JP6667507B2 - ピラゾロ[3,4−c]ピリジン誘導体 - Google Patents
ピラゾロ[3,4−c]ピリジン誘導体 Download PDFInfo
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- JP6667507B2 JP6667507B2 JP2017512022A JP2017512022A JP6667507B2 JP 6667507 B2 JP6667507 B2 JP 6667507B2 JP 2017512022 A JP2017512022 A JP 2017512022A JP 2017512022 A JP2017512022 A JP 2017512022A JP 6667507 B2 JP6667507 B2 JP 6667507B2
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- pyrazolo
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- 150000005231 pyrazolo[3,4-c]pyridines Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 252
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 50
- 125000000217 alkyl group Chemical group 0.000 claims description 50
- 229910052757 nitrogen Inorganic materials 0.000 claims description 46
- 150000003839 salts Chemical class 0.000 claims description 39
- 230000003287 optical effect Effects 0.000 claims description 37
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 239000001257 hydrogen Substances 0.000 claims description 30
- 125000003545 alkoxy group Chemical group 0.000 claims description 23
- 201000010099 disease Diseases 0.000 claims description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 15
- 208000032843 Hemorrhage Diseases 0.000 claims description 14
- 125000004429 atom Chemical group 0.000 claims description 14
- 208000034158 bleeding Diseases 0.000 claims description 13
- 230000000740 bleeding effect Effects 0.000 claims description 13
- 238000004519 manufacturing process Methods 0.000 claims description 13
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 13
- 206010047249 Venous thrombosis Diseases 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 108010074860 Factor Xa Proteins 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 206010051055 Deep vein thrombosis Diseases 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 208000010378 Pulmonary Embolism Diseases 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- 208000010125 myocardial infarction Diseases 0.000 claims description 7
- 125000004043 oxo group Chemical group O=* 0.000 claims description 7
- 208000037803 restenosis Diseases 0.000 claims description 7
- 206010002383 Angina Pectoris Diseases 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 206010010904 Convulsion Diseases 0.000 claims description 5
- 208000005189 Embolism Diseases 0.000 claims description 5
- 206010061334 Partial seizures Diseases 0.000 claims description 5
- 208000001435 Thromboembolism Diseases 0.000 claims description 5
- 238000002399 angioplasty Methods 0.000 claims description 5
- 210000004351 coronary vessel Anatomy 0.000 claims description 5
- 230000008092 positive effect Effects 0.000 claims description 5
- 238000001356 surgical procedure Methods 0.000 claims description 5
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 208000009190 disseminated intravascular coagulation Diseases 0.000 claims description 4
- 230000001052 transient effect Effects 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 3
- 150000002431 hydrogen Chemical group 0.000 claims 11
- 239000000203 mixture Substances 0.000 description 497
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 141
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 134
- 239000011541 reaction mixture Substances 0.000 description 131
