T3、2.1mm×50mm、C18、1.7μm;移動相:A:水中0.1%ギ酸(v/v);移動相B:アセトニトリル中0.1%ギ酸(v/v);流速−1.25ml/分;初期条件:A−95%:B−5%;0.0〜0.1分は初期に保持;0.1〜2.6分にかけてA−5%:B−95%に直線ランプ;2.6〜2.95分はA−5%:B−95%に保持;2.95〜3.0分で初期条件に戻した。
((2R,3S,4R,5R,6R)−5−アジド−6−メトキシ−3,4−ビス((トリメチルシリル)オキシ)テトラヒドロ−2H−ピラン−2−イル)メタノール(I−b)
1H), 3.45 (dd, J=7.3, 4.6 Hz, 1H), 3.54 (dd, J=10.0, 8.0 Hz, 1H), 3.59 (s, 3H),
3.65 (dd, J=11.3, 4.7 Hz, 1H), 3.77 (d, J=2.7 Hz, 1H), 3.87 (dd, J=11.2, 7.3
Hz, 1H), 4.14 (d, J=8.0 Hz, 1H); 13C NMR (100 MHz, クロロホルム-d) δ ppm 0.27 (3C), 0.6
(3C), 57.3, 62.6, 64.0, 71.1, 73.7, 75.2, 103.4; HRMS (ESI): C13H29N3O5Si2
(m/z) [M + Na]+の計算値386.1538, 実測値386.1539.
5H), 3.80 - 3.83 (m, 1H), 4.54 (d, J=8.0 Hz, 1 H); 13C NMR (100 MHz,
メタノール-d4)
δ ppm
57.2, 61.2, 63.6, 65.9, 69.9, 71.2, 80.9, 101.2; HRMS (ESI): C8H15N3O6
(m/z) [M + Na]+の計算値272.0853, 実測値272.0856.
1H), 3.83 (d, J=7.8 Hz, 1H), 3.86 (d, J=11.6 Hz, 1H), 3.90 (d, J=11.3 Hz, 1H),
3.91 - 3.94 (m, 1H), 4.14 - 4.19 (m, 1H), 4.29 (d, J=6.0 Hz, 1H), 5.23 (d,
J=2.0 Hz, 1H); 13C NMR (100 MHz, メタノール-d4) δ ppm 22.7, 26.9,
28.5, 56.8, 61.9, 70.2, 76.1, 76.6, 83.0, 102.6, 112.5, 173.6; HRMS (ESI): C12H19NO6
(m/z) [M + H]+の計算値274.1285, 実測値274.1274.
J=8.0 Hz, 1H), 3.80 (d, J=11.3 Hz, 1H), 3.83 - 3.89 (m, 2H), 3.90 (d, J=11.5
Hz, 1H), 5.32 (d, J=1.4 Hz, 1H); 13C NMR (100 MHz, メタノール-d4) δ ppm 61.9, 66.1,
69.5, 69.6, 71.0, 85.3, 102.7; HRMS (ESI): C7H11N3O5
(m/z) [M + Na]+の計算値240.0591, 実測値240.0596.
(d, J=8.6 Hz, 1H), 4.06 (d, J=8.6 Hz, 1H), 4.13 (d, J=11.6 Hz, 1H), 4.20 (d,
J=10.6 Hz, 1H), 4.46 (d, J=11.3 Hz, 1H), 5.13 (dd, J=10.4, 4.4 Hz, 1H), 5.35
(d, J=1.0 Hz, 1H), 5.38 (d, J=4.3 Hz, 1H); 13C NMR (100 MHz, メタノール-d4) δ ppm 20.6, 20.7
(2C), 22.6, 53.3, 63.0, 68.9, 69.1, 70.3, 82.6, 103.0, 171.8, 171.9, 172.1,
173.8; HRMS (ESI): C15H21NO9 (m/z) [M + H]+の計算値360.1289, 実測値360.1290.
(d, J=7.8 Hz, 1H), 3.81 (d, J=11.3 Hz, 1H), 3.87 (d, J=4.3 Hz, 1H), 3.92 (d,
J=11.3 Hz, 1H), 3.95 (dd, J=9.9, 1.1 Hz, 1H), 5.22 (d, J=1.3 Hz, 1 H); 13C
NMR (100 MHz, メタノール-d4) δ ppm 22.7, 56.4, 62.1, 69.2, 69.3, 70.6, 85.1, 102.8, 174.1; HRMS
(ESI): C9H15NO6 (m/z) [M + H]+の計算値234.0972, 実測値234.0974.
2H), 3.62 - 3.71 (m, 14H), 3.75 - 3.80 (m, 2H), 3.86 (d, J=8.1 Hz, 1H) 3.90 -
3.97 (m, 2H), 4.12 - 4.19 (m, 1H), 4.31 (d, J=5.8 Hz, 1H), 5.23 (d, J=2.0 Hz,
1H); 13C NMR (100 MHz, メタノール-d4) δ ppm 22.7, 26.9, 28.5, 51.9, 56.7, 70.9, 71.1, 71.3, 71.6, 71.7,
71.8, 71.81, 71.82, 72.7, 76.1, 76.5, 82.1, 102.4, 112.4, 173.6; HRMS (ESI): C20H34N4O9
(m/z) [M + H]+の計算値475.2399, 実測値475.2386.
中間体(I−f−2)は次のように合成することができる:テトラヒドロフラン(21mL)中のBoc−セリノール(1000mg、5.1mmol)の溶液に、ヨウ化テトラブチルアンモニウム(287mg、0.76mmol)、ヨウ化ナトリウム(153mg、1.02mmol)および臭化プロパルギル(1.8mL、16mmol、トルエン中80%)を室温で添加した。水酸化カリウム(569mg、10.1mmol)を30分間かけて少量ずつ添加し、次いで混合物を室温で16時間撹拌した。反応混合物を酢酸エチルおよび水で希釈した。水相を酢酸エチルで1回抽出した。合わせた有機層を硫酸マグネシウムで脱水し、濾過し、濃縮した。粗物質をシリカゲルでのフラッシュクロマトグラフィー(30%酢酸エチル/ヘキサン)により精製して、化合物(I−f−2)を油状物(530mg、収率39%)として得た。1H NMR (400 MHz, クロロホルム-d/TMS) δ ppm 1.44 (s, 9H),
2.44 (t, J=2.4 Hz, 2H), 3.53 - 3.67 (m, 4H), 3.92 (br. s., 1H), 4.16 (d, J=2.5
Hz, 4H), 4.90 (br. s., 1H); 13C NMR (100 MHz, クロロホルム-d/TMS) δ ppm 28.4 (3C),
49.5, 58.5 (2C), 68.6 (2C), 74.6 (2C), 77.2, 79.5 (2C), 155.4; HRMS (ESI): C14H21NO4
(m/z) [M + H]+の計算値268.1543, 実測値268.1536.
中間体(I−f−3)は公知であり、R.Royら、J.Org.Chem.73、5602(2008)に記載されている。
中間体(I−g−1):精製条件:100%酢酸エチル、定量的、油状物。1H NMR (400 MHz, クロロホルム-d/TMS) δ ppm 1.80 - 1.91 (m,
2H), 2.24 (t, J=7.1 Hz, 2H), 2.46 (t, J=2.3 Hz, 1H), 3.22 - 3.31 (m, 2H), 3.43
- 3.51 (m, 2H), 3.56 - 3.64 (m, 2H), 4.16 (d, J=2.3 Hz, 2H), 5.07 (br. s., 1H),
5.10 (s, 2H), 6.09 (br. s., 1H), 7.28 - 7.42 (m, 5H); 13C NMR (100
MHz, クロロホルム-d/TMS) δ ppm 25.9, 33.7, 39.1, 40.5, 58.3, 66.7, 68.7, 74.8, 79.4, 128.1,
128.5 (4C), 136.6, 156.7, 172.5; HRMS (ESI): C17H22N2O4
(m/z) [M + H]+の計算値319.1652, 実測値319.1646.
中間体(I−g−2):精製条件:70%酢酸エチル/ヘキサン、65mg、油状物(収率76%)、油状物。1H NMR (400 MHz, クロロホルム-d/TMS) δ ppm 1.79 - 1.91 (m,
2H), 2.24 (t, J=7.1 Hz, 2H), 2.44 (t, J=2.4 Hz, 2H), 3.20 - 3.29 (m, 2H), 3.54
- 3.69 (m, 4H), 4.16 (d, J=1.5 Hz, 4H), 4.22 - 4.33 (m, 1H), 5.10 (br. s, 3H),
6.04 (d, J=7.8 Hz, 1H), 7.28 - 7.42 (m, 5H); 13C NMR (100 MHz, クロロホルム-d/TMS) δ ppm 25.8, 33.7,
40.4, 48.2, 58.4 (2C), 66.6, 68.3 (2C), 74.7 (2C), 79.4 (2C), 128.1, 128.5
(4C), 136.6, 156.6, 172.2; HRMS (ESI): C21H26N2O5
(m/z) [M + H]+の計算値387.1914, 実測値387.1904.
中間体(I−g−3):精製条件:70%酢酸エチル/ヘキサン、42mg、油状物(収率60%)。1H NMR (400 MHz, クロロホルム-d) δ ppm 1.76 - 1.88 (m,
2H), 2.21 (t, J=7.1 Hz, 2H), 2.44 (t, J=2.3 Hz, 3H), 3.18 - 3.30 (m, 2H), 3.84
(s, 6H), 4.14 (d, J=2.3 Hz, 6H), 5.10 (s, 2H), 5.12 (br. s., 1H), 5.89 (br. s.,
1H), 7.28 - 7.40 (m, 5H); 13C NMR (100 MHz, クロロホルム-d/TMS) δ ppm 25.7, 34.3,
40.3, 58.6 (3C), 59.2, 66.6, 68.5 (3C), 74.6 (3C), 79.5 (3C), 128.1, 128.5
(4C), 136.6, 156.6, 172.6; HRMS (ESI): C25H30N2O6
(m/z) [M + H]+の計算値455.2177, 実測値455.2167.
トリス(3−ヒドロキシプロピルトリアゾリルメチル)アミン(THPTA;Angewandte Chemie International Edition 48、9879(2009)におけるM.G.Finnらを参照)(2mg、0.005mmol)および硫酸銅(1mg、0.004mmol)を水(50μL)に溶解し、次いでメタノール(0.9mL)中の(I−e−2)(42mg、0.089mmol)およびアルキン(I−g−1)(40mg、0.125mmol)の溶液に添加した。次いで、水(30μL)に溶解したアスコルビン酸ナトリウム(1.8mg、0.009mmol)を添加し、反応混合物を室温で24時間撹拌した。溶媒を蒸発させ、粗物質をシリカゲルでのフラッシュクロマトグラフィー(ジクロロメタン中5%〜10%メタノール)により精製して、所望の化合物(I−h−1)を油状物(54mg、収率76%)として得た;[α]D 48.2 (c 0.54, メタノール); 1H NMR (400 MHz, メタノール-d4) δ ppm 1.33 (s, 3H), 1.48 (s, 3H), 1.70 - 1.83 (m, 2H), 1.98 (s, 3H),
2.21 (t, J=7.4 Hz, 2H), 3.13 (t, J=6.9 Hz, 2H), 3.37 (t, J=5.4 Hz, 2H), 3.51 -
3.70 (m, 14H), 3.71 - 3.95 (m, 7H), 4.15 (t, J=6.5 Hz, 1H), 4.29 (d, J=5.8 Hz,
1H), 4.56 (t, J=5.0 Hz, 2H), 4.60 (s, 2H), 5.06 (s, 2H), 5.22 (d, J=1.8 Hz,
1H), 7.25 - 7.38 (m, 5H), 8.01 (s, 1 H); 13C NMR (100 MHz, メタノール-d4) δ ppm 22.7, 27.0,
27.4, 28.5, 34.4, 40.5, 41.4, 51.6, 56.7, 62.4, 64.9, 67.5, 70.0, 70.5, 70.8,
71.1, 71.5, 71.6, 71.65, 71.7, 71.73, 72.6, 73.8, 76.2, 76.5, 82.1, 102.4,
112.4, 126.1, 129.0, 129.1, 129.6, 138.6, 146.1, 159.0, 173.6, 175.7; HRMS
(ESI): C37H56N6O13 (m/z) [M + H]+の計算値793.3978, 実測値793.3959.
中間体(I−h−2)
THPTA(22mg、0.051mmol)および硫酸銅(2.5mg、0.01mmol)を水(70μL)に溶解し、次いでメタノール(1mL)中の(I−e−2)(48mg、0.1mmol)およびアルキン(I−g−2)(20mg、0.051mmol)の溶液に添加した。次いで、水(30μL)に溶解したアスコルビン酸ナトリウム(4mg、0.02mmol)を添加し、反応混合物を室温で72時間撹拌した。溶媒を蒸発させ、残留物をジクロロメタンおよび塩化アンモニウムの飽和水溶液に溶かした。水相をジクロロメタンで3回抽出した。合わせた有機層を硫酸マグネシウムで脱水し、濾過し、濃縮した。粗物質をさらに精製することなく次のステップにおいて使用した。
中間体(I−h−3)
THPTA(34mg、0.079mmol)および硫酸銅(4mg、0.016mmol)を水(200μL)に溶解し、次いでメタノール(1mL)中の(I−e−2)(50mg、0.1mmol)およびアルキン(I−g−3)(24mg、0.053mmol)の溶液に添加した。次いで、水(30μL)に溶解したアスコルビン酸ナトリウム(6.5mg、0.032mmol)を添加し、反応混合物を室温で72時間撹拌した。溶媒を蒸発させ、残留物をジクロロメタンおよび塩化アンモニウムの飽和水溶液に溶かした。水相をジクロロメタンで3回抽出した。合わせた有機層を硫酸マグネシウムで脱水し、濾過し、濃縮した。粗物質をさらに精製することなく次のステップにおいて使用した。
アセトニド除去のための一般的手順:
化合物(I−h−1)、(I−h−2)または(I−h−3)(0.030〜0.068mmol)を、酢酸、メタノールおよび水の混合物(それぞれ1.6〜1.8mL、0.5mL、0.5mL)に溶解し、70℃で24時間撹拌した。溶媒を蒸発させ、残留物をトルエンと2回共蒸発させた。粗物質をシリカゲルでのフラッシュクロマトグラフィーにより精製した。
精製条件:ジクロロメタン中10%メタノール、43.3mg、油状物(収率85%)。[α]D 45 (c 1, メタノール); 1H NMR (400 MHz, メタノール-d4) δ ppm 1.72 - 1.83 (m, 2H), 1.99 (s, 3H), 2.22 (t, J=7.4 Hz, 2H), 3.13
(t, J=6.8 Hz, 2H), 3.37 (t, J=5.4 Hz, 2H), 3.52 - 3.79 (m, 20H), 3.85 - 4.00
(m, 3H), 4.57 (t, J=5.0 Hz, 2H), 4.61 (s, 2H), 5.07 (s, 2H), 5.21 (s, 1H), 7.24
- 7.41 (m, 5H), 8.02 (s, 1H); 13C NMR (100 MHz, メタノール-d4) δ ppm 22.8, 27.4,
34.4, 40.4, 41.4, 51.6, 56.4, 64.9, 67.5, 69.0, 70.0, 70.1, 70.4, 70.5, 71.4,
71.5 (2C), 71.6, 71.65, 71.7, 72.5, 84.3, 102.6, 126.0, 129.0 (2C), 129.1,
129.6 (2C), 138.6, 145.8, 159.0, 174.0, 175.8; HRMS (ESI): C34H52N6O13
(m/z) [M + H]+の計算値753.3665, 実測値753.3679.
精製条件:ジクロロメタン中20%メタノール、25mg、油状物(2ステップにわたって収率20%)。[α]D 56 (c 1.25, メタノール); 1H NMR (400 MHz, メタノール-d4) δ ppm 1.72 - 1.81 (m, 2H), 1.99 (s, 6H), 2.23 (t, J=7.5 Hz, 2H), 3.13
(t, J=6.9 Hz, 2H), 3.50 - 3.80 (m, 36H), 3.85 - 3.91 (m, 6H), 3.92 - 4.00 (m,
4H), 4.13 - 4.25 (m, 1H), 4.52 - 4.63 (m, 8H), 5.07 (s, 2H), 5.21 (d, J=1.3 Hz,
2H), 7.23 - 7.40 (m, 5H), 8.01 (s, 2H); 13C NMR (100 MHz, メタノール-d4) δ ppm 22.6 (2C),
27.2, 34.2, 41.2, 50.2, 51.4 (2C), 56.2 (2C), 65.0 (2C), 67.3, 68.8 (2C), 69.9
(2C), 70.0 (2C), 70.2 (2C), 70.3 (2C), 71.2 (2C), 71.3 (4C), 71.4 (2C), 71.5
(2C), 71.52 (2C), 72.3 (2C), 84.1 (2C), 102.4 (2C), 125.8 (2C), 128.8 (2C),
128.9, 129.4 (2C), 138.4, 145.6 (2C), 158.8, 173.8 (2C), 175.3; HRMS (ESI): C55H86N10O23
(m/z) [M + H]+の計算値1255.5940, 実測値1255.5925.
精製条件:ジクロロメタン中20%メタノール、31mg、油状物(2ステップにわたって収率18%)。[α]D 53 (c 1, メタノール); 1H NMR (400 MHz, メタノール-d4) δ ppm 1.65 - 1.78 (m, 2H), 1.98 (s, 9H), 2.19 (t, J=7.3 Hz, 2H), 3.11
(t, J=6.8 Hz, 2H), 3.51 - 3.80 (m, 54H), 3.86 - 3.91 (m, 9H), 3.91 - 3.99 (m,
6H), 4.51 - 4.63 (m, 12H), 5.06 (s, 2H), 5.21 (d, J=1.3 Hz, 3H), 7.24 - 7.40
(m, 5H), 7.98 (s, 3H); HRMS (ESI): C76H120N14O33
(m/z) [M + 2H]+/2の計算値879.4144, 実測値879.4148.
