WO2003048159A1 - Derives de la quinoleine - Google Patents
Derives de la quinoleine Download PDFInfo
- Publication number
- WO2003048159A1 WO2003048159A1 PCT/GB2002/005493 GB0205493W WO03048159A1 WO 2003048159 A1 WO2003048159 A1 WO 2003048159A1 GB 0205493 W GB0205493 W GB 0205493W WO 03048159 A1 WO03048159 A1 WO 03048159A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- alkyl
- ethoxy
- propoxy
- yloxy
- Prior art date
Links
- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 title claims abstract description 8
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 title abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 37
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 34
- 238000004519 manufacturing process Methods 0.000 claims abstract description 33
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 16
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 13
- 230000001740 anti-invasion Effects 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 9
- 230000008569 process Effects 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- -1 cyano, isocyano, nitro, hydroxy, mercapto, amino, formyl Chemical group 0.000 claims description 959
- 125000000217 alkyl group Chemical group 0.000 claims description 286
- 125000001424 substituent group Chemical group 0.000 claims description 163
- 150000001875 compounds Chemical class 0.000 claims description 152
- 150000003248 quinolines Chemical class 0.000 claims description 75
- 150000003839 salts Chemical class 0.000 claims description 70
- 125000000623 heterocyclic group Chemical group 0.000 claims description 63
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 63
- 229910052760 oxygen Inorganic materials 0.000 claims description 63
- 125000003545 alkoxy group Chemical group 0.000 claims description 56
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 47
- 125000001153 fluoro group Chemical group F* 0.000 claims description 43
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 37
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 37
- 238000006243 chemical reaction Methods 0.000 claims description 36
- 125000005843 halogen group Chemical group 0.000 claims description 36
- 229910052757 nitrogen Inorganic materials 0.000 claims description 35
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 35
- 239000001257 hydrogen Substances 0.000 claims description 34
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 33
- 125000001072 heteroaryl group Chemical group 0.000 claims description 33
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 33
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 33
- 125000003282 alkyl amino group Chemical group 0.000 claims description 32
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 30
- 125000004432 carbon atom Chemical group C* 0.000 claims description 30
- 125000006239 protecting group Chemical group 0.000 claims description 28
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 26
- 125000003118 aryl group Chemical group 0.000 claims description 25
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 25
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 23
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 20
- 229910052717 sulfur Inorganic materials 0.000 claims description 20
- 125000003342 alkenyl group Chemical group 0.000 claims description 19
- 125000000304 alkynyl group Chemical group 0.000 claims description 18
- 125000001246 bromo group Chemical group Br* 0.000 claims description 18
- 241001465754 Metazoa Species 0.000 claims description 17
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 17
- 125000001589 carboacyl group Chemical group 0.000 claims description 17
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 17
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 16
- 241000282414 Homo sapiens Species 0.000 claims description 16
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 16
- 238000003780 insertion Methods 0.000 claims description 16
- 230000037431 insertion Effects 0.000 claims description 16
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 14
- 125000002947 alkylene group Chemical group 0.000 claims description 14
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 14
- 238000003776 cleavage reaction Methods 0.000 claims description 13
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 13
- 125000004423 acyloxy group Chemical group 0.000 claims description 12
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims 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 claims description 10
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 10
- 125000000524 functional group Chemical group 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 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 10
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 10
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 9
- 125000004414 alkyl thio group Chemical group 0.000 claims description 9
- 230000007017 scission Effects 0.000 claims description 9
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 9
- 229920002554 vinyl polymer Polymers 0.000 claims description 9
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 8
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 8
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 8
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 8
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 8
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 7
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 7
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 125000004043 oxo group Chemical group O=* 0.000 claims description 7
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 7
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 6
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims description 5
- 230000029936 alkylation Effects 0.000 claims description 4
- 238000005804 alkylation reaction Methods 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 230000003647 oxidation Effects 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 3
- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 230000008878 coupling Effects 0.000 claims description 2
- 238000010168 coupling process Methods 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 138
- 239000000203 mixture Substances 0.000 description 126
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 114
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 61
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 57
- 239000000243 solution Substances 0.000 description 55
- 238000001819 mass spectrum Methods 0.000 description 44
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 42
- 239000011541 reaction mixture Substances 0.000 description 35
- 239000000377 silicon dioxide Substances 0.000 description 30
- 238000004440 column chromatography Methods 0.000 description 29
- 239000003480 eluent Substances 0.000 description 29
- 239000000047 product Substances 0.000 description 29
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- 102000001332 SRC Human genes 0.000 description 27
- 108060006706 SRC Proteins 0.000 description 27
- 239000007787 solid Substances 0.000 description 27
- 210000004027 cell Anatomy 0.000 description 24
- 238000012360 testing method Methods 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 21
- 235000019341 magnesium sulphate Nutrition 0.000 description 21
- 239000000463 material Substances 0.000 description 21
- 239000007858 starting material Substances 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- 239000011369 resultant mixture Substances 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 17
- 230000000694 effects Effects 0.000 description 17
- 239000003112 inhibitor Substances 0.000 description 17
- 239000012074 organic phase Substances 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 16
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000012267 brine Substances 0.000 description 15
- 102000037979 non-receptor tyrosine kinases Human genes 0.000 description 15
- 108091008046 non-receptor tyrosine kinases Proteins 0.000 description 15
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 15
- 230000005764 inhibitory process Effects 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- YYWJHOJMCOIVNS-UHFFFAOYSA-N 1-benzofuran-7-amine Chemical compound NC1=CC=CC2=C1OC=C2 YYWJHOJMCOIVNS-UHFFFAOYSA-N 0.000 description 13
- 239000003208 petroleum Substances 0.000 description 13
- 238000010992 reflux Methods 0.000 description 13
- 239000003701 inert diluent Substances 0.000 description 12
- 239000000376 reactant Substances 0.000 description 12
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 11
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- 210000004881 tumor cell Anatomy 0.000 description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 235000011114 ammonium hydroxide Nutrition 0.000 description 10
- 230000000259 anti-tumor effect Effects 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 239000012458 free base Substances 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 10
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 10
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 description 9
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000003556 assay Methods 0.000 description 9
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 description 9
- 201000011510 cancer Diseases 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 230000002265 prevention Effects 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 8
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 8
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 8
- 108700020796 Oncogene Proteins 0.000 description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 8
- 229960000583 acetic acid Drugs 0.000 description 7
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical class N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 7
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 7
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 7
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 206010061289 metastatic neoplasm Diseases 0.000 description 7
- 239000002953 phosphate buffered saline Substances 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 6
- 108010021833 Proto-Oncogene Proteins c-yes Proteins 0.000 description 6
- 102100021788 Tyrosine-protein kinase Yes Human genes 0.000 description 6
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 6
- 230000004663 cell proliferation Effects 0.000 description 6
- 239000007810 chemical reaction solvent Substances 0.000 description 6
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 6
- 239000003102 growth factor Substances 0.000 description 6
- 239000012442 inert solvent Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 230000001617 migratory effect Effects 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 125000004076 pyridyl group Chemical group 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- 230000019491 signal transduction Effects 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 230000004614 tumor growth Effects 0.000 description 6
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 5
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 5
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 5
- 239000000443 aerosol Substances 0.000 description 5
- 229910052783 alkali metal Inorganic materials 0.000 description 5
- 239000003638 chemical reducing agent Substances 0.000 description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Natural products OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 5
- 230000000875 corresponding effect Effects 0.000 description 5
- 239000012362 glacial acetic acid Substances 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 230000001394 metastastic effect Effects 0.000 description 5
- 125000006533 methyl amino methyl group Chemical group [H]N(C([H])([H])[H])C([H])([H])* 0.000 description 5
- 230000005012 migration Effects 0.000 description 5
- 238000013508 migration Methods 0.000 description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- YZBIJVJJQQURKW-UHFFFAOYSA-N 5-(oxan-4-yloxy)quinoline Chemical compound C1COCCC1OC1=CC=CC2=NC=CC=C12 YZBIJVJJQQURKW-UHFFFAOYSA-N 0.000 description 4
- ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 description 4
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 4
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- 102000001301 EGF receptor Human genes 0.000 description 4
- 108060006698 EGF receptor Proteins 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 4
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000004147 Sorbitan trioleate Substances 0.000 description 4
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 4
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 4
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 229940088598 enzyme Drugs 0.000 description 4
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 125000005647 linker group Chemical group 0.000 description 4
- 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 230000003389 potentiating effect Effects 0.000 description 4
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 4
- 235000019337 sorbitan trioleate Nutrition 0.000 description 4
- 229960000391 sorbitan trioleate Drugs 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 4
- 229940029284 trichlorofluoromethane Drugs 0.000 description 4
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 4
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 3
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 3
- OBZJIIHZBPETTB-UHFFFAOYSA-N 4-(1-benzofuran-2-ylamino)quinoline-3-carbonitrile Chemical class C1=CC=C2OC(NC3=C4C=CC=CC4=NC=C3C#N)=CC2=C1 OBZJIIHZBPETTB-UHFFFAOYSA-N 0.000 description 3
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 3
- BEGHZKYNLSIHIA-UHFFFAOYSA-N 4-chloro-7-(3-chloropropoxy)-6-methoxyquinoline-3-carbonitrile Chemical compound N#CC1=CN=C2C=C(OCCCCl)C(OC)=CC2=C1Cl BEGHZKYNLSIHIA-UHFFFAOYSA-N 0.000 description 3
- QIORUBTUDLGIII-UHFFFAOYSA-N 4-chloro-7-hydroxy-6-methoxyquinoline-3-carbonitrile Chemical compound N#CC1=CN=C2C=C(O)C(OC)=CC2=C1Cl QIORUBTUDLGIII-UHFFFAOYSA-N 0.000 description 3
- VLJSBQSZEAUVQB-UHFFFAOYSA-N 4-chloro-7-methoxy-5-(1-methylpiperidin-4-yl)oxyquinoline-3-carbonitrile Chemical compound C=12C(Cl)=C(C#N)C=NC2=CC(OC)=CC=1OC1CCN(C)CC1 VLJSBQSZEAUVQB-UHFFFAOYSA-N 0.000 description 3
- HLBZNYOCYAXWMB-UHFFFAOYSA-N 6-chloro-1-benzofuran-7-amine Chemical compound NC1=C(Cl)C=CC2=C1OC=C2 HLBZNYOCYAXWMB-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 229920001817 Agar Polymers 0.000 description 3
- 229920000936 Agarose Polymers 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 3
- 101800003838 Epidermal growth factor Proteins 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 102000009465 Growth Factor Receptors Human genes 0.000 description 3
- 108010009202 Growth Factor Receptors Proteins 0.000 description 3
- 102000004877 Insulin Human genes 0.000 description 3
- 108090001061 Insulin Proteins 0.000 description 3
- 235000019759 Maize starch Nutrition 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- 102000043276 Oncogene Human genes 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000012979 RPMI medium Substances 0.000 description 3
- 239000007868 Raney catalyst Substances 0.000 description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 3
- 229910000564 Raney nickel Inorganic materials 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 3
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 3
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 3
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 3
- DGYIJVNZSDYBOE-UHFFFAOYSA-N [CH2]C1=CC=NC=C1 Chemical group [CH2]C1=CC=NC=C1 DGYIJVNZSDYBOE-UHFFFAOYSA-N 0.000 description 3
- 239000008272 agar Substances 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 150000001340 alkali metals Chemical class 0.000 description 3
- 239000000908 ammonium hydroxide Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 230000009087 cell motility Effects 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 229940116977 epidermal growth factor Drugs 0.000 description 3
