ZA200403200B - Quinazoline derivatives as antitumor agents. - Google Patents
Quinazoline derivatives as antitumor agents. Download PDFInfo
- Publication number
- ZA200403200B ZA200403200B ZA200403200A ZA200403200A ZA200403200B ZA 200403200 B ZA200403200 B ZA 200403200B ZA 200403200 A ZA200403200 A ZA 200403200A ZA 200403200 A ZA200403200 A ZA 200403200A ZA 200403200 B ZA200403200 B ZA 200403200B
- Authority
- ZA
- South Africa
- Prior art keywords
- alkyl
- group
- formula
- amino
- yloxy
- Prior art date
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- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title description 35
- 239000002246 antineoplastic agent Substances 0.000 title description 2
- -1 cyano, isocyano, nitro, hydroxy, mercapto, amino, formyl Chemical group 0.000 claims description 1813
- 125000000217 alkyl group Chemical group 0.000 claims description 1257
- 125000001424 substituent group Chemical group 0.000 claims description 431
- 239000001257 hydrogen Substances 0.000 claims description 267
- 229910052739 hydrogen Inorganic materials 0.000 claims description 267
- 125000000623 heterocyclic group Chemical group 0.000 claims description 232
- 125000003545 alkoxy group Chemical group 0.000 claims description 169
- 125000005843 halogen group Chemical group 0.000 claims description 150
- 229910052760 oxygen Inorganic materials 0.000 claims description 144
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 141
- 125000001072 heteroaryl group Chemical group 0.000 claims description 140
- 125000003118 aryl group Chemical group 0.000 claims description 132
- 125000003282 alkyl amino group Chemical group 0.000 claims description 127
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 124
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 119
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 108
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 107
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 106
- 229910052757 nitrogen Inorganic materials 0.000 claims description 102
- 125000000304 alkynyl group Chemical group 0.000 claims description 94
- 125000001589 carboacyl group Chemical group 0.000 claims description 92
- 125000001153 fluoro group Chemical group F* 0.000 claims description 92
- 125000003342 alkenyl group Chemical group 0.000 claims description 90
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 86
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 86
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 83
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 73
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 72
- 229910052717 sulfur Inorganic materials 0.000 claims description 68
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 61
- 125000004432 carbon atom Chemical group C* 0.000 claims description 58
- 125000004414 alkyl thio group Chemical group 0.000 claims description 56
- 150000003839 salts Chemical class 0.000 claims description 56
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 55
- 125000004423 acyloxy group Chemical group 0.000 claims description 52
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 52
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 51
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 51
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 50
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 47
- 150000001875 compounds Chemical class 0.000 claims description 46
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 44
- 238000003780 insertion Methods 0.000 claims description 44
- 230000037431 insertion Effects 0.000 claims description 44
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 41
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 41
- 125000003386 piperidinyl group Chemical group 0.000 claims description 40
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 35
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 35
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 34