- 239000007787 solid Substances 0.000 description 128
- 238000006243 chemical reaction Methods 0.000 description 119
- 239000012043 crude product Substances 0.000 description 119
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 105
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 102
- 239000012074 organic phase Substances 0.000 description 101
- 239000000243 solution Substances 0.000 description 89
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 72
- -1 hemiesters Chemical class 0.000 description 71
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 70
- 238000010898 silica gel chromatography Methods 0.000 description 70
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 68
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 67
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 51
- 239000004698 Polyethylene Substances 0.000 description 50
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 46
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- 239000012065 filter cake Substances 0.000 description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 44
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 38
- 229910000027 potassium carbonate Inorganic materials 0.000 description 36
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 36
- 239000005457 ice water Substances 0.000 description 35
- 239000003921 oil Substances 0.000 description 35
- 238000003756 stirring Methods 0.000 description 32
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 26
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 24
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- 239000008346 aqueous phase Substances 0.000 description 21
- 238000002360 preparation method Methods 0.000 description 19
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 18
- 235000010288 sodium nitrite Nutrition 0.000 description 18
- PSOYDCQSXGQZKM-UHFFFAOYSA-N ethyl 1-(4-methoxyphenyl)-7-oxo-5,6-dihydro-4h-pyrazolo[3,4-c]pyridine-3-carboxylate Chemical compound C1CNC(=O)C2=C1C(C(=O)OCC)=NN2C1=CC=C(OC)C=C1 PSOYDCQSXGQZKM-UHFFFAOYSA-N 0.000 description 16
- 238000010992 reflux Methods 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 238000002953 preparative HPLC Methods 0.000 description 15
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 15
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 15
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 14
- 238000000034 method Methods 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 239000001632 sodium acetate Substances 0.000 description 14
- 235000017281 sodium acetate Nutrition 0.000 description 14
- RDULEYWUGKOCMR-UHFFFAOYSA-N ethyl 2-chloro-3-oxobutanoate Chemical compound CCOC(=O)C(Cl)C(C)=O RDULEYWUGKOCMR-UHFFFAOYSA-N 0.000 description 13
- OYDSTJMVOOOYDW-UHFFFAOYSA-N 1-(4-iodophenyl)piperidin-2-one Chemical compound C1=CC(I)=CC=C1N1C(=O)CCCC1 OYDSTJMVOOOYDW-UHFFFAOYSA-N 0.000 description 11
- 239000008213 purified water Substances 0.000 description 11
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 10
- SRICXDSOENVWEU-UHFFFAOYSA-N 5-morpholin-4-yl-2,3-dihydro-1h-pyridin-6-one Chemical compound O=C1NCCC=C1N1CCOCC1 SRICXDSOENVWEU-UHFFFAOYSA-N 0.000 description 10
- 0 CCOc(ccc(NC(C(N(CC1)c(cc2)cc(C)c2N(C=CC=C2C)C2=O)=O)=C1C(C(*)=O)=N)c1)c1F Chemical compound CCOc(ccc(NC(C(N(CC1)c(cc2)cc(C)c2N(C=CC=C2C)C2=O)=O)=C1C(C(*)=O)=N)c1)c1F 0.000 description 10