25.5mg、油状物、収率76%;[α]D 57.6 (c 1.25, メタノール); 1H NMR (400 MHz, メタノール-d4) δ ppm 1.70 - 1.81 (m, 2H), 1.99 (s, 3H), 2.24 (t, J=7.4 Hz, 2H), 2.67
(t, J=6.8 Hz, 2H), 3.36 - 3.41 (m, 2H), 3.51 - 3.80 (m, 19H), 3.84 - 4.01 (m,
4H), 4.59 (t, J=5.2 Hz, 2H), 4.61 (s, 2H), 5.21 (s, 1H), 8.03 (s, 1H); 13C
NMR (100 MHz, メタノール-d4) δ ppm 22.8, 29.6, 34.5, 40.4, 42.0, 51.6, 56.4, 64.9, 69.0, 70.0,
70.1, 70.5, 70.6, 71.4, 71.5 (2C), 71.6, 71.66, 71.7, 72.5, 84.3, 102.6, 126.0,
145.8, 174.1, 175.9; HRMS (ESI): C26H46N6O11
(m/z) [M + H]+の計算値619.3297, 実測値619.3278.
粗物質を0.5mLのメタノール/水(50:50)に溶解し、HPLCカラム上に注入した。分取高速液体クロマトグラフィー(HPLC)は、Waters XBridge BEH C18 OBD分取カラム、130Å、5μm、19mm×100mm(Waters、部品番号186002978)を使用し、流速17mL/分にて直線傾斜勾配で溶出して行った。溶媒勾配:アセトニトリル/水/トリフルオロ酢酸、40分間で(2:98:0.1)から(22:58:0.1)。収集した画分を分析LCMSにより分析し、十分な純度を有すると判定された25.7〜27.3分の画分をプールし、蒸発させて、10.7mgの(8)を油状物、収率49%として得た;[α]D 56 (c 1, メタノール); 1H NMR (500 MHz, メタノール-d4) δ ppm 1.86 - 1.95 (m, 2H), 1.99 (s, 6H), 2.37 (t, J=7.0 Hz, 2H), 2.96
(t, J=7.4 Hz, 2H), 3.50 - 3.80 (m, 36H), 3.84 - 4.00 (m, 10H), 4.17 - 4.26 (m,
1H), 4.57 - 4.62 (m, 8H), 5.21 (s, 2H), 8.03 (s, 2 H); 13C NMR (100
MHz, メタノール-d4) δ ppm 22.8 (2C), 29.2, 34.5, 41.8, 50.4, 51.6 (2C), 56.4 (2C), 65.1
(2C), 69.0 (2C), 70.1 (2C), 70.3 (2C), 70.5 (2C), 70.6 (2C), 71.4 (2C), 71.5
(4C), 71.6 (2C), 7.67, (2C), 71.7 (2C), 72.5 (2C), 84.3 (2C), 102.6 (2C), 126.1
(2C), 145.8 (2C), 174.1 (2C), 175.6; HRMS (ESI): C47H80N10O21
(m/z) [M + H]+の計算値1121.5572, 実測値1121.5558.
粗物質を0.5mLのメタノール/水(50:50)に溶解し、HPLCカラム上に注入した。分取高速液体クロマトグラフィー(HPLC)は、Waters XBridge BEH C18 OBD分取カラム、130Å、5μm、19mm×100mm(Waters、部品番号186002978)を使用し、流速17mL/分にて直線傾斜勾配で溶出して行った。溶媒勾配:アセトニトリル/水/トリフルオロ酢酸、40分間で(2:98:0.1)から(22:58:0.1)。収集した画分を分析LCMSにより分析し、十分な純度を有すると判定された30.3〜32.0分の画分をプールし、蒸発させて、15mgの(9)を油状物、収率63%として得た;[α]D 59.1 (c 1.1, メタノール); 1H NMR (500 MHz, メタノール-d4) δ ppm 1.84 - 1.92 (m, 2H), 2.00 (s, 9H), 2.31 - 2.38 (m, 2H), 2.97
(t, J=7.3 Hz, 2H), 3.54 - 3.80 (m, 54H), 3.86 - 3.93 (m, 9H), 3.93 - 4.00 (m,
6H), 4.57 (s, 6H), 4.60 (t, J=4.9 Hz, 6H), 5.22 (s, 3H), 8.02 (s, 3H); HRMS
(ESI): C68H114N14O31 (m/z) [M + H]+の計算値1623.7847, 実測値1623.7803.
HPLC精製のための一般的手順:
分取高速液体クロマトグラフィー(HPLC)は、Waters XBridge BEH C18 OBD分取カラム、130Å、5μm、19mm×100mm(Waters、部品番号186002978)を使用し、流速17mL/分にて直線傾斜勾配で溶出して行った。溶媒勾配:アセトニトリル/水/トリフルオロ酢酸、40分間で(2:98:0.1)から(22:78:0.1)。収集した画分を分析LCMSにより分析し、十分な純度を有すると判定されたものをプールし、蒸発させた。
ジメチルスルホキシド(200μL)中の化合物(7)(3.0mg、4.8μmol)の溶液に、Alexa Fluor(登録商標)647カルボン酸スクシンイミジルエステル(5.0mg、4μmol)およびN,N−ジイソプロピルエチルアミン(10μL、10当量)を添加した。反応混合物を室温で1時間振とうし、次いで分取HPLCにより直接精製した。収集した画分を分析LCMSにより分析し、十分な純度を有すると判定されたものをプールした(Rt=22.7〜24分)。3.2mgの(10)を得た(収率55%)。溶液を等分し、真空遠心分離器内で蒸発させ、生成物を4℃で貯蔵した。MS (ESI) [M + H]+の計算値(m/z) 約1456, 実測値 1456.82。
ジメチルスルホキシド(200μL)中の化合物(8)(6.0mg、5μmol)の溶液に、Alexa Fluor(登録商標)647カルボン酸スクシンイミジルエステル(5.0mg、4μmol)およびN,N−ジイソプロピルエチルアミン(10μL、10当量)を添加した。反応混合物を室温で1時間振とうし、次いで分取HPLCにより直接精製した。収集した画分を分析LCMSにより分析し、十分な純度を有すると判定されたものをプールした(Rt=25.3〜26.7分)。4.8mgの(11)を得た(収率62%)。溶液を等分し、真空遠心分離器内で蒸発させ、生成物を4℃で貯蔵した。MS (ESI) [M + H]+の計算値(m/z) 約1958, 実測値 1958.74
ジメチルスルホキシド(200μL)中の化合物(9)(9.8mg、6μmol)の溶液に、Alexa Fluor(登録商標)647カルボン酸スクシンイミジルエステル(5.0mg、4.8μmol)およびN,N−ジイソプロピルエチルアミン(10μL、10当量)を添加した。反応混合物を室温で1時間振とうし、次いで分取HPLCにより直接精製した。収集した画分を分析LCMSにより分析し、十分な純度を有すると判定されたものをプールした(Rt=27.7分)。5.2mgの(12)を得た(収率52%)。溶液を等分し、真空遠心分離器内で蒸発させ、生成物を4℃で貯蔵した。MS (ESI) [M + H]+の計算値(m/z) 約2460, 実測値 2461.18。
1H), 3.72 (d, J=7.8 Hz, 1H), 3.74 (d, J=7.8 Hz, 1H), 3.75 (d, J=12.7 Hz, 1H),
4.02 - 4.10 (m, 2H), 4.11 (d, J=5.9 Hz, 1H), 5.35 (d, J=2.4 Hz, 1H), 5.95 (d,
J=8.8 Hz, 1H); 13C NMR (125 MHz, クロロホルム-d) δ ppm 23.2, 26.2, 27.7, 51.0, 54.2,
69.3, 74.8, 76.1, 80.6, 101.2, 111.6, 170.1; HRMS (ESI): C12H18N4O5
(m/z) [M + H]+の計算値299.1350, 実測値299.1344.
化合物(I−j−2):精製条件:20%酢酸エチル/ヘキサン、85mg、油状物(収率8%);1H NMR (400 MHz, クロロホルム-d/TMS) δ ppm 1.77 - 1.90 (m,
14 H), 2.23 (t, J=7.1 Hz, 2H), 2.43 (t, J=2.3 Hz, 2H), 3.20 - 3.29 (m, 2H),
3.39 - 3.55 (m, 24H), 3.60 (t, J=6.3 Hz, 4H), 4.13 (d, J=2.5 Hz, 4H), 4.15 -
4.24 (m, 1H), 5.09 (s, 2H), 5.16 (br. s., 1H), 6.05 (d, J=8.1 Hz, 1H), 7.28 -
7.41 (m, 5H); 13C NMR (100 MHz, クロロホルム-d/TMS) δ ppm 25.8, 29.8
(2C), 29.9 (2C), 30.0 (2C), 33.7, 40.4, 48.5, 58.1 (2C), 66.6, 67.2 (2C), 67.6
(2C), 67.7 (2C), 67.8 (2C), 67.9 (2C), 68.3 (2C), 69.0 (2C), 74.2 (2C), 79.9
(2C), 128.1, 128.5 (4C), 136.6, 156.6, 172.1; HRMS (ESI): C39H62N2O11
(m/z) [M + H]+の計算値735.4426, 実測値735.4424.
化合物(I−j−3):精製条件:85%酢酸エチル/ヘキサン、32.6mg、油状物、(収率71%);1H NMR (400 MHz, クロロホルム-d/TMS) δ ppm 1.75 - 1.90 (m,
20H), 2.18 (t, J=6.9 Hz, 2H), 2.43 (t, J=2.4 Hz, 3H), 3.23 (q, J=6.3 Hz, 2H),
3.40 - 3.53 (m, 30H), 3.59 (t, J=6.3 Hz, 6H), 3.67 (s, 6H), 4.13 (d, J=2.3 Hz,
6H), 5.08 (s, 2H), 5.27 (br. s., 1H), 5.85 (s, 1H), 7.27 - 7.40 (m, 5H); 13C
NMR (100 MHz, クロロホルム-d/TMS) δ ppm 25.7, 29.7 (3C), 29.9 (3C), 30.0 (3C), 34.4, 40.4, 58.1 (3C),
59.8, 66.5, 67.1 (3C), 67.6 (3C), 67.7 (3C), 67.8 (3C), 67.82 (3C), 68.4 (3C),
69.1 (3C), 74.2 (3C), 79.9 (3C), 128.0, 128.4 (4C), 136.6, 156.6, 172.3; HRMS
(ESI): C52H84N2O15 (m/z) [M + H]+の計算値977.5944, 実測値977.5943.
THPTA(22.6mg、0.052mmol)および硫酸銅(2.5mg、0.01mmol)を水(200μL)に溶解し、次いでメタノール(1.1mL)中の(I−e−3)(45mg、0.152mmol)および(I−j−2)(51mg、0.069mmol)の溶液に添加した。次いで、水(100μL)に溶解したアスコルビン酸ナトリウム(4.2mg、0.021mmol)を添加し、反応混合物を摂氏50度で24時間撹拌した。溶媒を蒸発させ、粗物質をシリカゲルでのフラッシュクロマトグラフィー(ジクロロメタン中5%メタノール)により精製して、所望の化合物(I−k−2)を油状物(72mg、収率78%)として得た。1H NMR (400 MHz, メタノール-d4) δ ppm 1.34 (s, 6H),
1.52 (s, 6H), 1.73 - 1.86 (m, 12H), 1.97 (s, 6H), 2.24 (t, J=7.4 Hz, 2H), 3.15
(t, J=6.8 Hz, 2H), 3.43 - 3.54 (m, 22H), 3.58 (t, J=6.3 Hz, 4H), 3.86 (d, J=8.1
Hz, 2H), 3.97 (dd, J=6.2, 1.9 Hz, 2H), 4.11 - 4.23 (m, 5H), 4.58 (s, 4H), 4.78
(s, 6H), 4.91 (d, J=14.1 Hz, 2H), 4.98 (d, J=14.4 Hz, 2H), 5.07 (s, 2H), 5.24
(d, J=1.8 Hz, 2H), 7.25 - 7.40 (m, 5H), 7.99 (s, 2H); 13C NMR (100
MHz, メタノール-d4) δ ppm 22.7 (2C), 26.8 (2C), 27.5, 28.4 (2C), 31.1 (4C), 31.2 (2C),
34.5, 41.4, 50.6, 51.0 (2C), 56.3 (2C), 64.8 (2C), 67.5 (2C), 68.7 (2C), 68.8
(2C), 68.9 (3C), 69.0 (2C), 69.4 (2C), 69.7 (2C), 70.9 (2C), 76.3 (2C), 76.6
(2C), 81.5 (2C), 102.5 (2C), 112.8 (2C), 127.2 (2C), 129.0 (2C), 129.1, 129.6
(2C), 138.6, 146.3 (2C), 159.0, 173.5 (2C), 175.5; HRMS (ESI): C63H98N10O21
(m/z) [M + H]+の計算値1331.6981, 実測値1331.6971.
化合物(I−k−3):
THPTA(16mg、0.037mmol)および硫酸銅(1.7mg、0.007mmol)を水(100μL)に溶解し、次いでメタノール(1.1mL)中の(I−e−3)(32.5mg、0.109mmol)および(I−j−3)(32mg、0.033mmol)の溶液に添加した。次いで、水(100μL)に溶解したアスコルビン酸ナトリウム(3mg、0.015mmol)を添加し、反応混合物を摂氏50度で24時間撹拌した。溶媒を蒸発させ、粗物質をシリカゲルでのフラッシュクロマトグラフィー(ジクロロメタン中10%メタノール)により精製して、所望の化合物(I−k−3)を油状物(43.5mg、収率70%)として得た。1H NMR (400 MHz, メタノール-d4) δ ppm 1.33 (s, 9H),
1.52 (s, 9H), 1.71 - 1.87 (m, 18H), 1.97 (s, 9H), 2.20 (t, J=7.3 Hz, 2H), 3.15
(t, J=6.8 Hz, 2H), 3.43 - 3.52 (m, 28H), 3.58 (t, J=6.3 Hz, 6H), 3.67 (s, 6H),
3.86 (d, J=8.3 Hz, 3H), 3.97 (dd, J=6.0, 1.8 Hz, 3H), 4.14 - 4.22 (m, 5H), 4.58
(s, 6H), 4.78 (s, 8H), 4.91 (d, J=14.6 Hz, 3H), 4.97 (d, J=14.6 Hz, 3H), 5.07
(s, 2H), 5.24 (d, J=2.0 Hz, 3H), 7.26 - 7.38 (m, 5H), 7.98 (s, 3H); 13C
NMR (100 MHz, メタノール-d4) δ ppm 22.7 (3C), 26.9 (3C), 27.7, 28.4 (3C), 31.1 (3C), 31.2 (3C),
31.3 (3C), 35.2, 41.3, 51.0 (3C), 56.3 (3C), 61.8, 64.9 (3C), 67.5 (3C), 68.7
(3C), 68.8 (3C), 68.9 (3C), 69.0 (4C), 69.6 (3C), 69.7 (3C), 70.0 (3C), 76.3
(3C), 76.6 (3C), 81.5 (3C), 102.5 (3C), 112.8 (3C), 127.2 (3C), 129.0 (2C),
129.1, 129.7 (2C), 138.6, 146.4 (3C), 159.0, 173.5 (3C), 175.6; HRMS (ESI): C88H138N14O30
(m/z) [M + H]+の計算値1871.9776, 実測値1871.9713.
粗物質を0.5mLのメタノール/水(50:50)に溶解し、HPLCカラム上に注入した。分取高速液体クロマトグラフィー(HPLC)は、Waters XBridge BEH C18 OBD分取カラム、130Å、5μm、19mm×100mm(Waters、部品番号186002978)を使用し、流速17mL/分にて直線傾斜勾配で溶出して行った。溶媒勾配:アセトニトリル/水/トリフルオロ酢酸、40分間で(2:98:0.1)から(22:58:0.1)。収集した画分を分析LCMSにより分析し、十分な純度を有すると判定された34.7〜35.6分の画分をプールし、蒸発させて、12.8mgの(13)を油状物(2ステップにわたって収率17%)として得た;1H NMR (500 MHz, メタノール-d4) δ ppm 1.73 - 1.87 (m,
12H), 1.88 - 1.96 (m, 2H), 1.98 (s, 6H), 2.39 (t, J=7.0 Hz, 2H), 2.98 (t, J=7.4
Hz, 2H), 3.42 (d, J=8.5 Hz, 2H), 3.45 - 3.55 (m, 24H), 3.59 (t, J=6.3 Hz, 4H),
3.71 - 3.75 (m, 4H), 3.77 (d, J=8.3 Hz, 2H), 3.96 - 4.02 (m, 2H), 4.13 - 4.20
(m, 1H), 4.58 (s, 4H), 4.91 - 4.95 (m, 4H), 5.20 (d, J=1.5 Hz, 2H), 7.98 (s,
2H); HRMS (ESI): C49H84N10O19 (m/z)
[M + H]+の計算値1117.5987, 実測値1117.5977.
粗物質を0.5mLのメタノール/水(50:50)に溶解し、HPLCカラム上に注入した。分取高速液体クロマトグラフィー(HPLC)は、Waters XBridge BEH C18 OBD分取カラム、130Å、5μm、19mm×100mm(Waters、部品番号186002978)を使用し、流速17mL/分にて直線傾斜勾配で溶出して行った。溶媒勾配:アセトニトリル/水/トリフルオロ酢酸、40分間で(2:98:0.1)から(42:58:0.1)。収集した画分を分析LCMSにより分析し、十分な純度を有すると判定された24.7〜25.6分の画分をプールし、蒸発させて、5.5mgの(14)を油状物(2ステップにわたって収率10%)として得た;1H NMR (500 MHz, メタノール-d4) δ ppm 1.75 - 1.86 (m,
18H), 1.87 - 1.94 (m, 2H), 1.98 (s, 9H), 2.37 (t, J=6.8 Hz, 2H), 2.98 (t, J=7.4
Hz, 2H), 3.43 (d, J=8.5 Hz, 3H), 3.46 - 3.53 (m, 31H), 3.59 (t, J=6.3 Hz, 6H),
3.68 (s, 6H), 3.72 - 3.76 (m, 5H), 3.77 (d, J=8.3 Hz, 3H), 3.97 - 4.02 (m, 3H),
4.59 (s, 6H), 4.90 - 4.96 (m, 6H), 5.20 (d, J=1.2 Hz, 3H) 7.98 (s, 3H); HRMS
(ESI): C71H120N14O28 (m/z) [M + H]+の計算値1617.8469, 実測値1617.8415.
