NO327003B1 - Diamin-derivater, medisinsk preparat omfattende slike, slike forbindelser for anvendelse som legemiddel samt anvendelse av disse for fremstilling av middel for forebygging og behandling av sykdom. - Google Patents
Diamin-derivater, medisinsk preparat omfattende slike, slike forbindelser for anvendelse som legemiddel samt anvendelse av disse for fremstilling av middel for forebygging og behandling av sykdom. Download PDFInfo
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- NO327003B1 NO327003B1 NO20040557A NO20040557A NO327003B1 NO 327003 B1 NO327003 B1 NO 327003B1 NO 20040557 A NO20040557 A NO 20040557A NO 20040557 A NO20040557 A NO 20040557A NO 327003 B1 NO327003 B1 NO 327003B1
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- Prior art keywords
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- alkyl
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- compound
- substituted
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 359
- 238000002360 preparation method Methods 0.000 title claims description 71
- 239000003795 chemical substances by application Substances 0.000 title claims description 18
- 230000002265 prevention Effects 0.000 title claims description 10
- 239000003814 drug Substances 0.000 title claims description 7
- 150000004985 diamines Chemical class 0.000 title description 47
- 201000010099 disease Diseases 0.000 title description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 150000001204 N-oxides Chemical class 0.000 claims abstract description 20
- 239000012453 solvate Substances 0.000 claims abstract description 20
- 208000007536 Thrombosis Diseases 0.000 claims description 20
- 230000015572 biosynthetic process Effects 0.000 claims description 16
- 208000011580 syndromic disease Diseases 0.000 claims description 6
- 208000010718 Multiple Organ Failure Diseases 0.000 claims description 5
- 206010051379 Systemic Inflammatory Response Syndrome Diseases 0.000 claims description 5
- 206010047249 Venous thrombosis Diseases 0.000 claims description 5
- 208000029744 multiple organ dysfunction syndrome Diseases 0.000 claims description 5
- 206010008088 Cerebral artery embolism Diseases 0.000 claims description 4
- 206010051055 Deep vein thrombosis Diseases 0.000 claims description 4
- 208000005189 Embolism Diseases 0.000 claims description 4
- 208000010378 Pulmonary Embolism Diseases 0.000 claims description 4
- 208000006193 Pulmonary infarction Diseases 0.000 claims description 4
- 206010038563 Reocclusion Diseases 0.000 claims description 4
- 206010043540 Thromboangiitis obliterans Diseases 0.000 claims description 4
- 238000002399 angioplasty Methods 0.000 claims description 4
- 230000023555 blood coagulation Effects 0.000 claims description 4
- 206010008118 cerebral infarction Diseases 0.000 claims description 4
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 4
- 208000009190 disseminated intravascular coagulation Diseases 0.000 claims description 4
- 201000010849 intracranial embolism Diseases 0.000 claims description 4
- 208000010125 myocardial infarction Diseases 0.000 claims description 4
- 230000007575 pulmonary infarction Effects 0.000 claims description 4
- 206010002383 Angina Pectoris Diseases 0.000 claims description 3
- 239000008280 blood Substances 0.000 claims description 3
- 210000004369 blood Anatomy 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- -1 heterocyclyl diamine compounds Chemical class 0.000 abstract description 1207
- 125000000217 alkyl group Chemical group 0.000 abstract description 212
- 125000000304 alkynyl group Chemical group 0.000 abstract description 81
- 125000001424 substituent group Chemical group 0.000 abstract description 66
- 125000003545 alkoxy group Chemical group 0.000 abstract description 61
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 61
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract description 56
- 125000002619 bicyclic group Chemical group 0.000 abstract description 54
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 51
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 45
- 125000003342 alkenyl group Chemical group 0.000 abstract description 42
- 125000001188 haloalkyl group Chemical group 0.000 abstract description 42