- 208000007536 Thrombosis Diseases 0.000 description 10
- 230000002785 anti-thrombosis Effects 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- PVNIIMVLHYAWGP-UHFFFAOYSA-M nicotinate Chemical compound [O-]C(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-M 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 102100029117 Coagulation factor X Human genes 0.000 description 8
- 108010014173 Factor X Proteins 0.000 description 8
- 241000700159 Rattus Species 0.000 description 8
- 108090000190 Thrombin Proteins 0.000 description 8
- 229940105756 coagulation factor x Drugs 0.000 description 8
- KVKFRMCSXWQSNT-UHFFFAOYSA-N n,n'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 description 8
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 229960004072 thrombin Drugs 0.000 description 8
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 7
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Substances IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 7
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 230000007935 neutral effect Effects 0.000 description 6
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 6
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 5
- VLVCDUSVTXIWGW-UHFFFAOYSA-N 4-iodoaniline Chemical compound NC1=CC=C(I)C=C1 VLVCDUSVTXIWGW-UHFFFAOYSA-N 0.000 description 5
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 5
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 5
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- 239000003114 blood coagulation factor Substances 0.000 description 5
- 229960002897 heparin Drugs 0.000 description 5
- 229920000669 heparin Polymers 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 238000010926 purge Methods 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 235000009518 sodium iodide Nutrition 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- JREJQAWGQCMSIY-UHFFFAOYSA-N 1-methyl-pyrazole-5-carboxylic acid Chemical compound CN1N=CC=C1C(O)=O JREJQAWGQCMSIY-UHFFFAOYSA-N 0.000 description 4
- RDVZKTUYZCMKJY-UHFFFAOYSA-N 3,3-dichloropiperidin-2-one Chemical compound ClC1(Cl)CCCNC1=O RDVZKTUYZCMKJY-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- MDCPVYOIYISUFL-UHFFFAOYSA-N 5-chloro-2,3-dihydro-1h-pyridin-6-one Chemical compound ClC1=CCCNC1=O MDCPVYOIYISUFL-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 239000003146 anticoagulant agent Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 210000001715 carotid artery Anatomy 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 210000004731 jugular vein Anatomy 0.000 description 4
- MZPYRLHUTZAOMB-UHFFFAOYSA-N n-ethyl-5-iodo-2-propoxyaniline Chemical compound CCCOC1=CC=C(I)C=C1NCC MZPYRLHUTZAOMB-UHFFFAOYSA-N 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- WHDKRPSSEZGGMR-UHFFFAOYSA-N 1-(4-iodophenyl)-4-methylpiperazine Chemical compound C1CN(C)CCN1C1=CC=C(I)C=C1 WHDKRPSSEZGGMR-UHFFFAOYSA-N 0.000 description 3
- IUSWJCWFXRTVCM-UHFFFAOYSA-N 1-(4-iodophenyl)pyrrolidin-2-one Chemical compound C1=CC(I)=CC=C1N1C(=O)CCC1 IUSWJCWFXRTVCM-UHFFFAOYSA-N 0.000 description 3
- XOAWHQBWIYBHCF-UHFFFAOYSA-N 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopyrrolidin-1-yl)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridine-3-carboxamide Chemical compound COC1=CC=C(C=C1)N1N=C(C2=C1C(N(CC2)C1=CC=C(C=C1)N1C(CCC1)=O)=O)C(=O)N XOAWHQBWIYBHCF-UHFFFAOYSA-N 0.000 description 3
