BR112017016465B1 - Composto heterocíclico e composição farmacêutica que o compreende - Google Patents

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Publication number

BR112017016465B1

BR112017016465B1 BR112017016465-5A BR112017016465A BR112017016465B1 BR 112017016465 B1 BR112017016465 B1 BR 112017016465B1 BR 112017016465 A BR112017016465 A BR 112017016465A BR 112017016465 B1 BR112017016465 B1 BR 112017016465B1

Authority

BR

Brazil

Prior art keywords

amino

bipyridin

fluoro

pyrimidin

hydrochloride

Prior art date

2015-02-04

Links

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• 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 20
• 150000002391 heterocyclic compounds Chemical class 0.000 title abstract description 6
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 46
• 150000003839 salts Chemical class 0.000 claims abstract description 25
• 102000003903 Cyclin-dependent kinases Human genes 0.000 claims abstract description 23
• 108090000266 Cyclin-dependent kinases Proteins 0.000 claims abstract description 23
• 230000003412 degenerative effect Effects 0.000 claims abstract description 11
• 208000014644 Brain disease Diseases 0.000 claims abstract description 10
• 230000002265 prevention Effects 0.000 claims abstract description 8
• 150000001875 compounds Chemical class 0.000 claims description 478
• -1 hydroxy, amino Chemical group 0.000 claims description 40
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 23
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 20
• 230000002401 inhibitory effect Effects 0.000 claims description 17
• BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 claims description 16
• 229960004964 temozolomide Drugs 0.000 claims description 15
• 201000011510 cancer Diseases 0.000 claims description 14
• 229910052757 nitrogen Inorganic materials 0.000 claims description 13
• UQHDKUFLWKTTDL-UHFFFAOYSA-N 6-(2-amino-3-fluoropyridin-4-yl)-2-(2-amino-6-methylpyrimidin-4-yl)pyridin-3-ol Chemical compound NC1=NC=CC(=C1F)C1=NC(=C(C=C1)O)C1=NC(=NC(=C1)C)N UQHDKUFLWKTTDL-UHFFFAOYSA-N 0.000 claims description 11
• 229910052736 halogen Chemical group 0.000 claims description 11
• 150000002367 halogens Chemical group 0.000 claims description 11
• VFVAQKKPFOPZEA-UHFFFAOYSA-N 2,6-bis(2-aminopyrimidin-4-yl)pyridin-3-ol Chemical compound NC1=NC=CC(=N1)C1=NC(=CC=C1O)C1=NC(=NC=C1)N VFVAQKKPFOPZEA-UHFFFAOYSA-N 0.000 claims description 10
• 208000024827 Alzheimer disease Diseases 0.000 claims description 10
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 10
• 125000001424 substituent group Chemical group 0.000 claims description 10
• SFMPGAKXIHSIGO-UHFFFAOYSA-N 6-(2-amino-3-fluoropyridin-4-yl)-2-(2-amino-6-morpholin-4-ylpyrimidin-4-yl)pyridin-3-ol Chemical compound NC1=NC=CC(=C1F)C1=NC(=C(C=C1)O)C1=NC(=NC(=C1)N1CCOCC1)N SFMPGAKXIHSIGO-UHFFFAOYSA-N 0.000 claims description 9
