AU758642B2 - Sulfonic acid or sulfonylamino N-(heteroaralkyl)-azaheterocyclylamide compounds - Google Patents
Sulfonic acid or sulfonylamino N-(heteroaralkyl)-azaheterocyclylamide compounds Download PDFInfo
- Publication number
- AU758642B2 AU758642B2 AU43298/99A AU4329899A AU758642B2 AU 758642 B2 AU758642 B2 AU 758642B2 AU 43298/99 A AU43298/99 A AU 43298/99A AU 4329899 A AU4329899 A AU 4329899A AU 758642 B2 AU758642 B2 AU 758642B2
- Authority
- AU
- Australia
- Prior art keywords
- chloro
- ylmethyl
- sulfonic acid
- amide
- oxo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
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- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 title description 3
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 482
- 108010074860 Factor Xa Proteins 0.000 claims abstract description 23
- 230000000694 effects Effects 0.000 claims abstract description 15
- 238000011282 treatment Methods 0.000 claims abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 3
- 239000002253 acid Substances 0.000 claims description 183
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 160
- -1 4 -Aminoquinolin-7-ylmethyl Chemical group 0.000 claims description 156
- CKARHIGQRRNVFD-UHFFFAOYSA-N 7-methoxynaphthalene-2-sulfonic acid Chemical compound C1=CC(S(O)(=O)=O)=CC2=CC(OC)=CC=C21 CKARHIGQRRNVFD-UHFFFAOYSA-N 0.000 claims description 95
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 76
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 73
- 229910052757 nitrogen Inorganic materials 0.000 claims description 73
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 71
- 229910052739 hydrogen Inorganic materials 0.000 claims description 67
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 66
- 238000000034 method Methods 0.000 claims description 66
- 125000000217 alkyl group Chemical group 0.000 claims description 46
- 150000001408 amides Chemical class 0.000 claims description 42
- 150000003839 salts Chemical class 0.000 claims description 41
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 39
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 38
- 125000001072 heteroaryl group Chemical group 0.000 claims description 38
- 239000001257 hydrogen Substances 0.000 claims description 31
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 29
- 229910052760 oxygen Inorganic materials 0.000 claims description 27
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 24
- 125000000623 heterocyclic group Chemical group 0.000 claims description 19
- BSXLLFUSNQCWJP-UHFFFAOYSA-N thiophene-2-sulfonic acid Chemical compound OS(=O)(=O)C1=CC=CS1 BSXLLFUSNQCWJP-UHFFFAOYSA-N 0.000 claims description 18
- 230000015572 biosynthetic process Effects 0.000 claims description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 14
- 125000003107 substituted aryl group Chemical group 0.000 claims description 14
- 229910052717 sulfur Inorganic materials 0.000 claims description 14
- ZYDGKFWFDVZKMG-UHFFFAOYSA-N 6-chloro-1-benzothiophene-2-sulfonic acid Chemical compound C1=C(Cl)C=C2SC(S(=O)(=O)O)=CC2=C1 ZYDGKFWFDVZKMG-UHFFFAOYSA-N 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 125000006514 pyridin-2-ylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 13
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 12
- 208000007536 Thrombosis Diseases 0.000 claims description 12
- 239000003146 anticoagulant agent Substances 0.000 claims description 12
- 238000002560 therapeutic procedure Methods 0.000 claims description 12
- KTVOMLQUDMNZLK-UHFFFAOYSA-N 1-benzothiophene-2-sulfonic acid Chemical compound C1=CC=C2SC(S(=O)(=O)O)=CC2=C1 KTVOMLQUDMNZLK-UHFFFAOYSA-N 0.000 claims description 11
- 125000002252 acyl group Chemical group 0.000 claims description 11
- UVLKAUNUFWQFID-UHFFFAOYSA-N thieno[3,2-b]pyridine-2-sulfonic acid Chemical compound C1=CC=C2SC(S(=O)(=O)O)=CC2=N1 UVLKAUNUFWQFID-UHFFFAOYSA-N 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 9