- FDWHMIVBLKBTFC-UHFFFAOYSA-N 3-bromo-n-(2-phenoxyethyl)aniline Chemical compound BrC1=CC=CC(NCCOC=2C=CC=CC=2)=C1 FDWHMIVBLKBTFC-UHFFFAOYSA-N 0.000 description 3
- HEROFNJKFRAPQN-UHFFFAOYSA-N 3-bromo-n-[(2-methylpyrazol-3-yl)methyl]aniline Chemical compound CN1N=CC=C1CNC1=CC=CC(Br)=C1 HEROFNJKFRAPQN-UHFFFAOYSA-N 0.000 description 3
- ASLWQZGYKULGPD-UHFFFAOYSA-N 4-ethoxy-3-fluoroaniline Chemical compound CCOC1=CC=C(N)C=C1F ASLWQZGYKULGPD-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- QNZCBYKSOIHPEH-UHFFFAOYSA-N Apixaban Chemical compound C1=CC(OC)=CC=C1N1C(C(=O)N(CC2)C=3C=CC(=CC=3)N3C(CCCC3)=O)=C2C(C(N)=O)=N1 QNZCBYKSOIHPEH-UHFFFAOYSA-N 0.000 description 3
- VCBYWTAXTXFFDA-UHFFFAOYSA-N COC1=CC(=C(C=C1)N1N=C(C2=C1C(N(CC2)C1=CC=C(C=C1)N1C(CCCC1)=O)=O)C(=O)N)C Chemical compound COC1=CC(=C(C=C1)N1N=C(C2=C1C(N(CC2)C1=CC=C(C=C1)N1C(CCCC1)=O)=O)C(=O)N)C VCBYWTAXTXFFDA-UHFFFAOYSA-N 0.000 description 3
- SNRHWCVENDIQLC-UHFFFAOYSA-N COC1=CC=C(C=C1)N1N=C(C2=C1C(N(CC2)C1=CC(=CC=C1)NCCOC1=CC=CC=C1)=O)C(=O)OCC Chemical compound COC1=CC=C(C=C1)N1N=C(C2=C1C(N(CC2)C1=CC(=CC=C1)NCCOC1=CC=CC=C1)=O)C(=O)OCC SNRHWCVENDIQLC-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- PCJBVBFDDZLXCP-UHFFFAOYSA-N O=C1N(C(CC1)=O)C1=CC=C(C=C1)N1C(C2=C(CC1)C(=NN2C1=CC=C(C=C1)OC)C(=O)OCC)=O Chemical compound O=C1N(C(CC1)=O)C1=CC=C(C=C1)N1C(C2=C(CC1)C(=NN2C1=CC=C(C=C1)OC)C(=O)OCC)=O PCJBVBFDDZLXCP-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 108010094028 Prothrombin Proteins 0.000 description 3
- 102100027378 Prothrombin Human genes 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 229910006124 SOCl2 Inorganic materials 0.000 description 3
- 208000006011 Stroke Diseases 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 229960003886 apixaban Drugs 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 3
- 208000029078 coronary artery disease Diseases 0.000 description 3
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- JHRJWKITOHSLCA-UHFFFAOYSA-N ethyl 1-(4-ethoxy-3-fluorophenyl)-7-oxo-5,6-dihydro-4H-pyrazolo[3,4-c]pyridine-3-carboxylate Chemical compound C(C)OC1=C(C=C(C=C1)N1N=C(C2=C1C(NCC2)=O)C(=O)OCC)F JHRJWKITOHSLCA-UHFFFAOYSA-N 0.000 description 3
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- 150000003973 alkyl amines Chemical class 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 150000007854 aminals Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000007953 anoxia Effects 0.000 description 1
- 230000002429 anti-coagulating effect Effects 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 229940127217 antithrombotic drug Drugs 0.000 description 1
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 239000012503 blood component Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 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
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000003593 chromogenic compound Substances 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 230000035602 clotting Effects 0.000 description 1
- 229940105772 coagulation factor vii Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- DMSZORWOGDLWGN-UHFFFAOYSA-N ctk1a3526 Chemical compound NP(N)(N)=O DMSZORWOGDLWGN-UHFFFAOYSA-N 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- DFVMTLWWDLZZFJ-UHFFFAOYSA-N ethyl 1-[2-(difluoromethoxy)phenyl]-7-oxo-5,6-dihydro-4H-pyrazolo[3,4-c]pyridine-3-carboxylate Chemical compound FC(OC1=C(C=CC=C1)N1N=C(C2=C1C(NCC2)=O)C(=O)OCC)F DFVMTLWWDLZZFJ-UHFFFAOYSA-N 0.000 description 1
