WO2006014357A1 - Cetp inhibitors - Google Patents
Cetp inhibitors Download PDFInfo
- Publication number
- WO2006014357A1 WO2006014357A1 PCT/US2005/023546 US2005023546W WO2006014357A1 WO 2006014357 A1 WO2006014357 A1 WO 2006014357A1 US 2005023546 W US2005023546 W US 2005023546W WO 2006014357 A1 WO2006014357 A1 WO 2006014357A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- trifluoromethyl
- isopropyl
- etoac
- methoxy
- mmol
- Prior art date
Links
- 239000003354 cholesterol ester transfer protein inhibitor Substances 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 165
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 89
- 150000003839 salts Chemical class 0.000 claims abstract description 42
- 125000001424 substituent group Chemical group 0.000 claims abstract description 21
- 201000001320 Atherosclerosis Diseases 0.000 claims abstract description 15
- 108010023302 HDL Cholesterol Proteins 0.000 claims abstract description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 63
- 229910052736 halogen Inorganic materials 0.000 claims description 58
- 150000002367 halogens Chemical class 0.000 claims description 58
- 238000000034 method Methods 0.000 claims description 51
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 44
- 125000000217 alkyl group Chemical group 0.000 claims description 31
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 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 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 229910052782 aluminium Inorganic materials 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 abstract description 17
- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 13
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 11
- 108010028554 LDL Cholesterol Proteins 0.000 abstract description 6
- 229910052740 iodine Inorganic materials 0.000 abstract description 4
- 238000008214 LDL Cholesterol Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 391
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 283
- 235000019439 ethyl acetate Nutrition 0.000 description 192
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 132
- 239000000243 solution Substances 0.000 description 125
- 238000006243 chemical reaction Methods 0.000 description 112
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 89
- 239000000203 mixture Substances 0.000 description 89
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 83
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 82
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
- 238000005481 NMR spectroscopy Methods 0.000 description 69
- 238000003818 flash chromatography Methods 0.000 description 60
- 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
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 58
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 56
- 125000006269 biphenyl-2-yl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C(*)C([H])=C([H])C([H])=C1[H] 0.000 description 53
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 50
- 229910052938 sodium sulfate Inorganic materials 0.000 description 50
- 235000011152 sodium sulphate Nutrition 0.000 description 49
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 48
- 239000007832 Na2SO4 Substances 0.000 description 45
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 42
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 42
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- 239000002904 solvent Substances 0.000 description 39
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 36
- 238000005160 1H NMR spectroscopy Methods 0.000 description 31
- 239000012044 organic layer Substances 0.000 description 31
- 235000019441 ethanol Nutrition 0.000 description 30
- 239000007787 solid Substances 0.000 description 30
- 239000000047 product Substances 0.000 description 29
- 238000000746 purification Methods 0.000 description 29
- -1 -C1-C5 alkyl Inorganic materials 0.000 description 28
- 239000000284 extract Substances 0.000 description 28
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 25
- 238000001819 mass spectrum Methods 0.000 description 23
- 102000012336 Cholesterol Ester Transfer Proteins Human genes 0.000 description 22
- 108010061846 Cholesterol Ester Transfer Proteins Proteins 0.000 description 22
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 22
- 239000010410 layer Substances 0.000 description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 22
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 21
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 229910052757 nitrogen Inorganic materials 0.000 description 17
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 16
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 16
- 229910000104 sodium hydride Inorganic materials 0.000 description 16
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 15
- 239000000460 chlorine Substances 0.000 description 15
- 125000004093 cyano group Chemical group *C#N 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 14
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- 238000003556 assay Methods 0.000 description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 14
- 239000012043 crude product Substances 0.000 description 14
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 14
- 239000003921 oil Substances 0.000 description 14
- 235000019198 oils Nutrition 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 238000010992 reflux Methods 0.000 description 14
- 229920006395 saturated elastomer Polymers 0.000 description 14
- 239000000741 silica gel Substances 0.000 description 14
- 229910002027 silica gel Inorganic materials 0.000 description 14
- 229960001866 silicon dioxide Drugs 0.000 description 14
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 13
- 239000008346 aqueous phase Substances 0.000 description 13
- 239000012312 sodium hydride Substances 0.000 description 13
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 12
- 239000002245 particle Substances 0.000 description 12
- 230000009467 reduction Effects 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 12
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 12
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 11
- UHOVQNZJYSORNB-MZWXYZOWSA-N benzene-d6 Chemical compound [2H]C1=C([2H])C([2H])=C([2H])C([2H])=C1[2H] UHOVQNZJYSORNB-MZWXYZOWSA-N 0.000 description 11
- 229910052717 sulfur Inorganic materials 0.000 description 11
- HMRRCUXJGOSJJA-UHFFFAOYSA-N (4-fluoro-2-methoxy-5-propan-2-ylphenyl)boronic acid Chemical compound COC1=CC(F)=C(C(C)C)C=C1B(O)O HMRRCUXJGOSJJA-UHFFFAOYSA-N 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- 241000282414 Homo sapiens Species 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 125000003342 alkenyl group Chemical group 0.000 description 9
- 150000001414 amino alcohols Chemical class 0.000 description 9
- 229910052760 oxygen Inorganic materials 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 239000002002 slurry Substances 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 8
- 150000001540 azides Chemical class 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 238000004296 chiral HPLC Methods 0.000 description 8
- 239000012230 colorless oil Substances 0.000 description 8
- 208000029078 coronary artery disease Diseases 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 125000005842 heteroatom Chemical group 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 8
- ATLQGZVLWOURFU-UHFFFAOYSA-N 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC(CBr)=CC(C(F)(F)F)=C1 ATLQGZVLWOURFU-UHFFFAOYSA-N 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 150000007513 acids Chemical class 0.000 description 7
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 150000002460 imidazoles Chemical group 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- UTKAEAGLVJFBMK-UHFFFAOYSA-N (2-methoxy-5-propan-2-ylphenyl)boronic acid Chemical compound COC1=CC=C(C(C)C)C=C1B(O)O UTKAEAGLVJFBMK-UHFFFAOYSA-N 0.000 description 6
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 108010010234 HDL Lipoproteins Proteins 0.000 description 6
- 102000015779 HDL Lipoproteins Human genes 0.000 description 6
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical class CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 150000001299 aldehydes Chemical class 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 239000003638 chemical reducing agent Substances 0.000 description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol group Chemical group [C@@H]1(CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)[C@H](C)CCCC(C)C HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 6
- 239000006185 dispersion Substances 0.000 description 6
- 238000003821 enantio-separation Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 6
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 6
- CRKFYUIXVLHGLN-UHFFFAOYSA-N 2-iodo-5-(trifluoromethyl)benzaldehyde Chemical compound FC(F)(F)C1=CC=C(I)C(C=O)=C1 CRKFYUIXVLHGLN-UHFFFAOYSA-N 0.000 description 5
- KSPKCPNOVAIBEE-UHFFFAOYSA-N 2-iodo-5-(trifluoromethyl)benzonitrile Chemical compound FC(F)(F)C1=CC=C(I)C(C#N)=C1 KSPKCPNOVAIBEE-UHFFFAOYSA-N 0.000 description 5
- 102000004895 Lipoproteins Human genes 0.000 description 5
- 108090001030 Lipoproteins Proteins 0.000 description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 5
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 5
- 239000007868 Raney catalyst Substances 0.000 description 5
- 229910000564 Raney nickel Inorganic materials 0.000 description 5
- 238000006619 Stille reaction Methods 0.000 description 5
- 238000006069 Suzuki reaction reaction Methods 0.000 description 5
- 125000000304 alkynyl group Chemical group 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 5
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- YMWUJEATGCHHMB-DICFDUPASA-N dichloromethane-d2 Chemical compound [2H]C([2H])(Cl)Cl YMWUJEATGCHHMB-DICFDUPASA-N 0.000 description 5
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 5
- 150000002576 ketones Chemical class 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
- 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 5
- 239000007858 starting material Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 5
- KFYDWIIILHRHEE-UHFFFAOYSA-N 2-(2-methoxy-5-propan-2-ylphenyl)-5-(trifluoromethyl)benzonitrile Chemical compound COC1=CC=C(C(C)C)C=C1C1=CC=C(C(F)(F)F)C=C1C#N KFYDWIIILHRHEE-UHFFFAOYSA-N 0.000 description 4
- XUOVYCDDWBUKRX-UHFFFAOYSA-N 2-fluoro-4-methoxy-1-prop-1-en-2-ylbenzene Chemical compound COC1=CC=C(C(C)=C)C(F)=C1 XUOVYCDDWBUKRX-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 4
- 0 C*Cc1ccc(C=O)c(I)c1 Chemical compound C*Cc1ccc(C=O)c(I)c1 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
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- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical class O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
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Classifications
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- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
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Definitions
- This invention relates to a class of chemical compounds that inhibit cholesterol ester transfer protein (CETP) and therefore may have utility in the treatment and prevention of atherosclerosis.
- CETP cholesterol ester transfer protein
- CHD coronary heart disease
- stroke and peripheral vascular disease represent a truly enormous burden to the health care systems of the industrialized world.
- CHD coronary heart disease
- stroke and peripheral vascular disease represent a truly enormous burden to the health care systems of the industrialized world.
- CHD coronary heart disease
- stroke and peripheral vascular disease represent a truly enormous burden to the health care systems of the industrialized world.
- CHD coronary heart disease
- stroke and peripheral vascular disease represent a truly enormous burden to the health care systems of the industrialized world.
- CHD coronary heart disease
- HMG-CoA Reductase inhibitors especially the statins
- LDL-C Low Density Lipoprotein cholesterol
- epidemiologic studies have demonstrated an inverse relationship between High Density Lipoprotein cholesterol (HDL-C) levels and atherosclerosis, leading to the conclusion that low serum HDL-C levels are associated with an increased risk for CHD.
- cholesteryl ester transfer protein a plasma glycoprotein that catalyzes the movement of cholesteryl esters from HDL to the apoB containing lipoproteins, especially VLDL (see Hesler, CB. , et. al. (1987) Purification and characterization of human plasma cholesteryl ester transfer protein. J. Biol. Chern. 262(5), 2275-2282)).
- CETP cholesteryl ester transfer protein
- VLDL cholesteryl ester transfer protein
- CETP plays a role in reverse cholesterol transport, the process whereby cholesterol is returned to the liver from peripheral tissues.
- many animals do not possess CETP, including animals that have high HDL levels and are known to be resistant to coronary heart disease, such as rodents (see Guyard-Dangremont, V., et. al., (1998) Phospholipid and cholesteryl p st ⁇ x. transfer activities in plasma from 14 vertebrate species. Relation to atherogenesis susceptibility; c ⁇ mp. Biochem. Physiol. B Biochem. MoI. Biol. 120(3), 517-525).
- statins such as simvastatin (ZOCOR®) represent
- statins only achieve a risk reduction of approximately one-third in the treatment and prevention of atherosclerosis and ensuing atherosclerotic disease events.
- pharmacologic therapies are available that favorably raise circulating levels of HDL-C.
- Certain statins and some fibrates offer modest HDL-C gains.
- Niacin which provides the most effective therapy for raising HDL-C that has been clinically documented, suffers from patient compliance issues, due in part to side effects such as flushing.
- An agent that safely and effectively raises HDL cholesterol levels can answer a significant, but as yet unmet medical need by offering a means of pharmacologic therapy that can significantly improve circulating lipid profiles through a mechanism that is complementary to existing therapies.
