PT1405852E - Derivados de diamina - Google Patents
Derivados de diamina Download PDFInfo
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- PT1405852E PT1405852E PT02743653T PT02743653T PT1405852E PT 1405852 E PT1405852 E PT 1405852E PT 02743653 T PT02743653 T PT 02743653T PT 02743653 T PT02743653 T PT 02743653T PT 1405852 E PT1405852 E PT 1405852E
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- compound
- group
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- 150000004985 diamines Chemical class 0.000 title description 53
- 150000001875 compounds Chemical class 0.000 claims description 645
- 239000000203 mixture Substances 0.000 claims description 246
- -1 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl Chemical group 0.000 claims description 239
- 239000000243 solution Substances 0.000 claims description 172
- 238000002360 preparation method Methods 0.000 claims description 120
- 238000000034 method Methods 0.000 claims description 72
- 229920006395 saturated elastomer Polymers 0.000 claims description 69
- 230000008569 process Effects 0.000 claims description 52
- 150000003839 salts Chemical class 0.000 claims description 36
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 35
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 34
- 208000007536 Thrombosis Diseases 0.000 claims description 27
- 239000003795 chemical substances by application Substances 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 239000012453 solvate Substances 0.000 claims description 23
- 150000001204 N-oxides Chemical class 0.000 claims description 22
- 230000015572 biosynthetic process Effects 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 21
- 125000004432 carbon atom Chemical group C* 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- 239000000725 suspension Substances 0.000 claims description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 239000003921 oil Substances 0.000 claims description 13
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 230000002265 prevention Effects 0.000 claims description 11
- 125000002947 alkylene group Chemical group 0.000 claims description 10
- 239000003146 anticoagulant agent Substances 0.000 claims description 9
- 229940127219 anticoagulant drug Drugs 0.000 claims description 9
- 125000004122 cyclic group Chemical group 0.000 claims description 9
- 239000003112 inhibitor Substances 0.000 claims description 9
- 208000005189 Embolism Diseases 0.000 claims description 8
- 208000010378 Pulmonary Embolism Diseases 0.000 claims description 8
- 208000011580 syndromic disease Diseases 0.000 claims description 8
- 208000010718 Multiple Organ Failure Diseases 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 208000029744 multiple organ dysfunction syndrome Diseases 0.000 claims description 7
- 108010074860 Factor Xa Proteins 0.000 claims description 6
- YIKSCQDJHCMVMK-UHFFFAOYSA-N Oxamide Chemical compound NC(=O)C(N)=O YIKSCQDJHCMVMK-UHFFFAOYSA-N 0.000 claims description 6
- 239000000945 filler Substances 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- 206010008088 Cerebral artery embolism Diseases 0.000 claims description 5
- 206010038563 Reocclusion Diseases 0.000 claims description 5
- 206010043540 Thromboangiitis obliterans Diseases 0.000 claims description 5
- 206010047249 Venous thrombosis Diseases 0.000 claims description 5
- 238000002399 angioplasty Methods 0.000 claims description 5
- 230000023555 blood coagulation Effects 0.000 claims description 5
- 206010008118 cerebral infarction Diseases 0.000 claims description 5
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 5
- 208000009190 disseminated intravascular coagulation Diseases 0.000 claims description 5
- 201000010849 intracranial embolism Diseases 0.000 claims description 5
- 208000010125 myocardial infarction Diseases 0.000 claims description 5
- 206010002383 Angina Pectoris Diseases 0.000 claims description 4
- 206010051055 Deep vein thrombosis Diseases 0.000 claims description 4
- 125000006165 cyclic alkyl group Chemical group 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 241000124008 Mammalia Species 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 3
- 239000011230 binding agent Substances 0.000 claims description 3
- 239000008280 blood Substances 0.000 claims description 3
