SK125099A3 - Combination of ileal bile acid transport inhibiting benzothiepines and hmg co-a reductase inhibitors - Google Patents

Info

Publication number

SK125099A3

SK125099A3 SK1250-99A SK125099A SK125099A3 SK 125099 A3 SK125099 A3 SK 125099A3 SK 125099 A SK125099 A SK 125099A SK 125099 A3 SK125099 A3 SK 125099A3

Authority

SK

Slovakia

Prior art keywords

heterocycle

heteroaryl

alkyl

quaternary

aryl

Prior art date

1997-03-11

Links

• Espacenet
• Global Dossier
• Discuss

• 239000003112 inhibitor Substances 0.000 title claims abstract description 43
• NIGNBCLEMMGDQP-UHFFFAOYSA-N 1-benzothiepine Chemical class S1C=CC=CC2=CC=CC=C12 NIGNBCLEMMGDQP-UHFFFAOYSA-N 0.000 title abstract description 17
• 239000003613 bile acid Substances 0.000 title description 32
• HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 title description 25
• 230000002401 inhibitory effect Effects 0.000 title description 6
• 150000001875 compounds Chemical class 0.000 claims abstract description 146
• 239000000203 mixture Substances 0.000 claims abstract description 104
• 238000000034 method Methods 0.000 claims abstract description 86
• 238000011282 treatment Methods 0.000 claims abstract description 24
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 20
• 238000002648 combination therapy Methods 0.000 claims abstract description 17
• 229940077672 Ileal bile acid transport inhibitor Drugs 0.000 claims abstract description 10
• 241000124008 Mammalia Species 0.000 claims abstract description 7
• -1 carboalkoxyalkyl Chemical group 0.000 claims description 421
• 125000000623 heterocyclic group Chemical group 0.000 claims description 158
• 125000001072 heteroaryl group Chemical group 0.000 claims description 150
• 229910005965 SO 2 Inorganic materials 0.000 claims description 118
• 125000000217 alkyl group Chemical group 0.000 claims description 112
• 125000003118 aryl group Chemical group 0.000 claims description 101
• 125000003342 alkenyl group Chemical group 0.000 claims description 91
• 125000000304 alkynyl group Chemical group 0.000 claims description 90
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 89
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 82
• 229910052757 nitrogen Inorganic materials 0.000 claims description 79
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 57
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 57
• 229910052739 hydrogen Inorganic materials 0.000 claims description 55
• 125000001424 substituent group Chemical group 0.000 claims description 55
• 125000001188 haloalkyl group Chemical group 0.000 claims description 50
• 239000004721 Polyphenylene oxide Substances 0.000 claims description 47
• 229920000570 polyether Polymers 0.000 claims description 47
• 108090000765 processed proteins & peptides Proteins 0.000 claims description 39
• 125000004432 carbon atom Chemical group C* 0.000 claims description 32
• 239000001257 hydrogen Substances 0.000 claims description 32
• 125000004043 oxo group Chemical group O=* 0.000 claims description 30
• 229910052760 oxygen Inorganic materials 0.000 claims description 30
• 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 27
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 23
• 150000001413 amino acids Chemical class 0.000 claims description 22
• 150000001720 carbohydrates Chemical class 0.000 claims description 22
• 229910052799 carbon Inorganic materials 0.000 claims description 20
• 150000004820 halides Chemical class 0.000 claims description 20
• 229920001184 polypeptide Polymers 0.000 claims description 19
• 102000004196 processed proteins & peptides Human genes 0.000 claims description 19
• 150000003839 salts Chemical class 0.000 claims description 16
• 125000003545 alkoxy group Chemical group 0.000 claims description 15
• 229940123934 Reductase inhibitor Drugs 0.000 claims description 12
• 125000004423 acyloxy group Chemical group 0.000 claims description 10
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 10
• 125000002252 acyl group Chemical group 0.000 claims description 9
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 9
• 150000002431 hydrogen Chemical class 0.000 claims description 9
• 229960005235 piperonyl butoxide Drugs 0.000 claims description 8
• 125000004414 alkyl thio group Chemical group 0.000 claims description 7
• 150000001450 anions Chemical class 0.000 claims description 7
• 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims description 6
• 150000001768 cations Chemical class 0.000 claims description 4
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 4
• 125000001624 naphthyl group Chemical group 0.000 claims description 4
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
• 230000002265 prevention Effects 0.000 claims description 4
• 229940002612 prodrug Drugs 0.000 claims description 4
• 239000000651 prodrug Substances 0.000 claims description 4
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
• 239000012453 solvate Substances 0.000 claims description 4
• 125000004964 sulfoalkyl group Chemical group 0.000 claims description 4
• 125000001425 triazolyl group Chemical group 0.000 claims description 4
• 125000004946 alkenylalkyl group Chemical group 0.000 claims description 3
• 150000003931 anilides Chemical group 0.000 claims description 3
• 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
• 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
• 125000004181 carboxyalkyl group Chemical group 0.000 claims description 3
• 125000004966 cyanoalkyl group Chemical group 0.000 claims description 3
• 125000002541 furyl group Chemical group 0.000 claims description 3
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 3
• 125000002883 imidazolyl group Chemical group 0.000 claims description 3
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 3
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 3
• 125000002971 oxazolyl group Chemical group 0.000 claims description 3
• 125000004193 piperazinyl group Chemical group 0.000 claims description 3
• 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 claims description 3
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
• 125000004076 pyridyl group Chemical group 0.000 claims description 3
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
• 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 3
• 125000005504 styryl group Chemical group 0.000 claims description 3
• 125000000335 thiazolyl group Chemical group 0.000 claims description 3
• 125000001544 thienyl group Chemical group 0.000 claims description 3
• 125000005038 alkynylalkyl group Chemical group 0.000 claims description 2
• 239000003524 antilipemic agent Substances 0.000 claims description 2
• ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 claims 4
• SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims 4
• PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 claims 4
• TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 claims 4
• RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 claims 4
• 229960003765 fluvastatin Drugs 0.000 claims 4
• 229960004844 lovastatin Drugs 0.000 claims 4
• PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical group C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 claims 4
• QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 claims 4
• 229960002965 pravastatin Drugs 0.000 claims 4
• TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 claims 4
• 229960002855 simvastatin Drugs 0.000 claims 4
• RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 claims 4
• XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims 3
• XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 claims 3
• 229960005370 atorvastatin Drugs 0.000 claims 3
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Chemical group NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims 2
• 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 claims 2
• 230000001315 anti-hyperlipaemic effect Effects 0.000 claims 2
• 125000005265 dialkylamine group Chemical group 0.000 claims 2
• 125000001475 halogen functional group Chemical group 0.000 claims 2
• PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims 2
• RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims 2
• 239000004927 clay Substances 0.000 claims 1
• 201000001320 Atherosclerosis Diseases 0.000 abstract description 11
• 239000003814 drug Substances 0.000 abstract description 7
• 238000011321 prophylaxis Methods 0.000 abstract description 7
• 208000035150 Hypercholesterolemia Diseases 0.000 abstract description 5
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 247
• FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 description 189
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 170
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 154
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 136
• 239000000243 solution Substances 0.000 description 131
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 124
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 124
• 239000011541 reaction mixture Substances 0.000 description 111
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 106
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 104
• 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 101
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 101
• 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 99
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 98
• 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 97
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 81
• 239000000047 product Substances 0.000 description 79
• 229910001868 water Inorganic materials 0.000 description 73
• 238000006243 chemical reaction Methods 0.000 description 72
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 64
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 62
• 235000019341 magnesium sulphate Nutrition 0.000 description 62
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 60