- 125000002947 alkylene group Chemical group 0.000 abstract description 39
- 125000004453 alkoxycarbonyl group Chemical group 0.000 abstract description 36
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 abstract description 36
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract description 30
- 229910052717 sulfur Inorganic materials 0.000 abstract description 29
- 125000004183 alkoxy alkyl group Chemical group 0.000 abstract description 28
- 125000003118 aryl group Chemical group 0.000 abstract description 27
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 abstract description 24
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 abstract description 24
- 125000002768 hydroxyalkyl group Chemical group 0.000 abstract description 23
- 125000004181 carboxyalkyl group Chemical group 0.000 abstract description 22
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 abstract description 20
- 125000004450 alkenylene group Chemical group 0.000 abstract description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 16
- 125000004390 alkyl sulfonyl group Chemical group 0.000 abstract description 14
- 229910052799 carbon Inorganic materials 0.000 abstract description 14
- 125000001072 heteroaryl group Chemical group 0.000 abstract description 13
- 229910052760 oxygen Inorganic materials 0.000 abstract description 13
- 125000004391 aryl sulfonyl group Chemical group 0.000 abstract description 9
- YIKSCQDJHCMVMK-UHFFFAOYSA-N Oxamide Chemical compound NC(=O)C(N)=O YIKSCQDJHCMVMK-UHFFFAOYSA-N 0.000 abstract description 8
- 125000004442 acylamino group Chemical group 0.000 abstract description 8
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 abstract description 8
- 125000003710 aryl alkyl group Chemical group 0.000 abstract description 8
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 abstract description 8
- 125000004945 acylaminoalkyl group Chemical group 0.000 abstract description 7
- 125000000266 alpha-aminoacyl group Chemical group 0.000 abstract description 7
- 125000004103 aminoalkyl group Chemical group 0.000 abstract description 7
- 239000003146 anticoagulant agent Substances 0.000 abstract description 7
- 125000004423 acyloxy group Chemical group 0.000 abstract description 6
- 125000005256 alkoxyacyl group Chemical group 0.000 abstract description 6
- 125000000676 alkoxyimino group Chemical group 0.000 abstract description 6
- 125000004688 alkyl sulfonyl alkyl group Chemical group 0.000 abstract description 6
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 abstract description 6
- 229940127219 anticoagulant drug Drugs 0.000 abstract description 6
- 125000005242 carbamoyl alkyl group Chemical group 0.000 abstract description 6
- 125000005252 haloacyl group Chemical group 0.000 abstract description 6
- 229910052702 rhenium Inorganic materials 0.000 abstract description 6
- 125000005041 acyloxyalkyl group Chemical group 0.000 abstract description 5
- 125000005154 alkyl sulfonyl amino alkyl group Chemical group 0.000 abstract description 5
- 125000005530 alkylenedioxy group Chemical group 0.000 abstract description 5
- 125000005018 aryl alkenyl group Chemical group 0.000 abstract description 5
- 125000004657 aryl sulfonyl amino group Chemical group 0.000 abstract description 5
- 125000004447 heteroarylalkenyl group Chemical group 0.000 abstract description 5
- 125000005015 aryl alkynyl group Chemical group 0.000 abstract description 4
- 125000004966 cyanoalkyl group Chemical group 0.000 abstract description 4
- 125000002102 aryl alkyloxo group Chemical group 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- 125000004446 heteroarylalkyl group Chemical group 0.000 abstract description 3
- 125000004043 oxo group Chemical group O=* 0.000 abstract description 2
- 125000004452 carbocyclyl group Chemical group 0.000 abstract 5
- 125000001589 carboacyl group Chemical group 0.000 abstract 3
- CCPHAMSKHBDMDS-UHFFFAOYSA-N Chetoseminudin B Natural products C=1NC2=CC=CC=C2C=1CC1(SC)NC(=O)C(CO)(SC)N(C)C1=O CCPHAMSKHBDMDS-UHFFFAOYSA-N 0.000 abstract 1
- 101710200938 Coagulation factor X inhibitor Proteins 0.000 abstract 1
- 230000003110 anti-inflammatory effect Effects 0.000 abstract 1
