JP5807006B2 - シクロアルキル基で置換されたイミダゾール誘導体 - Google Patents
シクロアルキル基で置換されたイミダゾール誘導体 Download PDFInfo
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- JP5807006B2 JP5807006B2 JP2012505676A JP2012505676A JP5807006B2 JP 5807006 B2 JP5807006 B2 JP 5807006B2 JP 2012505676 A JP2012505676 A JP 2012505676A JP 2012505676 A JP2012505676 A JP 2012505676A JP 5807006 B2 JP5807006 B2 JP 5807006B2
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- compound
- methyl
- embolism
- imidazol
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 23
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- PFFCLOFHTUNGHV-UHFFFAOYSA-N ethyl 1-(4-hydroxy-4-methylcyclohexyl)imidazole-4-carboxylate Chemical compound C1=NC(C(=O)OCC)=CN1C1CCC(C)(O)CC1 PFFCLOFHTUNGHV-UHFFFAOYSA-N 0.000 description 1
- KDTKSWSKHQIMLJ-UHFFFAOYSA-N ethyl 2-[(benzylamino)methyl]butanoate Chemical compound CCOC(=O)C(CC)CNCC1=CC=CC=C1 KDTKSWSKHQIMLJ-UHFFFAOYSA-N 0.000 description 1
- LLSDWDQGSHTVGW-UHFFFAOYSA-N ethyl 2-[[bis[(2-methylpropan-2-yl)oxycarbonyl]amino]methyl]butanoate Chemical compound CCOC(=O)C(CC)CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C LLSDWDQGSHTVGW-UHFFFAOYSA-N 0.000 description 1
- GYUCVQSNZFRDRL-UHFFFAOYSA-N ethyl 2-diethoxyphosphorylbutanoate Chemical compound CCOC(=O)C(CC)P(=O)(OCC)OCC GYUCVQSNZFRDRL-UHFFFAOYSA-N 0.000 description 1
- OUGJKAQEYOUGKG-UHFFFAOYSA-N ethyl 2-methylidenebutanoate Chemical compound CCOC(=O)C(=C)CC OUGJKAQEYOUGKG-UHFFFAOYSA-N 0.000 description 1
- NBEMQPLNBYYUAZ-UHFFFAOYSA-N ethyl acetate;propan-2-one Chemical compound CC(C)=O.CCOC(C)=O NBEMQPLNBYYUAZ-UHFFFAOYSA-N 0.000 description 1
- BLHLJVCOVBYQQS-UHFFFAOYSA-N ethyllithium Chemical compound [Li]CC BLHLJVCOVBYQQS-UHFFFAOYSA-N 0.000 description 1
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 1
- 125000004340 exo-2-norbornyl group Chemical group [H]C1([H])C([H])([H])[C@@]2([H])C([H])([H])[C@]1([H])C([H])([H])[C@]2([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 238000010575 fractional recrystallization Methods 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 239000002638 heterogeneous catalyst Substances 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- LXZAPTGWIXFPEX-UHFFFAOYSA-N iodomethyl ethylsulfanylformate Chemical compound CCSC(=O)OCI LXZAPTGWIXFPEX-UHFFFAOYSA-N 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 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
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 150000003951 lactams Chemical group 0.000 description 1
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- 150000002642 lithium compounds Chemical class 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- CCZVEWRRAVASGL-UHFFFAOYSA-N lithium;2-methanidylpropane Chemical compound [Li+].CC(C)[CH2-] CCZVEWRRAVASGL-UHFFFAOYSA-N 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- XBEREOHJDYAKDA-UHFFFAOYSA-N lithium;propane Chemical compound [Li+].CC[CH2-] XBEREOHJDYAKDA-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 150000002681 magnesium compounds Chemical class 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- DQDWATOXYCARFV-UHFFFAOYSA-M magnesium;2-methanidylpropane;bromide Chemical compound [Mg+2].[Br-].CC(C)[CH2-] DQDWATOXYCARFV-UHFFFAOYSA-M 0.000 description 1
- UKZCGMDMXDLAGZ-UHFFFAOYSA-M magnesium;2-methylpropane;bromide Chemical compound [Mg+2].[Br-].C[C-](C)C UKZCGMDMXDLAGZ-UHFFFAOYSA-M 0.000 description 1
- LWLPYZUDBNFNAH-UHFFFAOYSA-M magnesium;butane;bromide Chemical compound [Mg+2].[Br-].CCC[CH2-] LWLPYZUDBNFNAH-UHFFFAOYSA-M 0.000 description 1
- WSHFRLGXCNEKRX-UHFFFAOYSA-M magnesium;butane;bromide Chemical compound [Mg+2].[Br-].CC[CH-]C WSHFRLGXCNEKRX-UHFFFAOYSA-M 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- VXWPONVCMVLXBW-UHFFFAOYSA-M magnesium;carbanide;iodide Chemical compound [CH3-].[Mg+2].[I-] VXWPONVCMVLXBW-UHFFFAOYSA-M 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- LVKCSZQWLOVUGB-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].C[CH-]C LVKCSZQWLOVUGB-UHFFFAOYSA-M 0.000 description 1
- UGVPKMAWLOMPRS-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].CC[CH2-] UGVPKMAWLOMPRS-UHFFFAOYSA-M 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
- 239000001630 malic acid Substances 0.000 description 1
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- 239000003550 marker Substances 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
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- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 239000004200 microcrystalline wax Substances 0.000 description 1
- 235000019808 microcrystalline wax Nutrition 0.000 description 1
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- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 108700039855 mouse a Proteins 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 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
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- UWLFCNHEPBTLHT-UHFFFAOYSA-N neopentyllithium Chemical compound [Li]CC(C)(C)C UWLFCNHEPBTLHT-UHFFFAOYSA-N 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
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- 239000002674 ointment Substances 0.000 description 1
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- 125000002971 oxazolyl group Chemical group 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
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- 230000001575 pathological effect Effects 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
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- 235000021317 phosphate Nutrition 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
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- 230000036470 plasma concentration Effects 0.000 description 1
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- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 125000005592 polycycloalkyl group Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 230000002980 postoperative effect Effects 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
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 238000001144 powder X-ray diffraction data Methods 0.000 description 1
- DTGLZDAWLRGWQN-UHFFFAOYSA-N prasugrel Chemical compound C1CC=2SC(OC(=O)C)=CC=2CN1C(C=1C(=CC=CC=1)F)C(=O)C1CC1 DTGLZDAWLRGWQN-UHFFFAOYSA-N 0.000 description 1
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- 238000004237 preparative chromatography Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 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 1
- 239000001294 propane Substances 0.000 description 1
- FKRCODPIKNYEAC-UHFFFAOYSA-N propionic acid ethyl ester Natural products CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl 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
- 230000002285 radioactive effect Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000012419 sodium bis(2-methoxyethoxy)aluminum hydride Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 1
- 235000011067 sorbitan monolaureate Nutrition 0.000 description 1
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- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 229960005202 streptokinase Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000003459 sulfonic acid esters Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 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
- 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
- UPTAWHRIMOVUOS-UHFFFAOYSA-N tert-butyl 2-[(1-cyclohexylimidazol-4-yl)methyl]-5-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoate Chemical compound C1=NC(CC(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=CN1C1CCCCC1 UPTAWHRIMOVUOS-UHFFFAOYSA-N 0.000 description 1
- WQSVZIIDJBBGCF-UHFFFAOYSA-N tert-butyl 2-diethoxyphosphoryl-5-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoate Chemical compound CCOP(=O)(OCC)C(C(=O)OC(C)(C)C)CCCNC(=O)OC(C)(C)C WQSVZIIDJBBGCF-UHFFFAOYSA-N 0.000 description 1
- HJYNLENYMULSAS-UHFFFAOYSA-N tert-butyl 3-oxomorpholine-4-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCOCC1=O HJYNLENYMULSAS-UHFFFAOYSA-N 0.000 description 1
- YQGUMCOWQFEUDW-UHFFFAOYSA-N tert-butyl n-(4-phenoxycyclohexyl)carbamate Chemical compound C1CC(NC(=O)OC(C)(C)C)CCC1OC1=CC=CC=C1 YQGUMCOWQFEUDW-UHFFFAOYSA-N 0.000 description 1
- DQQJBEAXSOOCPG-ZETCQYMHSA-N tert-butyl n-[(3s)-pyrrolidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]1CCNC1 DQQJBEAXSOOCPG-ZETCQYMHSA-N 0.000 description 1
- KNSROTBVKXGNJD-UHFFFAOYSA-N tert-butyl n-[2-(hydroxymethyl)butyl]carbamate Chemical compound CCC(CO)CNC(=O)OC(C)(C)C KNSROTBVKXGNJD-UHFFFAOYSA-N 0.000 description 1
- 125000005942 tetrahydropyridyl group Chemical group 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 229960003279 thiopental Drugs 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- 229960005001 ticlopidine Drugs 0.000 description 1
- PHWBOXQYWZNQIN-UHFFFAOYSA-N ticlopidine Chemical compound ClC1=CC=CC=C1CN1CC(C=CS2)=C2CC1 PHWBOXQYWZNQIN-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
