JP2002500628A - 回腸胆汁酸輸送阻害ベンゾチエピンおよびＨＭＧ Ｃｏ−Ａレダクターゼ阻害剤を用いた併用療法 - Google Patents
回腸胆汁酸輸送阻害ベンゾチエピンおよびＨＭＧ Ｃｏ−Ａレダクターゼ阻害剤を用いた併用療法Info
- Publication number
- JP2002500628A JP2002500628A JP53959498A JP53959498A JP2002500628A JP 2002500628 A JP2002500628 A JP 2002500628A JP 53959498 A JP53959498 A JP 53959498A JP 53959498 A JP53959498 A JP 53959498A JP 2002500628 A JP2002500628 A JP 2002500628A
- Authority
- JP
- Japan
- Prior art keywords
- added
- compound
- solution
- aryl
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 229940123934 Reductase inhibitor Drugs 0.000 title claims abstract description 6
- NIGNBCLEMMGDQP-UHFFFAOYSA-N 1-benzothiepine Chemical compound S1C=CC=CC2=CC=CC=C12 NIGNBCLEMMGDQP-UHFFFAOYSA-N 0.000 title abstract description 21
- 238000002648 combination therapy Methods 0.000 title abstract description 14
- 239000003613 bile acid Substances 0.000 title description 34
- 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
- 239000000203 mixture Substances 0.000 claims abstract description 150
- 238000000034 method Methods 0.000 claims abstract description 90
- 238000011282 treatment Methods 0.000 claims abstract description 27
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 19
- 229940077672 Ileal bile acid transport inhibitor Drugs 0.000 claims abstract description 13
- 230000002265 prevention Effects 0.000 claims abstract description 10
- 241000124008 Mammalia Species 0.000 claims abstract description 7
- 239000003112 inhibitor Substances 0.000 claims description 44
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 11
- 102000004316 Oxidoreductases Human genes 0.000 claims description 9
- 108090000854 Oxidoreductases Proteins 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 7
- 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 description 6
- 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 description 6
- 229960003765 fluvastatin Drugs 0.000 claims description 6
- 229960004844 lovastatin Drugs 0.000 claims description 6
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound 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 description 6
- 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 description 6
- 229960002855 simvastatin Drugs 0.000 claims description 6
- 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 description 6
- 230000001315 anti-hyperlipaemic effect Effects 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 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 5
- 229960002965 pravastatin Drugs 0.000 claims 5
- 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 5
- FJLGEFLZQAZZCD-MCBHFWOFSA-N (3R,5S)-fluvastatin Chemical compound 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 FJLGEFLZQAZZCD-MCBHFWOFSA-N 0.000 claims 3
- 150000001875 compounds Chemical class 0.000 abstract description 184
- 239000003814 drug Substances 0.000 abstract description 16
- 208000035150 Hypercholesterolemia Diseases 0.000 abstract description 3
- 206010003210 Arteriosclerosis Diseases 0.000 abstract 1
- 208000011775 arteriosclerosis disease Diseases 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 204
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 194
- 239000000243 solution Substances 0.000 description 165
- 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 146
- 125000000623 heterocyclic group Chemical group 0.000 description 142
- -1 dialkylamido Chemical group 0.000 description 119
- 125000000217 alkyl group Chemical group 0.000 description 116
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 109
- 239000000047 product Substances 0.000 description 103
- 125000003118 aryl group Chemical group 0.000 description 92
- 239000011541 reaction mixture Substances 0.000 description 88
- 125000003342 alkenyl group Chemical group 0.000 description 87
- 238000006243 chemical reaction Methods 0.000 description 83
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 77
- 125000000753 cycloalkyl group Chemical group 0.000 description 75
- 125000000304 alkynyl group Chemical group 0.000 description 74
- 125000001072 heteroaryl group Chemical group 0.000 description 68
- 238000003756 stirring Methods 0.000 description 68
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
- 239000007787 solid Substances 0.000 description 58
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 55
- 125000003710 aryl alkyl group Chemical group 0.000 description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 53