- Compounds having Formula I including pharmaceutically acceptable salts of the compounds, are CETP inhibitors, having the utilities described below:
- X is selected from -O-, -NH-, -N(Ci-Cs alky 1)-, and -(CRR6)-;
- Each R is independently selected from the group consisting of H, -C1-C5 alkyl, and halogen, wherein -C1-C5 alkyl is optionally substituted with 1-11 halogens;
- B is selected from the group consisting of Al and A ⁇ , wherein Al has the structure:
- Rl and R6 are each independently selected from H, -C1-C5 alkyl, halogen, and -(C(R)2)nA2, wherein -C1-C5 alkyl is optionally substituted with 1-11 halogens;
- R2 is selected from the group consisting of H, -C1-C5 alkyl, halogen, Al, and -(C(R)2)nA ⁇ wherein -C1-C5 alkyl is optionally substituted with 1-11 halogens; Wherein one of B and R2 is Al; and one of B, Rl, R2, and R ⁇ is A2 or -(C(R)2)nA 2 ; so that the compound of Formula I comprises one group Al and one group A ⁇ ;
- A3 is selected from the group consisting of: (a) an aromatic ring selected from phenyl and naphthyl;
- a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6-membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and S, and optionally also having 1-2 double bonds (in addition to the double bond of the fused phenyl ring) wherein the point of attachment of A3 to the phenyl ring to which A3 is attached is a carbon atom;
- A2 is selected from the group consisting of:
- a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6-membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and S, and optionally also having 1-2 double bonds (in addition to the double bond of the fused phenyl ring);
- R5 is selected from the group consisting of H, -OH, -C1-C5 alkyl, and halogen, wherein -C1-C5 alkyl is optionally substituted with 1-11 halogens.
- Still other compounds of the invention have a structure in accordance with Formula Id, or a pharmaceutically acceptable salt thereof: Id
- R3 and R4 are each independently selected from H and -C1-C3 alkyl. hi many of the compounds of Formula I, Ia, Ib, Ic, and Id, and pharmaceutically acceptable salts thereof, p is 0-2.
- R7 and R.8 are each independently selected from the group consisting of H, halogen, -NR3R 4 , -C1-C3 alkyl, -OC1-C3 alkyl, -CN, -NO2, and pyridyl, wherein C1-C3 alkyl in all instances is optionally substituted with 1-3 halogens.
- a ⁇ is optionally substituted with 1-2 substituent groups independently selected from halogen, -C1-C4 alkyl, and -CN, wherein -C1-C4 alkyl is optionally substituted with 1-3 halogens.
- R? is selected from H, halogen, -NR3R4, -C1-C3 alkyl, -OC1-C3 alkyl, -CN, - NO2, and pyridyl, wherein C1-C3 alkyl in all instances is optionally substituted with 1-3 halogens; and
- R8 is selected from the group consisting of H, halogen, -CH3, -CF3, -OCH3, and -OCF3.
- A3 is phenyl which is optionally substituted with 1-3 substituents independently selected from the group consisting of Cl, F, -C1-C4 alkyl, and -OC1-C4 alkyl, wherein -Ci-C4 alkyl and -OC 1-C4 alkyl are optionally substituted with 1-5 F.
- a preferred subgroup of compounds has Formula Ie, including pharmaceutically acceptable salts thereof
- X is selected from the group consisting of -O-, -NH-,
- Each R is independently selected from the group consisting of H and -CH3;
- B is selected from the group consisting of Al and A2, wherein Al has the structure:
- Rl is selected from the group consisting of H, -C1-C5 alkyl, and -(C(R)2)nA ⁇ , wherein -C1-C5 alkyl is optionally substituted with 1-11 halogens;
- R 2 is selected from the group consisting of H, -C1-C5 alkyl, Al, and -(C(R)2) n A2, wherein -Ci-C5alkyl is optionally substituted with 1-11 halogens;
- one of B and R.2 is Al; and one of B, Rl, and R ⁇ is A ⁇ or -(C(R)2)nA ⁇ ; so that the compound of Formula Ie comprises one group Al and one group A ⁇ ;
- A2 is selected from the group consisting of phenyl, cyclohexyl, and pyridyl, wherein A2 is optionally substituted with 1-2 substituent groups independently selected from halogen, -C1-C4 alkyl, and -CN, wherein -Ci-C4 alkyl is optionally substituted with 1-3 halogens;
- Each R a is independently selected from the group consisting of -C1-C3 alkyl and halogen, wherein -C1-C3 alkyl is optionally substituted with 1-3 halogens;
- Each Rb is independently selected from the group consisting of Cl, F, -C1-C4 alkyl, and -OC1-C4 alkyl, wherein -C1-C4 alkyl and -OC1-C4 alkyl are optionally substituted with 1-5 F; n is 0 or 1; p is an integer from 0-2; and q is an integer from 0-3.
- Subsets of compounds having formula Ie include compounds of formula If, Ig, and Di, and pharmaceutically acceptable salts thereof:
- Rl and R2 are each independently selected from H and -C1-C5 alkyl, wherein -C1-C5 alkyl is optionally substituted with 1-11 halogens.
- a ⁇ may be selected from the group consisting of phenyl, cyclohexyl, and pyridyl, wherein A ⁇ is optionally substituted with 1-2 substituent groups independently selected from halogen, -CH3 -CF3 , and -CN.
- each R a independently is selected from the group consisting of -CF3 and Cl.
- each Rb is independently selected from the group consisting of -C1-C3 alkyl, -OCH3, and F.
- Rl and R2 are each independently selected from the group consisting of H and -C1-C2 alkyl.
- X is selected from -O-, -NH-, -N(CH3)-, .
- n is 0 or 1.
- p is 1.
- q is 2 or 3.
- a subset of compounds defined previously comprises compounds having formula Ii, and pharmaceutically acceptable salts thereof:
- R7 is selected from the group consisting of Cl and -CF3 ;
- R c is selected from the group consisting of halogen, -CH3 -CF3 , and -CN; and t is an integer from 0-2.
- Other groups are as defined previously.
- a subset of compounds defined previously comprises compounds having formula Ij, or a pharmaceutically acceptable acceptable salt thereof, wherein:
- R7 is selected from the group consisting of Cl and -CF3 ;
- R c is selected from the group consisting of halogen, -CH3 -CF3 , and -CN; and t is an integer from 0-2.
- Other groups are as defined previously. Definitions
- Alkyl means saturated carbon chains which may be linear or branched or combinations thereof, unless the carbon chain is defined otherwise.
- alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.
- Alkylene groups are alkyl groups that are difimctional rather than monofunctional. For example, methyl is an alkyl group and methylene (-CH/2-) is the corresponding alkylene group.
- alkenyl means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.
- Alkynyl means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-l-pentynyl, 2-heptynyl and the like.
- Cycloalkyl means a saturated carbocyclic ring having from 3 to 8 carbon atoms, unless otherwise stated (e.g., cycloalkyl may be defined as having one or more double bonds). The term also includes a cycloalkyl ring fused to an aryl group. Examples of cycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. "Cycloalkenyl” means a non-aromatic carbocyclic ring having one or more double binds.
- Aryl when used to describe a substituent or group in a structure means a monocyclic or bicyclic compound in which the rings are aromatic and which contains only carbon ring atoms.
- aryl can also refer to an aryl group that is fused to a cycloalkyl or heterocycle.
- Preferred "aryls” are phenyl and naphthyl. Phenyl is generally the most preferred aryl group.
- EDC is l-ethyl-3-(3-dimethylaminopropyl)carbodiimide.
- Heterocyclyl means a fully or partially saturated or aromatic 5-6 membered ring containing 1-4 heteroatoms independently selected from N, S and O, unless otherwise stated.
- “Benzoheterocycle” represents a phenyl ring fused to a 5-6-membered heterocyclic ring having 1-2 heteroatoms, each of which is O, N, or S, where the heterocyclic ring may be saturated or unsaturated. Examples include indole, benzofuran, 2,3-dihydrobenzofuran and quinoline.
- DIPEA diisopropylethylamine
- Halogen includes fluorine, chlorine, bromine and iodine.
- HOBT is 1-Hydroxybenzotriazole.
- IPAC is isopropyl acetate.
- Weight amine is N,O-dimethylhydroxylamine.
- composition as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
- pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
- tetrazole means a 2H-tetrazol-5-yl substituent group and tautomers thereof.
- Optical Isomers - Diastereomers - Geometric Isomers - Tautomers Compounds of Formula I may contain one or more asymmetric centers and can thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds of Formula I. When structures are shown with a stereochemical representation, other stereochemical structures are also included, such as enantiomers, other diastereoisomers (where diastereomers are possible), and mixtures of the enantiomers and/or diastereomers, including racemic mixtures.
- Some of the compounds described herein may contain olefmic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
- keto-enol tautomers Some of the compounds described herein may exist as tautomers.
- An example is a ketone and its enol form, known as keto-enol tautomers.
- keto-enol tautomers The individual tautomers as well as mixtures thereof are encompassed with compounds of Formula I.
- enantiomers and other compounds with chiral centers may be synthesized by stereospecific synthesis using optically pure starting materials and/or reagents of known configuration.
- biphenyl and biaryl compounds herein are observed as mixtures of atropisomers (rotamers) in the NMR spectra.
- the individual atropisomers as well as mixtures thereof are encompassed with the compounds of this invention.
- salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates.
- Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylarnine, trimethylamine, tripropylamine, tromethamine, and the like.
- basic ion exchange resins such
- salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
- acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
- Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
- Therapeutically active metabolites where the metabolites themselves fall within the scope of the claimed invention, are also compounds of the current invention.
- Prodrugs which are compounds that are converted to the claimed compounds as they are being administered to a patient or after they have been administered to a patient, are also compounds of this invention.
- Compounds of the current invention are potent inhibitors of CETP. They are therefore useful in treating diseases and conditions that are treated by inhibitors of CETP.
- One aspect of the present invention provides a method for treating or reducing the risk of developing a disease or condition that may be treated or prevented by inhibition of CETP by administering a therapeutically effective amount of a compound of this invention to a patient in need of treatment.
- a patient is a human or mammal, and is most often a human.
- a "therapeutically effective amount” is the amount of compound that is effective in obtaining a desired clinical outcome in the treatment of a specific disease.
- Diseases or conditions that may be treated with compounds of this invention, or which the patient may have a reduced risk of developing as a result of being treated with the compounds of this invention include: atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity and endotoxemia.
- the compounds of this invention are expected to be particularly effective in raising HDL-C and/or increasing the ratio of HDL-C to LDL-C. These changes in HDL-C and LDL-C may be beneficial in treating atherosclerosis, reducing or reversing the development of atherosclerosis, reducing the risk of developing atherosclerosis, or preventing atherosclerosis.
- Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention.
- oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
- Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
- compounds of Formula I are administered orally.
- the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
- the compounds of the present invention are administered at a daily dosage of from about 0.01 milligram to about 100 milligram per kilogram of animal or human body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form.
- the total daily dose will generally be from about 0.5 milligram to about 500 milligrams.
- the dosage for an adult human may be as low as 0.1 mg.
- the dosage regimen may be adjusted within this range or even outside of this range to provide the optimal therapeutic response.
- Oral administration will usually be carried out using tablets. Examples of doses in tablets are 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 250 mg, and 500 mg.
- Other oral forms can also have the same dosages (e.g. capsules).
