KR101699991B1 - 신규의 아미노 아자헤테로시클릭 카르복사미드 - Google Patents

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Publication number

KR101699991B1

KR101699991B1 KR1020117021335A KR20117021335A KR101699991B1 KR 101699991 B1 KR101699991 B1 KR 101699991B1 KR 1020117021335 A KR1020117021335 A KR 1020117021335A KR 20117021335 A KR20117021335 A KR 20117021335A KR 101699991 B1 KR101699991 B1 KR 101699991B1

Authority

KR

South Korea

Prior art keywords

quinazoline

carboxylic acid

phenyl

acid amide

ethylamino

Prior art date

2009-02-11

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

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• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 title claims description 52
• 150000003857 carboxamides Chemical class 0.000 title description 6
• -1 amino aza heterocyclic carboxamide compounds Chemical class 0.000 claims abstract description 451
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 30
• 201000011510 cancer Diseases 0.000 claims abstract description 24
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 24
• 201000010099 disease Diseases 0.000 claims abstract description 17
• 238000011282 treatment Methods 0.000 claims abstract description 17
• 230000003463 hyperproliferative effect Effects 0.000 claims abstract description 8
• 150000001875 compounds Chemical class 0.000 claims description 489
• 238000000034 method Methods 0.000 claims description 352
• 150000003839 salts Chemical class 0.000 claims description 48
• 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 44
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 40
• 239000012453 solvate Substances 0.000 claims description 31
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 28
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 24
• 229910052757 nitrogen Inorganic materials 0.000 claims description 22
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 20
• GYBHRTQLUQOYID-UHFFFAOYSA-N quinazoline-8-carboxamide Chemical compound N1=CN=C2C(C(=O)N)=CC=CC2=C1 GYBHRTQLUQOYID-UHFFFAOYSA-N 0.000 claims description 18
• 229920006395 saturated elastomer Polymers 0.000 claims description 15
• 239000008194 pharmaceutical composition Substances 0.000 claims description 14
• 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 13
• 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 13
• 239000004480 active ingredient Substances 0.000 claims description 11
• DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 claims description 11
• 150000002148 esters Chemical class 0.000 claims description 10
• 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 9
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 9
• 230000035755 proliferation Effects 0.000 claims description 9
• 125000004434 sulfur atom Chemical group 0.000 claims description 9
• 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 8
• 229910052731 fluorine Inorganic materials 0.000 claims description 8
• 238000004519 manufacturing process Methods 0.000 claims description 8
• 125000001424 substituent group Chemical group 0.000 claims description 8
• 229910052794 bromium Inorganic materials 0.000 claims description 7
• 125000004432 carbon atom Chemical group C* 0.000 claims description 7
