JP2008533136A5 - - Google Patents
Download PDFInfo
- Publication number
- 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
Links
- 150000001875 compounds Chemical class 0.000 claims description 78
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 23
- -1 cyano, carboxyl Chemical group 0.000 claims description 22
- 125000001424 substituent group Chemical group 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 18
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 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 heteroatom Chemical group 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms 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 10
- 201000010099 disease Diseases 0.000 claims description 8
- 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
- 229920006395 saturated elastomer Polymers 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
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 239000011593 sulfur Substances 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 5
- 206010014561 Emphysema Diseases 0.000 claims description 5
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 206010063837 Reperfusion injury Diseases 0.000 claims description 5
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 5
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims description 5
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 5
- 230000006378 damage Effects 0.000 claims description 5
- 208000027866 inflammatory disease Diseases 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 5
- 206010039073 rheumatoid arthritis Diseases 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
- 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 4
- 201000001320 Atherosclerosis 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
- 208000006673 asthma Diseases 0.000 claims description 4
- 201000009267 bronchiectasis Diseases 0.000 claims description 4
- 206010006451 bronchitis 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
- 208000012947 ischemia reperfusion injury 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
- 201000008482 osteoarthritis Diseases 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 206010039083 rhinitis Diseases 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
- 201000003883 Cystic fibrosis Diseases 0.000 claims description 3
- 208000027418 Wounds and injury Diseases 0.000 claims description 3
- 230000005856 abnormality Effects 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 230000002496 gastric effect Effects 0.000 claims description 3
- 208000014674 injury Diseases 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 238000011282 treatment 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
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 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
- 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
- 239000012038 nucleophile Substances 0.000 claims description 2
- 125000004430 oxygen atom 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
- 108010028275 Leukocyte Elastase Proteins 0.000 claims 2
- 102000016799 Leukocyte elastase Human genes 0.000 claims 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims 2
- 230000009286 beneficial effect Effects 0.000 claims 2
- 208000035475 disorder Diseases 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
- 208000032170 Congenital Abnormalities Diseases 0.000 claims 1
- 206010061619 Deformity Diseases 0.000 claims 1
- 125000001072 heteroaryl group Chemical group 0.000 claims 1
- 230000005764 inhibitory process Effects 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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
- FKRCODPIKNYEAC-UHFFFAOYSA-N propionic acid ethyl ester Natural products CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 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 Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 32
