JP2005514373A - ベンズアミド誘導体、その製造方法およびその医薬的使用 - Google Patents

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Publication number

JP2005514373A

JP2005514373A JP2003547365A JP2003547365A JP2005514373A JP 2005514373 A JP2005514373 A JP 2005514373A JP 2003547365 A JP2003547365 A JP 2003547365A JP 2003547365 A JP2003547365 A JP 2003547365A JP 2005514373 A JP2005514373 A JP 2005514373A

Authority

JP

Japan

Prior art keywords

formula

benzyl

compound

benzamide

hydroxypentyl

Prior art date

2001-11-30

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.)

Pending

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• 238000000034 method Methods 0.000 title claims abstract description 22
• 230000008569 process Effects 0.000 title claims abstract description 5
• 150000003936 benzamides Chemical class 0.000 title 1
• 102000013455 Amyloid beta-Peptides Human genes 0.000 claims abstract description 24
• 108010090849 Amyloid beta-Peptides Proteins 0.000 claims abstract description 24
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 17
• 238000011282 treatment Methods 0.000 claims abstract description 17
• 201000010099 disease Diseases 0.000 claims abstract description 15
• 238000001556 precipitation Methods 0.000 claims abstract description 15
• 150000001875 compounds Chemical class 0.000 claims description 140
• -1 3,3-dimethyl-butylcarbamoyl Chemical group 0.000 claims description 69
• 125000000217 alkyl group Chemical group 0.000 claims description 35
• 239000002904 solvent Substances 0.000 claims description 23
• 150000003839 salts Chemical class 0.000 claims description 21
• 125000003118 aryl group Chemical group 0.000 claims description 18
• 239000001257 hydrogen Substances 0.000 claims description 16
• 229910052739 hydrogen Inorganic materials 0.000 claims description 16
• KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 15
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
• 239000012453 solvate Substances 0.000 claims description 14
• 125000000623 heterocyclic group Chemical group 0.000 claims description 12
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
• 229910052736 halogen Inorganic materials 0.000 claims description 10
• 150000002367 halogens Chemical class 0.000 claims description 10
• 150000002431 hydrogen Chemical class 0.000 claims description 10
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
• 239000003814 drug Substances 0.000 claims description 9
• 229910052760 oxygen Inorganic materials 0.000 claims description 9
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 8
• 229910052717 sulfur Inorganic materials 0.000 claims description 8
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 7
