PL203782B1 - Pochodne chinazoliny,sposoby ich wytwarzania,ich kompozycje farmaceutyczne oraz ich zastosowania - Google Patents

Info

Publication number

PL203782B1

PL203782B1 PL355942A PL35594200A PL203782B1 PL 203782 B1 PL203782 B1 PL 203782B1 PL 355942 A PL355942 A PL 355942A PL 35594200 A PL35594200 A PL 35594200A PL 203782 B1 PL203782 B1 PL 203782B1

Authority

PL

Poland

Prior art keywords

quinazoline

ylmethoxy

methoxy

formula

compound

Prior art date

1999-11-05

Links

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• 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title abstract description 3
• 239000002525 vasculotropin inhibitor Substances 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 164
• 150000003839 salts Chemical class 0.000 claims abstract description 71
• 238000000034 method Methods 0.000 claims abstract description 43
• 230000000694 effects Effects 0.000 claims abstract description 27
• 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 claims abstract description 24
• 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 claims abstract description 24
• 238000011282 treatment Methods 0.000 claims abstract description 24
• 125000001424 substituent group Chemical group 0.000 claims abstract description 13
• 230000008569 process Effects 0.000 claims abstract description 12
• 125000005843 halogen group Chemical group 0.000 claims abstract description 11
• 238000002360 preparation method Methods 0.000 claims abstract description 10
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 5
• 239000004480 active ingredient Substances 0.000 claims abstract description 5
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract description 3
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims abstract description 3
• -1 2-fluoro-4-methylphenyl Chemical group 0.000 claims description 52
• 241001465754 Metazoa Species 0.000 claims description 17
• 239000002253 acid Substances 0.000 claims description 17
• 239000003814 drug Substances 0.000 claims description 15
• UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 claims description 14
• 150000003246 quinazolines Chemical class 0.000 claims description 12
• 230000003527 anti-angiogenesis Effects 0.000 claims description 10
• 238000004519 manufacturing process Methods 0.000 claims description 9
• 230000008728 vascular permeability Effects 0.000 claims description 9
• 241000282412 Homo Species 0.000 claims description 6
• KQEHWOWUWGAOSR-UHFFFAOYSA-N n-(4-chloro-2,6-difluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCC3CCN(C)CC3)C(OC)=CC2=C1NC1=C(F)C=C(Cl)C=C1F KQEHWOWUWGAOSR-UHFFFAOYSA-N 0.000 claims description 6
• KNAJKXGUAHBQTI-UHFFFAOYSA-N n-(4-chloro-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCC3CCN(C)CC3)C(OC)=CC2=C1NC1=CC=C(Cl)C=C1F KNAJKXGUAHBQTI-UHFFFAOYSA-N 0.000 claims description 6
• 230000001603 reducing effect Effects 0.000 claims description 6
• 230000002401 inhibitory effect Effects 0.000 claims description 5
• KIWKXIDEBINNAK-UHFFFAOYSA-N n-(4-bromo-2,6-difluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCC3CCN(C)CC3)C(OC)=CC2=C1NC1=C(F)C=C(Br)C=C1F KIWKXIDEBINNAK-UHFFFAOYSA-N 0.000 claims description 5
• AVQNSHZBOYOSQZ-UHFFFAOYSA-N n-(4-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCC3CCNCC3)C(OC)=CC2=C1NC1=CC=C(Cl)C=C1F AVQNSHZBOYOSQZ-UHFFFAOYSA-N 0.000 claims description 5
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
• NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 5
• PBESGEKOQIKSKI-UHFFFAOYSA-N n-(4-bromo-2,6-difluorophenyl)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCC3CCNCC3)C(OC)=CC2=C1NC1=C(F)C=C(Br)C=C1F PBESGEKOQIKSKI-UHFFFAOYSA-N 0.000 claims description 4
• FYZOPODRENDNJN-UHFFFAOYSA-N n-(4-chloro-2,6-difluorophenyl)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCC3CCNCC3)C(OC)=CC2=C1NC1=C(F)C=C(Cl)C=C1F FYZOPODRENDNJN-UHFFFAOYSA-N 0.000 claims description 4
• WJJZQSCOTJYYSP-INIZCTEOSA-N n-[(7s)-9-hydroxy-1,2,3-trimethoxy-6,7-dihydro-5h-dibenzo[5,3-b:1',2'-e][7]annulen-7-yl]acetamide Chemical compound C1C[C@H](NC(C)=O)C2=CC(O)=CC=C2C2=C1C=C(OC)C(OC)=C2OC WJJZQSCOTJYYSP-INIZCTEOSA-N 0.000 claims description 4
• HTCPERSEGREUFC-UHFFFAOYSA-N n-desmethyl vandetanib Chemical compound N1=CN=C2C=C(OCC3CCNCC3)C(OC)=CC2=C1NC1=CC=C(Br)C=C1F HTCPERSEGREUFC-UHFFFAOYSA-N 0.000 claims description 4
• 230000001093 anti-cancer Effects 0.000 claims description 3
