CA2467780A1 - N-carbacycle monosubstituted indolocarbazoles as protein kinase inhibitors - Google Patents
N-carbacycle monosubstituted indolocarbazoles as protein kinase inhibitors Download PDFInfo
- Publication number
- CA2467780A1 CA2467780A1 CA002467780A CA2467780A CA2467780A1 CA 2467780 A1 CA2467780 A1 CA 2467780A1 CA 002467780 A CA002467780 A CA 002467780A CA 2467780 A CA2467780 A CA 2467780A CA 2467780 A1 CA2467780 A1 CA 2467780A1
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- Prior art keywords
- indole
- group
- mmol
- different
- harom
- 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.)
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- 239000003909 protein kinase inhibitor Substances 0.000 title claims description 19
- -1 monosubstituted indolocarbazoles Chemical class 0.000 title abstract description 40
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 title description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 15
- 201000010099 disease Diseases 0.000 claims abstract description 12
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 7
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 7
- 230000006378 damage Effects 0.000 claims abstract description 6
- 230000004770 neurodegeneration Effects 0.000 claims abstract description 6
- 208000006011 Stroke Diseases 0.000 claims abstract description 5
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 5
- 239000003814 drug Substances 0.000 claims abstract description 5
- 230000003211 malignant effect Effects 0.000 claims abstract description 5
- 230000019491 signal transduction Effects 0.000 claims abstract description 5
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 5
- 230000000973 chemotherapeutic effect Effects 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 214
- 239000000203 mixture Substances 0.000 claims description 106
- 125000003118 aryl group Chemical group 0.000 claims description 102
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 91
- 125000000217 alkyl group Chemical group 0.000 claims description 79
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 65
- 229910052736 halogen Inorganic materials 0.000 claims description 59
- 150000002367 halogens Chemical class 0.000 claims description 59
- 125000001072 heteroaryl group Chemical group 0.000 claims description 55
- 229910052799 carbon Inorganic materials 0.000 claims description 32
- 229910052757 nitrogen Inorganic materials 0.000 claims description 21
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 150000002466 imines Chemical class 0.000 claims description 17
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 17
- 125000003342 alkenyl group Chemical group 0.000 claims description 15
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- 229940043355 kinase inhibitor Drugs 0.000 claims description 15
- 102000001253 Protein Kinase Human genes 0.000 claims description 14
- 108060006633 protein kinase Proteins 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 230000000694 effects Effects 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 125000004434 sulfur atom Chemical group 0.000 claims description 8
- 108010014905 Glycogen Synthase Kinase 3 Proteins 0.000 claims description 7
- 150000003839 salts Chemical group 0.000 claims description 7
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 claims description 7
- 102000003923 Protein Kinase C Human genes 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 125000005156 substituted alkylene group Chemical group 0.000 claims description 4
- 102000008130 Cyclic AMP-Dependent Protein Kinases Human genes 0.000 claims description 3
- 108010049894 Cyclic AMP-Dependent Protein Kinases Proteins 0.000 claims description 3
- 101710165576 Extracellular signal-regulated kinase 2 Proteins 0.000 claims description 3
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- 229910052727 yttrium Inorganic materials 0.000 claims description 2
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- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 14
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- 238000003821 enantio-separation Methods 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 150000002215 flavonoids Chemical class 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 125000001487 glyoxylate group Chemical class O=C([O-])C(=O)[*] 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000006951 hyperphosphorylation Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- JBOPQACSHPPKEP-UHFFFAOYSA-N indoxyl acetate Natural products C1=CC=C2C(OC(=O)C)=CNC2=C1 JBOPQACSHPPKEP-UHFFFAOYSA-N 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- JYQQWQJCEUMXQZ-UHFFFAOYSA-N methyl cyanate Chemical compound COC#N JYQQWQJCEUMXQZ-UHFFFAOYSA-N 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- 230000003957 neurotransmitter release Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- NLRKCXQQSUWLCH-UHFFFAOYSA-N nitrosobenzene Chemical compound O=NC1=CC=CC=C1 NLRKCXQQSUWLCH-UHFFFAOYSA-N 0.000 description 1
