ZA200300614B - 4-Phenyl-pyridine derivatives as neurokinin-1 receptor antagonists. - Google Patents
4-Phenyl-pyridine derivatives as neurokinin-1 receptor antagonists. Download PDFInfo
- Publication number
- ZA200300614B ZA200300614B ZA200300614A ZA200300614A ZA200300614B ZA 200300614 B ZA200300614 B ZA 200300614B ZA 200300614 A ZA200300614 A ZA 200300614A ZA 200300614 A ZA200300614 A ZA 200300614A ZA 200300614 B ZA200300614 B ZA 200300614B
- Authority
- ZA
- South Africa
- Prior art keywords
- trifluoromethyl
- methyl
- bis
- compound
- tolyl
- Prior art date
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- 239000002742 neurokinin 1 receptor antagonist Substances 0.000 title description 5
- 150000005362 4-phenylpyridines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 190
- -1 cyano, hydroxy Chemical group 0.000 claims description 63
- 125000000217 alkyl group Chemical group 0.000 claims description 62
- 125000001424 substituent group Chemical group 0.000 claims description 54
- 239000000203 mixture Substances 0.000 claims description 45
- 229910052736 halogen Chemical group 0.000 claims description 42
- 150000002367 halogens Chemical group 0.000 claims description 42
- 238000000034 method Methods 0.000 claims description 39
- 229910052739 hydrogen Inorganic materials 0.000 claims description 36
- 239000001257 hydrogen Substances 0.000 claims description 34
- 125000003545 alkoxy group Chemical group 0.000 claims description 32
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 26
- 125000003118 aryl group Chemical group 0.000 claims description 22
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 17
- 125000005842 heteroatom Chemical group 0.000 claims description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- ADTNSTHKMIPKIJ-UHFFFAOYSA-N 1-[3,5-bis(trifluoromethyl)phenyl]-n-methylmethanamine Chemical compound CNCC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 ADTNSTHKMIPKIJ-UHFFFAOYSA-N 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 102000002002 Neurokinin-1 Receptors Human genes 0.000 claims description 7
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 claims description 7
- 229910052740 iodine Inorganic materials 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- DDXRSSAMBKGDNC-UHFFFAOYSA-N n-[[3,5-bis(trifluoromethyl)phenyl]methyl]-6-chloro-n-methyl-4-(2-methylphenyl)pyridine-3-carboxamide Chemical compound C=1N=C(Cl)C=C(C=2C(=CC=CC=2)C)C=1C(=O)N(C)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 DDXRSSAMBKGDNC-UHFFFAOYSA-N 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 229940044551 receptor antagonist Drugs 0.000 claims description 6
- 239000002464 receptor antagonist Substances 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- OKFQQNPPMKCZAH-UHFFFAOYSA-N n-[[3,5-bis(trifluoromethyl)phenyl]methyl]-6-iodo-n-methyl-4-(2-methylphenyl)pyridine-3-carboxamide Chemical compound C=1N=C(I)C=C(C=2C(=CC=CC=2)C)C=1C(=O)N(C)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 OKFQQNPPMKCZAH-UHFFFAOYSA-N 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- FLQMVDRONZBQJR-UHFFFAOYSA-N n-[[3,5-bis(trifluoromethyl)phenyl]methyl]-6-(cyanomethyl)-n-methyl-4-(2-methylphenyl)pyridine-3-carboxamide Chemical compound C=1N=C(CC#N)C=C(C=2C(=CC=CC=2)C)C=1C(=O)N(C)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 FLQMVDRONZBQJR-UHFFFAOYSA-N 0.000 claims description 4
