DE60315146T2 - Heteroarylsubstituierte biphenylderivate als inhibitoren von p38-kinase - Google Patents
Heteroarylsubstituierte biphenylderivate als inhibitoren von p38-kinase Download PDFInfo
- Publication number
- DE60315146T2 DE60315146T2 DE60315146T DE60315146T DE60315146T2 DE 60315146 T2 DE60315146 T2 DE 60315146T2 DE 60315146 T DE60315146 T DE 60315146T DE 60315146 T DE60315146 T DE 60315146T DE 60315146 T2 DE60315146 T2 DE 60315146T2
- Authority
- DE
- Germany
- Prior art keywords
- methyl
- biphenyl
- oxadiazol
- cyclopropyl
- carboxamide
- 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.)
- Expired - Lifetime
Links
- 239000003112 inhibitor Substances 0.000 title abstract description 7
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical class C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 title description 5
- 108091000080 Phosphotransferase Proteins 0.000 title description 2
- 102000020233 phosphotransferase Human genes 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 97
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 claims abstract description 29
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 claims abstract description 29
- 238000011282 treatment Methods 0.000 claims abstract description 12
- 230000000694 effects Effects 0.000 claims abstract description 11
- 102000004127 Cytokines Human genes 0.000 claims abstract description 5
- 108090000695 Cytokines Proteins 0.000 claims abstract description 5
- 201000010099 disease Diseases 0.000 claims abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 5
- -1 CONHR 12 Chemical group 0.000 claims description 61
- 125000000217 alkyl group Chemical group 0.000 claims description 50
- 239000000203 mixture Substances 0.000 claims description 50
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 46
- 239000001257 hydrogen Substances 0.000 claims description 37
- 229910052739 hydrogen Inorganic materials 0.000 claims description 37
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 37
- 229910052757 nitrogen Inorganic materials 0.000 claims description 35
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 28
- 125000001072 heteroaryl group Chemical group 0.000 claims description 26
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 24
- 229910052717 sulfur Chemical group 0.000 claims description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
- 229910052760 oxygen Inorganic materials 0.000 claims description 19
- 239000001301 oxygen Substances 0.000 claims description 19
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 18
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 18
- 125000005842 heteroatom Chemical group 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 239000011593 sulfur Chemical group 0.000 claims description 18
- 150000002431 hydrogen Chemical class 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 15