- 235000014571 nuts Nutrition 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 150000005623 oxindoles Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 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
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 229940124606 potential therapeutic agent Drugs 0.000 description 1
- 150000003140 primary amides Chemical class 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 102000013498 tau Proteins Human genes 0.000 description 1
- 108010026424 tau Proteins Proteins 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—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 three hetero rings
- C07D487/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Diabetes (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10161940.5 | 2001-12-17 | ||
| DE10161940A DE10161940A1 (de) | 2001-12-17 | 2001-12-17 | N-Carbacyclus-monosubstitutierte Indolocarbazole als Proteinkinase-inhibitoren |
| PCT/EP2002/013753 WO2003051887A1 (en) | 2001-12-17 | 2002-12-04 | N-carbacycle monosubstituted indolocarbazoles as protein kinase inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2467780A1 true CA2467780A1 (en) | 2003-06-26 |
Family
ID=7709523
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002467780A Abandoned CA2467780A1 (en) | 2001-12-17 | 2002-12-04 | N-carbacycle monosubstituted indolocarbazoles as protein kinase inhibitors |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US7262215B2 (https=) |
| EP (1) | EP1456211A1 (https=) |
| JP (1) | JP2005518379A (https=) |
| AU (1) | AU2002356625A1 (https=) |
| CA (1) | CA2467780A1 (https=) |
| DE (1) | DE10161940A1 (https=) |
| WO (1) | WO2003051887A1 (https=) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7122526B2 (en) * | 2000-10-31 | 2006-10-17 | Nanosphere, Inc. | Indolocarbazole anticancer agents and methods of using same |
| CL2007003693A1 (es) | 2006-12-22 | 2008-06-27 | Actelion Pharmaceuticals Ltd | Compuestos derivados de pirido [3,2-b] [1,4] tiazina; composicion farmaceutica que contiene dichos compuestos; y su uso en el tratamiento de infecciones bacterianas. |
| US20100273769A1 (en) * | 2009-01-26 | 2010-10-28 | Hanno Roder | Composition and method for the treatment of parkinson's disease |
| CN102557967A (zh) * | 2011-12-28 | 2012-07-11 | 合肥科尚医药科技有限公司 | 一种盐酸氨溴索的制备方法 |
| CN103113379A (zh) * | 2013-03-12 | 2013-05-22 | 盛世泰科生物医药技术(苏州)有限公司 | 阿塞那平马来酸盐的合成工艺 |
| CN117886799B (zh) * | 2024-01-11 | 2025-07-29 | 浙江工业大学 | 一类靶向降解GSK-3β的蛋白降解靶向嵌合体化合物及其应用 |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5438050A (en) * | 1988-02-06 | 1995-08-01 | Godecke Aktiengesellschaft | Indolocarbazole derivatives, processes for their preparation and compositions containing them |
| US5547976A (en) * | 1992-03-20 | 1996-08-20 | Burroughs Wellcome Co. | Further indole derivatives with antiviral activity |
| DE4217964A1 (de) * | 1992-05-30 | 1993-12-02 | Goedecke Ag | Indolocarbazol-Imide und deren Verwendung |
| GB9416467D0 (en) * | 1994-08-13 | 1994-10-05 | Wellcome Found | Compounds for use in medicine |
| DK1044203T3 (da) * | 1997-12-31 | 2003-07-14 | Cephalon Inc | 3'-epimere K-252a-derivater |
| US6013646A (en) * | 1998-07-02 | 2000-01-11 | Bayer Corporation | Indolocarbazole derivatives useful for the treatment of neurodegenerative diseases and cancer |
| US7122526B2 (en) * | 2000-10-31 | 2006-10-17 | Nanosphere, Inc. | Indolocarbazole anticancer agents and methods of using same |
| EP1432721A4 (en) * | 2001-09-13 | 2008-02-20 | Bristol Myers Squibb Co | PROCESS FOR THE PREPARATION OF REBECCAMYCIN AND ANALOGUE THEREOF |
-
2001
- 2001-12-17 DE DE10161940A patent/DE10161940A1/de not_active Withdrawn
-
2002
- 2002-12-04 AU AU2002356625A patent/AU2002356625A1/en not_active Abandoned
- 2002-12-04 EP EP02804874A patent/EP1456211A1/en not_active Withdrawn
- 2002-12-04 CA CA002467780A patent/CA2467780A1/en not_active Abandoned
- 2002-12-04 US US10/496,505 patent/US7262215B2/en not_active Expired - Fee Related
- 2002-12-04 WO PCT/EP2002/013753 patent/WO2003051887A1/en not_active Ceased
- 2002-12-04 JP JP2003552769A patent/JP2005518379A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| JP2005518379A (ja) | 2005-06-23 |
| US20050075386A1 (en) | 2005-04-07 |
| DE10161940A1 (de) | 2003-07-03 |
| WO2003051887A1 (en) | 2003-06-26 |
| US7262215B2 (en) | 2007-08-28 |
| EP1456211A1 (en) | 2004-09-15 |
| AU2002356625A1 (en) | 2003-06-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |