JP2009167104A - Phenyl 5-thio glycoside compound - Google Patents
Phenyl 5-thio glycoside compound Download PDFInfo
- Publication number
- JP2009167104A JP2009167104A JP2006128680A JP2006128680A JP2009167104A JP 2009167104 A JP2009167104 A JP 2009167104A JP 2006128680 A JP2006128680 A JP 2006128680A JP 2006128680 A JP2006128680 A JP 2006128680A JP 2009167104 A JP2009167104 A JP 2009167104A
- Authority
- JP
- Japan
- Prior art keywords
- mmol
- phenyl
- group
- methyl
- compound
- 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.)
- Pending
Links
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 230000000694 effects Effects 0.000 claims abstract description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 7
- 108091006277 SLC5A1 Proteins 0.000 claims abstract 2
- 102000058090 Sodium-Glucose Transporter 1 Human genes 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 105
- 102100029795 Sodium-dependent glucose transporter 1 Human genes 0.000 claims description 17
- 101710181093 Sodium-dependent glucose transporter 1 Proteins 0.000 claims description 17
- 206010012601 diabetes mellitus Diseases 0.000 claims description 12
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 239000004480 active ingredient Substances 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 229940124597 therapeutic agent Drugs 0.000 claims description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 3
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 3
- 239000003112 inhibitor Substances 0.000 claims description 3
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 2
- 125000006590 (C2-C6) alkenylene group Chemical group 0.000 claims description 2
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 2
- 230000000069 prophylactic effect Effects 0.000 claims 1
- 208000002705 Glucose Intolerance Diseases 0.000 abstract description 13
- 201000009104 prediabetes syndrome Diseases 0.000 abstract description 13
- 230000002401 inhibitory effect Effects 0.000 abstract description 8
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 abstract description 7
- 239000008103 glucose Substances 0.000 abstract description 7
- 238000010521 absorption reaction Methods 0.000 abstract description 5
- 125000000217 alkyl group Chemical group 0.000 abstract description 5
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 2
- 150000004677 hydrates Chemical class 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 138
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 96
- 239000000243 solution Substances 0.000 description 70
- -1 phenyl 5-thio-β-D-glucopyranoside compound Chemical class 0.000 description 64
- 230000015572 biosynthetic process Effects 0.000 description 56
- 238000003786 synthesis reaction Methods 0.000 description 56
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 46
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 38
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 37
- 238000006243 chemical reaction Methods 0.000 description 37
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 36
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
- 238000005160 1H NMR spectroscopy Methods 0.000 description 32
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 32
- 239000000203 mixture Substances 0.000 description 32
- 239000002904 solvent Substances 0.000 description 30
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 29
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 230000002829 reductive effect Effects 0.000 description 27
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 26
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 239000011734 sodium Substances 0.000 description 22
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 22
- 238000010898 silica gel chromatography Methods 0.000 description 21
- 238000005481 NMR spectroscopy Methods 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 229910052763 palladium Inorganic materials 0.000 description 15
- 239000000843 powder Substances 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 9
- 235000011089 carbon dioxide Nutrition 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 9
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 8
- RIZBLVRXRWHLFA-UHFFFAOYSA-N 3,5-dimethoxytoluene Chemical compound COC1=CC(C)=CC(OC)=C1 RIZBLVRXRWHLFA-UHFFFAOYSA-N 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- IBYSJIRYGCFMFO-UHFFFAOYSA-N CC1=CC(=CC(=C1CC2=CC=C(C=C2)[N+](=O)[O-])O)OC Chemical compound CC1=CC(=CC(=C1CC2=CC=C(C=C2)[N+](=O)[O-])O)OC IBYSJIRYGCFMFO-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base 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
- 229910021529 ammonia Inorganic materials 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 210000000813 small intestine Anatomy 0.000 description 7
- 125000000981 3-amino-3-oxopropyl group Chemical group [H]C([*])([H])C([H])([H])C(=O)N([H])[H] 0.000 description 6
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- IJJLRUSZMLMXCN-SLPGGIOYSA-N (2r,3r,4s,5r)-2,3,4,6-tetrahydroxy-5-sulfanylhexanal Chemical class OC[C@@H](S)[C@@H](O)[C@H](O)[C@@H](O)C=O IJJLRUSZMLMXCN-SLPGGIOYSA-N 0.000 description 5
- SKDHHIUENRGTHK-UHFFFAOYSA-N 4-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=C(C(Cl)=O)C=C1 SKDHHIUENRGTHK-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 101000716688 Homo sapiens Sodium/glucose cotransporter 1 Proteins 0.000 description 5
- 101000716682 Homo sapiens Sodium/glucose cotransporter 2 Proteins 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 102000052194 human SLC5A1 Human genes 0.000 description 5
- 102000052543 human SLC5A2 Human genes 0.000 description 5
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 5
- 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
- YCWRFIYBUQBHJI-UHFFFAOYSA-N 2-(4-aminophenyl)acetonitrile Chemical group NC1=CC=C(CC#N)C=C1 YCWRFIYBUQBHJI-UHFFFAOYSA-N 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- 108091006269 SLC5A2 Proteins 0.000 description 4
- 102000058081 Sodium-Glucose Transporter 2 Human genes 0.000 description 4
- 230000009102 absorption Effects 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 239000002274 desiccant Substances 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- 239000001763 2-hydroxyethyl(trimethyl)azanium Substances 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- HEXQVDXDVUNDJD-UHFFFAOYSA-N CC1=CC(=C(C(=C1)O)CC2=CC=C(C=C2)[N+](=O)[O-])C Chemical compound CC1=CC(=C(C(=C1)O)CC2=CC=C(C=C2)[N+](=O)[O-])C HEXQVDXDVUNDJD-UHFFFAOYSA-N 0.000 description 3
- 235000019743 Choline chloride Nutrition 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 238000006751 Mitsunobu reaction Methods 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- BZGHTCWXQJEQFJ-UHFFFAOYSA-N OC1=C(C(=CC(=C1)C)C)C(=O)C1=CC=C(C=C1)[N+](=O)[O-] Chemical compound OC1=C(C(=CC(=C1)C)C)C(=O)C1=CC=C(C=C1)[N+](=O)[O-] BZGHTCWXQJEQFJ-UHFFFAOYSA-N 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- PVEOYINWKBTPIZ-UHFFFAOYSA-N but-3-enoic acid Chemical compound OC(=O)CC=C PVEOYINWKBTPIZ-UHFFFAOYSA-N 0.000 description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- SGMZJAMFUVOLNK-UHFFFAOYSA-M choline chloride Chemical compound [Cl-].C[N+](C)(C)CCO SGMZJAMFUVOLNK-UHFFFAOYSA-M 0.000 description 3
- 229960003178 choline chloride Drugs 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 3
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- HOVAGTYPODGVJG-UHFFFAOYSA-N methyl beta-galactoside Natural products COC1OC(CO)C(O)C(O)C1O HOVAGTYPODGVJG-UHFFFAOYSA-N 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 3
- 150000002989 phenols Chemical class 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000003449 preventive effect Effects 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- UQLWKAVEWDUEQN-UHFFFAOYSA-N (2,4-dimethoxy-6-methylphenyl)-(4-nitrophenyl)methanone Chemical compound COC1=CC(OC)=CC(C)=C1C(=O)C1=CC=C([N+]([O-])=O)C=C1 UQLWKAVEWDUEQN-UHFFFAOYSA-N 0.000 description 2
- HSVPQSQPHHVITQ-UHFFFAOYSA-N (3,5-dimethylphenyl) 4-nitrobenzoate Chemical compound CC1=CC(C)=CC(OC(=O)C=2C=CC(=CC=2)[N+]([O-])=O)=C1 HSVPQSQPHHVITQ-UHFFFAOYSA-N 0.000 description 2
- WIBCITOJDNRTAD-UHFFFAOYSA-N (3-methylphenyl) 4-nitrobenzoate Chemical compound CC1=CC=CC(OC(=O)C=2C=CC(=CC=2)[N+]([O-])=O)=C1 WIBCITOJDNRTAD-UHFFFAOYSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 2
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 2
- TUAMRELNJMMDMT-UHFFFAOYSA-N 3,5-xylenol Chemical compound CC1=CC(C)=CC(O)=C1 TUAMRELNJMMDMT-UHFFFAOYSA-N 0.000 description 2
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 2
- GAGJMOQGABUOBK-UHFFFAOYSA-N 3-aminopropanamide;hydrochloride Chemical compound Cl.NCCC(N)=O GAGJMOQGABUOBK-UHFFFAOYSA-N 0.000 description 2
- QHTJAZXUAIEKNZ-PFKOEMKTSA-N 4-[4-[[4-hydroxy-2-methyl-6-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)thian-2-yl]oxyphenyl]methyl]phenyl]butanoic acid Chemical compound C=1C=C(CCCC(O)=O)C=CC=1CC=1C(C)=CC(O)=CC=1O[C@@H]1S[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O QHTJAZXUAIEKNZ-PFKOEMKTSA-N 0.000 description 2
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 description 2
- FBSVFTVJSOTJQG-UHFFFAOYSA-N CC1=C(C(=CC=C1)O)CC2=CC=C(C=C2)[N+](=O)[O-] Chemical compound CC1=C(C(=CC=C1)O)CC2=CC=C(C=C2)[N+](=O)[O-] FBSVFTVJSOTJQG-UHFFFAOYSA-N 0.000 description 2
- JHDSJVUBVCEGED-UHFFFAOYSA-N CC1=CC(=C(C=C1)CC2=CC=C(C=C2)[N+](=O)[O-])O Chemical compound CC1=CC(=C(C=C1)CC2=CC=C(C=C2)[N+](=O)[O-])O JHDSJVUBVCEGED-UHFFFAOYSA-N 0.000 description 2
- WLYZCMNXWIGPNV-UHFFFAOYSA-N CC1=CC(=CC(=C1C(=O)C2=CC=C(C=C2)[N+](=O)[O-])O)OC Chemical compound CC1=CC(=CC(=C1C(=O)C2=CC=C(C=C2)[N+](=O)[O-])O)OC WLYZCMNXWIGPNV-UHFFFAOYSA-N 0.000 description 2
- JMEREVRKPFRVHM-UHFFFAOYSA-N CC1=CC(=CC(=C1CC2=CC=C(C=C2)Br)O)OC(=O)OC Chemical compound CC1=CC(=CC(=C1CC2=CC=C(C=C2)Br)O)OC(=O)OC JMEREVRKPFRVHM-UHFFFAOYSA-N 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 206010018429 Glucose tolerance impaired Diseases 0.000 description 2
- 238000007341 Heck reaction Methods 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 102100037202 Sodium/myo-inositol cotransporter 2 Human genes 0.000 description 2
- 101710090560 Sodium/myo-inositol cotransporter 2 Proteins 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- OSZSMFQZURNRHS-RQICVUQASA-N [(2r,3s,4s,5r)-3,4,5-triacetyloxy-6-hydroxythian-2-yl]methyl acetate Chemical compound CC(=O)OC[C@H]1SC(O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O OSZSMFQZURNRHS-RQICVUQASA-N 0.000 description 2
- UTAQUIVEPBXKLE-OUUBHVDSSA-N [3-[[4-hydroxy-2-methyl-6-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)thian-2-yl]oxyphenyl]methyl]phenyl]urea Chemical compound C=1C=CC(NC(N)=O)=CC=1CC=1C(C)=CC(O)=CC=1O[C@@H]1S[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UTAQUIVEPBXKLE-OUUBHVDSSA-N 0.000 description 2
- DJCAHUUMRZCIRJ-UJWQCDCRSA-N [4-[[4-hydroxy-2-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)thian-2-yl]oxyphenyl]methyl]phenyl]urea Chemical compound C1=CC(NC(=O)N)=CC=C1CC1=CC=C(O)C=C1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)S1 DJCAHUUMRZCIRJ-UJWQCDCRSA-N 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- ZGJLJEMLZMXNFD-UHFFFAOYSA-N but-3-enamide Chemical compound NC(=O)CC=[CH] ZGJLJEMLZMXNFD-UHFFFAOYSA-N 0.000 description 2
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- WRJWRGBVPUUDLA-UHFFFAOYSA-N chlorosulfonyl isocyanate Chemical compound ClS(=O)(=O)N=C=O WRJWRGBVPUUDLA-UHFFFAOYSA-N 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940125810 compound 20 Drugs 0.000 description 2
- 229940125846 compound 25 Drugs 0.000 description 2
- 229940125851 compound 27 Drugs 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- SVABQOITNJTVNJ-UHFFFAOYSA-N diphenyl-2-pyridylphosphine Chemical compound C1=CC=CC=C1P(C=1N=CC=CC=1)C1=CC=CC=C1 SVABQOITNJTVNJ-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 210000000981 epithelium Anatomy 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- BRZYSWJRSDMWLG-CAXSIQPQSA-N geneticin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](C(C)O)O2)N)[C@@H](N)C[C@H]1N BRZYSWJRSDMWLG-CAXSIQPQSA-N 0.000 description 2
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 2
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- HOVAGTYPODGVJG-ZFYZTMLRSA-N methyl alpha-D-glucopyranoside Chemical compound CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HOVAGTYPODGVJG-ZFYZTMLRSA-N 0.000 description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 2
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 description 2
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- DUCFGUKZGYZZCT-UHFFFAOYSA-N (2-hydroxy-4-methylphenyl)-(4-nitrophenyl)methanone Chemical compound Cc1ccc(C(=O)c2ccc(cc2)[N+]([O-])=O)c(O)c1 DUCFGUKZGYZZCT-UHFFFAOYSA-N 0.000 description 1
- HTTWERFYMAIXKG-UHFFFAOYSA-N (2-hydroxy-6-methylphenyl)-(4-nitrophenyl)methanone Chemical compound OC1=C(C(=CC=C1)C)C(=O)C1=CC=C(C=C1)[N+](=O)[O-] HTTWERFYMAIXKG-UHFFFAOYSA-N 0.000 description 1
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 description 1
- OPLSYGKRSSLBBB-OUUBHVDSSA-N (2R,3R,4S,5S,6R)-2-[2-[(4-aminophenyl)methyl]-5-hydroxy-3-methylphenoxy]-6-(hydroxymethyl)thiane-3,4,5-triol Chemical compound C=1C=C(N)C=CC=1CC=1C(C)=CC(O)=CC=1O[C@@H]1S[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O OPLSYGKRSSLBBB-OUUBHVDSSA-N 0.000 description 1
- BHFXPIIFGGLGFS-OUUBHVDSSA-N (2R,3S,4S,5R,6R)-3,4,5-trihydroxy-2-(hydroxymethyl)-6-[5-hydroxy-3-methyl-2-[[4-(sulfamoylamino)phenyl]methyl]phenoxy]thiane Chemical compound C=1C=C(NS(N)(=O)=O)C=CC=1CC=1C(C)=CC(O)=CC=1O[C@@H]1S[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O BHFXPIIFGGLGFS-OUUBHVDSSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- AZZFKYLGBHJEFE-UHFFFAOYSA-N (4-hydroxy-2-methylphenyl)-(4-nitrophenyl)methanone Chemical compound CC1=CC(O)=CC=C1C(=O)C1=CC=C([N+]([O-])=O)C=C1 AZZFKYLGBHJEFE-UHFFFAOYSA-N 0.000 description 1
- VLSDXINSOMDCBK-BQYQJAHWSA-N (E)-1,1'-azobis(N,N-dimethylformamide) Chemical compound CN(C)C(=O)\N=N\C(=O)N(C)C VLSDXINSOMDCBK-BQYQJAHWSA-N 0.000 description 1
- XBYRMPXUBGMOJC-UHFFFAOYSA-N 1,2-dihydropyrazol-3-one Chemical class OC=1C=CNN=1 XBYRMPXUBGMOJC-UHFFFAOYSA-N 0.000 description 1
- DPZNOMCNRMUKPS-UHFFFAOYSA-N 1,3-Dimethoxybenzene Chemical compound COC1=CC=CC(OC)=C1 DPZNOMCNRMUKPS-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- WTAPZWXVSZMMDG-UHFFFAOYSA-N 1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].C=1C=CC=CC=1C=CC(=O)C=CC1=CC=CC=C1 WTAPZWXVSZMMDG-UHFFFAOYSA-N 0.000 description 1
- LILUGTMLBWYTPC-QMCAAQAGSA-N 1-(2-hydroxyethyl)-3-[4-[[4-hydroxy-2-methyl-6-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)thian-2-yl]oxyphenyl]methyl]phenyl]urea Chemical compound C=1C=C(NC(=O)NCCO)C=CC=1CC=1C(C)=CC(O)=CC=1O[C@@H]1S[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O LILUGTMLBWYTPC-QMCAAQAGSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- BMVXCPBXGZKUPN-UHFFFAOYSA-N 1-hexanamine Chemical compound CCCCCCN BMVXCPBXGZKUPN-UHFFFAOYSA-N 0.000 description 1
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 description 1
- DLWRORPOJBKDBH-OUUBHVDSSA-N 2-[4-[[4-hydroxy-2-methyl-6-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)thian-2-yl]oxyphenyl]methyl]phenyl]guanidine Chemical compound C=1C=C(N=C(N)N)C=CC=1CC=1C(C)=CC(O)=CC=1O[C@@H]1S[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O DLWRORPOJBKDBH-OUUBHVDSSA-N 0.000 description 1
- 229940058020 2-amino-2-methyl-1-propanol Drugs 0.000 description 1
- WKNMKGVLOWGGOU-UHFFFAOYSA-N 2-aminoacetamide;hydron;chloride Chemical compound Cl.NCC(N)=O WKNMKGVLOWGGOU-UHFFFAOYSA-N 0.000 description 1
- CMWKITSNTDAEDT-UHFFFAOYSA-N 2-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC=C1C=O CMWKITSNTDAEDT-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- IQQYLBIFFAFHPD-UHFFFAOYSA-N 3-(iminomethylideneamino)propan-1-amine;hydrochloride Chemical compound Cl.NCCCN=C=N IQQYLBIFFAFHPD-UHFFFAOYSA-N 0.000 description 1
- NXTNASSYJUXJDV-UHFFFAOYSA-N 3-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=CC(C(Cl)=O)=C1 NXTNASSYJUXJDV-UHFFFAOYSA-N 0.000 description 1
- DENKGPBHLYFNGK-UHFFFAOYSA-N 4-bromobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Br)C=C1 DENKGPBHLYFNGK-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 1
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 101100313763 Arabidopsis thaliana TIM22-2 gene Proteins 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000002249 Diabetes Complications Diseases 0.000 description 1
- 206010012655 Diabetic complications Diseases 0.000 description 1
- DKMROQRQHGEIOW-UHFFFAOYSA-N Diethyl succinate Chemical compound CCOC(=O)CCC(=O)OCC DKMROQRQHGEIOW-UHFFFAOYSA-N 0.000 description 1
- 241000400611 Eucalyptus deanei Species 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 238000005618 Fries rearrangement reaction Methods 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 102000004157 Hydrolases Human genes 0.000 description 1
- 108090000604 Hydrolases Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- GRRNUXAQVGOGFE-UHFFFAOYSA-N Hygromycin-B Natural products OC1C(NC)CC(N)C(O)C1OC1C2OC3(C(C(O)C(O)C(C(N)CO)O3)O)OC2C(O)C(CO)O1 GRRNUXAQVGOGFE-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 239000012097 Lipofectamine 2000 Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- YMVWQYUQYDLEKX-QMCAAQAGSA-N N-[4-[[4-hydroxy-2-methyl-6-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)thian-2-yl]oxyphenyl]methyl]phenyl]acetamide Chemical compound C1=CC(NC(=O)C)=CC=C1CC1=C(C)C=C(O)C=C1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)S1 YMVWQYUQYDLEKX-QMCAAQAGSA-N 0.000 description 1
- JPJYARCPVRBTPV-WSGIOKLISA-N N-[4-[[4-hydroxy-2-methyl-6-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)thian-2-yl]oxyphenyl]methyl]phenyl]benzenesulfonamide Chemical compound C=1C=C(NS(=O)(=O)C=2C=CC=CC=2)C=CC=1CC=1C(C)=CC(O)=CC=1O[C@@H]1S[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O JPJYARCPVRBTPV-WSGIOKLISA-N 0.000 description 1
- WTYRBZNHKFXZHX-YMQHIKHWSA-N N-[4-[[4-hydroxy-2-methyl-6-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)thian-2-yl]oxyphenyl]methyl]phenyl]methanesulfonamide Chemical compound C=1C=C(NS(C)(=O)=O)C=CC=1CC=1C(C)=CC(O)=CC=1O[C@@H]1S[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O WTYRBZNHKFXZHX-YMQHIKHWSA-N 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 229930182475 S-glycoside Natural products 0.000 description 1
- 102000000070 Sodium-Glucose Transport Proteins Human genes 0.000 description 1
- 108010080361 Sodium-Glucose Transport Proteins Proteins 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- BIQJESKUKPEEAC-YMQHIKHWSA-N [4-[[2,4-dimethyl-6-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)thian-2-yl]oxyphenyl]methyl]phenyl]urea Chemical compound O([C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)S1)O)C1=CC(C)=CC(C)=C1CC1=CC=C(NC(N)=O)C=C1 BIQJESKUKPEEAC-YMQHIKHWSA-N 0.000 description 1
- AXFZEXDNPCZAAH-OUUBHVDSSA-N [4-[[2-methyl-6-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)thian-2-yl]oxyphenyl]methyl]phenyl]urea Chemical compound C=1C=C(NC(N)=O)C=CC=1CC=1C(C)=CC=CC=1O[C@@H]1S[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O AXFZEXDNPCZAAH-OUUBHVDSSA-N 0.000 description 1
- IPGPCUGSRCMJFT-OUUBHVDSSA-N [4-[[4-hydroxy-2-methyl-6-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)thian-2-yl]oxyphenyl]methyl]phenyl]urea Chemical compound C=1C=C(NC(N)=O)C=CC=1CC=1C(C)=CC(O)=CC=1O[C@@H]1S[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O IPGPCUGSRCMJFT-OUUBHVDSSA-N 0.000 description 1
- VEUHIZWXAUVBRZ-YMQHIKHWSA-N [4-[[4-methoxy-2-methyl-6-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)thian-2-yl]oxyphenyl]methyl]phenyl]urea Chemical compound O([C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)S1)O)C1=CC(OC)=CC(C)=C1CC1=CC=C(NC(N)=O)C=C1 VEUHIZWXAUVBRZ-YMQHIKHWSA-N 0.000 description 1
- FOKMXWZMFBPOPQ-OUUBHVDSSA-N [4-[[4-methyl-2-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)thian-2-yl]oxyphenyl]methyl]phenyl]urea Chemical compound O([C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)S1)O)C1=CC(C)=CC=C1CC1=CC=C(NC(N)=O)C=C1 FOKMXWZMFBPOPQ-OUUBHVDSSA-N 0.000 description 1
- 229960002632 acarbose Drugs 0.000 description 1
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009056 active transport Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000005210 alkyl ammonium group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 1
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- CBTVGIZVANVGBH-UHFFFAOYSA-N aminomethyl propanol Chemical compound CC(C)(N)CO CBTVGIZVANVGBH-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
- NRBUVVTTYMTSKM-UHFFFAOYSA-N benzyl n-[phenylmethoxycarbonylamino(pyrazol-1-yl)methylidene]carbamate Chemical compound C=1C=CC=CC=1COC(=O)NC(N1N=CC=C1)=NC(=O)OCC1=CC=CC=C1 NRBUVVTTYMTSKM-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 1
- FATUQANACHZLRT-KMRXSBRUSA-L calcium glucoheptonate Chemical compound [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O FATUQANACHZLRT-KMRXSBRUSA-L 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- LWJYMKDMGMOTSB-UHFFFAOYSA-L dichlorotin;hydrate Chemical compound O.Cl[Sn]Cl LWJYMKDMGMOTSB-UHFFFAOYSA-L 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000009207 exercise therapy Methods 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 1
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 230000004190 glucose uptake Effects 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- WMXNYROMFDJGQI-UHFFFAOYSA-N heptane;trichloroborane Chemical compound ClB(Cl)Cl.CCCCCCC WMXNYROMFDJGQI-UHFFFAOYSA-N 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- GRRNUXAQVGOGFE-NZSRVPFOSA-N hygromycin B Chemical compound O[C@@H]1[C@@H](NC)C[C@@H](N)[C@H](O)[C@H]1O[C@H]1[C@H]2O[C@@]3([C@@H]([C@@H](O)[C@@H](O)[C@@H](C(N)CO)O3)O)O[C@H]2[C@@H](O)[C@@H](CO)O1 GRRNUXAQVGOGFE-NZSRVPFOSA-N 0.000 description 1
- 229940097277 hygromycin b Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 229960001021 lactose monohydrate Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- OQJBFFCUFALWQL-UHFFFAOYSA-N n-(piperidine-1-carbonylimino)piperidine-1-carboxamide Chemical compound C1CCCCN1C(=O)N=NC(=O)N1CCCCC1 OQJBFFCUFALWQL-UHFFFAOYSA-N 0.000 description 1
- 125000006606 n-butoxy group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000006501 nitrophenyl group Chemical group 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- JRTYPQGPARWINR-UHFFFAOYSA-N palladium platinum Chemical compound [Pd].[Pt] JRTYPQGPARWINR-UHFFFAOYSA-N 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- HDOUGSFASVGDCS-UHFFFAOYSA-N pyridin-3-ylmethanamine Chemical compound NCC1=CC=CN=C1 HDOUGSFASVGDCS-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000030558 renal glucose absorption Effects 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical class OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- QKSQWQOAUQFORH-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonylimino]carbamate Chemical compound CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C QKSQWQOAUQFORH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- XREXPQGDOPQPAH-QKUPJAQQSA-K trisodium;[(z)-18-[1,3-bis[[(z)-12-sulfonatooxyoctadec-9-enoyl]oxy]propan-2-yloxy]-18-oxooctadec-9-en-7-yl] sulfate Chemical compound [Na+].[Na+].[Na+].CCCCCCC(OS([O-])(=O)=O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(CCCCCC)OS([O-])(=O)=O)COC(=O)CCCCCCC\C=C/CC(CCCCCC)OS([O-])(=O)=O XREXPQGDOPQPAH-QKUPJAQQSA-K 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
Description
本発明は、腎臓でのグルコース再吸収に関わるナトリウム依存性グルコース供輸送体１（ＳＧＬＴ１）の阻害活性を有するピラゾリル ５−チオグリコシド化合物に関する。 The present invention relates to a pyrazolyl 5-thioglycoside compound having an inhibitory activity on sodium-dependent glucose transporter 1 (SGLT1) involved in glucose reabsorption in the kidney.
