IL125686A - Quinazoline derivatives, processes for their preparation, pharmaceutical preparations containing them and their use in the manufacture of a drug with an anti-angiogenic effect and / or an effect of reducing vascular permeability - Google Patents

Info

Publication number

IL125686A

IL125686A IL12568697A IL12568697A IL125686A IL 125686 A IL125686 A IL 125686A IL 12568697 A IL12568697 A IL 12568697A IL 12568697 A IL12568697 A IL 12568697A IL 125686 A IL125686 A IL 125686A

Authority

IL

Israel

Prior art keywords

hydroxy

fluoro

group

quinazoline

methoxy

Prior art date

1996-02-13

Links

• Espacenet
• Global Dossier
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• 238000000034 method Methods 0.000 title claims description 47
• 230000008569 process Effects 0.000 title claims description 34
• 230000008728 vascular permeability Effects 0.000 title claims description 16
• 238000004519 manufacturing process Methods 0.000 title claims description 13
• 238000002360 preparation method Methods 0.000 title claims description 12
• 230000001772 anti-angiogenic effect Effects 0.000 title claims description 11
• 239000003814 drug Substances 0.000 title claims description 11
• 230000001603 reducing effect Effects 0.000 title claims description 10
• 239000008194 pharmaceutical composition Substances 0.000 title claims description 6
• 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title description 5
• -1 methoxy, amino Chemical group 0.000 claims abstract description 165
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 88
• 239000001257 hydrogen Substances 0.000 claims abstract description 87
• 150000003839 salts Chemical class 0.000 claims abstract description 82
• 125000005843 halogen group Chemical group 0.000 claims abstract description 53
• 150000002431 hydrogen Chemical group 0.000 claims abstract description 52
• 125000001424 substituent group Chemical group 0.000 claims abstract description 51
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 37
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 29
• 125000004043 oxo group Chemical group O=* 0.000 claims abstract description 28
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 27
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 23
• 150000003246 quinazolines Chemical class 0.000 claims abstract description 20
• 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 18
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 16
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims abstract description 12
• 229910052717 sulfur Inorganic materials 0.000 claims abstract description 12
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims abstract description 10
• 125000005842 heteroatom Chemical group 0.000 claims abstract description 10
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 10
• 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 9
• 229910052760 oxygen Inorganic materials 0.000 claims abstract description 8
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 6
• 125000004122 cyclic group Chemical group 0.000 claims abstract description 4
• 125000004103 aminoalkyl group Chemical group 0.000 claims abstract description 3
• 150000001875 compounds Chemical class 0.000 claims description 174
• 238000006243 chemical reaction Methods 0.000 claims description 41
• JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 32
• 125000003545 alkoxy group Chemical group 0.000 claims description 15
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
• 125000003386 piperidinyl group Chemical group 0.000 claims description 12
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 12
• 229910052799 carbon Inorganic materials 0.000 claims description 11
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
• 239000002253 acid Substances 0.000 claims description 10
• 125000004432 carbon atom Chemical group C* 0.000 claims description 10
• 125000001153 fluoro group Chemical group F* 0.000 claims description 10
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
• 230000009467 reduction Effects 0.000 claims description 8
• 125000003277 amino group Chemical group 0.000 claims description 7
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 7
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
• YMMYOYOZKAMGGJ-UHFFFAOYSA-N 2-[4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazolin-7-yl]oxyethyl acetate Chemical compound N1=CN=C2C=C(OCCOC(C)=O)C(OC)=CC2=C1NC1=CC(O)=C(C)C=C1F YMMYOYOZKAMGGJ-UHFFFAOYSA-N 0.000 claims description 5
• MLPJQRZMIKCLAE-UHFFFAOYSA-N 2-chloro-5-[(6,7-dimethoxyquinazolin-4-yl)amino]-4-fluorophenol Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC(O)=C(Cl)C=C1F MLPJQRZMIKCLAE-UHFFFAOYSA-N 0.000 claims description 5
• XHXOJKOXEKXDSQ-UHFFFAOYSA-N 5-[(6,7-dimethoxyquinazolin-4-yl)amino]-4-fluoro-2-methylphenol Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC(O)=C(C)C=C1F XHXOJKOXEKXDSQ-UHFFFAOYSA-N 0.000 claims description 5
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 5
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
• CLSDZDFPIGPTBE-UHFFFAOYSA-N 2,4-difluoro-5-[[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]amino]phenol Chemical compound C=12C=C(OC)C(OCCOC)=CC2=NC=NC=1NC1=CC(O)=C(F)C=C1F CLSDZDFPIGPTBE-UHFFFAOYSA-N 0.000 claims description 4
• UEUPJXFRYBVXCU-UHFFFAOYSA-N 2-chloro-4-fluoro-5-[[6-methoxy-7-(2-morpholin-4-ylethoxy)quinazolin-4-yl]amino]phenol Chemical compound N1=CN=C2C=C(OCCN3CCOCC3)C(OC)=CC2=C1NC1=CC(O)=C(Cl)C=C1F UEUPJXFRYBVXCU-UHFFFAOYSA-N 0.000 claims description 4
• VJINORGYVPPLAU-UHFFFAOYSA-N 2-chloro-4-fluoro-5-[[6-methoxy-7-(2-piperidin-1-ylethoxy)quinazolin-4-yl]amino]phenol Chemical compound N1=CN=C2C=C(OCCN3CCCCC3)C(OC)=CC2=C1NC1=CC(O)=C(Cl)C=C1F VJINORGYVPPLAU-UHFFFAOYSA-N 0.000 claims description 4
• KJHZBMRRZLEZEY-UHFFFAOYSA-N 2-chloro-4-fluoro-5-[[6-methoxy-7-(2-pyrrolidin-1-ylethoxy)quinazolin-4-yl]amino]phenol Chemical compound N1=CN=C2C=C(OCCN3CCCC3)C(OC)=CC2=C1NC1=CC(O)=C(Cl)C=C1F KJHZBMRRZLEZEY-UHFFFAOYSA-N 0.000 claims description 4
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 4
• 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 4
• QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 4
• LKTZZFOJGFXTKH-UHFFFAOYSA-N 4-fluoro-5-[[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]amino]-2-methylphenol Chemical compound C=12C=C(OC)C(OCCOC)=CC2=NC=NC=1NC1=CC(O)=C(C)C=C1F LKTZZFOJGFXTKH-UHFFFAOYSA-N 0.000 claims description 4
• POLXJKGYTJUZNO-UHFFFAOYSA-N 4-fluoro-5-[[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]amino]-2-methylphenol Chemical compound N1=CN=C2C=C(OCCCN3CCOCC3)C(OC)=CC2=C1NC1=CC(O)=C(C)C=C1F POLXJKGYTJUZNO-UHFFFAOYSA-N 0.000 claims description 4
