ES2902139T3 - Derivados de pirazol útiles como inhibidores de la proteína activadora de 5-lipoxigenasa (FLAP) - Google Patents
Derivados de pirazol útiles como inhibidores de la proteína activadora de 5-lipoxigenasa (FLAP) Download PDFInfo
- Publication number
- ES2902139T3 ES2902139T3 ES19199606T ES19199606T ES2902139T3 ES 2902139 T3 ES2902139 T3 ES 2902139T3 ES 19199606 T ES19199606 T ES 19199606T ES 19199606 T ES19199606 T ES 19199606T ES 2902139 T3 ES2902139 T3 ES 2902139T3
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- ES
- Spain
- Prior art keywords
- methyl
- pyrazol
- mmol
- benzoyl
- pyrazole
- 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.)
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- 239000003112 inhibitor Substances 0.000 title description 6
- 102000004023 5-Lipoxygenase-Activating Proteins Human genes 0.000 title description 5
- 108090000411 5-Lipoxygenase-Activating Proteins Proteins 0.000 title description 5
- 150000003217 pyrazoles Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 355
- 150000003839 salts Chemical class 0.000 claims abstract description 55
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 44
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 43
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 33
- 125000005843 halogen group Chemical group 0.000 claims abstract description 20
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 19
- 125000001424 substituent group Chemical group 0.000 claims abstract description 19
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 19
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 17
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 15
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 8
- 125000006677 (C1-C3) haloalkoxy group Chemical group 0.000 claims abstract description 5
- 125000004438 haloalkoxy group Chemical group 0.000 claims abstract description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 79
- PNZXMIKHJXIPEK-UHFFFAOYSA-N cyclohexanecarboxamide Chemical compound NC(=O)C1CCCCC1 PNZXMIKHJXIPEK-UHFFFAOYSA-N 0.000 claims description 54
- -1 -S (O) pR7 Chemical group 0.000 claims description 49
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 31
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 27
- 229910052799 carbon Inorganic materials 0.000 claims description 21
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 4
- HWRHVHFUHOPJNJ-HZPDHXFCSA-N (1R,2R)-2-[4-(5-methyl-1H-pyrazol-3-yl)benzoyl]-N-(1,3,4-oxadiazol-2-yl)cyclohexane-1-carboxamide Chemical compound CC1=NNC(=C1)C1=CC=C(C(=O)[C@H]2[C@@H](CCCC2)C(=O)NC=2OC=NN=2)C=C1 HWRHVHFUHOPJNJ-HZPDHXFCSA-N 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- NZHRAHHWSLNTHE-HZPDHXFCSA-N (1R,2R)-N-[3-(difluoromethoxy)-1-methylpyrazol-4-yl]-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexane-1-carboxamide Chemical compound FC(OC1=NN(C=C1NC(=O)[C@H]1[C@@H](CCCC1)C(C1=CC=C(C=C1)C1=CC=NN1)=O)C)F NZHRAHHWSLNTHE-HZPDHXFCSA-N 0.000 claims description 2
