NO313879B1 - Disubstituerte bisykliske heterosykler, anvendelse og fremstilling derav samt legemiddel - Google Patents
Disubstituerte bisykliske heterosykler, anvendelse og fremstilling derav samt legemiddel Download PDFInfo
- Publication number
- NO313879B1 NO313879B1 NO19993945A NO993945A NO313879B1 NO 313879 B1 NO313879 B1 NO 313879B1 NO 19993945 A NO19993945 A NO 19993945A NO 993945 A NO993945 A NO 993945A NO 313879 B1 NO313879 B1 NO 313879B1
- Authority
- NO
- Norway
- Prior art keywords
- group
- methyl
- amide
- carboxylic acid
- aminomethyl
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims description 28
- 125000002618 bicyclic heterocycle group Chemical group 0.000 title claims description 12
- 239000003814 drug Substances 0.000 title claims description 5
- 229940079593 drug Drugs 0.000 title claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 802
- 150000001875 compounds Chemical class 0.000 claims description 119
- -1 pyridinoyl Chemical group 0.000 claims description 117
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 51
- 150000003839 salts Chemical class 0.000 claims description 43
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 39
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 32
- 239000002253 acid Substances 0.000 claims description 29
- 229910052757 nitrogen Inorganic materials 0.000 claims description 26
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 22
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 229940002612 prodrug Drugs 0.000 claims description 18
- 239000000651 prodrug Substances 0.000 claims description 18
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 229910052801 chlorine Inorganic materials 0.000 claims description 14
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 14
- 230000007062 hydrolysis Effects 0.000 claims description 13
- 238000006460 hydrolysis reaction Methods 0.000 claims description 13
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 12
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 238000001149 thermolysis Methods 0.000 claims description 11
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 10
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 10
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 10
- 108090000190 Thrombin Proteins 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 238000001727 in vivo Methods 0.000 claims description 10
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 239000001301 oxygen Substances 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 125000004434 sulfur atom Chemical group 0.000 claims description 10
- 229960004072 thrombin Drugs 0.000 claims description 10
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 9
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 9
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
- 125000005605 benzo group Chemical group 0.000 claims description 8
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 239000011541 reaction mixture Substances 0.000 claims description 8
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 8
- 150000001408 amides Chemical class 0.000 claims description 7
- 230000000694 effects Effects 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 230000001681 protective effect Effects 0.000 claims description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
- AQKKRXMVSOXABZ-UHFFFAOYSA-N 3-anilinopropanoic acid Chemical compound OC(=O)CCNC1=CC=CC=C1 AQKKRXMVSOXABZ-UHFFFAOYSA-N 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 5
- 239000000969 carrier Substances 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 230000000269 nucleophilic effect Effects 0.000 claims description 5
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 claims description 4
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 125000004659 aryl alkyl thio group Chemical group 0.000 claims description 4
- 229910052796 boron Inorganic materials 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- IDWUSJOEYZAKSW-UHFFFAOYSA-N 3-(pyridin-1-ium-2-ylamino)propanoate Chemical compound OC(=O)CCNC1=CC=CC=N1 IDWUSJOEYZAKSW-UHFFFAOYSA-N 0.000 claims description 3
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 3
- 108010022999 Serine Proteases Proteins 0.000 claims description 3
- 102000012479 Serine Proteases Human genes 0.000 claims description 3
- 229940126601 medicinal product Drugs 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- 125000005551 pyridylene group Chemical group 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 2
- WHXFWSFZCBNZLK-UHFFFAOYSA-N 4-anilinobutanoic acid Chemical compound OC(=O)CCCNC1=CC=CC=C1 WHXFWSFZCBNZLK-UHFFFAOYSA-N 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000001070 dihydroindolyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 claims description 2
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 2
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 125000005550 pyrazinylene group Chemical group 0.000 claims description 2
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 125000005576 pyrimidinylene group Chemical group 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- 125000005651 substituted 1,4-phenylene group Chemical group 0.000 claims description 2
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000005557 thiazolylene group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000005556 thienylene group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000006594 (C1-C3) alkylsulfony group Chemical group 0.000 claims 1
- MZYXHLMULHPGKX-UHFFFAOYSA-N 2-(2h-tetrazol-5-yl)ethanamine Chemical compound NCCC1=NN=NN1 MZYXHLMULHPGKX-UHFFFAOYSA-N 0.000 claims 1
- JENOQAMUNLTFDK-UHFFFAOYSA-N 3-(4-fluoroanilino)propanoic acid Chemical compound OC(=O)CCNC1=CC=C(F)C=C1 JENOQAMUNLTFDK-UHFFFAOYSA-N 0.000 claims 1
- XPRXJFAFJFZWTC-UHFFFAOYSA-N hoso2 Chemical compound [O]S(O)=O XPRXJFAFJFZWTC-UHFFFAOYSA-N 0.000 claims 1
- UZCXPYDBYUEZCV-UHFFFAOYSA-N methyl 3-aminopropanoate Chemical compound COC(=O)CCN UZCXPYDBYUEZCV-UHFFFAOYSA-N 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 792
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 270
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 255
- 239000000741 silica gel Substances 0.000 description 254
- 229910002027 silica gel Inorganic materials 0.000 description 254
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 206
- 238000001819 mass spectrum Methods 0.000 description 194
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 186
- 239000011734 sodium Substances 0.000 description 165
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 150
- 239000002904 solvent Substances 0.000 description 114
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 90
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 82
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 81
- 239000001099 ammonium carbonate Substances 0.000 description 81
- 235000012501 ammonium carbonate Nutrition 0.000 description 81
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 81
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 80
- 239000000243 solution Substances 0.000 description 80
- 229960000583 acetic acid Drugs 0.000 description 70
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 60
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 59
- 239000012043 crude product Substances 0.000 description 54
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 51
- 235000011121 sodium hydroxide Nutrition 0.000 description 50
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 45
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 44
- 239000000203 mixture Substances 0.000 description 37
- 238000004587 chromatography analysis Methods 0.000 description 30
- 229910021529 ammonia Inorganic materials 0.000 description 29
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 26
- 235000019439 ethyl acetate Nutrition 0.000 description 26
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 26
- 238000010992 reflux Methods 0.000 description 25
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 24
- 239000012362 glacial acetic acid Substances 0.000 description 24
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 23
- 239000003208 petroleum Substances 0.000 description 23
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 22
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 21
- 229910052938 sodium sulfate Inorganic materials 0.000 description 21
- 235000011152 sodium sulphate Nutrition 0.000 description 21
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 20