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 52
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 51
- 235000019439 ethyl acetate Nutrition 0.000 description 51
- 238000001819 mass spectrum Methods 0.000 description 50
- 125000001424 substituent group Chemical group 0.000 description 50
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
- 239000003921 oil Substances 0.000 description 48
- 235000019198 oils Nutrition 0.000 description 48
- 239000000284 extract Substances 0.000 description 45
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 44
- 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 44
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 43
- 125000004043 oxo group Chemical group O=* 0.000 description 41
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 40
- 229910052757 nitrogen Inorganic materials 0.000 description 40
- 239000012044 organic layer Substances 0.000 description 40
- 125000001188 haloalkyl group Chemical group 0.000 description 39
- 229920000570 polyether Polymers 0.000 description 39
- 108090000765 processed proteins & peptides Chemical group 0.000 description 39
- 239000010410 layer Substances 0.000 description 37
- 239000004721 Polyphenylene oxide Substances 0.000 description 36
- 239000012267 brine Substances 0.000 description 34
- 229910052799 carbon Inorganic materials 0.000 description 34
- 229910052736 halogen Inorganic materials 0.000 description 34
- 150000002367 halogens Chemical class 0.000 description 34
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 34
- 235000008504 concentrate Nutrition 0.000 description 32
- 239000012141 concentrate Substances 0.000 description 32
- 238000004128 high performance liquid chromatography Methods 0.000 description 31
- 102000004196 processed proteins & peptides Human genes 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- 238000005481 NMR spectroscopy Methods 0.000 description 29
- 239000001257 hydrogen Substances 0.000 description 29
- 229910052739 hydrogen Inorganic materials 0.000 description 29
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 29
- 230000002829 reductive effect Effects 0.000 description 29
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 28
- 238000002360 preparation method Methods 0.000 description 27
- HEDRZPFGACZZDS-UHFFFAOYSA-N CHCl3 Substances ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 25
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 25
- 239000000463 material Substances 0.000 description 25
- 238000000746 purification Methods 0.000 description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- 238000010992 reflux Methods 0.000 description 24
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 24
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 22
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 22
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 21
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 20
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 20
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 20
- 150000001413 amino acids Chemical group 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 19
- 230000032258 transport Effects 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 235000001014 amino acid Nutrition 0.000 description 18
- 235000014633 carbohydrates Nutrition 0.000 description 18
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 18
- 239000007789 gas Substances 0.000 description 18
- 229920001184 polypeptide Chemical group 0.000 description 18
- 239000002253 acid Substances 0.000 description 17
- 150000001720 carbohydrates Chemical class 0.000 description 17
- 235000012000 cholesterol Nutrition 0.000 description 17
- 239000000706 filtrate Substances 0.000 description 17
- 238000004519 manufacturing process Methods 0.000 description 17
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 17
- 150000003839 salts Chemical class 0.000 description 17
- 239000007858 starting material Substances 0.000 description 17
- 238000004809 thin layer chromatography Methods 0.000 description 17
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 16
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 16
- 239000007788 liquid Substances 0.000 description 15
- 238000002844 melting Methods 0.000 description 15
- 230000008018 melting Effects 0.000 description 15
- 239000000741 silica gel Substances 0.000 description 15
- 229910002027 silica gel Inorganic materials 0.000 description 15
