IL127361A - History of N - (- 4 carbamimido-phenyl) - phenylglycinamide, process for their preparation, intermediates and pharmaceutical preparations containing them - Google Patents
History of N - (- 4 carbamimido-phenyl) - phenylglycinamide, process for their preparation, intermediates and pharmaceutical preparations containing themInfo
- Publication number
- IL127361A IL127361A IL12736198A IL12736198A IL127361A IL 127361 A IL127361 A IL 127361A IL 12736198 A IL12736198 A IL 12736198A IL 12736198 A IL12736198 A IL 12736198A IL 127361 A IL127361 A IL 127361A
- Authority
- IL
- Israel
- Prior art keywords
- alkyl
- aryl
- benzyloxy
- hydrogen
- cooh
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 4
- 238000000034 method Methods 0.000 title description 98
- 239000000543 intermediate Substances 0.000 title description 13
- -1 COO-alkyl Chemical group 0.000 claims abstract description 518
- 150000001875 compounds Chemical class 0.000 claims abstract description 108
- 239000001257 hydrogen Substances 0.000 claims abstract description 73
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 73
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 60
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 50
- 125000003118 aryl group Chemical group 0.000 claims abstract description 45
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 41
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 31
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims abstract description 26
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 19
- 150000002367 halogens Chemical class 0.000 claims abstract description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 18
- 239000012453 solvate Substances 0.000 claims abstract description 17
- 125000004104 aryloxy group Chemical group 0.000 claims abstract description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 15
- 125000005114 heteroarylalkoxy group Chemical group 0.000 claims abstract description 14
- 125000004663 dialkyl amino group Chemical group 0.000 claims abstract description 12
- 125000005530 alkylenedioxy group Chemical group 0.000 claims abstract description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 9
- 125000003435 aroyl group Chemical group 0.000 claims abstract description 8
- 150000004677 hydrates Chemical class 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 5
- 206010003210 Arteriosclerosis Diseases 0.000 claims abstract description 3
- 108010039209 Blood Coagulation Factors Proteins 0.000 claims abstract description 3
- 102000015081 Blood Coagulation Factors Human genes 0.000 claims abstract description 3
- 206010008190 Cerebrovascular accident Diseases 0.000 claims abstract description 3
- 206010061216 Infarction Diseases 0.000 claims abstract description 3
- 206010061218 Inflammation Diseases 0.000 claims abstract description 3
- 208000006011 Stroke Diseases 0.000 claims abstract description 3
- 108090000190 Thrombin Proteins 0.000 claims abstract description 3
- 208000007536 Thrombosis Diseases 0.000 claims abstract description 3
- 208000011775 arteriosclerosis disease Diseases 0.000 claims abstract description 3
- 239000003114 blood coagulation factor Substances 0.000 claims abstract description 3
- 230000000747 cardiac effect Effects 0.000 claims abstract description 3
- 230000007574 infarction Effects 0.000 claims abstract description 3
- 230000004054 inflammatory process Effects 0.000 claims abstract description 3
- 229960004072 thrombin Drugs 0.000 claims abstract description 3
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims abstract 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 67
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 65
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 49
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 40
