ZA200500138B - Flavone derivatives as inhibitors of cyclin-dependent kinases. - Google Patents

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Publication number

ZA200500138B

ZA200500138B ZA200500138A ZA200500138A ZA200500138B ZA 200500138 B ZA200500138 B ZA 200500138B ZA 200500138 A ZA200500138 A ZA 200500138A ZA 200500138 A ZA200500138 A ZA 200500138A ZA 200500138 B ZA200500138 B ZA 200500138B

Authority

ZA

South Africa

Prior art keywords

trans

pyrrolidin

chromen

methyl

phenyl

Prior art date

2002-07-08

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• 108091007914 CDKs Proteins 0.000 title claims description 32
• 102000003903 Cyclin-dependent kinases Human genes 0.000 title claims description 23
• 108090000266 Cyclin-dependent kinases Proteins 0.000 title claims description 22
• 239000003112 inhibitor Substances 0.000 title description 14
• 150000002212 flavone derivatives Chemical class 0.000 title description 6
• 150000001875 compounds Chemical class 0.000 claims description 325
• -1 cyano, carboxy Chemical group 0.000 claims description 143
• 229910052739 hydrogen Inorganic materials 0.000 claims description 114
• 239000001257 hydrogen Substances 0.000 claims description 114
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 100
• 229910052736 halogen Inorganic materials 0.000 claims description 98
• 150000002367 halogens Chemical class 0.000 claims description 98
• 125000001424 substituent group Chemical group 0.000 claims description 86
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 84
• 229910052757 nitrogen Inorganic materials 0.000 claims description 79
• 125000003118 aryl group Chemical group 0.000 claims description 75
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 72
• 150000003839 salts Chemical class 0.000 claims description 69
• 125000000217 alkyl group Chemical group 0.000 claims description 66
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 60
• 238000000034 method Methods 0.000 claims description 59
• 125000005842 heteroatom Chemical group 0.000 claims description 56
• 150000002431 hydrogen Chemical class 0.000 claims description 55
• 229910052717 sulfur Inorganic materials 0.000 claims description 54
• 125000000623 heterocyclic group Chemical group 0.000 claims description 52
• 229920006395 saturated elastomer Polymers 0.000 claims description 52
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 48
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 45
• 239000000203 mixture Substances 0.000 claims description 41
• 229910052760 oxygen Inorganic materials 0.000 claims description 40
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 39
• 239000001301 oxygen Substances 0.000 claims description 39
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 36
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 36
• 239000011593 sulfur Substances 0.000 claims description 36
• 238000011282 treatment Methods 0.000 claims description 35
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 34
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 32
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 31
• 229910052799 carbon Inorganic materials 0.000 claims description 30
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 27
• 239000002585 base Substances 0.000 claims description 25
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 25
• 230000008569 process Effects 0.000 claims description 25
• 150000001721 carbon Chemical group 0.000 claims description 24
• 239000000126 substance Substances 0.000 claims description 22
• 239000003814 drug Substances 0.000 claims description 19
• 150000002148 esters Chemical class 0.000 claims description 19
• 238000002360 preparation method Methods 0.000 claims description 19
• 125000004434 sulfur atom Chemical group 0.000 claims description 19
