JP2008533136A5 - - Google Patents
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- JP2008533136A5 JP2008533136A5 JP2008501839A JP2008501839A JP2008533136A5 JP 2008533136 A5 JP2008533136 A5 JP 2008533136A5 JP 2008501839 A JP2008501839 A JP 2008501839A JP 2008501839 A JP2008501839 A JP 2008501839A JP 2008533136 A5 JP2008533136 A5 JP 2008533136A5
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- phenyl
- oxo
- trifluoromethyl
- dihydropyridine
- Prior art date
- 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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- 150000001875 compounds Chemical class 0.000 claims description 78
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 23
- 125000001424 substituent group Chemical group 0.000 claims description 21
- -1 cyano, carboxyl Chemical group 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 18
- 239000011780 sodium chloride Substances 0.000 claims description 18
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 17
- 239000001301 oxygen Substances 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 125000005842 heteroatoms Chemical group 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 7
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- 239000011593 sulfur Substances 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- GJVTXNSAVBSGBO-UHFFFAOYSA-N 3-[5-[(3-cyclopropyl-1,2-oxazol-5-yl)methylcarbamoyl]-2-methyl-6-oxo-1-[3-(trifluoromethyl)phenyl]pyridin-3-yl]propanoic acid Chemical compound O=C1N(C=2C=C(C=CC=2)C(F)(F)F)C(C)=C(CCC(O)=O)C=C1C(=O)NCC(ON=1)=CC=1C1CC1 GJVTXNSAVBSGBO-UHFFFAOYSA-N 0.000 claims description 5
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 5
- 206010014561 Emphysema Diseases 0.000 claims description 5
- 208000002815 Pulmonary Hypertension Diseases 0.000 claims description 5
- 206010063837 Reperfusion injury Diseases 0.000 claims description 5
- 206010039073 Rheumatoid arthritis Diseases 0.000 claims description 5
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 5
- 200000000018 inflammatory disease Diseases 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 4
- 208000006673 Asthma Diseases 0.000 claims description 4
- 206010006451 Bronchitis Diseases 0.000 claims description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 4
- KNLUGTJFCBLSOC-UHFFFAOYSA-N N-[[3-(3-amino-3-oxopropyl)-1,2-oxazol-5-yl]methyl]-6-methyl-5-(2-methylpyrazol-3-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxamide Chemical compound O=C1N(C=2C=C(C=CC=2)C(F)(F)F)C(C)=C(C=2N(N=CC=2)C)C=C1C(=O)NCC1=CC(CCC(N)=O)=NO1 KNLUGTJFCBLSOC-UHFFFAOYSA-N 0.000 claims description 4
- 206010039083 Rhinitis Diseases 0.000 claims description 4
- 201000001320 atherosclerosis Diseases 0.000 claims description 4
