WO2012144551A1 - ケイ素含有カルボン酸誘導体 - Google Patents
ケイ素含有カルボン酸誘導体 Download PDFInfo
- Publication number
- WO2012144551A1 WO2012144551A1 PCT/JP2012/060552 JP2012060552W WO2012144551A1 WO 2012144551 A1 WO2012144551 A1 WO 2012144551A1 JP 2012060552 W JP2012060552 W JP 2012060552W WO 2012144551 A1 WO2012144551 A1 WO 2012144551A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- mmol
- methyl
- ethyl
- amino
- Prior art date
Links
- 150000001732 carboxylic acid derivatives Chemical class 0.000 title description 13
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 title description 8
- 229910052710 silicon Inorganic materials 0.000 title description 7
- 239000010703 silicon Substances 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 36
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 33
- 125000003118 aryl group Chemical group 0.000 claims abstract description 23
- 125000003277 amino group Chemical group 0.000 claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 17
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 11
- 125000001424 substituent group Chemical group 0.000 claims description 19
- 125000003342 alkenyl group Chemical group 0.000 claims description 15
- 125000000304 alkynyl group Chemical group 0.000 claims description 14
- 229910052805 deuterium Chemical group 0.000 claims description 10
- 125000004442 acylamino group Chemical group 0.000 claims description 4
- 125000004431 deuterium atom Chemical group 0.000 claims description 3
- -1 methoxybenzyl group Chemical group 0.000 description 50
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 43
- 238000002360 preparation method Methods 0.000 description 32
- 238000005160 1H NMR spectroscopy Methods 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 239000000203 mixture Substances 0.000 description 22
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 21
- 239000012230 colorless oil Substances 0.000 description 21
- 238000010898 silica gel chromatography Methods 0.000 description 20
- 239000000243 solution Substances 0.000 description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- WVXKDLMEWYLCPU-UHFFFAOYSA-N 3-(aminomethyl)-4-trimethylsilylbutanoic acid Chemical compound C[Si](C)(C)CC(CN)CC(O)=O WVXKDLMEWYLCPU-UHFFFAOYSA-N 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 229960002870 gabapentin Drugs 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 125000002252 acyl group Chemical group 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- DGEYTDCFMQMLTH-UHFFFAOYSA-N methanol;propan-2-ol Chemical compound OC.CC(C)O DGEYTDCFMQMLTH-UHFFFAOYSA-N 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 150000001975 deuterium Chemical group 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 229960001233 pregabalin Drugs 0.000 description 5
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- NDVFEBVLHRFRIG-UHFFFAOYSA-N 3-cyano-4-(1-methylsilinan-1-yl)butanoic acid Chemical compound OC(=O)CC(C#N)C[Si]1(C)CCCCC1 NDVFEBVLHRFRIG-UHFFFAOYSA-N 0.000 description 4
- XUSVGOCLLDVFBI-UHFFFAOYSA-N 4-amino-3-trimethylsilylbutanoic acid Chemical compound C[Si](C)(C)C(CN)CC(O)=O XUSVGOCLLDVFBI-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- FBZGGKHJNAORPF-UHFFFAOYSA-N 3-(aminomethyl)-4-(1-methylsilolan-1-yl)butanoic acid Chemical compound OC(=O)CC(CN)C[Si]1(C)CCCC1 FBZGGKHJNAORPF-UHFFFAOYSA-N 0.000 description 3
- DFWPWGOCKOHZKW-UHFFFAOYSA-N 3-cyano-4-(1-methylsilolan-1-yl)butanoic acid Chemical compound OC(=O)CC(C#N)C[Si]1(C)CCCC1 DFWPWGOCKOHZKW-UHFFFAOYSA-N 0.000 description 3
- OKRKGXXNOHSDJA-UHFFFAOYSA-N 3-cyano-4-trimethylsilylbutanoic acid Chemical compound C[Si](C)(C)CC(C#N)CC(O)=O OKRKGXXNOHSDJA-UHFFFAOYSA-N 0.000 description 3
- MEWCIONQNSQXFR-UHFFFAOYSA-N 4-amino-3-[dimethyl(octyl)silyl]butanoic acid Chemical compound CCCCCCCC[Si](C)(C)C(CN)CC(O)=O MEWCIONQNSQXFR-UHFFFAOYSA-N 0.000 description 3
- GSTCXJOOMCJDCE-UHFFFAOYSA-N 4-amino-3-[tert-butyl(dimethyl)silyl]butanoic acid Chemical compound CC(C)(C)[Si](C)(C)C(CN)CC(O)=O GSTCXJOOMCJDCE-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 239000012300 argon atmosphere Substances 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- NMDRZXJTTJFHRD-UHFFFAOYSA-N benzyl 3-trimethylsilylprop-2-enoate Chemical compound C[Si](C)(C)C=CC(=O)OCC1=CC=CC=C1 NMDRZXJTTJFHRD-UHFFFAOYSA-N 0.000 description 3
- SCUQQZAJWVSDOK-UHFFFAOYSA-N benzyl 4-nitro-3-trimethylsilylbutanoate Chemical compound [O-][N+](=O)CC([Si](C)(C)C)CC(=O)OCC1=CC=CC=C1 SCUQQZAJWVSDOK-UHFFFAOYSA-N 0.000 description 3
- 238000010531 catalytic reduction reaction Methods 0.000 description 3
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 3
- 239000000470 constituent Substances 0.000 description 3
- KUNXMBNTCCNVEI-UHFFFAOYSA-N diethyl 2-cyano-2-[(1-methylsilolan-1-yl)methyl]butanedioate Chemical compound CCOC(=O)CC(C(=O)OCC)(C#N)C[Si]1(C)CCCC1 KUNXMBNTCCNVEI-UHFFFAOYSA-N 0.000 description 3
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- OZFGHZCHKLSWNV-UHFFFAOYSA-N ethyl 2-cyano-3-trimethylsilylpropanoate Chemical compound CCOC(=O)C(C#N)C[Si](C)(C)C OZFGHZCHKLSWNV-UHFFFAOYSA-N 0.000 description 3
- FGZDWCRFVTYEEY-UHFFFAOYSA-N ethyl 2-cyano-4-(1-methylsilinan-1-yl)butanoate Chemical compound CCOC(=O)C(C#N)CC[Si]1(C)CCCCC1 FGZDWCRFVTYEEY-UHFFFAOYSA-N 0.000 description 3
- BAJDBDOTFKOCHL-UHFFFAOYSA-N ethyl 2-cyano-4-(1-methylsilolan-1-yl)butanoate Chemical compound CCOC(=O)C(C#N)CC[Si]1(C)CCCC1 BAJDBDOTFKOCHL-UHFFFAOYSA-N 0.000 description 3
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 3
- SDMQBRIQEMMSEP-UHFFFAOYSA-N ethyl 3-cyano-4-(1-methylsilinan-1-yl)butanoate Chemical compound CCOC(=O)CC(C#N)C[Si]1(C)CCCCC1 SDMQBRIQEMMSEP-UHFFFAOYSA-N 0.000 description 3
- QBBHGLHXUHAXJQ-UHFFFAOYSA-N ethyl 3-cyano-4-(1-methylsilolan-1-yl)butanoate Chemical compound CCOC(=O)CC(C#N)C[Si]1(C)CCCC1 QBBHGLHXUHAXJQ-UHFFFAOYSA-N 0.000 description 3
- RTDYHXKJBUQOGI-UHFFFAOYSA-N ethyl 3-cyano-4-trimethylsilylbutanoate Chemical compound CCOC(=O)CC(C#N)C[Si](C)(C)C RTDYHXKJBUQOGI-UHFFFAOYSA-N 0.000 description 3
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- KJATYLURJFGRCT-UHFFFAOYSA-N 3-(aminomethyl)-4-(1-methylsilinan-1-yl)butanoic acid Chemical compound OC(=O)CC(CN)C[Si]1(C)CCCCC1 KJATYLURJFGRCT-UHFFFAOYSA-N 0.000 description 2
- GENXFZFAIXAVEU-UHFFFAOYSA-N 4-amino-3-(1-methylsilinan-1-yl)butanoic acid Chemical compound OC(=O)CC(CN)[Si]1(C)CCCCC1 GENXFZFAIXAVEU-UHFFFAOYSA-N 0.000 description 2
- QSNKEWAYYQEXNM-UHFFFAOYSA-N 4-amino-3-[dimethyl(phenyl)silyl]butanoic acid Chemical compound OC(=O)CC(CN)[Si](C)(C)C1=CC=CC=C1 QSNKEWAYYQEXNM-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- 108010084311 Novozyme 435 Proteins 0.000 description 2
- 208000000114 Pain Threshold Diseases 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 239000002250 absorbent Substances 0.000 description 2
- 230000002745 absorbent Effects 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- FAPHXHQZUMJTIO-UHFFFAOYSA-N benzyl 3-[dimethyl(octyl)silyl]-4-nitrobutanoate Chemical compound CCCCCCCC[Si](C)(C)C(C[N+]([O-])=O)CC(=O)OCC1=CC=CC=C1 FAPHXHQZUMJTIO-UHFFFAOYSA-N 0.000 description 2
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 2
- CWFBCAIJFUFVTC-UHFFFAOYSA-N diethyl 2-cyano-2-(trimethylsilylmethyl)butanedioate Chemical compound CCOC(=O)CC(C[Si](C)(C)C)(C#N)C(=O)OCC CWFBCAIJFUFVTC-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