- 235000017557 sodium bicarbonate Nutrition 0.000 description 20
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 20
- 238000003756 stirring Methods 0.000 description 19
- 239000002585 base Substances 0.000 description 18
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 18
- 125000001841 imino group Chemical group [H]N=* 0.000 description 17
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- 239000012074 organic phase Substances 0.000 description 16
- 239000007787 solid Substances 0.000 description 16
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 15
- 238000004440 column chromatography Methods 0.000 description 14
- 150000002148 esters Chemical class 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- 239000011780 sodium chloride Substances 0.000 description 11
- 239000007858 starting material Substances 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 239000004480 active ingredient Substances 0.000 description 10
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 9
- 239000003480 eluent Substances 0.000 description 9
- KIWBRXCOTCXSSZ-UHFFFAOYSA-N hexyl carbonochloridate Chemical compound CCCCCCOC(Cl)=O KIWBRXCOTCXSSZ-UHFFFAOYSA-N 0.000 description 9
- 229910052739 hydrogen Inorganic materials 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 8
- 238000009835 boiling Methods 0.000 description 8
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 8
- 239000000284 extract Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 230000002441 reversible effect Effects 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
- 238000003776 cleavage reaction Methods 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 7
- 230000008020 evaporation Effects 0.000 description 7
- 239000005457 ice water Substances 0.000 description 7
- 150000007530 organic bases Chemical group 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- 230000007017 scission Effects 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- VFXVAXFIFHSGNR-UHFFFAOYSA-N octyl carbonochloridate Chemical compound CCCCCCCCOC(Cl)=O VFXVAXFIFHSGNR-UHFFFAOYSA-N 0.000 description 6
- KJRQMXRCZULRHF-UHFFFAOYSA-N 2-(4-cyanoanilino)acetic acid Chemical compound OC(=O)CNC1=CC=C(C#N)C=C1 KJRQMXRCZULRHF-UHFFFAOYSA-N 0.000 description 5
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- PCPATNZTKBOKOY-UHFFFAOYSA-N ethyl 3-[[3-amino-4-(methylamino)benzoyl]-pyridin-2-ylamino]propanoate Chemical compound C=1C=CC=NC=1N(CCC(=O)OCC)C(=O)C1=CC=C(NC)C(N)=C1 PCPATNZTKBOKOY-UHFFFAOYSA-N 0.000 description 5
- TXEPQFCHHDFYMO-UHFFFAOYSA-N ethyl 3-anilinopropanoate Chemical compound CCOC(=O)CCNC1=CC=CC=C1 TXEPQFCHHDFYMO-UHFFFAOYSA-N 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- NRDQFWXVTPZZAZ-UHFFFAOYSA-N butyl carbonochloridate Chemical compound CCCCOC(Cl)=O NRDQFWXVTPZZAZ-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 238000005345 coagulation Methods 0.000 description 2
- 230000015271 coagulation Effects 0.000 description 2
- 239000003245 coal Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- IWVJLGPDBXCTDA-UHFFFAOYSA-N cyclohexyl carbonochloridate Chemical compound ClC(=O)OC1CCCCC1 IWVJLGPDBXCTDA-UHFFFAOYSA-N 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- LIACWHDRNCJIKH-UHFFFAOYSA-N ethyl 2-(methoxymethyl)-1,3-benzothiazole-5-carboxylate Chemical compound CCOC(=O)C1=CC=C2SC(COC)=NC2=C1 LIACWHDRNCJIKH-UHFFFAOYSA-N 0.000 description 2
- UKPOFWWYDQZARP-UHFFFAOYSA-N ethyl 2-[[2-[(4-cyanoanilino)methyl]-1-methylbenzimidazole-5-carbonyl]-pyridin-2-ylamino]acetate Chemical compound C=1C=CC=NC=1N(CC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2CNC1=CC=C(C#N)C=C1 UKPOFWWYDQZARP-UHFFFAOYSA-N 0.000 description 2
- SILQODSVEKWRAN-UHFFFAOYSA-N ethyl 3-(n-(1-methyl-2-sulfanylidene-3h-benzimidazole-5-carbonyl)anilino)propanoate Chemical compound C=1C=C2N(C)C(S)=NC2=CC=1C(=O)N(CCC(=O)OCC)C1=CC=CC=C1 SILQODSVEKWRAN-UHFFFAOYSA-N 0.000 description 2
- WUVOXJGDADSBJV-UHFFFAOYSA-N ethyl 3-(n-[2-[(4-cyano-n-methylanilino)methyl]-1,3-benzothiazole-5-carbonyl]anilino)propanoate Chemical compound C=1C=CC=CC=1N(CCC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1SC=2CN(C)C1=CC=C(C#N)C=C1 WUVOXJGDADSBJV-UHFFFAOYSA-N 0.000 description 2
- LTXWCUKIPUUNCF-UHFFFAOYSA-N ethyl 3-(n-[2-[(4-cyanoanilino)methyl]-1,3-benzothiazole-5-carbonyl]anilino)propanoate Chemical compound C=1C=CC=CC=1N(CCC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1SC=2CNC1=CC=C(C#N)C=C1 LTXWCUKIPUUNCF-UHFFFAOYSA-N 0.000 description 2
- JYMGNHGESNTDQP-UHFFFAOYSA-N ethyl 3-(n-[2-[(4-cyanophenyl)methylsulfanyl]-1-methylbenzimidazole-5-carbonyl]anilino)propanoate Chemical compound C=1C=CC=CC=1N(CCC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2SCC1=CC=C(C#N)C=C1 JYMGNHGESNTDQP-UHFFFAOYSA-N 0.000 description 2
- PDLYZBATYYLNMK-UHFFFAOYSA-N ethyl 3-(n-[2-[2-(4-cyanophenyl)ethyl]-3-methylimidazo[1,2-a]pyridine-7-carbonyl]anilino)propanoate Chemical compound C=1C=CC=CC=1N(CCC(=O)OCC)C(=O)C(=CC1=N2)C=CN1C(C)=C2CCC1=CC=C(C#N)C=C1 PDLYZBATYYLNMK-UHFFFAOYSA-N 0.000 description 2
- RKCGVWDXDTVBMJ-UHFFFAOYSA-N ethyl 3-(n-[2-[2-(4-cyanophenyl)ethyl]-3-methylimidazo[4,5-b]pyridine-6-carbonyl]anilino)propanoate Chemical compound C=1C=CC=CC=1N(CCC(=O)OCC)C(=O)C(C=C1N=2)=CN=C1N(C)C=2CCC1=CC=C(C#N)C=C1 RKCGVWDXDTVBMJ-UHFFFAOYSA-N 0.000 description 2
- ILLRTURRZUEMKZ-UHFFFAOYSA-N ethyl 3-(n-[4-(methylamino)-3-nitrobenzoyl]anilino)propanoate Chemical compound C=1C=CC=CC=1N(CCC(=O)OCC)C(=O)C1=CC=C(NC)C([N+]([O-])=O)=C1 ILLRTURRZUEMKZ-UHFFFAOYSA-N 0.000 description 2
- HWXMBALJCCSHBE-UHFFFAOYSA-N ethyl 3-[[1-methyl-2-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]benzimidazole-5-carbonyl]-pyridin-2-ylamino]propanoate Chemical compound C=1C=C2N(C)C(CNC(=O)OC(C)(C)C)=NC2=CC=1C(=O)N(CCC(=O)OCC)C1=CC=CC=N1 HWXMBALJCCSHBE-UHFFFAOYSA-N 0.000 description 2
- QKULMVHECFYTEI-UHFFFAOYSA-N ethyl 3-[[2-(aminomethyl)-1-methylbenzimidazole-5-carbonyl]-pyridin-2-ylamino]propanoate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C=1C=C2N(C)C(CN)=NC2=CC=1C(=O)N(CCC(=O)OCC)C1=CC=CC=N1 QKULMVHECFYTEI-UHFFFAOYSA-N 0.000 description 2
- MAWIQJRIEXENQD-UHFFFAOYSA-N ethyl 3-[[2-[2-(4-cyanophenyl)ethyl]-1-methylbenzimidazole-5-carbonyl]-pyridin-2-ylamino]propanoate Chemical compound C=1C=CC=NC=1N(CCC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2CCC1=CC=C(C#N)C=C1 MAWIQJRIEXENQD-UHFFFAOYSA-N 0.000 description 2
- AARRGRGEAXCRRO-UHFFFAOYSA-N ethyl 3-[[2-[2-(5-cyanothiophen-2-yl)ethyl]-1-methylbenzimidazole-5-carbonyl]-pyridin-2-ylamino]propanoate Chemical compound C=1C=CC=NC=1N(CCC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2CCC1=CC=C(C#N)S1 AARRGRGEAXCRRO-UHFFFAOYSA-N 0.000 description 2
- VOUXLZSLTLQKPY-UHFFFAOYSA-N ethyl 3-[[4-(methylamino)-3-[[2-[(2-methylpropan-2-yl)oxycarbonylamino]acetyl]amino]benzoyl]-pyridin-2-ylamino]propanoate Chemical compound C=1C=CC=NC=1N(CCC(=O)OCC)C(=O)C1=CC=C(NC)C(NC(=O)CNC(=O)OC(C)(C)C)=C1 VOUXLZSLTLQKPY-UHFFFAOYSA-N 0.000 description 2
- FWOACYVHDUBZDT-UHFFFAOYSA-N ethyl 4-methyl-3-nitrobenzoate Chemical compound CCOC(=O)C1=CC=C(C)C([N+]([O-])=O)=C1 FWOACYVHDUBZDT-UHFFFAOYSA-N 0.000 description 2
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229960002510 mandelic acid Drugs 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- CQYJKJNQXJLNGD-UHFFFAOYSA-N methyl 2-[1-[1-(2-methoxy-2-oxoethyl)-2-[4-(methylamino)-3-nitrophenyl]cyclohexanecarbonyl]-2-[4-(methylamino)-3-nitrophenyl]cyclohexyl]acetate Chemical compound C1=C([N+]([O-])=O)C(NC)=CC=C1C1C(C(=O)C2(CC(=O)OC)C(CCCC2)C=2C=C(C(NC)=CC=2)[N+]([O-])=O)(CC(=O)OC)CCCC1 CQYJKJNQXJLNGD-UHFFFAOYSA-N 0.000 description 2
- FTELNQJNVCZWFJ-UHFFFAOYSA-N methyl 2-[2-(4-cyanophenyl)ethyl]quinazoline-7-carboxylate Chemical compound N=1C2=CC(C(=O)OC)=CC=C2C=NC=1CCC1=CC=C(C#N)C=C1 FTELNQJNVCZWFJ-UHFFFAOYSA-N 0.000 description 2
- SWJLYYDIKWZBAV-UHFFFAOYSA-N methyl 2-[2-[2-[(4-cyanophenoxy)methyl]-1-methylbenzimidazol-5-yl]-1-[2-[2-[(4-cyanophenoxy)methyl]-1-methylbenzimidazol-5-yl]-1-(2-methoxy-2-oxoethyl)cyclohexanecarbonyl]cyclohexyl]acetate Chemical compound C1CCCC(C=2C=C3N=C(COC=4C=CC(=CC=4)C#N)N(C)C3=CC=2)C1(CC(=O)OC)C(=O)C1(CC(=O)OC)CCCCC1C(C=C1N=2)=CC=C1N(C)C=2COC1=CC=C(C#N)C=C1 SWJLYYDIKWZBAV-UHFFFAOYSA-N 0.000 description 2
- PRUZMGXPGUQCJI-UHFFFAOYSA-N methyl 2-[2-[3-[[2-(4-cyanophenoxy)acetyl]amino]-4-(methylamino)phenyl]-1-[2-[3-[[2-(4-cyanophenoxy)acetyl]amino]-4-(methylamino)phenyl]-1-(2-methoxy-2-oxoethyl)cyclohexanecarbonyl]cyclohexyl]acetate Chemical compound CNC1=CC=C(C2C(CCCC2)(CC(=O)OC)C(=O)C2(CC(=O)OC)C(CCCC2)C=2C=C(NC(=O)COC=3C=CC(=CC=3)C#N)C(NC)=CC=2)C=C1NC(=O)COC1=CC=C(C#N)C=C1 PRUZMGXPGUQCJI-UHFFFAOYSA-N 0.000 description 2