- 125000000623 heterocyclic group Chemical group 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- PIGFYZPCRLYGLF-UHFFFAOYSA-N Aluminum nitride Chemical group [Al]#N PIGFYZPCRLYGLF-UHFFFAOYSA-N 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- OSITVSIIJTXZAS-UHFFFAOYSA-N 3-[4-[5-(aminomethyl)-1,3,4-oxadiazol-2-yl]phenyl]-n-cyclopropyl-5-fluoro-4-methylbenzamide Chemical compound CC1=C(F)C=C(C(=O)NC2CC2)C=C1C(C=C1)=CC=C1C1=NN=C(CN)O1 OSITVSIIJTXZAS-UHFFFAOYSA-N 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- DCGLVCMJNRMULJ-UHFFFAOYSA-N 3-[4-(5-amino-1,3,4-oxadiazol-2-yl)phenyl]-n-cyclopropyl-4-methylbenzamide Chemical compound CC1=CC=C(C(=O)NC2CC2)C=C1C(C=C1)=CC=C1C1=NN=C(N)O1 DCGLVCMJNRMULJ-UHFFFAOYSA-N 0.000 claims description 5
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 4
- YLCPHCGGXXXHRD-UHFFFAOYSA-N n-cyclopropyl-3-[4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl]-4-methylbenzamide Chemical compound O1C(CC)=NN=C1C1=CC=C(C=2C(=CC=C(C=2)C(=O)NC2CC2)C)C=C1 YLCPHCGGXXXHRD-UHFFFAOYSA-N 0.000 claims description 4
- MXBHVZATTLYLSM-UHFFFAOYSA-N n-cyclopropyl-3-[4-[5-(cyclopropylmethoxymethyl)-1,3,4-oxadiazol-2-yl]phenyl]-4-methylbenzamide Chemical compound CC1=CC=C(C(=O)NC2CC2)C=C1C(C=C1)=CC=C1C(O1)=NN=C1COCC1CC1 MXBHVZATTLYLSM-UHFFFAOYSA-N 0.000 claims description 4
- FHBVQIRYGQHIBT-UHFFFAOYSA-N n-cyclopropyl-3-[4-[5-(cyclopropylmethyl)-1,3,4-oxadiazol-2-yl]phenyl]-4-methylbenzamide Chemical compound CC1=CC=C(C(=O)NC2CC2)C=C1C(C=C1)=CC=C1C(O1)=NN=C1CC1CC1 FHBVQIRYGQHIBT-UHFFFAOYSA-N 0.000 claims description 4
- OYRHQEYMYFLPAO-UHFFFAOYSA-N n-cyclopropyl-3-[4-[5-(ethylaminomethyl)-1,3,4-oxadiazol-2-yl]phenyl]-4-methylbenzamide Chemical compound O1C(CNCC)=NN=C1C1=CC=C(C=2C(=CC=C(C=2)C(=O)NC2CC2)C)C=C1 OYRHQEYMYFLPAO-UHFFFAOYSA-N 0.000 claims description 4
- VSRUWPKXKDSOOQ-UHFFFAOYSA-N n-cyclopropyl-3-[4-[5-(methanesulfonamidomethyl)-1,3,4-oxadiazol-2-yl]phenyl]-4-methylbenzamide Chemical compound CC1=CC=C(C(=O)NC2CC2)C=C1C(C=C1)=CC=C1C1=NN=C(CNS(C)(=O)=O)O1 VSRUWPKXKDSOOQ-UHFFFAOYSA-N 0.000 claims description 4
- LGBSXTHUMXGOSO-UHFFFAOYSA-N n-cyclopropyl-3-[4-[5-[(3,3-dimethylbutanoylamino)methyl]-1,3,4-oxadiazol-2-yl]phenyl]-4-methylbenzamide Chemical compound CC1=CC=C(C(=O)NC2CC2)C=C1C(C=C1)=CC=C1C1=NN=C(CNC(=O)CC(C)(C)C)O1 LGBSXTHUMXGOSO-UHFFFAOYSA-N 0.000 claims description 4
- MBGPKRGRECBFQQ-UHFFFAOYSA-N n-cyclopropyl-3-[4-[5-[(cyclopropylamino)methyl]-1,3,4-oxadiazol-2-yl]phenyl]-4-methylbenzamide Chemical compound CC1=CC=C(C(=O)NC2CC2)C=C1C(C=C1)=CC=C1C(O1)=NN=C1CNC1CC1 MBGPKRGRECBFQQ-UHFFFAOYSA-N 0.000 claims description 4
- IPCLEDAOUINQDR-UHFFFAOYSA-N n-cyclopropyl-3-[4-[5-[[(2-cyclopropylacetyl)amino]methyl]-1,3,4-oxadiazol-2-yl]phenyl]-4-methylbenzamide Chemical compound CC1=CC=C(C(=O)NC2CC2)C=C1C(C=C1)=CC=C1C(O1)=NN=C1CNC(=O)CC1CC1 IPCLEDAOUINQDR-UHFFFAOYSA-N 0.000 claims description 4
- YMERFPDLXSRENN-UHFFFAOYSA-N n-cyclopropyl-4-methyl-3-[4-[5-(1-methylpyrrol-2-yl)-1,3,4-oxadiazol-2-yl]phenyl]benzamide Chemical compound CC1=CC=C(C(=O)NC2CC2)C=C1C(C=C1)=CC=C1C(O1)=NN=C1C1=CC=CN1C YMERFPDLXSRENN-UHFFFAOYSA-N 0.000 claims description 4
- DGNKXPYLGHSCLU-UHFFFAOYSA-N n-cyclopropyl-4-methyl-3-[4-[5-(methylamino)-1,3,4-oxadiazol-2-yl]phenyl]benzamide Chemical compound O1C(NC)=NN=C1C1=CC=C(C=2C(=CC=C(C=2)C(=O)NC2CC2)C)C=C1 DGNKXPYLGHSCLU-UHFFFAOYSA-N 0.000 claims description 4