- 125000001475 halogen functional group Chemical group 0.000 abstract 1
- 125000006517 heterocyclyl carbonyl group Chemical group 0.000 abstract 1
- 230000010534 mechanism of action Effects 0.000 abstract 1
- 125000000547 substituted alkyl group Chemical group 0.000 abstract 1
- 230000002537 thrombolytic effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 250
- 239000000543 intermediate Substances 0.000 description 143
- 239000002904 solvent Substances 0.000 description 135
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 132
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 121
- 229920006395 saturated elastomer Polymers 0.000 description 111
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 108
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 104
- 125000005843 halogen group Chemical group 0.000 description 98
- 125000004432 carbon atom Chemical group C* 0.000 description 90
- 238000006243 chemical reaction Methods 0.000 description 84
- 230000002829 reductive effect Effects 0.000 description 82
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 78
- 239000000203 mixture Substances 0.000 description 78
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 78
- 238000004519 manufacturing process Methods 0.000 description 70
- 239000000243 solution Substances 0.000 description 69
- 238000005160 1H NMR spectroscopy Methods 0.000 description 68
- 239000011541 reaction mixture Substances 0.000 description 68
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 67
- 125000003277 amino group Chemical group 0.000 description 64
- 238000000034 method Methods 0.000 description 63
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 60
- 125000002252 acyl group Chemical group 0.000 description 59
- 239000012044 organic layer Substances 0.000 description 59
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 58
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 51
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 50
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 45
- 239000007864 aqueous solution Substances 0.000 description 45
- 239000000741 silica gel Substances 0.000 description 44
- 229910002027 silica gel Inorganic materials 0.000 description 44
- 125000004093 cyano group Chemical group *C#N 0.000 description 43
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 42
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 41
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 40
- 238000004440 column chromatography Methods 0.000 description 40
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 38
- 125000006239 protecting group Chemical group 0.000 description 38
- 150000001412 amines Chemical class 0.000 description 37
- 125000004433 nitrogen atom Chemical group N* 0.000 description 35
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 34
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 33
- 239000002585 base Substances 0.000 description 33
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 238000001816 cooling Methods 0.000 description 29
- 150000002148 esters Chemical class 0.000 description 29
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 28
- 239000002253 acid Substances 0.000 description 28
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 27
- 125000005118 N-alkylcarbamoyl group Chemical group 0.000 description 25
- 239000012442 inert solvent Substances 0.000 description 25
- 150000002430 hydrocarbons Chemical group 0.000 description 24
- 125000000753 cycloalkyl group Chemical group 0.000 description 23
- 239000010410 layer Substances 0.000 description 23
- 239000003153 chemical reaction reagent Substances 0.000 description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 22
- 238000010992 reflux Methods 0.000 description 22
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 21
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 21
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 21
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 21
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
- 229910052801 chlorine Inorganic materials 0.000 description 20
- 238000001914 filtration Methods 0.000 description 20
- 229910052731 fluorine Inorganic materials 0.000 description 20