- FSBYNNYXTBENFK-UHFFFAOYSA-N methyl 2-[2-[3-amino-4-(methylamino)phenyl]-1-[2-[3-amino-4-(methylamino)phenyl]-1-(2-methoxy-2-oxoethyl)cyclohexanecarbonyl]cyclohexyl]acetate Chemical compound C1=C(N)C(NC)=CC=C1C1C(C(=O)C2(CC(=O)OC)C(CCCC2)C=2C=C(N)C(NC)=CC=2)(CC(=O)OC)CCCC1 FSBYNNYXTBENFK-UHFFFAOYSA-N 0.000 description 2
- DUCVDUMTPPUUQT-UHFFFAOYSA-N methyl 3-(n-(4-aminobenzoyl)anilino)propanoate Chemical compound C=1C=CC=CC=1N(CCC(=O)OC)C(=O)C1=CC=C(N)C=C1 DUCVDUMTPPUUQT-UHFFFAOYSA-N 0.000 description 2
- AXLOBDNRFOPVQH-UHFFFAOYSA-N methyl 3-(n-(4-nitrobenzoyl)anilino)propanoate Chemical compound C=1C=CC=CC=1N(CCC(=O)OC)C(=O)C1=CC=C([N+]([O-])=O)C=C1 AXLOBDNRFOPVQH-UHFFFAOYSA-N 0.000 description 2
- KYQZKLIKDFASTB-UHFFFAOYSA-N methyl 3-(n-[2-(methoxymethyl)-1-methylthieno[2,3-d]imidazole-5-carbonyl]anilino)propanoate Chemical compound C=1C=2N(C)C(COC)=NC=2SC=1C(=O)N(CCC(=O)OC)C1=CC=CC=C1 KYQZKLIKDFASTB-UHFFFAOYSA-N 0.000 description 2
- IBDOSCHKLYLJMA-UHFFFAOYSA-N methyl 3-(n-[2-[(4-cyanoanilino)methyl]-1h-indole-5-carbonyl]anilino)propanoate Chemical compound C=1C=CC=CC=1N(CCC(=O)OC)C(=O)C(C=C1C=2)=CC=C1NC=2CNC1=CC=C(C#N)C=C1 IBDOSCHKLYLJMA-UHFFFAOYSA-N 0.000 description 2
- JDYOMFVVHKGXGZ-UHFFFAOYSA-N methyl 3-(n-[2-[2-(4-cyanophenyl)ethyl]quinazoline-7-carbonyl]anilino)propanoate Chemical compound C=1C=CC=CC=1N(CCC(=O)OC)C(=O)C(C=C1N=2)=CC=C1C=NC=2CCC1=CC=C(C#N)C=C1 JDYOMFVVHKGXGZ-UHFFFAOYSA-N 0.000 description 2
- CKZDJCJSSSCYFN-UHFFFAOYSA-N methyl 3-(pyridin-2-ylamino)propanoate Chemical compound COC(=O)CCNC1=CC=CC=N1 CKZDJCJSSSCYFN-UHFFFAOYSA-N 0.000 description 2
- GGGQGDKTUXEDEY-UHFFFAOYSA-N methyl 3-[[2-[(4-cyanophenoxy)methyl]-1-methylimidazo[4,5-b]pyridine-5-carbonyl]-pyridin-2-ylamino]propanoate Chemical compound C=1C=CC=NC=1N(CCC(=O)OC)C(=O)C(N=C1N=2)=CC=C1N(C)C=2COC1=CC=C(C#N)C=C1 GGGQGDKTUXEDEY-UHFFFAOYSA-N 0.000 description 2
- XFULTVJWWNIPPO-UHFFFAOYSA-N methyl 3-amino-4-formylbenzoate Chemical compound COC(=O)C1=CC=C(C=O)C(N)=C1 XFULTVJWWNIPPO-UHFFFAOYSA-N 0.000 description 2
- RTGNZFSMKJWWKA-UHFFFAOYSA-N methyl 4-[2-(dimethylamino)ethenyl]-3-nitrobenzoate Chemical compound COC(=O)C1=CC=C(C=CN(C)C)C([N+]([O-])=O)=C1 RTGNZFSMKJWWKA-UHFFFAOYSA-N 0.000 description 2
- WGOOPYYIMZJWMA-UHFFFAOYSA-N methyl 4-formyl-3-nitrobenzoate Chemical compound COC(=O)C1=CC=C(C=O)C([N+]([O-])=O)=C1 WGOOPYYIMZJWMA-UHFFFAOYSA-N 0.000 description 2
- XPCXDDOGPNBUQL-UHFFFAOYSA-N methyl 5-amino-6-(methylamino)pyridine-3-carboxylate Chemical compound CNC1=NC=C(C(=O)OC)C=C1N XPCXDDOGPNBUQL-UHFFFAOYSA-N 0.000 description 2
- BENHZYFIGMDHEB-UHFFFAOYSA-N methyl 5-amino-6-chloropyridine-3-carboxylate Chemical compound COC(=O)C1=CN=C(Cl)C(N)=C1 BENHZYFIGMDHEB-UHFFFAOYSA-N 0.000 description 2
- GEARVKXKWRSFSW-UHFFFAOYSA-N methyl 6-chloro-5-[(2-methoxyacetyl)amino]pyridine-3-carboxylate Chemical compound COCC(=O)NC1=CC(C(=O)OC)=CN=C1Cl GEARVKXKWRSFSW-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- OFDPXJAEFDVKMC-UHFFFAOYSA-N n-methyl-4-(methylamino)-n-(1-methylpiperidin-4-yl)-3-nitrobenzenesulfonamide Chemical compound C1=C([N+]([O-])=O)C(NC)=CC=C1S(=O)(=O)N(C)C1CCN(C)CC1 OFDPXJAEFDVKMC-UHFFFAOYSA-N 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 150000004965 peroxy acids Chemical class 0.000 description 2
- 125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 2
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Inorganic materials [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- GCYZIHRKGRNYMG-UHFFFAOYSA-N tert-butyl 4-(n-[2-[(4-cyanoanilino)methyl]-1-methylbenzimidazole-5-carbonyl]anilino)butanoate Chemical compound N=1C2=CC(C(=O)N(CCCC(=O)OC(C)(C)C)C=3C=CC=CC=3)=CC=C2N(C)C=1CNC1=CC=C(C#N)C=C1 GCYZIHRKGRNYMG-UHFFFAOYSA-N 0.000 description 2
- QZJQNLTWEPQJLF-UHFFFAOYSA-N tert-butyl 5-[(3-methoxy-3-oxopropyl)-phenylcarbamoyl]-2-methylindole-1-carboxylate Chemical compound C=1C=C2N(C(=O)OC(C)(C)C)C(C)=CC2=CC=1C(=O)N(CCC(=O)OC)C1=CC=CC=C1 QZJQNLTWEPQJLF-UHFFFAOYSA-N 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- 229940075966 (+)- menthol Drugs 0.000 description 1
- NOOLISFMXDJSKH-AEJSXWLSSA-N (+)-menthol Chemical compound CC(C)[C@H]1CC[C@H](C)C[C@@H]1O NOOLISFMXDJSKH-AEJSXWLSSA-N 0.000 description 1
- VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 1
- TXTWXQXDMWILOF-UHFFFAOYSA-N (2-ethoxy-2-oxoethyl)azanium;chloride Chemical compound [Cl-].CCOC(=O)C[NH3+] TXTWXQXDMWILOF-UHFFFAOYSA-N 0.000 description 1
- AAWZDTNXLSGCEK-LNVDRNJUSA-N (3r,5r)-1,3,4,5-tetrahydroxycyclohexane-1-carboxylic acid Chemical compound O[C@@H]1CC(O)(C(O)=O)C[C@@H](O)C1O AAWZDTNXLSGCEK-LNVDRNJUSA-N 0.000 description 1
- MAYZWDRUFKUGGP-VIFPVBQESA-N (3s)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol Chemical compound CN1N=NN=C1CN1C2=NC(C(C)(C)C)=NC(N3C[C@@H](O)CC3)=C2N=N1 MAYZWDRUFKUGGP-VIFPVBQESA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- ZGYIXVSQHOKQRZ-COIATFDQSA-N (e)-n-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-[(3s)-oxolan-3-yl]oxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide Chemical compound N#CC1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 ZGYIXVSQHOKQRZ-COIATFDQSA-N 0.000 description 1
- MOWXJLUYGFNTAL-DEOSSOPVSA-N (s)-[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol Chemical compound N1=NC(OC)=CC=C1[C@@H](O)C1=CC(C=2C3=CC=C(C=C3N=CN=2)N2CCOCC2)=C(F)C=C1Cl MOWXJLUYGFNTAL-DEOSSOPVSA-N 0.000 description 1
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 1
- IAEOYUUPFYJXHN-UHFFFAOYSA-N 1,5-diiodopentane Chemical compound ICCCCCI IAEOYUUPFYJXHN-UHFFFAOYSA-N 0.000 description 1
- ABDDQTDRAHXHOC-QMMMGPOBSA-N 1-[(7s)-5,7-dihydro-4h-thieno[2,3-c]pyran-7-yl]-n-methylmethanamine Chemical compound CNC[C@@H]1OCCC2=C1SC=C2 ABDDQTDRAHXHOC-QMMMGPOBSA-N 0.000 description 1
- LNSCNEJNLACZPA-UHFFFAOYSA-N 2,3-dihydroxy-2,3-bis(2-methylphenyl)butanedioic acid Chemical compound CC1=CC=CC=C1C(O)(C(O)=O)C(O)(C(O)=O)C1=CC=CC=C1C LNSCNEJNLACZPA-UHFFFAOYSA-N 0.000 description 1
- WMHQLIKURWWBAO-UHFFFAOYSA-N 2-(2h-tetrazol-5-yl)ethanamine;hydrochloride Chemical compound Cl.NCCC1=NN=NN1 WMHQLIKURWWBAO-UHFFFAOYSA-N 0.000 description 1
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- QFNBBLVIIKQXPX-UHFFFAOYSA-N ethyl 2-(n-[2-[(4-cyanoanilino)methyl]-1-methylbenzimidazole-5-carbonyl]anilino)acetate Chemical compound C=1C=CC=CC=1N(CC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2CNC1=CC=C(C#N)C=C1 QFNBBLVIIKQXPX-UHFFFAOYSA-N 0.000 description 1
- OSNMVRJCZGWMIT-UHFFFAOYSA-N ethyl 2-(n-[2-[(4-cyanophenoxy)methyl]-1-methylbenzimidazole-5-carbonyl]anilino)acetate Chemical compound C=1C=CC=CC=1N(CC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2COC1=CC=C(C#N)C=C1 OSNMVRJCZGWMIT-UHFFFAOYSA-N 0.000 description 1
- NDNQGIMRQZEHSN-UHFFFAOYSA-N ethyl 2-(n-[2-[2-(4-cyanophenyl)ethyl]-1-methylbenzimidazole-5-carbonyl]anilino)acetate Chemical compound C=1C=CC=CC=1N(CC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2CCC1=CC=C(C#N)C=C1 NDNQGIMRQZEHSN-UHFFFAOYSA-N 0.000 description 1
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- SYOQAZDNTKWNCO-UHFFFAOYSA-N ethyl 2-[[2-[(4-cyano-n-methylanilino)methyl]-1-methylbenzimidazole-5-carbonyl]-pyridin-2-ylamino]acetate Chemical compound C=1C=CC=NC=1N(CC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2CN(C)C1=CC=C(C#N)C=C1 SYOQAZDNTKWNCO-UHFFFAOYSA-N 0.000 description 1
- YOMSKAJCKFUXEQ-UHFFFAOYSA-N ethyl 2-[[2-[2-(4-cyanophenyl)ethyl]-1,3-benzothiazole-5-carbonyl]-pyridin-2-ylamino]acetate Chemical compound C=1C=CC=NC=1N(CC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1SC=2CCC1=CC=C(C#N)C=C1 YOMSKAJCKFUXEQ-UHFFFAOYSA-N 0.000 description 1
- SAARQDFHLPAAHD-UHFFFAOYSA-N ethyl 2-[[2-[2-(4-cyanophenyl)ethyl]-1-methylbenzimidazole-5-carbonyl]-pyridin-2-ylamino]acetate Chemical compound C=1C=CC=NC=1N(CC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2CCC1=CC=C(C#N)C=C1 SAARQDFHLPAAHD-UHFFFAOYSA-N 0.000 description 1
- PVBRSNZAOAJRKO-UHFFFAOYSA-N ethyl 2-sulfanylacetate Chemical compound CCOC(=O)CS PVBRSNZAOAJRKO-UHFFFAOYSA-N 0.000 description 1
- GTMQHAGZQRPCNP-UHFFFAOYSA-N ethyl 3-(4-cyanophenyl)sulfanyl-2-oxopropanoate Chemical compound CCOC(=O)C(=O)CSC1=CC=C(C#N)C=C1 GTMQHAGZQRPCNP-UHFFFAOYSA-N 0.000 description 1
- FWFYQUMJCVGGFF-UHFFFAOYSA-N ethyl 3-(n-[2-(bromomethyl)-1,3-benzothiazole-5-carbonyl]anilino)propanoate Chemical compound C=1C=C2SC(CBr)=NC2=CC=1C(=O)N(CCC(=O)OCC)C1=CC=CC=C1 FWFYQUMJCVGGFF-UHFFFAOYSA-N 0.000 description 1
