BRPI0611922A2 - compostos orgánicos - Google Patents
compostos orgánicos Download PDFInfo
- Publication number
- BRPI0611922A2 BRPI0611922A2 BRPI0611922-0A BRPI0611922A BRPI0611922A2 BR PI0611922 A2 BRPI0611922 A2 BR PI0611922A2 BR PI0611922 A BRPI0611922 A BR PI0611922A BR PI0611922 A2 BRPI0611922 A2 BR PI0611922A2
- Authority
- BR
- Brazil
- Prior art keywords
- phenyl
- oxo
- methylamino
- propionamide
- alkyl
- Prior art date
Links
- 150000002894 organic compounds Chemical class 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 71
- -1 substituents halogen Chemical class 0.000 claims description 112
- 125000000217 alkyl group Chemical group 0.000 claims description 64
- 150000003839 salts Chemical class 0.000 claims description 39
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 38
- 229940080818 propionamide Drugs 0.000 claims description 36
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 29
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 25
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 claims description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 22
- 201000010099 disease Diseases 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 19
- 230000002062 proliferating effect Effects 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 238000011282 treatment Methods 0.000 claims description 13
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 150000001408 amides Chemical class 0.000 claims description 8
- 150000001412 amines Chemical class 0.000 claims description 8
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 125000002619 bicyclic group Chemical group 0.000 claims description 6
- QRKPPWPLSQRGSU-UHFFFAOYSA-N diazepine-1-carboxylic acid Chemical compound OC(=O)N1C=CC=CC=N1 QRKPPWPLSQRGSU-UHFFFAOYSA-N 0.000 claims description 6
- 125000002950 monocyclic group Chemical group 0.000 claims description 6
- 125000001624 naphthyl group Chemical group 0.000 claims description 6
- 229910052705 radium Inorganic materials 0.000 claims description 6
- 229910052701 rubidium Inorganic materials 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 3
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 3
- 241000124008 Mammalia Species 0.000 claims description 3
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 3
- 210000000170 cell membrane Anatomy 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 230000008878 coupling Effects 0.000 claims description 3
- 239000007822 coupling agent Substances 0.000 claims description 3
- 238000010168 coupling process Methods 0.000 claims description 3
- 238000005859 coupling reaction Methods 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 125000000539 amino acid group Chemical group 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 10
- QDKWLJJOYIFEBS-UHFFFAOYSA-N 1-fluoro-4-$l^{1}-oxidanylbenzene Chemical group [O]C1=CC=C(F)C=C1 QDKWLJJOYIFEBS-UHFFFAOYSA-N 0.000 claims 8
- QKNFFJHHPCWXTH-UHFFFAOYSA-N 2-(methylamino)propanamide Chemical compound CNC(C)C(N)=O QKNFFJHHPCWXTH-UHFFFAOYSA-N 0.000 claims 2
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims 2
- 125000006332 fluoro benzoyl group Chemical group 0.000 claims 2
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims 2
- ZPZWUJHYFIHAHK-RDJZCZTQSA-N (2s)-2-(methylamino)-n-[(3s)-2-oxo-1-[2-oxo-2-(2-phenylethylamino)ethyl]azepan-3-yl]propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)CCCCN1CC(=O)NCCC1=CC=CC=C1 ZPZWUJHYFIHAHK-RDJZCZTQSA-N 0.000 claims 1
- DRIZXPSWQXTWQI-FQEVSTJZSA-N (2s)-2-(methylamino)-n-[2-oxo-1-[(3-phenoxyphenyl)methyl]-6-phenylpyridin-3-yl]propanamide Chemical compound C=1C=CC(OC=2C=CC=CC=2)=CC=1CN1C(=O)C(NC(=O)[C@H](C)NC)=CC=C1C1=CC=CC=C1 DRIZXPSWQXTWQI-FQEVSTJZSA-N 0.000 claims 1
- OIMPUPSJBKWJNM-FQEVSTJZSA-N (2s)-2-(methylamino)-n-[2-oxo-1-[(3-phenoxyphenyl)methyl]pyridin-3-yl]butanamide Chemical compound O=C1C(NC(=O)[C@@H](NC)CC)=CC=CN1CC1=CC=CC(OC=2C=CC=CC=2)=C1 OIMPUPSJBKWJNM-FQEVSTJZSA-N 0.000 claims 1
- ZIRVTKGJZRUKQL-QFIPXVFZSA-N (2s)-2-(methylamino)-n-[2-oxo-6-phenyl-1-[2-(2-phenylethylsulfonyl)ethyl]pyridin-3-yl]butanamide Chemical compound C=1C=CC=CC=1CCS(=O)(=O)CCN1C(=O)C(NC(=O)[C@@H](NC)CC)=CC=C1C1=CC=CC=C1 ZIRVTKGJZRUKQL-QFIPXVFZSA-N 0.000 claims 1
- PVPRFXTYPXMQRR-IBGZPJMESA-N (2s)-2-(methylamino)-n-[2-oxo-6-phenyl-1-[2-(2-phenylethylsulfonyl)ethyl]pyridin-3-yl]propanamide Chemical compound C=1C=CC=CC=1CCS(=O)(=O)CCN1C(=O)C(NC(=O)[C@H](C)NC)=CC=C1C1=CC=CC=C1 PVPRFXTYPXMQRR-IBGZPJMESA-N 0.000 claims 1
- QRAOJRVXRGMWJF-BPUTZDHNSA-N (2s)-2-[[2-[(3s)-3-[[(2s)-2-aminopropanoyl]amino]-2-oxoazepan-1-yl]acetyl]amino]-3-phenylpropanamide Chemical compound O=C1[C@@H](NC(=O)[C@@H](N)C)CCCCN1CC(=O)N[C@H](C(N)=O)CC1=CC=CC=C1 QRAOJRVXRGMWJF-BPUTZDHNSA-N 0.000 claims 1
- UFSQVPXRLDGSJZ-NRFANRHFSA-N (2s)-n-[1-[2-(1,3-dihydroisoindol-2-yl)-2-oxoethyl]-2-oxo-6-phenylpyridin-3-yl]-2-(methylamino)butanamide Chemical compound C1C2=CC=CC=C2CN1C(=O)CN1C(=O)C(NC(=O)[C@@H](NC)CC)=CC=C1C1=CC=CC=C1 UFSQVPXRLDGSJZ-NRFANRHFSA-N 0.000 claims 1