- 150000002431 hydrogen Chemical group 0.000 claims description 27
- 150000002825 nitriles Chemical class 0.000 claims description 26
- 239000002253 acid Substances 0.000 claims description 24
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 24
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 22
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 10
- 239000005711 Benzoic acid Substances 0.000 claims description 9
- 235000010233 benzoic acid Nutrition 0.000 claims description 9
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 8
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 4
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 4
- 150000002527 isonitriles Chemical class 0.000 claims description 4
- WPANETAWYGDRLL-UHFFFAOYSA-N 4-aminobenzenecarboximidamide Chemical compound NC(=N)C1=CC=C(N)C=C1 WPANETAWYGDRLL-UHFFFAOYSA-N 0.000 claims description 3
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 3
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 3
- POLUWPJTKLBMTD-VXKWHMMOSA-N (2s)-2-[[(2s)-2-(4-carbamimidoylanilino)-2-(3,5-dimethoxyphenyl)acetyl]amino]-2-phenylacetic acid Chemical compound COC1=CC(OC)=CC([C@H](NC=2C=CC(=CC=2)C(N)=N)C(=O)N[C@H](C(O)=O)C=2C=CC=CC=2)=C1 POLUWPJTKLBMTD-VXKWHMMOSA-N 0.000 claims description 2
- BMDYWWBOVIRAFQ-UHFFFAOYSA-N 2-[[2-(4-carbamimidoylanilino)-2-(3-methoxy-4-phenylmethoxyphenyl)acetyl]amino]-2,2-diphenylacetic acid Chemical compound COC1=CC(C(NC=2C=CC(=CC=2)C(N)=N)C(=O)NC(C(O)=O)(C=2C=CC=CC=2)C=2C=CC=CC=2)=CC=C1OCC1=CC=CC=C1 BMDYWWBOVIRAFQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- WGEGXJPYFSZDMU-IZLXSDGUSA-N (2s)-2-[[(2r)-2-(4-carbamimidoylanilino)-2-(3-methoxy-4-phenylmethoxyphenyl)acetyl]amino]-2-phenylacetic acid Chemical compound COC1=CC([C@@H](NC=2C=CC(=CC=2)C(N)=N)C(=O)N[C@H](C(O)=O)C=2C=CC=CC=2)=CC=C1OCC1=CC=CC=C1 WGEGXJPYFSZDMU-IZLXSDGUSA-N 0.000 claims 1
- IXHWKNNMARHCLQ-SZAHLOSFSA-N (2s)-2-[[(2r)-2-[2-(benzenesulfonamido)-5-methoxy-4-phenylmethoxyphenyl]-2-(4-carbamimidoylanilino)acetyl]amino]-2-phenylacetic acid Chemical compound N([C@H](C=1C=C(C(=CC=1NS(=O)(=O)C=1C=CC=CC=1)OCC=1C=CC=CC=1)OC)C(=O)N[C@H](C(O)=O)C=1C=CC=CC=1)C1=CC=C(C(N)=N)C=C1 IXHWKNNMARHCLQ-SZAHLOSFSA-N 0.000 claims 1
- GOKMXGJLEDPKOL-ZPGRZCPFSA-N (2s)-2-[[(2s)-2-(4-carbamimidoylanilino)-2-[5-methoxy-2-[(2-phenylacetyl)amino]-4-phenylmethoxyphenyl]acetyl]amino]-2-phenylacetic acid Chemical compound N([C@@H](C=1C=C(C(=CC=1NC(=O)CC=1C=CC=CC=1)OCC=1C=CC=CC=1)OC)C(=O)N[C@H](C(O)=O)C=1C=CC=CC=1)C1=CC=C(C(N)=N)C=C1 GOKMXGJLEDPKOL-ZPGRZCPFSA-N 0.000 claims 1
- IXHWKNNMARHCLQ-HEVIKAOCSA-N (2s)-2-[[(2s)-2-[2-(benzenesulfonamido)-5-methoxy-4-phenylmethoxyphenyl]-2-(4-carbamimidoylanilino)acetyl]amino]-2-phenylacetic acid Chemical compound N([C@@H](C=1C=C(C(=CC=1NS(=O)(=O)C=1C=CC=CC=1)OCC=1C=CC=CC=1)OC)C(=O)N[C@H](C(O)=O)C=1C=CC=CC=1)C1=CC=C(C(N)=N)C=C1 IXHWKNNMARHCLQ-HEVIKAOCSA-N 0.000 claims 1
- HUWKQXRHVOWQGB-UHFFFAOYSA-N 2-[2-(benzenesulfonamido)-5-methoxy-4-phenylmethoxyphenyl]-n-benzyl-2-(4-carbamimidoylanilino)acetamide Chemical compound C=1C=CC=CC=1S(=O)(=O)NC=1C=C(OCC=2C=CC=CC=2)C(OC)=CC=1C(C(=O)NCC=1C=CC=CC=1)NC1=CC=C(C(N)=N)C=C1 HUWKQXRHVOWQGB-UHFFFAOYSA-N 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 230000000887 hydrating effect Effects 0.000 claims 1
- HHOIHLOXHFQCLM-UHFFFAOYSA-N n-benzyl-2-[4-[(z)-n'-hydroxycarbamimidoyl]anilino]-2-[2-(methanesulfonamido)-5-methoxy-4-phenylmethoxyphenyl]acetamide Chemical compound CS(=O)(=O)NC=1C=C(OCC=2C=CC=CC=2)C(OC)=CC=1C(C(=O)NCC=1C=CC=CC=1)NC1=CC=C(C(=N)NO)C=C1 HHOIHLOXHFQCLM-UHFFFAOYSA-N 0.000 claims 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 abstract description 12
- 108010000499 Thromboplastin Proteins 0.000 abstract description 4
- 102000002262 Thromboplastin Human genes 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 125000005843 halogen group Chemical group 0.000 abstract description 2
