TW520364B - Quinazoline derivatives, the preparation thereof and pharmaceutical compositions comprising them - Google Patents
Quinazoline derivatives, the preparation thereof and pharmaceutical compositions comprising them Download PDFInfo
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- TW520364B TW520364B TW086113896A TW86113896A TW520364B TW 520364 B TW520364 B TW 520364B TW 086113896 A TW086113896 A TW 086113896A TW 86113896 A TW86113896 A TW 86113896A TW 520364 B TW520364 B TW 520364B
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- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 6
- 238000002360 preparation method Methods 0.000 title abstract description 4
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title abstract 2
- 125000000217 alkyl group Chemical group 0.000 abstract description 91
- -1 methoxy, amino Chemical group 0.000 abstract description 48
- 150000001875 compounds Chemical class 0.000 abstract description 26
- 239000001257 hydrogen Substances 0.000 abstract description 24
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 24
- 150000003839 salts Chemical class 0.000 abstract description 20
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 18
- 125000000304 alkynyl group Chemical group 0.000 abstract description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 9
- 150000002431 hydrogen Chemical group 0.000 abstract description 7
- 239000004480 active ingredient Substances 0.000 abstract description 5
- 125000003342 alkenyl group Chemical group 0.000 abstract description 5
- 201000010099 disease Diseases 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 abstract description 2
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 abstract description 2
- 125000004093 cyano group Chemical group *C#N 0.000 abstract description 2
- 238000000034 method Methods 0.000 abstract description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract 4
- 125000005843 halogen group Chemical group 0.000 abstract 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract 3
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 abstract 2
- 125000002837 carbocyclic group Chemical group 0.000 abstract 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract 2
- 125000004455 (C1-C3) alkylthio group Chemical group 0.000 abstract 1
- 206010028980 Neoplasm Diseases 0.000 abstract 1
- 201000011510 cancer Diseases 0.000 abstract 1
- 125000005842 heteroatom Chemical group 0.000 abstract 1
- 125000005647 linker group Chemical group 0.000 abstract 1
- 206010039073 rheumatoid arthritis Diseases 0.000 abstract 1
- 125000000547 substituted alkyl group Chemical group 0.000 abstract 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 24