- compositions which comprise a compound of Formula I and a pharmaceutically acceptable carrier.
- the pharmaceutical compositions of the present invention comprise a compound of Formula I or a pharmaceutically acceptable salt as an active ingredient, as well as a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
- pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.
- a pharmaceutical composition may also comprise a prodrug, or a pharmaceutically acceptable salt thereof, if a prodrug is administered.
- Pharmaceutical compositions may also consist essentially of a compound of Formula I and a pharmaceutically acceptable carrier without other thereapeutic ingredients.
- the compounds of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
- the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
- any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
- oral liquid preparations such as, for example, suspensions, elixirs and solutions
- carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparation
- tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
- the active compounds can also be administered intranasally as, for example, liquid drops or spray.
- the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
- a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
- Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both.
- a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
- Compounds of formula I may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
- the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
- the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
- the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
- Compounds of the invention may be used in combination with other drugs that may also be useful in the treatment or amelioration of the diseases or conditions for which compounds of Formula I are useful.
- Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I.
- Therapeutic compounds that can be administered with the compounds of this invention include compounds that are useful in improving a patient's lipid profile (i.e. raising HDL-C and lowering LDL-C).
- Preferred compound are statins, including simvastatin, lovastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, and ZD-4522.
- statins including simvastatin, lovastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, and ZD-4522.
- Particles used in the assay were created from the following sources: Synthetic donor HDL particles containing DOPC (Dioleoyl Phosphatidyl Choline), BODIPY®-CE (Molecular Probes C- 3927), triolein (a triglyceride), and apoHDL were essentially created by probe sonication as described by Epps et al, but with the addition of a non-diffusable quencher molecule, dabcyl dicetylamide, in order to reduce background fluorescence. Dabcyl dicetylamide was made by heating dabcyl n-succinimide with dicetylamine in DMF at 95 °C overnight in the presence of diisopropylamine catalyst.
- DOPC Dioleoyl Phosphatidyl Choline
- BODIPY®-CE Molecular Probes C- 3927
- triolein a triglyceride
- apoHDL a non-diff
- Native lipoproteins from human blood were used as acceptor particles. Particles having a density less than 1.063 g/ml were collected by ultracentrifugation. These particles include VLDL, DDL, and LDL. Particle concentrations were expressed in terms of protein concentration as determined by BCA assay (Pierce, USA). Particles were stored at 4°C until use.
- Assays were performed in Dynex Microfluor 2 U-bottom black 96-well plates (Cat #7205).
- An assay cocktail containing CETP, IX CETP buffer (50 mM Tris, pH 7.4, 100 mM NaCl, 1 mM EDTA), and half the final concentration of acceptor particles was prepared, and 100 ⁇ L of the assay cocktail was added to each well of the plate.
- Test compounds in DMSO were added in a volume of 3 ⁇ L. The plate was mixed on a plate shaker and then incubated at 25 0 C for 1 hour.
- a second assay cocktail containing donor particles, the remaining acceptor particles and IX CETP buffer was prepared. 47 ⁇ L of the second assay cocktail was added to the reaction wells to start the assay.
- Assays were performed at 25°C in a final volume of 150 ⁇ L. Final concentrations of materials were: 5 ng/ ⁇ L donor particles, 30 ng/ ⁇ L acceptor particles (each expressed by protein content), IX CETP buffer, 0.8 nM recombinant human CETP (expressed in CHO cells and partially purified), and up to 2% DMSO when testing compounds.
- Iodides 1-3 are prepared by treatment of 1-2 with isoamylnitrite, n-pentylnitrite, t-butyl nitrite or the like in the presence of diiodomethane (see for example: Smith et al., J. Org. Chem. 55, 2543, (1990) and references cited therein) either neat or in a solvent such as THF or acetonitrile.
- the iodide can be prepared first by diazonium formation using isoamylnitrite, n-pentylnitrite, t-butyl nitrite, sodium nitrite, nitrous acid or the like followed by heating in the presence of iodine or an iodide salt such as copper iodide, sodium iodide, potassium iodide, tetrabutylammonium iodide or the like.
- iodine or an iodide salt such as copper iodide, sodium iodide, potassium iodide, tetrabutylammonium iodide or the like.
- Reduction of 1-3 with DBBAL in dichloromethane affords aldehyde 1-4.
- Reduction of aldehyde 1-4 with sodium borohydride or the like in methanol or ethanol or the like gives alcohol 1-5.
- nitrile 2-2 Reduction of nitrile 2-2 is accomplished with lithium aluminum hydride in diethyl ether to afford 2-aminomethyl aniline 2-3.
- the nitrile can be reduced with palladium on carbon or Raney nickel under hydrogen atmosphere in methanol, ethanol or the like.
- Other methods for reduction of a nitrile to an aminomethyl group can be found in Smith, M. B. and March, J. "March's Advanced Organic Chemistry", 5 th Ed., John Wiley and Sons, New York, pp. 1204 (2001) and references therein.
- the reaction may be run with or without a base such as triethylamine, diisopropylethylamine, N-methylmorpholine, or the like.
- a base such as triethylamine, diisopropylethylamine, N-methylmorpholine, or the like.
- Reduction of the ester functionality of 3-2 affords amino alcohol 3-3.
- the preferred reducing reagent is LiAlH 4 , in a solvent such as ether, tetrahydrofuran, dimethoxyethane, dioxane, or the like.
- Other methods for reduction of an ester can be found in "March's Advanced Organic Chemistry" 5 th Ed., John Wiley and Sons, New York, pp 1551.
- Enantiopure products may be obtained via chiral chromotography.
- the epoxide may be made from epoxidation of an olefin, cyclization of a halohydrin or 1, 2-diol, or other methods described in "March's Advanced Organic Chemistry” 5 th Ed., John Wiley and Sons, New York, pp 1051.
- the preferred solvent for this reaction is isopropanol.
- the epoxide opening may be carried out in a solvent such as acetonitrile or the like with the aid of a Lewis Acid catalyst such as Yb(OTf)3 or the like.
- a solvent such as dichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane, or the like
- a base such
- aminoalcohol 4-2 can be converted to an appropriate carbamate by treatment with reagents such as dibenzyl dicarbonate or benzyl chloroformate in the presence of bases such as triethylamine, diisopropylethylamine or the like in solvents such as dichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane or the like.
- bases such as triethylamine, diisopropylethylamine or the like in solvents such as dichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane or the like.
- the carbamates can then be converted into oxazolidinones 4-3 by treating with bases like lithium-, sodium- or potassium hexamethyldisilazide in solvents like tetrahydrofuran, dimethoxyethane or the like.
- Enantiopure products may be obtained via chiral chromatography
- Protection of the nitrogen with a BOC or Cbz group can be carried out by reaction of 5-1 with di-t-butyldicarbonate or dibenzyldicarbonate in an appropriate solvent such as dichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane, or the like.
- Alcohol 5-2 can be converted to azide 5-3 by reaction with methanesulfonyl chloride in dichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane, or the like in the presence of an appropriate base such as triethylamine, diisopropylethylamine, N- methylmorpholine, or the like.
- the alcohol may be converted to an alternative leaving group, such as tosylate, iodide, bromide, or the like.
- the mesylate is then displaced by an azide source, such as NaN3, LiN3, BU4NN3 or the like in an appropriate solvent, such as DMF, DMPU, or the like.
- Azide 5-3 can also be prepared by treatment of alcohol 5-2 with diphenylphosphoryl azide, diethylazodicarboxylate and triphenylphosphine in THF. Azide 5-3 can be reduced by hydrogenation over a metal catalyst such as Pt ⁇ 2 or Pd/C or the like in an appropriate solvent, such as EtOAc, THF,
- Enantiopure products may be obtained via chiral chromatography.
- a solvent such as dichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane, or the like
- a base such as
- the alcohol may be converted to an alternative leaving group, such as tosylate, iodide, bromide, or the like.
- the mesylate is then displaced by an azide source, such as NaN3, UN3, BU4NN3 or the like in an appropriate solvent, such as DMF, DMPU, or the like.
- Azide 7-3 can also be prepared by treatment of alcohol 5-2 with diphenylphosphoryl azide, diethylazodicarboxylate and triphenylphosphine in THF.
- Azide 7-3 can be reduced to amine 7-4 with H2 over Pt ⁇ 2 with THF as a solvent when R4 is benzyl.
- Cyclization of 7-4 to imidazolidinones 7-5 is accomplished through the use of an appropriate base, such as lithium diisopropylamide or lithium-, sodium-, or potassium bis(trimethylsilyl)amide or the like in an appropriate solvent, such as THF, dimethoxyethane, DMF, DMA, or the like.
- an appropriate base such as lithium diisopropylamide or lithium-, sodium-, or potassium bis(trimethylsilyl)amide or the like
- an appropriate solvent such as THF, dimethoxyethane, DMF, DMA, or the like.
- Enantiopure products may be obtained via chiral chromatography.
- Compound 8-1 (prepared as described in Schemes 5, 6, and 7) wherein R, R a , A ⁇ , A3, p, and n are as defined in the claims can be converted to 8-2 by treatment with an appropriate alkylating agent such as an alkyl halide, alkyl tosylate, alkyl mesylate, or the like (for example methyl iodide) in an appropriate solvent such as THF, dimethoxyethane, DMF, DMA, or the like, in the presence of an appropriate base, such as lithium diisopropylamide or lithium-, sodium-, or potassium bis(trimethylsilyl)amide or the like.
- an appropriate alkylating agent such as an alkyl halide, alkyl tosylate, alkyl mesylate, or the like (for example methyl iodide) in an appropriate solvent such as THF, dimethoxyethane, DMF, DMA, or the like
- an appropriate base such as lithium diisopropyl
- Benzoic acids 9-2 can be reduced to benzyl alcohols 9-3 with reducing agents such as borane in solvents such as tetrahydrofuran or the like(See: Smith, M. B. and March, J. "March's Advanced Organic Chemistry", 5 th Ed., John Wiley and Sons, New York, pp. 1549 (2001) and references therein).
- 9-2 can be esterified by known methods including treatment with trimethylsilyldiazomethane and the resulting ester reduced to alcohol 9-3 with L1AIH4 or the like.
- Intermediates 9-3 can be transformed into benzyl bromides 9-4 using reagents such as triphenylphosphine and carbon tetrabromide in solvents such as dichloromethane, dichloroethane or the like (See: Smith, M. B. and March, J. "March's Advanced Organic Chemistry", 5 th Ed., John Wiley and Sons, New York, pp. 518-519 (2001) and references therein).
- solvents such as dichloromethane, dichloroethane or the like
- Nitroalcohols 10-2 can be reduced to aminoalcohols 10-3 with reductants such as Raney nickel, palladium on activated carbon or platinum oxide in the presence of hydrogen gas and aqueous acid in alcoholic solvents such as methanol, ethanol or the like (See: Langer, O., et ah, Bioorg. Med. Chem., 2001, 9, 677-694).
- reductants such as Raney nickel, palladium on activated carbon or platinum oxide
- bases such as triethylamine, diisopropylethylamine or the like in solvents like dichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane or the like.
- Compounds 13-4 are then prepared via a Suzuki or Stille reaction or variation thereof employing palladium catalyzed cross coupling of iodide 13-3 with an appropriately substituted aryl- or heteroaryl-boronic acid, -boronate ester or -trialkyl tin as described in Miyaua et al., Chem. Rev. 95, 2457 (1995) and references cited within and as described in Smith, M. B. and March, J. "March's Advanced Organic Chemistry", 5 th Ed., John Wiley and Sons, New York, pp. 868-869 (2001) and references cited therein.
