RU96106055A - HINAZOLINE DERIVATIVES, METHOD FOR THEIR PRODUCTION, TREATMENT METHOD AND PHARMACEUTICAL COMPOSITION - Google Patents
HINAZOLINE DERIVATIVES, METHOD FOR THEIR PRODUCTION, TREATMENT METHOD AND PHARMACEUTICAL COMPOSITIONInfo
- Publication number
- RU96106055A RU96106055A RU96106055/04A RU96106055A RU96106055A RU 96106055 A RU96106055 A RU 96106055A RU 96106055/04 A RU96106055/04 A RU 96106055/04A RU 96106055 A RU96106055 A RU 96106055A RU 96106055 A RU96106055 A RU 96106055A
- Authority
- RU
- Russia
- Prior art keywords
- amine
- quinazolin
- phenyl
- alkyl
- ethynylphenyl
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims 2
- -1 hydroxy, amino, hydroxyamino, carboxy Chemical group 0.000 claims 53
- 229910052739 hydrogen Inorganic materials 0.000 claims 24
- 239000001257 hydrogen Substances 0.000 claims 24
- 229910052736 halogen Inorganic materials 0.000 claims 22
- 125000005843 halogen group Chemical group 0.000 claims 21
- 150000001875 compounds Chemical class 0.000 claims 20
- 150000002431 hydrogen Chemical class 0.000 claims 17
- 125000000217 alkyl group Chemical group 0.000 claims 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 15
- 125000004432 carbon atoms Chemical group C* 0.000 claims 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 12
- 229910052717 sulfur Inorganic materials 0.000 claims 10
- ASQUQUOEFDHYGP-UHFFFAOYSA-N 2-methoxyethanolate Chemical group COCC[O-] ASQUQUOEFDHYGP-UHFFFAOYSA-N 0.000 claims 8
- 150000004820 halides Chemical class 0.000 claims 8
- 125000005842 heteroatoms Chemical group 0.000 claims 8
- 229910052757 nitrogen Chemical group 0.000 claims 8
- 229910052760 oxygen Inorganic materials 0.000 claims 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 7
- 125000000033 alkoxyamino group Chemical group 0.000 claims 6
- 125000003282 alkyl amino group Chemical group 0.000 claims 6
- 125000004122 cyclic group Chemical group 0.000 claims 6
- 201000010099 disease Diseases 0.000 claims 6
- 150000002367 halogens Chemical class 0.000 claims 6
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 6
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical group O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims 6
- 239000001301 oxygen Substances 0.000 claims 6
- 125000001424 substituent group Chemical group 0.000 claims 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 6
- 239000011593 sulfur Chemical group 0.000 claims 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 5
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 4
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims 4
- 229910052799 carbon Inorganic materials 0.000 claims 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims 4
- 230000003463 hyperproliferative Effects 0.000 claims 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims 4
- 229920000642 polymer Polymers 0.000 claims 4
- 125000003118 aryl group Chemical group 0.000 claims 3
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 3
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 3
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene Chemical group C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 claims 2
- MTLKTHNRZJKPRP-UHFFFAOYSA-N 2-[4-(3-ethynylanilino)-6-(2-methoxyethoxy)quinazolin-7-yl]oxyethanol Chemical compound N1=CN=C2C=C(OCCO)C(OCCOC)=CC2=C1NC1=CC=CC(C#C)=C1 MTLKTHNRZJKPRP-UHFFFAOYSA-N 0.000 claims 2
- YWSAEKIQJPQSDJ-UHFFFAOYSA-N 2-[4-(3-ethynylanilino)-7-(2-hydroxyethoxy)quinazolin-6-yl]oxyethanol Chemical compound C=12C=C(OCCO)C(OCCO)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 YWSAEKIQJPQSDJ-UHFFFAOYSA-N 0.000 claims 2
- DUGLQQONGNNEMW-UHFFFAOYSA-N 2-[4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl]acetamide Chemical compound C=12C=C(CC(N)=O)C(OC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 DUGLQQONGNNEMW-UHFFFAOYSA-N 0.000 claims 2
- JLSORGGMGRVXKF-UHFFFAOYSA-N 2-[[1-(3-ethynylanilino)-7-(2-methoxyethoxy)-2H-quinazolin-6-yl]oxy]ethanol Chemical compound C1N=CC=2C=C(OCCO)C(OCCOC)=CC=2N1NC1=CC=CC(C#C)=C1 JLSORGGMGRVXKF-UHFFFAOYSA-N 0.000 claims 2
- AZMJCKIZWVLDEH-UHFFFAOYSA-N 6,7-diethoxy-N-(3-ethynylphenyl)-2H-quinazolin-1-amine Chemical compound C1=2C=C(OCC)C(OCC)=CC=2C=NCN1NC1=CC=CC(C#C)=C1 AZMJCKIZWVLDEH-UHFFFAOYSA-N 0.000 claims 2
- VAGMISGAVFFXMY-UHFFFAOYSA-N 6-(aminomethyl)-N-(3-ethynylphenyl)-7-methoxyquinazolin-4-amine Chemical compound C=12C=C(CN)C(OC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 VAGMISGAVFFXMY-UHFFFAOYSA-N 0.000 claims 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N Carbon tetrachloride Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims 2
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 2
- 201000011510 cancer Diseases 0.000 claims 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 2
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims 2
- 150000002829 nitrogen Chemical class 0.000 claims 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N oxygen atom Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims 2
- 125000004434 sulfur atoms Chemical group 0.000 claims 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 2
- BDGHRVPXZUKXIP-UHFFFAOYSA-N 1-N-(3-ethynylphenyl)-2H-quinazoline-1,6-diamine Chemical compound C1N=CC2=CC(N)=CC=C2N1NC1=CC=CC(C#C)=C1 BDGHRVPXZUKXIP-UHFFFAOYSA-N 0.000 claims 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims 1
- KOQIAZNBAWFSQM-UHFFFAOYSA-N 2-[4-(3-ethynylanilino)-7-(2-methoxyethoxy)quinazolin-6-yl]oxyethanol Chemical compound C=12C=C(OCCO)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 KOQIAZNBAWFSQM-UHFFFAOYSA-N 0.000 claims 1
- TYRDQXAAPHCGHJ-UHFFFAOYSA-N 2-[4-(3-ethynylanilino)-7-propoxyquinazolin-6-yl]acetamide Chemical compound C=12C=C(CC(N)=O)C(OCCC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 TYRDQXAAPHCGHJ-UHFFFAOYSA-N 0.000 claims 1
- RPBDPTCBOMUIEM-UHFFFAOYSA-N 2-[4-(3-ethynylanilino)quinazolin-6-yl]guanidine Chemical compound C12=CC(NC(=N)N)=CC=C2N=CN=C1NC1=CC=CC(C#C)=C1 RPBDPTCBOMUIEM-UHFFFAOYSA-N 0.000 claims 1
- OLQYOMSHERWQMA-UHFFFAOYSA-N 2-[7-ethoxy-4-(3-ethynylanilino)quinazolin-6-yl]acetamide Chemical compound C=12C=C(CC(N)=O)C(OCC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 OLQYOMSHERWQMA-UHFFFAOYSA-N 0.000 claims 1