- XETFBTXVGCQYBD-UHFFFAOYSA-N methanamine;2,2,2-trifluoroacetic acid Chemical compound [NH3+]C.[O-]C(=O)C(F)(F)F XETFBTXVGCQYBD-UHFFFAOYSA-N 0.000 claims description 9
- ZMULFNPBBJBUSJ-UHFFFAOYSA-N 2-(5-chlorothiophen-2-yl)ethenesulfonic acid Chemical compound OS(=O)(=O)C=CC1=CC=C(Cl)S1 ZMULFNPBBJBUSJ-UHFFFAOYSA-N 0.000 claims description 8
- 206010000891 acute myocardial infarction Diseases 0.000 claims description 8
- 230000002792 vascular Effects 0.000 claims description 8
- 230000001154 acute effect Effects 0.000 claims description 7
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 208000035475 disorder Diseases 0.000 claims description 7
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- 206010002388 Angina unstable Diseases 0.000 claims description 6
- 206010053567 Coagulopathies Diseases 0.000 claims description 6
- 208000005189 Embolism Diseases 0.000 claims description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 6
- 208000010378 Pulmonary Embolism Diseases 0.000 claims description 6
- 206010040070 Septic Shock Diseases 0.000 claims description 6
- 208000006011 Stroke Diseases 0.000 claims description 6
- 208000001435 Thromboembolism Diseases 0.000 claims description 6
- 208000032109 Transient ischaemic attack Diseases 0.000 claims description 6
- 208000007814 Unstable Angina Diseases 0.000 claims description 6
- 208000036142 Viral infection Diseases 0.000 claims description 6
- 230000003187 abdominal effect Effects 0.000 claims description 6
- 230000002159 abnormal effect Effects 0.000 claims description 6
- 208000015294 blood coagulation disease Diseases 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 6
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 6
- 201000004332 intermediate coronary syndrome Diseases 0.000 claims description 6
- 210000003127 knee Anatomy 0.000 claims description 6
- 210000003141 lower extremity Anatomy 0.000 claims description 6
- MGJXBDMLVWIYOQ-UHFFFAOYSA-N methylazanide Chemical compound [NH-]C MGJXBDMLVWIYOQ-UHFFFAOYSA-N 0.000 claims description 6
- 230000001575 pathological effect Effects 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 230000036303 septic shock Effects 0.000 claims description 6
- 238000001356 surgical procedure Methods 0.000 claims description 6
- 230000009885 systemic effect Effects 0.000 claims description 6
- GKTQKQTXHNUFSP-UHFFFAOYSA-N thieno[3,4-c]pyrrole-4,6-dione Chemical compound S1C=C2C(=O)NC(=O)C2=C1 GKTQKQTXHNUFSP-UHFFFAOYSA-N 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- 230000002537 thrombolytic effect Effects 0.000 claims description 6
- 201000010875 transient cerebral ischemia Diseases 0.000 claims description 6
- 210000003462 vein Anatomy 0.000 claims description 6
- 230000009385 viral infection Effects 0.000 claims description 6
- VSODCVYZGJLESS-UHFFFAOYSA-N 4-pyridin-3-ylthiophene-2-sulfonic acid Chemical compound S1C(S(=O)(=O)O)=CC(C=2C=NC=CC=2)=C1 VSODCVYZGJLESS-UHFFFAOYSA-N 0.000 claims description 5
- 150000001204 N-oxides Chemical class 0.000 claims description 5
- 238000007887 coronary angioplasty Methods 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 5
- 229910052721 tungsten Inorganic materials 0.000 claims description 5
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 4
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 4
- 125000002619 bicyclic group Chemical group 0.000 claims description 4
- 208000037803 restenosis Diseases 0.000 claims description 4
- WAAUNYAKSXNLAY-UHFFFAOYSA-N 5-(5-chlorothiophen-2-yl)thiophene-2-sulfonic acid Chemical compound S1C(S(=O)(=O)O)=CC=C1C1=CC=C(Cl)S1 WAAUNYAKSXNLAY-UHFFFAOYSA-N 0.000 claims description 3
- AVRWEULSKHQETA-UHFFFAOYSA-N Thiophene-2 Chemical compound S1C=2CCCCCC=2C(C(=O)OC)=C1NC(=O)C1=C(F)C(F)=C(F)C(F)=C1F AVRWEULSKHQETA-UHFFFAOYSA-N 0.000 claims description 3