- 2-Amino-l-phenylethanols 14-3 can be prepared from 14-2 via the corresponding silylated cyanohydrin by treatment with trimethylsilyl cyanide and catalytic zinc iodide followed by reduction with lithium aluminum hydride or the like reducing agent.
- 2-amino-l-phenylethanols 14-3 can be prepared from 14-2 via the corresponding cyanohydrin by treatment with potassium cyanide followed by reduction.
- Oxazolidinones 14-4 can be alkylated with alkyl, heteroalkyl, aryl, or heteroaryl bromides using bases such as sodium hexamethyldisiliazide or sodium hydride in solvents like tetrahydrofuran, dimethoxyethane, diethyl ether or the like to afford products 14-5.
- Enantiopure products may be obtained via chiral chromatography.
- Nitroalcohols 15-2 can be reduced to aminoalcohols 15-3 with reductants such as Raney nickel, palladium on activated carbon, or platinum oxide in the presence of hydrogen gas and aqueous acid in alcoholic solvents such as methanol, ethanol or the like (See: Langer, O., et al., Bioorg. Med. Chenu, 2001, 9, 677-694).
- reductants such as Raney nickel, palladium on activated carbon, or platinum oxide
- alcoholic solvents such as methanol, ethanol or the like
- bases such as triethylamine, diisopropylethylamine or the like in solvents like dichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane or the like.
- Oxazolidinones 15-5 are prepared via a Suzuki or Stille reaction or variation thereof employing palladium catalyzed cross coupling of iodides 15-4 with appropriately substituted aryl- or heteroaryl- boronic acids, -boronate esters or -trialkyl tin compounds, as described in Miyaura et al., Chem. Rev. 95, 2457 (1995) and references cited within, and as described in Smith, M. B. and March, J. "March's Advanced Organic Chemistry", 5 th Ed., John Wiley and Sons, New York, pp. 868-869 (2001) and references cited therein.
- Oxazolidinones 15-5 can be alkylated with alkyl, heteroalkyl, aryl, or heteroaryl bromides using bases such as sodium hexamethyldisiliazide or sodium hydride in solvents like tetrahydrofuran, dimethoxyethane, diethyl ether or the like to afford products 15-6.
- Enantiopure products may be obtained via chiral chromatography.
- Compounds 16-2 can be hydrolyzed to the corresponding acids and then treated with diphenylphosphorazidate and a trialkylamine base to effect a Curtius rearrangement, affording chiral oxazolidinones 16-3.
- Oxazolidinones 16-4 are prepared via a Suzuki or Stille reaction or variation thereof employing palladium catalyzed cross coupling of iodides 16-3 with appropriately substituted aryl- or heteroaryl-boronic acids, -boronate esters or -trialkyl tin compounds, as described in Miyaura et al., Chem. Rev. 95, 2457 (1995) and references cited within, and as described in Smith, M. B. and March, J.
- Oxazolidinones 16-4 can be alkylated with alkyl, heteroalkyl, aryl, or heteroaryl bromides using bases such as sodium hexamethyldisiliazide or sodium hydride in solvents like tetrahydrofuran, dimethoxyethane, diethyl ether or the like to afford products 16-5.
- oxazolidinones 16-3 are alkylated with the appropriate bromides to afford compounds 16-6, which are subjected to a Suzuki or Stille reaction or variation thereof with appropriately substituted aryl- or heteroaryl-boronic acids, -boronate esters or -trialkyl tin compounds to afford products 16-5.
- Step A methyl r3,5-bis(trifluoromethyl)phenyri(hvdroxy)acetate
- Step B methyl r3,5-bis(trifluoromethyl)phenyll(bromo)acetate
- Step C methvir3,5-bis(trifluoromethyl)phenyll( ⁇ r5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2- yll methyl 1 amino)acetate
- Step D 2-r3,5-bis(trifluoromethyl)phenyll-2-( ⁇ r5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2- yllmethyl I amino)ethanol
- Step E 4-r3,5-bis(trifluoromethyl)phenyll-3-lf5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2- y limethy 11-1,3 -oxazolidin-2-one
- phosgene 21 ⁇ L of a 20% solution in toluene, ⁇ 0.0535 mmol
- CH2CI2 0.5 mL
- 2-[3,5-bis(trifluoromethyl)phenyl]-2-( ⁇ [5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2- yl]methyl ⁇ amino)ethanol 3. mg, 0.00535 mmol
- CH2CI2 0.5 mL
- Step A 2-r3,5-bis(trifluoromethyl ' )phenylloxirane
- NaH 1.09 g of 60% NaH, 27.27 mmol
- DMSO 90 mL
- trimethylsulfoxonium iodide 7.0 g, 31.82 mmol
- the reaction was stirred for 5 minutes and then 3,5-bis(trifluoromethyl)benzaldehyde (1.5 mL, 9.09 mmol) was added as a solution in DMSO (15 mL).
- the reaction was stirred at room temperature for 1 hour and then poured into ice/water (300 mL). The mixture was extracted with pentanes (3 x 150 mL).
- Step B l-r3,5-bis(trifluoromethyl)phenyl1-2-( ⁇ r5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2- yll methyl ) amino)ethanol
- Step C 5-[3.5-bis(trifluoromethyl)phenyll-3-(r5'-isopropyl-2'-methoxy-4-rtrifluoromethyl)biphenyl-2- yll methyl ⁇ - 1 ,3-oxazolidin-2-one
- the 2 enantiomers could be separated by chiral HPLC using 15% EPA/heptanes and an AD chiral column.
- Step A 2-(
- Step B Benzyl (2-hydroxy-2-pyridin-2-ylethyl) ⁇ r5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2- ylimethyl ) carbamate
- Step C 3-ir5'-Isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-vnmethyl
- a solution of potassium bis(trimethylsilyl)amide (464 ⁇ L of a 0.5M solution in toluene, 0.232 mmol) was added dropwise to a stirred solution of benzyl (2-hydroxy-2-pyridin-2-ylethyl) ⁇ [5'-isopropyl-2'- methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl ⁇ carbamate (134.3 mg, 0.232 mmol) in dry THF (10 mL) at room temperature under N2- After stirring at room temperature for 1 h, the reaction was quenched with saturated NH4CI (10 mL) and extracted with EtOAc (3 x 20 mL).
- This compound was separated into its two enantiomers (4S, 5R)-5-[3,5- bis(trifluoromethyl)phenyl]-4-methyl-l,3-oxazolidin-2-one and (4R, 5S)-5-[3,5- bistrifluoromethyl)phenyl]-4-methyl-l,3-oxazolidin-2-one using chiral HPLC (AS column, 20 x 250 mm, 15% ⁇ -PrOH in heptane).
- the Weinreb amide from Step 1 (6kg, 22.5 mol) and 3,5-bis(trifluoromethyl)bromobenzene (4.85L, 28.1 mol) are dissolved in anhydrous THF (24L).
- the solution is purged with nitrogen to remove distilled oxygen.
- the solution is cooled to -1O 0 C and iso-PrMgCl in THF (56.4 mol) is slowly added (2 hours) to the reaction via addition funnel, maintaining a reaction temperature ⁇ - 5 0 C.
- the solution is allowed to warm to 20 0 C and aged overnight at 20° C.
- the reaction is then cooled to -10 0 C under nitrogen and is quenched slowly over 2 hours into 5N HCl (14L) that is maintained at 0-5 0 C.
- MTBE 60L is added and the biphasic mixture is agitated for 5 min. After warming to 20°-25°C, it is allowed to settle for 30 min, and then the layers are separated. The organic layer is washe
- the organic layer is vacuum transferred through a 1 -micron in-line PTFE filter into a distillation flask and is then concentrated to ⁇ 12L under vacuum (internal temperature ⁇ 40°C). Heptane is added and the distillation is continued under vacuum at 40°-55°C until the final volume is 4OL.
- the solution is cooled to 35°-37°C , seeded (-0.5%, 30gms) and then aged for 30min to allow for a full seed bed to grow.
- the slurry is cooled to 10°C over 2-3 hrs.
- the slurry is then filtered, washed with 5°C heptane (18L), and allowed to dry fully on the Filter pot using a vacuum/nitrogen sweep overnight.
- the dried solid is obtained with >99.9ee%.
- the amide can be recrystallized from straight heptane if the optical purity is not sufficient.
- TFA (9L) is added to a 100 L Buchi reactor under an inert atmosphere and is cooled to -5°C.
- the ketone product from Step 2 (5.50 kg, 13.1 mol) is added as a solid followed by a TFA rinse (2
- the reaction is quenched with ⁇ 2 L of the 50w/w% KOH solution with vigorous stirring and cooling, keeping temp at -20 0 C.
- Cold THF (16.5L, previously stored in freezer) is added, followed by slow addition of the remainder of the KOH solution (-13.7 L), followed by a 2 L water rinse while keeping temp ⁇ 20 0 C.
- the reaction is aged at room temperature.
- the reaction is quenched after 3 h with 27.5 L PAC and 20 L 20%w/v aq NaCl.
- the aqueous and organic layers are separated.
- the organic layer is washed with 26 L of 20%w/v aq NaCl, then with 36 L water, then with 31 L 0.5 N HCl, and finally with 32 L of water.
- the organic layer is concentrated to -10 L.
- Heptane (20 L) is added, yielding crystals.
- the organic layer is concentrated to -10 L.
- Heptane (20L) is added again, and the organic layer is concentrated to -10 L.
- Heptane (22 L) is added and the slurry is aged at rt.
- the solid is filtered and washed with 24 L heptane.
- a solid product is obtained (98.8% purity, >99.95%ee, by LC).
- the solid is then re-dissolved in 12.5 L MeOH (endothermic). At rt, 3 L water is added, and the mixture is aged to initiate crystallization. Water (9.5 L) is added over ⁇ 60min at rt. After aging for 60min, the slurry is filtered and the solid is washed with 5 L MeOH/water (1/1.5), 5 L MeOH/water (1/4) and then 4 L water. The solid product is dried at 50° C under vacuum (99.9% pure by LC, >99.95%ee).
- Step A terf-butyl ⁇ 2-r3,5-bis(trifluoromethyl)phenyll-2-hydroxyethylH r5'-isopropyl-2'-methoxy-4-
- Step B l-r3,5-bis(trifluoromethyl)phenyll-2-((ferf-butoxycarbonyl) ⁇ r5'-isopropyl-2'-methoxy-4- (trifluoromethyl)biphenyl-2-vnmethyl I amincOethyl methanesulfonate
- Step C terf-butvH 2-azido-2-r3,5-bis(trifluoromethyl)phenyllethyl I ⁇ r5'-isopropyl-2'-methoxy-4- (trifluoromethyl)biphenyl-2-vnmethyl 1 carbamate
- Step D mixture of fers-butyl
- Step E l-r3,5-bis(trifluoromethyl)phenyll- N 2 - ⁇ r5'-isopropyl-2'-methoxy-4-(trifluoromethyDbiphenyl-2- y 11 methyl ⁇ ethane- 1 ,2-diamine
- tert-butyl ⁇ 2-amino-2-[3,5- bis(trifluoromethyl)phenyl]ethyl ⁇ [5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2- yl]methyl ⁇ carbamate and tert-butyl [l-[3,5-bis(trifluoromethyl)phenyl]-2-( ⁇ [5'-isopropyl-2'-methoxy-4- (trifluoromethyl)biphenyl-2-yl]methyl ⁇ amino)ethyl]carbamate in CH
- Step F 4-r3,5-bis(trifluoromethyl)phenyll-l- ⁇ r5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2- yll methyl ) imidazolidin-2-one
- the two enantiomers of this compound could be separated using an AD chiral column with 5% ⁇ Wheptanes.