- QANOEVWADAGDAJ-UHFFFAOYSA-N ethyl 3-(n-[2-[(2-chloro-4-cyanoanilino)methyl]-1-methylbenzimidazole-5-carbonyl]anilino)propanoate Chemical compound C=1C=CC=CC=1N(CCC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2CNC1=CC=C(C#N)C=C1Cl QANOEVWADAGDAJ-UHFFFAOYSA-N 0.000 description 1
- PCMJYFYDDIQKBM-UHFFFAOYSA-N ethyl 3-(n-[2-[(4-cyano-2-ethylanilino)methyl]-1-methylbenzimidazole-5-carbonyl]anilino)propanoate Chemical compound C=1C=CC=CC=1N(CCC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2CNC1=CC=C(C#N)C=C1CC PCMJYFYDDIQKBM-UHFFFAOYSA-N 0.000 description 1
- XYUOKCOFVFDWMG-UHFFFAOYSA-N ethyl 3-(n-[2-[(4-cyano-2-methoxyanilino)methyl]-1-methylbenzimidazole-5-carbonyl]anilino)propanoate Chemical compound C=1C=CC=CC=1N(CCC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2CNC1=CC=C(C#N)C=C1OC XYUOKCOFVFDWMG-UHFFFAOYSA-N 0.000 description 1
- NKZGQMQIPUHVCR-UHFFFAOYSA-N ethyl 3-(n-[2-[(4-cyano-n-methylanilino)methyl]-1-methylbenzimidazole-5-carbonyl]anilino)propanoate Chemical compound C=1C=CC=CC=1N(CCC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2CN(C)C1=CC=C(C#N)C=C1 NKZGQMQIPUHVCR-UHFFFAOYSA-N 0.000 description 1
- UFGVKBBXCWGFJM-UHFFFAOYSA-N ethyl 3-(n-[2-[(4-cyanoanilino)methyl]-1-cyclopropylbenzimidazole-5-carbonyl]anilino)propanoate Chemical compound C=1C=CC=CC=1N(CCC(=O)OCC)C(=O)C(C=C1N=C2CNC=3C=CC(=CC=3)C#N)=CC=C1N2C1CC1 UFGVKBBXCWGFJM-UHFFFAOYSA-N 0.000 description 1
- RTPFYGKBJPKBTP-UHFFFAOYSA-N ethyl 3-(n-[2-[(4-cyanoanilino)methyl]-1-methylbenzimidazol-5-yl]sulfonylanilino)propanoate Chemical compound C=1C=C2N(C)C(CNC=3C=CC(=CC=3)C#N)=NC2=CC=1S(=O)(=O)N(CCC(=O)OCC)C1=CC=CC=C1 RTPFYGKBJPKBTP-UHFFFAOYSA-N 0.000 description 1
- IWQQSPHHZNQRIF-UHFFFAOYSA-N ethyl 3-(n-[2-[(4-cyanoanilino)methyl]-1-methylbenzimidazole-5-carbonyl]-2-fluoroanilino)propanoate Chemical compound C=1C=CC=C(F)C=1N(CCC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2CNC1=CC=C(C#N)C=C1 IWQQSPHHZNQRIF-UHFFFAOYSA-N 0.000 description 1
- YQGDXZIXHLVNMO-UHFFFAOYSA-N ethyl 3-(n-[2-[(4-cyanoanilino)methyl]-1-methylbenzimidazole-5-carbonyl]-3-fluoroanilino)propanoate Chemical compound C=1C=CC(F)=CC=1N(CCC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2CNC1=CC=C(C#N)C=C1 YQGDXZIXHLVNMO-UHFFFAOYSA-N 0.000 description 1
- NAQDEPNXELKLHN-UHFFFAOYSA-N ethyl 3-(n-[2-[(4-cyanoanilino)methyl]-1-methylbenzimidazole-5-carbonyl]-3-methylanilino)propanoate Chemical compound C=1C=CC(C)=CC=1N(CCC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2CNC1=CC=C(C#N)C=C1 NAQDEPNXELKLHN-UHFFFAOYSA-N 0.000 description 1
- FDIBIOAHWRTMQG-UHFFFAOYSA-N ethyl 3-(n-[2-[(4-cyanoanilino)methyl]-1-methylbenzimidazole-5-carbonyl]-4-fluoroanilino)propanoate Chemical compound C=1C=C(F)C=CC=1N(CCC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2CNC1=CC=C(C#N)C=C1 FDIBIOAHWRTMQG-UHFFFAOYSA-N 0.000 description 1
- WMIRWNUDSORLHU-UHFFFAOYSA-N ethyl 3-(n-[2-[(4-cyanoanilino)methyl]-[1,3]thiazolo[5,4-b]pyridine-6-carbonyl]anilino)propanoate Chemical compound C=1C=CC=CC=1N(CCC(=O)OCC)C(=O)C(C=C1N=2)=CN=C1SC=2CNC1=CC=C(C#N)C=C1 WMIRWNUDSORLHU-UHFFFAOYSA-N 0.000 description 1
- PSQQJEZRLKWNBM-UHFFFAOYSA-N ethyl 3-(n-[2-[(4-cyanophenoxy)methyl]-1-methylbenzimidazole-5-carbonyl]anilino)propanoate Chemical compound C=1C=CC=CC=1N(CCC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2COC1=CC=C(C#N)C=C1 PSQQJEZRLKWNBM-UHFFFAOYSA-N 0.000 description 1
- ANGKNYPYLRSQPV-UHFFFAOYSA-N ethyl 3-(n-[2-[(4-cyanophenyl)sulfanylmethyl]-1,3-benzothiazole-5-carbonyl]anilino)propanoate Chemical compound C=1C=CC=CC=1N(CCC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1SC=2CSC1=CC=C(C#N)C=C1 ANGKNYPYLRSQPV-UHFFFAOYSA-N 0.000 description 1
- BTOPULMVFIOIBV-UHFFFAOYSA-N ethyl 3-(n-[2-[(4-cyanophenyl)sulfanylmethyl]-1-methylbenzimidazole-5-carbonyl]anilino)propanoate Chemical compound C=1C=CC=CC=1N(CCC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2CSC1=CC=C(C#N)C=C1 BTOPULMVFIOIBV-UHFFFAOYSA-N 0.000 description 1
- FWZLNEYOFVCGRX-UHFFFAOYSA-N ethyl 3-(n-[2-[(n-butyl-4-cyanoanilino)methyl]-1-methylbenzimidazole-5-carbonyl]anilino)propanoate Chemical compound C=1C=C(C#N)C=CC=1N(CCCC)CC(N(C1=CC=2)C)=NC1=CC=2C(=O)N(CCC(=O)OCC)C1=CC=CC=C1 FWZLNEYOFVCGRX-UHFFFAOYSA-N 0.000 description 1
- KDQQAMKXRUZLNX-UHFFFAOYSA-N ethyl 3-(n-[2-[2-(4-cyanophenyl)ethyl]-1,3-benzothiazole-5-carbonyl]anilino)propanoate Chemical compound C=1C=CC=CC=1N(CCC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1SC=2CCC1=CC=C(C#N)C=C1 KDQQAMKXRUZLNX-UHFFFAOYSA-N 0.000 description 1
- LPWDBMIWXWANDZ-UHFFFAOYSA-N ethyl 3-(n-[2-[2-(4-cyanophenyl)ethyl]-1-methylbenzimidazole-5-carbonyl]anilino)propanoate Chemical compound C=1C=CC=CC=1N(CCC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2CCC1=CC=C(C#N)C=C1 LPWDBMIWXWANDZ-UHFFFAOYSA-N 0.000 description 1
- DDQBAVCCACVETH-UHFFFAOYSA-N ethyl 3-(n-[3-amino-4-(methylamino)phenyl]sulfonylanilino)propanoate Chemical compound C=1C=C(NC)C(N)=CC=1S(=O)(=O)N(CCC(=O)OCC)C1=CC=CC=C1 DDQBAVCCACVETH-UHFFFAOYSA-N 0.000 description 1
- BWZIAPDMMSZZOW-UHFFFAOYSA-N ethyl 3-(n-[4-(methylamino)-3-nitrophenyl]sulfonylanilino)propanoate Chemical compound C=1C=C(NC)C([N+]([O-])=O)=CC=1S(=O)(=O)N(CCC(=O)OCC)C1=CC=CC=C1 BWZIAPDMMSZZOW-UHFFFAOYSA-N 0.000 description 1
- UITNIDFEANEWPC-UHFFFAOYSA-N ethyl 3-(pyridin-2-ylamino)propanoate Chemical compound CCOC(=O)CCNC1=CC=CC=N1 UITNIDFEANEWPC-UHFFFAOYSA-N 0.000 description 1
- HJKBMWUQTDWQCG-UHFFFAOYSA-N ethyl 3-[3-(4-cyanophenyl)propanoylamino]-4-formylbenzoate Chemical compound CCOC(=O)C1=CC=C(C=O)C(NC(=O)CCC=2C=CC(=CC=2)C#N)=C1 HJKBMWUQTDWQCG-UHFFFAOYSA-N 0.000 description 1
- YPPLJHREEJOIDX-UHFFFAOYSA-N ethyl 3-[[1-methyl-2-[[4-[(e)-n'-phenylmethoxycarbonylcarbamimidoyl]anilino]methyl]benzimidazole-5-carbonyl]-pyridin-2-ylamino]propanoate Chemical compound C=1C=CC=NC=1N(CCC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2CNC(C=C1)=CC=C1C(=N)NC(=O)OCC1=CC=CC=C1 YPPLJHREEJOIDX-UHFFFAOYSA-N 0.000 description 1
- IMDULQYVQLSDOF-UHFFFAOYSA-N ethyl 3-[[2-[(4-cyano-2-methoxyanilino)methyl]-1-methylbenzimidazole-5-carbonyl]-pyridin-2-ylamino]propanoate Chemical compound C=1C=CC=NC=1N(CCC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2CNC1=CC=C(C#N)C=C1OC IMDULQYVQLSDOF-UHFFFAOYSA-N 0.000 description 1
- MJRMOBNZOREJPC-UHFFFAOYSA-N ethyl 3-[[2-[(4-cyano-n-methylanilino)methyl]-1-methylbenzimidazole-5-carbonyl]-pyridin-2-ylamino]propanoate Chemical compound C=1C=CC=NC=1N(CCC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2CN(C)C1=CC=C(C#N)C=C1 MJRMOBNZOREJPC-UHFFFAOYSA-N 0.000 description 1
- UHKDKXCPFZEIMF-UHFFFAOYSA-N ethyl 3-[[2-[(4-cyano-n-methylanilino)methyl]-1-methylbenzimidazole-5-carbonyl]-pyridin-3-ylamino]propanoate Chemical compound C=1C=CN=CC=1N(CCC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2CN(C)C1=CC=C(C#N)C=C1 UHKDKXCPFZEIMF-UHFFFAOYSA-N 0.000 description 1
- OCLNYRODWDMBAC-UHFFFAOYSA-N ethyl 3-[[2-[(4-cyanoanilino)methyl]-1-ethylbenzimidazole-5-carbonyl]-pyridin-2-ylamino]propanoate Chemical compound C=1C=CC=NC=1N(CCC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(CC)C=2CNC1=CC=C(C#N)C=C1 OCLNYRODWDMBAC-UHFFFAOYSA-N 0.000 description 1
- HGYUMFGQASIJBC-UHFFFAOYSA-N ethyl 3-[[2-[(4-cyanoanilino)methyl]-1-methylbenzimidazol-5-yl]sulfonyl-(1-methylpyrazol-4-yl)amino]propanoate Chemical compound C=1C=C2N(C)C(CNC=3C=CC(=CC=3)C#N)=NC2=CC=1S(=O)(=O)N(CCC(=O)OCC)C=1C=NN(C)C=1 HGYUMFGQASIJBC-UHFFFAOYSA-N 0.000 description 1
- UMAFMQRXAWOKQQ-UHFFFAOYSA-N ethyl 3-[[2-[(4-cyanoanilino)methyl]-1-methylbenzimidazole-5-carbonyl]-cyclopentylamino]propanoate Chemical compound C=1C=C2N(C)C(CNC=3C=CC(=CC=3)C#N)=NC2=CC=1C(=O)N(CCC(=O)OCC)C1CCCC1 UMAFMQRXAWOKQQ-UHFFFAOYSA-N 0.000 description 1
- MBOJKMRWKVLWQL-UHFFFAOYSA-N ethyl 3-[[2-[(4-cyanoanilino)methyl]-1-methylbenzimidazole-5-carbonyl]-pyridin-3-ylamino]propanoate Chemical compound C=1C=CN=CC=1N(CCC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2CNC1=CC=C(C#N)C=C1 MBOJKMRWKVLWQL-UHFFFAOYSA-N 0.000 description 1
- AVCFLUVAXOBCBK-UHFFFAOYSA-N ethyl 3-[[2-[2-(4-cyanophenyl)ethyl]-1-methylbenzimidazole-5-carbonyl]-cyclopentylamino]propanoate Chemical compound C=1C=C2N(C)C(CCC=3C=CC(=CC=3)C#N)=NC2=CC=1C(=O)N(CCC(=O)OCC)C1CCCC1 AVCFLUVAXOBCBK-UHFFFAOYSA-N 0.000 description 1
- RTLMHFJZEZBVDT-UHFFFAOYSA-N ethyl 3-[[2-[2-(4-cyanophenyl)ethyl]-1-methylbenzimidazole-5-carbonyl]-pyridin-3-ylamino]propanoate Chemical compound C=1C=CN=CC=1N(CCC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2CCC1=CC=C(C#N)C=C1 RTLMHFJZEZBVDT-UHFFFAOYSA-N 0.000 description 1