- 238000000668 atmospheric pressure chemical ionisation mass spectrometry Methods 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- 239000007787 solid Substances 0.000 description 25
- 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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 238000002953 preparative HPLC Methods 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 13
- 238000001704 evaporation Methods 0.000 description 13
- 230000008020 evaporation Effects 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000011734 sodium Substances 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 239000000377 silicon dioxide Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 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
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-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
- 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
- 239000012071 phase Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 201000004624 Dermatitis Diseases 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 239000007864 aqueous solution Substances 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
- 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 organ Anatomy 0.000 description 3
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 3
- JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical compound NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- ZMELLUBESPPMPK-UHFFFAOYSA-N trimethyl-(2-methylpyrazol-3-yl)stannane Chemical compound CN1N=CC=C1[Sn](C)(C)C ZMELLUBESPPMPK-UHFFFAOYSA-N 0.000 description 3
- AWNXKZVIZARMME-UHFFFAOYSA-N 1-[[5-[2-[(2-chloropyridin-4-yl)amino]pyrimidin-4-yl]-4-(cyclopropylmethyl)pyrimidin-2-yl]amino]-2-methylpropan-2-ol Chemical compound N=1C(NCC(C)(O)C)=NC=C(C=2N=C(NC=3C=C(Cl)N=CC=3)N=CC=2)C=1CC1CC1 AWNXKZVIZARMME-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- UJRKTWVTFGJSNS-UHFFFAOYSA-N 5-ethyl-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxylic acid Chemical compound CC1=C(CC)C=C(C(O)=O)C(=O)N1C1=CC=CC(C(F)(F)F)=C1 UJRKTWVTFGJSNS-UHFFFAOYSA-N 0.000 description 2
- LEDBIIVAMCPQPJ-UHFFFAOYSA-N 5-iodo-6-methyl-2-oxo-n-prop-2-ynyl-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxamide Chemical compound CC1=C(I)C=C(C(=O)NCC#C)C(=O)N1C1=CC=CC(C(F)(F)F)=C1 LEDBIIVAMCPQPJ-UHFFFAOYSA-N 0.000 description 2
- SQUAXDZIPZMFHL-UHFFFAOYSA-N 5-iodo-6-methyl-n-[[3-[2-(oxan-2-yloxy)ethyl]-1,2-oxazol-5-yl]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=1CCOC1CCCCO1 SQUAXDZIPZMFHL-UHFFFAOYSA-N 0.000 description 2
- HGSDSOKEXHWXMU-UHFFFAOYSA-N 6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxylic acid Chemical compound CC1=CC=C(C(O)=O)C(=O)N1C1=CC=CC(C(F)(F)F)=C1 HGSDSOKEXHWXMU-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VVPYXTJJNVOTDF-UHFFFAOYSA-N [3-(methoxymethyl)-1,2-oxazol-5-yl]methanamine Chemical compound COCC=1C=C(CN)ON=1 VVPYXTJJNVOTDF-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- VLQYXHUTOQHLOE-UHFFFAOYSA-N methyl 3-[5-[(3-cyclopropyl-1,2-oxazol-5-yl)methylcarbamoyl]-2-methyl-6-oxo-1-[3-(trifluoromethyl)phenyl]pyridin-3-yl]prop-2-enoate Chemical compound O=C1N(C=2C=C(C=CC=2)C(F)(F)F)C(C)=C(C=CC(=O)OC)C=C1C(=O)NCC(ON=1)=CC=1C1CC1 VLQYXHUTOQHLOE-UHFFFAOYSA-N 0.000 description 2
- GWNQBGHYBVGKHH-UHFFFAOYSA-N n-[(3-cyclopropyl-1,2-oxazol-5-yl)methyl]-5-[3-(methanesulfonamido)propyl]-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(CCCNS(C)(=O)=O)C=C1C(=O)NCC(ON=1)=CC=1C1CC1 GWNQBGHYBVGKHH-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 208000005069 pulmonary fibrosis Diseases 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000002753 trypsin inhibitor Substances 0.000 description 2