• 229940100198 alkylating agent Drugs 0.000 claims description 4
• 239000002168 alkylating agent Substances 0.000 claims description 4
• 238000010511 deprotection reaction Methods 0.000 claims description 4
• 125000004193 piperazinyl group Chemical group 0.000 claims description 4
• SPBPKQJZKCGMNA-UHFFFAOYSA-N 2-bromo-5-[(6,7-dimethoxyquinazolin-4-yl)amino]-4-fluorophenol Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC(O)=C(Br)C=C1F SPBPKQJZKCGMNA-UHFFFAOYSA-N 0.000 claims description 3
• UCSSQROSBFPVKH-UHFFFAOYSA-N 2-chloro-4-fluoro-5-[[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]amino]phenol Chemical compound C=12C=C(OC)C(OCCOC)=CC2=NC=NC=1NC1=CC(O)=C(Cl)C=C1F UCSSQROSBFPVKH-UHFFFAOYSA-N 0.000 claims description 3
• WKHGVOGOGAFWKY-UHFFFAOYSA-N 2-chloro-5-[[7-(2-cyclopentyloxyethoxy)-6-methoxyquinazolin-4-yl]amino]-4-fluorophenol Chemical compound N1=CN=C2C=C(OCCOC3CCCC3)C(OC)=CC2=C1NC1=CC(O)=C(Cl)C=C1F WKHGVOGOGAFWKY-UHFFFAOYSA-N 0.000 claims description 3
• MVYGSFKMASDTCN-UHFFFAOYSA-N 4-fluoro-5-[[6-methoxy-7-(2-methylsulfinylethoxy)quinazolin-4-yl]amino]-2-methylphenol Chemical compound N1=CN=C2C=C(OCCS(C)=O)C(OC)=CC2=C1NC1=CC(O)=C(C)C=C1F MVYGSFKMASDTCN-UHFFFAOYSA-N 0.000 claims description 3
• SOIKJFMWXGNLOF-UHFFFAOYSA-N 4-fluoro-5-[[7-(2-hydroxyethoxy)-6-methoxyquinazolin-4-yl]amino]-2-methylphenol Chemical compound N1=CN=C2C=C(OCCO)C(OC)=CC2=C1NC1=CC(O)=C(C)C=C1F SOIKJFMWXGNLOF-UHFFFAOYSA-N 0.000 claims description 3
• MQBJLYQZTQLXJP-UHFFFAOYSA-N 4-fluoro-5-[[7-(2-methoxyethoxy)quinazolin-4-yl]amino]-2-methylphenol Chemical compound N=1C=NC2=CC(OCCOC)=CC=C2C=1NC1=CC(O)=C(C)C=C1F MQBJLYQZTQLXJP-UHFFFAOYSA-N 0.000 claims description 3
• FHZCSNTVCRCIKT-UHFFFAOYSA-N 5-[(6,7-dimethoxyquinazolin-4-yl)amino]-2,4-difluorophenol Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC(O)=C(F)C=C1F FHZCSNTVCRCIKT-UHFFFAOYSA-N 0.000 claims description 3
• 239000004480 active ingredient Substances 0.000 claims description 3
• 125000001246 bromo group Chemical group Br* 0.000 claims description 3
• 239000003795 chemical substances by application Substances 0.000 claims description 3
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
• 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 2
• XDUSWBSGDKRQAF-UHFFFAOYSA-N 4-(3-chlorophenoxy)-6,7-dimethoxyquinazoline Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1OC1=CC=CC(Cl)=C1 XDUSWBSGDKRQAF-UHFFFAOYSA-N 0.000 claims description 2
• FRYNFLZWVRHSQU-UHFFFAOYSA-N 4-fluoro-5-[[6-methoxy-7-(2-methylsulfanylethoxy)quinazolin-4-yl]amino]-2-methylphenol Chemical compound N1=CN=C2C=C(OCCSC)C(OC)=CC2=C1NC1=CC(O)=C(C)C=C1F FRYNFLZWVRHSQU-UHFFFAOYSA-N 0.000 claims description 2
• BGPMVNFAGBHYEC-UHFFFAOYSA-N 5-(6,7-dimethoxyquinazolin-4-yl)oxy-2-methylphenol Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1OC1=CC=C(C)C(O)=C1 BGPMVNFAGBHYEC-UHFFFAOYSA-N 0.000 claims description 2
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 2
• 239000003937 drug carrier Substances 0.000 claims description 2
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
• OHUQJWOIRKREPF-UHFFFAOYSA-N n-(4-bromo-2,6-difluorophenyl)-6,7-dimethoxyquinazolin-4-amine Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=C(F)C=C(Br)C=C1F OHUQJWOIRKREPF-UHFFFAOYSA-N 0.000 claims description 2
