BRPI0720388A2 - Derivados de indolilmaleimida - Google Patents
Derivados de indolilmaleimida Download PDFInfo
- Publication number
- BRPI0720388A2 BRPI0720388A2 BRPI0720388-8A BRPI0720388A BRPI0720388A2 BR PI0720388 A2 BRPI0720388 A2 BR PI0720388A2 BR PI0720388 A BRPI0720388 A BR PI0720388A BR PI0720388 A2 BRPI0720388 A2 BR PI0720388A2
- Authority
- BR
- Brazil
- Prior art keywords
- alkyl
- hydrogen
- mmol
- alkoxy
- formula
- Prior art date
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- WIQRSJOCVVPMPS-UHFFFAOYSA-N 3-(1h-indol-2-yl)pyrrole-2,5-dione Chemical class O=C1NC(=O)C(C=2NC3=CC=CC=C3C=2)=C1 WIQRSJOCVVPMPS-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 135
- 125000000217 alkyl group Chemical group 0.000 claims description 71
- 239000001257 hydrogen Substances 0.000 claims description 56
- 229910052739 hydrogen Inorganic materials 0.000 claims description 56
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 34
- 102000003923 Protein Kinase C Human genes 0.000 claims description 33
- 108090000315 Protein Kinase C Proteins 0.000 claims description 33
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 28
- 125000003545 alkoxy group Chemical group 0.000 claims description 25
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 21
- 150000002367 halogens Chemical group 0.000 claims description 19
- 125000000623 heterocyclic group Chemical group 0.000 claims description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 13
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 239000003112 inhibitor Substances 0.000 claims description 11
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 10
- 230000002757 inflammatory effect Effects 0.000 claims description 10
- 230000001404 mediated effect Effects 0.000 claims description 10
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- 208000035475 disorder Diseases 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 230000001154 acute effect Effects 0.000 claims description 7
- 230000001028 anti-proliverative effect Effects 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 7
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- 239000003814 drug Substances 0.000 claims description 6
- 208000028867 ischemia Diseases 0.000 claims description 6
- 230000006044 T cell activation Effects 0.000 claims description 5
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- 125000004430 oxygen atom Chemical group O* 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 206010020772 Hypertension Diseases 0.000 claims description 4
- 229940127003 anti-diabetic drug Drugs 0.000 claims description 4
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- 206010052779 Transplant rejections Diseases 0.000 claims description 3
- 201000011510 cancer Diseases 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
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- 208000030507 AIDS Diseases 0.000 claims description 2
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- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 2
- 208000035473 Communicable disease Diseases 0.000 claims description 2
- 208000002705 Glucose Intolerance Diseases 0.000 claims description 2
- 206010019280 Heart failures Diseases 0.000 claims description 2
- 206010022680 Intestinal ischaemia Diseases 0.000 claims description 2
- 208000008589 Obesity Diseases 0.000 claims description 2
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 2
- 206010040070 Septic Shock Diseases 0.000 claims description 2
- 208000006011 Stroke Diseases 0.000 claims description 2
- 208000030886 Traumatic Brain injury Diseases 0.000 claims description 2
- 206010044541 Traumatic shock Diseases 0.000 claims description 2
- 208000024248 Vascular System injury Diseases 0.000 claims description 2
- 208000012339 Vascular injury Diseases 0.000 claims description 2
- 206010053648 Vascular occlusion Diseases 0.000 claims description 2
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims description 2
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 2
- 238000002399 angioplasty Methods 0.000 claims description 2
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- 235000020824 obesity Nutrition 0.000 claims description 2
- 210000000056 organ Anatomy 0.000 claims description 2
- 201000010065 polycystic ovary syndrome Diseases 0.000 claims description 2
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- 125000005843 halogen group Chemical group 0.000 claims 3
