ES2620451T3 - Moduladores de los LXR - Google Patents
Moduladores de los LXR Download PDFInfo
- Publication number
- ES2620451T3 ES2620451T3 ES10721902.4T ES10721902T ES2620451T3 ES 2620451 T3 ES2620451 T3 ES 2620451T3 ES 10721902 T ES10721902 T ES 10721902T ES 2620451 T3 ES2620451 T3 ES 2620451T3
- Authority
- ES
- Spain
- Prior art keywords
- propan
- hydroxymethyl
- biphenyl
- methylsulfonyl
- imidazol
- 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.)
- Active
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- 150000001875 compounds Chemical class 0.000 claims abstract description 79
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- -1 3-Chloro-3'-fluoro-4 '- (hydroxymethyl) -5' - (methylsulfonyl) biphenyl-4-yl Chemical group 0.000 claims description 107
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 59
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 7
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 7
- SHZMZJHKHVGRLS-UHFFFAOYSA-N 2-[1-[2-fluoro-4-[3-fluoro-4-(hydroxymethyl)-5-methylsulfonylphenyl]phenyl]-2-[(2-fluorophenyl)methyl]imidazol-4-yl]propan-2-ol Chemical compound N=1C(C(C)(O)C)=CN(C=2C(=CC(=CC=2)C=2C=C(C(CO)=C(F)C=2)S(C)(=O)=O)F)C=1CC1=CC=CC=C1F SHZMZJHKHVGRLS-UHFFFAOYSA-N 0.000 claims description 5
- PBDHWROHOZNQQU-UHFFFAOYSA-N 2-[1-[4-[3-fluoro-4-(hydroxymethyl)-5-methylsulfonylphenyl]phenyl]-2-[(2-methylphenyl)methyl]imidazol-4-yl]propan-2-ol Chemical compound CC1=CC=CC=C1CC1=NC(C(C)(C)O)=CN1C1=CC=C(C=2C=C(C(CO)=C(F)C=2)S(C)(=O)=O)C=C1 PBDHWROHOZNQQU-UHFFFAOYSA-N 0.000 claims description 5
- PABVYBCMEDLXBK-UHFFFAOYSA-N 2-[1-[4-[3-fluoro-4-(hydroxymethyl)-5-methylsulfonylphenyl]phenyl]-2-[2-(2-fluorophenyl)propan-2-yl]imidazol-4-yl]propan-2-ol Chemical compound N=1C(C(C)(O)C)=CN(C=2C=CC(=CC=2)C=2C=C(C(CO)=C(F)C=2)S(C)(=O)=O)C=1C(C)(C)C1=CC=CC=C1F PABVYBCMEDLXBK-UHFFFAOYSA-N 0.000 claims description 5
- LIURGOZWWMFDJM-UHFFFAOYSA-N 2-[2-[(2,4-dichlorophenyl)methyl]-1-[2-fluoro-4-[3-fluoro-4-(hydroxymethyl)-5-methylsulfonylphenyl]phenyl]imidazol-4-yl]propan-2-ol Chemical compound N=1C(C(C)(O)C)=CN(C=2C(=CC(=CC=2)C=2C=C(C(CO)=C(F)C=2)S(C)(=O)=O)F)C=1CC1=CC=C(Cl)C=C1Cl LIURGOZWWMFDJM-UHFFFAOYSA-N 0.000 claims description 5
- HBYUXALQTISNLW-UHFFFAOYSA-N 2-[2-[(2,4-dichlorophenyl)methyl]-1-[4-[3-fluoro-4-(hydroxymethyl)-5-methylsulfonylphenyl]phenyl]imidazol-4-yl]propan-2-ol Chemical compound N=1C(C(C)(O)C)=CN(C=2C=CC(=CC=2)C=2C=C(C(CO)=C(F)C=2)S(C)(=O)=O)C=1CC1=CC=C(Cl)C=C1Cl HBYUXALQTISNLW-UHFFFAOYSA-N 0.000 claims description 5
- YIPWZEZDOVPNDU-UHFFFAOYSA-N 2-[2-[(2,6-dichlorophenyl)methyl]-1-[4-[3-fluoro-4-(hydroxymethyl)-5-methylsulfonylphenyl]phenyl]imidazol-4-yl]propan-2-ol Chemical compound N=1C(C(C)(O)C)=CN(C=2C=CC(=CC=2)C=2C=C(C(CO)=C(F)C=2)S(C)(=O)=O)C=1CC1=C(Cl)C=CC=C1Cl YIPWZEZDOVPNDU-UHFFFAOYSA-N 0.000 claims description 5
- INGBFAQNZCKULI-UHFFFAOYSA-N 2-[2-[(2-chloro-5-fluorophenyl)methyl]-1-[4-[3-fluoro-4-(hydroxymethyl)-5-methylsulfonylphenyl]phenyl]imidazol-4-yl]propan-2-ol Chemical compound N=1C(C(C)(O)C)=CN(C=2C=CC(=CC=2)C=2C=C(C(CO)=C(F)C=2)S(C)(=O)=O)C=1CC1=CC(F)=CC=C1Cl INGBFAQNZCKULI-UHFFFAOYSA-N 0.000 claims description 5
- MBISJGBQIZXZBW-UHFFFAOYSA-N 2-[2-[(2-chlorophenyl)methyl]-1-[2-fluoro-4-[3-fluoro-4-(hydroxymethyl)-5-methylsulfonylphenyl]phenyl]imidazol-4-yl]propan-2-ol Chemical compound N=1C(C(C)(O)C)=CN(C=2C(=CC(=CC=2)C=2C=C(C(CO)=C(F)C=2)S(C)(=O)=O)F)C=1CC1=CC=CC=C1Cl MBISJGBQIZXZBW-UHFFFAOYSA-N 0.000 claims description 5
- OSCBEESEHIRILI-UHFFFAOYSA-N 2-[2-[1-(2,6-dichlorophenyl)ethyl]-1-[2-fluoro-4-[3-fluoro-4-(hydroxymethyl)-5-methylsulfonylphenyl]phenyl]imidazol-4-yl]propan-2-ol Chemical compound ClC=1C=CC=C(Cl)C=1C(C)C1=NC(C(C)(C)O)=CN1C(C(=C1)F)=CC=C1C1=CC(F)=C(CO)C(S(C)(=O)=O)=C1 OSCBEESEHIRILI-UHFFFAOYSA-N 0.000 claims description 5
- YXYSFWCWEVDQRV-UHFFFAOYSA-N 2-[2-[2-(2-chloro-6-fluorophenyl)propan-2-yl]-1-[4-[3-fluoro-4-(hydroxymethyl)-5-methylsulfonylphenyl]-2-methylphenyl]imidazol-4-yl]propan-2-ol Chemical compound CC1=CC(C=2C=C(C(CO)=C(F)C=2)S(C)(=O)=O)=CC=C1N1C=C(C(C)(C)O)N=C1C(C)(C)C1=C(F)C=CC=C1Cl YXYSFWCWEVDQRV-UHFFFAOYSA-N 0.000 claims description 5
- GUQJFTLEMOZJBL-UHFFFAOYSA-N 2-[2-[2-(2-chlorophenyl)propan-2-yl]-1-[2-fluoro-4-[3-fluoro-4-(hydroxymethyl)-5-methylsulfonylphenyl]phenyl]imidazol-4-yl]propan-2-ol Chemical compound N=1C(C(C)(O)C)=CN(C=2C(=CC(=CC=2)C=2C=C(C(CO)=C(F)C=2)S(C)(=O)=O)F)C=1C(C)(C)C1=CC=CC=C1Cl GUQJFTLEMOZJBL-UHFFFAOYSA-N 0.000 claims description 5
