CA2417897C - Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them - Google Patents
Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them Download PDFInfo
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- CA2417897C CA2417897C CA002417897A CA2417897A CA2417897C CA 2417897 C CA2417897 C CA 2417897C CA 002417897 A CA002417897 A CA 002417897A CA 2417897 A CA2417897 A CA 2417897A CA 2417897 C CA2417897 C CA 2417897C
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- CA
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- Prior art keywords
- amino
- quinazoline
- oxo
- chloro
- fluorophenyl
- Prior art date
- 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.)
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- 150000001875 compounds Chemical class 0.000 title claims description 85
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 6
- 125000002618 bicyclic heterocycle group Chemical group 0.000 title abstract description 4
- 238000000034 method Methods 0.000 title description 7
- 230000008569 process Effects 0.000 title description 2
- 150000003839 salts Chemical class 0.000 claims abstract description 42
- 201000010099 disease Diseases 0.000 claims abstract description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 20
- 210000004072 lung Anatomy 0.000 claims abstract description 7
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 4
- 150000007524 organic acids Chemical class 0.000 claims abstract description 4
- -1 methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy Chemical group 0.000 claims description 128
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 81
- 238000006243 chemical reaction Methods 0.000 claims description 52
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 42
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 15
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- RWAHVEYSYXHNAL-UHFFFAOYSA-N 4-[2-[4-(3-chloro-4-fluoroanilino)-6-cyclopentyloxyquinazolin-7-yl]oxyethyl]-6,6-dimethylmorpholin-2-one Chemical compound C1C(=O)OC(C)(C)CN1CCOC1=CC2=NC=NC(NC=3C=C(Cl)C(F)=CC=3)=C2C=C1OC1CCCC1 RWAHVEYSYXHNAL-UHFFFAOYSA-N 0.000 claims description 11
- NZBVKCLSEPVJHF-UHFFFAOYSA-N 4-[2-[4-(3-chloro-4-fluoroanilino)-6-(cyclopropylmethoxy)quinazolin-7-yl]oxyethyl]-6,6-dimethylmorpholin-2-one Chemical compound C1C(=O)OC(C)(C)CN1CCOC1=CC2=NC=NC(NC=3C=C(Cl)C(F)=CC=3)=C2C=C1OCC1CC1 NZBVKCLSEPVJHF-UHFFFAOYSA-N 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- KLUXUPFXUSDNOO-UHFFFAOYSA-N 4-[2-[4-(3-chloro-4-fluoroanilino)-6-cyclopentyloxyquinazolin-7-yl]oxyethyl-methylamino]oxolan-2-one Chemical compound C1OC(=O)CC1N(C)CCOC(C(=CC1=2)OC3CCCC3)=CC1=NC=NC=2NC1=CC=C(F)C(Cl)=C1 KLUXUPFXUSDNOO-UHFFFAOYSA-N 0.000 claims description 7
- DAIBLUSVAFXMJJ-UHFFFAOYSA-N 4-[2-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]oxyethyl]-6,6-dimethylmorpholin-2-one Chemical compound C=12C=C(OCCN3CC(C)(C)OC(=O)C3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 DAIBLUSVAFXMJJ-UHFFFAOYSA-N 0.000 claims description 7
