TWI380973B - 化合物 - Google Patents
化合物 Download PDFInfo
- Publication number
- TWI380973B TWI380973B TW095123240A TW95123240A TWI380973B TW I380973 B TWI380973 B TW I380973B TW 095123240 A TW095123240 A TW 095123240A TW 95123240 A TW95123240 A TW 95123240A TW I380973 B TWI380973 B TW I380973B
- Authority
- TW
- Taiwan
- Prior art keywords
- piperidinyl
- methyl
- ethylsulfonyl
- indole
- carboxamide
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 385
- 150000003839 salts Chemical class 0.000 claims description 41
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 27
- 239000008194 pharmaceutical composition Substances 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 17
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 14
- 208000006673 asthma Diseases 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 5
- IYYCUXXSVNEQKZ-UHFFFAOYSA-N 3-(1-ethylsulfonylpiperidin-4-yl)-5-(2-propan-2-yl-1,3-dihydroisoindol-5-yl)-1h-indole-7-carboxamide Chemical compound C1CN(S(=O)(=O)CC)CCC1C1=CNC2=C(C(N)=O)C=C(C=3C=C4CN(CC4=CC=3)C(C)C)C=C12 IYYCUXXSVNEQKZ-UHFFFAOYSA-N 0.000 claims 3
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims 1
- 238000013160 medical therapy Methods 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 382
- -1 1,2,3,4-tetrahydronaphthyl Chemical group 0.000 description 345
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 305
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 222
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 200
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 198
- 239000000243 solution Substances 0.000 description 198
- 238000006243 chemical reaction Methods 0.000 description 174
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 173
- 235000019439 ethyl acetate Nutrition 0.000 description 148
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 138
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 135
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 123
- 239000000203 mixture Substances 0.000 description 122
- 238000000034 method Methods 0.000 description 115
- 239000012043 crude product Substances 0.000 description 101
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 98
- 239000011541 reaction mixture Substances 0.000 description 93
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 81
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 76
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 73
- 229960000583 acetic acid Drugs 0.000 description 64
- 235000011054 acetic acid Nutrition 0.000 description 64
- 230000014759 maintenance of location Effects 0.000 description 61
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 59
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 58
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 54
- 239000002904 solvent Substances 0.000 description 53
- 125000001424 substituent group Chemical group 0.000 description 53
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 50
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 48
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 46
- 125000001072 heteroaryl group Chemical group 0.000 description 45
- 239000006196 drop Substances 0.000 description 44
- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 42
- 102100021854 Inhibitor of nuclear factor kappa-B kinase subunit beta Human genes 0.000 description 41
- 101710205525 Inhibitor of nuclear factor kappa-B kinase subunit beta Proteins 0.000 description 41
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 41
- 239000011734 sodium Substances 0.000 description 39
- 229910000027 potassium carbonate Inorganic materials 0.000 description 37
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 36
- 238000002953 preparative HPLC Methods 0.000 description 36
- 229940083542 sodium Drugs 0.000 description 36
- 229910052708 sodium Inorganic materials 0.000 description 36
- 150000001335 aliphatic alkanes Chemical class 0.000 description 35
- 239000012044 organic layer Substances 0.000 description 35
- 229910052757 nitrogen Inorganic materials 0.000 description 33
- ATBKVKDEMSGMTQ-UHFFFAOYSA-N hydrazine triphenylphosphane Chemical compound NN.C1(=CC=CC=C1)P(C1=CC=CC=C1)C1=CC=CC=C1 ATBKVKDEMSGMTQ-UHFFFAOYSA-N 0.000 description 32
- VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical compound NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 description 31
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 31
- 230000000694 effects Effects 0.000 description 31
- 229910052763 palladium Inorganic materials 0.000 description 31
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 30
- 239000002253 acid Substances 0.000 description 30
- 238000002360 preparation method Methods 0.000 description 30
- 238000000746 purification Methods 0.000 description 30
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- 239000002585 base Substances 0.000 description 27
- 239000003112 inhibitor Substances 0.000 description 27
- 239000000047 product Substances 0.000 description 27
- 238000003756 stirring Methods 0.000 description 26
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 26
- 108010057466 NF-kappa B Proteins 0.000 description 25
- 102000003945 NF-kappa B Human genes 0.000 description 25
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 25
- 230000002441 reversible effect Effects 0.000 description 25
- YSYDQWIOUPGJKJ-UHFFFAOYSA-N 5-bromo-3-(1-ethylsulfonylpiperidin-4-yl)-1h-indole-7-carboxamide Chemical compound C1CN(S(=O)(=O)CC)CCC1C1=CNC2=C(C(N)=O)C=C(Br)C=C12 YSYDQWIOUPGJKJ-UHFFFAOYSA-N 0.000 description 24
- 125000000753 cycloalkyl group Chemical group 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 23
- 125000004429 atom Chemical group 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- 150000001412 amines Chemical class 0.000 description 22
- 239000000460 chlorine Substances 0.000 description 22
- LIWAQLJGPBVORC-UHFFFAOYSA-N ethylmethylamine Chemical compound CCNC LIWAQLJGPBVORC-UHFFFAOYSA-N 0.000 description 22
- 239000007787 solid Substances 0.000 description 21
- OSIMXEMQOWKSPD-UHFFFAOYSA-N C(C)O[S+](OCC)OCC.[Na+] Chemical compound C(C)O[S+](OCC)OCC.[Na+] OSIMXEMQOWKSPD-UHFFFAOYSA-N 0.000 description 20
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 20
- 125000000217 alkyl group Chemical group 0.000 description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 20
- 230000003902 lesion Effects 0.000 description 20
- 125000003342 alkenyl group Chemical group 0.000 description 19
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 18
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 18
- 239000012279 sodium borohydride Substances 0.000 description 18
- 229910000033 sodium borohydride Inorganic materials 0.000 description 18
- 201000010099 disease Diseases 0.000 description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 17
- 230000008570 general process Effects 0.000 description 17
- 125000005843 halogen group Chemical group 0.000 description 17
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 description 17
- 230000002829 reductive effect Effects 0.000 description 17
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 17
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 16
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 16
- 239000000126 substance Substances 0.000 description 16
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 15
- 125000000392 cycloalkenyl group Chemical group 0.000 description 15
- 239000002552 dosage form Substances 0.000 description 15
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- 239000000843 powder Substances 0.000 description 15
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 14
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 14
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 14
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 14
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 14
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- 125000003118 aryl group Chemical group 0.000 description 13
- 239000012267 brine Substances 0.000 description 13
- 108060006633 protein kinase Proteins 0.000 description 13
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
- DIIIISSCIXVANO-UHFFFAOYSA-N 1,2-Dimethylhydrazine Chemical compound CNNC DIIIISSCIXVANO-UHFFFAOYSA-N 0.000 description 12
- KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 description 12
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- 238000003818 flash chromatography Methods 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
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- 108091000080 Phosphotransferase Proteins 0.000 description 11