- 229910000104 sodium hydride Inorganic materials 0.000 description 15
- 229910000027 potassium carbonate Inorganic materials 0.000 description 14
- 235000011181 potassium carbonates Nutrition 0.000 description 14
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 14
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 13
- 150000001412 amines Chemical class 0.000 description 13
- 238000003556 assay Methods 0.000 description 13
- 239000003054 catalyst Substances 0.000 description 13
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 13
- 229910052760 oxygen Inorganic materials 0.000 description 13
- 238000010926 purge Methods 0.000 description 13
- 238000010898 silica gel chromatography Methods 0.000 description 13
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 12
- 239000012298 atmosphere Substances 0.000 description 12
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 12
- 235000019341 magnesium sulphate Nutrition 0.000 description 12
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 12
- 239000000843 powder Substances 0.000 description 12
- 239000003826 tablet Substances 0.000 description 12
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 11
- 125000003545 alkoxy group Chemical group 0.000 description 11
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 229920000642 polymer Polymers 0.000 description 11
- 229920006395 saturated elastomer Polymers 0.000 description 11
- 239000012312 sodium hydride Substances 0.000 description 11
- 201000001320 Atherosclerosis Diseases 0.000 description 10
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 10
- 230000029936 alkylation Effects 0.000 description 10
- 238000005804 alkylation reaction Methods 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 239000002552 dosage form Substances 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 150000002431 hydrogen Chemical class 0.000 description 10
- 229910052763 palladium Inorganic materials 0.000 description 10
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 10
- 239000006188 syrup Substances 0.000 description 10
- 235000020357 syrup Nutrition 0.000 description 10
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 9
- 125000002252 acyl group Chemical group 0.000 description 9
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 9
- 239000002775 capsule Substances 0.000 description 9
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 9
- 125000004122 cyclic group Chemical group 0.000 description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- 238000009472 formulation Methods 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- 238000001953 recrystallisation Methods 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Natural products CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 8
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 8
- 230000037396 body weight Effects 0.000 description 8
- 239000012230 colorless oil Substances 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- 239000003480 eluent Substances 0.000 description 8
- 230000000968 intestinal effect Effects 0.000 description 8
- NWVVVBRKAWDGAB-UHFFFAOYSA-N p-methoxyphenol Chemical compound COC1=CC=C(O)C=C1 NWVVVBRKAWDGAB-UHFFFAOYSA-N 0.000 description 8
- 230000009467 reduction Effects 0.000 description 8
- 239000000523 sample Substances 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 229910052717 sulfur Inorganic materials 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 238000012546 transfer Methods 0.000 description 8
- GDVUGFJXFFCXMX-UHFFFAOYSA-N (2-ethyl-2-formylhexyl) methanesulfonate Chemical compound CCCCC(CC)(C=O)COS(C)(=O)=O GDVUGFJXFFCXMX-UHFFFAOYSA-N 0.000 description 7
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 7
- 125000004423 acyloxy group Chemical group 0.000 description 7
- 125000002877 alkyl aryl group Chemical group 0.000 description 7
- 125000004414 alkyl thio group Chemical group 0.000 description 7
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 7
- 150000001450 anions Chemical class 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 239000012259 ether extract Substances 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 125000005842 heteroatom Chemical group 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 239000003444 phase transfer catalyst Substances 0.000 description 7
- 150000003242 quaternary ammonium salts Chemical group 0.000 description 7