- 125000005466 alkylenyl group Chemical group 0.000 claims description 3
- 150000004702 methyl esters Chemical class 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000001475 halogen functional group Chemical group 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- OFSAAVMLXZHAJH-UHFFFAOYSA-N thieno[2,3-b]pyridine-2-sulfonic acid Chemical compound C1=CN=C2SC(S(=O)(=O)O)=CC2=C1 OFSAAVMLXZHAJH-UHFFFAOYSA-N 0.000 claims description 2
- NLVXSWCKKBEXTG-UHFFFAOYSA-N vinylsulfonic acid Chemical compound OS(=O)(=O)C=C NLVXSWCKKBEXTG-UHFFFAOYSA-N 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims 4
- 238000007891 venous angioplasty Methods 0.000 claims 2
- JGWFEHAQHDBHPP-JTQLQIEISA-N (3S)-3-amino-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pyrrolidin-2-one Chemical compound O=C1[C@@H](N)CCN1CC1=CC2=CN=CC=C2N1 JGWFEHAQHDBHPP-JTQLQIEISA-N 0.000 claims 1
- MSIJDNCRQCIIQR-UHFFFAOYSA-N 3-amino-1-[(4-aminoquinolin-7-yl)methyl]pyrrolidin-2-one Chemical compound O=C1C(N)CCN1CC1=CC=C(C(N)=CC=N2)C2=C1 MSIJDNCRQCIIQR-UHFFFAOYSA-N 0.000 claims 1
- QQZUUXAVSNVPTM-UHFFFAOYSA-N 5-chloro-1-benzothiophene-2-sulfonic acid Chemical compound ClC1=CC=C2SC(S(=O)(=O)O)=CC2=C1 QQZUUXAVSNVPTM-UHFFFAOYSA-N 0.000 claims 1
- WFPXVTGXHWCEQC-JIDHJSLPSA-N 7-methoxy-n-[(3s)-1-[(6-methoxyisoquinolin-7-yl)methyl]-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.N1=CC=C2C=C(OC)C(CN3CC[C@@H](C3=O)NS(=O)(=O)C=3C=CC4=CC=C(C=C4C=3)OC)=CC2=C1 WFPXVTGXHWCEQC-JIDHJSLPSA-N 0.000 claims 1
- NILZATXCXQXFCW-UHFFFAOYSA-N O=C1N(C=CC1)CCNC1=CC=NC=C1 Chemical compound O=C1N(C=CC1)CCNC1=CC=NC=C1 NILZATXCXQXFCW-UHFFFAOYSA-N 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 claims 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropyl acetate Chemical compound CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims 1
- MMPKCFIXJKMLPC-FTBISJDPSA-N n-[(3s)-1-[(2-aminoquinolin-7-yl)methyl]-2-oxopyrrolidin-3-yl]-7-methoxynaphthalene-2-sulfonamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1=CC(N)=NC2=CC(CN3CC[C@@H](C3=O)NS(=O)(=O)C=3C=CC4=CC=C(C=C4C=3)OC)=CC=C21 MMPKCFIXJKMLPC-FTBISJDPSA-N 0.000 claims 1
- 238000010577 post-coronary angioplasty Methods 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 108
- 239000003112 inhibitor Substances 0.000 abstract description 6
- 230000001668 ameliorated effect Effects 0.000 abstract description 2
- 230000000144 pharmacologic effect Effects 0.000 abstract description 2
- 230000004962 physiological condition Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 351
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 303
- 239000000243 solution Substances 0.000 description 294
- 229910052740 iodine Inorganic materials 0.000 description 254
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 248
- 239000007787 solid Substances 0.000 description 226
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 171
- 235000019439 ethyl acetate Nutrition 0.000 description 162
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 147
- 239000000047 product Substances 0.000 description 142
- 239000012043 crude product Substances 0.000 description 123
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 123
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 121
- 238000004440 column chromatography Methods 0.000 description 105
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 98
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 94
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 76
- 239000012044 organic layer Substances 0.000 description 76
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 72
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 70
- 239000000460 chlorine Substances 0.000 description 68
- 229920006395 saturated elastomer Polymers 0.000 description 65
- 239000011541 reaction mixture Substances 0.000 description 61