- 210000004369 blood Anatomy 0.000 claims description 3
- 239000003995 emulsifying agent Substances 0.000 claims description 3
- 239000000839 emulsion Substances 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 3
- 239000003755 preservative agent Substances 0.000 claims description 3
- 239000003381 stabilizer Substances 0.000 claims description 3
- 239000000375 suspending agent Substances 0.000 claims description 3
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 claims description 3
- 239000000080 wetting agent Substances 0.000 claims description 3
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 2
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 2
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
- 125000002619 bicyclic group Chemical group 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000006071 cream Substances 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 239000006210 lotion Substances 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 239000007921 spray Substances 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- 206010051379 Systemic Inflammatory Response Syndrome Diseases 0.000 claims 4
- 239000003937 drug carrier Substances 0.000 claims 3
- 230000000996 additive effect Effects 0.000 claims 2
- HGVDHZBSSITLCT-JLJPHGGASA-N Edoxaban Chemical compound N([C@H]1CC[C@@H](C[C@H]1NC(=O)C=1SC=2CN(C)CCC=2N=1)C(=O)N(C)C)C(=O)C(=O)NC1=CC=C(Cl)C=N1 HGVDHZBSSITLCT-JLJPHGGASA-N 0.000 claims 1
- 230000037396 body weight Effects 0.000 claims 1
- IZABLUDXAWYTNU-WCQGTBRESA-N n-[(1s,2r,4s)-2-amino-4-(dimethylcarbamoyl)cyclohexyl]-n'-(5-chloropyridin-2-yl)oxamide Chemical compound N[C@@H]1C[C@@H](C(=O)N(C)C)CC[C@@H]1NC(=O)C(=O)NC1=CC=C(Cl)C=N1 IZABLUDXAWYTNU-WCQGTBRESA-N 0.000 claims 1
- 239000011505 plaster Substances 0.000 claims 1
- 230000000699 topical effect Effects 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 420
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 402
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 231
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 228
- 239000002904 solvent Substances 0.000 description 220
- 238000005160 1H NMR spectroscopy Methods 0.000 description 200
- 230000002829 reductive effect Effects 0.000 description 193
- 239000011541 reaction mixture Substances 0.000 description 135
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 128
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 123
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 123
- 239000012044 organic layer Substances 0.000 description 119
- 238000006243 chemical reaction Methods 0.000 description 118
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 114
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 103
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 103
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 100
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 100
- 238000010898 silica gel chromatography Methods 0.000 description 92
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 88
- 238000004821 distillation Methods 0.000 description 86
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 80
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 78
- 239000007864 aqueous solution Substances 0.000 description 67
- 150000001414 amino alcohols Chemical class 0.000 description 65
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 64
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 64
- 238000001816 cooling Methods 0.000 description 55
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 52
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 51
- 238000003756 stirring Methods 0.000 description 51
- 235000017557 sodium bicarbonate Nutrition 0.000 description 50
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 50
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 49
- 239000012267 brine Substances 0.000 description 48
- 238000001914 filtration Methods 0.000 description 48
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 44
- 150000001412 amines Chemical class 0.000 description 40
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 36
- 125000006239 protecting group Chemical group 0.000 description 36
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 33
- 239000002585 base Substances 0.000 description 33