• 229910052801 chlorine Inorganic materials 0.000 claims description 7
• 229910052760 oxygen Inorganic materials 0.000 claims description 7
• 125000000217 alkyl group Chemical group 0.000 claims description 6
• 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 6
• 239000003814 drug Substances 0.000 claims description 6
• 239000003937 drug carrier Substances 0.000 claims description 6
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
• 125000004076 pyridyl group Chemical group 0.000 claims description 6
• 201000004624 Dermatitis Diseases 0.000 claims description 5
• 206010012689 Diabetic retinopathy Diseases 0.000 claims description 5
• 201000004681 Psoriasis Diseases 0.000 claims description 5
• 206010038933 Retinopathy of prematurity Diseases 0.000 claims description 5
• 206010039710 Scleroderma Diseases 0.000 claims description 5
• 206010064930 age-related macular degeneration Diseases 0.000 claims description 5
• 208000010668 atopic eczema Diseases 0.000 claims description 5
• 201000001441 melanoma Diseases 0.000 claims description 5
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 5
• 230000005747 tumor angiogenesis Effects 0.000 claims description 5
• 125000003386 piperidinyl group Chemical group 0.000 claims description 4
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
• DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 claims description 4
• 125000000335 thiazolyl group Chemical group 0.000 claims description 4
• 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 3
• 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 3
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 3
• 125000000623 heterocyclic group Chemical group 0.000 claims description 3
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
• 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 2
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
• 208000007766 Kaposi sarcoma Diseases 0.000 claims description 2
• 125000000815 N-oxide group Chemical group 0.000 claims description 2
• 125000002947 alkylene group Chemical group 0.000 claims description 2
• 125000004429 atom Chemical group 0.000 claims description 2
• RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 claims description 2
• 229910052740 iodine Inorganic materials 0.000 claims description 2
• 125000002950 monocyclic group Chemical group 0.000 claims description 2
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
• 125000006413 ring segment Chemical group 0.000 claims description 2
• 208000017520 skin disease Diseases 0.000 claims description 2
• 229910052727 yttrium Inorganic materials 0.000 claims description 2
• 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 4
• YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 claims 4
• 208000017169 kidney disease Diseases 0.000 claims 4
• 208000037803 restenosis Diseases 0.000 claims 4
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims 3
• 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims 3
• 206010039491 Sarcoma Diseases 0.000 claims 3
• GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims 2
• UFMCGKYLIYMLOY-CQSZACIVSA-N 4-[[(1s)-2-amino-1-phenylethyl]amino]quinazoline-8-carboxamide Chemical compound C1([C@H](NC=2C3=CC=CC(=C3N=CN=2)C(N)=O)CN)=CC=CC=C1 UFMCGKYLIYMLOY-CQSZACIVSA-N 0.000 claims 2