- DIIFZCPZIRQDIJ-UHFFFAOYSA-N (3,5-dimethyl-1,2-oxazol-4-yl)boronic acid Chemical compound CC1=NOC(C)=C1B(O)O DIIFZCPZIRQDIJ-UHFFFAOYSA-N 0.000 description 1
- NRXMOYDZMKXKMJ-UHFFFAOYSA-N (4-methylsulfonylphenyl)methylazanium;chloride Chemical compound [Cl-].CS(=O)(=O)C1=CC=C(C[NH3+])C=C1 NRXMOYDZMKXKMJ-UHFFFAOYSA-N 0.000 description 1
- VLLHEPHWWIDUSS-ONEGZZNKSA-N (e)-4-methoxybut-3-en-2-one Chemical compound CO\C=C\C(C)=O VLLHEPHWWIDUSS-ONEGZZNKSA-N 0.000 description 1
- NJQRAAHKQQPUIT-UHFFFAOYSA-N 1,2-dihydropyridine-3-carboxamide Chemical compound NC(=O)C1=CC=CNC1 NJQRAAHKQQPUIT-UHFFFAOYSA-N 0.000 description 1
- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical compound BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 description 1
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 1
- HSMSACRUDIFKIL-UHFFFAOYSA-N 1-phenyl-2H-pyridine-3-carboxylic acid Chemical compound C1(=CC=CC=C1)N1CC(=CC=C1)C(=O)O HSMSACRUDIFKIL-UHFFFAOYSA-N 0.000 description 1
- BOFJQXDJPKTPKY-UHFFFAOYSA-N 2-(3-nitropropoxy)oxane Chemical compound [O-][N+](=O)CCCOC1CCCCO1 BOFJQXDJPKTPKY-UHFFFAOYSA-N 0.000 description 1
- KFEISZAWONWZCB-UHFFFAOYSA-N 2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxylic acid Chemical compound O=C1C(C(=O)O)=CC=CN1C1=CC=CC(C(F)(F)F)=C1 KFEISZAWONWZCB-UHFFFAOYSA-N 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- VGSBFOIJNXDGML-UHFFFAOYSA-N 5-(2-bromoethoxy)-6-methyl-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(OCCBr)=C(C)N1C1=CC=CC(C(F)(F)F)=C1 VGSBFOIJNXDGML-UHFFFAOYSA-N 0.000 description 1
- HNXAHLRULHAYNU-UHFFFAOYSA-N 5-(3,5-dimethyl-1,2-oxazol-4-yl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxylic acid Chemical compound CC1=NOC(C)=C1C1=C(C)N(C=2C=C(C=CC=2)C(F)(F)F)C(=O)C(C(O)=O)=C1 HNXAHLRULHAYNU-UHFFFAOYSA-N 0.000 description 1
- QVMBLQTVMHGHDC-UHFFFAOYSA-N 5-(3-aminopropyl)-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(CCCN)C=C1C(=O)NCC(ON=1)=CC=1C1CC1 QVMBLQTVMHGHDC-UHFFFAOYSA-N 0.000 description 1
- IFPGKJFKHAKCFA-UHFFFAOYSA-N 5-cyclopropyl-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxylic acid Chemical compound CC1=C(C2CC2)C=C(C(O)=O)C(=O)N1C1=CC=CC(C(F)(F)F)=C1 IFPGKJFKHAKCFA-UHFFFAOYSA-N 0.000 description 1
- FZFNPLQNLXPFTE-UHFFFAOYSA-N 5-iodo-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxylic acid Chemical compound CC1=C(I)C=C(C(O)=O)C(=O)N1C1=CC=CC(C(F)(F)F)=C1 FZFNPLQNLXPFTE-UHFFFAOYSA-N 0.000 description 1
- SDUGJSSOHAJLSC-UHFFFAOYSA-N 5-iodo-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(I)C=C1C(=O)NCC1=CC=C(S(C)(=O)=O)C=C1 SDUGJSSOHAJLSC-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- SKGOFSBEVCGWCK-UHFFFAOYSA-N 6-methyl-5-(3-methylsulfanylpropyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxylic acid Chemical compound CC1=C(CCCSC)C=C(C(O)=O)C(=O)N1C1=CC=CC(C(F)(F)F)=C1 SKGOFSBEVCGWCK-UHFFFAOYSA-N 0.000 description 1
- MLJWUGIPUBJDDY-UHFFFAOYSA-N 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)=CC=C1C(=O)NCC1=CC=C(S(C)(=O)=O)C=C1 MLJWUGIPUBJDDY-UHFFFAOYSA-N 0.000 description 1
- PZASAAIJIFDWSB-CKPDSHCKSA-N 8-[(1S)-1-[8-(trifluoromethyl)-7-[4-(trifluoromethyl)cyclohexyl]oxynaphthalen-2-yl]ethyl]-8-azabicyclo[3.2.1]octane-3-carboxylic acid Chemical compound FC(F)(F)C=1C2=CC([C@@H](N3C4CCC3CC(C4)C(O)=O)C)=CC=C2C=CC=1OC1CCC(C(F)(F)F)CC1 PZASAAIJIFDWSB-CKPDSHCKSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000036487 Arthropathies Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- PRRUTFLGBDGKKZ-UHFFFAOYSA-N CC1=C(C=C(C(=O)N1C2=CC=CC(=C2)C(F)(F)F)C(=O)NCC3=CC(=NO3)CCO)C4CC4 Chemical compound CC1=C(C=C(C(=O)N1C2=CC=CC(=C2)C(F)(F)F)C(=O)NCC3=CC(=NO3)CCO)C4CC4 PRRUTFLGBDGKKZ-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 208000016192 Demyelinating disease Diseases 0.000 description 1