- 210000002950 fibroblast Anatomy 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 3
- 125000002883 imidazolyl group Chemical group 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 230000004899 motility Effects 0.000 description 3
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000000069 prophylactic effect Effects 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 239000011550 stock solution Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 125000001425 triazolyl group Chemical group 0.000 description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- SCZNXLWKYFICFV-UHFFFAOYSA-N 1,2,3,4,5,7,8,9-octahydropyrido[1,2-b]diazepine Chemical compound C1CCCNN2CCCC=C21 SCZNXLWKYFICFV-UHFFFAOYSA-N 0.000 description 2
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 2
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 2
- HNEGJTWNOOWEMH-UHFFFAOYSA-N 1-fluoropropane Chemical group [CH2]CCF HNEGJTWNOOWEMH-UHFFFAOYSA-N 0.000 description 2
- BAUWRHPMUVYFOD-UHFFFAOYSA-N 1-methylpiperidin-4-ol Chemical compound CN1CCC(O)CC1 BAUWRHPMUVYFOD-UHFFFAOYSA-N 0.000 description 2
- PKDPUENCROCRCH-UHFFFAOYSA-N 1-piperazin-1-ylethanone Chemical compound CC(=O)N1CCNCC1 PKDPUENCROCRCH-UHFFFAOYSA-N 0.000 description 2
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 2
- SBASXUCJHJRPEV-UHFFFAOYSA-N 2-(2-methoxyethoxy)ethanol Chemical compound COCCOCCO SBASXUCJHJRPEV-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 2
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 2
- MTJGVAJYTOXFJH-UHFFFAOYSA-N 3-aminonaphthalene-1,5-disulfonic acid Chemical compound C1=CC=C(S(O)(=O)=O)C2=CC(N)=CC(S(O)(=O)=O)=C21 MTJGVAJYTOXFJH-UHFFFAOYSA-N 0.000 description 2
- WUDXXKDFGZASJA-UHFFFAOYSA-N 3-chloro-1-benzofuran-7-amine Chemical compound NC1=CC=CC2=C1OC=C2Cl WUDXXKDFGZASJA-UHFFFAOYSA-N 0.000 description 2
- FTAHXMZRJCZXDL-UHFFFAOYSA-N 3-piperideine Chemical compound C1CC=CCN1 FTAHXMZRJCZXDL-UHFFFAOYSA-N 0.000 description 2
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- RVAMVCLDVCSLAK-UHFFFAOYSA-N 4-(1-benzofuran-7-ylamino)-7-(4-chlorobutoxy)-6-methoxyquinoline-3-carbonitrile;hydrochloride Chemical compound Cl.N#CC1=CN=C2C=C(OCCCCCl)C(OC)=CC2=C1NC1=CC=CC2=C1OC=C2 RVAMVCLDVCSLAK-UHFFFAOYSA-N 0.000 description 2
- SJBVKUZOGQKEAG-UHFFFAOYSA-N 4-chloro-5-(1-methylpiperidin-4-yl)oxyquinoline-3-carbonitrile Chemical compound C1CN(C)CCC1OC1=CC=CC2=NC=C(C#N)C(Cl)=C12 SJBVKUZOGQKEAG-UHFFFAOYSA-N 0.000 description 2
- HMLOMVBFQJAMCN-UHFFFAOYSA-N 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile Chemical compound C1=C(C#N)C(Cl)=C2C=C(OC)C(OC)=CC2=N1 HMLOMVBFQJAMCN-UHFFFAOYSA-N 0.000 description 2
- DLILOBLDMMRASC-UHFFFAOYSA-N 4-chloro-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile Chemical compound COC1=CC2=C(Cl)C(C#N)=CN=C2C=C1OCCCN1CCN(C)CC1 DLILOBLDMMRASC-UHFFFAOYSA-N 0.000 description 2
- HCXMIOZRXOIQHX-UHFFFAOYSA-N 4-chloroquinoline-3-carbonitrile Chemical compound C1=CC=C2C(Cl)=C(C#N)C=NC2=C1 HCXMIOZRXOIQHX-UHFFFAOYSA-N 0.000 description 2
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000004487 4-tetrahydropyranyl group Chemical group [H]C1([H])OC([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- QOFRDVZHEZZMRG-UHFFFAOYSA-N 5,7-difluoro-4-oxo-1h-quinoline-3-carbonitrile Chemical compound FC1=CC(F)=C2C(O)=C(C#N)C=NC2=C1 QOFRDVZHEZZMRG-UHFFFAOYSA-N 0.000 description 2
- UEKGFYDBXGBQLM-UHFFFAOYSA-N 5-fluoro-1-benzofuran-7-amine Chemical compound NC1=CC(F)=CC2=C1OC=C2 UEKGFYDBXGBQLM-UHFFFAOYSA-N 0.000 description 2
- NSAICFDJWJBFHA-UHFFFAOYSA-N 5-fluoro-7-nitro-1-benzofuran Chemical compound [O-][N+](=O)C1=CC(F)=CC2=C1OC=C2 NSAICFDJWJBFHA-UHFFFAOYSA-N 0.000 description 2
- WWUCOWNYDFJROQ-UHFFFAOYSA-N 7-(3-bromopropoxy)-4-chloro-6-methoxyquinoline-3-carbonitrile Chemical compound N#CC1=CN=C2C=C(OCCCBr)C(OC)=CC2=C1Cl WWUCOWNYDFJROQ-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- 108010069682 CSK Tyrosine-Protein Kinase Proteins 0.000 description 2
- 102000029330 CSK Tyrosine-Protein Kinase Human genes 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- 230000006820 DNA synthesis Effects 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 102400001368 Epidermal growth factor Human genes 0.000 description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical group C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 108091054455 MAP kinase family Proteins 0.000 description 2
- 102000043136 MAP kinase family Human genes 0.000 description 2
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 description 2
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 description 2
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 108010072960 Proto-Oncogene Proteins c-fyn Proteins 0.000 description 2
- 102000007131 Proto-Oncogene Proteins c-fyn Human genes 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- 229940124639 Selective inhibitor Drugs 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Chemical group 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000005092 alkenyloxycarbonyl group Chemical group 0.000 description 2
- 150000001348 alkyl chlorides Chemical class 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- 125000005336 allyloxy group Chemical group 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 2
- 230000000340 anti-metabolite Effects 0.000 description 2
- 230000001028 anti-proliverative effect Effects 0.000 description 2
- 229940100197 antimetabolite Drugs 0.000 description 2
- 239000002256 antimetabolite Substances 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 238000005341 cation exchange Methods 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 229960001681 croscarmellose sodium Drugs 0.000 description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- DIBHLCJAJIKHGB-UHFFFAOYSA-N dec-5-ene Chemical compound [CH2]CCCC=CCCCC DIBHLCJAJIKHGB-UHFFFAOYSA-N 0.000 description 2
- 239000012024 dehydrating agents Substances 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 229940087091 dichlorotetrafluoroethane Drugs 0.000 description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 2
- PKUFWXUXRIMHLM-UHFFFAOYSA-N ethyl 2-amino-6-chlorobenzoate Chemical compound CCOC(=O)C1=C(N)C=CC=C1Cl PKUFWXUXRIMHLM-UHFFFAOYSA-N 0.000 description 2
- ZTTKKVNUDLGBCI-UHFFFAOYSA-N ethyl 2-chloro-6-hydroxybenzoate Chemical compound CCOC(=O)C1=C(O)C=CC=C1Cl ZTTKKVNUDLGBCI-UHFFFAOYSA-N 0.000 description 2
- ZFMQPVALOWKRKZ-UHFFFAOYSA-N ethyl 2-cyano-3-(3,5-difluoroanilino)prop-2-enoate Chemical compound CCOC(=O)C(C#N)=CNC1=CC(F)=CC(F)=C1 ZFMQPVALOWKRKZ-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 230000009545 invasion Effects 0.000 description 2
- 125000002346 iodo group Chemical group I* 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- 229960005419 nitrogen Drugs 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- DRYRBWIFRVMRPV-UHFFFAOYSA-N quinazolin-4-amine Chemical compound C1=CC=C2C(N)=NC=NC2=C1 DRYRBWIFRVMRPV-UHFFFAOYSA-N 0.000 description 2
- QZZYYBQGTSGDPP-UHFFFAOYSA-N quinoline-3-carbonitrile Chemical class C1=CC=CC2=CC(C#N)=CN=C21 QZZYYBQGTSGDPP-UHFFFAOYSA-N 0.000 description 2
- SCPYDCQAZCOKTP-UHFFFAOYSA-N silanol Chemical compound [SiH3]O SCPYDCQAZCOKTP-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 2
- 239000008347 soybean phospholipid Substances 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 239000012258 stirred mixture Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000001117 sulphuric acid Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 2
- OWQOVPCSIOBQKO-UHFFFAOYSA-N tert-butyl 4-(2-fluoroethyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(CCF)CC1 OWQOVPCSIOBQKO-UHFFFAOYSA-N 0.000 description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 2
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 2
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 1
- CUNWUEBNSZSNRX-RKGWDQTMSA-N (2r,3r,4r,5s)-hexane-1,2,3,4,5,6-hexol;(z)-octadec-9-enoic acid Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O CUNWUEBNSZSNRX-RKGWDQTMSA-N 0.000 description 1
- IEJSCSAMMLUINT-NRFANRHFSA-N (2s)-2-[[4-[(2,7-dimethyl-4-oxo-1h-quinazolin-6-yl)methyl-prop-2-ynylamino]-2-fluorobenzoyl]amino]-4-(2h-tetrazol-5-yl)butanoic acid Chemical compound C([C@H](NC(=O)C1=CC=C(C=C1F)N(CC#C)CC=1C=C2C(=O)N=C(NC2=CC=1C)C)C(O)=O)CC=1N=NNN=1 IEJSCSAMMLUINT-NRFANRHFSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- LLAPDLPYIYKTGQ-UHFFFAOYSA-N 1-aminoethyl Chemical group C[CH]N LLAPDLPYIYKTGQ-UHFFFAOYSA-N 0.000 description 1
- WXVRAHOQLYAQCR-UHFFFAOYSA-N 1-benzofuran-7-ol Chemical compound OC1=CC=CC2=C1OC=C2 WXVRAHOQLYAQCR-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- 125000001478 1-chloroethyl group Chemical group [H]C([H])([H])C([H])(Cl)* 0.000 description 1
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 1
- JQCSUVJDBHJKNG-UHFFFAOYSA-N 1-methoxy-ethyl Chemical group C[CH]OC JQCSUVJDBHJKNG-UHFFFAOYSA-N 0.000 description 1
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 1
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- CZAQWQVAVLPLJI-UHFFFAOYSA-N 2-(5-fluoro-2-hydroxy-3-nitrophenyl)acetaldehyde Chemical compound OC1=C(CC=O)C=C(F)C=C1[N+]([O-])=O CZAQWQVAVLPLJI-UHFFFAOYSA-N 0.000 description 1
- SZCPTRGBOVXVCA-UHFFFAOYSA-N 2-amino-6-chlorobenzoic acid Chemical compound NC1=CC=CC(Cl)=C1C(O)=O SZCPTRGBOVXVCA-UHFFFAOYSA-N 0.000 description 1
- RWSFZKWMVWPDGZ-UHFFFAOYSA-N 2-amino-6-fluorobenzoic acid Chemical compound NC1=CC=CC(F)=C1C(O)=O RWSFZKWMVWPDGZ-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 description 1
- GHCZTIFQWKKGSB-UHFFFAOYSA-N 2-hydroxypropane-1,2,3-tricarboxylic acid;phosphoric acid Chemical compound OP(O)(O)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O GHCZTIFQWKKGSB-UHFFFAOYSA-N 0.000 description 1
- 125000004637 2-oxopiperidinyl group Chemical group O=C1N(CCCC1)* 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- KQOIBXZRCYFZSO-UHFFFAOYSA-N 3,5-difluoroaniline Chemical compound NC1=CC(F)=CC(F)=C1 KQOIBXZRCYFZSO-UHFFFAOYSA-N 0.000 description 1
- RQFUZUMFPRMVDX-UHFFFAOYSA-N 3-Bromo-1-propanol Chemical compound OCCCBr RQFUZUMFPRMVDX-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- ZTOJFFHGPLIVKC-UHFFFAOYSA-N 3-ethyl-2-[(3-ethyl-6-sulfo-1,3-benzothiazol-2-ylidene)hydrazinylidene]-1,3-benzothiazole-6-sulfonic acid Chemical compound S1C2=CC(S(O)(=O)=O)=CC=C2N(CC)C1=NN=C1SC2=CC(S(O)(=O)=O)=CC=C2N1CC ZTOJFFHGPLIVKC-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- VEGVCPVOZUQMBZ-UHFFFAOYSA-N 4-(1-benzofuran-7-ylamino)-5-(1-methylpiperidin-4-yl)oxyquinoline-3-carbonitrile;dihydrochloride Chemical compound Cl.Cl.C1CN(C)CCC1OC1=CC=CC2=NC=C(C#N)C(NC=3C=4OC=CC=4C=CC=3)=C12 VEGVCPVOZUQMBZ-UHFFFAOYSA-N 0.000 description 1
- FVUYBCBIKRHXSE-UHFFFAOYSA-N 4-(1-benzofuran-7-ylamino)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile Chemical compound COC1=CC2=C(NC=3C=4OC=CC=4C=CC=3)C(C#N)=CN=C2C=C1OCCCN1CCN(C)CC1 FVUYBCBIKRHXSE-UHFFFAOYSA-N 0.000 description 1
- KANYEAUZWSVQBH-UHFFFAOYSA-N 4-(1-benzofuran-7-ylamino)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile;dihydrochloride Chemical compound Cl.Cl.COC1=CC2=C(NC=3C=4OC=CC=4C=CC=3)C(C#N)=CN=C2C=C1OCCCN1CCN(C)CC1 KANYEAUZWSVQBH-UHFFFAOYSA-N 0.000 description 1
- XMQCBTHQBYJILJ-UHFFFAOYSA-N 4-(1-benzofuran-7-ylamino)-6-methoxy-7-[3-(4-prop-2-ynylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile Chemical compound COC1=CC2=C(NC=3C=4OC=CC=4C=CC=3)C(C#N)=CN=C2C=C1OCCCN1CCN(CC#C)CC1 XMQCBTHQBYJILJ-UHFFFAOYSA-N 0.000 description 1
- DLNRKIQEDLJLRV-UHFFFAOYSA-N 4-(1-benzofuran-7-ylamino)-7-(3-chloropropoxy)-6-methoxyquinoline-3-carbonitrile Chemical compound N#CC1=CN=C2C=C(OCCCCl)C(OC)=CC2=C1NC1=CC=CC2=C1OC=C2 DLNRKIQEDLJLRV-UHFFFAOYSA-N 0.000 description 1
- JGWRDVNGVDQYQM-UHFFFAOYSA-N 4-(1-benzofuran-7-ylamino)-7-hydroxy-6-methoxyquinoline-3-carbonitrile Chemical compound COc1cc2c(Nc3cccc4ccoc34)c(cnc2cc1O)C#N JGWRDVNGVDQYQM-UHFFFAOYSA-N 0.000 description 1
- BASUAWOHLFHYEK-UHFFFAOYSA-N 4-(1-benzofuran-7-ylamino)-7-methoxy-5-(1-methylpiperidin-4-yl)oxyquinoline-3-carbonitrile Chemical compound C=12C(NC=3C=4OC=CC=4C=CC=3)=C(C#N)C=NC2=CC(OC)=CC=1OC1CCN(C)CC1 BASUAWOHLFHYEK-UHFFFAOYSA-N 0.000 description 1
- XHDVZJYXFZMCBP-UHFFFAOYSA-N 4-[(4-cyano-1-benzofuran-7-yl)amino]-6,7-dimethoxyquinoline-3-carbonitrile Chemical compound C=12C=C(OC)C(OC)=CC2=NC=C(C#N)C=1NC1=CC=C(C#N)C2=C1OC=C2 XHDVZJYXFZMCBP-UHFFFAOYSA-N 0.000 description 1
- XLJDNGGBRPIVPY-UHFFFAOYSA-N 4-[(4-iodo-1-benzofuran-7-yl)amino]-6,7-dimethoxyquinoline-3-carbonitrile Chemical compound C=12C=C(OC)C(OC)=CC2=NC=C(C#N)C=1NC1=CC=C(I)C2=C1OC=C2 XLJDNGGBRPIVPY-UHFFFAOYSA-N 0.000 description 1
- IZEXXXVTFQFSFL-UHFFFAOYSA-N 4-[(6-chloro-1-benzofuran-7-yl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile Chemical compound COC1=CC2=C(NC=3C=4OC=CC=4C=CC=3Cl)C(C#N)=CN=C2C=C1OCCCN1CCN(C)CC1 IZEXXXVTFQFSFL-UHFFFAOYSA-N 0.000 description 1
- YRNWIFYIFSBPAU-UHFFFAOYSA-N 4-[4-(dimethylamino)phenyl]-n,n-dimethylaniline Chemical compound C1=CC(N(C)C)=CC=C1C1=CC=C(N(C)C)C=C1 YRNWIFYIFSBPAU-UHFFFAOYSA-N 0.000 description 1
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 description 1
- IYLIRRZCLARWKQ-UHFFFAOYSA-N 4-anilinoquinoline-3-carbonitrile Chemical class N#CC1=CN=C2C=CC=CC2=C1NC1=CC=CC=C1 IYLIRRZCLARWKQ-UHFFFAOYSA-N 0.000 description 1
- AFKXMNNFCNSZGI-UHFFFAOYSA-N 4-chloro-7-(4-chlorobutoxy)-6-methoxyquinoline-3-carbonitrile Chemical compound N#CC1=CN=C2C=C(OCCCCCl)C(OC)=CC2=C1Cl AFKXMNNFCNSZGI-UHFFFAOYSA-N 0.000 description 1
- KNDOFJFSHZCKGT-UHFFFAOYSA-N 4-chloroquinoline Chemical compound C1=CC=C2C(Cl)=CC=NC2=C1 KNDOFJFSHZCKGT-UHFFFAOYSA-N 0.000 description 1
- ZHRLVDHMIJDWSS-UHFFFAOYSA-N 4-fluoro-2-nitrophenol Chemical compound OC1=CC=C(F)C=C1[N+]([O-])=O ZHRLVDHMIJDWSS-UHFFFAOYSA-N 0.000 description 1
- SGOOQMRIPALTEL-UHFFFAOYSA-N 4-hydroxy-N,1-dimethyl-2-oxo-N-phenyl-3-quinolinecarboxamide Chemical compound OC=1C2=CC=CC=C2N(C)C(=O)C=1C(=O)N(C)C1=CC=CC=C1 SGOOQMRIPALTEL-UHFFFAOYSA-N 0.000 description 1
- WYRFAYFWKLFBGG-UHFFFAOYSA-N 4-methoxy-1-benzofuran-7-amine Chemical compound COC1=CC=C(N)C2=C1C=CO2 WYRFAYFWKLFBGG-UHFFFAOYSA-N 0.000 description 1
- DHSJZLBSVSAXDK-UHFFFAOYSA-N 5-(1-methylpiperidin-4-yl)oxy-4-oxo-1h-quinoline-3-carbonitrile Chemical compound C1CN(C)CCC1OC1=CC=CC2=C1C(=O)C(C#N)=CN2 DHSJZLBSVSAXDK-UHFFFAOYSA-N 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- WOVKYSAHUYNSMH-RRKCRQDMSA-N 5-bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 description 1
- SMWBPYDCERYFJZ-UHFFFAOYSA-N 5-fluoro-4-oxo-1h-quinoline-3-carbonitrile Chemical compound N1C=C(C#N)C(=O)C2=C1C=CC=C2F SMWBPYDCERYFJZ-UHFFFAOYSA-N 0.000 description 1
- BPHNVHYYTFDGHU-UHFFFAOYSA-N 6-chloro-1-benzofuran-7-carboxylic acid Chemical compound OC(=O)C1=C(Cl)C=CC2=C1OC=C2 BPHNVHYYTFDGHU-UHFFFAOYSA-N 0.000 description 1
- KQQWJKAFTJWWTA-UHFFFAOYSA-N 7-(3-bromopropoxy)quinoline Chemical compound C1=CC=NC2=CC(OCCCBr)=CC=C21 KQQWJKAFTJWWTA-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- MICNCNDVFQJZCG-UHFFFAOYSA-N 7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-(1-benzofuran-7-ylamino)-6-methoxyquinoline-3-carbonitrile Chemical compound COC1=CC2=C(NC=3C=4OC=CC=4C=CC=3)C(C#N)=CN=C2C=C1OCCCN1CCN(C(C)=O)CC1 MICNCNDVFQJZCG-UHFFFAOYSA-N 0.000 description 1
- KHTVVHHRVQJJSS-UHFFFAOYSA-N 7-fluoro-5-(oxan-4-yloxy)-4-oxo-1h-quinoline-3-carbonitrile Chemical compound C=12C(O)=C(C#N)C=NC2=CC(F)=CC=1OC1CCOCC1 KHTVVHHRVQJJSS-UHFFFAOYSA-N 0.000 description 1
- VRMSZELANUWMKR-UHFFFAOYSA-N 7-methoxy-5-(1-methylpiperidin-4-yl)oxy-4-oxo-1h-quinoline-3-carbonitrile Chemical compound C=12C(O)=C(C#N)C=NC2=CC(OC)=CC=1OC1CCN(C)CC1 VRMSZELANUWMKR-UHFFFAOYSA-N 0.000 description 1
- UWXIRVOEHNPCEV-UHFFFAOYSA-N 7-nitro-1-benzofuran Chemical compound [O-][N+](=O)C1=CC=CC2=C1OC=C2 UWXIRVOEHNPCEV-UHFFFAOYSA-N 0.000 description 1
- UWGHHWCSTCOGRB-UHFFFAOYSA-N 7-nitro-2,3-dihydro-1-benzofuran Chemical compound [O-][N+](=O)C1=CC=CC2=C1OCC2 UWGHHWCSTCOGRB-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 102000012936 Angiostatins Human genes 0.000 description 1
- 108010079709 Angiostatins Proteins 0.000 description 1
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 108010037003 Buserelin Proteins 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 0 CC1(*)C=C(C=CO2)C2=C(*c2c(C=C*(C=C3)I)c3ncc2C#N)C=C1 Chemical compound CC1(*)C=C(C=CO2)C2=C(*c2c(C=C*(C=C3)I)c3ncc2C#N)C=C1 0.000 description 1
- 102000000905 Cadherin Human genes 0.000 description 1
- 108050007957 Cadherin Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- NPOJQCVWMSKXDN-UHFFFAOYSA-N Dacthal Chemical compound COC(=O)C1=C(Cl)C(Cl)=C(C(=O)OC)C(Cl)=C1Cl NPOJQCVWMSKXDN-UHFFFAOYSA-N 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 description 1
- 239000004150 EU approved colour Substances 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 102000016621 Focal Adhesion Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108010067715 Focal Adhesion Protein-Tyrosine Kinases Proteins 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- 108010069236 Goserelin Proteins 0.000 description 1
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 1
- 108090000100 Hepatocyte Growth Factor Proteins 0.000 description 1
- 102100021866 Hepatocyte growth factor Human genes 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 description 1
- 101000904173 Homo sapiens Progonadoliberin-1 Proteins 0.000 description 1
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
- 101000922131 Homo sapiens Tyrosine-protein kinase CSK Proteins 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 102100037852 Insulin-like growth factor I Human genes 0.000 description 1
- 108010047852 Integrin alphaVbeta3 Proteins 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229940124041 Luteinizing hormone releasing hormone (LHRH) antagonist Drugs 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- ZKGNPQKYVKXMGJ-UHFFFAOYSA-N N,N-dimethylacetamide Chemical compound CN(C)C(C)=O.CN(C)C(C)=O ZKGNPQKYVKXMGJ-UHFFFAOYSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 108010058765 Oncogene Protein pp60(v-src) Proteins 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 208000010191 Osteitis Deformans Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 208000027868 Paget disease Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 102000018546 Paxillin Human genes 0.000 description 1
- ACNHBCIZLNNLRS-UHFFFAOYSA-N Paxilline 1 Natural products N1C2=CC=CC=C2C2=C1C1(C)C3(C)CCC4OC(C(C)(O)C)C(=O)C=C4C3(O)CCC1C2 ACNHBCIZLNNLRS-UHFFFAOYSA-N 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 102100024028 Progonadoliberin-1 Human genes 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- 101710100968 Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 101000996723 Sus scrofa Gonadotropin-releasing hormone receptor Proteins 0.000 description 1
- 108700031954 Tgfb1i1/Leupaxin/TGFB1I1 Proteins 0.000 description 1
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 102000004504 Urokinase Plasminogen Activator Receptors Human genes 0.000 description 1
- 108010042352 Urokinase Plasminogen Activator Receptors Proteins 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 229960001456 adenosine triphosphate Drugs 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 239000004479 aerosol dispenser Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- 201000009961 allergic asthma Diseases 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000091 aluminium hydride Inorganic materials 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 229960001220 amsacrine Drugs 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 230000003432 anti-folate effect Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940127074 antifolate Drugs 0.000 description 1
- 239000003080 antimitotic agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 229940046844 aromatase inhibitors Drugs 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 150000001543 aryl boronic acids Chemical class 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 description 1
- 239000012911 assay medium Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 238000011717 athymic nude mouse Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- OHDRQQURAXLVGJ-HLVWOLMTSA-N azane;(2e)-3-ethyl-2-[(e)-(3-ethyl-6-sulfo-1,3-benzothiazol-2-ylidene)hydrazinylidene]-1,3-benzothiazole-6-sulfonic acid Chemical compound [NH4+].[NH4+].S/1C2=CC(S([O-])(=O)=O)=CC=C2N(CC)C\1=N/N=C1/SC2=CC(S([O-])(=O)=O)=CC=C2N1CC OHDRQQURAXLVGJ-HLVWOLMTSA-N 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004601 benzofurazanyl group Chemical group N1=C2C(=NO1)C(=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 229960000997 bicalutamide Drugs 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- CUWODFFVMXJOKD-UVLQAERKSA-N buserelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 CUWODFFVMXJOKD-UVLQAERKSA-N 0.000 description 1
- 229960002719 buserelin Drugs 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 125000006309 butyl amino group Chemical group 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 229950002826 canertinib Drugs 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000003306 cell dissemination Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- BJDCWCLMFKKGEE-CMDXXVQNSA-N chembl252518 Chemical compound C([C@@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-CMDXXVQNSA-N 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 229940046044 combinations of antineoplastic agent Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- KFGVRWGDTLZAAO-UHFFFAOYSA-N cyclopenta-1,3-diene dicyclohexyl(cyclopenta-1,3-dien-1-yl)phosphane iron(2+) Chemical compound [Fe++].c1cc[cH-]c1.C1CCC(CC1)P(C1CCCCC1)c1ccc[cH-]1 KFGVRWGDTLZAAO-UHFFFAOYSA-N 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001887 cyclopentyloxy group Chemical group C1(CCCC1)O* 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229960000978 cyproterone acetate Drugs 0.000 description 1
- UWFYSQMTEOIJJG-FDTZYFLXSA-N cyproterone acetate Chemical compound C1=C(Cl)C2=CC(=O)[C@@H]3C[C@@H]3[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 UWFYSQMTEOIJJG-FDTZYFLXSA-N 0.000 description 1
- 210000004292 cytoskeleton Anatomy 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 230000003297 denaturating effect Effects 0.000 description 1
- CFCUWKMKBJTWLW-UHFFFAOYSA-N deoliosyl-3C-alpha-L-digitoxosyl-MTM Natural products CC=1C(O)=C2C(O)=C3C(=O)C(OC4OC(C)C(O)C(OC5OC(C)C(O)C(OC6OC(C)C(O)C(C)(O)C6)C5)C4)C(C(OC)C(=O)C(O)C(C)O)CC3=CC2=CC=1OC(OC(C)C1O)CC1OC1CC(O)C(O)C(C)O1 CFCUWKMKBJTWLW-UHFFFAOYSA-N 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000006264 diethylaminomethyl group Chemical group [H]C([H])([H])C([H])([H])N(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004655 dihydropyridinyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 125000005053 dihydropyrimidinyl group Chemical group N1(CN=CC=C1)* 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 229950004203 droloxifene Drugs 0.000 description 1
- 229940121647 egfr inhibitor Drugs 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- KTMGNAIGXYODKQ-VOTSOKGWSA-N ethyl (e)-2-cyano-3-ethoxyprop-2-enoate Chemical compound CCO\C=C(/C#N)C(=O)OCC KTMGNAIGXYODKQ-VOTSOKGWSA-N 0.000 description 1
- BWSJOFNDFWVHKR-UHFFFAOYSA-N ethyl 6-chloro-1-benzofuran-7-carboxylate Chemical compound CCOC(=O)C1=C(Cl)C=CC2=C1OC=C2 BWSJOFNDFWVHKR-UHFFFAOYSA-N 0.000 description 1
- HQEPEXVUMGSDSG-UHFFFAOYSA-N ethyl 6-chloro-2-hydroxy-3-(2-oxoethyl)benzoate Chemical compound CCOC(=O)C1=C(Cl)C=CC(CC=O)=C1O HQEPEXVUMGSDSG-UHFFFAOYSA-N 0.000 description 1
- 125000006534 ethyl amino methyl group Chemical group [H]N(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 125000005290 ethynyloxy group Chemical group C(#C)O* 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 238000010265 fast atom bombardment Methods 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 1
- 229960004039 finasteride Drugs 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 150000005699 fluoropyrimidines Chemical class 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 210000001650 focal adhesion Anatomy 0.000 description 1
- 239000004052 folic acid antagonist Substances 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- XLXSAKCOAKORKW-UHFFFAOYSA-N gonadorelin Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 XLXSAKCOAKORKW-UHFFFAOYSA-N 0.000 description 1
- 229960002913 goserelin Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 229940127121 immunoconjugate Drugs 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 238000011005 laboratory method Methods 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 1
- 229960004338 leuprorelin Drugs 0.000 description 1
- 239000008263 liquid aerosol Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 208000037841 lung tumor Diseases 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 208000027202 mammary Paget disease Diseases 0.000 description 1
- OCSMOTCMPXTDND-OUAUKWLOSA-N marimastat Chemical compound CNC(=O)[C@H](C(C)(C)C)NC(=O)[C@H](CC(C)C)[C@H](O)C(=O)NO OCSMOTCMPXTDND-OUAUKWLOSA-N 0.000 description 1
- 229950008959 marimastat Drugs 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 229960004296 megestrol acetate Drugs 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 239000003863 metallic catalyst Substances 0.000 description 1
- 239000003475 metalloproteinase inhibitor Substances 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- VKJYAPKCOSGXAD-UHFFFAOYSA-N methyl 2-amino-6-fluorobenzoate Chemical compound COC(=O)C1=C(N)C=CC=C1F VKJYAPKCOSGXAD-UHFFFAOYSA-N 0.000 description 1
- 238000010232 migration assay Methods 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 230000018791 negative regulation of catalytic activity Effects 0.000 description 1
- 229960002653 nilutamide Drugs 0.000 description 1
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- LMYJGUNNJIDROI-UHFFFAOYSA-N oxan-4-ol Chemical compound OC1CCOCC1 LMYJGUNNJIDROI-UHFFFAOYSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003551 oxepanyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- ACNHBCIZLNNLRS-UBGQALKQSA-N paxilline Chemical compound N1C2=CC=CC=C2C2=C1[C@]1(C)[C@@]3(C)CC[C@@H]4O[C@H](C(C)(O)C)C(=O)C=C4[C@]3(O)CC[C@H]1C2 ACNHBCIZLNNLRS-UBGQALKQSA-N 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 125000005633 phthalidyl group Chemical group 0.000 description 1
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920000223 polyglycerol Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 229940095055 progestogen systemic hormonal contraceptives Drugs 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 229960004432 raltitrexed Drugs 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229960003522 roquinimex Drugs 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 229960001922 sodium perborate Drugs 0.000 description 1
- QJDUDPQVDAASMV-UHFFFAOYSA-M sodium;ethanethiolate Chemical compound [Na+].CC[S-] QJDUDPQVDAASMV-UHFFFAOYSA-M 0.000 description 1
- YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 229960005078 sorbitan sesquioleate Drugs 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 208000017572 squamous cell neoplasm Diseases 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 1
- 229960001674 tegafur Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- FBDDQHPTNOSSGW-UHFFFAOYSA-N tert-butyl n-(6-chloro-1-benzofuran-7-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=C(Cl)C=CC2=C1OC=C2 FBDDQHPTNOSSGW-UHFFFAOYSA-N 0.000 description 1
- QKSQWQOAUQFORH-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonylimino]carbamate Chemical compound CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C QKSQWQOAUQFORH-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- DNGMYXZLJGHHOM-UHFFFAOYSA-N thiazinane 1,1-dioxide Chemical compound O=S1(=O)CCCCN1 DNGMYXZLJGHHOM-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical compound [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- 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
- C07D405/02—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 two hetero rings
- C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the invention concerns certain novel quinoline derivatives, or pharmaceutically-acceptable salts thereof, which possess anti-tumour activity and are accordingly useful in methods of treatment of the human or animal body.
- the invention also concerns processes for the manufacture of said quinoline derivatives, to pharmaceutical compositions containing them and to their use in therapeutic methods, for example in the manufacture of medicaments for use in the prevention or treatment of solid tumour disease in a warm-blooded animal such as man.
- Many of the current treatment regimes for cell proliferation diseases such as psoriasis and cancer utilise compounds which inhibit DNA synthesis. Such compounds are toxic to cells generally but their toxic effect on rapidly dividing cells such as tumour cells can be beneficial.
- Receptor tyrosine kinases are important in the transmission of biochemical signals which initiate cell replication. They are large enzymes which span the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor (EGF) and an intracellular portion which functions as a kinase to phosphorylate tyrosine amino acids in proteins and hence to influence cell proliferation.
- EGF epidermal growth factor
- Various classes of receptor tyrosine kinases are known (Wilks, Advances in Cancer Research, 1993, 60, 43-73) based on families of growth factors which bind to different receptor tyrosine kinases.
- the classification includes Class I receptor tyrosine kinases comprising the EGF family of receptor tyrosine kinases such as the EGF, TGF ⁇ , Neu and erbB receptors, Class ⁇ receptor tyrosine kinases comprising the insulin family of receptor tyrosine kinases such as the insulin and IGFI receptors and insulin-related receptor (IRR) and Class HI receptor tyrosine kinases comprising 5 the platelet-derived growth factor (PDGF) family of receptor tyrosine kinases such as the PDGF , PDGF ⁇ and colony-stimulating factor 1 (CSF1) receptors.
- EGF EGF family of receptor tyrosine kinases
- TGF ⁇ TGF ⁇
- Neu and erbB receptors Class ⁇ receptor tyrosine kinases comprising the insulin family of receptor tyrosine kinases such as the insulin and IGFI receptors and insulin-related receptor (IRR)
- tyrosine kinases belong to the class of non-receptor tyrosine kinases which are located intracellularly and are involved in the transmission of biochemical signals such as those that influence tumour cell motility, dissemination and
- Non-receptor tyrosine kinases include the Src family such as the Src, Lyn and Yes tyrosine kinases, the Abl family such as Abl and Arg and the Jak family such as Jak 1 and Tyk 2.
- Src family of non-receptor tyrosine kinases are highly regulated in normal cells and in the absence of extracellular stimuli are maintained in an inactive conformation.
- some Src family members for example c-Src tyrosine kinase, are frequently significantly activated (when compared to normal cell levels) in common human cancers such as gastrointestinal cancer, for example colon, rectal and stomach cancer
- NSCLCs non-small cell lung cancers
- c-Src non-receptor tyrosine kinase is to regulate the assembly of focal adhesion complexes through interaction with a number of cytoplasmic proteins including, for example, focal adhesion kinase and paxillin.
- cytoplasmic proteins including, for example, focal adhesion kinase and paxillin.
- c-Src is coupled to signalling pathways that regulate the actin cytoskeleton which facilitates cell motility.
- colon tumour progression from localised to disseminated, invasive metastatic disease has been correlated with c-Src non-receptor tyrosine kinase activity (Brunton et al, Oncogene, 1997, 14, 283-293, Fincham et al, EMBO J, 1998, 17, 81-92 and Verbeek et al, Exp. Cell Research, 1999, 248, 531-537).
- an inhibitor of such non-receptor tyrosine kinases should be of value as a selective inhibitor of the motility of tumour cells and as a selective inliibitor of the dissemination and invasiveness of mammalian cancer cells leading to inhibition of metastatic tumour growth.
- an inhibitor of such non-receptor tyrosine kinases should be of value as an anti-invasive agent for use in the containment and/or treatment of solid tumour disease.