- MKVKWNPWVAMZHR-KRWDZBQOSA-N (2s)-n-[1-[2-(1,3-dihydroisoindol-2-yl)-2-oxoethyl]-2-oxo-6-phenylpyridin-3-yl]-2-(methylamino)propanamide Chemical compound C1C2=CC=CC=C2CN1C(=O)CN1C(=O)C(NC(=O)[C@H](C)NC)=CC=C1C1=CC=CC=C1 MKVKWNPWVAMZHR-KRWDZBQOSA-N 0.000 claims 1
- DSWQOVAEVMDMLK-NRFANRHFSA-N (2s)-n-[1-[2-(2,2-diphenylethylamino)-2-oxoethyl]-6-(4-fluorophenyl)-2-oxopyridin-3-yl]-2-(methylamino)propanamide Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)CNC(=O)CN1C(=O)C(NC(=O)[C@H](C)NC)=CC=C1C1=CC=C(F)C=C1 DSWQOVAEVMDMLK-NRFANRHFSA-N 0.000 claims 1
- IVIBCTPZKXRZTA-SXMXNQBWSA-N (2s)-n-[1-[2-[ethyl(1,2,3,4-tetrahydronaphthalen-1-yl)amino]acetyl]-6-(4-fluorophenyl)-2-oxopyridin-3-yl]-2-(methylamino)propanamide Chemical compound C1CCC2=CC=CC=C2C1N(CC)CC(=O)N(C(C(NC(=O)[C@H](C)NC)=CC=1)=O)C=1C1=CC=C(F)C=C1 IVIBCTPZKXRZTA-SXMXNQBWSA-N 0.000 claims 1
- YTUMXTFLWANXIS-QFIPXVFZSA-N (2s)-n-[1-[2-[ethyl-[(4-fluorophenyl)methyl]amino]-2-oxoethyl]-6-(4-fluorophenyl)-2-oxopyridin-3-yl]-2-(methylamino)butanamide Chemical compound C=1C=C(F)C=CC=1CN(CC)C(=O)CN1C(=O)C(NC(=O)[C@@H](NC)CC)=CC=C1C1=CC=C(F)C=C1 YTUMXTFLWANXIS-QFIPXVFZSA-N 0.000 claims 1
- DXKGERZQZOHAAR-SFHVURJKSA-N (2s)-n-[1-[3-(4-fluorophenoxy)benzoyl]-2-oxo-6-phenylpyridin-3-yl]-2-(methylamino)propanamide Chemical compound C=1C=CC(OC=2C=CC(F)=CC=2)=CC=1C(=O)N1C(=O)C(NC(=O)[C@H](C)NC)=CC=C1C1=CC=CC=C1 DXKGERZQZOHAAR-SFHVURJKSA-N 0.000 claims 1
- ZGSDFIXETSEZTL-SANMLTNESA-N (2s)-n-[1-[[3-(4-fluoro-n-methylanilino)phenyl]methyl]-6-(4-fluorophenyl)-2-oxopyridin-3-yl]-2-(methylamino)butanamide Chemical compound C=1C=CC(N(C)C=2C=CC(F)=CC=2)=CC=1CN1C(=O)C(NC(=O)[C@@H](NC)CC)=CC=C1C1=CC=C(F)C=C1 ZGSDFIXETSEZTL-SANMLTNESA-N 0.000 claims 1
- HYUUDCAZTPMEMW-VWLOTQADSA-N (2s)-n-[1-[[3-(4-fluorobenzoyl)phenyl]methyl]-6-(4-fluorophenyl)-2-oxopyridin-3-yl]-2-(methylamino)butanamide Chemical compound C=1C=CC(C(=O)C=2C=CC(F)=CC=2)=CC=1CN1C(=O)C(NC(=O)[C@@H](NC)CC)=CC=C1C1=CC=C(F)C=C1 HYUUDCAZTPMEMW-VWLOTQADSA-N 0.000 claims 1
- VLFJFYXYZQIBCT-VWLOTQADSA-N (2s)-n-[1-[[3-(4-fluorophenoxy)phenyl]methyl]-2-oxo-6-phenylpyridin-3-yl]-2-(methylamino)butanamide Chemical compound C=1C=CC(OC=2C=CC(F)=CC=2)=CC=1CN1C(=O)C(NC(=O)[C@@H](NC)CC)=CC=C1C1=CC=CC=C1 VLFJFYXYZQIBCT-VWLOTQADSA-N 0.000 claims 1
- BCEYTJDBPKAJAY-VWLOTQADSA-N (2s)-n-[1-[[3-(4-fluorophenoxy)phenyl]methyl]-6-(4-fluorophenyl)-2-oxopyridin-3-yl]-2-(methylamino)butanamide Chemical compound C=1C=CC(OC=2C=CC(F)=CC=2)=CC=1CN1C(=O)C(NC(=O)[C@@H](NC)CC)=CC=C1C1=CC=C(F)C=C1 BCEYTJDBPKAJAY-VWLOTQADSA-N 0.000 claims 1
- AYNHTWSWUQVRMQ-VWLOTQADSA-N (2s)-n-[1-[[3-(4-fluorophenyl)sulfonylphenyl]methyl]-2-oxo-6-phenylpyridin-3-yl]-2-(methylamino)butanamide Chemical compound C=1C=CC(S(=O)(=O)C=2C=CC(F)=CC=2)=CC=1CN1C(=O)C(NC(=O)[C@@H](NC)CC)=CC=C1C1=CC=CC=C1 AYNHTWSWUQVRMQ-VWLOTQADSA-N 0.000 claims 1
- MEZFCJCDQYQNCR-IBGZPJMESA-N (2s)-n-[1-[[3-(4-fluorophenyl)sulfonylphenyl]methyl]-2-oxo-6-phenylpyridin-3-yl]-2-(methylamino)propanamide Chemical compound C=1C=CC(S(=O)(=O)C=2C=CC(F)=CC=2)=CC=1CN1C(=O)C(NC(=O)[C@H](C)NC)=CC=C1C1=CC=CC=C1 MEZFCJCDQYQNCR-IBGZPJMESA-N 0.000 claims 1
- PAFBFPBLROZSBY-FQEVSTJZSA-N (2s)-n-[6-(4-fluorophenyl)-1-[2-[(4-fluorophenyl)methylamino]-2-oxoethyl]-2-oxopyridin-3-yl]-2-(methylamino)butanamide Chemical compound C=1C=C(F)C=CC=1CNC(=O)CN1C(=O)C(NC(=O)[C@@H](NC)CC)=CC=C1C1=CC=C(F)C=C1 PAFBFPBLROZSBY-FQEVSTJZSA-N 0.000 claims 1
- FACGLOMYPPLPLQ-SFHVURJKSA-N (2s)-n-[6-(4-fluorophenyl)-1-[[3-(4-fluorophenyl)sulfanylphenyl]methyl]-2-oxopyridin-3-yl]-2-(methylamino)propanamide Chemical compound C=1C=CC(SC=2C=CC(F)=CC=2)=CC=1CN1C(=O)C(NC(=O)[C@H](C)NC)=CC=C1C1=CC=C(F)C=C1 FACGLOMYPPLPLQ-SFHVURJKSA-N 0.000 claims 1
- NKPVOQWPPJVFKQ-VWLOTQADSA-N (2s)-n-[6-(4-fluorophenyl)-1-[[3-(4-fluorophenyl)sulfonylphenyl]methyl]-2-oxopyridin-3-yl]-2-(methylamino)butanamide Chemical compound C=1C=CC(S(=O)(=O)C=2C=CC(F)=CC=2)=CC=1CN1C(=O)C(NC(=O)[C@@H](NC)CC)=CC=C1C1=CC=C(F)C=C1 NKPVOQWPPJVFKQ-VWLOTQADSA-N 0.000 claims 1
- OUVQBOSBRWVKPE-LBOXEOMUSA-N (2s)-n-[6-(4-fluorophenyl)-2-oxo-1-[2-oxo-2-(1,2,3,4-tetrahydronaphthalen-1-ylamino)ethyl]pyridin-3-yl]-2-(methylamino)propanamide Chemical compound C1CCC2=CC=CC=C2C1NC(=O)CN1C(=O)C(NC(=O)[C@H](C)NC)=CC=C1C1=CC=C(F)C=C1 OUVQBOSBRWVKPE-LBOXEOMUSA-N 0.000 claims 1
- HAFNXRMVEZQARL-HKUYNNGSSA-N (3s)-6-[[(2s)-2-(methylamino)butanoyl]amino]-5-oxo-n-(2-phenylethyl)-2,3-dihydro-1h-indolizine-3-carboxamide Chemical compound O=C([C@@H]1CCC2=CC=C(C(N21)=O)NC(=O)[C@@H](NC)CC)NCCC1=CC=CC=C1 HAFNXRMVEZQARL-HKUYNNGSSA-N 0.000 claims 1
- LRANPJDWHYRCER-UHFFFAOYSA-N 1,2-diazepine Chemical compound N1C=CC=CC=N1 LRANPJDWHYRCER-UHFFFAOYSA-N 0.000 claims 1
- HWVYFJFAWRNQPE-SANMLTNESA-N C=1C=CC(NCC=2C=CC(F)=CC=2)=CC=1CN1C(=O)C(NC(=O)[C@@H](NC)CC)=CC=C1C1=CC=CC=C1 Chemical compound C=1C=CC(NCC=2C=CC(F)=CC=2)=CC=1CN1C(=O)C(NC(=O)[C@@H](NC)CC)=CC=C1C1=CC=CC=C1 HWVYFJFAWRNQPE-SANMLTNESA-N 0.000 claims 1