• 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 6
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
• 125000003545 alkoxy group Chemical group 0.000 claims description 6
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
• 125000005843 halogen group Chemical group 0.000 claims description 6
• 238000006243 chemical reaction Methods 0.000 claims description 5
• 125000001072 heteroaryl group Chemical group 0.000 claims description 5
• 238000004519 manufacturing process Methods 0.000 claims description 5
• 239000008194 pharmaceutical composition Substances 0.000 claims description 5
• 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 4
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
• 125000005842 heteroatom Chemical group 0.000 claims description 4
• PQNBMVYYZQSYKU-IMZWENMBSA-N 1-n-[(2s,3s,5r)-6-(3-bicyclo[2.2.1]heptanylamino)-3-hydroxy-5-methyl-6-oxo-1-phenylhexan-2-yl]-3-n-methyl-5-(2-oxopyrrolidin-1-yl)-3-n-propylbenzene-1,3-dicarboxamide Chemical compound C([C@H](NC(=O)C=1C=C(C=C(C=1)C(=O)N(C)CCC)N1C(CCC1)=O)[C@@H](O)C[C@@H](C)C(=O)NC1C2CCC(C2)C1)C1=CC=CC=C1 PQNBMVYYZQSYKU-IMZWENMBSA-N 0.000 claims description 3
• DPPLEDWDEUCIBP-KSBJOJRMSA-N 3-[(4r)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-n-[(2s,3s,5r)-6-(3-bicyclo[2.2.1]heptanylamino)-3-hydroxy-5-methyl-6-oxo-1-phenylhexan-2-yl]benzamide Chemical compound C([C@@H]([C@@H](O)C[C@@H](C)C(=O)NC1C2CCC(C2)C1)NC(=O)C=1C=C(C=CC=1)N1C(OC[C@H]1CC=1C=CC=CC=1)=O)C1=CC=CC=C1 DPPLEDWDEUCIBP-KSBJOJRMSA-N 0.000 claims description 3
• HSMIQHKGVOFGKT-NWPQMPMLSA-N 3-acetamido-n-[(2s,3s,5r)-6-(3-bicyclo[2.2.1]heptanylamino)-3-hydroxy-5-methyl-6-oxo-1-phenylhexan-2-yl]-5-(2-oxopyrrolidin-1-yl)benzamide Chemical compound C([C@@H]([C@@H](O)C[C@@H](C)C(=O)NC1C2CCC(C2)C1)NC(=O)C=1C=C(C=C(NC(C)=O)C=1)N1C(CCC1)=O)C1=CC=CC=C1 HSMIQHKGVOFGKT-NWPQMPMLSA-N 0.000 claims description 3
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
• 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 3
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
• 229910052731 fluorine Inorganic materials 0.000 claims description 3
• 239000011737 fluorine Substances 0.000 claims description 3
• LOAODSDDDWBSTH-WWEDSPNTSA-N n-[(2s,3s,5r)-3-hydroxy-5-methyl-6-(2-methylpropylamino)-6-oxo-1-phenylhexan-2-yl]-3-(2-oxopyrrolidin-1-yl)-5-propan-2-yloxybenzamide Chemical compound C([C@@H]([C@@H](O)C[C@@H](C)C(=O)NCC(C)C)NC(=O)C=1C=C(C=C(OC(C)C)C=1)N1C(CCC1)=O)C1=CC=CC=C1 LOAODSDDDWBSTH-WWEDSPNTSA-N 0.000 claims description 3