- SXLUYXFPTUIYQL-UHFFFAOYSA-N ethyl 3-[[2-[[(5-cyano-1,3-thiazol-2-yl)amino]methyl]-1-methylbenzimidazole-5-carbonyl]-pyridin-2-ylamino]propanoate Chemical compound C=1C=CC=NC=1N(CCC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2CNC1=NC=C(C#N)S1 SXLUYXFPTUIYQL-UHFFFAOYSA-N 0.000 description 1
- HPWRWLRHILJBRM-UHFFFAOYSA-N ethyl 3-[[2-[[(5-cyanopyrazin-2-yl)amino]methyl]-1-methylbenzimidazole-5-carbonyl]-pyridin-2-ylamino]propanoate Chemical compound C=1C=CC=NC=1N(CCC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2CNC1=CN=C(C#N)C=N1 HPWRWLRHILJBRM-UHFFFAOYSA-N 0.000 description 1
- BIBDXNORJATXAG-UHFFFAOYSA-N ethyl 3-[[2-[[(5-cyanopyridin-2-yl)amino]methyl]-1-methylbenzimidazole-5-carbonyl]-pyridin-2-ylamino]propanoate Chemical compound C=1C=CC=NC=1N(CCC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2CNC1=CC=C(C#N)C=N1 BIBDXNORJATXAG-UHFFFAOYSA-N 0.000 description 1
- GTGQNVGRUYGFEU-UHFFFAOYSA-N ethyl 3-[[2-[[2-methoxy-4-(n'-pentoxycarbonylcarbamimidoyl)anilino]methyl]-1-methylbenzimidazole-5-carbonyl]-pyridin-2-ylamino]propanoate Chemical compound COC1=CC(C(=N)NC(=O)OCCCCC)=CC=C1NCC1=NC2=CC(C(=O)N(CCC(=O)OCC)C=3N=CC=CC=3)=CC=C2N1C GTGQNVGRUYGFEU-UHFFFAOYSA-N 0.000 description 1
- XRJOTWKQZHOXTM-UHFFFAOYSA-N ethyl 3-amino-4-fluorobenzoate Chemical compound CCOC(=O)C1=CC=C(F)C(N)=C1 XRJOTWKQZHOXTM-UHFFFAOYSA-N 0.000 description 1
- RJCGNNHKSNIUAT-UHFFFAOYSA-N ethyl 3-aminopropanoate;hydron;chloride Chemical compound Cl.CCOC(=O)CCN RJCGNNHKSNIUAT-UHFFFAOYSA-N 0.000 description 1
- ZCAMRLQIEMCYOA-UHFFFAOYSA-N ethyl 4-(n-[2-[(4-cyanophenoxy)methyl]-1-methylbenzimidazol-5-yl]sulfonylanilino)butanoate Chemical compound C=1C=C2N(C)C(COC=3C=CC(=CC=3)C#N)=NC2=CC=1S(=O)(=O)N(CCCC(=O)OCC)C1=CC=CC=C1 ZCAMRLQIEMCYOA-UHFFFAOYSA-N 0.000 description 1
- XODUYCZSMSVGQU-UHFFFAOYSA-N ethyl 4-fluoro-3-[(2-methoxyacetyl)amino]benzoate Chemical compound CCOC(=O)C1=CC=C(F)C(NC(=O)COC)=C1 XODUYCZSMSVGQU-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 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
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 125000004970 halomethyl group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- JBFYUZGYRGXSFL-UHFFFAOYSA-N imidazolide Chemical compound C1=C[N-]C=N1 JBFYUZGYRGXSFL-UHFFFAOYSA-N 0.000 description 1
- 150000005232 imidazopyridines Chemical group 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960004873 levomenthol Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940057948 magnesium stearate 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
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- OCAAZMCWHYYCLO-UHFFFAOYSA-N methyl 1-[2-[2-(4-cyanophenyl)ethyl]-3-methylimidazo[4,5-b]pyridine-6-carbonyl]-2,3-dihydroindole-2-carboxylate Chemical compound COC(=O)C1CC2=CC=CC=C2N1C(=O)C(C=C1N=2)=CN=C1N(C)C=2CCC1=CC=C(C#N)C=C1 OCAAZMCWHYYCLO-UHFFFAOYSA-N 0.000 description 1
- WPLXKPJAEJPGQK-UHFFFAOYSA-N methyl 2-[2-(4-cyanophenyl)ethyl]-3-methylimidazo[4,5-b]pyridine-6-carboxylate Chemical compound N=1C2=CC(C(=O)OC)=CN=C2N(C)C=1CCC1=CC=C(C#N)C=C1 WPLXKPJAEJPGQK-UHFFFAOYSA-N 0.000 description 1
- FQOLRTQRIBZHEZ-UHFFFAOYSA-N methyl 2-[[2-[(4-cyanoanilino)methyl]-1-methylbenzimidazole-5-carbonyl]-pyridin-2-ylamino]acetate Chemical compound C=1C=CC=NC=1N(CC(=O)OC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2CNC1=CC=C(C#N)C=C1 FQOLRTQRIBZHEZ-UHFFFAOYSA-N 0.000 description 1
- SVWWNEYBEFASMP-UHFFFAOYSA-N methyl 2-aminopyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC(N)=C1 SVWWNEYBEFASMP-UHFFFAOYSA-N 0.000 description 1
- FAFAYPAYUYYFOZ-UHFFFAOYSA-N methyl 3-(n-[2-[(4-carbamothioylanilino)methyl]-1-methylindole-5-carbonyl]anilino)propanoate Chemical compound C=1C=CC=CC=1N(CCC(=O)OC)C(=O)C(C=C1C=2)=CC=C1N(C)C=2CNC1=CC=C(C(N)=S)C=C1 FAFAYPAYUYYFOZ-UHFFFAOYSA-N 0.000 description 1
- YFFHVBMVNLXGEA-UHFFFAOYSA-N methyl 3-(n-[2-[(4-cyanoanilino)methyl]-3-methylimidazo[4,5-b]pyridine-6-carbonyl]anilino)propanoate Chemical compound C=1C=CC=CC=1N(CCC(=O)OC)C(=O)C(C=C1N=2)=CN=C1N(C)C=2CNC1=CC=C(C#N)C=C1 YFFHVBMVNLXGEA-UHFFFAOYSA-N 0.000 description 1
- DERAOUFQAXYBLO-UHFFFAOYSA-N methyl 3-(n-[2-[(4-cyanophenyl)sulfanylmethyl]-3-methylimidazo[4,5-b]pyridine-6-carbonyl]anilino)propanoate Chemical compound C=1C=CC=CC=1N(CCC(=O)OC)C(=O)C(C=C1N=2)=CN=C1N(C)C=2CSC1=CC=C(C#N)C=C1 DERAOUFQAXYBLO-UHFFFAOYSA-N 0.000 description 1
- MDYNUUNBSPGUKW-UHFFFAOYSA-N methyl 3-(n-[3-amino-4-(methylamino)benzoyl]anilino)propanoate Chemical compound C1=C(N)C(NC)=CC=C1C(=O)N(CCC(=O)OC)C1=CC=CC=C1 MDYNUUNBSPGUKW-UHFFFAOYSA-N 0.000 description 1
- YOJJGZRUCUEZHN-UHFFFAOYSA-N methyl 3-[3-(4-cyanophenyl)propanoylamino]-4-formylbenzoate Chemical compound COC(=O)C1=CC=C(C=O)C(NC(=O)CCC=2C=CC(=CC=2)C#N)=C1 YOJJGZRUCUEZHN-UHFFFAOYSA-N 0.000 description 1
- JWAZAEKBPGIMAE-UHFFFAOYSA-N methyl 3-[[2-[(4-cyanoanilino)methyl]-1,3-benzothiazole-5-carbonyl]-pyridin-2-ylamino]propanoate Chemical compound C=1C=CC=NC=1N(CCC(=O)OC)C(=O)C(C=C1N=2)=CC=C1SC=2CNC1=CC=C(C#N)C=C1 JWAZAEKBPGIMAE-UHFFFAOYSA-N 0.000 description 1
- NHLNCKBZUVTVHK-UHFFFAOYSA-N methyl 3-[[2-[(4-cyanoanilino)methyl]-1-methylbenzimidazole-5-carbonyl]-pyridin-2-ylamino]propanoate Chemical compound C=1C=CC=NC=1N(CCC(=O)OC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2CNC1=CC=C(C#N)C=C1 NHLNCKBZUVTVHK-UHFFFAOYSA-N 0.000 description 1
- OBZRSKGTTUAMFU-UHFFFAOYSA-N methyl 3-[[2-[2-(4-cyanophenyl)ethyl]-3-methylimidazo[1,2-a]pyridine-7-carbonyl]-pyridin-2-ylamino]propanoate;hydrochloride Chemical compound Cl.C=1C=CC=NC=1N(CCC(=O)OC)C(=O)C(=CC1=N2)C=CN1C(C)=C2CCC1=CC=C(C#N)C=C1 OBZRSKGTTUAMFU-UHFFFAOYSA-N 0.000 description 1
- BGHYSSCUBBIRFT-UHFFFAOYSA-N methyl 3-[[2-[2-(4-cyanophenyl)ethyl]-3-methylimidazo[4,5-b]pyridine-6-carbonyl]-pyridin-2-ylamino]propanoate Chemical compound C=1C=CC=NC=1N(CCC(=O)OC)C(=O)C(C=C1N=2)=CN=C1N(C)C=2CCC1=CC=C(C#N)C=C1 BGHYSSCUBBIRFT-UHFFFAOYSA-N 0.000 description 1
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 1
- KOAUQYGBBXPXBK-UHFFFAOYSA-N methyl 5-[3-(4-cyanophenyl)propanoylamino]-6-(methylamino)pyridine-3-carboxylate Chemical compound CNC1=NC=C(C(=O)OC)C=C1NC(=O)CCC1=CC=C(C#N)C=C1 KOAUQYGBBXPXBK-UHFFFAOYSA-N 0.000 description 1
- SKQONNBJDANXBF-UHFFFAOYSA-N methyl 6-(methylamino)-5-nitropyridine-3-carboxylate Chemical compound CNC1=NC=C(C(=O)OC)C=C1[N+]([O-])=O SKQONNBJDANXBF-UHFFFAOYSA-N 0.000 description 1
- BRPREIDVQXJOJH-UHFFFAOYSA-N methyl 6-chloro-5-nitropyridine-3-carboxylate Chemical compound COC(=O)C1=CN=C(Cl)C([N+]([O-])=O)=C1 BRPREIDVQXJOJH-UHFFFAOYSA-N 0.000 description 1
- 229940073584 methylene chloride Drugs 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- XRYGCVVVDCEPRL-UHFFFAOYSA-N n,1-dimethylpiperidin-4-amine Chemical compound CNC1CCN(C)CC1 XRYGCVVVDCEPRL-UHFFFAOYSA-N 0.000 description 1
- DUEAXBVXLPYGCB-UHFFFAOYSA-N n,6-dimethyl-2-nitropyridin-3-amine Chemical compound CNC1=CC=C(C)N=C1[N+]([O-])=O DUEAXBVXLPYGCB-UHFFFAOYSA-N 0.000 description 1
- PFVYSURSVXECJA-UHFFFAOYSA-N n,6-dimethylpyridin-2-amine Chemical compound CNC1=CC=CC(C)=N1 PFVYSURSVXECJA-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- VKOFPDUSOTWTPX-UHFFFAOYSA-N nonyl carbonochloridate Chemical compound CCCCCCCCCOC(Cl)=O VKOFPDUSOTWTPX-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002905 orthoesters Chemical class 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- ATBIAJXSKNPHEI-UHFFFAOYSA-N pyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC=CN=C1 ATBIAJXSKNPHEI-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- QBERHIJABFXGRZ-UHFFFAOYSA-M rhodium;triphenylphosphane;chloride Chemical compound [Cl-].[Rh].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QBERHIJABFXGRZ-UHFFFAOYSA-M 0.000 description 1
- 239000011833 salt mixture Substances 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
- 229910001958 silver carbonate Inorganic materials 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 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
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 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 1
- UIYBZSBGFIMASH-UHFFFAOYSA-N tert-butyl 4-(n-[2-[2-(4-cyanophenyl)ethyl]-1-methylbenzimidazole-5-carbonyl]anilino)butanoate Chemical compound N=1C2=CC(C(=O)N(CCCC(=O)OC(C)(C)C)C=3C=CC=CC=3)=CC=C2N(C)C=1CCC1=CC=C(C#N)C=C1 UIYBZSBGFIMASH-UHFFFAOYSA-N 0.000 description 1
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000026 trimethylsilyl group Chemical class [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 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
- 239000012588 trypsin Substances 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- 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