- IDCOXDSWWLEGFJ-UHFFFAOYSA-N n-cyclopropyl-4-methyl-3-[4-[5-[[[2-(3-methyl-1,2-oxazol-5-yl)acetyl]amino]methyl]-1,3,4-oxadiazol-2-yl]phenyl]benzamide Chemical compound O1N=C(C)C=C1CC(=O)NCC1=NN=C(C=2C=CC(=CC=2)C=2C(=CC=C(C=2)C(=O)NC2CC2)C)O1 IDCOXDSWWLEGFJ-UHFFFAOYSA-N 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- HULVUJNICBFQPK-UHFFFAOYSA-N 3-[4-[5-[(benzylsulfonylamino)methyl]-1,3,4-oxadiazol-2-yl]phenyl]-n-cyclopropyl-4-methylbenzamide Chemical compound CC1=CC=C(C(=O)NC2CC2)C=C1C(C=C1)=CC=C1C(O1)=NN=C1CNS(=O)(=O)CC1=CC=CC=C1 HULVUJNICBFQPK-UHFFFAOYSA-N 0.000 claims description 3
- TWXSTNYVNAJTNR-UHFFFAOYSA-N 4-methyl-3-[2-methyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]-n-(1,3-thiazol-2-yl)benzamide Chemical compound O1C(C)=NN=C1C1=CC=C(C=2C(=CC=C(C=2)C(=O)NC=2SC=CN=2)C)C(C)=C1 TWXSTNYVNAJTNR-UHFFFAOYSA-N 0.000 claims description 3
- ADHHHZTZVSEQOM-UHFFFAOYSA-N 4-methyl-3-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]-n-(1,3,4-thiadiazol-2-yl)benzamide Chemical compound O1C(C)=NN=C1C1=CC=C(C=2C(=CC=C(C=2)C(=O)NC=2SC=NN=2)C)C=C1 ADHHHZTZVSEQOM-UHFFFAOYSA-N 0.000 claims description 3
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 3
- UBVTVSINEVHYSY-UHFFFAOYSA-N N-cyclopropyl-2',6-dimethyl-4'-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl-3-carboxamide Chemical compound O1C(C)=NN=C1C1=CC=C(C=2C(=CC=C(C=2)C(=O)NC2CC2)C)C(C)=C1 UBVTVSINEVHYSY-UHFFFAOYSA-N 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- SCGCAKXHTPFUGN-UHFFFAOYSA-N n-(cyclopropylmethyl)-4-methyl-3-[2-methyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]benzamide Chemical compound O1C(C)=NN=C1C1=CC=C(C=2C(=CC=C(C=2)C(=O)NCC2CC2)C)C(C)=C1 SCGCAKXHTPFUGN-UHFFFAOYSA-N 0.000 claims description 3
- MGRWMSKYGRQHGB-UHFFFAOYSA-N n-[4-methyl-3-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]phenyl]furan-3-carboxamide Chemical compound O1C(C)=NN=C1C1=CC=C(C=2C(=CC=C(NC(=O)C3=COC=C3)C=2)C)C=C1 MGRWMSKYGRQHGB-UHFFFAOYSA-N 0.000 claims description 3
- QWAVSMHEVGAMTB-UHFFFAOYSA-N n-cyclopropyl-3-[4-[5-(methoxymethyl)-1,3,4-oxadiazol-2-yl]phenyl]-4-methylbenzamide Chemical compound O1C(COC)=NN=C1C1=CC=C(C=2C(=CC=C(C=2)C(=O)NC2CC2)C)C=C1 QWAVSMHEVGAMTB-UHFFFAOYSA-N 0.000 claims description 3
- CZZJHSKQVNDTIZ-UHFFFAOYSA-N n-cyclopropyl-3-[4-[5-[(cyclopropylamino)methyl]-1,3,4-oxadiazol-2-yl]phenyl]-5-fluoro-4-methylbenzamide Chemical compound CC1=C(F)C=C(C(=O)NC2CC2)C=C1C(C=C1)=CC=C1C(O1)=NN=C1CNC1CC1 CZZJHSKQVNDTIZ-UHFFFAOYSA-N 0.000 claims description 3
- RQROUXVESBPMMU-UHFFFAOYSA-N n-cyclopropyl-3-[4-[5-[(cyclopropylmethylamino)methyl]-1,3,4-oxadiazol-2-yl]phenyl]-4-methylbenzamide Chemical compound CC1=CC=C(C(=O)NC2CC2)C=C1C(C=C1)=CC=C1C(O1)=NN=C1CNCC1CC1 RQROUXVESBPMMU-UHFFFAOYSA-N 0.000 claims description 3
- FHWHYNJCNGPMDV-UHFFFAOYSA-N n-cyclopropyl-4-methyl-3-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]benzamide Chemical compound O1C(C)=NN=C1C1=CC=C(C=2C(=CC=C(C=2)C(=O)NC2CC2)C)C=C1 FHWHYNJCNGPMDV-UHFFFAOYSA-N 0.000 claims description 3
- HOHZBOGLXKHQJH-UHFFFAOYSA-N n-cyclopropyl-4-methyl-3-[4-[5-(thiomorpholin-4-ylmethyl)-1,3,4-oxadiazol-2-yl]phenyl]benzamide Chemical compound CC1=CC=C(C(=O)NC2CC2)C=C1C(C=C1)=CC=C1C(O1)=NN=C1CN1CCSCC1 HOHZBOGLXKHQJH-UHFFFAOYSA-N 0.000 claims description 3