• UBZJRFZZBTVLFL-ZUVGRRGESA-N n-[(2s,3s,5r)-5-(3-bicyclo[2.2.1]heptanylcarbamoyl)-3-hydroxy-1-phenyloct-7-yn-2-yl]-3,5-bis(2-oxopyrrolidin-1-yl)benzamide Chemical compound C([C@@H]([C@H](C[C@@H](CC#C)C(=O)NC1C2CCC(C2)C1)O)NC(=O)C=1C=C(C=C(C=1)N1C(CCC1)=O)N1C(CCC1)=O)C1=CC=CC=C1 UBZJRFZZBTVLFL-ZUVGRRGESA-N 0.000 claims description 3
• RGVBWXQYQAJRIU-KDGCPDPYSA-N n-[(2s,3s,5r)-5-(3-bicyclo[2.2.1]heptanylcarbamoyl)-3-hydroxy-8-methyl-1-phenylnonan-2-yl]-3,5-bis(2-oxopyrrolidin-1-yl)benzamide Chemical compound C([C@@H]([C@@H](O)C[C@@H](CCC(C)C)C(=O)NC1C2CCC(C2)C1)NC(=O)C=1C=C(C=C(C=1)N1C(CCC1)=O)N1C(CCC1)=O)C1=CC=CC=C1 RGVBWXQYQAJRIU-KDGCPDPYSA-N 0.000 claims description 3
• OBUJHUKTPPJUEC-LNMMVMNESA-N n-[(2s,3s,5r)-6-(3,3-dimethylbutylamino)-3-hydroxy-5-methyl-6-oxo-1-phenylhexan-2-yl]-3-(2-oxopyrrolidin-1-yl)-5-phenoxybenzamide Chemical compound C([C@@H]([C@@H](O)C[C@@H](C)C(=O)NCCC(C)(C)C)NC(=O)C=1C=C(C=C(OC=2C=CC=CC=2)C=1)N1C(CCC1)=O)C1=CC=CC=C1 OBUJHUKTPPJUEC-LNMMVMNESA-N 0.000 claims description 3
• XCDJJGUZKRCHNU-LNMMVMNESA-N n-[(2s,3s,5r)-6-(3,3-dimethylbutylamino)-3-hydroxy-5-methyl-6-oxo-1-phenylhexan-2-yl]-3-(2-oxopyrrolidin-1-yl)-5-phenylbenzamide Chemical compound C([C@@H]([C@@H](O)C[C@@H](C)C(=O)NCCC(C)(C)C)NC(=O)C=1C=C(C=C(C=1)N1C(CCC1)=O)C=1C=CC=CC=1)C1=CC=CC=C1 XCDJJGUZKRCHNU-LNMMVMNESA-N 0.000 claims description 3
• IPNQEHUEACIZGQ-MGONOCMRSA-N n-[(2s,3s,5r)-6-(3,3-dimethylbutylamino)-3-hydroxy-5-methyl-6-oxo-1-phenylhexan-2-yl]-3-(2-oxopyrrolidin-1-yl)-5-prop-2-enoxybenzamide Chemical compound C([C@@H]([C@@H](O)C[C@@H](C)C(=O)NCCC(C)(C)C)NC(=O)C=1C=C(C=C(OCC=C)C=1)N1C(CCC1)=O)C1=CC=CC=C1 IPNQEHUEACIZGQ-MGONOCMRSA-N 0.000 claims description 3
• SPPLJFPHJLHTOB-MGONOCMRSA-N n-[(2s,3s,5r)-6-(3,3-dimethylbutylamino)-3-hydroxy-5-methyl-6-oxo-1-phenylhexan-2-yl]-3-(2-oxopyrrolidin-1-yl)-5-propoxybenzamide Chemical compound C([C@H](NC(=O)C=1C=C(C=C(C=1)OCCC)N1C(CCC1)=O)[C@@H](O)C[C@@H](C)C(=O)NCCC(C)(C)C)C1=CC=CC=C1 SPPLJFPHJLHTOB-MGONOCMRSA-N 0.000 claims description 3
• JFBNTINWKSRMCU-BQQUOAEZSA-N n-[(2s,3s,5r)-6-(3,3-dimethylbutylamino)-3-hydroxy-5-methyl-6-oxo-1-phenylhexan-2-yl]-3-hydroxy-5-(2-oxopyrrolidin-1-yl)benzamide Chemical compound C([C@@H]([C@@H](O)C[C@@H](C)C(=O)NCCC(C)(C)C)NC(=O)C=1C=C(C=C(O)C=1)N1C(CCC1)=O)C1=CC=CC=C1 JFBNTINWKSRMCU-BQQUOAEZSA-N 0.000 claims description 3
• LXMHKVZXLJCHDW-PSUQPPDWSA-N n-[(2s,3s,5r)-6-(3,3-dimethylbutylamino)-3-hydroxy-5-methyl-6-oxo-1-phenylhexan-2-yl]-4-fluoro-3-(2-oxopyrrolidin-1-yl)benzamide Chemical compound C([C@@H]([C@@H](O)C[C@@H](C)C(=O)NCCC(C)(C)C)NC(=O)C=1C=C(C(F)=CC=1)N1C(CCC1)=O)C1=CC=CC=C1 LXMHKVZXLJCHDW-PSUQPPDWSA-N 0.000 claims description 3
