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) | EP1861370A1 (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) | WO2006098683A1 (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 |
| EP2077262A4 (en) * | 2006-10-23 | 2011-12-28 | Takeda Pharmaceutical | 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 |
| WO2009061271A1 (en) * | 2007-11-06 | 2009-05-14 | Astrazeneca Ab | Some 2-pyrazinone derivatives and their use as inhibitors of neutrophile elastase |
| US8481569B2 (en) * | 2008-04-23 | 2013-07-09 | Takeda Pharmaceutical Company Limited | Iminopyridine derivatives and use thereof |
| CL2009000964A1 (es) * | 2008-04-23 | 2010-03-26 | Takeda Pharmaceuticals Co | Compuestos derivados de 1-aril-2-imino-1,2-dihidropiridina-3-carboxamida, antagonista del receptor adrenergico alfa 1d, composicion farmaceutica que los comprende; y su uso para el tratamiento o profilaxis de enfermedades del tracto urinario inferior. |
| US20110039892A1 (en) * | 2008-04-23 | 2011-02-17 | Takeda Pharmaceutical Company Limited | Iminopyridine derivative and use thereof |
| KR101258331B1 (ko) | 2008-09-11 | 2013-04-26 | 화이자 인코포레이티드 | 헤테로아릴 아미드 유도체 및 글루코키나제 활성화제로서의 그의 용도 |
| 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 |
| MY151246A (en) | 2009-03-11 | 2014-04-30 | Pfizer | Benzofuranyl derivatives |
| CA2773618A1 (en) * | 2009-10-02 | 2011-04-07 | Astrazeneca Ab | 2-pyridone compounds used as inhibitors of neutrophil elastase |
| 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 |
| HK1249504A1 (zh) | 2015-09-02 | 2018-11-02 | Glaxosmithkline Intellectual Property (No. 2) Limited | 用作溴结构域抑制剂的吡啶酮二甲酰胺 |
| EP3749697A4 (en) | 2018-02-05 | 2021-11-03 | Bio-Rad Laboratories, Inc. | CHROMATOGRAPHY RESIN WITH LIGAND MIXED MODE ANIONIC / HYDROPHOBIC EXCHANGE |
| CN114650819A (zh) | 2019-09-17 | 2022-06-21 | 美莱奥生物制药第四有限公司 | 用于治疗移植物排斥、闭塞性细支气管炎综合征和移植物抗宿主病的阿维来司他 |
| WO2021209740A1 (en) | 2020-04-16 | 2021-10-21 | Mereo Biopharma 4 Limited | Methods involving neutrophil elastase inhibitor alvelestat for treating coronavirus infection |
| EP4419102A1 (en) | 2021-10-20 | 2024-08-28 | Mereo Biopharma 4 Limited | Neutrophil elastase inhibitors for use in the treatment of fibrosis |
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 |
| US6380258B2 (en) * | 1997-03-04 | 2002-04-30 | G. D. Searle, L.L.C. | Sulfonyl divalent aryl or heteroaryl hydroxamic acid compounds |
| IL152848A0 (en) * | 2000-06-12 | 2003-06-24 | Eisai Co Ltd | 1,2-dihydropyridine derivatives, pharmaceutical compositions containing the same and methods for the production thereof |
| ES2330719T3 (es) * | 2000-12-28 | 2009-12-15 | SHIONOGI & CO., LTD. | Derivados de 2-piridona con afinidad para el receptor cannabinoide de tipo 2. |
| GB0129260D0 (en) * | 2001-12-06 | 2002-01-23 | Eisai London Res Lab Ltd | Pharmaceutical compositions and their uses |
| JP4619122B2 (ja) * | 2002-08-27 | 2011-01-26 | バイエル・シェーリング・ファルマ・アクチェンゲゼルシャフト | Ｈｎｅインヒビターとしてのジヒドロピリジノン誘導体 |
| 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 AU AU2006223675A patent/AU2006223675B2/en not_active Ceased
- 2006-03-14 US US11/908,748 patent/US20090105239A1/en not_active Abandoned
- 2006-03-14 BR BRPI0608636-5A patent/BRPI0608636A2/pt not_active IP Right Cessation
- 2006-03-14 WO PCT/SE2006/000327 patent/WO2006098683A1/en not_active Ceased
- 2006-03-14 CN CNA2006800085728A patent/CN101142189A/zh active Pending
- 2006-03-14 CN CNA2006800085427A patent/CN101142188A/zh active Pending
- 2006-03-14 WO PCT/SE2006/000328 patent/WO2006098684A1/en not_active Ceased
- 2006-03-14 MX MX2007009372A patent/MX2007009372A/es not_active Application Discontinuation
- 2006-03-14 JP JP2008501839A patent/JP2008533136A/ja active Pending
- 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 KR KR1020077021054A patent/KR20070114154A/ko not_active Withdrawn
- 2006-03-14 EP EP06717012A patent/EP1861370A1/en not_active Withdrawn
- 2006-03-14 CA CA002600038A patent/CA2600038A1/en not_active Abandoned
- 2006-03-14 SA SA06270055A patent/SA06270055B1/ar unknown
- 2006-03-14 EP EP06717013A patent/EP1861371A4/en not_active Withdrawn
- 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 |