- 201000009267 bronchiectasis Diseases 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 201000008482 osteoarthritis Diseases 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- TWICYNPLLFUXDQ-UHFFFAOYSA-N 5-(3-amino-3-oxopropyl)-N-[(3-cyclopropyl-1,2-oxazol-5-yl)methyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxamide Chemical compound O=C1N(C=2C=C(C=CC=2)C(F)(F)F)C(C)=C(CCC(N)=O)C=C1C(=O)NCC(ON=1)=CC=1C1CC1 TWICYNPLLFUXDQ-UHFFFAOYSA-N 0.000 claims description 3
- 206010022114 Injury Diseases 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- 230000000240 adjuvant Effects 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- 239000000969 carrier Substances 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- 201000003883 cystic fibrosis Diseases 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 230000002496 gastric Effects 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 2
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 2
- COSQTMHNLRVTHS-UHFFFAOYSA-N 5-(3,5-dimethyl-1,2-oxazol-4-yl)-N-[[3-(2-hydroxyethyl)-1,2-oxazol-5-yl]methyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxamide Chemical compound CC1=NOC(C)=C1C1=C(C)N(C=2C=C(C=CC=2)C(F)(F)F)C(=O)C(C(=O)NCC=2ON=C(CCO)C=2)=C1 COSQTMHNLRVTHS-UHFFFAOYSA-N 0.000 claims description 2
- DAYWDQZBIGYIFL-UHFFFAOYSA-N 5-(3,5-dimethyl-1,2-oxazol-4-yl)-N-[[3-(hydroxymethyl)-1,2-oxazol-5-yl]methyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxamide Chemical compound CC1=NOC(C)=C1C1=C(C)N(C=2C=C(C=CC=2)C(F)(F)F)C(=O)C(C(=O)NCC=2ON=C(CO)C=2)=C1 DAYWDQZBIGYIFL-UHFFFAOYSA-N 0.000 claims description 2
- HAKJOMGHAYBTOZ-UHFFFAOYSA-N 5-(3-amino-3-oxopropyl)-N-[(4-cyclopropylsulfonylphenyl)methyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxamide Chemical compound O=C1N(C=2C=C(C=CC=2)C(F)(F)F)C(C)=C(CCC(N)=O)C=C1C(=O)NCC(C=C1)=CC=C1S(=O)(=O)C1CC1 HAKJOMGHAYBTOZ-UHFFFAOYSA-N 0.000 claims description 2
- BLXUJXBMVFDAJN-UHFFFAOYSA-N 5-ethyl-N-[[3-(hydroxymethyl)-1,2-oxazol-5-yl]methyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxamide Chemical compound O=C1N(C=2C=C(C=CC=2)C(F)(F)F)C(C)=C(CC)C=C1C(=O)NCC1=CC(CO)=NO1 BLXUJXBMVFDAJN-UHFFFAOYSA-N 0.000 claims description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 2
- UCNJJMZFTWRANH-UHFFFAOYSA-N 6-methyl-5-(2-morpholin-4-ylethoxy)-2-oxo-N-[(4-propan-2-ylsulfonylphenyl)methyl]-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxamide Chemical compound C1=CC(S(=O)(=O)C(C)C)=CC=C1CNC(=O)C(C1=O)=CC(OCCN2CCOCC2)=C(C)N1C1=CC=CC(C(F)(F)F)=C1 UCNJJMZFTWRANH-UHFFFAOYSA-N 0.000 claims description 2
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- GGUOPOQNLBPBPO-UHFFFAOYSA-N N-[(3-cyclopropyl-1,2-oxazol-5-yl)methyl]-6-methyl-5-(3-methylsulfonylpropyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxamide Chemical compound O=C1N(C=2C=C(C=CC=2)C(F)(F)F)C(C)=C(CCCS(C)(=O)=O)C=C1C(=O)NCC(ON=1)=CC=1C1CC1 GGUOPOQNLBPBPO-UHFFFAOYSA-N 0.000 claims description 2
- AFDXYIDOLKOCQU-UHFFFAOYSA-N N-[[3-(2-cyanoethyl)-1,2-oxazol-5-yl]methyl]-6-methyl-5-(2-methylpyrazol-3-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxamide Chemical compound O=C1N(C=2C=C(C=CC=2)C(F)(F)F)C(C)=C(C=2N(N=CC=2)C)C=C1C(=O)NCC1=CC(CCC#N)=NO1 AFDXYIDOLKOCQU-UHFFFAOYSA-N 0.000 claims description 2