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 58
• 239000007787 solid Substances 0.000 description 49
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 48
• 235000019439 ethyl acetate Nutrition 0.000 description 47
• RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 47
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 46
• 238000002360 preparation method Methods 0.000 description 44
• 239000000126 substance Substances 0.000 description 43
• 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 42
• 238000005481 NMR spectroscopy Methods 0.000 description 40
• 239000003921 oil Substances 0.000 description 38
• 235000019198 oils Nutrition 0.000 description 38
• 238000004949 mass spectrometry Methods 0.000 description 37
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 36
• 238000004128 high performance liquid chromatography Methods 0.000 description 35
• 238000003756 stirring Methods 0.000 description 35
• 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 34
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 34
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 34
• 239000012267 brine Substances 0.000 description 32
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 32
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 32
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 30
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 28
• 239000012044 organic layer Substances 0.000 description 28
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 27
• 238000007792 addition Methods 0.000 description 27
• 239000010410 layer Substances 0.000 description 27
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
• GDVUGFJXFFCXMX-UHFFFAOYSA-N (2-ethyl-2-formylhexyl) methanesulfonate Chemical compound CCCCC(CC)(C=O)COS(C)(=O)=O GDVUGFJXFFCXMX-UHFFFAOYSA-N 0.000 description 23
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 23
• 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 23
• OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 21
• RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 21
• 230000032258 transport Effects 0.000 description 21
• 239000000463 material Substances 0.000 description 20
• 238000010898 silica gel chromatography Methods 0.000 description 20
• NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 18
• LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 18
• AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 18
• 229910052736 halogen Inorganic materials 0.000 description 17
• 150000002367 halogens Chemical class 0.000 description 17
• XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 16
• 239000012299 nitrogen atmosphere Substances 0.000 description 16
• 229910000027 potassium carbonate Inorganic materials 0.000 description 16
• 239000007858 starting material Substances 0.000 description 16
• 239000000284 extract Substances 0.000 description 15
• 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 15
• UOLPWQTZNSRMCK-UHFFFAOYSA-N 3-butyl-3-ethyl-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound OC1C(CCCC)(CC)CS(=O)(=O)C2=CC=CC=C2C1C1=CC=CC=C1 UOLPWQTZNSRMCK-UHFFFAOYSA-N 0.000 description 14
• ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 14
• 235000014633 carbohydrates Nutrition 0.000 description 14
• JRLTTZUODKEYDH-UHFFFAOYSA-N 8-methylquinoline Chemical group C1=CN=C2C(C)=CC=CC2=C1 JRLTTZUODKEYDH-UHFFFAOYSA-N 0.000 description 13
• 239000003480 eluent Substances 0.000 description 13
• 239000000706 filtrate Substances 0.000 description 13
• 238000009472 formulation Methods 0.000 description 13
• 238000002844 melting Methods 0.000 description 13
• 230000008018 melting Effects 0.000 description 13
• 239000002904 solvent Substances 0.000 description 13
• 238000004809 thin layer chromatography Methods 0.000 description 13
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 12
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
• 150000001412 amines Chemical class 0.000 description 12
• 229920000642 polymer Polymers 0.000 description 12
• 238000000746 purification Methods 0.000 description 12
• 239000000725 suspension Substances 0.000 description 12
• 239000006188 syrup Substances 0.000 description 12
• 235000020357 syrup Nutrition 0.000 description 12
• ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 11
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 11
• 230000037396 body weight Effects 0.000 description 11
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 11
• 239000003826 tablet Substances 0.000 description 11
• HKQWVTWXDVJYOD-UHFFFAOYSA-N 2-[(2-benzoylphenyl)sulfanylmethyl]-2-ethylhexanal Chemical compound CCCCC(CC)(C=O)CSC1=CC=CC=C1C(=O)C1=CC=CC=C1 HKQWVTWXDVJYOD-UHFFFAOYSA-N 0.000 description 10
• JCXXJUFQEJDNJX-UHFFFAOYSA-N 3-butyl-3-ethyl-8-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound OC1C(CCCC)(CC)CS(=O)(=O)C2=CC(OC)=CC=C2C1C1=CC=CC=C1 JCXXJUFQEJDNJX-UHFFFAOYSA-N 0.000 description 10
• 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 10
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 10
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
• YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 10
• 230000029936 alkylation Effects 0.000 description 10
• 238000005804 alkylation reaction Methods 0.000 description 10
• 239000002775 capsule Substances 0.000 description 10
• 239000003054 catalyst Substances 0.000 description 10
• MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 10
• 201000010099 disease Diseases 0.000 description 10
• NWVVVBRKAWDGAB-UHFFFAOYSA-N p-methoxyphenol Chemical compound COC1=CC=C(O)C=C1 NWVVVBRKAWDGAB-UHFFFAOYSA-N 0.000 description 10
• 229910052763 palladium Inorganic materials 0.000 description 10
• 229910052938 sodium sulfate Inorganic materials 0.000 description 10
• 235000011152 sodium sulphate Nutrition 0.000 description 10
• 229910052717 sulfur Inorganic materials 0.000 description 10
• LIUWXFDZLUUPNO-UHFFFAOYSA-N 3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound OC1C(CCCC)(CC)CS(=O)(=O)C2=CC=C(OC)C=C2C1C1=CC=CC=C1 LIUWXFDZLUUPNO-UHFFFAOYSA-N 0.000 description 9
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 9
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 9
• ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 9
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
• 239000002253 acid Substances 0.000 description 9
• 235000001014 amino acid Nutrition 0.000 description 9
• SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 9
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
• 238000001819 mass spectrum Methods 0.000 description 9
• 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 9
• 229910000104 sodium hydride Inorganic materials 0.000 description 9
• 238000003786 synthesis reaction Methods 0.000 description 9
• ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 9
• ZTWKMAVJNRKHNH-UHFFFAOYSA-N 3-butyl-3-ethyl-2h-1-benzothiepine Chemical compound C1=CC(CCCC)(CC)CSC2=CC=CC=C21 ZTWKMAVJNRKHNH-UHFFFAOYSA-N 0.000 description 8
• QGOXWYNDZSFSGE-UHFFFAOYSA-N 3-butyl-3-ethyl-5-(4-fluorophenyl)-7-methyl-1,1-dioxo-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound OC1C(CCCC)(CC)CS(=O)(=O)C2=CC=C(C)C=C2C1C1=CC=C(F)C=C1 QGOXWYNDZSFSGE-UHFFFAOYSA-N 0.000 description 8
• VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 8
• 238000004458 analytical method Methods 0.000 description 8
• RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 8
• 239000012298 atmosphere Substances 0.000 description 8
• 230000015572 biosynthetic process Effects 0.000 description 8
• 235000012000 cholesterol Nutrition 0.000 description 8
• 239000002552 dosage form Substances 0.000 description 8
• GLNWILHOFOBOFD-UHFFFAOYSA-N lithium sulfide Chemical compound [Li+].[Li+].[S-2] GLNWILHOFOBOFD-UHFFFAOYSA-N 0.000 description 8
• 239000003444 phase transfer catalyst Substances 0.000 description 8
• 229920001223 polyethylene glycol Polymers 0.000 description 8
• 239000000843 powder Substances 0.000 description 8
• LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 8
• 239000000741 silica gel Substances 0.000 description 8
• 229910002027 silica gel Inorganic materials 0.000 description 8
• 239000003643 water by type Substances 0.000 description 8
• QANJZEAVQNLIOJ-UHFFFAOYSA-N 2-[(2-benzoyl-4-methoxyphenyl)sulfanylmethyl]-2-ethylhexanal Chemical compound CCCCC(CC)(C=O)CSC1=CC=C(OC)C=C1C(=O)C1=CC=CC=C1 QANJZEAVQNLIOJ-UHFFFAOYSA-N 0.000 description 7
• 102000004316 Oxidoreductases Human genes 0.000 description 7
• 108090000854 Oxidoreductases Proteins 0.000 description 7
• UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 7
• 239000004480 active ingredient Substances 0.000 description 7
• HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 7
• 239000003795 chemical substances by application Substances 0.000 description 7
• 238000004440 column chromatography Methods 0.000 description 7
• 239000013078 crystal Substances 0.000 description 7
• 230000003647 oxidation Effects 0.000 description 7
• 238000007254 oxidation reaction Methods 0.000 description 7
• 230000009467 reduction Effects 0.000 description 7
• 238000006722 reduction reaction Methods 0.000 description 7
• 230000002829 reductive effect Effects 0.000 description 7
• 238000001228 spectrum Methods 0.000 description 7
• 150000003457 sulfones Chemical class 0.000 description 7
• 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
• DEPBQKDMVZBVHV-UHFFFAOYSA-N 2-(2-ethyl-2-formylhex-3-enyl)sulfanylbenzaldehyde Chemical compound CCC=CC(CC)(C=O)CSC1=CC=CC=C1C=O DEPBQKDMVZBVHV-UHFFFAOYSA-N 0.000 description 6
• BLDXZLIMYAPSAH-UHFFFAOYSA-N 3-butyl-3-ethyl-5-(3-fluorophenyl)-7-methoxy-1,1-dioxo-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound OC1C(CCCC)(CC)CS(=O)(=O)C2=CC=C(OC)C=C2C1C1=CC=CC(F)=C1 BLDXZLIMYAPSAH-UHFFFAOYSA-N 0.000 description 6
• VQRPUTKDKGKBNK-UHFFFAOYSA-N 3-butyl-3-ethyl-5-phenyl-4,5-dihydro-2h-1-benzothiepin-4-ol Chemical compound OC1C(CCCC)(CC)CSC2=CC=CC=C2C1C1=CC=CC=C1 VQRPUTKDKGKBNK-UHFFFAOYSA-N 0.000 description 6