- AWMNVQSGOCRGQW-UHFFFAOYSA-N n-cyclopropyl-4-methyl-3-[4-[5-[[(2-phenylacetyl)amino]methyl]-1,3,4-oxadiazol-2-yl]phenyl]benzamide Chemical compound CC1=CC=C(C(=O)NC2CC2)C=C1C(C=C1)=CC=C1C(O1)=NN=C1CNC(=O)CC1=CC=CC=C1 AWMNVQSGOCRGQW-UHFFFAOYSA-N 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 229910052770 Uranium Inorganic materials 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims description 2
- YJEKRWXNGQEKFK-UHFFFAOYSA-N n-cyclopropyl-3-fluoro-4-methyl-5-[4-(2h-tetrazol-5-yl)phenyl]benzamide Chemical compound CC1=C(F)C=C(C(=O)NC2CC2)C=C1C(C=C1)=CC=C1C1=NN=NN1 YJEKRWXNGQEKFK-UHFFFAOYSA-N 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- 125000004509 1,3,4-oxadiazol-2-yl group Chemical group O1C(=NN=C1)* 0.000 claims 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims 1
- 230000001404 mediated effect Effects 0.000 abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 351
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 165
- 239000002904 solvent Substances 0.000 description 126
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 123
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 121
- 230000014759 maintenance of location Effects 0.000 description 119
- 238000006243 chemical reaction Methods 0.000 description 107
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 103
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 99
- 239000000377 silicon dioxide Substances 0.000 description 80
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 66
- 239000000243 solution Substances 0.000 description 57
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 53
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 52
- 239000000047 product Substances 0.000 description 50
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 44
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 42
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 39
- 230000002829 reductive effect Effects 0.000 description 39
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 35
- 239000012074 organic phase Substances 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- 238000001704 evaporation Methods 0.000 description 27
- 230000008020 evaporation Effects 0.000 description 27
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 26
- IHBPTBQXHHHEOU-UHFFFAOYSA-N 3-[4-[5-(aminomethyl)-1,3,4-oxadiazol-2-yl]phenyl]-n-cyclopropyl-4-methylbenzamide Chemical compound CC1=CC=C(C(=O)NC2CC2)C=C1C(C=C1)=CC=C1C1=NN=C(CN)O1 IHBPTBQXHHHEOU-UHFFFAOYSA-N 0.000 description 24
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 24
- 239000007787 solid Substances 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 22
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 21
- 235000019341 magnesium sulphate Nutrition 0.000 description 21
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 20
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- GLSSVRGOTTUQNM-UHFFFAOYSA-N n-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide Chemical compound CC1=CC=C(C(=O)NC2CC2)C=C1B1OC(C)(C)C(C)(C)O1 GLSSVRGOTTUQNM-UHFFFAOYSA-N 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 16
- 239000007821 HATU Substances 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 13
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 13
- 229910000029 sodium carbonate Inorganic materials 0.000 description 13