- 125000001424 substituent group Chemical group 0.000 description 21
- 229910052760 oxygen Inorganic materials 0.000 description 18
- 125000002757 morpholinyl group Chemical group 0.000 description 17
- 239000001301 oxygen Substances 0.000 description 17
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 16
- 239000000460 chlorine Substances 0.000 description 15
- CSFDTBRRIBJILD-UHFFFAOYSA-N 4-chloro-2-fluoroaniline Chemical compound NC1=CC=C(Cl)C=C1F CSFDTBRRIBJILD-UHFFFAOYSA-N 0.000 description 13
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 10
- 150000003246 quinazolines Chemical class 0.000 description 10
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 150000003254 radicals Chemical class 0.000 description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 5
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 5
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 5
- GZRMNMGWNKSANY-UHFFFAOYSA-N 4-bromo-2-fluoroaniline Chemical compound NC1=CC=C(Br)C=C1F GZRMNMGWNKSANY-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- 229910052801 chlorine Chemical group 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Chemical group 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 2
- JJYPMNFTHPTTDI-UHFFFAOYSA-N 3-methylaniline Chemical compound CC1=CC=CC(N)=C1 JJYPMNFTHPTTDI-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
- 241001465754 Metazoa Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000006630 butoxycarbonylamino group Chemical group 0.000 description 2
- 125000004312 morpholin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 description 2
- 150000002918 oxazolines Chemical class 0.000 description 2
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 2
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 2
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 2
- 230000008728 vascular permeability Effects 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- NZCZCNKLNYYFBC-BYPYZUCNSA-N (2s)-2-(chloroamino)-4-methylsulfanylbutanoic acid Chemical compound CSCC[C@H](NCl)C(O)=O NZCZCNKLNYYFBC-BYPYZUCNSA-N 0.000 description 1
- VZHJIJZEOCBKRA-UHFFFAOYSA-N 1-chloro-3-fluorobenzene Chemical compound FC1=CC=CC(Cl)=C1 VZHJIJZEOCBKRA-UHFFFAOYSA-N 0.000 description 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical compound NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 0.000 description 1
- ZTQNUTNKGQGWCM-UHFFFAOYSA-N 2-methoxyquinoline Chemical compound C1=CC=CC2=NC(OC)=CC=C21 ZTQNUTNKGQGWCM-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- FBKSHXJRRCENPH-UHFFFAOYSA-N 2-nitroquinazoline Chemical compound C1=CC=CC2=NC([N+](=O)[O-])=NC=C21 FBKSHXJRRCENPH-UHFFFAOYSA-N 0.000 description 1
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 description 1
