KR20070007112A - 이상지혈증 치료를 위한 화합물 및 방법 - Google Patents

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Publication number

KR20070007112A

KR20070007112A KR1020067019800A KR20067019800A KR20070007112A KR 20070007112 A KR20070007112 A KR 20070007112A KR 1020067019800 A KR1020067019800 A KR 1020067019800A KR 20067019800 A KR20067019800 A KR 20067019800A KR 20070007112 A KR20070007112 A KR 20070007112A

Authority

KR

South Korea

Prior art keywords

trifluoromethyl

ethyl

amino

dihydro

benzyl

Prior art date

2004-03-26

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Ceased

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• 150000001875 compounds Chemical class 0.000 title claims abstract description 227
• 238000000034 method Methods 0.000 title claims abstract description 94
• 208000032928 Dyslipidaemia Diseases 0.000 title claims abstract description 13
• 208000017170 Lipid metabolism disease Diseases 0.000 title claims abstract description 13
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
• -1 C 1 -C 6 alkyl Chemical group 0.000 claims description 208
• 239000000203 mixture Substances 0.000 claims description 103
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 75
• 125000003118 aryl group Chemical group 0.000 claims description 55
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 44
• 125000000623 heterocyclic group Chemical group 0.000 claims description 38
• 150000003839 salts Chemical class 0.000 claims description 37
• PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 35
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 33
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 32
• 230000000694 effects Effects 0.000 claims description 29
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 27
• 239000002253 acid Substances 0.000 claims description 26
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 26
• 238000011282 treatment Methods 0.000 claims description 26
• 239000012453 solvate Substances 0.000 claims description 24
• 229910052739 hydrogen Inorganic materials 0.000 claims description 23
• 239000001257 hydrogen Substances 0.000 claims description 23
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 23
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 22
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 21
• 201000001320 Atherosclerosis Diseases 0.000 claims description 21
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 21
• 125000005843 halogen group Chemical group 0.000 claims description 20
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 19
• 125000004043 oxo group Chemical group O=* 0.000 claims description 18
• 238000008214 LDL Cholesterol Methods 0.000 claims description 16
• 125000000217 alkyl group Chemical group 0.000 claims description 14
• 229910052757 nitrogen Inorganic materials 0.000 claims description 14
• FPQJBMBIIPSOBY-UHFFFAOYSA-N propan-2-yl 2-(fluoromethyl)-3,4-dihydro-2h-1,5-naphthyridine-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC(C)C)C(CF)CCC2=N1 FPQJBMBIIPSOBY-UHFFFAOYSA-N 0.000 claims description 14
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
• 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 12
• 101000880514 Homo sapiens Cholesteryl ester transfer protein Proteins 0.000 claims description 12
• 108010028554 LDL Cholesterol Proteins 0.000 claims description 11
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
• 229910052760 oxygen Inorganic materials 0.000 claims description 11
• 229910052717 sulfur Inorganic materials 0.000 claims description 11
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
• ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 9
• 230000002265 prevention Effects 0.000 claims description 9
• 241000124008 Mammalia Species 0.000 claims description 8
• KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 8
• YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 8
• 229910052736 halogen Inorganic materials 0.000 claims description 8
• 150000002367 halogens Chemical class 0.000 claims description 8