- the compounds disclosed in the present invention possess pharmacological activity only by virtue of an effect on a single biological process, it is believed that the compounds provide an anti-tumour effect by way of inhibition of one or more of the non-receptor tyrosine-specific protein kinases that are involved in the signal transduction steps which lead to the invasiveness and migratory ability of metastasising tumour cells, hi particular, it is believed that the compounds of the present invention provide an anti-tumour effect byway of inhibition of the Src family of non-receptor tyrosine kinases, for example by inhibition of one or more of c-Src, c-Yes and c-Fyn.
- c-Src non-receptor tyrosine kinase enzyme is involved in the control of osteoclast-driven bone resorption (Soriano et al, Cell, 1991, 64, 693-702; Boyce et al, J. Clin. Invest., 1992, 90, 1622-1627; Yoneda et al, J. Clin. Invest.. 1993, 91, 2791-2795 and Missbach et al, Bone, 1999, 24 , 437-49).
- An inhibitor of c-Src non-receptor tyrosine kinase is therefore of value in the prevention and treatment of bone diseases such as osteoporosis, Paget's disease, metastatic disease in bone and tumour-induced hypercalcaemia.
- the compounds of the present invention are also useful in inhibiting the uncontrolled cellular proliferation which arises from various non-malignant diseases such as inflammatory diseases (for example rheumatoid arthritis and inflammatory bowel disease), fibrotic diseases (for example hepatic cirrhosis and lung fibrosis), glomeralonephritis, multiple sclerosis, psoriasis, hypersensitivity reactions of the skin, blood vessel diseases (for example atherosclerosis and restenosis), allergic asthma, insulin-dependent diabetes, diabetic retinopathy and diabetic nephropathy.
- inflammatory diseases for example rheumatoid arthritis and inflammatory bowel disease
- fibrotic diseases for example hepatic cirrhosis and lung fibrosis
- glomeralonephritis for example hepatic cirrhosis and lung fibrosis
- multiple sclerosis for example herosclerosis and restenosis
- allergic asthma insulin-dependent diabetes
- diabetic retinopathy diabetic nopathy
- the compounds of the present invention possess potent inhibitory activity against the Src family of non-receptor tyrosine kinases, for example by inhibition of c-Src and/or c-Yes, whilst possessing less potent inhibitory activity against other tyrosine kinase enzymes such as the receptor tyrosine kinases, for example EGF receptor tyrosine kinase and/or VEGF receptor tyrosine kinase.
- the receptor tyrosine kinases for example EGF receptor tyrosine kinase and/or VEGF receptor tyrosine kinase.
- certain compounds of the present invention possess substantially better potency against the Src family of non-receptor tyrosine kinases, for example c-Src and/or c-Yes, than against VEGF receptor tyrosine kinase.
- Such compounds possess sufficient potency against the Src family of non-receptor tyrosine kinases, for example c-Src and/or c-Yes, that they may be used in an amount sufficient to inhibit, for example, c-Src and/or c-Yes whilst demonstrating little activity against VEGF receptor tyrosine kinase.
- Z is an O
- S may be the same or different, is hydrogen or (l-6C)alkyl
- m is O, 1, 2, 3 or 4
- each R 1 group which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, isocyano, nitro, hydroxy, mercapto, amino, formyl, carboxy, carbamoyl, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsul ⁇ honyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl
- N-(l-6C)alkylsulphamoyl N,N-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino and N-(l-6C)alkyl-(l-6C)alkanesulphonylamino, or from a group of the formula :
- X 1 is a direct bond or is selected from O, S, SO, SO 2 , N(R 4 ), CO, CH(OR 4 ), CON(R 4 ), N(R 4 )CO, SO 2 N(R 4 ), N(R 4 )SO 2 , OC(R 4 ) 2 , SC(R 4 ) 2 and N(R 4 )C(R 4 ) 2 , wherein R 4 is hydrogen or (l-6C)alkyl, and Q 1 is aryl, aryl-(l-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl- (l-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heteroaryl, heteroaryl- (l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, or (R ⁇ m is (l-3C)al
- X is a direct bond or is selected from CO and N(R )CO, wherein R is hydrogen or (l-6C)alkyl
- Q 2 is aryl, aryl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl 5 and wherein any CH 2 or CH 3 group within a R 1 substituent optionally bears on each said CH 2 or CH 3 group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsul ⁇ hinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)
- X 3 is a direct bond or is selected from O, S, SO, SO 2 , N(R 7 ), CO, CH(OR 7 ), CON(R 7 ), N(R 7 )CO, SO 2 N(R 7 ), N(R 7 )SO 2 , C(R 7 ) 2 O, C(R 7 ) 2 S and N(R 7 )C(R 7 ) 2 , wherein R 7 is hydrogen or (l-6C)alkyl, and Q 3 is aryl, aryl-(l-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl- (l-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heteroaryl, heteroaryl- (l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any aryl, heteroaryl
- X 4 is a direct bond or is selected from O and N(R 9 ), wherein R 9 is hydrogen or (l-6C)alkyl, and R 8 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino- (l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl or (l-6C)alkoxycarbonylamino-(l-6C)alkyl, or from a group of the formula :
- X 5 is a direct bond or is selected from O, N(R 10 ) and CO, wherein R 10 is hydrogen or (l-6C)alkyl
- Q 4 is aryl, aryl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (l-6C)alkoxy, and wherein any heterocyclyl group within a substituent on R 1 optionally bears 1 or 2 oxo or thioxo substituents; n is O, 1, 2 or 3; and
- R 3 is halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl] amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l -6C)alkyl
- X 6 is a direct bond or is selected from O and N(R 12 ), wherein R 12 is hydrogen or (l-6C)alkyl, and R 11 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl or di-[(l-6C)alkyl]amino-(l-6C)alkyl, or from a group of the formula :
- X 7 is a direct bond or is selected from O, S, SO, SO 2 , N(R 13 ), CO, CH(OR 13 ), CON(R 13 ), N(R 13 )CO, SO 2 N(R 13 ), N(R 13 )SO 2 , C(R 13 ) 2 O, C(R 13 ) 2 S and N(R 13 )C(R 13 ) 2 , wherein R 13 is hydrogen or (l-6C)alkyl, and Q 5 is aryl, aryl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl which optionally bears 1 or 2 substituents, which maybe the same or different, selected from halogeno, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (l-6C)alkoxy, and any heterocyclyl group within Q
- alkyl includes both straight-chain and branched-chain alkyl groups such as propyl, isopropyl and tert-butyl, and also (3-7C)cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
- references to individual alkyl groups such as "propyl” are specific for the straight-chain version only
- references to individual branched-chain alkyl groups such as "isopropyl” are specific for the branched-chain version only
- references to individual cycloalkyl groups such as "cyclopentyl” are specific for that 5-membered ring only.
- (l-6C)alkoxy includes methoxy, ethoxy, cyclopropyloxy and cyclopentyloxy
- (l-6C)alkylamino includes methylamino, ethylamino, cyclobutylamino and cyclohexylamino
- di-[(l-6Calkyl]amino includes dimethylamino, diethylamino, N-cyclobutyl-N-methylamino and N-cyclohexyl- N-ethylamino.
- the invention includes in its definition any such optically active or racemic form which possesses the above-mentioned activity.
- the synthesis of optically active forms maybe carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
- the above-mentioned activity may be evaluated using the standard laboratory techniques referred to hereinafter.
- Suitable values for the generic radicals referred to above include those set out below.
- a suitable value for any one of the 'Q' groups (Q 1 to Q 5 ) when it is aryl or for the aryl group within a 'Q' group is, for example, phenyl or naphthyl, preferably phenyl.
- a suitable value for any one of the 'Q' groups (Q 1 or Q 3 ) when it is (3-7C)cycloalkyl or for the (3-7C)cycloalkyl group within a 'Q' group is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2.1]heptyl and a suitable value for any one of the 'Q' groups (Q 1 or Q 3 ) when it is (3-7C)cycloalkenyl or for the (3-7C)cycloalkenyl group within a 'Q' group is, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl.
- a suitable value for any one of the 'Q' groups (Q 1 to Q 5 ) when it is heteroaryl or for the heteroaryl group within a 'Q' group is, for example, an aromatic 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring with up to five ring heteroatoms selected from oxygen, nitrogen and sulphur, for example furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, be
- a suitable value for any one of the 'Q' groups (Q 1 to Q 5 ) when it is heterocyclyl or for the heterocyclyl group within a 'Q' group is, for example, a non-aromatic saturated or partially saturated 3 to 10 membered monocyclic or bicyclic ring with up to five heteroatoms selected from oxygen, nitrogen and sulphur, for example oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, tetrahydrothienyl, 1,1-dioxotetrahydrothienyl, tetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, azetidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-l,4-thiazinyl, l,l-dioxo
- a suitable value for such a group which bears 1 or 2 oxo or thioxo substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.
- a suitable value for a 'Q' group when it is heteroaryl-(l-6C)alkyl is, for example, heteroarylmethyl, 2-heteroarylethyl and 3-heteroarylpropyl.
- the invention comprises corresponding suitable values for 'Q' groups when, for example, rather than a heteroaryl-(l-6C)alkyl group, an aryl-(l-6C)alkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyl-(l-6C)alkyl or heterocyclyl-(l-6C)alkyl group is present.
- Suitable values for any of the 'R' groups (R 1 to R 13 ) or for various groups within an R 1 or R substituent include :- for halogeno fluoro, chloro, bromo and iodo; for (l-6C)alkyl: methyl, ethyl, propyl, isopropyl and tert-butyl; for (2-8C)alkenyl: vinyl, isopropenyl, allyl and but-2-enyl; for (2-8C)alkynyl: ethynyl, 2-propynyl and but-2-ynyl; for (l-6C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for (2-6C)alkenyloxy: vinyloxy and allyloxy; for (2-6C)alkynyloxy: ethynyloxy and 2-propynyloxy; for (l-6C)alkylthio: methylthio,
- N-methylethanesulphonylamino for (3-6C)alkenoylamino: acrylamido, methacrylamido and crotonamido; for N-(l-6C)alkyl-(3-6C)alkenoylamino: N-methylacrylamido and N-methylcrotonamido; for (3-6C)alkynoylamino: propiolamido;
- N-(l-6C)alkyl-(3-6C)alkynoylamino N-methylpropiolamido
- amino-(l-6C)alkyl aminomethyl, 2-aminoethyl, 1 -aminoethyl and
- halogeno-(l-6C)alkyl chloromethyl, 2-chloroethyl, 1-chloroethyl and
- a suitable value for (R l ) m when it is a (l-3C)alkylenedioxy group is, for example, methylenedioxy or ethylenedioxy and the oxygen atoms thereof occupy adjacent ring positions.
- an R group forms a group of the formula Q -X - and, for example, X 1 is a OC(R 4 ) 2 linking group, it is the carbon atom, not the oxygen atom, of the OC(R 4 ) 2 linking group which is attached to the quinoline ring and the oxygen atom is attached to the Q 1 group.
- adjacent carbon atoms in any (2-6C)alkylene chain within a R 1 substituent may be optionally separated by the insertion into the chain of a group such as O, CON(R 5 ) or C ⁇ C.
- a group such as O, CON(R 5 ) or C ⁇ C.
- insertion of a C ⁇ C group into the ethylene chain within a 2-morpholinoethoxy group gives rise to a 4-morpholinobut-2-ynyloxy group and, for example, insertion of a CONH group into the ethylene chain within a 3-methoxypropoxy group gives rise to, for example, a 2-(2-methoxyacetamido)ethoxy group.
- suitable R 1 substituents so formed include, for example, N-[heterocyclyl- (l-6C)alkyl]carbamoylvinyl groups such as N-(2-pyrrolidin-l-ylethyl)carbamoylvinyl or N-[heterocyclyl-(l-6C)alkyl]carbamoylethynyl groups such as N-(2-pyrrolidin- l-ylethyl)carbamoylethynyl.
- any CH 2 or CH 3 group within a R 1 substituent optionally bears on each said CH 2 or CH 3 group one or more halogeno or (l-6C)alkyl substituents, there are suitably 1 or 2 halogeno or (l-6C)alkyl substituents present on each said CH 2 group and there are suitably 1, 2 or 3 such substituents present on each said CH 3 group.
- R 1 substituents so formed include, for example, hydroxy-substituted heterocyclyl- (l-6C)alkoxy groups such as 2-hydroxy-3-piperidinopropoxy and 2-hydroxy- 3-morpholinopropoxy, hydroxy-substituted amino-(2-6C)alkoxy groups such as 3-amino- 2-hydroxypropoxy, hydroxy-substituted (l-6C)alkylamino-(2-6C)alkoxy groups such as 2-hydroxy-3-methylaminopropoxy, hydroxy-substituted di-[(l-6C)alkyl]amino-(2-6C)alkoxy groups such as 3-dimethylamino-2-hydroxypropoxy, hydroxy-substituted heterocyclyl- (l-6C)alkylamino groups such as 2-hydroxy-3-piperidin
- hydroxy-substituted (l-6C)alkoxy groups such as 2-hydroxyethoxy, (l-6C)alkoxy-substituted (l-6C)alkoxy groups such as 2-methoxyethoxy and 3-ethoxypropoxy, (l-6C)alkylsulphonyl-substituted (l-6C)alkoxy groups such as 2-methylsulphonylethoxy and heterocyclyl-substituted (l-6C)alkylamino-(l-6C)alkyl groups such as 2-morpholinoethylaminomethyl, 2-piperazin-l-ylethylaminomethyl and 3-morpholinopropylaminomethyl.