- UUPVBNRHURJPDD-UHFFFAOYSA-N N-[[3-(2-hydroxyethyl)-1,2-oxazol-5-yl]methyl]-5-iodo-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxamide Chemical compound O=C1N(C=2C=C(C=CC=2)C(F)(F)F)C(C)=C(I)C=C1C(=O)NCC1=CC(CCO)=NO1 UUPVBNRHURJPDD-UHFFFAOYSA-N 0.000 claims description 2
- YUZMYSHVYKYCCM-UHFFFAOYSA-N N-[[3-(2-hydroxyethyl)-1,2-oxazol-5-yl]methyl]-6-methyl-5-(2-methylpyrazol-3-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxamide Chemical compound O=C1N(C=2C=C(C=CC=2)C(F)(F)F)C(C)=C(C=2N(N=CC=2)C)C=C1C(=O)NCC1=CC(CCO)=NO1 YUZMYSHVYKYCCM-UHFFFAOYSA-N 0.000 claims description 2
- ZHZXGMRTBFFBQA-UHFFFAOYSA-N N-[[3-(hydroxymethyl)-1,2-oxazol-5-yl]methyl]-6-methyl-5-(2-methylpyrazol-3-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxamide Chemical compound O=C1N(C=2C=C(C=CC=2)C(F)(F)F)C(C)=C(C=2N(N=CC=2)C)C=C1C(=O)NCC1=CC(CO)=NO1 ZHZXGMRTBFFBQA-UHFFFAOYSA-N 0.000 claims description 2
- PSTDSQBQASAKOM-UHFFFAOYSA-N N-[[3-(methoxymethyl)-1,2-oxazol-5-yl]methyl]-6-methyl-5-(2-methylpyrazol-3-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxamide Chemical compound O1N=C(COC)C=C1CNC(=O)C(C1=O)=CC(C=2N(N=CC=2)C)=C(C)N1C1=CC=CC(C(F)(F)F)=C1 PSTDSQBQASAKOM-UHFFFAOYSA-N 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 claims description 2
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 239000012038 nucleophile Substances 0.000 claims description 2
- 125000004430 oxygen atoms Chemical group O* 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- ATJFFYVFTNAWJD-UHFFFAOYSA-N tin hydride Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims description 2
- 102000016799 Leukocyte Elastase Human genes 0.000 claims 2
- 108010028275 Leukocyte Elastase Proteins 0.000 claims 2
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims 1
- MGNLYTUGWWGSAX-UHFFFAOYSA-N 3-[5-[(4-cyclopropylsulfonylphenyl)methylcarbamoyl]-2-methyl-6-oxo-1-[3-(trifluoromethyl)phenyl]pyridin-3-yl]propanoic acid Chemical compound O=C1N(C=2C=C(C=CC=2)C(F)(F)F)C(C)=C(CCC(O)=O)C=C1C(=O)NCC(C=C1)=CC=C1S(=O)(=O)C1CC1 MGNLYTUGWWGSAX-UHFFFAOYSA-N 0.000 claims 1
- WOEYEUCTCPVZQR-UHFFFAOYSA-N 5-(1-cyanoethyl)-6-methyl-N-[(4-methylsulfonylphenyl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxamide Chemical compound O=C1N(C=2C=C(C=CC=2)C(F)(F)F)C(C)=C(C(C#N)C)C=C1C(=O)NCC1=CC=C(S(C)(=O)=O)C=C1 WOEYEUCTCPVZQR-UHFFFAOYSA-N 0.000 claims 1
- BGIJJNJNCIKNDD-UHFFFAOYSA-N 5-(2-cyanoethyl)-N-[(3-cyclopropyl-1,2-oxazol-5-yl)methyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxamide Chemical compound O=C1N(C=2C=C(C=CC=2)C(F)(F)F)C(C)=C(CCC#N)C=C1C(=O)NCC(ON=1)=CC=1C1CC1 BGIJJNJNCIKNDD-UHFFFAOYSA-N 0.000 claims 1
- WYKZNMJRCHSBEM-UHFFFAOYSA-N 5-(3,5-dimethyl-1,2-oxazol-4-yl)-6-methyl-N-[[3-(methylsulfanylmethyl)-1,2-oxazol-5-yl]methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxamide Chemical compound O1N=C(CSC)C=C1CNC(=O)C(C1=O)=CC(C2=C(ON=C2C)C)=C(C)N1C1=CC=CC(C(F)(F)F)=C1 WYKZNMJRCHSBEM-UHFFFAOYSA-N 0.000 claims 1