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- 238000005406 washing Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Description
(1)一般式(I)
(2)Aが、フルオロ基、水酸基、C1〜C6アルキル基、C1〜C6アルコキシ基、アリールオキシ基及びへテロシクリルオキシ基から選ばれる同一又は異なる1〜3個の基で置換されていてもよい、シクロブチル基、シクロヘキシル基、シクロヘプチル基、ビシクロ〔3.1.0〕ヘキシル基、ビシクロ〔2.2.1〕ヘプチル基又はアダマンチル基である、前記(1)に記載の化合物、又はその薬理上許容される塩、
(3)Aが、水酸基、メチル基及びエチル基から選ばれる同一又は異なる1〜3個の基で置換されていてもよい、シクロブチル基、シクロヘキシル基、シクロヘプチル基、ビシクロ〔3.1.0〕ヘキシル基、ビシクロ〔2.2.1〕ヘプチル又はアダマンチル基である、前記(1)に記載の化合物、又はその薬理上許容される塩、
(4)Aが、フルオロ基、水酸基、C1〜C6アルキル基、C1〜C6アルコキシ基、アリールオキシ基及びへテロシクリルオキシ基から選ばれる同一又は異なる1〜3個の基で置換されていてもよいシクロヘキシル基である、前記(1)に記載の化合物、又はその薬理上許容される塩、
(5)Aが、同一又は異なる1又は2個のC1〜C6アルキル基で置換されているC3〜C12シクロアルキル基である、前記(1)に記載の化合物、又はその薬理上許容される塩、
(6)Aが、メチル基又はエチル基で置換されているC3〜C12シクロアルキル基である、前記(1)に記載の化合物、又はその薬理上許容される塩、
(7)Aが、同一又は異なる1又は2個のC1〜C6アルキル基で置換されているシクロヘキシル基である、前記(1)に記載の化合物、又はその薬理上許容される塩、
(8)Aが、メチル基又はエチル基で置換されているシクロヘキシル基である、前記(1)に記載の化合物、又はその薬理上許容される塩、
(9)Aが、基
(10)Aが、基
(11)Aが、基
(12)Aが、基
(13)Yが基−CH2−CHR5−CH2−NHR6(ここで、R5は水素原子、C1〜C6アルキル基又はC1〜C6アルコキシ基を示し、R6は水素原子又はプロドラッグ基を示す。)である、前記(1)〜(12)のいずれか1項に記載の化合物、又はその薬理上許容される塩、
(14)R5が水素原子である、前記(13)に記載の化合物、又はその薬理上許容される塩、
(15)R6が水素原子である、前記(13)又は(14)に記載の化合物、又はその薬理上許容される塩、
(16)R6がプロドラッグ基である、前記(13)又は(14)に記載の化合物、又はその薬理上許容される塩、
(17)R6におけるプロドラッグ基が、アミノ基、ハロゲノ基、水酸基、カルボキシ基、カルバモイル基、C1〜C6アルコキシ基、アリール基及びへテロシクリル基から選ばれる同一又は異なる1〜3個の基で置換されていてもよいC1〜C6アルカノイル基、C1〜C6アルキル基、C2〜C6アルカノイルオキシ基、(C3〜C6シクロアルキル)カルボニルオキシ基及びアリール基から選ばれる同一又は異なる1〜3個の基で置換されていてもよい(C1〜C6アルコキシ)カルボニル基、又は、オキソ基及びC1〜C6アルキル基から選ばれる同一又は異なる1〜3個の基で置換されていてもよいヘテロシクリルアルキルオキシカルボニル基である、前記(16)に記載の化合物、又はその薬理上許容される塩、
(18)R6におけるプロドラッグ基が、フェニルアラニル基、L−ノルロイシル基、[(5−メチル−2−オキソ−1,3−ジオキソール−4−イル)メトキシ]カルボニル基、[1−(イソブチリルオキシ)エトキシ]カルボニル基、[1−(2,2−ジメチルプロパノイルオキシ)エトキシ]カルボニル基、({1−[(シクロヘキシルカルボニル)オキシ]エトキシ}カルボニル)基、又は、(1−アセトキシエトキシ)カルボニル基である、前記(16)に記載の化合物、又はその薬理上許容される塩、
(19)Yが基−O−CHR7−CH2−NHR8(ここで、R7は水素原子、C1〜C6アルキル基又はC1〜C6アルコキシ基を示し、R8は水素原子又はプロドラッグ基を示す。)である、前記(1)〜(12)のいずれか1項に記載の化合物、又はその薬理上許容される塩、
(20)R7が水素原子である、前記(19)に記載の化合物、又はその薬理上許容される塩、
(21)R8が水素原子である、前記(19)又は(20)に記載の化合物、又はその薬理上許容される塩、
(22)R8がプロドラッグ基である、前記(19)又は(20)に記載の化合物、又はその薬理上許容される塩、
(23)R8におけるプロドラッグ基が、アミノ基、ハロゲノ基、水酸基、カルボキシ基、カルバモイル基、C1〜C6アルコキシ基、アリール基及びへテロシクリル基から選ばれる同一又は異なる1〜3個の基で置換されていてもよいC1〜C6アルカノイル基、C1〜C6アルキル基、C2〜C6アルカノイルオキシ基、(C3〜C6シクロアルキル)カルボニルオキシ基及びアリール基から選ばれる同一又は異なる1〜3個の基で置換されていてもよい(C1〜C6アルコキシ)カルボニル基、又は、オキソ基及びC1〜C6アルキル基から選ばれる同一又は異なる1〜3個の基で置換されていてもよいヘテロシクリルアルキルオキシカルボニル基である、前記(22)に記載の化合物、又はその薬理上許容される塩、
(24)Yが基
(25)Yが基
(26)Yが基
(27)R1、R2及びR3がいずれも水素原子である、前記(1)〜(26)のいずれか1項に記載の化合物、又はその薬理上許容される塩、
(28)R4が水素原子である、前記(1)〜(27)のいずれか1項に記載の化合物、又はその薬理上許容される塩、
(29)R4がプロドラッグ基である、前記(1)〜(27)のいずれか1項に記載の化合物、又はその薬理上許容される塩、
(30)R4におけるプロドラッグ基が、C2〜C6アルカノイルオキシ基、(C3〜C6シクロアルキル)カルボニルオキシ基及びアリール基から選ばれる同一又は異なる1〜3個の基で置換されていてもよいC1〜C6アルキル基、又は、オキソ基及びC1〜C6アルキル基から選ばれる同一又は異なる1〜3個の基で置換されていてもよいヘテロシクリルアルキル基である、前記(29)に記載の化合物、又はその薬理上許容される塩、
(31)R4におけるプロドラッグ基が、ベンジル基又は[(イソプロポキシカルボニル)オキシ]エチル基である、前記(29)に記載の化合物、又はその薬理上許容される塩、
(32)一般式(I−1)
(33)Aが、水酸基、メチル基及びエチル基から選ばれる同一又は異なる1〜3個の基で置換されていてもよい、シクロブチル基、シクロヘキシル基、シクロヘプチル基、ビシクロ〔3.1.0〕ヘキシル基、ビシクロ〔2.2.1〕ヘプチル又はアダマンチル基であり、R1、R2及びR3がいずれも水素原子であり、R4が、水素原子、C2〜C6アルカノイルオキシ基、(C3〜C6シクロアルキル)カルボニルオキシ基及びアリール基から選ばれる同一又は異なる1〜3個の基で置換されていてもよいC1〜C6アルキル基、又は、オキソ基及びC1〜C6アルキル基から選ばれる同一又は異なる1〜3個の基で置換されていてもよいヘテロシクリルアルキル基であり、R5が水素原子であり、R6が、水素原子、アミノ基、ハロゲノ基、水酸基、カルボキシ基、カルバモイル基、C1〜C6アルコキシ基、アリール基及びへテロシクリル基から選ばれる同一又は異なる1〜3個の基で置換されていてもよいC1〜C6アルカノイル基、C1〜C6アルキル基、C2〜C6アルカノイルオキシ基、(C3〜C6シクロアルキル)カルボニルオキシ基及びアリール基から選ばれる同一又は異なる1〜3個の基で置換されていてもよい(C1〜C6アルコキシ)カルボニル基、又は、オキソ基及びC1〜C6アルキル基から選ばれる同一又は異なる1〜3個の基で置換されていてもよいヘテロシクリルアルキルオキシカルボニル基である、前記(32)に記載の化合物、又はその薬理上許容される塩、
(34)Aが、同一又は異なる1又は2個のC1〜C6アルキル基で置換されているシクロヘキシル基であり、R1、R2及びR3がいずれも水素原子であり、R4が、水素原子、ベンジル基又は[(イソプロポキシカルボニル)オキシ]エチル基であり、R5が水素原子であり、R6が、水素原子、フェニルアラニル基、L−ノルロイシル基、[(5−メチル−2−オキソ−1,3−ジオキソール−4−イル)メトキシ]カルボニル基、[1−(イソブチリルオキシ)エトキシ]カルボニル基、[1−(2,2−ジメチルプロパノイルオキシ)エトキシ]カルボニル基、({1−[(シクロヘキシルカルボニル)オキシ]エトキシ}カルボニル)基、又は、(1−アセトキシエトキシ)カルボニル基である、前記(32)に記載の化合物、又はその薬理上許容される塩、
(35)一般式(I−1a)
(36)Aが、同一又は異なる1又は2個のC1〜C6アルキル基で置換されているシクロヘキシル基であり、R1、R2及びR3がいずれも水素原子であり、R4が、水素原子、ベンジル基又は[(イソプロポキシカルボニル)オキシ]エチル基であり、R5が水素原子であり、R6が、水素原子、フェニルアラニル基、L−ノルロイシル基、[(5−メチル−2−オキソ−1,3−ジオキソール−4−イル)メトキシ]カルボニル基、[1−(イソブチリルオキシ)エトキシ]カルボニル基、[1−(2,2−ジメチルプロパノイルオキシ)エトキシ]カルボニル基、({1−[(シクロヘキシルカルボニル)オキシ]エトキシ}カルボニル)基、又は、(1−アセトキシエトキシ)カルボニル基である、前記(35)に記載の化合物、又はその薬理上許容される塩、
(37)Aが、メチル基又はエチル基で置換されているシクロヘキシル基であり、R4、R5及びR6がいずれも水素原子である、前記(35)に記載の化合物、又はその薬理上許容される塩、
(38)一般式(I−2)
(39)Aが、水酸基、メチル基及びエチル基から選ばれる同一又は異なる1〜3個の基で置換されていてもよい、シクロブチル基、シクロヘキシル基、シクロヘプチル基、ビシクロ〔3.1.0〕ヘキシル基、ビシクロ〔2.2.1〕ヘプチル又はアダマンチル基であり、R1、R2及びR3がいずれも水素原子であり、R4が、水素原子、C2〜C6アルカノイルオキシ基、(C3〜C6シクロアルキル)カルボニルオキシ基及びアリール基から選ばれる同一又は異なる1〜3個の基で置換されていてもよいC1〜C6アルキル基、又は、オキソ基及びC1〜C6アルキル基から選ばれる同一又は異なる1〜3個の基で置換されていてもよいヘテロシクリルアルキル基であり、R7が水素原子であり、R8が、水素原子、アミノ基、ハロゲノ基、水酸基、カルボキシ基、カルバモイル基、C1〜C6アルコキシ基、アリール基及びへテロシクリル基から選ばれる同一又は異なる1〜3個の基で置換されていてもよいC1〜C6アルカノイル基、C1〜C6アルキル基、C2〜C6アルカノイルオキシ基、(C3〜C6シクロアルキル)カルボニルオキシ基及びアリール基から選ばれる同一又は異なる1〜3個の基で置換されていてもよい(C1〜C6アルコキシ)カルボニル基、又は、オキソ基及びC1〜C6アルキル基から選ばれる同一又は異なる1〜3個の基で置換されていてもよいヘテロシクリルアルキルオキシカルボニル基である、前記(38)に記載の化合物、又はその薬理上許容される塩、
(40)Aが、同一又は異なる1又は2個のC1〜C6アルキル基で置換されているシクロヘキシル基であり、R1、R2及びR3がいずれも水素原子であり、R4が、水素原子、ベンジル基又は[(イソプロポキシカルボニル)オキシ]エチル基であり、R7及びR8がいずれも水素原子である、前記(38)に記載の化合物、又はその薬理上許容される塩、
(41)一般式(I−2a)
(42)Aが、同一又は異なる1又は2個のC1〜C6アルキル基で置換されているシクロヘキシル基であり、R1、R2及びR3がいずれも水素原子であり、R4が、水素原子、ベンジル基又は[(イソプロポキシカルボニル)オキシ]エチル基であり、R7が水素原子であり、R8が、水素原子、アミノ基、ハロゲノ基、水酸基、カルボキシ基、カルバモイル基、C1〜C6アルコキシ基、アリール基及びへテロシクリル基から選ばれる同一又は異なる1〜3個の基で置換されていてもよいC1〜C6アルカノイル基、C1〜C6アルキル基、C2〜C6アルカノイルオキシ基、(C3〜C6シクロアルキル)カルボニルオキシ基及びアリール基から選ばれる同一又は異なる1〜3個の基で置換されていてもよい(C1〜C6アルコキシ)カルボニル基、又は、オキソ基及びC1〜C6アルキル基から選ばれる同一又は異なる1〜3個の基で置換されていてもよいヘテロシクリルアルキルオキシカルボニル基である、前記(41)に記載の化合物、又はその薬理上許容される塩、
(43)Aが、メチル基又はエチル基で置換されているシクロヘキシル基であり、R4、R7及びR8がいずれも水素原子である、前記(41)に記載の化合物、又はその薬理上許容される塩、
(44)一般式(I−3)
(45)Aが、水酸基、メチル基及びエチル基から選ばれる同一又は異なる1〜3個の基で置換されていてもよい、シクロブチル基、シクロヘキシル基、シクロヘプチル基、ビシクロ〔3.1.0〕ヘキシル基、ビシクロ〔2.2.1〕ヘプチル又はアダマンチル基であり、R1、R2及びR3がいずれも水素原子であり、R4が、水素原子、C2〜C6アルカノイルオキシ基、(C3〜C6シクロアルキル)カルボニルオキシ基及びアリール基から選ばれる同一又は異なる1〜3個の基で置換されていてもよいC1〜C6アルキル基、又は、オキソ基及びC1〜C6アルキル基から選ばれる同一又は異なる1〜3個の基で置換されていてもよいヘテロシクリルアルキル基であり、R9が、水素原子、アミノ基、ハロゲノ基、水酸基、カルボキシ基、カルバモイル基、C1〜C6アルコキシ基、アリール基及びへテロシクリル基から選ばれる同一又は異なる1〜3個の基で置換されていてもよいC1〜C6アルカノイル基、C1〜C6アルキル基、C2〜C6アルカノイルオキシ基、(C3〜C6シクロアルキル)カルボニルオキシ基及びアリール基から選ばれる同一又は異なる1〜3個の基で置換されていてもよい(C1〜C6アルコキシ)カルボニル基、又は、オキソ基及びC1〜C6アルキル基から選ばれる同一又は異なる1〜3個の基で置換されていてもよいヘテロシクリルアルキルオキシカルボニル基である、前記(44)に記載の化合物、又はその薬理上許容される塩、
(46)Aが、同一又は異なる1又は2個のC1〜C6アルキル基で置換されているシクロヘキシル基であり、R1、R2及びR3がいずれも水素原子であり、R4が、水素原子、ベンジル基又は[(イソプロポキシカルボニル)オキシ]エチル基であり、R9が水素原子である、前記(44)に記載の化合物、又はその薬理上許容される塩、
(47)一般式(I−3a)
(48)Aが、同一又は異なる1又は2個のC1〜C6アルキル基で置換されているシクロヘキシル基であり、R4が、水素原子、ベンジル基又は[(イソプロポキシカルボニル)オキシ]エチル基である、前記(47)に記載の化合物、又はその薬理上許容される塩、
(49)Aが、メチル基又はエチル基で置換されているシクロヘキシル基であり、R4が水素原子である、前記(48)に記載の化合物、又はその薬理上許容される塩、
(50)5−アミノ−2−[(1−シクロヘキシル−1H−イミダゾール−4−イル)メチル]吉草酸、
5−アミノ−2−{[1−(4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸、
5−アミノ−2−{[1−(4−エチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸、
5−アミノ−2−{[1−(3−エチルシクロブチル)−1H−イミダゾール−4−イル]メチル}吉草酸、
5−アミノ−2−{[1−(3−メチルシクロブチル)−1H−イミダゾール−4−イル]メチル}吉草酸、
5−アミノ−2−({1−[(1R,3s,5S)−ビシクロ[3.1.0]ヘキサ−3−イル]−1H−イミダゾール−4−イル}メチル)吉草酸、
5−アミノ−2−{[1−(4−ヒドロキシシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸、
5−アミノ−2−{[1−(4−ヒドロキシ−4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸、
5−アミノ−2−{[1−(3−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸、
5−アミノ−2−[(1−シクロヘプチル−1H−イミダゾール−4−イル)メチル]吉草酸、
5−アミノ−2−({1−[exo−ビシクロ[2.2.1]ヘプト−2−イル]−1H−イミダゾール−4−イル}メチル)吉草酸、
5−アミノ−2−({1−[endo−ビシクロ[2.2.1]ヘプト−2−イル]−1H−イミダゾール−4−イル}メチル)吉草酸、
2−[(1−アダマンタン−2−イル−1H−イミダゾール−4−イル)メチル]−5−アミノ吉草酸、
5−アミノ−2−{[1−(4−フェノキシシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸、
5−アミノ−2−{[1−(4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸ベンジル、
2−{[1−(4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}−5−(L−フェニルアラニルアミノ)吉草酸、
2−{[1−(4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}−5−(L−ノルロイシルアミノ)吉草酸、
2−{[1−(4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}−5−({[(5−メチル−2−オキソ−1,3−ジオキソール−4−イル)メトキシ]カルボニル}アミノ)吉草酸、
5−({[1−(イソブチリルオキシ)エトキシ]カルボニル}アミノ)−2−{[1−(4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸、
5−({[1−(イソブチリルオキシ)エトキシ]カルボニル}アミノ)−2−{[1−(4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸1−[(イソプロポキシカルボニル)オキシ]エチル、
5−({[1−(2,2−ジメチルプロパノイルオキシ)エトキシ]カルボニル}アミノ)−2−{[1−(4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸、
5−[({1−[(シクロヘキシルカルボニル)オキシ]エトキシ}カルボニル)アミノ]−2−{[1−(4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸、
2−(2−アミノエトキシ)−3−[1−(4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]プロピオン酸、
2−[(1R)−2−アミノ−1−メチルエトキシ]−3−[1−(4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]プロピオン酸、及び、
2−[(3S)−3−アミノピロリジン−1−イル]−3−[1−(4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]プロピオン酸からなる群より選ばれる前記(1)に記載の化合物、又はその薬理上許容される塩、
(51)5−アミノ−2−{[1−(4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸、又はその薬理上許容される塩、
(52)5−アミノ−2−{[1−(トランス−4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸、又はその薬理上許容される塩、
(53)(2S)−5−アミノ−2−{[1−(トランス−4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸、又はその薬理上許容される塩、
(54)薬理上許容される塩が、p−トルエンスルホン酸塩又はベンゼンスルホン酸塩である、前記(1)〜(53)のいずれか1項に記載の化合物の薬理上許容される塩、