- YWVBYGXNNDSQKE-UHFFFAOYSA-N 2-[3,5-bis(trifluoromethyl)phenyl]-n-[6-[(2-hydroxyacetyl)-methylamino]-4-(2-methylphenyl)pyridin-3-yl]-n,2-dimethylpropanamide Chemical compound C1=NC(N(C(=O)CO)C)=CC(C=2C(=CC=CC=2)C)=C1N(C)C(=O)C(C)(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 YWVBYGXNNDSQKE-UHFFFAOYSA-N 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- UIVMYEZJWVDITM-UHFFFAOYSA-N n-[[3,5-bis(trifluoromethyl)phenyl]methyl]-6-(hydroxymethyl)-n-methyl-4-(2-methylphenyl)pyridine-3-carboxamide Chemical compound C=1N=C(CO)C=C(C=2C(=CC=CC=2)C)C=1C(=O)N(C)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 UIVMYEZJWVDITM-UHFFFAOYSA-N 0.000 claims description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- POYFDVRKSTZYLN-UHFFFAOYSA-N 2-[3,5-bis(trifluoromethyl)phenyl]-n-[4-(2-chlorophenyl)-6-(3-oxomorpholin-4-yl)pyridin-3-yl]-n,2-dimethylpropanamide Chemical compound C=1N=C(N2C(COCC2)=O)C=C(C=2C(=CC=CC=2)Cl)C=1N(C)C(=O)C(C)(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 POYFDVRKSTZYLN-UHFFFAOYSA-N 0.000 claims description 2
- MZHINWSDMUFLTK-UHFFFAOYSA-N 2-[3,5-bis(trifluoromethyl)phenyl]-n-[4-(2-chlorophenyl)-6-[hydroxy(2-hydroxyethyl)amino]pyridin-3-yl]-n,2-dimethylpropanamide Chemical compound C=1N=C(N(O)CCO)C=C(C=2C(=CC=CC=2)Cl)C=1N(C)C(=O)C(C)(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 MZHINWSDMUFLTK-UHFFFAOYSA-N 0.000 claims description 2
- DJHXZQUFUCQSCF-UHFFFAOYSA-N 2-[3,5-bis(trifluoromethyl)phenyl]-n-[6-(2,5-dioxopyrrolidin-1-yl)-4-(2-methylphenyl)pyridin-3-yl]-n,2-dimethylpropanamide Chemical compound C=1N=C(N2C(CCC2=O)=O)C=C(C=2C(=CC=CC=2)C)C=1N(C)C(=O)C(C)(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 DJHXZQUFUCQSCF-UHFFFAOYSA-N 0.000 claims description 2
- PNXNHPPZWZQPFC-UHFFFAOYSA-N 2-[3,5-bis(trifluoromethyl)phenyl]-n-[6-(3-hydroxyprop-1-ynyl)-4-(2-methylphenyl)pyridin-3-yl]-n,2-dimethylpropanamide Chemical compound C=1N=C(C#CCO)C=C(C=2C(=CC=CC=2)C)C=1N(C)C(=O)C(C)(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 PNXNHPPZWZQPFC-UHFFFAOYSA-N 0.000 claims description 2
- QZOBMOMOIREETP-UHFFFAOYSA-N 2-[3,5-bis(trifluoromethyl)phenyl]-n-[6-(3-methoxyphenyl)sulfinyl-4-(2-methylphenyl)pyridin-3-yl]-n,2-dimethylpropanamide Chemical compound COC1=CC=CC(S(=O)C=2N=CC(=C(C=2)C=2C(=CC=CC=2)C)N(C)C(=O)C(C)(C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)=C1 QZOBMOMOIREETP-UHFFFAOYSA-N 0.000 claims description 2
- MFAORAGGPFAHFN-UHFFFAOYSA-N 2-[3,5-bis(trifluoromethyl)phenyl]-n-[6-[3-(hydroxymethyl)-1,2-oxazol-5-yl]-4-(2-methylphenyl)pyridin-3-yl]-n,2-dimethylpropanamide Chemical compound C=1N=C(C=2ON=C(CO)C=2)C=C(C=2C(=CC=CC=2)C)C=1N(C)C(=O)C(C)(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 MFAORAGGPFAHFN-UHFFFAOYSA-N 0.000 claims description 2
- YULOPNYEHDHEAK-UHFFFAOYSA-N 2-[3,5-bis(trifluoromethyl)phenyl]-n-[6-ethynyl-4-(2-methylphenyl)pyridin-3-yl]-n,2-dimethylpropanamide Chemical compound C=1N=C(C#C)C=C(C=2C(=CC=CC=2)C)C=1N(C)C(=O)C(C)(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 YULOPNYEHDHEAK-UHFFFAOYSA-N 0.000 claims description 2
- UTGQQKFIXUWNSS-UHFFFAOYSA-N 6-(3-aminoprop-1-ynyl)-n-[[3,5-bis(trifluoromethyl)phenyl]methyl]-n-methyl-4-(2-methylphenyl)pyridine-3-carboxamide Chemical compound C=1N=C(C#CCN)C=C(C=2C(=CC=CC=2)C)C=1C(=O)N(C)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 UTGQQKFIXUWNSS-UHFFFAOYSA-N 0.000 claims description 2