- 125000002947 alkylene group Chemical group 0.000 claims description 34
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 33
- 125000002619 bicyclic group Chemical group 0.000 claims description 31
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 31
- 125000001246 bromo group Chemical group Br* 0.000 claims description 29
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 28
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 28
- 206010028980 Neoplasm Diseases 0.000 claims description 27
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 26
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 24
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 24
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 24
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 24
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 23
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 22
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 22
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 18
- 238000004519 manufacturing process Methods 0.000 claims description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 17
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 17
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 16
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 15
- 102100033668 Cartilage matrix protein Human genes 0.000 claims description 15
- 101001018382 Homo sapiens Cartilage matrix protein Proteins 0.000 claims description 15
- DGYIJVNZSDYBOE-UHFFFAOYSA-N [CH2]C1=CC=NC=C1 Chemical group [CH2]C1=CC=NC=C1 DGYIJVNZSDYBOE-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 15
- 238000011282 treatment Methods 0.000 claims description 15
- 125000001041 indolyl group Chemical group 0.000 claims description 13
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims description 12
- 125000003396 thiol group Chemical class [H]S* 0.000 claims description 11
- 125000004484 1-methylpiperidin-4-yl group Chemical group CN1CCC(CC1)* 0.000 claims description 10
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 10
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 10
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 10
- 125000002393 azetidinyl group Chemical group 0.000 claims description 10
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- 125000006479 2-pyridyl methyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 9
- 125000004742 propyloxycarbonyl group Chemical group 0.000 claims description 9
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- 125000000464 thioxo group Chemical group S=* 0.000 claims description 9
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 8
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 8
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 claims description 7
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 claims description 7
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims description 7
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 7
- 102000001301 EGF receptor Human genes 0.000 claims description 6
- 108060006698 EGF receptor Proteins 0.000 claims description 6
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims description 6
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims description 6
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 6
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 6
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 6
- 125000004518 1,2,5-thiadiazol-3-yl group Chemical group S1N=C(C=N1)* 0.000 claims description 5
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 5
- 230000005764 inhibitory process Effects 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- 125000005302 thiazolylmethyl group Chemical group [H]C1=C([H])N=C(S1)C([H])([H])* 0.000 claims description 5
- 241001465754 Metazoa Species 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 241000252095 Congridae Species 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 2
