JP2010536876A - Ｈｄａｃインヒビター - Google Patents

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Publication number

JP2010536876A

JP2010536876A JP2010522030A JP2010522030A JP2010536876A JP 2010536876 A JP2010536876 A JP 2010536876A JP 2010522030 A JP2010522030 A JP 2010522030A JP 2010522030 A JP2010522030 A JP 2010522030A JP 2010536876 A JP2010536876 A JP 2010536876A

Authority

JP

Japan

Prior art keywords

dihydro

pyrrolo

compound

amino

cancer

Prior art date

2007-08-21

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

Withdrawn

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• 239000003276 histone deacetylase inhibitor Substances 0.000 title description 8
• 229940121372 histone deacetylase inhibitor Drugs 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 144
• 238000000034 method Methods 0.000 claims abstract description 133
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 61
• 201000011510 cancer Diseases 0.000 claims abstract description 50
• 238000011282 treatment Methods 0.000 claims abstract description 44
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 35
• 230000002062 proliferating effect Effects 0.000 claims abstract description 23
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 15
• 206010025323 Lymphomas Diseases 0.000 claims abstract description 4
• 208000006994 Precancerous Conditions Diseases 0.000 claims abstract description 4
• 208000034578 Multiple myelomas Diseases 0.000 claims abstract description 3
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• 206010039491 Sarcoma Diseases 0.000 claims abstract 2
• 208000009956 adenocarcinoma Diseases 0.000 claims abstract 2
• 206010041823 squamous cell carcinoma Diseases 0.000 claims abstract 2
• -1 —CH 2 -aryl Chemical group 0.000 claims description 91
• 125000000217 alkyl group Chemical group 0.000 claims description 40
• 125000003118 aryl group Chemical group 0.000 claims description 40
• 210000004027 cell Anatomy 0.000 claims description 36
• 208000035475 disorder Diseases 0.000 claims description 27
• 229910052799 carbon Inorganic materials 0.000 claims description 24
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 22
• 125000001072 heteroaryl group Chemical group 0.000 claims description 21
• 229910052739 hydrogen Inorganic materials 0.000 claims description 16
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
• 150000003839 salts Chemical class 0.000 claims description 15
• 239000002246 antineoplastic agent Substances 0.000 claims description 13
• 229910052736 halogen Inorganic materials 0.000 claims description 13
• 150000002367 halogens Chemical class 0.000 claims description 13
• 229940127089 cytotoxic agent Drugs 0.000 claims description 12
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• 210000003169 central nervous system Anatomy 0.000 claims description 10
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
• 229920006395 saturated elastomer Polymers 0.000 claims description 10
• 229910052717 sulfur Inorganic materials 0.000 claims description 10
• CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 9
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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 claims description 8
• 229910052760 oxygen Inorganic materials 0.000 claims description 8
• FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 7
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
• 229960000485 methotrexate Drugs 0.000 claims description 7
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• RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 claims description 6
• AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 claims description 6
• JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 claims description 6
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• 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 claims description 5
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• 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
• RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 5
• AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 claims description 4
• ONEUCCISOJRBMM-UHFFFAOYSA-N 5,6-dihydro-4h-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid (5-hydroxy carbamoyl-pentyl)-amide Chemical compound C1CCC2=CC=CC3=C2N1C=C3C(=O)NCCCCCC(=O)NO ONEUCCISOJRBMM-UHFFFAOYSA-N 0.000 claims description 4
• HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 claims description 4
• BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 claims description 4
• 108010069236 Goserelin Proteins 0.000 claims description 4
• 208000023105 Huntington disease Diseases 0.000 claims description 4
• 239000005411 L01XE02 - Gefitinib Substances 0.000 claims description 4
• LZZMIITWPJDCBZ-UHFFFAOYSA-N N-[5-(hydroxyamino)-5-oxopentyl]-1-azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraene-3-carboxamide Chemical compound C1CCC2=CC=CC3=C2N1C=C3C(=O)NCCCCC(=O)NO LZZMIITWPJDCBZ-UHFFFAOYSA-N 0.000 claims description 4
• ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 4
• 229960001904 epirubicin Drugs 0.000 claims description 4
• XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 claims description 4
• SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 4
• MWNIBCCCJVALQB-UHFFFAOYSA-N n-[7-(hydroxyamino)-7-oxoheptyl]-6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazole-2-carboxamide Chemical compound COC1=CC=CC(C=2N=C3SC(=CN3C=2)C(=O)NCCCCCCC(=O)NO)=C1 MWNIBCCCJVALQB-UHFFFAOYSA-N 0.000 claims description 4
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
• 125000003107 substituted aryl group Chemical group 0.000 claims description 4
• 230000004083 survival effect Effects 0.000 claims description 4
• 208000011580 syndromic disease Diseases 0.000 claims description 4
• 229960001603 tamoxifen Drugs 0.000 claims description 4
• 230000004614 tumor growth Effects 0.000 claims description 4
• CYZDKOSGLHTOBO-UHFFFAOYSA-N 3-[1-(5,6-dihydro-4h-pyrrolo[3,2,1-ij]quinoline-1-carbonyl)-piperidin-4-yl]-n-hydroxy-propionamide Chemical compound C1CC(CCC(=O)NO)CCN1C(=O)C1=CN2C3=C1C=CC=C3CCC2 CYZDKOSGLHTOBO-UHFFFAOYSA-N 0.000 claims description 3
• WAFYQXMJDRSPSG-UHFFFAOYSA-N 4-[[2-(1-azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-3-yl)-2-oxoacetyl]amino]-N-hydroxybutanamide Chemical compound C1CCC2=CC=CC3=C2N1C=C3C(=O)C(=O)NCCCC(=O)NO WAFYQXMJDRSPSG-UHFFFAOYSA-N 0.000 claims description 3
• CYMDMEIWWITWNA-UHFFFAOYSA-N 4-[[2-(1-azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-3-yl)-2-oxoacetyl]amino]-N-hydroxypentanamide Chemical compound C1CCC2=CC=CC3=C2N1C=C3C(=O)C(=O)NC(CCC(=O)NO)C CYMDMEIWWITWNA-UHFFFAOYSA-N 0.000 claims description 3
• MVVPTNAUYQYMKV-UHFFFAOYSA-N 6-(1-azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-3-ylcarbamoylamino)-N-hydroxyhexanamide Chemical compound C1CCC2=CC=CC3=C2N1C=C3NC(=O)NCCCCCC(=O)NO MVVPTNAUYQYMKV-UHFFFAOYSA-N 0.000 claims description 3
• YNHWIAIXSNSJRH-UHFFFAOYSA-N 6-[[2-(1-azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-3-yl)-2-oxoacetyl]amino]-N-hydroxyhexanamide Chemical compound C1CCC2=CC=CC3=C2N1C=C3C(=O)C(=O)NCCCCCC(=O)NO YNHWIAIXSNSJRH-UHFFFAOYSA-N 0.000 claims description 3
• FTQMHSQPUYFMNX-UHFFFAOYSA-N 7-{[5,6-dihydro-4h-pyrrolo[3,2,1-ij]quinolin-1-yl(oxo)acetyl]amino}-n-hydroxyheptanamide Chemical compound C1CCC2=CC=CC3=C2N1C=C3C(=O)C(=O)NCCCCCCC(=O)NO FTQMHSQPUYFMNX-UHFFFAOYSA-N 0.000 claims description 3
• 208000024827 Alzheimer disease Diseases 0.000 claims description 3
• BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 claims description 3
• 101100002068 Bacillus subtilis (strain 168) araR gene Proteins 0.000 claims description 3
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• YXVYWXJQRXAWQI-UHFFFAOYSA-N N-[8-(hydroxyamino)-8-oxooctyl]-1-azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraene-3-carboxamide Chemical compound C1CCC2=CC=CC3=C2N1C=C3C(=O)NCCCCCCCC(=O)NO YXVYWXJQRXAWQI-UHFFFAOYSA-N 0.000 claims description 3
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• RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 claims description 3
• XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 claims description 3
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• 101150044616 araC gene Proteins 0.000 claims description 3
• VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 claims description 3
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• VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 3
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• DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 3
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