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

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

Info

Publication number: IL125686A
Authority: IL; Israel
Prior art keywords: hydroxy; fluoro; group; quinazoline; methoxy
Prior art date: 1996-02-13

Application number

IL12568697A

Other languages

English (en)

Hebrew (he)

Other versions

IL125686A0 (en

Original Assignee

Zeneca Ltd

Zeneca Pharma Sa

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1996-02-13

Filing date

1997-02-10

Publication date

2002-11-10

1997-02-10 Application filed by Zeneca Ltd, Zeneca Pharma Sa filed Critical Zeneca Ltd

1999-04-11 Publication of IL125686A0 publication Critical patent/IL125686A0/xx

2002-11-10 Publication of IL125686A publication Critical patent/IL125686A/en

Links

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
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 180
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 147
238000001704 evaporation Methods 0.000 description 118
230000008020 evaporation Effects 0.000 description 118
239000000243 solution Substances 0.000 description 102
238000001914 filtration Methods 0.000 description 96
238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 93
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 93
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 90
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 82
239000007787 solid Substances 0.000 description 82
ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 78
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 77
239000002904 solvent Substances 0.000 description 74
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 73
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 72
239000007858 starting material Substances 0.000 description 63
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 57
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 54
238000010992 reflux Methods 0.000 description 54
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 52
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 50
229940093499 ethyl acetate Drugs 0.000 description 49
235000019439 ethyl acetate Nutrition 0.000 description 49
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 42
238000000921 elemental analysis Methods 0.000 description 36
239000000047 product Substances 0.000 description 35
125000004356 hydroxy functional group Chemical group O* 0.000 description 31
239000003039 volatile agent Substances 0.000 description 31
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238000004440 column chromatography Methods 0.000 description 29
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235000017557 sodium bicarbonate Nutrition 0.000 description 26
229910000030 sodium bicarbonate Inorganic materials 0.000 description 26
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 24
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HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 23
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239000002244 precipitate Substances 0.000 description 22
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239000003054 catalyst Substances 0.000 description 19
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WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 18
229910000041 hydrogen chloride Inorganic materials 0.000 description 18
239000012265 solid product Substances 0.000 description 17
239000000725 suspension Substances 0.000 description 17
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
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239000012044 organic layer Substances 0.000 description 14
238000011282 treatment Methods 0.000 description 14
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
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JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
239000002585 base Substances 0.000 description 12
229910000027 potassium carbonate Inorganic materials 0.000 description 12
238000003556 assay Methods 0.000 description 11
210000004027 cell Anatomy 0.000 description 11
239000003701 inert diluent Substances 0.000 description 11
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238000012360 testing method Methods 0.000 description 11
DTQVDTLACAAQTR-DYCDLGHISA-N trifluoroacetic acid-d1 Chemical compound [2H]OC(=O)C(F)(F)F DTQVDTLACAAQTR-DYCDLGHISA-N 0.000 description 11
239000005909 Kieselgur Substances 0.000 description 10
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239000010410 layer Substances 0.000 description 10
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AFZLCOLNTRPSIF-UHFFFAOYSA-N 5-amino-2-chloro-4-fluorophenol Chemical compound NC1=CC(O)=C(Cl)C=C1F AFZLCOLNTRPSIF-UHFFFAOYSA-N 0.000 description 9
206010028980 Neoplasm Diseases 0.000 description 9
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239000012298 atmosphere Substances 0.000 description 9
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
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
102000004190 Enzymes Human genes 0.000 description 8
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Classifications

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- 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
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- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- C—CHEMISTRY; METALLURGY
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
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- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms

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IL12568697A 1996-02-13 1997-02-10 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 IL125686A (en)

Applications Claiming Priority (4)

Application Number	Priority Date	Filing Date	Title
EP96400293		1996-02-13
EP96401756		1996-08-08
EP96402764		1996-12-17
PCT/GB1997/000365 WO1997030035A1 (fr)	1996-02-13	1997-02-10	Derives de la quinazoline utilises comme inhibiteurs du vegf

Publications (2)

Publication Number	Publication Date
IL125686A0 IL125686A0 (en)	1999-04-11
IL125686A true IL125686A (en)	2002-11-10

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Application Number	Title	Priority Date	Filing Date
IL12568697A IL125686A (en)	1996-02-13	1997-02-10	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

Country Status (24)

Country	Link
US (1)	US6184225B1 (fr)
EP (1)	EP0880508B1 (fr)
JP (2)	JP4471404B2 (fr)
KR (1)	KR19990082463A (fr)
CN (1)	CN1125817C (fr)
AT (1)	ATE237596T1 (fr)
AU (1)	AU719434B2 (fr)
BR (1)	BR9707495A (fr)
CA (1)	CA2242425C (fr)
CZ (1)	CZ291386B6 (fr)
DE (1)	DE69720965T2 (fr)
DK (1)	DK0880508T3 (fr)
ES (1)	ES2194181T3 (fr)
HU (1)	HUP9901155A3 (fr)
IL (1)	IL125686A (fr)
NO (1)	NO311359B1 (fr)
NZ (1)	NZ330868A (fr)
PL (1)	PL194689B1 (fr)
PT (1)	PT880508E (fr)
SI (1)	SI0880508T1 (fr)
SK (1)	SK285141B6 (fr)
TR (1)	TR199801530T2 (fr)
TW (1)	TW581765B (fr)
WO (1)	WO1997030035A1 (fr)

