JP4342437B2 - 興奮性アミノ酸のプロドラッグ - Google Patents
興奮性アミノ酸のプロドラッグ Download PDFInfo
- Publication number
- JP4342437B2 JP4342437B2 JP2004511287A JP2004511287A JP4342437B2 JP 4342437 B2 JP4342437 B2 JP 4342437B2 JP 2004511287 A JP2004511287 A JP 2004511287A JP 2004511287 A JP2004511287 A JP 2004511287A JP 4342437 B2 JP4342437 B2 JP 4342437B2
- Authority
- JP
- Japan
- Prior art keywords
- hexane
- mmol
- amino
- dicarboxylic acid
- bicyclo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 229940002612 prodrug Drugs 0.000 title abstract description 14
- 239000000651 prodrug Substances 0.000 title abstract description 14
- 230000002461 excitatory amino acid Effects 0.000 title abstract description 7
- 239000003257 excitatory amino acid Substances 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 252
- 238000004519 manufacturing process Methods 0.000 claims description 120
- 150000003839 salts Chemical class 0.000 claims description 39
- 239000001257 hydrogen Substances 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 12
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 5
- IFNXFIJXYVEYLF-UHFFFAOYSA-N 2-Propylglutaric acid Chemical compound CCCC(C(O)=O)CCC(O)=O IFNXFIJXYVEYLF-UHFFFAOYSA-N 0.000 claims description 4
- PPTOPCBILCUEBB-UHFFFAOYSA-N O.CCCC(CCC(O)=O)C(O)=O Chemical compound O.CCCC(CCC(O)=O)C(O)=O PPTOPCBILCUEBB-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 98
- 238000002360 preparation method Methods 0.000 abstract description 83
- 208000012902 Nervous system disease Diseases 0.000 abstract description 11
- 208000025966 Neurological disease Diseases 0.000 abstract description 9
- 230000008569 process Effects 0.000 abstract description 6
- 208000020016 psychiatric disease Diseases 0.000 abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 421
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 203
- 239000000243 solution Substances 0.000 description 194
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 176
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 174
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 171
- 238000005481 NMR spectroscopy Methods 0.000 description 151
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 138
- -1 SO Inorganic materials 0.000 description 114
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 112
- 239000007787 solid Substances 0.000 description 111
- 239000000203 mixture Substances 0.000 description 109
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 101
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 90
- 230000002829 reductive effect Effects 0.000 description 84
- 239000010410 layer Substances 0.000 description 80
- 238000006243 chemical reaction Methods 0.000 description 79
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 68
- 239000002002 slurry Substances 0.000 description 67
- 238000000921 elemental analysis Methods 0.000 description 58
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 54
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 53
- 239000011541 reaction mixture Substances 0.000 description 53
- 239000012044 organic layer Substances 0.000 description 50
- 238000003756 stirring Methods 0.000 description 49
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 44
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 41
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 41
- 239000000047 product Substances 0.000 description 35
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 34
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 30
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 30
- 229940024606 amino acid Drugs 0.000 description 30
- 239000003921 oil Substances 0.000 description 29
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 29
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
- 239000012267 brine Substances 0.000 description 28
- 238000004809 thin layer chromatography Methods 0.000 description 27
- 235000001014 amino acid Nutrition 0.000 description 26
- 150000001413 amino acids Chemical group 0.000 description 26
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 26
- 229960004756 ethanol Drugs 0.000 description 25
- 239000000725 suspension Substances 0.000 description 25
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 239000006260 foam Substances 0.000 description 24
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 23
- 239000002904 solvent Substances 0.000 description 23
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N N,N-Diethylethanamine Substances CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 22
- PUXYECYTXXMEPX-UHFFFAOYSA-N dimethyl 2-propylpentanedioate Chemical compound CCCC(C(=O)OC)CCC(=O)OC PUXYECYTXXMEPX-UHFFFAOYSA-N 0.000 description 22
- 229910052938 sodium sulfate Inorganic materials 0.000 description 21
- 235000011152 sodium sulphate Nutrition 0.000 description 21
- 239000002253 acid Substances 0.000 description 20
- 239000012299 nitrogen atmosphere Substances 0.000 description 20
- 239000011734 sodium Substances 0.000 description 20
- 125000003118 aryl group Chemical group 0.000 description 19
- 238000010438 heat treatment Methods 0.000 description 18
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 18
- 235000019341 magnesium sulphate Nutrition 0.000 description 18
- 238000010992 reflux Methods 0.000 description 18
- 239000000377 silicon dioxide Substances 0.000 description 18
- 235000017557 sodium bicarbonate Nutrition 0.000 description 18
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 18
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 18
- 238000001816 cooling Methods 0.000 description 17
- 229920006395 saturated elastomer Polymers 0.000 description 17
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 16
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- LVGHOOBZAPGKIH-UHFFFAOYSA-N diethyl 2-methylheptanedioate Chemical compound CCOC(=O)CCCCC(C)C(=O)OCC LVGHOOBZAPGKIH-UHFFFAOYSA-N 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 15
- 229910052757 nitrogen Chemical group 0.000 description 15
- 238000000746 purification Methods 0.000 description 15
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 14
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
- 239000012043 crude product Substances 0.000 description 12
- 239000000284 extract Substances 0.000 description 12
- 125000001153 fluoro group Chemical group F* 0.000 description 12
- 125000001072 heteroaryl group Chemical group 0.000 description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 12
- 239000000463 material Substances 0.000 description 12
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 12
- 239000000741 silica gel Substances 0.000 description 12
- 229910002027 silica gel Inorganic materials 0.000 description 12
- 238000010898 silica gel chromatography Methods 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 12
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 12
- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 12
- AAZHGCOKWKMYEX-UHFFFAOYSA-N 1-amino-4-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid Chemical compound FC1CC(C(O)=O)C2(N)C1C2C(O)=O AAZHGCOKWKMYEX-UHFFFAOYSA-N 0.000 description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 11
- 239000013058 crude material Substances 0.000 description 11
- 238000002425 crystallisation Methods 0.000 description 11
- 230000008025 crystallization Effects 0.000 description 11
- 229910052717 sulfur Inorganic materials 0.000 description 11
- 0 CC(C)(C)OC(NC(C(*)*)C(N[C@@](C1)(C(C)([C@]2C(OC)=O)C2(C)S1(=O)=O)*=*)=O)=O Chemical compound CC(C)(C)OC(NC(C(*)*)C(N[C@@](C1)(C(C)([C@]2C(OC)=O)C2(C)S1(=O)=O)*=*)=O)=O 0.000 description 10
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 238000003556 assay Methods 0.000 description 10
- 239000008367 deionised water Substances 0.000 description 10
- 229910021641 deionized water Inorganic materials 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 229910052760 oxygen Inorganic materials 0.000 description 10
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 9
- TVQGDYNRXLTQAP-UHFFFAOYSA-N ethyl heptanoate Chemical compound CCCCCCC(=O)OCC TVQGDYNRXLTQAP-UHFFFAOYSA-N 0.000 description 9
- 239000007789 gas Substances 0.000 description 9
- 235000012239 silicon dioxide Nutrition 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- 239000011593 sulfur Chemical group 0.000 description 9
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 8
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 8
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 8
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 238000004821 distillation Methods 0.000 description 8
- 239000003480 eluent Substances 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 150000002431 hydrogen Chemical class 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 239000001301 oxygen Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 description 8
- 108010010914 Metabotropic glutamate receptors Proteins 0.000 description 7
- 102000016193 Metabotropic glutamate receptors Human genes 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- YVPJCJLMRRTDMQ-UHFFFAOYSA-N ethyl diazoacetate Chemical compound CCOC(=O)C=[N+]=[N-] YVPJCJLMRRTDMQ-UHFFFAOYSA-N 0.000 description 7
- 125000005842 heteroatom Chemical group 0.000 description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- QVHJQCGUWFKTSE-YFKPBYRVSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound OC(=O)[C@H](C)NC(=O)OC(C)(C)C QVHJQCGUWFKTSE-YFKPBYRVSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- 241000282414 Homo sapiens Species 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 6
- 125000003342 alkenyl group Chemical group 0.000 description 6
- 125000000266 alpha-aminoacyl group Chemical group 0.000 description 6
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
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- 125000006239 protecting group Chemical group 0.000 description 6
- 238000011084 recovery Methods 0.000 description 6
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 6
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 6
- SZRLPRUZKCFHTQ-UHFFFAOYSA-N 2-propylpentanedioic acid;hydrochloride Chemical compound Cl.CCCC(C(O)=O)CCC(O)=O SZRLPRUZKCFHTQ-UHFFFAOYSA-N 0.000 description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 5
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- JBCCTQFSQRFTGE-UHFFFAOYSA-N [O-]C(C(CCC12)C1[S+]2C(O)=O)=O.Cl Chemical compound [O-]C(C(CCC12)C1[S+]2C(O)=O)=O.Cl JBCCTQFSQRFTGE-UHFFFAOYSA-N 0.000 description 5
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- 238000012512 characterization method Methods 0.000 description 5
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- 238000000434 field desorption mass spectrometry Methods 0.000 description 5
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- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 5
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- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- ANUFAWHRSIJTHW-UHFFFAOYSA-N 2-methylheptanedioic acid Chemical compound OC(=O)C(C)CCCCC(O)=O ANUFAWHRSIJTHW-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- SBEBIYKRKGAEQJ-UHFFFAOYSA-N COC(C(CCC12)C1[S+]2C(OC)=O)=O Chemical compound COC(C(CCC12)C1[S+]2C(OC)=O)=O SBEBIYKRKGAEQJ-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- BZKFMUIJRXWWQK-UHFFFAOYSA-N Cyclopentenone Chemical compound O=C1CCC=C1 BZKFMUIJRXWWQK-UHFFFAOYSA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 150000001371 alpha-amino acids Chemical class 0.000 description 4
- 239000000908 ammonium hydroxide Substances 0.000 description 4
- 206010008118 cerebral infarction Diseases 0.000 description 4
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- 125000002114 valyl group Chemical group 0.000 description 1
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- 239000003643 water by type Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
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Description
神経または精神障害、例えば不安障害の処置は、代謝調節型興奮性アミノ酸受容体の選択的活性化に関連している。例えば、(+)−4−アミノ−2−スルホニルビシクロ[3.1.0]ヘキサン−4,6−ジカルボン酸は、1997年11月18日に発行された米国特許番号5,688,826(’826特許)において、活性なmGluR2受容体アゴニストとして開示されている。さらに、(+)−2−アミノ−4−フルオロビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸は、1999年9月28日に発行された米国特許番号5,958,960(’960特許)にて、活性なmGluR2受容体アゴニストとして開示されている。
本発明は、式I
AはH−(Q)p−であり、
Qはそれぞれ、アミノアシル基から独立して選択され、
pは、1から10までの整数であり、
Xは、O、S、SO、SO2またはCR3R4であり、
R3は、フルオロ、X’OR5、SO3H、テトラゾール−5−イル、CN、PO3R6 2、ヒドロキシもしくはNO2であり、そしてR4は水素であり、またはR3およびR4はそれぞれフルオロであり、またはR3およびR4は一緒になって=O、=NOR7もしくは=CR8R9であり、またはR3もしくはR4のうち一方はアミノであり、他方はカルボキシルであり、またはR3は、N3、(CH2)mCOOR5a、(CH2)mPO3R6a 2、NHCONHR5bもしくはNHSO2R5cであり、そしてR4は水素であり、またはR3およびR4は一緒になって=CHCOOR5b、=CHPO3R6a 2もしくは=CHCNであり、
X’は、結合、CH2またはCOであり、
mは、1から3までの整数であり、
R5、R5a、R5b、R5c、R7、R8およびR9は独立して、水素原子、置換されていることもある(1〜6C)アルキル基、置換されていることもある(2〜6C)アルケニル基、置換されていることもある(2〜6C)アルキニル基、置換されていることもある芳香族基、置換されていることもあるヘテロ芳香族基、非芳香族炭素環式基、非芳香族ヘテロ環式基、1つもしくは2つの単環式芳香族もしくはヘテロ芳香族基と縮合している非芳香族単環式炭素環式基、または1つもしくは2つの単環式芳香族もしくはヘテロ芳香族基と縮合している非芳香族単環式ヘテロ環式基であり、
R6およびR6aは独立して、水素または(1〜6C)アルキル基であり、
R10は、水素またはフルオロであり、および
R11は、水素、フルオロまたはヒドロキシである]
で示される化合物、またはその製薬的に許容される塩を提供する。
PgN−A− (III)
[式中、PgNは窒素保護基であり、Aは上に定義されている]
で示される、対応するアミノアシルによりアシル化し、
次いで、上記いずれかの手順について、官能基が保護基を用いて保護されているとき、保護基を除去し、
次いで、上記いずれかの手順について、式Iの化合物の製薬的に許容される塩が必要であるとき、そのような式Iの化合物の塩基性形態を製薬的に許容される対イオンを与える酸と反応させ、または酸性部分を有する式Iの化合物については、そのような式Iの化合物の酸性形態を製薬的に許容されるカチオンを与える塩基と反応させ、または式Iの双性イオン化合物については、そのような式Iの化合物の酸付加塩形態もしくは塩基付加塩形態を中和し、または他のいずれかの従来手順による方法を提供する。
本発明の化合物は、代謝型グルタミン酸受容体の選択的アゴニストである化合物の有用なプロドラッグであることが見出され、それゆえに本発明化合物は神経疾患のような中枢神経系の疾患、例えば神経変性疾患の処置に有用であり、抗精神病剤、抗不安剤、薬物離脱剤、抗鬱剤、抗痙攣剤、鎮痛剤および制吐剤として有用である。
B) Qがアラニルである。
C) Qがメチオニルである。
D) pが1である。
E) pが2である。
F) XがSO2である。
G) XがCR3R4である。
H) R3がフルオロであり、R4が水素である。
I) R3がヒドロキシであり、R4が水素である。
J) R3およびR4が一緒になって=Oを示す。
K) R10が水素である。
L) R10がフルオロである。
M) R11が水素である。
N) 化合物が遊離塩基である。
O) 化合物が塩である。
P) 化合物が塩酸塩である。
Q) 化合物がメシレート塩である。
R) 化合物がエシレート塩である。
S) 化合物がトシレート塩である。
式Iの化合物は哺乳動物の障害の処置に有用であり、好ましい哺乳動物はヒトである。
反応式1
反応式2
反応式3
反応式4
の分割に関し、(R)−α−メチルベンジルアミンおよびキニンが好ましいことが見出されている。(R)−α−メチルベンジルアミンが特に好ましい。
Ac=アセチル
Anal.=元素分析
ATR=減衰全内部反射
BnまたはBzl=ベンジル
Bu=ブチル
BOC=t−ブトキシカルボニル
calcd=計算値
D2O=重水
DCC=ジシクロヘキシルカルボジイミド
DCM=1,2−ジクロロメタン
DIBAL−H=水素化ジイソブチルアルミニウム
DMAP=4−ジメチルアミノピリジン
DMF=ジメチルホルムアミド
DMSO=ジメチルスルホキシド
DSC=示差走査熱量測定
EDC=N−エチル−N’N’−ジメチルアミノプロピルカルボジイミド塩酸塩
ES=エレクトロスプレー
Et=エチル
EtOH=エタノール
FAB=高速原子衝撃(質量分析)
FDMS=電界脱離質量スペクトル
FTIR=フーリエ変換赤外分光分析
HOAt=1−ヒドロキシ−7−アザベンゾトリアゾール
HOBt=1−ヒドロキシベンゾトリアゾール
HPLC=高速液体クロマトグラフィー
HRMS=高分解能質量スペクトル
i−PrOH=イソプロパノール
IR=赤外スペクトル
L=リットル
Me=メチル
MeOH=メタノール
MPLC=中圧液体クロマトグラフィー
Mp=融点
MTBE=t−ブチルメチルエーテル
NBS=N−ブロモスクシンイミド
NMR=核磁気共鳴
PC−TLC=分取用遠心分離薄層クロマトグラフィー
Ph=フェニル
p.o.=経口投与
i−Pr=イソプロピル
ロッシェル塩=酒石酸カリウムナトリウム
rt=室温
SM=出発物質
TBS=tert−ブチルジメチルシリル
TEA=トリエチルアミン
Temp.=温度
TFA=トリフルオロ酢酸
THF=テトラヒドロフラン
TLC=薄層クロマトグラフィー
t−BOC=tert−ブトキシカルボニル
アミンとN−BOC−(L)−アミノ酸のEDCカップリング
出発アミノジアルキルエステル(反応式3、式iiの化合物)1.0当量を窒素雰囲気下、乾燥ジクロロメタン中にて懸濁する。対応するN−BOC−(L)−アミノ酸1.5〜2.0当量、EDC1.5〜2.0当量、HOBt1.5〜2.0当量およびジメチルアミノピリジン(DMAP)0.1〜0.2当量を続けて加える。特に明記されなければ、TLCにより完了と判断するまで反応混合物を室温にて撹拌する。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液および/または硫酸水素ナトリウム水溶液、ならびにブラインで続けて洗浄する。硫酸ナトリウムで乾燥し、溶媒を減圧留去した後、粗製の残渣(式iiiの化合物)を適切な溶離液(典型的には酢酸エチル/ヘキサン)を用いたシリカゲルクロマトグラフィーにより精製する。
アミンとN−BOC−(L)−アミノ酸イソブチル無水物の無水物カップリング
対応するN−BOC−(L)−アミノ酸1.5当量の乾燥ジクロロメタン10mL溶液に、−20℃窒素雰囲気下にてN−メチルモルホリン(NMM)1.5当量(ジクロロメタン1mL中)を加えた後、クロロギ酸イソブチル(IBCF)1.5当量(ジクロロメタン5mL中)を内部反応温度が−15℃を超えない速度にて滴加する。得られた混合物を−20℃にて30分間撹拌した後、(1S,2S,4S,5R,6R)−2−(2’−アミノ−プロピオニルアミノ)−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ジエチルエステル塩酸塩1.0当量の−20℃ジクロロメタン10mL溶液を、内部反応温度が−15℃を超えない速度にて加える。添加完了後、冷却バスを除去し、TLCにより完了と判断するまで反応混合物を室温にて撹拌する。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、硫酸水素ナトリウム水溶液およびブラインで続けて洗浄する。硫酸マグネシウムで乾燥し、溶媒を減圧留去した後、粗製の残渣を適切な溶離液(典型的にはヘキサン/酢酸エチル)を用いたシリカゲルクロマトグラフィーにより精製する。
N−BOCおよびエステル保護基の連続的除去
対応するN−BOCジエステルペプチド誘導体(反応式2、式iiiの化合物)1.0当量をTHF/2.5N水酸化リチウム10〜20当量の1:1混液中、室温にて4時間にわたって撹拌する。反応物を水で希釈し、酢酸エチルで洗浄する。有機層を廃棄する。水相を1N塩酸でpH2に調節し(抽出率を増強するために随時、水相に塩化ナトリウムを加える)、N−BOCジカルボン酸生成物(式ivの化合物)を酢酸エチルで徹底的に抽出する。すべての有機抽出物を集め、ブラインで洗浄し、硫酸マグネシウムで乾燥し、濃縮し、減圧乾燥し、所望のカルボン酸生成物を泡沫状固体として得る。酢酸エチルに溶解し、0℃まで冷却する。塩酸で飽和するまで反応混合物を無水塩酸ガスでパージする。得られた反応混合物を0℃にて4時間にわたって撹拌する。窒素雰囲気下ろ過することにより、または反応混合物を濃縮し、乾燥した後、酢酸エチルまたはジエチルエーテルで粉末化して濃縮し、白色粉状物を得ることにより、完全に脱保護されたペプチド誘導体(式Iの化合物)をその塩酸塩として単離する。場合により、残存する溶媒および過剰の塩酸を除去するために、生成物を水中にて再構成し、凍結させた後、凍結乾燥し、所望の塩酸塩生成物を得る。
(1R,4S,5S,6S)−4−アミノ−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0]ヘキサン−4,6−ジカルボン酸ジエチルエステル
標記化合物200mgの酢酸エチル800μL中の混合物を56℃まで加熱し、このとき溶解が起こった。15分間56℃にて撹拌した後、ヘプタン1mLを溶液に滴加した。加熱を止めた。溶液を52℃まで冷却し、このとき沈殿が起こった。冷却し、さらにヘプタン600μLで希釈した後、スラリーを形成した。得られたスラリーを室温にて1時間撹拌した後、ろ過し、ヘプタン(2x500μL)で洗浄し、45℃にて一晩乾燥し、標記化合物145mg(73%回収率)を白色固体として得た。
mp 80-83℃.