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 125000003709 fluoroalkyl group Chemical group 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- PQXKHYXIUOZZFA-UHFFFAOYSA-M lithium fluoride Chemical compound [Li+].[F-] PQXKHYXIUOZZFA-UHFFFAOYSA-M 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 2
- 125000004043 oxo group Chemical group O=* 0.000 description 2
- 230000037040 pain threshold Effects 0.000 description 2
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 description 1
- BVOBEKTUNHUKRO-UHFFFAOYSA-N 1,2-dimethoxyethane;methanol Chemical compound OC.COCCOC BVOBEKTUNHUKRO-UHFFFAOYSA-N 0.000 description 1
- TWILKNARHWTHKP-UHFFFAOYSA-N 1,2-dimethoxyethane;methanol;hydrate Chemical compound O.OC.COCCOC TWILKNARHWTHKP-UHFFFAOYSA-N 0.000 description 1
- BIBDQBUZOZINPX-UHFFFAOYSA-N 1-(chloromethyl)-1-methylsilinane Chemical compound ClC[Si]1(C)CCCCC1 BIBDQBUZOZINPX-UHFFFAOYSA-N 0.000 description 1
- RZGBDFROBUVABV-UHFFFAOYSA-N 1-(chloromethyl)-1-methylsilolane Chemical compound ClC[Si]1(C)CCCC1 RZGBDFROBUVABV-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- YMCHHEXSTGTRIZ-UHFFFAOYSA-N 1-chloro-1-methylsilinane Chemical compound C[Si]1(Cl)CCCCC1 YMCHHEXSTGTRIZ-UHFFFAOYSA-N 0.000 description 1
- HQAXHIGPGBPPFU-UHFFFAOYSA-N 2-prop-2-ynoxyoxane Chemical compound C#CCOC1CCCCO1 HQAXHIGPGBPPFU-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- ZIQNVUWPNGNYQW-UHFFFAOYSA-N 3-[dimethyl(phenyl)silyl]prop-2-enoic acid Chemical compound OC(=O)C=C[Si](C)(C)C1=CC=CC=C1 ZIQNVUWPNGNYQW-UHFFFAOYSA-N 0.000 description 1
- BSFBEXRZAZEBTM-UHFFFAOYSA-N 3-[tert-butyl(dimethyl)silyl]prop-2-yn-1-ol Chemical compound CC(C)(C)[Si](C)(C)C#CCO BSFBEXRZAZEBTM-UHFFFAOYSA-N 0.000 description 1
- OVQUACJOKNYUQL-UHFFFAOYSA-N 3-trimethylsilylprop-2-enoic acid Chemical compound C[Si](C)(C)C=CC(O)=O OVQUACJOKNYUQL-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- HISJYDWBRQXJEO-UHFFFAOYSA-N C[Si](C)(C)C(C(=O)OCC)C(C)C#N Chemical compound C[Si](C)(C)C(C(=O)OCC)C(C)C#N HISJYDWBRQXJEO-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-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
- 208000002193 Pain Diseases 0.000 description 1
- 206010036376 Postherpetic Neuralgia Diseases 0.000 description 1
- 239000004820 Pressure-sensitive adhesive Substances 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 125000003435 aroyl group Chemical group 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
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- GCTPMLUUWLLESL-UHFFFAOYSA-N benzyl prop-2-enoate Chemical compound C=CC(=O)OCC1=CC=CC=C1 GCTPMLUUWLLESL-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- DBKNGKYVNBJWHL-UHFFFAOYSA-N chloro-dimethyl-octylsilane Chemical compound CCCCCCCC[Si](C)(C)Cl DBKNGKYVNBJWHL-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Substances ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 1
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- KPVWDKBJLIDKEP-UHFFFAOYSA-L dihydroxy(dioxo)chromium;sulfuric acid Chemical compound OS(O)(=O)=O.O[Cr](O)(=O)=O KPVWDKBJLIDKEP-UHFFFAOYSA-L 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 208000018685 gastrointestinal system disease Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000004054 inflammatory process 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
- 206010022437 insomnia Diseases 0.000 description 1
- VZNYXGQMDSRJAL-UHFFFAOYSA-N iodomethyl(trimethyl)silane Chemical compound C[Si](C)(C)CI VZNYXGQMDSRJAL-UHFFFAOYSA-N 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
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229940049920 malate Drugs 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
- 230000037323 metabolic rate Effects 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 239000013641 positive control 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
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
- C07F7/0816—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring comprising Si as a ring atom
Definitions
- the present invention relates to a silicon-containing carboxylic acid derivative.
- the carboxyl group is one of important functional groups in pharmaceutical compounds and is widely used in combination with various functional groups such as amino group, hydroxyl group and halogen atom.
- various functional groups such as amino group, hydroxyl group and halogen atom.
- gabapentin (2- [1- (aminomethyl) cyclohexyl] acetic acid) used as an antiepileptic drug and pregabalin ((S) -3- (amino) used for peripheral neuropathic pain (such as postherpetic neuralgia) Methyl) -5-methylhexanoic acid) is an example of a medicine having a combination with an amino group.
- An object of the present invention is to provide a novel silicon-containing carboxylic acid derivative useful as an active ingredient of a medicine.
- R 1 , R 2 , and R 3 are each independently an alkyl group, alkenyl group, alkynyl group, or aryl group (the alkyl group, alkenyl group, alkynyl group, or aryl group has a substituent) 2 or 3 groups selected from R 1 , R 2 and R 3 may be bonded to each other to form a ring; n represents 0 or 1; R 4 Is an amino group (the amino group may have a substituent) or-(CX 2 ) m -COOH (m represents an integer of 0 to 3, and X represents a hydrogen atom or a deuterium atom).
- R 5 represents — (CY 2 ) p —COOR 6 (p represents an integer of 0 to 3, Y represents a hydrogen atom or a deuterium atom, R 6 represents a hydrogen atom or an alkyl group (the alkyl group is substituted) Or a salt thereof, which may have a group).
- R 1 , R 2 , and R 3 are each independently an alkyl group or an aryl group, n is 0 or 1, and R 4 is an amino group, a monoalkylamino group, or Provided is the above compound or a salt thereof, which is an acylamino group and R 5 is — (CH 2 ) p —COOR 6 (p represents an integer of 0 to 3, and R 6 is a hydrogen atom or an alkyl group).
- the present invention provides a medicament comprising the compound represented by the above general formula (I) or a physiologically acceptable salt thereof as an active ingredient.
- a compound represented by the above general formula (I) or a physiologically acceptable salt thereof for the manufacture of the medicament; a method for preventing and / or treating diseases of mammals including humans,
- a method comprising the step of administering to a mammal, including a human, a prophylactic and / or therapeutically effective amount of a compound represented by the above general formula (I) or a physiologically acceptable salt thereof.
- the compound represented by the above general formula (I) or a salt thereof provided by the present invention can be used, for example, as an active ingredient of a medicine, has excellent in vivo stability, and delays the metabolic rate. It is useful as an active ingredient of medicine.
- R 1 , R 2 , and R 3 each independently represents an alkyl group, an alkenyl group, an alkynyl group, or an aryl group.
- an alkyl group includes an alkyl group composed of a straight chain, a branched chain, a ring, or a combination thereof.
- the number of carbon atoms of the alkyl group is not particularly limited, but is, for example, about 1 to 18, preferably 1 to 12, more preferably 1 to 6, and particularly preferably about 1 to 4.
- an alkenyl group includes an alkenyl group composed of a straight chain, a branched chain, a ring, or a combination thereof.