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1997
- 1997-02-10 ES ES97904512T patent/ES2194181T3/es not_active Expired - Lifetime
- 1997-02-10 EP EP97904512A patent/EP0880508B1/fr not_active Expired - Lifetime
- 1997-02-10 AU AU17290/97A patent/AU719434B2/en not_active Ceased
- 1997-02-10 HU HU9901155A patent/HUP9901155A3/hu unknown
- 1997-02-10 IL IL12568697A patent/IL125686A/en not_active IP Right Cessation
- 1997-02-10 BR BR9707495A patent/BR9707495A/pt not_active Application Discontinuation
- 1997-02-10 CN CN97192221A patent/CN1125817C/zh not_active Expired - Fee Related
- 1997-02-10 SI SI9730539T patent/SI0880508T1/xx unknown
- 1997-02-10 AT AT97904512T patent/ATE237596T1/de active
- 1997-02-10 CZ CZ19982535A patent/CZ291386B6/cs not_active IP Right Cessation
- 1997-02-10 PT PT97904512T patent/PT880508E/pt unknown
- 1997-02-10 JP JP52907897A patent/JP4471404B2/ja not_active Expired - Lifetime
- 1997-02-10 KR KR1019980706196A patent/KR19990082463A/ko not_active Ceased
- 1997-02-10 DE DE69720965T patent/DE69720965T2/de not_active Expired - Lifetime
- 1997-02-10 CA CA002242425A patent/CA2242425C/fr not_active Expired - Fee Related
- 1997-02-10 DK DK97904512T patent/DK0880508T3/da active
- 1997-02-10 PL PL97328310A patent/PL194689B1/pl not_active IP Right Cessation
- 1997-02-10 WO PCT/GB1997/000365 patent/WO1997030035A1/fr not_active Ceased
- 1997-02-10 SK SK1087-98A patent/SK285141B6/sk not_active IP Right Cessation
- 1997-02-10 NZ NZ330868A patent/NZ330868A/xx not_active IP Right Cessation
- 1997-02-10 US US09/125,271 patent/US6184225B1/en not_active Expired - Lifetime
- 1997-02-10 TR TR1998/01530T patent/TR199801530T2/xx unknown
- 1997-02-12 TW TW086101670A patent/TW581765B/zh not_active IP Right Cessation
1998
- 1998-08-12 NO NO19983687A patent/NO311359B1/no not_active IP Right Cessation
2008
- 2008-09-11 JP JP2008234068A patent/JP2009013181A/ja not_active Withdrawn

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Publication number	Publication date
WO1997030035A1 (fr)	1997-08-21
CN1125817C (zh)	2003-10-29
IL125686A0 (en)	1999-04-11
NO311359B1 (no)	2001-11-19
KR19990082463A (ko)	1999-11-25
JP2000504714A (ja)	2000-04-18
SK108798A3 (en)	1999-01-11
BR9707495A (pt)	1999-07-27
SI0880508T1 (en)	2003-10-31
US6184225B1 (en)	2001-02-06
HUP9901155A2 (hu)	1999-07-28
SK285141B6 (sk)	2006-07-07
DK0880508T3 (da)	2003-06-30
ATE237596T1 (de)	2003-05-15
EP0880508A1 (fr)	1998-12-02
DE69720965D1 (de)	2003-05-22
NZ330868A (en)	2000-01-28
HUP9901155A3 (en)	2003-04-28
CN1211239A (zh)	1999-03-17
TR199801530T2 (xx)	1998-11-23
AU719434B2 (en)	2000-05-11
NO983687L (no)	1998-08-13
AU1729097A (en)	1997-09-02
HK1016607A1 (en)	1999-11-05
PL328310A1 (en)	1999-01-18
NO983687D0 (no)	1998-08-12
ES2194181T3 (es)	2003-11-16
JP2009013181A (ja)	2009-01-22
JP4471404B2 (ja)	2010-06-02
PL194689B1 (pl)	2007-06-29
PT880508E (pt)	2003-07-31
DE69720965T2 (de)	2004-02-05
CZ253598A3 (cs)	1998-11-11
CA2242425C (fr)	2006-07-18
TW581765B (en)	2004-04-01
CA2242425A1 (fr)	1997-08-21
CZ291386B6 (cs)	2003-02-12
EP0880508B1 (fr)	2003-04-16

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EP0880508B1 (fr)	2003-04-16	Derives de la quinazoline utilises comme inhibiteurs du vegf
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KR100567649B1 (ko)	2006-04-05	혈관 내피 성장 인자와 같은 성장 인자의 효과를 억제하는 퀴놀린 유도체
AU729968B2 (en)	2001-02-15	Quinazoline derivatives and pharmaceutical compositions containing them
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