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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
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/12—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/14—Radicals substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/28—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D277/70—Sulfur atoms
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
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- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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DE19706229A DE19706229A1 (de) | 1997-02-18 | 1997-02-18 | Disubstituierte bicyclische Heterocyclen, ihre Herstellung und ihre Verwendung als Arzneimittel |
DE1997151939 DE19751939A1 (de) | 1997-11-24 | 1997-11-24 | Disubstituierte bicyclische Heterocyclen, ihre Herstellung und ihre Verwendung als Arzneimittel |
PCT/EP1998/000865 WO1998037075A1 (de) | 1997-02-18 | 1998-02-16 | Disubstituierte bicyclische heterocyclen, ihre herstellung und ihre verwendung als arzneimittel |
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NO2008012C NO2008012I2 (no) | 1997-02-18 | 2008-07-31 | Dabigatran-eteksilat og salter derav - spesielt dabigatran-eteksilat-mesylat |
NO2021005C NO2021005I1 (no) | 1997-02-18 | 2021-02-05 | Pradaxa - Dabigatranetexilatmesilat - forlenget SPC |
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NO2021005C NO2021005I1 (no) | 1997-02-18 | 2021-02-05 | Pradaxa - Dabigatranetexilatmesilat - forlenget SPC |
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JP (1) | JP3343359B2 (hu) |
KR (1) | KR100619458B1 (hu) |
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Families Citing this family (171)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999026933A1 (en) * | 1997-11-26 | 1999-06-03 | Axys Pharmaceuticals, Inc. | Substituted amidinoaryl derivatives and their use as anticoagulants |
AU2720199A (en) * | 1998-02-03 | 1999-08-23 | Boehringer Ingelheim Pharma Kg | Five-membered, benzo-condensed heterocycles used as antithrombotic agents |
US6114532A (en) * | 1998-02-03 | 2000-09-05 | Boehringer Ingelheim Pharma Kg | Bicyclic heterocycles, the preparation thereof, and their use as pharmaceuticals |
US6291514B1 (en) | 1998-02-09 | 2001-09-18 | 3-Dimensional Pharmaceuticals, Inc. | Heteroaryl amidines, methylamidines and guanidines, preparation thereof, and use thereof as protease inhibitors |
EP1054886B1 (en) * | 1998-02-09 | 2002-09-04 | 3-Dimensional Pharmaceuticals, Inc. | Heteroaryl amidines, methylamidines and guanidines as protease inhibitors, in particular as urokinase inhibitors |
TWI248435B (en) * | 1998-07-04 | 2006-02-01 | Boehringer Ingelheim Pharma | Benzimidazoles, the preparation thereof and their use as pharmaceutical compositions |
US6248770B1 (en) | 1998-07-09 | 2001-06-19 | Boehringer Ingelheim Pharma Kg | Benzimidazoles having antithrombotic activity |
EA200100882A1 (ru) * | 1999-02-09 | 2002-04-25 | 3-Дименшенл Фамэсьютикэлс, Инк. | Гетероарильные производные амидина, метиламидина и гуанидина (варианты), способ их получения, фармацевтическая композиция (варианты), способ ингибирования протеазы (варианты) и способ лечения различных заболеваний (варианты) |
DE19907813A1 (de) * | 1999-02-24 | 2000-08-31 | Boehringer Ingelheim Pharma | Substituierte bicyclische Heterocyclen, deren Herstellung und deren Verwendung als Arzneimittel |
AR023510A1 (es) | 1999-04-21 | 2002-09-04 | Astrazeneca Ab | Un equipo de partes, formulacion farmaceutica y uso de un inhibidor de trombina. |
DE19939463A1 (de) * | 1999-08-20 | 2001-02-22 | Boehringer Ingelheim Pharma | Aminocarbonyl-substituierte Benzimidazolderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
US6512000B1 (en) | 1999-08-20 | 2003-01-28 | Boehringer Ingelheim Pharma Kg | Aminocarbonyl-substituted benzimidazoles having tryptase-inhibitory activity |
DE50001742D1 (de) * | 1999-09-24 | 2003-05-15 | Boehringer Ingelheim Pharma | Arylsulfonamid-substituierte benzimidazolderivate und ihre verwendung als tryptase-inhibitoren |
DE19945810A1 (de) * | 1999-09-24 | 2001-03-29 | Boehringer Ingelheim Pharma | Substituierte Benzimidazolderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
US6413990B1 (en) | 1999-09-24 | 2002-07-02 | Boehringer Ingelheim Pharma Kg | Arylsulphonamide-substituted benzimidazoles having tryptase-inhibiting activity |
DE19945787A1 (de) | 1999-09-24 | 2001-03-29 | Boehringer Ingelheim Pharma | Arylsulfonamid-substituierte Benzimidazolderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
US6407130B1 (en) | 1999-11-10 | 2002-06-18 | Boehringer Ingelheim Pharma Kg | Carboxamide-substituted benzimidazoles having tryptase-inhibiting activity |
US6451832B2 (en) | 1999-12-23 | 2002-09-17 | Boehringer Ingelheim Pharma Kg | Benzimidazoles with antithrombotic activity |
US6448281B1 (en) * | 2000-07-06 | 2002-09-10 | Boehringer Ingelheim (Canada) Ltd. | Viral polymerase inhibitors |
US20040242627A1 (en) | 2001-04-19 | 2004-12-02 | Shuichi Suzuki | 2-Iminoimidazole derivatives (1) |
DE10133786A1 (de) * | 2001-07-16 | 2003-02-06 | Boehringer Ingelheim Pharma | Verwendung von Thrombin-Inhibitoren zur Behandlung von Arthritis |
US20030181488A1 (en) | 2002-03-07 | 2003-09-25 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester and the salts thereof |
EP1485094B2 (de) * | 2002-03-07 | 2020-03-25 | Boehringer Ingelheim International GmbH | Oral zu applizierende darreichungsform für 3- [(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino] -propionsäure-ethylester oder dessen salze |
DE10235639A1 (de) * | 2002-08-02 | 2004-02-19 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Prodrugs von 1-Methyl-2-(4-amidinophenylaminomethyl)-benzimidazol-5-yl-carbonsäure-(N-2-pyridyl-N-2-hydroxycarbonylethyl)-amid, ihre Herstellung und ihre Verwendung als Arzneimittel |
AU2003265398A1 (en) | 2002-08-09 | 2004-02-25 | Transtech Pharma, Inc. | Aryl and heteroaryl compounds and methods to modulate coagulation |
PE20040804A1 (es) * | 2002-12-19 | 2004-12-31 | Boehringer Ingelheim Pharma | DERIVADOS DE CARBOXAMIDAS COMO INHIBIDORES DEL FACTOR Xa |
US7429597B2 (en) | 2002-12-23 | 2008-09-30 | Boehringer Ingelheim Pharma Gmbh & Co., Kg | Substituted nitrogen-containing heterobicycles, the preparation thereof and their use as pharmaceutical compositions |
DE10260730A1 (de) | 2002-12-23 | 2004-07-01 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue substituierte stickstoffhaltige Heterobicyclen, deren Herstellung und deren Verwendung als Arzneimittel |
AU2004218187C1 (en) | 2003-02-19 | 2011-04-07 | Eisai R&D Management Co., Ltd. | Methods for producing cyclic benzamidine derivatives |
DE10310278A1 (de) * | 2003-03-10 | 2004-09-23 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue aromatische Bicyclen, deren Herstellung und deren Verwendung als Arzneimittel |
AU2004231306A1 (en) | 2003-04-24 | 2004-11-04 | Boehringer Ingelheim International Gmbh | Use of dipyridamole or mopidamole for treatment and prevention of thrombo-embolic diseases and disorders caused by excessive formation of thrombin and/or by elevated expression of thrombin receptors |
US7208601B2 (en) | 2003-08-08 | 2007-04-24 | Mjalli Adnan M M | Aryl and heteroaryl compounds, compositions, and methods of use |
CA2531796A1 (en) | 2003-08-08 | 2005-02-17 | Transtech Pharma, Inc. | Aryl and heteroaryl compounds, compositions, and methods of use |
WO2005014534A1 (en) * | 2003-08-08 | 2005-02-17 | Transtech Pharma, Inc. | Aryl and heteroaryl compounds, compositions, and methods of use |
DE10337697A1 (de) * | 2003-08-16 | 2005-03-24 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Tablette enthaltend 3-[(2-{[4-(Hexyloxycarbonylamino-imino-methyl)-phenyl-amino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionsäure-ethylester oder dessen Salze |
DE10339862A1 (de) * | 2003-08-29 | 2005-03-24 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 3-[(2-{[4-(Hexyloxycarbonylamino-imino-methyl)- phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionsäure-ethylester-Methansulfonat und dessen Verwendung als Arzneimittel |
DE10341043A1 (de) * | 2003-09-03 | 2005-03-31 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue oral zu applizierende Darreichungsform für 3-[(2-{[4-Hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionsäure-ethylester und dessen Salze |
EP1609784A1 (de) * | 2004-06-25 | 2005-12-28 | Boehringer Ingelheim Pharma GmbH & Co.KG | Verfahren zur Herstellung von 4-(Benzimidazolylmethylamino)-Benzamidinen |
