NO316176B1 - Bicykliske heteroaromatiske forbindelser som proteintyrosinkinaseinhibitorer, anvendelse og fremstilling derav, samt farmasoytisk formulering - Google Patents
Bicykliske heteroaromatiske forbindelser som proteintyrosinkinaseinhibitorer, anvendelse og fremstilling derav, samt farmasoytisk formulering Download PDFInfo
- Publication number
- NO316176B1 NO316176B1 NO20003561A NO20003561A NO316176B1 NO 316176 B1 NO316176 B1 NO 316176B1 NO 20003561 A NO20003561 A NO 20003561A NO 20003561 A NO20003561 A NO 20003561A NO 316176 B1 NO316176 B1 NO 316176B1
- Authority
- NO
- Norway
- Prior art keywords
- methyl
- amine
- fluorobenzyloxy
- phenyl
- benzyloxy
- Prior art date
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- -1 Bicyclic heteroaromatic compounds Chemical class 0.000 title claims abstract description 72
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 6
- 239000005483 tyrosine kinase inhibitor Substances 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 157
- 150000003839 salts Chemical class 0.000 claims abstract description 51
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000012453 solvate Substances 0.000 claims abstract description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 25
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 19
- 150000002367 halogens Chemical class 0.000 claims abstract description 19
- 239000001257 hydrogen Substances 0.000 claims abstract description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 10
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 6
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 162
- 238000006243 chemical reaction Methods 0.000 claims description 69
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims description 23
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims description 23
- 238000011282 treatment Methods 0.000 claims description 23
- 239000003153 chemical reaction reagent Substances 0.000 claims description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 21
- 230000000694 effects Effects 0.000 claims description 18
- 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 claims description 16
- 101710100968 Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims description 15
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims description 15
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 206010028980 Neoplasm Diseases 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 230000001404 mediated effect Effects 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 108091005682 Receptor kinases Proteins 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 150000002240 furans Chemical class 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- QEHYWVNDAWPVRJ-UHFFFAOYSA-N n-[4-[(3-fluorophenyl)methoxy]phenyl]-6-[2-[(2-methylsulfonylethylamino)methyl]-1,3-thiazol-4-yl]quinazolin-4-amine Chemical compound S1C(CNCCS(=O)(=O)C)=NC(C=2C=C3C(NC=4C=CC(OCC=5C=C(F)C=CC=5)=CC=4)=NC=NC3=CC=2)=C1 QEHYWVNDAWPVRJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- PSLPNMRXSBQHQB-UHFFFAOYSA-N n-(3-bromo-4-phenylmethoxyphenyl)-6-[2-[(2-methylsulfonylethylamino)methyl]-1,3-thiazol-4-yl]quinazolin-4-amine Chemical compound S1C(CNCCS(=O)(=O)C)=NC(C=2C=C3C(NC=4C=C(Br)C(OCC=5C=CC=CC=5)=CC=4)=NC=NC3=CC=2)=C1 PSLPNMRXSBQHQB-UHFFFAOYSA-N 0.000 claims description 2
- UGLDUUSMNMDDMH-UHFFFAOYSA-N n-[3-bromo-4-[(3-fluorophenyl)methoxy]phenyl]-7-fluoro-6-[2-[(2-methylsulfonylethylamino)methyl]-1,3-thiazol-4-yl]quinazolin-4-amine Chemical compound S1C(CNCCS(=O)(=O)C)=NC(C=2C(=CC3=NC=NC(NC=4C=C(Br)C(OCC=5C=C(F)C=CC=5)=CC=4)=C3C=2)F)=C1 UGLDUUSMNMDDMH-UHFFFAOYSA-N 0.000 claims description 2
- ZHQNAWZWCCTYIT-UHFFFAOYSA-N n-[4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[(2-methylsulfonylethylamino)methyl]-1,3-thiazol-2-yl]quinazolin-4-amine Chemical compound S1C(CNCCS(=O)(=O)C)=CN=C1C1=CC=C(N=CN=C2NC=3C=CC(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 ZHQNAWZWCCTYIT-UHFFFAOYSA-N 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 2
- 125000004546 quinazolin-4-yl group Chemical group N1=CN=C(C2=CC=CC=C12)* 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims 1
- MNNXRVSQOABRRP-UHFFFAOYSA-N N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[2-[(2-methylsulfonylethylamino)methyl]-4-thiazolyl]-4-quinazolinamine Chemical group S1C(CNCCS(=O)(=O)C)=NC(C=2C=C3C(NC=4C=C(Cl)C(OCC=5C=C(F)C=CC=5)=CC=4)=NC=NC3=CC=2)=C1 MNNXRVSQOABRRP-UHFFFAOYSA-N 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- AXVKGZLOECWENV-UHFFFAOYSA-N n-(3-chloro-4-phenylmethoxyphenyl)-6-[2-[(2-methylsulfonylethylamino)methyl]-1,3-thiazol-4-yl]quinazolin-4-amine Chemical compound S1C(CNCCS(=O)(=O)C)=NC(C=2C=C3C(NC=4C=C(Cl)C(OCC=5C=CC=CC=5)=CC=4)=NC=NC3=CC=2)=C1 AXVKGZLOECWENV-UHFFFAOYSA-N 0.000 claims 1