(55)(2S)−5−アミノ−2−{[1−(トランス−4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸、
(56)(2S)−5−アミノ−2−{[1−(トランス−4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸・ベンゼンスルホン酸塩、
(57)(2S)−5−アミノ−2−{[1−(トランス−4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸・p−トルエンスルホン酸塩、
(58)(2S)−5−アミノ−2−{[1−(トランス−4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸・p−トルエンスルホン酸塩・無水物、
(59)銅のKα線の照射で得られる粉末X線回折において、面間隔d=23.9、11.9、4.5、4.3及び3.6オングストロームに主要なピークを示す結晶である(58)に記載の(2S)−5−アミノ−2−{[1−(トランス−4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸・p−トルエンスルホン酸塩・無水物、
(60)(2S)−5−アミノ−2−{[1−(トランス−4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸・p−トルエンスルホン酸塩・一水和物、
(61)銅のKα線の照射で得られる粉末X線回折において、面間隔d=22.9、5.0、4.9、4.7及び4.0オングストロームに主要なピークを示す結晶である(60)に記載の(2S)−5−アミノ−2−{[1−(トランス−4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸・p−トルエンスルホン酸塩・一水和物、
(62)前記(1)〜(61)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する医薬、
(63)前記(1)〜(61)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有するTAFIa阻害薬、
(64)前記(1)〜(61)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する線溶促進剤、
(65)前記(1)〜(61)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、線溶が阻害されることにより引き起こされる疾患の予防薬若しくは治療薬、
(66)前記(1)〜(61)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、心筋梗塞、狭心症(安定狭心症、不安定狭心症)などの急性冠症候群;深部静脈血栓症、肺塞栓症などの静脈血栓塞栓症;血管再開通術、血管形成術、ステント留置術、バイパス出術などの外科的手術後の心臓血管系に起こる血栓症若しくは塞栓症;膝関節置換手術、股関節置換手術などの人工関節置換手術後の血栓症若しくは塞栓症;敗血症、播種性血管内凝固症候群(DIC)のような炎症に関連する血管内の疾患;末梢動脈塞栓症(PAO)、動脈硬化、糖尿病などの末梢血管障害に由来・関連する疾患;固形癌、血液癌などの腫瘍に関連する疾患;又は、肺塞栓、脳梗塞、腎梗塞などの血栓・塞栓に起因する臓器の障害のような血栓症・塞栓症及びそれらの後遺症の予防薬若しくは治療薬、
(67)前記(1)〜(61)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、関節置換術時の人工関節、血管カテーテル、人工血管、血管ステント、人工弁などの医療機器のような体内の異物との接触によって起こる疾患;又は、心臓手術時の人工心肺装置、血液透析時の医療器具などの体外の医療器具と血液が接触することによって起こる疾患のような血栓症・塞栓症の予防薬若しくは治療薬、
(68)前記(1)〜(61)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、肺高血圧症、成人呼吸切迫症候群、肺線維症、慢性血栓塞栓性肺高血圧症などの肺の疾患;糸球体腎炎(急性糸球体腎炎、慢性糸球体腎炎、ネフローゼ性腎炎、急性進行性糸球体腎炎など)、腎臓梗塞、糖尿病性腎炎などの腎臓の疾患;肝線維症、肝炎、肝硬変などの肝臓の疾患;眼部フィブリン沈着に伴う眼部の疾患;臓器移植又は切除術後の臓器機能障害;血栓性微小血管症を始めとする微小血栓による微小循環障害;又は、癌細胞の遊走・転移に伴う疾患・症状のような血栓・塞栓症に関連する又はフィブリン沈着若しくは線維化を伴う疾患の予防薬若しくは治療薬、
(69)前記(1)〜(61)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、心筋梗塞、狭心症、急性冠不全症候群、脳梗塞、深部静脈血栓症、肺塞栓症、末梢動脈塞栓症、敗血症、播種性血管内凝固症候群又は肺線維症の治療薬、
(70)前記(1)〜(61)のいずれか1項に記載の化合物又はその薬理上許容される塩及び薬理上許容される担体を含有する医薬組成物、
(71)前記(1)〜(61)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物を投与することによる、心筋梗塞、狭心症、急性冠不全症候群、脳梗塞、深部静脈血栓症、肺塞栓症、末梢動脈塞栓症、敗血症、播種性血管内凝固症候群又は肺線維症の治療方法、
(72)心筋梗塞、狭心症、急性冠不全症候群、脳梗塞、深部静脈血栓症、肺塞栓症、末梢動脈塞栓症、敗血症、播種性血管内凝固症候群又は肺線維症の治療における使用のための前記(1)〜(61)のいずれか1項に記載の化合物又はその薬理上許容される塩、
(73)前記(1)〜(61)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する注射用医薬、
(74)前記(1)〜(61)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する注射用TAFIa阻害薬、
(75)前記(1)〜(61)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、心筋梗塞、狭心症、急性冠不全症候群、脳梗塞、深部静脈血栓症、肺塞栓症、末梢動脈塞栓症、敗血症、播種性血管内凝固症候群又は肺線維症の注射用治療薬、
(76)前記(1)〜(61)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、血栓塞栓症に由来する疾患の注射用治療薬、
(77)前記(1)〜(61)のいずれか1項に記載の化合物又はその薬理上許容される塩及び薬理上許容される担体を含有する注射用医薬組成物、
(78)前記(1)〜(61)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する注射用医薬組成物を投与することによる、心筋梗塞、狭心症、急性冠不全症候群、脳梗塞、深部静脈血栓症、肺塞栓症、末梢動脈塞栓症、敗血症、播種性血管内凝固症候群又は肺線維症の治療方法、
(79)心筋梗塞、狭心症、急性冠不全症候群、脳梗塞、深部静脈血栓症、肺塞栓症、末梢動脈塞栓症、敗血症、播種性血管内凝固症候群又は肺線維症の注射での治療における使用のための前記(1)〜(61)のいずれか1項に記載の化合物又はその薬理上許容される塩、並びに、
(80)前記(1)〜(61)のいずれか1項に記載の化合物又はその薬理上許容される塩、並びに、抗凝固薬、抗血小板薬、線溶に関わる酵素、抗癌薬、抗炎症薬、抗線維化薬、降圧薬、抗肺高血圧薬及び免疫抑制薬から選ばれる1種又は2種以上の薬剤を有効成分として含有する医薬組成物を提供するものである。
(81)一般式
で表される化合物又はその塩、
(82)一般式
で表される化合物又はその塩、
(83)一般式
で表される化合物又はその塩、
を提供するものである。
5−アミノ−2−[(1−シクロヘキシル−1H−イミダゾール−4−イル)メチル]吉草酸、
5−アミノ−2−{[1−(4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸、
5−アミノ−2−{[1−(4−エチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸、
5−アミノ−2−{[1−(3−エチルシクロブチル)−1H−イミダゾール−4−イル]メチル}吉草酸、
5−アミノ−2−{[1−(3−メチルシクロブチル)−1H−イミダゾール−4−イル]メチル}吉草酸、
5−アミノ−2−({1−[(1R,3s,5S)−ビシクロ[3.1.0]ヘキサ−3−イル]−1H−イミダゾール−4−イル}メチル)吉草酸、
5−アミノ−2−{[1−(4−ヒドロキシシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸、
5−アミノ−2−{[1−(4−ヒドロキシ−4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸、
5−アミノ−2−{[1−(3−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸、
5−アミノ−2−[(1−シクロヘプチル−1H−イミダゾール−4−イル)メチル]吉草酸、
5−アミノ−2−({1−[exo−ビシクロ[2.2.1]ヘプト−2−イル]−1H−イミダゾール−4−イル}メチル)吉草酸、
5−アミノ−2−({1−[endo−ビシクロ[2.2.1]ヘプト−2−イル]−1H−イミダゾール−4−イル}メチル)吉草酸、
2−[(1−アダマンタン−2−イル−1H−イミダゾール−4−イル)メチル]−5−アミノ吉草酸、
5−アミノ−2−{[1−(4−フェノキシシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸、
5−アミノ−2−{[1−(4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸ベンジル、
2−{[1−(4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}−5−(L−フェニルアラニルアミノ)吉草酸、
2−{[1−(4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}−5−(L−ノルロイシルアミノ)吉草酸、
2−{[1−(4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}−5−({[(5−メチル−2−オキソ−1,3−ジオキソール−4−イル)メトキシ]カルボニル}アミノ)吉草酸、
5−({[1−(イソブチリルオキシ)エトキシ]カルボニル}アミノ)−2−{[1−(4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸、
5−({[1−(イソブチリルオキシ)エトキシ]カルボニル}アミノ)−2−{[1−(4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸1−[(イソプロポキシカルボニル)オキシ]エチル、
5−({[1−(2,2−ジメチルプロパノイルオキシ)エトキシ]カルボニル}アミノ)−2−{[1−(4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸、
5−[({1−[(シクロヘキシルカルボニル)オキシ]エトキシ}カルボニル)アミノ]−2−{[1−(4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸、
2−(2−アミノエトキシ)−3−[1−(4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]プロピオン酸、
2−[(1R)−2−アミノ−1−メチルエトキシ]−3−[1−(4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]プロピオン酸、及び、
2−[(3S)−3−アミノピロリジン−1−イル]−3−[1−(4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]プロピオン酸。
一般式(I)で表される化合物、その塩、それらの溶媒和物は、例えば下記の方法で製造することができる。
本製造方法により化合物(II)のイミダゾール部分の窒素原子をシクロアルキル化することによって化合物(III)を製造し、さらに化合物(III)の保護基を除去することで化合物(Ia)を製造することができる。
本発明の化合物(I)は、下記の方法でも製造することができる。
化合物(IV)を出発原料に、Knoevenagel縮合又はWittig反応により化合物(VIIa)及び/又は(VIIb)を合成することができる。得られた化合物(VIIa)及び/又は(VIIb)のオレフィンを還元することで化合物(VIII)を合成し、化合物(VIII)の保護基を除去することで化合物(Ib)を製造することができる。
本発明の化合物(I)は、下記の方法でも製造することができる。
化合物(IV)と化合物(IX)をアルドール反応、及び脱水反応により化合物(Xa)及び/又は(Xb)を製造することができる。得られた化合物(Xa)及び/又は(Xb)のオレフィンを還元することで化合物(XI)を合成し、化合物(XI)を加水分解することで化合物(Ic)を製造することができる。
本発明の化合物(I)は、下記の方法でも製造することができる。
化合物(XII)をブロモ化することにより化合物(XIII)を合成し、化合物(XIII)をアルキル化剤として、化合物(XIV)をアルキル化することによって化合物(XV)を合成することができる。得られた化合物(XV)の保護基を除去することで化合物(Id)を製造することができる。
本発明化合物の中間体である化合物(IV)は、例えば下記の方法で製造することができる。
市販、又は周知の方法を利用して合成される化合物(XVI)を、化合物(XVII)(Liebigs Annalen der Chemie、1979年、1444頁)と反応させることによってイミダゾール環を構築し、化合物(XVIII)が合成できる。下記の文献を参考に製造することが可能である。Org.Lett.2002年,4巻,4133頁。
本発明の化合物(I)のうち、プロドラッグ基を導入した化合物は、下記の方法で製造することができる。
製造方法1で得られる化合物(III)のアミノ基の保護基を除去し、化合物(XX)を得ることができる。化合物(XX)のアミノ基をプロドラッグ化することで化合物(XXI)を合成し、化合物(XXI)のカルボキシ基の保護基を除去することで、プロドラッグ体である化合物(Ie)を製造することができる。
本発明の化合物(I)のうち、プロドラッグ基を導入した化合物は、下記の方法で製造することができる。
製造方法1で得られた化合物(III)のカルボキシ基の保護基を除去して、化合物(XXII)が製造できる。続いて、化合物(XXII)のカルボキシ基にプロドラッグ基を導入し、アミノ基の保護基を除去することで、プロドラッグ体である化合物(Ig)を製造することができる。
本発明の化合物(I)のうち、プロドラッグ基を導入した化合物は、下記の方法で製造することができる。
製造方法6又は7と同様の方法で、化合物(Ic)、化合物(XXIV)、化合物(Id)及び化合物(XXV)から、プロドラッグ体である化合物(Ih)又は化合物(Ii)を製造することができる。
アルキル化反応は、マロン酸ジエステル(XXVI)を、塩基存在下、市販又は周知の反応により製造できる化合物(XXVII)を用いてアルキル化する反応である。塩基としては、例えば、炭酸ナトリウム、炭酸カリウム、ナトリウムエトキシド、カリウムブトキシド、水酸化ナトリウム、水酸化カリウムのようなアルカリ金属水酸化物;水素化ナトリウム、水素化カリウムのようなアルカリ金属水素化物;アルカリ金属若しくはアルカリ土類金属の炭酸塩;アルカリ金属アルコキシド;又は、n−ブチルリチウムのようなアルキルリチウム、リチウムジイソプロピルアミドのようなジアルキルアミノリチウム、リチウムヘキサメチルジシラジドのようなビスシリルアミンのアルカリ金属塩のような有機金属塩基などを使用することができる。さらに、LG3としては塩素、臭素、ヨウ素などのハロゲン原子;又は、メシレート、トシレート、若しくは、トリフレートのようなアルキルスルホニルオキシ基若しくはアリールスルホニルオキシ基などを挙げることができる。
化合物(XIIa)と化合物(XXIX)をアルドール反応させることにより、化合物(XXX)を製造し、得られた化合物(XXX)を脱水反応させることで化合物(XXXI)を製造することができる。続いて、オレフィン部分を還元、及び保護基を除去することで、化合物(Ij)を製造することができる。
CD3OD:重メタノール、
Me:メチル基、
Et:エチル基、
tBu:tert−ブチル基、
Boc:tert−ブトキシカルボニル基、
Cbz:(ベンジルオキシ)カルボニル基、
TBDMS:tert−ブチル(ジメチル)シリル基、
TBDPS:tert−ブチル(ジフェニル)シリル基。
1H-NMR (CDCl3) δ: 1.31-1.36 (6H, m), 1.44 (9H, m), 1.48 (9H, m), 1.51-1.59 (2H, m), 1.78-2.00 (2H, m), 2.83 (1H, ddd, J = 22.9, 10.7, 4.4 Hz), 3.06-3.18 (2H, m), 4.10-4.18 (4H, m), 4.58 (1H, br)。
1H-NMR (CDCl3) δ: 1.41 (9H, s), 1.44 (9H, s), 1.48-1.57 (3H, m), 1.57-1.66 (1H, m), 2.58-2.68 (1H, m), 2.73 (1H, dd, J = 14.7, 5.3 Hz), 2.89 (1H, dd, J = 14.7, 8.4 Hz), 3.02-3.19 (2H, m), 4.67 (1H, br s), 6.79 (1H, s), 7.54 (1H, s)。
1H-NMR (CDCl3) δ: 1.44 (9H, m), 1.50-1.60 (2H, m), 1.86-2.01 (2H, m), 3.07-3.20 (2H, m), 3.43 (1H, m), 3.77 (3H, s), 4.64 (1H, br)。
[工程1]1−(trans−4−メチルシクロヘキシル)−1H−イミダゾール−4−カルボン酸エチル
1H-NMR (CDCl3) δ: 0.96 (3H, d, J = 6.6 Hz), 1.13 (2H, m), 1.39 (3H, d, J = 7.0 Hz), 1.47 (1H, m), 1.68 (2H, m), 1.88 (2H, m), 2.12 (2H, m), 3.91 (1H, tt, J = 12.1, 3.9 Hz), 4.36 (2H, q, J = 7.0 Hz), 7.54 (1H, s), 7.66 (1H, s)。
1H-NMR (CDCl3) δ: 0.95 (3H, d, J = 6.6 Hz), 1.04-1.17 (2H, m), 1.44 (1H, m), 1.59-1.73 (2H, m), 1.81-1.89 (2H, m), 2.04-2.13 (2H, m), 2.78 (1H, br), 3.84 (1H, tt, J = 12.1, 3.9 Hz), 4.59 (2H, s), 6.91 (1H, s), 7.49 (1H, s)。
1H-NMR (CDCl3) δ: 0.97 (3H, d, J = 6.8 Hz), 1.09-1.19 (2H, m), 1.48 (1H, m), 1.65-1.75 (2H, m), 1.87-1.93 (2H, m), 2.11-2.18 (2H, m), 3.95 (1H, tt, J = 12.2, 3.9 Hz), 7.62 (1H, s), 7.68 (1H, s), 9.87 (1H, s)。
[工程1][1−(4−エチルシクロヘキシル)−1H−イミダゾール−4−イル]メタノール