US20060222640A1 (en) * | 2005-03-29 | 2006-10-05 | Boehringer Ingelheim International Gmbh | New pharmaceutical compositions for treatment of thrombosis |
DE102005020002A1 (de) * | 2005-04-27 | 2006-11-02 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Physiologisch verträgliche Salze von 3-[(2-{[4-(Hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionsäure-ethylester |
DE102005025728A1 (de) * | 2005-06-04 | 2006-12-07 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Polymorphe von 3-[(2-{[4-(Hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-Propionsäure-ethylester |
ATE485269T1 (de) | 2005-06-27 | 2010-11-15 | Bristol Myers Squibb Co | C-verknüpfte zyklische antagonisten des p2y1- rezeptors mit eignung bei der behandlung thrombotischer leiden |
DE102005061623A1 (de) | 2005-12-21 | 2007-06-28 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verbessertes Verfahren zur Herstellung von 4-(Benzimidazolylmethylamino)-Benzamidinen und deren Salzen |
DE102005061624A1 (de) * | 2005-12-21 | 2007-06-28 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verbessertes Verfahren zur Herstellung von Salzen von 4-(Benzimidazolylmethylamino)-Benzamidinen |
US8044242B2 (en) | 2006-03-09 | 2011-10-25 | Bristol-Myers Squibb Company | 2-(aryloxy) acetamide factor VIIa inhibitors useful as anticoagulants |
WO2007146719A2 (en) | 2006-06-08 | 2007-12-21 | Bristol-Myers Squibb Company | 2-aminocarbonylphenylamino-2-phenylacetamides as factor viia inhibitors useful as anticoagulants |
JP2009543843A (ja) * | 2006-07-17 | 2009-12-10 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 直接トロンビン阻害剤に関する新規適応 |
WO2008009638A2 (en) * | 2006-07-17 | 2008-01-24 | Boehringer Ingelheim International Gmbh | New indications for direct thrombin inhibitors in the cardiovascular field |
CA2666396A1 (en) * | 2006-10-10 | 2008-04-17 | Boehringer Ingelheim International Gmbh | Physiologically acceptable salts of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester |
WO2008076805A2 (en) | 2006-12-15 | 2008-06-26 | Bristol-Myers Squibb Company | Arylpropionamide, arylacrylamide, arylpropynamide, or arylmethylurea analogs as factor xia inhibitors |
PE20081775A1 (es) | 2006-12-20 | 2008-12-18 | Bristol Myers Squibb Co | Compuestos macrociclicos como inhibidores del factor viia |
EP1956018A1 (de) * | 2007-02-06 | 2008-08-13 | Boehringer Ingelheim Pharma GmbH & Co. KG | Verfahren zur Herstellung eines Benzimidazolderivats |
MX2009011089A (es) | 2007-04-23 | 2009-10-30 | Sanofi Aventis | Derivados de quinolina-carboxamida en calidad de antagonistas de p2y12. |
US8350032B2 (en) | 2007-07-31 | 2013-01-08 | Medibeacon Development, Llc | Integrated photoactive agents for real-time monitoring of hemostasis |
EP2238128B1 (en) | 2007-12-26 | 2012-08-22 | Sanofi | Heterocyclic pyrazole-carboxamides as p2y12 antagonists |
CZ305085B6 (cs) * | 2008-03-14 | 2015-04-29 | Zentiva, K.S. | Způsob přípravy dabigatranu |
TWI436994B (zh) * | 2008-07-14 | 2014-05-11 | Boehringer Ingelheim Int | 製備含有達比加群(dabigatran)之藥物組合物的新穎方法 |
JP2012500243A (ja) * | 2008-08-19 | 2012-01-05 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 肺高血圧症患者の治療のためのダビガトランエテキシラートの使用 |
CZ2008669A3 (cs) * | 2008-10-24 | 2010-05-05 | Zentiva, A. S. | Zpusob prípravy dabigatranu a jeho meziprodukty |
NZ593787A (en) | 2009-02-02 | 2013-09-27 | Boehringer Ingelheim Int | Lyophilised dabigatran |
JP2012526766A (ja) | 2009-05-14 | 2012-11-01 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 腫瘍性及び線維性疾患の処置における新規な併用療法 |
ES2436076T3 (es) | 2009-08-24 | 2013-12-26 | Boehringer Ingelheim International Gmbh | Intervenciones de urgencia de carbón vegetal activo con sobredosificación con etexilato de dabigatrán |
CN102050815B (zh) * | 2009-11-06 | 2014-04-02 | 北京美倍他药物研究有限公司 | 作为前药的达比加群的酯衍生物 |
CN102050814B (zh) * | 2009-11-06 | 2014-05-28 | 北京美倍他药物研究有限公司 | 达比加群的酯衍生物 |
US8399678B2 (en) | 2009-11-18 | 2013-03-19 | Boehringer Ingelheim International Gmbh | Process for the manufacture of dabigatran etexilate |
AR079944A1 (es) * | 2010-01-20 | 2012-02-29 | Boehringer Ingelheim Int | Anticuerpo neutralizante de la actividad de un anticoagulante |
HUP1000069A2 (en) | 2010-02-02 | 2012-05-02 | Egis Gyogyszergyar Nyilvanosan M Kod Ruszvunytarsasag | New salts for the preparation of pharmaceutical composition |
CA2789622C (en) | 2010-02-11 | 2018-04-03 | Bristol-Myers Squibb Company | Macrocycles as factor xia inhibitors |
WO2011107427A1 (en) | 2010-03-01 | 2011-09-09 | Ratiopharm Gmbh | Dabigatran etexilate-containing oral pharmaceutical composition |
JP2013521318A (ja) | 2010-03-08 | 2013-06-10 | ラティオファルム ゲー・エム・ベー・ハー | ダビガトランエテキシラートを含有する医薬組成物 |
PL2588090T3 (pl) | 2010-07-01 | 2017-12-29 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Doustne farmaceutyczne postacie dawkowania zawierające eteksylan dabigatranu i jego farmaceutycznie dopuszczalne sole |
JP2013532164A (ja) | 2010-07-09 | 2013-08-15 | エステヴェ キミカ, エス.エー. | トロンビン特異的インヒビターを調製する方法 |
JP2013531004A (ja) | 2010-07-09 | 2013-08-01 | エステヴェ キミカ, エス.エー. | トロンビン特異的インヒビターの調製のための中間体及び方法 |
WO2012027543A1 (en) | 2010-08-25 | 2012-03-01 | Teva Pharmaceuticals Usa, Inc. | Solid state forms of dabigatran etexilate, dabigatran etexilate mesylate and processes for preparation thereof |
WO2012077136A2 (en) | 2010-12-06 | 2012-06-14 | Msn Laboratories Limited | Process for the preparation of benzimidazole derivatives and its salts |
US9000186B2 (en) | 2011-02-01 | 2015-04-07 | Kyowa Hakko Kirin Co., Ltd. | Ring-fused heterocyclic derivative |
AP2013007046A0 (en) | 2011-03-30 | 2013-08-31 | Boehringer Ingelheim Int | Anticoagulant antidotes |
HUP1100244A2 (hu) | 2011-05-11 | 2012-11-28 | Egis Gyogyszergyar Nyilvanosan Muekoedoe Reszvenytarsasag | Gyógyszeripari intermedierek és eljárás elõállításukra |
CN102250099B (zh) * | 2011-05-16 | 2013-10-16 | 中国药科大学 | 一类非肽类抗凝血酶抑制剂、其制法以及医药用途 |
CN102838588B (zh) * | 2011-06-24 | 2014-03-19 | 中国药科大学 | 一类可用于口服的凝血酶抑制剂、其制法以及医药用途 |
HUE032862T2 (hu) * | 2011-07-25 | 2017-11-28 | Dritte Patentportfolio Beteili | Dabigatran-amidoximsav-észterek mint prodrug formák és ezek alkalmazása gyógyszerként |
TW201311689A (zh) | 2011-08-05 | 2013-03-16 | 必治妥美雅史谷比公司 | 作為因子xia抑制劑之新穎巨環化合物 |
TW201319068A (zh) | 2011-08-05 | 2013-05-16 | 必治妥美雅史谷比公司 | 作為xia因子抑制劑之環狀p1接合劑 |
WO2013024394A1 (en) * | 2011-08-12 | 2013-02-21 | Alembic Pharmaceuticals Limited | Novel reference markers of dabigatran etexilate |
CN102993174A (zh) * | 2011-09-08 | 2013-03-27 | 天津药物研究院 | 作为前药的达比加群的酯衍生物 |
CN102993175B (zh) * | 2011-09-08 | 2014-08-13 | 天津药物研究院 | 达比加群的酯衍生物及其制备方法和用途 |
SI2766346T1 (sl) | 2011-10-14 | 2017-05-31 | Bristol-Myers Squibb Company | Substituirane tetrahidroizokinolinske spojine kot faktor xia inhibitorji |
WO2013055984A1 (en) | 2011-10-14 | 2013-04-18 | Bristol-Myers Squibb Company | Substituted tetrahydroisoquinoline compounds as factor xia inhibitors |
ES2579832T3 (es) | 2011-10-14 | 2016-08-17 | Bristol-Myers Squibb Company | Compuestos de tetrahidroisoquinolina sustituida como inhibidores del factor XIa |
US20130183384A1 (en) | 2011-12-22 | 2013-07-18 | Boehringer Ingelheim International Gmbh | Immediate release multi unit pellet system |
WO2013111163A2 (en) | 2012-01-20 | 2013-08-01 | Cadila Healthcare Limited | Process for the preparation of dabigatran etexilate mesylate and polymorphs of intermediates thereof |
JP2015504903A (ja) | 2012-01-24 | 2015-02-16 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 新規の経口投与用ダビガトラン製剤 |
HRP20211606T1 (hr) | 2012-02-21 | 2022-01-21 | Towa Pharmaceutical Europe, S.L. | Oralni farmaceutski pripravci dabigatran-eteksilata |
EP2631234A1 (en) | 2012-02-23 | 2013-08-28 | Esteve Química, S.A. | Solid forms of dabigatran etexilate mesylate and processes for their preparation |
WO2013144971A1 (en) | 2012-03-27 | 2013-10-03 | Cadila Healthcare Limited | New solid forms of dabigatran etexilate bisulfate and mesylate and processes to prepare them |
US9273030B2 (en) | 2012-04-02 | 2016-03-01 | Msn Laboratories Private Limited | Process for the preparation of benzimidazole derivatives and salts thereof |
CN103387566B (zh) * | 2012-05-09 | 2015-09-09 | 上海医药工业研究院 | 制备3-[[[2-[[(4-氰基苯基)氨基]甲基]-1-甲基-1h-苯并咪唑-5-基]羰基](吡啶-2-基)氨基]丙酸乙酯的方法 |
CN103420980A (zh) * | 2012-05-22 | 2013-12-04 | 北京美倍他药物研究有限公司 | 达比加群衍生物 |
US20130345262A1 (en) | 2012-06-25 | 2013-12-26 | Boehringer Ingelheim International Gmbh | Method for prevention of stroke |
WO2014012880A1 (en) | 2012-07-16 | 2014-01-23 | Interquim, S.A. | Process for the preparation of intermediates for the synthesis of dabigatran etexilate, and crystalline forms of said intermediates |