- 239000003112 inhibitor Substances 0.000 abstract description 2
- 230000002265 prevention Effects 0.000 abstract description 2
- 108010054265 Factor VIIa Proteins 0.000 abstract 1
- 239000002246 antineoplastic agent Substances 0.000 abstract 1
- 229940012414 factor viia Drugs 0.000 abstract 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 102
- 239000007787 solid Substances 0.000 description 102
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 88
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 85
- 239000000243 solution Substances 0.000 description 78
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 76
- 239000000203 mixture Substances 0.000 description 75
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 63
- 239000013078 crystal Substances 0.000 description 59
- RIWNFZUWWRVGEU-UHFFFAOYSA-N isocyanomethylbenzene Chemical compound [C-]#[N+]CC1=CC=CC=C1 RIWNFZUWWRVGEU-UHFFFAOYSA-N 0.000 description 58
- 239000000047 product Substances 0.000 description 57
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 51
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 45
- 235000019439 ethyl acetate Nutrition 0.000 description 41
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 38
- 239000011734 sodium Substances 0.000 description 35
- YBAZINRZQSAIAY-UHFFFAOYSA-N 4-aminobenzonitrile Chemical compound NC1=CC=C(C#N)C=C1 YBAZINRZQSAIAY-UHFFFAOYSA-N 0.000 description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- GHEHNICLPWTXJC-UHFFFAOYSA-N p-Aminobenzamidine dihydrochloride Chemical compound [Cl-].[Cl-].NC(=[NH2+])C1=CC=C([NH3+])C=C1 GHEHNICLPWTXJC-UHFFFAOYSA-N 0.000 description 29
- 238000010898 silica gel chromatography Methods 0.000 description 29
- 239000002904 solvent Substances 0.000 description 25
- 239000011541 reaction mixture Substances 0.000 description 24
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 19
- 239000000463 material Substances 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 239000000706 filtrate Substances 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 239000012074 organic phase Substances 0.000 description 18
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- 239000003054 catalyst Substances 0.000 description 16
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 16
- 239000008259 solid foam Substances 0.000 description 16
- 238000013375 chromatographic separation Methods 0.000 description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- 229910004373 HOAc Inorganic materials 0.000 description 13
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 12
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 11
- MFYSUUPKMDJYPF-UHFFFAOYSA-N 2-[(4-methyl-2-nitrophenyl)diazenyl]-3-oxo-n-phenylbutanamide Chemical compound C=1C=CC=CC=1NC(=O)C(C(=O)C)N=NC1=CC=C(C)C=C1[N+]([O-])=O MFYSUUPKMDJYPF-UHFFFAOYSA-N 0.000 description 10
- 229960000583 acetic acid Drugs 0.000 description 10
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 9
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 9
- OPHQOIGEOHXOGX-UHFFFAOYSA-N 3,4,5-trimethoxybenzaldehyde Chemical compound COC1=CC(C=O)=CC(OC)=C1OC OPHQOIGEOHXOGX-UHFFFAOYSA-N 0.000 description 8
- JSHLOPGSDZTEGQ-UHFFFAOYSA-N 3-methoxy-4-phenylmethoxybenzaldehyde Chemical compound COC1=CC(C=O)=CC=C1OCC1=CC=CC=C1 JSHLOPGSDZTEGQ-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- SKZKKFZAGNVIMN-UHFFFAOYSA-N Salicilamide Chemical compound NC(=O)C1=CC=CC=C1O SKZKKFZAGNVIMN-UHFFFAOYSA-N 0.000 description 8
- 229910052786 argon Inorganic materials 0.000 description 8
- SFZULDYEOVSIKM-UHFFFAOYSA-N chembl321317 Chemical compound C1=CC(C(=N)NO)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=N)NO)O1 SFZULDYEOVSIKM-UHFFFAOYSA-N 0.000 description 8
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 description 8