糖尿病に罹患すると、空腹時の血糖値は１２６ｍｇ／ｄＬ以上を示す。また、空腹時の血糖値が正常であっても、食事の後に１４０〜２００ｍｇ／ｄＬという高い血糖値を示す場合には、耐糖能異常（以下、ＩＧＴ（impaired glucose tolerance）という。）と診断される。そして、このＩＧＴの状態は、「境界型」と呼ばれ、糖尿病予備群と位置付けられている。この境界型から糖尿病の発症を遅らせることは、心血管障害のリスクを低減させると考えられ、それを示す幾つかの知見が得られている。例えば、１９９７年に中国で行われたDa Qing IGT and Diabetes Studyでは、ダイエットや運動を行うことでＩＧＴから２型糖尿病への移行を有意に抑制したと報告されている(非特許文献１参照)。また、薬剤治療が有効な例として、糖の加水分解酵素を阻害し、小腸からの糖の吸収を遅延させるα−グルコシダーゼ阻害剤アカルボースを投与すると、ＩＧＴから２型糖尿病への移行を抑制し、さらに高血圧の発症も有意に抑制することが報告されている(非特許文献２参照)。 When suffering from diabetes, the fasting blood glucose level is 126 mg / dL or more. Moreover, even if the fasting blood glucose level is normal, if it shows a high blood glucose level of 140 to 200 mg / dL after meal, it is diagnosed as abnormal glucose tolerance (hereinafter referred to as IGT (impaired glucose tolerance)). The This IGT state is called “border type” and is positioned as a diabetic preparatory group. Delaying the onset of diabetes from this borderline type is thought to reduce the risk of cardiovascular disorders, and several findings have been obtained. For example, in Da Qing IGT and Diabetes Study conducted in China in 1997, it was reported that the transition from IGT to type 2 diabetes was significantly suppressed by performing diet and exercise (see Non-Patent Document 1). . In addition, as an effective example of drug treatment, the administration of acarbose, an α-glucosidase inhibitor that inhibits sugar hydrolase and delays sugar absorption from the small intestine, suppresses the transition from IGT to type 2 diabetes, Furthermore, it has been reported that the onset of hypertension is also significantly suppressed (see Non-Patent Document 2).
以上のことから、糖尿病の発症を抑えるには、食事療法、運動及び薬物療法によってＩＧＴをコントロールすることが重要である。 From the above, in order to suppress the onset of diabetes, it is important to control IGT by diet therapy, exercise and drug therapy.
ここで、小腸上皮には高い頻度でナトリウム依存性グルコース共輸送体１（ＳＧＬＴ１）が発現している。このＳＧＬＴ１は小腸において、ナトリウムに依存し、グルコース又はガラクトースの能動輸送を司っている。そこで、ＳＧＬＴ１活性を阻害し、血糖値の上昇を抑制して、ＩＧＴの改善を図るピラゾール誘導体の合成例が報告されている（特許文献１〜６参照）。 Here, sodium-dependent glucose cotransporter 1 (SGLT1) is expressed in the small intestine epithelium at a high frequency. This SGLT1 is dependent on sodium in the small intestine and is responsible for the active transport of glucose or galactose. Then, the synthesis example of the pyrazole derivative which inhibits SGLT1 activity and suppresses the raise of a blood glucose level and aims at improvement of IGT is reported (refer patent documents 1-6).
また、腎臓に高頻度で発現するＳＧＬＴ２の阻害活性を有するフェニル ５−チオグリコシド誘導体も開示されている（特許文献７参照）。 In addition, a phenyl 5-thioglycoside derivative having an inhibitory activity on SGLT2 that is frequently expressed in the kidney is also disclosed (see Patent Document 7).
しかしながら、選択的にＳＧＬＴ１活性を阻害するフェニル ５−チオグリコシド誘導体については知られていない。 However, there is no known phenyl 5-thioglycoside derivative that selectively inhibits SGLT1 activity.
本発明は、選択的にＳＧＬＴ１活性を阻害し、消化管からのグルコース吸収を抑制することで、ＩＧＴをコントロールする新規なフェニル ５−チオ−β−Ｄ−グルコピラノシド化合物を提供することを課題とする。 An object of the present invention is to provide a novel phenyl 5-thio-β-D-glucopyranoside compound that controls IGT by selectively inhibiting SGLT1 activity and suppressing glucose absorption from the digestive tract. .
本発明者らは前記課題を解決するために鋭意研究した結果、ある種のヒドロキシピラゾール誘導体を５−チオグルコシル化した化合物が、優れたＳＧＬＴ１活性阻害作用を有することを見出し、本発明を完成するに至った。 As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that a compound obtained by 5-thioglucosylating a certain kind of hydroxypyrazole derivative has an excellent SGLT1 activity inhibitory action, thereby completing the present invention. It came to.
すなわち、本発明は、下記式（Ｉ）で表されるフェニル ５−チオグルコシド化合物若しくはその製薬学的に許容される塩又はそれらの水和物である。 That is, the present invention is a phenyl 5-thioglucoside compound represented by the following formula (I), a pharmaceutically acceptable salt thereof, or a hydrate thereof.
［式（Ｉ）中、
Ｒ1及びＲ2は、同一又は異なって、水素原子、水酸基、Ｃ1-6アルキル基、又はＣ1-6アルコキシ基を示す。
Ｚは、−ＮＨＳＯ2フェニル、−ＮＨＳＯ2ＮＨ2、−ＮＨＣ（＝ＮＨ）ＮＨ2、−ＮＨＣＯＮ（ＲA）ＲB（式中、ＲA及びＲBは、同一又は異なって、水素原子、Ｃ1-6アルキル基、Ｃ3-7シクロアルキル基、又は“水酸基、−ＣＯＮＨ2、フェニル基及びピリジル基からなる群より選択される１〜３個の基で置換されたＣ1-6アルキル基”を示す。）、又は“メチル基及びオキソ基の少なくとも１種で置換された４〜６員へテロシクロアルキル基”、又は−Ｙ−ＣＯＮ(ＲC)ＲD（式中、Ｙは、Ｃ1-6アルキレン基又はＣ2-6アルケニレン基を示し、ＲC及びＲDの一方が“−ＣＯＮＨ2で置換されたＣ1-6アルキル基”を示すとき、他方は水素原子を示す。）を示す。］
[In the formula (I),
R 1 and R 2 are the same or different and each represents a hydrogen atom, a hydroxyl group, a C 1-6 alkyl group, or a C 1-6 alkoxy group.
Z is —NHSO 2 phenyl, —NHSO 2 NH 2 , —NHC (═NH) NH 2 , —NHCON (R A ) R B (wherein, R A and R B are the same or different and represent a hydrogen atom, C 1-6 alkyl, C 3-7 cycloalkyl group, or "hydroxyl, -CONH 2, C 1-6 alkyl substituted with one to three groups selected from the group consisting of phenyl and pyridyl groups Or a “4- to 6-membered heterocycloalkyl group substituted with at least one of a methyl group and an oxo group”, or —Y—CON (R C ) R D (wherein Y represents , C 1-6 alkylene group or C 2-6 alkenylene group, and when one of R C and R D represents “C 1-6 alkyl group substituted with —CONH 2 ”, the other represents a hydrogen atom. .) ]
本発明の他の態様は、前記式（Ｉ）で表されるフェニル ５−チオグルコシド化合物若しくはその製薬学的に許容される塩又はそれらの水和物を有効成分として含有することを特徴とするＳＧＬＴ１活性阻害剤である。 Another aspect of the present invention is characterized in that it comprises a phenyl 5-thioglucoside compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. SGLT1 activity inhibitor.
本発明の他の態様は、前記式（Ｉ）で表されるフェニル ５−チオグルコシド化合物若しくはその製薬学的に許容される塩又はそれらの水和物を有効成分として含有することを特徴とする糖尿病の予防又は治療剤である。 Another aspect of the present invention is characterized in that it comprises a phenyl 5-thioglucoside compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. It is a preventive or therapeutic agent for diabetes.
本発明により、ＳＧＬＴ１活性を選択的に阻害する新規なフェニル ５−チオグルコシド化合物を提供することが可能となった。 According to the present invention, it has become possible to provide a novel phenyl 5-thioglucoside compound that selectively inhibits SGLT1 activity.
本発明において使用する用語を以下に定義する。 The terms used in the present invention are defined below.
「Ｃ1-6アルキル基」とは、炭素原子を１−６個有する直鎖状又は分枝状のアルキル基を意味する。例えば、メチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、イソブチル基、ｔｅｒｔ−ブチル基、ｓｅｃ−ブチル基、ｎ−ペンチル基、ｎ−ヘキシル基が挙げられる。 The “C 1-6 alkyl group” means a linear or branched alkyl group having 1-6 carbon atoms. For example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, and n-hexyl group can be mentioned.
「Ｃ1-6アルコキシ基」とは、炭素原子を１−６個有する直鎖状又は分枝状のアルコキシ基を意味し、Ｃ1-4アルコキシ基が好ましい。Ｃ1-4アルコキシ基としては、例えば、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ｎ−ブトキシ基、イソブトキシ基、ｔｅｒｔ−ブトキシ基が挙げられる。 The “C 1-6 alkoxy group” means a linear or branched alkoxy group having 1-6 carbon atoms, and a C 1-4 alkoxy group is preferable. Examples of the C 1-4 alkoxy group include methoxy group, ethoxy group, propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, and tert-butoxy group.
「メチル基及びオキソ基の少なくとも１種で置換された４〜６員へテロシクロアルキル基」とは、Ｏ、Ｓ及びＮから選択された１〜２個のヘテロ原子を含有する原子数４〜６個からなるヘテロシクロアルキル基において、その基上の水素原子がメチル基及びオキソ基の少なくとも１種で置換された基である。例えば、２−オキソピロリジニル基、５,５−ジメチル−イミダゾリジン−２,４−ジオン−３−イル基が挙げられる。 “A 4 to 6-membered heterocycloalkyl group substituted with at least one of a methyl group and an oxo group” means an atom having 4 to 2 atoms containing 1 to 2 heteroatoms selected from O, S and N In a 6-heterocycloalkyl group, a hydrogen atom on the group is a group substituted with at least one of a methyl group and an oxo group. Examples thereof include a 2-oxopyrrolidinyl group and a 5,5-dimethyl-imidazolidin-2,4-dione-3-yl group.
「水酸基、−ＣＯＮＨ2、フェニル基及びピリジル基からなる群より選択される１〜３個の基で置換されたＣ1-6アルキル基」とは、その基上の水素原子が１〜３個の水酸基、−ＣＯＮＨ2、フェニル基及びピリジル基の少なくとも１種の基によって置換されたアルキル基を示す。例えば、ヒドロキシメチル基、ヒドロキシエチル基、２−ヒドロキシ−１,１−ジメチルエチル基、１,３−ジヒドロキシ−２−メチルプロパン−２−イル基、カルバモイルメチル基、２−カルバモイルエチル基、ベンジル基、フェネチル基、３−ピリジルメチル基が挙げられる。 “C 1-6 alkyl group substituted with 1 to 3 groups selected from the group consisting of hydroxyl group, —CONH 2 , phenyl group and pyridyl group” means 1 to 3 hydrogen atoms on the group. indicating hydroxyl, a -CONH 2, alkyl group substituted by at least one group of the phenyl and pyridyl groups. For example, hydroxymethyl group, hydroxyethyl group, 2-hydroxy-1,1-dimethylethyl group, 1,3-dihydroxy-2-methylpropan-2-yl group, carbamoylmethyl group, 2-carbamoylethyl group, benzyl group , A phenethyl group, and a 3-pyridylmethyl group.
「製薬学的に許容される塩」とは、アルカリ金属類、アルカリ土類金属類、アンモニウム、アルキルアンモニウムなどとの塩、鉱酸又は有機酸との塩であり、例えば、ナトリウム塩、カリウム塩、カルシウム塩、アンモニウム塩、アルミニウム塩、トリエチルアンモニウム塩、酢酸塩、プロピオン酸塩、酪酸塩、ぎ酸塩、トリフルオロ酢酸塩、マレイン酸塩、酒石酸塩、クエン酸塩、ステアリン酸塩、コハク酸塩、エチルコハク酸塩、ラクトビオン酸塩、グルコン酸塩、グルコヘプトン酸塩、安息香酸塩、メタンスルホン酸塩、エタンスルホン酸塩、２−ヒドロキシエタンスルホン酸塩、ベンゼンスルホン酸塩、パラトルエンスルホン酸塩、ラウリル硫酸塩、リンゴ酸塩、アスパラギン酸塩、グルタミン酸塩、アジピン酸塩、システインとの塩、Ｎ−アセチルシステインとの塩、塩酸塩、臭化水素酸塩、リン酸塩、硫酸塩、よう化水素酸塩、ニコチン酸塩、シュウ酸塩、ピクリン酸塩、チオシアン酸塩、ウンデカン酸塩、アクリル酸ポリマーとの塩、カルボキシビニルポリマーとの塩などが挙げられる。 “Pharmaceutically acceptable salt” is a salt with an alkali metal, alkaline earth metal, ammonium, alkylammonium, or the like, a salt with a mineral acid or an organic acid, such as a sodium salt or potassium salt. , Calcium salt, ammonium salt, aluminum salt, triethylammonium salt, acetate, propionate, butyrate, formate, trifluoroacetate, maleate, tartrate, citrate, stearate, succinic acid Salt, ethyl succinate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, paratoluenesulfonate With, lauryl sulfate, malate, aspartate, glutamate, adipate, cysteine , Salts with N-acetylcysteine, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nicotinate, oxalate, picrate, thiocyanate, undecanoate , Salts with acrylic acid polymers, salts with carboxyvinyl polymers, and the like.
「水和物」とは、本発明の化合物又はその塩の製薬学的に許容される水和物である。本発明の化合物又はその塩は、大気にさらされ、あるいは再結晶することなどにより、水分を吸収し、吸着水がつく場合や、水和物となる場合がある。本発明における水和物には、そのような水和物も含まれる。 “Hydrate” is a pharmaceutically acceptable hydrate of the compound of the present invention or a salt thereof. The compound of the present invention or a salt thereof may be exposed to air or recrystallized to absorb moisture and form adsorbed water, or may become a hydrate. The hydrate in the present invention includes such a hydrate.
以下に、本発明化合物（Ｉ）の製造方法を説明する。 Below, the manufacturing method of this invention compound (I) is demonstrated.
製造法１
本発明化合物（Ｉ）において、Ｚが−ＮＨＳＯ2フェニル、−ＮＨＳＯ2ＮＨ2、−ＮＨＣ（＝ＮＨ）ＮＨ2、又は−ＮＨＣＯＮ(ＲA)ＲBである化合物は以下の方法で合成することができる。
ただし、Ｐ1、Ｐ2、Ｐ3及びＰ4は、アセチル基、ピバロイル基等のＣ2-6アルカノイル基又はベンゾイル基を示し、その他の記号は前記と同義である。
Manufacturing method 1
In the present invention the compound (I), Z is -NHSO 2 phenyl, -NHSO 2 NH 2, -NHC ( = NH) NH 2, or -NHCON (R A) compound is R B be synthesized by the following method Can do.
However, P 1, P 2, P 3 and P 4 represents an acetyl group, C 2-6 alkanoyl group or a benzoyl group such as pivaloyl group, and other symbols are as defined above.
ここに、フェノール誘導体（IIa）は、国際公開ＷＯ２００４／０５０１２２号に準拠して合成することができる。５−チオグルコース誘導体（III）は、国際公開ＷＯ２００４／０１４９３１号に準拠して合成することができる。 Here, the phenol derivative (IIa) can be synthesized in accordance with International Publication WO 2004/050122. The 5-thioglucose derivative (III) can be synthesized in accordance with International Publication WO 2004/014931.
（１）工程１（光延反応）
光延反応（国際公開ＷＯ２００４／０８９９６６号）によって、フェノール誘導体（IIa）と５−チオグルコース誘導体（III）からフェニル ５−チオ−β−Ｄ−グルコシド誘導体（IVa）を選択的に製造することができる。この反応における試薬として必要なホスフィン類の例としては、トリフェニルホスフィン、トリ−ｎ−ブチルホスフィン、トリ−ｔ−ブチルホスフィン、トリストリルホスフィンやジフェニル−２−ピリジルホスフィンが挙げられる。中でもトリフェニルホスフィン、ジフェニル−２−ピリジルホスフィンが好ましく、トリフェニルホスフィンがより好ましい。
(1) Step 1 (Mitsunobu reaction)
Phenyl 5-thio-β-D-glucoside derivative (IVa) can be selectively produced from phenol derivative (IIa) and 5-thioglucose derivative (III) by Mitsunobu reaction (International Publication WO2004 / 089966). . Examples of phosphines necessary as reagents in this reaction include triphenylphosphine, tri-n-butylphosphine, tri-t-butylphosphine, tristolylphosphine, and diphenyl-2-pyridylphosphine. Of these, triphenylphosphine and diphenyl-2-pyridylphosphine are preferable, and triphenylphosphine is more preferable.
アゾ試薬の例としては、ジエチルアゾジカルボキシレート、ジイソプロピルアゾジカルボキシレートやジ−ｔｅｒｔ−ブチルアゾジカルボキシレート、１，１’−アゾビス（Ｎ，Ｎ−ジメチルホルムアミド）や１，１’−（アゾジカルボニル）ジピペリジンを用いることができる。中でも、ジエチルアゾジカルボキシレート（ＤＥＡＤ）、ジイソプロピルアゾジカルボキシレートが好ましい。 Examples of the azo reagent include diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, 1,1′-azobis (N, N-dimethylformamide), 1,1 ′-( Azodicarbonyl) dipiperidine can be used. Of these, diethyl azodicarboxylate (DEAD) and diisopropyl azodicarboxylate are preferable.
本反応に用いる溶媒はテトラヒドロフラン、ジオキサン、トルエン、ジクロロメタン、クロロホルム、アセトニトリル、酢酸エチル、ジメチルスルホキシド、Ｎ，Ｎ−ジメチルホルムアミド等であり、好ましくはテトラヒドロフラン、トルエンである。 The solvent used in this reaction is tetrahydrofuran, dioxane, toluene, dichloromethane, chloroform, acetonitrile, ethyl acetate, dimethyl sulfoxide, N, N-dimethylformamide, or the like, preferably tetrahydrofuran or toluene.
反応温度は−２０℃から室温が好ましく、−５℃から＋５℃がより好ましい。 The reaction temperature is preferably -20 ° C to room temperature, more preferably -5 ° C to + 5 ° C.
（２）工程２（ニトロ基の還元）
上記で得られた化合物（IVa）をパラジウム活性炭、水酸化パラジウム、又は白金−パラジウム活性炭等の触媒を用いて水素雰囲気下にて接触水素添加することによりニトロ基をアミノ基に変換し、化合物（IVb）が得られる。中でもパラジウム活性炭、水酸化パラジウムが触媒として好ましい。この反応に使用する溶媒としては、メタノール、エタノール、イソプロパノール、酢酸エチル、酢酸等が挙げられる。反応温度は室温から還流温度であるが、室温が好ましい。
(2) Step 2 (Reduction of nitro group)
The compound (IVa) obtained above is converted to an amino group by catalytic hydrogenation under a hydrogen atmosphere using a catalyst such as palladium activated carbon, palladium hydroxide, or platinum-palladium activated carbon. IVb) is obtained. Of these, palladium activated carbon and palladium hydroxide are preferred as the catalyst. Examples of the solvent used in this reaction include methanol, ethanol, isopropanol, ethyl acetate, acetic acid and the like. The reaction temperature is from room temperature to reflux temperature, but room temperature is preferred.
また、塩化スズ(II)１水和物、塩化アンモニウムの存在下、鉄を用いることもできる。この反応に使用する溶媒としては、メタノール、エタノール、イソプロパノール等が挙げられる。反応温度は室温から還流温度である。 Further, iron can also be used in the presence of tin (II) chloride monohydrate and ammonium chloride. Examples of the solvent used for this reaction include methanol, ethanol, isopropanol and the like. The reaction temperature is from room temperature to reflux temperature.
引き続いて、化合物（IVb）を中間体として以下に示す方法で本発明化合物（Ｉ）を製造することができる。 Subsequently, the compound (I) of the present invention can be produced by the following method using the compound (IVb) as an intermediate.
ＲEはベンジルオキシカルボニル基又はｔ−ブトキシカルボニル基を示し、その他の記号は前記と同義である。 R E represents a benzyloxycarbonyl group or a t-butoxycarbonyl group, and other symbols are as defined above.
（３）工程３（スルホニル基の導入）
化合物（IVb）から適当な塩基の存在下、フェニルスルホニルクロリド又はイソシアン酸クロロスルホニルを用い、化合物（IVc）又は（IVd）に誘導することができる。適当な塩基としては、トリエチルアミン、Ｎ−エチル−Ｎ，Ｎ−ジイソプロピルアミン、ピリジン、ＤＢＵ、炭酸カリウム、炭酸カルシウム、炭酸セシウム等が挙げられる。また、使用する溶媒としては、クロロホルム、ジクロロメタン、ジエチルエーテル、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミド、アセトニトリル、酢酸エチル等、又はそれらの混合溶媒が挙げられる。反応温度は０℃から還流温度である。
(3) Step 3 (Introduction of sulfonyl group)
It can be derived from compound (IVb) to compound (IVc) or (IVd) using phenylsulfonyl chloride or chlorosulfonyl isocyanate in the presence of a suitable base. Suitable bases include triethylamine, N-ethyl-N, N-diisopropylamine, pyridine, DBU, potassium carbonate, calcium carbonate, cesium carbonate and the like. In addition, examples of the solvent to be used include chloroform, dichloromethane, diethyl ether, tetrahydrofuran, N, N-dimethylformamide, acetonitrile, ethyl acetate, and the like, or a mixed solvent thereof. The reaction temperature is from 0 ° C. to reflux temperature.