1H-NMR (CDCl3) δ: 0.91 (0.6H, t, J = 7.0 Hz), 0.92 (2.4H, t, J = 7.0 Hz), 1.01-1.13 (1.6H, m), 1.16-1.40 (2.8H, m), 1.50-1.97 (5H, m), 2.07-2.15 (1.6H, m), 3.85 (0.8H, tt, J = 12.1, 3.9 Hz), 3.99 (0.2H, tt, J = 8.6, 4.3 Hz), 4.59 (1.6H, s), 4.60 (0.4H, s), 6.91 (0.8H, s), 6.94 (0.2H, s), 7.49 (0.8H, s), 7.53 (0.2H, s)。
1H-NMR (CDCl3) δ: 0.92 (3H, t, J = 7.0 Hz), 1.10 (2H, m), 1.19-1.34 (3H, m), 1.68 (2H, m), 1.97 (2H, m), 2.17 (2H, m), 3.95 (1H, tt, J = 12.1, 3.5 Hz), 7.62 (1H, s), 7.69 (1H, s), 9.87 (1H, s)。
[工程1](3−エチルシクロブチル)カルバミン酸ベンジル
1H-NMR (CDCl3) δ: 0.78 (1.5H, t, J = 7.4 Hz), 0.81 (1.5H, t, J = 7.4 Hz), 1.38 (1H, dq, J = 7.4, 7.4 Hz), 1.46 (1H, dq, J = 7.4, 7.4 Hz), 1.31-1.42 (2H, m), 1.89-2.03 (2H, m), 2.41-2.54 (1H, m), 4.00 (0.5H, m), 4.23 (0.5H, m), 4.75-4.90 (1H, br), 5.06 (2H, s), 7.22-7.40 (5H, m)。
1H-NMR (CDCl3) δ: 0.86 (1.5H, t, J = 7.4 Hz), 0.90 (1.5H, t, J = 7.4 Hz), 1.48 (1H, dq, J = 7.4, 7.4 Hz), 1.56 (1H, dq, J = 7.4, 7.4 Hz), 1.84-1.93 (1H, m), 1.96-2.08 (0.5H, m), 2.20-2.32 (1.5H, m), 2.39-2.49 (1H, m), 2.59-2.67 (1H, m), 4.38 (0.5H, tt, J = 9.4, 7.8 Hz), 4.59 (1H, s), 4.60 (1H, s), 4.63 (0.5H, tt, J = 7.8, 7.4 Hz), 6.93 (0.5H, s), 6.98 (0.5H, s), 7.46 (0.5H, s), 7.49 (0.5H, s)。
1H-NMR (CDCl3) δ: 0.86 (1.5H, t, J = 7.3 Hz), 0.90 (1.5H, t, J = 7.3 Hz), 1.44 (9H, s), 1.51 (1H, dq, J = 7.4, 7.4 Hz), 1.59 (1H, dq, J = 7.4, 7.4 Hz), 1.87-1.97 (1H, m), 2.04-2.13 (0.5H, m), 2.28-2.38 (1.5H, m), 2.42-2.52 (1H, m), 2.66-2.75 (1H, m), 4.48 (0.5H, tt, J = 9.0, 7.8 Hz), 4.72 (0.5H, tt, J = 7.8, 7.4 Hz), 7.58 (0.5H, s), 7.61 (0.5H, s), 7.69 (0.5H, s), 7.74 (0.5H, s), 9.87 (0.5H, s), 9.88 (0.5H, s)。
1H-NMR (CDCl3) δ: 1.18 (1.5H, d, J = 6.6 Hz), 1.27 (1.5H, d, J = 6.6 Hz), 1.93 (1H, m), 2.22-2.32 (1.5H, m), 2.46-2.60 (1.5H, m), 2.74 (1H, m), 4.46 (0.5H, tt, J = 9.4, 7.4 Hz), 4.79 (0.5H, tt, J = 7.8, 7.4 Hz), 7.58 (0.5H, s), 7.61 (0.5H, s), 7.70 (0.5H, s), 7.73 (0.5H, s), 9.87 (0.5H, s), 9.88 (0.5H, s)。
[工程1][1−(trans−4−{[tert−ブチル(ジメチル)シリル]オキシ}シクロヘキシル)−1H−イミダゾール−4−イル]メタノール
1H-NMR (CD3OD) δ: 0.09 (6H, s), 0.90 (9H, s), 1.50 (2H, m), 1.81 (2H, m), 1.96-2.10 (4H, m), 3.76 (1H, m), 4.05 (1H, m), 4.48 (2H, s), 7.12 (1H, s), 7.64 (1H, s)。
1H-NMR (CDCl3) δ: 0.08 (6H, s), 0.90 (9H, s), 1.52 (2H, m), 1.75 (2H, m), 2.02 (2H, m), 2.16 (2H, m), 3.68 (1H, m), 4.00 (1H, m), 7.62 (1H, s), 7.67 (1H, s), 9.87 (1H, s)。
1H-NMR (CDCl3) δ: 1.52 (2H, m), 1.78 (2H, m), 2.11-2.25 (4H, m), 3.76 (1H, m), 4.03 (1H, m), 7.63 (1H, s), 7.68 (1H, s), 9.87 (1H, s)。
[工程1](4−ヒドロキシ−4−メチルシクロヘキシル)カルバミン酸ベンジル
1H-NMR (CDCl3) δ: 1.23 (3H, s), 1.44-1.67 (6H, m), 1.81 (2H, m), 3.48 (1H, m), 4.65 (1H, m), 5.08 (2H, s), 7.29-7.41 (5H, m)。
1H-NMR (CDCl3) δ: 1.31 (2.25H, s), 1.34 (0.75H, s), 1.38 (3H, t, J = 7.0 Hz), 1.52-1.70 (2H, m), 1.77-1.96 (4H, m), 2.08-2.19 (2H, m), 3.93 (0.75H, tt, J = 12.2, 3.9 Hz), 4.06 (0.25H, m), 4.12 (0.5H, q, J = 7.0 Hz), 4.36 (1.5H, q, J = 7.0 Hz), 7.57 (1H, s), 7.68 (0.25H, s), 7.70 (0.75H, s)。
1H-NMR (CDCl3) δ: 1.32 (2.25H, s), 1.36 (0.75H, s), 1.54-1.73 (2H, m), 1.78-2.00 (4H, m), 2.11-2.23 (2H, m), 3.97 (0.75H, tt, J = 12.2, 3.9 Hz), 4.10 (0.25H, m), 7.66 (1H, s), 7.72 (0.25H, s), 7.75 (0.75H, s), 9.86 (0.75H, s), 9.87 (0.25H, s)。
[工程1]1−[exo−ビシクロ[2.2.1]ヘプト−2−イル]−1H−イミダゾール−4−カルボン酸エチル
1H-NMR (CDCl3) δ: 1.22-1.37 (3H, m), 1.38 (3H, t, J = 7.1 Hz), 1.56-1.65 (2H, m), 1.65-1.73 (1H, m), 1.75-1.82 (1H, m), 1.97-2.04 (1H, m), 2.48 (1H, m), 2.52-2.55 (1H, m), 4.04-4.09 (1H, m), 4.37 (2H, q, J = 7.1 Hz), 7.57 (1H, s), 7.67 (1H, s)。
1H-NMR (CDCl3) δ: 1.23-1.41 (3H, m), 1.56-1.66 (2H, m), 1.67-1.75 (1H, m), 1.75-1.82 (1H, m), 2.01-2.07 (1H, m), 2.49 (1H, m), 2.53-2.57 (1H, m), 4.08-4.12 (1H, m), 7.63 (1H, s), 7.69 (1H, s), 9.87 (1H, s)。
[工程1]1−[endo−ビシクロ[2.2.1]ヘプト−2−イル]−1H−イミダゾール−4−カルボン酸エチル
1H-NMR (CDCl3) δ: 1.19-1.71 (7H, m), 1.40 (3H, t, J = 7.1 Hz), 2.19-2.27 (1H, m), 2.42 (1H, m), 2.60 (1H, m), 4.38 (2H, q, J = 7.1 Hz), 4.44-4.49 (1H, m), 7.54 (1H, s), 7.65 (1H, s)。
1H-NMR (CDCl3) δ: 1.18-1.25 (1H, m), 1.30-1.37 (1H, m), 1.44-1.73 (5H, m), 2.22-2.30 (1H, m), 2.45 (1H, m), 2.62 (1H, m), 4.47-4.53 (1H, m), 7.61 (1H, s), 7.68 (1H, s), 9.89 (1H, s)。
[工程1]1−アダマンタン−2−イル−1H−イミダゾール−4−カルボン酸エチル
1H-NMR (CDCl3) δ: 1.40 (3H, t, J = 7.2 Hz), 1.61-2.08 (12H, m), 2.52 (2H, m), 4.20 (1H, m), 4.38 (2H, q, J = 7.2 Hz), 7.67 (1H, s), 7.76 (1H, s)。
1H-NMR (CDCl3) δ: 1.49-2.10 (12H, m), 2.53 (2H, m), 4.24 (1H, m), 7.74 (1H, s), 7.80 (1H, s), 9.90 (1H, s)。
[工程1](trans−4−フェノキシシクロヘキシル)カルバミン酸tert−ブチル
1H-NMR (CDCl3) δ: 1.20-1.30 (2H, m), 1.45 (9H, s), 1.51-1.61 (2H, m), 2.05-2.16 (4H, m), 3.47-3.58 (1H, m), 4.17 (1H, m), 6.81-6.95 (3H, m), 7.21-7.29 (2H, m)。
1H-NMR (CD3OD) δ: 1.48-1.61 (4H, m), 2.07-2.14 (2H, m), 2.18-2.25 (2H, m), 3.13-3.21 (1H, m), 4.28 (1H, m), 6.87-6.94 (3H, m), 7.21-7.28 (2H, m)。
1H-NMR (CDCl3) δ: 1.39 (3H, t, J = 7.1 Hz), 1.57-1.71 (2H, m), 1.80-1.90 (2H, m), 2.22-2.37 (4H, m), 4.08 (1H, m), 4.29 (1H, m), 4.37 (2H, q, J = 7.1 Hz), 6.85-7.00 (3H, m), 7.26-7.32 (2H, m), 7.59 (1H, s), 7.69 (1H, s)。
1H-NMR (CDCl3) δ: 1.62-1.73 (2H, m), 1.80-1.91 (2H, m), 2.24-2.38 (4H, m), 4.11 (1H, m), 4.30 (1H, m), 6.88-7.01 (3H, m), 7.26-7.33 (2H, m), 7.66 (1H, s), 7.71 (1H, s), 9.88 (1H, s)。
[工程1]1−(3,3−ジメチルシクロヘキシル)−1H−イミダゾール−4−カルボン酸エチル
1H-NMR (CDCl3) δ: 0.92-0.96 (1H, m), 1.03 (6H, s), 1.18-1.26 (1H, m), 1.46-1.68 (3H, m), 1.76-1.85 (2H, m), 2.11-2.17 (1H, m), 4.11-4.19 (1H, m), 7.62 (1H, s), 7.68 (1H, s), 9.86 (1H, s)。
[工程1]2−メチレン酪酸エチル
1H-NMR (CDCl3) δ: 1.08 (3H, t, J= 7.4 Hz), 1.31 (3H, t, J = 7.0 Hz), 2.30-2.36 (2H, m), 4.21 (2H, q, J= 7.0 Hz), 5.51-5.52 (1H, m), 6.12-6.14 (1H, m)。
1H-NMR (CDCl3) δ: 0.91 (3H, t, J = 7.4 Hz), 1.26 (3H, t, J = 7.2 Hz), 1.53-1.70 (2H, m), 2.47-2.55 (1H, m), 2.69 (1H, dd, J = 11.9, 4.9 Hz), 2.88 (1H, dd, J= 11.9, 8.8 Hz), 3.79 (2H, d, J= 4.3 Hz), 4.13-4.19 (2H, m), 7.22-7.26 (2H, m), 7.29-7.32 (3H, m)。
1H-NMR (CDCl3) δ: 0.94 (3H, t, J = 7.4 Hz), 1.27 (3H, t, J = 7.4 Hz), 1.43 (9H, s), 1.49-1.71 (2H, m), 2.48-2.56 (1H, m), 3.21-3.28 (1H, m), 3.32-3.39 (1H, m), 4.11-4.20 (3H, m), 4.86 (1H, br s)。
1H-NMR (CDCl3) δ: 0.93 (3H, t, J = 7.4 Hz), 1.19-1.37 (2H, m), 1.45 (9H, s), 3.06-3.13 (1H, m), 3.28-3.36 (2H, m), 3.37-3.44 (1H, m), 3.56-3.62 (1H, m), 4.78 (1H, br s)。
1H-NMR (CDCl3) δ: 1.02 (3H, t, J= 7.8 Hz), 1.42 (9H, s), 1.48-1.54 (1H, m), 1.70-1.81 (1H, m), 2.43-2.51 (1H, m), 3.27-3.40 (2H, m), 4.82 (1H, br s), 9.68-9.69 (1H, m)。
[工程1](cis−4−{[tert−ブチル(ジフェニル)シリル]オキシ}シクロヘキシル)カルバミン酸tert−ブチル
1H-NMR (CDCl3) δ: 1.07 (9H, s), 1.45 (9H, s), 1.57-1.71 (8H, m), 3.40-3.49 (1H, m), 3.88-3.92 (1H, m), 4.50-4.57 (1H, m), 7.34-7.44 (6H, m), 7.64-7.66 (4H, m)。
1H-NMR (CDCl3) δ: 1.11 (9H, s), 1.42-1.49 (2H, m), 1.81-1.93 (4H, m), 2.24-2.32 (2H, m), 3.95-4.01 (1H, m), 4.07-4.10 (1H, m), 7.37-7.41 (4H, m), 7.43-7.47 (2H, m), 7.65-7.67 (5H, m), 7.75 (1H, s), 9.90 (1H, s)。
[工程1]1−(cis−4−メチルシクロヘキシル)−1H−イミダゾール−4−カルボン酸エチル
1H-NMR (CDCl3) δ: 1.00 (3H, d, J = 7.0 Hz), 1.45-1.52 (2H, m), 1.64-1.73 (3H, m), 1.85-2.07 (4H, m), 4.06-4.13 (1H, m), 7.67 (1H, d, J = 1.2 Hz), 7.74 (1H, d, J = 1.2 Hz), 9.89 (1H, s)。
[工程1]5−[(tert−ブトキシカルボニル)アミノ]−2−[(1−シクロヘキサ−2−エン−1−イル−1H−イミダゾール−4−イル)メチル]吉草酸tert−ブチル
1H-NMR (CDCl3) δ: 1.39 (9H, s), 1.44 (9H, s), 1.47-2.15 (10H, m), 2.60-2.70 (2H, m), 2.85 (1H, m), 3.02-3.18 (2H, m), 4.61 (1H, m), 4.76 (1H, br), 5.70 (1H, m), 6.05 (1H, m), 6.68 (1H, s), 7.42 (1H, s)。
1H-NMR (CDCl3) δ: 1.19-1.36 (4H, m), 1.38 (9H, s), 1.44 (9H, s), 1.48-1.64 (5H, m), 1.73 (1H, m), 1.88 (2H, m), 2.06 (2H, m), 2.59-2.70 (2H, m), 2.84 (1H, m), 3.05-3.16 (2H, m), 3.81 (1H, m), 4.76 (1H, br), 6.68 (1H, s), 7.42 (1H, s)。
1H-NMR (CD3OD) δ: 1.23-1.75 (10H, m), 1.87 (2H, m), 2.04 (2H, m), 2.46-2.59 (2H, m), 2.84-2.95 (3H, m), 3.95 (1H, m), 6.95 (1H, s), 7.57 (1H, s).
HRMS (ESI): m/z calcd for C15H25N3NaO2: 302.1845 [M + Na]+; found: 302.1835。
[工程1]5−[(tert−ブトキシカルボニル)アミノ]−2−{[1−(trans−4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸tert−ブチル
1H-NMR (CDCl3) δ: 0.94 (3H, d, J = 6.3 Hz), 1.05-1.14 (2H, m), 1.38 (9H, s), 1.41-1.68 (7H, m), 1.44 (9H, s), 1.81-1.87 (2H, m), 2.03-2.08 (2H, m), 2.60-2.69 (2H, m), 2.84 (1H, m), 3.05-3.15 (2H, m), 3.78 (1H, tt, J = 11.7, 3.9 Hz), 4.73 (1H, br), 6.67 (1H, s), 7.40 (1H, s)。
1H-NMR (CD3OD) δ: 0.95 (3H, d, J = 6.6 Hz), 1.07-1.20 (2H, m), 1.38-1.77 (7H, m), 1.79-1.87 (2H, m), 1.97-2.06 (2H, m), 2.43-2.57 (2H, m), 2.81-2.95 (3H, m), 3.92 (1H, tt, J = 11.7, 3.5 Hz), 6.93 (1H, s), 7.54 (1H, s).
HRMS (ESI): m/z calcd for C16H28N3O2: 294.2182 [M + H]+; found: 294.2183。
[工程1]5−[(tert−ブトキシカルボニル)アミノ]−2−{[1−(trans−4−エチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸メチル
1H-NMR (CDCl3) δ: 0.91 (3H, t, J = 7.0 Hz), 1.06 (2H, m), 1.15-1.68 (9H, m), 1.44 (9H, s), 1.93 (2H, m), 2.09 (2H, m), 2.71 (1H, dd, J = 13.7, 5.9 Hz), 2.80 (1H, m), 2.89 (1H, dd, J = 13.7, 7.8 Hz), 3.03-3.17 (2H, m), 3.63 (3H, s), 3.81 (1H, tt, J = 12.1, 3.9 Hz), 4.76 (1H, br), 6.68 (1H, s), 7.47 (1H, s)。
1H-NMR (CD3OD) δ: 0.92 (3H, t, J = 7.0 Hz), 1.10 (2H, m), 1.17-1.33 (3H, m), 1.42-1.75 (6H, m), 1.91 (2H, m), 2.05 (2H, m), 2.43-2.58 (2H, m), 2.79-2.95 (3H, m), 3.93 (1H, tt, J = 12.1, 3.5 Hz), 6.94 (1H, s), 7.56 (1H, s).