- 150000003246 quinazolines Chemical class 0.000 claims 33
- 150000002431 hydrogen Chemical class 0.000 claims 18
- 125000000524 functional group Chemical group 0.000 claims 12
- 239000000203 mixture Substances 0.000 claims 10
- 239000000126 substance Substances 0.000 claims 8
- 238000006243 chemical reaction Methods 0.000 claims 7
- 125000006239 protecting group Chemical group 0.000 claims 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 3
- 150000001412 amines Chemical class 0.000 claims 3
- 230000008878 coupling Effects 0.000 claims 3
- 238000010168 coupling process Methods 0.000 claims 3
- 238000005859 coupling reaction Methods 0.000 claims 3
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 claims 3
- 239000002253 acid Substances 0.000 claims 2
- 125000003277 amino group Chemical group 0.000 claims 2
- 238000003776 cleavage reaction Methods 0.000 claims 2
- 230000007017 scission Effects 0.000 claims 2
- VAJRZYCXBHKDQM-UHFFFAOYSA-N 2-(oxan-4-yloxy)quinazoline Chemical compound C1COCCC1OC1=NC=C(C=CC=C2)C2=N1 VAJRZYCXBHKDQM-UHFFFAOYSA-N 0.000 claims 1
- IWKAXCOAQXMTJI-UHFFFAOYSA-N 2-[3-[4-(3-chloro-4-fluoroanilino)-5-(oxan-4-yloxy)quinazolin-7-yl]oxypropyl-methylamino]ethanol Chemical compound C=12C(NC=3C=C(Cl)C(F)=CC=3)=NC=NC2=CC(OCCCN(CCO)C)=CC=1OC1CCOCC1 IWKAXCOAQXMTJI-UHFFFAOYSA-N 0.000 claims 1
- ZCROTVJMBVJMTC-UHFFFAOYSA-N 7-methoxy-5-(1-methylpiperidin-4-yl)oxy-n-[3-methyl-4-(1,3-thiazol-4-ylmethoxy)phenyl]quinazolin-4-amine Chemical compound C=12C(NC=3C=C(C)C(OCC=4N=CSC=4)=CC=3)=NC=NC2=CC(OC)=CC=1OC1CCN(C)CC1 ZCROTVJMBVJMTC-UHFFFAOYSA-N 0.000 claims 1
- AEUSZNVUMDOVLL-UHFFFAOYSA-N 7-methoxy-n-(3-methylphenyl)-5-(1-methylpiperidin-4-yl)oxyquinazolin-4-amine Chemical compound C=12C(NC=3C=C(C)C=CC=3)=NC=NC2=CC(OC)=CC=1OC1CCN(C)CC1 AEUSZNVUMDOVLL-UHFFFAOYSA-N 0.000 claims 1
- LDOXZKYFYSFOSU-UHFFFAOYSA-N 7-methoxy-n-[3-methyl-4-[(5-methyl-1,2-oxazol-3-yl)methoxy]phenyl]-5-(1-methylpiperidin-4-yl)oxyquinazolin-4-amine Chemical compound C=12C(NC=3C=C(C)C(OCC4=NOC(C)=C4)=CC=3)=NC=NC2=CC(OC)=CC=1OC1CCN(C)CC1 LDOXZKYFYSFOSU-UHFFFAOYSA-N 0.000 claims 1
- 150000001204 N-oxides Chemical class 0.000 claims 1
- 230000010933 acylation Effects 0.000 claims 1
- 238000005917 acylation reaction Methods 0.000 claims 1
- 150000003973 alkyl amines Chemical class 0.000 claims 1
- 230000029936 alkylation Effects 0.000 claims 1
- 238000005804 alkylation reaction Methods 0.000 claims 1
- 239000003638 chemical reducing agent Substances 0.000 claims 1
- 239000012024 dehydrating agents Substances 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 125000000468 ketone group Chemical group 0.000 claims 1
- XMVKPIXFNJYUSW-UHFFFAOYSA-N n-(1h-indol-5-yl)-7-methoxy-5-(1-methylpiperidin-4-yl)oxyquinazolin-4-amine Chemical compound C=12C(NC=3C=C4C=CNC4=CC=3)=NC=NC2=CC(OC)=CC=1OC1CCN(C)CC1 XMVKPIXFNJYUSW-UHFFFAOYSA-N 0.000 claims 1
- ZXNJYEMOJBYQIG-UHFFFAOYSA-N n-(3-bromo-1h-indol-5-yl)-7-methoxy-5-(1-methylpiperidin-4-yl)oxyquinazolin-4-amine Chemical compound C=12C(NC=3C=C4C(Br)=CNC4=CC=3)=NC=NC2=CC(OC)=CC=1OC1CCN(C)CC1 ZXNJYEMOJBYQIG-UHFFFAOYSA-N 0.000 claims 1
- NFTRWLJBWYWZJH-UHFFFAOYSA-N n-(3-bromophenyl)-7-(2-methoxyethoxy)-5-(1-methylpiperidin-4-yl)oxyquinazolin-4-amine Chemical compound C=12C(NC=3C=C(Br)C=CC=3)=NC=NC2=CC(OCCOC)=CC=1OC1CCN(C)CC1 NFTRWLJBWYWZJH-UHFFFAOYSA-N 0.000 claims 1
- ZZDLDXZKLALEKT-UHFFFAOYSA-N n-(3-bromophenyl)-7-methoxy-5-(1-methylpiperidin-4-yl)oxyquinazolin-4-amine Chemical compound C=12C(NC=3C=C(Br)C=CC=3)=NC=NC2=CC(OC)=CC=1OC1CCN(C)CC1 ZZDLDXZKLALEKT-UHFFFAOYSA-N 0.000 claims 1
- HPLPZQXVSXASSV-UHFFFAOYSA-N n-(3-chloro-1h-indol-5-yl)-5-(1-methylpiperidin-4-yl)oxyquinazolin-4-amine Chemical compound C1CN(C)CCC1OC1=CC=CC2=NC=NC(NC=3C=C4C(Cl)=CNC4=CC=3)=C12 HPLPZQXVSXASSV-UHFFFAOYSA-N 0.000 claims 1
- HQPQWDCOALZSAB-UHFFFAOYSA-N n-(3-chloro-1h-indol-5-yl)-7-methoxy-5-(1-methylpiperidin-4-yl)oxyquinazolin-4-amine Chemical compound C=12C(NC=3C=C4C(Cl)=CNC4=CC=3)=NC=NC2=CC(OC)=CC=1OC1CCN(C)CC1 HQPQWDCOALZSAB-UHFFFAOYSA-N 0.000 claims 1