- Step A ferf-butyl l(li?)-2-hydroxy-l-phenylethy 11 carbamate
- Step B fe?t-butyl r(l/?)-2-oxo-l-phenylethvHcarbamate
- CH2CI2 20 mL
- Dess-Martin periodinane 447 mg, 1.05 mmol
- the reaction was stirred at 0 0 C for 15 minutes and then at room temperature for 30 minutes.
- the reaction was then diluted with EtOAc (75 mL) and washed rapidly with 10% K2CO3 (2 x 30 mL). The organic layer was dried over Na2SO4, filtered, and concentrated.
- Step C fer?-butyir(li?)-2-( ⁇ r5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-vnmethyl)amino)-l- phenylethyll carbamate
- Step D (lJ?)-N2- ⁇ r5'-isopropyl-2'-methoxy-4-(trifluoromethyl ' )biphenyl-2-yllmethyl
- Step E (4i?)-l- ⁇ r5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-vnmethyl)-4- phenylimidazolidin-2-one.
- Step B benzyl r2-(4-chlorophenylV2-hydroxyethyni r5'-isopropyl-2'-methoxy-4- (trifluoromethyl)biphenyl-2-vH methyl I carbamate
- Step C benzyl r2-azido-2-(4-chlorophenyl)ethyn I r5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl- 2-yll methyl ⁇ carbamate
- Step D benzyl r2-amino-2-(4-chlorophenyl)ethyl] I r5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl- 2-yllmethyl ⁇ carbamate
- benzyl [2-azido-2-(4-chlorophenyl)ethyl] ⁇ [5'-isopropyl-2'-methoxy-4- (trifluoromethyl)biphenyl-2-yl]methyl ⁇ carbamate (30 mg, 0.05 mmol) in THF (1 mL) was added Pt ⁇ 2 (8 mg) and the reaction was stirred at room temperature under hydrogen for 1 hour.
- Step E 4-(4-chlorophenvD-l-i r5'4sopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2- ylimethyl ⁇ imidazolidin-2-one
- Step B 5'-isopropyl-2'-methoxy-4-(trifluorornethyl')biphenyl-2-carbaldehvde
- a solution of 0.725 g of [5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol in 10 mL of CH2CI2 was added 1.14 g of Dess-Martin periodinane. The mixture was stirred at room temperature for 30 min, then filtered and concentrated.
- Step C 2-amino-l-r5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl1ethanol
- a solution of 0.679 g of 5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbaldehyde in 1.5 mL of CH2CI2 was added ca. 5 mg of Znl2, then 0.23 g of trimethylsilyl cyanide.
- the mixture was stirred at room temperature for 3 h, and then partitioned between 15 mL of water and 10 mL of Et2 ⁇ .
- the aqueous phase was extracted with 2 x 10 mL of Et2 ⁇ .
- Step D 5-r5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yll-l ,3-oxazolidin ⁇ 2-one
- Step B (4S)-4-benzyl-3-ir5'-isopropyl-2'-methoxy-4-(trifluoromehtyl)biphenyl-2-vnmethyl ⁇ -13- oxazolidin-2-one.
- the ether layer was then dried over anhydrous MgSO 4 , filtered and concentrated.
- the material is chromatographed on SiO 2 using a step gradient of 1:3 CH 2 Cl 2 /hexanes, then 1: 1 CH 2 Cl 2 /hexanes, then 100% CH 2 Cl 2 to afford [2-iodo-5-(trifluoromethyl)phenyl]methanol as a white solid.
- Carbon tetrabromide (1.86 g; 5.6 mmol) and triphenylphosphine (1.47 g; 5.6 mmol) were added successively to a stirred solution of [2-iodo-5-(trifluoromethyl)phenyl]methanol (1.13 g; 3.74 mmol) in CH2CI2 (25 mL) at 0°C under N2.
- the reaction was stirred at room temperature for 48 h.
- a second equivalent of carbon tetrabromide (1.2 g; 3.74 mmol) and triphenylphosphine (0.98 g; 3.74 mmol) was added and the reaction was stirred an additional 14 h.
- the racemic material was separated by chiral HPLC using 15% IP A/heptane and an OD column into its two enantiomers.
- Step l (4S,5R)-5-r3.5-bis(trifluoromethvDphenyll-3-12-iodo-5-(trifluoromethyDbenzyll-4-methyl-L3- oxazolidin-2-one
- Step 2 (4S,5R)-5-r3.5-bis(trifluorometr ⁇ vnphenyl1-3- ⁇ r4'-fluoro-5'isopropyl-2'-methoxy-4- (trifluoromethyDbiphenyl-2-yll methyl ⁇ -4-methyl- 1 ,3 -oxazolidin-2-one
- Step A (4S,5S)-5-r3,5-bis(trifluoromethyl)phenyri-3- ⁇ r5'-isopropyl-2'-methoxy-4-
- Step B (15,2.y)-l-r3,5-bis(trifluoromethyl)phenyll-2-(( r5'-isopropyl-2'-methoxy-4- (trifluoromethyl)biphenyl-2-yllmethyl ⁇ amino)propan-l-ol.
- Step C fer?-butyl ⁇ (l l S,25)-2-r3,5-bis(trifluoromethyl)phenyn-2-hydroxy-l-methylethy ⁇ r5'-isopropyl-
- Step D fe?t-butyl ⁇ (l l S,2J?)-2-azido-2-r3,5-bis(trifluoromethyl)phenvn-l-methylethyll ⁇ r5'-isopropyl-2'- methoxy-4-(trifluoromethyl)biphenyl-2-yllmethyl ⁇ carbamate.
- Step E (IR, 2SVl-azido4-r3,5-bis(trifluoromethyl)phenyl1-N- ⁇ r5'-isopropyl-2'-methoxy-4-
- Step F (lR,2S)-l-r3,5-bis(ttifluoromethvDphenyri-N 2 - ⁇ r5'-iso ⁇ ro ⁇ yl-2'-methoxy-4- (trifluoromethyl)biphenyl-2-yllmethyllpropane-l,2-diamine.
- Step G (4R,5S)-4-r3,5-bis(trifluoromethyl)phenyl1-l-l r5'-isopropyl-2'-methoxy-4-
- Reaction mixture was allowed to warm to room temperature for one hour, quenched with acetic acid ( ⁇ 80ml) where color change was observed from yellow to off white and stirred for 30 minutes (pH ⁇ 7)(slight exotherm noted).
- the mixture was concentrated to a slush, diluted with 7:2 hexane:ethyl acetate, and was allowed to sit overnight. Solids were removed by filtration and the filtrate was concentrated to yellow oil.
- the title compound was obtained after flash column using 9: 1 hexane:ethyl as the eluant.
- Step B (4S,5R)-5-r3,5-bis(trifluoromethyl)phenvn-3-(2-bromo-5-chlorobenzyl)-4-methyl-l,3-oxazolidin-
- trans-3-r3,5-bis(trifluoromethyl)benzyll-5-r5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yll-4- methyl-l,3-oxazolidin-2-one (racemic)
- Step B (4i?,5 J R)-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl- 1 ,3-oxazolidin-2-one
- Step B (45,55)-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-l ,3-oxazolidin-2-one
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Priority Applications (10)
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MX2007000035A MX2007000035A (en) | 2004-07-02 | 2005-07-01 | Cetp inhibitors. |
BRPI0512910-9A BRPI0512910A (en) | 2004-07-02 | 2005-07-01 | compound, use of same, method to raise hdl-c in a patient in need of treatment, and, pharmaceutical composition |
KR1020077000039A KR101204336B1 (en) | 2004-07-02 | 2005-07-01 | CETP inhibitors |
EA200700259A EA011130B1 (en) | 2004-07-02 | 2005-07-01 | Cetp inhibitors |
NZ552061A NZ552061A (en) | 2004-07-02 | 2005-07-01 | CETP Inhibitors |
IL180432A IL180432A (en) | 2004-07-02 | 2006-12-28 | Cetp inhibitors and pharmaceutical compositions comprising the same for treating atherosclerosis |
TNP2006000456A TNSN06456A1 (en) | 2004-07-02 | 2006-12-29 | Cetp inhibitors |
EGNA2007000001 EG27138A (en) | 2004-07-02 | 2007-01-03 | Derivatives of 5-membered nitrogen-containing hetero cycle as cholesteryl ester transfer protein inhibitors |
NO20070607A NO339808B1 (en) | 2004-07-02 | 2007-02-01 | A compound or a pharmaceutically acceptable salt thereof which is CETP inhibitors, its pharmaceutical composition, and its use for the manufacture of a medicament for the treatment of atherosclerosis. |
IL217530A IL217530A0 (en) | 2004-07-02 | 2012-01-12 | Cetp inhibitors |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7270971B2 (en) * | 2003-10-16 | 2007-09-18 | Merck & Co., Inc. | Fluorescence assay for measuring the rate of cholesterol ester transfer |
WO2007081569A2 (en) * | 2005-12-30 | 2007-07-19 | Merck & Co., Inc. | Cetp inhibitors |
WO2007079186A2 (en) * | 2005-12-30 | 2007-07-12 | Merck & Co., Inc. | 1, 3-oxazolidin-2-one derivatives useful as cetp inhibitors |
AU2006335109B2 (en) * | 2005-12-30 | 2011-04-07 | Merck Sharp & Dohme Corp. | Cholesteryl ester transfer protein inhibitors |
WO2007081571A2 (en) * | 2005-12-30 | 2007-07-19 | Merck & Co., Inc. | Cetp inhibitors |
WO2008082567A1 (en) * | 2006-12-29 | 2008-07-10 | Merck & Co., Inc. | Process for synthesizing a cetp inhibitor |
ES2559838T3 (en) | 2007-03-16 | 2016-02-16 | Concert Pharmaceuticals, Inc. | Cholesterol ester transfer protein inhibitors |
CN102015606B (en) | 2007-06-08 | 2015-02-04 | 满康德股份有限公司 | IRE-1a inhibitors |
JP2010530417A (en) * | 2007-06-20 | 2010-09-09 | メルク・シャープ・エンド・ドーム・コーポレイション | CETP inhibitors derived from benzoxazole arylamides |
AU2008266957A1 (en) * | 2007-06-20 | 2008-12-24 | Merck Sharp & Dohme Corp. | CETP inhibitors derived from benzoxazole arylamides |
CA2689575A1 (en) * | 2007-06-20 | 2008-12-24 | Merck Sharp & Dohme Corp. | Cetp inhibitors derived from benzoxazole arylamides |
RU2010103104A (en) | 2007-07-02 | 2011-08-10 | Ф.Хоффманн-Ля Рош Аг (Ch) | IMIDAZOLE DERIVATIVES AS CCR2 RECEPTOR ANTAGONISTS |
ATE554078T1 (en) * | 2007-07-26 | 2012-05-15 | Vitae Pharmaceuticals Inc | SYNTHESIS OF 11-BETA-HYDROXYSTEROID DEHYDROGENASE-1 INHIBITORS |
TW200934490A (en) * | 2008-01-07 | 2009-08-16 | Vitae Pharmaceuticals Inc | Lactam inhibitors of 11 &abgr;-hydroxysteroid dehydrogenase 1 |
US8592409B2 (en) * | 2008-01-24 | 2013-11-26 | Vitae Pharmaceuticals, Inc. | Cyclic carbazate and semicarbazide inhibitors of 11β-hydroxysteroid dehydrogenase 1 |