- 239000007858 starting material Substances 0.000 description 56
- 238000004007 reversed phase HPLC Methods 0.000 description 55
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 53
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 52
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 51
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 51
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 50
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 41
- 239000012267 brine Substances 0.000 description 30
- 239000010410 layer Substances 0.000 description 30
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 27
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 27
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 26
- 125000003118 aryl group Chemical group 0.000 description 25
- 150000002500 ions Chemical class 0.000 description 25
- 239000007921 spray Substances 0.000 description 25
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 24
- 238000000746 purification Methods 0.000 description 24
- 238000010992 reflux Methods 0.000 description 24
- 238000005160 1H NMR spectroscopy Methods 0.000 description 23
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 23
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
- 239000000843 powder Substances 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 21
- 238000003756 stirring Methods 0.000 description 21
- 229940086542 triethylamine Drugs 0.000 description 21
- 125000005843 halogen group Chemical group 0.000 description 20
- 239000003921 oil Substances 0.000 description 20
- 235000019198 oils Nutrition 0.000 description 20
- 125000001309 chloro group Chemical group Cl* 0.000 description 19
- 239000000706 filtrate Substances 0.000 description 19
- 239000002904 solvent Substances 0.000 description 19
- 239000002585 base Substances 0.000 description 18
- 238000000921 elemental analysis Methods 0.000 description 18
- 150000002431 hydrogen Chemical class 0.000 description 18
- 239000007864 aqueous solution Substances 0.000 description 16
- 238000010828 elution Methods 0.000 description 16
- 239000000463 material Substances 0.000 description 16
- 229910000104 sodium hydride Inorganic materials 0.000 description 16
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 15
- 235000011054 acetic acid Nutrition 0.000 description 15
- 239000012312 sodium hydride Substances 0.000 description 15
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 14
- 239000000543 intermediate Substances 0.000 description 14
- 125000003342 alkenyl group Chemical group 0.000 description 13
- 125000001246 bromo group Chemical group Br* 0.000 description 13
- 238000010626 work up procedure Methods 0.000 description 13
- ZEXCZHWVXMIOFB-UHFFFAOYSA-N 7-methoxynaphthalene-2-sulfonyl chloride Chemical compound C1=CC(S(Cl)(=O)=O)=CC2=CC(OC)=CC=C21 ZEXCZHWVXMIOFB-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 125000004104 aryloxy group Chemical group 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 12
- 239000012458 free base Substances 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 11
- 239000005695 Ammonium acetate Substances 0.000 description 11
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 11
- 235000019257 ammonium acetate Nutrition 0.000 description 11
- 229940043376 ammonium acetate Drugs 0.000 description 11
- 239000002244 precipitate Substances 0.000 description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- FNKLGGIAXFTGTF-UHFFFAOYSA-N methyl acetate;2,2,2-trifluoroacetic acid Chemical compound COC(C)=O.OC(=O)C(F)(F)F FNKLGGIAXFTGTF-UHFFFAOYSA-N 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- 239000000377 silicon dioxide Substances 0.000 description 10
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 239000003960 organic solvent Substances 0.000 description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 125000004122 cyclic group Chemical group 0.000 description 8