- BLEIGNISAJGLGG-UHFFFAOYSA-N 2-[[1-(3-ethynylanilino)-7-(2-hydroxyethoxy)-2H-quinazolin-6-yl]oxy]ethanol Chemical compound C1=2C=C(OCCO)C(OCCO)=CC=2C=NCN1NC1=CC=CC(C#C)=C1 BLEIGNISAJGLGG-UHFFFAOYSA-N 0.000 claims 1
- 125000006012 2-chloroethoxy group Chemical group 0.000 claims 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims 1
- XCMVOGXJGDEPQM-UHFFFAOYSA-N 3-[4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl]propanamide Chemical compound C=12C=C(CCC(N)=O)C(OC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 XCMVOGXJGDEPQM-UHFFFAOYSA-N 0.000 claims 1
- HZDFRVLTROVMEI-UHFFFAOYSA-N 3-[4-(3-ethynylanilino)-7-propan-2-yloxyquinazolin-6-yl]propanamide Chemical compound C=12C=C(CCC(N)=O)C(OC(C)C)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 HZDFRVLTROVMEI-UHFFFAOYSA-N 0.000 claims 1
- OIESHIYYNQZRCL-UHFFFAOYSA-N 3-[4-(3-ethynylanilino)-7-propoxyquinazolin-6-yl]propanamide Chemical compound C=12C=C(CCC(N)=O)C(OCCC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 OIESHIYYNQZRCL-UHFFFAOYSA-N 0.000 claims 1
- JIKUZGKMYUACPU-UHFFFAOYSA-N 3-[7-ethoxy-4-(3-ethynylanilino)quinazolin-6-yl]propanamide Chemical compound C=12C=C(CCC(N)=O)C(OCC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 JIKUZGKMYUACPU-UHFFFAOYSA-N 0.000 claims 1
- NRKMCAKKJSZIRN-UHFFFAOYSA-N 4-N-(3-ethynylphenyl)quinazoline-4,6-diamine Chemical compound C12=CC(N)=CC=C2N=CN=C1NC1=CC=CC(C#C)=C1 NRKMCAKKJSZIRN-UHFFFAOYSA-N 0.000 claims 1
- MLFVZJQGCZIVJI-UHFFFAOYSA-N 4-N-(3-ethynylphenyl)quinazoline-4,7-diamine Chemical compound N=1C=NC2=CC(N)=CC=C2C=1NC1=CC=CC(C#C)=C1 MLFVZJQGCZIVJI-UHFFFAOYSA-N 0.000 claims 1
- KNIMCHSAQRHRKH-UHFFFAOYSA-N 6,7-dibutoxy-N-(3-ethynylphenyl)-2H-quinazolin-1-amine Chemical compound C1=2C=C(OCCCC)C(OCCCC)=CC=2C=NCN1NC1=CC=CC(C#C)=C1 KNIMCHSAQRHRKH-UHFFFAOYSA-N 0.000 claims 1
- DBLVDARHJKFUSK-UHFFFAOYSA-N 6-(2-chloroethoxy)-N-(3-ethynylphenyl)-7-(2-methoxyethoxy)quinazolin-4-amine Chemical compound C=12C=C(OCCCl)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 DBLVDARHJKFUSK-UHFFFAOYSA-N 0.000 claims 1
- BIHHIONDWPZXJC-UHFFFAOYSA-N 7-(2-chloroethoxy)-N-(3-ethynylphenyl)-6-(2-methoxyethoxy)quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCCCl)C(OCCOC)=CC2=C1NC1=CC=CC(C#C)=C1 BIHHIONDWPZXJC-UHFFFAOYSA-N 0.000 claims 1
- 210000004556 Brain Anatomy 0.000 claims 1
- 210000000481 Breast Anatomy 0.000 claims 1
- NDBICEMWAFJQRX-UHFFFAOYSA-N C(C)S(=O)(=O)C=1C=C2C(=NC=NC2=CC=1)NC1=CC(=CC=C1)C#C Chemical compound C(C)S(=O)(=O)C=1C=C2C(=NC=NC2=CC=1)NC1=CC(=CC=C1)C#C NDBICEMWAFJQRX-UHFFFAOYSA-N 0.000 claims 1
- 229940116441 DIVINYLBENZENE Drugs 0.000 claims 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N Erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 claims 1
- 210000003128 Head Anatomy 0.000 claims 1
- 206010020718 Hyperplasia Diseases 0.000 claims 1
- 241000229754 Iva xanthiifolia Species 0.000 claims 1
- 210000004072 Lung Anatomy 0.000 claims 1
- 241000124008 Mammalia Species 0.000 claims 1
- FKTOOVAYMNBBOM-UHFFFAOYSA-N N-(3-ethynylphenyl)-6,7-di(propan-2-yloxy)-2H-quinazolin-1-amine Chemical compound C1=2C=C(OC(C)C)C(OC(C)C)=CC=2C=NCN1NC1=CC=CC(C#C)=C1 FKTOOVAYMNBBOM-UHFFFAOYSA-N 0.000 claims 1
- YHGQPRLZLURJKG-UHFFFAOYSA-N N-(3-ethynylphenyl)-6,7-dimethoxy-2H-quinazolin-1-amine Chemical compound C1=2C=C(OC)C(OC)=CC=2C=NCN1NC1=CC=CC(C#C)=C1 YHGQPRLZLURJKG-UHFFFAOYSA-N 0.000 claims 1
- XOTGKYTUNDYTBS-UHFFFAOYSA-N N-(3-ethynylphenyl)-6,7-dimethoxyquinazolin-4-amine Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 XOTGKYTUNDYTBS-UHFFFAOYSA-N 0.000 claims 1
- OHTXAZFSJVRZLD-UHFFFAOYSA-N N-(3-ethynylphenyl)-6-(2-methoxyethoxy)-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCCN3CCN(C)CC3)C(OCCOC)=CC2=C1NC1=CC=CC(C#C)=C1 OHTXAZFSJVRZLD-UHFFFAOYSA-N 0.000 claims 1
- XNMSCKOLUZHGET-UHFFFAOYSA-N N-(3-ethynylphenyl)-6-methylsulfonylquinazolin-4-amine Chemical compound C12=CC(S(=O)(=O)C)=CC=C2N=CN=C1NC1=CC=CC(C#C)=C1 XNMSCKOLUZHGET-UHFFFAOYSA-N 0.000 claims 1
- DOAMPDMHUHJVAU-UHFFFAOYSA-N N-(3-ethynylphenyl)-6-nitroquinazolin-4-amine Chemical compound C12=CC([N+](=O)[O-])=CC=C2N=CN=C1NC1=CC=CC(C#C)=C1 DOAMPDMHUHJVAU-UHFFFAOYSA-N 0.000 claims 1
- AWQMPORAKHHXOC-UHFFFAOYSA-N N-(3-ethynylphenyl)-7-methoxyquinazolin-4-amine Chemical compound N=1C=NC2=CC(OC)=CC=C2C=1NC1=CC=CC(C#C)=C1 AWQMPORAKHHXOC-UHFFFAOYSA-N 0.000 claims 1
- PXVOMAUMUFQFKF-UHFFFAOYSA-N N-(3-ethynylphenyl)-7-nitroquinazolin-4-amine Chemical compound N=1C=NC2=CC([N+](=O)[O-])=CC=C2C=1NC1=CC=CC(C#C)=C1 PXVOMAUMUFQFKF-UHFFFAOYSA-N 0.000 claims 1
- LBAXXGJEHLZEQP-UHFFFAOYSA-N N-(3-ethynylphenyl)-[1,3]dioxolo[4,5-g]quinazolin-8-amine Chemical compound C#CC1=CC=CC(NC=2C3=CC=4OCOC=4C=C3N=CN=2)=C1 LBAXXGJEHLZEQP-UHFFFAOYSA-N 0.000 claims 1
- OVBFNQKSLJYVCB-UHFFFAOYSA-N N-(4-ethynylphenyl)-6,7-dimethoxyquinazolin-4-amine Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC=C(C#C)C=C1 OVBFNQKSLJYVCB-UHFFFAOYSA-N 0.000 claims 1
- UWWQPGAHDVXTLK-UHFFFAOYSA-N N-[1-(3-ethynylanilino)-2H-quinazolin-6-yl]methanesulfonamide Chemical compound C1N=CC2=CC(NS(=O)(=O)C)=CC=C2N1NC1=CC=CC(C#C)=C1 UWWQPGAHDVXTLK-UHFFFAOYSA-N 0.000 claims 1
- NPWROGXMBGWEJT-UHFFFAOYSA-N N-[4-(3-ethynylanilino)quinazolin-6-yl]methanesulfonamide Chemical compound C12=CC(NS(=O)(=O)C)=CC=C2N=CN=C1NC1=CC=CC(C#C)=C1 NPWROGXMBGWEJT-UHFFFAOYSA-N 0.000 claims 1
- 210000003739 Neck Anatomy 0.000 claims 1
- 210000000496 Pancreas Anatomy 0.000 claims 1
- 210000002307 Prostate Anatomy 0.000 claims 1
- 210000003491 Skin Anatomy 0.000 claims 1
- 210000002784 Stomach Anatomy 0.000 claims 1
- 210000003932 Urinary Bladder Anatomy 0.000 claims 1
- 150000001345 alkine derivatives Chemical class 0.000 claims 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- 210000004027 cells Anatomy 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- MJGHBVDYEIMCDA-UHFFFAOYSA-N methyl 4-(3-ethynylanilino)quinazoline-6-carboxylate Chemical compound C12=CC(C(=O)OC)=CC=C2N=CN=C1NC1=CC=CC(C#C)=C1 MJGHBVDYEIMCDA-UHFFFAOYSA-N 0.000 claims 1