JP5538356B2 (en) * | 2008-03-18 | 2014-07-02 | ヴァイティー ファーマシューティカルズ,インコーポレイテッド | Inhibitors of 11β-hydroxysteroid dehydrogenase type 1 |
AR071236A1 (en) | 2008-05-01 | 2010-06-02 | Vitae Pharmaceuticals Inc | CYCLE INHIBITORS OF 11BETA-HYDROXIESTEROID DEHYDROGENASE 1 |
EP2291370B1 (en) | 2008-05-01 | 2013-11-27 | Vitae Pharmaceuticals, Inc. | Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
US8063088B2 (en) * | 2008-06-11 | 2011-11-22 | Hoffmann-La Roche Inc. | Imidazolidine derivatives |
DE102008049675A1 (en) | 2008-09-30 | 2010-04-01 | Markus Dr. Heinrich | Process for the preparation of 3-aminobiphenyls |
WO2010039474A1 (en) * | 2008-10-01 | 2010-04-08 | Merck Sharp & Dohme Corp. | Prodrugs of oxazolidinone cetp inhibitors |
JP2011057661A (en) | 2009-08-14 | 2011-03-24 | Bayer Cropscience Ag | Pesticidal carboxamides |
EP2397473A1 (en) | 2010-06-14 | 2011-12-21 | LEK Pharmaceuticals d.d. | A stable highly crystalline anacetrapib |
EP2632269B1 (en) | 2010-10-29 | 2017-03-15 | Merck Sharp & Dohme Corp. | Cyclic amine substituted oxazolidinones as cetp inhibitors |
CA2840985A1 (en) | 2011-07-07 | 2013-01-10 | Mochida Phamaceutical Co., Ltd. | Anti-obesity agent comprising high-purity epa |
AU2012282109B2 (en) | 2011-07-08 | 2016-06-23 | Novartis Ag | Method of treating atherosclerosis in high triglyceride subjects |
JO3210B1 (en) | 2011-10-28 | 2018-03-08 | Merck Sharp & Dohme | Fused bicyclic oxazolidinone cetp inhibitor |
WO2013064188A1 (en) | 2011-11-03 | 2013-05-10 | Lek Pharmaceuticals D.D. | A stable highly crystalline anacetrapib |
EP2844252B1 (en) * | 2012-05-02 | 2016-11-30 | Merck Sharp & Dohme Corp. | Cyclic amine substituted heterocyclic compounds as cetp inhibitors |
MX347400B (en) | 2012-06-29 | 2017-04-18 | Univ Nac Autónoma De México | Nasal vaccine against the development of atherosclerosis disease and fatty liver. |
CN103958484B (en) * | 2012-07-19 | 2015-11-25 | 上海恒瑞医药有限公司 | Oxazolidone analog derivative, its preparation method and in application pharmaceutically |
WO2014099836A1 (en) | 2012-12-19 | 2014-06-26 | Merck Sharp & Dohme Corp. | Spirocyclic cetp inhibitors |
EP2934519B1 (en) | 2012-12-20 | 2021-05-12 | Merck Sharp & Dohme Corp. | Therapeutic thiazolidinone compounds |
WO2014111953A1 (en) * | 2013-01-17 | 2014-07-24 | Glenmark Pharmaceuticals Limited; Glenmark Generics Limited | Process for preparation of anacetrapib and intermediates thereof |
US9981970B2 (en) | 2013-07-30 | 2018-05-29 | Merck Sharp & Dohme Corp. | Bicyclic ureas and thiadiazolidine-1, 1-dioxides as CETP inhibitors |
EP3054945B1 (en) | 2013-10-10 | 2018-08-15 | Merck Sharp & Dohme Corp. | 3,3'-disubstituted indolines as inhibitors of cholesterol ester transfer protein |
US9663534B2 (en) | 2013-12-17 | 2017-05-30 | Merck Sharp & Dohme Corp. | Fused bicyclic isoxazolines as inhibitors of cholesterol ester transfer protein |
CN104955816B (en) * | 2014-01-14 | 2016-08-31 | 杭州普晒医药科技有限公司 | Crystal formation that a kind of Ansai is bent and preparation method thereof, its pharmaceutical composition and purposes |
CN103923030B (en) * | 2014-03-27 | 2015-07-22 | 汕头经济特区鮀滨制药厂 | Synthesis method of key intermediate of anacetrapib |
CN103923031A (en) * | 2014-04-01 | 2014-07-16 | 汕头经济特区鮀滨制药厂 | Synthetic method of anacetrapib intermediate |
WO2016018729A1 (en) * | 2014-07-29 | 2016-02-04 | Merck Sharp & Dohme Corp. | Monocyclic isoxazolines as inhibitors of cholesterol ester transfer protein |
CN104230835B (en) * | 2014-09-01 | 2017-01-25 | 福建师范大学 | Method for synthesizing N-styryl oxazolidine-2-ketone derivative |
WO2016067194A1 (en) * | 2014-10-27 | 2016-05-06 | Sun Pharmaceutical Industries Limited | Process for the preparation of anacetrapib and an intermediate thereof |
CN106032362B (en) * | 2015-03-10 | 2018-06-19 | 湖南千金湘江药业股份有限公司 | The preparation method of Ansai Qu |
WO2018016743A1 (en) * | 2016-07-19 | 2018-01-25 | 재단법인 대구경북첨단의료산업진흥재단 | Oxazolidinone derivative compound as cetp inhibitor |
CN109563019A (en) * | 2016-08-17 | 2019-04-02 | 诺华股份有限公司 | The new method and intermediate of nep inhibitor synthesis |
CN106496154A (en) * | 2016-10-18 | 2017-03-15 | 湖南德魅信息技术有限公司 | The preparation method of Ansai Qu |
WO2019043018A1 (en) | 2017-08-29 | 2019-03-07 | Dalcor Pharma Uk Ltd., Stockport Zug Branch | Methods for treating or preventing cardiovascular disorders and lowering risk of cardiovascular events |
JOP20180092A1 (en) | 2017-10-13 | 2019-04-13 | Gilead Sciences Inc | Hiv protease inhibitors |
SG11202101086YA (en) | 2018-08-09 | 2021-03-30 | Dalcor Pharma Uk Ltd Leatherhead | Methods for delaying occurrence of new-onset type 2 diabetes and for slowing progression of and treating type 2 diabetes |
KR20210137442A (en) | 2019-03-07 | 2021-11-17 | 달코어 파마 유케이 리미티드 레더헤드 저그 브랜치 | How to treat or prevent heart failure and reduce the risk of heart failure |
TW202104210A (en) | 2019-04-17 | 2021-02-01 | 美商基利科學股份有限公司 | Hiv protease inhibitors |
CA3148300A1 (en) | 2019-07-19 | 2021-01-28 | Biosynth Ag | Method of making nicotinamide ribofuranoside salts, nicotinamide ribofuranoside salts as such, and uses thereof |
KR102651062B1 (en) * | 2020-10-08 | 2024-03-25 | 재단법인 대구경북첨단의료산업진흥재단 | Aminoalcohol derivatives as PCSK9 inhibitor and pharmaceutical composition comprising the same for preventing or treating hypercholesterolemia |
WO2023278698A1 (en) * | 2021-06-30 | 2023-01-05 | Apellis Pharmaceuticals, Inc. | Complement inhibition |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0605729A1 (en) * | 1992-04-30 | 1994-07-13 | Taiho Pharmaceutical Co., Ltd. | Oxazolidine derivative and pharmaceutically acceptable salt thereof |
WO1999015487A1 (en) * | 1997-09-19 | 1999-04-01 | Bayer Aktiengesellschaft | Benzyl-biphenyls and analogous compounds and the application thereof in order to treat arteriosclerosis and dyslipidaemia |
Family Cites Families (38)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4179442A (en) * | 1975-08-29 | 1979-12-18 | York Hartleben | 4-(Alpha-hydroxy-isopropyl)-5-phenyl-oxazolidin-2-one |
DE2655369A1 (en) * | 1976-12-03 | 1978-06-08 | Schering Ag | 5- (SUBST. PHENYL) -OXAZOLIDINONE AND THEIR SULFUR ANALOGS AND PROCESS FOR THEIR PRODUCTION |
US4851423A (en) | 1986-12-10 | 1989-07-25 | Schering Corporation | Pharmaceutically active compounds |
HU203330B (en) * | 1987-06-10 | 1991-07-29 | Pfizer | Process for producing oxazolidin-2-one derivatives and hypoglychemic pharmaceutical compositions containing them |
WO1995010508A1 (en) * | 1993-10-15 | 1995-04-20 | Shionogi & Co., Ltd. | Oxazolinone derivative having intracellular phospholipase a2 inhibitor activity |
US5482971A (en) * | 1993-10-01 | 1996-01-09 | American Cyanamid Company | Beta3 -adrenergic agents and their use in pharmaceutical compositions |
AU699085B2 (en) * | 1994-04-21 | 1998-11-19 | Schering Aktiengesellschaft | PDE IV inhibitors for treating Multiple Sclerosis |
FR2729954B1 (en) * | 1995-01-30 | 1997-08-01 | Sanofi Sa | SUBSTITUTED HETEROCYCLIC COMPOUNDS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
JPH11500110A (en) * | 1995-02-10 | 1999-01-06 | シエーリング アクチエンゲゼルシヤフト | TNF-suppressing preparation |
PL323498A1 (en) * | 1995-05-17 | 1998-03-30 | Du Pont | Cyclic amides acting as fungicides |
US5612363A (en) | 1995-06-02 | 1997-03-18 | Berlex Laboratories, Inc. | N,N-di(aryl) cyclic urea derivatives as anti-coagulants |
MX9710259A (en) | 1995-06-20 | 1998-03-29 | Du Pont | Arthropodicidal and fungicidal cyclic amides. |
US5846990A (en) * | 1995-07-24 | 1998-12-08 | Bristol-Myers Squibb Co. | Substituted biphenyl isoxazole sulfonamides |
US6310095B1 (en) * | 1995-11-06 | 2001-10-30 | University Of Pittsburgh | Inhibitors of protein isoprenyl transferases |
WO1997028149A1 (en) | 1996-02-02 | 1997-08-07 | Merck & Co., Inc. | Method for raising hdl cholesterol levels |
DE19647380A1 (en) * | 1996-11-15 | 1998-05-20 | Hoechst Ag | 5-ring heterocycles as inhibitors of leukocyte adhesion and VLA-4 antagonists |
WO1998023155A1 (en) | 1996-11-26 | 1998-06-04 | E.I. Du Pont De Nemours And Company | Arthropodicidal and fungicidal cyclic amides |
DE19704243A1 (en) * | 1997-02-05 | 1998-08-06 | Bayer Ag | New 2-amino-substituted pyridines |
DK0966447T3 (en) * | 1997-03-03 | 2003-06-23 | Boehringer Ingelheim Pharma | Useful small molecules for the treatment of inflammatory diseases |
AU7473398A (en) | 1997-05-07 | 1998-11-27 | University Of Pittsburgh | Inhibitors of protein isoprenyl transferases |
EP1049682A1 (en) | 1998-01-23 | 2000-11-08 | Versicor, Inc. | Oxazolidinone combinatorial libraries, compositions and methods of preparation |
DE19816880A1 (en) * | 1998-04-17 | 1999-10-21 | Boehringer Ingelheim Pharma | New diaryl substituted heterocyclic compounds are AMPA receptor antagonists useful in treatment of neurodegenerative disorders and cerebral ischemia |