• QLGASNJOKSCXCB-UHFFFAOYSA-N 3-butyl-3-ethyl-7-(hydroxyamino)-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound OC1C(CCCC)(CC)CS(=O)(=O)C2=CC=C(NO)C=C2C1C1=CC=CC=C1 QLGASNJOKSCXCB-UHFFFAOYSA-N 0.000 description 6
• QVKOWDUHBZJBOC-UHFFFAOYSA-N 3-butyl-3-ethyl-7-fluoro-5-(4-fluorophenyl)-1,1-dioxo-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound OC1C(CCCC)(CC)CS(=O)(=O)C2=CC=C(F)C=C2C1C1=CC=C(F)C=C1 QVKOWDUHBZJBOC-UHFFFAOYSA-N 0.000 description 6
• WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
• QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 6
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
• 125000005605 benzo group Chemical group 0.000 description 6
• 229910002092 carbon dioxide Inorganic materials 0.000 description 6
• 239000012230 colorless oil Substances 0.000 description 6
• 125000004122 cyclic group Chemical group 0.000 description 6
• 239000002027 dichloromethane extract Substances 0.000 description 6
• 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 6
• 238000001914 filtration Methods 0.000 description 6
• 125000005842 heteroatom Chemical group 0.000 description 6
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
• 239000012071 phase Substances 0.000 description 6
• 150000003242 quaternary ammonium salts Chemical group 0.000 description 6
• 238000010992 reflux Methods 0.000 description 6
• 239000012312 sodium hydride Substances 0.000 description 6
• GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 6
• KMOMYYQPSMRALT-UHFFFAOYSA-N (1-formylcyclohexyl)methyl methanesulfonate Chemical compound CS(=O)(=O)OCC1(C=O)CCCCC1 KMOMYYQPSMRALT-UHFFFAOYSA-N 0.000 description 5
• UPJIKDUARWRZGR-UHFFFAOYSA-N 3-butyl-3-ethyl-5-phenyl-2h-1$l^{6}-benzothiepine 1,1-dioxide Chemical compound C=1C(CCCC)(CC)CS(=O)(=O)C2=CC=CC=C2C=1C1=CC=CC=C1 UPJIKDUARWRZGR-UHFFFAOYSA-N 0.000 description 5
• JFUWHXRFYNRIHP-UHFFFAOYSA-N 3-butyl-3-ethyl-7-(hexylamino)-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound C=1C(NCCCCCC)=CC=C(S(CC(CC)(CCCC)C2O)(=O)=O)C=1C2C1=CC=CC=C1 JFUWHXRFYNRIHP-UHFFFAOYSA-N 0.000 description 5
• BRUPDJCPCGJHKU-UHFFFAOYSA-N 7-amino-3-butyl-3-ethyl-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound OC1C(CCCC)(CC)CS(=O)(=O)C2=CC=C(N)C=C2C1C1=CC=CC=C1 BRUPDJCPCGJHKU-UHFFFAOYSA-N 0.000 description 5
• HAVLYCOBDKCESG-UHFFFAOYSA-N 7-bromo-3-butyl-3-ethyl-5-(3-methoxyphenyl)-1,1-dioxo-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound OC1C(CCCC)(CC)CS(=O)(=O)C2=CC=C(Br)C=C2C1C1=CC=CC(OC)=C1 HAVLYCOBDKCESG-UHFFFAOYSA-N 0.000 description 5
• BKZFXMRDRDHMCE-UHFFFAOYSA-N 8b-phenylspiro[1a,3-dihydro-[1]benzothiepino[4,5-b]oxirene-2,1'-cyclohexane] 4,4-dioxide Chemical compound C12OC2(C=2C=CC=CC=2)C2=CC=CC=C2S(=O)(=O)CC21CCCCC2 BKZFXMRDRDHMCE-UHFFFAOYSA-N 0.000 description 5
• 208000031226 Hyperlipidaemia Diseases 0.000 description 5
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 5
• 239000002202 Polyethylene glycol Substances 0.000 description 5
• HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 5
• 239000013543 active substance Substances 0.000 description 5
• 125000004429 atom Chemical group 0.000 description 5
• 239000002585 base Substances 0.000 description 5
• 239000012043 crude product Substances 0.000 description 5
• 239000008187 granular material Substances 0.000 description 5
• 238000005984 hydrogenation reaction Methods 0.000 description 5
• 239000007788 liquid Substances 0.000 description 5
• 239000012074 organic phase Substances 0.000 description 5
• 238000001953 recrystallisation Methods 0.000 description 5
• RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 description 5
• SEPPVOUBHWNCAW-FNORWQNLSA-N (E)-4-oxonon-2-enal Chemical compound CCCCCC(=O)\C=C\C=O SEPPVOUBHWNCAW-FNORWQNLSA-N 0.000 description 4
• YZWJRUFHOBINIK-UHFFFAOYSA-N 1-ethoxy-2-iodoethane Chemical compound CCOCCI YZWJRUFHOBINIK-UHFFFAOYSA-N 0.000 description 4
• PXLCKXNRBHILEC-UHFFFAOYSA-N 2-[(2-benzylphenyl)sulfonylmethyl]-2-ethylhexanal Chemical compound CCCCC(CC)(C=O)CS(=O)(=O)C1=CC=CC=C1CC1=CC=CC=C1 PXLCKXNRBHILEC-UHFFFAOYSA-N 0.000 description 4
• 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 4
• CYWOXKDZYSNWAC-UHFFFAOYSA-N 3-butyl-3-ethyl-5-(2-fluorophenyl)-7-methoxy-1,1-dioxo-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound OC1C(CCCC)(CC)CS(=O)(=O)C2=CC=C(OC)C=C2C1C1=CC=CC=C1F CYWOXKDZYSNWAC-UHFFFAOYSA-N 0.000 description 4
• PHTOFROJNXPBGG-UHFFFAOYSA-N 3-butyl-3-ethyl-7-fluoro-5-(3-methoxyphenyl)-1,1-dioxo-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound OC1C(CCCC)(CC)CS(=O)(=O)C2=CC=C(F)C=C2C1C1=CC=CC(OC)=C1 PHTOFROJNXPBGG-UHFFFAOYSA-N 0.000 description 4
• JQZAGTDYBBJHIX-UHFFFAOYSA-N CCCCC1(CS(=O)(=O)C2=CC=CC=C2C(C1O)(C3=CC=CC=C3)C4=CC=C(C=C4)C(=O)OC)CC Chemical compound CCCCC1(CS(=O)(=O)C2=CC=CC=C2C(C1O)(C3=CC=CC=C3)C4=CC=C(C=C4)C(=O)OC)CC JQZAGTDYBBJHIX-UHFFFAOYSA-N 0.000 description 4
• VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
• GUUVPOWQJOLRAS-UHFFFAOYSA-N Diphenyl disulfide Chemical compound C=1C=CC=CC=1SSC1=CC=CC=C1 GUUVPOWQJOLRAS-UHFFFAOYSA-N 0.000 description 4
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
• KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
• GNVMUORYQLCPJZ-UHFFFAOYSA-M Thiocarbamate Chemical compound NC([S-])=O GNVMUORYQLCPJZ-UHFFFAOYSA-M 0.000 description 4
• 239000008346 aqueous phase Substances 0.000 description 4
• 239000003153 chemical reaction reagent Substances 0.000 description 4
• 239000000460 chlorine Substances 0.000 description 4
• 238000002425 crystallisation Methods 0.000 description 4
• 230000008025 crystallization Effects 0.000 description 4
• 238000000502 dialysis Methods 0.000 description 4
• 230000000694 effects Effects 0.000 description 4
• 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 4
• 239000012259 ether extract Substances 0.000 description 4
• 210000001035 gastrointestinal tract Anatomy 0.000 description 4
• AVXURJPOCDRRFD-UHFFFAOYSA-N hydroxylamine group Chemical group NO AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 4
• 239000012442 inert solvent Substances 0.000 description 4
• 238000002347 injection Methods 0.000 description 4
• 239000007924 injection Substances 0.000 description 4
• UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 4
• 229910052698 phosphorus Inorganic materials 0.000 description 4
• 238000001556 precipitation Methods 0.000 description 4
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
• 210000002966 serum Anatomy 0.000 description 4
• 239000012279 sodium borohydride Substances 0.000 description 4
• 229910000033 sodium borohydride Inorganic materials 0.000 description 4
• 229910001220 stainless steel Inorganic materials 0.000 description 4
• 239000010935 stainless steel Substances 0.000 description 4
• 229930192474 thiophene Natural products 0.000 description 4
• 238000012546 transfer Methods 0.000 description 4
• 238000011269 treatment regimen Methods 0.000 description 4
• 125000005208 trialkylammonium group Chemical group 0.000 description 4
• DRWFGONWDUTLBQ-PMACEKPBSA-N (4s,5s)-1,1-dioxo-5-phenylspiro[4,5-dihydro-2h-1$l^{6}-benzothiepine-3,1'-cyclohexane]-4-ol Chemical compound C1([C@@H]2[C@@H](C3(CCCCC3)CS(=O)(=O)C3=CC=CC=C32)O)=CC=CC=C1 DRWFGONWDUTLBQ-PMACEKPBSA-N 0.000 description 3
• GUJIEECSCPXZRG-UHFFFAOYSA-N (5-methoxy-2-sulfanylphenyl)-phenylmethanone Chemical compound COC1=CC=C(S)C(C(=O)C=2C=CC=CC=2)=C1 GUJIEECSCPXZRG-UHFFFAOYSA-N 0.000 description 3
• NBWRHTJEHJHXCK-UHFFFAOYSA-N 1-(hydroxymethyl)cyclohexane-1-carbaldehyde Chemical compound OCC1(C=O)CCCCC1 NBWRHTJEHJHXCK-UHFFFAOYSA-N 0.000 description 3
• SIRCASMGGILITF-UHFFFAOYSA-N 1-chloro-2-[(4-methoxyphenyl)methyl]-4-nitrobenzene Chemical compound C1=CC(OC)=CC=C1CC1=CC([N+]([O-])=O)=CC=C1Cl SIRCASMGGILITF-UHFFFAOYSA-N 0.000 description 3
• KUKRUCOSBIJPJE-UHFFFAOYSA-N 2-[(2-benzoylphenyl)sulfanylmethyl]butanal Chemical compound CCC(C=O)CSC1=CC=CC=C1C(=O)C1=CC=CC=C1 KUKRUCOSBIJPJE-UHFFFAOYSA-N 0.000 description 3
• KXJLESOARKPUOX-UHFFFAOYSA-N 2-[(2-benzyl-4-methoxyphenyl)sulfonylmethyl]-2-ethylhexanal Chemical compound CCCCC(CC)(C=O)CS(=O)(=O)C1=CC=C(OC)C=C1CC1=CC=CC=C1 KXJLESOARKPUOX-UHFFFAOYSA-N 0.000 description 3
• HTNLNYQXDQKJOF-UHFFFAOYSA-N 2-[(2-benzyl-4-nitrophenyl)sulfanylmethyl]-2-ethylhexanal Chemical compound CCCCC(CC)(C=O)CSC1=CC=C([N+]([O-])=O)C=C1CC1=CC=CC=C1 HTNLNYQXDQKJOF-UHFFFAOYSA-N 0.000 description 3
• IHINCNFDYOPPFN-UHFFFAOYSA-N 2-[(2-benzyl-4-nitrophenyl)sulfonylmethyl]-2-ethylhexanal Chemical compound CCCCC(CC)(C=O)CS(=O)(=O)C1=CC=C([N+]([O-])=O)C=C1CC1=CC=CC=C1 IHINCNFDYOPPFN-UHFFFAOYSA-N 0.000 description 3
• GXWCNKNXEIMGGV-UHFFFAOYSA-N 2-[(2-benzylphenyl)sulfanylmethyl]-2-ethylhexanal Chemical compound CCCCC(CC)(C=O)CSC1=CC=CC=C1CC1=CC=CC=C1 GXWCNKNXEIMGGV-UHFFFAOYSA-N 0.000 description 3
• NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
• JJUDCQAZKNKAQD-UHFFFAOYSA-N 2-[[2-benzyl-4-(hexylamino)phenyl]sulfonylmethyl]-2-ethylhexanal Chemical compound CCCCCCNC1=CC=C(S(=O)(=O)CC(CC)(CCCC)C=O)C(CC=2C=CC=CC=2)=C1 JJUDCQAZKNKAQD-UHFFFAOYSA-N 0.000 description 3
• WHKOFFPFEDYKEO-UHFFFAOYSA-N 2-ethyl-2-[[2-(hydroxymethyl)phenyl]sulfanylmethyl]hex-3-enal Chemical compound CCC=CC(CC)(C=O)CSC1=CC=CC=C1CO WHKOFFPFEDYKEO-UHFFFAOYSA-N 0.000 description 3
• BSTJYEHXNQXLSR-UHFFFAOYSA-N 3,5-dibutyl-4-fluorophthalaldehyde Chemical compound CCCCC1=CC(C=O)=C(C=O)C(CCCC)=C1F BSTJYEHXNQXLSR-UHFFFAOYSA-N 0.000 description 3
• BPITVROXPFMGQD-UHFFFAOYSA-N 3-butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxo-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound OC1C(CCCC)(CC)CS(=O)(=O)C2=CC=C(OC)C=C2C1C1=CC=C(F)C=C1 BPITVROXPFMGQD-UHFFFAOYSA-N 0.000 description 3
• FIMYYRWZVJCULV-UHFFFAOYSA-N 3-butyl-3-ethyl-5-(4-fluorophenyl)-7-methylsulfanyl-1,1-dioxo-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound OC1C(CCCC)(CC)CS(=O)(=O)C2=CC=C(SC)C=C2C1C1=CC=C(F)C=C1 FIMYYRWZVJCULV-UHFFFAOYSA-N 0.000 description 3