- 235000002639 sodium chloride Nutrition 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 239000012267 brine Substances 0.000 description 12
- 150000003839 salts Chemical class 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- 101150003085 Pdcl gene Proteins 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 239000000843 powder Substances 0.000 description 11
- DKPNWDYEHCWNTQ-UHFFFAOYSA-N 2-(4-bromo-3-methylphenyl)-5-methyl-1,3,4-oxadiazole Chemical compound O1C(C)=NN=C1C1=CC=C(Br)C(C)=C1 DKPNWDYEHCWNTQ-UHFFFAOYSA-N 0.000 description 10
- JVESMAXHJNNUAI-UHFFFAOYSA-N 2-(4-iodophenyl)-5-methyl-1,3,4-oxadiazole Chemical compound O1C(C)=NN=C1C1=CC=C(I)C=C1 JVESMAXHJNNUAI-UHFFFAOYSA-N 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 10
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Classifications
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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| PCT/GB2003/001834 WO2003093248A1 (en) | 2002-04-30 | 2003-04-29 | Heteroaryl substituted biphenyl derivatives as p38 kinase inhibitors |
Publications (2)
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| DE60315146D1 DE60315146D1 (de) | 2007-09-06 |
| DE60315146T2 true DE60315146T2 (de) | 2008-04-17 |
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| US7683097B2 (en) * | 2004-05-27 | 2010-03-23 | Propharmacon Inc. | Topoisomerase inhibitors |
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| GB0512429D0 (en) * | 2005-06-17 | 2005-07-27 | Smithkline Beecham Corp | Novel compound |
| DK1940786T3 (da) * | 2005-09-16 | 2010-11-08 | Arrow Therapeutics Ltd | Biphenylderivater og deres anvendelse ved behandling af hepatitis C |
| GB0612026D0 (en) | 2006-06-16 | 2006-07-26 | Smithkline Beecham Corp | New use |
| JP5564251B2 (ja) | 2006-06-29 | 2014-07-30 | キネックス ファーマシューティカルズ, エルエルシー | キナーゼカスケードを調節するためのビアリール組成物および方法 |
| SI2511301T1 (en) | 2006-08-04 | 2018-05-31 | MedImmune Limited, | Human antibodies to ERBB 2 |
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| US7935697B2 (en) | 2006-12-28 | 2011-05-03 | Kinex Pharmaceuticals, Llc | Compositions for modulating a kinase cascade and methods of use thereof |
| US8124605B2 (en) | 2007-07-06 | 2012-02-28 | Kinex Pharmaceuticals, Llc | Compositions and methods for modulating a kinase cascade |
| CN104644639A (zh) * | 2007-10-20 | 2015-05-27 | 金克斯医药品有限公司 | 用于调控激酶级联的药物组合物及其使用方法 |
| TWI490214B (zh) | 2008-05-30 | 2015-07-01 | 艾德克 上野股份有限公司 | 苯或噻吩衍生物及該等作為vap-1抑制劑之用途 |
| CA2728769A1 (en) * | 2008-07-04 | 2010-01-07 | Bruno Villoutreix | Nitrogen heterocycle derivatives as proteasome modulators |
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| PH12013501268A1 (en) | 2010-12-17 | 2016-04-01 | Mitsubishi Tanabe Pharma Corp | Continuous arycyclic compound |
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| CA2883144C (en) | 2012-08-30 | 2023-01-17 | Kinex Pharmaceuticals, Llc | N-(3-fluorobenzyl)-2-(5-(4-morpholinophenyl)pyridin-2-yl) acetamide as protein|tyrosine kinase modulators |
| WO2014121055A2 (en) * | 2013-02-04 | 2014-08-07 | Janssen Pharmaceutica Nv | Flap modulators |
| TWI644899B (zh) | 2013-02-04 | 2018-12-21 | 健生藥品公司 | Flap調節劑 |