HRMS (ESI): m/z calcd for C17H30N3O2: 308.2338 [M + H]+; found: 308.2338。
[工程1]5−[(tert−ブトキシカルボニル)アミノ]−2−{[1−(3−エチルシクロブチル)−1H−イミダゾール−4−イル]メチル}吉草酸メチル
1H-NMR (CDCl3) δ: 0.86 (1.5H, t, J = 7.3 Hz), 0.90 (1.5H, t, J = 7.3 Hz), 1.44 (9H, s), 1.44-1.70 (6H, m), 1.81-1.90 (1H, m), 1.94-2.04 (0.5H, m), 2.18-2.30 (1.5H, m), 2.37-2.47 (1H, m), 2.57-2.64 (1H, m), 2.66-2.73 (1H, m), 2.76-2.83 (1H, m), 2.86-2.93 (1H, m), 3.04-3.17 (2H, m), 3.64 (3H, s), 4.34 (0.5H, tt, J = 9.3, 7.8 Hz), 4.58 (0.5H, tt, J = 7.8, 7.3 Hz), 4.79 (1H, br), 6.68 (0.5H, s), 6.73 (0.5H, s), 7.39 (0.5H, s), 7.42 (0.5H, s)。
1H-NMR (CD3OD) δ: 0.87 (1.5H, t, J = 7.4 Hz), 0.91 (1.5H, t, J = 7.4 Hz), 1.45-1.73 (6H, m), 1.85-2.06 (1H, m), 2.17-2.29 (1.5H, m), 2.41-2.64 (4H, m), 2.82-2.95 (3H, m), 4.47 (0.5H, tt, J = 9.4, 7.8 Hz), 4.72 (0.5H, tt, J = 8.2, 7.8 Hz), 6.97 (0.5H, s), 7.03 (0.5H, s), 7.53 (0.5H, s), 7.56 (0.5H, s).
HRMS (ESI): m/z calcd for C15H26N3O2: 280.2025 [M + H]+; found: 280.2015。
1H-NMR (CD3OD) δ: 1.15 (1.5H, d, J = 6.6 Hz), 1.24 (1.5H, d, J = 6.6 Hz), 1.44-1.72 (4H, m), 1.85-1.96 (1H, m), 2.10-2.22 (1.5H, m), 2.41-2.63 (4.5H, m), 2.81-2.95 (3H, m), 4.45 (0.5H, tt, J = 9.4, 7.4 Hz), 4.79 (0.5H, tt, J = 7.8, 7.8 Hz), 6.98 (0.5H, s), 7.02 (0.5H, s), 7.54 (0.5H, s), 7.57 (0.5H, s).
HRMS (ESI): m/z calcd for C14H24N3O2: 266.1869 [M + H]+; found: 266.1874。
[工程1]メタンスルホン酸(1R,3r,5S)−ビシクロ[3.1.0]ヘキサ−3−イル
1H-NMR (CDCl3) δ: 0.44 (1H, m), 0.54 (1H, m), 1.35 (2H, m), 2.10 (2H, m), 2.26 (2H, m), 2.96 (3H, s), 5.19 (1H, m)。
1H-NMR (CDCl3) δ: 0.26 (1H, dt, J = 5.7, 3.9 Hz), 0.47 (1H, td, J = 7.8, 5.7 Hz), 1.38 (9H, s), 1.44 (9H, s), 1.35-2.07 (8H, m), 2.26-2.33 (2H, m), 2.58-2.68 (2H, m), 2.83 (1H, m), 3.05-3.15 (2H, m), 4.03 (1H, tt, J = 10.2, 7.4 Hz), 4.75 (1H, br), 6.65 (1H, s), 7.37 (1H, s)。
1H-NMR (CD3OD) δ: 0.34 (1H, dt, J = 5.4, 3.9 Hz), 0.45 (1H, td, J = 7.4, 5.4 Hz), 1.38-1.45 (2H, m), 1.46-1.71 (4H, m), 2.03-2.11 (2H, m), 2.23-2.30 (2H, m), 2.44-2.57 (2H, m), 2.82-2.95 (3H, m), 4.21 (1H, tt, J = 10.2, 7.4 Hz), 6.92 (1H, s), 7.50 (1H, s).
HRMS (ESI): m/z calcd for C15H23N3NaO2: 300.1688 [M + Na]+; found: 300.1679。
[工程1]5−[(tert−ブトキシカルボニル)アミノ]−2−{[1−(trans−4−ヒドロキシシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸メチル
1H-NMR (CDCl3) δ: 1.40-1.88 (8H, m), 1.43 (9H, s), 2.08-2.16 (4H, m), 2.70 (1H, dd, J = 14.6, 6.3 Hz), 2.80 (1H, m), 2.89 (1H, dd, J = 14.6, 8.3 Hz), 3.03-3.15 (2H, m), 3.63 (3H, s), 3.72 (1H, m), 3.88 (1H, m), 4.73 (1H, br), 6.67 (1H, s), 7.47 (1H, s)。
1H-NMR (CD3OD) δ: 1.39-1.87 (8H, m), 2.01-2.13 (4H, m), 2.53-2.69 (2H, m), 2.84-2.97 (3H, m), 3.64 (1H, m), 4.09 (1H, m), 7.10 (1H, s), 8.01 (1H, s).
HRMS (ESI): m/z calcd for C15H26N3O3: 296.1974 [M + H]+; found: 296.1975。
[工程1]5−[(tert−ブトキシカルボニル)アミノ]−2−{[1−(4−ヒドロキシ−4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸tert−ブチル
1H-NMR (CDCl3) δ: 1.29 (2.25H, s), 1.33 (0.75H, s), 1.38 (9H, s), 1.43 (9H, s), 1.47-1.69 (6H, m), 1.75-1.90 (4H, m), 2.05-2.12 (2H, m), 2.61-2.70 (2H, m), 2.80-2.88 (1H, m), 3.04-3.17 (2H, m), 3.81 (0.75H, tt, J = 12.2, 3.9 Hz), 3.93 (0.25H, m), 4.74 (1H, br), 6.70 (0.25H, s), 6.72 (0.75H, s), 7.44 (0.25H, s), 7.45 (0.75H, s)。
1H-NMR (CDCl3) δ: 1.23 (2.25H, s), 1.31 (0.75H, s), 1.47-1.90 (10H, m), 1.97-2.11 (2H, m), 2.46-2.59 (2H, m), 2.83-2.95 (3H, m), 3.97 (0.75H, tt, J = 12.2, 3.9 Hz), 4.04 (0.25H, m), 6.97 (0.25H, s), 6.99 (0.75H, s), 7.63 (0.25H, s), 7.64 (0.75H, s).
HRMS (ESI): m/z calcd for C16H28N3O3: 310.2131 [M + H]+; found: 310.2123。
1H-NMR (CD3OD) δ: 1.05 (3H, d, J = 6.8 Hz), 1.32-1.40 (1H, m), 1.47-1.55 (1H, m), 1.55-1.76 (7H, m), 1.78-1.87 (1H, m), 1.90-2.05 (3H, m), 2.46-2.58 (2H, m), 2.84-2.95 (3H, m), 4.24 (1H, m), 6.96 (1H, s), 7.57 (1H, s).
HRMS (ESI): m/z calcd for C16H28N3O2: 294.21815 [M + H]+; found: 294.21898。
1H-NMR (CD3OD) δ: 1.46-1.74 (10H, m), 1.74-1.88 (2H, m), 1.85-1.94 (2H, m), 1.99-2.08 (2H, m), 2.45-2.58 (2H, m), 2.82-2.95 (3H, m), 4.16 (1H, m), 6.93 (1H, s), 7.57 (1H, s).
HRMS (ESI): m/z calcd for C16H28N3O2: 294.21815 [M + H]+; found: 294.21863。
1H-NMR (CD3OD) δ: 1.21-1.37 (3H, m), 1.46-1.71 (7H, m), 1.77-1.84 (1H, m), 1.90-1.97 (1H, m), 2.38-2.45 (2H, m), 2.45-2.57 (2H, m), 2.83-2.95 (3H, m), 4.04-4.10 (1H, m), 6.93 (1H, s), 7.56 (1H, s).
HRMS (ESI): m/z calcd for C16H26N3O2: 292.20250 [M + H]+; found: 292.20319。
1H-NMR (CD3OD) δ: 1.15-1.23 (1H, m), 1.33-1.43 (2H, m), 1.44-1.55 (2H, m), 1.55-1.71 (6H, m), 2.10-2.18 (1H, m), 2.33-2.37 (1H, m), 2.46-2.59 (3H, m), 2.83-2.95 (3H, m), 4.43-4.50 (1H, m), 6.93 (1H, s), 7.57 (1H, s).
HRMS (ESI): m/z calcd for C16H26N3O2: 292.20250 [M + H]+; found: 292.20252。
1H-NMR (CD3OD) δ: 1.48-1.57 (1H, m), 1.58-1.72 (5H, m), 1.77-1.86 (5H, m), 1.92-1.99 (3H, m), 2.01-2.07 (2H, m), 2.48-2.61 (4H, m), 2.85-2.95 (3H, m), 4.17 (1H, s), 7.03 (1H, s), 7.65 (1H, s).
HRMS (ESI): m/z calcd for C19H30N3O2: 332.23380 [M + H]+; found: 332.23325。
1H-NMR (CD3OD) δ: 1.47-1.73 (6H, m), 1.84-1.95 (2H, m), 2.08-2.16 (2H, m), 2.21-2.28 (2H, m), 2.46-2.59 (2H, m), 2.84-2.95 (3H, m), 4.09 (1H, m), 4.36 (1H, m), 6.88-6.95 (3H, m), 6.97 (1H, s), 7.23-7.28 (2H, m), 7.59 (1H, s).
HRMS (ESI): m/z calcd for C21H30N3O3: 372.22872 [M + H]+; found: 372.22850。
[工程1]5−[(tert−ブトキシカルボニル)アミノ]−2−{[1−(trans−4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸メチル
1H-NMR (CDCl3) δ: 0.94 (3H, d, J = 6.6 Hz), 1.02-1.15 (2H, m), 1.34-1.69 (7H, m), 1.43 (9H, s), 1.80-1.87 (2H, m), 1.99-2.09 (2H, m), 2.69 (1H, dd, J = 13.7, 6.3 Hz), 2.79 (1H, m), 2.88 (1H, dd, J = 13.7, 7.4 Hz), 3.03-3.13 (2H, m), 3.63 (3H, s), 3.79 (1H, tt, J = 12.1, 3.9 Hz), 4.76 (1H, br), 6.67 (1H, s), 7.47 (1H, s)。
[工程1]5−[(tert−ブトキシカルボニル)アミノ]−2−{[1−(trans−4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸
MS (ESI) m/z 394 [M + H]+。
1H-NMR (CDCl3) δ: 0.94 (3H, d, J = 6.3 Hz), 1.01-1.13 (2H, m), 1.38-1.72 (16H, m), 1.79-1.86 (2H, m), 1.97-2.04 (2H, m), 2.71 (1H, dd, J = 14.1, 5.9 Hz), 2.80-2.87 (1H, m), 2.91 (1H, dd, J = 14.1, 7.8 Hz), 3.07 (2H, br s), 3.68-3.76 (1H, m), 4.68 (1H, br s), 5.10 (2H, s), 6.57 (1H, s), 7.29-7.40 (6H, m).
MS (ESI) m/z 484 [M + H]+。
1H-NMR (CD3OD) δ: 0.97 (3H, d, J = 6.7 Hz), 1.11-1.22 (2H, m), 1.43-1.54 (1H, m), 1.62-1.89 (8H, m), 1.99-2.06 (2H, m), 2.88-3.04 (5H, m), 4.10 (1H, tt, J = 12.1, 3.9 Hz), 5.07 (1H, d, J = 12.1 Hz), 5.15 (1H, d, J = 12.1 Hz), 7.28-7.37 (6H, m), 8.82 (1H, d, J= 1.6 Hz).
MS (ESI) m/z 384 [M + H]+。
[工程1]5−({N−[(ベンジルオキシ)カルボニル]−L−フェニルアラニル}アミノ)−2−{[1−(trans−4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸ベンジル
1H-NMR (CDCl3) δ: 0.94 (3H, d, J = 6.7 Hz), 1.07 (2H, q, J = 12.9 Hz), 1.43-1.55 (7H, m), 1.80-1.84 (2H, m), 1.97-1.99 (2H, m), 2.67-2.88 (3H, m), 3.08-3.15 (3H, m), 3.68-3.70 (0.5H, m), 4.40-4.41 (0.5H, m), 5.05-5.10 (4H, m), 5.60-5.63 (1H, m), 6.54-6.56 (2H, m), 7.16-7.21 (4H, m), 7.29-7.52 (7H, m).
MS (ESI) m/z 665 [M + H]+。
1H-NMR (CDCl3) δ: 0.95 (3H, d, J = 6.7 Hz), 1.07-1.14 (2H, m), 1.41-1.44 (2H, m), 1.59-1.72 (5H, m), 1.84-1.88 (2H, m), 2.07-2.11 (2H, m), 2.71-2.80 (4H, m), 3.23-3.25 (3H, m), 3.62-3.65 (1H, m), 3.82-3.83 (1H, m), 6.75 (1H, s), 7.23-7.30 (5H, m).
HRMS (ESI): m/z calcd for C25H37N4O3: 441.28656 [M + H]+; found: 441.28690。
[工程1]5−({N−[(ベンジルオキシ)カルボニル]−L−ノルロイシル}アミノ)−2−{[1−(trans−4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸ベンジル
1H-NMR (CDCl3) δ: 0.83-0.88 (3H, m), 0.94 (3H, d, J = 6.7 Hz), 1.02-1.12 (2H, m), 1.23-1.74 (12H, m), 1.78-1.85 (2H, m), 1.96-2.02 (2H, m), 2.73-2.95 (3H, m), 3.17-3.32 (2H, m), 3.67-3.76 (1H, m), 4.10-4.18 (1H, m), 5.09-5.11 (4H, m), 5.55-5.58 (1H, m), 6.55 (0.5H, s), 6.57 (0.5H, s), 6.84-6.93 (1H, m), 7.30-7.36 (9H, m), 7.51 (1H, s)。
1H-NMR (CDCl3) δ: 0.84-0.89 (3H, m), 0.94 (3H, d, J = 6.3 Hz), 1.04-1.14 (2H, m), 1.26-1.68 (13H, m), 1.79-1.87 (2H, m), 2.03-2.10 (2H, m), 2.58-2.69 (2H, m), 2.85 (1H, dd, J= 14.5, 7.4 Hz), 3.11-3.27 (2H, m), 3.45-3.52 (1H, m), 3.77-3.83 (1H, m), 6.72 (1H, s), 7.52 (1H, s), 8.03 (1H, br s).
HRMS (ESI): m/z calcd for C22H39N4O3: 407.30221 [M + H]+; found: 407.30257。
1H-NMR (CDCl3) δ: 0.96 (3H, d, J = 6.5 Hz), 1.08-1.18 (2H, m), 1.40-1.51 (2H, m), 1.55-1.78 (5H, m), 1.82-1.90 (2H, m), 2.07-2.15 (2H, m), 2.18 (3H, s), 2.70-2.84 (3H, m), 3.13-3.20 (2H, m), 3.86-3.95 (1H, m), 4.79 (2H, s), 5.18 (1H, br s), 6.78 (1H, s), 7.74 (1H, s).
HRMS (ESI): m/z calcd for C22H32N3O7: 450.22402 [M + H]+; found: 450.22369。
[工程1]2−メチルプロピオン酸1−[(クロロカルボニル)オキシ]エチル
1H-NMR (CDCl3) δ: 0.96 (3H, d, J = 6.3 Hz), 1.07-1.13 (2H, m), 1.16 (6H, d, J = 7.0 Hz), 1.41-1.49 (5H, m), 1.57-1.78 (5H, m), 1.84-1.90 (2H, m), 2.08-2.14 (2H, m), 2.53 (1H, tt, J = 7.0, 7.0 Hz), 2.70-2.85 (3H, m), 3.12-3.20 (2H, m), 3.84-3.92 (1H, m), 4.96 (1H, br s), 6.76-6.80 (2H, m), 7.71 (1H, s).