- a suitable pharmaceutically-acceptable salt of a compound of the Formula I is, for example, an acid-addition salt of a compound of the Formula I, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid; or, for example, a salt of a compound of the Formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
- an acid-addition salt of a compound of the Formula I for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid
- novel compounds of the invention include, for example, quinoline derivatives of the Formula I, or pharmaceutically-acceptable salts thereof, wherein, unless otherwise stated, each of Z, m, R 1 , n and R 3 has any of the meanings defined hereinbefore or in paragraphs (a) to (q) hereinafter :- (a) Z is O, S, SO, SO 2 , CH 2 or NH;
- each R 1 group which may be the same or different, is selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (l-6C)alkyl, (2-8C)alkenyl,
- X 1 is a direct bond or is selected from O, N(R 4 ), CON(R 4 ), N(R 4 )CO and OC(R 4 ) 2 wherein R 4 is hydrogen or (l-6C)alkyl
- X 2 is a direct bond or is CO or N(R 6 )CO, wherein R 6 is hydrogen or (l-6C)alkyl, and Q 2 is heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl orheterocyclyl-(l-6C)alkyl, and wherein any CH 2 or CH 3 group within a R 1 substituent optionally bears on each said CH 2 or CH 3 group one or more halogeno groups or a substituent selected from hydroxy, amino, (l-6C)alkoxy, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyloxy, (2-6C)alkanoylamino and N-(l-6C)alkyl-(2-6C)alkanoylamino, or from a group of the formula :
- X 3 is a direct bond or is selected from O, N(R 6 ), CON(R 7 ), N(R 7 )CO and C(R 7 ) 2 O, wherein R 7 is hydrogen or (l-6C)alkyl
- Q 3 is heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R 1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (l-6C)alkylsulphonyl, N-(l-6C)alkylcarbamoyL N,N-di-[(l)
- X 5 is a direct bond or is selected from O, N(R 10 ) and CO, wherein R 10 is hydrogen or (l-6C)alkyl, and Q 4 is heterocyclyl or heterocyclyl-(l-6C)alkyl which optionally bears 1 or 2 substituents, which maybe the same or different, selected from halogeno, (l-6C)alkyl and (l-6C)alkoxy, and wherein any heterocyclyl group within a substituent on R 1 optionally bears 1 or 2 oxo substituents;
- each R 1 group which may be the same or different, is selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, propyl, butyl, vinyl, allyl, but-3-enyl, pent-4-enyl, hex-5-enyl, ethynyl, 2-propynyl, but-3-ynyl, pent-4-ynyl, hex-5-ynyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, allyloxy, but-3-enyloxy, pent-4-enyloxy, hex-5-enyloxy, ethynyloxy, 2-propynyloxy, but-3-ynyloxy, pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino, propyla
- Q 2 -X 2 - wherein X 2 is a direct bond or is CO, NHCO or N(Me)CO and Q 2 is pyridyl, pyridylmethyl, 2-pyridylethyl, pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, pyrrolidin-1-ylmethyl, 2-pyrrolidin-l-ylethyl,
- X 4 is a direct bond or is selected from O and NH and R 8 is 2-hydroxyethyl, 3 -hydroxypropyl, 2-methoxyethyl, 3 -methoxypropyl, cyanomethyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-ethylaminoethyl, 3-ethylaminopropyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, acetamidomethyl, methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl or tert-butoxycarbonylaminomethyl, and from a group of the formula :
- X 5 is a direct bond or is selected from O, NH and CO and Q 4 is pyrrolidin-1-ylmethyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl, piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl, piperazin-1 -ylmethyl, 2-piperazin-l -ylethyl or 3-piperazin-l-ylpropyl, each of which optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, methyl and methoxy, and wherein any heterocyclyl group within a substituent on R 1 optionally bears 1 or 2 oxo substituents; and
- m is 1 and the R 1 group is located at the 5-, 6- or 7-position or m is 2 and each R 1 group, which may be the same or different, is located at the 5- and 7-positions or at the 6- and 7-positions and R 1 is selected from hydroxy, amino, methyl, ethyl, propyl, butyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, but-3-enyloxy, pent-4-enyloxy, hex-5-enyloxy, but-3-ynyloxy, pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, cyclopentyloxy, cyclohexyloxy, phenoxy, benzyloxy, tetrahydro
- X 2 is a direct bond or is NHCO or N(Me)CO and Q 2 is imidazolylmethyl, 2-imidazolylethyl, 3-imidazolylpropyl, pyridylmethyl, 2-pyridylethyl, 3-pyridylpropyl, pyrrolidin-1-ylmethyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, 4-pyrrolidin-l-ylbutyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl, piperidinomethyl, 2-piperidinoethyl, 3-piperidin
- (g) m is 1 and the R 1 group is located at the 6- or 7-position and is selected from hydroxy, amino, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylamino, ethylamino, dimethylammo, diethylamino, acetamido, propionamido, benzyloxy, 2-imidazol-l -ylethoxy, 2-(l,2,3-triazol-l-yl)ethoxy, 2-(l,2,4-triazol-l-yl)ethoxy, 2-pyrrolidin- 1 -ylethoxy, 3 -pyrrolidin- 1 -ylpropoxy, 4-pyrrolidin- 1 -ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy,
- n 1 or 2 and the R groups, which may be the same or different, are located at the
- n is 1 or 2 and the R 3 groups, which may be the same or different, are located at the
- 3-, 5- and/or 6-positions of the benzofuran-7-yl group are selected from fluoro, chloro, bromo, iodo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl, isopropenyl, ethynyl,
- (k) n is 1 and the R 3 group is located at the 5- or 6-position of the benzofuran-7-yl group, especially the 6-position, and is selected from chloro, bromo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, methoxy and ethoxy;
- each R 1 group which may be the same or different, is selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (l-6C)alkyl, (l-6C)alkoxy,
- X 1 is selected from O, N(R 4 ), CON(R 4 ), N(R 4 )CO and OC(R 4 ) 2 wherein R 4 is hydrogen or (l-6C)alkyl
- Q 1 is aryl, aryl-(l-6C)alkyl, cycloalkyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, or X 1 is a direct bond and
- X 3 is a direct bond or is selected from O, N(R 6 ), CON(R 7 ), N(R 7 )CO and C(R 7 ) 2 O, wherein R 7 is hydrogen or (l-6C)alkyl
- Q 3 is heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R 1 optionally bears 1 , 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (l-6C)alkylsulphonyl, N-(l-6C)alkylcarbamoyl, N,N-di-
- X 4 is a direct bond or is selected from O and N(R 9 ), wherein R 9 is hydrogen or (l-6C)alkyl, and R 8 is hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl or (l-6C)alkoxycarbonylamino-(l-6C)alkyl, and from a group of the formula : -X 5 -Q 4 wherein X 5 is a direct bond or is selected from O, N(R 10 ) and CO, wherein R 10 is hydrogen or (l-6C)alkyl, and Q 4
- each R 1 group which may be the same or different, is selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, acetamido, propionamido, acrylamido and propiolamido, or from a group of the formula :
- X 1 is selected from O, NH, CONH, NHCO and OCH 2 and Q 1 is phenyl, benzyl, cyclopropylmethyl, 2-thienyl, 1-imidazolyl, 1,2,3-triazol-l-yl, 1,2,4-triazol-l-yl, 2-, 3- or 4-pyridyl, 2-imidazol-l -ylethyl, 3 -imidazol-1 -ylpropyl, 2-(l,2,3-triazolyl)ethyl, 3-(l,2,3-triazolyl)propyl, 2-(l,2,4-triazolyl)ethyl, 3-(l,2,4-triazolyl)propyl, 2-, 3- or 4-pyridylmethyl, 2-(2-, 3- or 4-pyridyl)ethyl, 3-(2-, 3- or 4-pyridyl)propyl, tetrahydrofuran-3-
- X 3 is a direct bond or is selected from O, NH, CONH, NHCO and CH 2 O and Q 3 is pyridyl, pyridylmethyl, pyrrolidin-1-yl, pyrrolidin-2-yl, mo ⁇ holino, piperidino, piperidin-3-yl, piperidin-4-yl, piperazin-1 -yl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, pyrrolidin- 2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, 2-mo ⁇ holinoethyl, 3-mo ⁇ holinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, piperidin-3-ylmethyl, 2-piperidin- 3-ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylmethyl, 2-piperidin-4
- X is a direct bond or is selected from O and NH and R is 2-hydroxyethyl, 3 -hydroxypropyl, 2-methoxyethyl, 3 -methoxypropyl, cyanomethyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, methylaminomethyl, 2-methylaminoethyl,
- m is 1 and the R 1 group is located at the 5-, 6- or 7-position or m is 2 and each R 1 group, which maybe the same or different, is located at the 5- and 7-positions or at the 6- and 7-positions and R 1 is selected from hydroxy, amino, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, cyclopentyloxy, cyclohexyloxy, phenoxy, benzyloxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, cyclopropylmethoxy, 2-imidazol- 1 -ylethoxy, 3 -imidazol- 1 -yl
- n is 1 or 2 and the R 3 groups, which may be the same or different, are located at the 3-, 4-, 5- and/or 6-positions of the benzofuran-7-yl group and are selected from fluoro, chloro, bromo, iodo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl, isopropenyl, ethynyl, 1-propynyl, 2-propynyl, methoxy and ethoxy; and
- n 1 and the R 3 group is located at the 4-, 5- or 6-position of the benzofuran-7-yl group, especially the 6-position, and is selected from chloro, bromo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, methoxy and ethoxy.
- novel compounds of the invention include, for example, quinoline derivatives of the Formula I, or pharmaceutically-acceptable salts thereof, wherein, unless otherwise stated, each of Z, m, R , n and R has any of the meanings defined hereinbefore provided that :- (A) R 1 substituents may only be located at the 5-, 6- and/or 7-positions on the quinoline ring i.e. the 2- and 8-positions remain unsubstituted; or
- R 1 substituents may only be located at the 6- and/or 7-positions on the quinoline ring i.e. the 2-, 5- and 8-positions remain unsubstituted.
- a particular compound of the invention is a quinoline derivative of the Formula I wherein :
- Z is O orNH; m is 1 and the R 1 group is located at the 5-, 6- or 7-position or m is 2 and each R 1 group, which may be the same or different, is located at the 5- and 7-positions or at the 6- and 7-positions and R 1 is selected from hydroxy, amino, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, 2-imidazol-l -ylethoxy, 2-(l ,2,4-triazol-l-yl)ethoxy, tefrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, 2-pyrrolidin- 1 -ylethoxy, 3
- substituents each optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, methyl and methoxy, and wherein any heterocyclyl group within a substituent on R 1 optionally bears 1 or 2 oxo substituents; and n is 0 or 1 and the R group, if present, is located at the 3-, 4-, 5- or 6-position of the benzofuran-7-yl group and is selected from fluoro, chloro, bromo, iodo, trifluoromethyl, cyano, hydroxy, methyl, ethyl
- a particular compound of the invention is a quinoline derivative of the Formula I wherein :
- Z is O or NH; m is 1 and the R 1 group is located at the 5-, 6- or 7-position or m is 2 and each R 1 group, which may be the same or different, is located at the 5- and 7-positions or at the 6- and 7-positions and R 1 is selected from hydroxy, amino, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, 2-imidazol-l -ylethoxy, 2-(l,2,4-triazol-l-yl)ethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, 2-pyrrolidin- 1 -ylethoxy, 3 -pyr
- substituents each optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, methyl and methoxy, and wherein any heterocyclyl group within a substituent on R 1 optionally bears 1 or 2 oxo substituents; and n is 0 or 1 and the R group, if present, is located at the 3-, 5- or 6-position of the benzofuran-7-yl group and is selected from fluoro, chloro, bromo, trifluoromethyl, cyano, hydroxy, methyl, e
- Formula I wherein : Z is O or NH; m is 2 and the first R 1 group is located at the 6-position and is selected from hydroxy, methoxy, ethoxy and propoxy, and the second R 1 group is located at the 7-position and is selected from 2-hydroxyethoxy, 3-hydroxypropoxy, 4-hydroxybutoxy, 2-methoxyethoxy, 3-methoxypropoxy, 4-methoxybutoxy, 2-(2-hydroxyethoxy)ethoxy, 2-(2-methoxyethoxy)ethoxy, 2-dimethylaminoethoxy, 3 -dimethylaminopropoxy, 4-dimethylaminobutoxy, 2-diethylaminoethoxy, 3 -diethylaminopropoxy, 4-diethylaminobutoxy, 2-diisopropylaminoethoxy, 3 -diisopropylaminopropoxy, 4-diisopropylaminobutoxy, 2-(N-isopropyl-N-methylamino)
- any CH 2 group within the second R 1 group that is attached to two carbon atoms optionally bears a hydroxy group or acetoxy group on said CH 2 group, and wherein any heterocyclyl group within the second R 1 group optionally bears 1 or 2 substituents selected from fluoro, hydroxy, methyl and oxo; and n is 0 or n is 1 and the R group, if present, is located at the 5- or 6-position of the benzofuran-7-yl group and is selected from fluoro, chloro, bromo, trifluoromethyl, cyano, methyl, ethyl, ethynyl, methoxy and ethoxy; or a pharmaceutically-acceptable acid-addition salt thereof.
- a further particular compound of the invention is a quinoline derivative of the
- Formula I wherein : Z is O orNH; m is 2 and the first R 1 group is a 6-methoxy group and the second R 1 group is located at the 7-position and is selected from 2-dimethylaminoethoxy, 3-dimethylaminopropoxy,
- any CH 2 group within the second R 1 group that is attached to two carbon atoms optionally bears a hydroxy group on said CH 2 group
- any heteroaryl group within the second R 1 group optionally bears 1 or 2 substituents selected from chloro, cyano, hydroxy and methyl
- any heterocyclyl group within the second R 1 group optionally bears 1 or 2 substituents selected from fluoro, hydroxy, methyl and oxo
- n is 0 or n is 1 and the R 3 group, if present, is located at the 4-, 5- or 6-position of the benzofuran-7-yl group and is selected from fluoro, chloro, bromo, iodo and cyano; or a pharmaceutically-acceptable acid-addition salt thereof.
- a further particular compound of the invention is a quinoline derivative of the Formula I wherein : Z is O or NH; m is 2 and the first R 1 group is a 6-methoxy group and the second R 1 group is located at the 7-position and is selected from 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 4-dimethylaminobutoxy, 2-diethylaminoethoxy, 3-diethylaminopropoxy, 4-diethylaminobutoxy, 2-diisopropylaminoethoxy, 3-diisopropylaminopropoxy, 4-diisopropylaminobutoxy, 2-(N-isopropyl-N-methylamino)ethoxy,
- a further particular compound of the invention is a quinoline derivative of the Formula I wherein : Z is H; m is 2 and the first R 1 group is a 6-methoxy group and the second R 1 group is located at the 7-position and is selected from 2-pyrrolidin-l -ylethoxy, 3 -pyrrolidin-1 -ylpropoxy, 2-mo ⁇ holinoethoxy, 3 -mo ⁇ holinopropoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin- 4-yl)ethoxy, 3-(l,l-dioxotetrahydro-4H-l,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, 2-pipe
- a further particular compound of the invention is a quinoline derivative of the Formula I wherein : Z is NH; m is 2 and the first R 1 group is a 6-methoxy group and the second R 1 group is located at the 7-position and is selected from 2-pyrrolidin-l -ylethoxy, 3 -pyrrolidin-1 -ylpropoxy, 2-mo ⁇ holinoethoxy, 3 -mo ⁇ holinopropoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin- 4-yl)ethoxy, 3-(l , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmeth
- a further particular compound of the invention is a quinoline derivative of the Formula I wherein :
- Z is NH; m is 2 and the first R 1 group is a 6-methoxy group and the second R 1 group is located at the 7-position and is selected from methoxy, ethoxy, 2-pyrrolidin-l -ylethoxy, 3 -pyrrolidin-1 -ylpropoxy, 2-mo ⁇ holinoethoxy, 3-mo ⁇ holinopropoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-tl iazin-4-yl)ethoxy, 3 -( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin- 4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-(l,2,3,6-tetrahydropyridin- l-yl)ethoxy, 3-(l,2,3,6-tetrahydropyridin-l-yl)propoxy, 4-(l,2,3,
- a further particular compound of the invention is a quinoline derivative of the Formula I wherein :
- Z is NH; m is 2 and the first R 1 group is a 6-methoxy group and the second R 1 group is located at the 7-position and is selected from methoxy, 3-mo ⁇ holinopropoxy, 3-(l , 1 -dioxotetrahydro-4H-l ,4-thiazin-4-yl)propoxy, 3-(l ,2,3,6-tetrahydropyridin- 1 -yl)propoxy, 4-( 1 ,2,3 ,6-tetrahydropyridin- 1 -yl)butoxy, 3-(4-hydroxypiperidin-l-yl)propoxy, 3-piperazin-l-ylpropoxy, 3 -(4-methylpiperazin- 1 -yl)propoxy, 4-(4-methylpiperazin- 1 -yl)butoxy, 3-(4-prop-2-ynylpiperazin-l-yl)propoxy, 3-(4-acetylpiperazin-l-yl)
- a further particular compound of the invention is a quinoline derivative of the Formula I wherein : Z is NH; m is 2 and the first R 1 group is a 6-methoxy group and the second R 1 group is located at the 7-position and is selected from 2-pyrrolidin-l -ylethoxy, 3 -pyrrolidin-1 -ylpropoxy, 2-mo ⁇ holinoethoxy, 3 -mo ⁇ holinopropoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin- 4-yl)ethoxy, 3 -(1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-yl
- a further particular compound of the invention is a quinoline derivative of the Formula I wherein : Z is NH; m is 2 and the first R 1 group is a 6-methoxy group and the second R 1 group is located at the 7-position and is selected from 3-(4-methylpiperazin-l-yl)propoxy, n is 1 and the R 3 group is a chloro or bromo group located at the 6-position of the benzofuran-7-yl group; or a pharmaceutically-acceptable acid-addition salt thereof.
- a particular compound of the invention is, for example, a quinoline derivative of the Formula I selected from :-
- a particular compound of the invention is, for example, a quinoline derivative of the Formula I selected from :-
- a further particular compound of the invention is, for example, the quinoline derivative of the Formula I being :- 4-benzofuran-7-ylamino-3-cyano-6-methoxy-7-[4-(4-methylpiperazin-l-yl)butoxy]quinoline, or a pharmaceutically-acceptable acid-addition salt thereof.