- SRGSZEVWWPMFLC-UHFFFAOYSA-N methyl 4-(3-ethynylanilino)quinazoline-7-carboxylate Chemical compound N=1C=NC2=CC(C(=O)OC)=CC=C2C=1NC1=CC=CC(C#C)=C1 SRGSZEVWWPMFLC-UHFFFAOYSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 239000000651 prodrug Substances 0.000 claims 1
- 229940002612 prodrugs Drugs 0.000 claims 1
- 125000004546 quinazolin-4-yl group Chemical group N1=CN=C(C2=CC=CC=C12)* 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 239000011780 sodium chloride Substances 0.000 claims 1
- 201000002510 thyroid cancer Diseases 0.000 claims 1
Claims (24)
и его фармацевтические приемлемые соли и пролекарства, где
m представляет 1, 2 или 3;
каждый R1 независимо выбран из водорода, галоида, гидрокси, амино, гидроксиамино, карбокси, (1-4)C-алкоксикарбонила, нитро, гуанидино, уреидо, карбамоила, циано, трифторметила, (R6)2N-карбонила, и фенил-W-алкила, в котором W выбран из одинарной связи, O, S и NH;
или каждый R1 независимо выбран из циано-(1-4)С-алкила и R9, где R9 выбран из группы, состоящей из R5, R5O, (R6)2N, R7C(=O), R5ONH, A и R5Y; где R5 представляет (1-4)С-алкил; R6 представляет водород или R5, где символы R5 являются одинаковыми или различными; R7 представляет R5, R5O или (R6)2N; A выбран из пиперидино, морфолино, пирролидино и 4-R6-пиперазин-1-ила, имидазол-1-ила, 4-пиридон-1-ила, карбокси-(1-4)С-алкила, фенокси, фенила, фенилсульфанила, (2-4)С-алкенила, (R6)2N-карбонил-(1-4)С-алкила; и Y выбран из S, SO, SO2; алкильные фрагменты в (R6)2N являются необязательно замещенными галоидом или R9, где R9 имеет значения, определенные выше, а алкильные фрагменты в R5 и R5O являются необязательно замещенными галоидом, R6О или R9, где R6 и R9 имеют значения, определенные выше, и где получающиеся в результате группы являются необязательно замещенными галоидом или R9, при условии, что атом азота, кислорода или серы и еще один гетероатом не могут быть присоединены к одному и тому же атому углерода и при дальнейшем условии, что не более чем три "R9" звена могут составлять R1;
или каждый R1 независимо выбран из R5-сульфониламино, фталимидо-(1-4)С-алкилсульфониламино, бензамидо, бензолсульфониламино, 3-фенилуреидо, 2-оксопирролидин-1-ила, 2,5-диоксопирролидин-1-ила и R10-(2-4)C-алканоиламино, где R10 выбран из галоида, R6О, (2-4)C-алканоилокси, R7C(=О), и (R6)2N; и где указанные бензамидо, или бензолсульфониламино, или фенильный, или фенокси, или анилино, или фенилсульфанильный заместитель в R1 могут необязательно нести один или два галогена, (1-4)С-алкильных, циано, метансульфонильных или (1-4)С-алкокси заместителя;
или любые два радикала R1, взятые вместе с углеродами, к которым они присоединены, образуют 5-8-членное кольцо, включающее по крайней мере один или два гетероатома, выбранных из кислорода, серы или азота, и где алкильные группы и алкильные части алкокси или алкиламиногрупп могут быть с прямой цепью, или если они составлены из по крайней мере трех атомов углерода, могут быть разветвленными или циклическими;
R2 выбран из водорода и необязательно замещенного (1-6)С-алкила;
n представляет 1 или 2 и каждый R3 независимо выбран из водорода, необязательно замещенного (1-6)С-алкила, необязательно замещенного амино, галоида, гидрокси, необязательно замещенного гидрокси;
R4 представляет азидо или R11-этинил, где R11 выбран из водорода, необязательно замещенного (1-6)С-алкила, где заместители выбраны из водорода, амино, гидрокси, R5O, R5NH и (R5)2N.1. The compound of formula I
and its pharmaceutical acceptable salts and prodrugs, where
m is 1, 2 or 3;
each R 1 is independently selected from hydrogen, halo, hydroxy, amino, hydroxyamino, carboxy, (1-4) C-alkoxycarbonyl, nitro, guanidino, ureido, carbamoyl, cyano, trifluoromethyl, (R 6 ) 2 N-carbonyl, and phenyl -W-alkyl, in which W is selected from a single bond, O, S and NH;
or each R 1 is independently selected from cyano (1-4) C-alkyl and R 9 , where R 9 is selected from the group consisting of R 5 , R 5 O, (R 6 ) 2 N, R 7 C (= O ), R 5 ONH, A and R 5 Y; where R 5 is (1-4) C-alkyl; R 6 is hydrogen or R 5 , where the symbols R 5 are the same or different; R 7 is R 5 , R 5 O or (R 6 ) 2 N; A is selected from piperidino, morpholino, pyrrolidino and 4-R 6 -piperazin-1-yl, imidazol-1-yl, 4-pyridon-1-yl, carboxy- (1-4) C-alkyl, phenoxy, phenyl, phenylsulfanyl , (2-4) C-alkenyl, (R 6 ) 2 N-carbonyl- (1-4) C-alkyl; and Y is selected from S, SO, SO 2 ; the alkyl moieties in (R 6 ) 2 N are optionally substituted with halogen or R 9 , where R 9 is as defined above, and the alkyl moieties in R 5 and R 5 O are optionally substituted with halogen, R 6 O or R 9 , where R 6 and R 9 are as defined above, and where the resulting groups are optionally substituted with halogen or R 9 , provided that the nitrogen, oxygen or sulfur atom and another heteroatom cannot be attached to the same carbon atom and with the further proviso that no more than three "R 9" units may composition ive R 1;
or each R 1 is independently selected from R 5 -sulfonylamino, phthalimido- (1-4) C-alkylsulfonylamino, benzamido, benzenesulfonylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl and R 10 - (2-4) C-alkanoylamino, where R 10 is selected from halogen, R 6 O, (2-4) C-alkanoyloxy, R 7 C (= O), and (R 6 ) 2 N; and where said benzamido, or benzenesulfonylamino, or phenyl, or phenoxy, or anilino, or phenylsulfanyl substituent in R 1 may optionally bear one or two halogen, (1-4) C-alkyl, cyano, methanesulfonyl, or (1-4) C alkoxy substituent;
or any two radicals R 1 taken together with the carbon to which they are attached form a 5–8 membered ring containing at least one or two heteroatoms selected from oxygen, sulfur or nitrogen, and where the alkyl groups and alkyl parts are alkoxy or alkylamino groups may be straight chain, or if they are composed of at least three carbon atoms, they may be branched or cyclic;
R 2 is selected from hydrogen and optionally substituted (1-6) C-alkyl;
n is 1 or 2 and each R 3 is independently selected from hydrogen, optionally substituted (1-6) C-alkyl, optionally substituted amino, halo, hydroxy, optionally substituted hydroxy;
R 4 is azido or R 11 -ethynyl, where R 11 is selected from hydrogen, optionally substituted (1-6) C-alkyl, where the substituents are selected from hydrogen, amino, hydroxy, R 5 O, R 5 NH and (R 5 ) 2 N.