HPLC精製のための一般的手順:
分取高速液体クロマトグラフィー(HPLC)は、Waters XBridge BEH C18 OBD分取カラム、130Å、5μm、19mm×100mm(Waters、部品番号186002978)を使用し、流速17mL/分にて直線傾斜勾配で溶出して行った。溶媒勾配:アセトニトリル/水/トリフルオロ酢酸、40分間で(2:98:0.1)から(22:78:0.1)。収集した画分を分析LCMSにより分析し、十分な純度を有すると判定されたものをプールし、蒸発させた。
ジメチルスルホキシド(200μL)中の化合物(13)(4.5mg、4μmol)の溶液に、Alexa Fluor(登録商標)647カルボン酸スクシンイミジルエステル(5.0mg、4μmol)およびN,N−ジイソプロピルエチルアミン(10μL、10当量)を添加した。反応混合物を室温で1時間振とうし、次いで分取HPLCにより直接精製した。収集した画分を分析LCMSにより分析し、十分な純度を有すると判定されたものをプールした(Rt=37.3〜39分)。4.0mgの(15)を得た(収率50%)。溶液を等分し、真空遠心分離器内で蒸発させ、生成物を摂氏4度で貯蔵した。MS (ESI) [M + H]+の計算値(m/z) 約1955, 実測値 1955.32。
ジメチルスルホキシド(200μL)中の化合物(14)(5.2mg、3.2μmol)の溶液に、Alexa Fluor(登録商標)647カルボン酸スクシンイミジルエステル(5.0mg、4μmol)およびN,N−ジイソプロピルエチルアミン(10μL、10当量)を添加した。反応混合物を室温で1時間振とうし、次いで分取HPLCにより直接精製した。収集した画分を分析LCMSにより分析し、十分な純度を有すると判定されたものをプールした(Rt=24.3〜25.3分)。4.0mgの(16)を得た(収率51%)。溶液を等分し、真空遠心分離器内で蒸発させ、生成物を4℃で貯蔵した。MS (ESI) [M + H]+の計算値(m/z) 約2455, 実測値 2456.90。
ジクロロメタン中の(I−e−1)の溶液に、所望のヨードアルキル、硫酸水素テトラブチルアンモニウムおよび12.5M水酸化ナトリウム水溶液を添加した。反応混合物を室温で終夜撹拌し、水およびジクロロメタンで希釈し、水相をジクロロメタンでさらに2回抽出した。合わせた有機層を1M塩酸の水溶液、水で洗浄し、硫酸マグネシウムで脱水し、濾過し、減圧下で濃縮した。得られた物質は、粗製のまま次の反応に持ち込むか、またはシリカゲルでのフラッシュクロマトグラフィーを使用して精製することができる。得られた物質を酢酸/メタノール/水の混合物(3:1:1v/v)に溶解し、溶液を摂氏60〜70度に終夜加熱した。反応混合物を減圧下で濃縮し、トルエンと2回共蒸発させ、粗物質をシリカゲルでのフラッシュクロマトグラフィーまたは逆相クロマトグラフィーにより精製した。
Hz, 1 H), 3.97 (dd, J=9.7, 1.4 Hz, 1 H), 3.94 (d, J=9.3 Hz, 1 H), 3.88 (d,
J=4.3 Hz, 1 H), 3.79 (d, J=8.1 Hz, 1 H), 3.73 (dd, J=9.8, 4.3 Hz, 1 H), 3.66
(d, J=8.1 Hz, 1 H), 3.60 (d, J=9.6 Hz, 1 H), 3.59 (dq, J=9.6, 7.1 Hz, 1 H),
3.55 (dq, J=9.6, 7.1 Hz, 1 H), 2.00 (s, 3 H), 1.19 (t, J=6.9 Hz, 3 H). LCMS
(APCI) m/z: 262.1 [M+H] (100 %).
Hz, 1 H), 3.97 (dd, J=9.7, 1.4 Hz, 1 H), 3.95 (d, J=9.6 Hz, 1 H), 3.89 (d,
J=4.3 Hz, 1 H), 3.79 (d, J=7.8 Hz, 1 H), 3.73 (dd, J=9.8, 4.3 Hz, 1 H), 3.66
(d, J=8.1 Hz, 1 H), 3.59 (d, J=9.3 Hz, 1 H), 3.49 (dt, J=9.3, 6.5 Hz, 1 H),
3.46 (dt, J=9.3, 6.5 Hz, 1 H), 2.01 (s, 3 H), 1.60 (qt, J=7.4, 6.5 Hz, 2 H),
0.94 (t, J=7.4 Hz, 3 H). LCMS (APCI) m/z: 276.2 [M+H] (100 %).
Hz, 1 H), 3.97 (dd, J=9.6, 1.3 Hz, 1 H), 3.94 (d, J=9.6 Hz, 1 H), 3.88 (d,
J=4.3 Hz, 1 H), 3.79 (d, J=7.8 Hz, 1 H), 3.73 (dd, J=9.8, 4.3 Hz, 1 H), 3.66
(d, J=7.8 Hz, 1 H), 3.59 (d, J=9.3 Hz, 1 H), 3.54 (dt, J=9.3, 6.5 Hz, 1 H),
3.50 (dt, J=9.3, 6.5 Hz, 1 H), 2.00 (s, 3 H), 1.52 - 1.61 (m, 2 H), 1.34 - 1.45
(m, 2 H), 0.95 (t, J=7.3 Hz, 3 H). LCMS (APCI) m/z: 290.2 [M+H] (100 %).
Hz, 1 H), 3.97 (dd, J=9.8, 1.3 Hz, 1 H), 3.94 (d, J=9.6 Hz, 1 H), 3.88 (d,
J=4.3 Hz, 1 H), 3.79 (d, J=8.1 Hz, 1 H), 3.73 (dd, J=9.8, 4.3 Hz, 1 H), 3.66
(d, J=8.1 Hz, 1 H), 3.59 (d, J=9.6 Hz, 1 H), 3.53 (dt, J=9.3, 6.5 Hz, 1 H),
3.49 (dt, J=9.3, 6.5 Hz, 1 H), 2.01 (s, 3 H), 1.53 - 1.63 (m, 2 H), 1.29 - 1.41
(m, 4 H), 0.89 - 0.97 (m, 3 H). LCMS (APCI) m/z: 304.1 [M+H] (100 %).
Hz, 1 H), 3.96 (dd, J=10.1, 1.3 Hz, 1 H), 3.94 (d, J=9.6 Hz, 1 H), 3.88 (d,
J=4.3 Hz, 1 H), 3.79 (d, J=7.8 Hz, 1 H), 3.73 (dd, J=9.8, 4.3 Hz, 1 H), 3.66
(d, J=8.1 Hz, 1 H), 3.59 (d, J=9.6 Hz, 1 H), 3.53 (dt, J=9.3, 6.5 Hz, 1 H),
3.49 (dt, J=9.3, 6.5 Hz, 1 H), 2.00 (s, 3 H), 1.53 - 1.62 (m, 2 H), 1.27 - 1.50
(m, 6 H), 0.89 - 0.97 (m, 3 H). LCMS (APCI) m/z: 318.1 [M+H] (100 %).
Hz, 1 H), 3.96 (d, J=9.6 Hz, 1 H), 3.95 (dd, J=9.9, 1.3 Hz, 1 H), 3.89 (d,
J=4.3 Hz, 1 H), 3.78 (d, J=8.1 Hz, 1 H), 3.59 - 3.74 (m, 17 H), 3.53 - 3.56 (m,
2 H), 3.36 (s, 3 H), 1.99 (s, 3 H). LCMS (APCI) m/z: 424.2 [M+H] (13 %),
441.3 [M+NH4] (100 %).
H), 7.41 - 7.46 (m, 2 H), 5.87 (d, J=8.8 Hz, 1 H), 5.80 (d, J=4.3 Hz, 1 H),
5.60 (d, J=1.1 Hz, 1 H), 5.44 (dd, J=10.2, 4.5 Hz, 1 H), 4.54 - 4.64 (m, 3 H),
4.15 (d, J=8.6 Hz, 1 H), 3.93 (d, J=8.6 Hz, 1 H), 1.95 (s, 3 H). 13C
NMR (101 MHz, CDCl3) δ ppm 170.6, 165.6, 165.0, 164.9, 132.1, 131.9, 131.8, 131.4, 131.2,
131.2, 129.3, 129.0, 128.9, 127.7, 127.5, 127.4, 101.8, 81.6, 69.5, 68.8, 68.4,
62.5, 52.7, 23.2.メタノールおよびヘプタンを溶媒として使用する蒸気拡散技術により、単結晶を得た。単結晶X線解析:データ収集は室温にてBruker APEX回折計で行った。データ収集は、それぞれ0.5ステップで低角度での3回および高角度での3回のオメガスキャンからなるものであった。加えて、2回のファイスキャンを収集して、吸収補正の質を改善した。構造は非欠面双晶であり、第2のドメインを無視することにより精密化した。空間群P2(1)においてSHELXソフトウェアスイート(SHELXTL、バージョン5.1、Bruker AXS、1997を参照)を使用する直接法により、構造を解明した。その後、構造を完全行列最小二乗法(full−matrix least squares method)により精密化した。異方性変位パラメーターを使用して、すべての非水素原子を見出し、精密化した。窒素上にある水素原子はこの位置に置き、合理的な位置に拘束した。残りの水素原子は算出された位置に置き、その担体原子に乗せた。最終精密化は、すべての水素原子についての等方性変位パラメーターを包含するものであった。尤度法(R.W.W.Hooftら、J.Appl.Cryst.、41、96〜103(2008))を使用する絶対構造の解析を、PLATON(A.L.Spek、J.Appl.Cryst.、36、7〜13(2003))を使用して行った。結果は、絶対構造が正確に割り当てられたことを示す。方法は、構造が正確である確率が100.0であると算出する。Hooftパラメーターは、0.013のesdで0.036として報告される。加えて、Flackパラメーターは、0.04のesdで0.03である。最終R指数は5.6%であった。最終差フーリエは、欠落したまたは間違って配置された電子密度がないことを明らかにした。関連する結晶、データ収集および精密化を、表1および図1に要約する。
15H), 5.31 (s, 1H), 4.81 (d, J=5.1 Hz, 1H), 4.78 (d, J=5.5 Hz, 1H), 4.68-4.74
(m, 1H), 4.47-4.51 (m, 1H), 4.46 (d, J=6.6 Hz, 1H), 4.35-4.42 (m, 1H), 4.12 (d,
J=3.9 Hz, 1H), 3.87-3.91 (m, 2H), 3.86 (d, J=8.2 Hz, 1H), 3.62 (d, J=8.2 Hz,
1H), 3.58 (d, J=9.4 Hz, 1H), 3.46 (d, J=8.6 Hz, 1H)
Hz, 1H), 4.90 (d, 11.5 Hz, 1H), 4.79 (d, J=11.5 Hz, 1H), 4.57 (d, J=11.7 Hz,
1H), 4.56 (d, J=12.1 Hz, 1H), 4.43 (d, J=12.1Hz, 1H), 4.39 (d, J=11.7 Hz, 1H),
3.97 (d, J=3.9 Hz, 1H), 3.90 (d, J=9.0 Hz, 1H), 3.69 (d, J=8.2 Hz, 1H), 3.59
(d, J=8.2 Hz, 1H), 3.42 (d, J=8.6 Hz, 1H), 3.37 (dd, J=9.4, 3.5 Hz, 1H), 3.07
(dd, J=9.4, 1.2 Hz, 1H); 13C NMR (クロロホルム-d) δ: 131.8, 131.6, 131.5, 128.2, 128.2,
128.1, 128.1, 128.0, 127.7, 127.6, 127.6, 127.4, 103.5, 82.6, 80.3, 74.5, 73.3,
73.1, 72.2, 69.9, 69.3, 55.1; LCMS (ES+): 1.18分, 484.2 (M+Na)+.
Hz, 1H), 5.06 (d, J=8.6 Hz, 1H), 4.96 (d, J=11.3 Hz, 1H), 4.74 (d, J=12.5 Hz,
1H), 4.58 (d, J=11.3 Hz, 1H), 4.42 (d, J=12.5 Hz, 1H), 4.40 (s, 2H), 4.30-4.36
(m, 1H), 4.04 (d, J=3.9 Hz, 1H), 3.96 (d, J=8.6 Hz, 1H), 3.67-3.70 (m, 1H),
3.58-3.61 (m, 1H), 3.41-3.47 (m, 2H), 1.87 (s, 3H); 13C NMR (クロロホルム-d) δ: 170.0, 138.2,
137.8, 137.4, 128.7, 128.5, 128.4, 128.3, 128.3, 128.2, 128.1, 128.0, 127.8,
101.6, 82.8, 75.7, 75.0, 73.8, 73.2, 71.5, 70.1, 69.5, 53.5, 23.3; LCMS (ES+):
1.87分,
526.3 (M+Na)+.
Hz, 1H), 5.35 (d, J=1.2 Hz, 1H), 4.95 (d, J=11.3 Hz, 1H), 4.72 (d, J=12.5 Hz,
1H), 4.58 (d, J=11.3 Hz, 1H), 4.41 (s, 2H), 4.40 (d, J=12.5 Hz, 1H), 4.36 (t,
J=9.8 Hz, 1H), 4.08 (d, J=3.9 Hz, 1H), 3.96 (d, J=9.0 Hz, 1H), 3.68-3.72 (m,
1H), 3.60-3.63 (m, 1H), 3.50 (dd, J=10.0, 3.7 Hz, 1H), 3.45 (d, J=8.6 Hz, 1H); 13C
NMR (クロロホルム-d) δ: 137.9, 137.1, 136.1, 128.9, 128.5, 128.5, 128.4, 128.4, 128.1,
128.1, 128.1, 127.9, 100.6, 83.0, 75.0, 74.9, 73.8, 72.7, 71.4, 70.3, 69.2,
54.1; 19F NMR (クロロホルム-d) δ: -75.7 (s); LCMS (ES-): 2.11分, 556.2 (M-H)-.
Hz, 1H), 4.93 (d, J=11.3 Hz, 1H), 4.79 (d, J=11.7 Hz, 1H), 4.62 (br.s., 1H),
4.56 (d, J=11.7 Hz, 1H), 4.54 (d, J=11.3 Hz, 1H), 4.41 (d, J=12.1 Hz, 1H), 4.37
(d, J=12.1 Hz, 1H), 4.05 (d, J=3.9 Hz, 1H), 3.92 (d, J=8.6 Hz, 1H), 3.74 (d,
J=8.6 Hz, 1H), 3.68-3.72 (m, 1H), 3.62 (d, J=8.6 Hz, 1H), 3.54 (dd, J=10.0, 3.7
Hz, 1H), 3.44 (d, J=9.0 Hz, 1H), 2.90 (s, 3H); 13C NMR (クロロホルム-d) δ: 138.0, 137.3,
137.2, 128.7(2), 128.5(2), 128.4(2), 128.3, 128.1(2), 128.1, 127.9(2),
127.8(2), 102.7, 82.9, 77.2, 77.1, 75.0, 73.7, 73.5, 72.8, 70.2, 69.3, 57.7,
41.2;; LCMS (ES-): 1.97分, 538.3 (M-H)-.
5.09 (d, J=8.2 Hz, 1H), 4.95 (d, J=11.3 Hz, 1H), 4.72 (d, J=12.1 Hz, 1H), 4.57
(d, J=11.3 Hz, 1H), 4.43 (d, J=12.1 Hz, 1H), 4.39 (s, 2H), 4.31-4.38 (m, 1H),
4.04 (d, J=3.9 Hz, 1H), 3.95 (d, J=9.0 Hz, 1H), 3.68 (d, J=8.2 Hz, 1H), 3.59
(d, J=8.2 Hz, 1H), 3.44-3.49 (m, 1H), 3.44 (d, J=8.6 Hz, 1H), 2.08 (q, J=7.4
Hz, 2H), 1.11 (t, J=7.6 Hz, 3H) ; 13C NMR (クロロホルム-d) δ: 173.5, 138.1,
137.8, 137.4, 128.6, 128.5, 128.3, 128.3, 128.2, 128.1, 128.0, 128.0, 127.7,
101.6, 82.7, 75.7, 74.9, 73.7, 73.2, 71.5, 70.1, 69.4, 53.3, 29.6, 9.5; LCMS
(ES-): 1.94分, 516.4 (M-H)-; LCMS (AP+): 1.94分, 518.5 (M+H)+.
Hz, 1H), 5.35 (d, J=1.6 Hz, 1H), 4.95 (d, J=11.3 Hz, 1H), 4.71 (d, J=12.1 Hz,
1H), 4.56 (d, J=11.3 Hz, 1H), 4.45 (d, J=12.1 Hz, 1H), 4.40 (s, 2H), 4.35-4.40
(m, 1H), 4.05 (d, J=3.5 Hz, 1H), 3.95 (d, J=8.6 Hz, 1H), 3.71 (d, J=8.2 Hz,
1H), 3.61 (d, J=8.2 Hz, 1H), 3.50 (dd, J=10.0, 3.7 Hz, 1H), 3.45 (d, J=8.6 Hz,
1H), 2.92 (q, J=10.5 Hz, 2H); 13C NMR (クロロホルム-d) δ: 162.3, 138.0, 137.6,
137.3, 128.7, 128.5, 128.4, 128.3, 128.3, 128.2, 128.0, 128.0, 127.8, 101.1,
82.8, 75.8, 75.0, 73.7, 73.2, 71.9, 70.2, 69.3, 54.0, 41.7; 19F NMR
(クロロホルム-d)
δ: -62.8
(s); LCMS (ES-): 2.05分, 570.3 (M-H)-.