• ZRSLMHHLRAYXSW-UHFFFAOYSA-N 3-butyl-3-ethyl-5-(4-hydroxyphenyl)-7-methoxy-1,1-dioxo-2,4,5,6-tetrahydro-1lambda6-benzothiepine-4,7-diol Chemical compound CCCCC1(CS(=O)(=O)C2=C(CC(C=C2)(O)OC)C(C1O)C3=CC=C(C=C3)O)CC ZRSLMHHLRAYXSW-UHFFFAOYSA-N 0.000 description 3
• PPFBHLNIPFHQGD-UHFFFAOYSA-N 3-butyl-3-ethyl-5-(4-iodophenyl)-1,1-dioxo-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound OC1C(CCCC)(CC)CS(=O)(=O)C2=CC=CC=C2C1C1=CC=C(I)C=C1 PPFBHLNIPFHQGD-UHFFFAOYSA-N 0.000 description 3
• QGJJBZPIRVZQPJ-UHFFFAOYSA-N 3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-[3-(trifluoromethyl)phenyl]-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound OC1C(CCCC)(CC)CS(=O)(=O)C2=CC=C(OC)C=C2C1C1=CC=CC(C(F)(F)F)=C1 QGJJBZPIRVZQPJ-UHFFFAOYSA-N 0.000 description 3
• WIVGBMRIWPSGHW-UHFFFAOYSA-N 3-ethyl-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1$l^{6}-benzothiepin-4-ol Chemical compound OC1C(CC)CS(=O)(=O)C2=CC=CC=C2C1C1=CC=CC=C1 WIVGBMRIWPSGHW-UHFFFAOYSA-N 0.000 description 3
• 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 3
• 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 description 3
• 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
• CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
• YCSCQZASDNBBEX-UHFFFAOYSA-N CCCC(C(C)(CC)C=O)S(=O)(=O)C1=CC=CC=C1C(=O)C2=CC=CC=C2 Chemical compound CCCC(C(C)(CC)C=O)S(=O)(=O)C1=CC=CC=C1C(=O)C2=CC=CC=C2 YCSCQZASDNBBEX-UHFFFAOYSA-N 0.000 description 3
• 229920001268 Cholestyramine Polymers 0.000 description 3
• ZNZYKNKBJPZETN-WELNAUFTSA-N Dialdehyde 11678 Chemical compound N1C2=CC=CC=C2C2=C1[C@H](C[C@H](/C(=C/O)C(=O)OC)[C@@H](C=C)C=O)NCC2 ZNZYKNKBJPZETN-WELNAUFTSA-N 0.000 description 3
• 238000008214 LDL Cholesterol Methods 0.000 description 3
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
• CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
• 229930006000 Sucrose Natural products 0.000 description 3
• 229910010068 TiCl2 Inorganic materials 0.000 description 3
• 229960000583 acetic acid Drugs 0.000 description 3
• 150000001299 aldehydes Chemical class 0.000 description 3
• 150000001335 aliphatic alkanes Chemical class 0.000 description 3
• 150000001336 alkenes Chemical class 0.000 description 3
• 150000001345 alkine derivatives Chemical class 0.000 description 3
• 239000003529 anticholesteremic agent Substances 0.000 description 3
• JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
• SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 3
• 210000004369 blood Anatomy 0.000 description 3
• 239000008280 blood Substances 0.000 description 3
• 239000000969 carrier Substances 0.000 description 3
• 239000012141 concentrate Substances 0.000 description 3
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 3
• 239000008298 dragée Substances 0.000 description 3
• 229940079593 drug Drugs 0.000 description 3
• 239000003937 drug carrier Substances 0.000 description 3
• 238000000605 extraction Methods 0.000 description 3
• 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 3
• 238000004817 gas chromatography Methods 0.000 description 3
• 230000002440 hepatic effect Effects 0.000 description 3
• 230000000055 hyoplipidemic effect Effects 0.000 description 3
• 230000000968 intestinal effect Effects 0.000 description 3
• 150000004694 iodide salts Chemical group 0.000 description 3
• INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
• 239000000314 lubricant Substances 0.000 description 3
• XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 description 3
• 238000002156 mixing Methods 0.000 description 3
• 230000004048 modification Effects 0.000 description 3
• 238000012986 modification Methods 0.000 description 3
• 239000000546 pharmaceutical excipient Substances 0.000 description 3
• SPEXCGKGVJUPGG-UHFFFAOYSA-N phenyl-(2-sulfanylphenyl)methanone Chemical compound SC1=CC=CC=C1C(=O)C1=CC=CC=C1 SPEXCGKGVJUPGG-UHFFFAOYSA-N 0.000 description 3
• 210000002381 plasma Anatomy 0.000 description 3
• 230000008569 process Effects 0.000 description 3
• 229920006395 saturated elastomer Polymers 0.000 description 3
• 238000000926 separation method Methods 0.000 description 3
• 239000011734 sodium Substances 0.000 description 3
• 235000010265 sodium sulphite Nutrition 0.000 description 3
• 239000005720 sucrose Substances 0.000 description 3
• 230000001225 therapeutic effect Effects 0.000 description 3
• ZWYDDDAMNQQZHD-UHFFFAOYSA-L titanium(ii) chloride Chemical compound [Cl-].[Cl-].[Ti+2] ZWYDDDAMNQQZHD-UHFFFAOYSA-L 0.000 description 3
• GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 3
• PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
• HRPHZUAPQWJPCZ-UHFFFAOYSA-N (2-chloro-5-nitrophenyl)-phenylmethanone Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)C=2C=CC=CC=2)=C1 HRPHZUAPQWJPCZ-UHFFFAOYSA-N 0.000 description 2
• GDGBEHMHWKTMAA-UHFFFAOYSA-N (4-methoxy-2-sulfanylphenyl)-phenylmethanone Chemical compound SC1=CC(OC)=CC=C1C(=O)C1=CC=CC=C1 GDGBEHMHWKTMAA-UHFFFAOYSA-N 0.000 description 2
• DRWFGONWDUTLBQ-UXHICEINSA-N (4s,5r)-1,1-dioxo-5-phenylspiro[4,5-dihydro-2h-1$l^{6}-benzothiepine-3,1'-cyclohexane]-4-ol Chemical compound C1([C@H]2[C@@H](C3(CCCCC3)CS(=O)(=O)C3=CC=CC=C32)O)=CC=CC=C1 DRWFGONWDUTLBQ-UXHICEINSA-N 0.000 description 2
• CKQFWQCSMNUSRI-UHFFFAOYSA-N 1,1-dimethylpiperazin-1-ium Chemical compound C[N+]1(C)CCNCC1 CKQFWQCSMNUSRI-UHFFFAOYSA-N 0.000 description 2
• BCAGFJXMCZSAHD-UHFFFAOYSA-N 1,2-bis(2-iodoethoxy)ethane Chemical compound ICCOCCOCCI BCAGFJXMCZSAHD-UHFFFAOYSA-N 0.000 description 2
• XBDXMDVEZLOGMC-UHFFFAOYSA-N 1-(chloromethyl)-3-fluorobenzene Chemical compound FC1=CC=CC(CCl)=C1 XBDXMDVEZLOGMC-UHFFFAOYSA-N 0.000 description 2
• VGISFWWEOGVMED-UHFFFAOYSA-N 1-(chloromethyl)-3-methoxybenzene Chemical compound COC1=CC=CC(CCl)=C1 VGISFWWEOGVMED-UHFFFAOYSA-N 0.000 description 2
• IZXWCDITFDNEBY-UHFFFAOYSA-N 1-(chloromethyl)-4-fluorobenzene Chemical compound FC1=CC=C(CCl)C=C1 IZXWCDITFDNEBY-UHFFFAOYSA-N 0.000 description 2
• PWMWNFMRSKOCEY-UHFFFAOYSA-N 1-Phenyl-1,2-ethanediol Chemical compound OCC(O)C1=CC=CC=C1 PWMWNFMRSKOCEY-UHFFFAOYSA-N 0.000 description 2
• DNAYDBYAXQKBDH-UHFFFAOYSA-N 1-[(2-benzoylphenyl)sulfanylmethyl]cyclohexane-1-carbaldehyde Chemical compound C=1C=CC=C(C(=O)C=2C=CC=CC=2)C=1SCC1(C=O)CCCCC1 DNAYDBYAXQKBDH-UHFFFAOYSA-N 0.000 description 2
• QYTJZBUUVWEPAI-UHFFFAOYSA-N 2-[(2-benzoyl-5-methoxyphenyl)sulfonylmethyl]-2-ethylhexanal Chemical compound CCCCC(CC)(C=O)CS(=O)(=O)C1=CC(OC)=CC=C1C(=O)C1=CC=CC=C1 QYTJZBUUVWEPAI-UHFFFAOYSA-N 0.000 description 2
• CDMGNVWZXRKJNS-UHFFFAOYSA-N 2-benzylphenol Chemical compound OC1=CC=CC=C1CC1=CC=CC=C1 CDMGNVWZXRKJNS-UHFFFAOYSA-N 0.000 description 2
• LLWADFLAOKUBDR-UHFFFAOYSA-N 2-methyl-4-chlorophenoxybutyric acid Chemical compound CC1=CC(Cl)=CC=C1OCCCC(O)=O LLWADFLAOKUBDR-UHFFFAOYSA-N 0.000 description 2
• QUEKGYQTRJVEQC-UHFFFAOYSA-N 2516-96-3 Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl QUEKGYQTRJVEQC-UHFFFAOYSA-N 0.000 description 2
• HKOMRBZBGBHSFR-UHFFFAOYSA-N 3-butyl-3-ethyl-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6}-benzothiepine-4,8-diol Chemical compound OC1C(CCCC)(CC)CS(=O)(=O)C2=CC(O)=CC=C2C1C1=CC=CC=C1 HKOMRBZBGBHSFR-UHFFFAOYSA-N 0.000 description 2
• LYZKBYRRZOTXBZ-UHFFFAOYSA-N 3-butyl-3-ethyl-5-(3-methoxyphenyl)-7-methylsulfanyl-1,1-dioxo-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound OC1C(CCCC)(CC)CS(=O)(=O)C2=CC=C(SC)C=C2C1C1=CC=CC(OC)=C1 LYZKBYRRZOTXBZ-UHFFFAOYSA-N 0.000 description 2
• UDQNLQUBJXZEPT-UHFFFAOYSA-N 3-butyl-3-ethyl-5-(4-fluorophenyl)-1,1-dioxo-7-pyrrolidin-1-yl-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound OC1C(CCCC)(CC)CS(=O)(=O)C2=CC=C(N3CCCC3)C=C2C1C1=CC=C(F)C=C1 UDQNLQUBJXZEPT-UHFFFAOYSA-N 0.000 description 2
• BGLHQHFVTIAFBN-UHFFFAOYSA-N 3-butyl-3-ethyl-7-methoxy-5-(3-methoxyphenyl)-1,1-dioxo-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound OC1C(CCCC)(CC)CS(=O)(=O)C2=CC=C(OC)C=C2C1C1=CC=CC(OC)=C1 BGLHQHFVTIAFBN-UHFFFAOYSA-N 0.000 description 2
• LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 2
• 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 2
• RHMPLDJJXGPMEX-UHFFFAOYSA-N 4-fluorophenol Chemical compound OC1=CC=C(F)C=C1 RHMPLDJJXGPMEX-UHFFFAOYSA-N 0.000 description 2
• NIFAOMSJMGEFTQ-UHFFFAOYSA-N 4-methoxybenzenethiol Chemical compound COC1=CC=C(S)C=C1 NIFAOMSJMGEFTQ-UHFFFAOYSA-N 0.000 description 2
• LLBZPESJRQGYMB-UHFFFAOYSA-N 4-one Natural products O1C(C(=O)CC)CC(C)C11C2(C)CCC(C3(C)C(C(C)(CO)C(OC4C(C(O)C(O)C(COC5C(C(O)C(O)CO5)OC5C(C(OC6C(C(O)C(O)C(CO)O6)O)C(O)C(CO)O5)OC5C(C(O)C(O)C(C)O5)O)O4)O)CC3)CC3)=C3C2(C)CC1 LLBZPESJRQGYMB-UHFFFAOYSA-N 0.000 description 2
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
• FJNCXZZQNBKEJT-UHFFFAOYSA-N 8beta-hydroxymarrubiin Natural products O1C(=O)C2(C)CCCC3(C)C2C1CC(C)(O)C3(O)CCC=1C=COC=1 FJNCXZZQNBKEJT-UHFFFAOYSA-N 0.000 description 2
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
• VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
• KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 2
• 108010010803 Gelatin Proteins 0.000 description 2
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
• 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 2
• 241000282412 Homo Species 0.000 description 2
• 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 2
• 108010007622 LDL Lipoproteins Proteins 0.000 description 2
• 102000007330 LDL Lipoproteins Human genes 0.000 description 2
• 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
• 240000007472 Leucaena leucocephala Species 0.000 description 2
• 239000005575 MCPB Substances 0.000 description 2
• 101150039283 MCPB gene Proteins 0.000 description 2
• NPPQSCRMBWNHMW-UHFFFAOYSA-N Meprobamate Chemical group NC(=O)OCC(C)(CCC)COC(N)=O NPPQSCRMBWNHMW-UHFFFAOYSA-N 0.000 description 2
• 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
• HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 2
• ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
• ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
• WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 2
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
• FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
• 238000010521 absorption reaction Methods 0.000 description 2
• 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 2
• 230000009471 action Effects 0.000 description 2
• 125000003277 amino group Chemical group 0.000 description 2
• 150000003863 ammonium salts Chemical class 0.000 description 2
• 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
• 125000005427 anthranyl group Chemical group 0.000 description 2
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
• 239000011324 bead Substances 0.000 description 2
• 230000009286 beneficial effect Effects 0.000 description 2
• 235000019445 benzyl alcohol Nutrition 0.000 description 2
• 239000011230 binding agent Substances 0.000 description 2
• 230000033228 biological regulation Effects 0.000 description 2
• 150000001649 bromium compounds Chemical class 0.000 description 2
• 125000001246 bromo group Chemical group Br* 0.000 description 2
• 230000005587 bubbling Effects 0.000 description 2
• 238000004177 carbon cycle Methods 0.000 description 2
• 229910002091 carbon monoxide Inorganic materials 0.000 description 2
• 150000007942 carboxylates Chemical class 0.000 description 2
• 210000004027 cell Anatomy 0.000 description 2
• 229920002678 cellulose Polymers 0.000 description 2
• 239000001913 cellulose Substances 0.000 description 2
• 238000004587 chromatography analysis Methods 0.000 description 2
• 239000007891 compressed tablet Substances 0.000 description 2
• 235000008504 concentrate Nutrition 0.000 description 2
• 125000006612 decyloxy group Chemical group 0.000 description 2
• 239000008367 deionised water Substances 0.000 description 2
• 229910021641 deionized water Inorganic materials 0.000 description 2
• 239000003085 diluting agent Substances 0.000 description 2
• USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 2
• 239000002270 dispersing agent Substances 0.000 description 2
• 239000006185 dispersion Substances 0.000 description 2
• 238000004821 distillation Methods 0.000 description 2
• 230000010235 enterohepatic circulation Effects 0.000 description 2
• DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 2
• ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 2
• 230000029142 excretion Effects 0.000 description 2
• 238000002474 experimental method Methods 0.000 description 2
• 229910052731 fluorine Inorganic materials 0.000 description 2
• 239000006260 foam Substances 0.000 description 2
• 210000003918 fraction a Anatomy 0.000 description 2
• 239000008273 gelatin Substances 0.000 description 2
• 229920000159 gelatin Polymers 0.000 description 2
• 235000019322 gelatine Nutrition 0.000 description 2
• 235000011852 gelatine desserts Nutrition 0.000 description 2
• JARKCYVAAOWBJS-UHFFFAOYSA-N hexanal Chemical compound CCCCCC=O JARKCYVAAOWBJS-UHFFFAOYSA-N 0.000 description 2
• 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
• 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 2
• 150000002430 hydrocarbons Chemical group 0.000 description 2
• 230000007062 hydrolysis Effects 0.000 description 2
• 238000006460 hydrolysis reaction Methods 0.000 description 2
• 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 2
• 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
• 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
• 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
• 210000003405 ileum Anatomy 0.000 description 2
• 238000000338 in vitro Methods 0.000 description 2
• 239000004615 ingredient Substances 0.000 description 2
• 229940102223 injectable solution Drugs 0.000 description 2
• 229940102213 injectable suspension Drugs 0.000 description 2
• 238000007918 intramuscular administration Methods 0.000 description 2
• 239000011630 iodine Substances 0.000 description 2
• 229910052740 iodine Inorganic materials 0.000 description 2
• 238000002955 isolation Methods 0.000 description 2
• 239000007937 lozenge Substances 0.000 description 2
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
• 239000002609 medium Substances 0.000 description 2
• QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
• PNEQQYWNXTTZDD-UHFFFAOYSA-M methyl-tri(octanoyl)azanium;chloride Chemical compound [Cl-].CCCCCCCC(=O)[N+](C)(C(=O)CCCCCCC)C(=O)CCCCCCC PNEQQYWNXTTZDD-UHFFFAOYSA-M 0.000 description 2
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
• 239000012452 mother liquor Substances 0.000 description 2
• PHWISQNXPLXQRU-UHFFFAOYSA-N n,n-dimethylcarbamothioyl chloride Chemical compound CN(C)C(Cl)=S PHWISQNXPLXQRU-UHFFFAOYSA-N 0.000 description 2
• 239000000346 nonvolatile oil Substances 0.000 description 2
• 239000004533 oil dispersion Substances 0.000 description 2
• 230000003287 optical effect Effects 0.000 description 2
• 125000005702 oxyalkylene group Chemical group 0.000 description 2
• 239000001301 oxygen Substances 0.000 description 2
• IWDCLRJOBJJRNH-UHFFFAOYSA-N p-cresol Chemical compound CC1=CC=C(O)C=C1 IWDCLRJOBJJRNH-UHFFFAOYSA-N 0.000 description 2
• 239000002245 particle Substances 0.000 description 2
• 230000035699 permeability Effects 0.000 description 2
• UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 2
• 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 description 2
• 229920000768 polyamine Polymers 0.000 description 2
• 239000011591 potassium Substances 0.000 description 2
• 229910052700 potassium Inorganic materials 0.000 description 2
• 239000002244 precipitate Substances 0.000 description 2
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
• 238000010791 quenching Methods 0.000 description 2
• 238000011160 research Methods 0.000 description 2
• 238000007363 ring formation reaction Methods 0.000 description 2
• 238000002390 rotary evaporation Methods 0.000 description 2
• 239000000523 sample Substances 0.000 description 2
• 238000007493 shaping process Methods 0.000 description 2
• 229910052708 sodium Inorganic materials 0.000 description 2
• 238000010561 standard procedure Methods 0.000 description 2
• 238000007920 subcutaneous administration Methods 0.000 description 2
• 239000000758 substrate Substances 0.000 description 2
• 239000011593 sulfur Substances 0.000 description 2
• 239000004094 surface-active agent Substances 0.000 description 2
• 239000000375 suspending agent Substances 0.000 description 2
• 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 2
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
• HQHCYKULIHKCEB-UHFFFAOYSA-N tetradecanedioic acid Chemical compound OC(=O)CCCCCCCCCCCCC(O)=O HQHCYKULIHKCEB-UHFFFAOYSA-N 0.000 description 2
• 238000002560 therapeutic procedure Methods 0.000 description 2
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
• 230000000699 topical effect Effects 0.000 description 2
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
• UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 description 2
• HHZHIYCBQKSFLC-UHFFFAOYSA-N (2,5-dinitrophenyl)-phenylmethanone Chemical compound [N+](=O)([O-])C1=C(C(=O)C2=CC=CC=C2)C=C(C=C1)[N+](=O)[O-] HHZHIYCBQKSFLC-UHFFFAOYSA-N 0.000 description 1
• IOWGHQGLUMEZKG-UHFFFAOYSA-N (2-bromophenyl)methanol Chemical compound OCC1=CC=CC=C1Br IOWGHQGLUMEZKG-UHFFFAOYSA-N 0.000 description 1
• PGIPTXFXNUVZFZ-UHFFFAOYSA-N (2-chloro-4-nitrophenyl)-phenylmethanone Chemical compound ClC1=CC([N+](=O)[O-])=CC=C1C(=O)C1=CC=CC=C1 PGIPTXFXNUVZFZ-UHFFFAOYSA-N 0.000 description 1
• FYWFCRHZXORPFH-UHFFFAOYSA-N (2-sulfanylphenyl)methanol Chemical compound OCC1=CC=CC=C1S FYWFCRHZXORPFH-UHFFFAOYSA-N 0.000 description 1
• CABVTRNMFUVUDM-VRHQGPGLSA-N (3S)-3-hydroxy-3-methylglutaryl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@@](O)(CC(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CABVTRNMFUVUDM-VRHQGPGLSA-N 0.000 description 1
• WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
• KJTLQQUUPVSXIM-ZCFIWIBFSA-M (R)-mevalonate Chemical compound OCC[C@](O)(C)CC([O-])=O KJTLQQUUPVSXIM-ZCFIWIBFSA-M 0.000 description 1
• DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
• MELSXQFXKQWAOF-UHFFFAOYSA-N 1,1-dioxo-2,3,4,5-tetrahydro-1$l^{6}-benzothiepin-4-ol Chemical compound C1C(O)CCS(=O)(=O)C2=CC=CC=C21 MELSXQFXKQWAOF-UHFFFAOYSA-N 0.000 description 1
• SBGMJPVSLWKXLE-UHFFFAOYSA-N 1,2-dibutyl-4-fluorobenzene Chemical compound CCCCC1=CC=C(F)C=C1CCCC SBGMJPVSLWKXLE-UHFFFAOYSA-N 0.000 description 1
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
• YSJRELMTRCIWOS-UHFFFAOYSA-N 1-(5-bromononan-5-yl)-4-fluorobenzene Chemical compound CCCCC(Br)(CCCC)C1=CC=C(F)C=C1 YSJRELMTRCIWOS-UHFFFAOYSA-N 0.000 description 1
• MOBRMRJUKNQBMY-UHFFFAOYSA-N 1-(chloromethyl)-2-fluorobenzene Chemical compound FC1=CC=CC=C1CCl MOBRMRJUKNQBMY-UHFFFAOYSA-N 0.000 description 1
• UXCRGHVZPKOQPJ-UHFFFAOYSA-N 1-(chloromethyl)-3-(fluoromethyl)benzene Chemical compound FCC1=CC=CC(CCl)=C1 UXCRGHVZPKOQPJ-UHFFFAOYSA-N 0.000 description 1
• OSOLMNHQPVMESZ-UHFFFAOYSA-N 1-[bromo(sulfonyl)methyl]-4-fluorobenzene Chemical compound FC1=CC=C(C(Br)=S(=O)=O)C=C1 OSOLMNHQPVMESZ-UHFFFAOYSA-N 0.000 description 1
• VJPHZHLJQUTEAW-UHFFFAOYSA-N 1-benzothiepine;1,6-diiodohexane Chemical compound ICCCCCCI.S1C=CC=CC2=CC=CC=C12 VJPHZHLJQUTEAW-UHFFFAOYSA-N 0.000 description 1
• FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical class C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 1
• NAMDIHYPBYVYAP-UHFFFAOYSA-N 1-methoxy-2-(2-methoxyethoxy)ethane Chemical compound COCCOCCOC.COCCOCCOC NAMDIHYPBYVYAP-UHFFFAOYSA-N 0.000 description 1
• AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 1
• 238000005160 1H NMR spectroscopy Methods 0.000 description 1
• ZYDUNXCLPOKBNQ-UHFFFAOYSA-N 2,2,6,6-tetramethyl-1,3-dihydropyridine Chemical compound CC1(C)CC=CC(C)(C)N1 ZYDUNXCLPOKBNQ-UHFFFAOYSA-N 0.000 description 1
• OJMJOSRCBAXSAQ-UHFFFAOYSA-N 2,2-dibutylpropane-1,3-diol Chemical compound CCCCC(CO)(CO)CCCC OJMJOSRCBAXSAQ-UHFFFAOYSA-N 0.000 description 1
• TZSDMELQUACXIN-UHFFFAOYSA-N 2,3,4,5-tetrahydro-1$l^{6}-benzothiepine 1,1-dioxide Chemical compound O=S1(=O)CCCCC2=CC=CC=C12 TZSDMELQUACXIN-UHFFFAOYSA-N 0.000 description 1
• QBSVEFGWBSANTE-UHFFFAOYSA-N 2,3,4,6-Tetramethyl-pyridin Natural products CC1=CC(C)=C(C)C(C)=N1 QBSVEFGWBSANTE-UHFFFAOYSA-N 0.000 description 1
• VVVOJODFBWBNBI-UHFFFAOYSA-N 2,5-difluorobenzaldehyde Chemical compound FC1=CC=C(F)C(C=O)=C1 VVVOJODFBWBNBI-UHFFFAOYSA-N 0.000 description 1
• RLRUKKDFNWXXRT-UHFFFAOYSA-N 2,5-difluorobenzoyl chloride Chemical compound FC1=CC=C(F)C(C(Cl)=O)=C1 RLRUKKDFNWXXRT-UHFFFAOYSA-N 0.000 description 1
• RCQMOSJJIVCPJO-UHFFFAOYSA-N 2-(5-methyl-2,4-dioxopyrimidin-1-yl)ethoxymethylphosphonic acid Chemical compound CC1=CN(CCOCP(O)(O)=O)C(=O)NC1=O RCQMOSJJIVCPJO-UHFFFAOYSA-N 0.000 description 1
• GMYSAWFMLYXQTN-UHFFFAOYSA-N 2-[(2-benzylphenyl)sulfonylmethyl]-2-ethylhex-3-enal Chemical compound CCC=CC(CC)(C=O)CS(=O)(=O)C1=CC=CC=C1CC1=CC=CC=C1 GMYSAWFMLYXQTN-UHFFFAOYSA-N 0.000 description 1
• BIBVWHQRJYHXLL-UHFFFAOYSA-N 2-[(2-fluorophenyl)methyl]-4-methoxyphenol Chemical compound COC1=CC=C(O)C(CC=2C(=CC=CC=2)F)=C1 BIBVWHQRJYHXLL-UHFFFAOYSA-N 0.000 description 1
• JBUWQHJXPPZMMT-UHFFFAOYSA-N 2-[(3-fluorophenyl)methyl]-4-methoxyphenol Chemical compound COC1=CC=C(O)C(CC=2C=C(F)C=CC=2)=C1 JBUWQHJXPPZMMT-UHFFFAOYSA-N 0.000 description 1
• ZZUKXKQTQPJMRF-UHFFFAOYSA-N 2-[(4-fluorophenyl)methyl]-4-methoxyphenol Chemical compound COC1=CC=C(O)C(CC=2C=CC(F)=CC=2)=C1 ZZUKXKQTQPJMRF-UHFFFAOYSA-N 0.000 description 1
• NULXWWUYOIYNOF-UHFFFAOYSA-N 2-[(4-fluorophenyl)methyl]-4-methylbenzenethiol Chemical compound CC1=CC=C(S)C(CC=2C=CC(F)=CC=2)=C1 NULXWWUYOIYNOF-UHFFFAOYSA-N 0.000 description 1
• WLQACAAWMAXJHV-UHFFFAOYSA-N 2-[[2-benzyl-4-(hydroxyamino)phenyl]sulfonylmethyl]-2-ethylhexanal Chemical compound CCCCC(CC)(C=O)CS(=O)(=O)C1=CC=C(NO)C=C1CC1=CC=CC=C1 WLQACAAWMAXJHV-UHFFFAOYSA-N 0.000 description 1
• HONDHIZNTVBLPX-UHFFFAOYSA-N 2-butyl-2-[[2-[(4-fluorophenyl)methyl]-4-methylphenyl]sulfanylmethyl]hexanal Chemical compound CCCCC(CCCC)(C=O)CSC1=CC=C(C)C=C1CC1=CC=C(F)C=C1 HONDHIZNTVBLPX-UHFFFAOYSA-N 0.000 description 1
• VIDHASAJQMWIMS-UHFFFAOYSA-N 2-butyl-2-[[2-[(4-fluorophenyl)methyl]-4-methylphenyl]sulfonylmethyl]hexanal Chemical compound CCCCC(CCCC)(C=O)CS(=O)(=O)C1=CC=C(C)C=C1CC1=CC=C(F)C=C1 VIDHASAJQMWIMS-UHFFFAOYSA-N 0.000 description 1
• LLYXJBROWQDVMI-UHFFFAOYSA-N 2-chloro-4-nitrotoluene Chemical compound CC1=CC=C([N+]([O-])=O)C=C1Cl LLYXJBROWQDVMI-UHFFFAOYSA-N 0.000 description 1
• ULQQGOGMQRGFFR-UHFFFAOYSA-N 2-chlorobenzenecarboperoxoic acid Chemical compound OOC(=O)C1=CC=CC=C1Cl ULQQGOGMQRGFFR-UHFFFAOYSA-N 0.000 description 1
• UVEFAZXHHJHMGK-UHFFFAOYSA-N 2-ethyl-2-(hydroxymethyl)hexanal Chemical compound CCCCC(CC)(CO)C=O UVEFAZXHHJHMGK-UHFFFAOYSA-N 0.000 description 1
• ZWDVQMVZZYIAHO-UHFFFAOYSA-N 2-fluorobenzaldehyde Chemical class FC1=CC=CC=C1C=O ZWDVQMVZZYIAHO-UHFFFAOYSA-N 0.000 description 1
• OIOASXNVXSNIKG-UHFFFAOYSA-N 2-iodoethyl hypoiodite Chemical compound ICCOI OIOASXNVXSNIKG-UHFFFAOYSA-N 0.000 description 1
• GMLDCZYTIPCVMO-UHFFFAOYSA-N 2-methylidenebutanal Chemical compound CCC(=C)C=O GMLDCZYTIPCVMO-UHFFFAOYSA-N 0.000 description 1
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
• 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 1
• LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
• 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
• LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical group NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 description 1
• FDMKURWUCOKIAL-UHFFFAOYSA-N 3-butyl-3-ethyl-1,1-dioxo-5-phenyl-2,4-dihydro-1$l^{6}-benzothiepine-4,5-diol Chemical compound OC1C(CCCC)(CC)CS(=O)(=O)C2=CC=CC=C2C1(O)C1=CC=CC=C1 FDMKURWUCOKIAL-UHFFFAOYSA-N 0.000 description 1
• LDJSTNLFHYPREB-UHFFFAOYSA-N 3-butyl-3-ethyl-5-(4-hydroxyphenyl)-7-methoxy-1,1-dioxo-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound OC1C(CCCC)(CC)CS(=O)(=O)C2=CC=C(OC)C=C2C1C1=CC=C(O)C=C1 LDJSTNLFHYPREB-UHFFFAOYSA-N 0.000 description 1
• BIFISZCEOIHOPW-UHFFFAOYSA-N 3-butyl-3-ethyl-5-phenyl-2h-1-benzothiepine Chemical compound C=1C(CCCC)(CC)CSC2=CC=CC=C2C=1C1=CC=CC=C1 BIFISZCEOIHOPW-UHFFFAOYSA-N 0.000 description 1
• RBGBDUCONFGBJG-UHFFFAOYSA-N 3-fluorophthalaldehyde Chemical compound FC1=CC=CC(C=O)=C1C=O RBGBDUCONFGBJG-UHFFFAOYSA-N 0.000 description 1
• ZNRGSYUVFVNSAW-UHFFFAOYSA-N 3-nitrophenylboronic acid Chemical compound OB(O)C1=CC=CC([N+]([O-])=O)=C1 ZNRGSYUVFVNSAW-UHFFFAOYSA-N 0.000 description 1
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
• LWGXOSXIBVNPLY-UHFFFAOYSA-N 4-fluoro-2-[(4-fluorophenyl)methyl]phenol Chemical compound OC1=CC=C(F)C=C1CC1=CC=C(F)C=C1 LWGXOSXIBVNPLY-UHFFFAOYSA-N 0.000 description 1
• IMXDWZHGVUZVOW-UHFFFAOYSA-N 4-fluoro-2-[(4-methoxyphenyl)methyl]phenol Chemical compound C1=CC(OC)=CC=C1CC1=CC(F)=CC=C1O IMXDWZHGVUZVOW-UHFFFAOYSA-N 0.000 description 1
• LDNCTFATTLVEBX-UHFFFAOYSA-N 4-methoxy-2-[(3-methoxyphenyl)methyl]phenol Chemical compound COC1=CC=CC(CC=2C(=CC=C(OC)C=2)O)=C1 LDNCTFATTLVEBX-UHFFFAOYSA-N 0.000 description 1
• 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
• OKRUMSWHDWKGHA-UHFFFAOYSA-N 5-bromopentanoyl chloride Chemical compound ClC(=O)CCCCBr OKRUMSWHDWKGHA-UHFFFAOYSA-N 0.000 description 1
• MMRBKQPNLMBMGI-UHFFFAOYSA-N 5-propylnonan-5-ol Chemical compound CCCCC(O)(CCC)CCCC MMRBKQPNLMBMGI-UHFFFAOYSA-N 0.000 description 1
• XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
• MITKPYOGRCLXLB-UHFFFAOYSA-N 7-(azetidin-1-yl)-3-butyl-3-ethyl-5-(4-fluorophenyl)-1,1-dioxo-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound OC1C(CCCC)(CC)CS(=O)(=O)C2=CC=C(N3CCC3)C=C2C1C1=CC=C(F)C=C1 MITKPYOGRCLXLB-UHFFFAOYSA-N 0.000 description 1
• 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 1
• IRBAWVGZNJIROV-SFHVURJKSA-N 9-(2-cyclopropylethynyl)-2-[[(2s)-1,4-dioxan-2-yl]methoxy]-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one Chemical compound C1=C2C3=CC=C(C#CC4CC4)C=C3CCN2C(=O)N=C1OC[C@@H]1COCCO1 IRBAWVGZNJIROV-SFHVURJKSA-N 0.000 description 1
• QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
• GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
• 241000416162 Astragalus gummifer Species 0.000 description 1
• 125000006847 BOC protecting group Chemical group 0.000 description 1
• COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
• DPLFBXISFAIEFZ-UHFFFAOYSA-N C1=CC=C(C=C1)C(=O)C2=CC=CC=C2OC(=S)N Chemical compound C1=CC=C(C=C1)C(=O)C2=CC=CC=C2OC(=S)N DPLFBXISFAIEFZ-UHFFFAOYSA-N 0.000 description 1
• XEKJBSKSLRKIMZ-UHFFFAOYSA-N CCCC(C(C)(CC)C=O)S(=O)(=O)C1=CC=CC=C1CC2=CC=CC=C2 Chemical compound CCCC(C(C)(CC)C=O)S(=O)(=O)C1=CC=CC=C1CC2=CC=CC=C2 XEKJBSKSLRKIMZ-UHFFFAOYSA-N 0.000 description 1
• YNNZJSJJOPCIJJ-UHFFFAOYSA-N CCCCC1(CC(=CC(=C1O)C2=CC(=CC=C2)OC)C3CCCC4=C(S3(=O)=O)C=CC(=C4)OC)CC Chemical compound CCCCC1(CC(=CC(=C1O)C2=CC(=CC=C2)OC)C3CCCC4=C(S3(=O)=O)C=CC(=C4)OC)CC YNNZJSJJOPCIJJ-UHFFFAOYSA-N 0.000 description 1
• UHNRLQRZRNKOKU-UHFFFAOYSA-N CCN(CC1=NC2=C(N1)C1=CC=C(C=C1N=C2N)C1=NNC=C1)C(C)=O Chemical compound CCN(CC1=NC2=C(N1)C1=CC=C(C=C1N=C2N)C1=NNC=C1)C(C)=O UHNRLQRZRNKOKU-UHFFFAOYSA-N 0.000 description 1
• CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
• UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
• BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
• 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
• 229920001661 Chitosan Polymers 0.000 description 1
• 235000013162 Cocos nucifera Nutrition 0.000 description 1
• 244000060011 Cocos nucifera Species 0.000 description 1
• 241000699800 Cricetinae Species 0.000 description 1
• XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
• KJTLQQUUPVSXIM-UHFFFAOYSA-N DL-mevalonic acid Natural products OCCC(O)(C)CC(O)=O KJTLQQUUPVSXIM-UHFFFAOYSA-N 0.000 description 1
• 101000737983 Enterobacter agglomerans Monofunctional chorismate mutase Proteins 0.000 description 1
• 102000004190 Enzymes Human genes 0.000 description 1
• 108090000790 Enzymes Proteins 0.000 description 1
• WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
• 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 1
• 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 1
• 101710156096 Ileal sodium/bile acid cotransporter Proteins 0.000 description 1
• 102100021711 Ileal sodium/bile acid cotransporter Human genes 0.000 description 1
• 239000005909 Kieselgur Substances 0.000 description 1
• 102000000853 LDL receptors Human genes 0.000 description 1
• 108010001831 LDL receptors Proteins 0.000 description 1
• GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
• 239000004166 Lanolin Substances 0.000 description 1
• 102000011965 Lipoprotein Receptors Human genes 0.000 description 1
• 108010061306 Lipoprotein Receptors Proteins 0.000 description 1
• FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
• 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 1
• CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
• LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
• QXKHYNVANLEOEG-UHFFFAOYSA-N Methoxsalen Chemical group C1=CC(=O)OC2=C1C=C1C=COC1=C2OC QXKHYNVANLEOEG-UHFFFAOYSA-N 0.000 description 1
• VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
• KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
• KBXILIYZUWEKCM-UHFFFAOYSA-N N-amino-N-ethylsulfanylhydroxylamine Chemical compound CCSN(N)O KBXILIYZUWEKCM-UHFFFAOYSA-N 0.000 description 1
• WUQWJIDWKRLSMG-UHFFFAOYSA-N NC([O-])=[S+]C1=C(CC2=CC=CC=C2)C=CC=C1 Chemical compound NC([O-])=[S+]C1=C(CC2=CC=CC=C2)C=CC=C1 WUQWJIDWKRLSMG-UHFFFAOYSA-N 0.000 description 1
• 239000005642 Oleic acid Substances 0.000 description 1
• ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
• 235000019502 Orange oil Nutrition 0.000 description 1
• 239000004264 Petrolatum Substances 0.000 description 1
• 241000255969 Pieris brassicae Species 0.000 description 1
• GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical group CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
• CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
• VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
• 229920002472 Starch Polymers 0.000 description 1
• LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
• 229920001615 Tragacanth Polymers 0.000 description 1
• 108010069201 VLDL Cholesterol Proteins 0.000 description 1
• FDSYOFCVZBGPOV-UHFFFAOYSA-N [4-(cyclopropylamino)piperidin-1-yl]-[6-[[5-fluoro-4-(2-methyl-3-propan-2-ylbenzimidazol-5-yl)pyrimidin-2-yl]amino]-2-methylpyridin-3-yl]methanone Chemical compound CC(C)n1c(C)nc2ccc(cc12)-c1nc(Nc2ccc(C(=O)N3CCC(CC3)NC3CC3)c(C)n2)ncc1F FDSYOFCVZBGPOV-UHFFFAOYSA-N 0.000 description 1
• KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 description 1
• DGAXYDCFAIZNGZ-UHFFFAOYSA-N [ethoxy(methoxy)methyl]-dimethyl-propan-2-yloxyazanium Chemical compound COC([N+](C)(C)OC(C)C)OCC DGAXYDCFAIZNGZ-UHFFFAOYSA-N 0.000 description 1
• SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 1
• GAMPNQJDUFQVQO-UHFFFAOYSA-N acetic acid;phthalic acid Chemical class CC(O)=O.OC(=O)C1=CC=CC=C1C(O)=O GAMPNQJDUFQVQO-UHFFFAOYSA-N 0.000 description 1
• 230000002378 acidificating effect Effects 0.000 description 1
• 239000000654 additive Substances 0.000 description 1
• 239000000853 adhesive Substances 0.000 description 1
• 230000001070 adhesive effect Effects 0.000 description 1
• 239000002671 adjuvant Substances 0.000 description 1
• 239000000443 aerosol Substances 0.000 description 1
• 150000001298 alcohols Chemical class 0.000 description 1
• QBYJBZPUGVGKQQ-SJJAEHHWSA-N aldrin Chemical compound C1[C@H]2C=C[C@@H]1[C@H]1[C@@](C3(Cl)Cl)(Cl)C(Cl)=C(Cl)[C@@]3(Cl)[C@H]12 QBYJBZPUGVGKQQ-SJJAEHHWSA-N 0.000 description 1
• 229910052783 alkali metal Inorganic materials 0.000 description 1
• 150000001447 alkali salts Chemical class 0.000 description 1
• 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
• 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
• 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
• 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 1
• 150000001350 alkyl halides Chemical class 0.000 description 1
• 150000001351 alkyl iodides Chemical class 0.000 description 1
• 125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
• 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
• 125000002947 alkylene group Chemical group 0.000 description 1
• HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
• 125000003705 anilinocarbonyl group Chemical group O=C([*])N([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
• 229920006318 anionic polymer Polymers 0.000 description 1
• 230000003466 anti-cipated effect Effects 0.000 description 1
• 229940127226 anticholesterol agent Drugs 0.000 description 1
• 238000013459 approach Methods 0.000 description 1
• 239000007864 aqueous solution Substances 0.000 description 1
• 239000003125 aqueous solvent Substances 0.000 description 1
• 125000005199 aryl carbonyloxy group Chemical group 0.000 description 1
• 125000000732 arylene group Chemical group 0.000 description 1
• 125000004104 aryloxy group Chemical group 0.000 description 1
• 238000003556 assay Methods 0.000 description 1
• 230000008901 benefit Effects 0.000 description 1
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
• RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
• 239000012965 benzophenone Substances 0.000 description 1
• AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
• HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
• WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
• 210000000941 bile Anatomy 0.000 description 1
• 230000035587 bioadhesion Effects 0.000 description 1
• 230000004071 biological effect Effects 0.000 description 1
• 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
• 238000009835 boiling Methods 0.000 description 1
• 239000006172 buffering agent Substances 0.000 description 1
• 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
• 235000014121 butter Nutrition 0.000 description 1
• 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
• 229910000019 calcium carbonate Inorganic materials 0.000 description 1
• 159000000007 calcium salts Chemical class 0.000 description 1
• 150000001721 carbon Chemical group 0.000 description 1
• 235000011089 carbon dioxide Nutrition 0.000 description 1
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
• 239000000919 ceramic Substances 0.000 description 1
• 230000008859 change Effects 0.000 description 1
• 150000001805 chlorine compounds Chemical class 0.000 description 1
• 238000011210 chromatographic step Methods 0.000 description 1
• 239000011248 coating agent Substances 0.000 description 1
• 238000000576 coating method Methods 0.000 description 1
• 238000009833 condensation Methods 0.000 description 1
• 230000005494 condensation Effects 0.000 description 1
• 235000009508 confectionery Nutrition 0.000 description 1
• 238000013270 controlled release Methods 0.000 description 1
• 238000007796 conventional method Methods 0.000 description 1
• 208000029078 coronary artery disease Diseases 0.000 description 1
• 239000006071 cream Substances 0.000 description 1
• 239000000287 crude extract Substances 0.000 description 1
• 239000002178 crystalline material Substances 0.000 description 1
• KVFDZFBHBWTVID-UHFFFAOYSA-N cyclohexane-carboxaldehyde Natural products O=CC1CCCCC1 KVFDZFBHBWTVID-UHFFFAOYSA-N 0.000 description 1
• 230000002950 deficient Effects 0.000 description 1
• 230000002939 deleterious effect Effects 0.000 description 1
• 230000001419 dependent effect Effects 0.000 description 1
• 238000001212 derivatisation Methods 0.000 description 1
• 239000008121 dextrose Substances 0.000 description 1
• LMEDOLJKVASKTP-UHFFFAOYSA-N dibutyl sulfate Chemical compound CCCCOS(=O)(=O)OCCCC LMEDOLJKVASKTP-UHFFFAOYSA-N 0.000 description 1
• FEYYOXFAQQJEIG-UHFFFAOYSA-N dibutyl sulfite Chemical compound CCCCOS(=O)OCCCC FEYYOXFAQQJEIG-UHFFFAOYSA-N 0.000 description 1
• 239000002037 dichloromethane fraction Substances 0.000 description 1
• 235000005911 diet Nutrition 0.000 description 1
• 230000037213 diet Effects 0.000 description 1
• 235000014113 dietary fatty acids Nutrition 0.000 description 1
• 238000010790 dilution Methods 0.000 description 1
• 239000012895 dilution Substances 0.000 description 1
• 150000004656 dimethylamines Chemical class 0.000 description 1
• UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
• 230000008034 disappearance Effects 0.000 description 1
• 238000012377 drug delivery Methods 0.000 description 1
• 238000001035 drying Methods 0.000 description 1
• 230000009977 dual effect Effects 0.000 description 1
• 230000008030 elimination Effects 0.000 description 1
• 238000003379 elimination reaction Methods 0.000 description 1
• 239000003995 emulsifying agent Substances 0.000 description 1
• 239000000839 emulsion Substances 0.000 description 1
• 239000002702 enteric coating Substances 0.000 description 1
• 238000009505 enteric coating Methods 0.000 description 1
• 230000002255 enzymatic effect Effects 0.000 description 1
• 238000006735 epoxidation reaction Methods 0.000 description 1
• 230000003628 erosive effect Effects 0.000 description 1
• 150000002148 esters Chemical group 0.000 description 1
• 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
• 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
• 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 1
• 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
• 239000004744 fabric Substances 0.000 description 1
• 239000000194 fatty acid Substances 0.000 description 1
• 229930195729 fatty acid Natural products 0.000 description 1
• 230000004129 fatty acid metabolism Effects 0.000 description 1
• 150000004665 fatty acids Chemical class 0.000 description 1
• 230000002550 fecal effect Effects 0.000 description 1
• 238000003818 flash chromatography Methods 0.000 description 1
• 239000000796 flavoring agent Substances 0.000 description 1
• 150000004673 fluoride salts Chemical class 0.000 description 1
• XJUJXVATKIRSAM-UHFFFAOYSA-N fluoro(phenyl)methanol Chemical compound OC(F)C1=CC=CC=C1 XJUJXVATKIRSAM-UHFFFAOYSA-N 0.000 description 1
• 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
• 238000001640 fractional crystallisation Methods 0.000 description 1
• 125000000524 functional group Chemical group 0.000 description 1
• 208000001130 gallstones Diseases 0.000 description 1
• 239000007789 gas Substances 0.000 description 1
• 230000002496 gastric effect Effects 0.000 description 1
• 239000000499 gel Substances 0.000 description 1
• 238000005227 gel permeation chromatography Methods 0.000 description 1
• 239000011521 glass Substances 0.000 description 1
• 150000004676 glycans Chemical class 0.000 description 1
• 235000011187 glycerol Nutrition 0.000 description 1
• 229940093915 gynecological organic acid Drugs 0.000 description 1
• 125000006456 halo alkyl cycloalkyl group Chemical group 0.000 description 1
• 125000004438 haloalkoxy group Chemical group 0.000 description 1
• 125000004440 haloalkylsulfinyl group Chemical group 0.000 description 1
• 125000004441 haloalkylsulfonyl group Chemical group 0.000 description 1
• 125000004995 haloalkylthio group Chemical group 0.000 description 1
• 230000003862 health status Effects 0.000 description 1
• 238000010438 heat treatment Methods 0.000 description 1
• 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
• 239000008241 heterogeneous mixture Substances 0.000 description 1
• ALBYIUDWACNRRB-UHFFFAOYSA-N hexanamide Chemical compound CCCCCC(N)=O ALBYIUDWACNRRB-UHFFFAOYSA-N 0.000 description 1
• 125000006038 hexenyl group Chemical group 0.000 description 1
• 125000001245 hexylamino group Chemical group [H]N([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
• 239000003906 humectant Substances 0.000 description 1
• XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
• 238000007327 hydrogenolysis reaction Methods 0.000 description 1
