BR112016022342B1 - Derivados de (5,6-di-hidro)pirimido[4,5-e] indolizinas, suas composições farmacêuticas, e seus usos - Google Patents

Info

Publication number

BR112016022342B1

BR112016022342B1 BR112016022342-0A BR112016022342A BR112016022342B1 BR 112016022342 B1 BR112016022342 B1 BR 112016022342B1 BR 112016022342 A BR112016022342 A BR 112016022342A BR 112016022342 B1 BR112016022342 B1 BR 112016022342B1

Authority

BR

Brazil

Prior art keywords

indolizine

carboxamide

dihydropyrimido

anilino

methoxy

Prior art date

2014-04-07

Links

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• 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 16
• 150000002478 indolizines Chemical class 0.000 title abstract description 11
• 150000001875 compounds Chemical class 0.000 claims abstract description 542
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 31
• 238000011282 treatment Methods 0.000 claims abstract description 20
• 201000011510 cancer Diseases 0.000 claims abstract description 17
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 14
• 125000003118 aryl group Chemical group 0.000 claims abstract description 9
• 125000000217 alkyl group Chemical group 0.000 claims description 163
• 125000003545 alkoxy group Chemical group 0.000 claims description 93
• 150000003839 salts Chemical class 0.000 claims description 59
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 47
• -1 piperidinylamino, azetidinylamino, tetra -hydropyranylamino Chemical group 0.000 claims description 40
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 36
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 34
• 229910052736 halogen Inorganic materials 0.000 claims description 32
• 150000002367 halogens Chemical class 0.000 claims description 32
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 25
• URGAFFAIKGXTJC-UHFFFAOYSA-N indolizine-7-carboxamide Chemical compound C1=C(C(=O)N)C=CN2C=CC=C21 URGAFFAIKGXTJC-UHFFFAOYSA-N 0.000 claims description 25
• 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 17
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 15
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 15
• 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims description 15
• 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 14
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 13
• 125000001153 fluoro group Chemical group F* 0.000 claims description 13
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 12
• 239000011737 fluorine Substances 0.000 claims description 12
• 229910052731 fluorine Inorganic materials 0.000 claims description 12
• 125000004043 oxo group Chemical group O=* 0.000 claims description 12
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
• 125000003282 alkyl amino group Chemical group 0.000 claims description 10
• 201000010099 disease Diseases 0.000 claims description 10
• 125000002393 azetidinyl group Chemical group 0.000 claims description 9
• 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 9
• 239000003814 drug Substances 0.000 claims description 9
• 125000003342 alkenyl group Chemical group 0.000 claims description 8
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
• 125000003566 oxetanyl group Chemical group 0.000 claims description 8
• 125000003386 piperidinyl group Chemical group 0.000 claims description 8
• UYPNZGVGCJECJV-UHFFFAOYSA-N CC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC12)C=NC(=N3)NC3=C(C=C(C=C3)N3CCNCC3)OC Chemical compound CC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC12)C=NC(=N3)NC3=C(C=C(C=C3)N3CCNCC3)OC UYPNZGVGCJECJV-UHFFFAOYSA-N 0.000 claims description 6
• 206010027476 Metastases Diseases 0.000 claims description 6
• 239000013543 active substance Substances 0.000 claims description 6
• 125000002757 morpholinyl group Chemical group 0.000 claims description 6
• 206010006187 Breast cancer Diseases 0.000 claims description 5
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
• 239000000460 chlorine Substances 0.000 claims description 5
• 229910052801 chlorine Inorganic materials 0.000 claims description 5
• 229910052739 hydrogen Inorganic materials 0.000 claims description 5
• 208000003174 Brain Neoplasms Diseases 0.000 claims description 4
• NIFYAXNEECFWPW-UHFFFAOYSA-N N-[1-[2-(2-ethoxyethoxy)ethyl]-3,5-diethylpyrazol-4-yl]-2-[4-[4-[2-(ethylamino)acetyl]piperazin-1-yl]-2-methoxyanilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide Chemical compound C(C)OCCOCCN1N=C(C(=C1CC)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C(CNCC)=O)OC)CC NIFYAXNEECFWPW-UHFFFAOYSA-N 0.000 claims description 4
• RWHBUXPJZMGWIZ-UHFFFAOYSA-N N-[1-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-3,5-dimethylpyrazol-4-yl]-2-[2-methoxy-4-(1,3,5-trimethylpyrazol-4-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide Chemical compound COCCOCCOCCN1N=C(C(=C1C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)C=1C(=NN(C=1C)C)C)OC)C RWHBUXPJZMGWIZ-UHFFFAOYSA-N 0.000 claims description 4
• UFIJTGYZCFZMPA-UHFFFAOYSA-N N-[1-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-3,5-dimethylpyrazol-4-yl]-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide Chemical compound COCCOCCOCCN1N=C(C(=C1C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C)OC)C UFIJTGYZCFZMPA-UHFFFAOYSA-N 0.000 claims description 4
• PXOSVHWTKXCACO-UHFFFAOYSA-N N-[3,5-diethyl-1-[2-(2-methoxyethoxy)ethyl]pyrazol-4-yl]-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide Chemical compound C(C)C1=NN(C(=C1NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C)OC)CC)CCOCCOC PXOSVHWTKXCACO-UHFFFAOYSA-N 0.000 claims description 4
• 239000001257 hydrogen Substances 0.000 claims description 4
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
• 239000000546 pharmaceutical excipient Substances 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
• 125000004193 piperazinyl group Chemical group 0.000 claims description 4
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
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• VNJBBYDSYFLEEE-UHFFFAOYSA-N CC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)C(NC1CN(CCC1)C)=O)OC Chemical compound CC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)C(NC1CN(CCC1)C)=O)OC VNJBBYDSYFLEEE-UHFFFAOYSA-N 0.000 claims description 3
• KMCOURQJISZVKR-UHFFFAOYSA-N CC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)C(NCC(C)(C)O)=O)OC Chemical compound CC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)C(NCC(C)(C)O)=O)OC KMCOURQJISZVKR-UHFFFAOYSA-N 0.000 claims description 3
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
• WRYZBCKSXQMHKO-UHFFFAOYSA-N N-(2,6-dimethylphenyl)-2-[2-methoxy-4-(oxan-4-ylcarbamoyl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide Chemical compound CC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)C(NC1CCOCC1)=O)OC WRYZBCKSXQMHKO-UHFFFAOYSA-N 0.000 claims description 3
• XPORPDHLTHKBQR-UHFFFAOYSA-N N-(2,6-dimethylphenyl)-2-[2-methoxy-4-[4-(2-methoxyacetyl)piperazin-1-yl]anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide Chemical compound CC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C(COC)=O)OC XPORPDHLTHKBQR-UHFFFAOYSA-N 0.000 claims description 3
• 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 3
• 125000000304 alkynyl group Chemical group 0.000 claims description 3
• 125000005169 cycloalkylcarbonylamino group Chemical group 0.000 claims description 3
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 3
• 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 3
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