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 32
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 32
- 125000003277 amino group Chemical group 0.000 description 31
- 150000002148 esters Chemical class 0.000 description 29
- 239000010410 layer Substances 0.000 description 29
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 28
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 27
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 27
- 239000002253 acid Substances 0.000 description 27
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 26
- 239000000706 filtrate Substances 0.000 description 25
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 24
- 239000012442 inert solvent Substances 0.000 description 24
- 238000010992 reflux Methods 0.000 description 24
- 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 24
- 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 24
- 239000000047 product Substances 0.000 description 23
- 239000012046 mixed solvent Substances 0.000 description 22
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- 239000003153 chemical reaction reagent Substances 0.000 description 20
- 239000000543 intermediate Substances 0.000 description 20
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 18
- 238000000605 extraction Methods 0.000 description 18
- 239000011780 sodium chloride Substances 0.000 description 18
- 150000001540 azides Chemical class 0.000 description 17
- 150000004820 halides Chemical class 0.000 description 17
- 238000000926 separation method Methods 0.000 description 17
- 239000007787 solid Substances 0.000 description 17
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 16
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 15
- 239000003054 catalyst Substances 0.000 description 15
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 14
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-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
- 239000002244 precipitate Substances 0.000 description 14
- 239000000741 silica gel Substances 0.000 description 14
- 229910002027 silica gel Inorganic materials 0.000 description 14
- 229960001866 silicon dioxide Drugs 0.000 description 14
- 239000012298 atmosphere Substances 0.000 description 13
- 239000007788 liquid Substances 0.000 description 13
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 13
- 229910052717 sulfur Inorganic materials 0.000 description 13
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 13
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 12
- FUQOTYRCMBZFOL-UHFFFAOYSA-N 5-chloro-1H-indole-2-carboxylic acid Chemical compound ClC1=CC=C2NC(C(=O)O)=CC2=C1 FUQOTYRCMBZFOL-UHFFFAOYSA-N 0.000 description 12
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 12
- 150000008065 acid anhydrides Chemical class 0.000 description 12
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 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
- 238000005755 formation reaction Methods 0.000 description 12
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 description 12
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
- SSJXIUAHEKJCMH-WDSKDSINSA-N (1s,2s)-cyclohexane-1,2-diamine Chemical compound N[C@H]1CCCC[C@@H]1N SSJXIUAHEKJCMH-WDSKDSINSA-N 0.000 description 10
- SCZNXLWKYFICFV-UHFFFAOYSA-N 1,2,3,4,5,7,8,9-octahydropyrido[1,2-b]diazepine Chemical compound C1CCCNN2CCCC=C21 SCZNXLWKYFICFV-UHFFFAOYSA-N 0.000 description 10
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 10
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 10
- 125000000217 alkyl group Chemical group 0.000 description 10
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 10
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 9
- 150000001408 amides Chemical class 0.000 description 9
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
- 125000004430 oxygen atom Chemical group O* 0.000 description 9
- 150000003461 sulfonyl halides Chemical class 0.000 description 9
- 125000004434 sulfur atom Chemical group 0.000 description 9
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 8
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 8
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 8
- 108090000190 Thrombin Proteins 0.000 description 8
- 235000019270 ammonium chloride Nutrition 0.000 description 8