- a further particular compound of the invention is a quinoline derivative of the Formula I wherein :
- Z is O orNH; m is 1 and the R 1 group is located at the 5 -position and is selected from tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrothien-3 -yloxy, 1 , 1 -dioxotetrahydrothien-3 -yloxy, tetrahydrothiopyran-4-yloxy,
- a further particular compound of the invention is a quinoline derivative of the Formula I wherein : m is 2 and the first R 1 group is located at the 5-position and is selected from tefrahydrofuran-3 -yloxy, tetrahydropyran-4-yloxy, tetrahydrothien-3 -yloxy, 1 , 1 -dioxotetrahydrothien-3-yloxy, tetrahydrothiopyran-4-yloxy, 1 , 1 -dioxotetraliydrothiopyran-4-yloxy, N-methylazetidin-3 -yloxy, N-ethylazetidin-3-yloxy, N-isopropylazetidin-3 -yloxy, pyrrolidin-3 -yloxy, N-methylpyrrolidin-3 -yloxy, pyrrolidin-2-ylmethoxy, 3-piperidinyloxy, N
- a further particular compound of the invention is a quinoline derivative of the Formula I wherein : m is 2 and the first R 1 group is located at the 5-position and is selected from tetrahydropyran-4-yloxy, N-methylpyrrolidin-3 -yloxy, 4-piperidinyloxy, N-methylpiperidin-4-yloxy, piperidin-4-ylmethoxy and N-methylpiperidin-4-ylmethoxy, and the second R 1 is located at the 7-position and is selected from methoxy, benzyloxy, 2-pyrrolidin-l -ylethoxy, 3 -pyrrolidin-1 -ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-mo ⁇ holinoethoxy, 3-mo ⁇ holinopropoxy, 2-(4-methylpiperazin- l-yl)ethoxy, 3 -(4-methylpiperazin- l-yl)propoxy and 3-methylsulphonyl
- a further particular compound of the invention is a quinoline derivative of the Formula I wherein : m is 2 and the first R 1 group is located at the 5-position and is selected from tetrahydropyran-4-yloxy, 4-piperidinyloxy, N-methylpiperidin-4-yloxy, piperidin-4-ylmethoxy and N-methylpiperidin-4-ylmethoxy, and the second R 1 is located at the 7-position and is selected from methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, benzyloxy, 2-pyrrolidin-l -ylethoxy, 3 -pyrrolidin-1 -ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 3-(4-hydroxypiperidin- 1 -yl)propoxy, 2-piperidin-4-ylethoxy, 2-(N-methylpiperidin-4-yl)eth
- a further particular compound of the invention is a quinoline derivative of the Formula I wherein :
- Z is NH; m is 1 and the R 1 group is located at the 5-position and is selected from tetrahydropyran-4-yloxy, 4-piperidinyloxy and N-methylpiperidin-4-yloxy, or m is 2 and the first R 1 group is located at the 5-position and is selected from tetrahydropyran-4-yloxy, 4-piperidinyloxy and N-methylpiperidin-4-yloxy, and the second R 1 group is located at the 7-position and is selected from methoxy, ethoxy, propoxy,
- n 0 or n is 1 and the R 3 group, if present, is a chloro group located at the 6-position of the benzofuran-7-yl group; or a pharmaceutically-acceptable acid-addition salt thereof.
- a further particular compound of the invention is a quinoline derivative of the Formula I wherein : Z is NH; m is 1 and the R 1 group is located at the 5-position and is selected from tetrahydro ⁇ yran-4-yloxy and N-methylpiperidin-4-yloxy, or m is 2 and the first R 1 group is located at the 5-position and is selected from tetrahydropyran-4-yloxy and N-methylpiperidin-4-yloxy, and the second R 1 group is located at the 7-position and is selected from methoxy and 3-mo ⁇ holinopropoxy; and n is 0; or a pharmaceutically-acceptable acid-addition salt thereof.
- a further particular compound of the invention is, for example, a quinoline derivative of the Formula I selected from:-
- a further particular compound of the invention is, for example, a quinoline derivative of the Formula I selected from:-
- a quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof may be prepared by any process known to be applicable to the preparation of chemically- related compounds. Such processes, when used to prepare a quinoline derivative of the Formula I are provided as a further feature of the invention and are illustrated by the following representative process variants in which, unless otherwise stated, m, R 1 , Z, n and R 3 have any of the meanings defined hereinbefore. Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variants and within the accompanying Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.
- L is a displaceable group and m and R 1 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a compound of the Formula in wherein Z is O, S, or N(R ) and n, R and R have any of the meanings defined hereinbefore except that any functional group is protected if necessary, whereafter any protecting group that is present is removed by conventional means.
- the reaction may conveniently be carried out in the presence of a suitable acid or in the presence of a suitable base.
- a suitable acid is, for example, an inorganic acid such as, for example, hydrogen chloride or hydrogen bromide.
- a suitable base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, mo ⁇ holine, N-methylmo ⁇ holine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide, or, for example, an alkali metal amide, for example sodium hexamethyldisilazane, or, for example, an alkali metal hydride, for example sodium hydride.
- an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, mo ⁇ holine, N-methylmo ⁇ holine or diazabicyclo[5.4.0]undec-7-ene
- a suitable displaceable group L is, for example, a halogeno, alkoxy, aryloxy or sulphonyloxy group, for example a chloro, bromo, methoxy, phenoxy, pentafluorophenoxy, methanesulphonyloxy or toluene-4-sulphonyloxy group.
- reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene, or a dipolar aprotic solvent such as
- a suitable inert solvent or diluent for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene, or a dipolar aprotic solvent such as
- reaction is conveniently carried out at a temperature in the range, for example, 0 to 250°C, preferably in the range 0 to 120°C.
- the quinoline of the Formula II may be reacted with a compound of the Formula in in the presence of an aprotic solvent such as N,N-dimethylformamide, conveniently in the presence of a base, for example potassium carbonate or sodium hexamethyldisilazane, and at a temperature in the range, for example, 0 to 150°C, preferably in the range, for example, 0 to 70°C.
- an aprotic solvent such as N,N-dimethylformamide
- a base for example potassium carbonate or sodium hexamethyldisilazane
- the quinoline derivative of the Formula I may be obtained from this process in the form of the free base or alternatively it may be obtained in the form of a salt with the acid of the formula H-L wherein L has the meaning defined hereinbefore.
- the salt may be treated with a suitable base, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, mo ⁇ holine, N-methylmo ⁇ holine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.
- a suitable base for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, mo ⁇ holine, N-methylmo ⁇ hol
- Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question and may be introduced by conventional methods. Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule. Specific examples of protecting groups are given below for the sake of convenience, in which "lower", as in, for example, lower alkyl, signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned are, of course, within the scope of the invention.
- a carboxy protecting group maybe the residue of an ester-forming aliphatic or arylaliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms).
- carboxy protecting groups include straight or branched chain (l-12C)alkyl groups (for example isopropyl, and tert-butyl); lower alkoxy- lower alkyl groups (for example methoxymethyl, ethoxymethyl and isobutoxymethyl); lower acyloxy-lower alkyl groups, (for example acetoxymethyl, propionyloxymethyl, butyryloxymethyl and pivaloyloxymethyi); lower alkoxycarbonyloxy-lower alkyl groups (for example 1-methoxycarbonyloxyethyl and 1-ethoxycarbonyloxyethyl); aryl-lower alkyl groups (for example benzyl, 4-methoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl
- hydroxy protecting groups include lower alkyl groups (for example tert-butyl), lower alkenyl groups (for example allyl); lower alkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl groups (for example allyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for example benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl); tri(lower alkyl)silyl (for example trimethylsilyl and tert-butyldimethylsilyl) and aryl-lower alkyl (for example benzyl) groups.
- lower alkyl groups for example tert-butyl
- lower alkenyl groups for example allyl
- lower alkanoyl groups for example acetyl
- amino protecting groups include formyl, aryl-lower alkyl groups (for example benzyl and substituted benzyl, 4-methoxybenzyl, 2-nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-4-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl (for example allyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for example benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl); trialkylsilyl (for example trimethylsilyl and tert-butyldimethylsilyl); alkylidene (for example methylidene) and benzylidene and substituted benzylidene groups.
- aryl-lower alkyl groups for example benzy
- Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, base-, metal- or enzymically-catalysed hydrolysis for groups such as 2-nitrobenzyloxycarbonyl, hydrogenation for groups such as benzyl and photolytically for groups such as 2-nitrobenzyloxycarbonyl.
- Quinoline starting materials of the Formula ⁇ may be obtained by conventional procedures such as those disclosed in International Patent Applications WO 98/43960 and WO 00/68201.
- a l,4-dihydroquinolin-4-one of Formula IV may be obtained by conventional procedures such as those disclosed in International Patent Applications WO 98/43960 and WO 00/68201.
- m and R 1 have any of the meanings defined hereinbefore except that any fiinctional group is protected if necessary, may be reacted with a halogenating agent such as thionyl chloride, phosphoryl chloride or a mixture of carbon tetrachloride and triphenylphosphine whereafter any protecting group that is present is removed by conventional means.
- a halogenating agent such as thionyl chloride, phosphoryl chloride or a mixture of carbon tetrachloride and triphenylphosphine whereafter any protecting group that is present is removed by conventional means.
- the 4-chloroquinoline so obtained may be converted, if required, into a
- 4-pentafluorophenoxyquinoline by reaction with pentafluorophenol in the presence of a suitable base such as potassium carbonate and in the presence of a suitable solvent such as N,N-dimethylformamide.
- R 1 group is a group of the formula wherein Q 1 is an aryl-(l-6C)alkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyl- (l-6C)alkyl, heteroaryl-(l-6C)alkyl or heterocyclyl-(l-6C)alkyl group or an optionally substituted alkyl group and X 1 is an oxygen atom, the coupling, conveniently in the presence of a suitable dehydrating agent, of a quinoline of the Formula V
- a suitable dehydrating agent is, for example, a carbodiimide reagent such as dicyclohexylcarbodiimide or l-(3-dimethylaminopropyl)-3-ethylcarbodiimide or a mixture of an azo compound such as diethyl or di-tert-butyl azodicarboxylate and a phosphine such as triphenylphosphine.
- reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride and at a temperature in the range, for example, 10 to 150°C, preferably at or near ambient temperature.
- a suitable inert solvent or diluent for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride
- reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride and at a temperature in the range, for example, 10 to 150°C, preferably at or near ambient temperature.
- a suitable inert solvent or diluent for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride
- a suitable inert solvent or diluent for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride
- L is a displaceable group as defined hereinbefore and Z, n and R have any ofthe meanings defined hereinbefore except that any functional group is protected if necessary, with an alcohol or amine as appropriate whereafter any protecting group that is present is removed by conventional means.
- reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near 50°C.
- the cleavage reaction may conveniently be carried out by any ofthe many procedures known for such a transformation.
- the cleavage reaction of a compound ofthe Formula I wherein R 1 is a (l-6C)alkoxy group may be carried out, for example, by treatment ofthe quinoline derivative with an alkali metal (l-6C)alkylsulphide such as sodium ethanethiolate or, for example, by treatment with an alkali metal diarylphosphide such as lithium diphenylphosphide.
- the cleavage reaction may conveniently be carried out, for example, by treatment ofthe quinoline derivative with a boron or aluminium trihalide such as boron tribromide.
- the cleavage reaction of a compound ofthe Formula I wherein R 1 is a arylmethoxy group may be carried out, for example, by hydrogenation ofthe quinoline derivative in the presence of a suitable metallic catalyst such as palladium or by reaction with an organic or inorganic acid, for example trifluoroacetic acid.
- a suitable metallic catalyst such as palladium
- an organic or inorganic acid for example trifluoroacetic acid.
- Such reactions are preferably carried out in the presence of a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 10 to 150°C, preferably at or near ambient temperature.
- Suitable protecting groups for an amino group are, for example, any ofthe protecting groups disclosed hereinbefore for an amino group. Suitable methods for the cleavage of such amino protecting groups are also disclosed hereinbefore.
- a suitable protecting group is a lower alkoxycarbonyl group such as a tert-butoxycarbonyl group which may be cleaved under conventional reaction conditions such as under acid-catalysed hydrolysis, for example in the presence of trifluoroacetic acid.
- a suitable alkylating agent is, for example, any agent known in the art for the alkylation of hydroxy to alkoxy or substituted alkoxy, or for the alkylation of amino to alkylamino or substituted alkylamino, for example an alkyl or substituted alkyl halide, for example a (l-6C)alkyl chloride, bromide or iodide or a substituted (l-6C)alkyl chloride, bromide or iodide, conveniently in the presence of a suitable base as defined hereinbefore, in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 10 to 140°C, conveniently at or near ambient temperature.
- an alkyl or substituted alkyl halide for example a (l-6C)alkyl chloride, bromide or iodide or a substituted (l-6C)alkyl chloride, bromide or iodide, conveniently in the presence
- a reductive amination reaction may be employed.
- the conesponding compound containing a N-H group may be reacted with formaldehyde in the presence of a suitable reducing agent.
- a suitable reducing agent is, for example, a hydride reducing agent, for example an alkali metal aluminium hydride such as lithium aluminium hydride or, preferably, an alkali metal borohydride such as sodium borohydride, sodium cyanoborohydride, sodium triethylborohydride, sodium trimethoxyborohydri.de and sodium triacetoxyborohydride.
- a hydride reducing agent for example an alkali metal aluminium hydride such as lithium aluminium hydride or, preferably, an alkali metal borohydride such as sodium borohydride, sodium cyanoborohydride, sodium triethylborohydride, sodium trimethoxyborohydri.de and sodium triacetoxyborohydride.
- the reaction is conveniently performed in a suitable inert solvent or diluent, for example tefrahydrofuran and diethyl ether for the more powerful reducing agents such as lithium aluminium hydride, and, for example, methylene chloride or a protic solvent such as methanol and ethanol for the less powerful reducing agents such as sodium triacetoxyborohydride and sodium cyanoborohydride.
- a suitable inert solvent or diluent for example tefrahydrofuran and diethyl ether for the more powerful reducing agents such as lithium aluminium hydride, and, for example, methylene chloride or a protic solvent such as methanol and ethanol for the less powerful reducing agents such as sodium triacetoxyborohydride and sodium cyanoborohydride.
- the reaction is performed at a temperature in the range, for example, 10 to 80°C, conveniently at or near ambient temperature, (h)
- R 1 is an amino-hydroxy-disubstitute
- reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near ambient temperature.
- a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near ambient temperature.
- Suitable protecting groups for a hydroxy group are, for example, any ofthe protecting groups disclosed hereinbefore. Suitable methods for the cleavage of such hydroxy protecting groups are also disclosed hereinbefore, h particular, a suitable protecting group is a lower alkanoyl group such as an acetyl group which may be cleaved under conventional reaction conditions such as under base-catalysed conditions, for example in the presence of ammonia, (j) For the production ofthose compounds ofthe Formula I wherein Z is a SO or SO 2 group, the oxidation of a compound of Formula I wherein Z is a S group.
- a compound ofthe Formula I wherein an R or R substituent is a halogeno group may be reacted with a metal cyanide to form a compound ofthe Formula I wherein an R 1 or R 3 substituent is a cyano group.
- the reaction may be carried out in the presence of a suitable catalyst.
- a suitable metal cyanide is, for example, a heavy metal cyanide such as zinc cyanide.
- a suitable catalyst is, for example, an organometaUic reagent, for example an organoiron compound such as diphenylphosphinoferrocene.
- the conversion reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near 100°C.
- a compound ofthe Formula I wherein an R or R substituent is a halogeno group may be reacted with a (2-6C)alkyne to form a compound ofthe Formula I wherein an R or R substituent is a (2-6C)alkynyl group such as an ethynyl group.
- the reaction may conveniently be carried out in the presence of a suitable base as defined hereinbefore and in the presence of a suitable catalyst.
- a suitable catalyst is, for example, an organometaUic reagent, for example an organopalladium compound such as tetrakis(triphenylphosphine)palladiixm(0).
- the conversion reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near 60°C.
- a compound ofthe Formula I wherein an R 1 or R 3 substituent is a halogeno group may be reacted with an arylboron reagent to form a compound ofthe
- R or R substituent is an aryl group such as a phenyl group.
- a suitable arylboron reagent is, for example, an arylboronic acid.
- the reaction may conveniently be 5 carried out in the presence of a suitable catalyst, for example, an organopalladium compound such as tetrakis(triphenylphosphine)palladium(0).
