BRPI1008325A2 - carboxamidas azaeterocíclicas de amino - Google Patents

Info

Publication number

BRPI1008325A2

BRPI1008325A2 BRPI1008325-1A BRPI1008325A BRPI1008325A2 BR PI1008325 A2 BRPI1008325 A2 BR PI1008325A2 BR PI1008325 A BRPI1008325 A BR PI1008325A BR PI1008325 A2 BRPI1008325 A2 BR PI1008325A2

Authority

BR

Brazil

Prior art keywords

amino

carboxylic acid

phenyl

quinazoline

methoxy

Prior art date

2009-02-11

Links

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• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 title claims description 359
• 150000003857 carboxamides Chemical class 0.000 title abstract description 8
• -1 AMINO Chemical class 0.000 claims abstract description 343
• 238000002360 preparation method Methods 0.000 claims abstract description 167
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 31
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 30
• 201000010099 disease Diseases 0.000 claims abstract description 27
• 201000011510 cancer Diseases 0.000 claims abstract description 21
• 230000003463 hyperproliferative effect Effects 0.000 claims abstract description 9
• 150000001875 compounds Chemical class 0.000 claims description 470
• 238000000034 method Methods 0.000 claims description 348
• 229910052757 nitrogen Inorganic materials 0.000 claims description 126
• 150000003839 salts Chemical class 0.000 claims description 100
• 150000001408 amides Chemical class 0.000 claims description 99
• 229910052739 hydrogen Inorganic materials 0.000 claims description 59
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 56
• 239000002253 acid Substances 0.000 claims description 55
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 54
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 53
• 229910052727 yttrium Inorganic materials 0.000 claims description 51
• 229910052760 oxygen Inorganic materials 0.000 claims description 42
• 239000002904 solvent Substances 0.000 claims description 40
• 239000000651 prodrug Substances 0.000 claims description 31
• 229940002612 prodrug Drugs 0.000 claims description 31
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 27
• 239000012453 solvate Substances 0.000 claims description 27
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 26
• 229910052799 carbon Inorganic materials 0.000 claims description 18
• UPGZAERNNNZSPM-UHFFFAOYSA-N quinazoline-8-carboxylic acid Chemical compound N1=CN=C2C(C(=O)O)=CC=CC2=C1 UPGZAERNNNZSPM-UHFFFAOYSA-N 0.000 claims description 17
• 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 14
• 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 14
• 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 14
• 229920006395 saturated elastomer Polymers 0.000 claims description 14
• 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 13
• DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 claims description 12
• 239000008194 pharmaceutical composition Substances 0.000 claims description 12
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 10
• 125000002672 4-bromobenzoyl group Chemical group BrC1=CC=C(C(=O)*)C=C1 0.000 claims description 9
• 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 9
• 239000004480 active ingredient Substances 0.000 claims description 8
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
• 239000003814 drug Substances 0.000 claims description 8
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 8
• 230000008569 process Effects 0.000 claims description 8
• 125000004434 sulfur atom Chemical group 0.000 claims description 8
• 125000000217 alkyl group Chemical group 0.000 claims description 7
• 125000004432 carbon atom Chemical group C* 0.000 claims description 7
• 239000004615 ingredient Substances 0.000 claims description 7
• 206010061218 Inflammation Diseases 0.000 claims description 6