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- 239000010410 layer Substances 0.000 description 11
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 11
- 102000020233 phosphotransferase Human genes 0.000 description 11
- 125000003386 piperidinyl group Chemical group 0.000 description 11
- 150000004032 porphyrins Chemical class 0.000 description 11
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- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 10
- 125000000304 alkynyl group Chemical group 0.000 description 10
- 239000011777 magnesium Substances 0.000 description 10
- 229920000642 polymer Polymers 0.000 description 10
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 9
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- JQGPTWOSQMRKLG-UHFFFAOYSA-N 3-(1-ethylsulfonylpiperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-indole-7-carboxamide Chemical compound C1CN(S(=O)(=O)CC)CCC1C1=CNC2=C(C(N)=O)C=C(B3OC(C)(C)C(C)(C)O3)C=C12 JQGPTWOSQMRKLG-UHFFFAOYSA-N 0.000 description 8
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- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 5
- IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical compound C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 description 5
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- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 5
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| WO2010080474A1 (en) * | 2008-12-19 | 2010-07-15 | Bristol-Myers Squibb Company | Carbazole and carboline kinase inhibitors |
| US8354539B2 (en) | 2009-03-10 | 2013-01-15 | Glaxo Group Limited | Indole derivatives as IKK2 inhibitors |
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- 2006-06-28 AR ARP060102790A patent/AR055343A1/es not_active Application Discontinuation
- 2006-06-28 TW TW095123240A patent/TWI380973B/zh not_active IP Right Cessation
- 2006-06-28 NZ NZ563687A patent/NZ563687A/en not_active IP Right Cessation
- 2006-06-28 KR KR1020077030656A patent/KR20080021077A/ko not_active Ceased
- 2006-06-28 PE PE2006000761A patent/PE20070173A1/es not_active Application Discontinuation
- 2006-06-28 JP JP2008519569A patent/JP5059756B2/ja not_active Expired - Fee Related
- 2006-06-28 AU AU2006266028A patent/AU2006266028B2/en not_active Ceased
- 2006-06-28 MX MX2007016541A patent/MX2007016541A/es active IP Right Grant
- 2006-06-28 CN CN2006800304481A patent/CN101247804B/zh not_active Expired - Fee Related
- 2006-06-28 BR BRPI0611674-4A patent/BRPI0611674A2/pt not_active IP Right Cessation
- 2006-06-28 CA CA002613068A patent/CA2613068A1/en not_active Abandoned
- 2006-06-28 EP EP06785861A patent/EP1896014A4/en not_active Withdrawn
- 2006-06-28 UA UAA200714940A patent/UA99699C2/ru unknown
- 2006-06-28 WO PCT/US2006/025402 patent/WO2007005534A2/en not_active Ceased
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- 2007-11-19 ZA ZA2007/09948A patent/ZA200709948B/en unknown
- 2007-11-29 IL IL187786A patent/IL187786A0/en unknown
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| TW200616967A (en) * | 2004-06-24 | 2006-06-01 | Smithkline Beecham Corp | Novel indazole carboxamides and their use |
| TW200626142A (en) * | 2004-09-21 | 2006-08-01 | Glaxo Group Ltd | Chemical compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| NO20080457L (no) | 2008-01-29 |
| KR20080021077A (ko) | 2008-03-06 |
| WO2007005534A2 (en) | 2007-01-11 |
| WO2007005534A8 (en) | 2008-01-17 |
| MA29566B1 (fr) | 2008-06-02 |
| MX2007016541A (es) | 2008-03-07 |
| AU2006266028A1 (en) | 2007-01-11 |
| EA014083B1 (ru) | 2010-08-30 |
| EA200800183A1 (ru) | 2008-08-29 |
| PE20070173A1 (es) | 2007-03-14 |
| ZA200709948B (en) | 2009-03-25 |
| UA99699C2 (ru) | 2012-09-25 |
| NZ563687A (en) | 2011-07-29 |
| JP2009500338A (ja) | 2009-01-08 |
| EP1896014A4 (en) | 2010-07-21 |
| CN101247804B (zh) | 2012-09-26 |
| JP5059756B2 (ja) | 2012-10-31 |
| CA2613068A1 (en) | 2007-01-11 |
| AR055343A1 (es) | 2007-08-22 |
| WO2007005534A3 (en) | 2007-04-26 |
| IL187786A0 (en) | 2008-08-07 |
| BRPI0611674A2 (pt) | 2009-04-28 |
| AU2006266028B2 (en) | 2012-03-15 |
| EP1896014A2 (en) | 2008-03-12 |
| TW200738588A (en) | 2007-10-16 |
| CN101247804A (zh) | 2008-08-20 |
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