JP6469711B2 - ジペプチジルペプチダーゼ１阻害剤としての（２ｓ）−ｎ−［（１ｓ）−１−シアノ−２−フェニルエチル］−１，４−オキサゼパン−２−カルボキサミド - Google Patents

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Publication number

JP6469711B2

JP6469711B2 JP2016548068A JP2016548068A JP6469711B2 JP 6469711 B2 JP6469711 B2 JP 6469711B2 JP 2016548068 A JP2016548068 A JP 2016548068A JP 2016548068 A JP2016548068 A JP 2016548068A JP 6469711 B2 JP6469711 B2 JP 6469711B2

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JP

Japan

Prior art keywords

ethyl

oxazepan

cyano

carboxamide

phenyl

Prior art date

2014-01-24

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

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• 239000003112 inhibitor Substances 0.000 title claims description 24
• 102100029921 Dipeptidyl peptidase 1 Human genes 0.000 title description 39
• 101710087078 Dipeptidyl peptidase 1 Proteins 0.000 title description 37
• NKLBVYYBRRBLAE-KBPBESRZSA-N (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamide Chemical compound C(#N)[C@H](CC1=CC=CC=C1)NC(=O)[C@H]1OCCCNC1 NKLBVYYBRRBLAE-KBPBESRZSA-N 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims description 280
• -1 4'-cyanobiphenyl-4-yl Chemical group 0.000 claims description 84
• 150000003839 salts Chemical class 0.000 claims description 83
• 125000000217 alkyl group Chemical group 0.000 claims description 45
• 208000006673 asthma Diseases 0.000 claims description 36
• 229910052739 hydrogen Inorganic materials 0.000 claims description 33
• 238000011282 treatment Methods 0.000 claims description 31
• 239000001257 hydrogen Substances 0.000 claims description 30
• 229910052757 nitrogen Inorganic materials 0.000 claims description 28
• 239000003814 drug Substances 0.000 claims description 25
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 24
• 229910052731 fluorine Inorganic materials 0.000 claims description 23
• 229910052801 chlorine Inorganic materials 0.000 claims description 19
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 18
• 238000004519 manufacturing process Methods 0.000 claims description 18
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 16
• 201000010099 disease Diseases 0.000 claims description 16
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• 229910052794 bromium Inorganic materials 0.000 claims description 11
• 229910052760 oxygen Inorganic materials 0.000 claims description 11
• 229910052717 sulfur Inorganic materials 0.000 claims description 11
• 206010039083 rhinitis Diseases 0.000 claims description 9
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 8
• AEXFXNFMSAAELR-RXVVDRJESA-N brensocatib Chemical compound C(#N)[C@H](CC1=CC=C(C=C1)C=1C=CC2=C(N(C(O2)=O)C)C1)NC(=O)[C@H]1OCCCNC1 AEXFXNFMSAAELR-RXVVDRJESA-N 0.000 claims description 8
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• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
• FCRODBUNBQJNPU-SFTDATJTSA-N (2S)-N-[(1S)-1-cyano-2-[4-(4-cyanophenyl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide Chemical compound C(#N)[C@H](CC1=CC=C(C=C1)C1=CC=C(C=C1)C#N)NC(=O)[C@H]1OCCCNC1 FCRODBUNBQJNPU-SFTDATJTSA-N 0.000 claims description 6
• DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 6
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
• 239000003085 diluting agent Substances 0.000 claims description 6
• 229940079593 drug Drugs 0.000 claims description 6
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 5