- PENJTVNVWKGZKD-UHFFFAOYSA-N 4-[3-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypropyl]-6,6-dimethylmorpholin-2-one Chemical compound C=12C=C(OCCCN3CC(C)(C)OC(=O)C3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 PENJTVNVWKGZKD-UHFFFAOYSA-N 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- QTQNMKOQYNBYDT-UHFFFAOYSA-N 4-[2-[4-(3-chloro-4-fluoroanilino)-6-(cyclopentylmethoxy)quinazolin-7-yl]oxyethyl]-6,6-dimethylmorpholin-2-one Chemical compound C1C(=O)OC(C)(C)CN1CCOC1=CC2=NC=NC(NC=3C=C(Cl)C(F)=CC=3)=C2C=C1OCC1CCCC1 QTQNMKOQYNBYDT-UHFFFAOYSA-N 0.000 claims description 6
- AROYRXOYFGHXLP-UHFFFAOYSA-N 4-[3-[4-(3-chloro-4-fluoroanilino)-7-cyclopentyloxyquinazolin-6-yl]oxypropyl]-6,6-dimethylmorpholin-2-one Chemical compound C1C(=O)OC(C)(C)CN1CCCOC(C(=CC1=NC=N2)OC3CCCC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 AROYRXOYFGHXLP-UHFFFAOYSA-N 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- HBQDVCAYRXMBGM-ZWKOTPCHSA-N (6s)-4-[3-[7-methoxy-4-[[(1r)-1-phenylethyl]amino]quinazolin-6-yl]oxypropyl]-6-methylmorpholin-2-one Chemical compound C1([C@@H](C)NC=2N=CN=C3C=C(C(=CC3=2)OCCCN2CC(=O)O[C@@H](C)C2)OC)=CC=CC=C1 HBQDVCAYRXMBGM-ZWKOTPCHSA-N 0.000 claims description 5
- BAUCTDMQPYLVQN-UHFFFAOYSA-N 4-[2-[4-(3-bromoanilino)-7-methoxyquinazolin-6-yl]oxyethyl]-3-methylmorpholin-2-one Chemical compound C=12C=C(OCCN3C(C(=O)OCC3)C)C(OC)=CC2=NC=NC=1NC1=CC=CC(Br)=C1 BAUCTDMQPYLVQN-UHFFFAOYSA-N 0.000 claims description 5
- JSLMOUXQBQDGLP-UHFFFAOYSA-N 4-[2-[4-(3-bromoanilino)-7-methoxyquinazolin-6-yl]oxyethyl]-6,6-dimethylmorpholin-2-one Chemical compound C=12C=C(OCCN3CC(C)(C)OC(=O)C3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Br)=C1 JSLMOUXQBQDGLP-UHFFFAOYSA-N 0.000 claims description 5
- GYVRDMNWJPTXML-UHFFFAOYSA-N 4-[2-[4-(3-chloro-4-fluoroanilino)-7-(cyclopropylmethoxy)quinazolin-6-yl]oxyethyl]-6,6-dimethylmorpholin-2-one Chemical compound C1C(=O)OC(C)(C)CN1CCOC(C(=CC1=NC=N2)OCC3CC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 GYVRDMNWJPTXML-UHFFFAOYSA-N 0.000 claims description 5
- OFWKTIYGKIJXOE-UHFFFAOYSA-N 4-[2-[4-(3-chloro-4-fluoroanilino)-7-cyclobutyloxyquinazolin-6-yl]oxyethyl]-6,6-dimethylmorpholin-2-one Chemical compound C1C(=O)OC(C)(C)CN1CCOC(C(=CC1=NC=N2)OC3CCC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 OFWKTIYGKIJXOE-UHFFFAOYSA-N 0.000 claims description 5
- LIKMFAJDPFCRSP-UHFFFAOYSA-N 4-[2-[4-(3-chloro-4-fluoroanilino)-7-cyclopentyloxyquinazolin-6-yl]oxyethyl]-6,6-dimethylmorpholin-2-one Chemical compound C1C(=O)OC(C)(C)CN1CCOC(C(=CC1=NC=N2)OC3CCCC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 LIKMFAJDPFCRSP-UHFFFAOYSA-N 0.000 claims description 5
- 210000000013 bile duct Anatomy 0.000 claims description 5
- 201000011510 cancer Diseases 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 210000000232 gallbladder Anatomy 0.000 claims description 5
