NO311359B1 - Kinazolin-derivater som VEGF-inhibitorer, farmasöytisk preparat, anvendelse og fremgangsmåte for fremstilling derav - Google Patents
Kinazolin-derivater som VEGF-inhibitorer, farmasöytisk preparat, anvendelse og fremgangsmåte for fremstilling derav Download PDFInfo
- Publication number
- NO311359B1 NO311359B1 NO19983687A NO983687A NO311359B1 NO 311359 B1 NO311359 B1 NO 311359B1 NO 19983687 A NO19983687 A NO 19983687A NO 983687 A NO983687 A NO 983687A NO 311359 B1 NO311359 B1 NO 311359B1
- Authority
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- Norway
- Prior art keywords
- formula
- quinazoline
- hydroxy
- fluoro
- methoxy
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title claims abstract description 7
- 239000000825 pharmaceutical preparation Substances 0.000 title claims description 5
- 239000002525 vasculotropin inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 173
- -1 trifluorometlyl Chemical group 0.000 claims abstract description 130
- 150000003839 salts Chemical class 0.000 claims abstract description 83
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 49
- 239000001257 hydrogen Substances 0.000 claims abstract description 49
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 36
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 26
- 230000000694 effects Effects 0.000 claims abstract description 25
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 19
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 9
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract description 7
- 239000004480 active ingredient Substances 0.000 claims abstract description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 5
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 4
- 230000008569 process Effects 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 35
- 150000003246 quinazolines Chemical class 0.000 claims description 30
- 125000001424 substituent group Chemical group 0.000 claims description 27
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 150000002367 halogens Chemical class 0.000 claims description 23
- 125000003545 alkoxy group Chemical group 0.000 claims description 17
- 125000004043 oxo group Chemical group O=* 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 11
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 10
- 238000010511 deprotection reaction Methods 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- 241001465754 Metazoa Species 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 230000009467 reduction Effects 0.000 claims description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 6
- 230000001772 anti-angiogenic effect Effects 0.000 claims description 6
- 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 description 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 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
- 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 4
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 4
- 230000002137 anti-vascular effect Effects 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000004193 piperazinyl group Chemical group 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 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 3
- PKPDNFNJEGKHGS-UHFFFAOYSA-N 2-chloro-4-fluoro-5-[[6-methoxy-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinazolin-4-yl]amino]phenol Chemical compound N1=CN=C2C=C(OCCN3CCN(C)CC3)C(OC)=CC2=C1NC1=CC(O)=C(Cl)C=C1F PKPDNFNJEGKHGS-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
- 239000000654 additive Substances 0.000 claims description 3
- 229940100198 alkylating agent Drugs 0.000 claims description 3
- 239000002168 alkylating agent Substances 0.000 claims description 3
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 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 2
- 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 2
- 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 2
- 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 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
- 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 claims description 2
- 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 claims description 2
- 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 2
- 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 2
- 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 2
- 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 2
- KXAGMEUPTWULJN-UHFFFAOYSA-N 4-fluoro-5-[[7-(2-methoxyethylamino)quinazolin-4-yl]amino]-2-methylphenol Chemical compound N=1C=NC2=CC(NCCOC)=CC=C2C=1NC1=CC(O)=C(C)C=C1F KXAGMEUPTWULJN-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
- 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 2
- 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 2
- 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 claims description 2
- 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 claims description 2
- 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 claims description 2
- 101000983970 Conus catus Alpha-conotoxin CIB Proteins 0.000 claims description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 230000000996 additive effect Effects 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 230000007717 exclusion Effects 0.000 claims description 2
- QJQYPZZUKLQGGT-UHFFFAOYSA-N methyl hypobromite Chemical compound COBr QJQYPZZUKLQGGT-UHFFFAOYSA-N 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
- WDTZDAYILMUQLA-UHFFFAOYSA-N n-(4-bromo-2,6-difluorophenyl)-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCCCN3CCOCC3)C(OC)=CC2=C1NC1=C(F)C=C(Br)C=C1F WDTZDAYILMUQLA-UHFFFAOYSA-N 0.000 claims description 2
- NWEVEWXSLYZWJA-UHFFFAOYSA-N n-[4-(2-fluoro-5-hydroxy-4-methylanilino)quinazolin-7-yl]-2-methoxyacetamide Chemical compound N=1C=NC2=CC(NC(=O)COC)=CC=C2C=1NC1=CC(O)=C(C)C=C1F NWEVEWXSLYZWJA-UHFFFAOYSA-N 0.000 claims description 2
- 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 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
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 2
- 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 1
- PDFCFEZKAPFQOW-UHFFFAOYSA-N 2-chloro-4-fluoro-5-[[6-methoxy-7-(2-thiomorpholin-4-ylethoxy)quinazolin-4-yl]amino]phenol Chemical compound N1=CN=C2C=C(OCCN3CCSCC3)C(OC)=CC2=C1NC1=CC(O)=C(Cl)C=C1F PDFCFEZKAPFQOW-UHFFFAOYSA-N 0.000 claims 1
- ICSJRTHEPBTIHO-UHFFFAOYSA-N 2-chloro-4-fluoro-5-[[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]amino]phenol Chemical compound N1=CN=C2C=C(OCCCN3CCOCC3)C(OC)=CC2=C1NC1=CC(O)=C(Cl)C=C1F ICSJRTHEPBTIHO-UHFFFAOYSA-N 0.000 claims 1
- 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 1
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Classifications
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- C07—ORGANIC CHEMISTRY
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- 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
- C07D239/88—Oxygen atoms
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- 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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- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
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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
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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
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EP96400293 | 1996-02-13 | ||
EP96401756 | 1996-08-08 | ||
EP96402764 | 1996-12-17 | ||
PCT/GB1997/000365 WO1997030035A1 (en) | 1996-02-13 | 1997-02-10 | Quinazoline derivatives as vegf inhibitors |
Publications (3)
Publication Number | Publication Date |
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NO983687D0 NO983687D0 (no) | 1998-08-12 |
NO983687L NO983687L (no) | 1998-08-13 |
NO311359B1 true NO311359B1 (no) | 2001-11-19 |
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NO19983687A NO311359B1 (no) | 1996-02-13 | 1998-08-12 | Kinazolin-derivater som VEGF-inhibitorer, farmasöytisk preparat, anvendelse og fremgangsmåte for fremstilling derav |
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US (1) | US6184225B1 (xx) |
EP (1) | EP0880508B1 (xx) |
JP (2) | JP4471404B2 (xx) |
KR (1) | KR19990082463A (xx) |
CN (1) | CN1125817C (xx) |
AT (1) | ATE237596T1 (xx) |
AU (1) | AU719434B2 (xx) |
BR (1) | BR9707495A (xx) |
CA (1) | CA2242425C (xx) |
CZ (1) | CZ291386B6 (xx) |
DE (1) | DE69720965T2 (xx) |
DK (1) | DK0880508T3 (xx) |
ES (1) | ES2194181T3 (xx) |
HK (1) | HK1016607A1 (xx) |
HU (1) | HUP9901155A3 (xx) |
IL (1) | IL125686A (xx) |
NO (1) | NO311359B1 (xx) |
NZ (1) | NZ330868A (xx) |
PL (1) | PL194689B1 (xx) |
PT (1) | PT880508E (xx) |
SI (1) | SI0880508T1 (xx) |
SK (1) | SK285141B6 (xx) |
TR (1) | TR199801530T2 (xx) |
TW (1) | TW581765B (xx) |
WO (1) | WO1997030035A1 (xx) |
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