R5O необязательно замещенного галоидом, R6O, (2-4)C-алканоилокси, HOC(= O), (R6)2N, A, фенилом;
R5NH, (R5)2N, R5NH2, (R5)2NH, R5NHC(=O), (R5)2NC(=O), R5S, фенил-(2-4)С-алкокси, R12O, где R12 представляет HK, и K представляет (2-4)С-алкил, необязательно замещенный галоидом, R6O, (2-4)C-алканоилокси, HOC(=O) A и (R6)2N, R6OKO, R6OKNH, CN и фенилом; R5NH, необязательно замещенного галоидом, (2-4)С-алканоилокси, R6O, R7C(=О), (R6)2N, A, R6OKO, R6OKNH, C6H5Y, CN; (R6)2NC(=О), R5ОNH, R5S, (1-4)С-алкилсульфониламино, фталимидо-(1-4)С-алкилсульфониламино, 3-фенилуреидо, 2-оксопирролидин-1-ила, 2,5-диоксопирролидин-1-ила, галоид-(2-4)С-алканоиламино, гидрокси-(2-4)С-алканоиламино, (2-4)С-алканоилокси-(2-4)С-алканоиламино, (1-4)С-алкокси-(2-4)С-алканоиламино, карбокси-(2-4)С-алканоиламино, (1-4)С-алкоксикарбонил-(2-4)С-алканоиламино, карбамоил-(2-4)С-алканоиламино, N-(1-4)С-алкилкарбамоил-(2-4)С-алканоиламино, N,N-ди[(1-4)C-алкил]карбамоил-(2-4)С-алканоиламино, амино-(2-4)С-алканоиламино, (1-4)С-алкил-амино-(2-4)С-алканоиламино, ди-(1-4)С-алкил-амино-(2-4)С-алканоиламино, и где указанный фенильный или фенокси, или анилино заместитель в R1 может необязательно нести один или два галоида, (1-4)С-алкильных или (1-4)С-алкокси заместителя; или любые два R1, взятые вместе с углеродами, к которым они присоединены, образуют 5-8-членное кольцо, включающее по крайней мере один или два гетероатома, выбранных из кислорода, серы или азота, и где алкильные группы и алкильные части алкокси или алкиламино групп могут быть с прямой цепью, или, если они составлены из по крайней мере трех атомов углерода, они могут быть разветвленными или циклическими,
каждый R3 независимо выбран из водорода, метила, этила, амино, галоида и гидрокси;
R4 представляет R11-этинил, где R11 представляет водород.3. The compound according to claim 2, in which m is 1 or 2, each R 1 is independently selected from hydrogen, hydroxy, amino, hydroxyamino, carboxy, nitro, carbamoyl, ureido, R 5 , optionally substituted with halogen, R 6 O, HOC (= O), (R 6 ) 2 NC (= O), A and (R 6 ) 2 N;
R 5 O is optionally substituted with halo, R 6 O, (2-4) C-alkanoyloxy, HOC (= O), (R 6 ) 2 N, A, phenyl;
R 5 NH, (R 5 ) 2 N, R 5 NH 2 , (R 5 ) 2 NH, R 5 NHC (= O), (R 5 ) 2 NC (= O), R 5 S, phenyl- (2 -4) C-alkoxy, R 12 O, where R 12 is HK, and K is (2-4) C-alkyl, optionally substituted with halogen, R 6 O, (2-4) C-alkanoyloxy, HOC (= O ) A and (R 6 ) 2 N, R 6 OKO, R 6 OKNH, CN and phenyl; R 5 NH, optionally substituted by halogen, (2-4) C-alkanoyloxy, R 6 O, R 7 C (= O), (R 6 ) 2 N, A, R 6 OKO, R 6 OKNH, C 6 H 5 Y, CN; (R 6 ) 2 NC (= O), R 5 ONH, R 5 S, (1-4) C-alkylsulfonylamino, phthalimido- (1-4) C-alkylsulfonylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl , 2,5-dioxopyrrolidin-1-yl, halo- (2-4) C-alkanoylamino, hydroxy- (2-4) C-alkanoylamino, (2-4) C-alkanoyloxy- (2-4) C-alkanoylamino , (1-4) C-alkoxy- (2-4) C-alkanoylamino, carboxy- (2-4) C-alkanoylamino, (1-4) C-alkoxycarbonyl- (2-4) C-alkanoylamino, carbamoyl- (2-4) C-alkanoylamino, N- (1-4) C-alkyl-carbamoyl- (2-4) C-alkanoylamino, N, N-di [(1-4) C-alkyl] carbamoyl- (2-4 ) C-alkanoylamino, amino- (2-4) C-alkanoylamino, (1-4) C-alkyl-amino- (2-4) C-alkanoylamino, di- (1-4) C-alkyl-amino- ( 2-4) C-alkane Oilylamino, and where said phenyl or phenoxy or anilino substituent in R 1 may optionally bear one or two halides, (1-4) C-alkyl or (1-4) C-alkoxy substituent; or any two R 1 taken together with the carbon to which they are attached form a 5–8 membered ring comprising at least one or two heteroatoms selected from oxygen, sulfur or nitrogen, and where the alkyl groups and alkyl parts are alkoxy or alkylamino groups can be straight chain, or, if they are composed of at least three carbon atoms, they can be branched or cyclic,
each R 3 is independently selected from hydrogen, methyl, ethyl, amino, halide, and hydroxy;
R 4 is R 11 -ethynyl, where R 11 is hydrogen.
R5O, необязательно замещенного галоидом, R6O, (2-4)C-алканоилокси, HOC(= О), (R6)2N, A, фенилом;
R5NH, (R5)2N, R5NH2, (R5)2NH, R5NHC(=O), (R5)2NC(=O), R5S, фенил-(2-4)С-алкокси, где указанный фенильный заместитель в R1 может необязательно нести один или два галоида, R5 или R5O заместителя; или любые два R1, взятые вместе с атомами углерода, к которым они присоединены, образуют 5-8-членное кольцо, включающее по крайней мере один или два гетероатома, выбранных из кислорода, серы или азота; где алкильные группы и алкильные части алкокси или алкиламиногрупп могут быть с прямой цепью или, если они включают по крайней мере три атома углерода, могут быть разветвленными или циклическими.4. The compound according to claim 3, in which each R 1 is independently selected from hydrogen, hydroxy, amino, hydroxyamino, nitro, carbamoyl, ureido, R 5 optionally substituted with halogen, R 6 O, HOC (= O), H 2 NC (= O);
R 5 O, optionally substituted by halogen, R 6 O, (2-4) C-alkanoyloxy, HOC (= O), (R 6 ) 2 N, A, phenyl;
R 5 NH, (R 5 ) 2 N, R 5 NH 2 , (R 5 ) 2 NH, R 5 NHC (= O), (R 5 ) 2 NC (= O), R 5 S, phenyl- (2 -4) C-alkoxy, wherein said phenyl substituent in R 1 may optionally bear one or two halides, R 5 or R 5 O substituent; or any two R 1 taken together with the carbon atoms to which they are attached form a 5–8 membered ring comprising at least one or two heteroatoms selected from oxygen, sulfur or nitrogen; wherein the alkyl groups and the alkyl moieties of the alkoxy or alkylamino groups may be straight chain or, if they include at least three carbon atoms, may be branched or cyclic.