[α]25 D -57.7°(c 1.04, CH3OH).
500MHz 1H NMR (CD3Cl3) δ4.31 (q, 2H, J = 7.0Hz), 4.20 (m, 2H), 3.78 (d, 1H, J = 15.0Hz), 3.36 (dd, 1H, J = 4.0, 7.0Hz), 2.93 (dd, 1H, J = 4.0, 7.0Hz), 2.81 (d, 1H, J = 15.0Hz), 2.46 (t, 1H, J = 4.0), 1.34 (t, 3H, J = 7.0), 1.30 (t, 3H, J = 7.0).
13C NMR (125MHz, CD3Cl3) δ171.68, 168.57, 63.26, 62.42, 59.96, 56.06, 43.78, 32.25, 22.49, 14.31, 14.25.
FTIR (ATR) 3364.15 (s), 1725.95 (s), 1304.91 (s), 1259.24 (s), 1200.84 (s), 1104.91 (s), 1022.99 (s), 896.45 (s), 851.21 (s) cm-1.
元素分析 C11H17NO6Sとして計算値: C, 45.35; H, 5.88; N, 4.81. 実測値: C, 45.02; H, 5.75; N, 4.82.
(1R,4S,5S,6S)−4−(2’S−tert−ブトキシカルボニルアミノ−プロピオニルアミノ)−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0]ヘキサン−4,6−ジカルボン酸ジエチルエステル
1H NMR (300MHz, CDCl3) δ: 7.62 (brs, 1H), 4.90 (brd, 1H, J = 7.1Hz), 4.34-4.10 (m, 6H), 3.39 (ddd, 1H, J = 7.2, 3.9, 1.0Hz), 3.00 (dd, 1H, J = 7.1, 3.9Hz), 2.90 (brd, 1H, J = 14.9Hz), 2.43 (t, 1H, J = 4.1Hz), 1.46 (s, 9H), 1.31 (m, 9H).
13C NMR (75MHz, CDCl3) δ: 173.0, 168.6, 167.6, 80.9, 76.5, 63.3, 62.3, 59.9, 55.7, 42.8, 31.5, 28.2, 22.7, 16.6, 14.0, 13.9. MS (ES) m/z 461.0 [M-H]-.
(1R,4S,5S,6S)−4−(2’S−tert−ブトキシカルボニルアミノ−プロピオニルアミノ)−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0]ヘキサン−4,6−ジカルボン酸
(1R,4S,5S,6S)−4−アミノ−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0]ヘキサン−4,6−ジカルボン酸ジメチルエステル
[α]23 D = -84°(c = 0.5, MeOH).
元素分析 C9H13NO6Sとして計算値: C, 41.06; H, 4.98; N, 5.32. 実測値: C, 40.94; H, 4.93; N, 5.30.
MS (ES) m/z 264.0 [M+H]+.
(1R,4S,5S,6S)−4−(2’S−tert−ブトキシカルボニルアミノ−3’−フェニル−プロピオニルアミノ)−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0]ヘキサン−4,6−ジカルボン酸ジメチルエステル
[α]23 D = -35.2°(c = 0.45, CHCl3).
1H NMR (300MHz, CDCl3) δ1.43 (9H, s), 2.38-2.40 (1H, m), 2.86 (1H, d, J = 15.0Hz), 2.91 (1H, dd, J = 4.4, 7.3Hz), 3.04 (2H, d, J = 7.3Hz), 3.35-3.39 (1H, m), 3.77 (3H, s), 3.84 (3H, s), 4.11 (1H, d, J = 14.3), 4.30 (1H, app. q, J = 7.3), 4.96 (1H, bd, J = 6.6Hz), 6.96 (1H, bs), 7.22-7.36 (5H, m).
元素分析 C23H30N2O9S・0.1H2Oとして計算値: C, 53.92; H, 5.94; N, 5.47. 実測値: C, 53.62; H, 5.90; N, 5.28.
MS (ES) m/z 509.16 [M-H]-; 411.2 [M-Boc]+.
(1R,4S,5S,6S)−4−(2’S−tert−ブトキシカルボニルアミノ−3’S−メチル−ペンタノイルアミノ)−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0]ヘキサン−4,6−ジカルボン酸ジメチルエステル
[α]23 D = -32.65°(c = 0.49, CHCl3).
1H NMR (300MHz, CDCl3) δ0.91 (3H, t, J = 7.3Hz), 0.93 (3H, d, J = 6.6Hz), 1.10-1.18 (1H, m), 1.46 (9H, s), 1.42-1.52 (1H, m), 1.81-1.86 (1H, bm), 2.51 (1H, t, J = 4.0Hz), 2.95 (1H, d, J = 15.0Hz), 3.06 (1H, dd, J = 4.4, 7.3Hz), 3.43 (3H, dd, J = 3.7, 7.0Hz), 3.78 (3H, s), 3.85 (3H, s), 3.82-3.90 (1H, m), 4.20 (1H, d, J = 14.7Hz), 4.94 (1H, d, J = 8.4Hz), 7.19 (1H, bs).
元素分析 C20H32N2O9Sとして計算値: C, 50.41; H, 6.77; N, 5.88. 実測値: C, 50.32; H, 6.92; N, 5.76.
MS (ES) m/z 475.1 [M-H]-.
(1R,4S,5S,6S)−4−(2’S−tert−ブトキシカルボニルアミノ−3’−メチル−ブチリルアミノ)−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0]ヘキサン−4,6−ジカルボン酸ジメチルエステル
[α]23 D = -35.36°(c = 0.51, CHCl3).
1H NMR (300MHz, CDCl3) δ0.93 (3H, d, J = 7.0Hz), 0.96 (3H, d, J = 6.6Hz), 1.46 (9H, s), 2.06-2.13 (1H, m), 2.50 (1H, t, J = 4.0Hz), 2.94 (1H, d, J = 15.0Hz), 3.04 (1H, dd, J = 4.4, 7.3Hz), 3.43 (1H, dd, J = 3.3, 6.6), 3.78 (3H, s), 3.80-3.86 (1H, m), 3.86 (3H, s), 4.24 (1H, d, J = 15.0Hz), 4.94 (1H, d, J = 8.1Hz), 7.15 (1H, bs).
元素分析 C19H30N2O9Sとして計算値: C, 49.34; H, 6.54; N, 6.06. 実測値: C, 49.33; H, 6.44; N, 6.05.
MS (ES) m/z 461.2 [M-H]-
(1R,4S,5S,6S)−4−(2’S−tert−ブトキシカルボニルアミノ−4’−メチル−ペンタノイルアミノ)−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0]ヘキサン−4,6−ジカルボン酸ジメチルエステル
[α]23 D = -46.15°(c = 1.04, CHCl3).
1H NMR (300MHz, CDCl3) δ0.92 (3H, d, J = 6.2Hz), 0.95 (3H, d, J = 6.6Hz), 1.47 (9H, s), 1.42-1.47 (1H, m), 1.63-1.67 (1H, m), 2.46 (1H, t, J = 3.7Hz), 2.87 (1H, d, J = 15.0Hz), 3.04 (1H, dd, J = 4.4, 7.3Hz), 3.41 (1H, dd, J = 3.7, 7.0), 3.78 (3H, s), 3.86 (3H, s), 4.00-4.05 (1H, m), 4.20 (1H, d, J = 15.0Hz), 4.75 (1H, d, J = 6.6Hz), 7.43 (1H, bs).
元素分析 C20H32N2O9Sとして計算値: C, 50.41; H, 6.77; N, 5.88. 実測値: C, 50.30; H, 6.82; N, 5.75.
MS (ES) m/z 475.2 [M-H]-.
(1R,4S,5S,6S)−4−(2’S,6’−ビス−tert−ブトキシカルボニルアミノ−ヘキサノイルアミノ)−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0]ヘキサン−4,6−ジカルボン酸ジメチルエステル
[α]23 D = -32.0°(c = 0.5, CHCl3).
1H NMR (300MHz, CDCl3) δ1.44 (9H, s), 1.46 (9H, s), 1.39-1.53 (3H, m), 1.56-1.65 (1H, m), 1.77-1.84 (2H, m), 2.50 (1H, t, J = 4.4Hz), 2.98-3.20 (4H, m), 3.42 (1H, dd, J = 3.7, 7.0Hz), 3.76 (3H, s), 3.86 (3H, s), 4.01 (1H, dd, J = 7.7, 13.2Hz), 4.09-4.19 (1H, m), 4.71 (1H, t, J = 7.3Hz), 5.13 (1H, bs), 7.59 (1H, bs).
元素分析 C25H41N3O11Sとして計算値: C, 50.75; H, 6.98; N, 7.10. 実測値: C, 50.36; H, 6.99; N, 6.87.
MS (ES) m/z 590.2 [M-H]-.
(1R,4S,5S,6S)−4−[2’S−tert−ブトキシカルボニルアミノ−4’−(トリチル−カルバモイル)ブチリルアミノ]−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0]ヘキサン−4,6−ジカルボン酸ジメチルエステル
[α]23 D = -8.0°(c = 0.50, MeOH).
1H NMR (300MHz, CDCl3) δ1.42 (9H, s), 1.83-1.88 (1H, m), 2.03-2.18 (1H, m), 2.16 (1H, t, J = 4.0Hz), 2.57-2.64 (1H, m), 2.60 (1H, d, J = 15.0Hz), 2.64-2.80 (1H, m), 2.88 (1H, dd, J = 4.4, 7.3Hz), 3.26 (1H, dd, J = 4.0, 7.0Hz), 3.47 (3H, s), 3.76-3.90 (1H, m), 3.81 (3H, s), 4.05 (1H, d, J = 15.0Hz), 5.47 (1H, bs), 7.02 (1H, bs), 7.20-7.35 (15H, m), 8.68 (1H, bs).
元素分析 C38H43N3O10Sとして計算値: C, 62.20; H, 5.91; N, 5.73. 実測値: C, 61.83; H, 6.09; N, 5.57.
MS (ES) m/z 731.9 [M-H]-;
HRMS C38H43N3O10S [M+Na]+として計算値, 756.2567. 実測値, 756.2585.
(1R,4S,5S,6S)−4−[(1’−tert−ブトキシカルボニル−ピロリジン−2’S−カルボニル)アミノ]−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0.]ヘキサン−4,6−ジカルボン酸ジメチルエステル
[α]23 D = -61.2 (c=0.49, CHCl3).
1H NMR (300MHz, CDCl3) δ1.51 (9H, s), 1.75-1.98 (3H, m), 2.35-2.5 (2H, m), 2.84 (1H, d, J=14.7Hz), 2.9-3.03 (1H, m), 3.25-3.4 (1H, m), 3.3-4.1 (2H, m), 3.76 (3H, s), 3.86 (3H, s), 4.14-4.31 (2H, m), 8.66 (1H, s).
MS (ES) m/z 459.2 [M-1]-.
(1R,4S,5S,6S)−4−(2’S−tert−ブトキシカルボニルアミノ−4’−メチルスルファニル−ブチリルアミノ)−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0.]ヘキサン−4,6−ジカルボン酸ジメチルエステル
[α]23 D = -20.4 (c=0.49, CHCl3).
1H NMR (300MHz, CDCl3) δ1.46 (9H, s), 1.69 (1H, s), 1.8-2.05 (2H, m), 1.9-2.0 (1H, m), 1.95-2.3 (3H, bs), 2.0-2.2 (1H, m), 2.4-2.8 (2H, m), 2.48 (1H, t, J=4.0Hz), 2.58 (1H, bs), 2.92 (1H, d, J=14.7Hz), 3.01 (1H, dd, J=4.4, 7.0Hz), 3.42 (1H, dd, , J=3.7, 7.3Hz), 3.78 (3H, s), 3.87 (3H, s), 4.22-4.24 (2H, m), 5.06 (1H, d, J=7.7Hz), 7.27 (1H, s).
MS (ES) m/z 493.1[M-1]-.
(1R,4S,5S,6S)−4−[2’S−tert−ブトキシカルボニルアミノ−3’−(1−tert−ブトキシカルボニル−1H−インドール−3−イル)プロピオニルアミノ]−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0.]ヘキサン−4,6−ジカルボン酸ジメチルエステル
1H NMR (300MHz, CDCl3) δ1.44 (9H, s), 1.67 (9H, s), 2.37 (1H, bs), 2.86 (1H, d, J=15.0Hz), 2.88 (1H, t, J=4.4Hz), 3.15 (2H, d, J=6.6Hz), 3.39 (1H, dd, J=3.7, 7.0Hz), 3.73 (3H, s), 3.83 (3H, s), 4.18 (1H, d, J=14.7Hz), 4.37-4.44 (1H, m), 5.01 (1H, bd, J=8.1Hz), 7.11 (1H, bs), 7.25-7.59 (4H, m), 8.14 (1H, bd, J=8.4Hz).
[α]23 D = -19.6 (c=0.51, CHCl3).
元素分析 C30H39N3O11S・1.0 C4H8O2として計算値: C, 55.35; H, 6.42; N, 5.70. 実測値: C, 54.98; H, 6.09; N, 6.07.
HRMS C30H39N3O11Na1Sとして計算値, 672.2203. 実測値, 672.2180.
(1R,4S,5S,6S)−4−[2’S−tert−ブトキシカルボニルアミノ−3’−(4−tert−ブトキシカルボニルオキシ−フェニル)プロピオニルアミノ]−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0.]ヘキサン−4,6−ジカルボン酸ジメチルエステル
[α]23 D = +4 (c=1.00, CH3OH).
1H NMR (300MHz, CDCl3) δ1.44 (9H, s), 1.56 (9H, s), 2.44 (1H, t, J=4.0Hz), 2.88 (1H, d, J=14.7Hz), 2.98 (1H, dd, J=4.4, 7.3Hz), 3.04 (2H, d, J=7.3Hz), 3.38 (1H, dd, J=4.0, 7.3Hz), 3.77 (3H, s), 3.83 (3H, s), 4.11 (1H, d, J=14.3Hz), 4.22-4.29 (1H, app q, J=7.3Hz), 4.92 (1H, bd, J=7.7Hz), 7.07 (1H, bs), 7.1-7.26 (4H, m).
HRMS C28H38N2O12SNaとして計算値, 649.2043. 実測値, 649.2001.
(1R,4S,5S,6S)−4−(3’−アセトキシ−2’S−tert−ブトキシカルボニルアミノ−プロピオニル)アミノ−2,2−ジオキソ−2λ6−チアビシクロ[3.1.0]ヘキサン−4,6−ジカルボン酸ジメチルエステル
[α]23 D = -24 (c=1.0, CH3OH).
1H NMR (300MHz, CDCl3) δ1.47 (9H, s), 2.10 (3H, s), 2.51 (1H, t, J=4.4Hz), 2.99-3.07 (2H, m), 3.43 (1H, dd, J=4.0, 7.3Hz), 3.77(3H, s), 3.86 (3H, s), 4.14-4.40 (4H, m), 5.29 (1H, bd, J=7.3Hz), 7.64 (1H, bs).
HRMS C19H28N2O11SNaとして計算値, 515.1312. 実測値, 515.1305.
(1R,2S,4R,5R,6R)−2−アミノ−4−フルオロビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ジエチルエステル
[α]23 D = +20.37°(c = 1.1, MeOH).
m.p. = 64-66℃.
1H NMR (400MHz, CDCl3) δ1.28 (3H, t, J = 7.3Hz), 1.31 (3H, t, J = 6.8Hz), 1.34-1.45 (1H, m), 1.85 (2H, bs), 2.17-2.21 (2H, m), 2.32-2.34 (1H, m), 2.49 (1H, dd, J = 7.8, 14.1Hz), 4.24 (2H, dq, J = 1.5, 7.3Hz), 5.33-5.52 (1H, m).
元素分析 C12H18FNO4として計算値: C, 55.59; H, 7.00; N, 5.40. 実測値: C, 55.29; H, 6.75; N, 5.45.
MS (ES) m/z 実測値 260.3 [M+H]+.
(1R,2S,4R,5R,6R)−2−[2’S−(tert−ブトキシカルボニルアミノ)プロピオニル]アミノ−4−フルオロビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ジエチルエステル
元素分析 C20H31FN2O7・0.1 CH2Cl2として計算値: C, 55.00; H, 7.16; N, 6.38. 実測値: C, 55.18; H, 7.18; N, 6.49.
MS (ES) m/z 431.3 [M+H]+, 331.2 [M+H-Boc]+.
(1R,2S,4R,5R,6R)−2−[2’S−(tert−ブトキシカルボニルアミノ)プロピオニル]アミノ−4−フルオロビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸
(1S,2S,4S,5R,6R)−4−アセチルオキシ−2−(tert−ブトキシカルボニル)アミノビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ジエチルエステル
LCMS: m/z 400 [M+H]+およびm/z 300 [M+H-CO2 tBu]+ 室温にて1.39分.