• 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
• VMJNTFXCTXAXTC-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-5-carbonitrile Chemical group C1=C(C#N)C=C2OC(F)(F)OC2=C1 VMJNTFXCTXAXTC-UHFFFAOYSA-N 0.000 claims 1
• GGCNLONOSMUHFB-UHFFFAOYSA-N BrC1=CC(=C(NC2=NC=NC3=CC(=C(C=C23)OC)OCCCN2CCOCC2)C(=C1)F)F.FC1=C(NC2=NC=NC3=CC(=CC=C23)NC(COC)=O)C=C(C(=C1)C)O Chemical compound BrC1=CC(=C(NC2=NC=NC3=CC(=C(C=C23)OC)OCCCN2CCOCC2)C(=C1)F)F.FC1=C(NC2=NC=NC3=CC(=CC=C23)NC(COC)=O)C=C(C(=C1)C)O GGCNLONOSMUHFB-UHFFFAOYSA-N 0.000 claims 1
• AEKNYBWUEYNWMJ-QWOOXDRHSA-N Pramiconazole Chemical compound O=C1N(C(C)C)CCN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(CO3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 AEKNYBWUEYNWMJ-QWOOXDRHSA-N 0.000 claims 1
• 229920006395 saturated elastomer Polymers 0.000 abstract description 7
• 125000003342 alkenyl group Chemical group 0.000 abstract description 5
• 125000000304 alkynyl group Chemical group 0.000 abstract description 5
• IKLSIDTUVXSHJB-UHFFFAOYSA-N 6,7-dimethoxy-4-(3,4,5-trimethoxyphenoxy)quinazoline Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1OC1=CC(OC)=C(OC)C(OC)=C1 IKLSIDTUVXSHJB-UHFFFAOYSA-N 0.000 abstract description 2
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract 12
• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 abstract 7
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 3
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 2
• 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 abstract 2
• 125000004455 (C1-C3) alkylthio group Chemical group 0.000 abstract 1
• DLSREUWBAOWMKZ-UHFFFAOYSA-N 4-(3-chlorophenyl)sulfanyl-6,7-dimethoxyquinazoline Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1SC1=CC=CC(Cl)=C1 DLSREUWBAOWMKZ-UHFFFAOYSA-N 0.000 abstract 1
• VFCGGDJQUYSDNZ-UHFFFAOYSA-N 4-(3-chlorophenyl)sulfanyl-6,7-dimethylquinazoline Chemical compound C=12C=C(C)C(C)=CC2=NC=NC=1SC1=CC=CC(Cl)=C1 VFCGGDJQUYSDNZ-UHFFFAOYSA-N 0.000 abstract 1
• FGMVWDJVELFKJI-UHFFFAOYSA-N 6,7-dimethoxy-4-(3-methoxyphenyl)sulfanylquinazoline Chemical compound COC1=CC=CC(SC=2C3=CC(OC)=C(OC)C=C3N=CN=2)=C1 FGMVWDJVELFKJI-UHFFFAOYSA-N 0.000 abstract 1
• RNCVPFCGSMNPPO-UHFFFAOYSA-N 6,7-dimethoxy-n-(3,4,5-trimethoxyphenyl)quinazolin-4-amine Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC(OC)=C(OC)C(OC)=C1 RNCVPFCGSMNPPO-UHFFFAOYSA-N 0.000 abstract 1
• 125000004423 acyloxy group Chemical group 0.000 abstract 1
• 125000003709 fluoroalkyl group Chemical group 0.000 abstract 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 260
• 239000000203 mixture Substances 0.000 description 193
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• 238000001704 evaporation Methods 0.000 description 118
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• 239000007787 solid Substances 0.000 description 82
• ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 78
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• 239000002904 solvent Substances 0.000 description 74
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• 238000011282 treatment Methods 0.000 description 14
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• YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 9
• 238000010626 work up procedure Methods 0.000 description 9
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