- the number of carbon atoms of the alkenyl group is not particularly limited, but is, for example, 2 to 18, preferably 2 to 12, more preferably 2 to 6, and particularly preferably about 2 to 4.
- the number of double bonds contained in the alkenyl group is, for example, 1 to 3, preferably 1 or 2, particularly preferably about 1.
- the alkynyl group includes a linear or branched alkynyl group.
- the number of carbon atoms of the alkynyl group is not particularly limited, but is, for example, 2 to 18, preferably 2 to 12, more preferably 2 to 6, and particularly preferably about 2 to 4.
- the number of triple bonds contained in the alkynyl group is, for example, 1 to 3, preferably 1 or 2, particularly preferably about 1.
- the alkenyl group may contain about 1 or 2 triple bonds.
- the aryl group includes an aromatic group containing a hetero atom as a ring constituent atom in addition to an aromatic hydrocarbon group.
- the aryl group may be monocyclic or condensed polycyclic.
- a hetero atom is included as a ring constituent atom, a nitrogen atom, an oxygen atom, a sulfur atom, or the like can be used as the hetero atom.
- aryl group containing a hetero atom as a ring constituent atom examples include a pyridyl group, a pyrimidinyl group, an imidazolyl group, an indolyl group, a quinolyl group, a phthalazinyl group, a naphthyridinyl group, a pyrrolyl group, a thienyl group, a furyl group, and a flazanyl group. It can be mentioned, but is not limited to these.
- the monocyclic aryl group for example, a 5- to 7-membered aryl group is preferable.
- the aryl group an aromatic hydrocarbon group is preferable, and a phenyl group is preferable.
- the alkyl group, alkenyl group, alkynyl group, or aryl group represented by R 1 , R 2 , and R 3 may have one or more substituents. When having two or more substituents, they may be the same or different.
- the position of the substituent is not particularly limited, and may have a substituent at an arbitrary position.
- Examples of the substituent when the alkyl group, alkenyl group, alkynyl group, or aryl group represented by R 1 , R 2 , and R 3 have a substituent include a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or Iodine atom), hydroxyl group, oxo group, carboxyl group, alkoxycarbonyl group, acyl group, amino group, alkyl group, alkenyl group, alkynyl group, alkoxy group, aryl group, or aralkyl group, but are not limited thereto. None happen.
- These substituents may be further substituted with another substituent. Examples of such include, but are not limited to, a fluoroalkyl group, a fluoroacetyl group, a methoxybenzyl group, and the like.
- Two or three groups selected from R 1 , R 2 , and R 3 may be bonded to each other to form a ring.
- the size of the ring formed is not particularly limited, but for example, it is about 4 to 8 membered ring, preferably about 5 to 7 membered ring.
- R 1 and R 2 are bonded to form a 5- or 6-membered ring, or R 1 , R 2 , and R 3 are bonded to each other to form a bicyclo ring (for example, a bicyclo [2.2.2] structure)
- a bicyclo ring for example, a bicyclo [2.2.2] structure
- a bicyclo ring such as a bicyclo [3.2.2] structure.
- R 1 , R 2 , and R 3 are preferably each independently an alkyl group or an aryl group.
- R 1 , R 2 , and R 3 are preferably each independently an alkyl group having about 1 to 6 carbon atoms.
- R 1 and R 2 are methyl groups
- R 3 is an isopropyl group or tert A case where it is a -butyl group is preferred.
- 1 to 3 of R 1 , R 2 , and R 3 are an aryl group such as a phenyl group.
- R 1 , R 2 , and R 3 are an aryl group, for example, a phenyl group, the remaining group is preferably an alkyl group having about 1 to 6 carbon atoms.
- n represents 0 or 1, but n is preferably 0. When n is 0, it means that there is no methylene group.
- R 4 represents an amino group or — (CX 2 ) m —COOH.
- the amino group represented by R 4 may have one or two substituents.
- substituents for example, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, or an acyl group (for example, an alkanoyl group such as an acetyl group or an aroyl group such as a benzoyl group) can be used. It will never be done.
- amino group substituted with an acyl group examples include an acylamino group that forms an amide bond with a carboxyl group of an amino acid (for example, International Publication WO 02/100344), or a carbamate (for example, (2-methyl-1- Oxopropyloxy) ethoxycarbonyl group bonded to an amino group, etc.), but is not limited thereto.
- These amino group modification means with acyl groups are useful as prodrugs or sustained release means.
- the amino group represented by R 4 is preferably unsubstituted or has one alkyl group or acyl group. In the case of having one alkyl group, the alkyl group has, for example, about 1 to 6 carbon atoms.
- m represents an integer of 0 to 3, preferably m is 1 or 2, and more preferably m is 1.
- X represents a hydrogen atom or a deuterium atom, but when X is a deuterium atom, the substitution rate of deuterium (ratio of hydrogen atoms replaced by deuterium atoms) is at least 50%, preferably 70% More preferably, it means 80%, particularly preferably 90%, most preferably 95% or more, but does not need to be completely substituted with deuterium. Therefore, when X is a deuterium atom, it is necessary to interpret it including that a part of X is a hydrogen atom.
- R 4 is preferably an amino group, and the amino group is preferably an unsubstituted amino group or a monoalkylamino group.
- p represents an integer of 0 to 3, but p is preferably 1 or 2, and p is more preferably 1.
- Y represents a hydrogen atom or a deuterium atom, and is the same as described for X.
- R 6 represents a hydrogen atom or an alkyl group
- the alkyl group represented by R 6 may have a substituent
- the substituent include a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or Iodine atom), hydroxyl group, oxo group, carboxyl group, alkoxycarbonyl group, acyl group, amino group, alkyl group, alkenyl group, alkynyl group, alkoxy group, aryl group, or aralkyl group, but are not limited thereto. None happen.
- These substituents may be further substituted with another substituent. Examples of such include, but are not limited to, a fluoroalkyl group, a methoxymethyl group, an ethoxymethyl group, and the like.
- ester formed when R 6 represents an optionally substituted alkyl group include, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, t-butyl group, Benzyl group, acetoxymethyl group, 1- (acetoxy) ethyl group, propionyloxymethyl group, 1- (propionyloxy) ethyl group, butyryloxymethyl group, 1- (butyryloxy) ethyl group, isobutyryloxymethyl group, 1- (isobutyryloxy) ethyl group, valeryloxymethyl group, 1- (valeryloxy) ethyl group, isovaleryloxymethyl group, 1- (isovaleryloxy) ethyl group, pivaloyloxymethyl group, 1- (pivaloyloxy) ethyl group, methoxycarbonyloxymethyl group, 1- (methoxycarbonyloxy) e
- the compound represented by the general formula (I) may form an acid addition salt or a base addition salt.
- acid addition salts include mineral acid salts such as hydrochloride, sulfate, and nitrate, and organic acid salts such as p-toluenesulfonate, oxalate, and malate.
- base addition salt include metal salts such as sodium salt, potassium salt, magnesium salt, or calcium salt, ammonium salts, and organic amine salts such as triethylamine salt or ethanolamine salt.
- physiologically acceptable salts are preferred when the compounds of the present invention are used as active pharmaceutical ingredients.
- the compound represented by the general formula (I) may have one or more asymmetric carbons depending on the type of substituent, and any optical isomer based on these asymmetric carbons. Any mixture of optical isomers, racemates, diastereoisomers based on two or more asymmetric carbons, any mixture of diastereoisomers, and the like are all encompassed within the scope of the present invention.
- the compound represented by the general formula (I) contains a double bond, geometric isomers exist, but in addition to the pure form of Z-form or E-form, mixtures of any proportions of the present invention Included in the range.
- any hydrate or solvate of the free compound or the compound in the form of a salt is also included in the scope of the present invention.
- the compound of the present invention represented by the general formula (I) can be synthesized by the method specifically shown in the examples of the present specification. Since a method for synthesizing ⁇ -carbonylsilanes in which a silicon atom is introduced instead of a carbon atom has been reported (for example, GB 2,397,576A and Journal of Organometallic Chemistry, 690, pp.678-684, 2005) Any compound included in the general formula (I) can be easily produced by referring to the synthesis methods specifically shown in the examples of the present specification with reference to the publications of Further, as a method for synthesizing a compound having an amino acid and a carboxyl group, for example, a method for synthesizing pregabalin and its analog (U.S. Pat.Nos. 5,563,175, 5,840,956, 5,637,767, 5,629,447, 5,616,793) , And No. 5,563,175).