- 210000003734 kidney Anatomy 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- YTKFKKLZSIVJMX-CYBMUJFWSA-N (6r)-4-[2-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]oxyethyl]-6-methylmorpholin-2-one Chemical compound C=12C=C(OCCN3CC(=O)O[C@H](C)C3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 YTKFKKLZSIVJMX-CYBMUJFWSA-N 0.000 claims description 4
- WSRABTAALVGLSH-UHFFFAOYSA-N 4-[2-[4-(3-chloro-4-fluoroanilino)-6-(cyclopentylmethoxy)quinazolin-7-yl]oxyethyl-methylamino]oxolan-2-one Chemical compound C1OC(=O)CC1N(C)CCOC(C(=CC1=2)OCC3CCCC3)=CC1=NC=NC=2NC1=CC=C(F)C(Cl)=C1 WSRABTAALVGLSH-UHFFFAOYSA-N 0.000 claims description 4
- CCEJFLUXVPEPKO-UHFFFAOYSA-N 4-[2-[4-(3-chloro-4-fluoroanilino)-6-cyclobutyloxyquinazolin-7-yl]oxyethyl]-6,6-dimethylmorpholin-2-one Chemical compound C1C(=O)OC(C)(C)CN1CCOC1=CC2=NC=NC(NC=3C=C(Cl)C(F)=CC=3)=C2C=C1OC1CCC1 CCEJFLUXVPEPKO-UHFFFAOYSA-N 0.000 claims description 4
- TYTIBVDKISSGSI-UHFFFAOYSA-N 4-[2-[4-(3-chloro-4-fluoroanilino)-6-methoxyquinazolin-7-yl]oxyethyl-methylamino]oxolan-2-one Chemical compound N1=CN=C2C=C(OCCN(C)C3CC(=O)OC3)C(OC)=CC2=C1NC1=CC=C(F)C(Cl)=C1 TYTIBVDKISSGSI-UHFFFAOYSA-N 0.000 claims description 4
- ZCWYAZUJPZABLJ-UHFFFAOYSA-N 4-[2-[4-(3-chloro-4-fluoroanilino)-6-methoxyquinazolin-7-yl]oxyethyl]-6,6-dimethylmorpholin-2-one Chemical compound N1=CN=C2C=C(OCCN3CC(C)(C)OC(=O)C3)C(OC)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ZCWYAZUJPZABLJ-UHFFFAOYSA-N 0.000 claims description 4
- MQNVZWJAFPETRQ-UHFFFAOYSA-N 4-[2-[4-(3-chloro-4-fluoroanilino)-7-(cyclopentylmethoxy)quinazolin-6-yl]oxyethyl-methylamino]oxolan-2-one Chemical compound C1OC(=O)CC1N(C)CCOC(C(=CC1=NC=N2)OCC3CCCC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 MQNVZWJAFPETRQ-UHFFFAOYSA-N 0.000 claims description 4
- MJWGUQUVMQNFPO-UHFFFAOYSA-N 4-[3-[4-(3-chloro-4-fluoroanilino)-6-(cyclopentylmethoxy)quinazolin-7-yl]oxypropyl]-6,6-dimethylmorpholin-2-one Chemical compound C1C(=O)OC(C)(C)CN1CCCOC1=CC2=NC=NC(NC=3C=C(Cl)C(F)=CC=3)=C2C=C1OCC1CCCC1 MJWGUQUVMQNFPO-UHFFFAOYSA-N 0.000 claims description 4
- DFENXCTZLWKHRS-UHFFFAOYSA-N 4-[3-[4-(3-chloro-4-fluoroanilino)-6-cyclopentyloxyquinazolin-7-yl]oxypropyl]-6,6-dimethylmorpholin-2-one Chemical compound C1C(=O)OC(C)(C)CN1CCCOC1=CC2=NC=NC(NC=3C=C(Cl)C(F)=CC=3)=C2C=C1OC1CCCC1 DFENXCTZLWKHRS-UHFFFAOYSA-N 0.000 claims description 4
- BNQKFXMIUFAING-UHFFFAOYSA-N 4-[3-[4-(3-chloro-4-fluoroanilino)-6-methoxyquinazolin-7-yl]oxypropyl]-6,6-dimethylmorpholin-2-one Chemical compound N1=CN=C2C=C(OCCCN3CC(C)(C)OC(=O)C3)C(OC)=CC2=C1NC1=CC=C(F)C(Cl)=C1 BNQKFXMIUFAING-UHFFFAOYSA-N 0.000 claims description 4
- NWNSEKIWSUBXNV-UHFFFAOYSA-N 4-[3-[4-(3-chloro-4-fluoroanilino)-7-(cyclopentylmethoxy)quinazolin-6-yl]oxypropyl]-6,6-dimethylmorpholin-2-one Chemical compound C1C(=O)OC(C)(C)CN1CCCOC(C(=CC1=NC=N2)OCC3CCCC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 NWNSEKIWSUBXNV-UHFFFAOYSA-N 0.000 claims description 4