- CAERSDJFKGMKLY-UHFFFAOYSA-N ethyl 2-(3-bromophenyl)acetate Chemical compound CCOC(=O)CC1=CC=CC(Br)=C1 CAERSDJFKGMKLY-UHFFFAOYSA-N 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 125000005469 ethylenyl group Chemical group 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- KANJSNBRCNMZMV-ABRZTLGGSA-N fondaparinux Chemical compound O[C@@H]1[C@@H](NS(O)(=O)=O)[C@@H](OC)O[C@H](COS(O)(=O)=O)[C@H]1O[C@H]1[C@H](OS(O)(=O)=O)[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O[C@@H]4[C@@H]([C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O4)NS(O)(=O)=O)[C@H](O3)C(O)=O)O)[C@@H](COS(O)(=O)=O)O2)NS(O)(=O)=O)[C@H](C(O)=O)O1 KANJSNBRCNMZMV-ABRZTLGGSA-N 0.000 description 1
- 229960001318 fondaparinux Drugs 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 150000003948 formamides Chemical class 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002373 hemiacetals Chemical class 0.000 description 1
- 150000002374 hemiaminals Chemical class 0.000 description 1
- 208000031169 hemorrhagic disease Diseases 0.000 description 1
- 230000002439 hemostatic effect Effects 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 208000028867 ischemia Diseases 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
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 238000013150 knee replacement Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- CDGNLUSBENXDGG-UHFFFAOYSA-N meta-Cresidine Chemical compound COC1=CC=C(N)C(C)=C1 CDGNLUSBENXDGG-UHFFFAOYSA-N 0.000 description 1
- PEECTLLHENGOKU-UHFFFAOYSA-N n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC=C1.CN(C)C1=CC=NC=C1 PEECTLLHENGOKU-UHFFFAOYSA-N 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000001323 posttranslational effect Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 235000004252 protein component Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 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 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- GJGLBUZZTLPCOT-UHFFFAOYSA-N tert-butyl n-(3-hydroxypropyl)-n-methylcarbamate Chemical compound OCCCN(C)C(=O)OC(C)(C)C GJGLBUZZTLPCOT-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 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
- 230000000699 topical effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
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- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
式(I)の化合物、その互変異性体、もしくはそれらの光学異性体、またはそれらの薬学的に許容される塩
Xは、CHおよびNから選択され、
Zは、
RNaおよびRNbはそれぞれ独立して、水素、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、C1−6アルコキシ−C0−6アルキル、(C0−6アルキル)(C0−6アルキル)N−C1−6アルキル、(C2−6アルキレン)N−C1−6アルキルまたはカルバモイル−C1−6アルキルから選択されるか、あるいは
RNaおよびRNbは、それらに結合している原子とともに5員環、6員環または7員環部分を形成しており、
ここで、
5員環、6員環または7員環部分は、1つのRNgで置換されており、該RNgは水素、C1−4アルキル、ヒドロキシル、C1−4アルコキシ、ハロゲン、オキソおよびアミノから選択され、
5員環、6員環または7員環部分は、RNbに結合しているN原子以外に、N、OおよびSから選択される0、1、2、3または4個のヘテロ原子を含み、
5員環、6員環または7員環部分は、0、1、2または3個の二重結合を含み、
RNcは、水素、C1−6アルキルおよびC1−6アルコキシから選択され、
RNdは、水素、C1−6アルコキシ、ハロゲン置換C1−6アルコキシ、カルバモイル−C1−6アルキルおよびC1−6アルコキシ−C1−6アルキルから選択され、
RNeは、水素、ハロゲン、C1−6アルコキシ、ハロゲン置換C1−6アルコキシ、カルバモイル−C1−6アルキルおよびC1−6アルコキシ−C1−6アルキルから選択され、
RNfは、水素、ハロゲン、C1−6アルコキシ、ハロゲン置換C1−6アルコキシ、カルバモイル−C1−6アルキルおよびC1−6アルコキシ−C1−6アルキルから選択される。)