- 229910002092 carbon dioxide Inorganic materials 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 8
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 229960004072 thrombin Drugs 0.000 description 8
- 150000001350 alkyl halides Chemical class 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 238000003818 flash chromatography Methods 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 7
- 239000012279 sodium borohydride Substances 0.000 description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 description 7
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
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- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
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- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
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- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical class OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000002008 hemorrhagic effect Effects 0.000 description 1
- 125000005241 heteroarylamino group Chemical group 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical class I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
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- 208000015181 infectious disease Diseases 0.000 description 1
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- 230000005764 inhibitory process Effects 0.000 description 1
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical class OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- DWKPPFQULDPWHX-VKHMYHEASA-N l-alanyl ester Chemical compound COC(=O)[C@H](C)N DWKPPFQULDPWHX-VKHMYHEASA-N 0.000 description 1
- XIDYXYSFAQGULL-UHFFFAOYSA-M lithium 4-thia-1,6,9-triazatricyclo[7.4.0.03,7]trideca-3(7),5-diene-5-carboxylate Chemical compound [Li+].C1N2CCCCN2CC2=C1N=C(C(=O)[O-])S2 XIDYXYSFAQGULL-UHFFFAOYSA-M 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- DZPQUXKGXSJKGZ-UHFFFAOYSA-M lithium;5,6-dimethyl-4,7-dihydro-[1,3]thiazolo[4,5-d]pyridazine-2-carboxylate Chemical compound [Li+].C1N(C)N(C)CC2=C1SC(C([O-])=O)=N2 DZPQUXKGXSJKGZ-UHFFFAOYSA-M 0.000 description 1
- OEIMBMPZVNXQPH-UHFFFAOYSA-M lithium;5-(1-methylcyclopropyl)-6,7-dihydro-4h-[1,3]thiazolo[5,4-c]pyridine-2-carboxylate Chemical compound [Li+].C1CC=2N=C(C([O-])=O)SC=2CN1C1(C)CC1 OEIMBMPZVNXQPH-UHFFFAOYSA-M 0.000 description 1
- OXZFABXSIQFPET-UHFFFAOYSA-M lithium;5-methyl-6,7-dihydro-4h-[1,3]oxazolo[5,4-c]pyridine-2-carboxylate Chemical compound [Li+].C1N(C)CCC2=C1OC(C([O-])=O)=N2 OXZFABXSIQFPET-UHFFFAOYSA-M 0.000 description 1
- VEZNEEKSJKRDDW-UHFFFAOYSA-M lithium;5-methyl-6,7-dihydro-4h-[1,3]thiazolo[4,5-c]pyridine-2-carboxylate Chemical compound [Li+].C1N(C)CCC2=C1N=C(C([O-])=O)S2 VEZNEEKSJKRDDW-UHFFFAOYSA-M 0.000 description 1
- YBZCHTKTODOIOB-UHFFFAOYSA-M lithium;5-propan-2-yl-6,7-dihydro-4h-[1,3]thiazolo[5,4-c]pyridine-2-carboxylate Chemical compound [Li+].C1N(C(C)C)CCC2=C1SC(C([O-])=O)=N2 YBZCHTKTODOIOB-UHFFFAOYSA-M 0.000 description 1
- ZOKRNTGZVAXUDE-UHFFFAOYSA-M lithium;6,7-dihydro-4h-pyrano[4,3-d][1,3]thiazole-2-carboxylate Chemical compound [Li+].C1COCC2=C1N=C(C(=O)[O-])S2 ZOKRNTGZVAXUDE-UHFFFAOYSA-M 0.000 description 1
- DJLOFGLBIWJCKA-UHFFFAOYSA-M lithium;6-(dimethylamino)-4,5,6,7-tetrahydro-1,3-benzothiazole-2-carboxylate Chemical compound [Li+].C1C(N(C)C)CCC2=C1SC(C([O-])=O)=N2 DJLOFGLBIWJCKA-UHFFFAOYSA-M 0.000 description 1
- XMNOZVJUCZKWTB-UHFFFAOYSA-N lithium;benzyl(trimethylsilyl)azanide Chemical compound [Li+].C[Si](C)(C)[N-]CC1=CC=CC=C1 XMNOZVJUCZKWTB-UHFFFAOYSA-N 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 150000004701 malic acid derivatives Chemical class 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 229960004452 methionine Drugs 0.000 description 1
- GPFGVZAQKJPYAT-UHFFFAOYSA-N methyl 1-(bromomethyl)cyclopropane-1-carboxylate Chemical compound COC(=O)C1(CBr)CC1 GPFGVZAQKJPYAT-UHFFFAOYSA-N 0.000 description 1
- YLNAXTUVFOXHTI-UHFFFAOYSA-N methyl 1-(hydroxymethyl)cyclopropane-1-carboxylate Chemical compound COC(=O)C1(CO)CC1 YLNAXTUVFOXHTI-UHFFFAOYSA-N 0.000 description 1
- CFTUQSLVERGMHL-UHFFFAOYSA-N methyl 2-(bromomethyl)prop-2-enoate Chemical compound COC(=O)C(=C)CBr CFTUQSLVERGMHL-UHFFFAOYSA-N 0.000 description 1