Hz, 1H), 5.83 (t, J=54.2 Hz, 1H), 5.35 (s, 1H), 4.96 (d, J=11.3 Hz, 1H), 4.73
(d, J=12.5 Hz, 1H), 4.58 (d, J=11.3 Hz, 1H), 4.45 (d, J=12.1 Hz, 1H), 4.41 (s,
2H), 4.34-4.40 (m, 1H), 4.08 (d, J=3.9 Hz, 1H), 3.96 (d, J=9.0 Hz, 1H),
3.67-3.75 (m, 1H), 3.59-3.65 (m, 1H), 3.53 (dd, J=9.8, 3.9 Hz, 1H), 3.46 (d,
J=8.6 Hz, 1H);13C NMR (クロロホルム-d) δ: 162.6, 138.0, 137.3, 128.8, 128.5, 128.4, 128.3, 128.1, 128.0,
127.8, 108.3 (t, J=253.1 Hz), 100.9, 82.9, 75.3, 75.0, 73.8, 72.9, 71.6, 70.2,
69.3, 53.5; 19F NMR (クロロホルム-d) δ: -126.1 (d, J=53.1 Hz); LCMS (ES-): 2.05分, 538.2 (M-H)-.
4.97 (d, J=11.3 Hz, 1H), 4.74 (d, J=12.1 Hz, 1H), 4.57 (d, J=11.3 Hz, 2H), 4.47
(d, J=7.0 Hz, 1H), 4.39 (s, 2H), 4.09 (br. s., 1H), 4.01 (d, J=3.9 Hz, 1H),
3.93 (d, J=9.0 Hz, 1H), 3.63-3.71 (m, 1H), 3.54-3.62 (m, 1H), 3.38-3.48 (m,
2H), 1.47 (s, 9H); 13C NMR (クロロホルム-d) δ: 155.2, 138.2, 137.8, 137.4, 128.5, 128.4, 128.3, 128.3, 128.0,
127.9, 127.8, 127.7, 102.2, 82.8, 79.4, 74.8, 73.7, 73.4, 72.0, 70.0, 69.4,
54.6, 31.9, 28.4; LCMS (AP+): 2.25分, 462.2 (M-Boc+H)+.
1H), 3.95 (dd, J=10.1, 1.2 Hz, 1H), 3.92 (d, J=11.3 Hz, 1H), 3.87 (d, J=3.9 Hz,
1H), 3.81 (d, J=11.3 Hz, 1H), 3.75 (d, J=8.2 Hz, 1H), 3.71-3.76 (m, 2H), 3.68
(d, J=8.2 Hz, 1H),, 3.35 (s, 1H), 2.26 (q, J=7.4 Hz, 2H), 1.13 (t, J=7.4 Hz,
3H); 13C NMR (メタノール-d4) δ: 177.7, 102.6, 84.9, 70.4, 69.1, 69.0, 61.9, 56.0, 30.0, 10.3; LCMS
(AP+): 0.25分, 248.2 (M+H)+.
1H), 4.02 (d, J=8.6 Hz, 1H), 3.90 (d, J=7.0 Hz, 1H), 3.88-3.95 (m, 2H), 3.82
(d, J=11.7 Hz, 1H), 3.78 (d, J=7.8 Hz, 1H), 3.71 (d, J=7.8 Hz, 1H), 3.35 (s,
1H); 13C NMR (メタノール-d4) δ: 159.8, 102.3, 85.5, 70.8, 69.7, 68.4, 62.2, 57.4; 19F NMR
(クロロホルム-d)
δ: -77.0
(s); LCMS (AP+): 0.42分, 288.2 (M+H)+.
1H), 3.91 (d, J=11.3 Hz, 1H), 3.87 (d, J=4.3 Hz, 1H), 3.80 (d, J=11.3 Hz, 1H),
3.73 (d, J=7.8 Hz, 1H), 3.68 (d, J=7.8 Hz, 1H), 3.66-3.71 (m, 1H), 3.37
(dd, J=9.8, 1.6 Hz, 1H), 3.35(s, 1H), 3.04 (s, 3H); 13C NMR (メタノール-d4) δ: 104.6, 85.1, 70.9,
69.8, 69.3, 62.0, 60.2, 41.7; LCMS (ES-): 0.15分, 268.0 (M-H)-.
Hz, 1H), 5.25 (s, 1H), 4.02 (d, J=9.4 Hz, 1H), 3.92 (d, J=11.7 Hz, 1H),
3.84-3.90 (m, 2H), 3.81 (d, J=11.7 Hz, 1H), 3.78 (d, J=8.2 Hz, 1H), 3.70 (d,
J=8.2 Hz, 1H)
(d, J=9.8 Hz, 1H), 3.92 (d, J=11.3 Hz, 1H), 3.87 (d, J=4.3 Hz, 1H), 3.81 (d,
J=11.3 Hz, 1H), 3.76 (d, J=8.2 Hz, 1H), 3.71-3.74 (m, 1H), 3.69 (d, J=8.2 Hz,
1H), 3.22 (qd, J=10.7, 2.5 Hz, 2H)
(s, 1H), 4.93 (d, J=10.9 Hz, 1H), 4.65 (d, J=11.7 Hz, 1H), 4.54 (d, J=11.3 Hz,
1H), 4.50 (d, J=11.7 Hz, 1H), 4.37-4.45 (m, 2H), 4.15 (d, J=9.8 Hz, 1H), 4.09
(d, J=3.5 Hz, 1H), 3.93 (d, J=8.6 Hz, 1H), 3.85 (dd, J=10.1, 3.5 Hz, 1H), 3.78
(d, J=8.2 Hz, 1H), 3.64 (d, J=8.2 Hz, 1H), 3.45 (d, J=8.6 Hz, 1H), 2.80 (s,
3H), 2.19 (s, 3H)回転異性体2:1H NMR (クロロホルム-d) d: 7.21-7.43 (m, 15H), 5.27
(s, 1H), 5.12 (d, J=10.9 Hz, 1H), 4.94-4.98 (m, 1H), 4.74 (d, J=12.1 Hz, 1H),
4.56 (d, J=11.7 Hz, 1H), 4.46 (d, J=11.3 Hz, 1H), 4.37-4.46 (m, 2H), 4.14-4.17
(m, 1H), 3.97 (d, J=8.6 Hz, 1H), 3.82-3.89 (m, 2H), 3.79 (d, J=8.2 Hz, 1H),
3.60-3.63 (m, 1H), 2.71 (s, 3H), 2.08 (s, 3H); 13C NMR (クロロホルム-d) d: 172.2,
138.0, 137.3, 137.2, 128.6, 128.5, 128.5, 128.4, 128.1, 128.0, 127.9, 127.9,
127.9, 127.8, 103.2, 83.2, 75.2, 74.1, 73.8, 73.7, 73.0, 72.4, 70.1, 69.2,
61.2, 28.0, 22.2; LCMS (AP+): 1.99分, 518.0 (M+H)+.
Hz, 1H), 4.93 (d, J=11.7 Hz, 1H), 4.80 (d, J=11.3 Hz, 1H), 4.58 (d, J=11.3 Hz,
1H), 4.45 (d, J=11.7 Hz, 1H), 4.43 (d, J=11.7 Hz, 1H), 4.41 (d, J=11.7 Hz, 1H),
4.21 (d, J=3.5 Hz, 1H), 4.18 (d, J=10.5 Hz, 1H), 3.98 (d, J=8.6 Hz, 1H), 3.87
(dd, J=10.5, 3.9 Hz, 1H), 3.82 (d, J=8.6 Hz, 1H), 3.62 (d, J=8.2 Hz, 1H), 3.45
(d, J=9.0 Hz, 1H), 2.83 (s, 3H), 2.68 (s, 3H); 13C NMR (クロロホルム-d) δ: 138.1, 137.3,
136.8, 128.7, 128.5, 128.4, 128.4, 128.1, 128.1, 128.0, 127.8, 104.6, 82.9,
74.9, 73.8, 73.5, 73.3, 71.6, 70.3, 69.4, 59.7, 37.5, 29.5; LCMS (AP+): 2.08分, 575.8 (M+Na)+.
回転異性体1:1H NMR (メタノール-d4) δ: 7.08-7.48 (m,
15H), 5.26 (s, 1H), 4.83-4.90 (m, 1H), 4.73 (d, J=11.7 Hz, 1H), 4.47-4.58 (m,
3H), 4.36-4.47 (m, 2H), 4.21 (d, J=3.5 Hz, 1H), 3.98 (dd, J=10.7, 3.3 Hz, 1H),
3.92 (d, J=8.2 Hz, 2H), 3.61 (d, J=7.8 Hz, 1H), 3.47 (dd, J=8.6, 3.9 Hz, 1H),
2.75 (s, 3H), 1.42 (s, 9H)
回転異性体2:1H NMR (メタノール-d4) δ: 7.08-7.48 (m,
15H), 5.21 (s, 1H), 4.83-4.90 (m, 1H), 4.73 (d, J=11.7 Hz, 1H), 4.47-4.58 (m,
3H), 4.36-4.47 (m, 2H), 4.21 (d, J=3.5 Hz, 1H), 3.98 (dd, J=10.7, 3.3 Hz, 1H),
3.92 (d, J=8.2 Hz, 2H), 3.61 (d, J=7.8 Hz, 1H), 3.47 (dd, J=8.6, 3.9 Hz, 1H),
2.70 (s, 3H), 1.44-1.52 (m, 9H)
回転異性体1:1H NMR (メタノール-d4) δ: 5.20 (s, 1H), 4.65
(d, J=10.5 Hz, 1H), 4.02-4.09 (m, 1H), 3.89-3.98 (m, 2H), 3.84 (s, 1H),
3.78-3.82 (m, 1H), 3.68 (s, 1H), 3.11 (s, 3H), 2.15 (s, 3H)
回転異性体2:1H NMR (メタノール-d4) δ: 5.37 (s, 1H),
4.02-4.09 (m, 1H), 3.89-3.98 (m, 3H), 3.84-3.87 (m, 1H), 3.79-3.83 (m, 1H),
3.71 (d, J=8.2 Hz, 1H), 2.98 (s, 3H), 2.15 (s, 3H)
13C NMR
(メタノール-d4)
δ:
175.4, 104.6, 85.8, 71.3, 69.7, 66.2, 62.3, 59.1, 28.8, 22.7; LCMS (ES-): 0.41分, 246.2 (M-H)-.
1H), 4.00-4.05 (m, 1H), 3.92-3.96 (m, 1H), 3.89-3.91 (m, 1H), 3.84 (d, J=1.2
Hz, 1H), 3.77-3.83 (m, 2H), 3.68 (d, J=7.8 Hz, 1H), 3.35 (s, 3H), 2.93 (s, 3H);
13C NMR (メタノール-d4) δ: 106.1, 85.5, 71.5, 69.7, 65.9, 62.6, 62.2, 37.8, 30.4; LCMS (ES-):
0.42分,
282.0 (M-H)-.
回転異性体1:1H NMR (メタノール-d4) δ: 5.22 (br. s., 1H),
4.19 (d, J=10.6 Hz, 1H), 4.00 (d, J=10.6 Hz, 1H), 3.90-3.95 (m, 2H), 3.77-3.82
(m, 2H), 3.67 (d, J=7.6 Hz, 1H), 2.94 (s, 3H), 1.47 (s, 9H)
回転異性体2:1H NMR (メタノール-d4) δ: 5.21 (br. s., 1H),
4.05-4.10 (m, 1H), 4.00 (d, J=10.6 Hz, 1H), 3.90-3.95 (m, 2H), 3.77-3.82 (m,
2H), 3.67 (d, J=7.6 Hz, 1H), 2.94 (s, 3H), 1.47 (s, 9H)
3.90-3.97 (m, 3H), 3.84 (s, 2H), 3.78 (d, J=8.2 Hz, 1H), 3.10-3.20 (m, 1H),
2.84 (s, 3H)
5.22 (d, J=1.6 Hz, 1H), 4.55 (s, 2H), 4.30 (d, J=5.9 Hz, 1H), 4.15 (t, J=6.4
Hz, 1H), 3.89-3.97 (m, 2H), 3.85 (d, J=7.8 Hz, 1H), 3.73-3.79 (m, 2H),
3.58-3.71 (m, 16H), 1.98 (s, 3H), 1.48 (s, 3H), 1.33 (s, 3H)
5.21 (s, 1H), 4.55 (s, 2H), 3.92-4.01 (m, 2H), 3.88 (d, J=4.3 Hz, 1H), 3.77 (d,
J=7.8 Hz, 1H), 3.70 (dd, J=9.8, 3.9 Hz, 1H), 3.58-3.68 (m, 18H), 1.98 (s, 3H)
1H), 4.31 (d, J=5.9 Hz, 1H), 4.16 (t, J=6.6 Hz, 1H), 3.93-3.97 (m, 1H),
3.90-3.93 (m, J=2.0 Hz, 1H), 3.86 (d, J=7.8 Hz, 1H), 3.78 (d, J=3.9 Hz, 1H),
3.75 (d, J=1.6 Hz, 1H), 3.61-3.71 (m, 14H), 3.37 (t, J=4.9 Hz, 2H), 1.98 (s,
3H), 1.49 (s, 3H), 1.34 (s, 3H)
1H), 3.98 (d, J=9.8 Hz, 1H), 3.94 (d, J=9.8 Hz, 1H), 3.89 (d, J=4.3 Hz, 1H),
3.78 (d, J=7.8 Hz, 1H), 3.72 (dd, J=10.1, 4.3 Hz, 1H), 3.61-3.69 (m, 16H), 3.38
(t, J=4.9 Hz, 2H), 1.99 (s, 3H)
10.9, 5.7 Hz, 1H), 5.28 (dd, J=17.4, 1.4 Hz, 1H), 5.23 (d, J=1.6 Hz, 1H), 5.16
(dd, J=10.3, 1.0 Hz, 1H), 4.31 (d, J=5.9 Hz, 1H), 4.15 (t, J=6.4 Hz, 1H), 4.02
(d, J=5.5 Hz, 2H), 3.89-3.97 (m, 2H), 3.86 (d, J=7.8 Hz, 1H), 3.73-3.80 (m,
2H), 3.56-3.72 (m, 12H), 1.98 (s, 3H), 1.49 (s, 3H), 1.34 (s, 3H).
5.28 (dd, J=17.2, 1.6 Hz, 1H), 5.21 (d, J=0.8 Hz, 1H), 5.16 (dd, J=10.5, 1.2
Hz, 1H), 4.02 (d, J=5.5 Hz, 2H), 3.98 (d, J=9.8 Hz, 1H), 3.95 (d, J=10.1 Hz,
1H), 3.89 (d, J=3.9 Hz, 1H), 3.78 (d, J=8.2 Hz, 1H), 3.71 (dd, J=10.0, 4.5 Hz,
1H), 3.57-3.68 (m, 14H), 1.99 (s, 3H).
1H), 4.31 (d, J=5.9 Hz, 1H), 4.19 (d, J=2.3 Hz, 2H), 4.16 (t, J=6.4 Hz, 1H),
3.90-3.97 (m, 2H), 3.86 (d, J=7.8 Hz, 1H), 3.74-3.79 (m, 2H), 3.60-3.72 (m,
12H), 2.85 (t, J=2.3 Hz, 1H), 1.98 (s, 3H), 1.49 (s, 3H), 1.34 (s, 3H)
(d, J=1.8 Hz, 2H), 3.98 (d, J=10.0 Hz, 1H), 3.94 (d, J=10.0 Hz, 1H), 3.89 (d,
J=4.1 Hz, 1H), 3.78 (d, J=8.2 Hz, 1H), 3.71 (dd, J=10.0, 4.1 Hz, 1H), 3.60-3.69
(m, 14H), 2.86 (s, 1H), 1.99 (s, 3H)
3.92-4.00 (m, 2H), 3.89 (d, J=3.9 Hz, 1H), 3.78 (d, J=8.2 Hz, 1H), 3.69-3.74
(m, 1H), 3.61-3.69 (m, 14H), 3.56 (t, J=5.1 Hz, 2H), 2.85 (t, J=5.1 Hz, 2H),
1.99 (s, 3H)
(d, J=9.4 Hz, 1H), 3.95 (d, J=10.1 Hz, 1H), 3.89 (d, J=4.3 Hz, 1H), 3.78 (d,
J=8.2 Hz, 1H), 3.71 (dd, J=9.8, 4.3 Hz, 1H), 3.61-3.69 (m, 16H), 3.54-3.59 (m,
2H), 1.99 (s, 3H). 13C NMR (メタノール-d4) δ: 174.1, 102.6,
84.3, 73.8, 72.5, 71.7, 71.7(2), 71.6, 71.5, 71.4, 70.5, 70.2, 69.0, 62.4,
56.4, 22.7
1H), 4.31 (d, J=5.9 Hz, 1H), 4.16 (t, J=6.4 Hz, 1H), 3.89-3.97 (m, 2H), 3.86
(d, J=7.8 Hz, 1H), 3.74-3.80 (m, 2H), 3.60-3.71 (m, 14H), 3.53-3.59 (m, 2H),
1.98 (s, 3H), 1.49 (s, 3H), 1.34 (s, 3H)
5.34 (d, J=1.6 Hz, 1H), 4.23 (d, J=5.9 Hz, 1H), 4.17 (s, 2H), 4.09-4.15 (m,
1H), 4.01 (t, J=6.2 Hz, 1H), 3.97 (d, J=10.1 Hz, 1H), 3.77-3.85 (m, 3H),
3.68-3.76 (m, 5H), 3.61-3.68 (m, 7H), 2.03 (s, 3H), 1.56 (s, 3H), 1.36 (s, 3H).
