JP2008533136A5 - - Google Patents
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- JP2008533136A5 JP2008533136A5 JP2008501839A JP2008501839A JP2008533136A5 JP 2008533136 A5 JP2008533136 A5 JP 2008533136A5 JP 2008501839 A JP2008501839 A JP 2008501839A JP 2008501839 A JP2008501839 A JP 2008501839A JP 2008533136 A5 JP2008533136 A5 JP 2008533136A5
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- phenyl
- oxo
- trifluoromethyl
- dihydropyridine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 150000001875 compounds Chemical class 0.000 claims description 78
- 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
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| WO (2) | WO2006098683A1 (enExample) |
| ZA (1) | ZA200706761B (enExample) |
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 |
| TW200808763A (en) | 2006-05-08 | 2008-02-16 | Astrazeneca Ab | Novel compounds I |
| TW200808771A (en) | 2006-05-08 | 2008-02-16 | Astrazeneca Ab | Novel compounds II |
| US8470859B2 (en) * | 2006-10-23 | 2013-06-25 | 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 |
| CA2703996A1 (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 |
| US20110039892A1 (en) * | 2008-04-23 | 2011-02-17 | Takeda Pharmaceutical Company Limited | Iminopyridine derivative 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. |
| PE20110303A1 (es) | 2008-09-11 | 2011-05-21 | Pfizer | Derivados de heteroaril acetamidas como activadores de glucoquinasa |
| JP2012515760A (ja) | 2009-01-20 | 2012-07-12 | ファイザー・インク | 置換ピラジノンアミド |
| TW201036957A (en) * | 2009-02-20 | 2010-10-16 | Astrazeneca Ab | Novel salt 628 |
| ES2427279T3 (es) | 2009-03-11 | 2013-10-29 | Pfizer Inc. | Derivados de benzofuranilo usados como inhibidores de glucocinasa |
| RU2012116877A (ru) * | 2009-10-02 | 2013-11-10 | Астразенека Аб | Соединения 2-пиридона, применяемые в качестве ингибиторов нейтрофильной эластазы |
| CN104507936A (zh) * | 2012-03-02 | 2015-04-08 | 基因科技股份有限公司 | 吡啶基和嘧啶基亚砜和砜衍生物 |
| 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 |
| US20140057926A1 (en) | 2012-08-23 | 2014-02-27 | Boehringer Ingelheim International Gmbh | Substituted 4-pyridones and their use as inhibitors of neutrophil elastase activity |
| UY36875A (es) | 2015-09-02 | 2017-03-31 | Glaxosmithkline Intellectual Property (No 2) Ltd | Composiciones inhibidoras de bromodominios para el tratamiento de diversas enfermedades |
| EP3749697A4 (en) | 2018-02-05 | 2021-11-03 | Bio-Rad Laboratories, Inc. | CHROMATOGRAPHY RESIN WITH LIGAND MIXED MODE ANIONIC / HYDROPHOBIC EXCHANGE |
| WO2021053058A1 (en) | 2019-09-17 | 2021-03-25 | Mereo Biopharma 4 Limited | Alvelestat for use in the treatment of graft rejection, bronchiolitis obliterans syndrome and graft versus host disease |
| LT4106757T (lt) | 2020-04-16 | 2023-11-10 | Mereo Biopharma 4 Limited | Neutrofilų elastazės inhibitoriaus alvelestato panaudojimas kvėpavimo sistemos ligų, nulemtų alfa-1 antitripsino nepakankamumo, gydymui |
| JP2024540952A (ja) | 2021-10-20 | 2024-11-06 | メレオ バイオファーマ ４ リミテッド | 線維化の治療における使用のための好中球エラスターゼ阻害剤 |
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 |
| WO1998038859A1 (en) * | 1997-03-04 | 1998-09-11 | Monsanto Company | Sulfonyl divalent aryl or heteroaryl hydroxamic acid compounds |
| PT1300396E (pt) * | 2000-06-12 | 2009-04-20 | Eisai R&D Man Co Ltd | Compostos de 1,2-di-hidropiridina, processos para a sua preparação e sua utilização |
| 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 |
| CA2496815C (en) * | 2002-08-27 | 2011-04-26 | Bayer Healthcare Ag | Dihydropyridinone derivatives |
| TW200500341A (en) * | 2002-11-12 | 2005-01-01 | Astrazeneca Ab | Novel compounds |
| SE0302324D0 (sv) * | 2003-08-28 | 2003-08-28 | Astrazeneca Ab | Novel compounds |
| SE0302323D0 (sv) * | 2003-08-28 | 2003-08-28 | Astrazeneca Ab | Novel compounds |
| SE0302486D0 (sv) * | 2003-09-18 | 2003-09-18 | Astrazeneca Ab | Novel compounds |
| SE0302487D0 (sv) * | 2003-09-18 | 2003-09-18 | Astrazeneca Ab | Novel compounds |
-
2006
- 2006-03-06 TW TW095107354A patent/TW200700392A/zh unknown
- 2006-03-14 WO PCT/SE2006/000327 patent/WO2006098683A1/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 EP EP06717013A patent/EP1861371A4/en not_active Withdrawn
- 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 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 BR BRPI0608636-5A patent/BRPI0608636A2/pt not_active IP Right Cessation
- 2006-03-14 EP EP06717012A patent/EP1861370A1/en not_active Withdrawn
- 2006-03-14 JP JP2008501840A patent/JP2008533137A/ja active Pending
- 2006-03-14 AU AU2006223675A patent/AU2006223675B2/en not_active Ceased
- 2006-03-14 MX MX2007009372A patent/MX2007009372A/es not_active Application Discontinuation
- 2006-03-14 KR KR1020077021054A patent/KR20070114154A/ko not_active Withdrawn
- 2006-03-14 SA SA06270055A patent/SA06270055B1/ar unknown
- 2006-03-15 UY UY29420A patent/UY29420A1/es unknown
- 2006-03-16 AR ARP060101041A patent/AR053180A1/es unknown
-
2007
- 2007-07-26 IL IL184842A patent/IL184842A0/en unknown
- 2007-08-14 ZA ZA200706761A patent/ZA200706761B/xx unknown
- 2007-10-08 NO NO20075059A patent/NO20075059L/no not_active Application Discontinuation
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