- the conversion reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near 80°C.
- the following assays can be used to measure the effects ofthe compounds ofthe present invention as c-Src tyrosine kinase inhibitors, as inhibitors in vitro ofthe proliferation
- test compounds to inhibit the phosphorylation of a tyrosine containing polypeptide substrate by the enzyme c-Src kinase was assessed using a conventional Elisa
- a substrate solution [lOO ⁇ l of a 20 ⁇ g/ml solution ofthe polyamino acid Poly(Glu, Tyr) 4:1 (Sigma Catalogue No. P0275) in phosphate buffered saline (PBS) containing 0.2mg/ml of sodium azide] was added to each well of a number of Nunc 96-well immunoplates (Catalogue No. 439454) and the plates were sealed and stored at 4°C for
- Bovine Serum Albumin (BSA; 150 ⁇ l of a 5% solution in PBS) were transferred into each substrate-coated assay well and incubated for 1 hour at ambient temperature to block non specific binding.
- the assay plate wells were washed in turn with PBS containing 0.05% v/v Tween 20 (PBST) and with Hepes pH7.4 buffer (50mM, 300 ⁇ l/well) before being blotted dry.
- test compound was dissolved in dimethyl sulphoxide and diluted with distilled water to give a series of dilutions (from lOO ⁇ M to O.OOl ⁇ M). Portions (25 ⁇ l) of each dilution of test compound were transferred to wells in the washed assay plates. "Total" control wells contained diluted DMSO instead of compound. Aliquots (25 ⁇ l) of an aqueous magnesium chloride solution (80mM) containing adenosine-5'-triphosphate (ATP; 40 ⁇ M) was added to all test wells except the "blank" control wells which contained magnesium chloride without ATP.
- aqueous magnesium chloride solution 80mM
- ATP adenosine-5'-triphosphate
- Active human c-Src kinase (recombinant enzyme expressed in Sf9 insect cells; obtained from Upstate Biotechnology Inc. product 14-117) was diluted immediately prior to use by a factor of 1:10,000 with an enzyme diluent which comprised lOOmM Hepes pH7.4 buffer, 0.2mM sodium orthovanadate, 2mM dithiothreitol and 0.02% BSA.
- enzyme diluent which comprised lOOmM Hepes pH7.4 buffer, 0.2mM sodium orthovanadate, 2mM dithiothreitol and 0.02% BSA.
- aliquots (50 ⁇ l) of freshly diluted enzyme were added to each well and the plates were incubated at ambient temperature for 20 minutes. The supernatant liquid in each well was discarded and the wells were washed twice with PBST.
- Mouse IgG anti-phosphotyrosine antibody (Upstate Biotechnology h e. product 05-321; lOO ⁇ l) was diluted by a factor of 1 :6000 with PBST containing 0.5% w/v BSA and added to each well. The plates were incubated for 1 hour at ambient temperature. The supernatant liquid was discarded and each well was washed with PBST (x4).
- Horse radish peroxidase (HRP)-linked sheep anti-mouse lg antibody (Amersham Catalogue No. NXA 931 ; lOO ⁇ l) was diluted by a factor of 1 :500 with PBST containing 0.5% w/v BSA and added to each well. The plates were incubated for 1 hour at ambient temperature. The supernatant liquid was discarded and the wells were washed with PBST (x4).
- a PCSB capsule (Sigma Catalogue No. P4922) was dissolved in distilled water
- phosphate-citrate pH5 buffer 50mM containing 0.03% sodium perborate.
- An aliquot (50ml) of this buffer was mixed with a 50mg tablet of 2,2'-azinobis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS; Boehringer Catalogue No. 1204 521). Aliquots (lOO ⁇ l) ofthe resultant solution were added to each well. The plates were incubated for 20 to 60 minutes at ambient temperature until the optical density value of the "total" control wells, measured at 405nm using a plate reading spectrophotometer, was approximately 1.0.
- NTH National Institute of Health
- the resultant c-Src 3T3 cells were typically seeded at 1.5 x 10 4 cells per well into 96-well tissue- culture-treated clear assay plates (Costar) each containing an assay medium comprising Dulbecco's modified Eagle's medium (DMEM; Sigma) plus 0.5% foetal calf serum (FCS), 2mM glutamine, 100 units/ml penicillin and O.lmg/ml streptomycin in 0.9% aqueous sodium chloride solution.
- DMEM Dulbecco's modified Eagle's medium
- FCS foetal calf serum
- 2mM glutamine 100 units/ml penicillin and O.lmg/ml streptomycin in 0.9% aqueous sodium chloride solution.
- the plates were incubated overnight at 37°C in a humidified (7.5% CO 2 : 95% air) incubator.
- Test compounds were solubilised in DMSO to form a lOmM stock solution. Aliquots ofthe stock solution were diluted with the DMEM medium described above and added to appropriate wells. Serial dilutions were made to give a range of test concentrations. Control wells to which test compound was not added were included on each plate. The plates were incubated overnight at 37°C in a humidified (7.5% CO 2 : 95% air) incubator.
- BrdU labelling reagent (Boehringer Mannheim Catalogue No. 647 229) was diluted by a factor of 1 : 100 in DMEM medium containing 0.5% FCS and aliquots (20 ⁇ l) were added to each well to give a final concentration of lO ⁇ M). The plates were incubated at 37°C for 2 hours. The medium was decanted. A denaturating solution (FixDenat solution, Boehringer Mannheim Catalogue No. 647 229; 50 ⁇ l) was added to each well and the plates were placed on a plate shaker at ambient temperature for 45 minutes. The supernatant was decanted and the wells were washed with PBS (200 ⁇ l per well).
- Anti-BrdU-Peroxidase solution (Boehringer Mannheim Catalogue No. 647 229) was diluted by a factor of 1 : 100 in PBS containing 1% BSA and 0.025% dried skimmed milk (Marvel (registered trade mark), Premier Beverages, Stafford, GB) and an aliquot (lOO ⁇ l) ofthe resultant solution was added to each well.
- the plates were placed on a plate shaker at ambient temperature for 90 minutes. The wells were washed with PBS (x5) to ensure removal of non-bound antibody conjugate.
- the plates were blotted dry and tetramethylbenzidine substrate solution (Boehringer Mannheim Catalogue No. 647 229; lOO ⁇ l) was added to each well.
- This assay determines the ability of a test compoxind to inhibit the migration of adherent mammalian cell lines, for example the human tumour cell line A549.
- RPMI medium(Sigma) containing 10% FCS, 1% L-glutamine and 0.3% agarose (Difco Catalogue No. 0142-01) was warmed to 37°C in a water bath.
- a stock 2% aqueous agar solution was autoclaved and stored at 42°C.
- An aliquot (1.5 ml) ofthe agar solution was added to RPMI medium (10 ml) immediately prior to its use.
- A549 cells (Accession No. ATCC CCL185) were suspended at a concentration of 2 x 10 7 cells/ml in the medium and maintained at a temperature of 37°C.
- a droplet (2 ⁇ l) ofthe cell/agarose mixture was transferred by pipette into the centre of each well of a number of 96-well, flat bottomed non-tissue-culture-treated microtitre plate (Bibby Sterilin Catalogue No. 642000). The plates were placed briefly on ice to speed the gelling ofthe agarose-containing droplets. Aliquots (90 ⁇ l) of medium which had been cooled to 4°C were transfened into each well, taking care not to disturb the microdroplets. Test compounds were diluted from a lOmM stock solution in DMSO using RPMI medium as described above. Aliquots (lO ⁇ l) ofthe diluted test compounds were transferred to the wells, again taking care not to disturb the microdroplets. The plates were incubated at 37°C in a humidified (7.5% CO 2 : 95% air) incubator for about 48 hours.
- a migratory inhibitory IC 50 was derived by plotting the mean migration measurement against test compound concentration.
- This test measures the ability of compounds to inhibit the growth ofthe A549 human carcinoma grown as a tumour in athymic nude mice (Alderley Park nu/nu strain).
- a total of about 5 x 10 6 A549 cells in matrigel (Beckton Dickinson Catalogue No. 40234) were injected subcutaneously into the left flank of each test mouse and the resultant tumours were allowed to grow for about 14 days. Tumour size was measured twice weekly using callipers and a theoretical volume was calculated. Animals were selected to provide control and treatment groups of approximately equal average tumour volume.
- Test compounds were prepared as a ball-milled suspension in 1% polysorbate vehicle and dosed orally once daily for a period of about 28 days. The effect on tumour growth was assessed.
- Test (d) No physiologically-unacceptable toxicity was observed in Test (d) at the effective dose for compounds tested ofthe present invention. Accordingly no untoward toxicological effects are expected when a compound of Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore is administered at the dosage ranges defined hereinafter.
- a pharmaceutical composition which comprises a quinoline derivative ofthe Formula I, or a pharmaceutically- acceptable salt thereof, as defined hereinbefore in association with a pharmaceutically- acceptable diluent or carrier.
- compositions ofthe invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
- the compositions ofthe invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
- compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and
- a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight ofthe total composition.
- the size ofthe dose for therapeutic or prophylactic pu ⁇ oses of a compound ofthe Formula I will naturally vary according to the nature and severity ofthe conditions, the age and sex ofthe animal or patient and the route of administration, according to well known principles of medicine.
- a daily dose in the range for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses.
- a parenteral route is employed.
- a dose in the range for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used.
- a dose in the range for example, 0.05 mg/kg to 25 mg/kg body weight will be used.
- Oral administration is however prefened, particularly in tablet form.
- unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.
- a quinoline derivative ofthe Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use in a method of treatment ofthe human or animal body by therapy.
- c-Src non-receptor tyrosine kinase the predominant role of c-Src non-receptor tyrosine kinase is to regulate cell motility which is necessarily required for a localised tumour to progress through the stages of dissemination into the blood stream, invasion of other tissues and initiation of metastatic tumour growth.
- the quinoline derivatives of the present invention possess potent anti-tumour activity which it is believed is obtained by way of inhibition of one or more ofthe non-receptor tyrosine-specific protein kinases such as c-Src kinase that are involved in the signal transduction steps which lead to the invasiveness and migratory ability of metastasising tumour cells.
- the quinoline derivatives ofthe present invention are of value as anti- tumour agents, in particular as selective inhibitors ofthe motility, dissemination and invasiveness of mammalian cancer cells leading to inhibition of metastatic tumour growth.
- the quinoline derivatives ofthe present invention are of value as anti-invasive agents in the containment and/or treatment of solid tumour disease.
- the compounds ofthe present invention are expected to be useful in the prevention or treatment of those tumours which are sensitive to inhibition of one or more ofthe multiple non-receptor tyrosine kinases such as c-Src kinase that are involved in the signal transduction steps which lead to the invasiveness and migratory ability of metastasising tumour cells.
- the compounds ofthe present invention are expected to be useful in the prevention or treatment of those tumours which are mediated alone or in part by inhibition ofthe enzyme c-Src, i.e. the compounds may be used to produce a c-Src enzyme inhibitory effect in a warm-blooded animal in need of such treatment.
- the compounds ofthe present invention are expected to be useful in the prevention or treatment of solid tumour disease.
- quinoline derivative ofthe Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use as an anti-invasive agent in the containment and/or treatment of solid tumour disease.
- a quinoline derivative ofthe Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use as an anti-invasive agent in the containment and/or treatment of solid tumour disease.
- a method for producing an anti-invasive effect by the containment and/or treatment of solid tumour disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a quinoline derivative ofthe Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
- a quinoline derivative ofthe Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the prevention or treatment of solid tumour disease in a warm-blooded animal such as man.
- a method for the prevention or treatment of solid tumour disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a quinoline derivative ofthe Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
- a quinoline derivative ofthe Fonnula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the prevention or treatment of those tumours which are sensitive to inhibition of non-receptor tyrosine kinases such as c-Src kinase that are involved in the signal transduction steps which lead to the invasiveness and migratory ability of metastasising tumour cells.
- a quinoline derivative ofthe Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in providing a c-Src kinase inhibitory effect.
- a method for providing a c-Src kinase inhibitory effect which comprises administering to said animal an effective amo int of a quinoline derivative ofthe Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
- the anti-invasive treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the quinoline derivative ofthe invention, conventional surgery or radiotherapy or chemotherapy.
- Such chemotherapy may include one or more ofthe following categories of anti-tumour agents :-
- anti-invasion agents for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function
- antiproliferative/antineoplastic drugs and combinations thereof as used in medical oncology, such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea, or, for example, one ofthe prefened antimetabolites disclosed in European Patent Application No.
- alkylating agents for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitro
- cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrazole, vorazole and exemestane) and inhibitors of 5 -reductase such as finasteride; (iv) inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors ofthe epidermal
- antiangiogenic agents such as those which inhibit vascular endothelial growth factor such as the compounds disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and those that work by other mechanisms (for example linomide, inl ibitors of integrin ⁇ v ⁇ 3 function and angiostatin).
- Such conjoint treatment may be achieved by way ofthe simultaneous, sequential or separate dosing ofthe individual components ofthe treatment.
- Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other phannaceutically-active agent within its approved dosage range.
- a pharmaceutical product comprising a quinoline derivative ofthe formula I as defined hereinbefore and an additional anti-tumour agent as defined hereinbefore for the conjoint treatment of cancer.
- the compounds ofthe Formula I are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to inhibit the effects of c-Src. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
- the invention will now be illustrated in the following Examples in which, generally :
- melting points are unconected and were determined using a Mettler SP62 automatic melting point apparatus or an oil-bath apparatus; melting points for the end-products ofthe Formula I were determined after crystallisation from a conventional organic solvent such as ethanol, methanol, acetone, ether or hexane, alone or in admixture;
- the organic phase was washed with water and with brine, dried over magnesium sulphate and evaporated.
- the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a saturated methanolic ammonia solution as eluent.
- the material so obtained was dissolved in diethyl ether and a solution of hydrogen chloride in diethyl ether (1M, 2 ml) was added.
- the resultant solid was washed with diethyl ether and dried.
- the 7-aminobenzofuran used as a starting material was prepared as follows :- Hydrazine hydrate (0.45 ml) was added dropwise to a stined mixture of
- Diethyl azodicarboxylate (0.25 g) was added dropwise to a suspension of 4-chloro- 3-cyano-7-hydroxy-6-methoxyquinoline (0.2 g; prepared as described in international Patent Application WO 00/68201, disclosed as compound (7) within Preparation 1 therein), l-(3-hydroxypropyl)-4-methylpiperazine (0.202 g), triphenylphosphine (0.447 g) and methylene chloride (5 ml) and the mixture was stined at ambient temperature for 2 hours.
- the resultant mixture was evaporated and the residue was purified by column chromatography on silica using initially increasingly polar mixtures of methylene chloride and ethyl acetate followed by increasingly polar mixtures of methylene chloride, ethyl acetate and a saturated methanolic ammonia solution as eluent.
- the material so obtained was triturated under diethyl ether.
- the 7-amino-6-chlorobenzofuran used as a starting material was prepared as follows :- Sodium hydride (60% dispersion in mineral oil; 4.6 g) was added to a stined solution of 6-chloroanthranilic acid (18 g) in DMF (100 ml) and the mixture was stined at ambient temperature for 30 minutes. Ethyl iodide (10 ml) was added and the reaction mixture was stined at ambient temperature for 2 days. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed in turn with water and brine, dried over magnesium sulphate and evaporated.
- the 7-amino-5-fluorobenzofuran used as a starting material was prepared as follows :- Allyl bromide (6 ml) was added to a stined mixture of 4-fluoro-2-nitrophenol (10 g), l,5,7-triazabicyclo[4,4,0]dec-5-ene (11.5 g) and DMF (120 ml) and the reaction mixture was stined at ambient temperature for 20 hours. The reaction mixture was then heated to 50°C for 1.5 hours. The mixture was evaporated and the residue was partitioned between diethyl ether and water. The organic phase was washed in turn with a IN aqueous hydrochloric acid solution, water and brine, dried over magnesium sulphate and evaporated.