(s, 2H), 3.97 (d, J=10.1 Hz, 2H), 3.90 (d, J=3.9 Hz, 1H), 3.81 (d, J=7.8 Hz,
1H), 3.63-3.77 (m, 15H), 2.01 (s, 3H)
1H), 4.34-4.40 (m, 2H), 4.31 (d, J=5.9 Hz, 1H), 4.15 (t, J=6.4 Hz, 1H),
3.89-3.97 (m, 2H), 3.86 (d, J=7.8 Hz, 1H), 3.72-3.81 (m, 4H), 3.59-3.71 (m,
12H), 3.11 (s, 3H), 1.98 (s, 3H), 1.48 (s, 3H), 1.34 (s, 3H)
1H), 4.31 (d, J=5.9 Hz, 1H), 4.16 (t, J=6.4 Hz, 1H), 3.90-3.97 (m, 2H), 3.86
(d, J=7.8 Hz, 1H), 3.74-3.79 (m, 2H), 3.55-3.72 (m, 14H), 3.08 (t, J=6.6 Hz,
2H), 2.32 (s, 3H), 1.98 (s, 3H), 1.49 (s, 3H), 1.34 (s, 3H)
(d, J=9.8 Hz, 1H), 3.97 (d, J=9.8 Hz, 1H), 3.91 (d, J=4.3 Hz, 1H), 3.80 (d,
J=7.8 Hz, 1H), 3.73 (dd, J=10.1, 4.3 Hz, 1H), 3.63-3.70 (m, 14H), 3.60 (t,
J=6.6 Hz, 2H), 3.10 (t, J=6.4 Hz, 2H), 2.34 (s, 3H), 2.01 (s, 3H)
1H), 7.94 (d, J=8.2 Hz, 1H), 7.83 (td, J=7.8, 1.6 Hz, 1H), 7.22 (dd, J=6.8, 5.3
Hz, 1H), 5.21 (s, 1H), 3.92-4.00 (m, 2H), 3.88 (d, J=4.3 Hz, 1H), 3.77 (d,
J=7.8 Hz, 1H), 3.71 (t, J=6.0 Hz, 3H), 3.59-3.67 (m, 12H), 3.52-3.58 (m, 2H),
3.02 (t, J=6.0 Hz, 2H), 1.99 (s, 3H)
(s, 6H), 2.97 (s, 3H).
NMR (メタノール-d4) δ: 7.10-7.46 (m, 5H), 5.06 (s, 2H), 4.14 (d, J=2.0 Hz, 6H), 3.79 (s,
6H), 3.03-3.20 (m, 2H), 2.83 (t, J=2.1 Hz, 3H), 2.18 (t, J=7.2 Hz, 2H), 1.59 (五重線, J=7.3 Hz, 2H),
1.44-1.54 (m, 2H), 1.28-1.40 (m, 2H)
1H), 7.85-7.90 (m, 1H), 7.77-7.84 (m, 1H), 7.21 (dd, J=6.6, 5.5 Hz, 1H),
2.77-2.90 (m, 6H), 2.61 (t, J=7.2 Hz, 2H), 1.63-1.83 (m, 4H), 1.46-1.59 (m, 2H)
1H), 7.85-7.90 (m, 1H), 7.78-7.84 (m, 1H), 7.19-7.25 (m, 1H), 4.06-4.23 (m,
6H), 3.72-3.84 (m, 6H), 2.78-2.87 (m, 5H), 2.12-2.20 (m, 2H), 1.71 (五重線, J=7.3 Hz, 2H),
1.57 (五重線, J=7.3 Hz, 2H), 1.36-1.50 (m, 2H)
4.51 (s, 2H), 3.56 (t, J=6.0 Hz, 2H), 2.81 (s, 4H), 2.73 (t, J=7.2 Hz, 2H),
1.99 (五重線, J=6.6 Hz, 2H)
4.51 (s, 2H), 4.12 (d, J=2.3 Hz, 6H), 3.78 (s, 6H), 3.51 (t, J=6.2 Hz, 2H),
2.82 (t, J=2.3 Hz, 3H), 2.28 (t, J=7.2 Hz, 2H), 1.79-1.94 (m, 2H)
(d, J=1.6 Hz, 3H), 4.51-4.63 (m, 12H), 4.29 (d, J=5.9 Hz, 3H), 4.16 (t, J=6.4
Hz, 3H), 3.87-3.96 (m, 12H), 3.84 (d, J=7.8 Hz, 3H), 3.73-3.80 (m, 6H),
3.64-3.72 (m, 12H), 3.54-3.63 (m, 30H), 1.98 (s, 9H), 1.48 (s, 9H), 1.40 (s,
9H), 1.33 (s, 9H)
NMR (メタノール-d4) δ: 8.38 (d, J=4.7 Hz, 1H), 7.97 (s, 3H), 7.82-7.88 (m, 1H), 7.78-7.81
(m, 1H), 7.20 (t, J=5.9 Hz, 1H), 5.23 (s, 3H), 4.52-4.62 (m, 12H), 4.29 (d,
J=5.9 Hz, 3H), 4.15 (t, J=6.4 Hz, 3H), 3.86-3.96 (m, 12H), 3.81-3.85 (m, 3H),
3.72-3.80 (m, 12H), 3.54-3.71 (m, 36H), 2.79 (t, J=7.2 Hz, 2H), 2.16 (t, J=7.2
Hz, 2H), 1.98 (s, 9H), 1.64-1.73 (m, 2H), 1.50-1.57 (m, 2H), 1.48 (s, 9H), 1.42
(d, J=6.6 Hz, 2H), 1.32 (s, 9H)
7.21-7.47 (m, 5H), 5.25 (d, J=1.6 Hz, 3H), 5.07 (s, 2H), 4.53-4.62 (m, 12H),
4.31 (d, J=5.9 Hz, 3H), 4.18 (t, J=6.4 Hz, 3H), 3.88-3.98 (m, 12H), 3.85 (d,
J=7.8 Hz, 3H), 3.74-3.81 (m, 12H), 3.53-3.71 (m, 36H), 3.10 (q, J=6.2 Hz, 2H),
2.18 (t, J=7.2 Hz, 2H), 2.00 (s, 9H), 1.53-1.65 (m, 2H), 1.50 (s, 11H), 1.34
(s, 11H)
残留物をジメチルスルホキシド(1mL)に溶解し、逆相HPLCにより精製した。カラム:Waters Sunfire C18 19×100、5u;移動相A:水中0.05%TFA(v/v);移動相B:アセトニトリル中0.05%TFA(v/v);勾配:8.5分間で80.0%H2O/20.0%アセトニトリルから直線的に65%H2O/35%アセトニトリルにし、9.0分までに0%H2O/100%MeCNにし、9.0から10.0分まで0%H2O/100%アセトニトリルに保持した。流速:25mL/分。47.6mgの表題化合物をガム状物として得た(保持時間2.87、観察された質量=890.4376)。
カラム:Waters Atlantis dC18 4.6×50、5u;移動相A:水中0.05%TFA(v/v);移動相B:アセトニトリル中0.05%TFA(v/v);3.75分間で95.0%H2O/5.0%アセトニトリルから直線的に50%H2O/50%アセトニトリルにし、4.0分までに5%H2O/95%アセトニトリルにし、4.0分から5.0分まで5%H2O/95%アセトニトリルに保持した。流速:2mL/分。保持時間=2.87;観察された質量=890.4376。方法C: 3 分間実行 LRMS [1/2M = 889]。1H NMR (メタノール-d4) δ: 8.41 (d, J=4.7 Hz,
1H), 7.99 (s, 3H), 7.84-7.91 (m, 2H), 7.26 (t, J=5.9 Hz, 1H), 5.21 (s, 3H),
4.58 (t, J=5.0 Hz, 6H), 4.56 (s, 6H), 3.95 (t, J=8.8 Hz, 6H), 3.89 (t, J=5.0
Hz, 6H), 3.86-3.88 (m, 3H), 3.74-3.78 (m, 9H), 3.71 (dd, J=9.4, 4.1 Hz, 3H),
3.54-3.67 (m, 42H), 2.80 (t, J=7.0 Hz, 2H), 2.16 (t, J=7.3 Hz, 2H), 1.99 (s,
9H), 1.68 (五重線, J=7.3 Hz, 2H), 1.50-1.57 (m, 2H), 1.35-1.44 (m, 2H)
5.22 (s, 3H), 4.71 (s, 9H), 4.65 (d, J=4.7 Hz, 6H), 3.92-4.00 (m, 12H), 3.90
(d, J=4.3 Hz, 3H), 3.58-3.80 (m, 51H), 2.02 (s, 9H)
精製条件
残留物をジメチルスルホキシド(1mL)に溶解し、逆相HPLCにより精製した。(カラム:Waters Sunfire C18 19×100、5u;移動相A:水中0.05%TFA(v/v);移動相B:アセトニトリル中0.05%TFA(v/v);10.5分間で90.0%H2O/10.0%アセトニトリルから直線的に70%H2O/30%アセトニトリルにし、0.5分間で70%H2O/30%アセトニトリルから直線的に0%H2O/100%MeCNにし、11.0分から12.0分まで0%H2O/100%アセトニトリルに保持した。流速:25mL/分。
QC条件
カラム:Waters Atlantis dC18 4.6×50、5u;移動相A:水中0.05%TFA(v/v);移動相B:アセトニトリル中0.05%TFA(v/v);4.0分間で95.0%H2O/5.0%アセトニトリルから直線的に5%H2O/95%アセトニトリルにし、4.0分から5.0分まで5%H2O/95%アセトニトリルに保持した。流速:2mL/分;保持時間=1.77分;観察された質量=839.7097。方法C: 3 分間実行 LRMS [M+1 = 1678]。1H NMR (メタノール-d4) δ: 8.00 (s, 3H), 5.21
(s, 3H), 4.58 (t, J=4.7 Hz, 6H), 4.57 (s, 6H), 3.95 (t, J=10.0 Hz, 6H),
3.85-3.92 (m, 9H), 3.74-3.80 (m, 9H), 3.71 (dd, J=10.0, 4.1 Hz, 3H), 3.55-3.68
(m, 42H), 3.25 (t, J=6.5 Hz, 2H), 2.19 (t, J=7.3 Hz, 2H), 1.99 (s, 9H),
1.52-1.62 (m, 4H), 1.33-1.41 (m, 2H)
精製条件:
残留物をジメチルスルホキシド(1mL)に溶解し、逆相HPLCにより精製した。(カラム:Waters Sunfire C18 19×100、5u;移動相A:水中0.05%TFA(v/v);移動相B:アセトニトリル中0.05%TFA(v/v);10.5分間で95.0%H2O/5.0%アセトニトリルから直線的に55%H2O/45%アセトニトリルにし、0.5分間で55%H2O/45%アセトニトリルから直線的に0%H2O/100%MeCNにし、11.0分から12.0分まで0%H2O/100%アセトニトリルに保持した。流速:25mL/分。
QC条件:
カラム:Waters Atlantis dC18 4.6×50、5u;移動相A:水中0.05%TFA(v/v);移動相B:アセトニトリル中0.05%TFA(v/v);4.0分間で95.0%H2O/5.0%アセトニトリルから直線的に5%H2O/95%アセトニトリルにし、4.0分から5.0分まで5%H2O/95%アセトニトリルに保持した。流速:2mL/分;保持時間=1.81;観察された質量=825.2381)。方法C: 3 分間実行 LRMS [M-1 = 1647]。1H NMR (メタノール-d4) δ: 7.99 (s, 3H), 5.69-5.88
(m, 1H), 5.21 (s, 3H), 4.95 (m, 2H), 4.51-4.63 (m, 12H), 3.95 (t, J=9.7 Hz,
6H), 3.85-3.91 (m, 9H), 3.74-3.81 (m, 9H), 3.71 (dd, J=9.4, 4.1 Hz, 3H),
3.54-3.68 (m, 42H), 2.17 (t, J=7.3 Hz, 2H), 2.01-2.09 (m, 2H), 1.99 (s, 9H),
1.52-1.61 (m, 2H), 1.39 (五重線, J=7.5 Hz, 2H)
精製条件:
残留物をジメチルスルホキシド(1mL)に溶解し、逆相HPLCにより精製した。(カラム:Waters Sunfire C18 19×100、5u;移動相A:水中0.05%TFA(v/v);移動相B:アセトニトリル中0.05%TFA(v/v);10.5分間で95.0%H2O/5.0%アセトニトリルから直線的に55%H2O/45%アセトニトリルにし、0.5分間で55%H2O/45%アセトニトリルから直線的に0%H2O/100%MeCNにし、11.0分から12.0分まで0%H2O/100%アセトニトリルに保持した。流速:25mL/分。
QC条件:
カラム:Waters Atlantis dC18 4.6×50、5u;移動相A:水中0.05%TFA(v/v);移動相B:アセトニトリル中0.05%TFA(v/v);4.0分間で95.0%H2O/5.0%アセトニトリルから直線的に5%H2O/95%アセトニトリルにし、4.0分から5.0分まで5%H2O/95%アセトニトリルに保持した。流速:2mL/分;保持時間=1.68;観察された質量=824.2237。方法C: 3 分間実行 LRMS [1/2M= 823]。1H NMR (メタノール-d4) δ: 7.99 (s, 3H), 5.21
(s, 3H), 4.59 (t, J=5.0 Hz, 6H), 4.56 (s, 6H), 3.95 (t, J=10.0 Hz, 6H),
3.85-3.92 (m, 9H), 3.74-3.79 (m, 9H), 3.71 (dd, J=10.0, 4.1 Hz, 3H), 3.54-3.67
(m, 41H), 2.13-2.24 (m, 6H), 1.99 (s, 9H), 1.66 (五重線, J=7.5 Hz, 2H), 1.50 (五重線, J=7.3 Hz, 2H)
2H), 2.83 (s, 4H), 2.64 (t, J=7.2 Hz, 2H), 2.33 (t, J=7.2 Hz, 2H), 1.74 (五重線, J=7.4 Hz, 2H),
1.58-1.68 (m, 2H), 1.40-1.53 (m, 2H), 1.24 (t, J=7.0 Hz, 3H).
精製条件
残留物をジメチルスルホキシド(1mL)に溶解し、逆相HPLCにより精製した。(カラム:Waters Sunfire C18 19×100、5u;移動相A:水中0.05%TFA(v/v);移動相B:アセトニトリル中0.05%TFA(v/v);10.5分間で90.0%H2O/10.0%アセトニトリルから直線的に70%H2O/30%アセトニトリルにし、0.5分間で70%H2O/30%アセトニトリルから直線的に0%H2O/100%MeCNにし、11.0分から12.0分まで0%H2O/100%アセトニトリルに保持した。流速:25mL/分。
QC条件
カラム:Waters Atlantis dC18 4.6×50、5u;移動相A:水中0.05%TFA(v/v);移動相B:アセトニトリル中0.05%TFA(v/v);4.0分間で95.0%H2O/5.0%アセトニトリルから直線的に5%H2O/95%アセトニトリルにし、4.0分から5.0分まで5%H2O/95%アセトニトリルに保持した。流速:2mL/分;保持時間=1.58分;観察された質量=839.7097)。方法C: MassLynx\Acid_3.0Min.olp - LRMS [M+1 = 1681]。1H
NMR (メタノール-d4) δ: 7.99 (s, 3H), 5.21 (s, 3H), 4.58 (t, J=4.7 Hz, 6H), 4.56 (s, 6H),
3.95 (t, J=9.7 Hz, 6H), 3.89 (dt, J=9.8, 4.8 Hz, 9H), 3.74-3.79 (m, 9H), 3.71
(dd, J=10.0, 4.1 Hz, 3H), 3.53-3.67 (m, 42H), 2.25 (t, J=7.3 Hz, 2H), 2.17 (t,
J=7.3 Hz, 2H), 1.99 (s, 9H), 1.58 (二重の五重線, J=14.3, 7.3 Hz, 4H), 1.31-1.39 (m, 2H)
(m, 5H), 5.21 (s, 3H), 5.06 (s, 2H), 4.50-4.66 (m, 12H), 3.95 (dd, J=9.6, 5.7
Hz, 6H), 3.86-3.91 (m, 9H), 3.74-3.78 (m, 9H), 3.71 (dd, J=10.0, 4.1 Hz, 3H),
3.54-3.67 (m, 42H), 3.03-3.12 (m, 2H), 2.11-2.24 (m, 2H), 1.98 (s, 9H),
1.51-1.63 (m, 2H), 1.43-1.51 (m, 2H), 1.33 (d, J=6.6 Hz, 2H).