- QSKWRGMGPSZVFY-UHFFFAOYSA-N 2-[1-[2-fluoro-4-[3-fluoro-4-(hydroxymethyl)-5-methylsulfonylphenyl]phenyl]-2-[2-(2-fluorophenyl)propan-2-yl]imidazol-4-yl]propan-2-ol Chemical compound N=1C(C(C)(O)C)=CN(C=2C(=CC(=CC=2)C=2C=C(C(CO)=C(F)C=2)S(C)(=O)=O)F)C=1C(C)(C)C1=CC=CC=C1F QSKWRGMGPSZVFY-UHFFFAOYSA-N 0.000 claims description 3
- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 claims description 3
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 56
- 239000000243 solution Substances 0.000 description 42
- 238000006243 chemical reaction Methods 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 23
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 22
- 235000019439 ethyl acetate Nutrition 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 16
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 102000004311 liver X receptors Human genes 0.000 description 15
- 108090000865 liver X receptors Proteins 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000012074 organic phase Substances 0.000 description 14
- 229910052938 sodium sulfate Inorganic materials 0.000 description 14
- 235000011152 sodium sulphate Nutrition 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000007832 Na2SO4 Substances 0.000 description 10
- 206010012601 diabetes mellitus Diseases 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 208000031226 Hyperlipidaemia Diseases 0.000 description 9
- 208000035475 disorder Diseases 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- 239000000377 silicon dioxide Substances 0.000 description 8
- WPBNYEWIKNQBJT-UHFFFAOYSA-N 4-bromo-2-fluoro-6-methylsulfanylbenzoic acid Chemical compound CSC1=CC(Br)=CC(F)=C1C(O)=O WPBNYEWIKNQBJT-UHFFFAOYSA-N 0.000 description 7
- 208000033962 Fontaine progeroid syndrome Diseases 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 7
- 235000011007 phosphoric acid Nutrition 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 102000005962 receptors Human genes 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- 235000012239 silicon dioxide Nutrition 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 229910052681 coesite Inorganic materials 0.000 description 6
- 229910052906 cristobalite Inorganic materials 0.000 description 6
- 102000006255 nuclear receptors Human genes 0.000 description 6
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- 229910052682 stishovite Inorganic materials 0.000 description 6
- 229910052905 tridymite Inorganic materials 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 208000008589 Obesity Diseases 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
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- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
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- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
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- 235000019270 ammonium chloride Nutrition 0.000 description 4
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 4
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
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Landscapes
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| PCT/US2010/036211 WO2010138598A2 (en) | 2009-05-28 | 2010-05-26 | Lxr modulators |
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| ES2620451T3 true ES2620451T3 (es) | 2017-06-28 |
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| DK2435410T3 (da) * | 2009-05-28 | 2017-04-10 | Exelixis Patent Co Llc | LXR-modulatorer |
| AR088728A1 (es) | 2011-03-25 | 2014-07-02 | Bristol Myers Squibb Co | Moduladores de lxr como prodroga de imidazol |
| HUE040231T2 (hu) | 2012-03-02 | 2019-02-28 | Ralexar Therapeutics Inc | Máj X receptor (LXR) modulátorok bõrbetegségek, rendellenességek és állapotok kezelésére |
| EP3626309B1 (en) | 2012-08-13 | 2023-03-08 | The Rockefeller University | Lxrbeta agonist for the treatment of cancer |
| ES2694001T3 (es) | 2013-03-15 | 2018-12-17 | Bristol-Myers Squibb Company | Moduladores de LXR |
| WO2014144037A1 (en) * | 2013-03-15 | 2014-09-18 | Bristol-Myers Squibb Company | Lxr modulators |
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