- FHGRHSAUCVRESR-HUUCEWRRSA-N (1R,2R)-N-[5-(difluoromethyl)-1H-pyrazol-4-yl]-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexane-1-carboxamide Chemical compound FC(C1=C(C=NN1)NC(=O)[C@H]1[C@@H](CCCC1)C(C1=CC=C(C=C1)C1=NNC=C1)=O)F FHGRHSAUCVRESR-HUUCEWRRSA-N 0.000 claims description 2
- SLKIJLWTLRMCBG-QZTJIDSGSA-N (1R,2R)-N-[5-(dimethylsulfamoyl)-1-methylpyrazol-4-yl]-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexane-1-carboxamide Chemical compound CN(S(=O)(=O)C1=C(C=NN1C)NC(=O)[C@H]1[C@@H](CCCC1)C(C1=CC=C(C=C1)C1=CC=NN1)=O)C SLKIJLWTLRMCBG-QZTJIDSGSA-N 0.000 claims description 2
- BCBVJZNXVUCEDS-UHFFFAOYSA-N 1-methyl-4-[[2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarbonyl]amino]pyrazole-3-carboxamide Chemical compound Cn1cc(NC(=O)C2CCCCC2C(=O)c2ccc(cc2)-c2ccn[nH]2)c(n1)C(N)=O BCBVJZNXVUCEDS-UHFFFAOYSA-N 0.000 claims description 2
- NOIXNOMHHWGUTG-UHFFFAOYSA-N 2-[[4-[4-pyridin-4-yl-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]phenoxy]methyl]quinoline Chemical compound C=1C=C(OCC=2N=C3C=CC=CC3=CC=2)C=CC=1C1=NN(CC(F)(F)F)C=C1C1=CC=NC=C1 NOIXNOMHHWGUTG-UHFFFAOYSA-N 0.000 claims description 2
- MOZZQVGMVJMETL-HZPDHXFCSA-N 2-methyl-4-[[(1R,2R)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarbonyl]amino]pyrazole-3-carboxamide Chemical compound CN1N=CC(=C1C(=O)N)NC(=O)[C@H]1[C@@H](CCCC1)C(C1=CC=C(C=C1)C1=NNC=C1)=O MOZZQVGMVJMETL-HZPDHXFCSA-N 0.000 claims description 2
- XLIITAXAJSQSQY-UHFFFAOYSA-N 4-[[2-[2-fluoro-4-(5-methyl-1H-pyrazol-3-yl)benzoyl]cyclohexanecarbonyl]amino]-1H-pyrazole-5-carboxamide Chemical compound Cc1cc(n[nH]1)-c1ccc(C(=O)C2CCCCC2C(=O)Nc2cn[nH]c2C(N)=O)c(F)c1 XLIITAXAJSQSQY-UHFFFAOYSA-N 0.000 claims description 2
- SYYGGCPIEFSBST-UHFFFAOYSA-N CN1C=C(NC(=O)C2CCCCC2C(=O)C2=C(F)C=C(C=C2)C2=CC=NN2)C(=N1)C(N)=O Chemical compound CN1C=C(NC(=O)C2CCCCC2C(=O)C2=C(F)C=C(C=C2)C2=CC=NN2)C(=N1)C(N)=O SYYGGCPIEFSBST-UHFFFAOYSA-N 0.000 claims description 2
- VBEWZIAHRRCBAX-QZTJIDSGSA-N N,2-dimethyl-4-[[(1R,2R)-2-[4-(5-methyl-1H-pyrazol-3-yl)benzoyl]cyclohexanecarbonyl]amino]pyrazole-3-carboxamide Chemical compound CNC(=O)C1=C(C=NN1C)NC(=O)[C@H]1[C@@H](CCCC1)C(C1=CC=C(C=C1)C1=NNC(=C1)C)=O VBEWZIAHRRCBAX-QZTJIDSGSA-N 0.000 claims description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 2
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 claims description 2
- 150000003852 triazoles Chemical class 0.000 claims description 2
- IVYACETTWFJKQK-IAGOWNOFSA-N (1R,2R)-2-[4-(5-methyl-1H-pyrazol-3-yl)benzoyl]-N-(1-methyl-5-sulfamoylpyrazol-4-yl)cyclohexane-1-carboxamide Chemical compound CC1=NNC(=C1)C1=CC=C(C(=O)[C@H]2[C@@H](CCCC2)C(=O)NC=2C=NN(C=2S(N)(=O)=O)C)C=C1 IVYACETTWFJKQK-IAGOWNOFSA-N 0.000 claims 2
- TZQFPWWHWMTHNA-IAGOWNOFSA-N (1R,2R)-2-[4-(5-methyl-1H-pyrazol-3-yl)benzoyl]-N-(1-methyl-3-sulfamoylpyrazol-4-yl)cyclohexane-1-carboxamide Chemical compound CC1=NNC(=C1)C1=CC=C(C(=O)[C@H]2[C@@H](CCCC2)C(=O)NC=2C(=NN(C=2)C)S(N)(=O)=O)C=C1 TZQFPWWHWMTHNA-IAGOWNOFSA-N 0.000 claims 1