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 8
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 8
- 235000019260 propionic acid Nutrition 0.000 description 8
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 239000012298 atmosphere Substances 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 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 7
- 150000003254 radicals Chemical class 0.000 description 7
- VFZRZRDOXPRTSC-UHFFFAOYSA-N 3,5-Dimethoxybenzaldehyde Chemical compound COC1=CC(OC)=CC(C=O)=C1 VFZRZRDOXPRTSC-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 6
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 229940047583 cetamide Drugs 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 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 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 239000007868 Raney catalyst Substances 0.000 description 5
- 229910000564 Raney nickel Inorganic materials 0.000 description 5
- 150000001299 aldehydes Chemical class 0.000 description 5
- 239000006260 foam Substances 0.000 description 5
- 239000007903 gelatin capsule Substances 0.000 description 5
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 239000000825 pharmaceutical preparation Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000011877 solvent mixture Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 4
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 description 4
- NCOFQZRLIYPMNJ-UHFFFAOYSA-N 3-ethoxy-4-phenylmethoxybenzaldehyde Chemical compound CCOC1=CC(C=O)=CC=C1OCC1=CC=CC=C1 NCOFQZRLIYPMNJ-UHFFFAOYSA-N 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- YZWMUTWKHHJGHC-UHFFFAOYSA-N acetamide;acetic acid Chemical compound CC(N)=O.CC(O)=O YZWMUTWKHHJGHC-UHFFFAOYSA-N 0.000 description 4
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- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 4
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- 230000023555 blood coagulation Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000003593 chromogenic compound Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- JBDSSBMEKXHSJF-UHFFFAOYSA-M cyclopentanecarboxylate Chemical compound [O-]C(=O)C1CCCC1 JBDSSBMEKXHSJF-UHFFFAOYSA-M 0.000 description 1
- 125000001511 cyclopentyl group Chemical class [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
- BADXJIPKFRBFOT-UHFFFAOYSA-N dimedone Chemical compound CC1(C)CC(=O)CC(=O)C1 BADXJIPKFRBFOT-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- LZCLXQDLBQLTDK-SCSAIBSYSA-N ethyl (2R)-lactate Chemical compound CCOC(=O)[C@@H](C)O LZCLXQDLBQLTDK-SCSAIBSYSA-N 0.000 description 1
- GKLWWGAFDIKVQY-UHFFFAOYSA-N ethyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate;hydron;chloride Chemical compound Cl.C1=CC=C2CNC(C(=O)OCC)CC2=C1 GKLWWGAFDIKVQY-UHFFFAOYSA-N 0.000 description 1
- ADFASIQRQWKXSJ-UHFFFAOYSA-N ethyl 1-aminocyclopentane-1-carboxylate;hydrochloride Chemical compound Cl.CCOC(=O)C1(N)CCCC1 ADFASIQRQWKXSJ-UHFFFAOYSA-N 0.000 description 1
- RHEGPPNTCIEMRJ-UHFFFAOYSA-N ethyl 3-(4-formyl-2-methoxyphenoxy)benzoate Chemical compound CCOC(=O)C1=CC=CC(OC=2C(=CC(C=O)=CC=2)OC)=C1 RHEGPPNTCIEMRJ-UHFFFAOYSA-N 0.000 description 1
- ZHQIWOHLVNCHSI-UHFFFAOYSA-N ethyl 3-[4-[2-(benzylamino)-1-(4-cyanoanilino)-2-oxoethyl]-2-methoxyphenoxy]benzoate Chemical compound CCOC(=O)C1=CC=CC(OC=2C(=CC(=CC=2)C(NC=2C=CC(=CC=2)C#N)C(=O)NCC=2C=CC=CC=2)OC)=C1 ZHQIWOHLVNCHSI-UHFFFAOYSA-N 0.000 description 1
- HAIVPGYEDLOZAM-UHFFFAOYSA-N ethyl 4-[[2-(4-cyanoanilino)-2-(3-methoxy-4-phenylmethoxyphenyl)acetyl]amino]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1NC(=O)C(C=1C=C(OC)C(OCC=2C=CC=CC=2)=CC=1)NC1=CC=C(C#N)C=C1 HAIVPGYEDLOZAM-UHFFFAOYSA-N 0.000 description 1