(1S,2S,4S,5R,6R)−4−アセチルオキシ−2−アミノビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ジエチルエステル
LCMS: m/z 300 [M+H]+ 室温にて0.92分.
(1S,2S,4S,5R,6R)−4−アセチルオキシ−2−[2’S−(tert−ブトキシ)カルボニルアミノプロピオニル]アミノビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ジエチルエステル
1H NMR (CD3OD)*: δ5.05 (1H, d, 5.7Hz), 4.09 (2H, q, 7.3Hz), 4.02 (2H, q, 7.3Hz), 4.01-3.94 (1H, m), 2.65-2.59 (2H, m), 2.38 (1H, d, 14Hz), 2.10-2.03 (3H, m), 1.91 (3H, s), 1.78 (1H, dd, 5.9Hz, 16Hz), 1.59 (1H, br s), 1.34 (9H, s), 1.16 (6H, 2 x t, 7.3Hz);
*注 NMRにより観察されない交換可能なプロトン=2
LCMS: m/z 471 [M+H]+およびm/z 371 [M+H-CO2 tBu]+ 室温にて1.30分.
Rf 0.50 (80%酢酸エチル:ヘプタン).
(1S,2S,4S,5R,6R)−2−アミノ−4−ヒドロキシ−ビシクロ[3.1.0.]ヘキサン−2,6−ジカルボン酸ジエチルエステル
[α]23 D = -30.8 (c=0.52, CH3OH).
1H NMR (300MHz, CDCl3) δ1.26 (3H, t, J=7.33Hz), 1.36 (3H, t, 7.33Hz), 1.60 (1H, dd, J=5.87, 15.40Hz), 1.64 (1H, t, J=2.93Hz), 2.27 (2H, bs), 2.15-2.29 (3H, m), 3.93 (1H, bs), 4.13 (2H, q, J=6.97Hz), 4,27-4.36 (3H, m).
元素分析 C12H19NO5として計算値: C, 56.02; H, 7.44; N, 5.44. 実測値: C, 55.75; H, 7.36; N, 5.40.
MS (ES) m/z 258.1 [M+H]+.
(1S,2S,4S,5R,6R)−2−(2’−tert−ブトキシカルボニルアミノ−アセチルアミノ)−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ジエチルエステル
収率: 560mg(77%)
1H NMR (400MHz, CDCl3) δ1.28 (3H, t, J=7.3Hz), 1.29 (3H, t, J=7.3Hz), 1.48 (9H, s), 1.57 (2H, m), 2.21 (1H, m), 2.41 (1H, dd, J=2.9, 5.8Hz), 2.81 (1H, d, J=15.6Hz), 3.76 (1H, d, J=5.8Hz), 4.10-4.18 (3H, m), 4.26 (2H, q, J=7.3Hz), 4.33 (1H, m), 5.10 (1H, bs), 6.86 (1H, bs).
元素分析 C19H30N2O8として計算値: C, 55.06; H, 7.30; N, 6.76. 実測値: C, 55.24; H, 7.50; N, 6.76.
MS (ES) m/z 415.2 [M+H]+, 437.2 [M+Na]+.
(1S,2S,4S,5R,6R)−2−(2’S−tert−ブトキシカルボニルアミノ−3’−メチル−ブチリルアミノ)−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ジエチルエステル
収率: 白色泡沫状物694mg(87%)
1H NMR (400MHz, CDCl3) δ0.95 (3H, d, J=6.8Hz), 1.00 (3H, d, J=6.8Hz), 1.29 (6H, t, J=7.3Hz), 1.45 (9H, s), 1.52-1.60 (2H, m), 2.08 (1H, m), 2.20 (1H, m), 2.42 (1H, m), 2.81 (1H, d, J=15.6Hz), 3.86 (1H, dd, J=6.3, 8.8Hz), 4.14 (2H, q, J=7.3Hz), 4.21-4.32 (4H, m), 5.00 (1H, d, J=8.3Hz), 6.63 (1H, s).
元素分析 C22H36N2O8として計算値: C, 57.88; H, 7.95; N, 6.14. 実測値: C, 57.87; H, 8.03; N, 6.12.
MS (ES) m/z 457.2 [M+H]+, 479.2 [M+Na]+.
(1S,2S,4S,5R,6R)−2−(2’S−tert−ブトキシカルボニルアミノ−4’−メチル−ペンタノイルアミノ)−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ジエチルエステル
収率: 白色泡沫状物689mg(84%)
1H NMR (400MHz, CDCl3) δ0.96 (6H, m), 1.28 (3H, t, J=7.3Hz), 1.29 (3H, t, J=7.3Hz), 1.46 (9H, s), 1.45-1.73 (5H, m), 2.20 (1H, m), 2.42 (1H, m), 2.80 (1H, d, J=16.1Hz), 4.07-4.35 (7H, m), 4.81 (1H, bd), 6.86 (1H, bs).
元素分析 C23H38N2O8・0.1H2Oとして計算値: C, 58.48; H, 8.15; N, 5.93. 実測値: C, 58.22; H, 7.94; N, 5.92.
MS (ES) m/z 471.2 [M+H]+, 493.2 [M+Na]+.
(1S,2S,4S,5R,6R)−2−(2’S−tert−ブトキシカルボニルアミノ−3’S−メチル−ペンタノイルアミノ)−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ジエチルエステル
収率: 731mg(89%)
1H NMR (400MHz, CDCl3) δ0.92 (3H, t, J=7.3Hz), 0.97 (3H, d, J=6.8Hz), 1.17 (1H, m), 1.29 (6H, t, J=6.8Hz), 1.46 (9H, s), 1.53 (1H, dd, J=5.8, 15.6Hz), 1.58 (1H, t, J=2.4Hz), 1.74 (1H, m), 1.83 (1H, m), 2.20 (1H, m), 2.43 (1H, m), 2.80 (1H, d, J=15.6Hz), 3.88 (1H, dd, J=7.3, 8.8Hz), 4.12-4.32 (6H, m), 4.98 (1H, d, J=7.3Hz), 6.60 (1H, s).
元素分析 C23H38N2O8・0.2H2Oとして計算値: C, 58.25; H, 8.16; N, 5.91. 実測値: C, 58.17; H, 8.11; N, 5.91.
MS (ES) m/z 471.2 [M+H]+, 493.2 [M+Na]+.
(1S,2S,4S,5R,6R)−2−[2’−(2−tert−ブトキシカルボニルアミノ−アセチルアミノ)アセチルアミノ]−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ジエチルエステル
収率: 517mg(81%)
[α]23 D = -18.18 (c=0.55, MeOH).
1H NMR (300MHz, CDCl3) δ1.26 (3H, t, J=6.8Hz), 1.27 (1H, t, J=7.3Hz), 1.28 (3H, t, J=6.8Hz), 1.46 (9H, s), 1.59 (1H, t, J=3.4Hz), 1.62 (1H, dd, J=6.3, 16.1Hz), 2.21 (1H, dd, J=2.9, 5.8Hz), 2.46 (1H, dd, J=2.4, 5.8Hz), 2.73 (1H, d, J=15.6Hz), 3.78-3.91 (3H, m), 4.01-4.15 (3H, m), 4.24 (2H, q, J=6.8Hz), 4.32 (1H, d, J=5.8Hz), 5.28 (1H, b), 6.87 (1H, bt, J=4.9Hz), 7.39 (1H, bs).
HRMS C21H34N3O9として計算値, 472.2295. 実測値, 472.2303.
HPLC: 16.755分. カラム: C18対称, 3.5um, 4.6X150 mm. λ= 230 nM. 流速: 1 mL/分. 濃度勾配: 25分にわたって0.1%TFAを含む10%〜50%ACN/水
(1S,2S,4S,5R,6R)−2−[2’−(2S−tert−ブトキシカルボニルアミノ−プロピオニルアミノ)アセチルアミノ]−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ジエチルエステル
収率: 500mg(76%)
[α]23 D = -31.37(c=0.55, MeOH).
1H NMR (300MHz, CDCl3) δ1.27 (3H, t, J=6.8Hz), 1.28 (3H, t, J=6.8Hz), 1.42 (3H, d, J=6.8Hz), 1.45 (9H, s), 1.58 (1H, t, J=3.4Hz), 1.64 (1H, dd, J=5.8, 15.6Hz), 2.23 (1H, dd, J=3.4, 5.8Hz), 2.50 (1H, dd, J=2.9, 6.3Hz), 2.69 (1H, d, J=15.6Hz), ABq of doublets (2H, vA = 3.87, vB = 3.98 JAB=17.1Hz, Jd=6.3Hz), 3.92 (1H, m), 4.07-4.16 (3H, m), 4.24 (2H, q, J=7.3Hz), 4.32 (1H, b), 5.08 (1H, b), 6.84 (1H, bt, J=4.88Hz), 7.14 (1H, bs).
HRMS C22H36N3O9として計算値, 486.2452. 実測値, 486.2451.
(1S,2S,4S,5R,6R)−2−(2’−tert−ブトキシカルボニルアミノ−3’−フェニル−プロピオニルアミノ)−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ジエチルエステル
[α]23 D = -23.66 (c=0.93, MeOH).
1H NMR (400MHz, CD3OD) δ1.22-1.30 (6H, m), 1.35 (9H, s), 1.59 (1H, t, J = 2.9Hz), 1.70 (1H, dd, J = 5.5, 15.4Hz), 2.06 (1H, m), 2.40 (1H, d, J = 15.4Hz), 2.63 (1H, dd, J = 2.9, 5.9Hz), 2.76 (1H, dd, J = 9.2, 13.9Hz), 4.08-4.33 (6H, m), 7.20-7.29 (5H, m).
MS 実測値 505.0 [M+H]+.
HRMS C26H36N2O8として計算値, 505.2550. 実測値, 505.2559.
(1S,2S,4S,5R,6R)−2−[2’−tert−ブトキシカルボニルアミノ−4’−(トリチル−カルバモイル)ブチリルアミノ]−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ジエチルエステル
[α]23 D = -21.28 (c=0.94, MeOH).
1H NMR (400MHz, CD3OD) δ1.18-1.26 (6H, m), 1.44 (9H, s), 1.62-1.74 (3H, m), 1.91-2.00 (1H, m), 2.05 (1H, m), 2.38-2.48 (3H, m), 2.54 (1H, m), 4.00-4.27 (6H, m), 7.18-7.30 (15H, m).
MS 実測値 728.2 [M+H]+.
HRMS C41H49N3O9として計算値, 728.3547. 実測値, 728.3533.
(1S,2S,4S,5R,6R)−2−(2’S,6’−ビス−tert−ブトキシカルボニルアミノ−ヘキサノイルアミノ)−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ジエチルエステル
[α]23 D = -30.19 (c=0.53, MeOH).
1H NMR (400MHz, CD3OD) δ1.21-1.24 (6H, m), 1.26-1.77 (27H, m), 2.07 (1H, m), 2.42 (1H, d, J = 15.8Hz), 2.59 (1H, dd, J = 2.6, 5.5Hz), 3.03 (1H, t, J = 6.2Hz), 3.99 (1H, m), 4.07-4.28 (5H, m).
MS 実測値 586.1 [M+H]+.
HRMS C28H47N3O10として計算値, 586.3340. 実測値, 586.3348.
(1S,2S,4S,5R,6R)−2−[2’−tert−ブトキシカルボニルアミノ−3’−(トリチル−カルバモイル)プロピオニルアミノ]−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ジエチルエステル
[α]23 D = -25.45 (c=0.55, MeOH).
1H NMR (400MHz, CD3OD) δ1.19-1.26 (6H, m), 1.45 (9H, s), 1.61-1.69 (2H, m), 2.05 (1H, m), 2.44 (1H, d, J = 15.4Hz), 2.51-2.72 (3H, m), 4.02-4.21 (4H, m), 4.25 (1H, d, J = 5.5Hz), 4.36 (1H, dd, J = 4.8, 8.8Hz), 7.18-7.30 (15H, m).
MS 実測値 714.1 [M+H]+.
HRMS C40H47N3O9として計算値, 714.3391. 実測値, 714.3380.
(1S,2S,4S,5R,6R)−2−[2’−tert−ブトキシカルボニルアミノ−3’−(1’−tert−ブトキシカルボニル−1H−インドール−3’−イル)プロピオニルアミノ]−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ジエチルエステル
[α]23 D = -12.5 (c=0.96, MeOH).
1H NMR (400MHz, CD3OD) δ1.18-1.27 (6H, m), 1.34 (9H, s), 1.62 (1H, t, J = 2.9Hz), 1.67 (9H, s), 1.74 (1H, dd, J = 5.9, 15.2Hz), 2.07 (1H, m), 2.46 (1H, d, J = 15.7Hz), 2.60 (1H, d, J = 2.9, 5.9Hz), 2.89 (1H, dd, J = 9.3, 15.0Hz), 3.16 (1H, dd, J = 4.9, 15.2Hz), 4.04-4.12 (2H, m), 4.18-4.24 (2H, m), 4.27 (1H, d, J = 5.4Hz), 4.43 (1H, dd, J = 5.4, 9.3Hz), 7.26 (2H, m), 7.52 (1H, s), 7.64 (1H, d, J = 7.3Hz), 8.10 (1H, d, J = 8.3Hz).
MS 実測値 644.8 [M+H]+, 666.8 [M+Na]+.
HRMS C33H44N3O10として計算値, 666.3002. 実測値, 666.2988.
(1S,2S,4S,5R,6R)−2−(1’−tert−ブトキシカルボニル−ピロリジン−2’S−カルボニル)−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ジエチルエステル
[α]23 D = -52.53 (c=0.99, MeOH).
1H NMR (400MHz, CD3OD) δ1.26 (6H, m), 1.44 (9H, s), 1.62 (1H, m), 1.73(1H, dd, J= 5.4, 15.3Hz), 1.84 (1H, m), 1.97 (1H, m), 2.07 (4H, m), 2.41 (1H, d, J= 15.3Hz), 2.50 (1H, m), 2.59 (1H, m), 4.12 (2H, m), 4.20 (1H, q, J= 7.4Hz), 4.27 (1H, d, J= 5.4Hz).
MS 実測値 454.9 [M+H]+, 476.8 [M+Na]+.
HRMS C22H34N2O8Naとして計算値, 477.2213. 実測値, 477.2210
(1S,2S,4S,5R,6R)−2−[2’S−tert−ブトキシカルボニルアミノ−3’−(4−tert−ブトキシカルボニルオキシ−フェニル)プロピオニルアミノ]−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ジエチルエステル
[α]23 D = -12 (c=1.0, MeOH).
1H NMR (400MHz, CD3OD) δ1.25 (6H, m), 1.37 (9H, s), 1.52 (9H, s), 1.68 (1H, dd, J= 5.4, 15.3Hz), 2.06 (1H, m), 2.38 (1H, d, J= 15.3Hz), 2.64 (1H, m), 2.79 (1H, dd, J= 8.4, 13.9Hz), 3.05 (1H, dd, J= 5.4, 13.9Hz), 4.20 (6H, m), 7.04 (2H, d, J= 8.4Hz), 7.26 (2H, d, J= 8.4Hz).
MS 実測値 621.8 [M+H]+, 643.8 [M+Na]+.
HRMS C31H44N2O11Naとして計算値, 643.2843. 実測値, 643.2845.
(1S,2S,4S,5R,6R)−2−(2’S−tert−ブトキシカルボニルアミノ−4’−メチルスルファニル−ブチリルアミノ)−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ジエチルエステル
[α]23 D = -30 (c=1.0, MeOH).
1H NMR (400MHz, CD3OD) δ1.26 (6H, m), 1.43 (9H, s), 1.84 (6H, m), 2.06 (1H, m), 2.2 (1H, m), 2.48 (1H, m), 2.61 (1H, m), 3.37 (1H, m), 2.49 (1H, m), 4.2 (6H, m).
MS 実測値 488.8 [M+H]+, 510.8 [M+Na]+.
HRMS C22H36N2O8SNaとして計算値, 511.2090. 実測値, 511.2071.
(1S,2S,4S,5R,6R)−2−(2’S−tert−ブトキシカルボニルアミノ−プロピオニルアミノ)−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ジエチルエステル
白色泡沫状物の収率3.0g(90%、7.00mmol)。
[α]23 D = -32.31°(c = 0.37, CHCl3).
1H NMR (300MHz, CDCl3) δ1.28 (6H, t, J = 7.3Hz), 1.34 (3H, d, J = 7.3Hz), 1.46 (9H, s), 1.51-1.58 (2H, m), 1.64 (1H, s), 2.19 (1H, dd, J = 3.3, 6.2Hz), 2.40 (1H, dd, J = 2.9, 6.2Hz), 2.80 (1H, d, J = 15.8Hz), 4.10-4.36 (6H, m), 4.92 (1H, bs), 6.94 (1H, bs).
元素分析 C20H32N2O8・0.1H2Oとして計算値: C, 55.83; H, 7.54; N, 6.51. 実測値: C, 55.57; H, 7.64; N, 6.44.
MS (ES) m/z 429.2 [M+H]+, 329.1 [M-Boc]+.
(1S,2S,4S,5R,6R)−2−(2’S−アミノ−プロピオニルアミノ)−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ジエチルエステル塩酸塩
[α]23 D = -28.0°(c = 0.50, MeOH).
1H NMR (300MHz, CDCl) δ1.24 (3H, t, J = 7.0Hz), 1.28 (3H, t, J=7.3Hz), 1.50 (3H, d, J = 7.3Hz), 1.61 (1H, t, J = 2.9Hz), 1.76 (1H, dd, J = 5.9, 15.8Hz), 2.10 (1H, dd, J = 3.3, 5.9Hz), 2.43 (1H, d, J = 15.4Hz), 2.60 (1H, dd, J = 2.9, 6.2Hz), 3.90 (1H, q, J = 7.0, 13.9Hz), 4.15 (2H, q, J = 7.3Hz), 4.14-4.31 (3H, m).
元素分析 C15H24N2O6・HCl・0.7H2Oとして計算値: C, 47.73; H, 7.05; N, 7.42. 実測値: C, 47.96; H, 6.91; N, 7.04.
MS (ES) m/z 329.1 [M+H]+.
(1S,2S,4S,5R,6R)−2−[2’S−(2S−tert−ブトキシカルボニルアミノ−プロピオニルアミノ)プロピオニルアミノ]−4−ヒドロキシ−ビシクロ[3.1.0.]ヘキサン−2,6−ジカルボン酸ジエチルエステル
[α]23 D = -46.2 (c=0.52, CHCl3).