(ただし、式(I)の化合物は請求項1から除外されている化合物を含まない。)
XがCHである、上述の解決策のいずれかによる式(I)の化合物、その互変異性体もしくはそれらの光学異性体、またはそれらの薬学的に許容される塩。
Zは、
RNaおよびRNbは、それに結合される原子とともに5員環、6員環または7員環部分を形成しており、
ここで、
5員環、6員環または7員環部分は、1つのRNgで置換されており、該RNgは水素、C1−4アルキル、ヒドロキシル、C1−4アルコキシ、ハロゲン、オキソおよびアミノから選択され、
5員環、6員環または7員環部分は、RNbに結合しているN原子以外に、N、OおよびSから選択される0、1、2、3または4個のヘテロ原子を含み、
5員環、6員環または7員環部分は、0、1、2または3個の二重結合を含む、上述の解決策のいずれかによる式(I)の化合物、その互変異性体もしくはそれらの光学異性体、またはそれらの薬学的に許容される塩。
RNcが水素およびメチルから選択される、上述の解決策のいずれかによる式(I)の化合物、その互変異性体もしくはそれらの光学異性体、またはそれらの薬学的に許容される塩。
RNdは、C1−3アルコキシから選択される、上述の解決策のいずれかによる式(I)の化合物、その互変異性体もしくはそれらの光学異性体、またはそれらの薬学的に許容される塩。
RNeは、水素、塩素およびフッ素から選択される、上述の解決策のいずれかによる式(I)の化合物、その互変異性体もしくはそれらの光学異性体、またはそれらの薬学的に許容される塩。
RNfは、水素、塩素およびフッ素から選択される、上述の解決策のいずれかによる式(I)の化合物、その互変異性体もしくはそれらの光学異性体、またはそれらの薬学的に許容される塩。
Zは、
RNaおよびRNbは、それに結合される原子とともに5員環、6員環または7員環部分を形成しており、
ここで、
5員環、6員環または7員環部分は、1つのRNgで置換されており、該RNgは水素、C1−4アルキル、ヒドロキシル、C1−4アルコキシ、ハロゲン、オキソおよびアミノから選択され、
5員環、6員環または7員環部分は、RNbに結合しているN原子以外に、N、OおよびSから選択される0、1、2、3または4個のヘテロ原子を含み、
5員環、6員環または7員環部分は0、1、2または3個の二重結合を含み、
RNdは、C1−6アルコキシから選択され、
RNc、RNg、RNeおよびRNfのうち少なくとも1つは水素ではない、上述の解決策のいずれかによる式(I)の化合物、その互変異性体もしくはそれらの光学異性体、またはそれらの薬学的に許容される塩。
Xは、CHであり、
Zは、
RNaおよびRNbは、それに結合される原子とともに5員環、6員環または7員環部分を形成しており、
ここで、
5員環、6員環または7員環部分は、1つのRNgで置換されており、該RNgは水素およびメチルから選択され、
5員環、6員環または7員環部分は、RNbに結合しているN原子以外に、N、OおよびSから選択される0、1、2、3または4個のヘテロ原子を含み、
5員環、6員環または7員環部分は0、1、2または3個の二重結合を含み、
RNdは、エトキシから選択され、
RNc、RNg、RNeおよびRNfのうち少なくとも1つは水素ではない、上述の解決策のいずれかによる式(I)の化合物、その互変異性体もしくはそれらの光学異性体、またはそれらの薬学的に許容される塩。
Xは、CHであり、
Zは、
RNaおよびRNbは、それに結合される原子とともに5員環、6員環または7員環部分を形成しており、
ここで、
5員環、6員環または7員環部分は、1つのRNgで置換されており、該RNgは水素およびメチルから選択され、
5員環、6員環または7員環部分は、RNbに結合しているN原子以外に、N、OおよびSから選択される0、1、2、3または4個のヘテロ原子を含み、
5員環、6員環または7員環部分は0、1、2または3個の二重結合を含み、
RNdは、エトキシから選択され、
RNcは、メチルである、上述の解決策のいずれかによる式(I)の化合物、その互変異性体もしくはそれらの光学異性体、またはそれらの薬学的に許容される塩。
以下の化合物、その互変異性体もしくはそれらの光学異性体、またはそれらの薬学的に許容される塩
材料:
酵素:第Xa因子(MERK)
基質:CS−1122(Hyphen)
緩衝液:50mMのTrisHCl、150mMのNaCl、PH8.3
100μLの緩衝液、50μLの濃度の異なる化合物(緩衝液で希釈)および50μlの0.1U/ml第Xa因子酵素(緩衝液で希釈)を96ウェルプレートに添加した。15分の曝露後、50μLの2.5mg/ml発色性基質CS−11(22)を添加した。マイクロプレート分光光度計を使用して、最大30分間(間隔30秒)、37℃で405nmでの吸光指数を測定することにより、基質加水分解をモニターした。IC50をblissにより算出した。以下に記載する化合物の値を測定した。
雄性SDラットをランダムに割り付けて投与した。投与後、10%の抱水クロラールの腹腔内注射によってラットを麻酔した。投与後0.5〜4時間の時点(PKのTmax)で、麻酔したラット尾部を先端から3mmで横断切開し、37℃の生理食塩水に垂直に浸漬した。連続血流が30秒より長く停止した時点を測定した。出血時間の延長は、処置群の値とビヒクル群の平均値との比で表した。以下に記載するように、化合物の効果を決定した。
6cmの絹糸を通し、ヘパリン(3.125U/ml)を充填した中心部(長さ8cm、内径2.11mmおよび外径3.77mm)に連結されている2つの長さ10cmのポリエチレン管(内径1.50mmおよび外径2.88mm)をラットの右頸動脈と左頸静脈の間に留置した。
Boc t−ブチルオキシカルボリル
DCM メチレンクロリド
DEAD ジエチルアゾジカルボキシレート
DIPEA N,N−ジイソプロピルエチルアミン
DMF ジメチルホルムアミド
DMSO ジメチルスルホキシド
EA エチルアセテート
EDCI 1−(3−ジメチルアミノプロピル)−3−エチルカルボジイミド塩酸塩
HOBt ヒドロキシベンゾトリゾール
MeOH メタノール
PE 石油エーテル
THF テトラヒドロフラン
NIS N−ヨードスクシンイミド
分取HPLC 分取高速液体クロマトグラフィー
(Boc)2O 二炭酸ジ−tert−ブチル
NBS N−ブロモスクシンイミド
HATU O−(7−アザベンゾトリアゾール−1−イル)−N,N,N′,N′−テトラメチルウロニウムヘキサフルオロホスフェート
MTBE メチル−t−ブチルエーテル
NIS N−ヨードスクシンイミド
KTB カリウムtert−ブトキシド
TEA トリエチルアミン
MsCl 塩化メタンスルホニル
EG エタンジオール
DMAP 4−ジメチルアミノピリジン
(1)化合物C1〜C6の製造方法
50mLフラスコに、化合物G(例えば40.0mmol)およびカリウムtert−ブトキシド(例えば40.0mmol)を添加し、次いでDMF(例えば30mL)を添加した。混合物を0℃で1時間撹拌し、化合物F−a(例えば20.0mmol)を添加した。混合物を90℃に加熱し、6時間反応させた。反応完了後、反応混合物を室温に冷却し、精製水およびエチルアセテートを添加した。有機相を分離して濃縮し、約70%の収率で生成物を得た。
50mLフラスコに、化合物F−b(例えば10.0mmol)、Pd/C(例えば0.5g)およびメタノール(例えば20mL)を添加した。混合物を室温および常圧で、4時間水素添加した。反応完了後、反応混合物を濾過し、濾液を真空下で濃縮して、98%超の収率で油を得た。