• 125000004432 carbon atom Chemical group C* 0.000 claims description 18
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
• OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 17
• 229910052698 phosphorus Inorganic materials 0.000 claims description 17
• 239000011574 phosphorus Substances 0.000 claims description 17
• 239000002253 acid Substances 0.000 claims description 16
• 239000011541 reaction mixture Substances 0.000 claims description 16
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
• 239000002904 solvent Substances 0.000 claims description 14
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 13
• 125000003545 alkoxy group Chemical group 0.000 claims description 13
• 150000003857 carboxamides Chemical class 0.000 claims description 13
• 238000006243 chemical reaction Methods 0.000 claims description 13
• 150000007529 inorganic bases Chemical class 0.000 claims description 13
• 150000007530 organic bases Chemical class 0.000 claims description 13
• 230000002265 prevention Effects 0.000 claims description 13
• 230000002062 proliferating effect Effects 0.000 claims description 13
• 229940124530 sulfonamide Drugs 0.000 claims description 13
• 150000003456 sulfonamides Chemical class 0.000 claims description 13
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
• JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 12
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• 238000005859 coupling reaction Methods 0.000 claims description 11
• 230000004663 cell proliferation Effects 0.000 claims description 10
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• 238000010168 coupling process Methods 0.000 claims description 10
• 239000005711 Benzoic acid Substances 0.000 claims description 9
• 230000000694 effects Effects 0.000 claims description 9
• 238000007363 ring formation reaction Methods 0.000 claims description 9
• NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 8
• 125000000524 functional group Chemical group 0.000 claims description 8
• 239000003960 organic solvent Substances 0.000 claims description 8
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
• 125000006413 ring segment Chemical group 0.000 claims description 7
• ARFUTALOPVWOBA-UHFFFAOYSA-N 2-(ethoxymethyl)-5, 7-dimethoxy-4H-chromen-4-one Natural products O1C(C)=CC(=O)C=2C1=CC(OC)=CC=2OC ARFUTALOPVWOBA-UHFFFAOYSA-N 0.000 claims description 6
• 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 6
• ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 claims description 6
• 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 5
• 208000036142 Viral infection Diseases 0.000 claims description 5
• 201000011510 cancer Diseases 0.000 claims description 5
• 239000003153 chemical reaction reagent Substances 0.000 claims description 5
• 239000003638 chemical reducing agent Substances 0.000 claims description 5
• 239000003795 chemical substances by application Substances 0.000 claims description 5
• 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 5
• 229910001867 inorganic solvent Inorganic materials 0.000 claims description 5
• 239000003049 inorganic solvent Substances 0.000 claims description 5
• 229910052751 metal Inorganic materials 0.000 claims description 5
• 239000002184 metal Substances 0.000 claims description 5
• 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 claims description 5
• 230000009385 viral infection Effects 0.000 claims description 5
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
• SGOPLMPANFDPFL-ZBFHGGJFSA-N 2-(2-chlorophenyl)-8-[(2r,3s)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]-5,7-dimethoxychromen-4-one Chemical compound C=1([C@H]2[C@@H](N(C)CC2)CO)C(OC)=CC(OC)=C(C(C=2)=O)C=1OC=2C1=CC=CC=C1Cl SGOPLMPANFDPFL-ZBFHGGJFSA-N 0.000 claims description 4
• 125000001627 3 membered heterocyclic group Chemical group 0.000 claims description 4