- VSCPXIGUZBDNSV-UHFFFAOYSA-N n-(3-fluoro-4-phenylmethoxyphenyl)-6-[5-[(2-methylsulfonylethylamino)methyl]furan-3-yl]quinazolin-4-amine Chemical compound O1C(CNCCS(=O)(=O)C)=CC(C=2C=C3C(NC=4C=C(F)C(OCC=5C=CC=CC=5)=CC=4)=NC=NC3=CC=2)=C1 VSCPXIGUZBDNSV-UHFFFAOYSA-N 0.000 claims 1
- IZSWEZTZKROPAX-UHFFFAOYSA-N n-[4-[(3-fluorophenyl)methoxy]phenyl]-6-[2-[(2-methylsulfonylethylamino)methyl]-1,3-thiazol-5-yl]quinazolin-4-amine Chemical compound S1C(CNCCS(=O)(=O)C)=NC=C1C1=CC=C(N=CN=C2NC=3C=CC(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 IZSWEZTZKROPAX-UHFFFAOYSA-N 0.000 claims 1
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 16
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 13
- 125000000217 alkyl group Chemical group 0.000 abstract description 10
- 229910052720 vanadium Inorganic materials 0.000 abstract description 5
- 125000003282 alkyl amino group Chemical group 0.000 abstract description 2
- 125000004414 alkyl thio group Chemical group 0.000 abstract description 2
- 150000002431 hydrogen Chemical group 0.000 abstract description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 abstract 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 abstract 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 abstract 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 2
- 125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 abstract 1
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 abstract 1
- 125000005955 1H-indazolyl group Chemical group 0.000 abstract 1
- 125000005236 alkanoylamino group Chemical group 0.000 abstract 1
- 125000003342 alkenyl group Chemical group 0.000 abstract 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 abstract 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 abstract 1
- 125000000304 alkynyl group Chemical group 0.000 abstract 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 abstract 1
- 125000004093 cyano group Chemical group *C#N 0.000 abstract 1
- 150000002390 heteroarenes Chemical class 0.000 abstract 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 abstract 1
- 125000001041 indolyl group Chemical group 0.000 abstract 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 abstract 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 abstract 1
- 125000004076 pyridyl group Chemical group 0.000 abstract 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 abstract 1
- 229930192474 thiophene Natural products 0.000 abstract 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract 1
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- 239000007787 solid Substances 0.000 description 88
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 82
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 54
- 238000005481 NMR spectroscopy Methods 0.000 description 50
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 47
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- 150000001412 amines Chemical class 0.000 description 34
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 34
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 32
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 29
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Classifications
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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GBGB9800569.7A GB9800569D0 (en) | 1998-01-12 | 1998-01-12 | Heterocyclic compounds |
PCT/EP1999/000048 WO1999035146A1 (en) | 1998-01-12 | 1999-01-08 | Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors |
Publications (3)
Publication Number | Publication Date |
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NO20003561D0 NO20003561D0 (no) | 2000-07-11 |
NO20003561L NO20003561L (no) | 2000-09-11 |
NO316176B1 true NO316176B1 (no) | 2003-12-22 |
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NO20003561A NO316176B1 (no) | 1998-01-12 | 2000-07-11 | Bicykliske heteroaromatiske forbindelser som proteintyrosinkinaseinhibitorer, anvendelse og fremstilling derav, samt farmasoytisk formulering |
NO2008017C NO2008017I1 (no) | 1998-01-12 | 2008-11-13 | N-[3-klor-4-{[(3-fluorfenyl)metyl]oksy}fenyl]-6[5-({[2-metylsulfonyl)etyl]amino}metyl)-2-furanyl]-4-kinazolinamin eller salt eller solvat derav |
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NO2008017C NO2008017I1 (no) | 1998-01-12 | 2008-11-13 | N-[3-klor-4-{[(3-fluorfenyl)metyl]oksy}fenyl]-6[5-({[2-metylsulfonyl)etyl]amino}metyl)-2-furanyl]-4-kinazolinamin eller salt eller solvat derav |
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