1H NMR (300MHz, CDCl3) δ1.27 (3H, t, J=7.0Hz), 1.28 (3H, t, J=7.0Hz), 1.36 (3H, d, J = 7.0Hz), 1.37 (3H, d, J = 7.0Hz), 1.44 (9H, s), 1.58-1.65 (2H, m), 2.19 (1H, dd, J=3.0, 5.9Hz), 2.46 (1H, dd, J=2.6, 5.9Hz), 2.70 (1H, d, J=15.4Hz), 4.09-4.33 (7H, m), 4.48 (1H, app p, J=7.0Hz), 5.05 (1H, bd, J=6.6Hz), 6.79 (1H, bd, J=7.7Hz), 7.26 (1H, s).
HRMS C23H38N3O9として計算値, 500.2608. 実測値, 500.2598.
(1S,2S,4S,5R,6R)−2−[2’S−(2−tert−ブトキシカルボニルアミノ−アセチルアミノ)プロピオニルアミノ]−4−ヒドロキシ−ビシクロ[3.1.0.]ヘキサン−2,6−ジカルボン酸ジエチルエステル
[α]23 D = -14 (c=1.00, CDCl3).
1H NMR (300MHz, CDCl3) δ1.27 (3H, t, J=7.3Hz), 1.29 (3H, t, J=7.3Hz), 1.38 (3H, d, J=7.0Hz), 1.45 (9H, s), 1.57-1.65 (2H, m), 2.19 (1H, dd, J=3.3, 5.9Hz), 2.44 (1H, dd, J=2.9, 5.9Hz), 2.74 (1H, d, J=15.8Hz) 3.70-3.86 (2H, m), 4.08-4.34 (6H, m), 4.56 (1H, app p, J=7.0Hz), 5.31 (1H, bs), 6.88 (1H, bd, J=7.0Hz), 7.50 (1H, s).
HRMS C22H36N3O9として計算値, 486.2452. 実測値, 486.2444.
(1S,2S,4S,5R,6R)−2−[2’−(2S−tert−ブトキシカルボニルアミノ−4−メチル−ペンタノイルアミノ)プロピオニルアミノ]−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ジエチルエステル
白色泡沫状物の収率0.54g(62%、1.00mmol)。
[α]23 D = -61.2°(c = 0.49, MeOH).
1H NMR (300MHz, CDCl3) δ0.93 (3H, d, J=6.2Hz), 0.94 (3H, d, J=6.2Hz), 1.25 (3H, t, J=7.3Hz), 1.27 (3H, t, J=7.3Hz), 1.36 (3H, d, J=7.0Hz), 1.43 (9H, s), 1.53 (1H, d, J=9.5Hz), 1.55-1.69 (5H, m), 2.18 (1H, dd, J=2.9, 5.9Hz), 2.44 (1H, dd, J=2.9, 6.2Hz), 2.70 (1H, d, J=15.8Hz), 4.06 (1H, bs), 4.13 (4H, q, J=7.3Hz), 4.18-4.28 (2H, m), 4.31 (1H, d, J=5.9Hz), 4.41-4.45 (1H, m), 4.85 (1H, bs), 6.57 (1H, d, J=7.3Hz), 6.97 (1H, bs).
元素分析 C26H43N3O9・0.1H2Oとして計算値: C, 57.46; H, 8.01; N, 7.73. 実測値: C, 57.18; H, 8.00; N, 7.64.
HRMS C26H43N3O9 [M+Na]+として計算値, 564.2897. 実測値, 564.2922.
(1S,2S,4S,5R,6R)−2−[2’−(2S−tert−ブトキシカルボニルアミノ−3−メチル−ブチリルアミノ)プロピオニルアミノ]−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ジエチルエステル
白色泡沫状物の収率0.36g(43%、0.68mmol)。
[α]23 D = -65.5°(c = 0.58, MeOH).
1H NMR (300MHz, CDCl3) δ0.91 (3H, d, J=7.0Hz), 0.97 (3H, d, J=6.6Hz), 1.27 (3H, t, J=7.3Hz), 1.28 (3H, t, J=7.0Hz), 1.37 (3H, d, J=17.3Hz), 1.44 (9H, s), 1.54-1.61 (3H, m), 2.12-2.20 (2H, m), 2.42 (1H, dd, J=2.6, 5.9Hz), 2.70 (1H, d, J=15.4Hz), 3.90 (1H, t, J=6.6Hz), 4.13 (2H, q, J=7.0Hz), 4.20-4.29 (2H, m), 4.31 (1H, d, J=5.9Hz), 4.40-4.48 (1H, m), 4.93 (1H, bs), 6.41 (1H, d, J=7.3Hz), 6.91 (1H, bs).
元素分析 C25H41N3O9・0.2CH2Cl2として計算値: C, 55.58; H, 7.66; N, 7.72. 実測値: C, 55.76; H, 7.27; N, 7.49.
MS (ES) m/z 528.3 [M+H]+.
(1S,2S,4S,5R,6R)−2−(2’S−アセチルアミノ−プロピオニルアミノ]−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ジエチルエステル
[α]23 D = -48°(c = 0.5, MeOH).
1H NMR (300MHz, CDCl3) δ1.27 (3H, t, J=7.3Hz), 1.28 (3H, t, J=7.3Hz), 1.37 (3H, d, J=7.0Hz), 1.55-1.62 (2H, m), 1.99 (3H, s), 2.19 (1H, dd, J=3.3, 6.6Hz), 2.40 (1H, dd, J=2.6, 5.9Hz), 2.77 (1H, d, J=15.8Hz), 4.07 (2H, q, J = 7.0Hz), 4.21-4.31 (2H, m), 4.33 (1H, d, J=6.2Hz), 4.43-4.47 (1H, m), 6.13 (1H, bs), 7.06 (1H, bs).
元素分析 C17H26N2O7として計算値: C, 55.13; H, 7.08; N, 7.56. 実測値: C, 55.05; H, 7.12; N, 7.29.
HRMS C17H26N2O7 [M+Na]+として計算値, 393.1638. 実測値, 393.1644.
3−アセトキシ−2S−(tert−ブトキシカルボニルアミノ)プロピオン酸
(1S,5R)−3−(tert−ブトキシカルボニルアミノ)−3−(tert−ブトキシカルボニル)−6−オキサビシクロ[3.1.0]ヘキサン
1H NMR (300MHz, CDCl3) δ5.57 (s, 2H, CH=CH), 3.71 (s, 3H, CH3), 2.95 (s, 4H, 2CH2), 1.42 (s, 9H, C(CH3)3).
IR (film) 1734 (C=O), 1646, 1268, 1149 cm-1.
mp = 119℃.
1H NMR (300MHz, CDCl3), δ5.61 (s, 2H, CH=CH), 3.00 (s, 4H, 2CH2), 1.46 (s, 9H, C(CH3)3).
IR: 3800-3000 (br, COOH), 1741 (CO2R), 1705 (CO2H), 1283), 1149 cm-1.
1H NMR (300MHz, CDCl3) δ5.61 (s, 2H, CH=CH), 3.04 (app q, J = 15.1Hz, 4H, 2CH2), 1.49 (s, 9H, C(CH3)3).
IR (film) 1796 (COCl), 1743 (CO2R), 1274, 1233, 1158 cm-1.
1H NMR (300MHz, CDCl3) δ5.58 (s, 2H, CH=CH), 2.96 (app t, J = 2.3Hz, 4H, 2CH2), 1.46 (s, 9H, C(CH3)3).
IR (film) 2137 (CON3), 1720 (CO2R), 1246 (s, 1185, 1136 cm-1.
1H NMR (300MHz, CDCl3) δ5.67 (s, 2H, CH=CH), 3.01 (d, J = 15.6Hz, 2H), 2.61 (d, J = 15.6Hz, 2H), 1.50 (s, 9H, C(CH3)3).
IR (film) 2258 (-NCO), 1732 (-CO2R), 1157 cm-1.
m.p. 87-89℃.
1H NMR (500MHz, CDCl3) δ5.63 (s, 2H, CH=CH), 5.1 (bs, 1H, NH), 2.99 (d, J = 17.2Hz, 2H), 2.57 (d, J = 16.0Hz, 2H), 1.46 (s, 9H), 1.44 (s, 9H).
13C NMR (CDCl3) δ173.3, 154.9, 127.7, 81.1, 64.5, 44.8, 28.3, 27.8.
IR (KBr): 3451, 2981, 2932, 1712, 1489, 1369, 1154 cm-1.
MS (FIA) m/e (相対強度%) 284.2 (M++1, 56), 228.2 (73), 172.1 (97), 128.0 (100).
m.p. 130-133℃.
1H NMR (500MHz, CDCl3) δ5.0 (bs, 1H), 3.58 (s, 2H), 2.41 (d, J = 15.3Hz, 2H), 2.20 (d, J = 15.2Hz, 2H), 1.43 (s, 9H), 1.40 (s, 9H).
13C NMR (CDCl3) δ171.3, 154.3, 81.2, 79.5, 62.8, 57.0, 38.6, 28.3, 27.7.
IR (KBr): 3453, 2982, 2932, 1726, 1708, 1489, 1369, 1293, 1156, 840 cm-1.
MS (FIA) m/e (相対強度%) 300.3 (M++1, 65), 244.4 (68), 188.2 (100) 144.1 (99).
(1R,3R)−1,3−ジ(メチルベンジルアミノ)プロパン二塩酸塩
1H NMR (500MHz, DMSO-d6) δ9.93 (bs, 2H), 9.47 (bs, 2H), 7.56 (d, J = 7.0Hz, 4H), 7.37 (m, 6H), 4.27 (m, 2H), 2.84 (m, 2H) 2.48 (m, 2H), 2.1 (m, 2H), 1.56 (d, J = 6.7Hz, 6H).
(1S)−1−(tert−ブトキシカルボニルアミノ)−1−(tert−ブトキシカルボニル)シクロペンタ−4−エン−3−オン
m. p. 111-112℃.
キラルHPLCアッセイ: 99.7% ee.
[α]D = +114 (c 1, MeOH.
1H NMR (500MHz, CDCl3) δ6.1 (bs, 1H), 5.9 (bs, 1H), 5.55 (d, J = 5.0Hz, 1H), 4.8 (m, 1H), 4.44 (d, J = 10.5Hz, 1H), 2.87 (dd, J = 14.5, 7.5Hz, 1H), 2.00 (d, J = 14.5Hz, 1H), 1.45 (s, 9H), 1.42 (s, 9H).
IR (KBr): 3413, 2983, 1703, 1491, 1370, 1309, 1255, 1155, 1055 cm-1.
MS (FIA) m/e (相対強度%) 300.3 (M++1, 15), 226.2 (29), 170.1 (100), 126.1 (89), 108.3 (20).
m.p. 116-18℃.
[α]D = +123 (c 1, MeOH).
1H NMR (500MHz, CDCl3) δ7.4 (bs, 1H), 6.32 (d, J = 5.5Hz, 1H), 5.6 (bs, 1H), 2.87 (d, J = 18.2Hz, 1H), 2.9 (d, J = 18.2Hz, 1H), 1.43 (s, 18H). 13C NMR (CDCl3) δ206.1, 170.2, 160.8, 154.9, 136.1, 84.5, 66.1, 46.6, 28.9, 28.4.
IR (KBr): 3419, 2983, 1722, 1487, 1730, 1300, 1259, 1151, 1012 cm-1.
MS (FIA) m/e (相対強度%) 254.2 (M++1, 11), 242.3 (18), 228.2 (13), 186.1 (76), 143.2 (11), 242.3 (100).
臭化1−(2−tert−ブトキシ−2−オキソエチル)テトラヒドロチオフェニウム
1H NMR (500MHz, DMSO d-6) δ4.40 (s, 1H), 3.51 (m, 2H), 3.48 (m, 2H), 2.23 (m, 2H), 2.13 (M, 2H), 1.42 (s, 9H).
(1S,2S,5R,6R)−2−(tert−ブトキシカルボニルアミノ)−4−オキソ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ジ−tert−ブチルエステル
(1S,2S,5R,6R)−2−(tert−ブトキシカルボニルアミノ)−4−オキソ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ジ−tert−ブチルエステル
飽和炭酸カリウム水溶液1.7Lを臭化1−(2−tert−ブトキシ−2−オキソエチル)テトラヒドロチオフェニウム757g(2.67mol、製造例48)の0℃ジクロロメタン2.2L溶液に、温度を10℃以下に保ちながら加えた。二相混合物を1.5時間撹拌した後、50%水酸化ナトリウム溶液223mLを、温度を5℃以下に保ちながら滴加した。混合物を3時間撹拌し、ろ過した。塩をジクロロメタンですすいだ。層を分離し、水層をジクロロメタン600mLで抽出した。集めた有機層を固体炭酸カリウムで乾燥し、減圧濃縮し、(2−tert−ブトキシ−2−オキソエチル)テトラヒドロチオフェニウム533.3g(98%収率)を淡黄色油状物として得た。冷蔵庫に貯蔵し、油状物を結晶化させ、灰白色固体を得た。
mp 48-50℃.
1H NMR (500MHz, CDCl3) δ3.12 (m, 2H), 3.00 (m, 2H), 2.85 (s, 1H), 2.41 (m, 2H), 1.84 (m, 2H), 1.38 (s, 9H).
mp 144-46℃.
[α]D = +30.5 (c 1, CHCl3).
1H NMR (500MHz, CDCl3) δ5.36 (d, 1H), 2.88 (m, 1H), 2.64 (dd, J = 5.2, 3.2Hz, 1H), 2.37 (d, J = 2.7Hz, 1H), 2.23 (bs, 1H), 1.45 (s, 9H), 1.43 (s, 18H).
13C NMR (125MHz, CDCl3) δ206.2, 171.2, 168.5, 155.3, 83.4, 82.7, 80.7, 61.2, 43.2, 36.0, 34.3 28.4, 28.2, 28.0, 25.3.
IR (CHCl3): 2982, 1744, 1719, 1485, 1394, 1309 cm-1.
MS (ES+) m/e (相対強度%) 412.2 (M++1, 79), 356.2 (50), 300.1 (97), 276.1 (68), 244.1 (100).
元素分析 C21H33NO7として計算値 (411.29): C, 61.30; H, 8.08; N, 3.40. 実測値: C, 61.32; H, 8.04; N, 3.51.
(1S,2S,4S,5R,6R)−2−(tert−ブトキシカルボニルアミノ)−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ジ−tert−ブチルエステル
m.p. 187-88℃.
1H NMR (CDCl3, 500MHz) δ5.31(bs, 1H), 4.38 (d, JAB = 10.5Hz, 1H), 4.30 (dd, J = 11.0, 6.0Hz, 1H), 2.68 (d, J = 15.3Hz, 1H), 2.17 (m, 1H), 2.07 (m, 1H), 1.58 (m, J = 15.2Hz, 1H), 1.45 (s, 9H), 1.44 (s, 9H), 1.43 (s, 9H).
13C NMR (75MHz, CDCl3) δ175.2, 170.5, 155, 83.2, 81.3, 80.1, 73.7, 66.9, 43.1, 36.0, 34.4, 29.3, 28.3, 28.1, 27.4, 22.1.
IR (CHCl3): 3445, 2982, 1714, 1485, 1361 cm-1.
MS (ES+) m/e (相対強度%) 414.2 (M++1, 58), 358.1 (75), 302.1 (78), 246.0 (100).
[α]D = -28.6 (c 1, MeOH).
(1R,2S,4R,5R,6R)−2−(2’S−2’−(tert−ブトキシカルボニルアミノ)プロピオニル)アミノ−4−フルオロ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸
m.p. 140-143℃.
[α]D = + 20.6 (c 1, CHCl3).
1H NMR (CDCl3, 500MHz) δ5.45 (dd, JH-F = 56, JH-H = 4.8Hz, 1H), 5.28 (bs, 1H), 3.00 (m, 1H), 2.23 (bs, 1H), 2.11 (m, 1H), 2.08 (m, 1H), 1.46 (s, 9H), 1.45 (s, 9H), 1.43 (s, 9H), 1.37 (m, 1H).
13C NMR (CDCl3, 75MHz) δ177.7, 170.5, 155.0, 94.4, 92.0, 82.2, 81.5, 80.2, 64.7, 37.7, 33.2, 29.7, 29.3, 28.3, 28.1, 27.8, 20.4.
MS (ES+) m/e (相対強度%) 416.2 (M++1, 66), 360.1 (67), 304.1 (100), 248.0 (60).
IR (CHCl3): 3444, 2981, 1715, 1485, 1369 cm-1.
(1R,4S,5S,6S)−4−アミノ−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0]ヘキサン−4,6−ジカルボン酸ジエチルエステル
m.p. 80-83℃.
[α]25 D -57.7 (c 1.04, CH3OH).
500MHz 1H NMR (CDCl3) δ4.31 (q, 2H, J = 7.0Hz), 4.20 (m, 2H), 3.78 (d, 1H, J = 15.0Hz), 3.36 (dd, 1H, J = 4.0, 7.0Hz), 2.93 (dd, 1H, J = 4.0, 7.0Hz), 2.81 (d, 1H, J = 15.0Hz), 2.46 (t, 1H, J = 4.0), 1.34 (t, 3H, J = 7.0), 1.30 (t, 3H, J = 7.0).
13C NMR (125MHz, CD3Cl3) δ171.68, 168.57, 63.26, 62.42, 59.96, 56.06, 43.78, 32.25, 22.49, 14.31, 14.25.
FTIR (ATR) 3364.15 (s), 1725.95 (s), 1304.91 (s), 1259.24 (s), 1200.84 (s), 1104.91 (s), 1022.99 (s), 896.45 (s), 851.21 (s) cm-1.
元素分析 C11H17NO6Sとして計算値: C, 45.35; H, 5.88; N, 4.81. 実測値: C, 45.02; H, 5.75; N, 4.82.
(1R,4S,5S,6S)−4−(2’S−4’−メチルチオ−2’−(tert−ブトキシカルボニル)アミノブタノニル)アミノ−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0]ヘキサン−4,6−ジカルボン酸ジエチルエステル
[α]25 D -12.7 (c 1.2, CH3OH).
500MHz 1H NMR (CDCl3) δ7.53 (s, 1H), 5.06 (d, 1H, J = 8.0Hz), 4.34-4.20 (m, 6H), 3.41 (dd, 1H, J = 4.0, 7.0), 2.97-2.89 (m, 2H), 2.64-2.59 (m, 2H, J = 4.0), 2.12-1.89 (m, 5H), 1.47 (s, 9H), 1.32 (t, 6H, J = 7.0).
13C NMR (125MHz, CD3OD) δ172.53, 169.03, 167.88, 156.00, 80.62, 63.45, 62.56, 60.20, 55.33, 52.78, 42.81, 31.52, 31.38, 30.12, 28.49, 22.69, 15.44, 14.23, 14.143.