- 125000004430 oxygen atom Chemical group O* 0.000 description 20
- 235000017557 sodium bicarbonate Nutrition 0.000 description 20
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 18
- 150000001540 azides Chemical class 0.000 description 18
- 125000004122 cyclic group Chemical group 0.000 description 18
- 230000008569 process Effects 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 17
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 17
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 17
- 239000000460 chlorine Substances 0.000 description 17
- 239000011737 fluorine Substances 0.000 description 17
- 150000004820 halides Chemical class 0.000 description 17
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 16
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 16
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 16
- 150000001414 amino alcohols Chemical class 0.000 description 16
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 16
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 16
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 15
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 15
- 125000004434 sulfur atom Chemical group 0.000 description 15
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 14
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 14
- 239000011780 sodium chloride Substances 0.000 description 14
- 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 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- 150000008065 acid anhydrides Chemical class 0.000 description 12
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 12
- 125000006165 cyclic alkyl group Chemical group 0.000 description 11
- 150000003461 sulfonyl halides Chemical class 0.000 description 11
- 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
- 125000003341 7 membered heterocyclic group Chemical group 0.000 description 10
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- 125000005842 heteroatom Chemical group 0.000 description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 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 10
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 9
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 9
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 9
- 150000001408 amides Chemical class 0.000 description 9
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 9
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 8
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 8
- 108090000190 Thrombin Proteins 0.000 description 8
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 8
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 8
- 239000012046 mixed solvent Substances 0.000 description 8
- 125000001624 naphthyl group Chemical group 0.000 description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 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
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
- 125000003435 aroyl group Chemical group 0.000 description 7
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 7
- 238000009833 condensation Methods 0.000 description 7
- 230000005494 condensation Effects 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 125000004076 pyridyl group Chemical group 0.000 description 7
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- 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
- 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
- 239000006210 lotion Substances 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
- 239000012528 membrane Substances 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
- HGKJLQHBKFKJEE-FJXQXJEOSA-N methyl (2s)-2-(4-chloroanilino)propanoate;hydrochloride Chemical compound Cl.COC(=O)[C@H](C)NC1=CC=C(Cl)C=C1 HGKJLQHBKFKJEE-FJXQXJEOSA-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
- GCIFKUKRHHEWOO-UHFFFAOYSA-N methyl 3-(4-chlorophenyl)-2-formamidopropanoate Chemical compound COC(=O)C(NC=O)CC1=CC=C(Cl)C=C1 GCIFKUKRHHEWOO-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
- 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
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 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