- ZTWKRCFZLOBWQF-UHFFFAOYSA-N 5-[3-(methanesulfonamido)propyl]-6-methyl-N-[(4-methylsulfonylphenyl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxamide Chemical compound O=C1N(C=2C=C(C=CC=2)C(F)(F)F)C(C)=C(CCCNS(C)(=O)=O)C=C1C(=O)NCC1=CC=C(S(C)(=O)=O)C=C1 ZTWKRCFZLOBWQF-UHFFFAOYSA-N 0.000 claims 1
- OZKVINOUMXQNJG-UHFFFAOYSA-N 5-cyclopropyl-N-[[3-(hydroxymethyl)-1,2-oxazol-5-yl]methyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxamide Chemical compound O=C1N(C=2C=C(C=CC=2)C(F)(F)F)C(C)=C(C2CC2)C=C1C(=O)NCC1=CC(CO)=NO1 OZKVINOUMXQNJG-UHFFFAOYSA-N 0.000 claims 1
- 208000001590 Congenital Abnormality Diseases 0.000 claims 1
- 206010061619 Deformity Diseases 0.000 claims 1
- WZOBVWSWRSCPCI-UHFFFAOYSA-N N-[(3-cyclopropyl-1,2-oxazol-5-yl)methyl]-5-[3-(dimethylamino)-3-oxopropyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxamide Chemical compound O=C1N(C=2C=C(C=CC=2)C(F)(F)F)C(C)=C(CCC(=O)N(C)C)C=C1C(=O)NCC(ON=1)=CC=1C1CC1 WZOBVWSWRSCPCI-UHFFFAOYSA-N 0.000 claims 1
- WOKYCFQWVGYZMM-UHFFFAOYSA-N N-[(4-cyclopropylsulfonylphenyl)methyl]-6-methyl-5-(methylsulfonylmethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxamide Chemical compound O=C1N(C=2C=C(C=CC=2)C(F)(F)F)C(C)=C(CS(C)(=O)=O)C=C1C(=O)NCC(C=C1)=CC=C1S(=O)(=O)C1CC1 WOKYCFQWVGYZMM-UHFFFAOYSA-N 0.000 claims 1
- SULWKDQKKVLBSK-UHFFFAOYSA-N N-[[3-(3-hydroxypropyl)-1,2-oxazol-5-yl]methyl]-6-methyl-5-(2-methylpyrazol-3-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxamide Chemical compound O=C1N(C=2C=C(C=CC=2)C(F)(F)F)C(C)=C(C=2N(N=CC=2)C)C=C1C(=O)NCC1=CC(CCCO)=NO1 SULWKDQKKVLBSK-UHFFFAOYSA-N 0.000 claims 1
- 125000004414 alkyl thio group Chemical group 0.000 claims 1
- 150000001642 boronic acid derivatives Chemical class 0.000 claims 1
- 125000001072 heteroaryl group Chemical group 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 230000000051 modifying Effects 0.000 claims 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 32
- 238000000668 atmospheric pressure chemical ionisation mass spectrometry Methods 0.000 description 28
- 239000007787 solid Substances 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 238000004108 freeze drying Methods 0.000 description 17
- 235000019439 ethyl acetate Nutrition 0.000 description 16
- 238000000746 purification Methods 0.000 description 15
- 238000002953 preparative HPLC Methods 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 13
- 238000001704 evaporation Methods 0.000 description 13
- 239000011734 sodium Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 239000000377 silicon dioxide Substances 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N N,N-Diethylethanamine Substances CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- AKJQHGTVHVRCDZ-UHFFFAOYSA-N 6-methyl-5-(2-methylpyrazol-3-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxylic acid Chemical compound CC1=C(C=2N(N=CC=2)C)C=C(C(O)=O)C(=O)N1C1=CC=CC(C(F)(F)F)=C1 AKJQHGTVHVRCDZ-UHFFFAOYSA-N 0.000 description 4