FTIR (ATR) 3341.88 (w), 2979.38 (s), 1733.03 (s), 1674.92 (s), 1514.58 (s), 1315.80 (s), 1255.15 (s), 1161.47 (s), 1142.63 (s), 1025.68 (s), 854.85 (s), 763.53 (s) cm-1.
(1R,4S,5S,6S)−4−(2’S−4’−メチルチオ−2’−(tert−ブトキシカルボニル)アミノブタノニル)アミノ−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0]ヘキサン−4,6−ジカルボン酸モノナトリウム塩
2N水酸化ナトリウム141mL(282mmol)を(1R,4S,5S,6S)−4−(2’S−4’−メチルチオ−2’−(tert−ブトキシカルボニル)アミノブタノニル)アミノ−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0]ヘキサン−4,6−ジカルボン酸ジエチルエステル58.95g(理論値112.8mmol、製造例54)のテトラヒドロフラン141mL溶液に、室温にて加えた。混合物を室温にて2分間激しく撹拌した。溶液をtert−ブチルメチルエーテル141mLで希釈した後、層を分離した。さらに水層を水141mLで希釈し、濃塩酸を滴加し、pHを4.46まで低下させた。10分間撹拌し、粘稠なスラリーを得た。より濃い塩酸をスラリーに滴加し、pHを1.4とした(全濃塩酸の使用量17mL、204mmol)。2時間撹拌した後、スラリーをろ過した。ケーキを水(2x118mL)で洗浄し、天秤に移す前に45℃にて1時間減圧乾燥した。ケーキを再び45℃にて16時間減圧乾燥し、58℃にて5時間減圧乾燥し、標記化合物52.96g(96%重量収率)を白色固体として得た。
mp (分解) 258℃.
[α]25 D -25.2 (c 1.03, H2O).
500MHz 1H NMR (D2O) δ4.07-4.01 (m, 2H), 3.45-3.43 (m, 1H), 3.11 (d, 1H, J = 15.0Hz), 2.85 (m, 1H), 2.71 (s, 3H), 2.47-2.35 (m, 3H), 1.96-1.90 (m, 4H), 1.78-1.72 (m, 1H), 1.28 (s, 9H).
13C NMR (125MHz, CD3OD) δ174.45, 173.58, 172.80, 157.46, 81.71, 61.41, 55.04, 53.24, 42.29, 31.71, 30.85, 29.41, 27.79, 23.65, 14.41.
FTIR (ATR) 3287.62 (s), 1698.00 (s), 1528.91 (s), 1327.36 (s), 1283.74 (s), 1245.90 (s), 1174.81 (s), 1109.06 (s), 1053.05 (s), 874.27 (s), 808.95 (s) cm-1.
(1R,4S,5S,6S)−4−(2’S−4’−メチルチオ−2’−(tert−ブトキシカルボニル)アミノブタノニル)アミノ−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0]ヘキサン−4,6−ジカルボン酸
2−ブロモ−2−フルオロ−2−(3−オキソシクロペンチル)酢酸エチル
1H-NMR (300MHz, CDCl3): 1.34-1.41 (m, 6H), 1.91-1.95 (m, 1H), 2.04-2.68 (m, 11H), 3.12-3.31 (m, 2H), 4.33-4.43 (m, 4H).
(1RS,5RS,6RS)−6−フルオロ−2−オキソビシクロ[3.1.0]ヘキサン−6−カルボン酸エチル
1H-NMR (300MHz, CDCl3): 1.33 (t, 3H, J = 7.1Hz), 2.19-2.34 (m, 3H), 2.41-2.49 (m, 1H), 2.59 (d, 1H, J = 6.6Hz), 2.71-2.76 (m, 1H), 4.29 (q, 2H, J= 7.1Hz).
(1RS,2SR,5RS,6RS)−2−スピロ−5’−ヒダントイン−6−フルオロ−ビシクロ[3.1.0]ヘキサン−6−カルボン酸
(1R,2S,5R,6R)−ジエチル−2−(2’R-tert−ブトキシカルボニルアミノ−プロピオニルアミノ)−6−フルオロ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸および(1S,2R,5S,6S)−ジエチル−2−(2’R-tert−ブトキシカルボニルアミノ−プロピオニルアミノ)−6−フルオロ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸
1H-NMR (300MHz, CDCl3): 1.18 (t, 3H, J = 7.1Hz), 1.23 (t, 1H, J = 7.1Hz) , 1.36 (s, 9H), 1.56-1.68 (m, 1H), 2.03-2.11 (m, 2H), 2.21-2.31 (m, 1H), 2.37-2.45 (m, 1H), 2.61-2.63 (m, 1H), 4.09-4.16 (m, 5H), 5.10 (bd, 1H, J= 6.6Hz), 7.11 (bs, 1H).
13C-NMR (75MHz, CDCl3): 13.9, 14.0, 17.7, 24.9 (d, J = 1.0Hz), 28.1, 31.5 (d, J = 10.9Hz), 34.9 (d, J = 9.4Hz), 36.4 (d, J = 8.8Hz), 49.1, 61.5, 61.8, 67.4, 77.2, 81.5 (d, J = 242.6Hz), 155.4, 168.6 (d, J = 25.1Hz), 171.8および172.7ppm.
異性体B: (1S,2R,5S,6S,2’R)−ジエチル−2−(2’−tert−ブトキシカルボニルアミノ−プロピオニルアミノ)−6−フルオロ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸
1H-NMR (300MHz, CDCl3): 1.13 (t, 3H, J = 7.1Hz), 1.18 (t, 1H, J = 7.1Hz) , 1.31 (s, 9H), 1.51-1.60 (m, 1H), 1.98-2.07 (m, 2H), 2.15-2.22 (m, 1H), 2.26-2.39 (m, 1H), 2.55-2.60 (m, 1H), 4.07-4.12 (m, 5H), 5.20 (sd, 1H), 7.22 (bs, 1H).
13C-NMR (75MHz, CDCl3): 13.7, 13.8, 18.0, 24.7, 28.0, 31.4 (d, J = 10.9Hz), 34.5 (d, J = 8.9Hz), 36.3 (d, J = 9.4Hz), 49.1, 61.4, 61.7, 67.3, 77.2, 81.4 (d, J = 242.6Hz), 155.2, 168.5 (d, J = 25.1Hz), 171.7および172.8 ppm.
(1R,2S,5R,6R)−2−アミノ−6−フルオロ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸
[α]D = -25.0 (c=0.80 mg/mL, H2O).
(1S,2R,5S,6S)−2−アミノ−6−フルオロ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸
[α]D = 21.7 (c=0.46 mg/mL, H2O).
(6S)−4−チアビシクロ[3.1.0]ヘキサ−2−エン−6−カルボン酸エチル
(4S,6S)−4−ヒドロキシ−2−チアビシクロ[3.1.0]ヘキサン−6−カルボン酸エチル
(6S)−4−オキソ−2−チアビシクロ[3.1.0]ヘキサン−6−カルボン酸エチル
(6S,11S)−8,10−ジオキソ−2−チアスピロ[ビシクロ[3.1.0]ヘキサン−4,5’−イミダゾリジン]−6−カルボン酸
ラセミ酸15g(65.7mmol、ヒダントインのジアステレオマー比約6:1)のエタノール300mLおよび水75mLスラリーに、(R)−フェニルグリシノール9.0g(65.7mmol)を加えた。混合物を約80℃まで加熱し、溶解させた。暗色溶液をゆっくり冷却し、沈殿物を40〜45℃にて観察した。スラリーをさらに0℃まで冷却し、1〜1.5時間保った。固体を集め、4:1エタノール:水(1x60mL、0℃まで予め冷やす)で(撹拌しながら)洗浄し、65℃にて12〜24時間減圧乾燥した。分割した塩の典型的な収率は、観測される>98%deおよび>98%eeを伴った37〜45%の範囲であった。分割した塩は6倍容積(mL/g)の水に溶解させた後、1.1当量の濃塩酸で処理した。スラリーを0℃まで冷却し、1時間撹拌した後、ろ過し、1倍容積の冷水ですすぎ、60℃にて減圧乾燥した。標記化合物の典型的収率は、%deおよび%ee>99%を伴った>90%であった。
(6S,11S)−2,2,8,10−テトラオキソ−2−チアスピロ[ビシクロ[3.1.0]ヘキサン−4,5’−イミダゾリジン]−6−カルボン酸
[α]25 D -48.6 (c, 1.19, 1N NaOH).
mp 275℃ (灰色), 295℃ (茶色).
500MHz 1H NMR (DMSO-d6) δ13.15 (br s, 1H), 10.99 (s, 1H), 8.13 (s, 1H), 3.85 (d, 1H, J = 15.0Hz), 3.74 (dd, 1H, J = 7.0, 4.0Hz), 3.03 (d, 1H, J = 15.5Hz), 2.80 (dd, 1H, 7.0, 4.0Hz), 2.39 (t, 1H, J = 4.0Hz).
13C NMR (125MHz, DMSO-d6) δ174.39, 169.87, 156.35, 62.67, 52.59, 44.16, 31.69, 21.92;
FTIR (KBr) 3317 (s), 3250 (s), 3211 (s), 3086 (w), 1791 (s), 1742 (s), 1713 (s), 1327 (s), 1192 (s), 1140 (s) cm-1.
元素分析 C8H8N2O6Sとして計算値: C, 36.93; H, 3.10; N, 10.77. 実測値: C, 36.76; H, 3.07; N, 10.60.
(1R,4S,5S,6S)−4−アミノ−(2−スルホニルビシクロ[3.1.0]ヘキサン)−4,6−ジカルボン酸
(6S)−2−オキソビシクロ[3.1.0]ヘキサン−6−カルボン酸エチル
(±)(6S)−2−オキソビシクロ[3.1.0]ヘキサン−6−カルボン酸
(+)(6S)−2−オキソビシクロ[3.1.0]ヘキサン−6−カルボン酸N−ベンジル−α−メチルベンジルアミン塩
GC条件: 30 m X 0.25 mm X 0.25 μ β-DEX 325 カラム, 140℃オーブン温度, 1 mL/分におけるヘリウムキャリアガス, 250℃でのFID検出, 1 μLスプリット1:100, ジクロロメタン中1mg/mLにおけるサンプル.
(6S)−2−オキソビシクロ[3.1.0]ヘキサン−6−カルボン酸エチル
(6S)−6−(エトキシカルボニル)ビシクロ[3.1.0]ヘキサ−2−エン−2−イルアセテート
[α]25 D +185 (c 1.48, CHCl3).
500MHz 1H NMR (CDCl3) δ5.19-5.18 (m, 1H), 4.12 (q, 1H, J = 7.0Hz), 4.11 (q, 1H, J = 7.0Hz), 2.74-2.69 (m, 1H), 2.48-2.43 (m, 2H), 2.22-2.19 (m, 1H), 2.16 (s, 3H), 1.39 (dd, 1H, J = 2.5, 2.5Hz), 1.25 (t, 3H, J = 7.0Hz).
13C NMR (125MHz, CDCl3) δ173.37, 169.01, 152.26, 111.56, 61.28, 32.47, 32.40, 29.72, 24.97, 21.67, 14.95.
FTIR (CHCl3) 3026 (m), 2985 (m), 1724 (s), 1272 (s), 1187 (s) cm-1.
ES HRMS C11H18NO4 [M+NH4]+として計算値 228.1236, 実測値 228.1252.
(3S,1R,6R)−7−オキサ−5−オキソトリシクロ[4.1.0.0<2,4>]ヘプタン−3−カルボン酸エチル
[α]25 D +2.3 (c 1.20, CHCl3), +8.4°(c 1.28, アセトン); mp 129-130℃.
500MHz 1H NMR (CDCl3) δ4.16 (q, 2H, J = 7.0Hz), 3.99 (t, 1H, J = 2.5Hz), 3.24-3.23 (m, 1H), 2.96-2.94 (m, 1H), 2.21-2.19, (m, 1H), 2.08 (t, 1H, J = 3.0Hz), 1.26 (t, 3H, J = 7.0Hz).
13C NMR (125MHz, CDCl3) δ201.19, 168.84, 62.42, 57.04, 51.25, 31.16, 30.54, 29.60, 14.79.
FTIR (KBr) 3087 (w), 3059 (w), 3051 (w), 3007 (w), 2993 (w), 2963 (w), 1753 (s), 1719 (s), 1273 9s), 1191 (s), 1009 (m), 848 (m) cm-1.
元素分析 C9H10O4として計算値: C, 59.34; H, 5.53. 実測値: C, 59.32; H, 5.43.
(6S)−4−オキソビシクロ[3.1.0]ヘキサ−2−エン−6−カルボン酸エチル
[α]25 D -268 (c 1.17, CHCl3).
mp 97-98℃.
500MHz 1H NMR (CDCl3) δ7.60 (ddd, 1H, J = 5.5, 2.5, 0.75Hz), 5.73 (dd, 1H, J = 5.0, 0.5Hz), 4.15 (q, 2H, J = 7.0Hz), 2.96-2.94 (m, 1H), 2.63-2.61 (m, 1H), 2.60 (t, 1H, J = 2.5Hz), 1.26 (t, 3H, J = 7.0Hz).
13C NMR (125MHz, CDCl3) δ203.96, 168.61, 160.33, 130.29, 62.03, 46.53, 30.72, 29.62, 14.82.
FTIR (KBr) 3080 (m), 2996 (m), 1717 (s), 1695 (s), 1266 (s), 1291 (m), 1191 (s), 1179 (s) cm-1.
元素分析 C9H10O3として計算値: C, 65.05; H, 6.07. 実測値: C, 64.97; H, 6.01.
(4S,6S)−4−ヒドロキシ−2−オキソビシクロ[3.1.0]ヘキサン−6−カルボン酸エチル
[α]25 D +3.9 (c 1.39, CHCl3), +6.0°(c 1.69, MeOH).
mp 81-82℃.
500MHz 1H NMR (CDCl3) δ4.60 (br s, 1H), 4.16 (q, 2H, J = 7.0Hz), 2.66 (dd, 1H, J = 5.0, 4.0Hz), 2.42-2.40 (m, 1H), 2.34 (dd, 1H, J = 19.0, 5.5Hz), 2.24, (br d, 1H, J = 3.0Hz), 2.07 (d, 1H, J = 19.0Hz), 1.91 (t, 1H, J = 3.0Hz), 1.27 (t, 3H, J = 7.0Hz).
13C NMR (125MHz, CDCl3) δ209.74, 170.07, 69.04, 62.32, 43.47, 36.89, 34.95, 26.14, 14.83.
FTIR (CHCl3) 3607 (w), 3447 (w), 3025 (m), 2985 (w), 1739 (s), 1728 (s), 1270 (s).1187 (s) cm-1.
元素分析 C9H12O4として計算値: C, 58.69; H, 6.57. 実測値: C, 58.48; H, 6.63.
2−[((1R)−1−フェニルエチル)アミノ](2S,4S,6R)−2−シアノ−4−ヒドロキシビシクロ[3.1.0]ヘキサン−6−カルボン酸エチル
[α]25 D +81.6 (c 1.18, CHCl3).
mp 70-72℃ (分解).
500MHz 1H NMR (CDCl3) δ7.39 (d, 2H, J = 7.0Hz), 7.26-7.16 (m, 3H), 4.31 (d, 1H, J = 5.0Hz), 4.22 (q, 1 H, J = 6.5Hz), 3.93-3.85 (m, 2H), 2.33 (d, 1H, J = 15.0Hz), 2.01 (br t, 1H, J = 4.5Hz), 1.64 (dd, 1H, J = 15.0, 5.0Hz), 1.55-1.54 (m, 1H), 1.40-1.39 (m, 4H), 1.17 (t, 3H, J = 7.0Hz).
13C NMR (125MHz, CDCl3) δ170.54, 144.85, 128.61, 127.45, 127.38, 121.88, 72.17, 61.02, 60.66, 56.57, 45.82, 36.70, 34.45, 25.83, 21.75, 14.22.
FTIR (KBr) 3568 (m), 3489 (m), 3285 (m), 2923 (m), 2228 (w), 1712 (s), 1298 (m).1197 (m) cm-1.
FAB HRMS C18H23N2O3 [M+H]+として計算値 315.1709, 実測値 315.1704.
2−[((1R)−1−フェニルエチル)アミノ](2S,4S,6R)−4−ヒドロキシビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸
[α]25 D +4.5 (c 1.41, 1N NaOH).
mp 220℃ (灰白色から灰色), 280℃ (茶色).
500MHz 1H NMR (D2O, KOD) δ7.39 (d, 2H, J = 7.0Hz), 7.19-7.04 (m, 5H), 3.92 (d, 1H, J = 5.0Hz), 3.67 (q, 1H, J = 7.0Hz), 1.76 (d, 1H, J = 15.0Hz), 1.54-152 (m, 1H), 1.37 (dd, 1H, J = 15.0, 5.0Hz), 1.15 (d, 3H, J = 6.5Hz), 1.12 (dd, 1H, J = 6.0, 3.0Hz), 0.92 (t, 1H, J = 3.3Hz).
13C NMR (125MHz, D2O, KOD) δ185.82, 182.96, 148.01, 131.31, 129.97, 129.78, 74.99, 73.84, 58.78, 46.91, 38.05, 35.02, 27.34, 27.15.
FTIR (KBr) 3366 (m), 3072 (s), 2886 (s), 1696 (m), 1611 (m), 1560 (m), 1455 (m), 1377 (m), 1278 (m), 1202 (m), 1188 (m) cm-1.
元素分析 C16H19NO5として計算値: C, 62.94; H, 6.27; N, 4.59. 実測値: C, 62.70; H, 6.21; N, 4.67.
2−[((1R)−1−フェニルエチル)アミノ](2S,4S,6R)−2−カルバモイル−4−ヒドロキシビシクロ[3.1.0]ヘキサン−6−カルボン酸エチル
[α]25 D +61.3 (c 1.20, CHCl3).
500MHz 1H NMR (CDCl3) δ7.32-7.20 (m, 5H), 7.19 (br d, 1H, J = 4.0Hz), 5.49 (br d, 1H, J = 4.0Hz), 4.88 (d, 1 H, J = 11.5Hz), 4.24 (dd, 1H, J = 11.5, 6.0Hz), 4.06-4.00 (m, 2H), 3.77 (q, 1H, J = 7.0Hz), 2.21 (d, 1H, J = 15.0Hz), 2.18-2.15 (m, 2H), 1.71 (br s, 1H), 1.54 (dd, 1H, J = 14.5, 6.0Hz), 1.38, (d, 3H, J = 6.5Hz), 1.32 (t, 1H, J = 3.3Hz), 1.24 (t, 3H, J = 7.0Hz).