- 208000009329 Graft vs Host Disease Diseases 0.000 claims 1
- 208000001647 Renal Insufficiency Diseases 0.000 claims 1
- 208000027418 Wounds and injury Diseases 0.000 claims 1
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims 1
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- 230000010410 reperfusion Effects 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 166
- 239000000243 solution Substances 0.000 description 98
- 235000019439 ethyl acetate Nutrition 0.000 description 82
- 239000011541 reaction mixture Substances 0.000 description 71
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 70
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 50
- 238000005160 1H NMR spectroscopy Methods 0.000 description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 44
- 239000011734 sodium Substances 0.000 description 43
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 40
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 40
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 40
- 239000000203 mixture Substances 0.000 description 39
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 33
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 32
- -1 [4- (7-methyl-1H-indol-3-yl) -2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl] pyrazolo [1,5-a] pyridin Chemical compound 0.000 description 29
- 238000001816 cooling Methods 0.000 description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- 239000012300 argon atmosphere Substances 0.000 description 27
- 238000000746 purification Methods 0.000 description 27
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 23
- 238000003556 assay Methods 0.000 description 17
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 229920006395 saturated elastomer Polymers 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- 108010029485 Protein Isoforms Proteins 0.000 description 13
- 102000001708 Protein Isoforms Human genes 0.000 description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 13
- 238000010992 reflux Methods 0.000 description 13
- 238000012360 testing method Methods 0.000 description 13
- 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 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
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- 239000000741 silica gel Substances 0.000 description 12
- 229910002027 silica gel Inorganic materials 0.000 description 12
- 239000003039 volatile agent Substances 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- 150000003254 radicals Chemical group 0.000 description 11
- 239000008346 aqueous phase Substances 0.000 description 10
- 150000002431 hydrogen Chemical group 0.000 description 10
- VFIJGAWYVXDYLK-UHFFFAOYSA-N methyl 2-(1h-indol-3-yl)-2-oxoacetate Chemical compound C1=CC=C2C(C(=O)C(=O)OC)=CNC2=C1 VFIJGAWYVXDYLK-UHFFFAOYSA-N 0.000 description 10
- 238000002390 rotary evaporation Methods 0.000 description 10
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
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- 102000001253 Protein Kinase Human genes 0.000 description 8
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
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- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 7
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- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 229940124639 Selective inhibitor Drugs 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 238000011534 incubation Methods 0.000 description 6
- PHEDXBVPIONUQT-RGYGYFBISA-N phorbol 13-acetate 12-myristate Chemical compound C([C@]1(O)C(=O)C(C)=C[C@H]1[C@@]1(O)[C@H](C)[C@H]2OC(=O)CCCCCCCCCCCCC)C(CO)=C[C@H]1[C@H]1[C@]2(OC(C)=O)C1(C)C PHEDXBVPIONUQT-RGYGYFBISA-N 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 5
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 4
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
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Classifications
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Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| EP06126534 | 2006-12-19 | ||
| EP06126534.4 | 2006-12-19 | ||
| PCT/EP2007/064010 WO2008074752A2 (en) | 2006-12-19 | 2007-12-14 | Indolylmaleimide derivatives as kinase inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| BRPI0720388A2 true BRPI0720388A2 (pt) | 2014-01-14 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| BRPI0720388-8A BRPI0720388A2 (pt) | 2006-12-19 | 2007-12-14 | Derivados de indolilmaleimida |