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 claims description 2
- 229940047889 isobutyramide Drugs 0.000 claims description 2
- 125000002757 morpholinyl group Chemical group 0.000 claims description 2
- TWTBZPPWONNSJG-UHFFFAOYSA-N n-[[3,5-bis(trifluoromethyl)phenyl]methyl]-6-(2-hydroxyethylsulfinylmethyl)-n-methyl-4-(2-methylphenyl)pyridine-3-carboxamide Chemical compound C=1N=C(CS(=O)CCO)C=C(C=2C(=CC=CC=2)C)C=1C(=O)N(C)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 TWTBZPPWONNSJG-UHFFFAOYSA-N 0.000 claims description 2
- AHOSRDROAZBLDX-UHFFFAOYSA-N n-[[3,5-bis(trifluoromethyl)phenyl]methyl]-6-(3-hydroxypropoxy)-n-methyl-4-(2-methylphenyl)pyridine-3-carboxamide Chemical compound C=1N=C(OCCCO)C=C(C=2C(=CC=CC=2)C)C=1C(=O)N(C)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 AHOSRDROAZBLDX-UHFFFAOYSA-N 0.000 claims description 2
- HNZXVWBAYFGNJK-UHFFFAOYSA-N n-[[3,5-bis(trifluoromethyl)phenyl]methyl]-6-[4-(hydroxymethyl)phenyl]-n-methyl-4-(2-methylphenyl)pyridine-3-carboxamide Chemical compound C=1N=C(C=2C=CC(CO)=CC=2)C=C(C=2C(=CC=CC=2)C)C=1C(=O)N(C)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 HNZXVWBAYFGNJK-UHFFFAOYSA-N 0.000 claims description 2
- KXGXHJWTQFOKTP-UHFFFAOYSA-N n-[[3,5-bis(trifluoromethyl)phenyl]methyl]-n-methyl-4-(2-methylphenyl)-6-pyridin-2-ylsulfonylpyridine-3-carboxamide Chemical compound C=1N=C(S(=O)(=O)C=2N=CC=CC=2)C=C(C=2C(=CC=CC=2)C)C=1C(=O)N(C)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 KXGXHJWTQFOKTP-UHFFFAOYSA-N 0.000 claims description 2
- XIVWYJQCGCJDBA-UHFFFAOYSA-N n-[[3,5-bis(trifluoromethyl)phenyl]methyl]-n-methyl-6-[(1-methylimidazol-2-yl)sulfanylmethyl]-4-(2-methylphenyl)pyridine-3-carboxamide Chemical compound C=1N=C(CSC=2N(C=CN=2)C)C=C(C=2C(=CC=CC=2)C)C=1C(=O)N(C)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 XIVWYJQCGCJDBA-UHFFFAOYSA-N 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 14
- 201000010099 disease Diseases 0.000 claims 4
- MEPJOJIYUPXTTQ-UHFFFAOYSA-N 6-(5-acetylthiophen-2-yl)-n-[[3,5-bis(trifluoromethyl)phenyl]methyl]-n-methyl-4-(2-methylphenyl)pyridine-3-carboxamide Chemical compound C=1N=C(C=2SC(=CC=2)C(C)=O)C=C(C=2C(=CC=CC=2)C)C=1C(=O)N(C)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 MEPJOJIYUPXTTQ-UHFFFAOYSA-N 0.000 claims 1
- CMZFMMQINFTXMB-UHFFFAOYSA-N n-[[3,5-bis(trifluoromethyl)phenyl]methyl]-n-methyl-4-(2-methylphenyl)-6-pyridin-2-ylsulfinylpyridine-3-carboxamide Chemical compound C=1N=C(S(=O)C=2N=CC=CC=2)C=C(C=2C(=CC=CC=2)C)C=1C(=O)N(C)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 CMZFMMQINFTXMB-UHFFFAOYSA-N 0.000 claims 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 114
- 239000000243 solution Substances 0.000 description 99
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 57
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 45
- 239000007787 solid Substances 0.000 description 39
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 27
- 229910052938 sodium sulfate Inorganic materials 0.000 description 27
- 235000011152 sodium sulphate Nutrition 0.000 description 27
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- 238000003818 flash chromatography Methods 0.000 description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 24
- 239000012044 organic layer Substances 0.000 description 23
- 239000010410 layer Substances 0.000 description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 19