- MSWAPRHYKIDXQU-OAQYLSRUSA-N 4-[3-[7-cyclopentyloxy-4-[[(1r)-1-phenylethyl]amino]quinazolin-6-yl]oxypropyl]-6,6-dimethylmorpholin-2-one Chemical compound N([C@H](C)C=1C=CC=CC=1)C(C1=CC=2OCCCN3CC(C)(C)OC(=O)C3)=NC=NC1=CC=2OC1CCCC1 MSWAPRHYKIDXQU-OAQYLSRUSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- VHKZTIYWIQXOBG-CQSZACIVSA-N (6r)-4-[2-[4-(3-bromoanilino)-7-methoxyquinazolin-6-yl]oxyethyl]-6-methylmorpholin-2-one Chemical compound C=12C=C(OCCN3CC(=O)O[C@H](C)C3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Br)=C1 VHKZTIYWIQXOBG-CQSZACIVSA-N 0.000 claims description 3
- MZNBOOZVWZELQB-CQSZACIVSA-N (6r)-4-[3-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypropyl]-6-methylmorpholin-2-one Chemical compound C=12C=C(OCCCN3CC(=O)O[C@H](C)C3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 MZNBOOZVWZELQB-CQSZACIVSA-N 0.000 claims description 3
- YTKFKKLZSIVJMX-ZDUSSCGKSA-N (6s)-4-[2-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]oxyethyl]-6-methylmorpholin-2-one Chemical compound C=12C=C(OCCN3CC(=O)O[C@@H](C)C3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 YTKFKKLZSIVJMX-ZDUSSCGKSA-N 0.000 claims description 3
- PXDBSNNJZMFALW-DLBZAZTESA-N (6s)-4-[2-[7-methoxy-4-[[(1r)-1-phenylethyl]amino]quinazolin-6-yl]oxyethyl]-6-methylmorpholin-2-one Chemical compound C1([C@@H](C)NC=2N=CN=C3C=C(C(=CC3=2)OCCN2CC(=O)O[C@@H](C)C2)OC)=CC=CC=C1 PXDBSNNJZMFALW-DLBZAZTESA-N 0.000 claims description 3
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- GVMFBYFHOKWOFP-UHFFFAOYSA-N 4-[2-[4-(3-bromoanilino)-7-methoxyquinazolin-6-yl]oxyethyl]-5,5-dimethylmorpholin-2-one Chemical compound C=12C=C(OCCN3C(COC(=O)C3)(C)C)C(OC)=CC2=NC=NC=1NC1=CC=CC(Br)=C1 GVMFBYFHOKWOFP-UHFFFAOYSA-N 0.000 claims description 3
- XILCDKHRLVBGRM-UHFFFAOYSA-N 4-[2-[4-(3-chloro-4-fluoroanilino)-6-(cyclopropylmethoxy)quinazolin-7-yl]oxyethyl-methylamino]oxolan-2-one Chemical compound C1OC(=O)CC1N(C)CCOC(C(=CC1=2)OCC3CC3)=CC1=NC=NC=2NC1=CC=C(F)C(Cl)=C1 XILCDKHRLVBGRM-UHFFFAOYSA-N 0.000 claims description 3
- KAZLMIBQIIGVMX-UHFFFAOYSA-N 4-[2-[4-(3-chloro-4-fluoroanilino)-7-cyclopentyloxyquinazolin-6-yl]oxyethyl-methylamino]oxolan-2-one Chemical compound C1OC(=O)CC1N(C)CCOC(C(=CC1=NC=N2)OC3CCCC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 KAZLMIBQIIGVMX-UHFFFAOYSA-N 0.000 claims description 3
- VBCDIYXYEHUGQT-UHFFFAOYSA-N 4-[2-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]oxyethyl-methylamino]oxolan-2-one Chemical compound C=12C=C(OCCN(C)C3CC(=O)OC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 VBCDIYXYEHUGQT-UHFFFAOYSA-N 0.000 claims description 3
- SNVKZKSVYQHPOI-UHFFFAOYSA-N 4-[3-[4-(3-chloro-4-fluoroanilino)-7-(cyclopropylmethoxy)quinazolin-6-yl]oxypropyl]-6,6-dimethylmorpholin-2-one Chemical compound C1C(=O)OC(C)(C)CN1CCCOC(C(=CC1=NC=N2)OCC3CC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 SNVKZKSVYQHPOI-UHFFFAOYSA-N 0.000 claims description 3
- JTQXMFAVYKQORF-UHFFFAOYSA-N 4-[3-[4-(3-chloro-4-fluoroanilino)-7-cyclobutyloxyquinazolin-6-yl]oxypropyl]-6,6-dimethylmorpholin-2-one Chemical compound C1C(=O)OC(C)(C)CN1CCCOC(C(=CC1=NC=N2)OC3CCC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 JTQXMFAVYKQORF-UHFFFAOYSA-N 0.000 claims description 3