(s, 3H), 4.59 (t, J=4.9 Hz, 6H), 4.56 (s, 6H), 3.95 (d, J=9.8 Hz, 6H),
3.85-3.92 (m, 9H), 3.74-3.79 (m, 9H), 3.69-3.74 (m, 3H), 3.55-3.69 (m, 42H),
2.91 (t, J=7.6 Hz, 2H), 2.20 (t, J=7.2 Hz, 2H), 1.99 (s, 9H), 1.90 (s, 3H),
1.52-1.68 (m, 4H), 1.34-1.43 (m, 2H)
精製条件
残留物をジメチルスルホキシド(1mL)に溶解し、逆相HPLCにより精製した。カラム:Waters Sunfire C18 19×100、5u;移動相A:水中0.05%TFA(v/v);移動相B:アセトニトリル中0.05%TFA(v/v);勾配:10.5分間で80.0%H2O/20.0%アセトニトリルから直線的に75%H2O/25%アセトニトリルにし、11.0分までに0%H2O/100%MeCNにし、11.0から12.0分まで0%H2O/100%アセトニトリルに保持した。流速:25mL/分。
QC条件
カラム:Waters Atlantis dC18 4.6×50、5u;移動相A:水中0.05%TFA(v/v);移動相B:アセトニトリル中0.05%TFA(v/v);勾配:4.0分間で95.0%H2O/5.0%アセトニトリルから直線的に5%H2O/95%アセトニトリルにし、4.0分から5.0分まで5%H2O/95%アセトニトリルに保持した。流速:2mL/分;保持時間=1.69分;観察された質量=923.4907。方法C: 3 分間実行 LRMS [M-1 = 1843]。1H NMR (メタノール-d4) δ: 8.00 (s, 3H), 6.80
(s, 2H), 5.21 (s, 3H), 4.59 (t, J=5.0 Hz, 6H), 4.56 (s, 6H), 3.95 (t, J=9.7 Hz,
6H), 3.90 (t, J=5.0 Hz, 6H), 3.88 (d, J=4.1 Hz, 3H), 3.74-3.79 (m, 9H), 3.71
(dd, J=10.0, 4.1 Hz, 3H), 3.55-3.68 (m, 42H), 3.48 (t, J=7.0 Hz, 2H), 3.12 (t,
J=7.0 Hz, 2H), 2.11-2.23 (m, 4H), 1.99 (s, 9H), 1.53-1.66 (m, 6H), 1.48 (五重線, J=7.2 Hz, 2H),
1.24-1.36 (m, 4H)
精製条件
残留物をジメチルスルホキシド(1mL)に溶解し、逆相HPLCにより精製した。カラム:Waters Sunfire C18 19×100、5u;移動相A:水中0.05%TFA(v/v);移動相B:アセトニトリル中0.05%TFA(v/v);勾配:10.5分間で80.0%H2O/20.0%アセトニトリルから直線的に75%H2O/25%アセトニトリルにし、11.0分までに0%H2O/100%MeCNにし、11.0から12.0分まで0%H2O/100%アセトニトリルに保持した。流速:25mL/分。
QC条件
カラム:Waters Atlantis dC18 4.6×50、5u;移動相A:水中0.05%TFA(v/v);移動相B:アセトニトリル中0.05%TFA(v/v);勾配:4.0分間で95.0%H2O/5.0%アセトニトリルから直線的に5%H2O/95%アセトニトリルにし、4.0分から5.0分まで5%H2O/95%アセトニトリルに保持した。流速:2mL/分;保持時間=1.64分;観察された質量=944.1543。方法C: 3 分間実行 LRMS [M+1 = 1886]。1H NMR (メタノール-d4) δ: 7.99 (s, 3H), 5.21
(s, 3H), 4.57-4.62 (m, 6H), 4.56 (s, 6H), 3.92-3.98 (m, 6H), 3.83-3.91 (m,
10H), 3.80 (s, 2H), 3.69-3.79 (m, 12H), 3.54-3.68 (m, 43H), 3.13 (t, J=6.7 Hz,
2H), 2.18 (d, J=6.5 Hz, 4H), 1.98 (s, 9H), 1.59-1.67 (m, 2H), 1.51-1.59 (m,
4H), 1.48 (br. s., 2H), 1.27-1.41 (m, 4H)
7.55-7.53 (t, 2H), 7.41 (t, 2H), 7.34-7.30 (t, 2H), 7.24-7.22 (d, 2H), 5.96 (t,
1H), 5.39 (s, 2H), 5.11-5.08 (t, 1H), 4.44-4.42 (d, 3H), 4.32-4.23 (m, 3H),
3.96-3.92 (t, 1H), 3.01-3.00 (m, 3H), 2.15-2.13 (m, 1H), 1.66-1.24 (m, 12H),
m/z、C35H41N5O6
:628.4 (M+H)+, 保持時間: 4.213分
精製条件:
カラム:DIKMA Diamonsil(2) C18 200×20mm×5um;移動相:水中30%アセトニトリル(0.1%TFA)から水中50%アセトニトリル(0.1%TFA);波長=220nm;後処理:濃縮し、凍結乾燥した。
QC条件:
カラム:Ultimate XB−C18、3×50mm、3um;保持時間:4.33分;移動相:A、水(4Lの水中2.7mLのTFA)、B、アセトニトリル(4Lのアセトニトリル中2.5mLのTFA)、溶出勾配1%〜100%;波長:220nm;ee値:100%。カラム:Chiralcel OD−3 50×4.6mm I.D.、3um;保持時間:1.923分;移動相:CO2中エタノール(0.05%DEA)、5%から40%;流速:2.5mL/分;波長:254nm;ee値=100%。カラム:AD−3 50×4.6mm I.D.、3um;保持時間:1.981分;移動相:CO2中エタノール(0.05%DEA)、5%から40%;流速:2.5mL/分;波長:220nm
(m, 6H), 7.01 (s, 2H), 5.98 (br, 1H), 5.43 (s, 2H), 5.25 (s, 2H), 4.39 (m, 1H),
4.23-4.19 (m, 1H), 3.37 (m, 1H), 3.03-2.96 (m, 2H), 2.14-2.11 (m, 3H),
1.70-1.19 (m, 19H).LC-MS: m/z、C37H45N7O11 :764.3 (M+H)+; 保持時間: 0.823分.
精製条件:
残留物をジメチルスルホキシド(1mL)に溶解し、逆相HPLCにより精製した。カラム:Waters Sunfire C18 19×100、5u;移動相A:水中0.05%TFA(v/v);移動相B:アセトニトリル中0.05%TFA(v/v);勾配:10.5分間で75.0%H2O/25.0%アセトニトリルから直線的に65%H2O/35%アセトニトリルにし、11.0分までに0%H2O/100%MeCNにし、11.0から12.0分まで0%H2O/100%アセトニトリルに保持した。流速:25mL/分。
QC条件:
カラム:Waters Atlantis dC18 4.6×50、5u;移動相A:水中0.05%TFA(v/v);移動相B:アセトニトリル中0.05%TFA(v/v);4.0分間で95.0%H2O/5.0%アセトニトリルから直線的に5%H2O/95%アセトニトリルにし、4.0分から5.0分まで5%H2O/95%アセトニトリルに保持した。流速:2mL/分;保持時間=1.99分;保持時間=1.99分;観察された質量=1139.1254。方法C: 1.5 分間実行 LRMS [1/2M= 1138]。1H NMR (メタノール-d4) δ: 7.99 (s, 3H), 7.57
(d, J=8.2 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 6.79 (s, 2H), 5.21 (s, 3H), 5.01 (s,
2H), 4.55-4.64 (m, 12H), 4.51 (dd, J=9.0, 5.1 Hz, 1H), 4.43 (q, J=7.2 Hz, 1H),
4.16 (d, J=9.4 Hz, 1H), 3.95 (d, J=9.8 Hz, 6H), 3.85-3.91 (m, 9H), 3.74-3.79
(m, 9H), 3.71 (dd, J=9.8, 4.3 Hz, 3H), 3.54-3.67 (m, 41H), 3.47 (t, J=7.0 Hz,
2H), 3.16-3.26 (m, 1H), 3.10-3.16 (m, 1H), 3.07 (t, J=6.8 Hz, 2H), 2.24 (q,
J=7.7 Hz, 3H), 2.16 (t, J=7.4 Hz, 2H), 1.99 (s, 9H), 1.85-1.95 (m, 1H),
1.42-1.84 (m, 16H), 1.37 (t, J=7.0 Hz, 2H), 1.23-1.34 (m, 5H)
1H), 8.01 (s, 3H), 7.93 (d, J=3.5 Hz, 2H), 7.30-7.38 (m, 1H), 5.21 (s, 3H),
4.57-4.62 (m, 6H), 4.57 (s, 6H), 3.92-3.99 (m, 6H), 3.89 (dd, J=10.7, 4.9 Hz,
9H), 3.74-3.80 (m, 9H), 3.72 (dd, J=9.8, 4.7 Hz, 6H), 3.51-3.68 (m, 55H),
3.35-3.41 (m, 2H), 3.14 (t, J=7.0 Hz, 2H), 3.10 (t, J=6.8 Hz, 2H), 2.64 (t,
J=7.0 Hz, 2H), 2.43 (t, J=6.0 Hz, 2H), 2.17 (t, J=7.4 Hz, 2H), 1.99 (s, 9H),
1.52-1.61 (m, 2H), 1.43-1.51 (m, 2H), 1.27-1.38 (m, 2H)
精製条件
残留物をジメチルスルホキシド(1mL)に溶解し、逆相HPLCにより精製した。カラム:Waters Sunfire C18 19×100、5u;移動相A:水中0.05%TFA(v/v);移動相B:アセトニトリル中0.05%TFA(v/v);勾配:8.5分間で80.0%H2O/20.0%アセトニトリルから直線的に70%H2O/30%アセトニトリルにし、9.0分までに0%H2O/100%MeCNにし、9.0から10.0分まで0%H2O/100%アセトニトリルに保持した。流速:25mL/分。
QC条件
カラム:Waters Atlantis dC18 4.6×50、5u;移動相A:水中0.05%TFA(v/v);移動相B:アセトニトリル中0.05%TFA(v/v);勾配:4.0分間で95.0%H2O/5.0%アセトニトリルから直線的に5%H2O/95%アセトニトリルにし、4.0分から5.0分まで5%H2O/95%アセトニトリルに保持した。流速:2mL/分;保持時間=1.78分;観察された質量=699.6404
1H), 8.01 (s, 3H), 7.92 (d, J=3.5 Hz, 2H), 7.30-7.39 (m, 1H), 5.21 (s, 3H),
4.57-4.62 (m, 6H), 4.57 (s, 6H), 3.92-3.99 (m, 6H), 3.86-3.92 (m, 9H), 3.77 (s,
9H), 3.69-3.74 (m, 6H), 3.50-3.68 (m, 73H), 3.14 (t, J=7.0 Hz, 2H), 3.10 (t,
J=7.0 Hz, 2H), 2.64 (t, J=6.8 Hz, 2H), 2.43 (t, J=6.0 Hz, 2H), 2.17 (t, J=7.4
Hz, 2H), 1.99 (s, 9H), 1.53-1.63 (m, 2H), 1.42-1.52 (m, 2H), 1.32 (dt, J=15.1,
7.5 Hz, 2H)
精製条件
残留物をジメチルスルホキシド(1mL)に溶解し、逆相HPLCにより精製した。カラム:Waters Sunfire C18 19×100、5u;移動相A:水中0.05%TFA(v/v);移動相B:アセトニトリル中0.05%TFA(v/v);勾配:8.5分間で80.0%H2O/20.0%アセトニトリルから直線的に70%H2O/30%アセトニトリルにし、9.0分までに0%H2O/100%MeCNにし、9.0から10.0分まで0%H2O/100%アセトニトリルに保持した。流速:25mL/分。
QC条件
カラム:Waters Atlantis dC18 4.6×50、5u;移動相A:水中0.05%TFA(v/v);移動相B:アセトニトリル中0.05%TFA(v/v);勾配:4.0分間で95.0%H2O/5.0%アセトニトリルから直線的に5%H2O/95%アセトニトリルにし、4.0分から5.0分まで5%H2O/95%アセトニトリルに保持した。流速:2mL/分;保持時間=1.85分;観察された質量=758.405
(d, J=1.6 Hz, 3H), 4.45-4.62 (m, 12H), 4.29 (d, J=5.9 Hz, 3H), 4.16 (t, J=6.4
Hz, 3H), 3.87-3.98 (m, 12H), 3.73-3.85 (m, 15H), 3.54-3.70 (m, 36H), 2.87 (t,
J=7.6 Hz, 2H), 2.20 (t, J=7.2 Hz, 2H), 1.98 (s, 9H), 1.53-1.69 (m, 4H), 1.48
(s, 9H), 1.34-1.41 (m, 2H), 1.33 (s, 9H)
NMR (メタノール-d4) δ: 8.39 (d, J=4.7 Hz, 1H), 7.98 (s, 3H), 7.83-7.87 (m, 1H), 7.77-7.83
(m, 1H), 7.21 (t, J=5.9 Hz, 1H), 5.23 (d, J=1.6 Hz, 3H), 4.50-4.64 (m, 12H),
4.29 (d, J=5.9 Hz, 3H), 4.16 (t, J=6.4 Hz, 3H), 3.87-3.96 (m, 12H), 3.84 (d,
J=7.8 Hz, 3H), 3.71-3.79 (m, 15H), 3.54-3.70 (m, 31H), 3.18-3.28 (m, 2H), 3.13
(q, J=6.5 Hz, 2H), 2.82 (t, J=7.2 Hz, 2H), 2.12-2.23 (m, 4H), 1.98 (s, 9H),
1.71 (五重線, J=7.3 Hz, 2H), 1.51-1.64 (m, 6H), 1.44-1.51 (m, 11H), 1.28-1.34
(m, 11H)
精製条件:
残留物をジメチルスルホキシド(1mL)に溶解し、逆相HPLCにより精製した。カラム:Waters Sunfire C18 19×100、5u;移動相A:水中0.05%TFA(v/v);移動相B:アセトニトリル中0.05%TFA(v/v);勾配:10.5分間で80.0%H2O/20.0%アセトニトリルから直線的に70%H2O/30%アセトニトリルにし、11.0分までに0%H2O/100%MeCNにし、11.0から12.0分まで0%H2O/100%アセトニトリルに保持した。流速:25mL/分。
QC条件:
カラム:Waters Atlantis dC18 4.6×50、5u;移動相A:水中0.05%TFA(v/v);移動相B:アセトニトリル中0.05%TFA(v/v);4.0分間で95.0%H2O/5.0%アセトニトリルから直線的に5%H2O/95%アセトニトリルにし、4.0分から5.0分まで5%H2O/95%アセトニトリルに保持した。流速:2mL/分;保持時間=1.96分;観察された質量=946.5137。方法C: MassLynx\Acid_3.0Min.olp - LRMS [1/2M+1 = 946]。1H
NMR (メタノール-d4) δ: 8.45 (d, J=5.1 Hz, 1H), 8.01 (s, 3H), 7.94 (d, J=3.1 Hz, 2H),
7.29-7.36 (m, 1H), 5.21 (s, 3H), 4.57-4.62 (m, 6H), 4.57 (s, 6H), 3.92-4.00 (m,
6H), 3.89 (dd, J=10.7, 4.9 Hz, 9H), 3.74-3.80 (m, 9H), 3.71 (dd, J=10.1, 4.3
Hz, 3H), 3.53-3.68 (m, 42H), 3.13 (t, J=6.8 Hz, 2H), 2.85 (t, J=7.2 Hz, 2H),
2.17 (t, J=7.2 Hz, 4H), 1.99 (s, 9H), 1.71 (五重線, J=7.4 Hz, 2H), 1.52-1.64 (m, 4H),
1.45 (td, J=15.0, 7.8 Hz, 4H), 1.26-1.37 (m, 2H)
NMR (メタノール-d4) δ: 8.40 (d, J=4.3 Hz, 1H), 7.98 (s, 3H), 7.83-7.89 (m, 1H), 7.75-7.83
(m, 1H), 7.15-7.25 (m, 1H), 5.22 (d, J=1.2 Hz, 3H), 4.51-4.64 (m, 12H), 4.29
(d, J=5.9 Hz, 3H), 4.23 (t, J=6.2 Hz, 2H), 4.15 (t, J=6.4 Hz, 3H), 3.86-3.97
(m, 12H), 3.83 (d, J=7.8 Hz, 3H), 3.72-3.79 (m, 12H), 3.53-3.69 (m, 36H), 3.05
(t, J=5.7 Hz, 4H), 2.17 (t, J=7.0 Hz, 2H), 1.98 (s, 9H), 1.51-1.61 (m, 2H),
1.48 (s, 11H), 1.33 (s, 11H)
精製条件:
残留物をジメチルスルホキシド(1mL)に溶解し、逆相HPLCにより精製した。カラム:Waters Sunfire C18 19×100、5u;移動相A:水中0.05%TFA(v/v);移動相B:アセトニトリル中0.05%TFA(v/v);勾配:10.5分間で80.0%H2O/20.0%アセトニトリルから直線的に70%H2O/30%アセトニトリルにし、11.0分までに0%H2O/100%MeCNにし、11.0から12.0分まで0%H2O/100%アセトニトリルに保持した。流速:25mL/分。
QC条件:
カラム:Waters Atlantis dC18 4.6×50、5u;移動相A:水中0.05%TFA(v/v);移動相B:アセトニトリル中0.05%TFA(v/v);4.0分間で95.0%H2O/5.0%アセトニトリルから直線的に5%H2O/95%アセトニトリルにし、4.0分から5.0分まで5%H2O/95%アセトニトリルに保持した。流速:2mL/分;保持時間=1.91分;観察された質量=933.4313。方法C: MassLynx\Acid_3.0Min.olp - LRMS [1/2M+1 = 933]。1H
NMR (メタノール-d4) δ: 8.46 (d, J=4.7 Hz, 1H), 8.01 (s, 3H), 7.86-7.97 (m, 2H), 7.32 (t,
J=5.3 Hz, 1H), 5.21 (s, 3H), 4.55-4.62 (m, 12H), 4.24 (t, J=6.0 Hz, 2H),
3.92-3.99 (m, 6H), 3.85-3.92 (m, 9H), 3.74-3.79 (m, 9H), 3.71 (dd, J=9.8, 4.3
Hz, 3H), 3.52-3.68 (m, 42H), 2.99-3.15 (m, 4H), 2.17 (t, J=7.2 Hz, 2H), 1.99
(s, 9H), 1.56 (五重線, J=7.4 Hz, 2H), 1.42-1.50 (m, 2H), 1.24-1.38 (m, 2H)
(t, J=7.4 Hz, 2H), 1.71 (五重線, J=7.1 Hz, 2H), 1.38-1.50 (m, 4H), 1.24 (s, 12H), 0.75 (t, J=6.8
Hz, 2H).