- QAYPFHIZJSDUSF-UHFFFAOYSA-N azepin-3-one Chemical compound O=C1C=CC=CN=C1 QAYPFHIZJSDUSF-UHFFFAOYSA-N 0.000 claims 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims 1
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- CEFUKQQDKWWARF-NMBKAPMMSA-N n-[(3s,6s,8as)-3-(2,3-dihydro-1h-inden-2-yloxymethyl)-5-oxo-2,3,6,7,8,8a-hexahydro-1h-indolizin-6-yl]-2-(methylamino)butanamide Chemical compound C1C2=CC=CC=C2CC1OC[C@@H]1CC[C@@H]2CC[C@H](NC(=O)C(NC)CC)C(=O)N21 CEFUKQQDKWWARF-NMBKAPMMSA-N 0.000 claims 1
- XWYZYCQNOJRXLI-JHMFPGRKSA-N n-[(3s,6s,8as)-3-[3-(4-fluorophenoxy)phenyl]-5-oxo-2,3,6,7,8,8a-hexahydro-1h-indolizin-6-yl]-2-(methylamino)butanamide Chemical compound C=1C([C@@H]2CC[C@@H]3CC[C@@H](C(N32)=O)NC(=O)C(NC)CC)=CC=CC=1OC1=CC=C(F)C=C1 XWYZYCQNOJRXLI-JHMFPGRKSA-N 0.000 claims 1
- MMPQWWQVUVFHRK-QTMSITBTSA-N n-[(3s,6s,8as)-5-oxo-3-(2-phenylethylsulfonylmethyl)-2,3,6,7,8,8a-hexahydro-1h-indolizin-6-yl]-2-(methylamino)propanamide Chemical compound C([C@@H]1CC[C@@H]2CC[C@@H](C(N21)=O)NC(=O)C(C)NC)S(=O)(=O)CCC1=CC=CC=C1 MMPQWWQVUVFHRK-QTMSITBTSA-N 0.000 claims 1
- 235000001968 nicotinic acid Nutrition 0.000 claims 1
- 239000011664 nicotinic acid Substances 0.000 claims 1
- 125000000547 substituted alkyl group Chemical group 0.000 claims 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 77
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 37
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 25
- 239000000203 mixture Substances 0.000 description 22
- 238000005481 NMR spectroscopy Methods 0.000 description 20
- 239000000460 chlorine Substances 0.000 description 20
- 238000003756 stirring Methods 0.000 description 20
- 206010028980 Neoplasm Diseases 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- 239000011541 reaction mixture Substances 0.000 description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 15
- 235000019439 ethyl acetate Nutrition 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
- 102100033189 Diablo IAP-binding mitochondrial protein Human genes 0.000 description 12
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 238000012512 characterization method Methods 0.000 description 11
- 101710101225 Diablo IAP-binding mitochondrial protein Proteins 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 9
- 201000011510 cancer Diseases 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 108091007065 BIRCs Proteins 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 102100024319 Intestinal-type alkaline phosphatase Human genes 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- 238000004587 chromatography analysis Methods 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000006907 apoptotic process Effects 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 5
- 102100037024 E3 ubiquitin-protein ligase XIAP Human genes 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 108700031544 X-Linked Inhibitor of Apoptosis Proteins 0.000 description 5
- 125000001475 halogen functional group Chemical group 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 102000004039 Caspase-9 Human genes 0.000 description 4
- 108090000566 Caspase-9 Proteins 0.000 description 4
- 102000011727 Caspases Human genes 0.000 description 4
- 108010076667 Caspases Proteins 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 101100381510 Mus musculus Bcl10 gene Proteins 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- YJVXITGDBMCJEU-NRFANRHFSA-N benzyl n-[(2s)-1-[[6-chloro-2-oxo-1-[(3-phenoxyphenyl)methyl]pyridin-3-yl]amino]-1-oxopropan-2-yl]-n-methylcarbamate Chemical compound CN([C@@H](C)C(=O)NC=1C(N(CC=2C=C(OC=3C=CC=CC=3)C=CC=2)C(Cl)=CC=1)=O)C(=O)OCC1=CC=CC=C1 YJVXITGDBMCJEU-NRFANRHFSA-N 0.000 description 4
- CZDAVNCGIMKPEP-SANMLTNESA-N benzyl n-methyl-n-[(2s)-1-oxo-1-[[2-oxo-1-[(3-phenoxyphenyl)methyl]-6-phenylpyridin-3-yl]amino]propan-2-yl]carbamate Chemical compound CN([C@@H](C)C(=O)NC=1C(N(CC=2C=C(OC=3C=CC=CC=3)C=CC=2)C(C=2C=CC=CC=2)=CC=1)=O)C(=O)OCC1=CC=CC=C1 CZDAVNCGIMKPEP-SANMLTNESA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 4
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- KWUOSYNEPXOKQA-UEWDXFNNSA-N (2s)-5-hydroxy-1-methyl-n-(2-phenylethyl)pyrrolidine-2-carboxamide Chemical compound CN1C(O)CC[C@H]1C(=O)NCCC1=CC=CC=C1 KWUOSYNEPXOKQA-UEWDXFNNSA-N 0.000 description 3
- JPHLZZHHKOBKQH-LBPRGKRZSA-N (4s)-4-benzyl-3-(4-bromobutanoyl)-1,3-oxazolidin-2-one Chemical compound C1OC(=O)N(C(=O)CCCBr)[C@H]1CC1=CC=CC=C1 JPHLZZHHKOBKQH-LBPRGKRZSA-N 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 3
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical class C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- 241000713321 Intracisternal A-particles Species 0.000 description 3
- 206010027476 Metastases Diseases 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 150000003863 ammonium salts Chemical class 0.000 description 3
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 3