| WO2017151409A1 (en) | 2016-02-29 | 2017-09-08 | University Of Florida Research Foundation, Incorporated | Chemotherapeutic methods |
| US10342786B2 (en) | 2017-10-05 | 2019-07-09 | Fulcrum Therapeutics, Inc. | P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD |
| CA3127373A1 (en) | 2017-10-05 | 2019-04-11 | Fulcrum Therapeutics, Inc. | P38 kinase inhibitors reduce dux4 and downstream gene expression for the treatment of fshd |
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| US12076315B2 (en) | 2020-03-20 | 2024-09-03 | Clear Creek Bio, Inc. | Stable polymorphic compositions of brequinar sodium and methods of use and manufacture thereof |
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| TW240217B (enExample) * | 1992-12-30 | 1995-02-11 | Glaxo Group Ltd | |
| AU1108395A (en) * | 1993-12-07 | 1995-06-27 | Smithkline Beecham Plc | Heterocyclic biphenylylamides useful as 5ht1d antagonists |
| ES2179254T3 (es) * | 1996-11-04 | 2003-01-16 | Bayer Cropscience Sa | 1-poliarilpirazoles plaguicidas. |
| PE20020506A1 (es) * | 2000-08-22 | 2002-07-09 | Glaxo Group Ltd | Derivados de pirazol fusionados como inhibidores de la proteina cinasa |
| GB0119863D0 (en) * | 2001-08-14 | 2001-10-10 | Cancer Res Campaign Tech | DNA-PK inhibitors |
| GB0124939D0 (en) | 2001-10-17 | 2001-12-05 | Glaxo Group Ltd | Chemical compounds |
| GB0124941D0 (en) * | 2001-10-17 | 2001-12-05 | Glaxo Group Ltd | Chemical compounds |
| GB0124933D0 (en) | 2001-10-17 | 2001-12-05 | Glaxo Group Ltd | Chemical compounds |
| GB0124936D0 (en) | 2001-10-17 | 2001-12-05 | Glaxo Group Ltd | Chemical compounds |
| GB0124931D0 (en) | 2001-10-17 | 2001-12-05 | Glaxo Group Ltd | Chemical compounds |
| GB0124934D0 (en) | 2001-10-17 | 2001-12-05 | Glaxo Group Ltd | Chemical compounds |
| GB0124938D0 (en) * | 2001-10-17 | 2001-12-05 | Glaxo Group Ltd | Chemical compounds |
| GB0124928D0 (en) | 2001-10-17 | 2001-12-05 | Glaxo Group Ltd | Chemical compounds |
| GB0124932D0 (en) | 2001-10-17 | 2001-12-05 | Glaxo Group Ltd | Chemical compounds |
| ATE375980T1 (de) | 2002-02-12 | 2007-11-15 | Smithkline Beecham Corp | Nicotinamide und deren verwendung als p38 inhibitoren |
| GB0209891D0 (en) | 2002-04-30 | 2002-06-05 | Glaxo Group Ltd | Novel compounds |
| GB0217757D0 (en) | 2002-07-31 | 2002-09-11 | Glaxo Group Ltd | Novel compounds |
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2002
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- 2003-04-29 EP EP03747504A patent/EP1499600B1/en not_active Expired - Lifetime
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- 2003-04-29 AT AT03747504T patent/ATE368034T1/de not_active IP Right Cessation
- 2003-04-29 AU AU2003226572A patent/AU2003226572A1/en not_active Abandoned
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| GB0209891D0 (en) | 2002-06-05 |
| WO2003093248A1 (en) | 2003-11-13 |
| EP1499600B1 (en) | 2007-07-25 |
| DE60315146D1 (de) | 2007-09-06 |
| ES2290486T3 (es) | 2008-02-16 |
| AU2003226572A1 (en) | 2003-11-17 |
| US7425555B2 (en) | 2008-09-16 |
| ATE368034T1 (de) | 2007-08-15 |
| US20060089393A1 (en) | 2006-04-27 |
| EP1499600A1 (en) | 2005-01-26 |
| JP2005535586A (ja) | 2005-11-24 |
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