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• 239000002671 adjuvant Substances 0.000 claims description 5
• 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims description 5
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• 125000001424 substituent group Chemical group 0.000 claims description 5
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• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 4
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• WCWJGAFMGPMBQG-FPOVZHCZSA-N (2S)-N-[(1S)-1-cyano-2-[4-(3,7-dimethyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide Chemical compound C(#N)[C@H](CC1=CC=C(C=C1)C=1C=C(C2=C(N(C(O2)=O)C)C1)C)NC(=O)[C@H]1OCCCNC1 WCWJGAFMGPMBQG-FPOVZHCZSA-N 0.000 claims description 3
• YMWLPANQQFJYBL-UHFFFAOYSA-N (3-phenylphenyl)methanesulfonic acid Chemical compound OS(=O)(=O)CC1=CC=CC(C=2C=CC=CC=2)=C1 YMWLPANQQFJYBL-UHFFFAOYSA-N 0.000 claims description 3
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• BQIZWZAQEICNDG-GMAHTHKFSA-N (2S)-N-[(1S)-1-cyano-2-[4-(1-methyl-2-oxoquinolin-7-yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide Chemical compound C(#N)[C@H](CC1=CC=C(C=C1)C1=CC=C2C=CC(N(C2=C1)C)=O)NC(=O)[C@H]1OCCCNC1 BQIZWZAQEICNDG-GMAHTHKFSA-N 0.000 claims description 2
• WOBKXJRTDASPHQ-REWPJTCUSA-N (2S)-N-[(1S)-1-cyano-2-[4-(2-oxo-3-propan-2-yl-1,3-benzoxazol-5-yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide Chemical compound C(#N)[C@H](CC1=CC=C(C=C1)C=1C=CC2=C(N(C(O2)=O)C(C)C)C1)NC(=O)[C@H]1OCCCNC1 WOBKXJRTDASPHQ-REWPJTCUSA-N 0.000 claims description 2
• SABYNPLHFAPZQF-RXVVDRJESA-N (2S)-N-[(1S)-1-cyano-2-[4-(3,3-difluoro-1-methyl-2-oxoindol-6-yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide Chemical compound C(#N)[C@H](CC1=CC=C(C=C1)C1=CC=C2C(C(N(C2=C1)C)=O)(F)F)NC(=O)[C@H]1OCCCNC1 SABYNPLHFAPZQF-RXVVDRJESA-N 0.000 claims description 2
• HSWVIXGRFREZJG-PXNSSMCTSA-N (2S)-N-[(1S)-1-cyano-2-[4-(3,4-difluorophenyl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide Chemical compound C(#N)[C@H](CC1=CC=C(C=C1)C1=CC(=C(C=C1)F)F)NC(=O)[C@H]1OCCCNC1 HSWVIXGRFREZJG-PXNSSMCTSA-N 0.000 claims description 2
• HZZYFVOLMKQYKP-UGKGYDQZSA-N (2S)-N-[(1S)-1-cyano-2-[4-(3-ethyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide Chemical compound C(#N)[C@H](CC1=CC=C(C=C1)C=1C=CC2=C(N(C(O2)=O)CC)C1)NC(=O)[C@H]1OCCCNC1 HZZYFVOLMKQYKP-UGKGYDQZSA-N 0.000 claims description 2
• ORHUZDNZRYZSJO-UNMCSNQZSA-N (2S)-N-[(1S)-1-cyano-2-[4-(3-ethyl-7-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide Chemical compound C(#N)[C@H](CC1=CC=C(C=C1)C=1C=C(C2=C(N(C(O2)=O)CC)C1)C)NC(=O)[C@H]1OCCCNC1 ORHUZDNZRYZSJO-UNMCSNQZSA-N 0.000 claims description 2
• QCTYSVBOKIUUFU-UGKGYDQZSA-N (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-1,2-benzoxazol-5-yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide Chemical compound C(#N)[C@H](CC1=CC=C(C=C1)C=1C=CC2=C(C(=NO2)C)C1)NC(=O)[C@H]1OCCCNC1 QCTYSVBOKIUUFU-UGKGYDQZSA-N 0.000 claims description 2
• DRQDONWWFWYTII-ICSRJNTNSA-N (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzothiazol-5-yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide Chemical compound C(#N)[C@H](CC1=CC=C(C=C1)C=1C=CC2=C(N(C(S2)=O)C)C1)NC(=O)[C@H]1OCCCNC1 DRQDONWWFWYTII-ICSRJNTNSA-N 0.000 claims description 2
