PL194689B1 - Pochodne chinazoliny, ich kompozycje farmaceutyczne oraz ich zastosowania - Google Patents

Info

Publication number

PL194689B1

PL194689B1 PL97328310A PL32831097A PL194689B1 PL 194689 B1 PL194689 B1 PL 194689B1 PL 97328310 A PL97328310 A PL 97328310A PL 32831097 A PL32831097 A PL 32831097A PL 194689 B1 PL194689 B1 PL 194689B1

Authority

PL

Poland

Prior art keywords

fluoro

quinazoline

methoxy

group

mmol

Prior art date

1996-02-13

Links

• Espacenet
• Global Dossier
• Discuss

• 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title description 7
• -1 morpholino, piperazin-1-yl Chemical group 0.000 claims abstract description 124
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 38
• 239000001257 hydrogen Substances 0.000 claims abstract description 38
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 23
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 18
• 150000003246 quinazolines Chemical class 0.000 claims abstract description 18
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
• 125000001424 substituent group Chemical group 0.000 claims abstract description 11
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract description 7
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims abstract description 7
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims abstract description 6
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 3
• 150000001875 compounds Chemical class 0.000 claims description 141
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 106
• 150000003839 salts Chemical class 0.000 claims description 72
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 26
• 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 26
• 238000011282 treatment Methods 0.000 claims description 20
• JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 17
• 239000003814 drug Substances 0.000 claims description 14
• 241001465754 Metazoa Species 0.000 claims description 12
• 206010028980 Neoplasm Diseases 0.000 claims description 12
• 150000002431 hydrogen Chemical class 0.000 claims description 12
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
• 238000004519 manufacturing process Methods 0.000 claims description 8
• 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 7
• 201000011510 cancer Diseases 0.000 claims description 7
• 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 6
• 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 6
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
• 230000035755 proliferation Effects 0.000 claims description 6
• 239000011734 sodium Substances 0.000 claims description 6
• 229910052708 sodium Inorganic materials 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
• 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 5
• 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 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
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
• 201000004681 Psoriasis Diseases 0.000 claims description 5
• 239000000460 chlorine Substances 0.000 claims description 5
• 229910052731 fluorine Inorganic materials 0.000 claims description 5
• 239000011737 fluorine Substances 0.000 claims description 5
• 230000002792 vascular Effects 0.000 claims description 5
• 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 4
• 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 4
• 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 4
• 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 4
• 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 4
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
• 239000004480 active ingredient Substances 0.000 claims description 4
• 229910052801 chlorine Inorganic materials 0.000 claims description 4
• 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 4
• 206010039073 rheumatoid arthritis Diseases 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
• 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 description 3
• 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 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
• 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
• 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 3
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
• 208000030533 eye disease Diseases 0.000 claims description 3
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 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 2
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
• 229910052794 bromium Inorganic materials 0.000 claims description 2
• 239000003937 drug carrier Substances 0.000 claims description 2
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 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
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
• 230000002207 retinal effect Effects 0.000 claims description 2
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
• 241001112258 Moca Species 0.000 claims 1
• 241000286209 Phasianidae Species 0.000 claims 1
• 241000220317 Rosa Species 0.000 claims 1
• 125000001475 halogen functional group Chemical group 0.000 claims 1
• 125000005843 halogen group Chemical group 0.000 abstract description 8
• 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 8
• 125000000623 heterocyclic group Chemical group 0.000 abstract description 3
• 125000005505 thiomorpholino group Chemical group 0.000 abstract description 3
• 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 abstract description 2
• 125000006274 (C1-C3)alkoxy 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
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 267
• 239000000203 mixture Substances 0.000 description 204
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 183
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 141
• 239000000243 solution Substances 0.000 description 110
• 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 99
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• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 82
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 79
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 77
• 239000002904 solvent Substances 0.000 description 72
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• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 64
• 239000007858 starting material Substances 0.000 description 62
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