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| Country | Link |
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| US (2) | US8193236B2 (OSRAM) |
| EP (1) | EP2094689B1 (OSRAM) |
| JP (1) | JP2010513386A (OSRAM) |
| KR (1) | KR20090100363A (OSRAM) |
| CN (1) | CN101558062A (OSRAM) |
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| ES (1) | ES2410955T3 (OSRAM) |
| MX (1) | MX2009006533A (OSRAM) |
| WO (1) | WO2008074752A2 (OSRAM) |
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| MX2009006533A (es) | 2006-12-19 | 2009-06-26 | Novartis Ag | Derivados de indolil-maleimida como inhibidores de cinasa. |
| US8193235B2 (en) | 2009-06-12 | 2012-06-05 | University Of Kansas | Compositions and methods for establishing and maintaining stem cells in an undifferentiated state |
| CN101973993A (zh) * | 2010-11-05 | 2011-02-16 | 天津药物研究院 | 一种制备2-[咪唑并(1,2-a)吡啶-3-基]乙酸的方法 |
| GB201111427D0 (en) * | 2011-07-05 | 2011-08-17 | Amakem Nv | Novel bisindolylmaleimides, pan-pkc inhibitors |
| CN103130790B (zh) * | 2013-03-15 | 2015-10-28 | 浙江工业大学 | 一种3-苯并异噁唑-4-吲哚马来酰亚胺衍生物及其用途 |
| CN103965093A (zh) * | 2014-04-04 | 2014-08-06 | 华南理工大学 | 2-全氟烷基吲哚类化合物及其制备方法和应用 |
| RS62273B1 (sr) | 2014-04-29 | 2021-09-30 | Fmc Corp | Piridazinonski herbicidi |
| CN104693198B (zh) * | 2014-12-13 | 2017-03-08 | 浙江工业大学 | 3‑(1,2,4‑三氮唑并[4,3‑a]吡啶‑3‑基)‑4‑(1H‑吲哚‑3‑基)马来酰亚胺类衍生物及其制备方法和应用 |
| US10750743B2 (en) | 2015-10-28 | 2020-08-25 | Fmc Corporation | Pyridazinone herbicides |
| EP3920885A1 (en) | 2019-02-08 | 2021-12-15 | Frequency Therapeutics, Inc. | Valproic acid compounds and wnt agonists for treating ear disorders |
| TW202126617A (zh) | 2019-09-20 | 2021-07-16 | 美商富曼西公司 | 間二醯胺類殺蟲劑 |
Family Cites Families (16)
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| US5491242A (en) * | 1994-06-22 | 1996-02-13 | Eli Lilly And Company | Protein kinase C inhibitors |
| US5821072A (en) * | 1996-02-20 | 1998-10-13 | Sloan-Kettering Institute For Cancer Research | Combinations of PKC inhibitors and therapaeutic agents for treating cancers |
| PE91598A1 (es) * | 1996-07-29 | 1998-12-24 | Hoffmann La Roche | Pirroles sustituidos |
| PE91698A1 (es) * | 1996-07-29 | 1998-12-24 | Hoffmann La Roche | Pirroles sustituidos |
| WO1999042100A1 (en) * | 1998-02-23 | 1999-08-26 | Sagami Chemical Research Center | Cell death inhibitors |
| US6867198B2 (en) * | 1999-12-16 | 2005-03-15 | Eli Lilly And Company | Agents and methods for the treatment of proliferative diseases |
| SG159378A1 (en) * | 2000-11-07 | 2010-03-30 | Novartis Ag | Indolylmaleimide derivatives as protein kinase c inhibitors |
| DE60112611T2 (de) * | 2000-12-08 | 2006-06-14 | Ortho Mcneil Pharm Inc | Makroheterocyclische verbindungen als kinase inhibitoren |
| CA2477984A1 (en) * | 2002-03-08 | 2003-09-18 | Pamela Ann Albaugh | Pyrrole-2, 5-dione derivatives and their use as gsk-3 inhibitors |
| PE20040079A1 (es) | 2002-04-03 | 2004-04-19 | Novartis Ag | Derivados de indolilmaleimida |
| JP2005531607A (ja) * | 2002-06-05 | 2005-10-20 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | キナーゼ阻害剤として置換ピロリン |
| GB0303319D0 (en) * | 2003-02-13 | 2003-03-19 | Novartis Ag | Organic compounds |
| BRPI0411366A (pt) | 2003-06-13 | 2006-07-25 | Janssen Pharmaceutica Nv | derivados de indazolil (indolil) maleimida substituìdos como inibidores de cinase |
| DK1846406T5 (da) * | 2005-02-09 | 2011-10-31 | Arqule Inc | Maleimidderivater, farmaceutiske sammensætninger og fremgangsmåder til behandling af cancer |
| PL1904482T3 (pl) | 2005-07-11 | 2011-06-30 | Novartis Ag | Pochodne indolilomaleimidowe |
| MX2009006533A (es) | 2006-12-19 | 2009-06-26 | Novartis Ag | Derivados de indolil-maleimida como inhibidores de cinasa. |
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Also Published As
| Publication number | Publication date |
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| JP2010513386A (ja) | 2010-04-30 |
| AU2007336338A1 (en) | 2008-06-26 |
| US8193236B2 (en) | 2012-06-05 |
| US20120219593A1 (en) | 2012-08-30 |
| EP2094689A2 (en) | 2009-09-02 |
| EP2094689B1 (en) | 2013-04-03 |
| WO2008074752A2 (en) | 2008-06-26 |
| KR20090100363A (ko) | 2009-09-23 |
| MX2009006533A (es) | 2009-06-26 |
| US8742132B2 (en) | 2014-06-03 |
| US20100041693A1 (en) | 2010-02-18 |
| ES2410955T3 (es) | 2013-07-04 |
| WO2008074752A3 (en) | 2008-10-30 |
| CN101558062A (zh) | 2009-10-14 |
| CA2671525A1 (en) | 2008-06-26 |
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