- 239000006260 foam Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000011347 resin Substances 0.000 description 8
- 229920005989 resin Polymers 0.000 description 8
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- 239000002808 molecular sieve Substances 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- GCRNRKBKZTYKTG-UHFFFAOYSA-N n-(1-chloro-7-methylisoquinolin-6-yl)-1,1-diphenylmethanimine Chemical compound CC1=CC2=C(Cl)N=CC=C2C=C1N=C(C=1C=CC=CC=1)C1=CC=CC=C1 GCRNRKBKZTYKTG-UHFFFAOYSA-N 0.000 description 1
- ZXYUIFVPXYYAAW-UHFFFAOYSA-N n-(5-formyl-2-methylphenyl)acetamide Chemical compound CC(=O)NC1=CC(C=O)=CC=C1C ZXYUIFVPXYYAAW-UHFFFAOYSA-N 0.000 description 1
- UHIDEBGCLBNILN-UHFFFAOYSA-N n-(7-methyl-1-oxo-2h-isoquinolin-6-yl)acetamide Chemical compound C1=CNC(=O)C2=C1C=C(NC(=O)C)C(C)=C2 UHIDEBGCLBNILN-UHFFFAOYSA-N 0.000 description 1
- BZEWBQBOIMODSF-KRWDZBQOSA-N n-[(3s)-1-[(1-chloroisoquinolin-7-yl)methyl]-2-oxopyrrolidin-3-yl]-2-(5-chlorothiophen-2-yl)ethenesulfonamide Chemical compound S1C(Cl)=CC=C1C=CS(=O)(=O)N[C@@H]1C(=O)N(CC=2C=C3C(Cl)=NC=CC3=CC=2)CC1 BZEWBQBOIMODSF-KRWDZBQOSA-N 0.000 description 1
- GCMGYPBAYJUMGE-QFIPXVFZSA-N n-[(3s)-1-[(2-chloroquinolin-7-yl)methyl]-2-oxopyrrolidin-3-yl]-7-methoxynaphthalene-2-sulfonamide Chemical compound C1=CC(Cl)=NC2=CC(CN3CC[C@@H](C3=O)NS(=O)(=O)C=3C=CC4=CC=C(C=C4C=3)OC)=CC=C21 GCMGYPBAYJUMGE-QFIPXVFZSA-N 0.000 description 1
- CQCNXBKXGYFOAA-NRFANRHFSA-N n-[(3s)-1-[(3,4-diaminophenyl)methyl]-2-oxopyrrolidin-3-yl]-7-methoxynaphthalene-2-sulfonamide Chemical compound C([C@@H](C1=O)NS(=O)(=O)C=2C=CC3=CC=C(C=C3C=2)OC)CN1CC1=CC=C(N)C(N)=C1 CQCNXBKXGYFOAA-NRFANRHFSA-N 0.000 description 1
- FCXRLMLQWKVYHB-NSHDSACASA-N n-[(3s)-1-[(4-acetamido-3-nitrophenyl)methyl]-2-oxopyrrolidin-3-yl]-2,2,2-trifluoroacetamide Chemical compound C1=C([N+]([O-])=O)C(NC(=O)C)=CC=C1CN1C(=O)[C@@H](NC(=O)C(F)(F)F)CC1 FCXRLMLQWKVYHB-NSHDSACASA-N 0.000 description 1
- AJSROYFPIKTAMT-LBPRGKRZSA-N n-[(3s)-1-[(4-acetamidophenyl)methyl]-2-oxopyrrolidin-3-yl]-2,2,2-trifluoroacetamide Chemical compound C1=CC(NC(=O)C)=CC=C1CN1C(=O)[C@@H](NC(=O)C(F)(F)F)CC1 AJSROYFPIKTAMT-LBPRGKRZSA-N 0.000 description 1
- MSNIVFOQWJYUME-FQEVSTJZSA-N n-[(3s)-1-[(4-amino-3-nitrophenyl)methyl]-2-oxopyrrolidin-3-yl]-7-methoxynaphthalene-2-sulfonamide Chemical compound C([C@@H](C1=O)NS(=O)(=O)C=2C=CC3=CC=C(C=C3C=2)OC)CN1CC1=CC=C(N)C([N+]([O-])=O)=C1 MSNIVFOQWJYUME-FQEVSTJZSA-N 0.000 description 1
- GBBXMLBCKLWXCT-IBGZPJMESA-N n-[(3s)-1-[(4-chlorothieno[3,2-c]pyridin-3-yl)methyl]-2-oxopyrrolidin-3-yl]-7-methoxynaphthalene-2-sulfonamide Chemical group C1=NC(Cl)=C2C(CN3CC[C@@H](C3=O)NS(=O)(=O)C=3C=CC4=CC=C(C=C4C=3)OC)=CSC2=C1 GBBXMLBCKLWXCT-IBGZPJMESA-N 0.000 description 1
- XQYHQVFBDDWDCG-UHFFFAOYSA-N n-[1-[(1-aminoisoquinolin-7-yl)methyl]-2-oxopyrrolidin-3-yl]-7-methoxynaphthalene-2-sulfonamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1=CN=C(N)C2=CC(CN3CCC(C3=O)NS(=O)(=O)C=3C=CC4=CC=C(C=C4C=3)OC)=CC=C21 XQYHQVFBDDWDCG-UHFFFAOYSA-N 0.000 description 1
- RBEDYBJZPKTQSA-UHFFFAOYSA-N n-[7-(bromomethyl)-1-chloroisoquinolin-6-yl]-1,1-diphenylmethanimine Chemical compound BrCC=1C=C2C(Cl)=NC=CC2=CC=1N=C(C=1C=CC=CC=1)C1=CC=CC=C1 RBEDYBJZPKTQSA-UHFFFAOYSA-N 0.000 description 1
- VPPRYJIONRCDTN-BDQAORGHSA-N n-[[(3s)-1-[(2-aminoquinolin-7-yl)methyl]-2-oxopyrrolidin-3-yl]methyl]-7-methoxynaphthalene-2-sulfonamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1=CC(N)=NC2=CC(CN3CC[C@H](C3=O)CNS(=O)(=O)C=3C=CC4=CC=C(C=C4C=3)OC)=CC=C21 VPPRYJIONRCDTN-BDQAORGHSA-N 0.000 description 1
- QVIHSSLMKIHKCE-SFHVURJKSA-N n-[[(3s)-1-[(2-chloroquinolin-5-yl)methyl]-2-oxopyrrolidin-3-yl]methyl]-7-methoxynaphthalene-2-sulfonamide Chemical compound ClC1=CC=C2C(CN3CC[C@H](C3=O)CNS(=O)(=O)C=3C=CC4=CC=C(C=C4C=3)OC)=CC=CC2=N1 QVIHSSLMKIHKCE-SFHVURJKSA-N 0.000 description 1