50mLフラスコに、化合物F−c(例えば8.0mmol)、精製水(例えば10mL)および濃塩酸(例えば1.7mL、20.0mmol)を添加した。混合物を撹拌しながら0〜5℃に冷却した。0〜5℃の温度を維持したまま、亜硝酸ナトリウム水溶液(例えば10mL)を混合物に滴加した。滴加完了後、温度を維持したまま混合物を20分間撹拌した。次に、ヨウ化ナトリウム(2.99g、20.0mmol)を反応混合物に添加し、得られた混合物を室温で2時間撹拌した。反応完了後、酢酸エチルを反応混合物に添加した。水相と有機相とを分離した。水相を酢酸エチルで抽出した。有機相を混合して濃縮し、80%の収率で生成物を得た。
50mLフラスコに、化合物F−c(例えば8.0mmol)、精製水(例えば10mL)および濃塩酸(例えば1.7mL、20.0mmol)を添加した。混合物を撹拌しながら0〜5℃に冷却した。0〜5℃の温度を維持したまま、亜硝酸ナトリウム水溶液(例えば10mL)を混合物に滴加した。滴加完了後、温度を維持したまま混合物を20分間撹拌した。次に、ヨウ化ナトリウム(2.99g、20.0mmol)を反応混合物に添加し、得られた混合物を室温で2時間撹拌した。反応完了後、酢酸エチルを反応混合物に添加した。水相と有機相とを分離した。水相を酢酸エチルで抽出した。有機相を混合して濾過した。トリフルオロ酢酸(例えば10.0mmol)を濾液に添加した。得られた混合物を室温で4時間撹拌した。水を混合物に添加して抽出した。有機相を真空下で濃縮し、約80%の収率で生成物を得た。
50mLフラスコに、化合物F−a(例えば20.0mmol)、アルキルアミン(例えばメチルアミンおよびイソプロピルアミン)水溶液(例えば60.0mmol)および炭酸カリウム(例えば5.5g、39.8mmol)を添加し、次いでDMF(例えば30mL)を添加した。混合物を50℃に加熱し、4時間反応させた。反応完了後、反応混合物を室温に冷却し、精製水に注いだ。得られた混合物を濾過し、約80%の収率で生成物を得た。
50mLフラスコに、化合物F−d(例えば5.0mmol)、トリエチルアミン(例えば1.0mmol)およびジクロロメタン(例えば20mL)を添加した。混合物を0℃まで冷却し、化合物G(例えば6.0mmol)を滴加した。滴加完了後、混合物を室温で1時間撹拌した。得られた混合物に、5%の炭酸ナトリウム水溶液(例えば40mL)を添加した。有機相を分離して濃縮し、約90%の収率で生成物を得た。
50mLフラスコに、化合物F−e(例えば3.8mmol)、Pd/C(例えば0.2g)およびメタノール(例えば20mL)を添加した。混合物を室温および常圧で、4時間水素添加した。反応完了後、反応混合物を濾過し、濾液を濃縮して95%超の収率で生成物を得た。
50mLフラスコに、化合物F−f(例えば3.9mmol)、精製水(例えば10mL)および濃塩酸(例えば0.8mL、9.6mmol)を添加した。混合物を撹拌しながら0〜5℃に冷却した。0〜5℃の温度を維持したまま、亜硝酸ナトリウム水溶液(例えば10mL)を混合物に滴加した。滴加完了後、温度を維持したまま混合物を20分間撹拌した。次に、ヨウ化ナトリウム(例えば、1.17g、7.8mmol)を反応混合物に添加し、得られた混合物を室温で2時間撹拌した。反応完了後、酢酸エチルを反応混合物に添加した。水相と有機相とを分離した。水相を酢酸エチルで抽出した。有機相を混合して濃縮し、約80%の収率で生成物を得た。
50mLフラスコに、化合物F−g(例えば5.52mmol)および塩化チオニル(例えば16.8g、141.2mmol)を添加した。得られた混合物を50℃に加熱し、2時間撹拌し、反応させた。反応完了後、反応混合物を真空下で濃縮した。濃縮完了後、DCM(例えば30mL)を混合物に添加し、化合物G(例えば6.07mmol)を0℃で添加した。添加完了後、混合物を室温で1時間撹拌し、精製水(例えば30mL)を添加した。有機相を得られた混合物から分離して濃縮し、約95%の収率で生成物を得た。
100mLフラスコに、化合物F−h(例えば5.24mmol)、Pd/C(例えば0.5g)およびメタノール(例えば50mL)を添加した。混合物を室温および常圧で、4時間水素添加した。反応完了後、反応混合物を濾過し、濾液を真空下で濃縮して95%超の収率で生成物を得た。
50mLフラスコに、化合物F−i(例えば3.91mmol)、精製水(例えば10mL)および濃塩酸(例えば0.8mL、9.6mmol)を添加した。
フラスコに、化合物C(例えば63.2mmol)を添加し、次いで精製水(例えば60mL)を添加した。混合物を撹拌しながら−5〜0℃に冷却し、濃塩酸(例えば26mL)を添加した。−5〜0℃の温度を維持したまま、亜硝酸ナトリウム水溶液(例えば30mL)を混合物に滴加した。添加完了後、温度を維持したまま混合物を20分間撹拌した。得られた混合物に、エチル2−クロロ−3−オキソブタノエート(例えば10.7g、65.1mmol)のエタノール(例えば100mL)溶液および酢酸ナトリウム(例えば15.5g、189.0mmol)の水(60mL)溶液を添加した。添加完了後、混合物を0.5時間撹拌した。次に、混合物を室温に温め、6時間撹拌して反応させた。反応中に、固体が析出した。反応完了後、反応混合物を濾過し、濾過ケークを乾燥させ、約70%の収率で黄色固体を得た。
室温で、フラスコ(例えば100mL)に、化合物D(例えば4.7mmol)、3−モルホリノ−5,6−ジヒドロピリジン−2(1H)−オン(例えば0.94g、5.2mmol)を添加し、次いでトルエン(例えば20mL)およびトリエチルアミンを添加した。添加完了後、混合物を100℃に加熱し、還流下で12時間反応させた。反応混合物を室温まで冷却し、濃縮した。残渣に、ジクロロメタン(例えば20mL)を添加し、室温でトリフルオロ酢酸(例えば5.0mL)を滴加した。得られた混合物を2時間撹拌し、反応させた。反応完了後、反応混合物を真空下で濃縮した。濃縮完了後、酢酸エチルおよび精製水(適量)を混合物に添加した。混合物を撹拌して、固体を析出させた。得られた混合物を濾過した濾過ケークを真空下で乾燥させ、約30%の収率で生成物を得た。
フラスコ(50mL)に、化合物E(例えば1.3mmol)、化合物F(例えば1.4mmol)および炭酸カリウム(376mg、2.7mmol)を添加し、次いでDMSO(例えば10mL)を添加した。ヨウ化第二銅(例えば114mg、0.6mmol)および1,10−フェナントロリン(例えば110mg、0.6mmol)を窒素雰囲気下で添加した。混合物を120℃に加熱し、12時間撹拌して、窒素雰囲気下で反応させた。反応完了後、反応混合物を室温に冷却し、精製水を添加した。得られた混合物を酢酸エチルで抽出した。有機相を濃縮し、約75%の収率で生成物を得た。
封管に化合物II(例えば0.45mmol)を添加し、次いでエチレングリコール(例えば10mL)を添加した。混合物を撹拌した。次に、アンモニアガスを0.5時間封管に導入した。封管を密閉した。混合物を120℃に加熱し、3時間反応させた。反応混合物を室温に冷却した後、冷水に注入した。固体が析出した。混合物を濾過した。濾過ケークを乾燥させ、目的生成物を得た。
本発明はまた、実施例1〜35の化合物にそれぞれ対応する以下の化合物1〜35を提供する。
6−(4−((3−(ジメチルアミノ)プロピル)アミノ)フェニル)−1−(4−メトキシフェニル)−7−オキソ−4,5,6,7−テトラヒドロ−1H−ピラゾロ[3,4−c]ピリジン−3−カルボキサミド
1−(4−メトキシフェニル)−7−オキソ−6−(3−(2−(ピペラジン−1−イル)エチル)フェニル)−4,5,6,7−テトラヒドロ−1H−ピラゾロ[3,4−c]ピリジン−3−カルボキサミド
