ES2300619T3 - Derivados de quinolina como inhibidores de src tirosina quinasa. - Google Patents
Derivados de quinolina como inhibidores de src tirosina quinasa. Download PDFInfo
- Publication number
- ES2300619T3 ES2300619T3 ES03769689T ES03769689T ES2300619T3 ES 2300619 T3 ES2300619 T3 ES 2300619T3 ES 03769689 T ES03769689 T ES 03769689T ES 03769689 T ES03769689 T ES 03769689T ES 2300619 T3 ES2300619 T3 ES 2300619T3
- Authority
- ES
- Spain
- Prior art keywords
- alkyl
- group
- ethoxy
- amino
- pyrrolidin
- 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.)
- Expired - Lifetime
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- 239000003112 inhibitor Substances 0.000 title description 18
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 title description 5
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical class N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 title description 3
- -1 halogen halogen Chemical class 0.000 claims abstract description 1017
- 125000001424 substituent group Chemical group 0.000 claims abstract description 186
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 142
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 99
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 80
- 150000001335 aliphatic alkanes Chemical class 0.000 claims abstract description 76
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 75
- 150000003839 salts Chemical class 0.000 claims abstract description 75
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 68
- 125000001589 carboacyl group Chemical group 0.000 claims abstract description 61
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 61
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 46
- 239000001257 hydrogen Substances 0.000 claims abstract description 42
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 42
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 39
- 150000002367 halogens Chemical class 0.000 claims abstract description 36
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 36
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 34
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 33
- 125000003118 aryl group Chemical group 0.000 claims abstract description 32
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims abstract description 31
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 30
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 30
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 28
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 27
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 24
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims abstract description 24
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims abstract description 22
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 20
- 125000000392 cycloalkenyl group Chemical group 0.000 claims abstract description 20
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims abstract description 19
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 claims abstract description 17
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims abstract description 16
- 238000003780 insertion Methods 0.000 claims abstract description 16
- 230000037431 insertion Effects 0.000 claims abstract description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 15
- 229910002091 carbon monoxide Inorganic materials 0.000 claims abstract description 15
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims abstract description 14
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims abstract description 13
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims abstract description 12
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims abstract description 12
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract description 9
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 9
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims abstract description 8
- 241000790917 Dioxys <bee> Species 0.000 claims abstract description 7
- 125000004043 oxo group Chemical group O=* 0.000 claims abstract description 7
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 6
- 125000000464 thioxo group Chemical group S=* 0.000 claims abstract description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 5
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims abstract description 5
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims abstract description 4
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims abstract description 3
- 125000006529 (C3-C6) alkyl group Chemical group 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 135
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 59
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 58
- 238000000034 method Methods 0.000 claims description 52
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 44
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 44