13C NMR (125MHz, CDCl3) δ180.42, 171.47, 146.05, 128.97, 127.43, 126.48, 73.16, 70.76, 61.08, 56.00, 42.82, 35.97, 35.67, 26.13, 21.53, 14.34.
FTIR (CHCl3) 3441 (m), 3345 (m), 2975 (w), 1725 (s), 1665 (s), 1288, 1186 (m) cm-1.
元素分析 C18H24N2O4として計算値: C, 65.04; H, 7.28; N, 8.43. 実測値: C, 65.41; H, 7.58; N, 8.32.
2−[((1R)−1−フェニルエチル)アミノ](2S,4S,6R)−2−(エトキシカルボニル)−4−ヒドロキシビシクロ[3.1.0]ヘキサン−6−カルボン酸エチル
[α]25 D +52.5 (c 1.30, CHCl3).
mp 73-74℃.
500MHz 1H NMR (CDCl3) δ7.29-7.14 (m, 5H), 4.25 (dq, 1H, 11.0, 7.0Hz), 4.18 (dd, 1H, J = 9.5, 5.5Hz), 4.10 (dq, 1H, J = 11.0, 7.0Hz), 3.92 (dq, 1H, J = 11.0, 7.0Hz) 3.82 (dq, 1H, J = 11.0 Hz, 7.0Hz), 3.67 (q, 1H, J = 7.0Hz), 2.73 (d, 1H, J = 9.5Hz), 2.15-2.12 (m, 2H), 2.01-1.99 (m, 1H), 1.89 (dd, 1H, J = 6.0, 3.0Hz), 1.61 (dd, 1H, J = 15.0, 6.0Hz), 1.36 (t, 1H, J = 3.5Hz), 1.33-1.30 (m, 6H), 1.18 (t, 3H, J = 7.0Hz).
13C NMR (125MHz, CDCl3) δ178.11, 171.59, 146.32, 128.41, 127.07, 126.85, 73.33, 70.15, 62.07, 60.75, 56.66, 44.72, 36.78, 33.61, 26.24, 20.07, 14.37, 14.23.
FTIR (KBr) 3492 (s), 3303 (m), 3055 (w), 2981 (w), 2896 (w), 1722 (s), 1705 (s), 1289 (m), 1251 (m), 1177 (m) cm-1.
元素分析 C20H27NO5として計算値: C, 66.46; H, 7.52; N, 3.88. 実測値: C, 66.42; H, 7.44; N, 3.92.
2−[((1R)−1−フェニルエチル)アミノ](2S,4R,6R)−2−(エトキシカルボニル)−4−フルオロビシクロ[3.1.0]ヘキサン−6−カルボン酸エチル
[α]25 D +36.2 (c 1.30, CHCl3).
500MHz 1H NMR (CDCl3) δ7.29-7.14 (m, 5H), 5.22 (ddt, 1H, J = 8.0, 4.5Hz, JHF = 56.0Hz), 4.16 (dq, 1H, J = 11.0, 7.0Hz), 4.05 (dq, 1H, 11.0, 7.0Hz), 3.96 (dq, 1H, 10.5, 7.0Hz), 3.85 (dq, 10.5, 7.0Hz), 3.66 (q, 1H, 6.5Hz), 2.45 (dd, 1H, J = 14.0, 8.0Hz), 2.16-2.12 (m, 1H), 1.95 (t, 1H, J = 3.5Hz), 1.81 (dt, 1H, J = 3.5Hz, JHF = 3.5Hz), 1.51 (ddd, 1H, J = 14.0, 8.0Hz, JHF = 22.0Hz), 1.32 (d, 3H, J = 6.5Hz), 1.27 (t, 3H, J = 7.0Hz), 1.21 (t, 3H, J = 7.0Hz).
13C NMR (125MHz, CDCl3) δ175.29, 171.66, 146.21, 128.45, 127.03, 126.90, 92.65 (d, JCF = 182Hz), 68.68 (d, JCF = 4.9Hz), 61.70, 60.92, 56.13, 38.60 (d, JCF = 23.0Hz), 33.07 (d, JCF = 7.6Hz), 32.23 (d, JCF = 22.0Hz), 26.26, 20.22 (d, JCF = 3.9Hz), 14.41, 14.24.
FTIR (CHCl3) 3028 (w), 2983 (w), 1724 (s), 1705 (s), 1293 (m), 1242 (m), 1190 (m), 1037 (m), 1013 (m) cm-1.
元素分析 C20H26FNO4として計算値: C, 66.10; H, 7.21; N, 3.85. 実測値: C, 66.02; H, 7.00; N, 3.95.
1R,2S,4R,5R,6R−2−アミノ−4−フルオロビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸塩酸塩
[α]25 D +55.6 (c 1.17, CHCl3).
mp 86-88℃.
500MHz 1H NMR (CDCl3) δ9.20 (br s, 2H), 5.50 (ddt, 1H, J = 8.0, 4.5Hz, JHF = 56.0Hz), 4.31 (q, 1H, J = 7.0Hz), 4.20-4.07 (m, 3H), 2.88 (t, 1H, J = 3.0Hz), 2.71 (dd, 1H, J = 14.5, 8.0Hz), 2.48-2.43 (m, 2H), 2.16 (ddd, 1H, J = 14.5, 7.5Hz, JHF = 22.0Hz), 1.34 (t, 3H, J = 7.0Hz), 1.25 (t, 3H, J = 7.0Hz)
13C NMR (125MHz,CDCl3) δ171.12, 169.41, 91.94 (d, JCF = 189Hz), 63.85, 63.66 (d, JCF = 3.8Hz), 61.73, 34.55 (d, JCF = 26.4Hz), 31.58 (d, JCF = 7.8Hz), 30.80 (d, JCF = 24.1Hz), 20.22, 14.31, 14.21.
FTIR (KBr) 3353 (m), 3173 (w), 2745 (m), 1729 (s), 1547 (m), 1294 (m), 1269 (m), 1195 (m), 1011 (m) cm-1.
元素分析 C12H18FNO4として計算値: C, 48.74; H, 6.48; N, 4.74. 実測値: C, 48.80; H, 6.41; N, 4.76.
1R,2S,4R,5R,6R−2−アミノ−4−フルオロビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸
1R,2S,4R,5R,6R−2−アミノ−4−フルオロビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸の再スラリー化
1R,2S,4R,5R,6R−2−アミノ−4−フルオロビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸33.0g(0.162mmol)の撹拌している水165mL懸濁液を89℃まで1時間にわたって昇温し、i−PrOH41mLを加えた。次いで混合物を5分間還流温度(83℃)にて撹拌した後、これを室温まで冷却し、4時間撹拌した。生成物を集め、i−PrOH/水(1:4)40mLおよびi−PrOH25mLで洗浄し、40℃にて18時間減圧乾燥し、標記化合物を白色固体30.6g(93%)として得た。
1R,2S,4R,5R,6R−2−アミノ−4−フルオロビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸エチルエステル
FDMS: M++1 = 260.
元素分析 C12H18FNO4・0.1 H2Oとして計算値: C, 55.21; H, 7.03; N, 5.37. 実測値: C, 55.10; H, 6.96; N, 5.22.
m.p. = 64-66℃.
[α]D 25 = +20 (c = 0.96, MeOH), [α]D 25 = +15 (c = 1.21, DMSO)
1R,2S,4R,5R,6R−2−[2’S−2’−(tert−ブトキシカルボニルアミノ)プロピオニル]アミノ−4−フルオロビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸エチルエステル
FDMS: M++1 = 260.
元素分析 C12H18FNO4・0.1 H2Oとして計算値: C, 55.21; H, 7.03; N, 5.37. 実測値: C, 55.10; H, 6.96; N, 5.22.
m.p. = 64-66℃.
[α]D 25 = +20 (c = 0.96, MeOH), [α]D 25 = +15 (c = 1.21, DMSO).
1R,2S,4R,5R,6R−2−[2’S−2’−(tert−ブトキシカルボニルアミノ)プロピオニル]アミノ−4−フルオロビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸
(1R,4S,5S,6S)−4−(2’S−アミノプロピオニル)アミノ]−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0.]ヘキサン−4,6−ジカルボン酸塩酸塩
1H NMR (300MHz, メタノール-d4) δ: 4.12 (brd, 1H, J = 14.6Hz), 3.94 (q, 1H, J = 7.1Hz), 3.52 (ddd, 1H, J = 7.0, 3.9, 0.9Hz), 3.16 (d, 1H, J = 14.6Hz), 3.02 (dd, 1H, J = 7.0, 4.4Hz), 2.49 (t, 1H, J = 4.1Hz), 1.52 (d, 3H, J = 7.1Hz).
(1R,4S,5S,6S)−4−(2’S−2’−アミノプロピオニル)アミノ−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0.]ヘキサン−4,6−ジカルボン酸トシレート
mp (DSC) 233℃.
1H NMR (500MHz, CD3OD) δ7.70 (d, 2H, J = 8.5Hz), 7.24 (d, 2H, J = 8.0Hz), 4.11 (d, 1H, J = 15Hz), 3.94 (q, 1H, J = 7.0Hz), 3.53 (dd, 1H, J = 7.0, 4.0Hz), 3.13 (dd, 1H, J = 14, 1.0Hz), 3.02 (dd, 1H, J = 7.0, 4.5Hz), 2.48 (t, 1H, J = 4.5Hz), 2.37 (s, 3H), 1.52 (d, 3H, J = 7.5Hz).
13C NMR (125MHz, CD3OD) δ170.70, 170.32, 169.80, 142.04, 140.78, 128.79, 125.79, 60.20, 54.73, 48.77, 42.44, 30.84, 22.22, 20.20, 16.09.
(1R,4S,5S,6S)−4−(2’S−アミノ−3’−ヒドロキシ−プロピオニル)アミノ−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0]ヘキサン−4,6−ジカルボン酸塩酸塩
[α]23 D = -19.23 (c=0.52, MeOH).
1H NMR (400MHz, CD3OD) δ2.48 (1H, t, J=4.0Hz), 3.04 (1H, dd, J=4.4, 7.3Hz), 3.17 (1H, d, J=14.7Hz), 3.51 (1H, dd, J=4.4, 7.0Hz), 3.77 (1H, dd, J=7.0, 10.6Hz), 3.94-4.12 (3H, m).
元素分析 C10H14N2O8S・HCl・H2Oとして計算値: C, 31.88; H, 4.55; N, 7.44; Cl, 9.41. 実測値: C, 31.53; H, 4.40; N, 7.32; Cl, 9.24.
HRMS C10H15N2O8Sとして計算値, 323.0549. 実測値, 323.0533.
(1R,4S,5S,6S)−4−[(ピロリジン−2’S−カルボニル)アミノ]−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0.]ヘキサン−4,6−ジカルボン酸塩酸塩
[α]23 D = -32 (c=1.00, CH3OH).
1H NMR (300MHz, CD3OD) δ1.98-2.12 (3H, m), 2.40-2.50 (1H, m), 2.52 (1H, t, J=4.4Hz), 2.99 (1H, dd, J=4.4, 7.0Hz), 3.2 (1H, d, J=14.7Hz), 3.29-3.42 (3H, m), 3.54 (1H, m), 4.13 (1H, d, J=15.8Hz), 4.30 (1H, dd, J=6.2, 9.2Hz).
HRMS C12H17N2O7Sとして計算値, 333.0756. 実測値, 333.0740.
(1R,4S,5S,6S)−4−(2’S−アミノ−4’−メチルスルファニル−ブチリルアミノ)−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0.]ヘキサン−4,6−ジカルボン酸塩酸塩
[α]23 D = +4 (c=1.00, MeOH).
1H NMR (300MHz, CD3OD) δ2.1-2.2 (2H, m), 2.13 (3H, s), 2.47 (1H, t, J=4.4Hz), 2.58-2.63 (2H, m), 3.02 (1H, dd, J=4.0, 7.0Hz), 3.12 (1H, d, J=14.7Hz), 3.52 (1H, dd, J=3.3, 6.6Hz), 3.98 (1H, t, J=6.2Hz), 4.14 (1H, d, J = 14.7Hz).
HRMS C12H19N2O7S2として計算値, 367.0634. 実測値, 367.0634.
(1R,4S,5S,6S)−4−[2’S−アミノ−3’−(1H−インドール−3−イル)プロピオニルアミノ]−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0]ヘキサン−4,6−ジカルボン酸塩酸塩
[α]23 D = +7.8 (c=1.02, CH3OH).
1H NMR (300MHz, CD3OD) δ2.47-2.53 (1H, m), 3.05-3.18 (3H, m), 3.44-3.57 (2H, m), 4.13-4.23 (2H, m), 7.07-7.41 (3H, m), 7.71-7.78 (2H, m), 8.22 (1H, app d, J=7.7Hz).
元素分析 C18H19N3O7S・HClとして計算値: C, 47.22; H, 4.40; N, 9.18. 実測値: C, 46.51; H, 3.96; N, 8.54.
MS (ES) m/z 420.1 [M-1]-.
(1R,4S,5S,6S)−4−[2’S−アミノ−3’−(4−ヒドロキシ-フェニル)プロピオニルアミノ]−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0.]ヘキサン−4,6−ジカルボン酸塩酸塩
[α]23 D = -6 (c=1.00, H2O).
1H NMR (300MHz, CD3OD) δ2.47 (1H, t, J=4.0Hz), 2.87 (1H, dd, J=9.2, 14.7Hz), 3.05-3.12 (2H, m), 3.23 (1H, dd, J=5.1, 14.7Hz), 3.55 (1H, dd, J=4.0, 7.0Hz), 4.00 (1H, dd, J=4.8, 9.2Hz), 4.13 (1H, d, J=14.7Hz), 6.80 (2H, d, J=8.4Hz), 7.13 (2H, d, 8.8Hz).
HRMS C16H19N2O8Sとして計算値, 399.0862. 実測値, 399.0844.
(1R,4S,5S,6S)−4−(2’S−アミノ−3’−フェニル−プロピオニルアミノ)−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0]ヘキサン−4,6−ジカルボン酸塩酸塩
[α]23 D = +4.17 (c = 0.48, MeOH).
1H NMR (300MHz, CD3OD) δ2.45 (1H, t, J=4.0Hz), 2.98 (1H, dd, J=9.2, 14.7Hz), 3.06 (1H, dd, J=4.4, 7.0Hz), 3.10 (1H, d, J=14.6Hz), 3.33 (1H, dd, J=4.8, 13.6Hz), 3.52 (1H, dd, J=3.3, 7.3Hz), 4.08 (1H, dd, J=5.1, 8.8Hz), 4.10 (1H, d, J=15.4Hz), 7.31-7.42 (5H, m).
13C NMR (300MHz, 1,4-ジオキサンを含むD2O): δ172.55, 171.94, 170.01, 134.31, 130.39, 130.27, 130.01, 129.00, 61.38, 54.76, 54.37, 43.07, 37.36, 31.57, 23.18.
元素分析 C16H18N2O7S・1.5 HClとして計算値: C, 43.97; H, 4.50; N, 6.41. 実測値: C, 43.59; H, 4.17; N, 6.46.
MS (ES) m/z 実測値 383.1 [M+H]+.
HRMS C16H19N2O7S [M+H]+として計算値: 383.0913. 実測値: 383.0923.
(1R,4S,5S,6S)−4−(2’S−アミノ−3’S−メチル−ペンタノニルアミノ)−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0]ヘキサン−4,6−ジカルボン酸塩酸塩
[α]23 D = +4.08 (c = 0.49, MeOH).
1H NMR (300MHz, CD3OD) δ0.98 (3H, t, J=7.3Hz), 1.07 (3H, d, J=7.0Hz), 1.15-1.24 (1H, m), 1.53-1.62 (1H, m), 1.95-2.04 (1H, m), 2.44 (1H, t, J=4.0Hz), 3.06 (1H, dd, J=4.4, 7.0Hz), 3.14 (1H, d, J = 15.0Hz), 3.52 (1H, dd, J=3.7, 7.0Hz), 3.73 (1H, d, J=5.1Hz), 4.10 (1H, d, J=14.7Hz).
元素分析 C13H20N2O7S・HCl・0.5 H2Oとして計算値: C, 39.64; H, 5.63; N, 7.11. 実測値: C, 39.38; H, 5.39; N, 7.04.
MS (ES) m/z 実測値 349.1 [M+H]+.
HRMS (ES) C13H21N2O7S [M+H]+として計算値, 349.1069. 実測値, 349.1086.
(1R,4S,5S,6S)−4−(2’S−アミノ−3’−メチル−ブチリルアミノ)−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0]ヘキサン−4,6−ジカルボン酸塩酸塩
[α]23 D = +7.84 (c = 0.51, MeOH).
1H NMR (300MHz, CD3OD) δ1.04 (3H, d, J=6.6Hz), 1.09 (3H, d, J=7.0Hz), 2.22-2.29 (1H, m), 2.44 (1H, t, J=4.0Hz), 3.05 (1H, dd, J=4.4, 7.0Hz), 3.10 (1H, d, J=14.7Hz), 3.52 (1H, dd, J=4.0, 7.3Hz), 3.67 (1H, d, J=5.5Hz), 4.10 (1H, d, J=14.7Hz).
元素分析 C12H18N2O7S・HCl・0.4H2Oとして計算値: C, 38.12; H, 5.20; N, 7.41. 実測値: C, 37.78; H, 4.90; N, 7.15.
MS (ES) m/z 実測値 335.1 [M+H]+.
(1R,4S,5S,6S)−4−(2’S−アミノ−4’−メチル−ペンタノイルアミノ)−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0]ヘキサン−4,6−ジカルボン酸塩酸塩
[α]23 D = -4.0 (c = 0.50, MeOH).
1H NMR (300MHz, CD3OD) δ1.00 (3H, d, J=5.5Hz), 1.02 (3H, d, J=5.9Hz), 1.62-1.79 (3H, m), 2.42 (1H, t, J=4.0Hz), 3.04 (1H, dd, J=4.4, 7.3Hz), 3.13 (1H, d, J=15.0Hz), 3.52 (1H, dd, J=3.3, 7.0Hz), 3.84-3.89 (1H, m), 4.10 (1H, d, J=15.0Hz).
元素分析 C13H20N2O7S・HCl・0.3H2Oとして計算値: C, 40.01; H, 5.58; N, 7.18. 実測値: C, 39.66; H, 5.57; N, 6.99.
MS (ES) m/z 実測値 349.1 [M+H]+.