- 239000011324 bead Substances 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- WRSQHQPXHPGOBV-OALUTQOASA-N ditert-butyl (3s)-3-[(4s)-4-benzyl-2-oxo-1,3-oxazolidine-3-carbonyl]diazinane-1,2-dicarboxylate Chemical compound CC(C)(C)OC(=O)N1N(C(=O)OC(C)(C)C)CCC[C@H]1C(=O)N1C(=O)OC[C@@H]1CC1=CC=CC=C1 WRSQHQPXHPGOBV-OALUTQOASA-N 0.000 description 3
- XZPKIPGHVFJWNN-HSZRJFAPSA-N ditert-butyl (3s)-3-carbamoyl-3-(2-phenylethyl)diazinane-1,2-dicarboxylate Chemical compound CC(C)(C)OC(=O)N1N(C(=O)OC(C)(C)C)CCC[C@]1(C(N)=O)CCC1=CC=CC=C1 XZPKIPGHVFJWNN-HSZRJFAPSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 108020001507 fusion proteins Proteins 0.000 description 3
- 102000037865 fusion proteins Human genes 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 208000020816 lung neoplasm Diseases 0.000 description 3
- 230000009401 metastasis Effects 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- OJGNVIIRCLSXRL-UHFFFAOYSA-N tert-butyl n-[6-chloro-2-oxo-1-[(3-phenoxyphenyl)methyl]pyridin-3-yl]carbamate Chemical compound O=C1C(NC(=O)OC(C)(C)C)=CC=C(Cl)N1CC1=CC=CC(OC=2C=CC=CC=2)=C1 OJGNVIIRCLSXRL-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- XZLAZKWKTVLZLN-LSLKUGRBSA-N (2s)-5-methoxy-1-methyl-n-(2-phenylethyl)pyrrolidine-2-carboxamide Chemical compound CN1C(OC)CC[C@H]1C(=O)NCCC1=CC=CC=C1 XZLAZKWKTVLZLN-LSLKUGRBSA-N 0.000 description 2
- MLXHSDCSBUGOLZ-JTQLQIEISA-N (3s)-1,2-bis[(2-methylpropan-2-yl)oxycarbonyl]diazinane-3-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@@H](C(O)=O)N1C(=O)OC(C)(C)C MLXHSDCSBUGOLZ-JTQLQIEISA-N 0.000 description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 description 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 2
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- DRIIALWPEHYWHX-UHFFFAOYSA-N C1(=CC=CC=C1)CCNC(=O)N1N=CC=CC=C1 Chemical compound C1(=CC=CC=C1)CCNC(=O)N1N=CC=CC=C1 DRIIALWPEHYWHX-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 101710156605 Diablo homolog, mitochondrial Proteins 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 238000012286 ELISA Assay Methods 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 2
- 102000001253 Protein Kinase Human genes 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 229910004298 SiO 2 Inorganic materials 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 230000006229 amino acid addition Effects 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 238000003782 apoptosis assay Methods 0.000 description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- KXJANVRZMZWSEC-IBGZPJMESA-N benzyl (3s)-3-(2-phenylethylcarbamoyl)diazinane-1-carboxylate Chemical compound O=C([C@H]1NN(CCC1)C(=O)OCC=1C=CC=CC=1)NCCC1=CC=CC=C1 KXJANVRZMZWSEC-IBGZPJMESA-N 0.000 description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000001516 cell proliferation assay Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 230000004761 fibrosis Effects 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 208000014829 head and neck neoplasm Diseases 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- 208000037841 lung tumor Diseases 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- 230000002438 mitochondrial effect Effects 0.000 description 2
- 229960005181 morphine Drugs 0.000 description 2
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229940117803 phenethylamine Drugs 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 230000005522 programmed cell death Effects 0.000 description 2
- 208000023958 prostate neoplasm Diseases 0.000 description 2
- 229940121649 protein inhibitor Drugs 0.000 description 2
- 239000012268 protein inhibitor Substances 0.000 description 2
- 108060006633 protein kinase Proteins 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 150000008054 sulfonate salts Chemical class 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- MQUZTINHMZQECR-INIZCTEOSA-N (2s)-2-(1,3-dioxoisoindol-2-yl)-5-oxo-5-phenylmethoxypentanoic acid Chemical compound C([C@@H](C(=O)O)N1C(C2=CC=CC=C2C1=O)=O)CC(=O)OCC1=CC=CC=C1 MQUZTINHMZQECR-INIZCTEOSA-N 0.000 description 1
- QIXDRLIEARGEQY-ZETCQYMHSA-N (2s)-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]butanoic acid Chemical compound CC[C@@H](C(O)=O)N(C)C(=O)OC(C)(C)C QIXDRLIEARGEQY-ZETCQYMHSA-N 0.000 description 1
- VLHQXRIIQSTJCQ-LURJTMIESA-N (2s)-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid Chemical compound OC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C VLHQXRIIQSTJCQ-LURJTMIESA-N 0.000 description 1
- VHSFUGXCSGOKJX-JTQLQIEISA-N (2s)-5-oxo-1-phenylmethoxycarbonylpyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCC(=O)N1C(=O)OCC1=CC=CC=C1 VHSFUGXCSGOKJX-JTQLQIEISA-N 0.000 description 1
- WGOIHPRRFBCVBZ-VKHMYHEASA-N (2s)-5-oxopyrrolidine-2-carboxamide Chemical compound NC(=O)[C@@H]1CCC(=O)N1 WGOIHPRRFBCVBZ-VKHMYHEASA-N 0.000 description 1
- RQYAKJJIFYWIJX-SFTDATJTSA-N (4s)-4-(1,3-dioxoisoindol-2-yl)-5-oxo-5-[(6s)-6-(2-phenylethylcarbamoyl)diazinan-1-yl]pentanoic acid Chemical compound O=C([C@@H]1CCCNN1C(=O)[C@@H](N1C(C2=CC=CC=C2C1=O)=O)CCC(=O)O)NCCC1=CC=CC=C1 RQYAKJJIFYWIJX-SFTDATJTSA-N 0.000 description 1