- 239000002253 acid Substances 0.000 claims description 41
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 37
- 125000001153 fluoro group Chemical group F* 0.000 claims description 36
- 206010028980 Neoplasm Diseases 0.000 claims description 34
- 238000011282 treatment Methods 0.000 claims description 30
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 23
- 238000004519 manufacturing process Methods 0.000 claims description 23
- 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
- 241000282414 Homo sapiens Species 0.000 claims description 19
- 229910052799 carbon Inorganic materials 0.000 claims description 19
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 18
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 18
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 18
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 18
- 125000006239 protecting group Chemical group 0.000 claims description 18
- 229910052740 iodine Inorganic materials 0.000 claims description 17
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 17
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 16
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 16
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 16
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 16
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 15
- 201000010099 disease Diseases 0.000 claims description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 claims description 14
- 241001465754 Metazoa Species 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 14
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 14
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 13
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims description 13
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 10
- 125000004076 pyridyl group Chemical group 0.000 claims description 10
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 10
- 229920002554 vinyl polymer Polymers 0.000 claims description 10
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 9
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 9
- 125000001246 bromo group Chemical group Br* 0.000 claims description 9
- 239000000460 chlorine Substances 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 claims description 9
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 9
- 150000001412 amines Chemical class 0.000 claims description 8
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 8
- 238000002560 therapeutic procedure Methods 0.000 claims description 8
- 230000001740 anti-invasion Effects 0.000 claims description 7
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 7
- 125000000524 functional group Chemical group 0.000 claims description 7
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 7
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 7
- 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 claims description 7
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 6
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 6
- 125000005153 alkyl sulfamoyl group Chemical group 0.000 claims description 6
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 6
- 125000006533 methyl amino methyl group Chemical group [H]N(C([H])([H])[H])C([H])([H])* 0.000 claims description 6
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 6
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 6
- HNEGJTWNOOWEMH-UHFFFAOYSA-N 1-fluoropropane Chemical group [CH2]CCF HNEGJTWNOOWEMH-UHFFFAOYSA-N 0.000 claims description 5
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 5
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 claims description 5
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 claims description 5
- 125000002883 imidazolyl group Chemical group 0.000 claims description 5
- 125000001425 triazolyl group Chemical group 0.000 claims description 5
- 125000006125 ethylsulfonyl group Chemical group 0.000 claims description 4
- MVWATCATLSSVBH-UHFFFAOYSA-N 1-[4-[2-[4-[(6-chloro-[1,3]dioxolo[4,5-b]pyridin-7-yl)amino]-5-propan-2-yloxyquinazolin-7-yl]oxyethyl]piperazin-1-yl]ethanone Chemical compound C=1C2=NC=NC(NC=3C(=CN=C4OCOC4=3)Cl)=C2C(OC(C)C)=CC=1OCCN1CCN(C(C)=O)CC1 MVWATCATLSSVBH-UHFFFAOYSA-N 0.000 claims description 3
- LXWLEHANZSZKOO-UHFFFAOYSA-N 6-chloro-n-[7-(2-piperazin-1-ylethoxy)-5-propan-2-yloxyquinazolin-4-yl]-[1,3]dioxolo[4,5-b]pyridin-7-amine Chemical compound C=1C2=NC=NC(NC=3C(=CN=C4OCOC4=3)Cl)=C2C(OC(C)C)=CC=1OCCN1CCNCC1 LXWLEHANZSZKOO-UHFFFAOYSA-N 0.000 claims description 3
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical group OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 claims description 2
- XQGNSUGMUSXKKB-UHFFFAOYSA-N 1-[4-[2-[4-[(6-chloro-[1,3]dioxolo[4,5-b]pyridin-7-yl)amino]-5-(oxan-4-yloxy)quinazolin-7-yl]oxyethyl]piperazin-1-yl]ethanone Chemical compound C1CN(C(=O)C)CCN1CCOC1=CC(OC2CCOCC2)=C(C(NC=2C(=CN=C3OCOC3=2)Cl)=NC=N2)C2=C1 XQGNSUGMUSXKKB-UHFFFAOYSA-N 0.000 claims description 2