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 125000006518 morpholino carbonyl group Chemical group [H]C1([H])OC([H])([H])C([H])([H])N(C(*)=O)C1([H])[H] 0.000 description 1
- 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- GPWOWVBOKQEMSC-KMBTUZTLSA-N n-[(1r,2s,5s)-2-[[2-(4-chloroanilino)-1-(methoxyamino)-2-oxoethylidene]amino]-5-(dimethylcarbamoyl)cyclohexyl]-5-methyl-6,7-dihydro-4h-[1,3]thiazolo[5,4-c]pyridine-2-carboxamide;hydrochloride Chemical compound Cl.N([C@@H]1[C@@H](C[C@H](CC1)C(=O)N(C)C)NC(=O)C=1SC=2CN(C)CCC=2N=1)C(=NOC)C(=O)NC1=CC=C(Cl)C=C1 GPWOWVBOKQEMSC-KMBTUZTLSA-N 0.000 description 1
- BIJITWILRSHIHU-QXXZOGQOSA-N n-[(1r,2s,5s)-2-[[2-[(6-chloropyridin-3-yl)amino]-2-oxoethanethioyl]amino]-5-(dimethylcarbamoyl)cyclohexyl]-5-methyl-6,7-dihydro-4h-[1,3]thiazolo[5,4-c]pyridine-2-carboxamide;hydrochloride Chemical compound Cl.N([C@H]1CC[C@@H](C[C@H]1NC(=O)C=1SC=2CN(C)CCC=2N=1)C(=O)N(C)C)C(=S)C(=O)NC1=CC=C(Cl)N=C1 BIJITWILRSHIHU-QXXZOGQOSA-N 0.000 description 1
- CNNNSWFGNXYLIJ-IIKXTNQWSA-N n-[(1r,2s,5s)-5-(dimethylcarbamoyl)-2-[[2-[(5-methylpyridin-2-yl)amino]-2-oxoethanethioyl]amino]cyclohexyl]-5-methyl-6,7-dihydro-4h-[1,3]thiazolo[5,4-c]pyridine-2-carboxamide;hydrochloride Chemical compound Cl.N([C@H]1CC[C@@H](C[C@H]1NC(=O)C=1SC=2CN(C)CCC=2N=1)C(=O)N(C)C)C(=S)C(=O)NC1=CC=C(C)C=N1 CNNNSWFGNXYLIJ-IIKXTNQWSA-N 0.000 description 1
- 125000005146 naphthylsulfonyl group Chemical group C1(=CC=CC2=CC=CC=C12)S(=O)(=O)* 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000012285 osmium tetroxide Substances 0.000 description 1
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 1
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- JMJRYTGVHCAYCT-UHFFFAOYSA-N oxan-4-one Chemical compound O=C1CCOCC1 JMJRYTGVHCAYCT-UHFFFAOYSA-N 0.000 description 1
- SFJGCXYXEFWEBK-UHFFFAOYSA-N oxazepine Chemical compound O1C=CC=CC=N1 SFJGCXYXEFWEBK-UHFFFAOYSA-N 0.000 description 1
- 125000005968 oxazolinyl group Chemical group 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 235000011837 pasties Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
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- 150000003904 phospholipids Chemical class 0.000 description 1
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- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 1
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- WLNXUYIIBVRGBH-UHFFFAOYSA-N potassium;propanedioic acid Chemical compound [K].OC(=O)CC(O)=O WLNXUYIIBVRGBH-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
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- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
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- 125000003373 pyrazinyl group Chemical group 0.000 description 1
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- 125000005400 pyridylcarbonyl group Chemical group N1=C(C=CC=C1)C(=O)* 0.000 description 1
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
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- 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
- 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
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000005504 styryl group Chemical group 0.000 description 1
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- 229960002317 succinimide Drugs 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
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- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide pyridine complex Chemical class O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 description 1
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- 239000000375 suspending agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
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- 150000003899 tartaric acid esters Chemical class 0.000 description 1
- 125000006633 tert-butoxycarbonylamino group Chemical group 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
- 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
- AUHQOOIWUXNGES-UHFFFAOYSA-N tert-butyl 6,7-dihydro-4h-[1,3]thiazolo[5,4-c]pyridine-5-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC2=C1SC=N2 AUHQOOIWUXNGES-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
