IL173936A - IMIDAZO[1,2-a]PYRIDINES AND USE THEREOF IN THE PREPARATION OF A MEDICAMENT FOR INHIBITING MEK AND FOR TREATING HYPERPROLIFERATIVE DISORDER - Google Patents

Info

Publication number

IL173936A

IL173936A IL173936A IL17393606A IL173936A IL 173936 A IL173936 A IL 173936A IL 173936 A IL173936 A IL 173936A IL 17393606 A IL17393606 A IL 17393606A IL 173936 A IL173936 A IL 173936A

Authority

IL

Israel

Prior art keywords

heteroaryl

heterocyclyl

arylalkyl

aryl

alkyl

Prior art date

2003-09-03

Links

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• 238000002360 preparation method Methods 0.000 title claims description 86
• 230000003463 hyperproliferative effect Effects 0.000 title claims description 20
• 230000002401 inhibitory effect Effects 0.000 title claims description 15
• 239000003814 drug Substances 0.000 title claims description 13
• 150000005234 imidazo[1,2-a]pyridines Chemical class 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims description 258
• 125000000623 heterocyclic group Chemical group 0.000 claims description 225
• 125000001072 heteroaryl group Chemical group 0.000 claims description 178
• 125000003118 aryl group Chemical group 0.000 claims description 158
• 125000000217 alkyl group Chemical group 0.000 claims description 140
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 134
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 113
• 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 105
• -1 hetoroaryl Chemical group 0.000 claims description 93
• 125000003342 alkenyl group Chemical group 0.000 claims description 78
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 77
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 76
• 229920006395 saturated elastomer Polymers 0.000 claims description 74
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 64
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 62
• 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 62
• 229940002612 prodrug Drugs 0.000 claims description 59
• 239000000651 prodrug Substances 0.000 claims description 59
• 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 55
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 52
• 150000003839 salts Chemical class 0.000 claims description 51
• 125000000304 alkynyl group Chemical group 0.000 claims description 50
• 229910052739 hydrogen Inorganic materials 0.000 claims description 42
• 238000011282 treatment Methods 0.000 claims description 40
• 239000001257 hydrogen Substances 0.000 claims description 39
• 241000124008 Mammalia Species 0.000 claims description 34
• 125000004043 oxo group Chemical group O=* 0.000 claims description 30
• 150000002431 hydrogen Chemical group 0.000 claims description 29
• 125000004429 atom Chemical group 0.000 claims description 28
• 125000002837 carbocyclic group Chemical group 0.000 claims description 28
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 23
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• 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 claims description 18
• 239000012453 solvate Substances 0.000 claims description 18
• 125000000539 amino acid group Chemical group 0.000 claims description 16
• 229910019142 PO4 Inorganic materials 0.000 claims description 15
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
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• 230000000694 effects Effects 0.000 claims description 12
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• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
• 125000005865 C2-C10alkynyl group Chemical group 0.000 claims description 9
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 7
• 239000003937 drug carrier Substances 0.000 claims description 7
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 5
• 125000003386 piperidinyl group Chemical group 0.000 claims description 5
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 4
• 125000002757 morpholinyl group Chemical group 0.000 claims description 4
• 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 claims description 3
• 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 claims description 3
• 125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
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• 239000004474 valine Substances 0.000 claims description 2
• 125000001475 halogen functional group Chemical group 0.000 claims 29
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• MPVDXIMFBOLMNW-UHFFFAOYSA-N chembl1615565 Chemical compound OC1=CC=C2C=C(S(O)(=O)=O)C=C(S(O)(=O)=O)C2=C1N=NC1=CC=CC=C1 MPVDXIMFBOLMNW-UHFFFAOYSA-N 0.000 claims 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 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 193
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 117
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• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 88
• 238000006243 chemical reaction Methods 0.000 description 87
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• 239000000203 mixture Substances 0.000 description 52
• 239000012267 brine Substances 0.000 description 47
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 47
• 239000002253 acid Substances 0.000 description 44
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 44
• 125000005843 halogen group Chemical group 0.000 description 42
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 37
• YHNRUSMOYCDMJS-UHFFFAOYSA-N o-(cyclopropylmethyl)hydroxylamine Chemical compound NOCC1CC1 YHNRUSMOYCDMJS-UHFFFAOYSA-N 0.000 description 36
• 239000012044 organic layer Substances 0.000 description 34
• WWWTWPXKLJTKPM-UHFFFAOYSA-N 2-aminooxyethanol Chemical compound NOCCO WWWTWPXKLJTKPM-UHFFFAOYSA-N 0.000 description 32
• 238000003818 flash chromatography Methods 0.000 description 32
• 239000000725 suspension Substances 0.000 description 31
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
• 238000000746 purification Methods 0.000 description 29
• 238000003756 stirring Methods 0.000 description 28
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 25
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 22
• 150000001732 carboxylic acid derivatives Chemical group 0.000 description 22
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• 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 14
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 13
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• JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 12
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