• 125000001072 heteroaryl group Chemical group 0.000 claims description 8
• 230000001575 pathological effect Effects 0.000 claims description 8
• 108010023302 HDL Cholesterol Proteins 0.000 claims description 7
• WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 7
• 125000004104 aryloxy group Chemical group 0.000 claims description 7
• 229910052799 carbon Inorganic materials 0.000 claims description 7
• 238000004519 manufacturing process Methods 0.000 claims description 7
• VYLOCWWSRRXEAY-UHFFFAOYSA-N propan-2-yl 2-methyl-3,4-dihydro-2h-1,5-naphthyridine-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC(C)C)C(C)CCC2=N1 VYLOCWWSRRXEAY-UHFFFAOYSA-N 0.000 claims description 7
• 125000006727 (C1-C6) alkenyl group Chemical group 0.000 claims description 6
• 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 6
• 239000003814 drug Substances 0.000 claims description 6
• 239000003085 diluting agent Substances 0.000 claims description 5
• 125000005842 heteroatom Chemical group 0.000 claims description 5
• CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 5
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
• PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 4
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
• FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 4
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
• 125000002837 carbocyclic group Chemical group 0.000 claims description 4
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
• 239000001301 oxygen Substances 0.000 claims description 4
• 239000011593 sulfur Chemical group 0.000 claims description 4
• 229930192474 thiophene Natural products 0.000 claims description 4
• 125000004122 cyclic group Chemical group 0.000 claims description 3
• 230000001965 increasing effect Effects 0.000 claims description 3
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
• QLQICZLTQHFGRS-AZUAARDMSA-N propan-2-yl (2s,4r)-4-[[2-(2-aminoethyl)tetrazol-5-yl]-[[3,5-bis(trifluoromethyl)phenyl]methyl]amino]-2-ethyl-6-(trifluoromethyl)-3,4-dihydro-2h-1,5-naphthyridine-1-carboxylate Chemical compound N1=NN(CCN)N=C1N([C@@H]1C[C@@H](N(C2=CC=C(N=C21)C(F)(F)F)C(=O)OC(C)C)CC)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 QLQICZLTQHFGRS-AZUAARDMSA-N 0.000 claims description 3
• RBSLKDOJYBQTCO-UHFFFAOYSA-N propan-2-yl 4-[[3,5-bis(trifluoromethyl)phenyl]methyl-(5,6,7,8-tetrahydroquinolin-3-yl)amino]-2,3-dimethyl-3,4,6,7,8,9-hexahydro-2h-benzo[g][1,5]naphthyridine-1-carboxylate Chemical compound C12=NC=3CCCCC=3C=C2N(C(=O)OC(C)C)C(C)C(C)C1N(C=1C=C2CCCCC2=NC=1)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 RBSLKDOJYBQTCO-UHFFFAOYSA-N 0.000 claims description 3
• PHPQWAVLQLGBBW-UHFFFAOYSA-N propan-2-yl 4-[acetyl-[[3,5-bis(trifluoromethyl)phenyl]methyl]amino]-2-ethyl-7-methyl-3,4-dihydro-2h-1,8-naphthyridine-1-carboxylate Chemical compound C12=CC=C(C)N=C2N(C(=O)OC(C)C)C(CC)CC1N(C(C)=O)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 PHPQWAVLQLGBBW-UHFFFAOYSA-N 0.000 claims description 3
• 125000006728 (C1-C6) alkynyl group Chemical group 0.000 claims description 2
• 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 claims description 2
• NUJGEWJYORDXMR-CTNGQTDRSA-N ethyl (2r,4s)-4-[[2-(2-aminoethyl)tetrazol-5-yl]-[[3,5-bis(trifluoromethyl)phenyl]methyl]amino]-2-ethyl-6-methyl-3,4-dihydro-2h-1,5-naphthyridine-1-carboxylate Chemical compound N1=NN(CCN)N=C1N([C@H]1C[C@@H](CC)N(C2=CC=C(C)N=C21)C(=O)OCC)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 NUJGEWJYORDXMR-CTNGQTDRSA-N 0.000 claims description 2
• NNUGXXYGVIZOOB-KUHUBIRLSA-N ethyl (2r,4s)-4-[[3,5-bis(trifluoromethyl)phenyl]methyl-(2-methyltetrazol-5-yl)amino]-2,6-dimethyl-3,4-dihydro-2h-1,5-naphthyridine-1-carboxylate Chemical compound N1=NN(C)N=C1N([C@H]1C[C@@H](C)N(C2=CC=C(C)N=C21)C(=O)OCC)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 NNUGXXYGVIZOOB-KUHUBIRLSA-N 0.000 claims description 2