- 206010058314 Dysplasia Diseases 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- 206010064147 Gastrointestinal inflammation Diseases 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 208000010191 Osteitis Deformans Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 208000027868 Paget disease Diseases 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 229920000388 Polyphosphate Polymers 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 206010040943 Skin Ulcer Diseases 0.000 description 1
- 206010072170 Skin wound Diseases 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 206010064996 Ulcerative keratitis Diseases 0.000 description 1
- FEVUUYXACWWJPZ-UHFFFAOYSA-N [5-(aminomethyl)-1,2-oxazol-3-yl]methanol Chemical compound NCC1=CC(CO)=NO1 FEVUUYXACWWJPZ-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003872 anastomosis Effects 0.000 description 1
- 229940019748 antifibrinolytic proteinase inhibitors Drugs 0.000 description 1
- 206010003230 arteritis Diseases 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 208000019664 bone resorption disease Diseases 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 230000037369 collagen remodeling Effects 0.000 description 1
- 230000000112 colonic effect Effects 0.000 description 1
- 201000007717 corneal ulcer Diseases 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
- WLVKDFJTYKELLQ-UHFFFAOYSA-N cyclopropylboronic acid Chemical compound OB(O)C1CC1 WLVKDFJTYKELLQ-UHFFFAOYSA-N 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- YOKXDIVHVFAWRF-UHFFFAOYSA-N ethyl 5-iodo-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxylate Chemical compound O=C1C(C(=O)OCC)=CC(I)=C(C)N1C1=CC=CC(C(F)(F)F)=C1 YOKXDIVHVFAWRF-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 208000007565 gingivitis Diseases 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 208000018937 joint inflammation Diseases 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 208000027202 mammary Paget disease Diseases 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- FFAWNJFEDMNSHM-UHFFFAOYSA-N methyl 3-[5-[[[5-iodo-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carbonyl]amino]methyl]-1,2-oxazol-3-yl]propanoate Chemical compound O1N=C(CCC(=O)OC)C=C1CNC(=O)C(C1=O)=CC(I)=C(C)N1C1=CC=CC(C(F)(F)F)=C1 FFAWNJFEDMNSHM-UHFFFAOYSA-N 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- BSLMFTOTDQVFIF-UHFFFAOYSA-N n-[(3-cyclopropyl-1,2-oxazol-5-yl)methyl]-5-(3-hydroxyprop-1-ynyl)-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(C#CCO)C=C1C(=O)NCC(ON=1)=CC=1C1CC1 BSLMFTOTDQVFIF-UHFFFAOYSA-N 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 208000028169 periodontal disease Diseases 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 1
- 239000001205 polyphosphate Substances 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019419 proteases Nutrition 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000012056 semi-solid material Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 231100000019 skin ulcer Toxicity 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 description 1
- 239000011973 solid acid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000000153 supplemental effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ZBNITNWQSAGWIF-UHFFFAOYSA-N tert-butyl n-[[3-(hydroxymethyl)-1,2-oxazol-5-yl]methyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC1=CC(CO)=NO1 ZBNITNWQSAGWIF-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE0500604 | 2005-03-16 | ||
| PCT/SE2006/000327 WO2006098683A1 (en) | 2005-03-16 | 2006-03-14 | 2-pyridine derivatives as inhibitors of neutrophile elastase |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2008533136A JP2008533136A (ja) | 2008-08-21 |
| JP2008533136A5 true JP2008533136A5 (https=) | 2009-04-16 |
Family
ID=36991969