GT199900147A (en) | 1998-09-17 | 1999-09-06 | 1, 2, 3, 4- TETRAHIDROQUINOLINAS 2-SUBSTITUTED 4-AMINO SUBSTITUTED. | |
EP1216228B1 (en) | 1999-09-17 | 2008-10-29 | Millennium Pharmaceuticals, Inc. | BENZAMIDES AND RELATED INHIBITORS OF FACTOR Xa |
HN2000000203A (en) * | 1999-11-30 | 2001-06-13 | Pfizer Prod Inc | PROCEDURE FOR OBTAINING 1,2,3,4-TETRAHYDROQUINOLINS 4-CARBOXYAMIN-2-SUBSTITUTED. |
US6462063B1 (en) | 2000-02-04 | 2002-10-08 | Fibrogen, Inc. | C-proteinase inhibitors |
WO2001072723A1 (en) | 2000-03-28 | 2001-10-04 | Nippon Soda Co.,Ltd. | Oxa(thia)zolidine derivative and anti-inflammatory drug |
ATE349425T1 (en) * | 2000-12-21 | 2007-01-15 | Sanofi Aventis Deutschland | NEW DIPHENZYLAZETIDINONES, METHOD FOR THE PRODUCTION THEREOF, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS AND THEIR USE FOR THE TREATMENT OF LIPID METABOLISM DISORDERS |
CN1639136A (en) | 2001-09-11 | 2005-07-13 | 阿斯特拉曾尼卡有限公司 | Oxazolidinone and/or isoxazoline as antibacterial agents |
RU2340600C2 (en) * | 2001-10-16 | 2008-12-10 | Мемори Фармасьютиклз Корпорейшн | Derivatives of 4-(4-alkoxy-3-hydroxyphenyl)-2-pyrrolidone as pde-4 inhibitors for treatment of neurological syndromes |
TW200420573A (en) * | 2002-09-26 | 2004-10-16 | Rib X Pharmaceuticals Inc | Bifunctional heterocyclic compounds and methods of making and using same |
MXPA05009848A (en) | 2003-03-17 | 2005-12-06 | Japan Tobacco Inc | Pharmaceutical compositions of cetp inhibitors. |
UA90269C2 (en) | 2004-04-02 | 2010-04-26 | Мицубиси Танабе Фарма Корпорейшн | Tetrahydroquinoline derivatives and a process for preparing the same |
DOP2005000123A (en) * | 2004-07-02 | 2011-07-15 | Merck Sharp & Dohme | CETP INHIBITORS |
US8580752B2 (en) | 2005-03-31 | 2013-11-12 | Council Of Scientitic And Industrial Research | Aromatic amides as potentiators of bioefficacy of anti-infective drugs |
WO2007081569A2 (en) * | 2005-12-30 | 2007-07-19 | Merck & Co., Inc. | Cetp inhibitors |
WO2007079186A2 (en) | 2005-12-30 | 2007-07-12 | Merck & Co., Inc. | 1, 3-oxazolidin-2-one derivatives useful as cetp inhibitors |
WO2007081571A2 (en) * | 2005-12-30 | 2007-07-19 | Merck & Co., Inc. | Cetp inhibitors |
-
2005
- 2005-01-31 DO DO2005000123A patent/DOP2005000123A/en unknown
- 2005-06-23 MY MYPI20052868A patent/MY167430A/en unknown
- 2005-06-26 JO JOP/2005/0091A patent/JO2994B1/en active
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- 2005-07-01 US US11/631,821 patent/US20080119476A1/en not_active Abandoned
- 2005-07-01 JP JP2007519533A patent/JP4695139B2/en not_active Expired - Fee Related
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- 2005-07-01 ES ES05771445T patent/ES2393721T3/en active Active
- 2005-07-01 KR KR1020077000039A patent/KR101204336B1/en active IP Right Grant
- 2005-07-01 EP EP05771445A patent/EP1765793B1/en active Active
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- 2005-07-01 MX MX2007000035A patent/MX2007000035A/en active IP Right Grant
- 2005-07-01 EA EA200700259A patent/EA011130B1/en not_active IP Right Cessation
- 2005-07-01 NZ NZ552061A patent/NZ552061A/en not_active IP Right Cessation
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- 2014-04-14 US US14/252,256 patent/US20140221383A1/en not_active Abandoned
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- 2015-10-05 US US14/875,438 patent/US20160075724A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0605729A1 (en) * | 1992-04-30 | 1994-07-13 | Taiho Pharmaceutical Co., Ltd. | Oxazolidine derivative and pharmaceutically acceptable salt thereof |
WO1999015487A1 (en) * | 1997-09-19 | 1999-04-01 | Bayer Aktiengesellschaft | Benzyl-biphenyls and analogous compounds and the application thereof in order to treat arteriosclerosis and dyslipidaemia |
Cited By (100)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8735435B2 (en) | 2004-07-02 | 2014-05-27 | Merck Sharp & Dohme Corp. | CETP inhibitors |
WO2007005572A1 (en) * | 2005-07-01 | 2007-01-11 | Merck & Co., Inc. | Process for synthesizing a cetp inhibitor |
US7863307B2 (en) | 2005-07-01 | 2011-01-04 | Merck Sharp & Dohme | Process for synthesizing a CETP inhibitor |
AU2006265975B2 (en) * | 2005-07-01 | 2011-12-15 | Merck Sharp & Dohme Corp. | Process for synthesizing a CETP inhibitor |
WO2007067593A2 (en) * | 2005-12-05 | 2007-06-14 | Merck & Co., Inc. | Self-emulsifyng formulations of cetp inhibitors |
WO2007067593A3 (en) * | 2005-12-05 | 2007-10-25 | Merck & Co Inc | Self-emulsifyng formulations of cetp inhibitors |
US8486983B2 (en) | 2005-12-05 | 2013-07-16 | Merck Sharp & Dohme Corp. | Self-emulsifying formulations of CETP inhibitors |
WO2007078523A3 (en) * | 2005-12-15 | 2007-11-15 | Astrazeneca Ab | 5-phenyl-3-benzyl-0xaz0lidin-2-0ne derivatives and related compounds as metabotropic glutamate receptor potentiators for the treatment of neurological and psychiatric disorders |
WO2007078523A2 (en) * | 2005-12-15 | 2007-07-12 | Astrazeneca Ab | 5-phenyl-3-benzyl-0xaz0lidin-2-0ne derivatives and related compounds as metabotropic glutamate receptor potentiators for the treatment of neurological and psychiatric disorders |
US7816354B2 (en) | 2005-12-15 | 2010-10-19 | Astrazeneca Ab | Oxazolidinone compounds and their use as metabotropic glutamate receptor potentiators |
US8030359B2 (en) | 2006-02-09 | 2011-10-04 | Merck Sharp & Dohme Corp. | Polymer formulations of CETP inhibitors |
JP2009526075A (en) * | 2006-02-09 | 2009-07-16 | メルク エンド カムパニー インコーポレーテッド | CETP inhibitor polymer formulation |
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WO2007092642A3 (en) * | 2006-02-09 | 2007-10-04 | Merck & Co Inc | Polymer formulations of cetp inhibitors |
US7919506B2 (en) | 2006-03-10 | 2011-04-05 | Pfizer Inc. | Dibenzyl amine compounds and derivatives |
US8383660B2 (en) | 2006-03-10 | 2013-02-26 | Pfizer Inc. | Dibenzyl amine compounds and derivatives |
WO2007136672A2 (en) * | 2006-05-19 | 2007-11-29 | Merck & Co., Inc. | Synthesis of a biaryl synthetic intermediate |
WO2007136672A3 (en) * | 2006-05-19 | 2008-04-03 | Merck & Co Inc | Synthesis of a biaryl synthetic intermediate |
WO2008089581A1 (en) | 2007-01-26 | 2008-07-31 | Merck Frosst Canada Ltd. | Fused aromatic ptp-1b inhibitors |
US8835426B2 (en) | 2007-02-26 | 2014-09-16 | Vitae Pharmaceuticals, Inc. | Cyclic urea and carbamate inhibitors of 11β-hydroxysteroid dehydrogenase 1 |
WO2008137105A1 (en) | 2007-05-07 | 2008-11-13 | Merck & Co., Inc. | Method of treatment using fused aromatic compounds having anti-diabetic activity |
US9079861B2 (en) | 2007-11-07 | 2015-07-14 | Vitae Pharmaceuticals, Inc. | Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1 |
US8748444B2 (en) | 2007-12-11 | 2014-06-10 | Vitae Pharmaceuticals, Inc. | Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1 |
US8362044B2 (en) | 2008-02-01 | 2013-01-29 | Panmira Pharmaceuticals, Llc | N,N-disubstituted aminoalkylbiphenyl antagonists of prostaglandin D2 receptors |
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GB2460597B (en) * | 2008-02-01 | 2010-04-21 | Amira Pharmaceuticals Inc | N,N-disubstituted aminoalkylbiphenyl antagonists of prostaglandin D2 receptors |
CN101952244A (en) * | 2008-02-01 | 2011-01-19 | 艾米拉制药公司 | PGD 2The N of acceptor, N-disubstituted amido alkyl biphenyl antagonist |
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US8168678B2 (en) | 2008-02-01 | 2012-05-01 | Panmira Pharmaceuticals, Inc. | N,N-disubstituted aminoalkylbiphenyl antagonists of prostaglandin D2 receptors |
GB2460597B8 (en) * | 2008-02-01 | 2014-03-12 | Amira Pharmaceuticals Inc | N,N-disubstituted aminoalkylbiphenyl antagonists of prostaglandin D2 receptors |
EA018901B1 (en) * | 2008-02-01 | 2013-11-29 | ПАНМИРА ФАРМАСЬЮТИКАЛС, ЭлЭлСи | N,n-disubstituted aminoalkylbiphenyl antagonists of prostaglandin dreceptors |
WO2009099901A1 (en) * | 2008-02-01 | 2009-08-13 | Amira Pharmaceuticals, Inc. | N,n-disubstituted aminoalkylbiphenyl antagonists of prostaglandin d2 receptors |
WO2009099902A1 (en) * | 2008-02-01 | 2009-08-13 | Amira Pharmaceuticals, Inc. | N,n-disubstituted aminoalkylbiphenyl antagonists of prostaglandin d2 receptors |
US8067445B2 (en) | 2008-02-01 | 2011-11-29 | Panmira Pharmaceuticals, Llc | N,N-disubstituted aminoalkylbiphenyl antagonists of prostaglandin D2 receptors |
CN101952244B (en) * | 2008-02-01 | 2014-11-05 | 潘米拉制药公司 | N,N-disubstituted aminoalkylbiphenyl antagonists of prostaglandin D2 receptors |
WO2009102428A2 (en) * | 2008-02-11 | 2009-08-20 | Vitae Pharmaceuticals, Inc. | 1,3-OXAZEPAN-2-ONE AND 1,3-DIAZEPAN-2-ONE INHIBITORS OF 11β -HYDROXYSTEROID DEHYDROGENASE 1 |
WO2009102428A3 (en) * | 2008-02-11 | 2009-10-22 | Vitae Pharmaceuticals, Inc. | 1,3-OXAZEPAN-2-ONE AND 1,3-DIAZEPAN-2-ONE INHIBITORS OF 11β -HYDROXYSTEROID DEHYDROGENASE 1 |