• ZYZBMJGMAZDXME-IJVOHCTGSA-N n-[(2s,3s,5r)-6-(3-bicyclo[2.2.1]heptanylamino)-3-hydroxy-5-methyl-6-oxo-1-phenylhexan-2-yl]-2-fluoro-3,5-bis(2-oxopyrrolidin-1-yl)benzamide Chemical compound C([C@@H]([C@@H](O)C[C@@H](C)C(=O)NC1C2CCC(C2)C1)NC(=O)C=1C(=C(N2C(CCC2)=O)C=C(C=1)N1C(CCC1)=O)F)C1=CC=CC=C1 ZYZBMJGMAZDXME-IJVOHCTGSA-N 0.000 claims description 3
• STJQNJREMJPCCI-MQOPCWFGSA-N n-[(2s,3s,5r)-6-(3-bicyclo[2.2.1]heptanylamino)-3-hydroxy-5-methyl-6-oxo-1-phenylhexan-2-yl]-2-fluoro-3-(2-oxopyrrolidin-1-yl)-5-(trifluoromethyl)benzamide Chemical compound C([C@@H]([C@@H](O)C[C@@H](C)C(=O)NC1C2CCC(C2)C1)NC(=O)C=1C(=C(N2C(CCC2)=O)C=C(C=1)C(F)(F)F)F)C1=CC=CC=C1 STJQNJREMJPCCI-MQOPCWFGSA-N 0.000 claims description 3
• BRSYDVMCNWCJTB-IABUABSESA-N n-[(2s,3s,5r)-6-(3-bicyclo[2.2.1]heptanylamino)-3-hydroxy-5-methyl-6-oxo-1-phenylhexan-2-yl]-2-fluoro-3-(2-oxopyrrolidin-1-yl)benzamide Chemical compound C([C@@H]([C@@H](O)C[C@@H](C)C(=O)NC1C2CCC(C2)C1)NC(=O)C=1C(=C(N2C(CCC2)=O)C=CC=1)F)C1=CC=CC=C1 BRSYDVMCNWCJTB-IABUABSESA-N 0.000 claims description 3
• SWHIKWQQPQXHAQ-JANXGGRPSA-N n-[(2s,3s,5r)-6-(3-bicyclo[2.2.1]heptanylamino)-3-hydroxy-5-methyl-6-oxo-1-phenylhexan-2-yl]-2-methoxy-6-(2-oxopyrrolidin-1-yl)pyridine-4-carboxamide Chemical compound N=1C(OC)=CC(C(=O)N[C@@H](CC=2C=CC=CC=2)[C@@H](O)C[C@@H](C)C(=O)NC2C3CCC(C3)C2)=CC=1N1CCCC1=O SWHIKWQQPQXHAQ-JANXGGRPSA-N 0.000 claims description 3
• NFXCWOXGGHRVTQ-LTXCQHPESA-N n-[(2s,3s,5r)-6-(3-bicyclo[2.2.1]heptanylamino)-3-hydroxy-5-methyl-6-oxo-1-phenylhexan-2-yl]-3-(2-oxopyrrolidin-1-yl)-5-propan-2-yloxybenzamide Chemical compound C([C@H](NC(=O)C=1C=C(C=C(C=1)OC(C)C)N1C(CCC1)=O)[C@@H](O)C[C@@H](C)C(=O)NC1C2CCC(C2)C1)C1=CC=CC=C1 NFXCWOXGGHRVTQ-LTXCQHPESA-N 0.000 claims description 3
• OTMFGIDOSDNFFD-DNFDBSLJSA-N n-[(2s,3s,5r)-6-(3-bicyclo[2.2.1]heptanylamino)-3-hydroxy-5-methyl-6-oxo-1-phenylhexan-2-yl]-3-(4-methoxybutoxy)-5-(2-oxopyrrolidin-1-yl)benzamide Chemical compound C([C@H](NC(=O)C=1C=C(C=C(C=1)OCCCCOC)N1C(CCC1)=O)[C@@H](O)C[C@@H](C)C(=O)NC1C2CCC(C2)C1)C1=CC=CC=C1 OTMFGIDOSDNFFD-DNFDBSLJSA-N 0.000 claims description 3
• GSKQPBJFQWHKEE-HJRDSUCGSA-N n-[(2s,3s,5r)-6-(3-bicyclo[2.2.1]heptanylamino)-3-hydroxy-5-methyl-6-oxo-1-phenylhexan-2-yl]-3-(cyclopropylmethoxy)-5-(2-oxopyrrolidin-1-yl)benzamide Chemical compound C([C@@H]([C@@H](O)C[C@@H](C)C(=O)NC1C2CCC(C2)C1)NC(=O)C=1C=C(C=C(OCC2CC2)C=1)N1C(CCC1)=O)C1=CC=CC=C1 GSKQPBJFQWHKEE-HJRDSUCGSA-N 0.000 claims description 3
• ZQXHHXRANFKMJJ-UXEANBLESA-N n-[(2s,3s,5r)-6-(3-bicyclo[2.2.1]heptanylamino)-3-hydroxy-5-methyl-6-oxo-1-phenylhexan-2-yl]-3-[(2s)-butan-2-yl]oxy-5-(2-oxopyrrolidin-1-yl)benzamide Chemical compound C([C@H](NC(=O)C=1C=C(C=C(C=1)O[C@@H](C)CC)N1C(CCC1)=O)[C@@H](O)C[C@@H](C)C(=O)NC1C2CCC(C2)C1)C1=CC=CC=C1 ZQXHHXRANFKMJJ-UXEANBLESA-N 0.000 claims description 3