- GHHPAZJHIPJJNU-UHFFFAOYSA-N N-[(3-cyclopropyl-1,2-oxazol-5-yl)methyl]-5-iodo-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxamide Chemical compound O=C1N(C=2C=C(C=CC=2)C(F)(F)F)C(C)=C(I)C=C1C(=O)NCC(ON=1)=CC=1C1CC1 GHHPAZJHIPJJNU-UHFFFAOYSA-N 0.000 description 4
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-Chlorosuccinimide Substances ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 201000004624 dermatitis Diseases 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 210000000056 organs Anatomy 0.000 description 3
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
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| GEP20135793B (en) | 2008-09-11 | 2013-03-25 | Pfizer | Heteroaryls amide derivatives and their use as glucokinase activators |
| WO2010084428A1 (en) | 2009-01-20 | 2010-07-29 | Pfizer Inc. | Substituted pyrazinone amides |
| TW201036957A (en) * | 2009-02-20 | 2010-10-16 | Astrazeneca Ab | Novel salt 628 |
| AU2010222589B2 (en) | 2009-03-11 | 2012-08-16 | Pfizer Inc. | Benzofuranyl derivatives used as glucokinase inhibitors |
| CN102639505A (zh) * | 2009-10-02 | 2012-08-15 | 阿斯利康(瑞典)有限公司 | 用作嗜中性白细胞弹性蛋白酶抑制剂的吡啶-2-酮化合物 |
| ES2620612T3 (es) * | 2012-03-02 | 2017-06-29 | Genentech, Inc. | Derivados de sulfóxidos y sulfonas de piridinilo y pirimidinilo |
| US9102624B2 (en) * | 2012-08-23 | 2015-08-11 | Boehringer Ingelheim International Gmbh | Substituted 4-pyridones and their use as inhibitors of neutrophil elastase activity |
| US20140057926A1 (en) | 2012-08-23 | 2014-02-27 | Boehringer Ingelheim International Gmbh | Substituted 4-pyridones and their use as inhibitors of neutrophil elastase activity |
| US20140057920A1 (en) * | 2012-08-23 | 2014-02-27 | Boehringer Ingelheim International Gmbh | Substituted 4-pyridones and their use as inhibitors of neutrophil elastase activity |
| CN108137542B (zh) | 2015-09-02 | 2023-10-27 | 葛兰素史克知识产权第二有限公司 | 用作溴结构域抑制剂的吡啶酮二甲酰胺 |
| CN111683976B (zh) | 2018-02-05 | 2022-11-18 | 生物辐射实验室股份有限公司 | 具有阴离子交换-疏水混合模式配体的色谱树脂 |
| US20220354833A1 (en) | 2019-09-17 | 2022-11-10 | Mereo Biopharma 4 Limited | Alvelestat for use in the treatment of graft rejection, bronchiolitis obliterans syndrome and graft versus host disease |
| EP4252850A3 (en) | 2020-04-16 | 2023-11-15 | Mereo Biopharma 4 Limited | Methods involving neutrophil elastase inhibitor alvelestat for treating respiratory disease mediated by alpha-1 antitrypsin deficiency |
| IL312002A (en) | 2021-10-20 | 2024-06-01 | Mereo Biopharma 4 Ltd | Neutrophil elastase inhibitors for use in the treatment of fibrosis |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE2706977A1 (de) * | 1977-02-18 | 1978-08-24 | Hoechst Ag | Benzoesaeuren und deren derivate sowie verfahren zu ihrer herstellung |
| US5521179A (en) * | 1991-04-18 | 1996-05-28 | Zeneca Limited | Heterocyclic amides |