- OURXRFYZEOUCRM-UHFFFAOYSA-N 4-hydroxymorpholine Chemical compound ON1CCOCC1 OURXRFYZEOUCRM-UHFFFAOYSA-N 0.000 description 1
- CNPURSDMOWDNOQ-UHFFFAOYSA-N 4-methoxy-7h-pyrrolo[2,3-d]pyrimidin-2-amine Chemical compound COC1=NC(N)=NC2=C1C=CN2 CNPURSDMOWDNOQ-UHFFFAOYSA-N 0.000 description 1
- UQRONKZLYKUEMO-UHFFFAOYSA-N 4-methyl-1-(2,4,6-trimethylphenyl)pent-4-en-2-one Chemical group CC(=C)CC(=O)Cc1c(C)cc(C)cc1C UQRONKZLYKUEMO-UHFFFAOYSA-N 0.000 description 1
- UZOFELREXGAFOI-UHFFFAOYSA-N 4-methylpiperidine Chemical compound CC1CCNCC1 UZOFELREXGAFOI-UHFFFAOYSA-N 0.000 description 1
- 239000004382 Amylase Substances 0.000 description 1
- 102000013142 Amylases Human genes 0.000 description 1
- 108010065511 Amylases Proteins 0.000 description 1
- 244000241257 Cucumis melo Species 0.000 description 1
- 235000015510 Cucumis melo subsp melo Nutrition 0.000 description 1
- 101100372758 Danio rerio vegfaa gene Proteins 0.000 description 1
- PNKUSGQVOMIXLU-UHFFFAOYSA-N Formamidine Chemical compound NC=N PNKUSGQVOMIXLU-UHFFFAOYSA-N 0.000 description 1
- 102000005133 Glutamate 5-kinase Human genes 0.000 description 1
- 108700023479 Glutamate 5-kinases Proteins 0.000 description 1
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 244000294411 Mirabilis expansa Species 0.000 description 1
- 235000015429 Mirabilis expansa Nutrition 0.000 description 1
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 1
- 101100521345 Mus musculus Prop1 gene Proteins 0.000 description 1
- 244000227633 Ocotea pretiosa Species 0.000 description 1
- 235000004263 Ocotea pretiosa Nutrition 0.000 description 1
- 241001674048 Phthiraptera Species 0.000 description 1
- 108700017836 Prophet of Pit-1 Proteins 0.000 description 1
- 101100111862 Schizosaccharomyces pombe (strain 972 / ATCC 24843) but2 gene Proteins 0.000 description 1
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 1
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 1
- 101150030763 Vegfa gene Proteins 0.000 description 1
- FJJCIZWZNKZHII-UHFFFAOYSA-N [4,6-bis(cyanoamino)-1,3,5-triazin-2-yl]cyanamide Chemical compound N#CNC1=NC(NC#N)=NC(NC#N)=N1 FJJCIZWZNKZHII-UHFFFAOYSA-N 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000019418 amylase Nutrition 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000001772 anti-angiogenic effect Effects 0.000 description 1
- 150000007980 azole derivatives Chemical class 0.000 description 1
- AIXAANGOTKPUOY-UHFFFAOYSA-N carbachol Chemical group [Cl-].C[N+](C)(C)CCOC(N)=O AIXAANGOTKPUOY-UHFFFAOYSA-N 0.000 description 1
- 125000005909 ethyl alcohol group Chemical group 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- QJQYPZZUKLQGGT-UHFFFAOYSA-N methyl hypobromite Chemical group COBr QJQYPZZUKLQGGT-UHFFFAOYSA-N 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 235000013536 miso Nutrition 0.000 description 1