- CETXQBFLIVLDTF-UHFFFAOYSA-N 1-[4-[2-[4-[(6-chloro-[1,3]dioxolo[4,5-b]pyridin-7-yl)amino]-5-propan-2-yloxyquinazolin-7-yl]oxyethyl]piperazin-1-yl]-2-(dimethylamino)ethanone Chemical compound C=1C2=NC=NC(NC=3C(=CN=C4OCOC4=3)Cl)=C2C(OC(C)C)=CC=1OCCN1CCN(C(=O)CN(C)C)CC1 CETXQBFLIVLDTF-UHFFFAOYSA-N 0.000 claims description 2
- IRGUKHGTSGTWOU-UHFFFAOYSA-N 1-[4-[3-[4-[(6-chloro-[1,3]dioxolo[4,5-b]pyridin-7-yl)amino]-6-methoxyquinazolin-7-yl]oxypropyl]piperazin-1-yl]-2-methylpropan-1-one Chemical compound COC1=CC2=C(NC=3C(=CN=C4OCOC4=3)Cl)N=CN=C2C=C1OCCCN1CCN(C(=O)C(C)C)CC1 IRGUKHGTSGTWOU-UHFFFAOYSA-N 0.000 claims description 2
- 125000000586 2-(4-morpholinyl)ethoxy group Chemical group [H]C([H])(O*)C([H])([H])N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 claims description 2
- XACGJHGLWHFNKU-UHFFFAOYSA-N 2-[4-[2-[4-[(6-chloro-[1,3]dioxolo[4,5-b]pyridin-7-yl)amino]-5-propan-2-yloxyquinazolin-7-yl]oxyethyl]piperazin-1-yl]ethanol Chemical compound C=1C2=NC=NC(NC=3C(=CN=C4OCOC4=3)Cl)=C2C(OC(C)C)=CC=1OCCN1CCN(CCO)CC1 XACGJHGLWHFNKU-UHFFFAOYSA-N 0.000 claims description 2
- FJNMDDYFEUEVLJ-UHFFFAOYSA-N 6-chloro-n-[5-propan-2-yloxy-7-(2-pyrrolidin-1-ylethoxy)quinazolin-4-yl]-[1,3]dioxolo[4,5-b]pyridin-7-amine Chemical compound C=1C2=NC=NC(NC=3C(=CN=C4OCOC4=3)Cl)=C2C(OC(C)C)=CC=1OCCN1CCCC1 FJNMDDYFEUEVLJ-UHFFFAOYSA-N 0.000 claims description 2
- LHNUBGOLVVVBFV-UHFFFAOYSA-N 6-chloro-n-[7-(2-morpholin-4-ylethoxy)-5-(oxan-4-yloxy)quinazolin-4-yl]-[1,3]dioxolo[4,5-b]pyridin-7-amine Chemical compound ClC1=CN=C2OCOC2=C1NC(C1=C(OC2CCOCC2)C=2)=NC=NC1=CC=2OCCN1CCOCC1 LHNUBGOLVVVBFV-UHFFFAOYSA-N 0.000 claims description 2
- CIYSACKPZCOGHC-UHFFFAOYSA-N 6-chloro-n-[7-(2-morpholin-4-ylethoxy)-5-propan-2-yloxyquinazolin-4-yl]-[1,3]dioxolo[4,5-b]pyridin-7-amine Chemical compound C=1C2=NC=NC(NC=3C(=CN=C4OCOC4=3)Cl)=C2C(OC(C)C)=CC=1OCCN1CCOCC1 CIYSACKPZCOGHC-UHFFFAOYSA-N 0.000 claims description 2
- STMAOZDCKQKDGH-UHFFFAOYSA-N 6-chloro-n-[7-(3-morpholin-4-ylpropoxy)-5-(oxan-4-yloxy)quinazolin-4-yl]-[1,3]dioxolo[4,5-b]pyridin-7-amine Chemical compound ClC1=CN=C2OCOC2=C1NC(C1=C(OC2CCOCC2)C=2)=NC=NC1=CC=2OCCCN1CCOCC1 STMAOZDCKQKDGH-UHFFFAOYSA-N 0.000 claims description 2
- QOCFWLMWEMNAJO-UHFFFAOYSA-N 6-chloro-n-[7-(3-morpholin-4-ylpropoxy)-5-propan-2-yloxyquinazolin-4-yl]-[1,3]dioxolo[4,5-b]pyridin-7-amine Chemical compound C=1C2=NC=NC(NC=3C(=CN=C4OCOC4=3)Cl)=C2C(OC(C)C)=CC=1OCCCN1CCOCC1 QOCFWLMWEMNAJO-UHFFFAOYSA-N 0.000 claims description 2
- NPLQFGONSPDLQX-UHFFFAOYSA-N 6-chloro-n-[7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-propan-2-yloxyquinazolin-4-yl]-[1,3]dioxolo[4,5-b]pyridin-7-amine Chemical compound C=1C2=NC=NC(NC=3C(=CN=C4OCOC4=3)Cl)=C2C(OC(C)C)=CC=1OCCN1CCN(C)CC1 NPLQFGONSPDLQX-UHFFFAOYSA-N 0.000 claims description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
- 239000004593 Epoxy Substances 0.000 claims description 2
- DANWDGOLHZFHLA-UHFFFAOYSA-N n-[7-[2-(3a,4,6,6a-tetrahydro-[1,3]dioxolo[4,5-c]pyrrol-5-yl)ethoxy]-5-(oxan-4-yloxy)quinazolin-4-yl]-6-chloro-[1,3]dioxolo[4,5-b]pyridin-7-amine Chemical compound ClC1=CN=C2OCOC2=C1NC(C=12)=NC=NC2=CC(OCCN2CC3OCOC3C2)=CC=1OC1CCOCC1 DANWDGOLHZFHLA-UHFFFAOYSA-N 0.000 claims description 2
- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 2
- 150000003246 quinazolines Chemical class 0.000 claims 21
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims 4
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 1
- 230000008878 coupling Effects 0.000 claims 1
- 238000010168 coupling process Methods 0.000 claims 1
- 238000005859 coupling reaction Methods 0.000 claims 1
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 abstract description 39
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract description 4
- 125000006323 alkenyl amino group Chemical group 0.000 abstract description 3
- 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 abstract description 3
- BWOVZCWSJFYBRM-UHFFFAOYSA-N carbononitridic isocyanate Chemical compound O=C=NC#N BWOVZCWSJFYBRM-UHFFFAOYSA-N 0.000 abstract description 2
- 125000004650 C1-C8 alkynyl group Chemical group 0.000 abstract 1
- 241001024304 Mino Species 0.000 abstract 1
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 abstract 1
- 125000002462 isocyano group Chemical group *[N+]#[C-] 0.000 abstract 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract 1
- 125000004963 sulfonylalkyl group Chemical group 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 237
- 239000000203 mixture Substances 0.000 description 188
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 122
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 116
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 115
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 99
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 93
- 238000001819 mass spectrum Methods 0.000 description 73
- 239000000243 solution Substances 0.000 description 69
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 64