- OJOFMLDBXPDXLQ-VIFPVBQESA-N (4s)-4-benzyl-1,3-oxazolidin-2-one Chemical compound C1OC(=O)N[C@H]1CC1=CC=CC=C1 OJOFMLDBXPDXLQ-VIFPVBQESA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- ZNGWEEUXTBNKFR-UHFFFAOYSA-N 1,4-oxazepane Chemical compound C1CNCCOC1 ZNGWEEUXTBNKFR-UHFFFAOYSA-N 0.000 description 1
- BHIUNIKMGDDAGW-UHFFFAOYSA-N 1-(iodomethyl)-3-phenoxybenzene Chemical compound ICC1=CC=CC(OC=2C=CC=CC=2)=C1 BHIUNIKMGDDAGW-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- GQIRIWDEZSKOCN-UHFFFAOYSA-N 1-chloro-n,n,2-trimethylprop-1-en-1-amine Chemical compound CN(C)C(Cl)=C(C)C GQIRIWDEZSKOCN-UHFFFAOYSA-N 0.000 description 1
- HIYWOHBEPVGIQN-UHFFFAOYSA-N 1h-benzo[g]indole Chemical compound C1=CC=CC2=C(NC=C3)C3=CC=C21 HIYWOHBEPVGIQN-UHFFFAOYSA-N 0.000 description 1
- MMQJZQKFTWIATR-UHFFFAOYSA-N 1h-pyrazole;1h-pyrrole Chemical compound C=1C=CNC=1.C=1C=NNC=1 MMQJZQKFTWIATR-UHFFFAOYSA-N 0.000 description 1
- XWIYUCRMWCHYJR-UHFFFAOYSA-N 1h-pyrrolo[3,2-b]pyridine Chemical compound C1=CC=C2NC=CC2=N1 XWIYUCRMWCHYJR-UHFFFAOYSA-N 0.000 description 1
- JZPGURKWXUBQLP-UHFFFAOYSA-N 2-[[2-(2-methylpropylsulfanyl)-1,3-benzothiazol-6-yl]iminomethyl]phenol Chemical compound CC(C)CSC1=NC2=C(S1)C=C(C=C2)N=CC3=CC=CC=C3O JZPGURKWXUBQLP-UHFFFAOYSA-N 0.000 description 1
- AAPOELDYPINJTH-UHFFFAOYSA-N 2-iodo-n-(2-phenylethyl)acetamide Chemical compound ICC(=O)NCCC1=CC=CC=C1 AAPOELDYPINJTH-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- OKRUMSWHDWKGHA-UHFFFAOYSA-N 5-bromopentanoyl chloride Chemical compound ClC(=O)CCCCBr OKRUMSWHDWKGHA-UHFFFAOYSA-N 0.000 description 1
- RXGJTUSBYWCRBK-UHFFFAOYSA-M 5-methylphenazinium methyl sulfate Chemical compound COS([O-])(=O)=O.C1=CC=C2[N+](C)=C(C=CC=C3)C3=NC2=C1 RXGJTUSBYWCRBK-UHFFFAOYSA-M 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 102000010565 Apoptosis Regulatory Proteins Human genes 0.000 description 1
- 108010063104 Apoptosis Regulatory Proteins Proteins 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZLFJDUQFZNNQNP-LBPRGKRZSA-N C1C=CNN[C@@H]1C(=O)NCCC2=CC=CC=C2 Chemical compound C1C=CNN[C@@H]1C(=O)NCCC2=CC=CC=C2 ZLFJDUQFZNNQNP-LBPRGKRZSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 102000003952 Caspase 3 Human genes 0.000 description 1
- 108090000397 Caspase 3 Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 101150082208 DIABLO gene Proteins 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000002699 Digestive System Neoplasms Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 102100021239 G protein-activated inward rectifier potassium channel 2 Human genes 0.000 description 1
- 101710158550 G protein-activated inward rectifier potassium channel 2 Proteins 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000871228 Homo sapiens Diablo IAP-binding mitochondrial protein Proteins 0.000 description 1
- 102000040104 IAP family Human genes 0.000 description 1
- 108091069885 IAP family Proteins 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 238000010934 O-alkylation reaction Methods 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 208000031481 Pathologic Constriction Diseases 0.000 description 1
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 108010016555 SmacN7 peptide Proteins 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 241001582429 Tetracis Species 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000008385 Urogenital Neoplasms Diseases 0.000 description 1
- BTKMJKKKZATLBU-UHFFFAOYSA-N [2-(1,3-benzothiazol-2-yl)-1,3-benzothiazol-6-yl] dihydrogen phosphate Chemical compound C1=CC=C2SC(C3=NC4=CC=C(C=C4S3)OP(O)(=O)O)=NC2=C1 BTKMJKKKZATLBU-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 230000005775 apoptotic pathway Effects 0.000 description 1
- 230000005756 apoptotic signaling Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000005228 aryl sulfonate group Chemical group 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- PNPBGYBHLCEVMK-UHFFFAOYSA-N benzylidene(dichloro)ruthenium;tricyclohexylphosphanium Chemical compound Cl[Ru](Cl)=CC1=CC=CC=C1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1 PNPBGYBHLCEVMK-UHFFFAOYSA-N 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- PZBGOSHECXCYFN-UHFFFAOYSA-N diazinane-1,2-dicarboxylic acid Chemical compound OC(=O)N1CCCCN1C(O)=O PZBGOSHECXCYFN-UHFFFAOYSA-N 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- KZTYYGOKRVBIMI-UHFFFAOYSA-N diphenyl sulfone Chemical compound C=1C=CC=CC=1S(=O)(=O)C1=CC=CC=C1 KZTYYGOKRVBIMI-UHFFFAOYSA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- YRTCKZIKGWZNCU-UHFFFAOYSA-N furo[3,2-b]pyridine Chemical compound C1=CC=C2OC=CC2=N1 YRTCKZIKGWZNCU-UHFFFAOYSA-N 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 239000011984 grubbs catalyst Substances 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 125000004404 heteroalkyl group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000003919 heteronuclear multiple bond coherence Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 230000003463 hyperproliferative effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000006882 induction of apoptosis Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 208000026037 malignant tumor of neck Diseases 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- BCVXHSPFUWZLGQ-UHFFFAOYSA-N mecn acetonitrile Chemical compound CC#N.CC#N BCVXHSPFUWZLGQ-UHFFFAOYSA-N 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 238000006140 methanolysis reaction Methods 0.000 description 1