（４）工程４（グアニジノ基の導入）
化合物（IVb）からグアニジノ化試薬Ｖを用いて化合物（IVe）に誘導することができる。この反応に使用する溶媒としては、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミド、メタノール、エタノール、イソプロパノール、酢酸エチル、トルエン等が挙げられる。反応温度は室温から還流温度である。
(4) Step 4 (Introduction of guanidino group)
Compound (IVe) can be derived from compound (IVb) using guanidinating reagent V. Examples of the solvent used in this reaction include tetrahydrofuran, N, N-dimethylformamide, methanol, ethanol, isopropanol, ethyl acetate, toluene and the like. The reaction temperature is from room temperature to reflux temperature.
（５）工程５（ウレイド基の構築）
化合物（IVb）から適当な塩基の存在下、ｐ−ニトロフェニルクロロホルメートやトリホスゲンを用いて、アミンＲAＲBＮＨと縮合することにより、化合物（IVf）に誘導することができる。適当な塩基としては、トリエチルアミン、Ｎ−エチル−Ｎ，Ｎ−ジイソプロピルアミン、ピリジン、ＤＢＵ、炭酸カリウム、炭酸カルシウム、炭酸セシウム等が挙げられる。また、使用する溶媒としては、クロロホルム、ジクロロメタン、ジエチルエーテル、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミド、アセトニトリル、酢酸エチル等が挙げられる。反応温度は０℃から還流温度である。
(5) Step 5 (construction of ureido group)
Compound (IVb) can be derived from compound (IVb) by condensation with amine R A R B NH using p-nitrophenyl chloroformate or triphosgene in the presence of a suitable base. Suitable bases include triethylamine, N-ethyl-N, N-diisopropylamine, pyridine, DBU, potassium carbonate, calcium carbonate, cesium carbonate and the like. Examples of the solvent to be used include chloroform, dichloromethane, diethyl ether, tetrahydrofuran, N, N-dimethylformamide, acetonitrile, ethyl acetate and the like. The reaction temperature is from 0 ° C. to reflux temperature.
（６）工程６（Ｐ1、Ｐ2、Ｐ3、Ｐ4及びＲEの脱保護）
５−チオグルコースの保護基を適当な塩基を用いて除去し、本発明化合物（Ｉ）が得られる。この反応に使用する塩基として、ナトリウムメトキシド、水酸化ナトリウム、水酸化リチウム、炭酸カリウム、炭酸セシウム、トリエチルアミン等を用いることができる。反応に適当な溶媒はメタノール、エタノール、水又はこれらの混合溶媒である。反応温度は０℃から室温であり、室温が好ましい。
(6) Step 6 (P 1, P 2, P 3, deprotection of P 4 and R E)
The protecting group of 5-thioglucose is removed using a suitable base to obtain the compound (I) of the present invention. As the base used in this reaction, sodium methoxide, sodium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, triethylamine, or the like can be used. Suitable solvents for the reaction are methanol, ethanol, water or a mixed solvent thereof. The reaction temperature is from 0 ° C. to room temperature, preferably room temperature.
また、グアニジノ基の保護基ＲEがベンジルオキシカルボニル基である場合は、製造法１に記載された接触水素添加にて除去することもできる。このときの好ましい触媒は水酸化パラジウムである。 Further, when the protecting group R E of the guanidino group is a benzyloxycarbonyl group, it can be removed by catalytic hydrogenation described in Production Method 1. A preferred catalyst at this time is palladium hydroxide.
製造法２
本発明の化合物（Ｉ）において、Ｚが−Ｙ−ＣＯＮ(ＲC)ＲDである化合物は以下の方法で合成できる。
ただし、Ｙ1は単結合又はＣ1-4アルキニル基を示し、その他の記号は前記と同義である。
Manufacturing method 2
In the compound (I) of the present invention, a compound in which Z is —Y—CON (R C ) R D can be synthesized by the following method.
Y 1 represents a single bond or a C 1-4 alkynyl group, and other symbols are as defined above.
まず、製造法１の工程１に示した光延反応により、フェノール誘導体（IIb）から化合物（IVg）を合成することができる。 First, the compound (IVg) can be synthesized from the phenol derivative (IIb) by the Mitsunobu reaction shown in Step 1 of Production Method 1.
（７）工程７（Heck反応）
化合物（IVg）とオレフィン酢酸（VI）をパラジウム触媒とホスフィンリガンド、及び適当な塩基の存在下、Heck反応を行うことにより化合物（IVh）を合成することができる。このとき用いるパラジウム触媒としては、酢酸パラジウム、テトラキストリフェニルホスフィンパラジウム、ジベンジリデンアセトンパラジウム、ビストリフェニルホスフィンパラジウムクロリド、パラジウム活性炭等が挙げられる。ホスフィンリガンドとしてはトリフェニルホスフィンやトリス(２−メチルフェニル)ホスフィン等が挙げられる。また、塩基にはトリエチルアミン、Ｎ−エチル−Ｎ，Ｎ−ジイソプロピルアミン、炭酸カリウム、炭酸カルシウム、炭酸セシウム、カリウムｔ−ブトキシド等が用いられる。反応に用いられる溶媒としては、アセトニトリル、トルエン、テトラヒドロフラン等が挙げられる。反応温度は０℃から還流温度であるが、マイクロウェーブを用いることもある。
(7) Step 7 (Heck reaction)
Compound (IVh) can be synthesized by subjecting compound (IVg) and olefin acetic acid (VI) to Heck reaction in the presence of a palladium catalyst, a phosphine ligand, and a suitable base. Examples of the palladium catalyst used at this time include palladium acetate, tetrakistriphenylphosphine palladium, dibenzylideneacetone palladium, bistriphenylphosphine palladium chloride, and palladium activated carbon. Examples of the phosphine ligand include triphenylphosphine and tris (2-methylphenyl) phosphine. As the base, triethylamine, N-ethyl-N, N-diisopropylamine, potassium carbonate, calcium carbonate, cesium carbonate, potassium t-butoxide and the like are used. Examples of the solvent used for the reaction include acetonitrile, toluene, tetrahydrofuran and the like. The reaction temperature is from 0 ° C. to reflux temperature, but microwaves may be used.
（８）工程８（アミド基への変換）
化合物（IVh）とアミン（ＲCＲDＮＨ）にて脱水縮合し、化合物（IVj）が得られる。この反応に使用する溶媒としては、クロロホルム、ジクロロメタン、Ｎ，Ｎ−ジメチルホルムアミド等が好ましく、脱水縮合剤としては、Ｎ，Ｎ−ジシクロカルボジイミド（ＤＣＣ）、Ｎ−エチル−Ｎ’−３−ジメチルアミノプロピルカルボジイミド塩酸（ＷＳＣ）、Ｎ，Ｎ−カルボニルジイミダゾール（ＣＤＩ）、ＷＳＣ／１−ヒドロキシベンゾトリアゾール１水和物等が好ましい。ここでの反応温度は０℃〜６０℃である。
(8) Step 8 (Conversion to amide group)
Dehydration condensation at compound (IVh) with an amine (R C R D NH), compound (IVj) can be obtained. As the solvent used in this reaction, chloroform, dichloromethane, N, N-dimethylformamide and the like are preferable. As the dehydrating condensing agent, N, N-dicyclocarbodiimide (DCC), N-ethyl-N′-3-dimethyl is used. Aminopropylcarbodiimide hydrochloride (WSC), N, N-carbonyldiimidazole (CDI), WSC / 1-hydroxybenzotriazole monohydrate and the like are preferable. The reaction temperature here is 0 ° C to 60 ° C.
（９）工程９
化合物（IVh）のオレフィン部分を製造法１の工程２に示した接触水素添加を行った後に、アミン（ＲCＲDＮＨ）と縮合することで、化合物（IVk）を製造することもできる。
(9) Step 9
Compound (IVk) can also be produced by condensing the olefin part of compound (IVh) with the amine (R C R D NH) after performing catalytic hydrogenation as shown in Step 2 of Production Method 1.
（１０）工程１０（脱保護）
最後に、Ｐ1、Ｐ2、Ｐ3及びＰ4を製造法１の工程６に示した方法で脱保護し、本発明化合物（Ｉ）が得られる。
(10) Step 10 (deprotection)
Finally, P 1 , P 2 , P 3 and P 4 are deprotected by the method shown in Step 6 of Production Method 1 to obtain the compound (I) of the present invention.
本発明の化合物は、ＳＧＬＴ１を選択的に阻害し、小腸からの糖の吸収を抑制して、ＩＧＴを改善することができる。 The compound of the present invention can selectively inhibit SGLT1, suppress absorption of sugar from the small intestine, and improve IGT.
よって、本発明の化合物は、ＳＧＬＴ１阻害剤、あるいは、糖尿病、糖尿病関連疾患及び糖尿病合併症の予防又は治療剤の有効成分として用いることができる。 Therefore, the compound of the present invention can be used as an active ingredient of a SGLT1 inhibitor or a preventive or therapeutic agent for diabetes, diabetes-related diseases and diabetic complications.
ここで、「糖尿病」には、１型糖尿病、２型糖尿病の他、特定の原因によるその他の型の糖尿病が含まれる。 Here, “diabetes” includes type 1 diabetes, type 2 diabetes, and other types of diabetes caused by a specific cause.
本発明の化合物は、医薬として、全身的又は局所的に、経口投与又は非経口投与することができる。 The compound of the present invention can be administered as a pharmaceutical systemically or locally, orally or parenterally.
本発明の化合物を医薬として提供する場合、固形剤、液剤等の種々の態様の製剤形態を適宜に採択することができる。その際、製薬学的に許容される担体を配合することも可能である。そのような担体の例としては、一般的な賦形剤、増量剤、結合剤、崩壊剤、被覆剤、糖衣剤、ｐＨ調整剤、溶解剤又は水性若しくは非水性溶媒などが挙げられる。本発明の化合物とこれらの担体から、錠剤、丸剤、カプセル剤、顆粒剤、粉剤、散剤、液剤、乳剤、懸濁剤、注射剤等を調製することができる。 When the compound of the present invention is provided as a pharmaceutical, various forms of preparations such as solid preparations and liquid preparations can be appropriately adopted. In that case, it is also possible to mix | blend a pharmaceutically acceptable carrier. Examples of such carriers include common excipients, bulking agents, binders, disintegrants, coating agents, dragees, pH adjusters, solubilizers or aqueous or non-aqueous solvents. Tablets, pills, capsules, granules, powders, powders, solutions, emulsions, suspensions, injections and the like can be prepared from the compound of the present invention and these carriers.
また、本発明の化合物は、α、β若しくはγ−シクロデキストリン又はメチル化シクロデキストリン等に包接させて、その溶解性を改善することも可能である。 Further, the solubility of the compound of the present invention can be improved by inclusion in α, β or γ-cyclodextrin or methylated cyclodextrin.
本発明の化合物の投与量は、疾患、症状、体重、年齢、性別、投与経路等により異なってくるが、成人に対し、１日当たり０．１〜１０００ｍｇ／ｋｇ体重であり、０．１〜２００ｍｇ／ｋｇ体重が好ましく、０．１〜１０ｍｇ／ｋｇ体重がより好ましい。これを１日１回から数回に分けて投与することができる。 The dose of the compound of the present invention varies depending on the disease, symptoms, body weight, age, sex, route of administration, etc., but is 0.1 to 1000 mg / kg body weight per day for an adult, 0.1 to 200 mg. / Kg body weight is preferable, and 0.1 to 10 mg / kg body weight is more preferable. This can be administered once to several times a day.
以下に、実施例及び参考例を挙げて、本発明をさらに詳しく説明する。
まず、参考例１〜１２において、本発明化合物の中間体の合成例を示す。
Hereinafter, the present invention will be described in more detail with reference to Examples and Reference Examples.
First, in Reference Examples 1 to 12, synthesis examples of intermediates of the compound of the present invention are shown.
参考例１
５−メトキシ−３−メチル−２−（４−ニトロベンジル）フェノールの合成
（１）３，５−ジメトキシトルエン（３．８３ｍＬ、２６．２ｍｍｏｌ）と４−ニトロベンゾイルクロリド（５．３５ｇ、２８．８ｍｍｏｌ）のクロロホルム（７５ｍＬ）溶液に氷冷下塩化アルミニウム（３．６７ｇ、２７．５ｍｍｏｌ）を加えて３０分攪拌した後、室温にて４時間攪拌した。反応混合物に氷水、１Ｎ塩酸を加えた後、クロロホルムで抽出した。有機層を１Ｎ塩酸、１Ｎ水酸化ナトリウム水溶液及び飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下に留去した。残渣をシリカゲルクロマトグラフィー（へキサン：酢酸エチル＝１０：１→３：１）にて精製し、（２，４−ジメトキシ−６−メチルフェニル）（４−ニトロフェニル）メタノンを得た。
Reference example 1
Synthesis of 5-methoxy-3-methyl-2- (4-nitrobenzyl) phenol (1) 3,5-dimethoxytoluene (3.83 mL, 26.2 mmol) and 4-nitrobenzoyl chloride (5.35 g, 28. To a solution of 8 mmol) in chloroform (75 mL) was added aluminum chloride (3.67 g, 27.5 mmol) under ice-cooling, and the mixture was stirred for 30 minutes, and then stirred at room temperature for 4 hours. Ice water and 1N hydrochloric acid were added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 10: 1 → 3: 1) to obtain (2,4-dimethoxy-6-methylphenyl) (4-nitrophenyl) methanone.
（２）次に、（２，４−ジメトキシ−６−メチルフェニル）（４−ニトロフェニル）メタノンをクロロホルム（３０ｍＬ）に溶解し、氷冷下１．０Ｍ三塩化ホウ素のへプタン溶液（１０．７ｍＬ、１０．７ｍｍｏｌ）を滴下して、室温にて１５時間攪拌した。反応混合物に氷水、１０％塩酸を加えた後、クロロホルムで抽出した。有機層を１０％塩酸、飽和炭酸水素ナトリウム水溶液及び飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をシリカゲルクロマトグラフィー（へキサン：酢酸エチル＝４：１→２：１）にて精製し、（２−ヒドロキシ−４−メトキシ−６−メチルフェニル）（４−ニトロフェニル）メタノンを得た。 (2) Next, (2,4-dimethoxy-6-methylphenyl) (4-nitrophenyl) methanone was dissolved in chloroform (30 mL), and a 1.0 M boron trichloride heptane solution (10. 7 mL, 10.7 mmol) was added dropwise, and the mixture was stirred at room temperature for 15 hours. Ice water and 10% hydrochloric acid were added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed successively with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 4: 1 → 2: 1) to give (2-hydroxy-4-methoxy-6-methylphenyl) (4-nitrophenyl) methanone.
（３）次に、（２−ヒドロキシ−４−メトキシ−６−メチルフェニル）（４−ニトロフェニル）メタノンをテトラヒドロフラン（２６ｍＬ）に溶解しトリエチルアミン（１．３９ｍＬ、９．９６ｍｍｏｌ）を加え、この溶液に氷冷下クロロギ酸メチル（０．６７ｍＬ、８．７６ｍｍｏｌ）を加えて、室温で２１時間攪拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をシリカゲルクロマトグラフィー（へキサン：酢酸エチル＝５：１）にて精製して５−メトキシ−３−メチル−２−（４−ニトロベンゾイル）フェニル メチル カルボナートを得た。 (3) Next, (2-hydroxy-4-methoxy-6-methylphenyl) (4-nitrophenyl) methanone was dissolved in tetrahydrofuran (26 mL), triethylamine (1.39 mL, 9.96 mmol) was added, and this solution was added. To the solution, methyl chloroformate (0.67 mL, 8.76 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 21 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 5: 1) to give 5-methoxy-3-methyl-2- (4-nitrobenzoyl) phenyl methyl carbonate.
（４）次に、５−メトキシ−３−メチル−２−（４−ニトロベンゾイル）フェニル メチル カルボナートをテトラヒドロフラン（２６ｍＬ）と水（２６ｍＬ）に懸濁させ、氷冷下水素化ホウ素ナトリウム（１．２０ｇ、３１．８ｍｍｏＬ）を加えて、室温で２．５時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をシリカゲルクロマトグラフィー（へキサン：酢酸エチル＝４：１）にて精製し、淡黄色粉末の表題化合物（２．０ｇ、２８％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.20 (s, 3 H) 3.77 (s, 3 H) 4.07 (s, 2 H) 4.75 - 4.77 (m, 1 H) 6.26 (d, J=2.49 Hz, 1 H) 6.39 (d, J=2.49 Hz, 1 H) 7.27 - 7.33 (m, 2 H) 8.07 - 8.13 (m, 2 H).
ESI m/z = 272 (M-H)．
(4) Next, 5-methoxy-3-methyl-2- (4-nitrobenzoyl) phenyl methyl carbonate was suspended in tetrahydrofuran (26 mL) and water (26 mL), and sodium borohydride (1. 20 g, 31.8 mmol) was added and stirred at room temperature for 2.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (2.0 g, 28%) as a pale yellow powder.
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.20 (s, 3 H) 3.77 (s, 3 H) 4.07 (s, 2 H) 4.75-4.77 (m, 1 H) 6.26 (d, J = 2.49 Hz , 1 H) 6.39 (d, J = 2.49 Hz, 1 H) 7.27-7.33 (m, 2 H) 8.07-8.13 (m, 2 H).
ESI m / z = 272 (MH).
参考例２
３，５−ジメチル−２−（４−ニトロベンジル）フェノールの合成
（１）３，５−ジメチルフェノール（８．０ｇ、０．０６６ｍｏｌ）とトリエチルアミン（９．９ｍＬ）のクロロホルム溶液に４℃にて４−ニトロベンゾイルクロリド（１２．０ｇ、０．０６５ｍｏｌ）を加えて、室温にて１．５時間攪拌した。反応混合物をクロロホルムで希釈し、有機層を水、飽和炭酸水素ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をへキサン：酢酸エチル＝１０：１の混合溶媒で洗浄し、無色粉末状の３，５−ジメチルフェニル ４−ニトロベンゾアート（１４．９ｇ、８５％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.36 (s, 6 H) 6.85 (s, 2 H) 6.95 (s, 1 H) 8.36 (s, 4 H)．
Reference example 2
Synthesis of 3,5-dimethyl-2- (4-nitrobenzyl) phenol (1) A chloroform solution of 3,5-dimethylphenol (8.0 g, 0.066 mol) and triethylamine (9.9 mL) at 4 ° C. 4-Nitrobenzoyl chloride (12.0 g, 0.065 mol) was added and stirred at room temperature for 1.5 hours. The reaction mixture was diluted with chloroform, and the organic layer was washed successively with water, saturated sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with a mixed solvent of hexane: ethyl acetate = 10: 1 to obtain colorless powdery 3,5-dimethylphenyl 4-nitrobenzoate (14.9 g, 85%).
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.36 (s, 6 H) 6.85 (s, 2 H) 6.95 (s, 1 H) 8.36 (s, 4 H).
（２）次に、３，５−ジメチルフェニル ４−ニトロベンゾアート（９．９ｇ、３６．５ｍｍｏｌ）に塩化アルミニウム（６．３ｇ、４７．４ｍｍｏｌ）を加え、１４０℃にて１時間攪拌した。反応混合物を室温まで冷却した後、１Ｎ塩酸を加えジエチルエーテルで抽出した。有機層を５％炭酸水素ナトリウム水溶液、５％炭酸ナトリウム水溶液で洗浄し、２％水酸化ナトリウム水溶液を加えて水層を分取した。氷冷下、水層に濃塩酸を加えて酸性にし、析出した結晶を濾過して黄色粉末状の（２−ヒドロキ−４，６−ジメチルフェニル）（４−ニトロフェニル）メタノン（３．３９ｇ、３４％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.91 (s, 3 H) 2.34 (s, 3 H) 6.59 (s, 1 H) 6.74 (s, 1 H) 7.76 - 7.83 (m, 2 H) 8.27 - 8.35 (m, 2 H) 9.60 (s, 1 H).
ESI m/z = 270 (M-H)．
(2) Next, aluminum chloride (6.3 g, 47.4 mmol) was added to 3,5-dimethylphenyl 4-nitrobenzoate (9.9 g, 36.5 mmol), and the mixture was stirred at 140 ° C. for 1 hour. The reaction mixture was cooled to room temperature, 1N hydrochloric acid was added, and the mixture was extracted with diethyl ether. The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and 5% aqueous sodium carbonate solution, 2% aqueous sodium hydroxide solution was added, and the aqueous layer was separated. Under ice-cooling, the aqueous layer was acidified by adding concentrated hydrochloric acid, and the precipitated crystals were filtered to give yellow powdery (2-hydroxy-4,6-dimethylphenyl) (4-nitrophenyl) methanone (3.39 g, 34%).
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.91 (s, 3 H) 2.34 (s, 3 H) 6.59 (s, 1 H) 6.74 (s, 1 H) 7.76-7.83 (m, 2 H) 8.27 -8.35 (m, 2 H) 9.60 (s, 1 H).
ESI m / z = 270 (MH).
（３）次に、（２−ヒドロキ−４，６−ジメチルフェニル）（４−ニトロフェニル）メタノン（３．３９ｇ、１２．５ｍｍｏｌ）及びトリエチルアミン（２．１７ｍＬ、１３．７ｍｍｏｌ）のテトラヒドロフラン（４０ｍＬ）溶液に氷冷下クロロギ酸メチル（１．０６ｍＬ、１３．７ｍｍｏｌ）を加え、室温で１６時間攪拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をシリカゲルクロマトグラフィー（へキサン：酢酸エチル＝５：１）にて精製して３，５−ジメチル−２−（４−ニトロベンゾイル）フェニル メチル カルボナートを得た。これをテトラヒドロフラン（４０ｍＬ）と水（４０ｍＬ）に懸濁し、氷冷下水素化ホウ素ナトリウム（１．８９ｇ、５０．０ｍｍｏｌ）を加えて、室温で２．５時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をシリカゲルクロマトグラフィー（へキサン：酢酸エチル＝４：１）にて精製し、淡黄色粉末の３，５−ジメチル−２−（４−ニトロベンジル）フェノール（２．５５ｇ、７９％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.17 (s, 3 H) 2.41 (s, 3 H) 3.67 (s, 3 H) 6.97 (s, 1 H) 7.03 (s, 1 H) 7.91 - 7.98 (m, 2 H) 8.25 - 8.32 (m, 2 H).
ESI m/z = 256 (M-H)．
(3) Next, (2-hydroxy-4,6-dimethylphenyl) (4-nitrophenyl) methanone (3.39 g, 12.5 mmol) and triethylamine (2.17 mL, 13.7 mmol) in tetrahydrofuran (40 mL) To the solution was added methyl chloroformate (1.06 mL, 13.7 mmol) under ice cooling, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 5: 1) to obtain 3,5-dimethyl-2- (4-nitrobenzoyl) phenyl methyl carbonate. This was suspended in tetrahydrofuran (40 mL) and water (40 mL), sodium borohydride (1.89 g, 50.0 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 2.5 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 4: 1) to obtain 3,5-dimethyl-2- (4-nitrobenzyl) phenol (2.55 g, 79%) as a pale yellow powder. It was.
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.17 (s, 3 H) 2.41 (s, 3 H) 3.67 (s, 3 H) 6.97 (s, 1 H) 7.03 (s, 1 H) 7.91-7.98 (m, 2 H) 8.25-8.32 (m, 2 H).
ESI m / z = 256 (MH).
参考例３
３−メチル−２−（４−ニトロベンジル）フェノールの合成
（１）３−メチルフェノールと４−ニトロベンゾイルクロリドから参考例２の（１）と同様の方法で、３−メチルフェニル ４−ニトロベンゾアートを得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.41 (s, 3 H) 7.00 - 7.07 (m, 2 H) 7.13 (d, J=6.84 Hz, 1 H) 7.34 (t, J=7.85 Hz, 1 H) 8.37 (s, 4 H)．
Reference example 3
Synthesis of 3-methyl-2- (4-nitrobenzyl) phenol (1) 3-methylphenyl 4-nitrobenzoate from 3-methylphenol and 4-nitrobenzoyl chloride in the same manner as (1) in Reference Example 2 Got art.