- PXALLAPTWSEEKF-UHFFFAOYSA-N methyl 2-amino-4-(2-methoxy-2-oxoethyl)-1,3-thiazole-5-carboxylate Chemical compound COC(=O)CC=1N=C(N)SC=1C(=O)OC PXALLAPTWSEEKF-UHFFFAOYSA-N 0.000 description 1
- ZMKCHSMRBSMDEX-UHFFFAOYSA-N methyl 2-azido-3-(3-chloro-4-fluorophenyl)prop-2-enoate Chemical compound COC(=O)C(N=[N+]=[N-])=CC1=CC=C(F)C(Cl)=C1 ZMKCHSMRBSMDEX-UHFFFAOYSA-N 0.000 description 1
- FMLBJOMKVCNUEY-UHFFFAOYSA-N methyl 2-bromo-4-(2-methoxy-2-oxoethyl)-1,3-thiazole-5-carboxylate Chemical compound COC(=O)CC=1N=C(Br)SC=1C(=O)OC FMLBJOMKVCNUEY-UHFFFAOYSA-N 0.000 description 1
- TWMLEMQRVQWZHF-UHFFFAOYSA-N methyl 3-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethylpropanoate Chemical compound C=1C=CC=CC=1[Si](C(C)(C)C)(OCC(C)(C)C(=O)OC)C1=CC=CC=C1 TWMLEMQRVQWZHF-UHFFFAOYSA-N 0.000 description 1
- WVPVQVXXTIVHIY-UHFFFAOYSA-N methyl 3-methoxy-2,2-dimethylpropanoate Chemical compound COCC(C)(C)C(=O)OC WVPVQVXXTIVHIY-UHFFFAOYSA-N 0.000 description 1
- BDEBNNDWGDNTMP-UHFFFAOYSA-N methyl 3-methoxy-2-(methoxymethyl)propanoate Chemical compound COCC(COC)C(=O)OC BDEBNNDWGDNTMP-UHFFFAOYSA-N 0.000 description 1
- BSCVUXIUVIUPCJ-UHFFFAOYSA-N methyl 5-chloro-6-fluoro-1h-indole-2-carboxylate Chemical compound ClC1=C(F)C=C2NC(C(=O)OC)=CC2=C1 BSCVUXIUVIUPCJ-UHFFFAOYSA-N 0.000 description 1
- UXWTYHNKRDDSON-UHFFFAOYSA-N methyl 5-methyl-6,7-dihydro-4h-[1,3]oxazolo[5,4-c]pyridine-2-carboxylate Chemical compound C1CN(C)CC2=C1N=C(C(=O)OC)O2 UXWTYHNKRDDSON-UHFFFAOYSA-N 0.000 description 1
- CMOINENCXVRJRP-UHFFFAOYSA-N methyl 7-chloroisoquinoline-3-carboxylate Chemical compound C1=C(Cl)C=C2C=NC(C(=O)OC)=CC2=C1 CMOINENCXVRJRP-UHFFFAOYSA-N 0.000 description 1
- NNBBQNFHCVVQHZ-UHFFFAOYSA-N methyl carbamimidothioate;sulfuric acid Chemical compound CSC(N)=N.OS(O)(=O)=O NNBBQNFHCVVQHZ-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- IYZDWWZDSIARIV-MHDYBILJSA-N n-[(1r,2r)-2-aminocyclopentyl]-5-chloro-1h-indole-2-carboxamide;hydrochloride Chemical compound Cl.N[C@@H]1CCC[C@H]1NC(=O)C1=CC2=CC(Cl)=CC=C2N1 IYZDWWZDSIARIV-MHDYBILJSA-N 0.000 description 1
- LFWYISVIXRUQIX-VTLYIQCISA-N n-[(1r,2r)-2-aminocyclopentyl]-5-methyl-6,7-dihydro-4h-[1,3]thiazolo[5,4-c]pyridine-2-carboxamide;hydrochloride Chemical compound Cl.S1C=2CN(C)CCC=2N=C1C(=O)N[C@@H]1CCC[C@H]1N LFWYISVIXRUQIX-VTLYIQCISA-N 0.000 description 1
- MKYQJWQNAMUVTG-WCBMZHEXSA-N n-[(1r,2s)-2-aminocyclopropyl]-5-chloro-1h-indole-2-carboxamide Chemical compound N[C@H]1C[C@H]1NC(=O)C1=CC2=CC(Cl)=CC=C2N1 MKYQJWQNAMUVTG-WCBMZHEXSA-N 0.000 description 1
- BEWWMDOTNGCGNW-VDZJLULYSA-N n-[(1s,2r,4s)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4h-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]-n'-phenyloxamide Chemical compound N([C@H]1CC[C@@H](C[C@H]1NC(=O)C=1SC=2CN(C)CCC=2N=1)C(=O)N(C)C)C(=O)C(=O)NC1=CC=CC=C1 BEWWMDOTNGCGNW-VDZJLULYSA-N 0.000 description 1
- JMFMUWNATYFJBD-SKDRFNHKSA-N n-[(3r,4s)-4-aminooxolan-3-yl]-5-chloro-1h-indole-2-carboxamide Chemical compound N[C@@H]1COC[C@@H]1NC(=O)C1=CC2=CC(Cl)=CC=C2N1 JMFMUWNATYFJBD-SKDRFNHKSA-N 0.000 description 1
- KXOXSXUOTAXFDG-SKDRFNHKSA-N n-[(3s,4r)-4-amino-1-methyl-2-oxopyrrolidin-3-yl]-5-chloro-1h-indole-2-carboxamide Chemical compound O=C1N(C)C[C@@H](N)[C@@H]1NC(=O)C1=CC2=CC(Cl)=CC=C2N1 KXOXSXUOTAXFDG-SKDRFNHKSA-N 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- BKIMMITUMNQMOS-UHFFFAOYSA-N normal nonane Natural products CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 229910000487 osmium oxide Inorganic materials 0.000 description 1
- 150000003901 oxalic acid esters Chemical class 0.000 description 1
- JMJRYTGVHCAYCT-UHFFFAOYSA-N oxan-4-one Chemical compound O=C1CCOCC1 JMJRYTGVHCAYCT-UHFFFAOYSA-N 0.000 description 1
- AVPKHOTUOHDTLW-UHFFFAOYSA-N oxane-4-carboxylic acid Chemical compound OC(=O)C1CCOCC1 AVPKHOTUOHDTLW-UHFFFAOYSA-N 0.000 description 1
- 125000003145 oxazol-4-yl group Chemical group O1C=NC(=C1)* 0.000 description 1
- JIWAALDUIFCBLV-UHFFFAOYSA-N oxoosmium Chemical compound [Os]=O JIWAALDUIFCBLV-UHFFFAOYSA-N 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 1
- SIOXPEMLGUPBBT-UHFFFAOYSA-M picolinate Chemical compound [O-]C(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-M 0.000 description 1
- JSSXHAMIXJGYCS-UHFFFAOYSA-N piperazin-4-ium-2-carboxylate Chemical compound OC(=O)C1CNCCN1 JSSXHAMIXJGYCS-UHFFFAOYSA-N 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 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