- XBPOBCXHALHJFP-UHFFFAOYSA-N ethyl 4-bromobutanoate Chemical compound CCOC(=O)CCCBr XBPOBCXHALHJFP-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000006332 fluoro benzoyl group Chemical group 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- BEBCJVAWIBVWNZ-UHFFFAOYSA-N glycinamide Chemical class NCC(N)=O BEBCJVAWIBVWNZ-UHFFFAOYSA-N 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 229960004931 histamine dihydrochloride Drugs 0.000 description 1
- PPZMYIBUHIPZOS-UHFFFAOYSA-N histamine dihydrochloride Chemical compound Cl.Cl.NCCC1=CN=CN1 PPZMYIBUHIPZOS-UHFFFAOYSA-N 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000008011 inorganic excipient Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- BRPYATNOOFKSJC-UHFFFAOYSA-N isocyanomethylcyclopropane Chemical compound [C-]#[N+]CC1CC1 BRPYATNOOFKSJC-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- XIRLIZNMBKEUDD-UHFFFAOYSA-N isoquinolin-6-ylmethanol Chemical compound C1=NC=CC2=CC(CO)=CC=C21 XIRLIZNMBKEUDD-UHFFFAOYSA-N 0.000 description 1
- 235000019359 magnesium stearate Nutrition 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
- 238000005259 measurement Methods 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- RMIODHQZRUFFFF-UHFFFAOYSA-N methoxyacetic acid Chemical compound COCC(O)=O RMIODHQZRUFFFF-UHFFFAOYSA-N 0.000 description 1
- DTHMTBUWTGVEFG-DDWIOCJRSA-N methyl (2r)-2-amino-2-phenylacetate;hydrochloride Chemical compound Cl.COC(=O)[C@H](N)C1=CC=CC=C1 DTHMTBUWTGVEFG-DDWIOCJRSA-N 0.000 description 1
- SWVMLNPDTIFDDY-FVGYRXGTSA-N methyl (2s)-2-amino-3-phenylpropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC1=CC=CC=C1 SWVMLNPDTIFDDY-FVGYRXGTSA-N 0.000 description 1
- BLWYXBNNBYXPPL-YFKPBYRVSA-N methyl (2s)-pyrrolidine-2-carboxylate Chemical compound COC(=O)[C@@H]1CCCN1 BLWYXBNNBYXPPL-YFKPBYRVSA-N 0.000 description 1
- BKNCSPZEGXUNTP-UHFFFAOYSA-N methyl (4-nitrophenyl) carbonate Chemical compound COC(=O)OC1=CC=C([N+]([O-])=O)C=C1 BKNCSPZEGXUNTP-UHFFFAOYSA-N 0.000 description 1
- LPEKGGXMPWTOCB-VKHMYHEASA-N methyl (S)-lactate Chemical compound COC(=O)[C@H](C)O LPEKGGXMPWTOCB-VKHMYHEASA-N 0.000 description 1
- ZKYACAJYBIDUNR-UHFFFAOYSA-N methyl 2-(4-cyanoanilino)-2-(3,5-dimethoxyphenyl)acetate Chemical compound C=1C(OC)=CC(OC)=CC=1C(C(=O)OC)NC1=CC=C(C#N)C=C1 ZKYACAJYBIDUNR-UHFFFAOYSA-N 0.000 description 1
- OPGKGGSYPPWQTC-UHFFFAOYSA-N methyl 2-[[2-(4-cyanoanilino)-2-(3-methoxy-4-phenylmethoxyphenyl)acetyl]amino]-2-methylpropanoate Chemical compound C=1C=C(OCC=2C=CC=CC=2)C(OC)=CC=1C(C(=O)NC(C)(C)C(=O)OC)NC1=CC=C(C#N)C=C1 OPGKGGSYPPWQTC-UHFFFAOYSA-N 0.000 description 1
- NVWZNEDLYYLQJC-UHFFFAOYSA-N methyl 2-amino-2-methylpropanoate;hydrochloride Chemical compound Cl.COC(=O)C(C)(C)N NVWZNEDLYYLQJC-UHFFFAOYSA-N 0.000 description 1
- BXXLTVBTDZXPTN-UHFFFAOYSA-N methyl 2-iodobenzoate Chemical compound COC(=O)C1=CC=CC=C1I BXXLTVBTDZXPTN-UHFFFAOYSA-N 0.000 description 1
- YUHSMQQNPRLEEJ-UHFFFAOYSA-N methyl 3-(bromomethyl)benzoate Chemical compound COC(=O)C1=CC=CC(CBr)=C1 YUHSMQQNPRLEEJ-UHFFFAOYSA-N 0.000 description 1
- JACGZMHJVCFSRR-UHFFFAOYSA-N methyl 4-(4-formyl-2-methoxyphenoxy)benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1OC1=CC=C(C=O)C=C1OC JACGZMHJVCFSRR-UHFFFAOYSA-N 0.000 description 1
- NLWBJPPMPLPZIE-UHFFFAOYSA-N methyl 4-(bromomethyl)benzoate Chemical compound COC(=O)C1=CC=C(CBr)C=C1 NLWBJPPMPLPZIE-UHFFFAOYSA-N 0.000 description 1
- VUNIQKJWGGADIK-UHFFFAOYSA-N methyl 4-[4-[2-(benzylamino)-1-(4-cyanoanilino)-2-oxoethyl]-2-methoxyphenoxy]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1OC1=CC=C(C(NC=2C=CC(=CC=2)C#N)C(=O)NCC=2C=CC=CC=2)C=C1OC VUNIQKJWGGADIK-UHFFFAOYSA-N 0.000 description 1
- FEIOASZZURHTHB-UHFFFAOYSA-N methyl 4-formylbenzoate Chemical compound COC(=O)C1=CC=C(C=O)C=C1 FEIOASZZURHTHB-UHFFFAOYSA-N 0.000 description 1
- DYUWQWMXZHDZOR-UHFFFAOYSA-N methyl 4-iodobenzoate Chemical compound COC(=O)C1=CC=C(I)C=C1 DYUWQWMXZHDZOR-UHFFFAOYSA-N 0.000 description 1