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.41 (s, 3 H) 7.00-7.07 (m, 2 H) 7.13 (d, J = 6.84 Hz, 1 H) 7.34 (t, J = 7.85 Hz, 1 H) 8.37 (s, 4 H).
（２）次に、３，５−ジメチルフェニル ４−ニトロベンゾアートの代わりに３−メチルフェニル ４−ニトロベンゾアート（１５．０ｇ、０．０５８ｍｏｌ）を用いて参考例２の（２）と同様のＦｒｉｅｓ転移を用いて、（２−ヒドロキシ−６−メチルフェニル）（４−ニトロフェニル）メタノン（０．４２ｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.99 (s, 3 H) 6.80 (d, J=6.84 Hz, 1 H) 6.90 (d, J=8.86 Hz, 1 H) 7.30 - 7.41 (m, 1 H) 7.77 - 7.90 (m, 2 H) 8.27 - 8.36 (m, 2 H) 8.62 - 8.71 (m, 1 H).
また、（２−ヒドロキシ−４−メチルフェニル）（４−ニトロフェニル）メタノン（１．３２ｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.40 (s, 3 H) 6.71 (d, J=8.24 Hz, 1 H) 6.92 (s, 1 H) 7.32 (d, J=8.24 Hz, 1 H) 7.81 (d, J=8.86 Hz, 2 H) 8.37 (d, J=8.86 Hz, 2 H) 11.86 (s, 1 H).さらに、（４−ヒドロキシ−２−メチルフェニル）（４−ニトロフェニル）メタノン（１．３１ｇ）を得た。
(2) Next, similar to (2) of Reference Example 2 using 3-methylphenyl 4-nitrobenzoate (15.0 g, 0.058 mol) instead of 3,5-dimethylphenyl 4-nitrobenzoate (2-hydroxy-6-methylphenyl) (4-nitrophenyl) methanone (0.42 g) was obtained using the Fries rearrangement.
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.99 (s, 3 H) 6.80 (d, J = 6.84 Hz, 1 H) 6.90 (d, J = 8.86 Hz, 1 H) 7.30-7.41 (m, 1 H) 7.77-7.90 (m, 2 H) 8.27-8.36 (m, 2 H) 8.62-8.71 (m, 1 H).
In addition, (2-hydroxy-4-methylphenyl) (4-nitrophenyl) methanone (1.32 g) was obtained.
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.40 (s, 3 H) 6.71 (d, J = 8.24 Hz, 1 H) 6.92 (s, 1 H) 7.32 (d, J = 8.24 Hz, 1 H) 7.81 (d, J = 8.86 Hz, 2 H) 8.37 (d, J = 8.86 Hz, 2 H) 11.86 (s, 1 H). Furthermore, (4-hydroxy-2-methylphenyl) (4-nitrophenyl) Methanone (1.31 g) was obtained.
（３）次に、（２−ヒドロキシ−４，６−ジメチルフェニル）（４−ニトロフェニル）メタノンの代わりに（２−ヒドロキシ−６−メチルフェニル）（４−ニトロフェニル）メタノンを用いて参考例２の（３）と同様の方法で３−メチル−２−（４−ニトロベンジル）フェノールを得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.24 (s, 3 H) 4.15 (s, 2 H) 4.68 (s, 1 H) 6.67 (d, J=8.08 Hz, 1 H) 6.82 (d, J=7.31 Hz, 1 H) 7.07 (t, J=7.77 Hz, 1 H) 7.28 - 7.35 (m, 2 H) 8.07 - 8.14 (m, 2 H)．
ESI m/z = 242 (M-H)．
(3) Next, a reference example using (2-hydroxy-6-methylphenyl) (4-nitrophenyl) methanone instead of (2-hydroxy-4,6-dimethylphenyl) (4-nitrophenyl) methanone 3-Methyl-2- (4-nitrobenzyl) phenol was obtained in the same manner as in (3).
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.24 (s, 3 H) 4.15 (s, 2 H) 4.68 (s, 1 H) 6.67 (d, J = 8.08 Hz, 1 H) 6.82 (d, J = 7.31 Hz, 1 H) 7.07 (t, J = 7.77 Hz, 1 H) 7.28-7.35 (m, 2 H) 8.07-8.14 (m, 2 H).
ESI m / z = 242 (MH).
参考例４
５−メチル−２−（４−ニトロベンジル）フェノールの合成
（２−ヒドロキシ−４，６−ジメチルフェニル）（４−ニトロフェニル）メタノンの代わりに（２−ヒドロキシ−４−メチルフェニル）（４−ニトロフェニル）メタノンを用いて参考例２の（３）と同様の方法で表題化合物を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.29 (s, 3 H) 4.03 (s, 2 H) 4.57 (s, 1 H) 6.59 (s, 1 H) 6.73 (d, J=8.39 Hz, 1 H) 7.00 (d, J=7.62 Hz, 1 H) 7.33 - 7.41 (m, 2 H) 8.07 - 8.16 (m, 2 H)．
ESI m/z = 242 (M-H)．
Reference example 4
Synthesis of 5-methyl-2- (4-nitrobenzyl) phenol Instead of (2-hydroxy-4,6-dimethylphenyl) (4-nitrophenyl) methanone, (2-hydroxy-4-methylphenyl) (4- The title compound was obtained in the same manner as (3) of Reference Example 2 using (nitrophenyl) methanone.
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.29 (s, 3 H) 4.03 (s, 2 H) 4.57 (s, 1 H) 6.59 (s, 1 H) 6.73 (d, J = 8.39 Hz, 1 H) 7.00 (d, J = 7.62 Hz, 1 H) 7.33-7.41 (m, 2 H) 8.07-8.16 (m, 2 H).
ESI m / z = 242 (MH).
参考例５
３−ヒドロキシ−５−メチル−４−（３−ニトロベンジル）フェニル メチル カルボナートの合成
３，５−ジメトキシトルエンと３−ニトロベンゾイルクロリドより、国際公開ＷＯ２００４／０５０１２２号に準拠して合成した。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.25 (s, 3 H) 3.91 (s, 3 H) 4.08 (s, 2 H) 5.29 (s, 1 H) 6.53 - 6.56 (m, 1 H) 6.63 - 6.65 (m, 1 H) 7.35 - 7.49 (m, 2 H) 7.99 - 8.07 (m, 2 H)．
ESI m/z = 316 (M-H)．
Reference Example 5
Synthesis of 3-hydroxy-5-methyl-4- (3-nitrobenzyl) phenyl methyl carbonate Synthesized from 3,5-dimethoxytoluene and 3-nitrobenzoyl chloride in accordance with International Publication No. WO2004 / 050122.
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.25 (s, 3 H) 3.91 (s, 3 H) 4.08 (s, 2 H) 5.29 (s, 1 H) 6.53-6.56 (m, 1 H) 6.63 -6.65 (m, 1 H) 7.35-7.49 (m, 2 H) 7.99-8.07 (m, 2 H).
ESI m / z = 316 (MH).
参考例６
３−ヒドロキシ−４−（４−ニトロベンジル）フェニル メチル カルボナートの合成
３，５−ジメトキシベンゼンと４−ニトロベンゾイルクロリドより国際公開ＷＯ２００４／０５０１２２号に準拠して合成した。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.90 (s, 3 H) 4.04 (s, 2 H) 6.65 (d, J=2.29 Hz, 1 H) 6.73 (dd, J=8.36, 2.29 Hz, 1 H) 7.09 (d, J=8.36 Hz, 1 H) 7.33 - 7.39 (m, 2 H) 8.09 - 8.15 (m, 2 H).
ESI m/z = 302 (M-H)．
Reference Example 6
Synthesis of 3-hydroxy-4- (4-nitrobenzyl) phenyl methyl carbonate The compound was synthesized from 3,5-dimethoxybenzene and 4-nitrobenzoyl chloride in accordance with International Publication No. WO2004 / 050122.
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.90 (s, 3 H) 4.04 (s, 2 H) 6.65 (d, J = 2.29 Hz, 1 H) 6.73 (dd, J = 8.36, 2.29 Hz, 1 H) 7.09 (d, J = 8.36 Hz, 1 H) 7.33-7.39 (m, 2 H) 8.09-8.15 (m, 2 H).
ESI m / z = 302 (MH).
参考例７
４−（４−ブロモベンジル）−３−ヒドロキシ−５−メチルフェニル メチル カルボナートの合成
３，５−ジメトキシトルエンと４−ブロモベンゾイルクロリドより国際公開ＷＯ２００４／０５０１２２号に準拠して合成した。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.23 (s, 3 H) 3.90 (s, 3 H) 3.94 (s, 2 H) 4.97 (s, 1 H) 6.52 - 6.55 (m, 1 H) 6.61 - 6.65 (m, 1 H) 6.98 - 7.04 (m, 2 H) 7.32 - 7.39 (m, 2 H)．
ESI m/z = 374 (M+Na)．
Reference Example 7
Synthesis of 4- (4-bromobenzyl) -3-hydroxy-5-methylphenyl methyl carbonate The compound was synthesized from 3,5-dimethoxytoluene and 4-bromobenzoyl chloride in accordance with International Publication WO2004 / 050122.
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.23 (s, 3 H) 3.90 (s, 3 H) 3.94 (s, 2 H) 4.97 (s, 1 H) 6.52-6.55 (m, 1 H) 6.61 -6.65 (m, 1 H) 6.98-7.04 (m, 2 H) 7.32-7.39 (m, 2 H).
ESI m / z = 374 (M + Na).
参考例８
Ｎ−（４−｛４−ヒドロキシ−２−メチル−６−［（５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）メタンスルホンアミド（化合物１３）の合成
（１）メチル ３−メチル−４−（４−ニトロベンジル）−５−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］フェニル カルボナートの合成
２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−Ｄ−グルコピラノース（３．４６ｇ、９．５０ｍｍｏｌ）、３−ヒドロキシ−５−メチル−４−（４−ニトロベンジル）フェニル メチル カルボナート（２．１９ｇ、６．３３ｍｍｏｌ；国際公開ＷＯ２００４／０５０１２２号に準拠して３，５−ジメトキシトルエンと４−ニトロベンゾイルクロリドより合成）及びトリフェニルホスフィン（２．４９ｇ、９．５０ｍｍｏｌ）のトルエン（１６ｍＬ）溶液に食塩を含む氷冷下、ジイソプロピルアゾジカルボキシレート（４０％トルエン溶液；５．１６ｍＬ、９．５０ｍｍｏｌ）をゆっくりと滴下した。氷冷下で３０分間攪拌し、室温で一晩攪拌した。反応液を減圧下留去し、得られた残渣をシリカゲルカラムクロマトグラフィ−（ヘキサン：酢酸エチル＝２：１〜１：１）にて精製し、褐色ガム状物質として表題化合物（１．８９ｇ、４５％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.83 (s, 3 H) 1.98 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.22 (s, 3 H) 3.21 - 3.31 (m, 1 H) 3.87 - 4.18 (m, 6 H) 4.28 (dd, J=12.05, 5.21 Hz, 1 H) 5.08 - 5.54 (m, 4 H) 6.78 - 6.81 (m, 1 H) 6.88 - 6.91 (m, 1 H) 7.17 - 7.24 (m, 2 H) 8.06 - 8.14 (m, 2 H)．
ESI m/z = 686 (M+Na)．
Reference Example 8
Synthesis of N- (4- {4-hydroxy-2-methyl-6-[(5-thio-β-D-glucopyranosyl) oxy] benzyl} phenyl) methanesulfonamide (Compound 13) (1) Methyl 3-methyl Synthesis of -4- (4-nitrobenzyl) -5-[(2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranosyl) oxy] phenyl carbonate 6-tetra-O-acetyl-5-thio-D-glucopyranose (3.46 g, 9.50 mmol), 3-hydroxy-5-methyl-4- (4-nitrobenzyl) phenyl methyl carbonate (2.19 g, 6.33 mmol; synthesized from 3,5-dimethoxytoluene and 4-nitrobenzoyl chloride according to International Publication WO2004 / 050122) and triphenylphospho Diisopropyl azodicarboxylate (40% toluene solution; 5.16 mL, 9.50 mmol) was slowly added dropwise to a solution of sphin (2.49 g, 9.50 mmol) in toluene (16 mL) under ice cooling containing sodium chloride. The mixture was stirred for 30 minutes under ice-cooling and stirred overnight at room temperature. The reaction mixture was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 to 1: 1) to give the title compound (1.89 g, 45) as a brown gum. %).
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.83 (s, 3 H) 1.98 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.22 (s, 3 H) 3.21-3.31 (m, 1 H) 3.87-4.18 (m, 6 H) 4.28 (dd, J = 12.05, 5.21 Hz, 1 H) 5.08-5.54 (m, 4 H) 6.78-6.81 (m, 1 H) 6.88-6.91 (m, 1 H) 7.17-7.24 (m, 2 H) 8.06-8.14 (m, 2 H).
ESI m / z = 686 (M + Na).
（２）４−（４−アミノベンジル）−３−メチル−５−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］フェニル メチル カルボナートの合成
メチル ３−メチル−４−（４−ニトロベンジル）−５−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］フェニル カルボナート（１．８９ｇ、２．８５ｍｍｏｌ）のメタノール（３０ｍＬ）溶液にパラジウム−活性炭素（１０％）（０．６３ｇ）を加え、水素雰囲気下、室温にて２．５日間攪拌した。反応液をセライトろ過後、減圧下留去し、得られた残渣をシリカゲルカラムクロマトグラフィ−（ヘキサン：酢酸エチル＝２：１〜１：１０）にて精製し、淡黄色粉末として表題化合物（１．１３ｇ、６３％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.97 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.06 (s, 3 H) 2.19 (s, 3 H) 3.20 - 3.31 (m, 1 H) 3.70 - 4.18 (m, 6 H) 4.25 - 4.36 (m, 1 H) 5.06 - 5.40 (m, 3 H) 5.49 - 5.62 (m, 1 H) 6.51 - 6.60 (m, 2 H) 6.71 - 6.95 (m, 4 H).
ESI m/z = 656 (M+Na)．
(2) 4- (4-aminobenzyl) -3-methyl-5-[(2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranosyl) oxy] phenyl methyl carbonate Synthesis Methyl 3-methyl-4- (4-nitrobenzyl) -5-[(2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranosyl) oxy] phenyl carbonate (1. To a solution of 89 g, 2.85 mmol) in methanol (30 mL) was added palladium-activated carbon (10%) (0.63 g), and the mixture was stirred at room temperature for 2.5 days in a hydrogen atmosphere. The reaction mixture was filtered through celite and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 to 1:10) to give the title compound (1. 13 g, 63%).
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.97 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.06 (s, 3 H) 2.19 (s, 3 H) 3.20-3.31 (m, 1 H) 3.70-4.18 (m, 6 H) 4.25-4.36 (m, 1 H) 5.06-5.40 (m, 3 H) 5.49-5.62 (m, 1 H) 6.51-6.60 (m, 2 H ) 6.71-6.95 (m, 4 H).
ESI m / z = 656 (M + Na).
（３）４−（４−アミノベンジル）−３−メチル−５−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］フェニル メチル カルボナート（２００ｍｇ、０．３１６ｍｍｏｌ）のクロロホルム（１０ｍＬ）溶液にピリジン（０．０６１ｍＬ、０．７５８ｍｍｏｌ）とメタンスルホニルクロリド（０．０４９ｍＬ、０．６３２ｍｍｏｌ）を加え、室温で一晩攪拌した。反応液を水にあけ、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤を炉別後、溶媒を減圧下留去し、得られた残渣にメタノール（２ｍＬ）とソディウムメトキシド（２５％メタノール溶液；０．１４ｍＬ、０．６３２ｍｍｏｌ）を加え、室温で１．５時間攪拌した。反応液にドライアイスを加え中和し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィ−（酢酸エチル：エタノール：水＝２０：２：１〜５：２：１で精製し、褐色粉末として表題化合物（１２５ｍｇ、８１％）を得た。得られた化合物の構造、ＮＭＲデータ及びＭＳデータを表１−１〜１−６に示す。 (3) 4- (4-aminobenzyl) -3-methyl-5-[(2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranosyl) oxy] phenyl methyl carbonate ( To a chloroform (10 mL) solution of 200 mg, 0.316 mmol) were added pyridine (0.061 mL, 0.758 mmol) and methanesulfonyl chloride (0.049 mL, 0.632 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. Methanol (2 mL) and sodium methoxide (25% methanol solution; 0.14 mL, 0.632 mmol) were added to the resulting residue, and the mixture was stirred at room temperature for 1.5. Stir for hours. The reaction solution was neutralized by adding dry ice, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: ethanol: water = 20: 2: 1 to 5: 2: 1) to give the title compound (125 mg, 81%) as a brown powder. The structure, NMR data and MS data of the compound are shown in Tables 1-1 to 1-6.
参考例９
Ｎ−（４−｛４−ヒドロキシ−２−メチル−６−［（５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）アセトアミド（化合物１５）の合成
参考例８の（２）で得られた４−（４−アミノベンジル）−３−メチル−５−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］フェニル メチル カルボナート（２００ｍｇ、０．３１６ｍｍｏｌ）のピリジン（０．０６０ｍL）溶液に無水酢酸（０．０６１ｍL）を加え室温で１．５時間攪拌した。反応液を濃縮後、得られた残渣にメタノール（２ｍＬ）とソディウムメトキシド（２５％メタノール溶液；０．２７ｍＬ）を加え、室温で４時間攪拌した。反応液にドライアイスを加え中和し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィ−（酢酸エチル：エタノール：水＝２０：２：１〜５：２：１で精製し、褐色粉末として表題化合物（１０６ｍｇ、７５％）を得た。得られた化合物の構造、ＮＭＲデータ及びＭＳデータを表１−１〜１−６に示す。
Reference Example 9
Synthesis of N- (4- {4-hydroxy-2-methyl-6-[(5-thio-β-D-glucopyranosyl) oxy] benzyl} phenyl) acetamide (Compound 15) Obtained by Reference Example 8 (2) 4- (4-aminobenzyl) -3-methyl-5-[(2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranosyl) oxy] phenyl methyl carbonate (200 mg) Acetic anhydride (0.061 mL) was added to a pyridine (0.060 mL) solution of 0.316 mmol) and stirred at room temperature for 1.5 hours. After concentration of the reaction solution, methanol (2 mL) and sodium methoxide (25% methanol solution; 0.27 mL) were added to the resulting residue, and the mixture was stirred at room temperature for 4 hours. The reaction solution was neutralized by adding dry ice, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: ethanol: water = 20: 2: 1 to 5: 2: 1) to give the title compound (106 mg, 75%) as a brown powder. The structure, NMR data and MS data of the compound are shown in Tables 1-1 to 1-6.
参考例１０
２−（４−アミノベンジル）−５−ヒドロキシ−３−メチルフェニル ５−チオ−β−Ｄ−グルコピラノシド（化合物１７）の合成
参考例８の（２）で得られた４−（４−アミノベンジル）−３−メチル−５−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］フェニル メチル カルボナート（２００ｍｇ、０．３１６ｍｍｏｌ）のメタノール（２ｍＬ）溶液にソディウムメトキシド（２５％メタノール溶液、０．２７ｍＬ、１．２６ｍｍｏｌ）を加え、室温で４時間攪拌した。反応液にドライアイスを加え中和し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィ−（酢酸エチル：エタノール：水＝２０：２：１〜５：２：１）で精製し、無色粉末として表題化合物（９４ｍｇ、７３％）を得た。得られた化合物の構造、ＮＭＲデータ及びＭＳデータを表１−１〜１−６に示す。
Reference Example 10
Synthesis of 2- (4-aminobenzyl) -5-hydroxy-3-methylphenyl 5-thio-β-D-glucopyranoside (Compound 17) 4- (4-aminobenzyl) obtained in Reference Example 8 (2) ) -3-Methyl-5-[(2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranosyl) oxy] phenyl methyl carbonate (200 mg, 0.316 mmol) in methanol (2 mL) ) Sodium methoxide (25% methanol solution, 0.27 mL, 1.26 mmol) was added to the solution and stirred at room temperature for 4 hours. The reaction solution was neutralized by adding dry ice, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: ethanol: water = 20: 2: 1 to 5: 2: 1) to obtain the title compound (94 mg, 73%) as a colorless powder. The structure, NMR data, and MS data of the obtained compound are shown in Tables 1-1 to 1-6.
参考例１１
４−（４−｛４−ヒドロキシ−２−メチル−６−［（５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）ブタノイックアシッド（化合物２５）の合成
（１）４−（４−ブロモベンジル）−３−メチル−５−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］フェニル メチル カルボナートの合成
２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−Ｄ−グルコピラノース（１５．４ｇ、４２．３ｍｍｏｌ）と４−（４−ブロモベンジル）−３−ヒドロキシ−５−メチルフェニル メチル カルボナート（９．９２ｇ、２８．２ｍｍｏｌ）、トリフェニルホスフィン（１１．１ｇ、４２．３ｍｍｏｌ）、ジイソプロピルアゾジカルボキシレート（４０％トルエン溶液；２３．０ｍＬ、４２．３ｍｍｏｌ）を用い、参考例８の（１）に示した方法と同様の方法で表題化合物（４．２４ｇ、２２％）を合成した。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.77 (s, 3 H) 1.97 (s, 3 H) 2.03 (s, 3 H) 2.06 (s, 3 H) 2.19 (s, 3 H) 3.21 - 3.33 (m, 1 H) 3.75 - 3.82 (m, 2 H) 3.93 (s, 3 H) 4.06 - 4.15 (m, 1 H) 4.25 - 4.34 (m, 1 H) 5.07 - 5.41 (m, 3 H) 5.48 - 5.59 (m, 1 H) 6.71 - 7.05 (m, 4 H) 7.29 - 7.38 (m, 2 H)．
ESI m/z = 719 (M+Na)．
Reference Example 11
Synthesis of 4- (4- {4-hydroxy-2-methyl-6-[(5-thio-β-D-glucopyranosyl) oxy] benzyl} phenyl) butanoic acid (Compound 25) (1) 4- ( Synthesis of 4-bromobenzyl) -3-methyl-5-[(2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranosyl) oxy] phenyl methyl carbonate 2,3,4 , 6-Tetra-O-acetyl-5-thio-D-glucopyranose (15.4 g, 42.3 mmol) and 4- (4-bromobenzyl) -3-hydroxy-5-methylphenyl methyl carbonate (9.92 g) , 28.2 mmol), triphenylphosphine (11.1 g, 42.3 mmol), diisopropyl azodicarboxylate (40% toluene solution; 23.0 mL, Using 2.3 mmol), the title compound in a manner similar to that shown in (1) of Reference Example 8 (4.24 g, were synthesized 22%).
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.77 (s, 3 H) 1.97 (s, 3 H) 2.03 (s, 3 H) 2.06 (s, 3 H) 2.19 (s, 3 H) 3.21-3.33 (m, 1 H) 3.75-3.82 (m, 2 H) 3.93 (s, 3 H) 4.06-4.15 (m, 1 H) 4.25-4.34 (m, 1 H) 5.07-5.41 (m, 3 H) 5.48 -5.59 (m, 1 H) 6.71-7.05 (m, 4 H) 7.29-7.38 (m, 2 H).
ESI m / z = 719 (M + Na).