- XPEIZFNNQVMTAI-QZTJIDSGSA-N (1R,2R)-2-[4-(5-methyl-1H-pyrazol-3-yl)benzoyl]-N-(1H-pyrazol-4-yl)cyclohexane-1-carboxamide Chemical compound CC1=NNC(=C1)C1=CC=C(C(=O)[C@H]2[C@@H](CCCC2)C(=O)NC=2C=NNC=2)C=C1 XPEIZFNNQVMTAI-QZTJIDSGSA-N 0.000 claims 1
- TUUOYKJYFABFEO-HZPDHXFCSA-N (1R,2R)-N-(1-methyl-3-sulfamoylpyrazol-4-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexane-1-carboxamide Chemical compound CN1N=C(C(=C1)NC(=O)[C@H]1[C@@H](CCCC1)C(C1=CC=C(C=C1)C1=CC=NN1)=O)S(N)(=O)=O TUUOYKJYFABFEO-HZPDHXFCSA-N 0.000 claims 1
- DMHSDGHSQKYUDC-IAGOWNOFSA-N (1R,2R)-N-(1-methyl-5-methylsulfonylpyrazol-4-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexane-1-carboxamide Chemical compound CN1N=CC(=C1S(=O)(=O)C)NC(=O)[C@H]1[C@@H](CCCC1)C(C1=CC=C(C=C1)C1=CC=NN1)=O DMHSDGHSQKYUDC-IAGOWNOFSA-N 0.000 claims 1
- NFZRIQNPHKJGBM-QZTJIDSGSA-N (1R,2R)-N-[1-methyl-5-(methylsulfamoyl)pyrazol-4-yl]-2-[4-(5-methyl-1H-pyrazol-3-yl)benzoyl]cyclohexane-1-carboxamide Chemical compound CN1N=CC(=C1S(NC)(=O)=O)NC(=O)[C@H]1[C@@H](CCCC1)C(C1=CC=C(C=C1)C1=CC(=NN1)C)=O NFZRIQNPHKJGBM-QZTJIDSGSA-N 0.000 claims 1
- DLOIQKSZLNORQH-HZPDHXFCSA-N (1R,2R)-N-[5-(difluoromethyl)-1H-pyrazol-4-yl]-2-[4-(5-methyl-1H-pyrazol-3-yl)benzoyl]cyclohexane-1-carboxamide Chemical compound FC(C1=C(C=NN1)NC(=O)[C@H]1[C@@H](CCCC1)C(C1=CC=C(C=C1)C1=NNC(=C1)C)=O)F DLOIQKSZLNORQH-HZPDHXFCSA-N 0.000 claims 1
- GFLOEPOZTVSVRQ-IRXDYDNUSA-N (1S,2S)-N-(5-cyano-1-methylpyrazol-4-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexane-1-carboxamide Chemical compound Cn1ncc(NC(=O)[C@H]2CCCC[C@@H]2C(=O)c2ccc(cc2)-c2ccn[nH]2)c1C#N GFLOEPOZTVSVRQ-IRXDYDNUSA-N 0.000 claims 1
- LTKXCXFALXANGC-QZTJIDSGSA-N 2-ethyl-4-[[(1R,2R)-2-[4-(5-methyl-1H-pyrazol-3-yl)benzoyl]cyclohexanecarbonyl]amino]pyrazole-3-carboxamide Chemical compound C(C)N1N=CC(=C1C(=O)N)NC(=O)[C@H]1[C@@H](CCCC1)C(C1=CC=C(C=C1)C1=CC(=NN1)C)=O LTKXCXFALXANGC-QZTJIDSGSA-N 0.000 claims 1
- MFMKTVNIVSWSTK-UHFFFAOYSA-N 2-methylpyrazole-3-carboxamide Chemical compound CN1N=CC=C1C(N)=O MFMKTVNIVSWSTK-UHFFFAOYSA-N 0.000 claims 1
- OTCSUNIYBXRXQU-IAGOWNOFSA-N 5-methyl-4-[[(1R,2R)-2-[4-(5-methyl-1H-pyrazol-3-yl)benzoyl]cyclohexanecarbonyl]amino]-1H-pyrazole-3-carboxamide Chemical compound CC1=C(C(=NN1)C(=O)N)NC(=O)[C@H]1[C@@H](CCCC1)C(C1=CC=C(C=C1)C1=CC(=NN1)C)=O OTCSUNIYBXRXQU-IAGOWNOFSA-N 0.000 claims 1
- RGSKELBQAKNHCP-UHFFFAOYSA-N CC1=C(C(N)=O)C(NC(=O)C2CCCCC2C(=O)C2=C(F)C=C(C=C2)C2=CC=NN2)=NO1 Chemical compound CC1=C(C(N)=O)C(NC(=O)C2CCCCC2C(=O)C2=C(F)C=C(C=C2)C2=CC=NN2)=NO1 RGSKELBQAKNHCP-UHFFFAOYSA-N 0.000 claims 1
- MGNZSIKQOCJNLD-UHFFFAOYSA-N CN1C=C(NC(=O)C2CCCCC2C(=O)C2=C(F)C=C(C=C2)C2=CC(C)=NN2)C(=N1)C(N)=O Chemical compound CN1C=C(NC(=O)C2CCCCC2C(=O)C2=C(F)C=C(C=C2)C2=CC(C)=NN2)C(=N1)C(N)=O MGNZSIKQOCJNLD-UHFFFAOYSA-N 0.000 claims 1
- WKTHEXQLOLUJGJ-UHFFFAOYSA-N CN1N=CC(NC(=O)C2CCCCC2C(=O)C2=C(F)C=C(C=C2)C2=CC(C)=NN2)=C1C(N)=O Chemical compound CN1N=CC(NC(=O)C2CCCCC2C(=O)C2=C(F)C=C(C=C2)C2=CC(C)=NN2)=C1C(N)=O WKTHEXQLOLUJGJ-UHFFFAOYSA-N 0.000 claims 1