• 125000001963 4 membered heterocyclic group Chemical group 0.000 claims description 4
• 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 4
• 150000008064 anhydrides Chemical class 0.000 claims description 4
• 150000001733 carboxylic acid esters Chemical class 0.000 claims description 4
• 125000002883 imidazolyl group Chemical group 0.000 claims description 4
• 208000015181 infectious disease Diseases 0.000 claims description 4
• 230000005764 inhibitory process Effects 0.000 claims description 4
• 239000008194 pharmaceutical composition Substances 0.000 claims description 4
• XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
• 125000004076 pyridyl group Chemical group 0.000 claims description 4
• UQDJHAYMWZNALO-ZBFHGGJFSA-N 2-(2-fluorophenyl)-8-[(2r,3s)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]-5,7-dimethoxychromen-4-one Chemical compound C=1([C@H]2[C@@H](N(C)CC2)CO)C(OC)=CC(OC)=C(C(C=2)=O)C=1OC=2C1=CC=CC=C1F UQDJHAYMWZNALO-ZBFHGGJFSA-N 0.000 claims description 3
• QKZDCWKGQNARJL-ZBFHGGJFSA-N 8-[(2r,3s)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]-2-(2-iodophenyl)-5,7-dimethoxychromen-4-one Chemical compound C=1([C@H]2[C@@H](N(C)CC2)CO)C(OC)=CC(OC)=C(C(C=2)=O)C=1OC=2C1=CC=CC=C1I QKZDCWKGQNARJL-ZBFHGGJFSA-N 0.000 claims description 3
• XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 3
• 241000124008 Mammalia Species 0.000 claims description 3
• CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims description 3
• 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 3
• 230000003412 degenerative effect Effects 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 3
• 239000003446 ligand Substances 0.000 claims description 3
• XKEKCNIHHDRNGV-DOMZBBRYSA-N 2-(2,6-difluorophenyl)-8-[(2r,3s)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]-5,7-dimethoxychromen-4-one Chemical compound C=1([C@H]2[C@@H](N(C)CC2)CO)C(OC)=CC(OC)=C(C(C=2)=O)C=1OC=2C1=C(F)C=CC=C1F XKEKCNIHHDRNGV-DOMZBBRYSA-N 0.000 claims description 2
• GBPYOBMJRSHVKK-RISCZKNCSA-N 2-(2-bromo-5-chlorophenyl)-5,7-dihydroxy-8-[(2r,3s)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]chromen-4-one Chemical compound OC[C@@H]1N(C)CC[C@H]1C1=C(O)C=C(O)C2=C1OC(C=1C(=CC=C(Cl)C=1)Br)=CC2=O GBPYOBMJRSHVKK-RISCZKNCSA-N 0.000 claims description 2
• JQXZUTOKJQMULO-RISCZKNCSA-N 2-(2-bromo-5-fluorophenyl)-5,7-dihydroxy-8-[(2r,3s)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]chromen-4-one Chemical compound OC[C@@H]1N(C)CC[C@H]1C1=C(O)C=C(O)C2=C1OC(C=1C(=CC=C(F)C=1)Br)=CC2=O JQXZUTOKJQMULO-RISCZKNCSA-N 0.000 claims description 2
• BNKOPTLXYPPYNP-CJNGLKHVSA-N 2-(2-bromo-5-fluorophenyl)-8-[(2r,3s)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]-5,7-dimethoxychromen-4-one Chemical compound C=1([C@H]2[C@@H](N(C)CC2)CO)C(OC)=CC(OC)=C(C(C=2)=O)C=1OC=2C1=CC(F)=CC=C1Br BNKOPTLXYPPYNP-CJNGLKHVSA-N 0.000 claims description 2
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• XITTXHUPPCSENT-CJNGLKHVSA-N 2-(2-chloro-5-iodophenyl)-8-[(2r,3s)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]-5,7-dimethoxychromen-4-one Chemical compound C=1([C@H]2[C@@H](N(C)CC2)CO)C(OC)=CC(OC)=C(C(C=2)=O)C=1OC=2C1=CC(I)=CC=C1Cl XITTXHUPPCSENT-CJNGLKHVSA-N 0.000 claims description 2
• PIGMBCOWWDVOLL-DOMZBBRYSA-N 2-(2-chloro-5-methylphenyl)-5,7-dihydroxy-8-[(2r,3s)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]chromen-4-one Chemical compound OC[C@@H]1N(C)CC[C@H]1C1=C(O)C=C(O)C2=C1OC(C=1C(=CC=C(C)C=1)Cl)=CC2=O PIGMBCOWWDVOLL-DOMZBBRYSA-N 0.000 claims description 2
• WIZAIQZEMFQXAY-OCCSQVGLSA-N 2-(2-fluorophenyl)-5,7-dihydroxy-8-[(2r,3s)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]chromen-4-one Chemical compound OC[C@@H]1N(C)CC[C@H]1C1=C(O)C=C(O)C2=C1OC(C=1C(=CC=CC=1)F)=CC2=O WIZAIQZEMFQXAY-OCCSQVGLSA-N 0.000 claims description 2