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2008501839A Pending JP2008533136A (ja) | 2005-03-16 | 2006-03-14 | 好中球エラスターゼの阻害剤としての２−ピリジン誘導体 |
| JP2008501840A Pending JP2008533137A (ja) | 2005-03-16 | 2006-03-14 | 好中球エラスターゼインヒビターとしての２−ピリジン誘導体 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2008501840A Pending JP2008533137A (ja) | 2005-03-16 | 2006-03-14 | 好中球エラスターゼインヒビターとしての２−ピリジン誘導体 |
Country Status (18)
| Country | Link |
|---|---|
| US (2) | US20090105239A1 (https=) |
| EP (2) | EP1861371A4 (https=) |
| JP (2) | JP2008533136A (https=) |
| KR (1) | KR20070114154A (https=) |
| CN (2) | CN101142189A (https=) |
| AR (1) | AR053180A1 (https=) |
| AU (1) | AU2006223675B2 (https=) |
| BR (1) | BRPI0608636A2 (https=) |
| CA (1) | CA2600038A1 (https=) |
| IL (1) | IL184842A0 (https=) |
| MX (1) | MX2007009372A (https=) |
| NO (1) | NO20075059L (https=) |
| RU (1) | RU2007134106A (https=) |
| SA (1) | SA06270055B1 (https=) |
| TW (1) | TW200700392A (https=) |
| UY (1) | UY29420A1 (https=) |
| WO (2) | WO2006098684A1 (https=) |
| ZA (1) | ZA200706761B (https=) |
Families Citing this family (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE0302486D0 (sv) * | 2003-09-18 | 2003-09-18 | Astrazeneca Ab | Novel compounds |
| TW200808771A (en) * | 2006-05-08 | 2008-02-16 | Astrazeneca Ab | Novel compounds II |
| TW200808763A (en) | 2006-05-08 | 2008-02-16 | Astrazeneca Ab | Novel compounds I |
| EP2535330A3 (en) * | 2006-10-23 | 2012-12-26 | Takeda Pharmaceutical Company Limited | Iminopyridine derivative and use thereof |
| WO2009037413A1 (en) * | 2007-09-19 | 2009-03-26 | Argenta Discovery Limited | Dimers of 5- [ (4-cyanophenyl) sulfinyl] -6-methyl-2-oxo-1- [3- (trifluoromethyl)phenyl] -1,2-dihydropyridine-3-carboxamide as inhibitors of human neutrophil elastase for treating respiratory diseases |
| WO2009058076A1 (en) * | 2007-11-02 | 2009-05-07 | Astrazeneca Ab | 2-pyrazinone derivatives and their use as inhibitors of neutrophile elastase |
| EP2217591A4 (en) * | 2007-11-06 | 2011-10-26 | Astrazeneca Ab | CERTAIN 2-PYRAZINONE DERIVATIVES AND THEIR USE AS NEUTROPHILES ELASTASE INHIBITORS |
| US8481569B2 (en) * | 2008-04-23 | 2013-07-09 | Takeda Pharmaceutical Company Limited | Iminopyridine derivatives and use thereof |
| AR071392A1 (es) * | 2008-04-23 | 2010-06-16 | Takeda Pharmaceutical | Derivados de iminopiridina y su uso |
| US20110039892A1 (en) * | 2008-04-23 | 2011-02-17 | Takeda Pharmaceutical Company Limited | Iminopyridine derivative and use thereof |
| AU2009290474A1 (en) | 2008-09-11 | 2010-03-18 | Pfizer Inc. | Heteroaryls amide derivatives and their use as glucokinase activators |
| EP2389374A1 (en) | 2009-01-20 | 2011-11-30 | Pfizer Inc. | Substituted pyrazinone amides |
| TW201036957A (en) * | 2009-02-20 | 2010-10-16 | Astrazeneca Ab | Novel salt 628 |
| EP2604604A1 (en) | 2009-03-11 | 2013-06-19 | Pfizer Inc | Benzofuranyl derivatives used as glucokinase inhibitors |
| AU2010302420B2 (en) * | 2009-10-02 | 2013-07-04 | Astrazeneca Ab | 2-pyridone compounds used as inhibitors of neutrophil elastase |
| JP2015508785A (ja) * | 2012-03-02 | 2015-03-23 | ジェネンテック， インコーポレイテッド | ピリジニル及びピリミジニルスルホキシド及びスルホン誘導体 |
| 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 |
| US9102624B2 (en) * | 2012-08-23 | 2015-08-11 | Boehringer Ingelheim International Gmbh | Substituted 4-pyridones and their use as inhibitors of neutrophil elastase activity |
| JP6532599B2 (ja) | 2015-09-02 | 2019-06-19 | グラクソスミスクライン、インテレクチュアル、プロパティー、（ナンバー２）、リミテッドＧｌａｘｏｓｍｉｔｈｋｌｉｎｅ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ （Ｎｏ．２） Ｌｉｍｉｔｅｄ | ブロモドメイン阻害薬としての使用のためのピリジノンジカルボキサミド |
| EP3749697A4 (en) | 2018-02-05 | 2021-11-03 | Bio-Rad Laboratories, Inc. | CHROMATOGRAPHY RESIN WITH LIGAND MIXED MODE ANIONIC / HYDROPHOBIC EXCHANGE |
| JP7672641B2 (ja) | 2019-09-17 | 2025-05-08 | メレオ バイオファーマ ４ リミテッド | 移植片拒絶反応、閉塞性細気管支炎症候群、及び移植片対宿主病の治療に使用するためのアルベレスタット |