HRMS (ESI): m/z calcd for C23H38N3O6: 452.27606 [M + H]+; found: 452.27610。
[工程1]1−ヨードエチル イソプロピル カルボナート
1H-NMR (CDCl3) δ: 1.32 (3H, d, J = 6.3 Hz), 1.34 (3H, d, J = 6.3 Hz), 2.24 (3H, d, J = 5.9 Hz), 4.95 (1H, tt, J = 6.3, 6.3 Hz), 6.76 (1H, q, J = 5.9 Hz)。
1H-NMR (CDCl3) δ: 0.95 (3H, d, J = 6.3 Hz), 1.05-1.17 (8H, m), 1.30-1.32 (6H, m), 1.42-1.69 (13H, m), 1.82-1.87 (2H, m), 2.05-2.11 (2H, m), 2.49-2.56 (1H, m), 2.68-2.96 (3H, m), 3.10-3.23 (2H, m), 3.76-3.85 (1H, m), 4.85-4.92 (1H, m), 5.23 (0.5H, br s), 5.31 (0.5H, br s), 6.68-6.73 (2H, m), 6.79 (1H, q, J = 5.5 Hz), 7.45 (0.5H, s), 7.46 (0.5H, s).
HRMS (ESI): m/z calcd for C29H48N3O9: 582.33905 [M +H]+; found: 582.33901。
[工程1]S−エチル O−(1−ヨードエチル)チオカルボナート
1H-NMR (CDCl3) δ: 1.31 (3H, t, J = 7.4 Hz), 2.18 (3H, d, J = 6.3 Hz), 2.84-2.91 (2H, m), 6.89 (1H, q, J = 6.3 Hz)。
1H-NMR (CDCl3) δ: 1.20 (9H, s), 1.31 (3H, t, J = 7.4 Hz), 1.50 (3H, d, J = 5.5 Hz), 2.84-2.90 (2H, m), 6.92 (1H, q, J = 5.5 Hz)。
1H-NMR (CDCl3) δ: 0.95 (3H, d, J = 6.3 Hz), 1.11-1.19 (11H, m), 1.43-1.76 (10H, m), 1.85-1.92 (2H, m), 2.13-2.19 (2H, m), 2.83-2.94 (2H, m), 2.99-3.08 (1H, m), 3.11-3.21 (2H, m), 4.09-4.17 (1H, m), 5.38 (1H, br s), 6.75 (1H, q, J = 5.4 Hz), 7.07 (1H, s), 8.79 (1H, s).
HRMS (ESI): m/z calcd for C24H40N3O6: 466.29171 [M + H]+; found: 466.29083。
[工程1]シクロヘキサンカルボン酸1−{[(エチルチオ)カルボニル]オキシ}エチル
1H-NMR (CDCl3) δ: 1.20-1.28 (3H, m), 1.31 (3H, t, J = 7.4 Hz), 1.39-1.48 (2H, m), 1.49 (3H, d, J = 5.5 Hz), 1.60-1.66 (1H, m), 1.73-1.77 (2H, m), 1.86-1.93 (2H, m), 2.27-2.37 (1H, m), 2.82-2.92 (2H, m), 6.94 (1H, q, J = 5.5 Hz)。
1H-NMR (CDCl3) δ: 0.96 (3H, d, J = 6.7 Hz), 1.07-1.31 (5H, m), 1.39-1.47 (7H, m), 1.57-1.78 (8H, m), 1.84-1.92 (4H, m), 2.07-2.14 (2H, m), 2.28 (1H, tt, J = 11.2, 3.6 Hz), 2.68-2.84 (3H, m), 3.12-3.21 (2H, m), 3.86 (1H, tt, J = 12.1, 3.7 Hz), 4.95 (1H, br s), 6.76 (1H, s), 6.78 (1H, q, J = 5.7 Hz), 7.63 (1H, s).
HRMS (ESI): m/z calcd for C26H42N3O6: 492.30736 [M + H]+; found: 492.30677。
[工程1](2Z)−2−{[1−(trans−4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチレン}モルホリン−3−オン
1H-NMR (CDCl3) δ: 0.92 (3H, d, J = 6.6 Hz), 1.08 (2H, m), 1.43 (1H, m), 1.67 (2H, m), 1.84 (2H, m), 2.09 (2H, m), 3.58 (2H, m), 3.85 (1H, tt, J = 12.1, 3.9 Hz), 4.24 (2H, m), 6.10 (1H, br), 6.93 (1H, s), 7.35 (1H, s), 7.58 (1H, s)。
1H-NMR (CDCl3) δ: 0.94 (3H, d, J = 6.6 Hz), 1.09 (2H, m), 1.44 (1H, m), 1.65 (2H, m), 1.84 (2H, m), 2.09 (2H, m), 3.02 (1H, dd, J = 15.2, 9.0 Hz), 3.25-3.32 (2H, m), 3.54 (1H, m), 3.75 (1H, m), 3.80 (1H, tt, J = 12.1, 3.9 Hz), 4.03 (1H, m), 4.47 (1H, dd, J = 9.0, 3.1 Hz), 6.31 (1H, br), 6.80 (1H, s), 7.45 (1H, s)。
1H-NMR (CD3OD) δ: 0.95 (3H, d, J = 6.6 Hz), 1.15 (2H, m), 1.47 (1H, m), 1.72 (2H, m), 1.84 (2H, m), 2.04 (2H, m), 2.83-3.07 (4H, m), 3.58-3.68 (2H, m), 3.90-4.01 (2H, m), 6.98 (1H, s), 7.58 (1H, s).
HRMS (ESI): m/z calcd for C15H26N3O3: 296.1974 [M + H]+; found: 296.1962。
[工程1](6R)−4−(メトキシメチル)−6−メチルモルホリン−3−オン
1H-NMR (CDCl3) δ: 1.30 (3H, d, J = 5.9 Hz), 3.22-3.34 (5H, m), 3.86-3.95 (1H, m), 4.19 (1H, d, J = 16.8 Hz), 4.31 (1H, d, J = 16.8 Hz), 4.75 (1H, d, J = 9.8 Hz), 4.88 (1H, d, J = 9.8 Hz)。
1H-NMR (CD3OD) δ: 0.95 (3H, d, J = 6.6 Hz), 1.15 (2H, m), 1.23 (3H, d, J = 6.3 Hz), 1.48 (1H, m), 1.71 (2H, m), 1.84 (2H, m), 2.03 (2H, m), 2.97 (1H, dd, J = 15.2, 7.0 Hz), 3.14 (1H, m), 3.18 (3H, s), 3.23-3.38 (2H, m), 3.91-3.99 (2H, m), 4.43 (1H, dd, J = 7.4, 3.5 Hz), 4.69 (1H, d, J = 10.2 Hz), 4.79 (1H, d, J = 10.2 Hz), 6.96 (1H, s), 7.58 (1H, s)。
1H-NMR (CD3OD) δ: 0.93 (3H, d, J = 6.3 Hz), 0.95 (3H, d, J = 6.8 Hz), 1.16 (2H, m), 1.48 (1H, m), 1.73 (2H, m), 1.84 (2H, m), 2.03 (2H, m), 2.75 (1H, m), 2.77 (1H, dd, J = 14.6, 9.8 Hz), 2.95 (1H, m), 3.08 (1H, dd, J = 14.6, 3.4 Hz), 3.55 (1H, m), 3.96 (1H, tt, J = 12.2, 3.9 Hz), 4.02 (1H, dd, J = 9.8, 3.4 Hz), 6.98 (1H, s), 7.59 (1H, s).
HRMS (ESI): m/z calcd for C16H28N3O3: 310.2131 [M + H]+; found: 310.2131。
[工程1]3−[1−(trans−4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]プロピオン酸エチル
1H-NMR (CDCl3) δ: 0.94 (3H, d, J = 6.6 Hz), 1.03-1.15 (2H, m), 1.23 (3H, t, J = 7.0 Hz), 1.45 (1H, m), 1.57-1.69 (2H, m), 1.80-1.88 (2H, m), 2.03-2.10 (2H, m), 2.66 (2H, t, J = 7.4 Hz), 2.88 (2H, t, J = 7.4 Hz), 3.79 (1H, tt, J = 12.1, 3.9 Hz), 4.13 (2H, q, J = 7.0 Hz), 6.70 (1H, s), 7.42 (1H, s)。
1H-NMR (CDCl3) δ: 0.95 (3H, d, J = 6.3 Hz), 1.05-1.14 (2H, m), 1.18 (1.5H, t, J = 7.3 Hz), 1.18 (1.5H, t, J = 7.3 Hz), 1.39-1.70 (13H, m), 1.81-1.88 (2H, m), 2.03-2.09 (2H, m), 2.11-2.21 (1H, m), 2.57-2.76 (2H, m), 2.85-3.05 (4H, m), 3.59-3.65 (1H, m), 3.79 (1H, tt, J = 12.2, 3.9 Hz), 4.06-4.22 (3H, m), 5.01 (0.5H, br), 5.18 (0.5H, br), 6.71 (1H, s), 7.43 (1H, s)。
1H-NMR (CD3OD) δ: 0.99 (3H, d, J = 6.7 Hz), 1.12-1.25 (2H, m), 1.51 (1H, m), 1.69-1.92 (5H, m), 2.03-2.13 (2H, m), 2.25 (1H, m), 2.65-2.74 (1H, m), 2.83-2.90 (1H, m), 2.91-3.14 (3H, m), 3.19 (0.5H, m), 3.27 (0.5H, m), 3.33-3.38 (1H, m), 3.74 (1H, m), 4.00 (1H, tt, J = 12.1, 3.9 Hz), 7.08 (1H, s), 7.70 (0.5H, s), 7.72 (0.5H, s).
HRMS (ESI): m/z calcd for C17H29N4O2: 321.2291 [M + H]+; found: 321.2283。
[工程1]酢酸1−{[(エチルチオ)カルボニル]オキシ}エチル
1H-NMR (CDCl3) δ: 1.32 (3H, t, J = 7.4 Hz), 1.51 (3H, d, J = 5.9 Hz), 2.09 (3H, s), 2.81-2.95 (2H, m), 6.94 (1H, q, J = 5.9 Hz)。
1H-NMR (CDCl3) δ: 0.96 (3H, d, J = 6.3 Hz), 1.09-1.21 (2H, m), 1.45 (3H, d, J = 5.5 Hz), 1.52-1.75 (6H, m), 1.86-1.93 (2H, m), 2.06 (3H, s), 2.13-2.19 (2H, m), 2.82-2.91 (2H, m), 2.97-3.05 (1H, m), 3.15-3.21 (2H, m), 4.03-4.11 (1H, m), 5.31 (1H, br s), 6.77-6.81 (1H, m), 6.99 (1H, s), 8.97 (1H, s)。
[工程1]S−エチル O−(ヨードメチル) チオカーボネート
1H-NMR (CDCl3) δ: 1.34 (3H, t, J= 7.4 Hz), 2.93 (2H, q, J = 7.4 Hz), 5.99 (2H, s)。
1H-NMR (CDCl3) δ: 1.19 (6H, d, J= 7.0 Hz), 1.33 (3H, t, J = 7.4 Hz), 2.57-2.64 (1H, m), 2.90 (2H, q, J= 7.4 Hz), 5.81 (2H, s)。
1H-NMR (CDCl3) δ: 1.22 (6H, d, J= 7.0 Hz), 2.60-2.70 (1H, m), 5.83 (2H, s)。
1H-NMR (CDCl3) δ: 0.96 (3H, d, J= 6.7 Hz), 1.07-1.17 (2H, m), 1.18 (6H, d, J = 7.0 Hz), 1.40-1.51 (2H, m), 1.57-1.81 (5H, m), 1.84-1.91 (2H, m), 2.07-2.14 (2H, m), 2.54-2.64 (1H, m), 2.67-2.75 (1H, m), 2.78-2.89 (2H, m), 3.17-3.22 (2H, m), 3.87 (1H, tt, J = 12.1, 3.9 Hz), 5.14 (1H, br s), 5.71 (2H, s), 6.75 (1H, s), 7.66 (1H, s).
LRMS (ESI) m/z 438 [M + H]+.
HRMS (ESI) m/z calcd for C22H36N3O6: 438.26041 [M + H]+; found: 438.26052。
[工程1]2,2−ジメチルプロパン酸{[(エチルスルファニル)カルボニル]オキシ}メチル
1H-NMR (CDCl3) δ: 1.22 (9H, s), 1.33 (3H, t, J = 7.4 Hz), 2.89 (2H, q, J = 7.4 Hz), 5.81 (2H, s)。
1H-NMR (CDCl3) δ: 0.96 (3H, d, J= 6.3 Hz), 1.07-1.17 (2H, m), 1.21 (9H, s), 1.41-1.50 (2H, m), 1.58-1.78 (5H, m), 1.84-1.90 (2H, m), 2.07-2.14 (2H, m), 2.67-2.74 (1H, m), 2.77-2.89 (2H, m), 3.17-3.22 (2H, m), 3.87 (1H, tt, J= 12.1, 3.9 Hz), 5.13 (1H, br s), 5.71 (2H, s), 6.75 (1H, s), 7.67 (1H, s).
LRMS (ESI) m/z 452 [M + H]+.
HRMS (ESI) m/z calcd for C23H38N3O6: 452.27606 [M + H]+; found: 452.27619。
[工程1]シクロヘキサンカルボン酸{[(エチルスルファニル)カルボニル]オキシ}メチル
1H-NMR (CDCl3) δ: 1.20-1.31 (3H, m), 1.33 (3H, t, J = 7.4 Hz), 1.40-1.50 (2H, m), 1.60-1.67 (1H, m), 1.72-1.79 (2H, m), 1.87-1.95 (2H, m), 2.36 (1H, tt, J = 11.3, 3.5 Hz), 2.89 (2H, q, J = 7.4 Hz), 5.80 (2H, s)。
1H-NMR (CDCl3) δ: 0.96 (3H, d, J= 6.3 Hz), 1.07-1.18 (2H, m), 1.19-1.33 (3H, m), 1.39-1.50 (4H, m), 1.58-1.78 (8H, m), 1.85-1.94 (4H, m), 2.08-2.14 (2H, m), 2.35 (1H, tt, J = 11.3, 3.9 Hz), 2.67-2.74 (1H, m), 2.76-2.90 (2H, m), 3.17-3.22 (2H, m), 3.87 (1H, tt, J = 12.1, 3.9 Hz), 5.17 (1H, br s), 5.71 (2H, s), 6.76 (1H, s), 7.68 (1H, s).
LRMS (ESI) m/z 478 [M + H]+.
HRMS (ESI) m/z calcd for C25H40N3O6: 478.29171 [M + H]+; found: 478.29145。
[工程1]酢酸{[(エチルスルファニル)カルボニル]オキシ}メチル
1H-NMR (CDCl3) δ: 1.34 (3H, t, J= 7.4 Hz), 2.14 (3H, s), 2.91 (2H, q, J= 7.4 Hz), 5.81 (2H, s)。
1H-NMR (CDCl3) δ: 0.96 (3H, d, J= 6.6 Hz), 1.07-1.18 (2H, m), 1.42-1.52 (2H, m), 1.59-1.80 (5H, m), 1.85-1.91 (2H, m), 2.09-2.14 (2H, m), 2.11 (3H, s), 2.68-2.75 (1H, m), 2.77-2.92 (2H, m), 3.18-3.23 (2H, m), 3.88 (1H, tt, J= 12.1, 3.9 Hz), 5.26-5.30 (1H, br m), 5.70 (2H, s), 6.78 (1H, s), 7.78 (1H, s).
LRMS (ESI) m/z 410 [M + H]+.