エチル 6−(3−(2−(4−(tert−ブトキシカルボニル)ピペラジン−1−イル)エチル)フェニル)−1−(4−メトキシフェニル)−7−オキソ−4,5,6,7−テトラヒドロ−1H−ピラゾロ[3,4−c]ピリジン−3−カルボキシレート
エチル 1−(4−メトキシフェニル)−7−オキソ−6−(4−(2−オキソピロリジン−1−イル)フェニル)−4,5,6,7−テトラヒドロ−1H−ピラゾロ[3,4−c]ピリジン−3−カルボキシレート
エチル 1−(2−(ジフルオロメトキシ)フェニル)−7−オキソ−4,5,6,7−テトラヒドロ−1H−ピラゾロ[3,4−c]ピリジン−3−カルボキシレート
Claims (19)
- 式(I):
Xは、CHであり、
Zは、
ここで、
RNaおよびRNbはそれぞれ独立して、水素、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、C1−6アルコキシ−C0−6アルキル、(C0−6アルキル)(C0−6アルキル)N−C1−6アルキル、(C2−6アルキレン)N−C1−6アルキルまたはカルバモイル−C1−6アルキルから選択されるか、あるいは
RNaおよびRNbは、それらに結合している原子とともに5員環、6員環または7員環部分を形成しており、
ここで、
5員環、6員環または7員環部分は、1つのRNgで置換されており、該RNgは水素、C1−4アルキル、ヒドロキシル、C1−4アルコキシ、ハロゲン、オキソおよびアミノから選択され、
5員環、6員環または7員環部分は、RNbに結合しているN原子以外に、N、OおよびSから選択される0、1、2、3または4個のヘテロ原子を含み、
5員環、6員環または7員環部分は0、1、2または3個の二重結合を含み、
RNcは、水素、C1−6アルキルおよびC1−6アルコキシから選択され、
RNdは、エトキシであり、
RNeは、水素、ハロゲン、C1−6アルコキシ、ハロゲン置換C1−6アルコキシ、カルバモイル−C1−6アルキルおよびC1−6アルコキシ−C1−6アルキルから選択され、
RNfは、水素、ハロゲン、C1−6アルコキシ、ハロゲン置換C1−6アルコキシ、カルバモイル−C1−6アルキルおよびC1−6アルコキシ−C1−6アルキルから選択される。)の化合物、その互変異性体もしくはそれらの光学異性体、またはそれらの医薬として許容され得る塩。 - Zは、
ここで、
RNaおよびRNbは、それらに結合している原子とともに5員環、6員環または7員環部分を形成しており、
ここで、
5員環、6員環または7員環部分は、1つのRNgで置換されており、該RNgは水素、C1−4アルキル、ヒドロキシル、C1−4アルコキシ、ハロゲン、オキソおよびアミノから選択され、
5員環、6員環または7員環部分は、RNbに結合しているN原子以外に、N、OおよびSから選択される0、1、2、3または4個のヘテロ原子を含み、
5員環、6員環または7員環部分は、0、1、2または3個の二重結合を含む、請求項1に記載の式(I)の化合物、その互変異性体もしくはそれらの光学異性体、またはそれらの医薬として許容され得る塩。 - RNcが水素およびメチルから選択される、請求項1〜3のいずれか一項に記載の式(I)の化合物、その互変異性体もしくはそれらの光学異性体、またはそれらの医薬として許容され得る塩。
- RNeが水素、塩素およびフッ素から選択される、請求項1〜4のいずれか一項に記載の式(I)の化合物、その互変異性体もしくはそれらの光学異性体、またはそれらの医薬として許容され得る塩。
- RNfが水素、塩素およびフッ素から選択される、請求項1〜5のいずれか一項に記載の式(I)の化合物、その互変異性体もしくはそれらの光学異性体、またはそれらの医薬として許容され得る塩。
- Zは、
ここで、
RNaおよびRNbは、それらに結合している原子とともに5員環、6員環または7員環部分を形成し、
ここで、
5員環、6員環または7員環部分は、1つのRNgで置換されており、該RNgは水素、C1−4アルキル、ヒドロキシル、C1−4アルコキシ、ハロゲン、オキソおよびアミノから選択され、
5員環、6員環または7員環部分は、RNbに結合しているN原子以外に、N、OおよびSから選択される0、1、2、3または4個のヘテロ原子を含み、
5員環、6員環または7員環部分は0、1、2または3個の二重結合を含み、
RNdは、エトキシであり、
RNc、RNg、RNeおよびRNfのうち少なくとも1つは水素ではない、請求項1〜6のいずれか一項に記載の式(I)の化合物、その互変異性体もしくはそれらの光学異性体、またはそれらの医薬として許容され得る塩。 - Zは、
ここで、
RNaおよびRNbは、それらに結合している原子とともに5員環、6員環または7員環部分を形成しており、
ここで、
5員環、6員環または7員環部分は、1つのRNgで置換されており、該RNgは水素およびメチルから選択され、
5員環、6員環または7員環部分は、RNbに結合しているN原子以外に、N、OおよびSから選択される0、1、2、3または4個のヘテロ原子を含み、
5員環、6員環または7員環部分は0、1、2または3個の二重結合を含み、
RNdは、エトキシであり、
RNc、RNg、RNeおよびRNfのうち少なくとも1つは水素ではない、請求項1〜7のいずれか一項に記載の式(I)の化合物、その互変異性体もしくはそれらの光学異性体、またはそれらの医薬として許容され得る塩。 - Zは、
ここで、
RNaおよびRNbは、それらに結合している原子とともに5員環、6員環または7員環部分を形成しており、
ここで、
5員環、6員環または7員環部分は、1つのRNgで置換されており、該RNgは水素およびメチルから選択され、
5員環、6員環または7員環部分は、RNbに結合しているN原子以外に、N、OおよびSから選択される0、1、2、3または4個のヘテロ原子を含み、
5員環、6員環または7員環部分は、0、1、2または3個の二重結合を含み、
RNdは、エトキシであり、
RNcは、メチルである、請求項1〜8のいずれか一項に記載の式(I)の化合物、その互変異性体もしくはそれらの光学異性体、またはそれらの医薬として許容され得る塩。 - 請求項1〜11のいずれか一項に記載の化合物、その互変異性体もしくはそれらの光学異性体、またはそれらの医薬として許容され得る塩を含有する医薬組成物。
- 第Xa因子の陽性効果を阻害する、疾患の予防および/または治療用医薬の製造における、請求項1〜11のいずれか一項に記載の化合物、その互変異性体もしくはそれらの光学異性体、もしくはそれらの医薬として許容され得る塩、または請求項12に記載の医薬組成物の使用。
- 前記疾患は、血栓塞栓症および播種性血管内凝固から選択される、請求項13に記載の使用。
- 前記疾患は、心筋梗塞、狭心症、血管形成術または大動脈冠動脈バイパス術後の再閉塞および再狭窄、脳卒中、一過性の部分発作、末梢動脈の閉塞性疾患、肺塞栓症または深部静脈血栓症から選択される、請求項14に記載の使用。
- 出血リスクが低い場合に第Xa因子の陽性効果を阻害する、疾患の予防および/または治療用医薬の製造における、請求項1〜11のいずれか一項に記載の化合物、その互変異性体もしくはそれらの光学異性体、もしくはそれらの医薬として許容され得る塩、または請求項12に記載の医薬組成物の使用。
- 前記疾患は、血栓塞栓症および播種性血管内凝固から選択される、請求項17に記載の使用。
- 前記疾患は、心筋梗塞、狭心症、血管形成術または大動脈冠動脈バイパス術後の再閉塞および再狭窄、脳卒中、一過性の部分発作、末梢動脈の閉塞性疾患、肺塞栓症または深部静脈血栓症から選択される、請求項18に記載の使用。
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