• GBGXOZJGKVXCTJ-QUCCMNQESA-N ethyl (2r,4s)-4-[[3,5-bis(trifluoromethyl)phenyl]methyl-(2-methyltetrazol-5-yl)amino]-2-ethyl-6-methyl-3,4-dihydro-2h-1,5-naphthyridine-1-carboxylate Chemical compound N1=NN(C)N=C1N([C@H]1C[C@@H](CC)N(C2=CC=C(C)N=C21)C(=O)OCC)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 GBGXOZJGKVXCTJ-QUCCMNQESA-N 0.000 claims description 2
• MOLCDSDOJLDXFF-CTNGQTDRSA-N ethyl (2r,4s)-4-[[3,5-bis(trifluoromethyl)phenyl]methyl-[2-(2-hydroxyethyl)tetrazol-5-yl]amino]-2-ethyl-6-methyl-3,4-dihydro-2h-1,5-naphthyridine-1-carboxylate Chemical compound N1=NN(CCO)N=C1N([C@H]1C[C@@H](CC)N(C2=CC=C(C)N=C21)C(=O)OCC)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 MOLCDSDOJLDXFF-CTNGQTDRSA-N 0.000 claims description 2
• PSHMSKVXFVFRIA-QUCCMNQESA-N methyl (2r,4s)-4-[[2-(2-aminoethyl)tetrazol-5-yl]-[[3,5-bis(trifluoromethyl)phenyl]methyl]amino]-2-ethyl-6-methyl-3,4-dihydro-2h-1,5-naphthyridine-1-carboxylate Chemical compound N1=NN(CCN)N=C1N([C@H]1C[C@H](N(C2=CC=C(C)N=C21)C(=O)OC)CC)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 PSHMSKVXFVFRIA-QUCCMNQESA-N 0.000 claims description 2
• WUKLOLBZWZYUHN-ACJLOTCBSA-N methyl (2r,4s)-4-[[3,5-bis(trifluoromethyl)phenyl]methyl-(2-methyltetrazol-5-yl)amino]-2,6-dimethyl-3,4-dihydro-2h-1,5-naphthyridine-1-carboxylate Chemical compound N1=NN(C)N=C1N([C@H]1C[C@@H](C)N(C2=CC=C(C)N=C21)C(=O)OC)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 WUKLOLBZWZYUHN-ACJLOTCBSA-N 0.000 claims description 2
• FJKXVDJUZWEPFR-MJGOQNOKSA-N methyl (2r,4s)-4-[[3,5-bis(trifluoromethyl)phenyl]methyl-(2-methyltetrazol-5-yl)amino]-2-ethyl-6-methyl-3,4-dihydro-2h-1,5-naphthyridine-1-carboxylate Chemical compound N1=NN(C)N=C1N([C@H]1C[C@H](N(C2=CC=C(C)N=C21)C(=O)OC)CC)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 FJKXVDJUZWEPFR-MJGOQNOKSA-N 0.000 claims description 2
• HFHKRMLIAQPQNF-QUCCMNQESA-N methyl (2r,4s)-4-[[3,5-bis(trifluoromethyl)phenyl]methyl-[2-(2-hydroxyethyl)tetrazol-5-yl]amino]-2-ethyl-6-methyl-3,4-dihydro-2h-1,5-naphthyridine-1-carboxylate Chemical compound N1=NN(CCO)N=C1N([C@H]1C[C@H](N(C2=CC=C(C)N=C21)C(=O)OC)CC)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 HFHKRMLIAQPQNF-QUCCMNQESA-N 0.000 claims description 2
• VHBLJIFFDINWGR-MJGOQNOKSA-N propan-2-yl (2r,4s)-2-ethyl-4-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl-(2-methyltetrazol-5-yl)amino]-6-(trifluoromethyl)-3,4-dihydro-2h-1,5-naphthyridine-1-carboxylate Chemical compound N1=NN(C)N=C1N([C@H]1C[C@H](N(C2=CC=C(N=C21)C(F)(F)F)C(=O)OC(C)C)CC)CC1=CC(F)=CC(C(F)(F)F)=C1 VHBLJIFFDINWGR-MJGOQNOKSA-N 0.000 claims description 2
• WHCDDXHSCVQHEZ-MJGOQNOKSA-N propan-2-yl (2r,4s)-4-[(3,5-dichlorophenyl)methyl-(2-methyltetrazol-5-yl)amino]-2-ethyl-6-(trifluoromethyl)-3,4-dihydro-2h-1,5-naphthyridine-1-carboxylate Chemical compound N1=NN(C)N=C1N([C@H]1C[C@H](N(C2=CC=C(N=C21)C(F)(F)F)C(=O)OC(C)C)CC)CC1=CC(Cl)=CC(Cl)=C1 WHCDDXHSCVQHEZ-MJGOQNOKSA-N 0.000 claims description 2
• WKWQGIRKCUNVJD-MJGOQNOKSA-N propan-2-yl (2r,4s)-4-[(3,5-difluorophenyl)methyl-(2-methyltetrazol-5-yl)amino]-2-ethyl-6-(trifluoromethyl)-3,4-dihydro-2h-1,5-naphthyridine-1-carboxylate Chemical compound N1=NN(C)N=C1N([C@H]1C[C@H](N(C2=CC=C(N=C21)C(F)(F)F)C(=O)OC(C)C)CC)CC1=CC(F)=CC(F)=C1 WKWQGIRKCUNVJD-MJGOQNOKSA-N 0.000 claims description 2
• PEYZVFFVKZVZPU-CTNGQTDRSA-N propan-2-yl (2r,4s)-4-[(3,5-dimethylphenyl)methyl-(2-methyltetrazol-5-yl)amino]-2-ethyl-6-(trifluoromethyl)-3,4-dihydro-2h-1,5-naphthyridine-1-carboxylate Chemical compound N1=NN(C)N=C1N([C@H]1C[C@H](N(C2=CC=C(N=C21)C(F)(F)F)C(=O)OC(C)C)CC)CC1=CC(C)=CC(C)=C1 PEYZVFFVKZVZPU-CTNGQTDRSA-N 0.000 claims description 2
• YZHZEHYIUCNFNN-CTNGQTDRSA-N propan-2-yl (2r,4s)-4-[[2-(2-aminoethyl)tetrazol-5-yl]-[[3-cyano-5-(trifluoromethyl)phenyl]methyl]amino]-2-ethyl-6-(trifluoromethyl)-3,4-dihydro-2h-1,5-naphthyridine-1-carboxylate Chemical compound N1=NN(CCN)N=C1N([C@H]1C[C@H](N(C2=CC=C(N=C21)C(F)(F)F)C(=O)OC(C)C)CC)CC1=CC(C#N)=CC(C(F)(F)F)=C1 YZHZEHYIUCNFNN-CTNGQTDRSA-N 0.000 claims description 2
• DVPLUSUSBHMUQS-QRWLVFNGSA-N propan-2-yl (2r,4s)-4-[[3,5-bis(trifluoromethyl)phenyl]methyl-(2-methyltetrazol-5-yl)amino]-2,6-dimethyl-3,4-dihydro-2h-1,5-naphthyridine-1-carboxylate Chemical compound N1=NN(C)N=C1N([C@H]1C[C@@H](C)N(C2=CC=C(C)N=C21)C(=O)OC(C)C)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 DVPLUSUSBHMUQS-QRWLVFNGSA-N 0.000 claims description 2