（２）（３Ｅ）−４−（４−｛４−［（メトキシカルボニル）オキシ］−２−メチル−６−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）ブタ−３−エノイックアシッドの合成
４−（４−ブロモベンジル）−３−メチル−５−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］フェニル メチル カルボナート（１．０８ｇ、１．５５ｍｍｏｌ）のアセトニトリル（１６ｍＬ）溶液にビニル酢酸（３２１ｍｇ、３．７３ｍｍｏｌ）、酢酸パラジウム（II）（３５ｍｇ、０．１５５ｍｍｏｌ）、トリ−Ｏ−トリルホスフィン（９４ｍｇ、０．３１０ｍｍｏｌ）、トリエチルアミン（１．０８ｍＬ、７．７５ｍｍｏｌ）を加え、ｂｉｏｔａｇｅ社製マイクロウェーブを用いて１２０℃、２０分間反応を行った。反応液を減圧下留去し、得られた残渣をシリカゲルカラムクロマトグラフィ−（クロロホルム：メタノール＝１００：１〜３０：１、ヘキサン：酢酸エチル＝１：４〜０：１）にて精製し、淡黄色粉末として表題化合物（９９０ｍｇ、９１％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.96 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.05 (s, 3 H) 2.18 (s, 3 H) 3.21 - 3.31 (m, 2 H) 3.79 - 4.17 (m, 7 H) 4.25 - 4.34 (m, 1 H) 5.06 - 5.38 (m, 3 H) 5.49 - 5.60 (m, 1 H) 6.13 - 6.26 (m, 1 H) 6.40 - 6.50 (m, 1 H) 6.74 - 6.77 (m, 1 H) 6.88 - 6.92 (m, 1 H) 6.94 - 6.99 (m, 2 H) 7.19 - 7.25 (m, 2 H)．
ESI m/z = 725 (M+Na)．
(2) (3E) -4- (4- {4-[(methoxycarbonyl) oxy] -2-methyl-6-[(2,3,4,6-tetra-O-acetyl-5-thio-β) Synthesis of -D-glucopyranosyl) oxy] benzyl} phenyl) but-3-enoic acid 4- (4-bromobenzyl) -3-methyl-5-[(2,3,4,6-tetra-O-acetyl) -5-thio-β-D-glucopyranosyl) oxy] phenyl methyl carbonate (1.08 g, 1.55 mmol) in acetonitrile (16 mL) in vinyl acetate (321 mg, 3.73 mmol), palladium (II) acetate (35 mg, 0.155 mmol), tri-O-tolylphosphine (94 mg, 0.310 mmol), triethylamine (1.08 mL, 7.75 mmol) were added and bio 120 ° C. using an age manufactured microwave was carried out for 20 minutes the reaction. The reaction solution was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 100: 1 to 30: 1, hexane: ethyl acetate = 1: 4 to 0: 1), and pale. The title compound (990 mg, 91%) was obtained as a yellow powder.
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.96 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.05 (s, 3 H) 2.18 (s, 3 H) 3.21-3.31 (m, 2 H) 3.79-4.17 (m, 7 H) 4.25-4.34 (m, 1 H) 5.06-5.38 (m, 3 H) 5.49-5.60 (m, 1 H) 6.13-6.26 (m, 1 H ) 6.40-6.50 (m, 1 H) 6.74-6.77 (m, 1 H) 6.88-6.92 (m, 1 H) 6.94-6.99 (m, 2 H) 7.19-7.25 (m, 2 H).
ESI m / z = 725 (M + Na).
（３）４−（４−｛４−［（メトキシカルボニル）オキシ］−２−メチル−６−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）ブタノイックアシッドの合成
（３Ｅ）−４−（４−｛４−［（メトキシカルボニル）オキシ］−２−メチル−６−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）ブタ−３−エノイックアシッド（１．９９ｇ、２．８３ｍｍｏｌ）のメタノール（２８ｍＬ）溶液にパラジウム−活性炭素（１０％）（６６０ｍｇ） を加え、水素雰囲気下、室温にて２時間攪拌した。反応液をセライトろ過後、減圧下留去し、得られた残渣をシリカゲルカラムクロマトグラフィ−（クロロホルム：メタノール＝５０：１〜３０：１）にて精製し、無色粉末として表題化合物（１．８１ｇ、９１％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.74 (s, 3 H) 1.85 - 1.94 (m, 2 H) 1.97 (s, 3 H) 2.03 (s, 3 H) 2.06 (s, 3 H) 2.19 (s, 3 H) 2.30 - 2.38 (m, 2 H) 2.55 - 2.64 (m, 2 H) 3.21 - 3.31 (m, 1 H) 3.77 - 4.17 (m, 6 H) 4.30 (dd, J=11.89, 5.21 Hz, 1 H) 5.06 - 5.39 (m, 3 H) 5.49 - 5.59 (m, 1 H) 6.68 - 7.09 (m, 6 H)．
ESI m/z = 727 (M+Na)．
(3) 4- (4- {4-[(methoxycarbonyl) oxy] -2-methyl-6-[(2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranosyl) ) Oxy] benzyl} phenyl) butanoic acid synthesis (3E) -4- (4- {4-[(methoxycarbonyl) oxy] -2-methyl-6-[(2,3,4,6-tetra) -O-acetyl-5-thio-β-D-glucopyranosyl) oxy] benzyl} phenyl) but-3-enoic acid (1.99 g, 2.83 mmol) in methanol (28 mL) in palladium-activated carbon (10 %) (660 mg) was added and stirred for 2 hours at room temperature under hydrogen atmosphere. The reaction solution was filtered through celite and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1 to 30: 1) to give the title compound (1.81 g, 91%).
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.74 (s, 3 H) 1.85-1.94 (m, 2 H) 1.97 (s, 3 H) 2.03 (s, 3 H) 2.06 (s, 3 H) 2.19 (s, 3 H) 2.30-2.38 (m, 2 H) 2.55-2.64 (m, 2 H) 3.21-3.31 (m, 1 H) 3.77-4.17 (m, 6 H) 4.30 (dd, J = 11.89, 5.21 Hz, 1 H) 5.06-5.39 (m, 3 H) 5.49-5.59 (m, 1 H) 6.68-7.09 (m, 6 H).
ESI m / z = 727 (M + Na).
（４）４−（４−｛４−ヒドロキシ−２−メチル−６−［（５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）ブタノイックアシッド（化合物２５）の合成
４−（４−｛４−［（メトキシカルボニル）オキシ］−２−メチル−６−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）ブタノイックアシッド（１６０ｍｇ、０．２２７ｍｍｏｌ）のメタノール溶液に、ソディウムメトキシド（２５％メタノール溶液；０．２０ｍＬ、０．９０８ｍｍｏｌ）を加え、室温で２時間攪拌した。反応液にドライアイスを加え中和し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィ−（酢酸エチル：エタノール：水＝２０：２：１〜５：２：１）で精製し、表題化合物（５１ｍｇ、４７％）を合成した。得られた化合物の構造、ＮＭＲデータ及びＭＳデータを表１−１〜１−６に示す。
(4) Synthesis of 4- (4- {4-hydroxy-2-methyl-6-[(5-thio-β-D-glucopyranosyl) oxy] benzyl} phenyl) butanoic acid (Compound 25) 4- ( 4- {4-[(methoxycarbonyl) oxy] -2-methyl-6-[(2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranosyl) oxy] benzyl} phenyl ) Sodium methoxide (25% methanol solution; 0.20 mL, 0.908 mmol) was added to a methanol solution of butanoic acid (160 mg, 0.227 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction solution was neutralized by adding dry ice, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: ethanol: water = 20: 2: 1 to 5: 2: 1) to synthesize the title compound (51 mg, 47%). The structure, NMR data, and MS data of the obtained compound are shown in Tables 1-1 to 1-6.
参考例１２
４−（４−｛４−ヒドロキシ−２−メチル−６−［（５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）ブタンアミド（化合物２８）の合成
（１）４−［４−（４−アミノ−４−オキソブチル）ベンジル］−３−メチル−５−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］フェニル メチル カルボナートの合成
参考例１１の（３）で得られた４−（４−｛４−［（メトキシカルボニル）オキシ］−２−メチル−６−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）ブタノイックアシッド（１８０ｍｇ、０．２５５ｍｍｏｌ）のクロロホルム（３ｍＬ）の溶液に、塩化アンモニウム（２７ｍｇ、０．５１１ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（４３ｍｇ、０．２８１ｍｍｏｌ）、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（６８ｍｇ、０．３５７ｍｍｏｌ）、トリエチルアミン（０．１８ｍＬ、１．２８ｍｍｏｌ）を加え、室温にて３時間攪拌した。反応液に水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤を炉別後、溶媒を減圧下留去し、得られた残渣をシリカゲルカラムクロマトグラフィ−（クロロホルム：メタノール＝５０：１〜１０：１）で精製し、表題化合物（１４０ｍｇ、７８％）を合成した。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.78 (s, 3 H) 1.88 - 1.96 (m, 2 H) 1.97 (s, 3 H) 2.03 (s, 3 H) 2.06 (s, 3 H) 2.10 - 2.19 (m, 2 H) 2.20 (s, 3 H) 2.55 - 2.66 (m, 2 H) 3.20 - 3.33 (m, 1 H) 3.78 - 4.17 (m, 6 H) 4.25 - 4.34 (m, 1 H) 5.06 - 5.60 (m, 6 H) 6.68 - 7.09 (m, 6 H)．
ESI m/z = 726 (M+Na)．
Reference Example 12
Synthesis of 4- (4- {4-hydroxy-2-methyl-6-[(5-thio-β-D-glucopyranosyl) oxy] benzyl} phenyl) butanamide (Compound 28) (1) 4- [4- ( Synthesis of 4-amino-4-oxobutyl) benzyl] -3-methyl-5-[(2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranosyl) oxy] phenyl methyl carbonate 4- (4- {4-[(methoxycarbonyl) oxy] -2-methyl-6-[(2,3,4,6-tetra-O-acetyl-5) obtained in (3) of Reference Example 11 To a solution of -thio-β-D-glucopyranosyl) oxy] benzyl} phenyl) butanoic acid (180 mg, 0.255 mmol) in chloroform (3 mL) was added ammonium chloride (27 mg, 0.511 m). ol), 1-hydroxybenzotriazole (43 mg, 0.281 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (68 mg, 0.357 mmol), triethylamine (0.18 mL, 1.28 mmol) And stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1 to 10: 1) to give the title compound (140 mg, 78%). Synthesized.
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.78 (s, 3 H) 1.88-1.96 (m, 2 H) 1.97 (s, 3 H) 2.03 (s, 3 H) 2.06 (s, 3 H) 2.10 -2.19 (m, 2 H) 2.20 (s, 3 H) 2.55-2.66 (m, 2 H) 3.20-3.33 (m, 1 H) 3.78-4.17 (m, 6 H) 4.25-4.34 (m, 1 H ) 5.06-5.60 (m, 6 H) 6.68-7.09 (m, 6 H).
ESI m / z = 726 (M + Na).
（２）４−（４−｛４−ヒドロキシ−２−メチル−６−［（５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）ブタンアミド（２８）の合成
４−［４−（４−アミノ−４−オキソブチル）ベンジル］−３−メチル−５−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］フェニル メチル カルボナート（１４０ｍｇ、０．１９９ｍｍｏｌ）のメタノール溶液に、ソディウムメトキシド（２５％メタノール溶液；０．１７ｍＬ、０．７９６ｍｍｏｌ）を加え、室温で２時間攪拌した。反応液にドライアイスを加え中和し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィ−（酢酸エチル：エタノール：水＝２０：２：１〜５：２：１）で精製し、表題化合物（６６ｍｇ、６９％）を合成した。得られた化合物の構造、ＮＭＲデータ及びＭＳデータを表１−１〜１−６に示す。
(2) Synthesis of 4- (4- {4-hydroxy-2-methyl-6-[(5-thio-β-D-glucopyranosyl) oxy] benzyl} phenyl) butanamide (28) 4- [4- (4 -Amino-4-oxobutyl) benzyl] -3-methyl-5-[(2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranosyl) oxy] phenyl methyl carbonate (140 mg, Sodium methoxide (25% methanol solution; 0.17 mL, 0.796 mmol) was added to a methanol solution of 0.199 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction solution was neutralized by adding dry ice, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: ethanol: water = 20: 2: 1 to 5: 2: 1) to synthesize the title compound (66 mg, 69%). The structure, NMR data, and MS data of the obtained compound are shown in Tables 1-1 to 1-6.
実施例１
Ｎ−（２−ヒドロキシエチル）−Ｎ’−（４−｛４−ヒドロキシ−２−メチル−６−［（５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）ウレア（化合物１）の合成
参考例８の（２）で合成した、４−（４−アミノベンジル）−３−メチル−５−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］フェニル メチル カルボナート（２００ｍｇ、０．３１６ｍｍｏｌ）のクロロホルム（８ｍＬ）溶液にピリジン（０．０３４ｍＬ、０．４２６ｍｍｏｌ）、クロロギ酸 ４−ニトロフェニル（７３ｍｇ、０．３６３ｍｍｏｌ）を加え、室温で１時間攪拌した。トリエチルアミン（０．０８８ｍＬ、０．６３１ｍｍｏｌ）と２−アミノエタノール（２１ｍｇ、０．３４７ｍｍｏｌ）を加え、室温で１時間攪拌した。反応液を減圧下留去し、得られた残渣にメタノール（２ｍＬ）とソディウムメトキシド（２５％メタノール溶液、０．３０ｍＬ、１．３８ｍｍｏｌ）を加え、室温で４時間攪拌した。反応液にドライアイスを加え中和し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィ−（酢酸エチル：エタノール：水＝２０：２：１〜５：２：１）で精製し、酢酸エチルで洗浄し、無色粉末として表題化合物（７１ｍｇ、４５％）を得た。得られた化合物の構造、ＮＭＲデータ及びＭＳデータを表１−１〜１−６に示す。
Example 1
N- (2-hydroxyethyl) -N ′-(4- {4-hydroxy-2-methyl-6-[(5-thio-β-D-glucopyranosyl) oxy] benzyl} phenyl) urea (Compound 1) Synthesis 4- (4-aminobenzyl) -3-methyl-5-[(2,3,4,6-tetra-O-acetyl-5-thio-β-D) synthesized in (2) of Reference Example 8 -Glucopyranosyl) oxy] phenyl methyl carbonate (200 mg, 0.316 mmol) in chloroform (8 mL) was added with pyridine (0.034 mL, 0.426 mmol) and 4-nitrophenyl chloroformate (73 mg, 0.363 mmol) at room temperature. For 1 hour. Triethylamine (0.088 mL, 0.631 mmol) and 2-aminoethanol (21 mg, 0.347 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was evaporated under reduced pressure, methanol (2 mL) and sodium methoxide (25% methanol solution, 0.30 mL, 1.38 mmol) were added to the resulting residue, and the mixture was stirred at room temperature for 4 hours. The reaction solution was neutralized by adding dry ice, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: ethanol: water = 20: 2: 1 to 5: 2: 1), washed with ethyl acetate, and the title compound (71 mg, 45%) as a colorless powder. Got. The structure, NMR data, and MS data of the obtained compound are shown in Tables 1-1 to 1-6.
実施例２ ウレイド誘導体の合成
参考例８の（２）で得られた４−（４−アミノベンジル）−３−メチル−５−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］フェニル メチル カルボナートとそれぞれ対応するアミン、すなわち、３−アミノメチルピリジン、２−アミノ−２−メチル−１−プロパノール、グリシンアミド塩酸塩、β−アラニンアミド塩酸塩、２−アミノイソブチリックアシッド、ベンジルアミン、イソプロピルアミン、ジメチルアミン、ｎ−ヘキシルアミン、シクロヘキシルアミンを用い、実施例１に示した方法と同様の方法で“化合物２”乃至“化合物１１”を製造した。得られた化合物の構造、ＮＭＲデータ及びＭＳデータを表１−１〜１−６に示す。
Example 2 Synthesis of Ureido Derivative 4- (4-aminobenzyl) -3-methyl-5-[(2,3,4,6-tetra-O-acetyl-5) obtained in (2) of Reference Example 8 -Thio-β-D-glucopyranosyl) oxy] phenyl methyl carbonate and the corresponding amine, respectively, ie 3-aminomethylpyridine, 2-amino-2-methyl-1-propanol, glycinamide hydrochloride, β-alaninamide hydrochloride “Compound 2” to “Compound 11” were prepared in the same manner as described in Example 1 using a salt, 2-aminoisobutyric acid, benzylamine, isopropylamine, dimethylamine, n-hexylamine and cyclohexylamine. Manufactured. The structure, NMR data, and MS data of the obtained compound are shown in Tables 1-1 to 1-6.
実施例３
Ｎ−（４−｛４−ヒドロキシ−２−メチル−６−［（５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）ウレア（化合物１２）の合成
参考例８の（２）で得られた４−（４−アミノベンジル）−３−メチル−５−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］フェニル メチル カルボナート（２００ｍｇ、０．３１６ｍｍｏｌ）のクロロホルム（８ｍＬ）溶液にピリジン（０．０３４ｍＬ、０．４２６ｍｍｏｌ）、クロロギ酸 ４−ニトロフェニル（７３ｍｇ、０．３６３ｍｍｏｌ）を加え、室温で３０分間攪拌した。アンモニア（２Ｍメタノール溶液；１．５８ｍＬ、３．１６ｍｍｏｌ）を加え、室温で１時間攪拌した。反応液を減圧下留去し、得られた残渣にメタノール（２ｍＬ）とソディウムメトキシド（２５％メタノール溶液；０．２７ｍＬ、１．２６ｍｍｏｌ）を加え、室温で３時間攪拌した。反応液にドライアイスを加え中和し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィ−（酢酸エチル：エタノール：水＝２０：２：１〜５：２：１）で精製し、酢酸エチルで洗浄し、無色粉末として表題化合物（８５ｍｇ、６０％）を得た。得られた化合物の構造、ＮＭＲデータ及びＭＳデータを表１−１〜１−６に示す。
Example 3
Synthesis of N- (4- {4-hydroxy-2-methyl-6-[(5-thio-β-D-glucopyranosyl) oxy] benzyl} phenyl) urea (Compound 12) Obtained in (2) of Reference Example 8 4- (4-aminobenzyl) -3-methyl-5-[(2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranosyl) oxy] phenyl methyl carbonate (200 mg) , 0.316 mmol) in chloroform (8 mL) was added pyridine (0.034 mL, 0.426 mmol) and 4-nitrophenyl chloroformate (73 mg, 0.363 mmol), and the mixture was stirred at room temperature for 30 minutes. Ammonia (2M methanol solution; 1.58 mL, 3.16 mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was evaporated under reduced pressure, methanol (2 mL) and sodium methoxide (25% methanol solution; 0.27 mL, 1.26 mmol) were added to the resulting residue, and the mixture was stirred at room temperature for 3 hr. The reaction solution was neutralized by adding dry ice, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: ethanol: water = 20: 2: 1 to 5: 2: 1), washed with ethyl acetate, and the title compound (85 mg, 60%) as a colorless powder. Got. The structure, NMR data, and MS data of the obtained compound are shown in Tables 1-1 to 1-6.
実施例４
Ｎ−（４−｛４−ヒドロキシ−２−メチル−６−［（５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）ベンゼンスルホンアミド（化合物１４）の合成
参考例８の（２）で得られた４−（４−アミノベンジル）−３−メチル−５−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］フェニル メチル カルボナートとそれぞれベンゼンスルホニルクロリドを用い、参考例８に示した方法と同様の方法で化合物１４を製造した。得られた化合物の構造、ＮＭＲデータ及びＭＳデータを表１−１〜１−６に示す。
Example 4
Synthesis of N- (4- {4-hydroxy-2-methyl-6-[(5-thio-β-D-glucopyranosyl) oxy] benzyl} phenyl) benzenesulfonamide (Compound 14) (2) in Reference Example 8 4- (4-Aminobenzyl) -3-methyl-5-[(2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranosyl) oxy] phenyl methyl carbonate obtained in Compound 14 was produced in the same manner as described in Reference Example 8 using benzenesulfonyl chloride. The structure, NMR data, and MS data of the obtained compound are shown in Tables 1-1 to 1-6.
実施例５
Ｎ−（４−｛４−ヒドロキシ−２−メチル−６−［（５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）スルファミド（化合物１６）の合成
イソシアン酸 クロロスルホニル（０．０８３ｍＬ、０．９４８ｍｍｏｌ）のアセトニトリル（４ｍＬ）溶液に水（０．０２ｍＬ）を加え、室温で１０分間攪拌した。この反応混合物を、参考例８の（２）で得られた４−（４−アミノベンジル）−３−メチル−５−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］フェニル メチル カルボナート（２００ｍｇ、０．３１６ｍｍｏｌ）および、トリエチルアミン（０．２０ｍＬ、１．４２ｍｍｏｌ）のクロロホルム（８ｍＬ）溶液に加え、室温で２．５日間攪拌した。反応液を水にあけ、クロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤を炉別後、溶媒を減圧下留去し、得られた残渣にメタノール（２ｍＬ）とソディウムメトキシド（２５％メタノール溶液、０．２７ｍＬ、１．２６ｍｍｏｌ）を加え、室温で２時間攪拌した。反応液にドライアイスを加え中和し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィ−（酢酸エチル：エタノール：水＝２０：２：１〜５：２：１）で精製し、無色粉末として表題化合物（７１ｍｇ、４６％）を得た。得られた化合物の構造、ＮＭＲデータ及びＭＳデータを表１−１〜１−６に示す。
Example 5
Synthesis of N- (4- {4-hydroxy-2-methyl-6-[(5-thio-β-D-glucopyranosyl) oxy] benzyl} phenyl) sulfamide (Compound 16) Chlorosulfonyl isocyanate (0.083 mL, Water (0.02 mL) was added to a solution of 0.948 mmol) in acetonitrile (4 mL), and the mixture was stirred at room temperature for 10 minutes. This reaction mixture was mixed with 4- (4-aminobenzyl) -3-methyl-5-[(2,3,4,6-tetra-O-acetyl-5-thio) obtained in (2) of Reference Example 8. -Β-D-Glucopyranosyl) oxy] phenyl methyl carbonate (200 mg, 0.316 mmol) and triethylamine (0.20 mL, 1.42 mmol) in chloroform (8 mL) were added and stirred at room temperature for 2.5 days. The reaction solution was poured into water and extracted with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. Methanol (2 mL) and sodium methoxide (25% methanol solution, 0.27 mL, 1.26 mmol) were added to the resulting residue, and the mixture was stirred at room temperature for 2 hours. did. The reaction solution was neutralized by adding dry ice, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: ethanol: water = 20: 2: 1 to 5: 2: 1) to obtain the title compound (71 mg, 46%) as a colorless powder. The structure, NMR data, and MS data of the obtained compound are shown in Tables 1-1 to 1-6.
実施例６
Ｎ−（４−｛４−ヒドロキシ−２−メチル−６−［（５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）グアニジン（化合物１８）の合成
参考例８の（２）で得られた４−（４−アミノベンジル）−３−メチル−５−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］フェニル メチル カルボナート（１８７ｍｇ、０．２９５ｍｍｏｌ）のテトラヒドロフラン（７ｍＬ）溶液にＮ，Ｎ’−ビス（ベンジルオキシカルボニル）−１Ｈ−ピラゾール−１−カルボキサミジン（１２３ｍｇ、０．３２５ｍｍｏｌ）を加え、室温で３時間、６０℃で４時間攪拌し、８時間過熱還流した。反応液を減圧下留去後、得られた残渣をシリカゲルカラムクロマトグラフィ−（ヘキサン：酢酸エチル＝１：１）で精製し、無色ガム状物質を得た。これにメタノール（２ｍＬ）とソディウムメトキシド（２５％メタノール溶液、０．２６ｍＬ、１．１８ｍｍｏｌ）を加え、室温で一晩攪拌した。ソディウムメトキシド（２５％メタノール溶液、０．５２ｍＬ、２．３６ｍｍｏｌ）を加え、室温で一晩攪拌した。さらにソディウムメトキシド（２５％メタノール溶液、０．５２ｍＬ、２．３６ｍｍｏｌ）を加え、室温で３日間攪拌した。反応液にドライアイスを加え中和し、溶媒を減圧留去した。得られた残渣を合成吸着剤ＨＰ２０（メタノール：水＝１：１〜１：０）で精製し、酢酸エチルで洗浄後、淡褐色粉末として表題化合物（２４ｍｇ、１８％）を得た。得られた化合物の構造、ＮＭＲデータ及びＭＳデータを表１−１〜１−６に示す。
Example 6
Synthesis of N- (4- {4-hydroxy-2-methyl-6-[(5-thio-β-D-glucopyranosyl) oxy] benzyl} phenyl) guanidine (Compound 18) Obtained by Reference Example 8 (2) 4- (4-aminobenzyl) -3-methyl-5-[(2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranosyl) oxy] phenyl methyl carbonate (187 mg) , 0.295 mmol) in tetrahydrofuran (7 mL) was added N, N′-bis (benzyloxycarbonyl) -1H-pyrazole-1-carboxamidine (123 mg, 0.325 mmol), 4 hours at 60 ° C. at room temperature for 3 hours. The mixture was stirred for an hour and refluxed for 8 hours. After evaporating the reaction solution under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain a colorless gum-like substance. Methanol (2 mL) and sodium methoxide (25% methanol solution, 0.26 mL, 1.18 mmol) were added thereto, and the mixture was stirred overnight at room temperature. Sodium methoxide (25% methanol solution, 0.52 mL, 2.36 mmol) was added and stirred overnight at room temperature. Further, sodium methoxide (25% methanol solution, 0.52 mL, 2.36 mmol) was added, and the mixture was stirred at room temperature for 3 days. The reaction solution was neutralized by adding dry ice, and the solvent was distilled off under reduced pressure. The obtained residue was purified with synthetic adsorbent HP20 (methanol: water = 1: 1 to 1: 0) and washed with ethyl acetate to give the title compound (24 mg, 18%) as a light brown powder. The structure, NMR data, and MS data of the obtained compound are shown in Tables 1-1 to 1-6.