- JCRXOOXQHWVXCX-OAQYLSRUSA-N 4-[3-[6-cyclopentyloxy-4-[[(1r)-1-phenylethyl]amino]quinazolin-7-yl]oxypropyl]-6,6-dimethylmorpholin-2-one Chemical compound N([C@H](C)C=1C=CC=CC=1)C(C1=CC=2OC3CCCC3)=NC=NC1=CC=2OCCCN1CC(=O)OC(C)(C)C1 JCRXOOXQHWVXCX-OAQYLSRUSA-N 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- VHKZTIYWIQXOBG-AWEZNQCLSA-N (6s)-4-[2-[4-(3-bromoanilino)-7-methoxyquinazolin-6-yl]oxyethyl]-6-methylmorpholin-2-one Chemical compound C=12C=C(OCCN3CC(=O)O[C@@H](C)C3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Br)=C1 VHKZTIYWIQXOBG-AWEZNQCLSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims 2
- ABTONHYLRHNDPJ-UHFFFAOYSA-N 4-[2-[4-(3-chloro-4-fluoroanilino)-7-(cyclopentylmethoxy)quinazolin-6-yl]oxyethyl]-6,6-dimethylmorpholin-2-one Chemical compound C1C(=O)OC(C)(C)CN1CCOC(C(=CC1=NC=N2)OCC3CCCC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 ABTONHYLRHNDPJ-UHFFFAOYSA-N 0.000 claims 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Immunology (AREA)
- Oncology (AREA)
- Dermatology (AREA)
- Gastroenterology & Hepatology (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10042058.3 | 2000-08-26 | ||
DE10042058A DE10042058A1 (de) | 2000-08-26 | 2000-08-26 | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
PCT/EP2001/009532 WO2002018351A1 (de) | 2000-08-26 | 2001-08-18 | Bicyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und vefahren zu ihrer herstellung |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2417897A1 CA2417897A1 (en) | 2003-01-30 |
CA2417897C true CA2417897C (en) | 2009-03-31 |
Family
ID=7653945
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002417897A Expired - Fee Related CA2417897C (en) | 2000-08-26 | 2001-08-18 | Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them |
Country Status (30)
Country | Link |
---|---|
EP (1) | EP1315705A1 (cs) |
JP (1) | JP4834282B2 (cs) |
KR (1) | KR100862873B1 (cs) |
CN (1) | CN100404517C (cs) |
AR (1) | AR033562A1 (cs) |
AU (2) | AU2001287694B2 (cs) |
BG (1) | BG107559A (cs) |
BR (1) | BR0113519A (cs) |
CA (1) | CA2417897C (cs) |
CZ (1) | CZ302567B6 (cs) |
DE (1) | DE10042058A1 (cs) |
EA (1) | EA005679B1 (cs) |
EC (1) | ECSP034464A (cs) |
EE (1) | EE05269B1 (cs) |
HR (1) | HRP20030138A2 (cs) |
HU (1) | HUP0300819A3 (cs) |
IL (2) | IL154602A0 (cs) |
ME (1) | MEP58708A (cs) |
MX (1) | MXPA03001483A (cs) |
MY (1) | MY126132A (cs) |
NO (1) | NO324866B1 (cs) |
NZ (1) | NZ524668A (cs) |
PL (1) | PL360248A1 (cs) |
RS (1) | RS52279B (cs) |
SK (1) | SK287747B6 (cs) |
TW (1) | TWI294422B (cs) |
UA (1) | UA73004C2 (cs) |
UY (1) | UY26903A1 (cs) |
WO (1) | WO2002018351A1 (cs) |
ZA (1) | ZA200300991B (cs) |
Families Citing this family (41)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MEP45508A (en) | 1999-06-21 | 2011-02-10 | Boehringer Ingelheim Pharma | Bicyclic heterocycles, medicaments containing these compounds, their use and methods for the production thereof |
DE10042059A1 (de) * | 2000-08-26 | 2002-03-07 | Boehringer Ingelheim Pharma | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