• PYXGGJVWIVBQRO-PMACEKPBSA-N (2S)-N-[(1S)-1-cyano-2-[4-(4-fluorophenyl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide Chemical compound C(#N)[C@H](CC1=CC=C(C=C1)C1=CC=C(C=C1)F)NC(=O)[C@H]1OCCCNC1 PYXGGJVWIVBQRO-PMACEKPBSA-N 0.000 claims description 2
• NSLGCWMFHWURGT-FPOVZHCZSA-N (2S)-N-[(1S)-1-cyano-2-[4-(4-methyl-3-oxo-1,4-benzothiazin-6-yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide Chemical compound C(#N)[C@H](CC1=CC=C(C=C1)C=1C=CC2=C(N(C(CS2)=O)C)C1)NC(=O)[C@H]1OCCCNC1 NSLGCWMFHWURGT-FPOVZHCZSA-N 0.000 claims description 2
• QKDQSHLZLZUQOA-UGKGYDQZSA-N (2S)-N-[(1S)-1-cyano-2-[4-(4-methyl-3-oxo-1,4-benzoxazin-6-yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide Chemical compound C(#N)[C@H](CC1=CC=C(C=C1)C=1C=CC2=C(N(C(CO2)=O)C)C1)NC(=O)[C@H]1OCCCNC1 QKDQSHLZLZUQOA-UGKGYDQZSA-N 0.000 claims description 2
• UBRDXNDHEGQOTI-FPOVZHCZSA-N (2S)-N-[(1S)-1-cyano-2-[4-(4-methylsulfonylphenyl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide Chemical compound C(#N)[C@H](CC1=CC=C(C=C1)C1=CC=C(C=C1)S(=O)(=O)C)NC(=O)[C@H]1OCCCNC1 UBRDXNDHEGQOTI-FPOVZHCZSA-N 0.000 claims description 2
• AYKAKRZDQIFHMD-WMZOPIPTSA-N (2S)-N-[(1S)-1-cyano-2-[4-(5-cyanothiophen-2-yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide Chemical compound C(#N)[C@H](CC1=CC=C(C=C1)C=1SC(=CC1)C#N)NC(=O)[C@H]1OCCCNC1 AYKAKRZDQIFHMD-WMZOPIPTSA-N 0.000 claims description 2
• UZXVZQQAOVNOKG-PMACEKPBSA-N (2S)-N-[(1S)-1-cyano-2-[4-(6-cyanopyridin-3-yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide Chemical compound C(#N)[C@H](CC1=CC=C(C=C1)C=1C=NC(=CC1)C#N)NC(=O)[C@H]1OCCCNC1 UZXVZQQAOVNOKG-PMACEKPBSA-N 0.000 claims description 2
• IVHOZTBKWBUDMJ-PXNSSMCTSA-N (2S)-N-[(1S)-1-cyano-2-[4-(7-fluoro-3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide Chemical compound C(#N)[C@H](CC1=CC=C(C=C1)C=1C=C(C2=C(N(C(O2)=O)C)C1)F)NC(=O)[C@H]1OCCCNC1 IVHOZTBKWBUDMJ-PXNSSMCTSA-N 0.000 claims description 2
• ANPJTTUBCRFBKA-RXVVDRJESA-N (2S)-N-[(1S)-1-cyano-2-[4-[3-(2,2-difluoroethyl)-2-oxo-1,3-benzoxazol-5-yl]phenyl]ethyl]-1,4-oxazepane-2-carboxamide Chemical compound C(#N)[C@H](CC1=CC=C(C=C1)C=1C=CC2=C(N(C(O2)=O)CC(F)F)C1)NC(=O)[C@H]1OCCCNC1 ANPJTTUBCRFBKA-RXVVDRJESA-N 0.000 claims description 2
• PVRGXPYTNXSTMU-PXNSSMCTSA-N (2S)-N-[(1S)-1-cyano-2-[4-[3-(2,2-difluoroethyl)-7-fluoro-2-oxo-1,3-benzoxazol-5-yl]phenyl]ethyl]-1,4-oxazepane-2-carboxamide Chemical compound C(#N)[C@H](CC1=CC=C(C=C1)C=1C=C(C2=C(N(C(O2)=O)CC(F)F)C1)F)NC(=O)[C@H]1OCCCNC1 PVRGXPYTNXSTMU-PXNSSMCTSA-N 0.000 claims description 2
• LRDOUIXCGZNESR-REWPJTCUSA-N (2S)-N-[(1S)-1-cyano-2-[4-[3-(2-hydroxy-2-methylpropyl)-2-oxo-1,3-benzoxazol-5-yl]phenyl]ethyl]-1,4-oxazepane-2-carboxamide Chemical compound C(#N)[C@H](CC1=CC=C(C=C1)C=1C=CC2=C(N(C(O2)=O)CC(C)(C)O)C1)NC(=O)[C@H]1OCCCNC1 LRDOUIXCGZNESR-REWPJTCUSA-N 0.000 claims description 2
• GRJJVLYWMJAVMA-UNMCSNQZSA-N (2S)-N-[(1S)-1-cyano-2-[4-[3-(2-methoxyethyl)-2-oxo-1,3-benzothiazol-5-yl]phenyl]ethyl]-1,4-oxazepane-2-carboxamide Chemical compound C(#N)[C@H](CC1=CC=C(C=C1)C=1C=CC2=C(N(C(S2)=O)CCOC)C1)NC(=O)[C@H]1OCCCNC1 GRJJVLYWMJAVMA-UNMCSNQZSA-N 0.000 claims description 2
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• WJXGZWWSCFPECN-URXFXBBRSA-N (2S)-N-[(1S)-1-cyano-2-[4-[3-(cyclopropylmethyl)-2-oxo-1,3-benzoxazol-5-yl]phenyl]ethyl]-1,4-oxazepane-2-carboxamide Chemical compound C(#N)[C@H](CC1=CC=C(C=C1)C=1C=CC2=C(N(C(O2)=O)CC2CC2)C1)NC(=O)[C@H]1OCCCNC1 WJXGZWWSCFPECN-URXFXBBRSA-N 0.000 claims description 2
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