R12O, где R12 представляет HK, и K представляет (2-4)С-алкил, необязательно замещенный галоидом, R6О, (2-4)С-алканоилокси, HOC(=О), A и (R6)2N, R6OKO, R6OKNH, CN и фенил; R5NH, необязательно замещенного галоидом, (2-4)С-алканоилокси, R6O, R7C(=О), (R6)2N, A, R6OKO, R6OKNH, C6H5Y, CN;
(R6)2NC(= О), R5ONH, R5S, (1-4)C-алкилсульфониламино, фталимидо-(1-4)С-алкилсульфониламино, 3-фенилуреидо, 2-оксопирролидин-1-ила, 2,5-диоксопирролидин-1-ила, галоид-(2-4)С-алканоиламино, гидрокси-(2-4)С-алканоиламино, (2-4)С-алканоилокси-(2-4)-алканоиламино, (1-4)С-алкокси-(2-4)С-алканоиламино, карбокси-(2-4)С-алканоиламино, (1-4)С-алкоксикарбонил-(2-4)С-алканоиламино, карбамоил-(2-4)С-алканоиламино, N-(1-4)С-алкилкарбамоил-(2-4)С-алканоиламино, N,N-ди-[(1-4)C-алкилкарбамоил-(2-4)С-алканоиламино, амино-(2-4)С-алканоиламино, (1-4)С-алкиламино-(2-4)С-алканоиламино, ди-(1-4)С-алкиламино-(2-4)С-алканоиламино, где указанный фенил, или фенокси, или анилино заместитель в R1 может необязательно нести один или два галоида, (1-4)С-алкильных или (1-4)С-алкокси заместителя; или любые два R1, взятые вместе с атомами углерода, к которым они присоединены, образуют 5-8-членное кольцо, включающее по крайней мере один или два гетероатома, выбранных из кислорода, серы или азота; где алкильные группы и алкильные части алкокси или алкиламино групп могут быть с прямой цепью, или, если они включают по крайней мере три атома углерода, они могут быть разветвленными или циклическими;
каждый R3 независимо выбран из водорода, метила, этила, амино, галоида и гидрокси.6. The compound according to claim 5, in which m is 1 or 2, each R 1 is independently selected from hydrogen, hydroxy, amino, hydroxyamino, carboxy, nitro, carbamoyl, ureido, R 5 , optionally substituted with halogen, R 6 O, HOC (= O), (R 6 ) 2 NC (= O), A, (R 6 ) 2 N;
R 12 O, where R 12 is HK, and K is (2-4) C-alkyl, optionally substituted by halogen, R 6 O, (2-4) C-alkanoyloxy, HOC (= O), A and (R 6 ) 2 N, R 6 OKO, R 6 OKNH, CN and phenyl; R 5 NH, optionally substituted by halogen, (2-4) C-alkanoyloxy, R 6 O, R 7 C (= O), (R 6 ) 2 N, A, R 6 OKO, R 6 OKNH, C 6 H 5 Y, CN;
(R 6 ) 2 NC (= O), R 5 ONH, R 5 S, (1-4) C-alkylsulfonylamino, phthalimido- (1-4) C-alkylsulfonylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl 2,5-dioxopyrrolidin-1-yl, halo- (2-4) C-alkanoylamino, hydroxy- (2-4) C-alkanoylamino, (2-4) C-alkanoyloxy- (2-4) -alkanoylamino, (1-4) C-alkoxy- (2-4) C-alkanoylamino, carboxy- (2-4) C-alkanoylamino, (1-4) C-alkoxycarbonyl- (2-4) C-alkanoylamino, carbamoyl- ( 2-4) C-alkanoylamino, N- (1-4) C-alkylcarbamoyl- (2-4) C-alkanoylamino, N, N-di - [(1-4) C-alkylcarbamoyl- (2-4) C -alkanoylamino, amino- (2-4) C-alkanoylamino, (1-4) C-alkylamino- (2-4) C-alkanoylamino, di- (1-4) C-alkylamino- (2-4) C- alkanoi amino, wherein said phenyl or phenoxy or anilino substituent in R 1 may optionally bear one or two halogen, (1-4) C-alkyl and (1-4) C-alkoxy substituent; or any two R 1 taken together with the carbon atoms to which they are attached form a 5–8 membered ring comprising at least one or two heteroatoms selected from oxygen, sulfur or nitrogen; wherein the alkyl groups and the alkyl moieties of the alkoxy or alkylamino groups may be straight chain, or, if they include at least three carbon atoms, they may be branched or cyclic;
each R 3 is independently selected from hydrogen, methyl, ethyl, amino, halo, and hydroxy.
R5O, необязательно замещенного галоидом, R6O, (2-4)C-алканоилокси, HOC(= О), (R6)2N, A, фенилом;
R5NH, (R5)2N, R5NH2, (R5)2NH, R5NHC(=О), (R5)2NC(=О), R5S, фенил-(2-4)С-алкокси, и где указанный фенильный заместитель в R1 может необязательно нести один или два галоида, R5 или R5O заместителя; или любые два R1, взятые вместе с атомами углерода, к которым они присоединены, образуют 5-8-членное кольцо, включающее по крайней мере один или два гетероатома, выбранных из кислорода, серы или азота; где алкильные группы и алкильные части алкокси или алкиламино групп могут быть с прямой цепью, или, если они включают по крайней мере три атома углерода, то они могут быть разветвленными или циклическими.7. The compound according to claim 6, in which each R 1 is independently selected from hydrogen, hydroxy, amino, hydroxyamino, nitro, carbamoyl, ureido, R 5 , optionally substituted with halogen, R 6 O, HOC (= O), H 2 NC (= O);
R 5 O, optionally substituted by halogen, R 6 O, (2-4) C-alkanoyloxy, HOC (= O), (R 6 ) 2 N, A, phenyl;
R 5 NH, (R 5 ) 2 N, R 5 NH 2 , (R 5 ) 2 NH, R 5 NHC (= O), (R 5 ) 2 NC (= O), R 5 S, phenyl- (2 -4) C-alkoxy, and wherein said phenyl substituent in R 1 may optionally bear one or two halides, R 5 or R 5 O substituent; or any two R 1 taken together with the carbon atoms to which they are attached form a 5–8 membered ring comprising at least one or two heteroatoms selected from oxygen, sulfur or nitrogen; where the alkyl groups and the alkyl portions of the alkoxy or alkylamino groups may be straight chain, or, if they include at least three carbon atoms, they may be branched or cyclic.