(d, J=1.6 Hz, 3H), 4.52-4.62 (m, 12H), 4.29 (d, J=5.9 Hz, 3H), 4.16 (t, J=6.4
Hz, 3H), 3.87-3.97 (m, 12H), 3.84 (d, J=8.2 Hz, 3H), 3.72-3.79 (m, 12H),
3.54-3.69 (m, 36H), 3.13 (q, J=6.6 Hz, 2H), 2.16 (q, J=7.3 Hz, 4H), 1.98 (s,
9H), 1.52-1.66 (m, 4H), 1.44-1.51 (m, 11H), 1.35-1.43 (m, 2H), 1.27-1.35 (m,
13H), 1.18-1.25 (m, 12H), 0.73 (t, J=7.6 Hz, 2H)
精製条件
残留物をジメチルスルホキシド(1mL)に溶解し、逆相HPLCにより精製した。カラム:Waters Sunfire C18 19×100、5u;移動相A:水中0.05%TFA(v/v);移動相B:アセトニトリル中0.05%TFA(v/v);勾配:8.5分間で80.0%H2O/20.0%アセトニトリルから直線的に65%H2O/35%アセトニトリルにし、9.0分までに0%H2O/100%MeCNにし、9.0から10.0分まで0%H2O/100%アセトニトリルに保持した。流速:25mL/分。
QC条件
カラム:Waters Atlantis dC18 4.6×50、5u;移動相A:水中0.05%TFA(v/v);移動相B:アセトニトリル中0.05%TFA(v/v);勾配:4.0分間で95.0%H2O/5.0%アセトニトリルから直線的に5%H2O/95%アセトニトリルにし、4.0分から5.0分まで5%H2O/95%アセトニトリルに保持した。流速:2mL/分;保持時間=2分;観察された質量=938.9628)。1H NMR (メタノール-d4) δ: 8.01 (s, 3H), 5.21
(s, 3H), 4.51-4.66 (m, 12H), 3.95 (dd, J=9.4, 5.9 Hz, 6H), 3.89 (dd, J=11.7,
4.7 Hz, 9H), 3.74-3.81 (m, 9H), 3.71 (dd, J=9.8, 4.3 Hz, 3H), 3.52-3.68 (m,
42H), 3.13 (t, J=6.8 Hz, 2H), 2.17 (q, J=7.0 Hz, 4H), 1.99 (s, 9H), 1.53-1.66
(m, 4H), 1.45-1.52 (m, 2H), 1.36-1.44 (m, 2H), 1.27-1.35 (m, 4H), 1.23 (s,
12H), 0.73 (t, J=7.6 Hz, 2H)
2H), 3.83-3.99 (m, 1H), 3.60 (d, J=5.5 Hz, 4H), 2.31 (t, J=7.2 Hz, 2H), 2.23
(t, J=7.4 Hz, 2H), 1.63 (五重線, J=7.5 Hz, 4H), 1.30-1.45 (m, 2H), 1.24 (t, J=7.0 Hz, 3H)
精製条件:
残留物をジメチルスルホキシド(1mL)に溶解し、逆相HPLCにより精製した。カラム:Waters Sunfire C18 19×100、5u;移動相A:水中0.05%TFA(v/v);移動相B:アセトニトリル中0.05%TFA(v/v);勾配:8.5分間で85.0%H2O/15.0%アセトニトリルから直線的に75%H2O/25%アセトニトリルにし、9.0分までに0%H2O/100%MeCNにし、9.0から10.0分まで0%H2O/100%アセトニトリルに保持した。流速:25mL/分。
QC条件:
カラム:Waters Atlantis dC18 4.6×50、5u;移動相A:水中0.05%TFA(v/v);移動相B:アセトニトリル中0.05%TFA(v/v);4.0分間で95.0%H2O/5.0%アセトニトリルから直線的に5%H2O/95%アセトニトリルにし、4.0分から5.0分まで5%H2O/95%アセトニトリルに保持した。流速:2mL/分;保持時間=1.53分;観察された質量=934.548。方法C: 3 分間実行 LRMS [M+Na = 1889]。1H NMR (メタノール-d4) δ: 8.00 (s, 3H), 5.21
(s, 3H), 4.52-4.62 (m, 12H), 3.95 (t, J=9.4 Hz, 6H), 3.85-3.91 (m, 9H),
3.74-3.79 (m, 9H), 3.71 (dd, J=10.0, 4.1 Hz, 3H), 3.55-3.67 (m, 47H), 3.12 (t,
J=6.7 Hz, 2H), 2.22 (t, J=7.3 Hz, 2H), 2.17 (t, J=7.3 Hz, 4H), 1.98 (s, 9H),
1.58-1.69 (m, 4H), 1.51-1.57 (m, 2H), 1.48 (五重線, J=7.2 Hz, 2H), 1.26-1.40 (m, 4H)
(s, 3H), 4.50-4.65 (m, 12H), 4.29 (d, J=5.9 Hz, 3H), 4.16 (t, J=6.5 Hz, 3H),
3.87-3.95 (m, 12H), 3.83 (d, J=7.6 Hz, 3H), 3.73-3.79 (m, 12H), 3.55-3.71 (m,
36H), 3.26-3.30 (m, 2H), 3.14 (q, J=6.5 Hz, 2H), 2.18 (q, J=7.6 Hz, 4H), 1.98
(s, 9H), 1.53-1.68 (m, 6H), 1.45-1.51 (m, 11H), 1.36-1.43 (m, 2H), 1.29-1.36
(m, 11H)
(s, 3H), 4.51-4.66 (m, 12H), 3.92-4.01 (m, 6H), 3.89 (dd, J=10.1, 4.7 Hz, 9H),
3.74-3.81 (m, 9H), 3.71 (dd, J=10.0, 4.1 Hz, 3H), 3.52-3.68 (m, 42H), 3.25-3.30
(m, 2H), 3.08-3.19 (m, 2H), 2.13-2.23 (m, 4H), 1.99 (s, 9H), 1.54-1.69 (m, 6H),
1.49 (dt, J=14.4, 7.2 Hz, 2H), 1.36-1.44 (m, 2H), 1.32 (dd, J=14.8, 6.2 Hz, 2H)
4.51 (s, 2H), 3.53 (t, J=6.4 Hz, 2H), 2.85 (s, 4H), 2.65 (t, J=7.4 Hz, 2H),
1.76 (五重線, J=7.5 Hz, 2H), 1.61-1.71 (m, 2H), 1.47-1.59 (m, 2H)
7.19-7.38 (m, 5H), 5.23 (d, J=1.2 Hz, 3H), 4.52-4.64 (m, 12H), 4.48 (s, 2H),
4.29 (d, J=5.9 Hz, 3H), 4.15 (t, J=6.4 Hz, 3H), 3.86-3.96 (m, 12H), 3.83 (d,
J=7.8 Hz, 3H), 3.72-3.80 (m, 12H), 3.54-3.70 (m, 36H), 3.49 (t, J=6.4 Hz, 2H),
3.08-3.15 (m, 2H), 2.12-2.26 (m, 4H), 1.98 (s, 9H), 1.51-1.68 (m, 6H), 1.48 (s,
11H), 1.37-1.44 (m, 2H), 1.33 (s, 11H)
7.25-7.39 (m, 5H), 5.21 (s, 3H), 4.52-4.66 (m, 12H), 4.48 (s, 2H), 3.92-3.99
(m, 6H), 3.84-3.91 (m, 9H), 3.74-3.81 (m, 9H), 3.71 (dd, J=9.8, 4.3 Hz, 3H),
3.54-3.67 (m, 42H), 3.49 (t, J=6.4 Hz, 2H), 3.08-3.17 (m, 2H), 2.13-2.22 (m,
4H), 1.99 (s, 9H), 1.51-1.68 (m, 6H), 1.48 (t, J=7.4 Hz, 2H), 1.39 (dt, J=15.3,
7.8 Hz, 2H), 1.26-1.35 (m, 2H)
7.16-7.39 (m, 5H), 5.44 (d, J=4.3 Hz, 3H), 5.32 (s, 3H), 5.10 (dd, J=10.5, 4.3
Hz, 3H), 4.52-4.60 (m, 12H), 4.48 (s, 2H), 4.18 (d, J=10.5 Hz, 3H), 3.99 (d,
J=8.2 Hz, 3H), 3.89 (t, J=5.1 Hz, 6H), 3.70-3.81 (m, 12H), 3.52-3.67 (m, 39H),
3.49 (t, J=6.2 Hz, 2H), 3.13 (q, J=6.6 Hz, 2H), 2.13-2.21 (m, 13H), 1.94 (d,
J=1.6 Hz, 18H), 1.51-1.68 (m, 6H), 1.45-1.50 (m, 2H), 1.37-1.43 (m, 2H),
1.28-1.35 (m, 2H)
(d, J=4.3 Hz, 3H), 5.32 (s, 3H), 5.10 (dd, J=10.5, 4.3 Hz, 3H), 4.50-4.64 (m, 12H),
4.18 (d, J=10.5 Hz, 3H), 3.99 (d, J=8.2 Hz, 3H), 3.90 (t, J=4.9 Hz, 6H),
3.71-3.82 (m, 9H), 3.44-3.66 (m, 44H), 3.08-3.19 (m, 2H), 2.16-2.22 (m, 4H),
2.15 (s, 9H), 1.94 (d, J=1.2 Hz, 18H), 1.44-1.68 (m, 8H), 1.27-1.42 (m, 4H)
(s, 3H), 4.49-4.63 (m, 12H), 3.92-4.00 (m, 6H), 3.89 (dd, J=10.3, 4.5 Hz, 9H),
3.74-3.79 (m, 9H), 3.71 (dd, J=9.8, 4.3 Hz, 3H), 3.53-3.67 (m, 44H), 3.02-3.16
(m, 2H), 2.18 (td, J=7.3, 3.3 Hz, 4H), 1.99 (s, 9H), 1.44-1.72 (m, 8H), 1.25-1.42
(m, 4H)
7.22-7.40 (m, 5H), 5.22 (d, J=1.2 Hz, 3H), 5.06 (s, 2H), 4.51-4.61 (m, 12H),
4.29 (d, J=5.9 Hz, 3H), 4.16 (t, J=6.4 Hz, 3H), 3.86-3.96 (m, 12H), 3.83 (d,
J=7.8 Hz, 3H), 3.73-3.79 (m, 12H), 3.53-3.70 (m, 36H), 3.04-3.19 (m, 4H), 2.17
(t, J=7.4 Hz, 4H), 1.98 (s, 9H), 1.58 (td, J=14.5, 7.6 Hz, 4H), 1.48 (s, 13H),
1.33 (s, 13H)
7.22-7.41 (m, 5H), 5.21 (s, 3H), 5.05 (s, 2H), 4.57 (t, J=5.0 Hz, 6H), 4.55 (s,
6H), 3.92-4.00 (m, 6H), 3.83-3.91 (m, 9H), 3.73-3.78 (m, 9H), 3.68-3.72 (m,
J=10.0, 4.1 Hz, 3H), 3.52-3.68 (m, 42H), 3.05-3.17 (m, 4H), 2.16 (t, J=7.3 Hz,
4H), 1.98 (s, 9H), 1.57-1.65 (m, 2H), 1.53-1.57 (m, 2H), 1.43-1.52 (m, 4H), 1.24-1.39
(m, 4H)
(s, 3H), 4.59-4.63 (m, 6H), 4.58 (s, 6H), 3.97 (dd, J=9.6, 5.3 Hz, 6H), 3.91
(dd, J=11.3, 4.7 Hz, 9H), 3.76-3.82 (m, 9H), 3.73 (dd, J=10.1, 4.3 Hz, 3H),
3.56-3.70 (m, 42H), 3.16 (t, J=6.8 Hz, 2H), 2.93 (t, J=7.6 Hz, 2H), 2.16-2.29
(m, 4H), 2.01 (s, 9H), 1.92 (s, 3H), 1.62-1.74 (m, 4H), 1.54-1.61 (m, 2H),
1.46-1.53 (m, 2H), 1.39-1.45 (m, 2H), 1.29-1.38 (m, 2H)
1H), 4.34-4.43 (m, 2H), 3.88-3.98 (m, 3H), 3.81-3.87 (m, 1H), 3.37 (dd, J=6.2,
1.6 Hz, 1H), 1.54 (s, 3H), 1.42 (s, 3H)
5.35 (d, J=1.6 Hz, 1H), 4.55 (s, 2H), 4.32-4.37 (m, 1H), 4.25-4.32 (m, 1H),
3.92 (d, J=10.1 Hz, 1H), 3.88 (d, J=8.2 Hz, 1H), 3.73-3.80 (m, 2H), 3.55-3.71
(m, 17H), 1.49 (s, 3H), 1.36 (s, 3H)
(d, J=5.9 Hz, 1H), 4.11 (t, J=6.4 Hz, 1H), 3.93 (d, J=10.1 Hz, 1H), 3.80-3.85
(m, 1H), 3.76 (d, J=6.2 Hz, 1H), 3.74 (d, J=3.9 Hz, 1H), 3.60-3.71 (m, 15H),
3.53-3.59 (m, 2H), 1.50 (s, 3H), 1.45 (s, 9H), 1.34 (s, 3H)
4.33-4.43 (m, 2H), 4.28 (d, J=5.9 Hz, 1H), 4.11 (t, J=6.4 Hz, 1H), 3.93 (d,
J=10.1 Hz, 1H), 3.80-3.86 (m, 1H), 3.72-3.79 (m, 4H), 3.61-3.70 (m, 12H), 3.58
(d, J=5.9 Hz, 1H), 3.11 (s, 3H), 1.50 (s, 3H), 1.45 (s, 9H), 1.34 (s, 3H)
(d, J=5.9 Hz, 1H), 4.13 (t, J=6.4 Hz, 1H), 3.95 (d, J=9.8 Hz, 1H), 3.82-3.88
(m, 1H), 3.75-3.80 (m, 2H), 3.53-3.74 (m, 15H), 3.39 (t, J=4.9 Hz, 2H), 1.52
(s, 3H), 1.47 (s, 9H), 1.36 (s, 3H)
7.17-7.43 (m, 5H), 5.21 (s, 3H), 4.52-4.60 (m, 12H), 4.45 (s, 2H), 4.25 (d,
J=5.9 Hz, 3H), 4.10 (t, J=6.2 Hz, 3H), 3.85-3.93 (m, 9H), 3.71-3.82 (m, 15H),
3.63-3.69 (m, 6H), 3.53-3.62 (m, 33H), 3.48 (t, J=6.2 Hz, 2H), 2.27 (t, J=7.2
Hz, 2H), 1.74-1.96 (m, 2H), 1.49 (s, 9H), 1.45 (s, 27H), 1.32 (s, 9H)
7.27-7.39 (m, 5H), 5.48 (s, 3H), 4.57-4.66 (m, 12H), 4.47 (s, 2H), 3.98 (d,
J=9.8 Hz, 3H), 3.90-3.95 (m, 9H), 3.82-3.89 (m, 6H), 3.79 (s, 6H), 3.76 (d,
J=8.2 Hz, 3H), 3.71 (d, J=9.8 Hz, 3H), 3.57-3.69 (m, 36H), 3.50 (t, J=6.2 Hz,
2H), 3.21 (d, J=9.4 Hz, 3H), 2.29 (t, J=7.2 Hz, 2H), 1.85 (五重線, J=6.8 Hz, 2H)
7.19-7.42 (m, 5H), 5.44 (d, J=4.3 Hz, 3H), 5.31 (s, 3H), 5.10 (dd, J=10.3, 4.1
Hz, 3H), 4.51-4.64 (m, 12H), 4.45 (s, 2H), 4.18 (d, J=10.1 Hz, 3H), 3.99 (d,
J=8.6 Hz, 3H), 3.88 (t, J=4.9 Hz, 6H), 3.68-3.82 (m, 12H), 3.52-3.64 (m, 39H),
3.48 (t, J=6.2 Hz, 2H), 2.26 (t, J=7.4 Hz, 2H), 2.15 (s, 9H), 1.94 (d, J=1.2
Hz, 18H), 1.84 (t, J=6.8 Hz, 2H).