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 229940039716 prothrombin Drugs 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004526 pyridazin-2-yl group Chemical group N1N(C=CC=C1)* 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 150000004040 pyrrolidinones Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000004043 responsiveness Effects 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
- 239000002002 slurry Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- XTIVBOWLUYDHKE-UHFFFAOYSA-M sodium;cyclohexanecarboxylate Chemical compound [Na+].[O-]C(=O)C1CCCCC1 XTIVBOWLUYDHKE-UHFFFAOYSA-M 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 101150035983 str1 gene Proteins 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical class O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000008718 systemic inflammatory response Effects 0.000 description 1
- 150000003899 tartaric acid esters Chemical class 0.000 description 1
- YJMKJQUSMRAAFO-RNFRBKRXSA-N tert-butyl (3r,4r)-3,4-diazidopyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@@H](N=[N+]=[N-])[C@H](N=[N+]=[N-])C1 YJMKJQUSMRAAFO-RNFRBKRXSA-N 0.000 description 1
- QEFAZXPWLQHESA-IUCAKERBSA-N tert-butyl (3s,4s)-3,4-bis(methylsulfonyloxy)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)[C@@H](OS(C)(=O)=O)C1 QEFAZXPWLQHESA-IUCAKERBSA-N 0.000 description 1
- TYKBMDDDNFOEBD-RITPCOANSA-N tert-butyl (3s,4s)-4-amino-5-oxooxolane-3-carboxylate Chemical compound CC(C)(C)OC(=O)[C@@H]1COC(=O)[C@H]1N TYKBMDDDNFOEBD-RITPCOANSA-N 0.000 description 1
- OFUWDLHCVDWULD-ANYFNZRUSA-N tert-butyl (4r)-4-[(e)-3-ethoxy-3-oxoprop-1-enyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate Chemical compound CCOC(=O)\C=C\[C@@H]1COC(C)(C)N1C(=O)OC(C)(C)C OFUWDLHCVDWULD-ANYFNZRUSA-N 0.000 description 1
- VWMUYQKBDWCFLQ-ZVAWYAOSSA-N tert-butyl (4r)-4-[1-(benzylamino)-3-ethoxy-3-oxopropyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate Chemical compound CCOC(=O)CC([C@H]1N(C(C)(C)OC1)C(=O)OC(C)(C)C)NCC1=CC=CC=C1 VWMUYQKBDWCFLQ-ZVAWYAOSSA-N 0.000 description 1
- PNJXYVJNOCLJLJ-QMMMGPOBSA-N tert-butyl (4r)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate Chemical compound CC(C)(C)OC(=O)N1[C@@H](C=O)COC1(C)C PNJXYVJNOCLJLJ-QMMMGPOBSA-N 0.000 description 1
- SNAAYYIAPRHITE-RRKGBCIJSA-N tert-butyl (4s)-4-(1-amino-3-ethoxy-3-oxopropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate Chemical compound CCOC(=O)CC(N)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C SNAAYYIAPRHITE-RRKGBCIJSA-N 0.000 description 1
- VWMUYQKBDWCFLQ-QRWMCTBCSA-N tert-butyl (4s)-4-[1-(benzylamino)-3-ethoxy-3-oxopropyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate Chemical compound CCOC(=O)CC([C@@H]1N(C(C)(C)OC1)C(=O)OC(C)(C)C)NCC1=CC=CC=C1 VWMUYQKBDWCFLQ-QRWMCTBCSA-N 0.000 description 1
- PNJXYVJNOCLJLJ-MRVPVSSYSA-N tert-butyl (4s)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate Chemical compound CC(C)(C)OC(=O)N1[C@H](C=O)COC1(C)C PNJXYVJNOCLJLJ-MRVPVSSYSA-N 0.000 description 1
- CPGOEXDHRDANBY-MDZDMXLPSA-N tert-butyl 2-[(e)-2-phenylethenyl]-6,7-dihydro-4h-[1,3]oxazolo[5,4-c]pyridine-5-carboxylate Chemical compound O1C=2CN(C(=O)OC(C)(C)C)CCC=2N=C1\C=C\C1=CC=CC=C1 CPGOEXDHRDANBY-MDZDMXLPSA-N 0.000 description 1
- QRJZLNBRXQAKCP-UHFFFAOYSA-N tert-butyl 2-amino-4,6-dihydropyrrolo[3,4-d][1,3]thiazole-5-carboxylate Chemical compound N1=C(N)SC2=C1CN(C(=O)OC(C)(C)C)C2 QRJZLNBRXQAKCP-UHFFFAOYSA-N 0.000 description 1
- BMLHPGOMLGKYIJ-UHFFFAOYSA-N tert-butyl 2-amino-6,7-dihydro-4h-[1,3]thiazolo[5,4-c]pyridine-5-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC2=C1SC(N)=N2 BMLHPGOMLGKYIJ-UHFFFAOYSA-N 0.000 description 1
- CDSSEIKIKLGYMP-UHFFFAOYSA-N tert-butyl 2-bromo-4,6-dihydropyrrolo[3,4-d][1,3]thiazole-5-carboxylate Chemical compound N1=C(Br)SC2=C1CN(C(=O)OC(C)(C)C)C2 CDSSEIKIKLGYMP-UHFFFAOYSA-N 0.000 description 1
- RXXKNZKFRAFFOH-UHFFFAOYSA-N tert-butyl 2-bromo-6,7-dihydro-4h-[1,3]thiazolo[5,4-c]pyridine-5-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC2=C1SC(Br)=N2 RXXKNZKFRAFFOH-UHFFFAOYSA-N 0.000 description 1
- YRJMOLPRUOARMU-UHFFFAOYSA-N tert-butyl 2-cyano-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate Chemical compound N1=C(C#N)N=C2CN(C(=O)OC(C)(C)C)CC2=C1 YRJMOLPRUOARMU-UHFFFAOYSA-N 0.000 description 1