- the 4-chloro-7-(3-chloropropoxy)-3-cyano-6-methoxyquinoline used as a starting material was prepared as follows :- A mixture of 4-chloro-3-cyano-7-hydroxy-6-methoxyquinoline (0.2 g, prepared as described in International Patent Application WO 00/68201, disclosed as compound (7) within Preparation 1 therein), potassium tert-butoxide (0.1 g) and DMF (8 ml) was stined at ambient temperature for 15 minutes. l-Bromo-3-choropropane (0.134 g) was added and the reaction mixture was stined at ambient temperature for 16 hours.
- the resultant mixture was evaporated and the residue was partitioned between methylene chloride and an aqueous sodium bicarbonate solution. The organic layer was dried using magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of ethyl acetate and hexane.
- reaction mixture was stined at 0°C for 90 minutes and then poured into a dilute aqueous ammonium chloride solution.
- the precipitate was isolated and purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent.
- the reactants were 4-chloro-7-(3-chloropropoxy)-3-cyano-6-methoxyquinoline (containing some 4-chloro-7-(3-bromopropoxy)-3-cyano-6-methoxyquinoline) and 7-aminobenzofuran and the reaction mixture was heated to 110°C for 3 hours.
- the l-(2-fluoroethyl)piperazine trifluoroacetate salt used as a starting material was prepared as follows :-
- Trifluoroacetic acid (20 ml) was added to a mixture of 4-(tert-butoxycarbonyl)- l-(2-fluoroethyl)piperazine (3.7 g), triethylsilane (8 ml) and methylene chloride (100 ml) and the resultant mixture was stined at ambient temperature for 1.5 hours. The mixture was evaporated and the residue was triturated under diethyl ether. The solid so obtained was isolated, washed with diethyl ether and dried.
- the reactants were 4-benzofuran-7-ylamino-7-(4-chlorobutoxy)-3-cyano- 6-methoxyquinoline hydrochloride and 1-acetylpiperazine and the reaction solvent was n-propanol.
- the reaction mixture was heated to 90°C for 18 hours.
- the resultant mixture was partitioned between ethyl acetate and IN aqueous sodium hydroxide solution.
- the organic layer was washed with brine, dried over magnesium sulphate and evaporated.
- the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a saturated methanolic ammonia solution as eluent.
- the reactants were 4-benzofuran-7-ylamino-7-(4-chlorobutoxy)-3-cyano- 6-methoxyquinoline hydrochloride and 1-methylpiperazine and the reaction solvent was n-propanol.
- the reaction mixture was heated to 90°C for 18 hours.
- the resultant mixture was partitioned between ethyl acetate and IN aqueous sodium hydroxide solution.
- the organic layer was washed with brine, dried over magnesium sulphate and evaporated.
- the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a saturated methanolic ammonia solution as eluent.
- Diisopropyl azodicarboxylate (0.414 g) was added dropwise to a stined suspension of 4-benzofuran-7-ylamino-3-cyano-7-hydroxy-6-methoxyquinoline (0.565 g), 2-(2-methoxyethoxy)ethanol (0.307 g), triphenylphosphine (0.627 g) and methylene chloride (30 ml).
- the mixture was stined at ambient temperature for 3 hours.
- the mixture was evaporated and the residue was purified by column chromatography on silica eluting with increasingly polar mixtures of ethyl acetate and methanol as eluent.
- Tris(dibenzylideneacetone)dipalladium (0.037 g) was added to a mixture of 3-cyano-4-(4-iodobenzofuran-7-ylamino)-6,7-dimethoxyquinoline (0.25 g), zinc cyanide (0.064 g), diphenylphosphinofenocene (0.038 g), zinc powder (0.014 g) and DMA (20 ml) and the resultant mixture was stined and heated to 110°C for 2 hours. The mixture was cooled to ambient temperature and partitioned between methylene chloride and water.
- the product was eluted off the column with methanol containing triethylamine (1%).
- the material so obtained was purified further using column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent.
- Compound X the active ingredient being termed "Compound X"
- Citric acid 0.38% w/v Polyethylene glycol 400 3.5% w/v
- the above formulations may be obtained by conventional procedures well known in the pharmaceutical art.
- the tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.
- the aerosol formulations (h)-(k) maybe used in conjunction with standard, metered dose aerosol dispensers, and the suspending agents sorbitan trioleate and soya lecithin may be replaced by an alternative suspending agent such as sorbitan monooleate, sorbitan sesquioleate, polysorbate 80, polyglycerol oleate or oleic acid.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2002347336A AU2002347336A1 (en) | 2001-12-05 | 2002-12-05 | Quinoline derivatives |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP01403124 | 2001-12-05 | ||
EP01403124.9 | 2001-12-05 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2003048159A1 true WO2003048159A1 (fr) | 2003-06-12 |
Family
ID=8182999
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB2002/005493 WO2003048159A1 (fr) | 2001-12-05 | 2002-12-05 | Derives de la quinoleine |
Country Status (2)
Country | Link |
---|---|
AU (1) | AU2002347336A1 (fr) |
WO (1) | WO2003048159A1 (fr) |
Cited By (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004041811A1 (fr) * | 2002-11-02 | 2004-05-21 | Astrazeneca Ab | Derives de la 3-cyano-quinoline |
US6849625B2 (en) | 2000-10-13 | 2005-02-01 | Astrazeneca Ab | Quinazoline derivatives with anti-tumour activity |
US6939866B2 (en) | 2000-10-13 | 2005-09-06 | Astrazeneca Ab | Quinazoline derivatives |
JP2007501210A (ja) * | 2003-08-06 | 2007-01-25 | アストラゼネカ アクチボラグ | 血管新生阻害剤としてのキナゾリン誘導体 |
US7501516B2 (en) | 2001-07-16 | 2009-03-10 | Astrazeneca Ab | Quinoline derivatives and their use as tyrosine kinase inhibitors |
US7884114B2 (en) | 2007-08-15 | 2011-02-08 | Glaxo Group Limited | Compounds |
JP2011519956A (ja) * | 2008-05-09 | 2011-07-14 | ハッチソン メディファーマ エンタープライジズ リミテッド | キナゾリン誘導体 |
US8153814B2 (en) | 2009-01-12 | 2012-04-10 | Pfizer Limited | Sulfonamide derivatives |
CN103819343A (zh) * | 2014-02-17 | 2014-05-28 | 青岛农业大学 | 化合物2-烯丙基-4-氟-6-硝基苯酚的制备方法和农用生物活性 |
US8877776B2 (en) | 2009-01-16 | 2014-11-04 | Exelixis, Inc. | (L)-malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide |
US9145407B2 (en) | 2010-07-09 | 2015-09-29 | Pfizer Limited | Sulfonamide compounds |
WO2016016894A1 (fr) | 2014-07-30 | 2016-02-04 | Yeda Research And Development Co. Ltd. | Milieux pour la culture de cellules souches pluripotentes |
US9359332B2 (en) | 2002-07-15 | 2016-06-07 | Symphony Evolution, Inc. | Processes for the preparation of substituted quinazolines |
US10487091B2 (en) | 2015-10-05 | 2019-11-26 | The Trustees Of Columbia University In The City Of New York | Activators of autophagic flux and phospholipase D and clearance of protein aggregates including tau and treatment of proteinopathies |
WO2020152686A1 (fr) | 2019-01-23 | 2020-07-30 | Yeda Research And Development Co. Ltd. | Milieux de culture pour cellules souches pluripotentes |
US10736886B2 (en) | 2009-08-07 | 2020-08-11 | Exelixis, Inc. | Methods of using c-Met modulators |
US11124482B2 (en) | 2003-09-26 | 2021-09-21 | Exelixis, Inc. | C-met modulators and methods of use |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998043960A1 (fr) * | 1997-04-03 | 1998-10-08 | American Cyanamid Company | 3-cyano quinolines substituees |
WO2000068201A1 (fr) * | 1999-05-08 | 2000-11-16 | Astrazeneca Ab | Derives quinoline inhibiteurs d'enzymes mek |
-
2002
- 2002-12-05 WO PCT/GB2002/005493 patent/WO2003048159A1/fr not_active Application Discontinuation
- 2002-12-05 AU AU2002347336A patent/AU2002347336A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998043960A1 (fr) * | 1997-04-03 | 1998-10-08 | American Cyanamid Company | 3-cyano quinolines substituees |
WO2000068201A1 (fr) * | 1999-05-08 | 2000-11-16 | Astrazeneca Ab | Derives quinoline inhibiteurs d'enzymes mek |
Cited By (34)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6849625B2 (en) | 2000-10-13 | 2005-02-01 | Astrazeneca Ab | Quinazoline derivatives with anti-tumour activity |
US6939866B2 (en) | 2000-10-13 | 2005-09-06 | Astrazeneca Ab | Quinazoline derivatives |
US7501516B2 (en) | 2001-07-16 | 2009-03-10 | Astrazeneca Ab | Quinoline derivatives and their use as tyrosine kinase inhibitors |
US10266518B2 (en) | 2002-07-15 | 2019-04-23 | Symphony Evolution, Inc. | Solid dosage formulations of substituted quinazoline receptor-type kinase modulators and methods of use thereof |
US9796704B2 (en) | 2002-07-15 | 2017-10-24 | Symphony Evolution, Inc. | Substituted quinazolines as receptor-type kinase inhibitors |
US9359332B2 (en) | 2002-07-15 | 2016-06-07 | Symphony Evolution, Inc. | Processes for the preparation of substituted quinazolines |
WO2004041811A1 (fr) * | 2002-11-02 | 2004-05-21 | Astrazeneca Ab | Derives de la 3-cyano-quinoline |
US7173136B2 (en) | 2002-11-02 | 2007-02-06 | Astrazeneca Ab | 3-Cyano-quinoline derivatives |
JP2007501210A (ja) * | 2003-08-06 | 2007-01-25 | アストラゼネカ アクチボラグ | 血管新生阻害剤としてのキナゾリン誘導体 |
JP4890249B2 (ja) * | 2003-08-06 | 2012-03-07 | アストラゼネカ アクチボラグ | 血管新生阻害剤としてのキナゾリン誘導体 |
US11124482B2 (en) | 2003-09-26 | 2021-09-21 | Exelixis, Inc. | C-met modulators and methods of use |
US7884114B2 (en) | 2007-08-15 | 2011-02-08 | Glaxo Group Limited | Compounds |
JP2011519956A (ja) * | 2008-05-09 | 2011-07-14 | ハッチソン メディファーマ エンタープライジズ リミテッド | キナゾリン誘導体 |
US8541588B2 (en) | 2009-01-12 | 2013-09-24 | Pfizer Limited | Sulfonamide derivatives |
US8907101B2 (en) | 2009-01-12 | 2014-12-09 | Pfizer Limited | Sulfonamide derivatives |
US8153814B2 (en) | 2009-01-12 | 2012-04-10 | Pfizer Limited | Sulfonamide derivatives |
US11091439B2 (en) | 2009-01-16 | 2021-08-17 | Exelixis, Inc. | Malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms therof for the treatment of cancer |
US12275706B2 (en) | 2009-01-16 | 2025-04-15 | Exelixis, Inc. | Malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms thereof for the treatment of cancer |
US9809549B2 (en) | 2009-01-16 | 2017-11-07 | Exelixis, Inc. | Malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms therof for the treatment of cancer |
US8877776B2 (en) | 2009-01-16 | 2014-11-04 | Exelixis, Inc. | (L)-malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide |
US11098015B2 (en) | 2009-01-16 | 2021-08-24 | Exelixis, Inc. | Malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms thereof for the treatment of cancer |
US11091440B2 (en) | 2009-01-16 | 2021-08-17 | Exelixis, Inc. | Malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)- N′-(4-fluorophenyl)cyclopropane-1,1 -dicarboxamide, and crystalline forms thereof for the treatment of cancer |
US11433064B2 (en) | 2009-08-07 | 2022-09-06 | Exelixis, Inc. | Methods of using c-Met modulators |
US10736886B2 (en) | 2009-08-07 | 2020-08-11 | Exelixis, Inc. | Methods of using c-Met modulators |
US9145407B2 (en) | 2010-07-09 | 2015-09-29 | Pfizer Limited | Sulfonamide compounds |
CN103819343B (zh) * | 2014-02-17 | 2016-03-23 | 青岛农业大学 | 化合物2-烯丙基-4-氟-6-硝基苯酚的制备方法和农用生物活性 |
CN103819343A (zh) * | 2014-02-17 | 2014-05-28 | 青岛农业大学 | 化合物2-烯丙基-4-氟-6-硝基苯酚的制备方法和农用生物活性 |
WO2016016894A1 (fr) | 2014-07-30 | 2016-02-04 | Yeda Research And Development Co. Ltd. | Milieux pour la culture de cellules souches pluripotentes |
US11008341B2 (en) | 2015-10-05 | 2021-05-18 | The Trustees Of Columbia University In The City Of New York | Activators of autophagic flux and phospholipase D and clearance of protein aggregates including tau and treatment of proteinopathies |
US10865214B2 (en) | 2015-10-05 | 2020-12-15 | The Trustees of Columbia University in they City of New York | Activators of autophagic flux and phospholipase D and clearance of protein aggregates including tau and treatment of proteinopathies |
US10487091B2 (en) | 2015-10-05 | 2019-11-26 | The Trustees Of Columbia University In The City Of New York | Activators of autophagic flux and phospholipase D and clearance of protein aggregates including tau and treatment of proteinopathies |
US11230558B2 (en) | 2015-10-05 | 2022-01-25 | The Trustees Of Columbia University In The City Of New York | Activators of autophagic flux and phospholipase D and clearance of protein aggregates including tau and treatment of proteinopathies |
US11261199B2 (en) | 2015-10-05 | 2022-03-01 | The Trustees Of Columbia University In The City Of New York | Activators of autophagic flux and phospholipase d and clearance of protein aggregates including tau and treatment of proteinopathies |
WO2020152686A1 (fr) | 2019-01-23 | 2020-07-30 | Yeda Research And Development Co. Ltd. | Milieux de culture pour cellules souches pluripotentes |
Also Published As
Publication number | Publication date |
---|---|
AU2002347336A1 (en) | 2003-06-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2419301C (fr) | Derives de quinazoline | |
EP1292594B1 (fr) | Derives de la quinazoline pour le traitement de tumeurs | |
US6849625B2 (en) | Quinazoline derivatives with anti-tumour activity | |
US20070213367A1 (en) | Substituted 3-cyanoquinolines as MEK inhibitors | |
US7501516B2 (en) | Quinoline derivatives and their use as tyrosine kinase inhibitors | |
AU2001278609A1 (en) | Quinazoline derivatives | |
EP1381599B1 (fr) | Derives quinazoline | |
US20040063733A1 (en) | Quinazoline derivatives | |
US20070191346A1 (en) | 3-Cyano-quinoline derivatives | |
WO2002092578A1 (fr) | Derives de quinazoline | |
WO2002092577A1 (fr) | Derives quinazoliniques | |
US6939866B2 (en) | Quinazoline derivatives | |
WO2003048159A1 (fr) | Derives de la quinoleine | |
WO2003047584A1 (fr) | Derives de la quinoline | |
WO2004056812A1 (fr) | Derives de 4-(pyridin-4-ylamino)-quinazoline utilises comme agents anticancereux | |
WO2004108704A1 (fr) | Derives de pyrimidin-4-yl 3-cyanoquinoline servant a traiter des tumeurs | |
WO2004069250A1 (fr) | Derives de 3-cyano-quinoline utilises comme inhibiteurs de la tyrosine kinase non associee a un recepteur | |
WO2004108703A1 (fr) | Derives de pyrazinyl 3-cyanoquinoline destines a etre utilises dans le traitement des tumeurs | |
WO2004108707A1 (fr) | Derives de pyridazinile quinazoline pour le traitement de tumeurs | |
WO2004108710A1 (fr) | Derives 4-pyrimidinylquinazoline a utiliser dans le traitement de tumeurs | |
WO2004069249A1 (fr) | Derives de la 3-cyano-quinoleine, en tant qu'inhibiteurs de tyrosine kinase non recepteurs | |
WO2004056801A1 (fr) | Derives quinazoliniques |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LU MC NL PT SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
122 | Ep: pct application non-entry in european phase | ||
NENP | Non-entry into the national phase |
Ref country code: JP |
|
WWW | Wipo information: withdrawn in national office |
Country of ref document: JP |