- 239000011541 reaction mixture Substances 0.000 description 63
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
- 239000000377 silicon dioxide Substances 0.000 description 57
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 51
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 51
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
- 239000000047 product Substances 0.000 description 47
- 238000004440 column chromatography Methods 0.000 description 46
- 239000007787 solid Substances 0.000 description 43
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 41
- 239000003480 eluent Substances 0.000 description 40
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 39
- 238000012360 testing method Methods 0.000 description 36
- 239000000463 material Substances 0.000 description 35
- 210000004027 cell Anatomy 0.000 description 32
- 239000007858 starting material Substances 0.000 description 32
- 239000000376 reactant Substances 0.000 description 30
- 239000002904 solvent Substances 0.000 description 30
- 102000001332 SRC Human genes 0.000 description 29
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Classifications
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Landscapes
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Applications Claiming Priority (4)
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| EP02292736 | 2002-11-04 | ||
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Families Citing this family (13)
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| CA2491191C (en) | 2002-07-15 | 2014-02-04 | Exelixis, Inc. | Receptor-type kinase modulators and methods of use |
| CA2744997A1 (en) | 2003-09-26 | 2005-04-07 | Exelixis, Inc. | C-met modulators and method of use |
| GB0406445D0 (en) * | 2004-03-23 | 2004-04-28 | Astrazeneca Ab | Combination therapy |
| GB0427697D0 (en) | 2004-12-17 | 2005-01-19 | Astrazeneca Ab | Chemical process |
| WO2009068906A2 (en) * | 2007-11-26 | 2009-06-04 | Astrazeneca Ab | Combinations comprising zd4054 and a src family kinase inhibitor 172 |
| DK2387563T4 (da) | 2009-01-16 | 2022-07-18 | Exelixis Inc | Malatsalt af n-(4-{ [ 6, 7-bis(methyloxy)quinolin-4-yl]oxy}phenyl-n'-(4-fluorphenyl)cyclopropan-1,1-dicarboxamid, og krystallinske former deraf til behandling af cancer |
| UA108618C2 (uk) | 2009-08-07 | 2015-05-25 | Застосування c-met-модуляторів в комбінації з темозоломідом та/або променевою терапією для лікування раку | |
| FI2621481T4 (fi) | 2010-09-27 | 2023-01-13 | Met- ja vegf-kaksoisestäjiä kastraatioresistentin eturauhassyövän ja osteoblastisten luun etäispesäkkeiden hoitamiseen | |
| TWI577671B (zh) * | 2011-11-14 | 2017-04-11 | Sunshine Lake Pharma Co Ltd | Aminoquinazoline derivatives and salts thereof and methods of use thereof |
| BR112018006873A2 (pt) | 2015-10-05 | 2018-11-06 | The Trustees Of Columbia University In The City Of New York | ativadores do fluxo autofágico e fosfolipase d e depuração de agregados de proteína incluindo tau e tratamento de proteinopatias |
| US10722484B2 (en) | 2016-03-09 | 2020-07-28 | K-Gen, Inc. | Methods of cancer treatment |
| US20220040181A1 (en) | 2018-09-10 | 2022-02-10 | Mirati Therapeutics, Inc. | Combination therapies |
| CN119504612A (zh) * | 2024-11-18 | 2025-02-25 | 中国海洋大学 | 一种喹唑啉茋类衍生物及其制备方法和应用 |
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- 2003-10-29 EP EP03769689A patent/EP1562955B1/en not_active Expired - Lifetime
- 2003-10-29 DE DE60319410T patent/DE60319410T2/de not_active Expired - Lifetime
- 2003-10-29 MX MXPA05004858A patent/MXPA05004858A/es active IP Right Grant
- 2003-10-29 PL PL376255A patent/PL215161B1/pl unknown
- 2003-10-29 ES ES03769689T patent/ES2300619T3/es not_active Expired - Lifetime
- 2003-10-29 US US10/533,931 patent/US7462623B2/en not_active Expired - Fee Related
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- 2003-10-29 AT AT03769689T patent/ATE387451T1/de active
- 2003-10-29 DK DK03769689T patent/DK1562955T3/da active
- 2003-10-29 AU AU2003278383A patent/AU2003278383B2/en not_active Ceased
- 2003-10-29 PT PT03769689T patent/PT1562955E/pt unknown
- 2003-10-29 SI SI200331192T patent/SI1562955T1/sl unknown
- 2003-10-29 WO PCT/GB2003/004703 patent/WO2004041829A1/en not_active Ceased
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- 2003-10-30 TW TW092130284A patent/TWI320786B/zh not_active IP Right Cessation
- 2003-11-03 MY MYPI20034197A patent/MY137835A/en unknown
- 2003-11-04 AR ARP030104036A patent/AR041884A1/es not_active Application Discontinuation
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- 2005-04-13 IL IL168013A patent/IL168013A/en not_active IP Right Cessation
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- 2005-04-30 EG EGNA2005000178 patent/EG24957A/xx active
- 2005-05-03 CO CO05042313A patent/CO5560578A2/es not_active Application Discontinuation
- 2005-05-19 IS IS7849A patent/IS2568B/is unknown
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