- LKZGUSCJTSTACP-UHFFFAOYSA-N methyl 5-[2-(benzylamino)-1-(4-cyanoanilino)-2-oxoethyl]-2,3-dimethoxybenzoate Chemical compound COC1=C(OC)C(C(=O)OC)=CC(C(NC=2C=CC(=CC=2)C#N)C(=O)NCC=2C=CC=CC=2)=C1 LKZGUSCJTSTACP-UHFFFAOYSA-N 0.000 description 1
- ACUWYCKFRBPSBW-UHFFFAOYSA-N methyl 5-formyl-2,3-dimethoxybenzoate Chemical compound COC(=O)C1=CC(C=O)=CC(OC)=C1OC ACUWYCKFRBPSBW-UHFFFAOYSA-N 0.000 description 1
- DWCZIOOZPIDHAB-UHFFFAOYSA-L methyl green Chemical compound [Cl-].[Cl-].C1=CC(N(C)C)=CC=C1C(C=1C=CC(=CC=1)[N+](C)(C)C)=C1C=CC(=[N+](C)C)C=C1 DWCZIOOZPIDHAB-UHFFFAOYSA-L 0.000 description 1
- CPRRHERYRRXBRZ-SRVKXCTJSA-N methyl n-[(2s)-1-[[(2s)-1-hydroxy-3-[(3s)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CO)C[C@@H]1CCNC1=O CPRRHERYRRXBRZ-SRVKXCTJSA-N 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- UKOJRLKYPPBKMN-UHFFFAOYSA-N n-[2-[2-(benzylamino)-1-(4-carbamimidoylanilino)-2-oxoethyl]-4,5-dimethoxyphenyl]benzamide Chemical compound C=1C=C(C(N)=N)C=CC=1NC(C(=O)NCC=1C=CC=CC=1)C=1C=C(OC)C(OC)=CC=1NC(=O)C1=CC=CC=C1 UKOJRLKYPPBKMN-UHFFFAOYSA-N 0.000 description 1
- DYKBLVKUTDPXSR-UHFFFAOYSA-N n-[2-[2-(benzylamino)-1-(4-carbamimidoylanilino)-2-oxoethyl]-4-methoxyphenyl]benzamide Chemical compound C=1C=C(C(N)=N)C=CC=1NC(C(=O)NCC=1C=CC=CC=1)C1=CC(OC)=CC=C1NC(=O)C1=CC=CC=C1 DYKBLVKUTDPXSR-UHFFFAOYSA-N 0.000 description 1
- RDURXKRVSFUYIP-UHFFFAOYSA-N n-[2-[2-(benzylamino)-1-(4-cyanoanilino)-2-oxoethyl]-4-methoxy-5-phenylmethoxyphenyl]benzamide Chemical compound C=1C=CC=CC=1C(=O)NC=1C=C(OCC=2C=CC=CC=2)C(OC)=CC=1C(C(=O)NCC=1C=CC=CC=1)NC1=CC=C(C#N)C=C1 RDURXKRVSFUYIP-UHFFFAOYSA-N 0.000 description 1
- CDYYCYDSTLNMJZ-UHFFFAOYSA-N n-[2-[2-(benzylamino)-1-[4-[(z)-n'-hydroxycarbamimidoyl]anilino]-2-oxoethyl]-4-methoxy-5-phenylmethoxyphenyl]benzamide Chemical compound C=1C=CC=CC=1C(=O)NC=1C=C(OCC=2C=CC=CC=2)C(OC)=CC=1C(C(=O)NCC=1C=CC=CC=1)NC1=CC=C(C(=N)NO)C=C1 CDYYCYDSTLNMJZ-UHFFFAOYSA-N 0.000 description 1
- QJRZWILLQODGLY-UHFFFAOYSA-N n-[2-[2-(benzylamino)-1-[4-[(z)-n'-hydroxycarbamimidoyl]anilino]-2-oxoethyl]-4-methoxyphenyl]benzamide Chemical compound C=1C=C(C(=N)NO)C=CC=1NC(C(=O)NCC=1C=CC=CC=1)C1=CC(OC)=CC=C1NC(=O)C1=CC=CC=C1 QJRZWILLQODGLY-UHFFFAOYSA-N 0.000 description 1
- CRIBDEFZUIWTRO-UHFFFAOYSA-N n-benzyl-2-(4-carbamimidoylanilino)-2-(3-methoxy-4-phenylmethoxyphenyl)-n-methylacetamide Chemical compound COC1=CC(C(NC=2C=CC(=CC=2)C(N)=N)C(=O)N(C)CC=2C=CC=CC=2)=CC=C1OCC1=CC=CC=C1 CRIBDEFZUIWTRO-UHFFFAOYSA-N 0.000 description 1
- HTEOLCFMMWOLDO-UHFFFAOYSA-N n-benzyl-2-(4-carbamimidoylanilino)-2-(3-phenylmethoxy-5-propoxyphenyl)acetamide;hydrochloride Chemical compound Cl.C=1C(C(NC=2C=CC(=CC=2)C(N)=N)C(=O)NCC=2C=CC=CC=2)=CC(OCCC)=CC=1OCC1=CC=CC=C1 HTEOLCFMMWOLDO-UHFFFAOYSA-N 0.000 description 1
- FNJMKCWJXRKISK-UHFFFAOYSA-N n-benzyl-2-(4-cyano-3-hydroxyanilino)-2-(3-ethoxy-4-phenylmethoxyphenyl)acetamide Chemical compound CCOC1=CC(C(NC=2C=C(O)C(C#N)=CC=2)C(=O)NCC=2C=CC=CC=2)=CC=C1OCC1=CC=CC=C1 FNJMKCWJXRKISK-UHFFFAOYSA-N 0.000 description 1
- AEJIVSFNPYSDMS-UHFFFAOYSA-N n-benzyl-2-(4-cyanoanilino)-2-(2-hydroxy-3,5-dimethylphenyl)acetamide Chemical compound CC1=CC(C)=C(O)C(C(NC=2C=CC(=CC=2)C#N)C(=O)NCC=2C=CC=CC=2)=C1 AEJIVSFNPYSDMS-UHFFFAOYSA-N 0.000 description 1
- HFPAYOMVAQITAB-UHFFFAOYSA-N n-benzyl-2-(4-cyanoanilino)-2-[2-(methanesulfonamido)-5-methoxy-4-phenylmethoxyphenyl]acetamide Chemical compound CS(=O)(=O)NC=1C=C(OCC=2C=CC=CC=2)C(OC)=CC=1C(C(=O)NCC=1C=CC=CC=1)NC1=CC=C(C#N)C=C1 HFPAYOMVAQITAB-UHFFFAOYSA-N 0.000 description 1
- ABGIVAPJUVEHCM-UHFFFAOYSA-N n-benzyl-2-[3,5-bis(phenylmethoxy)phenyl]-2-(4-carbamimidoylanilino)acetamide;hydrochloride Chemical compound Cl.C1=CC(C(=N)N)=CC=C1NC(C=1C=C(OCC=2C=CC=CC=2)C=C(OCC=2C=CC=CC=2)C=1)C(=O)NCC1=CC=CC=C1 ABGIVAPJUVEHCM-UHFFFAOYSA-N 0.000 description 1