- 238000001816 cooling Methods 0.000 description 19
- 238000002360 preparation method Methods 0.000 description 19
- 239000000284 extract Substances 0.000 description 16
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 12
- 235000019341 magnesium sulphate Nutrition 0.000 description 12
- 102100024304 Protachykinin-1 Human genes 0.000 description 11
- 239000000460 chlorine Substances 0.000 description 11
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- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- XXWHJXZNCFUWRQ-UHFFFAOYSA-N 2-[3,5-bis(trifluoromethyl)phenyl]-n-[6-chloro-4-(2-chlorophenyl)pyridin-3-yl]-n,2-dimethylpropanamide Chemical compound C=1N=C(Cl)C=C(C=2C(=CC=CC=2)Cl)C=1N(C)C(=O)C(C)(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 XXWHJXZNCFUWRQ-UHFFFAOYSA-N 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- 101800003906 Substance P Proteins 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 description 8
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 8
- KSXYRMAWJWGAPP-UHFFFAOYSA-N 2-[3,5-bis(trifluoromethyl)phenyl]-n-[4-(2-chlorophenyl)-6-iodopyridin-3-yl]-n,2-dimethylpropanamide Chemical compound C=1N=C(I)C=C(C=2C(=CC=CC=2)Cl)C=1N(C)C(=O)C(C)(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 KSXYRMAWJWGAPP-UHFFFAOYSA-N 0.000 description 7
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- RRCMGJCFMJBHQC-UHFFFAOYSA-N (2-chlorophenyl)boronic acid Chemical compound OB(O)C1=CC=CC=C1Cl RRCMGJCFMJBHQC-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 6
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- 238000000605 extraction Methods 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
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- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
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- QLULGIRFKAWHOJ-UHFFFAOYSA-N pyridin-4-ylboronic acid Chemical compound OB(O)C1=CC=NC=C1 QLULGIRFKAWHOJ-UHFFFAOYSA-N 0.000 description 5
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Classifications
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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EP00117003 | 2000-08-08 |
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AU (2) | AU2002212118B2 (da) |
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BRPI0412291A (pt) | 2003-07-03 | 2006-09-19 | Hoffmann La Roche | antagonistas duplos de nka/nk3 para o tratamento de esquizofrenia |
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KR20070094666A (ko) | 2005-02-25 | 2007-09-20 | 에프. 호프만-라 로슈 아게 | 약제 물질 분산성이 향상된 정제 |
US20060235028A1 (en) * | 2005-04-14 | 2006-10-19 | Li James J | Inhibitors of 11-beta hydroxysteroid dehydrogenase type I |
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ES2882684T3 (es) | 2006-04-07 | 2021-12-02 | Vertex Pharma | Preparación de moduladores de transportadores del casete de unión a ATP |
US7754739B2 (en) | 2007-05-09 | 2010-07-13 | Vertex Pharmaceuticals Incorporated | Modulators of CFTR |
EP2117538A1 (en) | 2007-01-24 | 2009-11-18 | Glaxo Group Limited | Pharmaceutical compositions comprising 2-methoxy-5- (5-trifluoromethyl-tetrazol-i-yl-benzyl) - (2s-phenyl-piperidin-3s-yl-) |
US8969386B2 (en) | 2007-05-09 | 2015-03-03 | Vertex Pharmaceuticals Incorporated | Modulators of CFTR |
UY31272A1 (es) * | 2007-08-10 | 2009-01-30 | Almirall Lab | Nuevos derivados de ácido azabifenilaminobenzoico |