| IL297211B2 (en) | 2020-04-16 | 2025-12-01 | Mereo Biopharma 4 Ltd | Methods involving neutrophil elastase inhibitor alvelestat for treating respiratory disease mediated by alpha-1 antitrypsin deficiency |
| KR20240090272A (ko) | 2021-10-20 | 2024-06-21 | 메레오 바이오파마 4 리미티드 | 섬유화 치료에 사용하기 위한 호중구 엘라스테이스 억제제 |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| NZ337326A (en) * | 1997-03-04 | 2001-05-25 | Monsanto Co | Sulfonyl divalent aryl or heteroaryl hydroxamic acid compounds to inhibit the activity of matrix metalloproteinases |
| ES2320973T3 (es) * | 2000-06-12 | 2009-06-01 | EISAI R&D MANAGEMENT CO., LTD. | Compuestos de 1,2-dihidropiridina, procedimiento para su preparacion y uso de los mismos. |
| KR100828982B1 (ko) * | 2000-12-28 | 2008-05-14 | 시오노기세이야쿠가부시키가이샤 | 칸나비노이드 2형 수용체 친화 작용을 갖는 피리돈 유도체 |
| GB0129260D0 (en) * | 2001-12-06 | 2002-01-23 | Eisai London Res Lab Ltd | Pharmaceutical compositions and their uses |
| ES2293077T3 (es) * | 2002-08-27 | 2008-03-16 | Bayer Healthcare Ag | Derivados de dihidropiridinona como inhbidores de hne. |
| TW200500341A (en) * | 2002-11-12 | 2005-01-01 | Astrazeneca Ab | Novel compounds |
| SE0302323D0 (sv) * | 2003-08-28 | 2003-08-28 | Astrazeneca Ab | Novel compounds |
| SE0302324D0 (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 SA SA06270055A patent/SA06270055B1/ar unknown
- 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 US US11/908,748 patent/US20090105239A1/en not_active Abandoned
- 2006-03-14 WO PCT/SE2006/000328 patent/WO2006098684A1/en not_active Ceased
- 2006-03-14 JP JP2008501839A patent/JP2008533136A/ja active Pending
- 2006-03-14 CN CNA2006800085728A patent/CN101142189A/zh active Pending
- 2006-03-14 CA CA002600038A patent/CA2600038A1/en not_active Abandoned
- 2006-03-14 CN CNA2006800085427A patent/CN101142188A/zh active Pending
- 2006-03-14 EP EP06717012A patent/EP1861370A1/en not_active Withdrawn
- 2006-03-14 JP JP2008501840A patent/JP2008533137A/ja active Pending
- 2006-03-14 BR BRPI0608636-5A patent/BRPI0608636A2/pt not_active IP Right Cessation
- 2006-03-14 KR KR1020077021054A patent/KR20070114154A/ko not_active Withdrawn
- 2006-03-14 WO PCT/SE2006/000327 patent/WO2006098683A1/en not_active Ceased
- 2006-03-14 MX MX2007009372A patent/MX2007009372A/es not_active Application Discontinuation
- 2006-03-14 US US11/908,746 patent/US20090131483A1/en not_active Abandoned
- 2006-03-14 RU RU2007134106/04A patent/RU2007134106A/ru 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
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2008533136A5 (https=) | ||
| KR101141464B1 (ko) | 중성구 엘라스타제 억제제로서의 2-피리돈 유도체 및 그의용도 | |
| AU2004272485B2 (en) | 2-pyridone derivatives as neutrophil elastase inhibitors and their use | |
| FI116219B (fi) | Aromaattiset aminoeetterit kipua lievittävinä aineina | |
| AU2003276802B2 (en) | 2-pyridone derivatives as inhibitors of neutrophile elastase | |
| ES2442003T3 (es) | Nuevo derivado de sulfonamida de ácido malónico y uso farmacéutico del mismo | |
| JP2008533136A (ja) | 好中球エラスターゼの阻害剤としての２−ピリジン誘導体 | |
| ES2236965T3 (es) | Acilguanidinas como inhibidores del intercambio sodio/proton y procedimiento. | |
| WO2001083463A1 (en) | Oxadiazole derivatives having anticancer effects | |
| JPWO2003080042A1 (ja) | 軟骨細胞外基質分解阻害剤 | |
| JP2003505367A (ja) | マトリックスメタロプロテイナーゼ阻害剤としての３−アリールスルホニル−２−（置換メチル）プロパン酸誘導体 | |
| JP2002105073A (ja) | 新規マトリックスメタロプロテアーゼ阻害剤 | |
| KR20010075447A (ko) | 치환 이속사졸릴 티오펜 화합물 | |
| JP2000169471A (ja) | 置換イソキサゾリルチオフェン化合物 | |
| HK1089166B (en) | 2-pyridone derivatives as neutrophil elastase inhibitors and their use | |
| UA81271C2 (en) | 2-pyridone derivatives as inhibitors of neutrophile elastase, process for the preparation thereof and pharmaceutical composition based thereon |