(6,7-диметоксихиназолин-4-ил)-(3-этинилфенил)-амин,
(6,7-диметоксихиназолин-4-ил)-[3-(3'-гидроксипропин-1-ил)фенил]-амин,
[3-(2'-(аминометил)-этинил)фенил]-(6,7-(диметоксихиназолин-4-ил)-амин,
(3-этинилфенил)-(6-нитрохиназолин-4-ил)-амин,
(6,7-диметоксихиназолин-4-ил)-(4-этинилфенил)-амин,
(6,7-диметоксихиназолин-4-ил)-(3-этинил-2-метилфенил)-амин,
(6-аминохиназолин-4-ил)-(3-этинилфенил)-амин,
(3-этинилфенил)-(6-метансульфониламинохиназолин-4-ил)-амин,
(3-этинилфенил)-(6,7-метилендиоксихиназолин-4-ил)-амин,
(6,7-диметоксихиназолин-4-ил)-(3-этинил-6-метилфенил)-амин,
(3-этинилфенил)-(7-нитрохиназолин-4-ил)-амин,
(3-этинилфенил)-[6-(4'-толуолсульфониламино)хиназолин-4-ил]-амин,
(3-этинилфенил)-{6-[2'-фталимидо-эт-1'-ил-сульфониламино]хиназолин-4-ил} -амин,
(3-этинилфенил)-(6-гуанидинохиназолин-4-ил)-амин,
(7-аминохиназолин-4-ил)-(3-этинилфенил)-амин,
(3-этинилфенил)-(7-метоксихиназолин-4-ил)-амин,
(6-карбометоксихиназолин-4-ил)-(3-этинилфенил)-амин,
(7-карбометоксихиназолин-4-ил)-(3-этинилфенил)-амин,
[6,7-бис(2-метоксиэтокси)хиназолин-4-ил]-(3-этинилфенил)амин,
(3-азидофенил)-(6,7-диметоксихиназолин-4-ил)амин,
(3-азидо-5-хлорфенил)-(6,7-диметоксихиназолин-4-ил)амин,
(4-азидофенил)-(6,7-диметоксихиназолин-4-ил)амин,
(3-этинилфенил)-(6-метансульфонил-хиназолин-4-ил)-амин,
(6-этансульфанил-хиназолин-4-ил)-(3-этинилфенил)-амин,
(6,7-диметокси-хиназолин-4-ил)-(3-этинил-4-фтор-фенил)-амин,
(6,7-диметокси-хиназолин-4-ил)-[3-(пропин-1'-ил-фенил)]-амин,
[6,7-бис-(2-метокси-этокси)-хиназолин-4-ил] -(5-этинил-2-метил-фенил)-амин,
[6,7-бис-(2-метокси-этокси)-хиназолин-4-ил]-(3-этинил-4-фторфенил)-амин,
[6,7-бис-(2-хлор-этокси)-хиназолин-4-ил]-(3-этинил-фенил)-амин,
[6-(2-хлор-этокси)-7-(2-метокси-этокси)-хиназолин-4-ил] -(3-этинил-фенил)-амин,
[6,7-бис(2-ацетокси-этокси)-хиназолин-4-ил]-(3-этинил-фенил)-амин,
2-[4-(3-этинил-фениламино)-7-(2-гидрокси-этокси)-хиназолин-6-илокси] -этанол,
[6-(2-ацетокси-этокси)-7-(2-метокси-этокси)-хиназолин-4-ил] -(3-этинил-фенил)-амин,
[7-(2-хлор-этокси)-6-(2-метокси-этокси)-хиназолин-4-ил] -(3-этинил-фенил)-амин,
[7-(2-ацетокси-этокси)-6-(2-метокси-этокси)-хиназолин-4-ил] -(3-этинил-фенил)-амин,
2-[4-(3-этинил-фениламино)-6-(2-гидрокси-этокси)-хиназолин-7-ил-окси] -этанол,
2-[4-(3-этинил-фениламино)-7-(2-метокси-этокси)-хиназолин-6-илокси] -этанол,
2-[4-(3-этинил-фениламино)-6-(2-метокси-этокси)-хиназолин-7-илокси] -этанол,
[6-(2-ацетокси-этокси)-7-(2-метокси-этокси)-хиназолин-4-ил] -(3-этинил-фенил)-амин,
(3-этинил-фенил)-{ 6-(2-метокси-этокси)-7-[2-(4-метил-пиперазин-1-ил)-этокси]-хиназолин-4-ил}-амин,
(3-этинил-фенил)-[7-(2-метокси-этокси)-6-(2-морфолин-4-ил)-этокси)-хиназолин-4-ил]-амин,
(6,7-диэтоксихиназолин-1-ил)-(3-этинилфенил)-амин,
(6,7-дибутоксихиназолин-1-ил)-(3-этинилфенил)-амин,
(6,7-диизопропоксихиназолин-1-ил)-(3-этинилфенил)-амин,
(6,7-диэтоксихиназолин-1-ил)-(3-этинил-2-метилфенил)-амин,
[6,7-бис(2-метокси-этокси)-хиназолин-1-ил]-(3-этинил-2-метилфенил)-амин,
(3-этинилфенил)-[6-(2-гидрокси-этокси)-7-(2-метокси-этокси)-хиназолин-1-ил]-амин,
[6,7-бис-(2-гидрокси-этокси)-хиназолин-1-ил]-(3-этинил-фенил)-амин и
2-[4-(3-этинил-фениламино)-6-(2-метокси-этокси)-хиназолин-7-илокси]-этанол.10. The compound according to claim 1, selected from the group consisting of the following compounds:
(6,7-dimethoxyquinazolin-4-yl) - (3-ethynylphenyl) -amine,
(6,7-dimethoxyquinazolin-4-yl) - [3- (3'-hydroxypropyn-1-yl) phenyl] -amine,
[3- (2 '- (aminomethyl) -ethenyl) phenyl] - (6,7- (dimethoxyquinazolin-4-yl) -amine,
(3-ethynylphenyl) - (6-nitroquinazolin-4-yl) -amine,
(6,7-dimethoxyquinazolin-4-yl) - (4-ethynylphenyl) -amine,
(6,7-dimethoxyquinazolin-4-yl) - (3-ethinyl-2-methylphenyl) -amine,
(6-aminoquinazolin-4-yl) - (3-ethynylphenyl) -amine,
(3-ethynylphenyl) - (6-methanesulfonylaminoquinazolin-4-yl) -amine,
(3-ethynylphenyl) - (6,7-methylenedioxyquinazolin-4-yl) -amine,
(6,7-dimethoxyquinazolin-4-yl) - (3-ethinyl-6-methylphenyl) -amine,
(3-ethynylphenyl) - (7-nitroquinazolin-4-yl) -amine,
(3-ethynylphenyl) - [6- (4'-toluenesulfonylamino) quinazolin-4-yl] -amine,
(3-ethynylphenyl) - {6- [2'-phthalimido-eth-1'-yl-sulfonylamino] -quinazolin-4-yl} -amin,
(3-ethynylphenyl) - (6-guanidinoquinazolin-4-yl) -amine,
(7-aminoquinazolin-4-yl) - (3-ethynylphenyl) -amine,
(3-ethynylphenyl) - (7-methoxyquinazolin-4-yl) -amine,
(6-carbomethoxyquinazolin-4-yl) - (3-ethynylphenyl) -amine,
(7-carbomethoxyquinazolin-4-yl) - (3-ethynylphenyl) -amine,
[6,7-bis (2-methoxyethoxy) quinazolin-4-yl] - (3-ethynylphenyl) amine,
(3-azidophenyl) - (6,7-dimethoxyquinazolin-4-yl) amine,
(3-azido-5-chlorophenyl) - (6,7-dimethoxyquinazolin-4-yl) amine,
(4-azidophenyl) - (6,7-dimethoxyquinazolin-4-yl) amine,
(3-ethynylphenyl) - (6-methanesulfonyl-quinazolin-4-yl) -amine,
(6-ethanesulfonyl-quinazolin-4-yl) - (3-ethynylphenyl) -amine,
(6,7-dimethoxy-quinazolin-4-yl) - (3-ethinyl-4-fluoro-phenyl) -amine,
(6,7-dimethoxy-quinazolin-4-yl) - [3- (propyn-1'-yl-phenyl)] - amine,
[6,7-bis- (2-methoxy-ethoxy) -quinazolin-4-yl] - (5-ethinyl-2-methyl-phenyl) -amine,
[6,7-bis- (2-methoxy-ethoxy) -quinazolin-4-yl] - (3-ethinyl-4-fluorophenyl) -amine,
[6,7-bis- (2-chloro-ethoxy) -quinazolin-4-yl] - (3-ethinyl-phenyl) -amine,
[6- (2-chloro-ethoxy) -7- (2-methoxy-ethoxy) -quinazolin-4-yl] - (3-ethynyl-phenyl) -amine,
[6,7-bis (2-acetoxy-ethoxy) -quinazolin-4-yl] - (3-ethinyl-phenyl) -amine,
2- [4- (3-ethynyl-phenylamino) -7- (2-hydroxy-ethoxy) -quinazolin-6-yloxy] -ethanol,
[6- (2-acetoxy-ethoxy) -7- (2-methoxy-ethoxy) -quinazolin-4-yl] - (3-ethinyl-phenyl) -amine,
[7- (2-chloro-ethoxy) -6- (2-methoxy-ethoxy) -quinazolin-4-yl] - (3-ethynyl-phenyl) -amine,
[7- (2-acetoxy-ethoxy) -6- (2-methoxy-ethoxy) -quinazolin-4-yl] - (3-ethinyl-phenyl) -amine,
2- [4- (3-ethynyl-phenylamino) -6- (2-hydroxy-ethoxy) -quinazolin-7-yl-oxy] -ethanol,
2- [4- (3-ethynyl-phenylamino) -7- (2-methoxy-ethoxy) quinazolin-6-yloxy] ethanol,
2- [4- (3-ethynyl-phenylamino) -6- (2-methoxy-ethoxy) -quinazolin-7-yloxy] ethanol,
[6- (2-acetoxy-ethoxy) -7- (2-methoxy-ethoxy) -quinazolin-4-yl] - (3-ethinyl-phenyl) -amine,
(3-ethynyl-phenyl) - {6- (2-methoxy-ethoxy) -7- [2- (4-methyl-piperazin-1-yl) -ethoxy] -quinazolin-4-yl} -amin,
(3-ethynyl-phenyl) - [7- (2-methoxy-ethoxy) -6- (2-morpholin-4-yl) -ethoxy) -quinazolin-4-yl] -amin,
(6,7-diethoxyquinazolin-1-yl) - (3-ethynylphenyl) -amine,
(6,7-dibutoxyquinazolin-1-yl) - (3-ethynylphenyl) -amine,
(6,7-diisopropoxyquinazolin-1-yl) - (3-ethynylphenyl) -amine,
(6,7-diethoxyquinazolin-1-yl) - (3-ethinyl-2-methylphenyl) -amine,
[6,7-bis (2-methoxy-ethoxy) -quinazolin-1-yl] - (3-ethinyl-2-methylphenyl) -amine,
(3-ethynylphenyl) - [6- (2-hydroxy-ethoxy) -7- (2-methoxy-ethoxy) -quinazolin-1-yl] -amine,
[6,7-bis- (2-hydroxy-ethoxy) -quinazolin-1-yl] - (3-ethinyl-phenyl) -amine and
2- [4- (3-ethynyl-phenylamino) -6- (2-methoxy-ethoxy) -quinazolin-7-yloxy] -ethanol.