- 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
- KRRBFUJMQBDDPR-UHFFFAOYSA-N tetrabutylazanium;cyanide Chemical compound N#[C-].CCCC[N+](CCCC)(CCCC)CCCC KRRBFUJMQBDDPR-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000004525 thiadiazinyl group Chemical group S1NN=C(C=C1)* 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- HSEBBGGKTDWAOT-UHFFFAOYSA-N thieno[2,3-c]azepine Chemical compound N1=CC=CC2=CC=[S]C2=C1 HSEBBGGKTDWAOT-UHFFFAOYSA-N 0.000 description 1
- QXWYLVQTEJWMKW-UHFFFAOYSA-N thieno[3,4-c]pyridine Chemical compound C1=NC=CC2=CSC=C21 QXWYLVQTEJWMKW-UHFFFAOYSA-N 0.000 description 1
- 125000005301 thienylmethyl group Chemical group [H]C1=C([H])C([H])=C(S1)C([H])([H])* 0.000 description 1
- QIQITDHWZYEEPA-UHFFFAOYSA-N thiophene-2-carbonyl chloride Chemical compound ClC(=O)C1=CC=CS1 QIQITDHWZYEEPA-UHFFFAOYSA-N 0.000 description 1
- 201000005665 thrombophilia Diseases 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N
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- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
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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 |
PCT/JP2002/006141 WO2003000680A1 (fr) | 2001-06-20 | 2002-06-20 | Derives de diamine |
PCT/JP2002/008119 WO2003016302A1 (fr) | 2001-08-09 | 2002-08-08 | Derives de diamine |
Publications (2)
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NO20040557L NO20040557L (no) | 2004-04-02 |
NO327003B1 true NO327003B1 (no) | 2009-04-06 |
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NO20040557A NO327003B1 (no) | 2001-08-09 | 2004-02-06 | Diamin-derivater, medisinsk preparat omfattende slike, slike forbindelser for anvendelse som legemiddel samt anvendelse av disse for fremstilling av middel for forebygging og behandling av sykdom. |
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EP (1) | EP1415992B1 (pt) |
JP (1) | JP4331595B2 (pt) |
KR (1) | KR100908966B1 (pt) |
CN (1) | CN100545160C (pt) |
AT (1) | ATE556066T1 (pt) |
AU (1) | AU2002328596B2 (pt) |
BR (1) | BR0211565A (pt) |
CA (1) | CA2456841A1 (pt) |
ES (1) | ES2383749T3 (pt) |
HK (1) | HK1095814A1 (pt) |
IL (2) | IL160204A0 (pt) |
MX (1) | MXPA04001272A (pt) |
NO (1) | NO327003B1 (pt) |
PL (1) | PL368402A1 (pt) |
RU (1) | RU2314303C2 (pt) |
WO (1) | WO2003016302A1 (pt) |
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IL159438A0 (en) * | 2001-06-20 | 2004-06-01 | Daiichi Seiyaku Co | Diamine derivatives |
US7365205B2 (en) | 2001-06-20 | 2008-04-29 | Daiichi Sankyo Company, Limited | Diamine derivatives |
CA2511493A1 (en) * | 2002-12-25 | 2004-07-15 | Daiichi Pharmaceutical Co., Ltd. | Diamine derivatives |
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ES2679744T3 (es) | 2003-11-12 | 2018-08-30 | Daiichi Sankyo Company, Limited | Procedimiento para producir derivados de tiazol |
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ES2569398T3 (es) * | 2005-09-16 | 2016-05-10 | Daiichi Sankyo Company, Limited | Derivado de diamina ópticamente activo y proceso para producir el mismo |
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CN101421228B (zh) | 2006-03-31 | 2014-05-21 | 塞普拉柯公司 | 手性酰胺和胺的制备 |
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US7902252B2 (en) | 2007-01-18 | 2011-03-08 | Sepracor, Inc. | Inhibitors of D-amino acid oxidase |
CN104324015B (zh) | 2007-03-29 | 2018-08-28 | 第一三共株式会社 | 药物组合物 |
US8669291B2 (en) | 2007-05-31 | 2014-03-11 | Sunovion Pharmaceuticals Inc. | Phenyl substituted cycloalkylamines as monoamine reuptake inhibitors |
EP2368870A1 (en) | 2008-12-12 | 2011-09-28 | Daiichi Sankyo Company, Limited | Process for producing optically active carboxylic acid |
RU2464271C1 (ru) * | 2008-12-17 | 2012-10-20 | Дайити Санкио Компани, Лимитед | Способ получения производного диамина |
EP2383272A4 (en) | 2009-01-13 | 2012-07-25 | Daiichi Sankyo Co Ltd | INHIBITOR OF AN ACTIVE FACTOR OF BLOOD COAGULATION |
CN102348688B (zh) | 2009-03-10 | 2014-07-09 | 第一三共株式会社 | 用于制备二胺衍生物的方法 |
CN102348680B (zh) | 2009-03-13 | 2014-11-05 | 第一三共株式会社 | 用于制备光学活性二胺衍生物的方法 |
WO2010131663A1 (ja) * | 2009-05-15 | 2010-11-18 | 第一三共株式会社 | オキサミド誘導体 |
WO2010147169A1 (ja) | 2009-06-18 | 2010-12-23 | 第一三共株式会社 | 溶出性の改善された医薬組成物 |