| US5441960A (en) * | 1992-04-16 | 1995-08-15 | Zeneca Limited | 1-pyrimidinylacetamide human leukocyte elastate inhibitors |
| JP2002513407A (ja) * | 1997-03-04 | 2002-05-08 | モンサント カンパニー | Ｎ−ヒドロキシ４−スルホニルブタンアミド化合物 |
| KR100850728B1 (ko) * | 2000-06-12 | 2008-08-06 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | 1,2-디하이드로피리딘 화합물, 그의 제조 방법 및 그의 용도 |
| ATE438624T1 (de) * | 2000-12-28 | 2009-08-15 | Shionogi & Co | 2-pyridonderivate mit affinität für den cannabinoid-typ-2-rezeptor |
| GB0129260D0 (en) * | 2001-12-06 | 2002-01-23 | Eisai London Res Lab Ltd | Pharmaceutical compositions and their uses |
| EP1554246B1 (en) * | 2002-08-27 | 2007-08-22 | Bayer HealthCare AG | Dihydropyridinone derivatives as hne inhibitors |
| TW200500341A (en) * | 2002-11-12 | 2005-01-01 | Astrazeneca Ab | Novel compounds |
| SE0302324D0 (sv) * | 2003-08-28 | 2003-08-28 | Astrazeneca Ab | Novel compounds |
| SE0302323D0 (sv) * | 2003-08-28 | 2003-08-28 | Astrazeneca Ab | Novel compounds |
| SE0302486D0 (sv) * | 2003-09-18 | 2003-09-18 | Astrazeneca Ab | Novel compounds |
| SE0302487D0 (sv) * | 2003-09-18 | 2003-09-18 | Astrazeneca Ab | Novel compounds |
-
2006
- 2006-03-06 TW TW095107354A patent/TW200700392A/zh unknown
- 2006-03-14 RU RU2007134106/04A patent/RU2007134106A/ru not_active Application Discontinuation
- 2006-03-14 US US11/908,746 patent/US20090131483A1/en not_active Abandoned
- 2006-03-14 JP JP2008501840A patent/JP2008533137A/ja active Pending
- 2006-03-14 SA SA06270055A patent/SA06270055B1/ar unknown
- 2006-03-14 BR BRPI0608636-5A patent/BRPI0608636A2/pt not_active IP Right Cessation
- 2006-03-14 CN CNA2006800085427A patent/CN101142188A/zh active Pending
- 2006-03-14 CA CA002600038A patent/CA2600038A1/en not_active Abandoned
- 2006-03-14 WO PCT/SE2006/000328 patent/WO2006098684A1/en active Application Filing
- 2006-03-14 US US11/908,748 patent/US20090105239A1/en not_active Abandoned
- 2006-03-14 KR KR1020077021054A patent/KR20070114154A/ko not_active Application Discontinuation
- 2006-03-14 EP EP06717012A patent/EP1861370A1/en not_active Withdrawn
- 2006-03-14 JP JP2008501839A patent/JP2008533136A/ja active Pending
- 2006-03-14 EP EP06717013A patent/EP1861371A4/en not_active Withdrawn
- 2006-03-14 AU AU2006223675A patent/AU2006223675B2/en not_active Ceased
- 2006-03-14 CN CNA2006800085728A patent/CN101142189A/zh active Pending
- 2006-03-14 WO PCT/SE2006/000327 patent/WO2006098683A1/en active Application Filing
- 2006-03-14 MX MX2007009372A patent/MX2007009372A/es not_active Application Discontinuation
- 2006-03-15 UY UY29420A patent/UY29420A1/es unknown
- 2006-03-16 AR ARP060101041A patent/AR053180A1/es unknown
-
2007
- 2007-07-26 IL IL184842A patent/IL184842A0/en unknown
- 2007-08-14 ZA ZA200706761A patent/ZA200706761B/xx unknown
- 2007-10-08 NO NO20075059A patent/NO20075059L/no not_active Application Discontinuation
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