• MHZHWUXLTWDLRF-XDLNGMLJSA-N n-[(2s,3s,5r)-6-(3-bicyclo[2.2.1]heptanylamino)-3-hydroxy-5-methyl-6-oxo-1-phenylhexan-2-yl]-3-[(4s)-2-oxo-4-propan-2-yl-1,3-oxazolidin-3-yl]benzamide Chemical compound CC(C)[C@H]1COC(=O)N1C1=CC=CC(C(=O)N[C@@H](CC=2C=CC=CC=2)[C@@H](O)C[C@@H](C)C(=O)NC2C3CCC(C3)C2)=C1 MHZHWUXLTWDLRF-XDLNGMLJSA-N 0.000 claims description 3
• MMVKWQJIMGCYDA-JIHHKYRASA-N n-[(2s,3s,5r)-6-(3-bicyclo[2.2.1]heptanylamino)-3-hydroxy-5-methyl-6-oxo-1-phenylhexan-2-yl]-3-cyclobutyloxy-5-(2-oxopyrrolidin-1-yl)benzamide Chemical compound C([C@@H]([C@@H](O)C[C@@H](C)C(=O)NC1C2CCC(C2)C1)NC(=O)C=1C=C(C=C(OC2CCC2)C=1)N1C(CCC1)=O)C1=CC=CC=C1 MMVKWQJIMGCYDA-JIHHKYRASA-N 0.000 claims description 3
• UIWIIOONOIPLEC-ZLRPTZMNSA-N n-[(2s,3s,5r)-6-(3-bicyclo[2.2.1]heptanylamino)-3-hydroxy-5-methyl-6-oxo-1-phenylhexan-2-yl]-3-methoxy-5-(2-oxopiperidin-1-yl)benzamide Chemical compound C([C@H](NC(=O)C=1C=C(C=C(C=1)OC)N1C(CCCC1)=O)[C@@H](O)C[C@@H](C)C(=O)NC1C2CCC(C2)C1)C1=CC=CC=C1 UIWIIOONOIPLEC-ZLRPTZMNSA-N 0.000 claims description 3
• BTXZKLNQHGCMMS-RAHIQWLESA-N n-[(2s,3s,5r)-6-(cyclobutylamino)-3-hydroxy-5-methyl-6-oxo-1-phenylhexan-2-yl]-2-fluoro-3,5-bis(2-oxopyrrolidin-1-yl)benzamide Chemical compound C([C@@H]([C@@H](O)C[C@@H](C)C(=O)NC1CCC1)NC(=O)C=1C(=C(N2C(CCC2)=O)C=C(C=1)N1C(CCC1)=O)F)C1=CC=CC=C1 BTXZKLNQHGCMMS-RAHIQWLESA-N 0.000 claims description 3
• WRXNUCYBHSBQSM-GTTXMTDLSA-N n-[(2s,3s,5r)-6-[(4,4-dimethylcyclohexyl)amino]-3-hydroxy-5-methyl-6-oxo-1-phenylhexan-2-yl]-3-(2-oxopyrrolidin-1-yl)-5-propan-2-yloxybenzamide Chemical compound C([C@H](NC(=O)C=1C=C(C=C(C=1)OC(C)C)N1C(CCC1)=O)[C@@H](O)C[C@@H](C)C(=O)NC1CCC(C)(C)CC1)C1=CC=CC=C1 WRXNUCYBHSBQSM-GTTXMTDLSA-N 0.000 claims description 3
• 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 claims description 3
• 239000001301 oxygen Substances 0.000 claims description 3
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
• 229910002091 carbon monoxide Inorganic materials 0.000 claims description 2
• 239000000969 carrier Substances 0.000 claims description 2
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• 239000003085 diluting agent Substances 0.000 claims description 2
• KIBZOPBJGHBVBM-LNMMVMNESA-N n-[(2s,3s,5r)-6-(2-cyclohexylethylamino)-3-hydroxy-5-methyl-6-oxo-1-phenylhexan-2-yl]-3-(2-oxopyrrolidin-1-yl)-5-propan-2-yloxybenzamide Chemical compound C([C@H](NC(=O)C=1C=C(C=C(C=1)OC(C)C)N1C(CCC1)=O)[C@@H](O)C[C@@H](C)C(=O)NCCC1CCCCC1)C1=CC=CC=C1 KIBZOPBJGHBVBM-LNMMVMNESA-N 0.000 claims description 2
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• 125000005476 oxopyrrolidinyl group Chemical group 0.000 claims 1
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