- 125000004370 n-butenyl group Chemical group [H]\C([H])=C(/[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005029 naphthylthio group Chemical group C1(=CC=CC2=CC=CC=C12)S* 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000006501 nitrophenyl group Chemical group 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 210000004789 organ system Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000005470 propylenyl group Chemical group 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- JQJOGAGLBDBMLU-UHFFFAOYSA-N pyridine-2-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=N1 JQJOGAGLBDBMLU-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- ZHNFLHYOFXQIOW-LPYZJUEESA-N quinine sulfate dihydrate Chemical compound [H+].[H+].O.O.[O-]S([O-])(=O)=O.C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21.C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 ZHNFLHYOFXQIOW-LPYZJUEESA-N 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 229910052702 rhenium Inorganic materials 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 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
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 229910052712 strontium Inorganic materials 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- XQQGXECPOLAACV-SFHVURJKSA-N tert-butyl 2-[[(3s)-3-[2-(5-chlorothiophen-2-yl)ethenylsulfonylamino]-2-oxopyrrolidin-1-yl]methyl]pyrrolo[3,2-c]pyridine-1-carboxylate Chemical compound N([C@H]1CCN(C1=O)CC=1N(C2=CC=NC=C2C=1)C(=O)OC(C)(C)C)S(=O)(=O)C=CC1=CC=C(Cl)S1 XQQGXECPOLAACV-SFHVURJKSA-N 0.000 description 1
- DOVFDMZDTSEESI-LBPRGKRZSA-N tert-butyl 2-[[(3s)-3-amino-2-oxopyrrolidin-1-yl]methyl]pyrrolo[3,2-b]pyridine-1-carboxylate Chemical compound C=1C2=NC=CC=C2N(C(=O)OC(C)(C)C)C=1CN1CC[C@H](N)C1=O DOVFDMZDTSEESI-LBPRGKRZSA-N 0.000 description 1
- UYQIXRBZGZLUAM-UHFFFAOYSA-N tert-butyl acetate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CC(=O)OC(C)(C)C UYQIXRBZGZLUAM-UHFFFAOYSA-N 0.000 description 1
- LUIWGLXCCZGKLA-ZDUSSCGKSA-N tert-butyl n-[(3s)-1-[(4-nitrophenyl)methyl]-2-oxopyrrolidin-3-yl]carbamate Chemical compound O=C1[C@@H](NC(=O)OC(C)(C)C)CCN1CC1=CC=C([N+]([O-])=O)C=C1 LUIWGLXCCZGKLA-ZDUSSCGKSA-N 0.000 description 1
- HTDXRDQUBBPYOZ-VIFPVBQESA-N tert-butyl n-[(3s)-2-oxo-1-prop-2-ynylpyrrolidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]1CCN(CC#C)C1=O HTDXRDQUBBPYOZ-VIFPVBQESA-N 0.000 description 1
- BIWPVUOWUMPXFZ-UHFFFAOYSA-N tert-butyl n-[1-(2-aminoethyl)-2-oxopyrrolidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC1CCN(CCN)C1=O BIWPVUOWUMPXFZ-UHFFFAOYSA-N 0.000 description 1
- WKHGDPZRLXDVMJ-UHFFFAOYSA-N tert-butyl n-pyridin-3-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CN=C1 WKHGDPZRLXDVMJ-UHFFFAOYSA-N 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000005302 thiazolylmethyl group Chemical group [H]C1=C([H])N=C(S1)C([H])([H])* 0.000 description 1
- KMEBXCPJAWYXAP-UHFFFAOYSA-N thieno[2,3-b]pyridine-2-sulfonyl chloride Chemical compound C1=CN=C2SC(S(=O)(=O)Cl)=CC2=C1 KMEBXCPJAWYXAP-UHFFFAOYSA-N 0.000 description 1
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 description 1
- KHXSHOAPGUCQLC-UHFFFAOYSA-N thieno[3,2-b]pyridine-2-sulfonyl chloride Chemical compound C1=CC=C2SC(S(=O)(=O)Cl)=CC2=N1 KHXSHOAPGUCQLC-UHFFFAOYSA-N 0.000 description 1
- 125000005297 thienyloxy group Chemical group S1C(=CC=C1)O* 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- VNNLHYZDXIBHKZ-UHFFFAOYSA-N thiophene-2-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CS1 VNNLHYZDXIBHKZ-UHFFFAOYSA-N 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
- 229910021511 zinc hydroxide Inorganic materials 0.000 description 1
- 229940007718 zinc hydroxide Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- 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
-
- 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