実施例７
Ｎ−（３−｛４−ヒドロキシ−２−メチル−６−［（５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）ウレア（化合物１９）の合成
（１）メチル ３−メチル−４−（３−ニトロベンジル）−５−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］フェニル カルボナートの合成
２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−Ｄ−グルコピラノース（３．４ｇ、９．４６ｍｍｏｌ）と３−ヒドロキシ−５−メチル−４−（３−ニトロベンジル）フェニル メチル カルボナート（２．０ｇ、６．３０ｍｍｏｌ）、トリフェニルホスフィン（２．５ｇ、９．４６ｍｍｏｌ）、ジイソプロピルアゾジカルボキシレート（４０％トルエン溶液；５．１ｍＬ、９．４６ｍｍｏｌ）を用い、参考例８の（１）に示した方法と同様の方法で表題化合物（１．６１ｇ、３９％）を合成した。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.85 (s, 3 H) 1.98 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.24 (s, 3 H) 3.22 - 3.31 (m, 1 H) 3.93 (s, 3 H) 3.99 - 4.15 (m, 3 H) 4.27 (dd, J=11.89, 5.36 Hz, 1 H) 5.09 - 5.17 (m, 1 H) 5.25 - 5.39 (m, 2 H) 5.46 - 5.55 (m, 1 H) 6.78 - 6.81 (m, 1 H) 6.89 - 6.93 (m, 1 H) 7.37 - 7.43 (m, 2 H) 7.90 - 7.95 (m, 1 H) 7.98 - 8.09 (m, 1 H)．
ESI m/z = 686 (M+Na)．
Example 7
Synthesis of N- (3- {4-hydroxy-2-methyl-6-[(5-thio-β-D-glucopyranosyl) oxy] benzyl} phenyl) urea (Compound 19) (1) Methyl 3-methyl-4 Synthesis of-(3-nitrobenzyl) -5-[(2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranosyl) oxy] phenyl carbonate 2,3,4,6- Tetra-O-acetyl-5-thio-D-glucopyranose (3.4 g, 9.46 mmol) and 3-hydroxy-5-methyl-4- (3-nitrobenzyl) phenyl methyl carbonate (2.0 g, 6. 30 mmol), triphenylphosphine (2.5 g, 9.46 mmol), diisopropyl azodicarboxylate (40% toluene solution; 5.1 mL, 9.46 mmol) The title compound in a manner similar to that shown in (1) of Reference Example 8 (1.61 g, 39%) was synthesized.
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.85 (s, 3 H) 1.98 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.24 (s, 3 H) 3.22-3.31 (m, 1 H) 3.93 (s, 3 H) 3.99-4.15 (m, 3 H) 4.27 (dd, J = 11.89, 5.36 Hz, 1 H) 5.09-5.17 (m, 1 H) 5.25-5.39 (m , 2 H) 5.46-5.55 (m, 1 H) 6.78-6.81 (m, 1 H) 6.89-6.93 (m, 1 H) 7.37-7.43 (m, 2 H) 7.90-7.95 (m, 1 H) 7.98 -8.09 (m, 1 H).
ESI m / z = 686 (M + Na).
（２）４−（３−アミノベンジル）−３−メチル−５−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］フェニル メチル カルボナートの合成
メチル ３−メチル−４−（３−ニトロベンジル）−５−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］フェニル カルボナート（１．５９ｇ、２．４０ｍｍｏｌ）とパラジウム−活性炭素（１０％）（０．７６ｇ）を用い、参考例８の（２）に示した方法と同様の方法で表題化合物（６６０ｍｇ、４３％）を合成した。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.78 (s, 3 H) 1.97 (s, 3 H) 2.04 (s, 3 H) 2.06 (s, 3 H) 2.21 (s, 3 H) 3.21 - 3.31 (m, 1 H) 3.73 - 3.81 (m, 1 H) 3.92 (s, 3 H) 4.07 - 4.18 (m, 2 H) 4.30 (dd, J=11.97, 5.13 Hz, 1 H) 5.08 - 5.40 (m, 3 H) 5.52 - 5.61 (m, 1 H) 6.34 - 6.38 (m, 1 H) 6.42 - 6.50 (m, 2 H) 6.73 - 6.76 (m, 1 H) 6.88 - 6.91 (m, 1 H) 6.96 - 7.03 (m, 1 H)．
(2) 4- (3-aminobenzyl) -3-methyl-5-[(2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranosyl) oxy] phenyl methyl carbonate Synthesis Methyl 3-methyl-4- (3-nitrobenzyl) -5-[(2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranosyl) oxy] phenyl carbonate (1. 59 g, 2.40 mmol) and palladium-activated carbon (10%) (0.76 g) were used to synthesize the title compound (660 mg, 43%) in the same manner as shown in Reference Example 8 (2). .
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.78 (s, 3 H) 1.97 (s, 3 H) 2.04 (s, 3 H) 2.06 (s, 3 H) 2.21 (s, 3 H) 3.21-3.31 (m, 1 H) 3.73-3.81 (m, 1 H) 3.92 (s, 3 H) 4.07-4.18 (m, 2 H) 4.30 (dd, J = 11.97, 5.13 Hz, 1 H) 5.08-5.40 (m , 3 H) 5.52-5.61 (m, 1 H) 6.34-6.38 (m, 1 H) 6.42-6.50 (m, 2 H) 6.73-6.76 (m, 1 H) 6.88-6.91 (m, 1 H) 6.96 -7.03 (m, 1 H).
（３）Ｎ−（３−｛４−ヒドロキシ−２−メチル−６−［（５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）ウレア（化合物１９）の合成
４−（３−アミノベンジル）−３−メチル−５−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］フェニル メチル カルボナート（２００ｍｇ、０．３１６ｍｍｏｌ）とピリジン（０．０３４ｍＬ、０．４２６ｍｍｏｌ）、クロロギ酸 ４−ニトロフェニル（７３ｍｇ、０．３６３ｍｍｏｌ）、アンモニア（２Ｍメタノール溶液；１．５８ｍＬ、３．１６ｍｍｏｌ）、ソディウムメトキシド（２５％メタノール溶液；、ｍｍｏｌ）を用い、実施例３に示した方法と同様の方法で表題化合物（１１０ｍｇ、７７％）を製造した。得られた化合物の構造、ＮＭＲデータ及びＭＳデータを表１−１〜１−６に示す。
(3) Synthesis of N- (3- {4-hydroxy-2-methyl-6-[(5-thio-β-D-glucopyranosyl) oxy] benzyl} phenyl) urea (compound 19) 4- (3-amino (Benzyl) -3-methyl-5-[(2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranosyl) oxy] phenyl methyl carbonate (200 mg, 0.316 mmol) and pyridine ( 0.034 mL, 0.426 mmol), 4-nitrophenyl chloroformate (73 mg, 0.363 mmol), ammonia (2M methanol solution; 1.58 mL, 3.16 mmol), sodium methoxide (25% methanol solution; mmol) Was used to prepare the title compound (110 mg, 77%) in the same manner as described in Example 3. The structure, NMR data, and MS data of the obtained compound are shown in Tables 1-1 to 1-6.
実施例８
Ｎ−（４−｛４−ヒドロキシ−２−［（５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）ウレア（化合物２０）の合成
（１）メチル ４−（４−ニトロベンジル）−３−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］フェニル カルボナートの合成
２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−Ｄ−グルコピラノース（５．３９ｇ、１４．８ｍｍｏｌ）と３−ヒドロキシ−４−（４−ニトロベンジル）フェニル メチル カルボナート（３．２７ｇ、９．８５ｍｍｏｌ）、トリフェニルホスフィン（３．８８ｇ、１４．８ｍｍｏｌ）、ジイソプロピルアゾジカルボキシレート（４０％トルエン溶液；８．０４ｍＬ、１４．８ｍｍｏｌ）を用い、参考例８の（１）に示した方法と同様の方法で表題化合物（０．９５ｇ、１５％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.94 (s, 3 H) 2.02 (s, 3 H) 2.04 (s, 3 H) 2.05 (s, 3 H) 3.23 - 3.31 (m, 1 H) 3.88 - 4.03 (m, 4 H) 4.06 - 4.17 (m, 2 H) 4.29 (dd, J=11.97, 5.28 Hz, 1 H) 5.10 - 5.58 (m, 4 H) 6.87 (dd, J=8.24, 2.26 Hz, 1 H) 6.98 (d, J=2.26 Hz, 1 H) 7.13 (d, J=8.24 Hz, 1 H) 7.29 - 7.35 (m, 2 H) 8.10 - 8.16 (m, 2 H)．
ESI m/z = 672 (M+Na)．
Example 8
Synthesis of N- (4- {4-hydroxy-2-[(5-thio-β-D-glucopyranosyl) oxy] benzyl} phenyl) urea (Compound 20) (1) Methyl 4- (4-nitrobenzyl)- Synthesis of 3-[(2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranosyl) oxy] phenyl carbonate 2,3,4,6-tetra-O-acetyl-5 Thio-D-glucopyranose (5.39 g, 14.8 mmol) and 3-hydroxy-4- (4-nitrobenzyl) phenyl methyl carbonate (3.27 g, 9.85 mmol), triphenylphosphine (3.88 g, 14 .8 mmol), diisopropyl azodicarboxylate (40% toluene solution; 8.04 mL, 14.8 mmol), and shown in (1) of Reference Example 8 The title compound by law a similar manner (0.95g, 15%) was obtained.
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.94 (s, 3 H) 2.02 (s, 3 H) 2.04 (s, 3 H) 2.05 (s, 3 H) 3.23-3.31 (m, 1 H) 3.88 -4.03 (m, 4 H) 4.06-4.17 (m, 2 H) 4.29 (dd, J = 11.97, 5.28 Hz, 1 H) 5.10-5.58 (m, 4 H) 6.87 (dd, J = 8.24, 2.26 Hz , 1 H) 6.98 (d, J = 2.26 Hz, 1 H) 7.13 (d, J = 8.24 Hz, 1 H) 7.29-7.35 (m, 2 H) 8.10-8.16 (m, 2 H).
ESI m / z = 672 (M + Na).
（２）４−（４−アミノベンジル）−３−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］フェニル メチル カルボナートの合成
メチル ４−（４−ニトロベンジル）−３−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］フェニル カルボナート（０．９５ｇ、１．４６ｍｍｏｌ）とパラジウム−活性炭素（１０％）（０．４８ｇ）を用い、参考例８の（２）に示した方法と同様の方法で表題化合物（０．５１ｇ、５６％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.95 (s, 3 H) 2.02 (s, 3 H) 2.05 (s, 3 H) 2.07 (s, 3 H) 3.23 - 3.32 (m, 1 H) 3.73 - 3.78 (m, 1 H) 3.92 (s, 3 H) 4.07 - 4.17 (m, 2 H) 4.32 (dd, J=11.97, 5.28 Hz, 1 H) 5.11 - 5.43 (m, 3 H) 5.57 - 5.66 (m, 1 H) 6.60 - 6.66 (m, 2 H) 6.77 - 6.82 (m, 1 H) 6.91 - 7.06 (m, 4 H)．
ESI m/z = 642 (M+Na)．
(2) Synthesis of 4- (4-aminobenzyl) -3-[(2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranosyl) oxy] phenyl methyl carbonate Methyl 4- (4-Nitrobenzyl) -3-[(2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranosyl) oxy] phenyl carbonate (0.95 g, 1.46 mmol) and palladium -The title compound (0.51 g, 56%) was obtained in the same manner as in (2) of Reference Example 8 using activated carbon (10%) (0.48 g).
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.95 (s, 3 H) 2.02 (s, 3 H) 2.05 (s, 3 H) 2.07 (s, 3 H) 3.23-3.32 (m, 1 H) 3.73 -3.78 (m, 1 H) 3.92 (s, 3 H) 4.07-4.17 (m, 2 H) 4.32 (dd, J = 11.97, 5.28 Hz, 1 H) 5.11-5.43 (m, 3 H) 5.57-5.66 (m, 1 H) 6.60-6.66 (m, 2 H) 6.77-6.82 (m, 1 H) 6.91-7.06 (m, 4 H).
ESI m / z = 642 (M + Na).
（３）Ｎ−（４−｛４−ヒドロキシ−２−［（５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）ウレア（化合物２０）の合成
４−（４−アミノベンジル）−３−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］フェニル メチル カルボナート（２００ｍｇ、０．３２３ｍｍｏｌ）とピリジン（０．０３５ｍＬ、０．４３６ｍｍｏｌ）、クロロギ酸 ４−ニトロフェニル（７５ｍｇ、０．３７１ｍｍｏｌ）、アンモニア（２Ｍメタノール溶液；１．６２ｍＬ、３．２３ｍｍｏｌ）、ソディウムメトキシド（２５％メタノール溶液；０．２８ｍＬ、１．２９ｍｍｏｌ）を用い、実施例３に示した方法と同様の方法で表題化合物（８９ｍｇ、６３％）を製造した。得られた化合物の構造、ＮＭＲデータ及びＭＳデータを表１−１〜１−６に示す。
(3) Synthesis of N- (4- {4-hydroxy-2-[(5-thio-β-D-glucopyranosyl) oxy] benzyl} phenyl) urea (Compound 20) 4- (4-aminobenzyl) -3 -[(2,3,4,6-Tetra-O-acetyl-5-thio-β-D-glucopyranosyl) oxy] phenyl methyl carbonate (200 mg, 0.323 mmol) and pyridine (0.035 mL, 0.436 mmol) , 4-nitrophenyl chloroformate (75 mg, 0.371 mmol), ammonia (2M methanol solution; 1.62 mL, 3.23 mmol), sodium methoxide (25% methanol solution; 0.28 mL, 1.29 mmol), The title compound (89 mg, 63%) was prepared in a manner similar to that shown in Example 3. The structure, NMR data, and MS data of the obtained compound are shown in Tables 1-1 to 1-6.
実施例９
Ｎ−（４−｛４−メトキシ−２−メチル−６−［（５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）ウレア（化合物２１）の合成
（１）５−メトキシ−３−メチル−２−（４−ニトロベンジル）フェニル ２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシドの合成
２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−Ｄ−グルコピラノース（２．０ｇ、５．４８ｍｍｏｌ）と５−メトキシ−３−メチル−２−（４−ニトロベンジル）フェノール（１．０ｇ、３．６６ｍｍｏｌ）、トリフェニルホスフィン（１．４ｇ、５．４８ｍｍｏｌ）、ジイソプロピルアゾジカルボキシレート（２．８ｍＬ、５．４８ｍｍｏｌ）を用い、参考例８の（１）に示した方法と同様の方法で表題化合物（０．７１ｇ、３１％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.82 (s, 3 H) 1.98 (s, 3 H) 2.03 (s, 3 H) 2.04 (s, 3 H) 2.19 (s, 3 H) 3.21 - 3.29 (m, 1 H) 3.82 (s, 3 H) 3.90 - 4.12 (m, 3 H) 4.28 (dd, J=11.97, 5.13 Hz, 1 H) 5.10 - 5.17 (m, 1 H) 5.26 - 5.36 (m, 2 H) 5.45 - 5.52 (m, 1 H) 6.48 (d, J=2.33 Hz, 1 H) 6.61 (d, J=2.49 Hz, 1 H) 7.17 - 7.23 (m, 2 H) 8.06 - 8.12 (m, 2 H)．
ESI m/z = 642 (M+Na)．
Example 9
Synthesis of N- (4- {4-methoxy-2-methyl-6-[(5-thio-β-D-glucopyranosyl) oxy] benzyl} phenyl) urea (Compound 21) (1) 5-methoxy-3- Synthesis of methyl-2- (4-nitrobenzyl) phenyl 2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranoside 2,3,4,6-tetra-O-acetyl- 5-thio-D-glucopyranose (2.0 g, 5.48 mmol) and 5-methoxy-3-methyl-2- (4-nitrobenzyl) phenol (1.0 g, 3.66 mmol), triphenylphosphine (1 4 g, 5.48 mmol) and diisopropyl azodicarboxylate (2.8 mL, 5.48 mmol) in the same manner as described in (1) of Reference Example 8 and the title compound (0.71 To obtain a 31%).
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.82 (s, 3 H) 1.98 (s, 3 H) 2.03 (s, 3 H) 2.04 (s, 3 H) 2.19 (s, 3 H) 3.21-3.29 (m, 1 H) 3.82 (s, 3 H) 3.90-4.12 (m, 3 H) 4.28 (dd, J = 11.97, 5.13 Hz, 1 H) 5.10-5.17 (m, 1 H) 5.26-5.36 (m , 2 H) 5.45-5.52 (m, 1 H) 6.48 (d, J = 2.33 Hz, 1 H) 6.61 (d, J = 2.49 Hz, 1 H) 7.17-7.23 (m, 2 H) 8.06-8.12 ( m, 2 H).
ESI m / z = 642 (M + Na).
（２）２−（４−アミノベンジル）−５−メトキシ−３−メチルフェニル ２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシドの合成
５−メトキシ−３−メチル−２−（４−ニトロベンジル）フェニル ２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシド（０．７１ｇ、１．１５ｍｍｏｌ）とパラジウム−活性炭素（１０％）（０．３ｇ）を用い、参考例８の（２）に示した方法と同様の方法で表題化合物（５４０ｍｇ、８０％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.77 (s, 3 H) 1.97 (s, 3 H) 2.03 (s, 3 H) 2.06 (s, 3 H) 2.17 (s, 3 H) 3.18 - 3.26 (m, 1 H) 3.69 - 3.77 (m, 1 H) 3.80 (s, 3 H) 3.84 - 3.92 (m, 1 H) 4.11 (dd, J=12.12, 3.89 Hz, 1 H) 4.30 (dd, J=12.05, 5.05 Hz, 1 H) 5.11 (t, J=9.25 Hz, 1 H) 5.25 (d, J=8.70 Hz, 1 H) 5.34 (dd, J=10.41, 9.48 Hz, 1 H) 5.55 (t, J=8.86 Hz, 1 H) 6.45 (d, J=2.33 Hz, 1 H) 6.59 (d, J=8.39 Hz, 2 H) 6.62 (d, J=2.18 Hz, 1 H) 6.82 (d, J=8.55 Hz, 2 H)．
ESI m/z = 612 (M+Na)．
(2) Synthesis of 2- (4-aminobenzyl) -5-methoxy-3-methylphenyl 2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranoside 5-methoxy-3 -Methyl-2- (4-nitrobenzyl) phenyl 2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranoside (0.71 g, 1.15 mmol) and palladium-activated carbon ( 10%) (0.3 g) was used to give the title compound (540 mg, 80%) in the same manner as described in (2) of Reference Example 8.
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.77 (s, 3 H) 1.97 (s, 3 H) 2.03 (s, 3 H) 2.06 (s, 3 H) 2.17 (s, 3 H) 3.18-3.26 (m, 1 H) 3.69-3.77 (m, 1 H) 3.80 (s, 3 H) 3.84-3.92 (m, 1 H) 4.11 (dd, J = 12.12, 3.89 Hz, 1 H) 4.30 (dd, J = 12.05, 5.05 Hz, 1 H) 5.11 (t, J = 9.25 Hz, 1 H) 5.25 (d, J = 8.70 Hz, 1 H) 5.34 (dd, J = 10.41, 9.48 Hz, 1 H) 5.55 (t , J = 8.86 Hz, 1 H) 6.45 (d, J = 2.33 Hz, 1 H) 6.59 (d, J = 8.39 Hz, 2 H) 6.62 (d, J = 2.18 Hz, 1 H) 6.82 (d, J = 8.55 Hz, 2 H).
ESI m / z = 612 (M + Na).
（３）Ｎ−（４−｛４−メトキシ−２−メチル−６−［（５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）ウレア
２−（４−アミノベンジル）−５−メトキシ−３−メチルフェニル ２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシド（２００ｍｇ、０．３４ｍｍｏｌ）とピリジン（０．０３７ｍＬ、０．４６ｍｍｏｌ）、クロロギ酸 ４−ニトロフェニル（７９ｍｇ、０．３９ｍｍｏｌ）、アンモニア（２Ｍ メタノール溶液、１．６９ｍＬ、３．３９ｍｍｏｌ）、ソディウムメトキシド（２５％ メタノール溶液、０．３ｍＬ、１．３６ｍｍｏｌ）を用い、実施例３に示した方法と同様の方法で表題化合物（８８ｍｇ、５６％）を得た。得られた化合物の構造、ＮＭＲデータ及びＭＳデータを表１−１〜１−６に示す。
(3) N- (4- {4-methoxy-2-methyl-6-[(5-thio-β-D-glucopyranosyl) oxy] benzyl} phenyl) urea 2- (4-aminobenzyl) -5-methoxy -3-methylphenyl 2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranoside (200 mg, 0.34 mmol) and pyridine (0.037 mL, 0.46 mmol), chloroformate 4 Example 3 using nitrophenyl (79 mg, 0.39 mmol), ammonia (2M methanol solution, 1.69 mL, 3.39 mmol), sodium methoxide (25% methanol solution, 0.3 mL, 1.36 mmol) The title compound (88 mg, 56%) was obtained in a similar manner as shown. The structure, NMR data, and MS data of the obtained compound are shown in Tables 1-1 to 1-6.
実施例１０
Ｎ−（４−｛２，４−ジメチル−６−［（５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）ウレア（化合物２２）の合成
（１）３，５−ジメチル−２−（４−ニトロベンジル）フェニル ２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシドの合成
２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−Ｄ−グルコピラノース（２．１２ｇ、５．８３ｍｍｏｌ）と３，５−ジメチル−２−（４−ニトロベンジル）フェノール（１．０ｇ、３．８９ｍｍｏｌ）、トリフェニルホスフィン（１．５３ｇ、５．８３ｍｍｏｌ）、ジイソプロピルアゾジカルボキシレート（２．９ｍＬ、５．８３ｍｍｏｌ）を用い、参考例８の（１）に示した方法と同様の方法で表題化合物（４４２ｍｇ、１９％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.84 (s, 3 H) 1.99 (s, 3 H) 2.04 (d, J=2.49 Hz, 6 H) 2.17 (s, 3 H) 2.35 (s, 3 H) 3.22 - 3.31 (m, 1 H) 3.92 - 4.14 (m, 3 H) 4.29 (dd, J=12.05, 5.05 Hz, 1 H) 5.10 - 5.19 (m, 1 H) 5.28 - 5.37 (m, 2 H) 5.45 - 5.53 (m, 1 H) 6.76 (s, 1 H) 6.82 (s, 1 H) 7.18 - 7.24 (m, 2 H) 8.05 - 8.12 (m, 2 H)．
ESI m/z = 626 (M+Na)．
Example 10
Synthesis of N- (4- {2,4-dimethyl-6-[(5-thio-β-D-glucopyranosyl) oxy] benzyl} phenyl) urea (Compound 22) (1) 3,5-dimethyl-2- Synthesis of (4-nitrobenzyl) phenyl 2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranoside 2,3,4,6-tetra-O-acetyl-5-thio- D-glucopyranose (2.12 g, 5.83 mmol) and 3,5-dimethyl-2- (4-nitrobenzyl) phenol (1.0 g, 3.89 mmol), triphenylphosphine (1.53 g, 5.83 mmol) ) And diisopropyl azodicarboxylate (2.9 mL, 5.83 mmol), and the title compound (442 mg, 19%) was obtained in the same manner as in (1) of Reference Example 8.