• QAWSAMDJZZDGDW-UHFFFAOYSA-N n-(2-fluoro-4-methylphenyl)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCC3CCNCC3)C(OC)=CC2=C1NC1=CC=C(C)C=C1F QAWSAMDJZZDGDW-UHFFFAOYSA-N 0.000 claims description 3
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
• 125000003386 piperidinyl group Chemical group 0.000 claims description 3
• 230000009471 action Effects 0.000 claims description 2
• 239000003937 drug carrier Substances 0.000 claims description 2
• WPCUQWCGLJALCN-UHFFFAOYSA-N n-(2-fluoro-4-methylphenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCC3CCN(C)CC3)C(OC)=CC2=C1NC1=CC=C(C)C=C1F WPCUQWCGLJALCN-UHFFFAOYSA-N 0.000 claims description 2
• 239000004066 vascular targeting agent Substances 0.000 claims description 2
• 230000035699 permeability Effects 0.000 claims 1
• 206010028980 Neoplasm Diseases 0.000 abstract description 19
• 125000000217 alkyl group Chemical group 0.000 abstract description 13
• 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 11
• 201000010099 disease Diseases 0.000 abstract description 7
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 7
• 201000011510 cancer Diseases 0.000 abstract description 6
• 206010039073 rheumatoid arthritis Diseases 0.000 abstract description 4
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract description 3
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 2
• 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 abstract 1
• 125000003342 alkenyl group Chemical group 0.000 abstract 1
• 125000000304 alkynyl group Chemical group 0.000 abstract 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 135
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 124
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
• 239000000243 solution Substances 0.000 description 59
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 54
• 229910001868 water Inorganic materials 0.000 description 47
• 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 45
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 39
• 230000002829 reductive effect Effects 0.000 description 36
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 34
• 238000001914 filtration Methods 0.000 description 33
• 239000000203 mixture Substances 0.000 description 33
• 239000007787 solid Substances 0.000 description 30
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 29
• 239000007858 starting material Substances 0.000 description 26
• 239000003039 volatile agent Substances 0.000 description 26
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 24
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
• 238000003756 stirring Methods 0.000 description 21
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
• 238000006243 chemical reaction Methods 0.000 description 20
• 238000001704 evaporation Methods 0.000 description 18
• 230000008020 evaporation Effects 0.000 description 18
• 239000000725 suspension Substances 0.000 description 18
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 17
• 235000019341 magnesium sulphate Nutrition 0.000 description 17
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
• 239000012044 organic layer Substances 0.000 description 16
• 239000002244 precipitate Substances 0.000 description 16
• 238000012360 testing method Methods 0.000 description 16
• 239000012267 brine Substances 0.000 description 15
• 238000000921 elemental analysis Methods 0.000 description 15
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 15
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
• 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 13
• 210000004027 cell Anatomy 0.000 description 13
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
• 238000003556 assay Methods 0.000 description 12
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 12
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 12
• 239000002904 solvent Substances 0.000 description 12
• 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 12
• 239000002585 base Substances 0.000 description 11
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• 239000003102 growth factor Substances 0.000 description 10
• 239000003701 inert diluent Substances 0.000 description 10
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
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• 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 9
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