• 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
• 230000000871 hypocholesterolemic effect Effects 0.000 description 1
• 239000005457 ice water Substances 0.000 description 1
• 230000006872 improvement Effects 0.000 description 1
• 238000001802 infusion Methods 0.000 description 1
• 239000003978 infusion fluid Substances 0.000 description 1
• 230000005764 inhibitory process Effects 0.000 description 1
• 238000011221 initial treatment Methods 0.000 description 1
• 239000007972 injectable composition Substances 0.000 description 1
• 230000003993 interaction Effects 0.000 description 1
• 210000000936 intestine Anatomy 0.000 description 1
• 238000010255 intramuscular injection Methods 0.000 description 1
• 239000007927 intramuscular injection Substances 0.000 description 1
• 238000001990 intravenous administration Methods 0.000 description 1
• 238000010253 intravenous injection Methods 0.000 description 1
• 230000026045 iodination Effects 0.000 description 1
• 238000006192 iodination reaction Methods 0.000 description 1
• HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
• 150000002500 ions Chemical class 0.000 description 1
• QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
• MGIYRDNGCNKGJU-UHFFFAOYSA-N isothiazolinone Chemical compound O=C1C=CSN1 MGIYRDNGCNKGJU-UHFFFAOYSA-N 0.000 description 1
• 239000000644 isotonic solution Substances 0.000 description 1
• 150000002576 ketones Chemical class 0.000 description 1
• 239000008101 lactose Substances 0.000 description 1
• 229940039717 lanolin Drugs 0.000 description 1
• 235000019388 lanolin Nutrition 0.000 description 1
• 230000000670 limiting effect Effects 0.000 description 1
• 125000005647 linker group Chemical group 0.000 description 1
• 150000002632 lipids Chemical class 0.000 description 1
• 239000008297 liquid dosage form Substances 0.000 description 1
• 210000004185 liver Anatomy 0.000 description 1
• 239000006210 lotion Substances 0.000 description 1
• 230000001050 lubricating effect Effects 0.000 description 1
• 239000011777 magnesium Substances 0.000 description 1
• 229910052749 magnesium Inorganic materials 0.000 description 1
• 235000019359 magnesium stearate Nutrition 0.000 description 1
• 230000014759 maintenance of location Effects 0.000 description 1
• 238000004519 manufacturing process Methods 0.000 description 1
• 239000011159 matrix material Substances 0.000 description 1
• 239000012528 membrane Substances 0.000 description 1
• 230000004060 metabolic process Effects 0.000 description 1
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
• AGJSNMGHAVDLRQ-IWFBPKFRSA-N methyl (2s)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-amino-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,3-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoate Chemical compound SC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCSC)C(=O)OC)CC1=CC=C(O)C(C)=C1C AGJSNMGHAVDLRQ-IWFBPKFRSA-N 0.000 description 1
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
• 239000002480 mineral oil Substances 0.000 description 1
• 235000010446 mineral oil Nutrition 0.000 description 1
• 238000012544 monitoring process Methods 0.000 description 1
• PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
• 125000005322 morpholin-1-yl group Chemical group 0.000 description 1
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
• 239000012454 non-polar solvent Substances 0.000 description 1
• 231100000252 nontoxic Toxicity 0.000 description 1
• 230000003000 nontoxic effect Effects 0.000 description 1
• 238000010899 nucleation Methods 0.000 description 1
• 239000012038 nucleophile Substances 0.000 description 1
• 230000000269 nucleophilic effect Effects 0.000 description 1
• 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
• 239000007764 o/w emulsion Substances 0.000 description 1
• 239000002674 ointment Substances 0.000 description 1
• ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
• 239000010502 orange oil Substances 0.000 description 1
• 150000007524 organic acids Chemical class 0.000 description 1
• 235000005985 organic acids Nutrition 0.000 description 1
• 239000011368 organic material Substances 0.000 description 1
• 150000002924 oxiranes Chemical class 0.000 description 1
• DXGLGDHPHMLXJC-UHFFFAOYSA-N oxybenzone Chemical compound OC1=CC(OC)=CC=C1C(=O)C1=CC=CC=C1 DXGLGDHPHMLXJC-UHFFFAOYSA-N 0.000 description 1
• 125000006353 oxyethylene group Chemical group 0.000 description 1
• 230000020477 pH reduction Effects 0.000 description 1
• PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
• NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
• UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
• 238000007911 parenteral administration Methods 0.000 description 1
• 230000036961 partial effect Effects 0.000 description 1
• 238000005192 partition Methods 0.000 description 1
• 239000006072 paste Substances 0.000 description 1
• 230000004796 pathophysiological change Effects 0.000 description 1
• 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
• 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
• 125000005981 pentynyl group Chemical group 0.000 description 1
• 239000002304 perfume Substances 0.000 description 1
• 150000004965 peroxy acids Chemical class 0.000 description 1
• 229940066842 petrolatum Drugs 0.000 description 1
• 235000019271 petrolatum Nutrition 0.000 description 1
• 230000000144 pharmacologic effect Effects 0.000 description 1
• 150000002989 phenols Chemical class 0.000 description 1
• DVCMYAIUSOSIQP-UHFFFAOYSA-N phenyl 2,2,2-trifluoroacetate Chemical compound FC(F)(F)C(=O)OC1=CC=CC=C1 DVCMYAIUSOSIQP-UHFFFAOYSA-N 0.000 description 1
• UQDHUTAFUQLDFX-UHFFFAOYSA-N phenyl(sulfanyl)methanol Chemical compound OC(S)C1=CC=CC=C1 UQDHUTAFUQLDFX-UHFFFAOYSA-N 0.000 description 1
• 230000000704 physical effect Effects 0.000 description 1
• 230000035479 physiological effects, processes and functions Effects 0.000 description 1
• 239000002798 polar solvent Substances 0.000 description 1
• 229940068917 polyethylene glycols Drugs 0.000 description 1
• 229920001282 polysaccharide Polymers 0.000 description 1
• 239000005017 polysaccharide Substances 0.000 description 1
• 229920002689 polyvinyl acetate Polymers 0.000 description 1
• 239000011118 polyvinyl acetate Substances 0.000 description 1
• 159000000001 potassium salts Chemical class 0.000 description 1
• 230000001376 precipitating effect Effects 0.000 description 1
• 239000003755 preservative agent Substances 0.000 description 1
• 230000002335 preservative effect Effects 0.000 description 1
• 208000000876 primary bile acid malabsorption Diseases 0.000 description 1
• 239000001294 propane Substances 0.000 description 1
• 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
• 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
• 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
• 238000010926 purge Methods 0.000 description 1
• 238000000197 pyrolysis Methods 0.000 description 1
• 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
• 238000003908 quality control method Methods 0.000 description 1
• 238000005956 quaternization reaction Methods 0.000 description 1
• 238000005932 reductive alkylation reaction Methods 0.000 description 1
• 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
• 230000002441 reversible effect Effects 0.000 description 1
• 125000006413 ring segment Chemical group 0.000 description 1
• YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 1
• 230000028327 secretion Effects 0.000 description 1
• 210000000813 small intestine Anatomy 0.000 description 1
• 239000001632 sodium acetate Substances 0.000 description 1
• 235000017281 sodium acetate Nutrition 0.000 description 1
• 235000017557 sodium bicarbonate Nutrition 0.000 description 1
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
• 229910000029 sodium carbonate Inorganic materials 0.000 description 1
• 239000011780 sodium chloride Substances 0.000 description 1
• AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
• 235000019345 sodium thiosulphate Nutrition 0.000 description 1
• 239000007909 solid dosage form Substances 0.000 description 1
• 239000011877 solvent mixture Substances 0.000 description 1
• 239000007921 spray Substances 0.000 description 1
• 239000008107 starch Substances 0.000 description 1
• 235000019698 starch Nutrition 0.000 description 1
• 239000008174 sterile solution Substances 0.000 description 1
• 210000002784 stomach Anatomy 0.000 description 1
• 238000010254 subcutaneous injection Methods 0.000 description 1
• 239000007929 subcutaneous injection Substances 0.000 description 1
• 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
• 150000003462 sulfoxides Chemical class 0.000 description 1
• 239000000829 suppository Substances 0.000 description 1
• 239000012730 sustained-release form Substances 0.000 description 1
• 239000003765 sweetening agent Substances 0.000 description 1
• WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
• 150000003573 thiols Chemical class 0.000 description 1
• 239000010936 titanium Substances 0.000 description 1
• XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
• 231100000583 toxicological profile Toxicity 0.000 description 1
• 239000000196 tragacanth Substances 0.000 description 1
• 235000010487 tragacanth Nutrition 0.000 description 1
• 229940116362 tragacanth Drugs 0.000 description 1
• 230000009466 transformation Effects 0.000 description 1
• 125000004385 trihaloalkyl group Chemical group 0.000 description 1
• 150000004043 trisaccharides Chemical class 0.000 description 1
• 208000019553 vascular disease Diseases 0.000 description 1
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
• 239000007762 w/o emulsion Substances 0.000 description 1
• 238000010792 warming Methods 0.000 description 1
• 229920003169 water-soluble polymer Polymers 0.000 description 1
• 239000011701 zinc Substances 0.000 description 1
• 229910052725 zinc Inorganic materials 0.000 description 1