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.84 (s, 3 H) 1.99 (s, 3 H) 2.04 (d, J = 2.49 Hz, 6 H) 2.17 (s, 3 H) 2.35 (s, 3 H) 3.22-3.31 (m, 1 H) 3.92-4.14 (m, 3 H) 4.29 (dd, J = 12.05, 5.05 Hz, 1 H) 5.10-5.19 (m, 1 H) 5.28-5.37 (m, 2 H) 5.45-5.53 (m, 1 H) 6.76 (s, 1 H) 6.82 (s, 1 H) 7.18-7.24 (m, 2 H) 8.05-8.12 (m, 2 H).
ESI m / z = 626 (M + Na).
（２）２−（４−アミノベンジル）−３，５−ジメチルフェニル ２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシドの合成
３，５−ジメチル−２−（４−ニトロベンジル）フェニル ２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシド（４４２ｍｇ、０．７３ｍｍｏｌ）とパラジウム−活性炭素（１０％）（２２１ｍｇ）を用い、参考例８の（２）に示した方法と同様の方法で表題化合物（３００ｍｇ、７１％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.79 (s, 3 H) 1.98 (s, 3 H) 2.05 (d, J=8.55 Hz, 6 H) 2.15 (s, 3 H) 2.33 (s, 3 H) 3.18 - 3.29 (m, 1 H) 3.72 - 3.82 (m, 1 H) 3.85 - 3.95 (m, 1 H) 4.07 - 4.16 (m, 1 H) 4.31 (dd, J=11.89, 5.05 Hz, 1 H) 5.12 (t, J=9.25 Hz, 1 H) 5.24 - 5.41 (m, 2 H) 5.55 (t, J=8.86 Hz, 1 H) 6.53 - 6.61 (m, 2 H) 6.72 (s, 1 H) 6.78 - 6.86 (m, 3 H)．
ESI m/z = 596 (M+Na)．
(2) Synthesis of 2- (4-aminobenzyl) -3,5-dimethylphenyl 2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranoside 3,5-dimethyl-2 -(4-Nitrobenzyl) phenyl 2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranoside (442 mg, 0.73 mmol) and palladium-activated carbon (10%) (221 mg) Was used to give the title compound (300 mg, 71%) in the same manner as in Reference Example 8 (2).
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.79 (s, 3 H) 1.98 (s, 3 H) 2.05 (d, J = 8.55 Hz, 6 H) 2.15 (s, 3 H) 2.33 (s, 3 H) 3.18-3.29 (m, 1 H) 3.72-3.82 (m, 1 H) 3.85-3.95 (m, 1 H) 4.07-4.16 (m, 1 H) 4.31 (dd, J = 11.89, 5.05 Hz, 1 H) 5.12 (t, J = 9.25 Hz, 1 H) 5.24-5.41 (m, 2 H) 5.55 (t, J = 8.86 Hz, 1 H) 6.53-6.61 (m, 2 H) 6.72 (s, 1 H ) 6.78-6.86 (m, 3 H).
ESI m / z = 596 (M + Na).
（３）Ｎ−（４−｛２，４−ジメチル−６−［（５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）ウレア
２−（４−アミノベンジル）−３，５−ジメチルフェニル２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシド（２８９ｍｇ、０．５０ｍｍｏｌ）とピリジン（０．０５５ｍＬ、０．６８ｍｍｏｌ）、クロロギ酸 ４−ニトロフェニル（１１７ｍｇ、０．５７９ｍｍｏｌ）、アンモニア（２Ｍ メタノール溶液、１．５ｍＬ、３．０ｍｍｏｌ）、ソディウムメトキシド（２５％ メタノール溶液、０．４４ｍＬ、２．０１ｍｍｏｌ）を用い、実施例３に示した方法と同様の方法で表題化合物（１７９ｍｇ、７９％）を得た。得られた化合物の構造、ＮＭＲデータ及びＭＳデータを表１−１〜１−６に示す。
(3) N- (4- {2,4-dimethyl-6-[(5-thio-β-D-glucopyranosyl) oxy] benzyl} phenyl) urea 2- (4-aminobenzyl) -3,5-dimethyl Phenyl 2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranoside (289 mg, 0.50 mmol) and pyridine (0.055 mL, 0.68 mmol), 4-nitrophenyl chloroformate ( 117 mg, 0.579 mmol), ammonia (2M methanol solution, 1.5 mL, 3.0 mmol), sodium methoxide (25% methanol solution, 0.44 mL, 2.01 mmol) and the method described in Example 3 The title compound (179 mg, 79%) was obtained in a similar manner. The structure, NMR data, and MS data of the obtained compound are shown in Tables 1-1 to 1-6.
実施例１１
Ｎ−（４−｛２−メチル−６−［（５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）ウレア（化合物２３）の合成
（１）３−メチル−２−（４−ニトロベンジル）フェニル ２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシドの合成
２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−Ｄ−グルコピラノース（６６７ｍｇ、１．８３ｍｍｏｌ）と３−メチル−２−（４−ニトロベンジル）フェノール（２９７ｍｇ、１．２２ｍｍｏｌ）、トリフェニルホスフィン（４８０ｍｇ、１．８３ｍｍｏｌ）、ジイソプロピルアゾジカルボキシレート（０．９３ｍＬ、１．８３ｍｍｏｌ）を用い、参考例８の（１）に示した方法と同様の方法で表題化合物を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.83 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.04 (s, 3 H) 2.22 (s, 3 H) 3.22 - 3.30 (m, 1 H) 3.98 - 4.16 (m, 3 H) 4.28 (dd, J=12.05, 5.21 Hz, 1 H) 5.11 - 5.19 (m, 1 H) 5.28 - 5.37 (m, 2 H) 5.46 - 5.54 (m, 1 H) 6.94 (d, J=7.15 Hz, 1 H) 7.02 (d, J=8.39 Hz, 1 H) 7.18 - 7.25 (m, 3 H) 8.06 - 8.12 (m, 2 H)．
ESI m/z = 588 (M-H)．
Example 11
Synthesis of N- (4- {2-methyl-6-[(5-thio-β-D-glucopyranosyl) oxy] benzyl} phenyl) urea (Compound 23) (1) 3-methyl-2- (4-nitro Synthesis of 2, benzyl, phenyl 2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranoside 2,3,4,6-tetra-O-acetyl-5-thio-D-glucopyranose (667 mg, 1.83 mmol) and 3-methyl-2- (4-nitrobenzyl) phenol (297 mg, 1.22 mmol), triphenylphosphine (480 mg, 1.83 mmol), diisopropyl azodicarboxylate (0.93 mL, 1.83 mmol) was used to obtain the title compound by a method similar to that shown in Reference Example 8 (1).
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.83 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.04 (s, 3 H) 2.22 (s, 3 H) 3.22-3.30 (m, 1 H) 3.98-4.16 (m, 3 H) 4.28 (dd, J = 12.05, 5.21 Hz, 1 H) 5.11-5.19 (m, 1 H) 5.28-5.37 (m, 2 H) 5.46-5.54 (m, 1 H) 6.94 (d, J = 7.15 Hz, 1 H) 7.02 (d, J = 8.39 Hz, 1 H) 7.18-7.25 (m, 3 H) 8.06-8.12 (m, 2 H).
ESI m / z = 588 (MH).
（２）２−（４−アミノベンジル）−３−メチルフェニル ２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシドの合成
３−メチル−２−（４−ニトロベンジル）フェニル ２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシド（１９５ｍｇ、０．３３ｍｍｏｌ）とパラジウム−活性炭素（１０％）（９８ｍｇ）を用い、参考例８の（２）に示した方法と同様の方法で表題化合物（７１ｍｇ、１０％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.78 (s, 3 H) 1.98 (s, 3 H) 2.03 (s, 3 H) 2.06 (s, 3 H) 2.19 (s, 3 H) 3.19 - 3.28 (m, 1 H) 3.82 (d, J=15.70 Hz, 1 H) 3.96 (d, J=15.70 Hz, 1 H) 4.08 - 4.15 (m, 1 H) 4.30 (dd, J=11.89, 5.36 Hz, 1 H) 5.13 (t, J=9.25 Hz, 1 H) 5.27 - 5.40 (m, 2 H) 5.56 (t, J=8.94 Hz, 1 H) 6.59 - 6.72 (m, 2 H) 6.81 - 6.92 (m, 3 H) 7.02 (d, J=7.31 Hz, 1 H) 7.10 - 7.17 (m, 1 H)．
ESI m/z = 582 (M+Na)．
(2) Synthesis of 2- (4-aminobenzyl) -3-methylphenyl 2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranoside 3-methyl-2- (4- Nitrobenzyl) phenyl 2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranoside (195 mg, 0.33 mmol) and palladium-activated carbon (10%) (98 mg) for reference The title compound (71 mg, 10%) was obtained by a method similar to the method shown in Example 8 (2).
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.78 (s, 3 H) 1.98 (s, 3 H) 2.03 (s, 3 H) 2.06 (s, 3 H) 2.19 (s, 3 H) 3.19-3.28 (m, 1 H) 3.82 (d, J = 15.70 Hz, 1 H) 3.96 (d, J = 15.70 Hz, 1 H) 4.08-4.15 (m, 1 H) 4.30 (dd, J = 11.89, 5.36 Hz, 1 H) 5.13 (t, J = 9.25 Hz, 1 H) 5.27-5.40 (m, 2 H) 5.56 (t, J = 8.94 Hz, 1 H) 6.59-6.72 (m, 2 H) 6.81-6.92 (m , 3 H) 7.02 (d, J = 7.31 Hz, 1 H) 7.10-7.17 (m, 1 H).
ESI m / z = 582 (M + Na).
（３）Ｎ−（４−｛２−メチル−６−［（５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）ウレアの合成
２−（４−アミノベンジル）−３−メチルフェニル ２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシド（７１ｍｇ、０．１２６ｍｍｏｌ）とピリジン（０．０１４ｍＬ、０．１７１ｍｍｏｌ）、クロロギ酸 ４−ニトロフェニル（２９ｍｇ、０．１４６ｍｍｏｌ）、アンモニア（２Ｍ メタノール溶液、０．６３ｍＬ、１．２６ｍｍｏｌ）、ソディウムメトキシド（２５％ メタノール溶液、０．１１ｍＬ、０．５０７ｍｍｏｌ）を用い、実施例３に示した方法と同様の方法で表題化合物（２３ｍｇ、４２％）を得た。得られた化合物の構造、ＮＭＲデータ及びＭＳデータを表１−１〜１−６に示す。
(3) Synthesis of N- (4- {2-methyl-6-[(5-thio-β-D-glucopyranosyl) oxy] benzyl} phenyl) urea 2- (4-aminobenzyl) -3-methylphenyl 2 , 3,4,6-Tetra-O-acetyl-5-thio-β-D-glucopyranoside (71 mg, 0.126 mmol) and pyridine (0.014 mL, 0.171 mmol), 4-nitrophenyl chloroformate (29 mg, 0.146 mmol), ammonia (2M methanol solution, 0.63 mL, 1.26 mmol), sodium methoxide (25% methanol solution, 0.11 mL, 0.507 mmol) and the same method as described in Example 3 The title compound (23 mg, 42%) was obtained by the method. The structure, NMR data, and MS data of the obtained compound are shown in Tables 1-1 to 1-6.
実施例１２
Ｎ−（４−｛４−メチル−２−［（５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）ウレア（化合物２４）の合成
（１）５−メチル−２−（４−ニトロベンジル）フェニル ２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシドの合成
２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−Ｄ−グルコピラノース（２．２４ｇ、６．１６ｍｍｏｌ）と５−メチル−２−（４−ニトロベンジル）フェノール（１．０ｇ、４．１１ｍｍｏｌ）、トリフェニルホスフィン（１．６２ｇ、６．１６ｍｍｏｌ）、ジイソプロピルアゾジカルボキシレート（３．１１ｍＬ、６．１６ｍｍｏｌ）を用い、参考例８の（１）に示した方法と同様の方法で表題化合物（０．５６ｇ、２３％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.93 (s, 3 H) 2.02 (s, 3 H) 2.04 (s, 6 H) 2.37 (s, 3 H) 3.23 - 3.31 (m, 1 H) 3.94 (d, J=3.42 Hz, 2 H) 4.09 (dd, J=12.12, 3.73 Hz, 1 H) 4.29 (dd, J=11.97, 5.13 Hz, 1 H) 5.12 - 5.21 (m, 1 H) 5.31 - 5.40 (m, 2 H) 5.49 - 5.56 (m, 1 H) 6.84 (d, J=8.55 Hz, 1 H) 6.90 (s, 1 H) 7.01 (d, J=7.77 Hz, 1 H) 7.29 - 7.34 (m, 2 H) 8.08 - 8.14 (m, 2 H)．
ESI m/z = 612 (M+Na)．
Example 12
Synthesis of N- (4- {4-methyl-2-[(5-thio-β-D-glucopyranosyl) oxy] benzyl} phenyl) urea (Compound 24) (1) 5-methyl-2- (4-nitro Synthesis of 2, benzyl, phenyl 2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranoside 2,3,4,6-tetra-O-acetyl-5-thio-D-glucopyranose (2.24 g, 6.16 mmol) and 5-methyl-2- (4-nitrobenzyl) phenol (1.0 g, 4.11 mmol), triphenylphosphine (1.62 g, 6.16 mmol), diisopropylazodicarboxy The title compound (0.56 g, 23%) was obtained in the same manner as in (1) of Reference Example 8 using the rate (3.11 mL, 6.16 mmol).
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.93 (s, 3 H) 2.02 (s, 3 H) 2.04 (s, 6 H) 2.37 (s, 3 H) 3.23-3.31 (m, 1 H) 3.94 (d, J = 3.42 Hz, 2 H) 4.09 (dd, J = 12.12, 3.73 Hz, 1 H) 4.29 (dd, J = 11.97, 5.13 Hz, 1 H) 5.12-5.21 (m, 1 H) 5.31- 5.40 (m, 2 H) 5.49-5.56 (m, 1 H) 6.84 (d, J = 8.55 Hz, 1 H) 6.90 (s, 1 H) 7.01 (d, J = 7.77 Hz, 1 H) 7.29-7.34 (m, 2 H) 8.08-8.14 (m, 2 H).
ESI m / z = 612 (M + Na).
（２）２−（４−アミノベンジル）−５−メチルフェニル ２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシドの合成
５−メチル−２−（４−ニトロベンジル）フェニル ２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシド（０．５６ｇ、０．９４９ｍｍｏｌ）とパラジウム−活性炭素（１０％）（０．２８ｇ）を用い、参考例８の（２）に示した方法と同様の方法で表題化合物（１７１ｍｇ、３２％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.94 (s, 3 H) 2.02 (s, 3 H) 2.04 (s, 3 H) 2.06 (s, 3 H) 2.33 (s, 3 H) 3.22 - 3.31 (m, 1 H) 3.76 (s, 2 H) 4.13 (dd, J=11.89, 3.50 Hz, 1 H) 4.32 (dd, J=11.81, 5.13 Hz, 1 H) 5.16 (t, J=9.25 Hz, 1 H) 5.29 - 5.44 (m, 2 H) 5.60 (t, J=8.86 Hz, 1 H) 6.64 (d, J=8.39 Hz, 2 H) 6.78 (d, J=7.62 Hz, 1 H) 6.87 - 7.00 (m, 4 H)．
ESI m/z = 582 (M+Na)．
(2) Synthesis of 2- (4-aminobenzyl) -5-methylphenyl 2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranoside 5-methyl-2- (4- Nitrobenzyl) phenyl 2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranoside (0.56 g, 0.949 mmol) and palladium-activated carbon (10%) (0.28 g) Was used to give the title compound (171 mg, 32%) in the same manner as in Reference Example 8 (2).
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.94 (s, 3 H) 2.02 (s, 3 H) 2.04 (s, 3 H) 2.06 (s, 3 H) 2.33 (s, 3 H) 3.22-3.31 (m, 1 H) 3.76 (s, 2 H) 4.13 (dd, J = 11.89, 3.50 Hz, 1 H) 4.32 (dd, J = 11.81, 5.13 Hz, 1 H) 5.16 (t, J = 9.25 Hz, 1 H) 5.29-5.44 (m, 2 H) 5.60 (t, J = 8.86 Hz, 1 H) 6.64 (d, J = 8.39 Hz, 2 H) 6.78 (d, J = 7.62 Hz, 1 H) 6.87- 7.00 (m, 4 H).
ESI m / z = 582 (M + Na).
（３）Ｎ−（４−｛４−メチル−２−［（５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）ウレアの合成
２−（４−アミノベンジル）−５−メチルフェニル ２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシド（１７１ｍｇ、０．３０５ｍｍｏｌ）とピリジン（０．０３３ｍＬ、０．４１２ｍｍｏｌ）、クロロギ酸 ４−ニトロフェニル（７１ｍｇ、０．３５１ｍｍｏｌ）、アンモニア（２Ｍ メタノール溶液）（１．５３ｍＬ、３．０６ｍｍｏｌ）、ソディウムメトキシド（２５％ メタノール溶液、０．２６ｍＬ、１．２２ｍｍｏｌ）を用い、実施例３に示した方法と同様の方法で表題化合物（６７ｍｇ、５０％）を得た。得られた化合物の構造、ＮＭＲデータ及びＭＳデータを表１−１〜１−６に示す。
(3) Synthesis of N- (4- {4-methyl-2-[(5-thio-β-D-glucopyranosyl) oxy] benzyl} phenyl) urea 2- (4-aminobenzyl) -5-methylphenyl 2 , 3,4,6-Tetra-O-acetyl-5-thio-β-D-glucopyranoside (171 mg, 0.305 mmol) and pyridine (0.033 mL, 0.412 mmol), 4-nitrophenyl chloroformate (71 mg, 0.351 mmol), ammonia (2M methanol solution) (1.53 mL, 3.06 mmol), sodium methoxide (25% methanol solution, 0.26 mL, 1.22 mmol) and the same method as described in Example 3 To give the title compound (67 mg, 50%). The structure, NMR data, and MS data of the obtained compound are shown in Tables 1-1 to 1-6.
実施例１３
（３Ｅ）−Ｎ−（３−アミノ−３−オキソプロピル）−４−（４−｛４−ヒドロキシ−２−メチル−６−［（５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）ブタ−３−エンアミド（化合物２６）の合成
（１）４−（４−｛（１Ｅ）−４−［（３−アミノ−３−オキソプロピル）アミノ］−４−オキソブタ−１−エン−１−イル｝ベンジル）−３−メチル−５−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］フェニル メチル カルボナートの合成
参考例１１の（２）で得られた（３Ｅ）−４−（４−｛４−［（メトキシカルボニル）オキシ］−２−メチル−６−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）ブタ−３−エノイックアシッド（３６０ｍｇ、０．５１２ｍｍｏｌ）のクロロホルム（５ｍＬ）溶液にβ−アラニンアミド塩酸塩（１２８ｍｇ、１．０２ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（８６ｍｇ、０．５６４ｍｍｏｌ）、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（１３７ｍｇ、０．７１７ｍｍｏｌ）、トリエチルアミン（０．３６ｍＬ、２．５６ｍｍｏｌ）を加え、一晩攪拌した。反応液に水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤を炉別後、溶媒を減圧下留去し、得られた残渣をシリカゲルカラムクロマトグラフィ−（クロロホルム：メタノール＝５０：１〜１０：１）で精製し、無色粉末として表題化合物（２４０ｍｇ、６１％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.75 (s, 3 H) 1.97 (s, 3 H) 2.03 (s, 3 H) 2.06 (s, 3 H) 2.19 (s, 3 H) 2.42 - 2.50 (m, 2 H) 3.06 - 3.14 (m, 2 H) 3.21 - 3.31 (m, 1 H) 3.49 - 3.59 (m, 2 H) 3.81 - 4.06 (m, 5 H) 4.11 (dd, J=12.16, 4.04 Hz, 1 H) 4.29 (dd, J=12.16, 5.52 Hz, 1 H) 5.07 - 5.39 (m, 3 H) 5.48 - 5.59 (m, 1 H) 5.67 (brs, 1 H) 6.11 - 6.25 (m, 1 H) 6.34 (brs, 1 H) 6.41 - 6.51 (m, 1 H) 6.74 - 6.78 (m, 1 H) 6.88 - 6.92 (m, 1 H) 6.94 - 7.00 (m, 2 H) 7.19 - 7.25 (m, 2 H)．
ESI m/z = 795 (M+Na)．
Example 13
(3E) -N- (3-amino-3-oxopropyl) -4- (4- {4-hydroxy-2-methyl-6-[(5-thio-β-D-glucopyranosyl) oxy] benzyl} phenyl ) Synthesis of But-3-enamide (Compound 26) (1) 4- (4-{(1E) -4-[(3-Amino-3-oxopropyl) amino] -4-oxobut-1-ene-1 Synthesis of -yl} benzyl) -3-methyl-5-[(2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranosyl) oxy] phenyl methyl carbonate (Reference Example 11) (3E) -4- (4- {4-[(methoxycarbonyl) oxy] -2-methyl-6-[(2,3,4,6-tetra-O-acetyl-5) obtained in 2) Thio-β-D-glucopyranosyl) oxy] benzyl} fe B) β-alanine amide hydrochloride (128 mg, 1.02 mmol), 1-hydroxybenzotriazole (86 mg, 0.564 mmol) in chloroform (5 mL) solution of but-3-enoic acid (360 mg, 0.512 mmol), 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (137 mg, 0.717 mmol) and triethylamine (0.36 mL, 2.56 mmol) were added and stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1 to 10: 1) to give the title compound (240 mg, 61) as a colorless powder. %).
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.75 (s, 3 H) 1.97 (s, 3 H) 2.03 (s, 3 H) 2.06 (s, 3 H) 2.19 (s, 3 H) 2.42-2.50 (m, 2 H) 3.06-3.14 (m, 2 H) 3.21-3.31 (m, 1 H) 3.49-3.59 (m, 2 H) 3.81-4.06 (m, 5 H) 4.11 (dd, J = 12.16, 4.04 Hz, 1 H) 4.29 (dd, J = 12.16, 5.52 Hz, 1 H) 5.07-5.39 (m, 3 H) 5.48-5.59 (m, 1 H) 5.67 (brs, 1 H) 6.11-6.25 (m , 1 H) 6.34 (brs, 1 H) 6.41-6.51 (m, 1 H) 6.74-6.78 (m, 1 H) 6.88-6.92 (m, 1 H) 6.94-7.00 (m, 2 H) 7.19-7.25 (m, 2 H).
ESI m / z = 795 (M + Na).
（２）（３Ｅ）−Ｎ−（３−アミノ−３−オキソプロピル）−４−（４−｛４−ヒドロキシ−２−メチル−６−［（５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）ブタ−３−エンアミド（化合物２６）の合成
４−（４−｛（１Ｅ）−４−［（３−アミノ−３−オキソプロピル）アミノ］−４−オキソブタ−１−エン−１−イル｝ベンジル）−３−メチル−５−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］フェニル メチル カルボナート（１２０ｍｇ、０．１５５ｍｍｏｌ）とソディウムメトキシド（２５％メタノール溶液；０．１４ｍＬ、０．６２１ｍｍｏｌ）を用い、実施例３に示す方法と同様の方法で表題化合物（５５ｍｇ、６５％）を合成した。得られた化合物の構造、ＮＭＲデータ及びＭＳデータを表１−１〜１−６に示す。
(2) (3E) -N- (3-amino-3-oxopropyl) -4- (4- {4-hydroxy-2-methyl-6-[(5-thio-β-D-glucopyranosyl) oxy] Synthesis of (benzyl} phenyl) but-3-enamide (Compound 26) 4- (4-{(1E) -4-[(3-amino-3-oxopropyl) amino] -4-oxobut-1-ene-1 -Yl} benzyl) -3-methyl-5-[(2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranosyl) oxy] phenyl methyl carbonate (120 mg, 0.155 mmol) And the sodium methoxide (25% methanol solution; 0.14 mL, 0.621 mmol) was used to synthesize the title compound (55 mg, 65%) in the same manner as in Example 3. The structure, NMR data, and MS data of the obtained compound are shown in Tables 1-1 to 1-6.