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000006501 nitrophenyl group Chemical group 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000008012 organic excipient Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- SEVSMVUOKAMPDO-UHFFFAOYSA-N para-Acetoxybenzaldehyde Natural products CC(=O)OC1=CC=C(C=O)C=C1 SEVSMVUOKAMPDO-UHFFFAOYSA-N 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- SHNUBALDGXWUJI-UHFFFAOYSA-N pyridin-2-ylmethanol Chemical compound OCC1=CC=CC=N1 SHNUBALDGXWUJI-UHFFFAOYSA-N 0.000 description 1
- PTMBWNZJOQBTBK-UHFFFAOYSA-N pyridin-4-ylmethanol Chemical compound OCC1=CC=NC=C1 PTMBWNZJOQBTBK-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- RDBBFCMDRBOXIG-UHFFFAOYSA-N quinolin-7-ylmethanol Chemical compound C1=CC=NC2=CC(CO)=CC=C21 RDBBFCMDRBOXIG-UHFFFAOYSA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- KCDXJAYRVLXPFO-UHFFFAOYSA-N syringaldehyde Chemical compound COC1=CC(C=O)=CC(OC)=C1O KCDXJAYRVLXPFO-UHFFFAOYSA-N 0.000 description 1
- COBXDAOIDYGHGK-UHFFFAOYSA-N syringaldehyde Natural products COC1=CC=C(C=O)C(OC)=C1O COBXDAOIDYGHGK-UHFFFAOYSA-N 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- ZMCBYSBVJIMENC-UHFFFAOYSA-N tricaine Chemical compound CCOC(=O)C1=CC=CC(N)=C1 ZMCBYSBVJIMENC-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Families Citing this family (26)
Publication number | Priority date | Publication date | Assignee | Title |
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CZ20012112A3 (cs) | 1998-12-14 | 2001-10-17 | F. Hoffmann-La Roche Ag | Derivát fenylglycinu |
DE10041402A1 (de) * | 2000-08-23 | 2002-03-14 | Morphochem Ag | Neue Verbindungen, die Faktor Xa-Aktivität inhibieren |
US6548694B2 (en) | 2000-05-23 | 2003-04-15 | Hoffman-La Roche Inc. | N-(4-carbamimidoyl-phenyl)-glycine derivatives |
WO2002062829A1 (fr) | 2001-02-02 | 2002-08-15 | Chugai Seiyaku Kabushiki Kaisha | Derives de peptide |
US7256194B2 (en) * | 2001-02-23 | 2007-08-14 | Morphochem | Compounds that inhibit factor Xa activity |
NZ534238A (en) * | 2002-01-31 | 2006-09-29 | Morphochem Ag Komb Chemie | Compounds that inhibit factor Xa activity |
DE10204072A1 (de) * | 2002-01-31 | 2003-08-14 | Morphochem Ag Komb Chemie | Neue Verbindungen, die Faktor Xa-Aktivität inhibieren |
DE10300049A1 (de) * | 2003-01-03 | 2004-07-15 | Morphochem AG Aktiengesellschaft für kombinatorische Chemie | Neue Verbindungen, die Faktor VIIa inhibieren |
TW200410921A (en) * | 2002-11-25 | 2004-07-01 | Hoffmann La Roche | Mandelic acid derivatives |
US7122559B2 (en) * | 2003-02-11 | 2006-10-17 | Bristol-Myers Squibb Company | Phenylglycine derivatives useful as serine protease inhibitors |
WO2004072102A2 (en) * | 2003-02-11 | 2004-08-26 | Bristol-Myers Squibb Company | Benzene acetamide compounds useful as serine protease inhibitors |
WO2004113316A1 (en) * | 2003-05-20 | 2004-12-29 | Genentech, Inc. | Benzofuran inhibitors of factor viia |
JP2007505160A (ja) * | 2003-05-20 | 2007-03-08 | ジェネンテック・インコーポレーテッド | 第VIIa因子のアシルスルファミド阻害剤 |
US7056932B2 (en) * | 2003-12-19 | 2006-06-06 | Hoffman-La Roche Inc. | Heterocyclyl substituted 1-alkoxy acetic acid amides |
DE602005009252D1 (de) * | 2004-12-08 | 2008-10-02 | Bristol Myers Squibb Co | Heterocyclische verbindungen als inhibitoren von faktor viia |
AR054321A1 (es) * | 2005-01-10 | 2007-06-20 | Bristol Myers Squibb Co | Derivados en fenilglicinamida utiles como anticoagulantes |
ES2337831T3 (es) * | 2005-06-24 | 2010-04-29 | Bristol-Myers Squibb Company | Derivados de fenilglicinamida y piridilclicinamida utiles como agentes anticoagulantes. |
US8044242B2 (en) * | 2006-03-09 | 2011-10-25 | Bristol-Myers Squibb Company | 2-(aryloxy) acetamide factor VIIa inhibitors useful as anticoagulants |
US7855194B2 (en) | 2006-03-27 | 2010-12-21 | Hoffmann-La Roche Inc. | Pyrimidine, quinazoline, pteridine and triazine derivatives |