- VSMGCADVQNGHFT-UHFFFAOYSA-N tert-butyl 2-formyl-6,7-dihydro-4h-[1,3]oxazolo[5,4-c]pyridine-5-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC2=C1OC(C=O)=N2 VSMGCADVQNGHFT-UHFFFAOYSA-N 0.000 description 1
- WYPNWMDBICFBAM-UHFFFAOYSA-N tert-butyl 2-methylsulfanyl-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate Chemical compound CSC1=NC=C2CN(C(=O)OC(C)(C)C)CC2=N1 WYPNWMDBICFBAM-UHFFFAOYSA-N 0.000 description 1
- OWHKZXFLURWFDL-UHFFFAOYSA-N tert-butyl 2-methylsulfonyl-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate Chemical compound N1=C(S(C)(=O)=O)N=C2CN(C(=O)OC(C)(C)C)CC2=C1 OWHKZXFLURWFDL-UHFFFAOYSA-N 0.000 description 1
- SHHHRQFHCPINIB-UHFFFAOYSA-N tert-butyl 3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC=CC1 SHHHRQFHCPINIB-UHFFFAOYSA-N 0.000 description 1
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 1
- YDMAGSOIJNDVIZ-GARJFASQSA-N tert-butyl N-[(1R,2S,5S)-2-amino-5-ethylcyclohexyl]carbamate Chemical compound C(C)[C@@H]1C[C@H]([C@H](CC1)N)NC(=O)OC(C)(C)C YDMAGSOIJNDVIZ-GARJFASQSA-N 0.000 description 1
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 1
- MKRKOWOVJQNWSY-UHFFFAOYSA-N tert-butyl n-(3-sulfanylpyridin-4-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=NC=C1S MKRKOWOVJQNWSY-UHFFFAOYSA-N 0.000 description 1
- HESMDBDUEDHPRG-UHFFFAOYSA-N tert-butyl n-(4-sulfanylidene-1h-pyridin-3-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CN=CC=C1S HESMDBDUEDHPRG-UHFFFAOYSA-N 0.000 description 1
- PAXDIBGWURAVIH-HTQZYQBOSA-N tert-butyl n-[(1r,2r)-2-aminocyclopentyl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]1CCC[C@H]1N PAXDIBGWURAVIH-HTQZYQBOSA-N 0.000 description 1
- JCHIBKSSZNWERE-GARJFASQSA-N tert-butyl n-[(1r,2s,5s)-2-amino-5-(dimethylcarbamoyl)cyclohexyl]carbamate Chemical compound CN(C)C(=O)[C@H]1CC[C@H](N)[C@H](NC(=O)OC(C)(C)C)C1 JCHIBKSSZNWERE-GARJFASQSA-N 0.000 description 1
- IBBVWOZAKKWMOG-TXEJJXNPSA-N tert-butyl n-[(1s,6r)-6-[(2-methylpropan-2-yl)oxycarbonylamino]cyclohex-3-en-1-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]1CC=CC[C@@H]1NC(=O)OC(C)(C)C IBBVWOZAKKWMOG-TXEJJXNPSA-N 0.000 description 1
- ANTWXCIRTOXBDJ-HIFRSBDPSA-N tert-butyl n-[(3r,4r)-4-[(5-chloro-1h-indole-2-carbonyl)amino]-6-oxooxan-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]1COC(=O)C[C@H]1NC(=O)C1=CC2=CC(Cl)=CC=C2N1 ANTWXCIRTOXBDJ-HIFRSBDPSA-N 0.000 description 1
- ANTWXCIRTOXBDJ-ZFWWWQNUSA-N tert-butyl n-[(3r,4s)-4-[(5-chloro-1h-indole-2-carbonyl)amino]-6-oxooxan-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]1COC(=O)C[C@@H]1NC(=O)C1=CC2=CC(Cl)=CC=C2N1 ANTWXCIRTOXBDJ-ZFWWWQNUSA-N 0.000 description 1
- XODLOLQRSQGSFE-LURJTMIESA-N tert-butyl n-[(3s)-5-oxooxolan-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]1COC(=O)C1 XODLOLQRSQGSFE-LURJTMIESA-N 0.000 description 1
- HTQSGCDIFAAIFM-KGLIPLIRSA-N tert-butyl n-[(3s,4s)-4-[(5-chloro-1h-indole-2-carbonyl)amino]-5-oxooxolan-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]1COC(=O)[C@H]1NC(=O)C1=CC2=CC(Cl)=CC=C2N1 HTQSGCDIFAAIFM-KGLIPLIRSA-N 0.000 description 1
- ZTHRPSKRSGFNII-RITPCOANSA-N tert-butyl n-[(3s,4s)-4-azido-5-oxooxolan-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]1COC(=O)[C@H]1N=[N+]=[N-] ZTHRPSKRSGFNII-RITPCOANSA-N 0.000 description 1
- IRBIWNJTHWLIMD-UHFFFAOYSA-N tert-butyl n-cyclohex-3-en-1-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCC=CC1 IRBIWNJTHWLIMD-UHFFFAOYSA-N 0.000 description 1
- DRZYCRFOGWMEES-UHFFFAOYSA-N tert-butyl n-pyridin-4-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=NC=C1 DRZYCRFOGWMEES-UHFFFAOYSA-N 0.000 description 1
- YIPRCAXZMPZCCU-UHFFFAOYSA-N tert-butyl-[2-(6,7-dihydro-4h-[1,3]thiazolo[5,4-c]pyridin-5-yl)-2-methylpropoxy]-diphenylsilane Chemical compound C1CC=2N=CSC=2CN1C(C)(C)CO[Si](C(C)(C)C)(C=1C=CC=CC=1)C1=CC=CC=C1 YIPRCAXZMPZCCU-UHFFFAOYSA-N 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- KRRBFUJMQBDDPR-UHFFFAOYSA-N tetrabutylazanium;cyanide Chemical compound N#[C-].CCCC[N+](CCCC)(CCCC)CCCC KRRBFUJMQBDDPR-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
- 201000005665 thrombophilia Diseases 0.000 description 1
- NDLIRBZKZSDGSO-UHFFFAOYSA-N tosyl azide Chemical compound CC1=CC=C(S(=O)(=O)[N-][N+]#N)C=C1 NDLIRBZKZSDGSO-UHFFFAOYSA-N 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- IIHPVYJPDKJYOU-UHFFFAOYSA-N triphenylcarbethoxymethylenephosphorane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC(=O)OCC)C1=CC=CC=C1 IIHPVYJPDKJYOU-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