US7019012B2 (en) | 2000-12-20 | 2006-03-28 | Boehringer Ingelheim International Pharma Gmbh & Co. Kg | Quinazoline derivatives and pharmaceutical compositions containing them |
TW200813014A (en) * | 2002-03-28 | 2008-03-16 | Astrazeneca Ab | Quinazoline derivatives |
JP4776882B2 (ja) * | 2002-03-30 | 2011-09-21 | ベーリンガー インゲルハイム ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト | 二環式複素環化合物、これらの化合物を含む医薬組成物、それらの使用及びそれらの調製方法 |
US6924285B2 (en) | 2002-03-30 | 2005-08-02 | Boehringer Ingelheim Pharma Gmbh & Co. | Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them |
DE10214412A1 (de) * | 2002-03-30 | 2003-10-09 | Boehringer Ingelheim Pharma | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
EP2277867B1 (en) | 2002-07-15 | 2012-12-05 | Symphony Evolution, Inc. | Compounds, pharmaceutical compositions thereof and their use in treating cancer |
DE10326186A1 (de) * | 2003-06-06 | 2004-12-23 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
DE10334226A1 (de) * | 2003-07-28 | 2005-02-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verwendung von Tyrosinkinase-Inhibitoren zur Behandlung inflammatorischer Prozesse |
GB0317665D0 (en) | 2003-07-29 | 2003-09-03 | Astrazeneca Ab | Qinazoline derivatives |
DE602004013806D1 (en) | 2003-09-16 | 2008-06-26 | Astrazeneca Ab | Chinazolinderivate als tyrosinkinaseinhibitoren |
ES2279441T3 (es) | 2003-09-19 | 2007-08-16 | Astrazeneca Ab | Derivados de quinazolina. |
ES2651730T3 (es) | 2003-09-26 | 2018-01-29 | Exelixis, Inc. | Moduladores c-Met y métodos de uso |
DE10345875A1 (de) * | 2003-09-30 | 2005-04-21 | Boehringer Ingelheim Pharma | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Vewendung und Verfahren zu ihrer Herstellung |
US7456189B2 (en) | 2003-09-30 | 2008-11-25 | Boehringer Ingelheim International Gmbh | Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation |
DE10350717A1 (de) * | 2003-10-30 | 2005-06-02 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verwendung von Tyrosinkinase-Inhibitoren zur Behandlung inflammatorischer Prozesse |
US20060035893A1 (en) | 2004-08-07 | 2006-02-16 | Boehringer Ingelheim International Gmbh | Pharmaceutical compositions for treatment of respiratory and gastrointestinal disorders |
PE20060777A1 (es) | 2004-12-24 | 2006-10-06 | Boehringer Ingelheim Int | Derivados de indolinona para el tratamiento o la prevencion de enfermedades fibroticas |
ATE521603T1 (de) | 2005-02-26 | 2011-09-15 | Astrazeneca Ab | Chinazolinderivate als tyrosinkinaseinhibitoren |
KR100673775B1 (ko) * | 2005-04-08 | 2007-01-24 | 엘지전자 주식회사 | 냉장고용 홈바 |
CA2619037A1 (en) * | 2005-08-22 | 2007-03-01 | Boehringer Ingelheim International Gmbh | Bicyclic heterocycles medicaments comprising said compounds use and method for production thereof |
WO2007054550A1 (en) | 2005-11-11 | 2007-05-18 | Boehringer Ingelheim International Gmbh | Quinazoline derivatives for the treatment of cancer diseases |
CA2643363A1 (en) * | 2006-03-09 | 2007-09-13 | Boehringer Ingelheim International Gmbh | Bicyclic heterocycles, medicaments containing these compounds, their use and process for preparing them |