• 230000033115 angiogenesis Effects 0.000 claims description 6
• 230000004054 inflammatory process Effects 0.000 claims description 6
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 5
• 206010012601 diabetes mellitus Diseases 0.000 claims description 5
• 239000003937 drug carrier Substances 0.000 claims description 5
• 210000002307 prostate Anatomy 0.000 claims description 5
• 125000004076 pyridyl group Chemical group 0.000 claims description 5
• 201000004624 Dermatitis Diseases 0.000 claims description 4
• 206010012689 Diabetic retinopathy Diseases 0.000 claims description 4
• 208000032612 Glial tumor Diseases 0.000 claims description 4
• 206010018338 Glioma Diseases 0.000 claims description 4
• 201000004681 Psoriasis Diseases 0.000 claims description 4
• 208000010668 atopic eczema Diseases 0.000 claims description 4
• 125000004744 butyloxycarbonyl group Chemical group 0.000 claims description 4
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 4
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 4
• 201000001441 melanoma Diseases 0.000 claims description 4
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 4
• 125000003386 piperidinyl group Chemical group 0.000 claims description 4
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
• 208000017520 skin disease Diseases 0.000 claims description 4
• 125000000335 thiazolyl group Chemical group 0.000 claims description 4
• 230000004862 vasculogenesis Effects 0.000 claims description 4
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
• 208000007766 Kaposi sarcoma Diseases 0.000 claims description 3
• 206010064930 age-related macular degeneration Diseases 0.000 claims description 3
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
• 125000000623 heterocyclic group Chemical group 0.000 claims description 3
• 208000002780 macular degeneration Diseases 0.000 claims description 3
• 125000002950 monocyclic group Chemical group 0.000 claims description 3
• 125000001424 substituent group Chemical group 0.000 claims description 3
• 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 2
• 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 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
• HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 2
• 125000004122 cyclic group Chemical group 0.000 claims description 2
• 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 2
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
• ABVYZAMNSCVWJA-UHFFFAOYSA-N quinazoline-2-carboxamide Chemical compound C1=CC=CC2=NC(C(=O)N)=NC=C21 ABVYZAMNSCVWJA-UHFFFAOYSA-N 0.000 claims description 2
• 125000006413 ring segment Chemical group 0.000 claims description 2
• 239000000344 soap Substances 0.000 claims description 2
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
• 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims 3
• 208000002193 Pain Diseases 0.000 claims 3
• 206010033645 Pancreatitis Diseases 0.000 claims 3
• 206010038933 Retinopathy of prematurity Diseases 0.000 claims 3
• 201000011066 hemangioma Diseases 0.000 claims 3
• 206010020718 hyperplasia Diseases 0.000 claims 3
• 208000019423 liver disease Diseases 0.000 claims 3
• 208000037803 restenosis Diseases 0.000 claims 3
• 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims 2
• 230000005747 tumor angiogenesis Effects 0.000 claims 2
• ATTVPTRJHXBZTN-UHFFFAOYSA-N 4-[1-[3-[(4-bromobenzoyl)amino]phenyl]ethylamino]quinazoline-8-carboxylic acid Chemical compound BrC1=CC=C(C(=O)NC=2C=C(C=CC=2)C(C)NC2=NC=NC3=C(C=CC=C23)C(=O)O)C=C1 ATTVPTRJHXBZTN-UHFFFAOYSA-N 0.000 claims 1
• TUVCZMWCKOCSGF-CQSZACIVSA-N 4-[[(1r)-1-[3-[(5-propan-2-yl-1h-pyrazole-3-carbonyl)amino]phenyl]ethyl]amino]quinazoline-8-carboxamide Chemical compound N1C(C(C)C)=CC(C(=O)NC=2C=C(C=CC=2)[C@@H](C)NC=2C3=CC=CC(=C3N=CN=2)C(N)=O)=N1 TUVCZMWCKOCSGF-CQSZACIVSA-N 0.000 claims 1