- 150000003457 sulfones Chemical class 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 239000003643 water by type Substances 0.000 description 7
- 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 6
- 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 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 6
- 108010007622 LDL Lipoproteins Proteins 0.000 description 6
- 102000007330 LDL Lipoproteins Human genes 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 6
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 description 6
- 125000005605 benzo group Chemical group 0.000 description 6
- 210000000941 bile Anatomy 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 6
- 239000003085 diluting agent Substances 0.000 description 6
- 238000005194 fractionation Methods 0.000 description 6
- 230000002440 hepatic effect Effects 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 210000004185 liver Anatomy 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 230000003647 oxidation Effects 0.000 description 6
- 238000007254 oxidation reaction Methods 0.000 description 6
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- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 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
- 125000006239 protecting group Chemical group 0.000 description 1
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- 125000003226 pyrazolyl group Chemical group 0.000 description 1
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- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000005956 quaternization reaction Methods 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 238000003345 scintillation counting Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000004460 silage Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 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
- 235000009518 sodium iodide Nutrition 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 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
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- 239000008107 starch Substances 0.000 description 1
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- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- CESKLHVYGRFMFP-UHFFFAOYSA-N sulfonmethane Chemical compound CCS(=O)(=O)C(C)(C)S(=O)(=O)CC CESKLHVYGRFMFP-UHFFFAOYSA-N 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide-pyridine complex Substances O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical class S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
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- 239000012730 sustained-release form Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- IDELNEDBPWKHGK-UHFFFAOYSA-N thiobutabarbital Chemical compound CCC(C)C1(CC)C(=O)NC(=S)NC1=O IDELNEDBPWKHGK-UHFFFAOYSA-N 0.000 description 1
- YONPGGFAJWQGJC-UHFFFAOYSA-K titanium(iii) chloride Chemical compound Cl[Ti](Cl)Cl YONPGGFAJWQGJC-UHFFFAOYSA-K 0.000 description 1
- 231100000027 toxicology 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
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 150000004043 trisaccharides Chemical class 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US4066097P | 1997-03-11 | 1997-03-11 | |
| US60/040,660 | 1997-03-11 | ||
| PCT/US1998/003792 WO1998040375A2 (en) | 1997-03-11 | 1998-03-10 | COMBINATION OF ILEAL BILE ACID TRANSPORT INHIBITING BENZOTHIEPINES AND HMG Co-A REDUCTASE INHIBITORS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2002500628A true JP2002500628A (ja) | 2002-01-08 |
| JP2002500628A5 JP2002500628A5 (https=) | 2005-11-10 |
Family
ID=21912237
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP53959498A Abandoned JP2002500628A (ja) | 1997-03-11 | 1998-03-10 | 回腸胆汁酸輸送阻害ベンゾチエピンおよびＨＭＧ Ｃｏ−Ａレダクターゼ阻害剤を用いた併用療法 |
Country Status (16)
| Country | Link |
|---|---|
| EP (1) | EP0971744A2 (https=) |
| JP (1) | JP2002500628A (https=) |
| CN (1) | CN1255864A (https=) |
| AU (1) | AU730024C (https=) |
| BG (1) | BG103793A (https=) |
| BR (1) | BR9808013A (https=) |
| CA (1) | CA2283575A1 (https=) |
| HU (1) | HUP0002395A3 (https=) |
| IL (1) | IL131872A0 (https=) |
| MX (1) | MXPA99008417A (https=) |
| NO (1) | NO994390L (https=) |
| NZ (1) | NZ337830A (https=) |
| PL (1) | PL336415A1 (https=) |
| RU (1) | RU2247579C2 (https=) |
| SK (1) | SK125099A3 (https=) |
| WO (1) | WO1998040375A2 (https=) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPWO2004020421A1 (ja) * | 2002-08-28 | 2005-12-15 | 旭化成ファーマ株式会社 | 新規な４級アンモニウム化合物 |