- the use of the compound of the present invention represented by the general formula (I) is not particularly limited, for example, it can be used as an active ingredient of a medicine.
- the use of the medicine include prevention and / or treatment of epilepsy, pain, inflammation, gastrointestinal disorder, insomnia, psychiatric disorder, diabetic peripheral neuropathy, etc.
- a compound having an amino acid and a carboxyl group is expected to have the same pharmacological action as, for example, pregabalin and gabapentin, and is therefore described in, for example, paragraph [0003] of International Publication WO 2010/017498 Can be used for specific applications.
- the entire disclosure of the above patent document is included in the disclosure of this specification by reference.
- the compound of the present invention represented by the general formula (I) or a physiologically acceptable salt thereof is used as a pharmaceutical
- the above compound as a pharmaceutical or a physiologically acceptable salt thereof, or a hydrate thereof Or a solvate may be directly administered to mammals including humans, but can be preferably administered as an oral or parenteral pharmaceutical composition that can be produced by methods well known to those skilled in the art.
- the pharmaceutical composition suitable for oral administration include tablets, capsules, powders, fine granules, granules, liquids, and syrups.
- the pharmaceutical composition suitable for parenteral administration includes Examples include injections, instillations, suppositories, inhalants, eye drops, nasal drops, ointments, creams, patches, transdermal absorbents, transmucosal absorbents, and the like.
- additives that can be used by those skilled in the art
- examples of the additive for preparation include excipients, disintegrants or disintegration aids, binders, lubricants, coating agents, dyes, diluents, bases, solubilizers or solubilizers, isotonic agents, Examples thereof include pH adjusters, stabilizers, propellants, and pressure-sensitive adhesives, and these can be appropriately selected by those skilled in the art depending on the form of the pharmaceutical composition, and can be used in combination of two or more. Also good.
- the dose of the drug is not particularly limited, and can be appropriately increased or decreased according to various factors that should be normally considered, such as the weight and age of the patient, the type and symptoms of the disease, and the route of administration.
- the dose of the drug can be used in the range of about 0.001 to 10,000 mg per day for an adult.
- Example 1 Preparation of benzyl 3- (trimethylsilyl) acrylate
- Ethyl bromide (4.18 ml, 56.0 mmol) was slowly added dropwise at room temperature to a suspension of magnesium (Mg: 1.34 g, 55.8 mgatom) in THF (20 ml) and stirred until Mg was dissolved.
- a solution of 2-propyn-1-ol (1.16 ml, 20.0 mmol) in THF (5 ml) was slowly added dropwise to the reaction solution under ice cooling, and the mixture was further stirred at room temperature for 15 hours.
- Dimethyl-n-octylchlorosilane (13.3 ml, 56.0 mmol) was added dropwise under ice cooling, and the mixture was further heated under reflux for 2.5 hours.
- Example 18 Preparation of benzyl 3- (1-methyl-1-silacyclohexane-1-yl) acrylate Magnesium metal (776 mg, 32.3 mg atom) in THF (15 ml) in ethyl bromide (15 ml) under ice-cooling 2.41 ml, 32.3 mmol) was added, and the mixture was stirred at room temperature for 15 minutes and further at 45-50 ° C. for 30 minutes. The reaction mixture was ice-cooled, 2- (2-propynyloxy) tetrahydropyran (4.48 ml, 32.3 mmol) in THF (5 ml) was added, and the mixture was stirred at 0 ° C. to room temperature for 16 hr.
- reaction mixture was ice-cooled, 1-chloro-1-methyl-1-silacyclohexane (2.40 g, 16.2 mmol) in THF (5 ml) was added and stirred for 5 minutes, then heated at room temperature for 10 minutes and further heated. Stirring was continued for 2 hours under reflux.
- the reaction mixture was ice-cooled, saturated aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate. Purification by silica gel chromatography [hexane: ethyl acetate (79: 1 to 59: 1 to 9: 1)] after usual treatment gave 3.919 g (96%) of a colorless oil.
- Example 31 Preparation of (+)-4-amino-3- (trimethylsilylmethyl) butanoic acid and (-)-4-amino-3- (trimethylsilylmethyl) butanoic acid ( ⁇ ) -4- obtained in Example 15 above
- Test Example 1 Binding to gabapentin receptor A gabapentin receptor was prepared from the brains of Wister rats according to the method of Suman-Chauhan et al. (Eur. J. Pharmacol, 244 (3), pp.293-301, 1993). As a result of examining the binding of the following compound (1 ⁇ M) to the gabapentin receptor by inhibition of gabapentin binding in the presence of [ 3 H] gabapentin 0.02 ⁇ M, the following inhibition rates were shown.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Pain & Pain Management (AREA)
- Anesthesiology (AREA)
- Rheumatology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
また、上記医薬の製造のための上記一般式(I)で表される化合物又は生理学的に許容されるその塩の使用;ヒトを含む哺乳類動物の疾病の予防及び/又は治療方法であって、上記一般式(I)で表される化合物又は生理学的に許容されるその塩の予防及び/又は治療有効量をヒトを含む哺乳類動物に投与する工程を含む方法が本発明により提供される。
nは0又は1を示すが、nが0であることが好ましい。nが0である場合にはメチレン基が存在しないことを意味する。
HRMS: Calcd for C13H18O2Si: 234.1075. Found: 234.1065
MS (m/z): 234 (M+, 0.5), 219 (6), 144 (17), 127 (13), 91 (100), 73 (28), 69 (30)
IR (neat) cm-1: 1720
1H-NMR (CDCl3) δ: 0.13 (9H, s), 5.19 (2H, s), 6.29 (1H, d, J=18.5 Hz), 7.31 (1H, d, J=18.5 Hz), 7.31-7.43 (5H, m)
HRMS: Calcd for C16H24O2Si: 276.1544. Found: 276.1528
MS (m/z): 276 (M+, 0.4), 219 (45), 165 (2), 129 (11), 91 (100), 75 (10), 73 (15), 69 (12), 41 (12)
IR (neat) cm-1: 1721
1H-NMR (CDCl3) δ: 0.09 (6H, s), 0.90 (9H, s), 5.20 (2H, s), 6.31 (1H, d, J=19 Hz), 7.30-7.42 (5H, m), 7.33 (1H, d, J=19 Hz)
1H-NMR (CDCl3) δ: 0.41 (6H, s), 5.18 (2H, s), 6.31 (1H, d, J=19 Hz), 7.30-7.55 (11H, m).
1H-NMR (CDCl3) δ: 0.10 (6H, s), 0.60 (2H, br t, J=7.5 Hz), 0.88 (3H, br t, J=7 Hz), 1.14-1.36 (12H, m), 5.19 (2H, s), 6.28 (1H, d, J=18.5 Hz), 7.31 (1H, d, J=18.5 Hz), 7.30-7.42 (5H, m).