実施例１４
Ｎ−（３−アミノ−３−オキソプロピル）−４−（４−｛４−ヒドロキシ−２−メチル−６−［（５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）ブタンアミド（化合物２７）の合成
（１）４−（４−｛４−［（３−アミノ−３−オキソプロピル）アミノ］−４−オキソブチル｝ベンジル）−３−メチル−５−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］フェニル メチル カルボナートの合成
実施例１３の（１）で得られた４−（４−｛（１Ｅ）−４−［（３−アミノ−３−オキソプロピル）アミノ］−４−オキソブタ−１−エン−１−イル｝ベンジル）−３−メチル−５−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］フェニル メチル カルボナート（１２０ｍｇ、０．１５５ｍｍｏｌ）とパラジウム−活性炭素（１０％）（４０ｍｇ）を用い、参考例１１の（３）に示した方法と同様の方法で表題化合物（８０ｍｇ、６７％）を合成した。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.76 (s, 3 H) 1.84 - 1.94 (m, 2 H) 1.97 (s, 3 H) 2.03 (s, 3 H) 2.06 (s, 3 H) 2.13 (t, J=7.38 Hz, 2 H) 2.20 (s, 3 H) 2.39 - 2.49 (m, 2 H) 2.57 (t, J=7.38 Hz, 2 H) 3.18 - 3.33 (m, 1 H) 3.44 - 3.58 (m, 2 H) 3.79 - 4.18 (m, 6 H) 4.25 - 4.34 (m, 1 H) 5.06 - 5.38 (m, 3 H) 5.49 - 5.57 (m, 1 H) 5.73 (brs, 1 H) 6.20 (brs, 1 H) 6.74 - 6.77 (m, 1 H) 6.88 - 6.91 (m, 1 H) 6.91 - 6.96 (m, 2 H) 6.98 - 7.04 (m, 2 H)．
ESI m/z = 797 (M+Na)．
Example 14
N- (3-amino-3-oxopropyl) -4- (4- {4-hydroxy-2-methyl-6-[(5-thio-β-D-glucopyranosyl) oxy] benzyl} phenyl) butanamide (compound 27) Synthesis (1) 4- (4- {4-[(3-amino-3-oxopropyl) amino] -4-oxobutyl} benzyl) -3-methyl-5-[(2,3,4, Synthesis of 6-tetra-O-acetyl-5-thio-β-D-glucopyranosyl) oxy] phenyl methyl carbonate 4- (4-{(1E) -4-[() obtained in (1) of Example 13 3-amino-3-oxopropyl) amino] -4-oxobut-1-en-1-yl} benzyl) -3-methyl-5-[(2,3,4,6-tetra-O-acetyl-5) -Thio-β-D-glucopyranosyl) oxy] The title compound (80 mg, 67%) was prepared in the same manner as shown in (3) of Reference Example 11 using phenyl methyl carbonate (120 mg, 0.155 mmol) and palladium-activated carbon (10%) (40 mg). Synthesized.
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.76 (s, 3 H) 1.84-1.94 (m, 2 H) 1.97 (s, 3 H) 2.03 (s, 3 H) 2.06 (s, 3 H) 2.13 (t, J = 7.38 Hz, 2 H) 2.20 (s, 3 H) 2.39-2.49 (m, 2 H) 2.57 (t, J = 7.38 Hz, 2 H) 3.18-3.33 (m, 1 H) 3.44- 3.58 (m, 2 H) 3.79-4.18 (m, 6 H) 4.25-4.34 (m, 1 H) 5.06-5.38 (m, 3 H) 5.49-5.57 (m, 1 H) 5.73 (brs, 1 H) 6.20 (brs, 1 H) 6.74-6.77 (m, 1 H) 6.88-6.91 (m, 1 H) 6.91-6.96 (m, 2 H) 6.98-7.04 (m, 2 H).
ESI m / z = 797 (M + Na).
（２）Ｎ−（３−アミノ−３−オキソプロピル）−４−（４−｛４−ヒドロキシ−２−メチル−６−［（５−チオ−β−Ｄ−グルコピラノシル）オキシ］ベンジル｝フェニル）ブタンアミド（化合物２７）の合成
４−（４−｛４−［（３−アミノ−３−オキソプロピル）アミノ］−４−オキソブチル｝ベンジル）−３−メチル−５−［（２，３，４，６−テトラ−Ｏ−アセチル−５−チオ−β−Ｄ−グルコピラノシル）オキシ］フェニル メチル カルボナート（８０ｍｇ、０．１０３ｍｍｏｌ）とソディウムメトキシド（２５％メタノール溶液；０．０９０ｍＬ、０．４１２ｍｍｏｌ）を用い、実施例３に示した方法と同様の方法で表題化合物（５５ｍｇ、９７％）を合成した。得られた化合物の構造、ＮＭＲデータ及びＭＳデータを表１−１〜１−６に示す。
(2) N- (3-amino-3-oxopropyl) -4- (4- {4-hydroxy-2-methyl-6-[(5-thio-β-D-glucopyranosyl) oxy] benzyl} phenyl) Synthesis of Butanamide (Compound 27) 4- (4- {4-[(3-Amino-3-oxopropyl) amino] -4-oxobutyl} benzyl) -3-methyl-5-[(2,3,4, 6-tetra-O-acetyl-5-thio-β-D-glucopyranosyl) oxy] phenyl methyl carbonate (80 mg, 0.103 mmol) and sodium methoxide (25% methanol solution; 0.090 mL, 0.412 mmol). The title compound (55 mg, 97%) was synthesized in the same manner as described in Example 3. The structure, NMR data, and MS data of the obtained compound are shown in Tables 1-1 to 1-6.
実施例８ Example 8
製造方法
薬物を乳糖一水和物、結晶セルロース、カルボキシメチルセルロースカルシウム及びヒドロキシプロピルセルロースと混合し、この混合物を粉砕機で粉砕する。粉砕された混合物を撹拌造粒機で１分間混合し、その後、水で４−８分間造粒する。得られた造粒物を７０℃で４０分間乾燥する。造粒乾燥末を５００μｍの篩で篩過する。篩過後の造粒乾燥末とステアリン酸マグネシウムを、Ｖ型混合機を用いて３０ｒｐｍ、３分間混合する。ロータリー式打錠機を用いて得られた打錠用顆粒を圧縮成形し製錠する。
Manufacturing Method The drug is mixed with lactose monohydrate, crystalline cellulose, carboxymethylcellulose calcium and hydroxypropylcellulose, and this mixture is pulverized with a pulverizer. The pulverized mixture is mixed with a stirring granulator for 1 minute and then granulated with water for 4-8 minutes. The resulting granulate is dried at 70 ° C. for 40 minutes. The granulated dry powder is sieved with a 500 μm sieve. The granulated dry powder after sieving and magnesium stearate are mixed at 30 rpm for 3 minutes using a V-type mixer. The tableting granules obtained using a rotary tableting machine are compression-molded and tableted.
試験例１
（１）ヒトＳＧＬＴ１とヒトＳＧＬＴ２のクローニングと発現ベクターへの導入
ヒト小腸由来ｍＲＮＡからヒトＳＧＬＴ１配列（ＮＭ＿０００３４３）を逆転写の後増幅し、ｐＣＭＶ−ｔａｇ５Ａ（ストラタジーン社）に導入した。また、ヒトＳＧＬＴ２配列（ＮＭ＿００３０４１）はヒト腎由来ｍＲＮＡから同様な方法で調製し、ｐｃＤＮＡ３．１＋ｈｙｇｒｏ（インビトロジェン社）に導入した。それぞれのクローンの配列が、報告されている配列と一致することを確認した。
Test example 1
(1) Cloning of human SGLT1 and human SGLT2 and introduction into expression vector Human SGLT1 sequence (NM_000343) was amplified from human small intestine-derived mRNA after reverse transcription and introduced into pCMV-tag5A (Stratagene). The human SGLT2 sequence (NM_003041) was prepared from human kidney-derived mRNA by the same method and introduced into pcDNA3.1 + hygro (Invitrogen). It was confirmed that the sequence of each clone matched the reported sequence.
（２）ヒトＳＧＬＴ１及びヒトＳＧＬＴ２を安定に発現するＣＨＯ―ｋ１細胞の作成
ヒトＳＧＬＴ１およびヒトＳＧＬＴ２発現ベクターを、リポフェクトアミン２０００（インビトロジェン社）を用いてＣＨＯ−Ｋ１細胞へトランスフェクションした。ＳＧＬＴ発現細胞は、５００μｇ／ｍＬの濃度のジェネティシン（ＳＧＬＴ１）またはハイグロマイシンＢ（ＳＧＬＴ２）の存在下で培養し耐性株を選択し、下記に示す系により糖取り込み比活性を指標に取得した。
(2) Production of CHO-k1 cells stably expressing human SGLT1 and human SGLT2 Human SGLT1 and human SGLT2 expression vectors were transfected into CHO-K1 cells using Lipofectamine 2000 (Invitrogen). SGLT-expressing cells were cultured in the presence of geneticin (SGLT1) or hygromycin B (SGLT2) at a concentration of 500 μg / mL, resistant strains were selected, and the sugar uptake specific activity was obtained using the system shown below as an index.
（３）細胞におけるナトリウム依存的糖取り込み阻害試験
ヒトＳＧＬＴ１又はヒトＳＧＬＴ２を安定に発現する細胞をナトリウム依存的グルコース取り込み活性阻害試験に用いた。
(3) Sodium-dependent sugar uptake inhibition test in cells Cells stably expressing human SGLT1 or human SGLT2 were used in sodium-dependent glucose uptake activity inhibition tests.
細胞を前処理用緩衝液（１４０ｍＭ 塩化コリン、２ｍＭ ＫＣｌ、１ｍＭ ＣａＣｌ2、１ｍＭ ＭｇＣｌ2、１０ｍＭ ＨＥＰＥＳ／５ｍＭ Ｔｒｉｓ、ｐＨ７．４）１ｍＬ中で２０分間インキュベーションした。前処理用緩衝液を除去し、試験化合物を含む取り込み用緩衝液（［14Ｃ］メチル α−Ｄ−グルコピラノシドを含むメチル α−Ｄ−グルコピラノシド（ＳＧＬＴ１阻害では０．１ｍＭ、ＳＧＬＴ２阻害では１ｍＭ）、１４０ｍＭ ＮａＣｌ、２ｍＭ ＫＣｌ、１ｍＭ ＣａＣｌ2、１ｍＭ ＭｇＣｌ2、１０ｍＭ ＨＥＰＥＳ／５ｍＭ Ｔｒｉｓ、ｐＨ７．４）を２００μＬ加え、３７℃にて３０分（ＳＧＬＴ１）又は１時間（ＳＧＬＴ２）取り込み反応を行った。反応後細胞を洗浄用緩衝液（１０ｍＭ メチル α−Ｄ−グルコピラノシド、１４０ｍＭ 塩化コリン２ｍＭ ＫＣｌ、１ｍＭ ＣａＣｌ2、１ｍＭ ＭｇＣｌ2、１０ｍＭ ＨＥＰＥＳ／５ｍＭ Ｔｒｉｓ、ｐＨ７．４）１ｍＬで２回洗浄し、０．２Ｍ ＮａＯＨ溶液４００μＬに溶かした。アクアゾール２（パーキンエルマー社）を加えよく混和した後、液体シンチレーションカウンター（ベックマンコールター社）で放射活性を測定した。対照群として試験化合物を含まない取り込み用緩衝液を調製した。また基礎取り込み用としてＮａＣｌに代えて塩化コリンを含む取り込み用緩衝液を調製した。 The cells were incubated in 1 mL of pretreatment buffer (140 mM choline chloride, 2 mM KCl, 1 mM CaCl 2 , 1 mM MgCl 2 , 10 mM HEPES / 5 mM Tris, pH 7.4) for 20 minutes. The pretreatment buffer is removed and the uptake buffer containing the test compound ([ 14 C] methyl α-D-glucopyranoside containing methyl α-D-glucopyranoside (0.1 mM for SGLT1 inhibition, 1 mM for SGLT2 inhibition), 200 μL of 140 mM NaCl, 2 mM KCl, 1 mM CaCl 2 , 1 mM MgCl 2 , 10 mM HEPES / 5 mM Tris, pH 7.4) was added, and an uptake reaction was performed at 37 ° C. for 30 minutes (SGLT1) or 1 hour (SGLT2). After the reaction, the cells were washed twice with 1 mL of washing buffer (10 mM methyl α-D-glucopyranoside, 140 mM choline chloride 2 mM KCl, 1 mM CaCl 2 , 1 mM MgCl 2 , 10 mM HEPES / 5 mM Tris, pH 7.4). Dissolved in 400 μL of 2M NaOH solution. Aquasol 2 (Perkin Elmer) was added and mixed well, and then the radioactivity was measured with a liquid scintillation counter (Beckman Coulter). As a control group, an uptake buffer containing no test compound was prepared. For basal uptake, an uptake buffer containing choline chloride instead of NaCl was prepared.
ＩＣ50値を求めるにあたり、適当な６濃度の試験化合物を用い、対照群の糖取り込み量（１００％）に対し、糖取り込み量が５０％阻害される試験化合物濃度（ＩＣ50値）を算出した。試験結果を表４に示す。 In determining the IC 50 value, the test compound concentration (IC 50 value) at which the sugar uptake amount was inhibited by 50% relative to the sugar uptake amount (100%) of the control group was calculated using appropriate 6 concentrations of the test compound. . The test results are shown in Table 4.
本発明により、小腸上皮に発現するＳＧＬＴ１（ナトリウム依存性グルコース共輸送体１）を選択的に阻害し、小腸からの糖吸収を阻害することによって、ＩＧＴ（耐糖能異常）を制御するフェニル ５−チオグリコシド化合物を有効成分として含有する糖尿病の予防又は治療剤を提供することが期待される。
According to the present invention, phenyl 5-55 regulates IGT (abnormal glucose tolerance) by selectively inhibiting SGLT1 (sodium-dependent glucose cotransporter 1) expressed in the small intestine epithelium and inhibiting sugar absorption from the small intestine. It is expected to provide a preventive or therapeutic agent for diabetes containing a thioglycoside compound as an active ingredient.
Claims (3)
Ｒ1及びＲ2は、同一または異なって、水素原子、水酸基、Ｃ1-6アルキル基、又はＣ1-6アルコキシ基を示す。
Ｚは、−ＮＨＳＯ2フェニル、−ＮＨＳＯ2ＮＨ2、−ＮＨＣ（＝ＮＨ）ＮＨ2、−ＮＨＣＯＮ（ＲA）ＲB、又は“メチル基及びオキソ基の少なくとも１種で置換された４〜６員へテロシクロアルキル基”、又は−Ｙ−ＣＯＮ(ＲC)ＲDを示す。
ただし、
ＲA及びＲBは、同一または異なって、水素原子、Ｃ1-6アルキル基、Ｃ3-7シクロアルキル基、又は“水酸基、−ＣＯＮＨ2、フェニル基及びピリジル基からなる群より選択される１〜３個の基で置換されたＣ1-6アルキル基”を示す。
Ｙは、Ｃ1-6アルキレン基又はＣ2-6アルケニレン基を示し、ＲC及びＲDの一方が“−ＣＯＮＨ2で置換されたＣ1-6アルキル基”を示すとき、他方は水素原子を示す。 A phenyl 5-thioglucoside compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof or a hydrate thereof.
R 1 and R 2 are the same or different and each represents a hydrogen atom, a hydroxyl group, a C 1-6 alkyl group, or a C 1-6 alkoxy group.
Z is —NHSO 2 phenyl, —NHSO 2 NH 2 , —NHC (═NH) NH 2 , —NHCON (R A ) R B , or “4-6 substituted with at least one of a methyl group and an oxo group” A membered heterocycloalkyl group "or -Y-CON (R C ) R D.
However,
R A and R B are the same or different and are selected from the group consisting of a hydrogen atom, a C 1-6 alkyl group, a C 3-7 cycloalkyl group, or a “hydroxyl group, —CONH 2 , a phenyl group, and a pyridyl group. C 1-6 alkyl group substituted by 1 to 3 groups ”.
Y represents a C 1-6 alkylene group or a C 2-6 alkenylene group, and when one of R C and R D represents “C 1-6 alkyl group substituted with —CONH 2 ”, the other is a hydrogen atom. Indicates.
A prophylactic or therapeutic agent for diabetes comprising the phenyl 5-thioglucoside compound represented by the formula (I) or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2006128680A JP2009167104A (en) | 2006-05-02 | 2006-05-02 | Phenyl 5-thio glycoside compound |
| PCT/JP2007/059394 WO2007126117A1 (en) | 2006-05-02 | 2007-05-02 | Phenyl 5-thioglucoside compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2006128680A JP2009167104A (en) | 2006-05-02 | 2006-05-02 | Phenyl 5-thio glycoside compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2009167104A true JP2009167104A (en) | 2009-07-30 |
Family
ID=38655635
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2006128680A Pending JP2009167104A (en) | 2006-05-02 | 2006-05-02 | Phenyl 5-thio glycoside compound |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JP2009167104A (en) |
| WO (1) | WO2007126117A1 (en) |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2025674A1 (en) | 2007-08-15 | 2009-02-18 | sanofi-aventis | Substituted tetra hydro naphthalines, method for their manufacture and their use as drugs |
| BRPI0916769A2 (en) | 2008-07-15 | 2017-09-26 | Theracos Inc | deuterated benzylbenzene derivatives and methods of use |
| DK2334687T5 (en) | 2008-08-28 | 2012-09-10 | Pfizer | Dioxa-bicyclo [3.2.1.] Octane-2,3,4-triol derivatives |
| BRPI1008653A2 (en) * | 2009-02-23 | 2016-03-08 | Taisho Pharmaceutical Co Ltd | 4-isopropyl phenyl glycitol compounds as sglt1 inhibitors |
| ES2527179T3 (en) | 2009-11-02 | 2015-01-21 | Pfizer Inc. | Dioxa-bicyclo derivatives [3.2.1] octane-2,3,4-triol |
| AR079438A1 (en) | 2009-12-09 | 2012-01-25 | Panacea Biotec Ltd | SUGAR DERIVATIVES, PHARMACEUTICAL COMPOSITIONS AND THEIR USES |
| WO2011107494A1 (en) | 2010-03-03 | 2011-09-09 | Sanofi | Novel aromatic glycoside derivatives, medicaments containing said compounds, and the use thereof |
| US8933024B2 (en) | 2010-06-18 | 2015-01-13 | Sanofi | Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases |
| US8530413B2 (en) | 2010-06-21 | 2013-09-10 | Sanofi | Heterocyclically substituted methoxyphenyl derivatives with an oxo group, processes for preparation thereof and use thereof as medicaments |
| TW201215388A (en) | 2010-07-05 | 2012-04-16 | Sanofi Sa | (2-aryloxyacetylamino)phenylpropionic acid derivatives, processes for preparation thereof and use thereof as medicaments |
| TW201215387A (en) | 2010-07-05 | 2012-04-16 | Sanofi Aventis | Spirocyclically substituted 1,3-propane dioxide derivatives, processes for preparation thereof and use thereof as a medicament |
| TW201221505A (en) | 2010-07-05 | 2012-06-01 | Sanofi Sa | Aryloxyalkylene-substituted hydroxyphenylhexynoic acids, process for preparation thereof and use thereof as a medicament |
| US8871758B2 (en) | 2011-03-08 | 2014-10-28 | Sanofi | Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof |
| EP2683699B1 (en) | 2011-03-08 | 2015-06-24 | Sanofi | Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
| US8828994B2 (en) | 2011-03-08 | 2014-09-09 | Sanofi | Di- and tri-substituted oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
| US8901114B2 (en) | 2011-03-08 | 2014-12-02 | Sanofi | Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof |
| US8828995B2 (en) | 2011-03-08 | 2014-09-09 | Sanofi | Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
| WO2013037390A1 (en) | 2011-09-12 | 2013-03-21 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
| EP2760862B1 (en) | 2011-09-27 | 2015-10-21 | Sanofi | 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
| CN110066302B (en) | 2018-01-23 | 2022-12-27 | 广东东阳光药业有限公司 | Glucopyranosyl derivative and use thereof |
| US11186602B2 (en) | 2018-01-31 | 2021-11-30 | Sunshine Lake Pharma Co., Ltd. | Glucopyranosyl derivative and use thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2003254904A1 (en) * | 2002-08-09 | 2004-02-25 | Taisho Pharmaceutical Co., Ltd. | Aryl 5-thio-beta-d-glucopyranoside derivatives and therapeutic agents for diabetes containing the same |
| JP2005247834A (en) * | 2004-02-04 | 2005-09-15 | Taisho Pharmaceut Co Ltd | Activity inhibitor of sodium-dependent glucose cotransporter 2 |
-
2006
- 2006-05-02 JP JP2006128680A patent/JP2009167104A/en active Pending
-
2007
- 2007-05-02 WO PCT/JP2007/059394 patent/WO2007126117A1/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| WO2007126117A1 (en) | 2007-11-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2009167104A (en) | Phenyl 5-thio glycoside compound | |
| JP2009167103A (en) | Pyrazolyl 5-thioglycoside compound | |
| EP3384908B1 (en) | Modulating ferroptosis and treating excitotoxic disorders | |
| JP5761173B2 (en) | Preventive or therapeutic agent for diabetes or obesity | |
| SA94140584B1 (en) | Arylsulfone amido-hydroxamic substituted | |
| EP2723338A2 (en) | Selective inhibitors of histone deacetylase isoform 6 and methods thereof | |
| CZ20012429A3 (en) | Thrombin inhibitors | |
| JP5240398B2 (en) | Alkylamine derivatives | |
| SK4382002A3 (en) | 2'-substituted 1,1'-biphenyl-2-carbonamides, method for the production thereof, use thereof as a medicament and pharmaceutical preparations containing said compounds | |
| DE60221508T2 (en) | Amino acid derivatives as HIV protease inhibitors | |
| RU2577861C2 (en) | N-hydroxy-benzamides for treating cancer | |
| JP2008543732A (en) | Novel hydroxamic acid derivatives as peptide deformylase inhibitors and methods for their preparation | |
| EP1214293A1 (en) | Non-peptidic cyclophilin binding compounds and their use | |
| PL198827B1 (en) | N-ARYLSULFONYL AMINO ACID OMEGA AMIDES, method of making them, pharmaceutical agent and their application | |
| JPH07247274A (en) | Pivalic acid tetrazolylphenyl ester derivative, elastase inhibitor containing the same as active ingredient and medicine for pulmonary disorder | |
| EP1480941B1 (en) | Urea derivatives as hiv aspartyl protease inhibitors | |
| JP5423854B2 (en) | Pharmaceuticals containing alkylamine derivatives as active ingredients | |
| EP3733684B9 (en) | Ursodeoxycholic acid derivatives for the treatment of polycystic diseases | |
| JP2009107948A (en) | Agent for treating diabetes, containing phenyl 5-thioglucoside compound as active ingredient | |
| EP3381908A1 (en) | 2-(4-(4-(bromo-methoxybenzamido)benzylamino)phenyl)benzazole derivatives and their use as anti-heparanase | |
| WO2021115188A1 (en) | Histone deacetylase, and proteasome dual-target inhibitor, preparation method therefor and application thereof | |
| CN105801464A (en) | Pyrrolic amide compound and its preparation method and use | |
| JP2004143053A (en) | beta-AMINOHYDROXAMIC ACID DERIVATIVE AND USE THEREOF | |
| JP2009107947A (en) | Agent for treating diabetes, containing pyrazolyl 5-thioglucoside compound as active ingredient | |
| Jia et al. | Design, synthesis, and biological evaluation of novel HDAC/CD13 dual inhibitors for the treatment of cancer |