-
- A—HUMAN NECESSITIES
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Applications Claiming Priority (5)
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JP2001187105 | 2001-06-20 | ||
JP2001243046 | 2001-08-09 | ||
JP2001311808 | 2001-10-09 | ||
JP2001398708 | 2001-12-28 | ||
PCT/JP2002/002683 WO2003000657A1 (fr) | 2001-06-20 | 2002-03-20 | Derives de diamine |
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Publication Number | Publication Date |
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PT1405852E true PT1405852E (pt) | 2012-10-30 |
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PT02743653T PT1405852E (pt) | 2001-06-20 | 2002-06-20 | Derivados de diamina |
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US (7) | US7365205B2 (en, 2012) |
EP (1) | EP2343290A1 (en, 2012) |
AR (1) | AR036102A1 (en, 2012) |
BE (1) | BE2015C046I2 (en, 2012) |
CY (2) | CY1113054T1 (en, 2012) |
FR (1) | FR15C0068I2 (en, 2012) |
MY (1) | MY153231A (en, 2012) |
NL (1) | NL300760I2 (en, 2012) |
PT (1) | PT1405852E (en, 2012) |
TW (1) | TWI298066B (en, 2012) |
WO (1) | WO2003000657A1 (en, 2012) |
ZA (1) | ZA200309866B (en, 2012) |
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AU2002350217A1 (en) | 2001-12-04 | 2003-06-17 | Bristol-Myers Squibb Company | Glycinamides as factor xa inhibitors |
WO2003099276A1 (en) | 2002-05-10 | 2003-12-04 | Bristol-Myers Squibb Company | 1,1-disubstituted cycloalkyl derivatives as factor xa inhibitors |
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RU2333203C2 (ru) * | 2002-12-25 | 2008-09-10 | Дайити Фармасьютикал Ко., Лтд. | Диаминовые производные |
-
2002
- 2002-03-20 WO PCT/JP2002/002683 patent/WO2003000657A1/ja active Application Filing
- 2002-03-20 US US10/481,262 patent/US7365205B2/en active Active
- 2002-06-19 MY MYPI20022307A patent/MY153231A/en unknown
- 2002-06-20 TW TW091113510A patent/TWI298066B/zh active
- 2002-06-20 AR ARP020102322A patent/AR036102A1/es active IP Right Grant
- 2002-06-20 PT PT02743653T patent/PT1405852E/pt unknown
- 2002-06-20 EP EP11002212A patent/EP2343290A1/en not_active Withdrawn
-
2003
- 2003-12-19 ZA ZA2003/09866A patent/ZA200309866B/en unknown
-
2004
- 2004-02-09 US US10/773,344 patent/US7342014B2/en not_active Expired - Lifetime
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2007
- 2007-09-06 US US11/850,788 patent/US20080015215A1/en not_active Abandoned
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2008
- 2008-12-30 US US12/259,496 patent/US20100093785A1/en not_active Abandoned
-
2009
- 2009-03-06 US US12/399,702 patent/US20090270446A1/en not_active Abandoned
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2010
- 2010-05-21 US US12/784,710 patent/US20110077266A1/en not_active Abandoned
- 2010-12-13 US US12/966,640 patent/US20110312990A1/en not_active Abandoned
-
2012
- 2012-08-20 CY CY20121100742T patent/CY1113054T1/el unknown
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2015
- 2015-07-16 BE BE2015C046C patent/BE2015C046I2/fr unknown
- 2015-08-20 CY CY2015034C patent/CY2015034I2/el unknown
- 2015-09-29 NL NL300760C patent/NL300760I2/en unknown
- 2015-10-09 FR FR15C0068C patent/FR15C0068I2/fr active Active
Also Published As
Publication number | Publication date |
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FR15C0068I2 (fr) | 2016-04-22 |
NL300760I2 (en) | 2017-07-20 |
US20080015215A1 (en) | 2008-01-17 |
HK1092461A1 (en) | 2007-02-09 |
US20050119486A1 (en) | 2005-06-02 |
CY2015034I1 (el) | 2016-04-13 |
US20090270446A1 (en) | 2009-10-29 |
ZA200309866B (en) | 2005-03-30 |
TWI298066B (en) | 2008-06-21 |
AR036102A1 (es) | 2004-08-11 |
US7342014B2 (en) | 2008-03-11 |
MY153231A (en) | 2015-01-29 |
BE2015C046I2 (en, 2012) | 2021-07-19 |
CY2015034I2 (el) | 2016-04-13 |
US20050020645A1 (en) | 2005-01-27 |
US20110077266A1 (en) | 2011-03-31 |
WO2003000657A1 (fr) | 2003-01-03 |
EP2343290A1 (en) | 2011-07-13 |
FR15C0068I1 (en, 2012) | 2015-12-04 |
US20110312990A1 (en) | 2011-12-22 |
US7365205B2 (en) | 2008-04-29 |
US20100093785A1 (en) | 2010-04-15 |
CY1113054T1 (el) | 2016-04-13 |
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