MS (m/z): 280 (M+-Me, 0.2), 224 (8), 143 (8), 99 (12), 91 (100), 73 (29), 56 (48), 41 (21)
IR (neat) cm-1: 1730, 1547
1H-NMR (CDCl3) δ: 0.07 (9H, s), 1.96-2.06 (1H, m), 2.49 (1H, dd, J=16.5, 7 Hz), 2.56 (1H, dd, J=16.5, 5.5 Hz), ca. 4.44-4.54 (2H, m), 5.10 (2H, s), 7.29-7.41 (5H, m)
MS (m/z): 280 (M+-tert-Bu, 9), 143 (18), 117 (14), 115 (24), 104 (64), 99 (34), 91 (100), 75 (98), 73 (96), 65 (95), 59 (93), 57 (94), 45 (54), 43 (55), 41 (94)
IR (neat) cm-1: 1730, 1549
1H-NMR (CDCl3) δ: 0.01 (3H, s), 0.04 (3H, s), 0.93 (9H, s), 2.15 (1H, dddd, J=10.5, 6.5, 5, 4.5 Hz), 2.52 (1H, dd, J=17.5, 6.5 Hz), 2.63 (1H, dd, J=17.5, 5 Hz), 4.50 (1H, dd, J=13.5, 4.5 Hz), 4.57 (1H, dd, J=13.5, 10.5 Hz), 5.11 (2H, s), 7.32-7.39 (5H, m)
1H-NMR (CDCl3) δ:0. 37 (6H, s), 2.20-2.32 (1H, dddd, J=7, 7, 7, 5.5 Hz), 2.45 (1H, dd, J=17, 7 Hz), 2.56 (1H, dd, J=17, 5.5 Hz), 4.42 (2H, J=7 Hz), 5.04 (2H, s), 7.26-7.50 (10H, m)
1H-NMR (CD3OD) δ:0.02 (3H, s), 0.04 (3H, s), 0.57 (1H, br t, J=8 Hz), 0.89 (3H, br t, J=7Hz), 1.26-1.38 (12H, m), 1.98-2.10 (1H, m), 2.48 (1H, dd, J=16.5, 7 Hz), 2.54 (1H, dd, J=16.5, 5.5 Hz), 4.50 (1H, dd, J=13.5, 10 Hz), 4.56 (1H, dd, J=13.5, 4 Hz), 5.08 (2H, s), 7.27-7.40 (5H, m)
Mp: 199-201℃ (メタノール-2-プロパノール)
HRMS: Calcd for C7H17NO2Si: 175.1028. Found: 175.1057
MS (m/z): 175 (M+, 0.3), 156 (20), 143 (8), 116 (10), 99 (11), 75 (49), 73 (100), 59 (18), 45 (29), 43 (25), 41 (19)
IR (KBr) cm-1: 1651
1H-NMR (CD3OD) δ: 0.07 (9H, s), 1.23 (1H, dddd, J=11, 11, 2, 1.5 Hz), 2.26 (1H, dd, J=16.5, 11 Hz), 2.56 (1H, ddd, J=16.5, 2, 1 Hz), 2.82 (1H, dd, J=13, 11 Hz), 3.16 (1H, ddd, J=13, 1.5, 1 Hz)
Mp: 163-164.5℃ (メタノール)
MS (m/z): 184 (M+-H2O-Me, 3), 142 (92), 114 (68), 99 (32), 75 (100), 73 (89), 59 (78), 45 (22), 43 (35), 41 (46)
IR (KBr) cm-1: 1653
1H-NMR (CD3OD) δ: 0.05 (3H, s), 0.06 (3H, s), 0.96 (9H, s), 1.42 (1H, dddd, J=11.5, 11, 2, 1.5 Hz), 2.32 (1H, dd, J=16.5, 11 Hz), 2.66 (1H, ddd, J=16.5, 2, 1.5 Hz), 2.89 (1H, dd, J=13, 11.5 Hz), 3.23 (1H, ddd, J=13, 1.5, 1.5 Hz)
MS (m/z): 219 (M+-H2O, 6), 218 (20), 141 (23), 135 (100)
1H-NMR (CD3OD) δ: 0.35 (3H, s), 0.36 (3H, s), 1.50 (1H, dddd, J=11, 11, 2, 1.5 Hz), 2.25 (1H, dd, J=16.5, 11 Hz), 2.59 (1H, ddd, J=16.5, 1.5, 1.5 Hz), 2.77 (1H, dd, J=13, 11 Hz), 3.23 (1H, ddd, J=13, 1.5, 1.5 Hz), 7.32-7.42 (3H, m), 7.50-7.58 (2H, m).
1H-NMR (CD3OD) δ: 0.04 (3H, s), 0.05 (3H, s), 0. 50-0.65 (2H, m), 0.89 (3H, br t, J=7 Hz), 1.25-1.40 (13H, m), 2. 26 (1H, dd, J=16.5, 11.5 Hz), 2.55 (1H, ddd, J=16.5, 2, 1.5 Hz), 2.82 (1H, dd, J=13, 11.5 Hz), 3.15 (1H, ddd J=13, 2, 1.5 Hz).
IR (neat) cm-1: 2245, 1741
1H-NMR (CDCl3) δ: 0.13 (9H, s), 1.22 (1H, dd, J=14.5, 8.5 Hz), 1.27 (1H, dd, J=14.5, 7 Hz), 1.33 (3H, t, J=7 Hz), 3.46 (1H, dd, J=8.5, 7 Hz), 4.26 (2H, q, J=7 Hz)
MS (m/z): 270 (M+-Me, 10), 212 (23), 196 (29), 168 (15), 75 (32), 73 (100), 57 (16), 45 (16)
IR (neat) cm-1: 2245, 1736
1H-NMR (CDCl3) δ: 0.15 (9H, s), 1.23 (1H, d, J=14.5 Hz), 1.27 (3H, t, J=7 Hz), 1.31 (1H, d, J=14.5 Hz), 1.36 (3H, t, J=7 Hz), 2.83 (1H, d, J=16.5 Hz), 3.07 (1H, d, J=16.5 Hz), 4.20 (2H, q, J=7 Hz), 4.25 (1H, dq, J=11, 7 Hz), 4.31 (1H, dq, J=11, 7 Hz)
HRMS: Calcd for C10H19NO2Si: 213.1184. Found: 213.1180
MS (m/z): 213 (M+, 0.6), 198 (3), 170 (15), 140 (12), 126 (20), 99 (17), 75 (41), 73 (100), 45 (20), 43 (14), 41 (21)
IR (neat) cm-1: 2240, 1732
1H-NMR (CDCl3) δ: 0.13 (9H, s), 0.85 (1H, dd, J=14.5, 5 Hz), 1.01 (1H, dd, J=14.5, 10.5 Hz), 1.29 (3H, t, J=7 Hz), 2.56 (1H, dd, J=16.5, 7 Hz), 2.74 (1H, dd, J=16.5, 7.5 Hz), 3.05 (1H, dddd, J=10.5, 7.5, 7, 5 Hz), 4.20 (2H, q, J=7 Hz)
Mp: 39-41℃ (ヘキサン)
HRMS: Calcd for C8H15NO2Si: 185.0871. Found: 185.0886
MS (m/z): 185 (M+, 0.4), 170 (17), 140 (17), 126 (19), 117 (14), 99 (22), 75 (77), 73 (100), 45 (14), 43 (17)
IR (KBr) cm-1: 2245, 1699
1H-NMR (CD3OD) δ:0.12 (9H, s), 0.91 (1H, dd, J=14.5, 5 Hz), 1.01 (1H, dd, J=14.5, 10.5 Hz), 2.61 (1H, dd, J=16.5, 6.5 Hz), 2.71 (1H, dd, J=16.5, 7.5 Hz), 3.06 (1H, dddd, J=10.5, 7.5, 6.5, 5 Hz)
Mp: 167-168℃(cap.)(メタノール-2-プロパノール)
HRMS: Calcd for C8H19NO2Si: 189.1184. Found: 189.1195
MS (m/z): 189 (M+, 0.7), 170 (10), 156 (21), 75 (43), 73 (100), 59 (16), 45 (26), 43 (21), 41(30)
IR (KBr) cm-1: 2175, 1651
1H-NMR (CD3OD) δ: 0.07 (9H, s), 0.61 (1H, dd, J=15, 6 Hz), 0.69 (1H, dd, J=15, 8.5 Hz), 2.10-2.23 (1H, m), 2.29 (1H, dd, J=15.5, 9 Hz), 2.46 (1H, dd, J=15.5, 3 Hz), 2.85 (1H, dd, J=12.5, 7.5 Hz), 2.92 (1H, dd, J=12.5, 4 Hz)
金属マグネシウム(776 mg, 32.3 mg atom)のTHF (15 ml)懸濁液に氷冷下エチルブロミド (2.41 ml, 32.3 mmol)を添加し、室温にて15分、さらに45-50℃にて30分撹拌した。反応液を氷冷し、2-(2-プロピニルオキシ)テトラヒドロピラン(4.48 ml, 32.3 mmol)のTHF(5 ml)溶液を添加、0℃~室温にて16時間撹拌した。反応液を氷冷し、1-クロロ-1-メチル-1-シラシクロヘキサン(2.40 g, 16.2 mmol)のTHF (5 ml)溶液を添加して5分撹拌後、室温にて10分、さらに加熱還流下2時間撹拌を続けた。反応液を氷冷し、飽和塩化アンモニウム水溶液を加え酢酸エチル抽出。定法処理後シリカゲルクロマト[ヘキサン-酢酸エチル(79:1~59:1~9:1)]にて精製することにより無色油状物3.919 g (96%)を得た。この一部(3.120 g, 12.4 mmol)をメタノール-ジメトキシエタン(1:1, 8 ml)に溶解し、10%塩酸水(4 ml)を添加し、室温下29時間撹拌した。飽和重曹水を徐々に加え中和し、酢酸エチル抽出。定法処理後シリカゲルクロマト[ヘキサン-酢酸エチル(19:1)]にて精製することにより無色油状物1.705 g (82%)を得た。この一部(1.702 g, 10.1 mmol)より上記例2と全く同様にして3工程を経た後、シリカゲルクロマト[ヘキサン-酢酸エチル(49:1)]精製、表記3-(1-メチル-1-シラシクロヘキサン-1-イル)アクリル酸ベンジル(2.152 g, 3工程通算78%)を無色油状物として得た。
HRMS: Calcd for C16H22O2Si: 274.1388. Found: 274.1371.