(6,7-/дипропокси-хиназолин-4-ил)-(3-этинил-фенил)-амин,
(6,7-/диэтокси-хиназолин-4-ил)-(3-этинил-5-фтор-фенил)-амин,
(6,7-/диэтокси-хиназолин-4-ил)-(3-этинил-4-фтор-фенил)-амин,
(6,7-/диэтокси-хиназолин-4-ил)-(5-этинил-2-метил-фенил)-амин,
(6,7-/диэтокси-хиназолин-4-ил)-(3-этинил-4-метил-фенил)-амин,
(6-аминометил-7-метокси-хиназолин-4-ил)-(3-этинилфенил)-амин,
(6-аминометил-7-метокси-хиназолин-4-ил)-(3-этинилфенил)-амин,
(6-аминокарбонилметил-7-метокси-хиназолин-4-ил)-(3-этинилфенил)-амин,
(6-аминокарбонилэтил-7-метокси-хиназолин-4-ил)-(3-этинилфенил)-амин,
(6-аминокарбонилметил-7-этокси-хиназолин-4-ил)-(3-этинилфенил)-амин,
(6-аминокарбонилэтил-7-этокси-хиназолин-4-ил)-(3-этинилфенил)-амин,
(6-аминокарбонилметил-7-изопропокси-хиназолин-4-ил)-(3-этинил-фенил)- амин,
(6-аминокарбонилметил-7-пропокси-хиназолин-4-ил)-(3-этинилфенил)-амин,
(6-аминокарбонилметил-7-метокси-хиназолин-4-ил)-(3-этинилфенил)-амин,
(6-аминокарбонилэтил-7-изопропокси-хиназолин-4-ил)-(3-этинилфенил)-амин, и
(6-аминокарбонилэтил-7-пропокси-хиназолин-4-ил)-(3-этинилфенил)-амин.11. The compound according to claim 1, selected from the group consisting of the following compounds:
(6,7- / Dipropoxy-quinazolin-4-yl) - (3-ethynyl-phenyl) -amin,
(6,7- / diethoxy-quinazolin-4-yl) - (3-ethynyl-5-fluoro-phenyl) -amine,
(6,7- / diethoxy-quinazolin-4-yl) - (3-ethynyl-4-fluoro-phenyl) -amine,
(6,7- / diethoxy-quinazolin-4-yl) - (5-ethynyl-2-methyl-phenyl) -amine,
(6,7- / diethoxy-quinazolin-4-yl) - (3-ethynyl-4-methyl-phenyl) -amine,
(6-aminomethyl-7-methoxy-quinazolin-4-yl) - (3-ethynylphenyl) -amine,
(6-aminomethyl-7-methoxy-quinazolin-4-yl) - (3-ethynylphenyl) -amine,
(6-aminocarbonylmethyl-7-methoxy-quinazolin-4-yl) - (3-ethynylphenyl) -amine,
(6-aminocarbonylethyl-7-methoxy-quinazolin-4-yl) - (3-ethynylphenyl) -amine,
(6-aminocarbonylmethyl-7-ethoxy-quinazolin-4-yl) - (3-ethynylphenyl) -amine,
(6-aminocarbonylethyl-7-ethoxy-quinazolin-4-yl) - (3-ethynylphenyl) -amine,
(6-aminocarbonylmethyl-7-isopropoxy-quinazolin-4-yl) - (3-ethinyl-phenyl) -amine,
(6-aminocarbonylmethyl-7-propoxy-quinazolin-4-yl) - (3-ethynylphenyl) -amine,
(6-aminocarbonylmethyl-7-methoxy-quinazolin-4-yl) - (3-ethynylphenyl) -amine,
(6-aminocarbonylethyl-7-isopropoxy-quinazolin-4-yl) - (3-ethynylphenyl) -amine, and
(6-aminocarbonylethyl-7-propoxy-quinazolin-4-yl) - (3-ethynylphenyl) -amine.
(6,7-диэтоксихиназолин-1-ил)-(3-этинилфенил)-амин,
(3-этинилфенил)-[6-(2-гидрокси-этокси)-7-(2-метокси-этокси)-хиназолин-1-ил]-амин,
[6,7-бис-(2-гидрокси-этокси)-хиназолин-1-ил]-(3-этинилфенил)-амин,
[6,7-бис-(2-метокси-этокси)-хиназолин-1-ил]-(3-этинил-фенил)-амин,
(6,7-диметоксихиназолин-1-ил)-(3-этинилфенил)-амин,
(3-этинилфенил)-(6-метансульфониламино-хиназолин-1-ил)-амин,
(6-амино-хиназолин-1-ил)-(3-этинилфенил)-амин.12. The compound according to claim 1, selected from the group consisting of the following compounds:
(6,7-diethoxyquinazolin-1-yl) - (3-ethynylphenyl) -amine,
(3-ethynylphenyl) - [6- (2-hydroxy-ethoxy) -7- (2-methoxy-ethoxy) -quinazolin-1-yl] -amine,
[6,7-bis- (2-hydroxy-ethoxy) -quinazolin-1-yl] - (3-ethynylphenyl) -amine,
[6,7-bis- (2-methoxy-ethoxy) -quinazolin-1-yl] - (3-ethinyl-phenyl) -amine,
(6,7-dimethoxyquinazolin-1-yl) - (3-ethynylphenyl) -amine,
(3-ethynylphenyl) - (6-methanesulfonylamino-quinazolin-1-yl) -amin,
(6-amino-quinazolin-1-yl) - (3-ethynylphenyl) -amine.