(d, J=4.3 Hz, 3H), 5.32 (s, 3H), 5.10 (dd, J=10.5, 3.9 Hz, 3H), 4.41-4.66 (m,
12H), 4.18 (d, J=10.5 Hz, 3H), 3.99 (d, J=8.6 Hz, 3H), 3.90 (t, J=5.1 Hz, 6H),
3.68-3.83 (m, 12H), 3.51-3.67 (m, 41H), 2.24 (t, J=7.6 Hz, 2H), 2.15 (s, 9H),
1.94 (s, 18H), 1.69-1.83 (m, 2H)
(s, 3H), 4.53-4.65 (m, 12H), 3.92-4.00 (m, 6H), 3.89 (dd, J=11.1, 4.9 Hz, 9H),
3.74-3.79 (m, 9H), 3.71 (dd, J=9.8, 4.3 Hz, 3H), 3.52-3.69 (m, 44H), 2.24 (t,
J=7.4 Hz, 2H), 1.99 (s, 9H), 1.76 (五重線, J=6.9 Hz, 2H)
1H), 7.84-7.89 (m, 1H), 7.77-7.83 (m, 1H), 7.21 (t, J=5.7 Hz, 1H), 3.92 (五重線, J=5.5 Hz, 1H),
3.51-3.70 (m, 4H), 2.82 (t, J=7.2 Hz, 2H), 2.21 (t, J=7.4 Hz, 2H), 1.71 (五重線, J=7.3 Hz, 2H),
1.60 (五重線, J=7.5 Hz, 2H), 1.37-1.51 (m, 2H)
異性体1:1H NMR (メタノール-d4) δ: 8.41 (d, J=4.7 Hz,
1H), 7.86-7.92 (m, 1H), 7.80-7.86 (m, 1H), 7.20-7.27 (m, 1H), 5.31 (s, 1H),
4.29 (d, J=2.7 Hz, 1H), 3.92-3.96 (m, 1H), 3.83 (br. s., 1H), 3.63 (d, J=5.1
Hz, 1H), 3.59 (dd, J=11.5, 3.7 Hz, 1H), 3.42 (s, 3H), 2.85 (t, J=7.2 Hz, 2H),
2.21-2.30 (m, 2H), 1.68-1.80 (m, 2H), 1.56-1.67 (m, 2H), 1.39-1.53 (m, 2H)
異性体2:1H NMR (メタノール-d4) δ: 8.41 (d, J=4.7 Hz,
1H), 7.86-7.92 (m, 1H), 7.80-7.86 (m, 1H), 7.20-7.27 (m, 1H), 5.27 (s, 1H),
4.26 (d, J=2.7 Hz, 1H), 3.92-3.96 (m, 2H), 3.86-3.91 (m, 1H), 3.59 (dd, J=11.5,
3.7 Hz, 1H), 3.38 (s, 3H), 2.85 (t, J=7.2 Hz, 2H), 2.21-2.30 (m, 2H), 1.68-1.80
(m, 2H), 1.56-1.67 (m, 2H), 1.39-1.53 (m, 2H)
本発明の化合物を使用してアシアロ糖タンパク質受容体(ASGPR)を標的化することによりモジュレートされる疾患を治療するための本発明の実施については、以下に記載する機能検定の1つまたは複数における活性によって証明することができる。供給元は括弧内に示す。
ビオチン化ASGPRの調製:
ASGPr H1野生型を、大腸菌(E.coli)において不溶性封入体(IB)として発現させた。細胞ペレットを、0.1mg/mLのリゾチーム+25マイクログラム/mLのDNase+10μg/mLのRNase+10mMのMgCl2を含有するTBS緩衝液pH8.0に再懸濁し、十分に混和されるまで氷上で撹拌した。混合物を2回マイクロフルイダイザーに通し、30,000×gで30分間遠心分離した。得られたIBペレットをTBS緩衝液pH8.0+3Mの尿素で洗浄し、遠心分離し、水を用いてこの過程をさらに3回繰り返した。IBペレットを10mMのTris+8Mの尿素+100mMのβ−メルカプトエタノール(pH8.5)に可溶化し、およそ20分間撹拌し、次いで遠心分離して沈殿を捨てた。以下の操作について、「緩衝液T」とは、20mMのTris+0.5MのNaCl+25mMのCaCl2を指す。上清を緩衝液T+2mMのβ−メルカプトエタノール+8Mの尿素(pH8.0)に希釈しておよそ0.5mg/mLとし、次いで、8〜10倍過剰体積の緩衝液T+2mMのβ−メルカプトエタノール+2Mの尿素(pH8.0)に対して4℃で終夜透析した。透析は、緩衝液T+1mMのβ−メルカプトエタノール+1Mの尿素(pH8.0)において4℃でおよそ24時間、何度か体積を変えながら繰り返し、最終の透析は、緩衝液T+5mMのGSH+1mMのGSSG(pH7.5)に対して、体積を3度変えながら行った。得られるサンプルを遠心分離し、上清を、N−アセチル−D−ガラクトサミンアガロースがローディングされたPharmacia XK26カラムに装入し、緩衝液T+2mMのTCEP(pH8.0)で平衡化した。ベースラインが再び確立するまで、カラムをこの緩衝液で洗浄した。結合したタンパク質を20mMのTris+0.5MのNaCl+2mMのTCEP+2mMのEDTA(pH8.0)で溶離させた。最終収量は、5L(70wgm)の大腸菌(E.coli)細胞ペレットからおよそ50mgであった。
化合物を用いたSPR測定はすべて、25℃でBiacore 3000(GE Healthcare)を使用して行った。SAセンサーチップ(GE Healthcare)、またはNeutravidin(Pierce Biochemical)が標準のアミンカップリングによってCM5センサーチップ(GE Healthcare)に固定されている、あつらえのセンサーチップのいずれかを使用して、ビオチン化ASGPRを、通常は2000〜3000共鳴単位(Ru)で固定化した。流動緩衝液は、HBS(10mMのHEPES、150mMのNaCl)、20mMのCaCl2、0.01%のp20、3%のDMSO、または50mMのトリス、150mMのNaCl、50mMのCaCl2、0.01%のp20、3%のDMSO pH7.5とした。化合物を900uMの濃度で流動緩衝液に希釈し、3.7uMまで3倍に段階希釈した。化合物溶液を、各濃度について二通りに、50ul/分で1分間注入した後、1分間解離させた。多量体コンジュゲート(二量体、三量体)については、コンジュゲートを流動緩衝液に希釈して100nMまたは10nMの濃度とし、段階希釈した。コンジュゲートを2分間注入し、解離速度(off rate)を300または600秒間検出した。解離相データが完成した後、900uMのGalNAの注入を使用して化合物を外し、受容体表面を空いた状態に戻した。データはすべて、Scrubber2(Biologic Software,Inc.)を使用してゼロに加工し、アラインし、参照しやすくし、除外された体積の影響について補正した。化合物およびコンジュゲートされた単一分子についての定常状態結合応答をScrubber2で適合させることにより、KDを求めた。動的な応答を示す多量体コンジュゲートについてのKDは、Scrubber2で加工し、BiaEval(GE Healthcare)で適合させて、結合(on)および解離(off)速度パラメーターを抽出して、KDを算出した。値は、いくつもの実験からの標準偏差を反映する。
Claims (1)
- 式(A)の化合物
R1は、−Z−X−Yであり、
Xは、構造L1〜L10のいずれかのリンカーであり、
各Qは、独立に、存在しないか、またはC(O)、C(O)−NR4、NR4−C(O)、O−C(O)−NR4、NR4−C(O)−O、−CH2−、ヘテロアリール、もしくはO、S、S−S、S(O)、S(O)2、およびNR4から選択されるヘテロ原子基であり、少なくとも2個の炭素原子が、ヘテロ原子基O、S、S−S、S(O)、S(O)2、およびNR4を、他のいずれかのヘテロ原子基と隔てており、
各Tは、独立に、存在しないか、またはアルキレン、アルケニレン、もしくはアルキニレンであり、アルキレン、アルケニレン、またはアルキニレンの1つまたは複数の−CH2−基は、−O−、−S−、および−N(R4)−から独立に選択されるヘテロ原子基でそれぞれ独立に置き換えられていてもよく、ヘテロ原子基は、少なくとも2個の炭素原子で隔てられており、
Yは、Cas9リボ核タンパク質、Cas9タンパク質、またはプラスミドであり、
Zは、存在しないか、または−C≡C−、−CH=CH−、−CH2−、−CH2−O−、−C(O)−N(R4)−、−CH2−S−、−CH2−S(O)−、−CH2−S(O)2−、−CH2−S(O)2−N(R4)−、−C(O)−O−、−CH2−N(R4)−、−CH2−N(R4)−C(O)−、−CH2−N(R4)−S(O)2−、−CH2−N(R4)−C(O)−O−、−CH2−N(R4)−C(O)−N(R4)−、−CH2−O−C(O)−、−CH2−O−C(O)−N(R4)−、−CH2−O−C(O)−O−、またはアリールもしくはヘテロアリールであり、アリールまたはヘテロアリールは、R5で置換されていてもよく、
各nは、独立に、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、または40であり、nが1より大きい場合、各(T−Q−T−Q)の各Tおよび各Qは、独立に選択され、
R2は、−OH、−N3、−N(R3)2、−N(R3)−C(O)−R3、−N(R3)−C(O)−N(R3)2、−N(R3)−C(O)−OR3、テトラゾール、またはトリアゾールであり、テトラゾールおよびトリアゾールは、R3で置換されていてもよく、
各R3は、独立に、−H、−(C1〜C5)アルキル、ハロ置換(C1〜C5)アルキル、または(C3〜C6)シクロアルキルであり、アルキルまたはシクロアルキルの−CH2−基は、−O−、−S−、および−N(R4)−から独立に選択されるヘテロ原子基でそれぞれ置き換えられていてもよく、アルキルの−CH3は、−N(R4)2、−OR4、および−S(R4)から選択されるヘテロ原子基で置き換えられていてもよく、ヘテロ原子基は、少なくとも2個の炭素原子で隔てられており、
各R4は、独立に、−H、−(C1〜C20)アルキル、または(C3〜C6)シクロアルキルであり、少なくとも2個の炭素原子で隔てられた、アルキルまたはシクロアルキルの1〜6つの−CH2−基は、−O−、−S−、または−N(R4)−で置き換えられていてもよく、アルキルの−CH3は、−N(R4)2、−OR4、および−S(R4)から選択されるヘテロ原子基で置き換えられていてもよく、ヘテロ原子基は、少なくとも2個の炭素原子で隔てられており、アルキルおよびシクロアルキルは、ハロ原子で置換されていてもよく、
各R5は、独立に、−H、(C3〜C20)シクロアルキル、または(C1〜C60)アルキルであり、少なくとも2個の炭素原子で隔てられた、アルキルまたはシクロアルキルの1〜6つの−CH2−基は、−O−、−S−、または−N(R4)−で置き換えられていてもよく、アルキルの−CH3は、−N(R4)2、−OR4、および−S(R4)から選択されるヘテロ原子基で置き換えられていてもよく、ヘテロ原子基は、少なくとも2個の炭素原子で隔てられており、アルキルおよびシクロアルキルは、1〜6つのハロ原子で置換されていてもよい]
または薬学的に許容できるその塩。
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Families Citing this family (33)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9987224B2 (en) | 2011-02-04 | 2018-06-05 | Joseph E. Kovarik | Method and system for preventing migraine headaches, cluster headaches and dizziness |
US10086018B2 (en) | 2011-02-04 | 2018-10-02 | Joseph E. Kovarik | Method and system for reducing the likelihood of colorectal cancer in a human being |
US10512661B2 (en) | 2011-02-04 | 2019-12-24 | Joseph E. Kovarik | Method and system for reducing the likelihood of developing liver cancer in an individual diagnosed with non-alcoholic fatty liver disease |
US11844720B2 (en) | 2011-02-04 | 2023-12-19 | Seed Health, Inc. | Method and system to reduce the likelihood of dental caries and halitosis |
US11419903B2 (en) | 2015-11-30 | 2022-08-23 | Seed Health, Inc. | Method and system for reducing the likelihood of osteoporosis |
US10842834B2 (en) | 2016-01-06 | 2020-11-24 | Joseph E. Kovarik | Method and system for reducing the likelihood of developing liver cancer in an individual diagnosed with non-alcoholic fatty liver disease |
US11951140B2 (en) | 2011-02-04 | 2024-04-09 | Seed Health, Inc. | Modulation of an individual's gut microbiome to address osteoporosis and bone disease |
US10687975B2 (en) | 2011-02-04 | 2020-06-23 | Joseph E. Kovarik | Method and system to facilitate the growth of desired bacteria in a human's mouth |
US11523934B2 (en) | 2011-02-04 | 2022-12-13 | Seed Health, Inc. | Method and system to facilitate the growth of desired bacteria in a human's mouth |
US11951139B2 (en) | 2015-11-30 | 2024-04-09 | Seed Health, Inc. | Method and system for reducing the likelihood of osteoporosis |
US11273187B2 (en) | 2015-11-30 | 2022-03-15 | Joseph E. Kovarik | Method and system for reducing the likelihood of developing depression in an individual |
US11998479B2 (en) | 2011-02-04 | 2024-06-04 | Seed Health, Inc. | Method and system for addressing adverse effects on the oral microbiome and restoring gingival health caused by sodium lauryl sulphate exposure |
US10548761B2 (en) | 2011-02-04 | 2020-02-04 | Joseph E. Kovarik | Method and system for reducing the likelihood of colorectal cancer in a human being |
US10245288B2 (en) | 2011-02-04 | 2019-04-02 | Joseph E. Kovarik | Method and system for reducing the likelihood of developing NASH in an individual diagnosed with non-alcoholic fatty liver disease |
US11980643B2 (en) | 2013-12-20 | 2024-05-14 | Seed Health, Inc. | Method and system to modify an individual's gut-brain axis to provide neurocognitive protection |
US11998574B2 (en) | 2013-12-20 | 2024-06-04 | Seed Health, Inc. | Method and system for modulating an individual's skin microbiome |
US11826388B2 (en) | 2013-12-20 | 2023-11-28 | Seed Health, Inc. | Topical application of Lactobacillus crispatus to ameliorate barrier damage and inflammation |
US11839632B2 (en) | 2013-12-20 | 2023-12-12 | Seed Health, Inc. | Topical application of CRISPR-modified bacteria to treat acne vulgaris |
US12005085B2 (en) | 2013-12-20 | 2024-06-11 | Seed Health, Inc. | Probiotic method and composition for maintaining a healthy vaginal microbiome |
US11833177B2 (en) | 2013-12-20 | 2023-12-05 | Seed Health, Inc. | Probiotic to enhance an individual's skin microbiome |
US11969445B2 (en) | 2013-12-20 | 2024-04-30 | Seed Health, Inc. | Probiotic composition and method for controlling excess weight, obesity, NAFLD and NASH |
PE20170024A1 (es) | 2014-05-19 | 2017-03-17 | Pfizer | Compuestos de 6,8-dioxabiciclo [3.2.1] octano-2,3-diol sustituidos como agentes de direccionamiento al asgpr |
CA3134610A1 (en) * | 2018-04-09 | 2019-10-17 | Yale University | Bifunctional small molecules to target the selective degradation of circulating proteins |
WO2019199621A1 (en) * | 2018-04-09 | 2019-10-17 | Yale University | Bi-functional molecules to degrade circulating proteins |
CN109232690A (zh) * | 2018-09-10 | 2019-01-18 | 南方医科大学南方医院 | 一种正电子显像剂标准品前体及其制备方法 |
JP2022513299A (ja) | 2018-12-19 | 2022-02-07 | ザ ボード オブ トラスティーズ オブ ザ レランド スタンフォード ジュニア ユニバーシティー | リソソーム標的化のための二官能性分子ならびに関連する組成物および方法 |
IL294515A (en) | 2020-01-31 | 2022-09-01 | Avilar Therapeutics Inc | Compounds bind asgpr to degrade extracellular proteins |
JP2023526533A (ja) | 2020-05-22 | 2023-06-21 | ウェイブ ライフ サイエンシズ リミテッド | 二本鎖オリゴヌクレオチド組成物及びそれに関連する方法 |
EP4281115A1 (en) | 2021-01-19 | 2023-11-29 | Novartis AG | Degradation of extracellular targets |
KR20240006496A (ko) * | 2021-02-08 | 2024-01-15 | 에멘도바이오 인코포레이티드 | Omni 90-99, 101, 104-110, 114, 116, 118-123, 125, 126, 128, 129, 및 131-138 crispr 뉴클레아제 |
CN116997337A (zh) * | 2021-03-10 | 2023-11-03 | 拜奥海芬治疗学有限公司 | 半乳糖缺陷型免疫球蛋白的双官能降解剂 |
WO2023009554A1 (en) * | 2021-07-26 | 2023-02-02 | Avilar Therapeutics, Inc. | Methods to reduce adverse effects of gene or biologics therapy |
EP4392430A1 (en) * | 2021-08-27 | 2024-07-03 | Yale University | Molecular degraders of extracellular proteins |
Family Cites Families (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS58121243A (ja) * | 1982-01-12 | 1983-07-19 | Sumitomo Chem Co Ltd | 新規ビシクロオクタン誘導体及びその製造法 |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US5064672A (en) * | 1988-05-05 | 1991-11-12 | The Procter & Gamble Company | Functional sugar substitutes with reduced calories |
US5041541A (en) * | 1988-05-05 | 1991-08-20 | The Procter & Gamble Company | Functional sugar substituted with reduced calories |
US5104797A (en) | 1988-05-05 | 1992-04-14 | The Procter & Gamble Company | Process for preparing 5-c-hydroxymethyl aldohexose-based compounds |
WO1991009537A1 (en) | 1989-12-21 | 1991-07-11 | The Procter & Gamble Company | Food compositions containing reduced calorie fats and reduced calorie sugars |
DE69225233T2 (de) | 1991-10-04 | 1998-11-19 | Procter & Gamble | Cholesterinsenkende Verbindungen und Verfahren zu ihrer Herstellung |
EP0733066B1 (en) * | 1993-12-07 | 2003-11-19 | NeoRx Corporation | Pretargeting methods and compounds |
EP1432724A4 (en) | 2002-02-20 | 2006-02-01 | Sirna Therapeutics Inc | RNA inhibition mediated inhibition of MAP KINASE GENES |
EP1783137A4 (en) * | 2004-08-26 | 2014-10-22 | Nippon Shinyaku Co Ltd | GALACTOSIS DERIVATIVE, DRUG VECTOR AND THERAPEUTIC PREPARATION |
WO2006120545A1 (en) | 2005-05-10 | 2006-11-16 | Glaxosmithkline Istrazivacki Centar Zagreb D.O.O. | 4' amino linked macrolides useful for the treatment of microbial infections |
WO2007056389A2 (en) | 2005-11-07 | 2007-05-18 | University Of South Carolina | Synthesis and use of novel inhibitors and inactivators of protein arginine deiminases |
US7919598B2 (en) | 2006-06-28 | 2011-04-05 | Bristol-Myers Squibb Company | Crystal structures of SGLT2 inhibitors and processes for preparing same |
PE20110288A1 (es) * | 2008-08-28 | 2011-05-26 | Pfizer | Derivados de dioxa-biciclo[3.2.1]octano-2,3,4-triol |
NZ599945A (en) * | 2009-11-02 | 2014-05-30 | Pfizer | Dioxa-bicyclo[3.2.1]octane-2,3,4-triol derivatives |
CN102372722A (zh) | 2010-08-10 | 2012-03-14 | 江苏恒瑞医药股份有限公司 | C-芳基葡萄糖苷衍生物、其制备方法及其在医药上的应用 |
WO2012041898A1 (en) | 2010-09-29 | 2012-04-05 | Celon Pharma Sp. Z O.O. | Combination of sglt2 inhibitor and a sugar compound for the treatment of diabetes |
WO2012172566A2 (en) | 2011-06-13 | 2012-12-20 | Panacea Biotec Ltd. | Novel sglt inhibitors |
JP2014530186A (ja) | 2011-09-13 | 2014-11-17 | パナセア バイオテック リミテッド | 新規sglt阻害剤 |
DK3401400T3 (da) | 2012-05-25 | 2019-06-03 | Univ California | Fremgangsmåder og sammensætninger til rna-styret mål-dna-modifikation og til rna-styret transskriptionsmodulering |
CN103570657A (zh) | 2012-07-19 | 2014-02-12 | 天津药物研究院 | 一类含偕二甲基的苯基c-葡萄糖苷衍生物、其制备方法和用途 |
WO2014018671A1 (en) * | 2012-07-24 | 2014-01-30 | Regents Of The University Of Minnesota | Therapeutic compounds for the treatment of cancer |
AR092924A1 (es) | 2012-10-09 | 2015-05-06 | Sanofi Sa | Derivados de pirrolidinona como moduladores de gpr119 para el tratamiento de diabetes, obesidad, dislipidemia y trastornos relacionados |
CN103772449B (zh) | 2012-10-26 | 2017-12-26 | 上海阳帆医药科技有限公司 | C‑芳基葡萄糖苷衍生物及其制备方法与用途 |
CN105658796B (zh) | 2012-12-12 | 2021-10-26 | 布罗德研究所有限公司 | 用于序列操纵的crispr-cas组分系统、方法以及组合物 |
CN103864737B (zh) | 2012-12-17 | 2016-08-17 | 天津药物研究院 | 含脱氧葡萄糖结构的苯基c-葡萄糖苷衍生物及其制备方法和用途 |
US9505734B2 (en) | 2012-12-17 | 2016-11-29 | Tianjin Institute Of Pharmaceutical Research | Phenyl C-glucoside derivative containing deoxyglucose structure, preparation method and use thereof |
EP2968375B1 (en) | 2013-03-14 | 2019-06-12 | MSD International GmbH | Methods for preparing sglt2 inhibitors |
EP4245765A3 (en) | 2013-04-04 | 2024-03-20 | Boehringer Ingelheim Vetmedica GmbH | Treatment of metabolic disorders in equine animals |
PE20170024A1 (es) * | 2014-05-19 | 2017-03-17 | Pfizer | Compuestos de 6,8-dioxabiciclo [3.2.1] octano-2,3-diol sustituidos como agentes de direccionamiento al asgpr |
CN104017031A (zh) | 2014-06-21 | 2014-09-03 | 李友香 | 降血糖药物和组合物 |
CN104031098A (zh) | 2014-06-21 | 2014-09-10 | 李友香 | 降糖药物 |
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