MS (m/z): 274 (M+, 12), 259 (2), 231 (7), 183 (11), 167 (11), 144 (28), 113 (21), 91 (100), 85 (26), 43 (23).
IR (neat) cm-1: 1718.
1H-NMR (CDCl3) δ: 0.13 (3H, s), 0.58-0.70 (2H, m), 0.71-0.82 (2H, m), 1.32-1.50 (2H, m), 1.60-1.76 (4H, m), 5.20 (2H, s), 6.34 (1H, d, J=19 Hz), 7.32-7.43 (5H, m), 7.34 (1H, d, J=19 Hz).
MS (m/z): 289 (M+-NO2, 0.3), 249 (0.2), 201 (1), 173 (1), 113 (5), 101 (6), 91 (100), 85 (7), 61 (4), 43 (5).
IR (neat) cm-1: 1730, 1547.
1H-NMR (CDCl3) δ: 0.08 (3H, s), 0.53-0.73 (4H, m), 1.18-1.31 (1H, m), 1.44-1.59 (3H, m), 1.73-1.86 (2H, m), 2.08 (1H, dddd, J=9, 6.5, 6, 5 Hz), 2.49 (1H, dd, J=16.5, 6.5 Hz), 2.56 (1H, dd, J=16.5, 6 Hz), 4.46 (1H, dd, J=13, 5 Hz), 4.51 (1H, dd, J=13, 9 Hz), 5.09 (1H, d, J=12.5 Hz), 5.13 (1H, d, J=12.5 Hz), 7.31-7.41 (5H, m).
Mp: 160-161.5℃ (メタノール-2-プロパノール).
HRMS: Calcd for C10H21NO2Si: 215.1340. Found: 215.1350.
MS (m/z): 215 (M+, 0.4), 214 (2), 198 (20), 197 (19), 196 (46), 168 (14), 155 (31), 113 (66), 85 (100), 59 (43), 45 (32), 43 (57), 41(33).
IR (neat) cm-1: 1636.
1H-NMR (CD3OD) δ: 0.60 (3H, s), 0.65-0.73 (4H, m), 1.25-1.39 (1H, m), 1.33 (1H, dddd, J=11.5, 11, 2.5, 2 Hz), 1.47-1.66 (3H, m), 1.75-1.90 (2H, m), 2.27 (1H, dd, J=16.5, 11 Hz), 2.54 (1H, ddd, J=16.5, 2.5, 1 Hz), 2.83 (1H, dd, J=13, 11.5 Hz), 3.14 (1H, ddd, J=13, 2, 1 Hz).
IR (neat) cm-1: 2245, 1740.
1H-NMR (CDCl3) δ: 0.21 (3H, s), 0.55-0.76 (4H, m), ca. 1.30-1.38 (2H, m), 1.33 (3H, dd, J=7, 7 Hz), 1.57-1.63 (4H, m), 3.50 (1H, dd, J=8.5, 7 Hz), 4.21-4.31 (2H, m).
IR (neat) cm-1: 2240, 1741.
1H-NMR (CDCl3) δ: 0.15 (3H, s), 0.63-0.76 (4H, m), ca. 1.25-1.31 (2H, m), 1.33 (3H, dd, J=7, 7 Hz), ca. 1.33-1.52 (2H, m), 1.58-1.79 (4H, m), 3.47 (1H, dd, J=8.5, 7 Hz), 4.20-4.31 (2H, m).
HRMS: Calcd for C15H25NO4Si: 311.1551. Found: 311.1549.
MS (m/z): 311 (M+, 2), 296 (4), 282 (37), 266 (13), 238 (100), 210 (68), 208 (31), 196 (23), 185 (27), 99 (49), 71 (33), 43 (34).
IR (neat) cm-1: 2240, 1735.
1H-NMR (CDCl3) δ: 0.28 (3H, s), 1.55-1.62 (4H, m), 1.27 (3H, t, J=7 Hz), 1.34 (1H, d, J=15 Hz), 1.36 (3H, dd, J=7, 7 Hz), 1.40 (1H, d, J=15 Hz), 1.55-1.62 (4H, m), 2.83 (1H, d, J=17 Hz), 3.08 (1H, d, J=17 Hz), 4.19 (2H, q, J=7 Hz), 4.26 (1H, dq, J=11, 7 Hz), 4.31(1H, dq, J=11, 7 Hz).
HRMS: Calcd for C16H27NO4Si: 325.1708. Found: 325.1722.
MS (m/z): 325 (M+, 4), 310 (5), 296 (24), 282 (55), 252 (100), 224 (35), 208 (68), 113 (48), 85 (80), 59 (38), 45 (19), 43 (44).
IR (neat) cm-1: 2240, 1734.
1H-NMR (CDCl3) δ: 0.20 (3H, s), 0.65-0.75 (4H, m), 1.27 (1H, d, J=15 Hz), 1.27 (3H, t, J=7 Hz), 1.35 (1H, d, J=15 Hz), 1.36 (3H, dd, J=7, 7 Hz), 1.43-1.66 (4H, m), 1.66-1.83 (2H, m), 2.83 (1H, d, J=17 Hz), 3.06 (1H, d, J=17 Hz), 4.19 (2H, q, J=7 Hz), 4.25 (1H, dq, J=11, 7 Hz), 4.31(1H, dq, J=11, 7 Hz).
HRMS: Calcd for C12H21NO2Si: 239.1340. Found: 239.1326.
MS (m/z): 239 (M+, 2), 210 (39), 197 (42), 183 (40), 182 (39), 142 (32), 128 (100), 99 (89), 71 (42), 45 (28), 43 (57).
IR (neat) cm-1: 2240, 1731.
1H-NMR (CDCl3) δ: 0.21 (3H, s), 0.54-0.79 (4H, m), 0.97 (1H, dd, J=14.5, 5.5 Hz), 1.10 (1H, dd, J=14.5, 10 Hz), 1.29 (3H, t, J=7 Hz), 1.57-1.64 (4H, m), 2.56 (1H, dd, J=16.5, 7 Hz), 2.74 (1H, dd, J=16.5, 7 Hz), 3.09 (1H, dddd, J=10, 7, 7, 5.5 Hz), 4.20 (2H, q, J=7 Hz).
HRMS: Calcd for C13H23NO2Si: 253.1497. Found: 253.1508.
MS (m/z): 253 (M+, 10), 224 (12), 210 (90), 197 (46), 182 (76), 128 (46), 113 (91), 85 (100), 59 (46), 43 (55).
IR (neat) cm-1: 2240, 1732.
1H-NMR (CDCl3) δ: 0.16 (3H, s), 0.63-0.77 (4H, m), 0.91 (1H, dd, J=14.5, 5 Hz), 1.05 (1H, dd, J=14.5, 10.5 Hz), 1.29 (3H, t, J=7 Hz), 1.32-1.52 (2H, m), 1.52-1.79 (4H, m), 2.55 (1H, dd, J=16, 7 Hz), 2.74 (1H, dd, J=16, 7 Hz), 3.05 (1H, dddd, J=10.5, 7, 7, 5 Hz), 4.20 (2H, q, J=7 Hz).
HRMS: Calcd for C10H17NO2Si: 211.1028. Found: 211.1035.
MS (m/z): 211 (M+, 2), 196 (6), 182 (30), 169 (22), 155 (18), 128 (100), 99 (49), 71 (27), 61 (30), 45 (30), 43 (46).
IR (neat) cm-1: 2245, 1713.
1H-NMR (CDCl3) δ: 0.22 (3H, s), 0.56-0.79 (4H, m), 1.00 (1H, dd, J=14.5, 5.5 Hz), 1.14 (1H, dd, J=14.5, 10 Hz), 1.56-1.66 (4H, m), 2.64 (1H, dd, J=17, 6.5 Hz), 2.82 (1H, dd, J=17, 7.5 Hz), 3.07 (1H, dddd, J=10, 7.5, 6.5, 5.5 Hz).
HRMS: Calcd for C11H19NO2Si: 225.1184. Found: 225.1199.
MS (m/z): 225 (M+, 9), 210 (7), 182 (100), 169 (46), 155 (25), 138 (56), 128 (74), 113 (65), 85 (90), 61 (42), 59 (38), 43 (63).