• UYHOXKMUSHARGA-QUCCMNQESA-N propan-2-yl (2r,4s)-4-[[3-cyano-5-(trifluoromethyl)phenyl]methyl-(2-methyltetrazol-5-yl)amino]-2-ethyl-6-(trifluoromethyl)-3,4-dihydro-2h-1,5-naphthyridine-1-carboxylate Chemical compound N1=NN(C)N=C1N([C@H]1C[C@H](N(C2=CC=C(N=C21)C(F)(F)F)C(=O)OC(C)C)CC)CC1=CC(C#N)=CC(C(F)(F)F)=C1 UYHOXKMUSHARGA-QUCCMNQESA-N 0.000 claims description 2
• QBAKTVOETIXULL-CTNGQTDRSA-N propan-2-yl (2r,4s)-4-[[3-cyano-5-(trifluoromethyl)phenyl]methyl-[2-(2-hydroxyethyl)tetrazol-5-yl]amino]-2-ethyl-6-(trifluoromethyl)-3,4-dihydro-2h-1,5-naphthyridine-1-carboxylate Chemical compound N1=NN(CCO)N=C1N([C@H]1C[C@H](N(C2=CC=C(N=C21)C(F)(F)F)C(=O)OC(C)C)CC)CC1=CC(C#N)=CC(C(F)(F)F)=C1 QBAKTVOETIXULL-CTNGQTDRSA-N 0.000 claims description 2
• KEWSCDNULKOKTG-UHFFFAOYSA-N 4-cyano-4-ethylsulfanylcarbothioylsulfanylpentanoic acid Chemical compound CCSC(=S)SC(C)(C#N)CCC(O)=O KEWSCDNULKOKTG-UHFFFAOYSA-N 0.000 claims 4
• 102100037637 Cholesteryl ester transfer protein Human genes 0.000 claims 4
• RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims 2
• 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 1
• DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims 1
• 229910052700 potassium Inorganic materials 0.000 abstract description 2
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 232
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 111
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 105
• 235000019439 ethyl acetate Nutrition 0.000 description 78
• 238000002360 preparation method Methods 0.000 description 68
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
• 239000002904 solvent Substances 0.000 description 56
• 102000012336 Cholesterol Ester Transfer Proteins Human genes 0.000 description 52
• 108010061846 Cholesterol Ester Transfer Proteins Proteins 0.000 description 52
• 239000000243 solution Substances 0.000 description 52
• HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 45
• 108010010234 HDL Lipoproteins Proteins 0.000 description 37
• 102000015779 HDL Lipoproteins Human genes 0.000 description 37
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
• 230000002829 reductive effect Effects 0.000 description 34
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 33
• 238000010898 silica gel chromatography Methods 0.000 description 33
• 239000012044 organic layer Substances 0.000 description 29
• 238000010828 elution Methods 0.000 description 28
• 239000011541 reaction mixture Substances 0.000 description 26
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
• 238000006243 chemical reaction Methods 0.000 description 23
• 238000000746 purification Methods 0.000 description 23
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
• 239000002585 base Substances 0.000 description 20
• 239000003354 cholesterol ester transfer protein inhibitor Substances 0.000 description 19
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
• 150000001412 amines Chemical class 0.000 description 18
• 239000000651 prodrug Substances 0.000 description 18
• 229940002612 prodrug Drugs 0.000 description 18
• 235000012000 cholesterol Nutrition 0.000 description 17
• 208000029078 coronary artery disease Diseases 0.000 description 17
• 238000009472 formulation Methods 0.000 description 17
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
• PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 16
• 238000003556 assay Methods 0.000 description 16
• 239000010410 layer Substances 0.000 description 16
• 239000012267 brine Substances 0.000 description 15
• 238000003818 flash chromatography Methods 0.000 description 15
• 150000002632 lipids Chemical class 0.000 description 15
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 15
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 14
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
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