HRMS (ESI) m/z calcd for C20H32N3O6: 410.22911 [M + H]+; found: 410.22892。
MS (FAB) m/z 452 [M + H]+.
HRMS (ESI): m/z calcd for C23H38N3O6: 452.27606 [M + H]+; found: 452.27582。
[工程1](2E)−5−[(tert−ブトキシカルボニル)アミノ]−2−{[1−(3,3−ジメチルシクロヘキシル)−1H−イミダゾール−4−イル]メチレン}吉草酸エチル
1H-NMR (CDCl3) δ: 1.02 (6H, s), 1.18-1.24 (1H, m), 1.32 (3H, t, J= 7.0 Hz), 1.45-1.63 (16H, m), 1.72-1.82 (4H, m), 2.10-2.15 (1H, m), 2.95 (2H, t, J = 7.2 Hz), 3.11-3.16 (2H, m), 4.05-4.12 (1H, m), 7.04 (1H, br s), 7.15 (1H, s), 7.47 (1H, s), 7.58 (1H, s)。
1H-NMR (CDCl3) δ: 0.99 (6H, s), 1.14-1.22 (4H, m), 1.41-1.77 (19H, m), 2.04-2.09 (1H, m), 2.68 (1H, dd, J = 13.9, 6.5 Hz), 2.73-2.80 (1H, m), 2.88 (1H, dd, J = 13.7, 7.4 Hz), 3.04-3.15 (2H, m), 4.00 (1H, tt, J= 12.1, 3.8 Hz), 4.10 (2H, q, J= 7.0 Hz), 4.73 (1H, br s), 6.67 (0H, s), 7.41 (1H, s)。
1H-NMR (CD3OD) δ: 0.99 (3H, s), 1.02 (3H, s), 1.21-1.28 (1H, m), 1.40-1.44 (1H, m), 1.50-1.78 (9H, m), 2.00-2.05 (1H, m), 2.47-2.58 (2H, m), 2.84-2.94 (2.33H, m), 3.55 (0.66H, t, J = 7.1 Hz), 4.13-4.20 (1H, m), 6.94 (0.66H, s), 6.96 (0.33H, s), 7.58 (0.66H, s), 7.62 (0.33H, s)。
[工程1](3E,5S)−5−メチル−3−{[1−(trans−4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチレン}ピペリジン−2−オン
1H-NMR (CDCl3) δ: 0.96 (3H, d, J = 6.7 Hz), 1.09 (3H, d, J = 6.7 Hz), 1.10-1.17 (2H, m), 1.42-1.52 (1H, m), 1.64-1.73 (2H, m), 1.84-1.91 (2H, m), 2.07-2.14 (3H, m), 2.47 (1H, ddd, J = 16.5, 11.1, 2.5 Hz), 3.06-3.12 (1H, m), 3.31-3.36 (1H, m), 3.55-3.61 (1H, m), 3.88 (1H, tt, J = 12.1, 3.9 Hz), 5.78 (1H, br s), 7.12 (1H, s), 7.57 (1H, s), 7.59 (1H, s)。
1H-NMR (CDCl3) δ: 0.96 (3H, d, J = 6.7 Hz), 1.11 (3H, d, J = 6.7 Hz), 1.11-1.18 (2H, m), 1.42-1.52 (1H, m), 1.55 (9H, s), 1.63-1.73 (2H, m), 1.84-1.91 (2H, m), 2.05-2.14 (3H, m), 2.44 (1H, ddd, J = 16.8, 11.0, 2.3 Hz), 3.21 (1H, dd, J = 12.5, 10.2 Hz), 3.41-3.47 (1H, m), 3.85-3.93 (2H, m), 7.15 (1H, s), 7.60 (1H, s), 7.68 (1H, s)。
1H-NMR (CDCl3) δ: 0.94 (3H, d, J = 6.7 Hz), 0.96 (2H, d, J = 6.7 Hz), 0.99 (1H, d, J = 6.7 Hz), 1.03-1.23 (3H, m), 1.40-1.48 (1H, m), 1.52 (6H, s), 1.53 (3H, s), 1.55-1.68 (3H, m), 1.81-1.87 (2H, m), 1.96-2.10 (3H, m), 2.60-2.91 (2H, m), 3.04-3.20 (2H, m), 3.65-3.97 (2H, m), 6.73 (0.7H, s), 6.76 (0.3H, s), 7.41 (1.0H, s)。
1H-NMR (CD3OD) δ: 0.95 (3H, d, J = 6.8 Hz), 0.97 (3H, d, J = 6.8 Hz), 1.10-1.19 (2H, m), 1.37-1.50 (2H, m), 1.64-1.75 (3H, m), 1.81-1.92 (3H, m), 2.00-2.05 (2H, m), 2.51 (1H, dd, J = 14.2, 6.3 Hz), 2.54-2.60 (1H, m), 2.71 (1H, dd, J= 12.7, 6.3 Hz), 2.92-2.85 (2H, m), 3.93 (1H, tt, J = 12.2, 3.9 Hz), 6.93 (1H, s), 7.56 (1H, s).
HRMS (ESI): m/z calcd for C17H29N3Na1O2: 330.21575 [M + H]+; found: 330.21629。
1H-NMR (CD3OD) δ: 0.95 (3H, d, J = 6.8 Hz), 0.98 (3H, d, J = 6.8 Hz), 1.10-1.19 (2H, m), 1.22-1.29 (1H, m), 1.43-1.51 (1H, m), 1.64-1.85 (6H, m), 2.01-2.05 (2H, m), 2.53 (1H, dd, J = 13.9, 6.6 Hz), 2.55-2.61 (1H, m), 2.77 (2H, d, J= 6.8 Hz), 2.88 (1H, dd, J = 13.9, 7.1 Hz), 3.93 (1H, tt, J= 12.0, 3.9 Hz), 6.94 (1H, s), 7.54 (1H, s).
HRMS (ESI): m/z calcd for C17H30N3O2: 308.23380 [M + H]+; found: 308.23370。
[工程1](3E,5R)−5−メチル−3−{[1−(trans−4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチレン}−ピペリジン−2−オン
1H-NMR (CD3OD) δ: 0.95 (3H, d, J = 6.7 Hz), 0.98 (3H, d, J = 6.7 Hz), 1.09-1.27 (3H, m), 1.43-1.52 (1H, m), 1.63-1.86 (6H, m), 2.00-2.06 (2H, m), 2.53 (1H, dd, J = 13.5, 6.5 Hz), 2.56-2.62 (1H, m), 2.77 (2H, d, J = 7.0 Hz), 2.88 (1H, dd, J = 13.9, 6.8 Hz), 3.93 (1H, tt, J = 12.1, 3.9 Hz), 6.95 (1H, s), 7.55 (1H, s)。
1H-NMR (CD3OD) δ: 0.95 (3H, d, J = 6.7 Hz), 0.97 (3H, d, J = 7.0 Hz), 1.09-1.19 (2H, m), 1.36-1.51 (2H, m), 1.63-1.77 (3H, m), 1.80-1.91 (3H, m), 2.00-2.05 (3H, m), 2.51 (1H, dd, J = 13.9, 5.7 Hz), 2.54-2.61 (1H, m), 2.71 (1H, dd, J= 12.9, 6.3 Hz), 2.84-2.93 (2H, m), 3.93 (1H, tt, J = 12.5, 3.5 Hz), 6.93 (1H, s), 7.57 (1H, s)。
[工程1]4−{[(tert−ブトキシカルボニル)アミノ]メチル}−2−{[1−(trans−4−メチルシクロヘキシル)−1H−イミダゾール−4イルl]メチル}ヘキサ−2−エン酸エチル
1H-NMR (CDCl3) δ: 0.89 (3H, t, J = 7.4 Hz), 0.94 (3H, d, J = 6.7 Hz), 1.05-1.16 (2H, m), 1.26 (3H, t, J = 7.0 Hz), 1.33-1.40 (2H, m), 1.44 (9H, s), 1.55-1.63 (3H, m), 1.80-1.87 (2H, m), 2.04-2.09 (2H, m), 2.85-2.94 (1H, m), 3.04-3.11 (1H, m), 3.32-3.37 (1H, m), 3.49 (1H, d, J = 14.1 Hz), 3.61 (1H, d, J = 14.5 Hz), 3.73-3.81 (1H, m), 4.05-4.19 (2H, m), 6.57 (0.5H, s), 6.59 (0.5H, s), 6.76 (1H, s), 7.39 (1H, s), 8.13 (1H, br s)。
1H-NMR (CDCl3) δ: 0.83 (1H, t, J = 7.4 Hz), 0.88 (2H, t, J = 7.4 Hz), 0.95 (3H, d, J = 6.3 Hz), 1.04-1.15 (2H, m), 1.19 (1H, t, J = 7.0 Hz), 1.20 (1H, t, J = 7.0 Hz), 1.25-1.34 (3H, m), 1.42-1.48 (11H, m), 1.58-1.68 (3H, m), 1.81-1.86 (2H, m), 2.03-2.09 (2H, m), 2.63-2.72 (1H, m), 2.82-2.99 (2H, m), 3.05-3.18 (2H, m), 3.75-3.83 (1H, m), 4.09 (1H, q, J = 7.0 Hz), 4.10 (1H, q, J = 7.0 Hz), 5.46 (1H, br s), 6.68 (1H, s), 7.42 (1H, s)。
1H-NMR (CD3OD) δ: 0.90-0.98 (6H, m), 1.16-1.24 (2H, m), 1.36-1.57 (4H, m), 1.74-1.92 (6H, m), 2.12-2.16 (2H, m), 2.85-3.03 (5H, m), 4.21-4.27 (1H, m), 7.55 (0.5H, s), 7.56 (0.5H, s), 8.90 (0.5H, s), 8.92 (0.5H, s).
HRMS (ESI): m/z calcd for C18H32N3O2: 322.24945 [M + H]+; found: 322.24948。
[工程1](2E)−5−[(tert−ブトキシカルボニル)アミノ]−2−{[1−(cis−4−{[tert−ブチル(ジフェニル)シリル]オキシ}シクロヘキシル)−1H−イミダゾール−4−イル]メチレン}吉草酸エチル
1H-NMR (CDCl3) δ: 1.10 (9H, s), 1.33 (3H, t, J = 7.1 Hz), 1.41-1.46 (2H, m), 1.48 (9H, s), 1.74-1.91 (6H, m), 2.22-2.31 (2H, m), 2.98 (2H, t, J = 7.3 Hz), 3.14-3.17 (2H, m), 3.89-3.95 (1H, m), 4.06-4.09 (1H, m), 4.24 (2H, q, J = 7.0 Hz), 7.19 (1H, s), 7.37-7.41 (4H, m), 7.43-7.46 (2H, m), 7.49 (1H, s), 7.64-7.67 (5H, m)。
1H-NMR (CDCl3) δ: 1.32 (3H, t, J = 7.3 Hz), 1.47 (9H, s), 1.66-1.78 (4H, m), 1.88-1.98 (4H, m), 2.12-2.20 (2H, m), 2.93 (2H, t, J = 7.3 Hz), 3.12-3.16 (2H, m), 3.93-4.00 (1H, m), 4.12-4.15 (1H, m), 4.23 (2H, q, J = 7.2 Hz), 6.94 (1H, br s), 7.21 (1H, s), 7.49 (1H, s), 7.61 (1H, s)。
1H-NMR (CDCl3) δ: 1.20 (3H, t, J = 7.4 Hz), 1.43 (9H, s), 1.48-1.71 (6H, m), 1.83-1.94 (4H, m), 2.05-2.15 (2H, m), 2.69 (1H, dd, J = 13.9, 6.5 Hz), 2.74-2.81 (1H, m), 2.89 (1H, dd, J = 13.7, 7.4 Hz), 3.05-3.14 (2H, m), 3.83-3.90 (1H, m), 4.07-4.13 (3H, m), 4.74 (1H, br s), 6.72 (1H, s), 7.45 (1H, s)。
1H-NMR (CD3OD) δ: 1.61-1.89 (10H, m), 2.04-2.12 (2H, m), 2.48-2.59 (2H, m), 2.85-2.92 (3H, m), 3.96-4.02 (2H, m), 6.96 (1H, s), 7.59 (1H, s)。
[工程1](2E)−5−[(tert−ブトキシカルボニル)アミノ]−2−({1−[trans−4−(ピリジン−4−イルオキシ)シクロヘキシル]−1H−イミダゾール−4−イル}メチレン)吉草酸エチル
1H-NMR (CDCl3) δ: 1.33 (3H, t, J = 7.0 Hz), 1.48 (9H, s), 1.68-1.79 (4H, m), 1.84-1.93 (2H, m), 2.25-2.36 (4H, m), 2.90-2.95 (2H, m), 3.12-3.17 (2H, m), 4.04-4.09 (1H, m), 4.24 (2H, q, J = 7.2 Hz), 4.39-4.45 (1H, m), 6.78-6.82 (3H, m), 7.19 (1H, s), 7.49 (1H, s), 7.62 (1H, s), 8.44 (2H, dd, J = 5.1, 1.6 Hz)。
1H-NMR (CDCl3) δ: 1.20 (3H, t, J = 7.0 Hz), 1.44 (9H, s), 1.51-1.70 (6H, m), 1.77-1.87 (2H, m), 2.20-2.32 (4H, m), 2.69 (1H, dd, J = 13.7, 6.7 Hz), 2.74-2.81 (1H, m), 2.90 (1H, dd, J = 13.7, 7.4 Hz), 3.06-3.14 (2H, m), 3.97 (1H, tt, J= 11.7, 3.9 Hz), 4.10 (3H, q, J= 7.0 Hz), 4.38 (1H, tt, J = 11.0, 3.9 Hz), 4.70 (1H, br s), 6.70 (1H, s), 6.80 (2H, dd, J = 4.7, 1.6 Hz), 7.45 (1H, s), 8.43 (2H, dd, J = 4.7, 1.6 Hz)。
1H-NMR (CD3OD) δ: 1.69-1.89 (6H, m), 2.06-2.17 (2H, m), 2.28-2.42 (4H, m), 2.79-2.85 (1H, m), 2.90-2.99 (3H, m), 3.04 (2H, dd, J = 15.3, 9.0 Hz), 4.47 (1H, tt, J= 12.1, 3.9 Hz), 4.96 (1H, tt, J= 11.3, 4.3 Hz), 7.60-7.64 (3H, m), 8.63-8.65 (2H, m), 8.96-8.97 (1H, m)。
[工程1](2E)−5−[(tert−ブトキシカルボニル)アミノ]−2−{[1−(cis−4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチレン}吉草酸メチル
1H-NMR (CDCl3) δ: 1.00 (3H, d, J = 7.0 Hz), 1.44-1.53 (3H, m), 1.48 (9H, s), 1.63-1.80 (4H, m), 1.85-2.04 (5H, m), 2.98 (2H, t, J = 7.2 Hz), 3.13-3.17 (2H, m), 3.78 (3H, s), 4.00-4.06 (1H, m), 7.19 (1H, s), 7.48 (1H, s), 7.65 (1H, s)。
1H-NMR (CDCl3) δ: 0.98 (3H, d, J = 6.7 Hz), 1.44 (9H, s), 1.44-1.69 (7H, m), 1.81-1.88 (4H, m), 1.92-2.01 (2H, m), 2.72 (1H, dd, J = 13.7, 5.9 Hz), 2.78-2.85 (1H, m), 2.90 (1H, dd, J = 13.7, 7.8 Hz), 3.05-3.15 (2H, m), 3.64 (3H, s), 3.90-3.96 (1H, m), 4.76 (1H, brs), 6.72 (1H, s), 7.50 (1H, s)。
1H-NMR (CD3OD) δ: 1.02 (3H, d, J = 7.3 Hz), 1.46-1.55 (3H, m), 1.58-1.72 (5H, m), 1.80-1.87 (3H, m), 1.98-2.06 (2H, m), 2.47-2.58 (2H, m), 2.85-2.94 (3H, m), 3.99-4.04 (1H, m), 6.98 (1H, s), 7.59 (1H, s).