DK3170818T3 (da) | 2007-12-07 | 2020-04-14 | Vertex Pharma | Faste former af 3-(6-(1-(2,2-difluorbenzo[d][1,3]dioxol-5-yl) cyclopropancarboxamido)-3-methylpyridin-2-yl)benzoesyre |
SI2639224T1 (sl) | 2007-12-07 | 2016-12-30 | Vertex Pharmaceuticals Incorporated | Postopek za pripravo cikloalkilkarboksiamido-piridinskih benzojskih kislin |
NZ602030A (en) | 2008-02-28 | 2014-02-28 | Vertex Pharma | Heteroaryl derivatives as cftr modulators |
GB0808747D0 (en) | 2008-05-14 | 2008-06-18 | Glaxo Wellcome Mfg Pte Ltd | Novel compounds |
UA107088C2 (xx) * | 2009-09-11 | 2014-11-25 | 5-(3,4-дихлорфеніл)-n-(2-гідроксициклогексил)-6-(2,2,2-трифторетокси)нікотинамід і його солі як засоби, що підвищують концентрацію лвщ холестерину | |
WO2011054773A1 (en) | 2009-11-03 | 2011-05-12 | Glaxosmithkline Llc | Novel lactam compounds |
FR2954315B1 (fr) * | 2009-12-23 | 2012-02-24 | Galderma Res & Dev | Nouveaux derives phenoliques, et leur utilisation pharmaceutique ou cosmetique |
US8802868B2 (en) | 2010-03-25 | 2014-08-12 | Vertex Pharmaceuticals Incorporated | Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxo1-5-yl)-N-(1-(2,3-dihydroxypropyl-6-fluoro-2-(1-hydroxy-2-methylpropan2-yl)-1H-Indol-5-yl)-Cyclopropanecarboxamide |
DK3150198T3 (da) | 2010-04-07 | 2021-11-01 | Vertex Pharma | Farmaceutiske sammensætninger af 3-(6-(1-(2,2-difluorbenzo[d][1,3]dioxol-5-yl)-cyclopropancarboxamido)-3-methylpyriodin-2-yl)benzoesyre og indgivelse deraf |
RS54783B1 (sr) | 2010-04-07 | 2016-10-31 | Vertex Pharma | Čvrste forme 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioksol-5-il)ciklopropankarboksiamido)-3-metilpiridin-2-il)benzoeve kiseline |
CN105130948A (zh) | 2010-04-22 | 2015-12-09 | 弗特克斯药品有限公司 | 制备环烷基甲酰胺基-吲哚化合物的方法 |
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CA2878057A1 (en) | 2012-07-16 | 2014-01-23 | Rossitza Gueorguieva Alargova | Pharmaceutical compositions of (r)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-n-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1h-indol-5-yl) cyclopropanecarboxamide and administration thereof |
JP5806420B1 (ja) | 2013-11-08 | 2015-11-10 | キッセイ薬品工業株式会社 | カルボキシメチルピペリジン誘導体 |
HUE054389T2 (hu) | 2013-11-12 | 2021-09-28 | Vertex Pharma | Eljárás CFTR-mediálta betegségek kezelésére szolgáló gyógyászati kompozíciók elõállítására |
RS57476B9 (sr) | 2014-04-15 | 2021-10-29 | Vertex Pharma | Farmaceutske kompozicije za lečenje bolesti posredovanih transmembranskim regulatorom provodljivosti cistične fibroze |
TWI649307B (zh) * | 2014-05-07 | 2019-02-01 | 日商橘生藥品工業股份有限公司 | Cyclohexylpyridine derivative |
ES2882656T3 (es) | 2014-11-18 | 2021-12-02 | Vertex Pharma | Proceso para realizar pruebas de alto rendimiento de cromatografía líquida de alta resolución |
US10538491B2 (en) * | 2015-03-16 | 2020-01-21 | Vanderbilt University | 4,5-substituted picolinamide and picolinonitrile metabotropic glutamate receptor 2 negative allosteric modulators |
CN115531553A (zh) * | 2015-12-22 | 2022-12-30 | 武田药品工业株式会社 | 内体g蛋白-偶联的受体的三部分调节剂 |
CN114728906A (zh) | 2019-11-15 | 2022-07-08 | 康堤医疗有限公司 | 制备nt-814的关键中间体6-氯-4-(4-氟-2-甲基苯基)吡啶-3-胺的新化学方法 |
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ATE253561T1 (de) * | 1999-11-29 | 2003-11-15 | Hoffmann La Roche | 2-(3,5-bis-trifluoromethyl-phenyl)-n-methyl-n-( - morpholin-4-yl-4-o-tolyl-pyridin-3-yl)- isobutyramid |
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