• 229960002504 capsaicin Drugs 0.000 claims 2
• 235000017663 capsaicin Nutrition 0.000 claims 2
• GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 claims 2
• 125000000896 monocarboxylic acid group Chemical group 0.000 claims 2
• UPGZAERNNNZSPM-UHFFFAOYSA-N quinazoline-8-carboxylic acid Chemical compound N1=CN=C2C(C(=O)O)=CC=CC2=C1 UPGZAERNNNZSPM-UHFFFAOYSA-N 0.000 claims 2
• YNPQIFHMRSVLHW-CQSZACIVSA-N 4-[[(1r)-1-[3-(1,3-benzodioxole-5-carbonylamino)phenyl]ethyl]amino]quinazoline-8-carboxamide Chemical compound C1=C2OCOC2=CC(C(=O)NC=2C=CC=C(C=2)[C@H](NC=2C3=CC=CC(=C3N=CN=2)C(N)=O)C)=C1 YNPQIFHMRSVLHW-CQSZACIVSA-N 0.000 claims 1
• VQTZMSIOEYJERT-ZVDHGWRTSA-N 4-[[(1r)-1-[3-[(2,2-difluorocyclopropanecarbonyl)amino]phenyl]ethyl]amino]quinazoline-8-carboxamide Chemical compound C=1C([C@H](NC=2C3=CC=CC(=C3N=CN=2)C(N)=O)C)=CC=CC=1NC(=O)C1CC1(F)F VQTZMSIOEYJERT-ZVDHGWRTSA-N 0.000 claims 1
• NXUJCUODKLXIPE-CQSZACIVSA-N 4-[[(1r)-1-[3-[(2-methoxypyridine-4-carbonyl)amino]phenyl]ethyl]amino]quinazoline-8-carboxamide Chemical compound C1=NC(OC)=CC(C(=O)NC=2C=C(C=CC=2)[C@@H](C)NC=2C3=CC=CC(=C3N=CN=2)C(N)=O)=C1 NXUJCUODKLXIPE-CQSZACIVSA-N 0.000 claims 1
• SHFIJZVQMKWQNN-CYBMUJFWSA-N 4-[[(1r)-1-[3-[(5-chloro-6-methoxypyridine-3-carbonyl)amino]phenyl]ethyl]amino]quinazoline-8-carboxamide Chemical compound C1=C(Cl)C(OC)=NC=C1C(=O)NC1=CC=CC([C@@H](C)NC=2C3=CC=CC(=C3N=CN=2)C(N)=O)=C1 SHFIJZVQMKWQNN-CYBMUJFWSA-N 0.000 claims 1
• SRJJNRIRROSSLD-CQSZACIVSA-N 4-[[(1r)-1-[3-[(5-tert-butyl-1h-pyrazole-3-carbonyl)amino]phenyl]ethyl]amino]quinazoline-8-carboxamide Chemical compound C=1C([C@H](NC=2C3=CC=CC(=C3N=CN=2)C(N)=O)C)=CC=CC=1NC(=O)C1=CC(C(C)(C)C)=NN1 SRJJNRIRROSSLD-CQSZACIVSA-N 0.000 claims 1
• GLMIBJBCEWSYSZ-CQSZACIVSA-N 4-[[(1r)-1-[3-[(6-cyanopyridine-3-carbonyl)amino]phenyl]ethyl]amino]quinazoline-8-carboxamide Chemical compound C=1C([C@H](NC=2C3=CC=CC(=C3N=CN=2)C(N)=O)C)=CC=CC=1NC(=O)C1=CC=C(C#N)N=C1 GLMIBJBCEWSYSZ-CQSZACIVSA-N 0.000 claims 1
• GTUAZZUFAUMXII-CQSZACIVSA-N 4-[[(1r)-1-[3-[(6-methoxypyridine-3-carbonyl)amino]phenyl]ethyl]amino]quinazoline-8-carboxamide Chemical compound C1=NC(OC)=CC=C1C(=O)NC1=CC=CC([C@@H](C)NC=2C3=CC=CC(=C3N=CN=2)C(N)=O)=C1 GTUAZZUFAUMXII-CQSZACIVSA-N 0.000 claims 1
• RBMOLIOJAWRTIV-OAHLLOKOSA-N 4-[[(1s)-1-(3-fluorophenyl)-2-(methylamino)ethyl]amino]quinazoline-8-carboxamide Chemical compound C1([C@H](NC=2C3=CC=CC(=C3N=CN=2)C(N)=O)CNC)=CC=CC(F)=C1 RBMOLIOJAWRTIV-OAHLLOKOSA-N 0.000 claims 1
• GEECDZLHNUPFCU-MRXNPFEDSA-N 4-[[(1s)-2-(ethylamino)-1-(3-fluorophenyl)ethyl]amino]quinazoline-8-carboxamide Chemical compound C1([C@H](NC=2C3=CC=CC(=C3N=CN=2)C(N)=O)CNCC)=CC=CC(F)=C1 GEECDZLHNUPFCU-MRXNPFEDSA-N 0.000 claims 1
• XAVPWAIYBBCDNE-QGZVFWFLSA-N 4-[[(1s)-2-(ethylamino)-1-phenylethyl]amino]-6-methoxyquinazoline-8-carboxamide Chemical compound C1([C@H](NC=2C3=CC(OC)=CC(=C3N=CN=2)C(N)=O)CNCC)=CC=CC=C1 XAVPWAIYBBCDNE-QGZVFWFLSA-N 0.000 claims 1
• HITVHYHCWXALKZ-MRXNPFEDSA-N 4-[[(1s)-2-(ethylamino)-1-phenylethyl]amino]quinazoline-8-carboxamide Chemical compound C1([C@H](NC=2C3=CC=CC(=C3N=CN=2)C(N)=O)CNCC)=CC=CC=C1 HITVHYHCWXALKZ-MRXNPFEDSA-N 0.000 claims 1