- 239000011733 molybdenum Substances 0.000 description 1
- 229910052750 molybdenum Inorganic materials 0.000 description 1
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 description 1
- FEKSQPIVDJSVJJ-UHFFFAOYSA-N n-chloro-2-fluoroaniline Chemical compound FC1=CC=CC=C1NCl FEKSQPIVDJSVJJ-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000005412 pyrazyl group Chemical group 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- AUKXFNABVHIUAC-UHFFFAOYSA-N pyrrolidin-2-ylmethylamine Chemical compound NCC1CCCN1 AUKXFNABVHIUAC-UHFFFAOYSA-N 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
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Description
520364 A8 B8 C8
基胺甲^基、祕二（Cl.4境基）胺甲酿基、CM燒酿基和 Cl-4燒氧基羰基之取代基）； 2) C2·5烯基R14(其中Ri4為吡咯啶基或嗎啉基）； 3) C2_5決基R15(其中Ri5為嗎啉基）； ’ 4) Cl.5烷基 X2Cl.5烷基 X3Ri6(其中 乂2為_〇nr17c〇_、_ NR20SO2-或-NR21-(其中Ri7、r20和r21各獨立代表， 基），X3為-〇-，及Ri6代表‘以完基）； -3疋 5 ) C,5^ ^ X4COR^(^ t X4^ ^ ^nr23_( ^ + r23^^ ^ ^
Cufe 基）及R22代表-NR24R25或-〇R26 (其中r24 為相同或不同，且各代表c1-4烷基））； " 6) Cw烷基X5R27(其中X5代表_〇_、羰基或_nr32_(其中及32代 表氫或C〗·3烷基），及R27代表環戊基或選自吡咯啶基、六 氫说淀基、四氫喊喃基、六氫心井基及嗎琳基之5❹員 飽和雜環基，其環戊基或雜環基可載有丨或2個選自 烷基之取代基，或r2、Ci·3烷基，且X5為-s·、_s〇_、_ so2-或-nr31so2-(其中R3i代表氫或Ci3烷基））； 7) C!·3烷氧基Gw烷基，其限制條件係^為_^、_s〇_或 -S 〇2~ f 8) C!·3烷氧基C2_4烷基或Cw烷基，其限制條件係义〇 · 9) Cl-5院基X6CW完基β(其中χ6代表4或视37s〇2_(其 中R37代表氫或(^·3烷基）及R33代表選自吡咯啶基、六氫 岐呼基及嗎琳基之5或6員飽和雜環基，其雜環基可載有 1或2個選自氧及Cl_4烷基之取代基）； 六氫吡啶-3-基和六 10) R39(其中R39為選自吡咯啶_3•基 -2 -
氫吡啶-4-基之基團 之取代基）； 其基團可載有1或2個選自Cm烷基 度）基R (其中R«為嗎啦基，其可載有i或2個選自 乳、Cw燒基、Cl-4幾基垸基、胺甲酿基、[Μ燒基胺甲 =基、随-二（Cl-4境基）胺甲醯基、CM㈣基和Cm境氧 基碳基之取代基），其限制條件係當R、c“5烷基r43時， X 為-S-、-SO-或-SO〗-;及 主）Cwk基R (其中R44為嗎琳基’其載有至少1個及視 兄2個選自氧、Ci.4烷基、c“4羥基烷基、胺甲醯基、 Cb4烷基胺甲醯基、腿二(Ci4烷基)胺甲醯基、烷醯 基和C!·4燒氧基羰基之取代基）； 其進一步之限制條件係當R4係選自群組8)時，…和/或… f基或至少1個r3為c〗3烷醯氧基；且排除4-(3_氯_仁 氟苯胺基）-7 -甲氧基-6 -硝基喹唑啉，6，7 -二甲氧基_ 4 _ (3 -甲基苯胺基）_ 5 •硝基喹唑啉，及7 _甲氧基_ 4 _ ( 3，·甲 基丰胺基）_ 6 -硝基峻吐淋；] 及其鹽。 2·根據申請專利範圍第i項之喹唑啉衍生物，其中r1代表 氫、硝基、甲氧基或乙氧基。 3.根據申請專利範圍第丨或2項之喳唑啉衍生物，其中…為 甲氧基。 ..... -3- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 520364
A B c D 、申請專利範圍 物，其中R2為 4·根據申請專利範圍第丨或2項之喳唑啉 氫。 其中攜有 根據申請專利範圍第1或2項之喹唑啉衍生物， (R3)m之苯基係式II者：
(II) 其中： R代表氫、甲基、氟或氯；
Rb代表氫、曱基、甲氧基、溴、氟或氯； 代表氫或羥基；
Rd代表氫、氟或氯。 6·根據申請專利範圍第1或2項之喹唑啉衍生物，其中㈤為 2 ° 7 ·根據申請專利範圍第1或2項之4峻4衍生物，其中样有 (R )m之冬基為4 -鼠-2-氟苯基或4 -溴-2-氟苯基。 8 ·根據申請專利範圍第1或2項之4唑咏衍生物，其中 表-Ο-或-S-。 9 ·根據申請專利範圍第1或2項之ρ奎嗅琳衍生物，其中X i代 表-Ο - 〇 10·根據申請專利範圍第1或2項之喹唑啉衍生物，其中R4係 選自以下1 1個群組之一： -4- 520364
1) Cm 烷基 R12(其中 ^ ^ 、 K為選自1，3-二氧五圜-2-基、毗咯 呢冬基P比各呢基，六氫响淀-2-基、六氫咕咬-3- 基、六氫吡啶-4-基、嗎啉_2_基、嗎啉_3_基和六氫吡畊_ 2- 基之基團，其基團^1 、 固了载有1或2個選自氧、Cl_3烷基、
CuUk基甲睡基、c“3燒基胺甲醯基、仏过-二 ((:“火基）、C2-成酿基和Cl·〗燒氧基窥基之取代 基）或C2.4燒基R45(其中R45為選自咪㈣小基”比嘻症小