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- 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
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- C07D401/06—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 carbon chain containing only aliphatic carbon atoms
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- 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
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- 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
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- C—CHEMISTRY; METALLURGY
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
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- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
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- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
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- Vascular Medicine (AREA)
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- Communicable Diseases (AREA)
- Oncology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Virology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US09/090492 | 1998-06-03 | ||
| US09/090,492 US6602864B1 (en) | 1996-12-13 | 1998-06-03 | Sulfonic acid or sulfonylamino N-(heteroaralkyl)-azaheterocyclylamide compounds |
| PCT/US1999/012312 WO1999062904A1 (en) | 1998-06-03 | 1999-06-03 | Sulfonic acid or sulfonylamino n-(heteroaralkyl)-azaheterocyclylamide compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU4329899A AU4329899A (en) | 1999-12-20 |
| AU758642B2 true AU758642B2 (en) | 2003-03-27 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU43298/99A Ceased AU758642B2 (en) | 1998-06-03 | 1999-06-03 | Sulfonic acid or sulfonylamino N-(heteroaralkyl)-azaheterocyclylamide compounds |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US6602864B1 (https=) |
| EP (1) | EP1086099B1 (https=) |
| JP (1) | JP4504564B2 (https=) |
| KR (1) | KR20010052501A (https=) |
| AT (1) | ATE305469T1 (https=) |
| AU (1) | AU758642B2 (https=) |
| BR (1) | BR9910899A (https=) |
| CA (1) | CA2333994A1 (https=) |
| DE (1) | DE69927497T2 (https=) |
| ES (1) | ES2246582T3 (https=) |
| NO (1) | NO20005912L (https=) |
| WO (1) | WO1999062904A1 (https=) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US6281227B1 (en) * | 1996-12-13 | 2001-08-28 | Aventis Pharma Deutschland Gmbh | Sulfonic acid sulfonylamino n-(heteroaralkyl)-azaheterocyclylamide compounds |
| AU753675B2 (en) | 1998-03-19 | 2002-10-24 | Ajinomoto Co., Inc. | Aminoisoquinoline derivatives |
| JP2001294572A (ja) * | 2000-02-09 | 2001-10-23 | Dai Ichi Seiyaku Co Ltd | 新規スルホニル誘導体 |
| US6506754B1 (en) * | 2000-04-14 | 2003-01-14 | Corvas International, Inc. | Non-covalent thrombin inhibitors |
| US7229986B2 (en) | 2000-05-16 | 2007-06-12 | Takeda Pharmaceutical Company Ltd. | Melanin-concentrating hormone antagonist |
| WO2002080853A2 (en) | 2001-04-09 | 2002-10-17 | Bristol-Myers Squibb Company | Fused heterocyclic inhibitors of factor xa |
| GB0114005D0 (en) | 2001-06-08 | 2001-08-01 | Glaxo Group Ltd | Chemical compounds |
| GB0114004D0 (en) | 2001-06-08 | 2001-08-01 | Glaxo Group Ltd | Chemical compounds |
| GB0127568D0 (en) * | 2001-11-16 | 2002-01-09 | Glaxo Group Ltd | Chemical compounds |
| AU2003302238A1 (en) | 2002-12-03 | 2004-06-23 | Axys Pharmaceuticals, Inc. | 2-(2-hydroxybiphenyl-3-yl)-1h-benzoimidazole-5-carboxamidine derivatives as factor viia inhibitors |
| GB0228552D0 (en) * | 2002-12-06 | 2003-01-15 | Glaxo Group Ltd | Chemical compounds |
| GB0228533D0 (en) * | 2002-12-06 | 2003-01-15 | Glaxo Group Ltd | Crystalline form |
| US7338975B2 (en) | 2003-02-12 | 2008-03-04 | Bristol-Myers Squibb Co. | Lactams as modulators of chemokine receptor activity |
| JP2008509222A (ja) * | 2004-08-09 | 2008-03-27 | グラクソ グループ リミテッド | 抗菌剤 |
| US7511035B2 (en) | 2005-01-25 | 2009-03-31 | Glaxo Group Limited | Antibacterial agents |