- RLVGSZOMIOBSAN-UHFFFAOYSA-N CN1N=CC(NC(=O)C2CCCCC2C(=O)C2=C(F)C=C(C=C2)C2=CC=NN2)=C1C(N)=O Chemical compound CN1N=CC(NC(=O)C2CCCCC2C(=O)C2=C(F)C=C(C=C2)C2=CC=NN2)=C1C(N)=O RLVGSZOMIOBSAN-UHFFFAOYSA-N 0.000 claims 1
- NOGGAYCFBWOSDJ-UHFFFAOYSA-N COC1=C(NC(=O)C2CCCCC2C(=O)C2=CC=C(C=C2)C2=NNC=C2)C=NN1C Chemical compound COC1=C(NC(=O)C2CCCCC2C(=O)C2=CC=C(C=C2)C2=NNC=C2)C=NN1C NOGGAYCFBWOSDJ-UHFFFAOYSA-N 0.000 claims 1
- QGZOXFFHNQDBLJ-UHFFFAOYSA-N N-(3-cyano-1-methylpyrazol-4-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexane-1-carboxamide Chemical compound Cn1cc(NC(=O)C2CCCCC2C(=O)c2ccc(cc2)-c2ccn[nH]2)c(n1)C#N QGZOXFFHNQDBLJ-UHFFFAOYSA-N 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract description 17
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract 2
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 496
- 239000011541 reaction mixture Substances 0.000 description 329
- 235000019439 ethyl acetate Nutrition 0.000 description 248
- 239000000543 intermediate Substances 0.000 description 235
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 216
- 239000000243 solution Substances 0.000 description 174
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 141
- 239000012071 phase Substances 0.000 description 122
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 105
- 239000000203 mixture Substances 0.000 description 92
- 239000012074 organic phase Substances 0.000 description 90
- 239000007787 solid Substances 0.000 description 86
- 238000005160 1H NMR spectroscopy Methods 0.000 description 82
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 69
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 68
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 67
- 239000012043 crude product Substances 0.000 description 64
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 59
- 239000012267 brine Substances 0.000 description 59
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 59
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 57
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 53
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 52
- 238000002953 preparative HPLC Methods 0.000 description 52
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 51
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 51
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 51
- 238000006243 chemical reaction Methods 0.000 description 50
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 48
- 238000003818 flash chromatography Methods 0.000 description 48
- 239000012044 organic layer Substances 0.000 description 48
- 239000007853 buffer solution Substances 0.000 description 47
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 43
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
- 239000000460 chlorine Chemical group 0.000 description 39
- 239000008346 aqueous phase Substances 0.000 description 37
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 30
- 239000002904 solvent Substances 0.000 description 26
- 239000002253 acid Substances 0.000 description 25