• AGDQZNITYJKXQO-UHFFFAOYSA-N 4-[[1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl]amino]quinazoline-8-carboxamide Chemical compound N=1C=NC2=C(C(N)=O)C=CC=C2C=1NC(CN(C)C)C1=CC=C(Cl)C(Cl)=C1 AGDQZNITYJKXQO-UHFFFAOYSA-N 0.000 claims 1
• ODIBHBBABRKJIO-UHFFFAOYSA-N 4-[[1-(3-chlorophenyl)-2-(dimethylamino)ethyl]amino]quinazoline-8-carboxamide Chemical compound N=1C=NC2=C(C(N)=O)C=CC=C2C=1NC(CN(C)C)C1=CC=CC(Cl)=C1 ODIBHBBABRKJIO-UHFFFAOYSA-N 0.000 claims 1
• OPYPJZSJHHSMJL-UHFFFAOYSA-N 4-[[1-(3-chlorophenyl)-2-(methylamino)ethyl]amino]-6-phenylmethoxyquinazoline-8-carboxamide Chemical compound C=1C=CC(Cl)=CC=1C(CNC)NC(C1=C2)=NC=NC1=C(C(N)=O)C=C2OCC1=CC=CC=C1 OPYPJZSJHHSMJL-UHFFFAOYSA-N 0.000 claims 1
• LAJUPICIRDRINN-UHFFFAOYSA-N 4-[[1-(3-chlorophenyl)-2-(methylamino)ethyl]amino]quinazoline-8-carboxamide Chemical compound N=1C=NC2=C(C(N)=O)C=CC=C2C=1NC(CNC)C1=CC=CC(Cl)=C1 LAJUPICIRDRINN-UHFFFAOYSA-N 0.000 claims 1
• ZJKRQNYRWHKMJV-UHFFFAOYSA-N 4-[[1-(4-methoxyphenyl)-2-(methylamino)ethyl]amino]quinazoline-8-carboxamide Chemical compound N=1C=NC2=C(C(N)=O)C=CC=C2C=1NC(CNC)C1=CC=C(OC)C=C1 ZJKRQNYRWHKMJV-UHFFFAOYSA-N 0.000 claims 1
• PPACVGVOVMKIML-UHFFFAOYSA-N 4-[[2-(dimethylamino)-1-(3-nitrophenyl)ethyl]amino]quinazoline-8-carboxamide Chemical compound N=1C=NC2=C(C(N)=O)C=CC=C2C=1NC(CN(C)C)C1=CC=CC([N+]([O-])=O)=C1 PPACVGVOVMKIML-UHFFFAOYSA-N 0.000 claims 1
• IUEUJHZZCUYXKU-UHFFFAOYSA-N 4-[[2-(dimethylamino)-1-[3-[(4-methoxybenzoyl)amino]phenyl]ethyl]amino]quinazoline-8-carboxamide Chemical compound C1=CC(OC)=CC=C1C(=O)NC1=CC=CC(C(CN(C)C)NC=2C3=CC=CC(=C3N=CN=2)C(N)=O)=C1 IUEUJHZZCUYXKU-UHFFFAOYSA-N 0.000 claims 1
• ZHHSRQFICBOYCE-UHFFFAOYSA-N 4-[[2-(methylamino)-1-[3-[[4-(trifluoromethoxy)benzoyl]amino]phenyl]ethyl]amino]quinazoline-8-carboxamide Chemical compound N=1C=NC2=C(C(N)=O)C=CC=C2C=1NC(CNC)C(C=1)=CC=CC=1NC(=O)C1=CC=C(OC(F)(F)F)C=C1 ZHHSRQFICBOYCE-UHFFFAOYSA-N 0.000 claims 1
• VXICAQQGSOIIMS-UHFFFAOYSA-N 4-[[2-amino-1-(3-chlorophenyl)ethyl]amino]quinazoline-8-carboxamide Chemical compound N=1C=NC2=C(C(N)=O)C=CC=C2C=1NC(CN)C1=CC=CC(Cl)=C1 VXICAQQGSOIIMS-UHFFFAOYSA-N 0.000 claims 1
• PRHCRPUDJXUXCO-UHFFFAOYSA-N 4-[[2-amino-1-(4-methoxyphenyl)ethyl]amino]quinazoline-8-carboxamide Chemical compound C1=CC(OC)=CC=C1C(CN)NC1=NC=NC2=C(C(N)=O)C=CC=C12 PRHCRPUDJXUXCO-UHFFFAOYSA-N 0.000 claims 1
• YZSOMODRJHNWOR-UHFFFAOYSA-N 4-[[4-(trifluoromethyl)phenyl]methylamino]quinazoline-8-carboxamide Chemical compound N1=CN=C2C(C(=O)N)=CC=CC2=C1NCC1=CC=C(C(F)(F)F)C=C1 YZSOMODRJHNWOR-UHFFFAOYSA-N 0.000 claims 1
• BXSXPCFESWIUHR-UHFFFAOYSA-N 4-[[4-chloro-3-(trifluoromethyl)phenyl]methylamino]quinazoline-8-carboxamide Chemical compound N1=CN=C2C(C(=O)N)=CC=CC2=C1NCC1=CC=C(Cl)C(C(F)(F)F)=C1 BXSXPCFESWIUHR-UHFFFAOYSA-N 0.000 claims 1
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 1
• 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims 1
• 238000007429 general method Methods 0.000 claims 1
• 238000002360 preparation method Methods 0.000 abstract description 167
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• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 126
• 235000019439 ethyl acetate Nutrition 0.000 description 110
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