• DJRWECZCVWWHFC-UHFFFAOYSA-N 6-(2-amino-3-fluoropyridin-4-yl)-2-(2-amino-6-propan-2-ylpyrimidin-4-yl)pyridin-3-ol Chemical compound NC1=NC=CC(=C1F)C1=NC(=C(C=C1)O)C1=NC(=NC(=C1)C(C)C)N DJRWECZCVWWHFC-UHFFFAOYSA-N 0.000 claims description 9
• 206010009944 Colon cancer Diseases 0.000 claims description 9
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
• JVFWWWWRIZOYBC-UHFFFAOYSA-N 2-[2-amino-6-(1-ethylpiperidin-4-yl)pyrimidin-4-yl]-6-(2-amino-3-fluoropyridin-4-yl)pyridin-3-ol Chemical compound NC1=NC=CC(=C1F)C1=NC(=C(C=C1)O)C1=NC(=NC(=C1)C1CCN(CC1)CC)N JVFWWWWRIZOYBC-UHFFFAOYSA-N 0.000 claims description 7
• PRLPSHTXKMUKHW-UHFFFAOYSA-N 6-(2-amino-3-fluoropyridin-4-yl)-2-(2-aminopyrimidin-4-yl)pyridin-3-ol Chemical compound NC1=NC=CC(=C1F)C1=NC(=C(C=C1)O)C1=NC(=NC=C1)N PRLPSHTXKMUKHW-UHFFFAOYSA-N 0.000 claims description 7
• 229940073770 avotaciclib Drugs 0.000 claims description 7
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
• VBKVZSGLBSHDDY-UHFFFAOYSA-N 2-(2-amino-5,6-dimethylpyrimidin-4-yl)-6-(2-amino-3-fluoropyridin-4-yl)pyridin-3-ol Chemical compound NC1=NC=CC(=C1F)C1=NC(=C(C=C1)O)C1=NC(=NC(=C1C)C)N VBKVZSGLBSHDDY-UHFFFAOYSA-N 0.000 claims description 6
• CDXHEZRZLZUFTF-UHFFFAOYSA-N 2-(2-amino-5-ethylpyrimidin-4-yl)-6-(2-amino-3-fluoropyridin-4-yl)pyridin-3-ol Chemical compound NC1=NC=CC(=C1F)C1=NC(=C(C=C1)O)C1=NC(=NC=C1CC)N CDXHEZRZLZUFTF-UHFFFAOYSA-N 0.000 claims description 6
• KOCDBXMUNMZOFD-UHFFFAOYSA-N 2-[2-amino-6-(1-ethylpiperidin-3-yl)pyrimidin-4-yl]-6-(2-amino-3-fluoropyridin-4-yl)pyridin-3-ol Chemical compound NC1=NC=CC(=C1F)C1=NC(=C(C=C1)O)C1=NC(=NC(=C1)C1CN(CCC1)CC)N KOCDBXMUNMZOFD-UHFFFAOYSA-N 0.000 claims description 6
• JEDMIJGQMNDEOO-UHFFFAOYSA-N 2-[2-amino-6-(1-ethylpiperidin-4-yl)-5-methylpyrimidin-4-yl]-6-(2-amino-3-fluoropyridin-4-yl)pyridin-3-ol Chemical compound NC1=NC=CC(=C1F)C1=NC(=C(C=C1)O)C1=NC(=NC(=C1C)C1CCN(CC1)CC)N JEDMIJGQMNDEOO-UHFFFAOYSA-N 0.000 claims description 6
• KHITZQQFUDDYOY-UHFFFAOYSA-N 2-[2-amino-6-(dimethylamino)pyrimidin-4-yl]-6-(2-amino-3-fluoropyridin-4-yl)pyridin-3-ol Chemical compound NC1=NC=CC(=C1F)C1=NC(=C(C=C1)O)C1=NC(=NC(=C1)N(C)C)N KHITZQQFUDDYOY-UHFFFAOYSA-N 0.000 claims description 6
• FKVHEFZQWCSWPF-UHFFFAOYSA-N 6-(2-amino-3-fluoropyridin-4-yl)-2-(2-amino-5-methylpyrimidin-4-yl)pyridin-3-ol Chemical compound NC1=NC=CC(=C1F)C1=NC(=C(C=C1)O)C1=NC(=NC=C1C)N FKVHEFZQWCSWPF-UHFFFAOYSA-N 0.000 claims description 6
• ZPIBLZXCXVBUFZ-UHFFFAOYSA-N 6-(2-amino-3-fluoropyridin-4-yl)-2-(2-amino-5-propylpyrimidin-4-yl)pyridin-3-ol Chemical compound NC1=NC=CC(=C1F)C1=NC(=C(C=C1)O)C1=NC(=NC=C1CCC)N ZPIBLZXCXVBUFZ-UHFFFAOYSA-N 0.000 claims description 6
• LWMNKYLPBXRTDQ-UHFFFAOYSA-N 6-(2-amino-3-fluoropyridin-4-yl)-2-[2-amino-6-(1-methylpiperidin-3-yl)pyrimidin-4-yl]pyridin-3-ol Chemical compound NC1=NC=CC(=C1F)C1=NC(=C(C=C1)O)C1=NC(=NC(=C1)C1CN(CCC1)C)N LWMNKYLPBXRTDQ-UHFFFAOYSA-N 0.000 claims description 6