- 239000011734 sodium Substances 0.000 description 25
- 229910052757 nitrogen Inorganic materials 0.000 description 24
- 239000012299 nitrogen atmosphere Substances 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 238000000034 method Methods 0.000 description 21
- 238000010898 silica gel chromatography Methods 0.000 description 21
- 101710187011 Arachidonate 5-lipoxygenase-activating protein Proteins 0.000 description 20
- 102100022278 Arachidonate 5-lipoxygenase-activating protein Human genes 0.000 description 20
- 239000007832 Na2SO4 Substances 0.000 description 20
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 20
- 239000003208 petroleum Substances 0.000 description 20
- 229910052938 sodium sulfate Inorganic materials 0.000 description 20
- 235000011152 sodium sulphate Nutrition 0.000 description 20
- 238000005481 NMR spectroscopy Methods 0.000 description 19
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- 238000011282 treatment Methods 0.000 description 19
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 18
- NEUWPDLMDVINSN-UHFFFAOYSA-N 1h-pyrazol-5-ylboronic acid Chemical compound OB(O)C=1C=CNN=1 NEUWPDLMDVINSN-UHFFFAOYSA-N 0.000 description 17
- 239000003960 organic solvent Substances 0.000 description 17
- OVZXXISOLDHARA-VXGBXAGGSA-N (1r,2r)-2-(4-bromobenzoyl)cyclohexane-1-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCC[C@H]1C(=O)C1=CC=C(Br)C=C1 OVZXXISOLDHARA-VXGBXAGGSA-N 0.000 description 16
- NZNMSOFKMUBTKW-UHFFFAOYSA-N Cyclohexanecarboxylic acid Natural products OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 16
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 16
- 125000005605 benzo group Chemical group 0.000 description 16
- ATJGEGCXZOEOJQ-UHFFFAOYSA-N 3-methyl-1-(oxan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole Chemical compound C1CCCOC1N1N=C(C)C=C1B1OC(C)(C)C(C)(C)O1 ATJGEGCXZOEOJQ-UHFFFAOYSA-N 0.000 description 14
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 14
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- 238000010998 test method Methods 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
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- 239000008096 xylene Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/38—Nitrogen atoms
- C07D231/40—Acylated on said nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/44—Oxygen and nitrogen or sulfur and nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/44—Oxygen and nitrogen or sulfur and nitrogen atoms
- C07D231/46—Oxygen atom in position 3 or 5 and nitrogen atom in position 4
- C07D231/50—Acylated on said nitrogen atom
-
- 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
- C07D413/12—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 linked by a chain containing hetero atoms as chain links
-
- 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
- C07D417/12—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 linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Epidemiology (AREA)
- Urology & Nephrology (AREA)