HRMS (ESI) m/z calcd C16H28N3O2: 294.21815 [M + H]+: found: 294.21739。
1H-NMR (CD3OD) δ: 0.95 (3H, d, J = 6.5 Hz), 1.11-1.21 (2H, m), 1.43-1.79 (7H, m), 1.83-1.89 (2H, m), 2.05-2.10 (2H, m), 2.37 (3H, s), 2.57-2.64 (1H, m), 2.70 (1H, dd, J = 14.5, 5.5 Hz), 2.85-2.95 (3H, m), 4.07 (1H, tt, J = 11.7, 3.9 Hz), 7.18 (1H, s), 7.23 (2H, d, J = 7.8 Hz), 7.70 (2H, d, J = 8.2 Hz), 8.22 (1H, s).
元素分析:C16H27N3O2・C7H8O3S、
理論値:C;59.33,H;7.58,N;9.02,O;17.18,S;6.89、
実測値:C;59.09,H;7.53,N;8.92,O;17.22,S;6.78。
―――――――――――――――――――――――――――――――――――
回折ピーク 2θ(°) 面間隔 d(Å) 相対強度(%)
―――――――――――――――――――――――――――――――――――
3.7 23.9 100
7.4 11.9 39.0
11.4 7.8 12.2
17.6 5.0 14.3
19.0 4.7 12.4
19.9 4.5 63.6
20.7 4.3 22.1
22.9 3.9 14.0
24.9 3.6 17.6
27.8 3.2 11.0
――――――――――――――――――――――――――――――――――。
元素分析:C16H27N3O2・C7H8O3S・1H2O、
理論値:C;57.12,H;7.71,N;8.69,O;19.85,S;6.63、
実測値:C;56.90,H;7.69,N;8.67,O;19.81,S;6.42。
得られた標題化合物の粉末X線回折の結果を図3及び表2に、熱分析(TG/DTA)の結果を図4に示す。尚、熱分析(TG/DTA)は乾燥窒素200mL/分気流下、昇温速度10℃/分で測定した。
―――――――――――――――――――――――――――――――――――
回折ピーク 2θ(°) 面間隔 d(Å) 相対強度(%)
―――――――――――――――――――――――――――――――――――
3.9 22.9 73.9
6.7 13.1 21.8
7.7 11.5 35.3
10.4 8.5 20.7
11.5 7.7 21.4
13.8 6.4 23.7
14.2 6.3 26.9
14.6 6.1 31.2
15.5 5.7 35.7
16.4 5.4 40.4
17.6 5.0 61.9
18.1 4.9 48.0
18.8 4.7 100
19.6 4.5 38.1
20.8 4.3 41.1
21.1 4.2 45.3
22.2 4.0 51.5
24.3 3.7 29.1
――――――――――――――――――――――――――――――――――。
(1) TAFIの活性化
反応液の調製にはHEPES buffered saline(20mM HEPES,150mM NaCl、pH7.4、以下HBS)を用いた。250μg/mLのTAFI溶液12μLに、4U/mLヒトトロンビン、12U/mLウサギ肺トロンボモジュリン、及び12mM CaCl2を含むHBS溶液を30μL添加し、穏やかに撹拌した後、室温でTAFIを活性化させた。10分後に100μM PPACK(トロンビン阻害剤)を10μL加え、トロンビンを中和することによりTAFIの活性化を終了させた。生成したTAFIaは氷中保存し、測定に用いる直前に終濃度0.1%となるように調製したBSA(ウシ血清アルブミン)を含むHBS溶液2050μLで希釈した。
被検物質はHBSで溶解し、評価濃度の10倍濃度からなる希釈系列を調製した。96wellプレートの各wellに80μLのTAFIa溶液及び10μLの被検物質を添加し、10分間振盪して混和させた。各wellに5mg/mLに調製したフリルアクリロイル−アラニル−リジン(FAAL)を10μLずつ添加し、この混合液の330nmにおける吸光度の推移を30分間読み取り、基質の分解速度を測定した。
各wellにおける基質の分解速度をTAFIa溶液の希釈系列よりなる標準曲線に当てはめ、TAFIa活性を算出した。被検化合物の濃度とTAFIa活性の相関より、50%阻害濃度(IC50)を算出した。なお、対照として、化合物A(国際公開第2002/014285号パンフレット中の実施例7の化合物)を用いた。結果を表3に示す。
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実施例番号 TAFIa IC50(μM)
―――――――――――――――――――――――――――――――――――
1 0.021
2 0.0083
3 0.0088
4 0.014
5 0.036
6 0.021
7 0.026
8 0.019
9 0.018
10 0.021
11 0.014
12 0.025
13 0.012
14 0.013
15(2R体) >0.10
15(2S体) 0.0078
24 0.0081
25 0.0070
26 0.021
33 0.0075
34(2R,4S体) 0.034
34(2S,4S体) 0.0054
35(2R,4R体) >0.10
35(2S,4R体) 0.0051
36 0.010
37 0.019
38 0.0098
39 0.0093
40 0.0026
化合物A 0.034
――――――――――――――――――――――――――――――――――。
96穴プレートに20μL/wellのHBS、50μL/wellのヒト正常血漿、10μL/wellの化合物溶液(HBSにより溶解し、同バッファーにて段階希釈して化合物溶液を調製した)、10μL/wellのtPA(アクチバシン(協和発酵キリン)を添付の溶解液により60万U/mLになるように調製し、HBSにより希釈)を添加して撹拌後、10μL/wellの反応液A(13.8U/mLのヒトトロンビン、170mMのCaCl2及び0.9U/mLのトロンボモジュリン)を添加して再び撹拌してプレートリーダーにて405nmの吸光度を、37℃で保温しながら30秒ごとに測定し、凝固の程度を測定した。吸光度の推移のうち線溶過程における最大吸光度(ABS−max)と最小吸光度(ABS−min)の平均値(ABS−ave:[(ABS−max)−(ABS−min)]/2)に最も近い吸光度を示す時点を1/2 lysis time(1/2 LT)として各ウェルの線溶活性の指標とした。被験物質の濃度と1/2 LTの関係から、1/2 LTを50%とする濃度をEC50として算出した。なお、対照として、化合物A(国際公開第2002/014285号パンフレット中の実施例7の化合物)を用いた。結果を表4に示す。
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実施例 血漿塊溶解 EC50(nM)
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15(2S体) 12
化合物A 65
――――――――――――――――――――――――――――――――――。
Wistarラット(購入先:日本SLC社)を使用した。任意の時点において0.5%メチルセルロース溶液で調製した被検物質を経口投与し、又は生理食塩水で調製した被験物質を静脈内投与し、40分後又は4時間後にチオペンタール麻酔下にて頸静脈より生理食塩水で2.25U/mLに調製したPT試薬(Thromboplastin C plus、Sysmex)を持続注入(16.8mL/kg/hr x 20min)した。陽性対照群として、過剰用量のTAFIa阻害薬投与群を設定した。PT試薬の注入開始から45分後に頚静脈よりクエン酸採血し、血漿を獲得した。全自動凝固測定装置ACL−9000又はACL−TOP500CTSを用いて血漿中に含まれるD−dimer量を測定し、陽性対照群の平均値に対する比率を算出し、D−dimer50%上昇させる用量としてED50を算出した。
(製剤例1)ハ−ドカプセル剤
標準二分式ハ−ドゼラチンカプセルの各々に、100mgの粉末状の実施例1の化合物、150mgのラクト−ス、50mgのセルロ−ス及び6mgのステアリン酸マグネシウムを充填することにより、単位カプセルを製造し、洗浄後、乾燥する。
消化性油状物、例えば、大豆油、綿実油又はオリ−ブ油中に入れた、実施例2の化合物の混合物を調製し、正置換ポンプでゼラチン中に注入して、100mgの活性成分を含有するソフトカプセルを得、洗浄後、乾燥する。
常法に従って、100mgの実施例3の化合物、0.2mgのコロイド性二酸化珪素、5mgのステアリン酸マグネシウム、275mgの微結晶性セルロ−ス、11mgのデンプン及び98.8mgのラクト−スを用いて製造する。
5mL中に、100mgの微粉化した実施例4の化合物、100mgのナトリウムカルボキシ基メチルセルロ−ス、5mgの安息香酸ナトリウム、1.0gのソルビト−ル溶液(日本薬局方)及び0.025mLのバニリンを含有するように製造する。
40%のホワイトペトロラトム、3%の微結晶性ワックス、10%のラノリン、5%のスパン20、0.3%のトゥイ−ン20及び41.7%の水からなる5gのクリ−ム中に100mgの微粉化した実施例5の化合物を混入することにより製造する。
Claims (32)
- 一般式(I−1a)
- (2S)−5−アミノ−2−{[1−(トランス−4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸、又はその薬理上許容される塩。
- (2S)−5−アミノ−2−{[1−(トランス−4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸。
- (2S)−5−アミノ−2−{[1−(トランス−4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸・ベンゼンスルホン酸塩。
- (2S)−5−アミノ−2−{[1−(トランス−4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸・p−トルエンスルホン酸塩。
- (2S)−5−アミノ−2−{[1−(トランス−4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸・p−トルエンスルホン酸塩・無水物。
- 銅のKα線の照射で得られる粉末X線回折において、面間隔d=23.9、11.9、4.5、4.3及び3.6オングストロームに主要なピークを示す結晶である請求項6に記載の(2S)−5−アミノ−2−{[1−(トランス−4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸・p−トルエンスルホン酸塩・無水物。
- (2S)−5−アミノ−2−{[1−(トランス−4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸・p−トルエンスルホン酸塩・一水和物。
- 銅のKα線の照射で得られる粉末X線回折において、面間隔d=22.9、5.0、4.9、4.7及び4.0オングストロームに主要なピークを示す結晶である請求項8に記載の(2S)−5−アミノ−2−{[1−(トランス−4−メチルシクロヘキシル)−1H−イミダゾール−4−イル]メチル}吉草酸・p−トルエンスルホン酸塩・一水和物。
- 請求項1〜9のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する医薬。
- 請求項1〜9のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有するTAFIa阻害薬。
- 請求項1〜9のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する線溶促進剤。
- 請求項1〜9のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、線溶が阻害されることにより引き起こされる疾患の予防薬若しくは治療薬。
- 請求項1〜9のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、血栓症・塞栓症及びそれらの後遺症の予防薬若しくは治療薬。ここで、該血栓症・塞栓症は、急性冠症候群;静脈血栓塞栓症;外科的手術後の心臓血管系に起こる血栓症若しくは塞栓症;人工関節置換手術後の血栓症若しくは塞栓症;炎症に関連する血管内の疾患;末梢血管障害に由来・関連する疾患;腫瘍に関連する疾患;又は、血栓・塞栓に起因する臓器の障害である。
- 血栓症・塞栓症が、心筋梗塞、安定狭心症、不安定狭心症;深部静脈血栓症、肺塞栓症;血管再開通術、血管形成術、ステント留置術、若しくはバイパス手術後の心臓血管系に起こる血栓症若しくは塞栓症;膝関節置換手術、若しくは股関節置換手術後の血栓症若しくは塞栓症;敗血症、若しくは播種性血管内凝固症候群(DIC)に関連する血管内の疾患;末梢動脈塞栓症(PAO)、動脈硬化、若しくは糖尿病に由来・関連する疾患;固形癌、若しくは血液癌に関連する疾患;又は、肺塞栓、脳梗塞、若しくは腎梗塞に起因する臓器の障害である、請求項14に記載の血栓症・塞栓症及びそれらの後遺症の予防薬若しくは治療薬。
- 請求項1〜9のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、血栓症・塞栓症の予防薬若しくは治療薬。ここで、該血栓症・塞栓症は、体内の異物との接触によって起こる疾患;又は、体外の医療器具と血液が接触することによって起こる疾患である。
- 血栓症・塞栓症が、医療機器との接触によって起こる疾患である、請求項16に記載の血栓症・塞栓症の予防薬若しくは治療薬。
- 血栓症・塞栓症が、関節置換術時の人工関節、血管カテーテル、人工血管、血管ステント、若しくは人工弁との接触によって起こる疾患である、請求項17に記載の血栓症・塞栓症の予防薬若しくは治療薬。
- 血栓症・塞栓症が、心臓手術時の人工心肺装置、若しくは血液透析時の医療器具と血液が接触することによって起こる疾患である、請求項16に記載の血栓症・塞栓症の予防薬若しくは治療薬。
- 請求項1〜9のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、血栓・塞栓症に関連する又はフィブリン沈着若しくは線維化を伴う疾患の予防薬若しくは治療薬。ここで、該疾患は、肺の疾患;腎臓の疾患;肝臓の疾患;眼部フィブリン沈着に伴う眼部の疾患;臓器移植若しくは切除術後の臓器機能障害;微小血栓による微小循環障害;又は、癌細胞の遊走・転移に伴う疾患・症状である。
- 疾患が、肺高血圧症、成人呼吸切迫症候群、肺線維症、慢性血栓塞栓性肺高血圧症;糸球体腎炎、腎臓梗塞、糖尿病性腎炎;肝線維症、肝炎、肝硬変;又は、血栓性微小血管症である、請求項20に記載の血栓・塞栓症に関連する又はフィブリン沈着若しくは線維化を伴う疾患の予防薬若しくは治療薬。
- 疾患が、急性糸球体腎炎、慢性糸球体腎炎、ネフローゼ性腎炎、若しくは急性進行性糸球体腎炎である、請求項21に記載の血栓・塞栓症に関連する又はフィブリン沈着若しくは線維化を伴う疾患の予防薬若しくは治療薬。
- 請求項1〜9のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、心筋梗塞、狭心症、急性冠不全症候群、脳梗塞、深部静脈血栓症、肺塞栓症、末梢動脈塞栓症、敗血症、播種性血管内凝固症候群又は肺線維症の治療薬。
- 請求項1〜9のいずれか1項に記載の化合物又はその薬理上許容される塩及び薬理上許容される担体を含有する医薬組成物。
- 心筋梗塞、狭心症、急性冠不全症候群、脳梗塞、深部静脈血栓症、肺塞栓症、末梢動脈塞栓症、敗血症、播種性血管内凝固症候群又は肺線維症の治療における使用のための請求項1〜9のいずれか1項に記載の化合物又はその薬理上許容される塩。
- 請求項1〜9のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する注射用医薬。
- 請求項1〜9のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する注射用TAFIa阻害薬。
- 請求項1〜9のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、心筋梗塞、狭心症、急性冠不全症候群、脳梗塞、深部静脈血栓症、肺塞栓症、末梢動脈塞栓症、敗血症、播種性血管内凝固症候群又は肺線維症の注射用治療薬。
- 請求項1〜9のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、血栓塞栓症に由来する疾患の注射用治療薬。
- 請求項1〜9のいずれか1項に記載の化合物又はその薬理上許容される塩及び薬理上許容される担体を含有する注射用医薬組成物。
- 心筋梗塞、狭心症、急性冠不全症候群、脳梗塞、深部静脈血栓症、肺塞栓症、末梢動脈塞栓症、敗血症、播種性血管内凝固症候群又は肺線維症の注射での治療における使用のための請求項1〜9のいずれか1項に記載の化合物又はその薬理上許容される塩。
- 請求項1〜9のいずれか1項に記載の化合物又はその薬理上許容される塩、並びに、抗凝固薬、抗血小板薬、線溶に関わる酵素、抗癌薬、抗炎症薬、抗線維化薬、降圧薬、抗肺高血圧薬及び免疫抑制薬から選ばれる1種又は2種以上の薬剤を有効成分として含有する医薬組成物。
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WO2017170460A1 (ja) * | 2016-03-29 | 2017-10-05 | 第一三共株式会社 | 炎症性腸疾患治療剤 |
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