PL2068880T3 (pl) | 2006-09-18 | 2012-09-28 | Boehringer Ingelheim Int | Sposób leczenia raka z mutacjami EGFR |
EP1921070A1 (de) | 2006-11-10 | 2008-05-14 | Boehringer Ingelheim Pharma GmbH & Co. KG | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstelllung |
MX2009007610A (es) | 2007-02-06 | 2009-07-24 | Boehringer Ingelheim Int | Heterociclicos biciclicos, medicamentos que contienen estos compuestos, su utilizacion y procedimientos para su preparacion. |
SI2245026T1 (sl) | 2008-02-07 | 2012-12-31 | Boehringer Ingelheim International Gmbh | Spirociklični heterocikli, zdravila, ki vsebujejo te spojine, njihova uporaba in postopek za njihovo pripravo |
NZ589883A (en) | 2008-05-13 | 2012-06-29 | Astrazeneca Ab | Fumarate salt of 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [1- (n-methylcarbamoylmethyl) piperidin- 4-yl] oxy} quinazoline |
JP5539351B2 (ja) | 2008-08-08 | 2014-07-02 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | シクロヘキシルオキシ置換ヘテロ環、これらの化合物を含有する医薬、およびそれらを生成するための方法 |
KR102187034B1 (ko) | 2009-01-16 | 2020-12-04 | 엑셀리시스, 인코포레이티드 | 암 치료용 n-(4-{〔6,7-비스(메틸옥시)퀴놀린-4-일〕옥시}페닐)-n'-(4-플루오로페닐)사이클로프로판-1,1-디카르복사미드의 말산염 및 그 결정형 |
ES2731901T3 (es) | 2009-07-06 | 2019-11-19 | Boehringer Ingelheim Int | Proceso para el secado de BIBW2992, de sus sales y de formulaciones farmacéuticas sólidas que comprenden este ingrediente activo |
UA108618C2 (uk) | 2009-08-07 | 2015-05-25 | Застосування c-met-модуляторів в комбінації з темозоломідом та/або променевою терапією для лікування раку | |
KR101317809B1 (ko) | 2011-06-07 | 2013-10-16 | 한미약품 주식회사 | 암세포의 성장을 억제하는 아마이드 유도체 및 비금속염 활택제를 포함하는 약학 조성물 |
KR20140096571A (ko) | 2013-01-28 | 2014-08-06 | 한미약품 주식회사 | 1-(4-(4-(3,4-디클로로-2-플루오로페닐아미노)-7-메톡시퀴나졸린-6-일옥시)피페리딘-1-일)프로프-2-엔-1-온의 제조방법 |
ME03041B (me) | 2013-03-06 | 2018-10-20 | Astrazeneca Ab | Inhibitori hinazolina aktivirajućih mutantnih oblika receptora epidermalnog faktora rasta |
US9242965B2 (en) | 2013-12-31 | 2016-01-26 | Boehringer Ingelheim International Gmbh | Process for the manufacture of (E)-4-N,N-dialkylamino crotonic acid in HX salt form and use thereof for synthesis of EGFR tyrosine kinase inhibitors |
MA39837B1 (fr) * | 2014-04-04 | 2020-05-29 | H Lundbeck As | Quinazoline-thf-amines halogénées en tant qu'inhibiteurs de la pde1 |
US20170176028A1 (en) | 2015-12-18 | 2017-06-22 | Lg Electronics Inc. | Air conditioner |
CA3044432A1 (en) | 2016-11-17 | 2018-05-24 | Board Of Regents, The University Of Texas System | Compounds with anti-tumor activity against cancer cells bearing egfr or her2 exon 20 mutations |
CN112321814B (zh) * | 2020-12-30 | 2021-03-23 | 广州初曲科技有限公司 | 一种吉非替尼艾地苯醌轭合物的制备及用途 |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9508538D0 (en) * | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivatives |
GB9624482D0 (en) * | 1995-12-18 | 1997-01-15 | Zeneca Phaema S A | Chemical compounds |
SI0880508T1 (en) * | 1996-02-13 | 2003-10-31 | Astrazeneca Ab | Quinazoline derivatives as vegf inhibitors |