• AQTUVYRUTYHIJX-UHFFFAOYSA-N 6-(2-amino-3-fluoropyridin-4-yl)-2-[2-amino-6-(1-methylpiperidin-4-yl)pyrimidin-4-yl]pyridin-3-ol Chemical compound NC1=NC=CC(=C1F)C1=NC(=C(C=C1)O)C1=NC(=NC(=C1)C1CCN(CC1)C)N AQTUVYRUTYHIJX-UHFFFAOYSA-N 0.000 claims description 6
• YVSZJKLHXVFEQB-UHFFFAOYSA-N 6-(2-amino-3-fluoropyridin-4-yl)-2-[2-amino-6-(1-propan-2-ylpiperidin-3-yl)pyrimidin-4-yl]pyridin-3-ol Chemical compound NC1=NC=CC(=C1F)C1=NC(=C(C=C1)O)C1=NC(=NC(=C1)C1CN(CCC1)C(C)C)N YVSZJKLHXVFEQB-UHFFFAOYSA-N 0.000 claims description 6
• YIGVHROHRQFAEZ-UHFFFAOYSA-N 6-(2-amino-3-fluoropyridin-4-yl)-2-[2-amino-6-(1-propan-2-ylpiperidin-4-yl)-5-propylpyrimidin-4-yl]pyridin-3-ol Chemical compound NC1=NC=CC(=C1F)C1=NC(=C(C=C1)O)C1=NC(=NC(=C1CCC)C1CCN(CC1)C(C)C)N YIGVHROHRQFAEZ-UHFFFAOYSA-N 0.000 claims description 6
• DFUJTWCORWDBOJ-UHFFFAOYSA-N 6-(2-amino-3-fluoropyridin-4-yl)-2-[2-amino-6-(1-propan-2-ylpiperidin-4-yl)pyrimidin-4-yl]pyridin-3-ol Chemical compound NC1=NC=CC(=C1F)C1=NC(=C(C=C1)O)C1=NC(=NC(=C1)C1CCN(CC1)C(C)C)N DFUJTWCORWDBOJ-UHFFFAOYSA-N 0.000 claims description 6
• XUJAXYRASNBVNZ-UHFFFAOYSA-N 6-(2-amino-3-fluoropyridin-4-yl)-2-[2-amino-6-(1-propylpiperidin-4-yl)pyrimidin-4-yl]pyridin-3-ol Chemical compound NC1=NC=CC(=C1F)C1=NC(=C(C=C1)O)C1=NC(=NC(=C1)C1CCN(CC1)CCC)N XUJAXYRASNBVNZ-UHFFFAOYSA-N 0.000 claims description 6
• MNJURBQBWJJSAF-UHFFFAOYSA-N 6-(2-amino-3-fluoropyridin-4-yl)-2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]pyridin-3-ol Chemical compound NC1=NC=CC(=C1F)C1=NC(=C(C=C1)O)C1=NC(=NC(=C1)N1CCN(CC1)C)N MNJURBQBWJJSAF-UHFFFAOYSA-N 0.000 claims description 6
• 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 6
• 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 6
• 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 6
• 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 6
• 206010035226 Plasma cell myeloma Diseases 0.000 claims description 6
• VJMAITQRABEEKP-UHFFFAOYSA-N [6-(phenylmethoxymethyl)-1,4-dioxan-2-yl]methyl acetate Chemical compound O1C(COC(=O)C)COCC1COCC1=CC=CC=C1 VJMAITQRABEEKP-UHFFFAOYSA-N 0.000 claims description 6
• 239000001257 hydrogen Substances 0.000 claims description 6
• 229910052739 hydrogen Inorganic materials 0.000 claims description 6
• XVKXFIJMBDLXDL-UHFFFAOYSA-N 2-(2-aminopyrimidin-4-yl)-6-(2-fluoro-4-hydroxyphenyl)pyridin-3-ol Chemical compound NC1=NC=CC(=N1)C1=NC(=CC=C1O)C1=C(C=C(C=C1)O)F XVKXFIJMBDLXDL-UHFFFAOYSA-N 0.000 claims description 5
• ICLXIERULPGRLV-UHFFFAOYSA-N 6-(2-amino-3-fluoropyridin-4-yl)-2-(2-amino-6-piperidin-4-ylpyrimidin-4-yl)pyridin-3-ol Chemical compound NC1=NC=CC(=C1F)C1=NC(=C(C=C1)O)C1=NC(=NC(=C1)C1CCNCC1)N ICLXIERULPGRLV-UHFFFAOYSA-N 0.000 claims description 5
• LKLSDUJWFPPVES-UHFFFAOYSA-N 6-(2-amino-3-fluoropyridin-4-yl)-2-[2-amino-5-methyl-6-(1-propan-2-ylpiperidin-3-yl)pyrimidin-4-yl]pyridin-3-ol Chemical compound NC1=NC=CC(=C1F)C1=NC(=C(C=C1)O)C1=NC(=NC(=C1C)C1CN(CCC1)C(C)C)N LKLSDUJWFPPVES-UHFFFAOYSA-N 0.000 claims description 5