в которой:
m представляет 1, 2 или 3;
каждый R1 независимо выбран из водорода, галоида, гидрокси, амино, гидроксиамино, карбокси, (1-4)С-алкоксикарбонила, нитро, гуанидино, уреидо, карбамоила, циано, трифторметила, (R6)2N-карбонила, и фенил-W-алкила, где W выбран из одинарной связи, O, S и NH;
или каждый R1 независимо выбран из циано-(1-4)С-алкила и R9, где R9 выбран из группы, состоящей из R5, R5O, (R6)2N, R7C(=O), R5ONH, A и R5Y; где R5 представляет (1-4)С-алкил; R6 представляет водород или R5, где радикалы R5 являются одинаковыми или различными; R7 представляет R5, R5O или (R6)2N; A выбран из пиперидино, морфолино, пирролидино, и 4-R6-пиперазин-1-ила, имидазол-1-ила, 4-пиридон-1-ила, карбокси(1-4)С-алкила, фенокси, фенила, фенилсульфанила, (2-4)С-алкенила, (R6)2N-карбонил-(1-4)С-алкила; Y выбран из S, SO, SO2; алкильные фрагменты в (R6)2N необязательно замещены галоидом или R9, где R9 имеет значения, определенные выше, а алкильные фрагменты в R5 и R5O являются необязательно замещенными галоидом, R6O или R9, где R6 и R9 имеют значения, определенные выше, и где получающиеся в результате группы являются необязательно замещенными галоидом или R9, при условии, что атом азота, кислорода или серы и еще один гетероатом не могут быть присоединены к одному и тому же атому углерода и при дальнейшем условии, что не более, чем три звена "R9" могут составлять R1;
или каждый из R1 независимо выбран из R5-сульфониламино, фталимидо-(1-4)С-алкилсульфониламино, бензамидо, бензолсульфониламино, 3-фенилуреидо, 2-оксопирролидин-1-ила, 2,5-диоксопирролидин-1-ила, и R10-(2-4)С-алканоиламино, где R10 выбран из галоида, R6O, (2-4)С-алканоилокси, R7C(=O), и (R6)2N; и где указанный бензамидо, или бензолсульфониламино, или фенильный, или фенокси, или анилино, или фенилсульфенильный заместитель в R1 может необязательно нести один или два галогена, (1-4)С-алкильных, циано, метансульфонильных или (1-4)С-алкокси заместителя;
или любые два R1, взятые вместе с атомами углерода, к которым они присоединены, образуют 5-8-членное кольцо, включающее по крайней мере один или два гетероатома, выбранных из кислорода, серы или азота; где алкильные группы и алкильные части алкокси или алкиламино групп могут быть с прямой цепью, или, если они включают по крайней мере три атома углерода, они могут быть разветвленными или циклическими;
R2 выбран из водорода и необязательно замещенного (1-6)С-алкила;
n представляет 1 или 2; каждый R3 независимо выбран из водорода, необязательно замещенного (1-6)С-алкила, необязательно замещенного амино, галоида, гидрокси, необязательно замещенного гидрокси;
R4 представляет азидо или R11-этинил, где R11 выбран из водорода, необязательно замещенного (1-6)С-алкила, где заместители выбраны из водорода, амино, гидрокси, R5O, R5NH и (R5)2N, который включает
а) обработку соединения формулы
или
где R1 и m имеют значения, определенные выше,
четыреххлористым углеродом и необязательно замещенным триарилфосфином, необязательно осажденным на инертном полимере, формулы Ar3P, где каждый Ar представляет необязательно замещенную (6-10)С-арильную группу и каждый из заместителей независимо выбран из (1-6)С-алкила;
b) обработку продукта стадии а) соединением формулы
где R2, R3 и n имеют значения, определенные выше, и J представляет Y или R4, где R4 имеет значения, определенные выше, при условии, что когда J представляет Y, тогда продукт стадии в) должен дополнительно обрабатываться алкином.13. The method of obtaining the compounds of formula I
wherein:
m is 1, 2 or 3;
each R 1 is independently selected from hydrogen, halo, hydroxy, amino, hydroxyamino, carboxy, (1-4) C-alkoxycarbonyl, nitro, guanidino, ureido, carbamoyl, cyano, trifluoromethyl, (R 6 ) 2 N-carbonyl, and phenyl -W-alkyl, where W is selected from a single bond, O, S, and NH;
or each R 1 is independently selected from cyano (1-4) C-alkyl and R 9 , where R 9 is selected from the group consisting of R 5 , R 5 O, (R 6 ) 2 N, R 7 C (= O ), R 5 ONH, A and R 5 Y; where R 5 is (1-4) C-alkyl; R 6 is hydrogen or R 5 , where the radicals R 5 are the same or different; R 7 is R 5 , R 5 O or (R 6 ) 2 N; A is selected from piperidino, morpholino, pyrrolidino, and 4-R 6 -piperazin-1-yl, imidazol-1-yl, 4-pyridon-1-yl, carboxy (1-4) C-alkyl, phenoxy, phenyl, phenylsulfanyl , (2-4) C-alkenyl, (R 6 ) 2 N-carbonyl- (1-4) C-alkyl; Y is selected from S, SO, SO 2 ; the alkyl moieties in (R 6 ) 2 N are optionally substituted with halogen or R 9 , where R 9 is as defined above, and the alkyl moieties in R 5 and R 5 O are optionally substituted with halogen, R 6 O or R 9 , where R 6 and R 9 are as defined above, and where the resulting groups are optionally substituted with halogen or R 9 , provided that a nitrogen, oxygen or sulfur atom and another heteroatom cannot be attached to the same carbon atom and further condition that no more than three links "R 9 " can be R 1 ;
or each of R 1 is independently selected from R 5 -sulfonylamino, phthalimido- (1-4) C-alkylsulfonylamino, benzamido, benzenesulfonylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, and R 10 - (2-4) C-alkanoylamino, where R 10 is selected from halogen, R 6 O, (2-4) C-alkanoyloxy, R 7 C (= O), and (R 6 ) 2 N; and where said benzamido, or benzenesulfonylamino, or phenyl, or phenoxy, or anilino, or phenylsulfenyl substituent in R 1 may optionally bear one or two halogen, (1-4) C-alkyl, cyano, methanesulfonyl, or (1-4) C alkoxy substituent;
or any two R 1 taken together with the carbon atoms to which they are attached form a 5–8 membered ring comprising at least one or two heteroatoms selected from oxygen, sulfur or nitrogen; wherein the alkyl groups and the alkyl moieties of the alkoxy or alkylamino groups may be straight chain, or, if they include at least three carbon atoms, they may be branched or cyclic;
R 2 is selected from hydrogen and optionally substituted (1-6) C-alkyl;
n is 1 or 2; each R 3 is independently selected from hydrogen, optionally substituted (1-6) C-alkyl, optionally substituted amino, halide, hydroxy, optionally substituted hydroxy;
R 4 is azido or R 11 -ethynyl, where R 11 is selected from hydrogen, optionally substituted (1-6) C-alkyl, where the substituents are selected from hydrogen, amino, hydroxy, R 5 O, R 5 NH and (R 5 ) 2 N, which includes
a) processing compounds of the formula
or
where R 1 and m are as defined above,
carbon tetrachloride and optionally substituted triarylphosphine, optionally deposited on an inert polymer, of formula Ar 3 P, where each Ar represents an optionally substituted (6-10) C-aryl group and each of the substituents is independently selected from (1-6) C-alkyl;
b) processing the product of step a) with a compound of the formula
where R 2 , R 3 and n are as defined above, and J is Y or R 4 , where R 4 is as defined above, provided that when J is Y, then the product of step c) should be further treated with alkyne.
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PCT/IB1995/000436 WO1996030347A1 (en) | 1995-03-30 | 1995-06-06 | Quinazoline derivatives |
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NZ243082A (en) | 1991-06-28 | 1995-02-24 | Ici Plc | 4-anilino-quinazoline derivatives; pharmaceutical compositions, preparatory processes, and use thereof |
GB9300059D0 (en) | 1992-01-20 | 1993-03-03 | Zeneca Ltd | Quinazoline derivatives |
US5258518A (en) * | 1992-04-01 | 1993-11-02 | G. D. Searle & Co. | 2-substituted tertiary carbinol derivatives of deoxynojirimycin |
GB9323290D0 (en) | 1992-12-10 | 1994-01-05 | Zeneca Ltd | Quinazoline derivatives |
GB9314893D0 (en) * | 1993-07-19 | 1993-09-01 | Zeneca Ltd | Quinazoline derivatives |
GB9314884D0 (en) | 1993-07-19 | 1993-09-01 | Zeneca Ltd | Tricyclic derivatives |
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1995
- 1995-06-06 EP EP09174228.8A patent/EP2163546B1/en not_active Expired - Lifetime
- 1995-06-06 MX MX9707453A patent/MX9707453A/en active IP Right Grant
- 1995-06-06 DE DE200512000053 patent/DE122005000053I2/en active Active
- 1995-06-06 AT AT95918713T patent/ATE205483T1/en active
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- 1995-06-06 DK DK95918713T patent/DK0817775T3/en active
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- 1995-06-06 EP EP95918713A patent/EP0817775B1/en not_active Expired - Lifetime
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1996
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- 1996-03-29 HU HU9600834A patent/HU229120B1/en active Protection Beyond IP Right Term
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- 1996-03-29 SI SI9600102A patent/SI9600102A/en active Search and Examination
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1999
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2001
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2005
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2006
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2014
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