GB9603095D0 (en) * | 1996-02-14 | 1996-04-10 | Zeneca Ltd | Quinazoline derivatives |
KR100489174B1 (ko) * | 1996-03-05 | 2005-09-30 | 제네카-파마 소시에떼아노님 | 4-아닐리노퀴나졸린유도체 |
RO121900B1 (ro) * | 1996-04-12 | 2008-07-30 | Warner-Lambert Company | Compuşi inhibitori, ireversibili, ai tirozin kinazelor, compoziţie farmaceutică care îi conţine şi utilizarea acestora |
GB9718972D0 (en) * | 1996-09-25 | 1997-11-12 | Zeneca Ltd | Chemical compounds |
DE19911509A1 (de) * | 1999-03-15 | 2000-09-21 | Boehringer Ingelheim Pharma | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
-
2000
- 2000-08-26 DE DE10042058A patent/DE10042058A1/de not_active Ceased
-
2001
- 2001-08-18 HU HU0300819A patent/HUP0300819A3/hu unknown
- 2001-08-18 IL IL15460201A patent/IL154602A0/xx unknown
- 2001-08-18 ME MEP-587/08A patent/MEP58708A/xx unknown
- 2001-08-18 UA UA2003032533A patent/UA73004C2/uk unknown
- 2001-08-18 HR HR20030138A patent/HRP20030138A2/hr not_active Application Discontinuation
- 2001-08-18 WO PCT/EP2001/009532 patent/WO2002018351A1/de active Application Filing
- 2001-08-18 EP EP01967285A patent/EP1315705A1/de not_active Ceased
- 2001-08-18 JP JP2002523469A patent/JP4834282B2/ja not_active Expired - Fee Related
- 2001-08-18 MX MXPA03001483A patent/MXPA03001483A/es active IP Right Grant
- 2001-08-18 CA CA002417897A patent/CA2417897C/en not_active Expired - Fee Related
- 2001-08-18 RS YU14003A patent/RS52279B/en unknown
- 2001-08-18 BR BR0113519-8A patent/BR0113519A/pt not_active Application Discontinuation
- 2001-08-18 NZ NZ524668A patent/NZ524668A/en not_active IP Right Cessation
- 2001-08-18 CZ CZ20030870A patent/CZ302567B6/cs not_active IP Right Cessation
- 2001-08-18 EA EA200300219A patent/EA005679B1/ru not_active IP Right Cessation
- 2001-08-18 SK SK231-2003A patent/SK287747B6/sk not_active IP Right Cessation
- 2001-08-18 CN CNB01814635XA patent/CN100404517C/zh not_active Expired - Fee Related
- 2001-08-18 KR KR1020037002744A patent/KR100862873B1/ko not_active Expired - Fee Related
- 2001-08-18 EE EEP200300077A patent/EE05269B1/xx not_active IP Right Cessation
- 2001-08-18 PL PL36024801A patent/PL360248A1/xx not_active Application Discontinuation
- 2001-08-18 AU AU2001287694A patent/AU2001287694B2/en not_active Ceased
- 2001-08-18 AU AU8769401A patent/AU8769401A/xx active Pending
- 2001-08-23 UY UY26903A patent/UY26903A1/es not_active Application Discontinuation
- 2001-08-24 AR ARP010104041A patent/AR033562A1/es unknown
- 2001-08-24 MY MYPI20013985A patent/MY126132A/en unknown
- 2001-08-24 TW TW090120905A patent/TWI294422B/zh not_active IP Right Cessation
-
2003
- 2003-02-03 EC EC2003004464A patent/ECSP034464A/es unknown
- 2003-02-05 ZA ZA200300991A patent/ZA200300991B/en unknown
- 2003-02-14 BG BG107559A patent/BG107559A/bg unknown
- 2003-02-24 IL IL154602A patent/IL154602A/en not_active IP Right Cessation
- 2003-02-25 NO NO20030870A patent/NO324866B1/no not_active IP Right Cessation
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