IR (neat) cm-1: 2240, 1712.
1H-NMR (CDCl3) δ: 0.17 (3H, s), 0.64-0.77 (4H, m), 0.93 (1H, dd, J=14.5, 5 Hz), 1.08 (1H, dd, J=14.5, 10.5 Hz), 1.29-1.53 (2H, m), 1.56-1.80 (4H, m), 2.64 (1H, dd, J=17, 6.5 Hz), 2.82 (1H, dd, J=17, 7.5 Hz), 3.04 (1H, dddd, J=10.5, 7.5, 6.5, 5 Hz).
Mp: 133-135℃ (メタノール-2-プロパノール).
MS (m/z): 197 (M+-H2O, 10), 186 (25), 168 (30), 113 (34), 99 (100), 85 (39), 71 (64), 45(56), 43 (61), 41 (48).
IR (KBr) cm-1: 1652.
1H-NMR (CD3OD) δ: 0.15 (3H, s), 0.53-0.70 (4H, m), 0.73 (1H, dd, J=14.5, 6 Hz), 0.80 (1H, dd, J=14.5, 8 Hz), 1.56-1.64 (4H, m), 2.15-2.26 (1H, m), 2.30 (1H, dd, J=15.5, 8.5 Hz), 2.47 (1H, dd, J=15.5, 3 Hz), 2.87 (1H, dd, J=12.5, 7 Hz), 2.93 (1H, dd, J=12.5, 4 Hz).
Mp: 140.5-143℃ (メタノール-2-プロパノール).
MS (m/z): 211 (M+-H2O, 5), 200 (12), 187 (18), 168 (38), 113 (55), 85 (100), 59 (42), 45(27), 43 (47), 41 (34).
IR (KBr) cm-1: 1650.
1H-NMR (CD3OD) δ: 0.11 (3H, s), 0.60-0.77 (6H, m), 1.28-1.83 (6H, m), 2.12-2.24 (1H, m), 2.29 (1H, dd, J=15.5, 9 Hz), 2.46 (1H, dd, J=15.5, 3.5 Hz), 2.85 (1H, dd, J=12.5, 7.5 Hz), 2.92 (1H, dd, J=12.5, 4 Hz).
上記例15で得た(±)-4-(トリメチルシリル)-3-シアノブタン酸エチル (2.06 g 9.67 mmol) を0.1 M phosphate buffer (45 ml) とDMSO (9 ml) の混合溶液中、Novozym 435 (81 mg) にて酵素加水分解し、カルボン酸 (836 mg, 42%) と未反応のエステル体 (858 mg, 47%) を得た。得たカルボン酸の一部 (825 mg, 4.46 mmol) をジクロロメタン(30 ml)に溶解し、0℃ で撹拌中、DMAP (54 mg, 0.446 mmol)、EDCI (1.02 g, 5.35 mmol)を加え一昼夜撹拌後定法処理しエチルエステル体(824 mg, 87%)に戻した。この光学純度を高めたエステル体(824 mg, 3.87 mmol)を上記方法に従い再度Novozym 435にて加水分解し、カルボン酸(366 mg, 51%)を得た。このカルボン酸の一部(250 mg, 1.35 mmol)を、上記例17と同様に接触還元を行い、再結晶することにより(-)-4-アミノ-3-(トリメチルシリルメチル)ブタン酸 (41 mg, 16%)を得た。
(-)-4-アミノ-3-(トリメチルシリルメチル)ブタン酸
Mp: 186-187℃ (cap.)(メタノール-2-プロパノール).
[α]25 D -25.3 (c 1.00, メタノール).
(+)-4-アミノ-3-(トリメチルシリルメチル)ブタン酸
Mp: 185-186℃ (cap.)(メタノール-2-プロパノール).
[α]25 D +26.0 (c 1.00, メタノール).
Wisterラットの脳からSuman-Chauhan らの方法(Eur. J. Pharmacol, 244(3), pp.293-301, 1993)に従ってガバペンチン受容体を調製した。下記化合物(1μM)のガバペンチン受容体への結合を[3H]ガバペンチン 0.02μMの存在下にガバペンチンの結合阻害により調べた結果、以下の阻害率を示した。
4-アミノ-3-(トリメチルシリル)ブタン酸:35%
4-アミノ-3-(t-ブチルジメチルシリル)ブタン酸:13%
4-アミノ-3-(トリメチルシリルメチル)ブタン酸:28%
4-アミノ-3-(ジメチル-n-オクチルシリル)ブタン酸:32%
ラットChungモデルを用い、4-アミノ-3-(トリメチルシリル)ブタン酸 (化合物A),4-アミノ-3-(トリメチルシリルメチル)ブタン酸 (化合物B),4-アミノ-3-[(1-メチル-1-シラシクロペンタン-1-イル)メチル]ブタン酸 (化合物C)、4-(1-メチル-1-シラシクロヘキサン-1-イル)-3-シアノブタン酸 (化合物D)、およびプレガバリン(陽性対照、化合物E)を経口にて単回投与し、30分後の鎮痛作用を機械刺激による疼痛閾値を用いて検討した(総群数11群、N=6)。その結果、各薬剤、ならびにコントロールの疼痛閾値(g)は以下の値を示した。
コントロール(0.5% MC): 5.3±0.4
化合物A: 7.8±0.5 (60 mg/kg); 6.2±0.4 (20 mg/kg)
化合物B: 7.9±0.4 (60 mg/kg); 5.4±0.2 (20 mg/kg)
化合物C: 8.8±0.3 (60 mg/kg); 5.7±0.6 (20 mg/kg)
化合物D: 7.3±0.5 (60 mg/kg); 4.8±0.2 (20 mg/kg)
化合物E: 8.3±0.2 (30 mg/kg); 6.3±0.3 (10 mg/kg)
Claims (3)
- 下記の一般式(I):
- R1、R2、及びR3がそれぞれ独立にアルキル基又はアリール基であり、nが0又は1であり、R4が無置換アミノ基、モノアルキルアミノ基、又はアシルアミノ基であり、R5が-(CH2)p-COOR6(pは0から3の整数を示し、R6は水素原子又はアルキル基である)である請求項1に記載の化合物又はその塩。
- R1、R2、及びR3がそれぞれ独立にアルキル基であり、nが0であり、R4が無置換アミノ基、モノアルキルアミノ基、又はアシルアミノ基であり、R5が-(CH2)p-COOR6(pは1であり、R6は水素原子又はアルキル基である)である請求項1に記載の化合物又はその塩。
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14/112,087 US8895769B2 (en) | 2011-04-20 | 2012-04-19 | Silicon-containing carboxylic acid derivative |
EP12774607.1A EP2700645A4 (en) | 2011-04-20 | 2012-04-19 | SILICONE-CONTAINING CARBOXYLENE DERIVATIVE |
JP2012544982A JP5230847B2 (ja) | 2011-04-20 | 2012-04-19 | ケイ素含有カルボン酸誘導体 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2011-093714 | 2011-04-20 | ||
JP2011093714 | 2011-04-20 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2012144551A1 true WO2012144551A1 (ja) | 2012-10-26 |
Family
ID=47041657
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2012/060552 WO2012144551A1 (ja) | 2011-04-20 | 2012-04-19 | ケイ素含有カルボン酸誘導体 |
Country Status (4)
Country | Link |
---|---|
US (1) | US8895769B2 (ja) |
EP (1) | EP2700645A4 (ja) |
JP (2) | JP5230847B2 (ja) |
WO (1) | WO2012144551A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014061714A1 (ja) * | 2012-10-18 | 2014-04-24 | 公益財団法人乙卯研究所 | ケイ素含有カルボン酸誘導体 |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023141364A1 (en) | 2022-01-24 | 2023-07-27 | The Regents Of The University Of California | Silyl-lipid n-acyl l-homoserine lactones as quorum sensing molecules |
WO2023146914A1 (en) | 2022-01-25 | 2023-08-03 | The Regents Of The University Of California | Silyl-lipid cannabinoids with enhanced biological activity |
US20230301912A1 (en) * | 2022-03-24 | 2023-09-28 | The Regents Of The University Of California | Silyl Lipids Suitable for Enhanced Delivery of Anti-Viral Therapeutics |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS4834166A (ja) * | 1971-09-08 | 1973-05-16 | ||
US5563175A (en) | 1990-11-27 | 1996-10-08 | Northwestern University | GABA and L-glutamic acid analogs for antiseizure treatment |
US5616798A (en) | 1991-02-25 | 1997-04-01 | Guerbet S.A. | Poly-iodinated compounds, process for their preparation, contrast medium containing them |
US5629447A (en) | 1995-06-02 | 1997-05-13 | Warner-Lambert Company | Methods of making (S)-3-(aminomethyl)-5-methylhexanoic acid |
US5637767A (en) | 1995-06-07 | 1997-06-10 | Warner-Lambert Company | Method of making (S)-3-(aminomethyl)-5-methylhexanoic acid |
WO2002100344A2 (en) | 2001-06-11 | 2002-12-19 | Xenoport, Inc. | Amino acid conjugates providing for sustained systemic concentrations of gaba analogues |
GB2397576A (en) | 2003-01-17 | 2004-07-28 | Amedis Pharm Ltd | Sila-cyclopentyl and sila-cyclohexyl analogues of gabapentin |
WO2010017498A1 (en) | 2008-08-07 | 2010-02-11 | Xenoport, Inc. | Methods of synthesizing n-hydroxysuccinimidyl carbonates |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2628245A (en) * | 1950-12-07 | 1953-02-10 | Dow Corning | Trialkylsilyladipic acid |