裝 基和硫嗎啉基之基團’其基困可載有！或2個選自氧、Cl_ 3坑基/ Cl_3幾基烷基、胺甲醯基、Cl3燒基胺甲醯基、 腿--（cN3坑基）胺甲酿基、C2 3燒酿基和Cm燒氧基談基 之取代基）； 2) 1-R46丙-1-埽-3·基、“眇丁士埽冰基、卜r“丁-卜烯_ 3- 基、1-R46戊-2-缔-4-基或2_R46戊_3_埽_5•基(其中r46為 峨哈淀基或嗎#基’其雜環基經碳原子與婦基鍵結），或 1-R47 丁-2-埽-4-基、no 戊 _2_ 締 _4_ 基或 2_r _5_ 基(其中R47為吡咯啶基或嗎啉基，其雜環基經 烯基鍵結）； . 八
3) mm基、丁 _2_块冬基、R48 丁小块· 3-基' 1-R48戊-2-块-4-基或2_汉48戊_3·块_5_基（其中r48為 嗎啉基，其雜環基經碳原子與炔基鍵結），或1 KM 丁 2 炔I基、Μ"戊_2·炔I基或2-R49戊基（其中R/9 為嗎啉基，其雜環基經氮原子與炔基鍵結）； 4) Cwfe基x2Cl.3烷基x3Ri6(其中&和&係如 利 圍第1項所定義，及Ri6代表Cl-3烷基）； '專利範 -5-
520364 申請專利範圍 5 ) C2-3 基 X 4COR22( Jt 中 γ4你』士 Μ 22 I、中X係如申請專利範圍第1項所 疋我，及R代表-NR24R25或_〇r26(其中r24 r25和r26可 相同或不同，且各代表CM烷基））； … )C2.3；k基XR (其中χ5係·〇_、羰基或-陳'(其中代 表氫或CN3燒基），及尺27代表選自環戊基”比錢基和二 氫峨淀之基團，其基團經碳原子與χ5鍵結，及其基團可 載有1個選自Cl.戌基之取代基，或r27aCi•戌基，且χ5 為-s-、-SO-、_s〇2_或.nr31s〇h其中r31代表氫或 基））； 7) Cw烷氧基C2·3烷基，其限制條件係义為·^、_s〇· "S〇2-； 8 ) CM烷基X6C2·3烷基r33(其中χ6係如申請專利範圍第i -所足我及R代表選自吡咯啶基、六氫吡啩基及嗎淋 基之5或6員飽和雜環基，其雜環基可載有丨或2個選自氧 及(^.3烷基之取代基）； 9) C2·3烷基R4G(其中R4〇為六氫吡畊基，其載有至少丨個 選自乙醯基、Cy烷氧基羰基和Ci·2羥基烷基之取代基； |〇) C2·3烷基R43(其中R43為嗎啉基，其可載有1或2個選自 氧、C!·2烷基、Cl·2羥基烷基、胺甲醯基、Cw烷基胺甲 I基Κ’ϋ- 一（ Cufe基）胺甲醯基、乙醯基和(^·2燒氧基羰 基之取代基），其限制條件係當1^4為C23烷基R43時，乂!為 -S-、-SO-或-S02-;及 11) C2·3烷基R44(其中R44為嗎啉基，其載有至少i個及視 情況2個選自氧、Cu烷基、Ci·2羥基烷基、胺甲醯基、 -6- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公董） 裝 訂 520364 圍範利 專請 中
A BCD 1 2心基月女甲ga基燒基）胺甲臨基、乙醯基和 C!-2烷氧基羰基之取代基）。 ，請專利範圍第10項之㈣木衍生物，其中r4係選 自以下9個群組之一： 裝 D ^戌基1^其中RU為選自仏二氧五園-2-基”比洛 哫-2-基、吡咯啶-3-基、六氫吡啶_2_基、六氫吡啶_3_ 基、六氫峨淀-4_基、嗎，林·2_基、嗎啦·3_基和六氫峨咯 2-基足基團，其基團可載有個選自氧、燒基、 Cm羥基烷基、胺甲酿基、Ci_2烷基胺甲醯基、过，士二 (CA基）胺甲醒基、乙酿基和燒氧基羰基之取代 基），或C2.3燒基以其中R45為選自咪嗤淀小基”比嘻咬_ 1- 基和硫嗎琳基之基團，其基團可載有iii2個選自氧、 U充基、Cl』基燒基、胺甲酿基、Ci_2燒基胺甲酿基、 訂 二（Cw烷基）胺甲醯基、乙醯基和a·〗烷氧基羰基之 取代基）； U 1β5()：Γ-2-“基（其中r5〇為選自吡咯啶·〗-基、吡咯 啶-3-基及嗎啉基）； 3) 1-R51 丁-2-玦·4_基（其中R”為嗎啉基）； 4) Cw烷基x2Cl·3烷基x3Ri6(其中χ2和X3係如申請專利範 圍第1項所定義，及R16代表Cw烷基）； 5) Cu烷氧基C2·3烷基，其限制條件係χι為·s_、_s〇-或 -SO!-; 6) 2-(3,3-二甲基脲基）乙基、3_(3,弘二甲基脲基）丙基、 2- (1，3,3-三甲基脲基）乙基、Mu，％三甲基脲基）丙基、 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 520364 々、申請專利範圍 2-(異丙氧基羰基胺基）乙基、3-(異丙氧基羰基胺基）丙 基、2 -(異丁氧基羰基胺基）乙基、3 _ (異丁氧基羰基胺基） 丙基、第三丁氧基羰基胺基）乙基或3•(第三丁氧基羰 基胺基）丙基； 7) C2.3 烷基 其中 R27 為 Ci_2 烷基及 、_s〇-、 -so2-或-nr31so2-(其中R3i代表氫或Ci_3烷基））； 8) CM烷基Xtw烷基R33(其中χ6係如申請專利範圍第工 項所定義，及R33代表選自嗎啉基、2_氧吡咯咬小基、 吡咯咬-1-基、六氫P比呼小基和甲基六氫吡_小基之 基厕）；及 9) C2.3烷基R43(其中R«為嗎啉基’其可載有“η個選自 氧、C!·2燒基、Cl_2^基燒基、胺甲醯基、Ci_2燒基胺甲 ftm·基Μ，ϋ- 一（Cl·2 L基）胺甲酿基、乙酿基和ο"燒氧基 羰基之取代基）’其限制條件係當尺4為C2.3燒基時，^ 為- S-、-SO-或-S〇2-。 12·根據申請專利範圍第10*u項之喹唑啉衍生物，其中y 係選自以下8個群組之一： 1) h院基RW其中r、。-二氧五圜基”比咯唆· 2-基、吡咯啶-3-基、六氫吡啶_2_基 '六氫吡啶_3_ 基、六氫吡啶-4·基、1-甲基六氫吡啶·2•基、卜甲夹 六氣Ρ比淀-3-基、丨-甲基-六氫峨啶_仁基、丨_甲基各 啶-2·基、1-曱基·峨咯淀·3·基、六氫吡啩·2-基、甲 基-六氫吡畊-2·基、4 -甲基六氫吡畊·2·基、！ * 一 基六氫吡畊-2 ·基、嗎啉· 2 -基、嗎啉 3 ·其^ ^ ^ 丞、4 -甲基嗎 -8- 圍 申請專利範 哺唉a :f基嗎琳小基），或C2·3燒基r45(其中R45為 基吡咯啶二二硫嗎啉基、ι,1-二氧基硫嗎啉基、2·氧 (Ν，Ν--甲其1、2U基胺甲酿基_各咬小基、2-基胺甲酿基）料咬]-基、2-胺甲酸基心 虱咪唑啶-1_基或3_甲基-2_氧咪唑啶_i· 啶_1-基 基）； :二°?