CN101500993A (zh) * | 2006-06-08 | 2009-08-05 | 百时美施贵宝公司 | 作为凝血因子Ⅶa抑制剂用作抗凝血药的2-氨基羰基苯基氨基-2-苯基乙酰胺 |
EP2099783A1 (en) * | 2006-12-20 | 2009-09-16 | Brystol-Myers Squibb Company | Bicyclic lactam factor viia inhibitors useful as anticoagulants |
EP1967522A1 (en) * | 2007-03-07 | 2008-09-10 | Novo Nordisk A/S | New blood coagulation factor inhibitors |
JP2011507909A (ja) * | 2007-12-20 | 2011-03-10 | エンビボ ファーマシューティカルズ インコーポレイテッド | 四置換ベンゼン |
CN102653980B (zh) * | 2012-03-05 | 2014-03-19 | 胡文超 | 一种发光玻璃地面砖 |
CN104370813A (zh) * | 2014-10-22 | 2015-02-25 | 上海大学 | 异喹啉-6-甲醛的制备方法 |
CN112939895B (zh) * | 2021-02-08 | 2022-11-04 | 桂林医学院 | 一种甘氨酰胺类衍生物及其制备方法和应用 |
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US5625093A (en) * | 1991-10-15 | 1997-04-29 | G. D. Searle & Co. | Substituted β-amino acid derivatives useful as platelet aggregation inhibitors |
KR0173034B1 (ko) * | 1995-04-28 | 1999-03-30 | 성재갑 | 선택적 트롬빈 억제제 |
EP0892780B1 (en) * | 1996-02-22 | 2002-11-20 | Bristol-Myers Squibb Pharma Company | M-AMIDINO PHENYL ANALOGS AS FACTOR Xa INHIBITORS |
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1998
- 1998-11-26 PT PT98122169T patent/PT921116E/pt unknown
- 1998-11-26 DE DE59808751T patent/DE59808751D1/de not_active Expired - Fee Related
- 1998-11-26 SI SI9830459T patent/SI0921116T1/xx unknown
- 1998-11-26 ES ES98122169T patent/ES2201396T3/es not_active Expired - Lifetime
- 1998-11-26 EP EP98122169A patent/EP0921116B1/de not_active Expired - Lifetime
- 1998-11-26 AT AT98122169T patent/ATE243192T1/de not_active IP Right Cessation
- 1998-11-26 DK DK98122169T patent/DK0921116T3/da active
- 1998-12-02 IL IL12736198A patent/IL127361A/en not_active IP Right Cessation
- 1998-12-02 US US09/204,373 patent/US6140353A/en not_active Expired - Fee Related
- 1998-12-02 MA MA25366A patent/MA26572A1/fr unknown
- 1998-12-02 NZ NZ333126A patent/NZ333126A/en unknown
- 1998-12-02 CA CA002255180A patent/CA2255180A1/en not_active Abandoned
- 1998-12-03 NO NO985646A patent/NO985646L/no not_active Application Discontinuation
- 1998-12-03 KR KR1019980052819A patent/KR100330610B1/ko not_active IP Right Cessation
- 1998-12-03 CZ CZ19983969A patent/CZ295105B6/cs not_active IP Right Cessation
- 1998-12-03 AU AU95210/98A patent/AU739769B2/en not_active Ceased
- 1998-12-03 MY MYPI98005489A patent/MY133897A/en unknown
- 1998-12-04 JP JP34587598A patent/JP3236267B2/ja not_active Expired - Fee Related
- 1998-12-04 HU HU9802808A patent/HUP9802808A3/hu unknown
- 1998-12-04 CN CN98126979A patent/CN1115330C/zh not_active Expired - Fee Related
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1999
- 1999-02-12 TW TW088102291A patent/TW544446B/zh not_active IP Right Cessation
- 1999-12-23 HK HK99106072A patent/HK1020941A1/xx not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
MA26572A1 (fr) | 2004-12-20 |
PT921116E (pt) | 2003-11-28 |
DE59808751D1 (de) | 2003-07-24 |
HK1020941A1 (en) | 2000-05-26 |
KR19990062766A (ko) | 1999-07-26 |
EP0921116B1 (de) | 2003-06-18 |
JPH11246507A (ja) | 1999-09-14 |
NO985646L (no) | 1999-06-07 |
US6140353A (en) | 2000-10-31 |
MY133897A (en) | 2007-11-30 |
IL127361A0 (en) | 1999-10-28 |
SI0921116T1 (en) | 2003-10-31 |
HUP9802808A3 (en) | 2000-03-28 |
HU9802808D0 (en) | 1999-02-01 |
NZ333126A (en) | 2000-06-23 |
KR100330610B1 (ko) | 2002-11-23 |
ES2201396T3 (es) | 2004-03-16 |
TW544446B (en) | 2003-08-01 |
JP3236267B2 (ja) | 2001-12-10 |
AU739769B2 (en) | 2001-10-18 |
CZ396998A3 (cs) | 1999-11-17 |
AU9521098A (en) | 1999-06-24 |
CN1224714A (zh) | 1999-08-04 |
NO985646D0 (no) | 1998-12-03 |
HUP9802808A2 (hu) | 1999-06-28 |
CZ295105B6 (cs) | 2005-05-18 |
CN1115330C (zh) | 2003-07-23 |
ATE243192T1 (de) | 2003-07-15 |
DK0921116T3 (da) | 2003-10-06 |
EP0921116A1 (de) | 1999-06-09 |
CA2255180A1 (en) | 1999-06-04 |
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