CN102766134B (zh) * | 2012-07-19 | 2014-06-25 | 北京普禄德医药科技有限公司 | 达比加群的酯衍生物及其制备方法和用途 |
WO2014021383A1 (ja) * | 2012-07-31 | 2014-02-06 | 協和発酵キリン株式会社 | 縮環複素環化合物 |
LT2882734T (lt) | 2012-08-03 | 2016-12-12 | Bristol-Myers Squibb Company | Dihidropiridonai, kaip xia faktoriaus slopikliai |
DK2880026T3 (en) | 2012-08-03 | 2017-06-06 | Bristol Myers Squibb Co | DIHYDROPYRIDON-P1 AS A FACTOR XIA INHIBITORS |
WO2014041559A2 (en) * | 2012-08-27 | 2014-03-20 | Glenmark Pharmaceuticals Limited; Glenmark Generics Limited | Process for the preparation of dabigatran etexilate and intermediates thereof |
EP2722033A1 (en) | 2012-10-19 | 2014-04-23 | Sanovel Ilac Sanayi ve Ticaret A.S. | Pharmaceutical Compositions of Dabigatran Free Base |
EP2722034B1 (en) | 2012-10-19 | 2020-09-16 | Sanovel Ilac Sanayi ve Ticaret A.S. | Oral pharmaceutical formulations comprising dabigatran |
US9399616B2 (en) | 2012-10-22 | 2016-07-26 | Boehringer Ingelheim International Gmbh | Process for the manufacture of 4-aminobenzoamidine dihydrochloride |
WO2014068587A2 (en) * | 2012-10-29 | 2014-05-08 | Biophore India Pharmaceuticals Pvt. Ltd. | An improved process for the synthesis of dabigatran and its intermediates |
US10077251B2 (en) | 2012-10-29 | 2018-09-18 | Biophore India Pharmaceuticals Pvt. Ltd. | Process for the synthesis of Dabigatran Etexilate and its intermediates |
CN102977077A (zh) * | 2012-11-28 | 2013-03-20 | 浙江燎原药业有限公司 | 一种达比加群酯中间体的制备方法 |
EP2740471B1 (en) | 2012-12-07 | 2015-05-27 | Hexal AG | Oral pharmaceutical composition comprising dabigatran etexilate |
CN103044404A (zh) * | 2013-01-14 | 2013-04-17 | 中国药科大学 | 达比加群衍生物、其制法及抗血栓用途 |
WO2014160668A1 (en) | 2013-03-25 | 2014-10-02 | Bristol-Myers Squibb Company | Tetrahydroisoquinolines containing substituted azoles as factor xia inhibitors |
CN103224469A (zh) * | 2013-05-16 | 2013-07-31 | 上海应用技术学院 | 一种以含氟基团修饰的苯环为中心的达比加群酯类似物及其合成方法 |
JP2016520110A (ja) | 2013-06-03 | 2016-07-11 | バイエル ファーマ アクチエンゲゼルシャフト | 置換ベンゾキサゾール |
UY35592A (es) | 2013-06-03 | 2014-12-31 | Bayer Pharma AG | Benzoxazoles sustituidos |
CN103288744A (zh) * | 2013-06-04 | 2013-09-11 | 上海应用技术学院 | 一种含氟基团修饰的达比加群酯类似物及其合成方法 |
EP2853260A1 (en) | 2013-09-27 | 2015-04-01 | ratiopharm GmbH | Pharmaceutical preparation comprising dabigatran etexilate bismesylate |
NO2760821T3 (hu) | 2014-01-31 | 2018-03-10 | ||
JP6464176B2 (ja) | 2014-01-31 | 2019-02-06 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | 芳香族p2’基を有する第xia因子阻害剤としてのマクロ環 |
IN2014MU00675A (hu) | 2014-02-26 | 2015-10-23 | Megafine Pharma P Ltd | |
WO2015137680A1 (ko) * | 2014-03-10 | 2015-09-17 | 동아에스티 주식회사 | 뇌졸중 및 전신색전증 치료 또는 예방용 약학적 조성물 |
WO2015145462A1 (en) | 2014-03-26 | 2015-10-01 | Cadila Healthcare Limited | Pharmaceutical compositions of dabigatran |
EP2933002A1 (en) | 2014-04-11 | 2015-10-21 | Sanovel Ilac Sanayi ve Ticaret A.S. | Pharmaceutical combinations of dabigatran and proton pump inhibitors |
WO2015155297A1 (en) | 2014-04-11 | 2015-10-15 | Sanovel Ilac Sanayi Ve Ticaret A.S. | Pharmaceutical combinations of dabigatran and h2-receptor antagonists |
CN104230888A (zh) * | 2014-06-03 | 2014-12-24 | 长春工业大学 | 一种苯并咪唑化合物的制备方法 |
CN105218519A (zh) * | 2014-06-04 | 2016-01-06 | 天津药物研究院 | 一种达比加群酯中间体的制备方法 |
CN104003977B (zh) * | 2014-06-05 | 2016-04-13 | 雅本化学股份有限公司 | N-(2-氯甲基-1-甲基-1h-苯并咪唑-5-酰基)-n-(吡啶-2-基) -3-氨基丙酸乙酯的制备方法 |
DE102014108210A1 (de) | 2014-06-11 | 2015-12-17 | Dietrich Gulba | Rodentizid |
CN104045628B (zh) * | 2014-06-13 | 2019-04-09 | 深圳翰宇药业股份有限公司 | 苯并咪唑衍生物的纯化方法 |
CN105315257A (zh) * | 2014-06-24 | 2016-02-10 | 华仁药业股份有限公司 | 一种达比加群酯的合成及纯化方法 |
CN106536505A (zh) * | 2014-08-06 | 2017-03-22 | 四川海思科制药有限公司 | 一种达比加群烷酯衍生物及其制备方法和在药学上的用途 |
WO2016019848A1 (zh) * | 2014-08-06 | 2016-02-11 | 四川海思科制药有限公司 | 一种达比加群硫酯衍生物及其制备方法和在药学上的用途 |
NO2721243T3 (hu) | 2014-10-01 | 2018-10-20 | ||
WO2016070696A1 (zh) | 2014-11-03 | 2016-05-12 | 杭州领业医药科技有限公司 | 达比加群酯或其盐的投药制剂及其制备方法 |
CN104592204B (zh) * | 2014-12-26 | 2017-05-17 | 华润赛科药业有限责任公司 | 达比加群衍生物及其制备方法和用途 |
CN104650037A (zh) * | 2014-12-30 | 2015-05-27 | 青岛黄海制药有限责任公司 | 一种达比加群酯的合成方法 |
TR201502223A2 (tr) | 2015-02-25 | 2016-09-21 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Dronedaron ve dabigatranın farmasötik kombinasyonları. |
CN104628733A (zh) * | 2015-03-02 | 2015-05-20 | 中国药科大学 | 四氢苯并[4,5]咪唑并[1,2-a]吡嗪类凝血酶抑制剂 |
EP3310777B1 (en) | 2015-06-19 | 2019-10-09 | Bristol-Myers Squibb Company | Diamide macrocycles as factor xia inhibitors |
CN104987323B (zh) * | 2015-07-10 | 2017-08-22 | 浙江美诺华药物化学有限公司 | 一种达比加群酯的制备方法 |
MA42480A (fr) | 2015-07-20 | 2018-05-30 | Sanovel Ilac Sanayi Ve Ticaret As | Préparations pharmaceutiques de dabigatran sous forme de base libre |
CN114874222A (zh) | 2015-07-29 | 2022-08-09 | 百时美施贵宝公司 | 携带非芳族p2,基团的因子xia新大环 |
JP6785838B2 (ja) | 2015-08-05 | 2020-11-18 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | 新規な置換グリシン誘導のfxia阻害剤 |
CN105294651A (zh) * | 2015-09-23 | 2016-02-03 | 烟台东诚药业集团股份有限公司 | 一种用于合成制备达比加群酯脒化中间体的方法 |
CN106866626A (zh) * | 2015-12-14 | 2017-06-20 | 天津药物研究院有限公司 | 一种达比加群酯中间体的制备方法 |
CN105481831B (zh) * | 2015-12-16 | 2018-06-12 | 开封明仁药业有限公司 | 一种制备达比加群酯中间体的方法 |
WO2017111637A1 (en) | 2015-12-23 | 2017-06-29 | Zaklady Farmaceutyczne Polpharma Sa | Pharmaceutical composition comprising dabigatran or a pharmaceutically acceptable salt thereof |
CN105566297A (zh) * | 2015-12-31 | 2016-05-11 | 哈药集团技术中心 | 一种达比加群酯甲磺酸盐的制备方法 |
JP2019507167A (ja) | 2016-03-02 | 2019-03-14 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | 第xia因子阻害活性を有するジアミド大員環 |
CN105669651B (zh) * | 2016-03-07 | 2018-03-06 | 山东罗欣药业集团股份有限公司 | 一种甲磺酸达比加群酯的制备工艺 |
CN106397400A (zh) * | 2016-04-14 | 2017-02-15 | 江苏康缘药业股份有限公司 | 一种达比加群酯的制备方法 |
TR201606697A2 (tr) | 2016-05-20 | 2017-12-21 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Dabi̇gatranin yeni̇ oral farmasöti̇k formülasyonlari |
CN106349221A (zh) * | 2016-08-29 | 2017-01-25 | 常州市阳光药业有限公司 | 高纯度达比加群酯的制备方法 |
WO2018104387A1 (en) | 2016-12-07 | 2018-06-14 | Sanovel Ilac Sanayi Ve Ticaret A.S. | Multilayered tablet compositions of dabigatran |
TR201617984A2 (tr) | 2016-12-07 | 2018-06-21 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Dabi̇gatranin farmasöti̇k kompozi̇syonlari |
JP2018184375A (ja) | 2017-04-27 | 2018-11-22 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | ダビガトランエテキシラート又は医薬的に許容されるその塩を含む錠剤及びその製造方法 |
TR201706848A2 (tr) | 2017-05-10 | 2018-11-21 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Dabigatran eteksi̇lat i̇çeren kati oral farmasöti̇k kompozi̇syonlar |
WO2019004980A2 (en) | 2017-05-10 | 2019-01-03 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | SOLID ORAL PHARMACEUTICAL COMPOSITIONS OF DABIGATRAN DEXILATE |
CN109010249A (zh) * | 2017-06-08 | 2018-12-18 | 上海美悦生物科技发展有限公司 | 注射用达比加群酯药物组合物及其制备方法和用途 |
KR20190036857A (ko) | 2017-09-28 | 2019-04-05 | 한미약품 주식회사 | 다비가트란 이텍실레이트를 포함하는 복합 캡슐제 |
TR201722323A2 (tr) | 2017-12-27 | 2019-07-22 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Dabi̇gatranin oral farmasöti̇k kompozi̇syonlari |
TR201722186A2 (tr) | 2017-12-27 | 2019-07-22 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Dabi̇gatranin farmasöti̇k kompozi̇syonlari |
TR201722630A2 (hu) | 2017-12-28 | 2019-07-22 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | |
CN111954532A (zh) * | 2018-04-13 | 2020-11-17 | 上海交通大学医学院附属瑞金医院 | 杂芳基酰胺类化合物的抗肿瘤多药耐药性、治疗癌症的用途和蛋白质-药物分子复合物 |
CN108864047A (zh) * | 2018-07-02 | 2018-11-23 | 河南师范大学 | 一种非肽类凝血酶抑制剂达比加群酯的制备方法 |
EP3771465A1 (en) | 2019-08-01 | 2021-02-03 | Zaklady Farmaceutyczne Polpharma SA | Pharmaceutical composition comprising dabigatran etexilate |
CN111606885A (zh) * | 2020-06-18 | 2020-09-01 | 安徽鼎旺医药有限公司 | 一种达比加群酯甲磺酸盐及其制备方法 |
CN113929661A (zh) * | 2020-06-29 | 2022-01-14 | 石药集团恩必普药业有限公司 | 一种达比加群酯中间体及其制备方法 |
EP4070658A1 (de) | 2021-04-06 | 2022-10-12 | BIORoxx GmbH | Verwendung von blutgerinnungshemmenden verbindungen als rodentizide |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4675405A (en) * | 1984-09-21 | 1987-06-23 | American Home Products Corporation | Quinoline compounds as antiallergic and antithrombotic agents |
DE4129603A1 (de) * | 1991-09-06 | 1993-03-11 | Thomae Gmbh Dr K | Kondensierte 5-gliedrige heterocyclen, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel |
US5416099A (en) * | 1991-10-29 | 1995-05-16 | Merck & Co., Inc. | Fibrinogen receptor antagonists |
ZA928276B (en) * | 1991-10-31 | 1993-05-06 | Daiichi Seiyaku Co | Aromatic amidine derivates and salts thereof. |
CA2134192A1 (en) * | 1993-11-12 | 1995-05-13 | Michael L. Denney | 5, 6-bicyclic glycoprotein iib/iiia antagonists |
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