-缔|基(其中R5°為咖小基' 1-甲基 比咯哫-3-基或嗎啉基）； ^ 1-R51 丁-2-炔-4-基（其中r51為嗎啉基）； )〇2·3烷基Xky烷基X3R、其中2 範III笼Uif αe h、甲入及X係如申請專利 圍弟1項:斤疋義，且R16代表cM烷基）； )氧基c2 3；fe基，其限制條件為^為-s·、_s〇·或 '^〇2- > 6) C2·3燒基x5R27(其中R27為k境基且χ5為_s_、_s〇、 S(V或·NR31S〇2-(其中R31代表氫或〜燒基））； :)C2:3垸基X燒基r33(其中χ 6係如申請專利範圍第】 ^所疋義，且R”代表選自峨錢]基、4_甲基六氯峨 开-1 -基及嗎琳基之基團）；及 8) C2_3烷基R«(其中r43為嗎啉基，其可攜有—或二個選 自4氧、Cl-2燒基、Cl-2舰基之取代基），其限制條件為當 R 為 C2.3 烷基 R43 時，χΐ 為-S-、-S〇·或 _s〇2 一。 13·根據申請專利範圍第1項之4也淋衍生物，其為式la之化 合物：. 〜’ a义 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐)
hnO(R33)-
R'X1 (la) [其中：
Rla*氫或甲氧基； R2a為氫； 載有（R3a)mai苯基為4 -惫 — < —分· 1 -2-氣冬基或4-溴-2-氟苯基； xla為-0-或-S-; R4a係選自以下7個群組之—·
1) CU4烷基 R7a(其中 R7aA κ為選自1，3-二氧五圜-2-基、吡咯 呢_2·基”比…-基、六氫…-基、六氫…-基、六氫…-基、嗎啉-2-基、嗎啉-3·基和六氫,比，- 2_基（基團，其基團可载有1或2個選自氧、Cl.3燒基、 匸1-3罗至基fe基、胺甲g故其、p t、# T、暴、Cy烷基胺甲醯基、R，士二 (Cl3燒基）胺甲醯基、c成酿基和氧基祕之取代 基），或〇2.4垸基R、其中R8a為選自味㈣+基”比哈淀· 1-基和硫嗎淋基之基團，其基團可載有_個選自氧、
Cm燒基、CM基燒基、胺甲酶&、Ci3燒基胺甲縫 基、腿-一（Cufe基）胺甲醯基、c23燒酿基和Ci-3燒氧基 羰基之取代基）； 2) 1-1^丙小婦-3-基、Hn埽|基、Wm 3-基、1-R9a戊-2-缔-4-基或2-R9a戊，3·婦_5_基（其中R9a為 峨洛淀基或嗎琳基，其雜環基經碳原子與烯基鍵結），或 i-RGm4j、i-RiGm4442_RH)m -10- 本纸張尺度適用中國國家標準(CNS) A4規格(210X297公釐)
申請專利範
5-基（其中Ri〇a為吡哈 與缔基鍵結）； 唉基或嗎琳基，其雜環基經氮原子 l-RUaT-2-炔-4-基、 3) leR 丙-1-炔_3-基 其RHa戊·2_块·4·基或2-Rna戊_3·块-5__基（其中 …馬林基，其雜環基經碳原子與炔基鍵結），或丨氺⑵ ” R為嗎啉基，其雜環基經炔基與氮原子鍵結）； 4) C2.3 烷基 XhCM 烷基 x3aRl3a(其中 x2a 為 _〇_、_NRi4ac〇_ 或NR”（其中R和R15a各獨立代表Ci 2垸基），x3n ’及R a代表CN3烷基）； 1) C2.3烷基X4aC〇Rl6a(其中χ43代表_NRna_(其中代表 氫Η或 Ci.3烷基）及 R16a 代表-NRl8aRl9a 或-〇R2〇a(其中 y8a、 R a和⑼可為相同或不同，且各代表燒基））； 6^C2_3烷基X5aR2U(其中χ53代表羰基、_〇•或-Nr24、其中 R代表氫或(^·2烷基），及以1&代表選自環戊基、吡咯啶 基和穴氫吡啶基之基團，其基團經碳原子與xSa鍵連及並 基圈可載有i個選自Cw烷基，或以^為^-3烷基，且xSa為、- S -、-S0-、-S〇2-或擺2、〇η其中R23a代表氫或c以 基））； 7) Cl-2fe氧基C2-3垸基，其限制條件係Xla為_s·; 8 ) Q·3燒基Χ%2 3燒基R25a(其中#代表或·Νγ、〇2_ (其中R27a代表氫或CM烷基）&R25a代表選自吡咯啶基、六 氫吡呼基及嗎啉基之5或6員飽和雜環基’其雜環基可載 有1或2個選自氧及Cw烷基之取代基）； -11 - 520364
A BCD 9) C2·3烷基R29a(其中rW為六氫吡畊·丨_基，其載有至少^ 個選自乙醯基、Cl·2烷氧基羰基和Ch羥基烷基之取代 基）； 10) Cw烷基R32a(其中尺仏為嗎啉基，其可載有個選 自氧、Cl_2纪基、ci_2^基烷基、胺甲醯基、Ci.2垸基胺 甲醯基、比士二（C1-2烷基）胺甲醯基、乙醯基和Ci.2烷氧基 羰基之取代基），其限制條件係當R4a為C2_3烷基R32a時， Xla4-S-;及 11) C2·3烷基R33a(其中R33a為嗎啉基，其載有i個及視情況 2個選自氧、C〗·2烷基、Cl·2羥基烷基、胺甲醯基、^“烷 基胺甲醯基、达过-二（Gw烷基）胺甲醯基、乙醯基和Cm烷 氧基羰基之取代基）；] 及其鹽。 14.根據申请專利範圍第1項之p奎嗅琳衍生物，其係選自以 下： 4-(4-氯-2-氟苯胺基）-7-(1，3-二氧五圜_2_基甲氧基甲 氧基p奎嗅淋， 4-(4-氯-2 -氟苯胺基）-6-甲氧基-7-(4-嗎啦基丁 _2_块-1-氧 基）ΪΤ奎U坐琳， (E)-4-(4-氯-2-氟苯胺基）-6-甲氧基-7-(4-嗎啉基丁-2-晞-1- 氧基）0奎嗅淋， 4-(4-氯-2-氟苯胺基）-7-(3-(2,6-二甲基嗎啉基）丙氧基）_6-甲氧基4峻琳， 4_(4·氣·2_氟本胺基）-6-曱氧基_7-(3-([过_甲基_ν·甲基石黃 -12- 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 520364