• MUTXAXOXPDZSGG-MRXNPFEDSA-N 4-[[(1s)-2-amino-1-phenylethyl]amino]quinoline-8-carboxamide Chemical compound C1([C@H](NC=2C3=CC=CC(=C3N=CC=2)C(N)=O)CN)=CC=CC=C1 MUTXAXOXPDZSGG-MRXNPFEDSA-N 0.000 claims 1
• YRQSEFHVBKRZFV-UHFFFAOYSA-N 4-[[1-[3-[(4-bromobenzoyl)amino]phenyl]-2-(dimethylamino)ethyl]amino]quinazoline-8-carboxamide Chemical compound N=1C=NC2=C(C(N)=O)C=CC=C2C=1NC(CN(C)C)C(C=1)=CC=CC=1NC(=O)C1=CC=C(Br)C=C1 YRQSEFHVBKRZFV-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
• PSRICGLSQBZSDR-UHFFFAOYSA-N 4-[[2-(dimethylamino)-1-[3-[(4-methoxybenzoyl)amino]phenyl]ethyl]amino]quinazoline-8-carboxylic acid Chemical compound COc1ccc(cc1)C(=O)Nc1cccc(c1)C(CN(C)C)Nc1ncnc2c(cccc12)C(O)=O PSRICGLSQBZSDR-UHFFFAOYSA-N 0.000 claims 1
• IKONXWFEIGCAGN-UHFFFAOYSA-N 4-[[2-amino-1-(3-fluorophenyl)ethyl]amino]quinazoline-8-carboxamide Chemical compound N=1C=NC2=C(C(N)=O)C=CC=C2C=1NC(CN)C1=CC=CC(F)=C1 IKONXWFEIGCAGN-UHFFFAOYSA-N 0.000 claims 1
• LJMKRAKDJVPMIO-UHFFFAOYSA-N 4-[[3-[(2,4-dichlorobenzoyl)amino]phenyl]methylamino]quinazoline-8-carboxamide Chemical compound N1=CN=C2C(C(=O)N)=CC=CC2=C1NCC(C=1)=CC=CC=1NC(=O)C1=CC=C(Cl)C=C1Cl LJMKRAKDJVPMIO-UHFFFAOYSA-N 0.000 claims 1
• DHNWCWGJFSTRBB-UHFFFAOYSA-N 4-[[3-[(2,4-difluorobenzoyl)amino]phenyl]methylamino]quinazoline-8-carboxamide Chemical compound N1=CN=C2C(C(=O)N)=CC=CC2=C1NCC(C=1)=CC=CC=1NC(=O)C1=CC=C(F)C=C1F DHNWCWGJFSTRBB-UHFFFAOYSA-N 0.000 claims 1
• FTCVWEWECUNCTD-UHFFFAOYSA-N 6-methoxy-4-[[4-(trifluoromethyl)phenyl]methylamino]quinazoline-8-carboxamide Chemical compound C12=CC(OC)=CC(C(N)=O)=C2N=CN=C1NCC1=CC=C(C(F)(F)F)C=C1 FTCVWEWECUNCTD-UHFFFAOYSA-N 0.000 claims 1
• UKWKLYFHSMNYKK-MRXNPFEDSA-N CNC[C@H](C1=CC(F)=CC=C1)NC(C1=CC(OC)=C2)=NC=NC1=C2C(O)=O Chemical compound CNC[C@H](C1=CC(F)=CC=C1)NC(C1=CC(OC)=C2)=NC=NC1=C2C(O)=O UKWKLYFHSMNYKK-MRXNPFEDSA-N 0.000 claims 1
• GYWHMEVTAFOHGR-UHFFFAOYSA-N COC1=C2C(=NC=NC2=C(C=C1)C(=O)O)NC(CNC)C1=CC=CC=C1 Chemical compound COC1=C2C(=NC=NC2=C(C=C1)C(=O)O)NC(CNC)C1=CC=CC=C1 GYWHMEVTAFOHGR-UHFFFAOYSA-N 0.000 claims 1
• WEVABJKJKCEINT-UHFFFAOYSA-N NCC(C1=CC(=C(C=C1)OC)OC)NC1=NC=NC2=C(C=CC=C12)C(=O)O Chemical compound NCC(C1=CC(=C(C=C1)OC)OC)NC1=NC=NC2=C(C=CC=C12)C(=O)O WEVABJKJKCEINT-UHFFFAOYSA-N 0.000 claims 1
• 206010039491 Sarcoma Diseases 0.000 claims 1
• 208000038018 age-related macular disease Diseases 0.000 claims 1
• 150000001733 carboxylic acid esters Chemical class 0.000 claims 1
• 230000007850 degeneration Effects 0.000 claims 1
• XPXMKIXDFWLRAA-UHFFFAOYSA-N hydrazinide Chemical compound [NH-]N XPXMKIXDFWLRAA-UHFFFAOYSA-N 0.000 claims 1
• PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims 1
• 229920001542 oligosaccharide Polymers 0.000 claims 1
• 150000002482 oligosaccharides Chemical class 0.000 claims 1
• JHLVEBNWCCKSGY-UHFFFAOYSA-N tert-butyl n-methylcarbamate Chemical compound CNC(=O)OC(C)(C)C JHLVEBNWCCKSGY-UHFFFAOYSA-N 0.000 claims 1
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 263
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 236
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• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 204
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• 239000000243 solution Substances 0.000 description 151
• 239000000047 product Substances 0.000 description 148
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• 239000002244 precipitate Substances 0.000 description 48
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• QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 44
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• 238000005481 NMR spectroscopy Methods 0.000 description 39
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• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 10
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