(1R,4S,5S,6S)−4−(2’S,6’−ジアミノ−ヘキサノイルアミノ)−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0]ヘキサン−4,6−ジカルボン酸ビス塩酸塩
[α]23 D = -4.0 (c = 0.50, MeOH).
1H NMR (300MHz, CD3OD) δ1.48-1.55 (2H, m), 1.67-1.74 (2H, m), 1.89-1.97 (2H, m), 2.47 (1H, t, J=4.0Hz), 2.97 (2H, app t, J=4.0), 3.08 (1H, dd, J=4.4, 7.0Hz), 3.20 (1H, d, J=15.0Hz), 3.53 (1H, dd, J=3.7, 7.0Hz), 3.93 (1H, app. t, J=6.2Hz), 4.08 (1H, d, J=14.7Hz).
元素分析 C13H21N3O7S・2HCl・0.2H2Oとして計算値: C, 35.49; H, 5.36; N, 9.55. 実測値: C, 35.30; H, 5.48; N, 9.42.
MS (ES) m/z 実測値 364.1 [M+H]+.
(1R,4S,5S,6S)−4−(2’S−アミノ−4’−カルバモイル−ブチリルアミノ)−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0]ヘキサン−4,6−ジカルボン酸塩酸塩
[α]23 D = +8.0 (c = 1.0, H2O).
1H NMR (300MHz, CD3OD) δ2.00-2.08 (2H, m), 2.37-2.41 (3H, m), 2.93 (1H, dd, J=4.4, 7.3Hz), 3.04 (1H, d, J=14.7Hz), 3.45 (1H, dd, J=3.7, 7.0Hz), 3.86 (1H, app. t, J=5.9Hz), 4.05 (1H, d, J=14.7Hz).
元素分析 C12H17N3O8S・HCl・2.0H2Oとして計算値: C, 33.07; H, 5.09; N, 9.64. 実測値: C, 33.37; H, 4.69; N, 9.39.
MS (ES) m/z 実測値 363.9 [M+H]+.
HRMS (ES) C12H18N3O8S [M+H]+として計算値: 364.0815. 実測値: 364.0825.
(1R,2S,4R,5R,6R)−2−(2’S−アミノ−プロピオニル)アミノ−4−フルオロビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸塩酸塩
1.06gを水0.5mLおよびアセトン2.12mLに、50℃にて加熱しながら溶解した後、さらにアセトン5.3mLで希釈し、場合により種晶添加した。さらにアセトン4.2mLをかすかに濁った混合物に加えた後、場合により再び種晶添加し、加熱を止め、1時間にわたって徐々に室温まで冷却した。得られたスラリーをさらなるアセトン9.5mLで30分にわたって希釈した後、15時間撹拌した。ろ過し、アセトン(2x5mL)で洗浄し、45℃にて10時間、室温にて60時間減圧乾燥した後、標記化合物0.905g(85%回収率)を白色固体として得た。
mp (DSC) 183℃.
[α]25 D +33°(c 1.06, CH3OH).
500MHz 1H NMR (CD3OD) δ5.58-5.42 (m, 1H), 3.92 (q, 1H, J = 7.0Hz), 2.96 (dd, 1H, J = 14, 8.0Hz), 2.41-2.39 (m, 1H), 2.35-2.30 (m, 1H), 2.10 (t, 1H, J = 3.0Hz), 1.52 (d, 3H, J = 7.5Hz), 1.51-1.42 (m, 1H).
13C NMR (125MHz, CD3OD) δ173.74, 173.62, 170.00, 93.48および92.04 (C-F分割), 63.95および63.92 (C-F分割), 48.80, 36.89および36.70 (C-F分割), 32.97および32.91 (C-F分割), 30.05および29.87 (C-F分割), 19.37, 16.28.
FTIR (DRIFT) 3430 (w), 3016 (s), 1721 (s), 1662 (s), 1496 (s), 1190 (m), 1024 (m), 637 (w) cm-1.
(1R,2S,4R,5R,6R)−2−(2’S−アミノ−プロピオニル)アミノ−4−フルオロビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸メシレート
mp (DSC) 206℃.
[α]25 D +30 (c 1.05, CH3OH).
1H NMR (500MHz, CD3OD) δ5.58-5.42 (m, 1H), 3.92 (q, 1H, J = 7.0Hz), 2.96 (dd, 1H, J = 14, 8.0Hz), 2.70 (s, 3H), 2.41-2.39 (m, 1H), 2.35-2.30 (m, 1H), 2.10 (t, 1H, J = 3.0Hz), 1.52 (d, 3H, J = 7.5Hz), 1.51-1.42 (m, 1H).
13C NMR (125MHz, CD3OD) δ173.73, 173.61, 170.02, 93.50および92.05 (C-F分割), 63.91, 48.79, 38.30, 36.89および36.70 (C-F分割), 32.97および32.91 (C-F分割), 30.02および29.84 (C-F分割), 19.37, 16.26.
FTIR (DRIFT) 3472 (w), 3077 (s), 1717 (s), 1691 (s), 1557 (m), 1220 (s), 1019 (m), 781 (m), 563 (m)cm-1.
元素分析 C12H19FN2O8Sとして計算値: C, 38.92; H, 5.17; N, 7.56. 実測値: C, 38.96; H, 4.97; N, 7.51.
(1R,2S,4R,5R,6R)−2−(2’S−アミノ−プロピオニル)アミノ−4−フルオロビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸エシレート
mp (DSC) 210℃ (分解).
1H NMR (500MHz, CD3OD) δ5.58-5.42 (m, 1H), 3.92 (q, 1H, J = 7.0Hz), 2.96 (dd, 1H, J = 14, 8.0Hz), 2.80 (q, 2H, 7.3Hz), 2.42-2.37 (m, 1H), 2.35-2.30 (m, 1H), 2.09 (t, 1H, J = 3.0Hz), 1.52 (d, 3H, J = 7.5Hz), 1.51-1.40 (m, 1H), 1.30 (t, 3H, J = 7.5Hz).
(1R,2S,4R,5R,6R)−2−(2’S−アミノ−プロピオニル)アミノ−4−フルオロビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ベシレート
mp (DSC) 132℃.
1H NMR (500MHz, CD3OD) δ7.86-7.80 (m, 2H), 7.46-7.37 (m, 3H), 5.58-5.42 (m, 1H), 3.92 (q, 1H, J = 7.0Hz), 2.96 (dd, 1H, J = 14, 8.0Hz), 2.42-2.37 (m, 1H), 2.35-2.30 (m, 2H), 2.09 (t, 1H, J = 3.0Hz), 1.52 (d, 3H, J = 7.5Hz), 1.51-1.40 (m, 1H).
(1R,2S,4R,5R,6R)−2−(2’S−アミノ−プロピオニル)アミノ−4−フルオロビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸トシレート
mp (DSC) 155℃.
1H NMR (500MHz, CD3OD) δ7.70 (d, 2H, J = 7.5Hz), 7.34 (d, 2H, J = 8.5Hz), 5.58-5.42 (m, 1H), 3.92 (q, 1H, J = 7.0Hz), 2.96 (dd, 1H, J = 14, 8.0Hz), 2.42-2.30 (m, 2H), 2.24 (s, 3H), 2.09 (t, 1H, J = 3.0Hz), 1.52 (d, 3H, J = 7.5Hz), 1.51-1.40 (m, 1H).
(1R,2S,4R,5R,6R)−2−(2’S−アミノ−プロピオニル)アミノ−4−フルオロビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸
1H NMR (500MHz, D2O) δ5.45-5.30 (m, 1H), 3.88 (q, 1H, J = 7.0Hz), 2.58 (dd, 1H, J = 14, 8.0Hz), 2.33-2.30 (m, 1H), 2.27-2.26 (m, 1H), 1.92 (t, 1H, J = 3.0Hz), 1.36 (d, 3H, J = 7.1Hz), 1.41-1.32 (m, 1H).
13C NMR (125MHz, D2O) δ177.46, 176.92, 170.42, 94.56および93.19 (C-F分割), 65.36, 49.01, 36.75および36.57 (C-F分割), 33.61および33.55 (C-F分割), 30.54および30.36 (C-F分割), 20.27, 16.67.
(1R,2S,4R,5R,6R)−2−(2’S−アミノ−プロピオニル)アミノ−4−フルオロビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ジナトリウム塩
1H NMR (500MHz, D2O) δ5.44-5.29 (m, 1H), 3.89 (q, 1H, J = 7.0Hz), 2.65 (s, 3H), 2.56 (dd, 1H, J = 14,.8.0Hz), 2.16-2.13 (m, 1H), 2.10-2.09 (m, 1H), 1.74 (t, 1H, J = 3.1Hz), 1.38 (d, 3H, J = 7.1Hz), 1.36-1.28 (m, 1H).
13C NMR (125MHz, D2O) δ180.00, 178.72, 170.13, 95.40および93.99 (C-F分割), 65.97, 49.06, 37.25および37.07 (C-F分割), 33.01および32.94 (C-F分割), 29.64および29.46 (C-F分割), 22.48, 16.68.
(1S,2S,4S,5R,6R)−2−(2’S−アミノプロピオニル)アミノ−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸塩酸塩
LCMS: m/z 273 [M+H]+ 室温にて0.20分.
1H NMR (CD3OD)*: 4.13 (1H, d, 5.9Hz), 3.80 (1H, q, 6.7Hz), 2.41-2.31 (2H, m), 1.93 (1H, dd, 6.0Hz, 2.7Hz), 1.62 (1H, dd, 5.9Hz, 15.5Hz), 1.44 (1H, t, 3.0Hz), 1.38 (3H, d, 6.8Hz); *注 NMRにより観察されない交換可能なプロトン=6
(1S,2S,4S,5R,6R)−2−(2’−アミノ−アセチルアミノ)−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸塩酸塩
[α]23 D = -36 (c=0.5, MeOH).
1H NMR (400MHz, CD3OD) δ1.56 (1H, t, J=2.9Hz), 1.74 (1H, dd, J=5.8, 15.4Hz), 2.12 (1H, m), 2.48 (1H, d, J=15.4Hz), 2.61 (1H, m), 3.62 (2H, s), 4.32 (1H, d, J=5.49Hz).
元素分析 C10H14N2O6・1.3HCl・H2Oとして計算値: C, 37.11; H, 5.39; N, 8.66. 実測値: C, 37.36; H, 4.99; N, 8.30.
MS (ES) m/z 258.8 [M+H]+.
(1S,2S,4S,5R,6R)−2−(2’S−アミノ−3’−メチル−ブチリルアミノ)−4−ヒドロキシビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸塩酸塩
[α]23 D = +8.33 (c=0.48, MeOH).
1H NMR (400MHz, CD3OD) δ1.07 (3H, d, J=6.8Hz), 1.11 (3H, d, J=7.3Hz), 1.55 (1H, t, J=2.9Hz), 1.76 (1H, dd, J=5.8, 15.6Hz), 2.14 (1H, dd, J=3.4, 5.8Hz), 2.24 (1H, m), 2.50 (1H, d, J=15.6Hz), 2.64 (1H, dd, J=2.9, 5.8Hz), 3.66 (1H, d, J=5.4Hz), 4.32 (1H, d, J=5.8Hz).
元素分析 C13H20N2O6・HCl・1.1H2Oとして計算値: C, 43.79; H, 6.56; N, 7.86. 実測値: C, 43.77; H, 6.20; N, 7.47.
HRMS C13H21N2O6として計算値, 301.1400. 実測値, 301.1400.
(1S,2S,4S,5R,6R)−2−(2’S−アミノ−4’−メチル−ペンタノイルアミノ)−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸塩酸塩
[α]23 D = +4 (c=0.5, MeOH).
1H NMR (400MHz, CD3OD) δ1.01 (3H, d, J=5.8Hz), 1.03 (3H, d, J=6.3Hz), 1.54 (1H, t, J=2.9Hz), 1.63-1.82 (4H, m), 2.14 (1H, dd, J=2.9, 5.8Hz), 2.49 (1H, d, J=15.6Hz), 2.62 (1H, dd, J=2.9, 5.8Hz), 3.83-3.86 (1H, m), 4.32 (1H, d, J=5.8Hz).
元素分析 C14H22N2O6・HCl・1.4H2Oとして計算値: C, 44.72; H, 6.92; N, 7.45. 実測値: C, 44.52; H, 6.57; N, 7.13.
HRMS C14H23N2O6として計算値, 315.1556. 実測値, 315.1569.
(1S,2S,4S,5R,6R)−2−(2’S−アミノ−3’S−メチル−ペンタノイルアミノ)−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸塩酸塩
[α]23 D = +8 (c=0.5, MeOH).
1H NMR (400MHz, CD3OD) δ0.99 (3H, t, J=7.3Hz), 1.08 (3H, t, J=7.3Hz), 1.17-1.27 (1H, m), 1.53 (1H, t, J=2.9Hz), 1.59-1.65 (1H, m), 1.76 (1H, dd, J=5.8, 15.6Hz), 1.96-2.00 (1H, m), 2.14 (1H, dd, J=2.9, 5.8Hz), 2.46 (1H, d, J=15.6Hz), 2.66 (1H, dd, J=2.9, 5.8Hz), 3.70 (1H, d, J=5.4Hz), 4.31 (1H, d, J=5.8Hz).
元素分析 C14H22N2O6・1.1HCl・1.2H2Oとして計算値: C, 44.71; H, 6.83; N, 7.45. 実測値: C, 44.38; H, 6.51; N, 7.08.
HRMS C14H23N2O6として計算値, 315.1556. 実測値, 315.1566.
(1S,2S,4S,5R,6R)−2−[2’−(2−アミノ−アセチルアミノ)アセチルアミノ]−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸
[α]23 D = +3.92 (c=0.51, H2O).
1H NMR 300MHz, D2O) δ1.43 (1H, t, J=2.9Hz), 1.53 (1H, dd, J=5.9, 15.4Hz), 1.98 (1H, m), 2.23-2.31 (2H, m), 3.70 (2H, s), 3.82 (2H, app d, J=1.1Hz), 4.16 (1H, d, J=5.9Hz).
HRMS C12H18N3O7として計算値, 316.1145. 実測値, 316.1123.
(1S,2S,4S,5R,6R)−2−[2’−(2S−アミノ−プロピオニルアミノ)アセチルアミノ]−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸
[α]23 D = +23.53 (c=0.51, H2O).
1H NMR 300MHz, D2O) δ1.36 (3H, d, J=7.0Hz), 1.37 (1H, t, J=3.3Hz), 1.49 (1H, dd, J=5.9, 15.4Hz), 1.91 (1H, dd, J=2.9, 5.9Hz), 2.15 (1H, dd, J=2.9, 5.9Hz), 2.27 (1H, d, J=15.4Hz), 3.79 (2H, s), 3.95 (1H, q, J=7.0Hz), 4.13 (1H, d, J=5.5Hz).
HRMS C13H19N3O7として計算値, 330.1301. 実測値, 330.1290.
(1S,2S,4S,5R,6R)−2−(2’S−アミノ−3’−フェニル−プロピオニルアミノ)−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸塩酸塩
[α]23 D = +3.64 (c=0.55, MeOH).
1H NMR (400MHz, CD3OD) δ1.45 (1H, t, J = 3.3Hz), 1.60 (1H, dd, J = 5.5, 15.4Hz), 2.03 (1H, dd, J = 2.6, 5.9Hz), 2.37 (1H, d, J = 15.4Hz), 2.55 (1H, dd, J = 2.9, 5.9Hz), 2.90 (1H, dd, J = 8.4, 14.3Hz), 3.22 (1H, dd, J = 5.1, 14.7Hz), 3.97 (1H, dd, J = 5.5, 8.8Hz), 4.21 (1H, d, J = 5.5Hz), 7.19-7.31 (5H, m).
HRMS C17H21N2O6として計算値, 349.1400. 実測値, 349.1388.
元素分析 C17H21N2O6・HCl・H2O: C, 50.69; H, 5.76; N, 6.95; Cl, 8.80. 実測値: C, 50.66; H, 5.65; N, 6.85; Cl, 8.20.
MS 実測値 349.0 [M+H]+.
(1S,2S,4S,5R,6R)−2−(2’S−アミノ−4’−カルバモイル−ブチリルアミノ)−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸塩酸塩
[α]23 D = +8.16 (c=0.49, MeOH).
1H NMR (400MHz, CD3OD) δ1.60 (1H, t, J = 3.3Hz), 1.79 (1H, dd, J = 5.5, 15.4Hz), 2.10-2.17 (3H, m), 2.46-2.55 (3H, m), 2.60 (1H, dd, J = 2.9, 5.9Hz), 3.94 (1H, t, J = 6.2Hz), 4.33 (1H, d, J=5.5Hz).
MS 実測値 330.0 [M+H]+, 351.9 [M+Na]+.
HRMS C13H19N3O7として計算値, 330.1301. 実測値, 330.1295.
(1S,2S,4S,5R,6R)−2−(2’S,6’−ジアミノ−ヘキサノイルアミノ)−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ビス塩酸塩
1H NMR (400MHz, CD3OD) δ1.47-1.59 (3H, m), 1.66-1.78 (2H, m), 1.84 (1H, dd, J=5.4, 15.2Hz), 1.91 (2H, m), 2.16 (1H, dd, J=3.4, 5.7Hz), 2.45 (1H, d, J=15.7Hz), 2.66 (1H, dd, J=2.9, 5.9Hz), 2.97 (2H, t, J=7.3Hz), 3.92 (1H, t, J=6.4Hz), 4.33 (1H, d, J=5.4Hz).
MS 実測値 330.0 [M+H]+.
(1S,2S,4S,5R,6R)−2−(2’S−アミノ−3’−カルバモイル−プロピオニルアミノ)−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸
[α]23 D = 0 (c=0.5, MeOH).
1H NMR (400MHz, CD3OD) δ1.59 (1H, t, 3.4Hz), 1.76 (1H, dd, J = 5.9, 16.1Hz), 2.11 (1H, dd, J = 2.9, 5.9Hz), 2.53 (1H, d, J = 16.1Hz), 2.55 (1H, dd, J = 2.9, 5.9Hz), 2.74 (1H, dd, J = 9.8, 17.1Hz), 2.95 (1H, dd, J = 3.9, 17.1Hz), 4.19 (1H, dd, J = 3.9, 9.8Hz), 4.32 (1H, d, J = 5.9Hz).
MS 実測値 316.0 [M+H]+, 337.9 [M+Na]+.
HRMS C12H16N3O7Naとして計算値, 338.0964. 実測値, 338.0953.
(1S,2S,4S,5R,6R)−2−[2’S−アミノ−3’−(1H−インドール−3−イル)プロピオニルアミノ]−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸
[α]23 D = +19.23 (c=0.52, MeOH).