8 8 8 8 A B c D 、申請專利範圍 酿基]胺基）丙氧基）啥吐琳， 7-(2-([ϋ-第三丁氧基羰基胺基]乙氧基）-4-(4-氯-2-氟苯胺 基）-6 -甲氧基u奎峻淋， 4-(4-溴-2-氟苯胺基）-6-甲氧基-7-(3-([过-甲基甲基磺醯 基]胺基）丙氧基）Ρ奎tr坐淋， 4-(心氯-2-氟苯胺基）-6-甲氧基-7-(2-(2-氧咪唑啶小基）乙 氧基）0奎嗅淋， 4-(4-氯-2-氟苯胺基）-6-甲氧基-7-(2-(3-氧嗎啉基）乙氧基） 口奎峻口林， 4-(4-溴-2-氟苯胺基）-6-甲氧基-7-(2-(3-氧嗎啉基）乙氧基） P奎嗅U林， 4-(4-氯-2 -氟苯胺基）-6-甲氧基-7-(2-硫嗎淋基乙氧基）4 也淋， (S)-4-(4-溴-2-氟苯胺基）_7-(3-(2-胺甲醯基吡咯啶-^基） 丙氧基）-6 -甲氧基p奎吐淋， 4-(4-氯-2-氟苯胺基）-6 -甲氧基- 7-(3-(2-氧p比p各淀-1-基）丙 氧基）0奎嗤淋， 4-(4 -氣-2-氟苯胺基）-6 -甲氧基- 7-(2-(2•氧p比嘻淀-1-基）乙 氧基）4 u全淋， (S)-7-(3-(2-胺甲酿基叶各淀-1-基）丙氧基）-4-(4 -氯-2-氟 苯胺基）-6-甲氧基喹唑啉， 4-(4-氯-2 -氟苯胺基）-6-甲氧基-7-(2-(2-嗎琳基乙氧基）乙 氧基）p奎吐淋及 4-(4 ->臭-2-氣冬胺基）-6 -甲氧基- 7- (3-(2 -氧p比p各淀-1_基）丙 -13- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 520364
A B c D 申請專利範圍 氧基）p奎峻p林 及其鹽。 15. 根據申請專利範圍第1項之喹唑琳衍生物，其係選自以 下： 4-(4-氯-2-氟苯胺基）-6-甲氧基-7_(2-(2-甲氧基乙氧基）乙 氧基）峻吐淋， 4-(4-氯-2-氟苯胺基）-6-甲氧基_7_(1_甲基六氫吡啶_3•基） 甲氧基峻Π坐淋， 4-(4-溴-2-氟苯胺基二氧硫嗎啉基）丙氧基>6_ 甲氧基17奎峻淋， 4-(4-溴-2-氟苯胺基）-6-甲氧基_7-(2_(2_甲氧基乙氧基）乙 氧基）峻咬琳， 4-(4-氯-2-氟苯胺基）-6-曱氧基-7-(2-(2_吡咯啶」·基乙氧 基）乙氧基）峻峻琳， 4-(4-氯-2-說苯胺基）冬甲氧基_7-(2_(2_[4_甲基六氯μι-基] 乙氧基 ） 乙氧基 ）p奎吐 p林， 4-(4_氣_2_氟苯胺基）冬甲氧基-7_(3_嗎啉基丙硫基）喹唑 淋， 心(4-氯-2-氟苯胺基）_6_甲氧基_ 7·(2·([过·甲基普甲氧基 乙酿基]胺基）乙氧基）U奎峻琳，及 4:(4-澡-2-氟苯胺基）冬甲氧基_7仆(2•氧心各淀小基）乙 氧基）p奎峻淋 及其鹽。_ 16. 根據申請專利範圍第i項之喹唑啉衍 17生物，其係選自以 -14- 520364
下： (E)-4-(4-氯-2-氟苯胺基）-6-甲氧基_7-(4-(吡咯啶-；μ基）丁 _ 2-烯-1-氧基）喳唑啉， 4^4•氯-2-氟苯胺基）-6-甲氧基-7_(3_(甲基磺醯基）丙氧基） 口奎口生琳， ⑻-4-(4氣-2-氣苯胺基）-6-甲氧基甲基六氫吡啶冬 基）甲氧基喹唑淋，及 (R)-4-(4-氯-2-氟苯胺基）.6-甲氧基·7-(1-甲基六氯峨淀小 基）甲氧基喹峻啉 及其鹽。 R根據申請專利範圍第！項之喳唑啉衍生物，其係 M4-氯-2-氟苯胺基）·6_甲氧基_7-(3_(曱基祕基）丙氧基） 及其鹽。 18. 根據申請專利範圍第！項之喹唑啉衍生物，其係呈醫藥 上可接受之鹽之形式。 19. 一種製備（根據申請專利範圍第丨項之）式][之喹唑啉衍生 物或其鹽之方法，其包括： (a)將式III之化合物：
y 一 χιΛ^Αν』 (III) -15-
(，中R1、R2、X1和R4係如申請專利範圍第i項所定義及 L1為可置換部分）與式Iv之化合物反應： (¾
NH2 (IV) (其中R3和m係如申請專利範圍第！項所定義），藉此獲得 式I之化合物及其鹽； & (b)為製備式I之化合物及其鹽，其中式na之基團： (的 m (Ha) (其中R3和m係如申請專利範圍第！項所定義）代表載有工 或多個羥基之苯基時，去保護式V之化合物：
, (V) (其中X、m、Ri、R2、R3和R4係如申請專利範圍第i項所 定義，P代表酚性羥基保護基，及pl為等於經保護羥基 -16- 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 520364
8 8 8 8 A BCD 申請專利範圍 數目之自1至5之整數及使m-pl等於其為未經保護羥基 之R3取代基之數目）； (c)為製備式I之該等化合物及其鹽，其中取代基X1為-0-、-S-或-S02-，將式VI之化合物：
.(R3)n (VI) (其中m、X1、R1、R2和R3係如申請專利範圍第1項所定義） 與式VII之化合物反應： R4-L1 (VII) (其中R4係如申請專利範圍第1項所定義，及L1係如在本 項中之定義）； (d)將式VIII之化合物：
.(R3)r (VIII) 與式IX之化合物反應： (IX)
R^X^H -17- 本紙張尺度適用中國國家標準(CNS) A4規格(210 χ 297公釐） 520364 __ 申請專利範園 (其中 Rl、R2、R3、p 4、 V1 . ^ M j 瓜和又係如申請專利範圍第1項所 (约為製備式I之化合物及其 r Jt φ〇53,, ^ 為 CM 烷基 R53， L具中R係選自以下3個群組之一： 1) X7R27(其中X7代表H… •NR56-(其中 r5>r56各獨 2 _ R S〇r 或 + _ 谷獨立代表虱或匚“烷基）及係如 申請專利範圍第1項所定義）； 2) X8Cm 烷基 X3Rl6(其中 χ8 代表 _〇_、-nr57c〇 -NRACV或-皿、其中r57、r58和r59各獨立代表入成 基），及X3和R16係如申請專利範圍第i項所定義）；及 3) Χ%·5燒基其中χ9代表_〇_或视61s〇2_(其中代 表氫或Cw烷基），及尺33係如申請專利範圍第丨項 義）；]， 將式X之化合物：
.(R3)n N (X) (其中X1、R1、R2、化3和m係如申請專利範圍第1項所定 義，L1係如在本項中之定義及烷基）與式XI之化 合物反應： R53-H (XI) -18- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公爱） (其中R53係如在本項中之定義），得到式I之化合物； 氣備式I之化合物，其中R/為C2 5烷基R45，（其中R45係選 自味"坐呢-1-基、吡咯啶-1-基和硫嗎啉基之基團，其基團 可載有1或2個選自氧、羥基、Cl.4烷基、Cm羥基烷基、 月女甲驗基、Cm烷基胺甲醯基、込士二（(：1·4烷基）胺甲醯 基、C!.4烷醯基*Ci·4烷氧基羰基之取代基），將式X之化 &物（其中R 3為C2-5坑基）與式XIa之化合物反應： R45-H (XIa) (其中R45係如在本項中之定義），得到式j之化合物； 及當需要式I喹唑啉衍生物醫藥上可接受之鹽時，將所得 之化合物與酸或鹼反應，藉此獲得所要之醫藥上可接受 之鹽。 2〇. 一種用於治療與血管生成及/或增加血管滲透性有關之 疾j之醫藥組合物，其包括作為活性成份之根據申請專 利範圍第1項之式J化合物或其醫藥上可接受之鹽，聯結 醫藥上可接受之賦形劑或載體。 21. —種用於在溫血動物中產生抗血管生成和/或血管滲透性 降低作用之醫藥組合物，其包括作為活性成份之根據申 凊專利範圍第1項之式][化合物或其醫藥上可接受之鹽， 聯結醫藥上可接受之賦形劑或載體。 22. -種用於治療與血管内皮生長因子（vegf)受體路胺酸 激酶活性有關之疾病之醫藥组合物，其包括作為活性成 份^根據申請專利範圍第i項之式！化合物或其醫藥上可 接文足鹽，聯結醫藥上可接受之賦形劑或載體。 -19_ 520364