US2805237A (en) | 1955-03-28 | 1957-09-03 | Union Carbide Corp | Process for preparing triorgano (1, 4-dicarboxy-2-butyl) silanes |
JPS4834166Y1 (ja) | 1968-06-14 | 1973-10-16 | ||
JPH0834166A (ja) | 1994-07-22 | 1996-02-06 | Yoshitomi Pharmaceut Ind Ltd | 顕色剤組成物 |
-
2012
- 2012-04-19 US US14/112,087 patent/US8895769B2/en not_active Expired - Fee Related
- 2012-04-19 JP JP2012544982A patent/JP5230847B2/ja active Active
- 2012-04-19 WO PCT/JP2012/060552 patent/WO2012144551A1/ja active Application Filing
- 2012-04-19 EP EP12774607.1A patent/EP2700645A4/en not_active Withdrawn
-
2013
- 2013-03-14 JP JP2013051541A patent/JP2013151531A/ja not_active Withdrawn
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS4834166A (ja) * | 1971-09-08 | 1973-05-16 | ||
US5563175A (en) | 1990-11-27 | 1996-10-08 | Northwestern University | GABA and L-glutamic acid analogs for antiseizure treatment |
US5616798A (en) | 1991-02-25 | 1997-04-01 | Guerbet S.A. | Poly-iodinated compounds, process for their preparation, contrast medium containing them |
US5629447A (en) | 1995-06-02 | 1997-05-13 | Warner-Lambert Company | Methods of making (S)-3-(aminomethyl)-5-methylhexanoic acid |
US5637767A (en) | 1995-06-07 | 1997-06-10 | Warner-Lambert Company | Method of making (S)-3-(aminomethyl)-5-methylhexanoic acid |
US5840956A (en) | 1995-06-07 | 1998-11-24 | Warner-Lambert Company | Method of making (S)-3-(Aminomethyl)-5-Methylhexanoic acid |
WO2002100344A2 (en) | 2001-06-11 | 2002-12-19 | Xenoport, Inc. | Amino acid conjugates providing for sustained systemic concentrations of gaba analogues |
GB2397576A (en) | 2003-01-17 | 2004-07-28 | Amedis Pharm Ltd | Sila-cyclopentyl and sila-cyclohexyl analogues of gabapentin |
WO2010017498A1 (en) | 2008-08-07 | 2010-02-11 | Xenoport, Inc. | Methods of synthesizing n-hydroxysuccinimidyl carbonates |
Non-Patent Citations (8)
Title |
---|
BURGESS,K. ET AL.: "Optically Active Building Blocks from the SPAC Reaction: A Completely Asymmetric Synthesis of (4S-cis)-5- (Cyclohexylmethyl)-4-hydroxy-2-pyrrolidinone, a Statine Analogue", JOURNAL OF ORGANIC CHEMISTRY, vol. 56, no. 6, 1991, pages 2050 - 2058, XP003002762 * |
HELV. CHIM. ACTA, vol. 85, 2002, pages 4165 - 4181 |
J. ORG. CHEM., vol. 56, 1991, pages 4766 - 4772 |
JOURNAL OF ORGANOMETALLIC CHEMISTRY, vol. 690, 2005, pages 678 - 684 |
JOURNAL OF ORGANOMETALLIC CHEMISTRY, vol. 690, pages 678 - 684 |
See also references of EP2700645A4 * |
SUMAN-CHAUHAN ET AL., EUR. J. PHARMACOL, vol. 244, no. 3, 1993, pages 293 - 301 |
VERMA,R. ET AL.: "A silicon controlled total synthesis of the antifungal agent (+)-preussin", CHEMICAL COMMUNICATIONS, no. 17, 1997, pages 1601 - 1602, XP055134711 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014061714A1 (ja) * | 2012-10-18 | 2014-04-24 | 公益財団法人乙卯研究所 | ケイ素含有カルボン酸誘導体 |
JP5572783B1 (ja) * | 2012-10-18 | 2014-08-13 | 有限会社ケムフィズ | ケイ素含有カルボン酸誘導体 |
CN104781264A (zh) * | 2012-10-18 | 2015-07-15 | 有限会社肯菲思 | 含有硅的羧酸衍生物 |
US9353134B2 (en) | 2012-10-18 | 2016-05-31 | Kemphys Ltd. | Silicon-containing carboxylic acid derivative |
Also Published As
Publication number | Publication date |
---|---|
JPWO2012144551A1 (ja) | 2014-07-28 |
US8895769B2 (en) | 2014-11-25 |
EP2700645A4 (en) | 2014-09-24 |
JP2013151531A (ja) | 2013-08-08 |
EP2700645A1 (en) | 2014-02-26 |
JP5230847B2 (ja) | 2013-07-10 |
US20140031575A1 (en) | 2014-01-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4479974B2 (ja) | 二環性γ−アミノ酸誘導体 | |
AU758792B2 (en) | Vitamin D3 derivatives and remedies for inflammatory respiratory diseases containing the same | |
TW536534B (en) | Difluoroprostaglandin derivatives and pharmaceutical composition comprising them | |
JP5230847B2 (ja) | ケイ素含有カルボン酸誘導体 | |
TW200526567A (en) | Prostaglandin derivatives | |
AU2009354014B2 (en) | Process for the preparation of F-series prostaglandins | |
JP2010241796A (ja) | 二環性γ−アミノ酸誘導体含有医薬組成物 | |
WO2001012596A1 (fr) | Derives de prostaglandine | |
EP1082299B1 (en) | C11 oxymyl and hydroxylamino prostaglandins useful as medicaments | |
US8633335B2 (en) | Retinoid prodrug compound | |
JP2024016314A (ja) | 一般式(i-a)で示される化合物、その薬学的に許容される塩、またはそれらの水和物と免疫チェックポイント阻害薬および/またはep4受容体拮抗薬との組み合わせ | |
JP5284574B2 (ja) | レチノイドプロドラッグ化合物 | |
JP6643308B2 (ja) | プロスタグランジン及びプロスタグランジン類似体をもたらす2−置換−4−オキシ−シクロペント−2−エン−1−オンへのビニルホウ素化合物の金属触媒による非対称1,4−共役付加 | |
EA004984B1 (ru) | Способ стереоселективного синтеза циклических аминокислот | |
JP2011136905A (ja) | ベンゼン化合物及びその医薬用途 | |
CA2324590C (en) | C11 oxymyl and hydroxylamino prostaglandins useful as fp agonists | |
JP5572783B1 (ja) | ケイ素含有カルボン酸誘導体 | |
JP5284964B2 (ja) | 5員複素環化合物 | |
JP2015137253A (ja) | フッ素含有カルボン酸誘導体 | |
JP2012246301A (ja) | F系プロスタグランジン類を調製する方法 | |
JPH07238068A (ja) | プロスタグランジンe1類縁体 | |
JPH06247919A (ja) | 安息香酸誘導体およびその用途 | |
HUT63401A (en) | Process for producing prostagladin i2 derivatives and pharmaceutical compositions comprising such active ingredient | |
MXPA00009630A (en) | C11 oxymyl and hydroxylamino prostaglandins useful as medicaments | |
MXPA00009628A (en) | C11 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
ENP | Entry into the national phase |
Ref document number: 2012544982 Country of ref document: JP Kind code of ref document: A |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 12774607 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 14112087 Country of ref document: US |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2012774607 Country of ref document: EP |