- ZETIQJIOZJGBJO-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)-5-(1-methylpiperidin-4-yl)oxy-7-(3-piperidin-1-ylpropoxy)quinazolin-4-amine Chemical compound C1CN(C)CCC1OC1=CC(OCCCN2CCCCC2)=CC2=NC=NC(NC=3C=C(Cl)C(F)=CC=3)=C12 ZETIQJIOZJGBJO-UHFFFAOYSA-N 0.000 claims 1
- UZMXZABPDQQTCY-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)-5-(oxolan-3-yloxy)-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-amine Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CCCC3)=CC(OC3COCC3)=C12 UZMXZABPDQQTCY-UHFFFAOYSA-N 0.000 claims 1
- TVIYMNMSDSRYOR-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)-7-(2-methoxyethoxy)-5-(1-methylpiperidin-4-yl)oxyquinazolin-4-amine Chemical compound C=12C(NC=3C=C(Cl)C(F)=CC=3)=NC=NC2=CC(OCCOC)=CC=1OC1CCN(C)CC1 TVIYMNMSDSRYOR-UHFFFAOYSA-N 0.000 claims 1
- PHAHMWKBVJWSRW-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)-7-[3-(4-methylpiperazin-1-yl)propoxy]-5-(oxolan-3-yloxy)quinazolin-4-amine Chemical compound C1CN(C)CCN1CCCOC1=CC(OC2COCC2)=C(C(NC=2C=C(Cl)C(F)=CC=2)=NC=N2)C2=C1 PHAHMWKBVJWSRW-UHFFFAOYSA-N 0.000 claims 1
- JJGWQXMAOXKYNE-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)-7-methoxy-5-(1-methylpiperidin-4-yl)oxyquinazolin-4-amine Chemical compound C=12C(NC=3C=C(Cl)C(F)=CC=3)=NC=NC2=CC(OC)=CC=1OC1CCN(C)CC1 JJGWQXMAOXKYNE-UHFFFAOYSA-N 0.000 claims 1
- JFJUDTHJJPEOAI-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)-7-methoxy-5-piperidin-4-yloxyquinazolin-4-amine Chemical compound C=12C(NC=3C=C(Cl)C(F)=CC=3)=NC=NC2=CC(OC)=CC=1OC1CCNCC1 JFJUDTHJJPEOAI-UHFFFAOYSA-N 0.000 claims 1
- ZQSVHYHVRLBHRQ-UHFFFAOYSA-N n-(3-chloro-4-phenylmethoxyphenyl)-7-methoxy-5-(1-methylpiperidin-4-yl)oxyquinazolin-4-amine Chemical compound C=12C(NC=3C=C(Cl)C(OCC=4C=CC=CC=4)=CC=3)=NC=NC2=CC(OC)=CC=1OC1CCN(C)CC1 ZQSVHYHVRLBHRQ-UHFFFAOYSA-N 0.000 claims 1
- DPDBPSDRMGEXOE-HXUWFJFHSA-N n-(3-chlorophenyl)-7-[(3r)-3-(dimethylamino)pyrrolidin-1-yl]-5-(1-methylpiperidin-4-yl)oxyquinazolin-4-amine Chemical compound C1[C@H](N(C)C)CCN1C1=CC(OC2CCN(C)CC2)=C(C(NC=2C=C(Cl)C=CC=2)=NC=N2)C2=C1 DPDBPSDRMGEXOE-HXUWFJFHSA-N 0.000 claims 1
- KJXIINIUXPYFOR-UHFFFAOYSA-N n-(3-chlorophenyl)-7-methoxy-5-(1-methylpiperidin-4-yl)oxyquinazolin-4-amine Chemical compound C=12C(NC=3C=C(Cl)C=CC=3)=NC=NC2=CC(OC)=CC=1OC1CCN(C)CC1 KJXIINIUXPYFOR-UHFFFAOYSA-N 0.000 claims 1
- XGTYOOCWZXWNGX-UHFFFAOYSA-N n-(3-ethynylphenyl)-7-methoxy-5-(1-methylpiperidin-4-yl)oxyquinazolin-4-amine Chemical compound C=12C(NC=3C=C(C=CC=3)C#C)=NC=NC2=CC(OC)=CC=1OC1CCN(C)CC1 XGTYOOCWZXWNGX-UHFFFAOYSA-N 0.000 claims 1
- BTXPGTQGSXUJHB-UHFFFAOYSA-N n-[1-[(2-fluorophenyl)methyl]indol-5-yl]-7-methoxy-5-(1-methylpiperidin-4-yl)oxyquinazolin-4-amine Chemical compound C=12C(NC=3C=C4C=CN(CC=5C(=CC=CC=5)F)C4=CC=3)=NC=NC2=CC(OC)=CC=1OC1CCN(C)CC1 BTXPGTQGSXUJHB-UHFFFAOYSA-N 0.000 claims 1
- ISAVFODCQKKGSP-UHFFFAOYSA-N n-[1-[(3-fluorophenyl)methyl]indol-5-yl]-7-methoxy-5-(1-methylpiperidin-4-yl)oxyquinazolin-4-amine Chemical compound C=12C(NC=3C=C4C=CN(CC=5C=C(F)C=CC=5)C4=CC=3)=NC=NC2=CC(OC)=CC=1OC1CCN(C)CC1 ISAVFODCQKKGSP-UHFFFAOYSA-N 0.000 claims 1
- FEDMNRRTHMURLW-UHFFFAOYSA-N n-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-7-methoxy-5-(1-methylpiperidin-4-yl)oxyquinazolin-4-amine Chemical compound C=12C(NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)=NC=NC2=CC(OC)=CC=1OC1CCN(C)CC1 FEDMNRRTHMURLW-UHFFFAOYSA-N 0.000 claims 1
- 230000003647 oxidation Effects 0.000 claims 1
- 238000007254 oxidation reaction Methods 0.000 claims 1
- 238000006268 reductive amination reaction Methods 0.000 claims 1
- 125000004434 sulfur atom Chemical group 0.000 claims 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 31
- 125000004043 oxo group Chemical group O=* 0.000 description 23
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 22
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 21
