CA2682231A1 - Imidazo[1,2-a]pyridine compounds as receptor tyrosine kinase inhibitors - Google Patents

Info

Publication number

CA2682231A1

CA2682231A1 CA002682231A CA2682231A CA2682231A1 CA 2682231 A1 CA2682231 A1 CA 2682231A1 CA 002682231 A CA002682231 A CA 002682231A CA 2682231 A CA2682231 A CA 2682231A CA 2682231 A1 CA2682231 A1 CA 2682231A1

Authority

CA

Canada

Prior art keywords

alkyl

mmol

compound

formula

reaction

Prior art date

2007-03-28

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.)

Abandoned

Links

• Espacenet
• Global Dossier
• CIPO
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• 229940127361 Receptor Tyrosine Kinase Inhibitors Drugs 0.000 title description 3
• 150000005234 imidazo[1,2-a]pyridines Chemical class 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 177
• 238000011282 treatment Methods 0.000 claims abstract description 19
• 108091008598 receptor tyrosine kinases Proteins 0.000 claims abstract description 16
• 102000027426 receptor tyrosine kinases Human genes 0.000 claims abstract description 16
• 230000001404 mediated effect Effects 0.000 claims abstract description 14
• 125000000217 alkyl group Chemical group 0.000 claims description 237
• 238000002360 preparation method Methods 0.000 claims description 184
• 238000000034 method Methods 0.000 claims description 74
• -1 C(O)NHMe Chemical compound 0.000 claims description 55
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 48
• 229910052739 hydrogen Inorganic materials 0.000 claims description 46
• 150000003839 salts Chemical class 0.000 claims description 31
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 27
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 25
• 229910052731 fluorine Inorganic materials 0.000 claims description 23
• 229910052801 chlorine Inorganic materials 0.000 claims description 17
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 17
• 206010028980 Neoplasm Diseases 0.000 claims description 16
• 229910052757 nitrogen Inorganic materials 0.000 claims description 16
• 239000001257 hydrogen Substances 0.000 claims description 15
• 125000004429 atom Chemical group 0.000 claims description 14
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 14
• 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 13
• CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 13
• 125000003118 aryl group Chemical group 0.000 claims description 12
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 11
• 229910052736 halogen Inorganic materials 0.000 claims description 11
• 150000002367 halogens Chemical class 0.000 claims description 11
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 11
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
• 125000004076 pyridyl group Chemical group 0.000 claims description 10
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 9
• 241000124008 Mammalia Species 0.000 claims description 9
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 9
• 229910052763 palladium Inorganic materials 0.000 claims description 9
• XXJGBENTLXFVFI-UHFFFAOYSA-N 1-amino-methylene Chemical compound N[CH2] XXJGBENTLXFVFI-UHFFFAOYSA-N 0.000 claims description 8
• 206010016654 Fibrosis Diseases 0.000 claims description 8
• 125000003386 piperidinyl group Chemical group 0.000 claims description 8
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 8
• 239000003054 catalyst Substances 0.000 claims description 7
• 230000008878 coupling Effects 0.000 claims description 7
• 238000010168 coupling process Methods 0.000 claims description 7
• 238000005859 coupling reaction Methods 0.000 claims description 7
• 230000004761 fibrosis Effects 0.000 claims description 7
• 239000003446 ligand Substances 0.000 claims description 7
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
• 229910052799 carbon Inorganic materials 0.000 claims description 6
• 239000003153 chemical reaction reagent Substances 0.000 claims description 6
• 125000000623 heterocyclic group Chemical group 0.000 claims description 6
• 125000002971 oxazolyl group Chemical group 0.000 claims description 6
• 125000004193 piperazinyl group Chemical group 0.000 claims description 6
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 5
• 239000003638 chemical reducing agent Substances 0.000 claims description 5
• VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 claims description 5
• 201000011510 cancer Diseases 0.000 claims description 4
• 125000003709 fluoroalkyl group Chemical group 0.000 claims description 4
• 239000008194 pharmaceutical composition Substances 0.000 claims description 4
• 230000008569 process Effects 0.000 claims description 4
• 125000006239 protecting group Chemical group 0.000 claims description 4
• 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 3
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 3
• 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 3
• 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 3
• 239000003085 diluting agent Substances 0.000 claims description 3
• 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 claims description 3
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
• MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 2
• 230000001335 demethylating effect Effects 0.000 claims description 2
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 18
• 239000003112 inhibitor Substances 0.000 abstract description 16
• 101001001642 Xenopus laevis Serine/threonine-protein kinase pim-3 Proteins 0.000 abstract description 11
• 201000010099 disease Diseases 0.000 abstract description 10
• 102000005962 receptors Human genes 0.000 abstract description 3
• 108020003175 receptors Proteins 0.000 abstract description 3
• OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 abstract 1
• OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 abstract 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 322
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 275
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 267
• 238000006243 chemical reaction Methods 0.000 description 235
• 239000000203 mixture Substances 0.000 description 133
• 239000007787 solid Substances 0.000 description 128
• 201000006417 multiple sclerosis Diseases 0.000 description 124
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 106
• 235000019439 ethyl acetate Nutrition 0.000 description 104
• 239000000243 solution Substances 0.000 description 103
• 239000000047 product Substances 0.000 description 102
• 238000007792 addition Methods 0.000 description 90
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 77
• 239000011541 reaction mixture Substances 0.000 description 76
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 74
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 66
• 229910001868 water Inorganic materials 0.000 description 59
• SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 54
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 53
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 48
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 44
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 44
• 239000010410 layer Substances 0.000 description 43
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 43
• 229910052938 sodium sulfate Inorganic materials 0.000 description 41
• 235000011152 sodium sulphate Nutrition 0.000 description 41
• 238000010992 reflux Methods 0.000 description 40
• 239000007832 Na2SO4 Substances 0.000 description 39
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
• 239000012044 organic layer Substances 0.000 description 39
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 36
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 36
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 35
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 34
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 32
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
• 238000003818 flash chromatography Methods 0.000 description 32
• BCIIMDOZSUCSEN-UHFFFAOYSA-N piperidin-4-amine Chemical compound NC1CCNCC1 BCIIMDOZSUCSEN-UHFFFAOYSA-N 0.000 description 32
• 238000003756 stirring Methods 0.000 description 32
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
• 239000003921 oil Substances 0.000 description 29
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 28
• 229920006395 saturated elastomer Polymers 0.000 description 28
• 239000012074 organic phase Substances 0.000 description 24
• CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 23
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 22
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 22
• 229910052786 argon Inorganic materials 0.000 description 22
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 22
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 22
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 21
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
• 235000011114 ammonium hydroxide Nutrition 0.000 description 21
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 18
• 229910000024 caesium carbonate Inorganic materials 0.000 description 17
• 210000004027 cell Anatomy 0.000 description 17
• 235000019341 magnesium sulphate Nutrition 0.000 description 17
• 238000010898 silica gel chromatography Methods 0.000 description 17
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 16
• 239000000706 filtrate Substances 0.000 description 15
• HBBYDTFNQNAFJA-UHFFFAOYSA-N 4-(2-methoxyethoxy)pyridin-2-amine Chemical compound COCCOC1=CC=NC(N)=C1 HBBYDTFNQNAFJA-UHFFFAOYSA-N 0.000 description 14
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• 101150041968 CDC13 gene Proteins 0.000 description 13
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• UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical group C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 13
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