- Diabetes (AREA)
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- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Gastroenterology & Hepatology (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Enzymes And Modification Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Applications Claiming Priority (1)
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| US201562156424P | 2015-05-04 | 2015-05-04 |
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| ES16720116T Active ES2760466T3 (es) | 2015-05-04 | 2016-05-03 | Derivados de pirazol útiles como inhibidores de la proteína activadora de 5-lipoxigenasa (FLAP) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EA032221B1 (ru) | 2015-05-04 | 2019-04-30 | Астразенека Аб | Производные пиразола, пригодные в качестве ингибиторов белка, активирующего 5-липоксигеназу (flap) |
| CN109890385B (zh) * | 2016-10-28 | 2022-08-02 | 阿斯利康(瑞典)有限公司 | (1r,2r)-2-[4-(3-甲基-1h-吡唑-5-基)苯甲酰基]-n-(4-氧代-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-3-基)环己烷甲酰胺的结晶形式 |
| GB201905721D0 (en) | 2019-04-24 | 2019-06-05 | Univ Dundee | Compounds |
| CN110169969B (zh) * | 2019-06-28 | 2022-05-27 | 南京医科大学 | Mk571在制备预防和治疗心脏病药物中应用 |
| CN111084775A (zh) * | 2020-02-17 | 2020-05-01 | 牡丹江医学院 | 一种用于治疗癫痫的药物组合物 |
| CN111419800B (zh) * | 2020-04-23 | 2021-03-19 | 温州医科大学附属第二医院、温州医科大学附属育英儿童医院 | 用于治疗红斑狼疮的药物制剂及其制备方法 |
| CN111643498B (zh) * | 2020-07-20 | 2021-05-07 | 黑龙江中医药大学 | 一种治疗肾结石的药物组合物及其用途 |
| CN111714499B (zh) * | 2020-07-27 | 2021-05-11 | 黑龙江中医药大学 | 一种用于治疗多囊卵巢综合征的药物组合物 |
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| AP9400632A0 (en) | 1993-04-29 | 1995-10-07 | Zeneca Ltd | Ether derivatives. |
| US5773422A (en) | 1996-01-29 | 1998-06-30 | Komer; Gene | Avermectin formulation |
| EP1670804A2 (en) * | 2003-09-10 | 2006-06-21 | GPC Biotech AG | Heterobicyclic compounds as pharmaceutically active agents |
| GB2431927B (en) * | 2005-11-04 | 2010-03-17 | Amira Pharmaceuticals Inc | 5-Lipoxygenase-activating protein (FLAP) inhibitors |
| TW200815351A (en) * | 2006-05-02 | 2008-04-01 | Astrazeneca Ab | Novel compounds |
| WO2008097930A1 (en) * | 2007-02-05 | 2008-08-14 | Amira Pharmaceuticals, Inc. | Reverse indoles as 5-lipoxygenase-activating protein (flap) inhibitors |
| GB0702456D0 (en) * | 2007-02-08 | 2007-03-21 | Astrazeneca Ab | New combination |
| JP2010524944A (ja) * | 2007-04-20 | 2010-07-22 | シェーリング コーポレイション | テトラヒドロピリド［４，３−ｄ］ピリミジノン誘導体およびそれらの使用方法 |
| BRPI0811204A8 (pt) * | 2007-05-10 | 2015-09-22 | Bristol Myers Squibb Co | Tetra-hidroibenzo-1,4-diazepinas substituídas por arila e heteroarila e uso das mesmas para bloquear a recaptação de norepinefrina, dopamina e serotonina |
| EP2207547A4 (en) * | 2007-10-05 | 2010-11-17 | Amira Pharmaceuticals Inc | PROTEIN INHIBITORS THAT ACTIVATE 5-LIPOXYGENASE |
| EA032221B1 (ru) * | 2015-05-04 | 2019-04-30 | Астразенека Аб | Производные пиразола, пригодные в качестве ингибиторов белка, активирующего 5-липоксигеназу (flap) |
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