- 229920002554 vinyl polymer Polymers 0.000 description 21
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 19
- 229910052799 carbon Inorganic materials 0.000 description 19
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 description 17
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 description 16
- 201000011510 cancer Diseases 0.000 description 16
- 230000000694 effects Effects 0.000 description 15
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 14
- 125000004193 piperazinyl group Chemical group 0.000 description 14
- 125000004076 pyridyl group Chemical group 0.000 description 14
- 150000001721 carbon Chemical group 0.000 description 13
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 12
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 12
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 12
- 125000000714 pyrimidinyl group Chemical group 0.000 description 11
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 11
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 9
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Classifications
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- C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
- C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
- C04B35/00—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
- C04B35/622—Forming processes; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
- C04B35/626—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B
- C04B35/63—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B using additives specially adapted for forming the products, e.g.. binder binders
- C04B35/632—Organic additives
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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
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- 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
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—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
- C07D417/14—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 three or more hetero rings
Landscapes
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- Engineering & Computer Science (AREA)
- Ceramic Engineering (AREA)
- Health & Medical Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Inorganic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Structural Engineering (AREA)
- Materials Engineering (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
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ZA200403200A ZA200403200B (en) | 2001-11-03 | 2004-04-28 | Quinazoline derivatives as antitumor agents. |
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ZA200403203A ZA200403203B (en) | 2001-11-03 | 2004-04-28 | Quinazoline derivatives as antitumor agents. |
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AT (1) | ATE421507T1 (is) |
BR (1) | BR0213843A (is) |
CA (1) | CA2465100A1 (is) |
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IL (1) | IL161620A0 (is) |
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NZ (1) | NZ532523A (is) |
PL (1) | PL369833A1 (is) |
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TW (1) | TW200302221A (is) |
WO (1) | WO2003040109A2 (is) |
ZA (2) | ZA200403203B (is) |
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TWI336328B (en) * | 2001-03-23 | 2011-01-21 | Bayer Healthcare Llc | Rho-kinase inhibitors |
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CA2465068A1 (en) * | 2001-11-03 | 2003-05-15 | Astrazeneca Ab | Quinazoline derivatives as antitumor agents |
CA2473572C (en) * | 2002-02-01 | 2011-05-10 | Astrazeneca Ab | Quinazoline compounds |
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 |
EP1521747B1 (en) | 2002-07-15 | 2018-09-05 | Symphony Evolution, Inc. | Receptor-type kinase modulators and methods of use |
GB0309009D0 (en) * | 2003-04-22 | 2003-05-28 | Astrazeneca Ab | Quinazoline derivatives |
