KR20090007319A - Ｈｓｐ90 억제제로서 사용되는 피롤로피리미딘 유도체 - Google Patents

Info

Publication number

KR20090007319A

KR20090007319A KR1020087024851A KR20087024851A KR20090007319A KR 20090007319 A KR20090007319 A KR 20090007319A KR 1020087024851 A KR1020087024851 A KR 1020087024851A KR 20087024851 A KR20087024851 A KR 20087024851A KR 20090007319 A KR20090007319 A KR 20090007319A

Authority

KR

South Korea

Prior art keywords

compound

pyrrolo

pyrimidine

phenyl

mmol

Prior art date

2006-03-11

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.)

Withdrawn

Links

• Espacenet
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• 239000003481 heat shock protein 90 inhibitor Substances 0.000 title description 12
• 150000004944 pyrrolopyrimidines Chemical class 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 254
• -1 chloro, bromo, methyl Chemical group 0.000 claims abstract description 140
• 102100034051 Heat shock protein HSP 90-alpha Human genes 0.000 claims abstract description 57
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 21
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 21
• 239000001257 hydrogen Substances 0.000 claims abstract description 19
• 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 17
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 15
• 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 13
• 125000002837 carbocyclic group Chemical group 0.000 claims abstract description 12
• 230000002401 inhibitory effect Effects 0.000 claims abstract description 12
• 201000011510 cancer Diseases 0.000 claims abstract description 11
• 101710113864 Heat shock protein 90 Proteins 0.000 claims abstract description 10
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 9
• 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 7
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 7
• XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims abstract description 6
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
• 125000001246 bromo group Chemical group Br* 0.000 claims abstract description 6
• 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 6
• 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 4
• 238000000034 method Methods 0.000 claims description 121
• 239000000203 mixture Substances 0.000 claims description 62
• 230000000694 effects Effects 0.000 claims description 28
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• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 20
• 238000011282 treatment Methods 0.000 claims description 17
• 125000004122 cyclic group Chemical group 0.000 claims description 16
• 239000003814 drug Substances 0.000 claims description 16
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
• 125000001424 substituent group Chemical group 0.000 claims description 14
• 125000003277 amino group Chemical group 0.000 claims description 13
• 150000003839 salts Chemical class 0.000 claims description 13
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 10
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
• 230000001681 protective effect Effects 0.000 claims description 9
• 229940079593 drug Drugs 0.000 claims description 8
• 230000006907 apoptotic process Effects 0.000 claims description 7
• 238000001727 in vivo Methods 0.000 claims description 7
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 6
• 241000124008 Mammalia Species 0.000 claims description 6
• 125000002947 alkylene group Chemical group 0.000 claims description 6
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
• 125000004076 pyridyl group Chemical group 0.000 claims description 6
• 101100507655 Canis lupus familiaris HSPA1 gene Proteins 0.000 claims description 5
• 125000000217 alkyl group Chemical group 0.000 claims description 5
• 229910052794 bromium Inorganic materials 0.000 claims description 5
• GPTFURBXHJWNHR-UHFFFAOYSA-N protopine Chemical compound C1=C2C(=O)CC3=CC=C4OCOC4=C3CN(C)CCC2=CC2=C1OCO2 GPTFURBXHJWNHR-UHFFFAOYSA-N 0.000 claims description 5
• 230000004044 response Effects 0.000 claims description 5
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• 229910052801 chlorine Inorganic materials 0.000 claims description 4
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
• 230000014509 gene expression Effects 0.000 claims description 4
• 125000003386 piperidinyl group Chemical group 0.000 claims description 4
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• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 3
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• 125000005336 allyloxy group Chemical group 0.000 claims description 3
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• 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 claims description 3
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• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
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• 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
• 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
• 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
• 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
• 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 claims description 2
• 125000003545 alkoxy group Chemical group 0.000 claims description 2
• 239000000969 carrier Substances 0.000 claims description 2
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• 230000001506 immunosuppresive effect Effects 0.000 claims description 2
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• 235000013305 food Nutrition 0.000 claims 1
• 125000005415 substituted alkoxy group Chemical group 0.000 claims 1
• 229910052731 fluorine Inorganic materials 0.000 abstract description 3
• 150000002431 hydrogen Chemical class 0.000 abstract 1
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• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 143
• 239000000243 solution Substances 0.000 description 98
• 235000019439 ethyl acetate Nutrition 0.000 description 97
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
• 239000007787 solid Substances 0.000 description 74
• 238000003818 flash chromatography Methods 0.000 description 63
• 238000005481 NMR spectroscopy Methods 0.000 description 60
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• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 49
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 49
• 238000002875 fluorescence polarization Methods 0.000 description 47
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
• 239000000741 silica gel Substances 0.000 description 44
• 229910002027 silica gel Inorganic materials 0.000 description 44
• 238000006243 chemical reaction Methods 0.000 description 40
• 239000011541 reaction mixture Substances 0.000 description 40
• FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 39
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• 239000012043 crude product Substances 0.000 description 33
• 239000011734 sodium Substances 0.000 description 32
• 108090000623 proteins and genes Proteins 0.000 description 29
• 239000002904 solvent Substances 0.000 description 29
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
• 102000004169 proteins and genes Human genes 0.000 description 27
• 229910004298 SiO 2 Inorganic materials 0.000 description 26
• 229920006395 saturated elastomer Polymers 0.000 description 24
• 238000000746 purification Methods 0.000 description 23
• 239000007795 chemical reaction product Substances 0.000 description 21
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 20
• 239000000706 filtrate Substances 0.000 description 20
• 230000002209 hydrophobic effect Effects 0.000 description 20
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• 235000019198 oils Nutrition 0.000 description 18
• 210000004027 cell Anatomy 0.000 description 17
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• 238000007792 addition Methods 0.000 description 16
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• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
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• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
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• 230000005764 inhibitory process Effects 0.000 description 12
• PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 11
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• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
• 125000004432 carbon atom Chemical group C* 0.000 description 10
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• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
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• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
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