• MYEGUQKXKLHJKL-UHFFFAOYSA-N 6-(2-amino-3-fluoropyridin-4-yl)-2-[2-amino-5-methyl-6-(1-propan-2-ylpiperidin-4-yl)pyrimidin-4-yl]pyridin-3-ol Chemical compound NC1=NC=CC(=C1F)C1=NC(=C(C=C1)O)C1=NC(=NC(=C1C)C1CCN(CC1)C(C)C)N MYEGUQKXKLHJKL-UHFFFAOYSA-N 0.000 claims description 5
• YWMJCIOQXWGOKM-UHFFFAOYSA-N 6-(2-amino-3-fluoropyridin-4-yl)-2-[2-amino-6-(oxan-4-yl)pyrimidin-4-yl]pyridin-3-ol Chemical compound NC1=NC=CC(=C1F)C1=NC(=C(C=C1)O)C1=NC(=NC(=C1)C1CCOCC1)N YWMJCIOQXWGOKM-UHFFFAOYSA-N 0.000 claims description 5
• GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 claims description 5
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• 239000002246 antineoplastic agent Substances 0.000 claims description 5
• 208000029742 colonic neoplasm Diseases 0.000 claims description 5
• KMNZHJDCEYZHIR-UHFFFAOYSA-N 6-(2-amino-3-fluoropyridin-4-yl)-2-[2-amino-5-methyl-6-(1-propylpiperidin-3-yl)pyrimidin-4-yl]pyridin-3-ol Chemical compound NC1=NC=CC(=C1F)C1=NC(=C(C=C1)O)C1=NC(=NC(=C1C)C1CN(CCC1)CCC)N KMNZHJDCEYZHIR-UHFFFAOYSA-N 0.000 claims description 4
• LSIUHPKQRVZZTE-UHFFFAOYSA-N 6-(2-amino-3-fluoropyridin-4-yl)-2-[2-amino-5-methyl-6-(1-propylpiperidin-4-yl)pyrimidin-4-yl]pyridin-3-ol Chemical compound NC1=NC=CC(=C1F)C1=NC(=C(C=C1)O)C1=NC(=NC(=C1C)C1CCN(CC1)CCC)N LSIUHPKQRVZZTE-UHFFFAOYSA-N 0.000 claims description 4
• JYTCKBDBQPIRRN-UHFFFAOYSA-N 6-(2-amino-3-fluoropyridin-4-yl)-2-[2-amino-6-(1-propylpiperidin-3-yl)pyrimidin-4-yl]pyridin-3-ol Chemical compound NC1=NC=CC(=C1F)C1=NC(=C(C=C1)O)C1=NC(=NC(=C1)C1CN(CCC1)CCC)N JYTCKBDBQPIRRN-UHFFFAOYSA-N 0.000 claims description 4
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• AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 4
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• NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 claims description 4
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• CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 4
• NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 claims description 4
• ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 claims description 4
• ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 claims description 4
• 201000001441 melanoma Diseases 0.000 claims description 4
• ULKJKOOARLOSTC-UHFFFAOYSA-N 2-(2-amino-6-chloropyrimidin-4-yl)-6-pyridin-4-ylpyridin-3-ol Chemical compound NC1=NC(=CC(=N1)C1=C(C=CC(=N1)C1=CC=NC=C1)O)Cl ULKJKOOARLOSTC-UHFFFAOYSA-N 0.000 claims description 3
• PXPDMILZOQXUSI-UHFFFAOYSA-N 2-(2-amino-6-methylpyrimidin-4-yl)-6-(2,3-difluoro-4-hydroxyphenyl)pyridin-3-ol Chemical compound NC1=NC(=CC(=N1)C1=NC(=CC=C1O)C1=C(C(=C(C=C1)O)F)F)C PXPDMILZOQXUSI-UHFFFAOYSA-N 0.000 claims description 3
• CJUCXVYWERHIBR-UHFFFAOYSA-N 2-(2-amino-6-methylpyrimidin-4-yl)-6-(2-fluoro-4-hydroxyphenyl)pyridin-3-ol Chemical compound NC1=NC(=CC(=N1)C1=NC(=CC=C1O)C1=C(C=C(C=C1)O)F)C CJUCXVYWERHIBR-UHFFFAOYSA-N 0.000 claims description 3
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