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GB0321648D0 (en) * | 2003-09-16 | 2003-10-15 | Astrazeneca Ab | Quinazoline derivatives |
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GB0322409D0 (en) * | 2003-09-25 | 2003-10-29 | Astrazeneca Ab | Quinazoline derivatives |
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DE602005010824D1 (de) * | 2004-02-03 | 2008-12-18 | Astrazeneca Ab | Chinazolinderivate |
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BRPI0511741A (pt) * | 2004-06-04 | 2008-01-02 | Astrazeneca Ab | derivado de quinazolina ou um sal farmaceuticamente aceitável do mesmo, composição farmacêutica, processo para a preparação de um derivado de quinazolina ou de um sal farmaceuticamente aceitável do mesmo |
AU2005293336B2 (en) | 2004-10-12 | 2009-05-28 | Astrazeneca Ab | Quinazoline derivatives |
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-
2001
- 2001-11-03 GB GBGB0126433.2A patent/GB0126433D0/en not_active Ceased
-
2002
- 2002-10-31 DE DE60230995T patent/DE60230995D1/de not_active Expired - Lifetime
- 2002-10-31 AT AT02774961T patent/ATE421507T1/de not_active IP Right Cessation
- 2002-10-31 WO PCT/GB2002/004932 patent/WO2003040109A2/en active Application Filing
- 2002-10-31 IL IL16162002A patent/IL161620A0/xx unknown
- 2002-10-31 MX MXPA04004220A patent/MXPA04004220A/es unknown
- 2002-10-31 ES ES02774961T patent/ES2319880T3/es not_active Expired - Lifetime
- 2002-10-31 CA CA002465100A patent/CA2465100A1/en not_active Abandoned
- 2002-10-31 JP JP2003542155A patent/JP2005511603A/ja not_active Ceased
- 2002-10-31 RU RU2004116908/04A patent/RU2004116908A/ru not_active Application Discontinuation
- 2002-10-31 BR BR0213843-3A patent/BR0213843A/pt not_active IP Right Cessation
- 2002-10-31 HU HU0401994A patent/HUP0401994A2/hu unknown
- 2002-10-31 PL PL02369833A patent/PL369833A1/xx not_active Application Discontinuation
- 2002-10-31 EP EP02774961A patent/EP1444211B1/en not_active Expired - Lifetime
- 2002-10-31 KR KR1020047006735A patent/KR20050042058A/ko not_active Application Discontinuation
- 2002-10-31 US US10/494,388 patent/US20050054662A1/en not_active Abandoned
- 2002-10-31 CN CNA028262824A patent/CN1764651A/zh active Pending
- 2002-10-31 NZ NZ532523A patent/NZ532523A/en unknown
- 2002-11-01 AR ARP020104182A patent/AR037193A1/es not_active Application Discontinuation
- 2002-11-01 TW TW091132368A patent/TW200302221A/zh unknown
-
2004
- 2004-04-28 ZA ZA200403203A patent/ZA200403203B/en unknown
- 2004-04-28 ZA ZA200403200A patent/ZA200403200B/en unknown
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- 2004-06-02 CO CO04051630A patent/CO5580775A2/es not_active Application Discontinuation
- 2004-06-03 NO NO20042288A patent/NO20042288L/no not_active Application Discontinuation
- 2004-11-08 HK HK04108771.4A patent/HK1065801A1/xx not_active IP Right Cessation
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2006
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Also Published As
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IS7241A (is) | 2004-04-30 |
HUP0401994A2 (hu) | 2005-01-28 |
KR20050042058A (ko) | 2005-05-04 |
CA2465100A1 (en) | 2003-05-15 |
JP2005511603A (ja) | 2005-04-28 |
MXPA04004220A (es) | 2004-09-10 |
IL161620A0 (en) | 2004-09-27 |
ATE421507T1 (de) | 2009-02-15 |
US20070088044A1 (en) | 2007-04-19 |
CO5580775A2 (es) | 2005-11-30 |
GB0126433D0 (en) | 2002-01-02 |
ZA200403203B (en) | 2005-07-28 |
EP1444211A2 (en) | 2004-08-11 |
DE60230995D1 (de) | 2009-03-12 |
BR0213843A (pt) | 2004-08-31 |
PL369833A1 (en) | 2005-05-02 |
NO20042288L (no) | 2004-06-03 |
HK1065801A1 (en) | 2005-03-04 |
CN1764651A (zh) | 2006-04-26 |
EP1444211B1 (en) | 2009-01-21 |
WO2003040109A2 (en) | 2003-05-15 |
AR037193A1 (es) | 2004-10-27 |
NZ532523A (en) | 2007-02-23 |
TW200302221A (en) | 2003-08-01 |
RU2004116908A (ru) | 2005-11-10 |
ES2319880T3 (es) | 2009-05-14 |
WO2003040109A3 (en) | 2003-06-26 |
US20050054662A1 (en) | 2005-03-10 |
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