8 8 8 8 A B c D 、申請專利範圍 23. —種用於在溫血動物中產生VEGF受體酪胺酸激酶活性 之抑制之醫藥組合物，其包括作為活性成份之根據申請 專利範圍第1項之式I化合物或其醫藥上可接受之鹽，聯 結醫藥上可接受之賦形劑或載體。 -20- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐）
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| US9731022B2 (en) | 2011-06-07 | 2017-08-15 | Hanmi Pharm. Co., Ltd. | Pharmaceutical composition comprising amide derivative inhibiting the growth of cancer cells and non-metallic salt lubricant |
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| US5747498A (en) | 1996-05-28 | 1998-05-05 | Pfizer Inc. | Alkynyl and azido-substituted 4-anilinoquinazolines |
| GB9707800D0 (en) | 1996-05-06 | 1997-06-04 | Zeneca Ltd | Chemical compounds |
| GB9718972D0 (en) | 1996-09-25 | 1997-11-12 | Zeneca Ltd | Chemical compounds |
| AU733551B2 (en) | 1996-09-25 | 2001-05-17 | Astrazeneca Ab | Qinoline derivatives inhibiting the effect of growth factors such as VEGF |
| EP1005470B1 (en) | 1997-08-22 | 2007-08-01 | AstraZeneca AB | Oxindolylquinazoline derivatives as angiogenesis inhibitors |
| US6706721B1 (en) | 1998-04-29 | 2004-03-16 | Osi Pharmaceuticals, Inc. | N-(3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate anhydrate and monohydrate |
| EP1115724A1 (en) | 1998-09-21 | 2001-07-18 | Shire Biochem Inc. | Quinolizinones as integrin inhibitors |
| TR200102505T2 (tr) | 1999-02-27 | 2003-01-21 | Boehringer Ingelheim Pharma Kg | 4-amino-kinazolin ve kinolin türevleri. |
| DE19911509A1 (de) * | 1999-03-15 | 2000-09-21 | Boehringer Ingelheim Pharma | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
| YU13200A (sh) * | 1999-03-31 | 2002-10-18 | Pfizer Products Inc. | Postupci i intermedijeri za dobijanje anti-kancernih jedinjenja |
| WO2000078735A1 (de) * | 1999-06-21 | 2000-12-28 | Boehringer Ingelheim Pharma Kg | Bicyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9731022B2 (en) | 2011-06-07 | 2017-08-15 | Hanmi Pharm. Co., Ltd. | Pharmaceutical composition comprising amide derivative inhibiting the growth of cancer cells and non-metallic salt lubricant |
| US9931406B2 (en) | 2011-06-07 | 2018-04-03 | Hanmi Pharm. Co., Ltd. | Pharmaceutical composition comprising amide derivative inhibiting the growth of cancer cells and non-metallic salt lubricant |
| US9518043B2 (en) | 2013-01-28 | 2016-12-13 | Hanmi Pharm. Co., Ltd. | Method for preparing 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yi)prop-2-en-1-one |
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