1H NMR (400MHz, CD3OD) δ1.43 (1H, t, J = 2.9Hz), 1.57 (1H, dd, J = 5.9, 15.2Hz), 2.05 (1H, dd, J = 3.4, 6.4Hz), 2.41 (1H, d, J = 14.7Hz), 2.46 (1H, dd, J = 2.4, 5.9Hz), 3.15 (1H, dd, J = 5.4, 14.7Hz), 3.49 (1H, dd, J = 5.4, 14.7Hz), 4.05 (1H, dd, J = 5.4, 9.3Hz), 4.17 (1H, d, J = 5.4Hz), 7.09 (2H, m), 7.27 (1H, s), 7.37 (1H, d, J = 8.3Hz), 7.75 (1H, d, J = 7.8Hz).
MS 実測値 388.0 [M+H]+, 409.9 [M+Na]+.
HRMS C19H21N3O6として計算値, 388.1508. 実測値, 388.1502.
(1S,2S,4S,5R,6R)−4−ヒドロキシ−2−[(ピロリジン−2’S−カルボニル)アミノ]ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸塩酸塩
[α]23 D = -40 (c=0.5, MeOH).
1H NMR (400MHz, CD3OD) δ1.59 (1H, t, J= 3Hz), 1.78 (1H, dd, J= 5.9, 15.3Hz), 2.06 (4H, m), 2.42 (1H, m), 2.59 (2H, m), 3.35 (m, 3H), 4.27 (1H, m), 4.32 (1H, d, J= 5.9Hz).
HRMS C13H19N2O6として計算値, 299.1243. 実測値, 299.1242.
元素分析 C13H18N2O6・HCl・H2Oとして計算値: C, 44.26; H, 6.00; N, 7.94. 実測値: C, 44.13; H, 5.78; N, 7.62.
(1S,2S,4S,5R,6R)−2−[2’S−アミノ−3’−(4−ヒドロキシ-フェニル)プロピオニルアミノ]−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸塩酸塩
[α]23 D = +8 (c=0.5, MeOH).
1H NMR (400MHz, CD3OD) δ1.48 (1H, t, J = 3Hz), 1.62 (1H, dd, J= 5.9, 15.3Hz), 2.03 (1H, m), 2.38 (1H, d, J= 15.3Hz), 2.55 (1H, m), 2.8 (1H, dd, J= 8.9, 14.4Hz), 3.12 (1H, dd, J = 5.4, 14.4Hz), 3.90 (1H, q, J= 5.4Hz), 4.21 (1H, d, J= 5.9Hz), 6.7 (2H, d, J= 8.4Hz), 7.05 (2H, d, J= 8.4Hz).
HRMS C17H21N2O7として計算値, 365.1349. 実測値, 365.1374.
元素分析 C17H20N2O7・1.1 HCl・1.1 H2O: C, 48.12; H, 5.54; N, 6.60. 実測値: C, 47.89; H, 5.37; N, 6.50.
(1S,2S,4S,5R,6R)−2−(2’S−アミノ−4’−メチルスルファニル−ブチリルアミノ)−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ビスアンモニウム塩
[α]23 D = +28 (c=1.0, MeOH).
1H NMR (400MHz, CD3OD) δ1.63 (1H, dd, J= 6.0, 15.6Hz), 2.03 (2H, m), 2.12 (3H, s), 2.18 (1H, m), 2.35 (1H, m), 2.49 (1H, d, J= 15.6Hz), 2.65 (2H, t, J= 8.4Hz), 3.84 (1H, t, J= 6.0Hz), 4.19 (1H, d, J= 6.0Hz).
HRMS C13H21N2O6Sとして計算値, 333.1120. 実測値, 333.1105.
(1S,2S,4S,5R,6R)−2−[2’S−(2S−アミノ−プロピオニルアミノ)プロピオニルアミノ]−4−ヒドロキシ−ビシクロ[3.1.0.]ヘキサン)−2,6−ジカルボン酸
1H NMR (300MHz, D2O) δ1.23 (3H, d, J=7.3Hz), 1.36 (3H, d, J=7.3Hz), 1.40-145 (1H, m), 1.50 (1H, dd, J=5.5, 15.4Hz), 1.90-1.96 (1H, m), 2.20 (1H, dd, J=2.6, 5.9Hz), 2.29 (1H, d, J=15.4Hz), 3.90 (1H, q, J=7.3Hz), 4.15-4.22 (2H, m).
MS (ES) m/z 342.1 [M-1]-.
HRMS C14H22N3O7として計算値, 344.1458. 実測値, 344.1457.
(1S,2S,4S,5R,6R)−2−[2’S−(2−アミノ−アセチルアミノ)プロピオニルアミノ]−4−ヒドロキシ−ビシクロ[3.1.0.]ヘキサン−2,6−ジカルボン酸
[α]23 D = -42.11 (c = 0.57, H2O).
1H NMR (300MHz, D2O) δ1.21 (3H, d, J=7.3Hz), 1.39 (1H, m), 1.50 (1H, dd, J=5.7, 15.8Hz), 1.91 (1H, m), 2.15 (1H, dd, J=2.6, 5.9Hz), 2.28 (1H, d, J=15.0Hz), 3.65 (2H, s), 4.14 (1H, app d, J=5.9Hz), 4.20 (1H, app q, J=7.3Hz).
HRMS C13H20N3O7として計算値, 330.1301. 実測値, 330.1299.
(1S,2S,4S,5R,6R)−2−[2’S−(2S−アミノ−4−メチル−ペンタノイルアミノ)プロピオニルアミノ]−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸
[α]23 D = -3.64°(c = 0.55, MeOH).
1H NMR (300MHz, CD3OD) δ0.89 (3H, d, J=4.4Hz), 0.91 (3H, d, J=4.0Hz), 1.29 (3H, d, J=7.0Hz), 1.52 (1H, t, J=3.3Hz), 1.55-1.67 (4H, m), 1.97 (1H, dd, J=2.9, 5.9Hz), 2.38 (1H, dd, J=2.9, 5.9Hz), 2.45 (1H, d, J=15.4Hz), 3.75-3.80 (1H, m), 4.18 (1H, d, J=5.9Hz), 4.33 (1H, app. q, J=7.0Hz),
元素分析 C17H27N3O7・1.0 HCl・1.6 H2Oとして計算値: C, 45.30; H, 6.98; N, 9.32; Cl, 7.87. 実測値: C, 44.95; H, 6.54; N, 9.12; Cl, 7.53.
HRMS (ES) C17H28N3O7 [M+H]+として計算値, 386.1927. 実測値, 386.1911.
(1S,2S,4S,5R,6R)−2−[2’S−(2−アミノ−3−メチル−ブチリルアミノ)プロピオニルアミノ]−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸
[α]23 D = -15.69°(c = 0.51, MeOH).
1H NMR (300MHz, CD3OD) δ0.92 (3H, d, J=7.0Hz), 0.95 (3H, d, J=7.0Hz), 1.28 (3H, d, J=7.0Hz), 1.52 (1H, t, J=2.9Hz), 1.60 (1H, dd, J=5.9, 15.4Hz), 1.98 (1H, dd, J=3.3, 5.9Hz), 2.03-2.15 (1H, m), 2.39 (1H, dd, J=2.9, 6.2Hz), 2.45 (1H, d, J=15.4Hz), 3.56 (1H, d, J=5.5Hz), 4.18 (1H, d, J=5.9Hz), 4.33 (1H, app. q, J=7.0Hz), 8.82 (1H, s).
元素分析 C16H25N3O7・1.0 HCl・1.5H2Oとして計算値: C, 44.19; H, 6.72; N, 9.66; Cl, 8.15. 実測値: C, 44.32; H, 6.48; N, 9.14; Cl, 7.66.
HRMS (ES) C16H26N3O7 [M+H]+として計算値, 372.1771. 実測値, 372.1758.
(1R,2S,4R,5R,6R)−2−(2’S−2’−アミノプロピオニル)アミノ−4−フルオロ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸メシレート一水和物
mp (DSC) 200℃.
[α]25 D +34°(c 1.0, CH3OH)
400MHz 1H NMR (DMSO-d6) δ12.76 (br s, 2H), 9.18 (s 1H), 8.07 (br s, 3H), 5.50-5.36 (m, 1H), 3.87 (d, 1H, J = 6.8Hz), 2.82 (dd, 1H, J = 14, 8.0Hz), 2.38 (s, 3H), 2.25 (m, 2H), 1.96 (t, 1H, J = 3.0Hz), 1.39 (m, 1H), 1.37 (d, 3H, J = 6.8Hz).
100MHz 13C NMR (DMSO-d6) δ173.1, 172.3, 169.7, 92.8 (d, C-F分割), 63.2 (d, C-F分割), 48.0, 39.7, 36.4 (d, C-F分割), 32.5(d, C-F分割), 29.3 (d, C-F分割), 19.3 (d, C-F分割), 16.9.
FTIR (KBr) 3461 (w), 3379 (w), 3269 (m), 2653 (s), 2591 (s), 2529 (s), 1724 (s), 1691 (s), 1353 (m), 1287 (s), 1271 (s), 1256 (s), 1212 (s), 1147 (s), 1052 (s), 1024 (s), 787 (m) cm-1.
元素分析 C12H21FN2O9Sとして計算値: C, 37.11; H, 5.45; N, 7.21. 実測値: C, 37.12; H, 5.45; N, 7.16.
(1R,4S,5S,6S)−4−(2’S−4’−メチルチオ−2’−アミノブタノニル)アミノ−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0]ヘキサン−4,6−ジカルボン酸一水和物
mp (DSC) 203℃.
[α]25 D +13.4 (c 1.19, 1N HCl).
500MHz 1H NMR (D2O) δ3.99 (t, 1H, J = 6.0Hz), 3.93 (d, 1H, J = 15.0Hz), 3.50 (dd, 1H, J = 1.0, 4.0Hz), 3.12 (d, 1H, J = 15.0Hz), 2.95 (dd, 1H, J = 4.0, 7.0Hz), 2.48 (t, 2H, J = 8.0Hz), 2.33 (t, 1H, J = 4.0), 2.09-1.98 (m, 5H).
13C NMR (125MHz, D2O) δ173.50, 172.60, 169.18, 61.66, 54.76, 52.19, 42.55, 31.70, 30.10, 28.09, 23.53, 14.14.
FTIR (ATR) 3558.54 (s), 3024.05 (s), 2959.87 (s), 1748.83 (s), 1692.89 (s), 1681.99 (s), 1617.50 (s), 1567.63 (s), 1497.65 (s), 1314.11 (s), 1282.22 (s), 1263.26 (s), 1239.01 (s), 1101.46 (s), 884.62 (s), 809.95 (s), 773.46 (s) cm-1.
元素分析 C12H18N2O7S2・H2Oとして計算値: C, 37.49; H, 5.24; N, 7.29. 実測値: C, 37.34; H, 5.04; N, 7.15.
(1R,4S,5S,6S)−4−(2’S−4’−メチルチオ−2’−アミノブタノニル)アミノ−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0]ヘキサン−4,6−ジカルボン酸トシレート
mp (DSC) 255℃.
[α]25 D +8.3 (c 1.2, CH3OH).
500MHz 1H NMR (CD3OD) δ7.71 (d, 2H, J = 8.0Hz), 7.24 (d, 2H, J = 8.0Hz), 4.14 (d, 1H, J = 15Hz), 4.00 (t, 1H, J = 6.0Hz), 3.54 (dd, 1H, J = 4.0, 7.0Hz), 3.13 (d, 1H, J = 15Hz), 3.01 (dd, 1H, J = 4.0, 7.0Hz), 2.60 (t, 2H, J = 8.0Hz), 2.49 (t, 1H, J = 4.0Hz), 2.37 (s, 3H), 2.19-2.12 (m, 5H).
13C NMR (125MHz, CD3OD) δ170.49, 169.69, 168.99, 142.18, 140.67, 182.73, 125.79, 60.26, 54.76, 52.21, 42.44, 30.90, 30.77, 27.20, 22.33, 20.17, 13.96.
FTIR (ATR) 3091.19 (w), 1730.91 (s), 1668.22 (s), 1563.97 (s), 1518.49 (s), 1312.69 (m), 1247.46 (s), 1212.05 (s), 1156.33 (s), 1123.09 (s), 1035.95 (s), 1011.36 (s), 892.41 (s), 814.02 (s), 683.69 (s) cm-1.
(1R,4S,5S,6S)−4−(2’S−4’−メチルチオ−2’−アミノブタノニル)アミノ−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0]ヘキサン−4,6−ジカルボン酸メシレート
mp (DSC) 244℃.
[α]25 D +10.2 (c 1.16, CH3OH).
500MHz 1H NMR (CD3OD) δ4.16 (d, 1H, J = 15Hz), 4.00 (t, 1H, J = 6.0Hz), 3.54 (dd, 1H, J = 4.0, 7.0Hz), 3.15 (d, 1H, J = 15Hz), 3.01 (dd, 1H, J = 4.0, 7.0Hz), 2.71 (s, 3H), 2.61 (t, 2H, J = 8.0), 2.51 (t, 1H, J = 4.0), 2.20-2.14 (m, 5H).
13C NMR (125MHz, CD3OD) δ170.50, 169.71, 169.00, 60.27, 54.78, 52.18, 42.43, 38.35, 30.90, 30.78, 28.20, 22.35, 13.96.
FTIR (ATR) 3055.57 (m), 1725.90 (s), 1693.60 (s), 1527.33 (s), 1528.96 (s), 1320.89 (s), 1176.86 (s), 1152.70 (s), 1118.55 (s), 1051.42 (s), 816.49 (s), 786.63 (s) cm-1.
元素分析 C12H18N2O7S2・CH4O3Sとして計算値: C, 33.76; H, 4.79; N, 6.06. 実測値: C, 33.98; H, 4.82; N, 5.98.
(1R,2S,5R,6R)−2−(2’R−アミノプロピオニル)アミノ−6−フルオロ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸塩酸塩
1H-NMR (300MHz, CDCl3): 1.28 (d, 3H, J = 7.1Hz), 1.64-1.69 (m, 1H), 1.86-2.02 (m, 1H), 2.11-2.21 (m, 3H), 2.54 (d, 1H, J = 7.1Hz), 3.84 (q, 1H, J = 7.1Hz).
(1S,2R,5S,6S)−2−(2’R−アミノプロピオニル)アミノ−6−フルオロ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸塩酸塩
1H-NMR (300MHz, CDCl3): 1.30 (d, 3H, J = 7.1Hz), 1.59-1.65 (m, 1H), 1.85-2.03 (m, 1H), 2.05-2.25 (m, 3H), 2.53 (d, 1H, J = 6.6Hz), 3.85 (q, 1H, J = 7.1Hz).
(1S,2S,4S,5R,6R)−2−(2’S−アミノプロピオニル)アミノ−4−ヒドロキシ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸塩酸塩
[α]23 D = -4.1 (c=0.49, MeOH).
1H NMR (CD3OD) δ1.51 (3H, d, J=7.0Hz), 1.56 (1H, t, J=2.9Hz), 1.77 (1H, dd, J=5.8, 15.8Hz), 2.1-2.13 (1H, m), 2.52 (1H, d, J=16.1Hz), 2.57 (1H, dd, J=2.9, 5.9Hz), 3.88 (1H, dd, J=7.0, 14.3Hz), 4.32 (1H, d, J=5.5Hz).
元素分析 C11H17N2O6・1.1HCl・0.9H2Oとして計算値: C, 40.12; H, 5.80; N, 8.53. 実測値: C, 39.85; H, 5.41; N, 8.36.
HRMS C11H16N2O6Naとして計算値, 295.0906. 実測値, 295.0883.
いくつかの経口投与されるペプチド模倣薬は、腸内ペプチドトランスポート系を通して吸収されると考えられている。Yangら, Pharm. Res. 16(9) (1999)。特に、腸内ペプチドトランスポーターhPepT1は、そのペプチジル取り込み阻害の発現およびその対応する細胞内認識レベルについて研究されている。Meredithら, Eur. J. Biochem., 267, 3723-3728 (2000)。さらに、hPepT1トランスポーターにおけるアミノ酸の腸内吸収機序の特性付けは、改善された経口薬吸収を同定するための効果的戦略と目されている。Hanら, Polym. Prepr. (Am. Chem. Soc., Div. Polym. Chem) 40(1): 259-260 (1999); Sawadaら, J. Pharmacol. Exp. Ther., 291(2): 705-709 (1999)。
本発明化合物の細胞への取り込みを測定する別の具体的な方法は、ヒト腸内細胞系Caco−2のペプチドトランスポートキャリアーを調べることである。10%ウシ胎仔血清および1%最小必須培地非必須アミノ酸溶液を含み、ピルビン酸ナトリウムまたは抗生剤の添加なしのダルベッコ改変イーグル培地中に、ヒト腺癌細胞(Memorial Sloan-Kettering Cancer Center, Rye, NYおよび/またはATCC, Rockville, MD)を継代する。これらの細胞は、マイコプラズマ不含であり、継代数28〜40にて使用した。フラックス測定(flux measurement)について、5〜10x104の細胞をコラーゲンコートされたマルチウェルディッシュ中にて13〜18日間成育させ、培地を2〜3日ごとに置き換える。
式Iの化合物を経口投与した後の、式IIの化合物のインビボ暴露を式IIの化合物と比較して研究するために、ラットにおける式IIの各化合物の血漿濃度を測定する研究を行う。成熟したFischer 344オスラット(190〜270グラム)をHarlan Sprague-Dawley, Cumberland, IN, USAから得、3日間飼育し、研究に順応させる。4日目、試験化合物を緩衝水(1mg/ml=試験化合物/20mMリン酸二水素カリウム、pH=2)に溶解し、単回用量5mg/kgとして経口投与する。眼窩洞を通してまたは心臓穿刺(最後の時間点)により、0.5および1時間、あるいは1および3時間にて血液サンプルを集める。分析の前は、フッ化フェニルメチルスルホニル、プロテアーゼ阻害剤の存在下に血漿サンプルを−20℃にて貯蔵する。血漿サンプルおよび内部標準化合物を固相抽出(SAXサポート、メタノール/水/希酢酸)により前処理する。
Claims (3)
- (1R,4S,5S,6S)−4−(2’S−4’−メチルチオ−2’−アミノブタノニル)アミノ−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0]ヘキサン−4,6−ジカルボン酸である、化合物またはその製薬的に許容される塩。
- (1R,4S,5S,6S)−4−(2’S−4’−メチルチオ−2’−アミノブタノニル)アミノ−2,2−ジオキソ−2λ6−チア−ビシクロ[3.1.0]ヘキサン−4,6−ジカルボン酸一水和物である、請求項1記載の化合物。
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