JP2011511790A (en) * | 2008-02-11 | 2011-04-14 | ヴァイティー ファーマシューティカルズ,インコーポレイテッド | 1,3-oxaazepan-2-one and 1,3-diazepan-2-one inhibitors of 11β-hydroxysteroid dehydrogenase 1 |
US8242145B2 (en) | 2008-02-14 | 2012-08-14 | Panmira Pharmaceuticals, Llc | Cyclic diaryl ether compounds as antagonists of prostaglandin D2 receptors |
WO2009102460A2 (en) * | 2008-02-15 | 2009-08-20 | Vitae Pharmaceuticals, Inc. | Inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
WO2009102460A3 (en) * | 2008-02-15 | 2009-11-05 | Vitae Pharmaceuticals, Inc. | Cycloalkyl lactame derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1 |
US8497381B2 (en) | 2008-02-25 | 2013-07-30 | Panmira Pharmaceuticals, Llc | Antagonists of prostaglandin D2 receptors |
US8426449B2 (en) | 2008-04-02 | 2013-04-23 | Panmira Pharmaceuticals, Llc | Aminoalkylphenyl antagonists of prostaglandin D2 receptors |
US8673899B2 (en) | 2008-05-01 | 2014-03-18 | Vitae Pharmaceuticals, Inc. | Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
US8754076B2 (en) | 2008-07-25 | 2014-06-17 | Vitae Pharmaceuticals, Inc./Boehringer-Ingelheim | Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
US8846668B2 (en) | 2008-07-25 | 2014-09-30 | Vitae Pharmaceuticals, Inc. | Inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
US8487094B2 (en) | 2008-07-25 | 2013-07-16 | Boehringer Ingelheim International Gmbh | Synthesis of inhibitors of 11β-hydroxysteroid dehydrogenase type 1 |
US8049015B2 (en) | 2008-09-29 | 2011-11-01 | Panmira Pharmaceuticals, Llc | Heteroaryl antagonists of prostaglandin D2 receptors |
US8378107B2 (en) | 2008-10-01 | 2013-02-19 | Panmira Pharmaceuticals, Llc | Heteroaryl antagonists of prostaglandin D2 receptors |
US8524748B2 (en) | 2008-10-08 | 2013-09-03 | Panmira Pharmaceuticals, Llc | Heteroalkyl biphenyl antagonists of prostaglandin D2 receptors |
WO2010047982A1 (en) | 2008-10-22 | 2010-04-29 | Merck Sharp & Dohme Corp. | Novel cyclic benzimidazole derivatives useful anti-diabetic agents |
WO2010051206A1 (en) | 2008-10-31 | 2010-05-06 | Merck Sharp & Dohme Corp. | Novel cyclic benzimidazole derivatives useful anti-diabetic agents |
US8383654B2 (en) | 2008-11-17 | 2013-02-26 | Panmira Pharmaceuticals, Llc | Heterocyclic antagonists of prostaglandin D2 receptors |
WO2010083136A1 (en) | 2009-01-16 | 2010-07-22 | Merck Sharp & Dohme Corp. | Oxadiazole beta carboline derivatives as antidiabetic compounds |
WO2010085525A1 (en) | 2009-01-23 | 2010-07-29 | Schering Corporation | Bridged and fused heterocyclic antidiabetic compounds |
WO2010085528A1 (en) | 2009-01-23 | 2010-07-29 | Schering Corporation | Bridged and fused antidiabetic compounds |
US8637505B2 (en) | 2009-02-04 | 2014-01-28 | Boehringer Ingelheim International Gmbh | Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
WO2010091176A1 (en) | 2009-02-05 | 2010-08-12 | Schering Corporation | Phthalazine-containing antidiabetic compounds |
US8680093B2 (en) | 2009-04-30 | 2014-03-25 | Vitae Pharmaceuticals, Inc. | Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
US8927539B2 (en) | 2009-06-11 | 2015-01-06 | Vitae Pharmaceuticals, Inc. | Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1 based on the 1,3-oxazinan-2-one structure |
US8883778B2 (en) | 2009-07-01 | 2014-11-11 | Vitae Pharmaceuticals, Inc. | Cyclic inhibitors of 11 beta-hydroxysteroid dehydrogenase 1 |
US8815917B2 (en) | 2009-08-05 | 2014-08-26 | Panmira Pharmaceuticals, Llc | DP2 antagonist and uses thereof |
US8552212B2 (en) | 2009-11-05 | 2013-10-08 | Boehringer Ingelheim International Gmbh | Chiral phosphorus ligands |
WO2011088025A1 (en) | 2010-01-15 | 2011-07-21 | Merck Sharp & Dohme Corp. | Oxadiazole beta carboline derivatives as antidiabetic compounds |
WO2011106273A1 (en) | 2010-02-25 | 2011-09-01 | Merck Sharp & Dohme Corp. | Novel cyclic benzimidazole derivatives useful anti-diabetic agents |
US8648192B2 (en) | 2010-05-26 | 2014-02-11 | Boehringer Ingelheim International Gmbh | 2-oxo-1,2-dihydropyridin-4-ylboronic acid derivatives |
US9090605B2 (en) | 2010-06-16 | 2015-07-28 | Vitae Pharmaceuticals, Inc. | Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use |
US8933072B2 (en) | 2010-06-16 | 2015-01-13 | Vitae Pharmaceuticals, Inc. | Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use |
US8765744B2 (en) | 2010-06-25 | 2014-07-01 | Boehringer Ingelheim International Gmbh | Azaspirohexanones |
WO2012046681A1 (en) | 2010-10-04 | 2012-04-12 | 興和株式会社 | Agent for inhibiting expression of lipid metabolism related mrna |
US8846613B2 (en) | 2010-11-02 | 2014-09-30 | Boehringer Ingelheim International Gmbh | Pharmaceutical combinations for the treatment of metabolic disorders |
US9212118B2 (en) | 2010-12-23 | 2015-12-15 | Lek Pharmaceuticals D.D. | Synthesis of intermediates for preparing anacetrapib and derivatives thereof |
CN103384663A (en) * | 2010-12-23 | 2013-11-06 | 力奇制药公司 | Synthesis of intermediates for preparing anacetrapib and derivatives thereof |
WO2012085133A1 (en) * | 2010-12-23 | 2012-06-28 | Lek Pharmaceuticals D.D. | Synthesis of intermediates for preparing anacetrapib and derivatives thereof |
EP2468735A1 (en) * | 2010-12-23 | 2012-06-27 | LEK Pharmaceuticals d.d. | Synthesis of intermediates for preparing anacetrapib and derivates thereof |
CN103384663B (en) * | 2010-12-23 | 2016-04-20 | 力奇制药公司 | For the preparation of the synthesis of the intermediate of bent of Ansai and derivative thereof |
EP2468736A1 (en) * | 2010-12-23 | 2012-06-27 | LEK Pharmaceuticals d.d. | Synthesis of intermediates for preparing anacetrapib and derivates thereof |
WO2012101142A1 (en) | 2011-01-26 | 2012-08-02 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Method for assessing a subject's risk of having a cardiovascular disease. |
WO2012116145A1 (en) | 2011-02-25 | 2012-08-30 | Merck Sharp & Dohme Corp. | Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents |
EP3243385A1 (en) | 2011-02-25 | 2017-11-15 | Merck Sharp & Dohme Corp. | Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents |
WO2012141487A2 (en) | 2011-04-12 | 2012-10-18 | Chong Kun Dang Pharmaceutical Corp. | Cycloalkenyl aryl derivatives for cetp inhibitor |
KR101442644B1 (en) * | 2011-04-12 | 2014-09-19 | 주식회사 종근당 | Cycloalkenyl Aryl Derivatives for CETP Inhibitor |
US9371294B2 (en) | 2011-04-12 | 2016-06-21 | Chong Kun Dang Pharmaceutical Corp. | Cycloalkenyl aryl derivatives for CETP inhibitor |
JP2014510786A (en) * | 2011-04-12 | 2014-05-01 | チョンクンダン ファーマシューティカル コーポレーション | Cycloalkenyl aryl derivatives as CETP inhibitors |
US20140303380A1 (en) * | 2011-10-31 | 2014-10-09 | Merck Sharp & Dohme Corp. | Process for a CETP Inhibitor |
US9145348B2 (en) * | 2011-10-31 | 2015-09-29 | Merck Sharpe & Dohme Corp. | Process for synthesizing a CETP inhibitor |
WO2013080999A1 (en) | 2011-11-29 | 2013-06-06 | 興和株式会社 | Agent for inhibiting expression of npc1l1 and/or lipg mrna and agent for preventing and/or treating obesity |
US9724336B2 (en) | 2011-11-30 | 2017-08-08 | Daewoong Pharmaceutical Co., Ltd. | Pharmaceutical composition for preventing or treating hyperlipidemia |
WO2013081373A1 (en) | 2011-11-30 | 2013-06-06 | Daewoong Pharmaceutical Co., Ltd. | Pharmaceutical composition for preventing or treating hypertriglyceridemia or hypertriglyceridemia-associated diseases |
US9486443B2 (en) | 2011-11-30 | 2016-11-08 | Daewoong Pharmaceutical Co., Ltd. | Pharmaceutical composition for preventing or treating hypertriglyceridemia or hypertriglyceridemia-associated diseases |
WO2013091696A1 (en) * | 2011-12-21 | 2013-06-27 | Lek Pharmaceuticals D.D. | Synthesis of intermediates for preparing anacetrapib and derivatives thereof |
WO2014031465A1 (en) | 2012-08-22 | 2014-02-27 | Merck Sharp & Dohme Corp. | Novel azabenzimidazole tetrahydropyran derivatives |
US9493430B2 (en) | 2013-01-31 | 2016-11-15 | Chong Kun Dang Pharmaceutical Corp. | Biaryl- or heterocyclic biaryl-substituted cyclohexene derivative compounds as CETP inhibitors |
WO2014119947A1 (en) | 2013-01-31 | 2014-08-07 | Chong Kun Dang Pharmaceutical Corp. | Biaryl- or heterocyclic biaryl-substituted cyclohexene derivative compounds as cetp inhibitors |
WO2014139388A1 (en) | 2013-03-14 | 2014-09-18 | Merck Sharp & Dohme Corp. | Novel indole derivatives useful as anti-diabetic agents |
EP3795695A1 (en) | 2014-07-30 | 2021-03-24 | F. Hoffmann-La Roche AG | Genetic markers for predicting responsiveness to therapy |
WO2018002437A1 (en) | 2016-06-29 | 2018-01-04 | Orion Corporation | Benzodioxane derivatives and their pharmaceutical use |
CN106496211A (en) * | 2016-10-18 | 2017-03-15 | 湖南德魅信息技术有限公司 | Oxazolidinone compounds that difluoromethyl replaces and application thereof |
CN106749075A (en) * | 2016-11-24 | 2017-05-31 | 山东新华制药股份有限公司 | Crystal formation of oxazolidone intermediate of Ah Nagqu ripple and preparation method thereof |
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