- UFEJKYYYVXYMMS-UHFFFAOYSA-N methylcarbamic acid Chemical compound CNC(O)=O UFEJKYYYVXYMMS-UHFFFAOYSA-N 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- YFLDHFZAVWZGAN-UHFFFAOYSA-N n-(2-phenylethyl)pyridazine-3-carboxamide Chemical compound C=1C=CN=NC=1C(=O)NCCC1=CC=CC=C1 YFLDHFZAVWZGAN-UHFFFAOYSA-N 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000006225 natural substrate Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 208000023983 oral cavity neoplasm Diseases 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000008823 permeabilization Effects 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical class OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 150000004291 polyenes Chemical group 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- LBKJNHPKYFYCLL-UHFFFAOYSA-N potassium;trimethyl(oxido)silane Chemical compound [K+].C[Si](C)(C)[O-] LBKJNHPKYFYCLL-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- YEYHFKBVNARCNE-UHFFFAOYSA-N pyrido[2,3-b]pyrazine Chemical compound N1=CC=NC2=CC=CN=C21 YEYHFKBVNARCNE-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 201000002793 renal fibrosis Diseases 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- WGRULTCAYDOGQK-UHFFFAOYSA-M sodium;sodium;hydroxide Chemical compound [OH-].[Na].[Na+] WGRULTCAYDOGQK-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- HNWRKOWMMUQXRW-UHFFFAOYSA-N tert-butyl n-(6-chloro-2-oxo-1h-pyridin-3-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=C(Cl)NC1=O HNWRKOWMMUQXRW-UHFFFAOYSA-N 0.000 description 1
- QKSQWQOAUQFORH-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonylimino]carbamate Chemical compound CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C QKSQWQOAUQFORH-UHFFFAOYSA-N 0.000 description 1
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- HYWCXWRMUZYRPH-UHFFFAOYSA-N trimethyl(prop-2-enyl)silane Chemical compound C[Si](C)(C)CC=C HYWCXWRMUZYRPH-UHFFFAOYSA-N 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/56—Amides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D223/08—Oxygen atoms
- C07D223/10—Oxygen atoms attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/06—Peri-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
- C07K5/1008—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pyridine Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US68863905P | 2005-06-08 | 2005-06-08 | |
| US60/688,639 | 2005-06-08 | ||
| PCT/US2006/021850 WO2006133147A2 (en) | 2005-06-08 | 2006-06-06 | Organic compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| BRPI0611922A2 true BRPI0611922A2 (pt) | 2010-10-05 |
Family
ID=37052743
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| BRPI0611922-0A BRPI0611922A2 (pt) | 2005-06-08 | 2006-06-06 | compostos orgánicos |
Country Status (11)
| Country | Link |
|---|---|
| US (2) | US7989441B2 (cg-RX-API-DMAC7.html) |
| EP (1) | EP1902065A2 (cg-RX-API-DMAC7.html) |
| JP (1) | JP2008545780A (cg-RX-API-DMAC7.html) |
| KR (1) | KR20080022092A (cg-RX-API-DMAC7.html) |
| CN (1) | CN101193908B (cg-RX-API-DMAC7.html) |
| AU (1) | AU2006255084A1 (cg-RX-API-DMAC7.html) |
| BR (1) | BRPI0611922A2 (cg-RX-API-DMAC7.html) |
| CA (1) | CA2610396A1 (cg-RX-API-DMAC7.html) |
| MX (1) | MX2007015419A (cg-RX-API-DMAC7.html) |
| RU (1) | RU2007147959A (cg-RX-API-DMAC7.html) |
| WO (1) | WO2006133147A2 (cg-RX-API-DMAC7.html) |
Families Citing this family (46)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5230865B2 (ja) | 2004-07-15 | 2013-07-10 | テトラロジック ファーマシューティカルズ コーポレーション | Ｉａｐ結合性化合物 |
| EA012810B1 (ru) | 2005-02-25 | 2009-12-30 | Тетралоджик Фармасеутикалс | Димерные ингибиторы ингибиторов белков апоптоза (iap) |
| AP2007004244A0 (en) | 2005-05-10 | 2007-12-31 | Intermune Inc | Method of modulating stress-activated protein kinase system |
| WO2006122408A1 (en) | 2005-05-18 | 2006-11-23 | Aegera Therapeutics Inc. | Bir domain binding compounds |
| AU2006308453B9 (en) | 2005-10-25 | 2011-12-01 | Pharmascience Inc. | IAP BIR domain binding compounds |
| WO2007101347A1 (en) * | 2006-03-07 | 2007-09-13 | Aegera Therapeutics Inc. | Bir domain binding compounds |
| TWI504597B (zh) | 2006-03-16 | 2015-10-21 | Pharmascience Inc | 結合於細胞凋亡抑制蛋白（ｉａｐ）之桿狀病毒ｉａｐ重複序列（ｂｉｒ）區域之化合物 |
| BRPI0711591A2 (pt) | 2006-05-16 | 2011-11-16 | Aegera Therapeutics, Inc. | composto de ligação de domìnio bir da iap |