WO2011059080A1 (ja) * | 2009-11-16 | 2011-05-19 | 第一三共株式会社 | 同位体置換されたジアミン誘導体 |
EP2540317A4 (en) | 2010-02-22 | 2014-04-16 | Daiichi Sankyo Co Ltd | SOLID PREPARATION WITH DELAYED RELEASE FOR ORAL ADMINISTRATION |
EP2540318B1 (en) | 2010-02-22 | 2018-10-24 | Daiichi Sankyo Company, Limited | Sustained-release solid preparation for oral use |
WO2011102506A1 (ja) | 2010-02-22 | 2011-08-25 | 第一三共株式会社 | 経口用徐放性固形製剤 |
BR112012023654B1 (pt) | 2010-03-19 | 2022-04-12 | Daiichi Sankyo Company, Limited | Método para produzir grânulos contendo agente anticoagulante e método para produzir uma composição farmacêutica contendo o dito agente |
WO2011115066A1 (ja) | 2010-03-19 | 2011-09-22 | 第一三共株式会社 | ジアミン誘導体の結晶およびその製造方法 |
WO2011149110A1 (en) | 2010-05-28 | 2011-12-01 | Daiichi Sankyo Company, Limited | Novel composition for the prevention and/or treatment of thromboembolism |
HUE031961T2 (en) | 2010-07-02 | 2017-09-28 | Daiichi Sankyo Co Ltd | A method for preparing an optically active salt of diamine derivative |
KR101848952B1 (ko) | 2010-08-04 | 2018-04-13 | 다이이찌 산쿄 가부시키가이샤 | 니트록시드 라디칼 화합물을 반응 촉매로 하는 신규 샌드마이어형 반응 성적체의 제조법 |
KR101940840B1 (ko) | 2011-08-10 | 2019-01-21 | 다이이찌 산쿄 가부시키가이샤 | 디아민 유도체 함유 의약 조성물 |
EP2893928B1 (en) | 2012-09-03 | 2018-10-24 | Daiichi Sankyo Company, Limited | Hydromorphone hydrochloride-containing oral sustained-release pharmaceutical composition |
TWI602803B (zh) | 2013-03-29 | 2017-10-21 | 第一三共股份有限公司 | 光學活性二胺衍生物之製造方法 |
KR20150138214A (ko) | 2013-03-29 | 2015-12-09 | 다이이찌 산쿄 가부시키가이샤 | (1s,4s,5s)-4-브로모-6-옥사비시클로[3.2.1]옥탄-7-온의 제조 방법 |
CN106459087B (zh) * | 2014-02-18 | 2019-04-09 | 第一三共株式会社 | 活化的凝血因子X (FXa)抑制剂的制备方法 |
JP2017210468A (ja) * | 2016-05-23 | 2017-11-30 | 宇部興産株式会社 | ヨードラクトン化合物の製造方法 |
JP6696474B2 (ja) * | 2016-06-24 | 2020-05-20 | 宇部興産株式会社 | オキサビシクロオクタン化合物の製造方法 |
CN106467475A (zh) * | 2016-08-29 | 2017-03-01 | 上海大学 | 邻位双叠氮化合物的制备方法 |
CN107573256B (zh) * | 2017-09-26 | 2020-02-21 | 安徽国星生物化学有限公司 | 一种对氯苯肼盐酸盐连续化生产方法及其装置 |
CN111138357B (zh) * | 2018-11-06 | 2022-11-04 | 天津药物研究院有限公司 | 2-氧代-1,2-二氢喹啉类衍生物、其制备方法及其在医药上的应用 |
CN111606827B (zh) * | 2020-06-23 | 2022-10-25 | 内蒙古京东药业有限公司 | 一种制备依度沙班手性胺中间体的方法 |
CN111763222B (zh) * | 2020-08-03 | 2021-05-25 | 珠海市海瑞德新材料科技有限公司 | 用于制备依度沙班游离碱的中间体及其制备方法和应用 |
WO2022129535A1 (en) | 2020-12-18 | 2022-06-23 | Krka, D.D., Novo Mesto | Edoxaban formulation containing no sugar alcohols |
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TWI288745B (en) * | 2000-04-05 | 2007-10-21 | Daiichi Seiyaku Co | Ethylenediamine derivatives |
IL159438A0 (en) * | 2001-06-20 | 2004-06-01 | Daiichi Seiyaku Co | Diamine derivatives |
US7365205B2 (en) * | 2001-06-20 | 2008-04-29 | Daiichi Sankyo Company, Limited | Diamine derivatives |
UA78232C2 (uk) * | 2001-09-21 | 2007-03-15 | Брістол-Майерс Сквібб Компані | Лактамвмісні сполуки та їх похідні як інгібітори фактора ха |
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2002
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- 2002-08-08 PL PL02368402A patent/PL368402A1/xx not_active Application Discontinuation
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- 2002-08-08 AU AU2002328596A patent/AU2002328596B2/en not_active Ceased
- 2002-08-08 BR BR0211565-4A patent/BR0211565A/pt not_active IP Right Cessation
- 2002-08-08 CA CA002456841A patent/CA2456841A1/en not_active Abandoned
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Also Published As
Publication number | Publication date |
---|---|
RU2004106625A (ru) | 2005-06-27 |
KR20040023720A (ko) | 2004-03-18 |
CN1894238A (zh) | 2007-01-10 |
WO2003016302A1 (fr) | 2003-02-27 |
EP1415992A1 (en) | 2004-05-06 |
IL160204A0 (en) | 2004-07-25 |
JPWO2003016302A1 (ja) | 2004-12-02 |
ATE556066T1 (de) | 2012-05-15 |
CN100545160C (zh) | 2009-09-30 |
BR0211565A (pt) | 2004-06-29 |
ES2383749T3 (es) | 2012-06-26 |
MXPA04001272A (es) | 2004-05-27 |
EP1415992B1 (en) | 2012-05-02 |
PL368402A1 (en) | 2005-03-21 |
RU2314303C2 (ru) | 2008-01-10 |
JP4331595B2 (ja) | 2009-09-16 |
KR100908966B1 (ko) | 2009-07-22 |
AU2002328596B2 (en) | 2007-09-20 |
IL160204A (en) | 2010-11-30 |
EP1415992A4 (en) | 2006-07-26 |
NO20040557L (no) | 2004-04-02 |
CA2456841A1 (en) | 2003-02-27 |
HK1095814A1 (en) | 2007-05-18 |
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