| EP1932839A4 (en) * | 2005-09-06 | 2014-09-10 | Shionogi & Co | INDOLECARBOXYLATE ACID DERIVATIVE HAVING ANTAGONIST EFFECT OF THE PGD2 RECEPTOR |
| US20100260751A1 (en) | 2007-09-28 | 2010-10-14 | Raju T Shantha | Methods and Structural Conformations of Antibody Preparations with Increased Resistance to Proteases |
| ES2622102T3 (es) | 2009-10-29 | 2017-07-05 | Janssen Biotech, Inc. | Variantes de anticuerpo de glicosilación |
| EP2606893A1 (en) | 2011-12-21 | 2013-06-26 | Sanofi | Sulphonylaminopyrrolidinone derivatives, their preparation and their therapeutic application |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5130323A (en) * | 1988-10-31 | 1992-07-14 | Fujisawa Pharmaceutical Co., Ltd. | Pyrrolidine derivatives |
| DE4121947A1 (de) * | 1991-07-03 | 1993-01-07 | Basf Ag | 2-(3-(4-amidino-phenyl))-propionsaeurederivate, ihre herstellung und verwendung |
| US5731315A (en) * | 1995-06-07 | 1998-03-24 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Substituted sulfonic acid n- (aminoiminomethyl)phenylalkyl!-azaheterocyclamide compounds |
| US5612353A (en) * | 1995-06-07 | 1997-03-18 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Substituted (sulfinic acid, sulfonic acid, sulfonylamino or sulfinylamino) N-[(aminoiminomethyl)phenylalkyl]-azaheterocyclylamide compounds |
| CN1079396C (zh) * | 1996-05-31 | 2002-02-20 | C&C新药研究所 | 用作选择性凝血酶抑制剂的芳族脒衍生物 |
| DE69718194T2 (de) * | 1996-08-16 | 2003-10-16 | Bristol-Myers Squibb Pharma Co., Wilmington | Amidinophenyl-pyrrolidine, -pyrroline und -isoxazolidine und ihre derivate |
| IL130152A0 (en) * | 1996-12-13 | 2000-06-01 | Rhone Poulenc Rorer Pharma | Sulfonic acid or sulfonylamino N-(heteroaralkyl)-azaheterocyclyamide compounds |
| US6281227B1 (en) * | 1996-12-13 | 2001-08-28 | Aventis Pharma Deutschland Gmbh | Sulfonic acid sulfonylamino n-(heteroaralkyl)-azaheterocyclylamide compounds |
| IL123986A (en) * | 1997-04-24 | 2011-10-31 | Organon Nv | Medicinal compounds |
-
1998
- 1998-06-03 US US09/090,492 patent/US6602864B1/en not_active Expired - Fee Related
-
1999
- 1999-06-03 WO PCT/US1999/012312 patent/WO1999062904A1/en not_active Ceased
- 1999-06-03 DE DE69927497T patent/DE69927497T2/de not_active Expired - Lifetime
- 1999-06-03 EP EP99955266A patent/EP1086099B1/en not_active Expired - Lifetime
- 1999-06-03 KR KR1020007013635A patent/KR20010052501A/ko not_active Withdrawn
- 1999-06-03 JP JP2000552115A patent/JP4504564B2/ja not_active Expired - Fee Related
- 1999-06-03 AT AT99955266T patent/ATE305469T1/de not_active IP Right Cessation
- 1999-06-03 CA CA002333994A patent/CA2333994A1/en not_active Abandoned
- 1999-06-03 ES ES99955266T patent/ES2246582T3/es not_active Expired - Lifetime
- 1999-06-03 BR BR9910899-2A patent/BR9910899A/pt not_active IP Right Cessation
- 1999-06-03 AU AU43298/99A patent/AU758642B2/en not_active Ceased
-
2000
- 2000-11-22 NO NO20005912A patent/NO20005912L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| AU4329899A (en) | 1999-12-20 |
| ES2246582T3 (es) | 2006-02-16 |
| NO20005912L (no) | 2001-01-31 |
| CA2333994A1 (en) | 1999-12-09 |
| BR9910899A (pt) | 2001-10-09 |
| KR20010052501A (ko) | 2001-06-25 |
| ATE305469T1 (de) | 2005-10-15 |
| DE69927497D1 (de) | 2006-02-09 |
| NO20005912D0 (no) | 2000-11-22 |
| US6602864B1 (en) | 2003-08-05 |
| EP1086099B1 (en) | 2005-09-28 |
| WO1999062904A1 (en) | 1999-12-09 |
| JP2002517393A (ja) | 2002-06-18 |
| JP4504564B2 (ja) | 2010-07-14 |
| EP1086099A1 (en) | 2001-03-28 |
| EP1086099A4 (en) | 2002-01-02 |
| DE69927497T2 (de) | 2006-06-29 |
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| TC | Change of applicant's name (sec. 104) |
Owner name: AVENTIS PHARMACEUTICALS INC. Free format text: FORMER NAME: AVENTIS PHARMACEUTICALS PRODUCTS INC. |
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| FGA | Letters patent sealed or granted (standard patent) |