| WO2008014229A2 (en) * | 2006-07-24 | 2008-01-31 | Tetralogic Pharmaceuticals Corporation | Dimeric iap inhibitors |
| JP5452223B2 (ja) | 2006-07-24 | 2014-03-26 | テトラロジック ファーマシューティカルズ コーポレーション | Ｉａｐ阻害剤 |
| MX2009000824A (es) | 2006-07-24 | 2009-02-04 | Tetralogic Pharmaceuticals Cor | Antagonistas dimericos de las proteinas inhibidoras de la apoptosis. |
| US20100056495A1 (en) * | 2006-07-24 | 2010-03-04 | Tetralogic Pharmaceuticals Corporation | Dimeric iap inhibitors |
| CA2670726A1 (en) | 2006-12-07 | 2008-06-19 | Novartis Ag | 6-oxo-1, 6-dihydropyrimidin-2-yls in the treatment of proliferative diseases |
| BRPI0720049A2 (pt) * | 2006-12-07 | 2014-01-07 | Novartis Ag | Derivados de piridina utilizados como inibidores de xiap |
| JP2010528587A (ja) * | 2007-05-07 | 2010-08-26 | テトラロジック ファーマシューティカルズ コーポレーション | アポトーシス阻害タンパク質のアンタゴニストに対する感受性のバイオマーカーとしてＴＮＦα遺伝子の発現を用いる方法 |
| US8871111B2 (en) * | 2008-03-18 | 2014-10-28 | Ngk Insulators, Ltd. | Piezoelectric/electrostrictive ceramic composition |
| EP2296653B1 (en) | 2008-06-03 | 2016-01-27 | Intermune, Inc. | Compounds and methods for treating inflammatory and fibrotic disorders |
| US20100317593A1 (en) * | 2009-06-12 | 2010-12-16 | Astrazeneca Ab | 2,3-dihydro-1h-indene compounds |
| US8283372B2 (en) | 2009-07-02 | 2012-10-09 | Tetralogic Pharmaceuticals Corp. | 2-(1H-indol-3-ylmethyl)-pyrrolidine dimer as a SMAC mimetic |
| NZ602368A (en) | 2010-02-12 | 2014-10-31 | Pharmascience Inc | Iap bir domain binding compounds |
| TW201249824A (en) | 2011-03-09 | 2012-12-16 | Glaxosmithkline Llc | Peptide deformylase inhibitors |
| JP2014528409A (ja) | 2011-09-30 | 2014-10-27 | テトラロジック ファーマシューティカルズ コーポレーション | 増殖性疾患（がん）の治療において使用するためのＳＭＡＣ模倣体（ビリナパント（ｂｉｒｉｎａｐａｎｔ）） |
| US8859541B2 (en) * | 2012-02-27 | 2014-10-14 | Boehringer Ingelheim International Gmbh | 6-alkynylpyridines |
| MX2015000362A (es) * | 2012-07-13 | 2015-04-14 | Hoffmann La Roche | Benzo(b)-azepin-2-onas antiproliferativas. |
| RU2015105561A (ru) | 2012-08-09 | 2016-09-27 | Ф. Хоффманн-Ля Рош Аг | Замещенные гетероазепиноны |
| BR112015004547A8 (pt) * | 2012-09-19 | 2018-01-23 | Hoffmann La Roche | compostos, composição farmacêutica, uso de um composto e método para o tratamento ou melhoria do cãncer |
| AR092742A1 (es) | 2012-10-02 | 2015-04-29 | Intermune Inc | Piridinonas antifibroticas |
| CA2896577C (en) | 2012-11-30 | 2024-01-23 | Sanford-Burnham Medical Research Institute | Inhibitor of apoptosis protein (iap) antagonists |
| KR20160030099A (ko) | 2013-06-25 | 2016-03-16 | 더 월터 앤드 엘리자 홀 인스티튜트 오브 메디컬 리서치 | 세포내 감염의 치료 방법 |
| CA2925084A1 (en) * | 2013-11-18 | 2015-05-21 | F. Hoffmann-La Roche Ag | Tetrahydro-benzodiazepinones |
| WO2015109391A1 (en) | 2014-01-24 | 2015-07-30 | Children's Hospital Of Eastern Ontario Research Institute Inc. | Smc combination therapy for the treatment of cancer |
| RU2692485C2 (ru) | 2014-04-02 | 2019-06-25 | Интермьюн, Инк. | Противофиброзные пиридиноны |
| JP6768522B2 (ja) | 2014-06-04 | 2020-10-14 | サンフォード−バーンハム メディカル リサーチ インスティテュート | Ｈｉｖ治療におけるアポトーシスタンパク質阻害剤（ｉａｐ）のアンタゴニストの使用 |
| AR101479A1 (es) | 2014-08-11 | 2016-12-21 | Boehringer Ingelheim Int | Derivados de 6-alquinil-piridina |
| WO2016079527A1 (en) | 2014-11-19 | 2016-05-26 | Tetralogic Birinapant Uk Ltd | Combination therapy |
| WO2016097773A1 (en) | 2014-12-19 | 2016-06-23 | Children's Cancer Institute | Therapeutic iap antagonists for treating proliferative disorders |
| EA038950B1 (ru) | 2016-05-19 | 2021-11-12 | Бёрингер Ингельхайм Интернациональ Гмбх | Способ получения производных 6-алкинил-пиридина |
| LT3552017T (lt) * | 2016-12-09 | 2022-05-10 | Denali Therapeutics Inc. | Junginiai, naudotini kaip ripk1 inhibitoriai |
| CN106674228B (zh) * | 2016-12-09 | 2018-12-04 | 河南农业大学 | 多元杂环化合物及其制备方法和用途 |
| CA3063938A1 (en) * | 2017-05-17 | 2018-11-22 | Denali Therapeutics Inc. | Compounds, compositions and methods |
| US12678509B2 (en) | 2019-11-08 | 2026-07-14 | Sanford Burnham Prebys Medical Discovery Institute | Inhibitor of apoptosis (IAP) protein antagonists |
| US20230056604A1 (en) | 2020-01-20 | 2023-02-23 | Astrazeneca Ab | Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of cancer |
| RS66874B1 (sr) * | 2020-09-17 | 2025-06-30 | Novartis Ag | Jedinjenja i kompozicije kao inhibitori sppl2a |
| KR20230153387A (ko) | 2021-02-02 | 2023-11-06 | 리미널 바이오사이언시스 리미티드 | Gpr84 길항제 및 이의 용도 |
| JP2024506858A (ja) | 2021-02-02 | 2024-02-15 | リミナル・バイオサイエンシーズ・リミテッド | Ｇｐｒ８４アンタゴニストおよびその使用 |
| WO2025061058A1 (en) * | 2023-09-18 | 2025-03-27 | Ascentage Pharma (Suzhou) Co., Ltd. | Novel compounds as iap antagonists |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5521179A (en) * | 1991-04-18 | 1996-05-28 | Zeneca Limited | Heterocyclic amides |
| GB9207145D0 (en) * | 1991-04-18 | 1992-05-13 | Ici Plc | Heterocyclic amides |
| US5283241A (en) * | 1992-08-28 | 1994-02-01 | Merck & Co., Inc. | Benzo-fused lactams promote release of growth hormone |