• DRFNMIASSQGEMC-CVEARBPZSA-N 2-(3-fluorophenyl)-8-[(2r,3s)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]-5,7-dimethoxychromen-4-one Chemical compound C=1([C@H]2[C@@H](N(C)CC2)CO)C(OC)=CC(OC)=C(C(C=2)=O)C=1OC=2C1=CC=CC(F)=C1 DRFNMIASSQGEMC-CVEARBPZSA-N 0.000 claims description 2
• HLAAITJEUGEEDZ-CABCVRRESA-N 2-(4-bromophenyl)-5-hydroxy-8-[(2r,3s)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]-7-methoxychromen-4-one Chemical compound C=1([C@H]2[C@@H](N(C)CC2)CO)C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(Br)C=C1 HLAAITJEUGEEDZ-CABCVRRESA-N 0.000 claims description 2
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• VRGDGGVQPBQORM-OCCSQVGLSA-N 8-[(2R,3S)-2-(aminomethyl)-1-methylpyrrolidin-3-yl]-2-(2-chlorophenyl)-5,7-dihydroxychromen-4-one Chemical compound NC[C@@H]1N(CC[C@H]1C=1C(=CC(=C2C(C=C(OC12)C1=C(C=CC=C1)Cl)=O)O)O)C VRGDGGVQPBQORM-OCCSQVGLSA-N 0.000 claims description 2
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• 241000012481 Xiha Species 0.000 claims description 2
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• 125000004185 ester group Chemical group 0.000 claims description 2
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• YMQPSSGYWXIJPA-CVEARBPZSA-N 8-[(2r,3s)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]-5,7-dimethoxy-2-[4-(trifluoromethyl)phenyl]chromen-4-one Chemical compound C=1([C@H]2[C@@H](N(C)CC2)CO)C(OC)=CC(OC)=C(C(C=2)=O)C=1OC=2C1=CC=C(C(F)(F)F)C=C1 YMQPSSGYWXIJPA-CVEARBPZSA-N 0.000 claims 3
• KGZRQWIOZZIRNQ-PBHICJAKSA-N 2-(2-bromo-5-methoxyphenyl)-8-[(2r,3s)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]-5,7-dimethoxychromen-4-one Chemical compound COC1=CC=C(Br)C(C=2OC3=C([C@H]4[C@@H](N(C)CC4)CO)C(OC)=CC(OC)=C3C(=O)C=2)=C1 KGZRQWIOZZIRNQ-PBHICJAKSA-N 0.000 claims 2
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• 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 2
• PZBHLMVVHAHMAW-MFKMUULPSA-N 2-(2,6-difluorophenyl)-5,7-dihydroxy-8-[(2r,3s)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]chromen-4-one Chemical compound OC[C@@H]1N(C)CC[C@H]1C1=C(O)C=C(O)C2=C1OC(C=1C(=CC=CC=1F)F)=CC2=O PZBHLMVVHAHMAW-MFKMUULPSA-N 0.000 claims 1
• ZMMIWNJEXSYVHQ-MFKMUULPSA-N 2-(2-bromo-3-fluorophenyl)-5,7-dihydroxy-8-[(2r,3s)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]chromen-4-one Chemical compound OC[C@@H]1N(C)CC[C@H]1C1=C(O)C=C(O)C2=C1OC(C=1C(=C(F)C=CC=1)Br)=CC2=O ZMMIWNJEXSYVHQ-MFKMUULPSA-N 0.000 claims 1
• VWMKVDDBMWLXRM-OCCSQVGLSA-N 2-(2-bromo-4-hydroxyphenyl)-5,7-dihydroxy-8-[(2r,3s)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]chromen-4-one Chemical compound OC[C@@H]1N(C)CC[C@H]1C1=C(O)C=C(O)C2=C1OC(C=1C(=CC(O)=CC=1)Br)=CC2=O VWMKVDDBMWLXRM-OCCSQVGLSA-N 0.000 claims 1
• DUFCTYSEEUHWIU-WBVHZDCISA-N 2-(2-bromo-4-methoxyphenyl)-8-[(2r,3s)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]-5,7-dimethoxychromen-4-one Chemical compound BrC1=CC(OC)=CC=C1C1=CC(=O)C2=C(OC)C=C(OC)C([C@H]3[C@@H](N(C)CC3)CO)=C2O1 DUFCTYSEEUHWIU-WBVHZDCISA-N 0.000 claims 1
• CBZBGXYVQVHJEQ-OCCSQVGLSA-N 2-(2-bromo-4-nitrophenyl)-5,7-dihydroxy-8-[(2r,3s)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]chromen-4-one Chemical compound OC[C@@H]1N(C)CC[C@H]1C1=C(O)C=C(O)C2=C1OC(C=1C(=CC(=CC=1)[N+]([O-])=O)Br)=CC2=O CBZBGXYVQVHJEQ-OCCSQVGLSA-N 0.000 claims 1
• MBYBPXMWCPUHFV-RISCZKNCSA-N 2-(2-bromo-5-hydroxyphenyl)-5,7-dihydroxy-8-[(2r,3s)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]chromen-4-one Chemical compound OC[C@@H]1N(C)CC[C@H]1C1=C(O)C=C(O)C2=C1OC(C=1C(=CC=C(O)C=1)Br)=CC2=O MBYBPXMWCPUHFV-RISCZKNCSA-N 0.000 claims 1
• FGYDDFAFJOOJLU-DOMZBBRYSA-N 2-(2-chloro-3-fluorophenyl)-8-[(2r,3s)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]-5,7-dimethoxychromen-4-one Chemical compound C=1([C@H]2[C@@H](N(C)CC2)CO)C(OC)=CC(OC)=C(C(C=2)=O)C=1OC=2C1=CC=CC(F)=C1Cl FGYDDFAFJOOJLU-DOMZBBRYSA-N 0.000 claims 1
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