| US5434261A (en) * | 1993-07-26 | 1995-07-18 | Merck & Co., Inc. | Benzo-fused lactams promote release of growth hormone |
| JPH08225586A (ja) * | 1995-02-22 | 1996-09-03 | Fujisawa Pharmaceut Co Ltd | 新規リン酸誘導体、その製造法およびそれを含有する医薬組成物 |
| ATE310528T1 (de) * | 1996-09-12 | 2005-12-15 | Idun Pharmaceuticals Inc | Hemmung der apoptose unter verwendung von inhibitoren der interleukin-1 beta converting enzym (ice)/ced-3 familie |
| US6423519B1 (en) * | 1998-07-15 | 2002-07-23 | Gpc Biotech Inc. | Compositions and methods for inhibiting fungal growth |
| JP2005522430A (ja) | 2002-02-04 | 2005-07-28 | メルク エンド カムパニー インコーポレーテッド | グランザイムｂ阻害剤 |
| ATE400812T1 (de) * | 2003-02-07 | 2008-07-15 | Genentech Inc | Zusammensetzungen und verfahren für verstärkte apoptose |
| PE20050159A1 (es) * | 2003-05-27 | 2005-04-19 | Vertex Pharma | Derivados de acido 3-[2-(3-amino-2-oxo-2h-piridin-1-il)-acetilamino]-4-oxo-pentanoico como inhibidores de caspasa |
| BRPI0506883A (pt) * | 2004-01-16 | 2007-05-29 | Univ Michigan | miméticos de smac conformacionalmente comprimidos e seus usos |
| WO2006010118A2 (en) | 2004-07-09 | 2006-01-26 | The Regents Of The University Of Michigan | Conformationally constrained smac mimetics and the uses thereof |
| BRPI0513310A (pt) | 2004-07-12 | 2008-05-06 | Idun Pharmaceuticals Inc | análogos de tetrapeptìdeo |
| US7652703B2 (en) * | 2004-07-12 | 2010-01-26 | Micron Technology, Inc. | Dual panel pixel readout in an imager |
| WO2006122408A1 (en) * | 2005-05-18 | 2006-11-23 | Aegera Therapeutics Inc. | Bir domain binding compounds |
-
2006
- 2006-06-06 AU AU2006255084A patent/AU2006255084A1/en not_active Abandoned
- 2006-06-06 EP EP06760702A patent/EP1902065A2/en not_active Withdrawn
- 2006-06-06 KR KR1020077028586A patent/KR20080022092A/ko not_active Withdrawn
- 2006-06-06 US US11/916,887 patent/US7989441B2/en not_active Expired - Fee Related
- 2006-06-06 BR BRPI0611922-0A patent/BRPI0611922A2/pt not_active IP Right Cessation
- 2006-06-06 JP JP2008515811A patent/JP2008545780A/ja active Pending
- 2006-06-06 WO PCT/US2006/021850 patent/WO2006133147A2/en not_active Ceased
- 2006-06-06 MX MX2007015419A patent/MX2007015419A/es not_active Application Discontinuation
- 2006-06-06 RU RU2007147959/04A patent/RU2007147959A/ru not_active Application Discontinuation
- 2006-06-06 CA CA002610396A patent/CA2610396A1/en not_active Abandoned
- 2006-06-06 CN CN2006800202223A patent/CN101193908B/zh not_active Expired - Fee Related
-
2011
- 2011-06-15 US US13/161,166 patent/US20110281845A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| CN101193908B (zh) | 2012-04-11 |
| WO2006133147A2 (en) | 2006-12-14 |
| JP2008545780A (ja) | 2008-12-18 |
| WO2006133147A3 (en) | 2007-05-03 |
| RU2007147959A (ru) | 2009-07-20 |
| US20090069294A1 (en) | 2009-03-12 |
| CN101193908A (zh) | 2008-06-04 |
| EP1902065A2 (en) | 2008-03-26 |
| US7989441B2 (en) | 2011-08-02 |
| CA2610396A1 (en) | 2006-12-14 |
| US20110281845A1 (en) | 2011-11-17 |
| AU2006255084A1 (en) | 2006-12-14 |
| MX2007015419A (es) | 2008-02-21 |
| KR20080022092A (ko) | 2008-03-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101193908B (zh) | 有机化合物 | |
| CN112218859B (zh) | 蛋白水解调节剂及相关使用方法 | |
| EP2882740B1 (en) | Iap antagonists | |
| EP2917218B1 (en) | Macrocyclic compounds for inhibition of inhibitors of apoptosis | |
| JP3133073B2 (ja) | 成長ホルモンの放出を促進するジペプチド類 | |
| EP2897949B1 (en) | Iap antagonists | |
| JP4323169B2 (ja) | メラノコルチン−４受容体作働薬としてのアシル化ピペリジン誘導体 | |
| JP5669691B2 (ja) | グリコーゲンホスホリラーゼのピロロピリジン−２−カルボン酸アミドインヒビター | |
| TW202413351A (zh) | 藉由irak4抑制劑與e3連接酶配體的軛合降解irak4及使用方法 | |
| EP2861581B1 (en) | 1,2,3,4-Tetrahydroisoquinoline-pyrrolidine derivatives as antagonists of apoptosis (IAPs) for the treatment of cancer. | |
| EP2903998A1 (en) | Iap antagonists | |
| JP2011102312A (ja) | テトラペプチド類似体 | |
| KR20150058222A (ko) | 2-옥소-2,3,4,5-테트라하이드로-1h-벤조[b]다이아제핀 및 암 치료에서의 이의 용도 | |
| JP2009545613A (ja) | Ｉａｐ阻害剤として有用なｓｍａｃペプチド模倣物 | |
| WO2022223034A1 (zh) | Sos1降解剂及其制备方法和应用 | |
| KR20070014166A (ko) | 염증 질환 치료에 유용한 베타-카르볼린 | |
| EP1819332B1 (en) | Pyrrolopyridine-2-carboxylic acid amides | |
| CA2930032A1 (en) | Macrocyclic compounds for inhibition of inhibitors of apoptosis | |
| US5821241A (en) | Fibrinogen receptor antagonists | |
| Pulka et al. | Synthesis of 4-amino-3-oxo-tetrahydroazepino [3, 4-b] indoles: new conformationally constrained Trp analogs | |
| ES2348702T3 (es) | Amidas de acidos pirrolopiridina-2-carboxilicos inhibidores de la glucogeno-fosforilasa. | |
| HK40082196A (en) | Pyrido[2,3-b][1,4]oxazines or tetrahydropyrido[2,3-b][1,4]oxazepines as iap antagonists |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| B08F | Application dismissed because of non-payment of annual fees [chapter 8.6 patent gazette] |
Free format text: REFERENTE AS 5A E 6A ANUIDADES. |
|
| B08K | Patent lapsed as no evidence of payment of the annual fee has been furnished to inpi [chapter 8.11 patent gazette] |
Free format text: REFERENTE AO DESPACHO 8.6 PUBLICADO NA RPI 2161 DE 05/06/2012. |