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| US6262277B1 (en) | 1994-09-13 | 2001-07-17 | G.D. Searle And Company | Intermediates and processes for the preparation of benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake |
| US5994391A (en) * | 1994-09-13 | 1999-11-30 | G.D. Searle And Company | Benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake |
| US6642268B2 (en) | 1994-09-13 | 2003-11-04 | G.D. Searle & Co. | Combination therapy employing ileal bile acid transport inhibiting benzothipines and HMG Co-A reductase inhibitors |
| US6083497A (en) | 1997-11-05 | 2000-07-04 | Geltex Pharmaceuticals, Inc. | Method for treating hypercholesterolemia with unsubstituted polydiallylamine polymers |
| US6221897B1 (en) | 1998-06-10 | 2001-04-24 | Aventis Pharma Deutschland Gmbh | Benzothiepine 1,1-dioxide derivatives, a process for their preparation, pharmaceuticals comprising these compounds, and their use |
| WO2000038721A1 (en) | 1998-12-23 | 2000-07-06 | G.D. Searle Llc | Combinations of cholesteryl ester transfer protein inhibitors and nicotinic acid derivatives for cardiovascular indications |
| AU2003241629B2 (en) * | 1999-04-19 | 2005-06-16 | Astrazeneca Ab | An oral formulation for ileum administering comprising an inhibitor compound of the ileal bile acid transport |
| SE0000772D0 (sv) | 2000-03-08 | 2000-03-08 | Astrazeneca Ab | Chemical compounds |
| WO2001068096A2 (en) * | 2000-03-10 | 2001-09-20 | Pharmacia Corporation | Combination therapy for the prophylaxis and treatment of hyperlipidemic conditions and disorders |
| SE0003766D0 (sv) * | 2000-10-18 | 2000-10-18 | Astrazeneca Ab | Novel formulation |
| EG26979A (en) | 2000-12-21 | 2015-03-01 | Astrazeneca Ab | Chemical compounds |
| WO2002051396A1 (en) * | 2000-12-26 | 2002-07-04 | Sankyo Company, Limited | Pharmaceutical compositions containing cyclobutene derivatives |
| GB0121337D0 (en) | 2001-09-04 | 2001-10-24 | Astrazeneca Ab | Chemical compounds |
| GB0121621D0 (en) | 2001-09-07 | 2001-10-31 | Astrazeneca Ab | Chemical compounds |
| GB0121622D0 (en) * | 2001-09-07 | 2001-10-31 | Astrazeneca Ab | Chemical compounds |
| AU2002329387B2 (en) | 2001-09-08 | 2007-06-07 | Albireo Ab | Benzothiazepine and benzothiadiazepine derivatives with ileal bile acid transport (IBAT) inhibitory activity for the treatment hyperlipidaemia |
| IL162533A0 (en) | 2001-12-19 | 2005-11-20 | Atherogenics Inc | Chalcone derivatives and their use to treat diseases |
| WO2003053359A2 (en) | 2001-12-19 | 2003-07-03 | Atherogenics, Inc. | 1,3-bis-(substituted-phenyl)-2-propyn-1-ones and their use to treat disorders |
| US6852753B2 (en) | 2002-01-17 | 2005-02-08 | Pharmacia Corporation | Alkyl/aryl hydroxy or keto thiepine compounds as inhibitors of apical sodium co-dependent bile acid transport (ASBT) and taurocholate uptake |
| GB0209467D0 (en) | 2002-04-25 | 2002-06-05 | Astrazeneca Ab | Chemical compounds |
| GB0213669D0 (en) | 2002-06-14 | 2002-07-24 | Astrazeneca Ab | Chemical compounds |
| GB0304194D0 (en) | 2003-02-25 | 2003-03-26 | Astrazeneca Ab | Chemical compounds |
| GB0307918D0 (en) | 2003-04-05 | 2003-05-14 | Astrazeneca Ab | Therapeutic use |
| KR20070026392A (ko) | 2004-02-27 | 2007-03-08 | 아사히 가세이 파마 가부시키가이샤 | 신규 벤조티아제핀 및 벤조티에핀 화합물 |
| ES2552657T3 (es) | 2010-05-26 | 2015-12-01 | Satiogen Pharmaceuticals, Inc. | Inhibidores del reciclado de ácidos biliares y saciógenos para el tratamiento de diabetes, obesidad, y afecciones gastrointestinales inflamatorias |
| ES2687027T3 (es) | 2010-11-04 | 2018-10-23 | Albireo Ab | Inhibidores de ibat para el tratamiento de enfermedades hepáticas |
| DK2637646T3 (en) | 2010-11-08 | 2016-08-29 | Albireo Ab | PHARMACEUTICAL COMBINATION CONTAINING AN IBAT inhibitor and a bile acid binder |
| AU2012328526B2 (en) | 2011-10-28 | 2017-05-25 | Shire Human Genetic Therapies, Inc. | Bile acid recycling inhibitors for treatment of pediatric cholestatic liver diseases |
| US20130108573A1 (en) | 2011-10-28 | 2013-05-02 | Lumena Pharmaceuticals, Inc. | Bile Acid Recycling Inhibitors for Treatment of Hypercholemia and Cholestatic Liver Disease |
| CA2907230A1 (en) | 2013-03-15 | 2014-09-18 | Lumena Pharmaceuticals, Inc. | Bile acid recycling inhibitors for treatment of primary sclerosing cholangitis and inflammatory bowel disease |
| AU2014229050A1 (en) | 2013-03-15 | 2015-10-22 | Lumena Pharmaceuticals Llc | Bile acid recycling inhibitors for treatment of Barrett's esophagus and gastroesophageal reflux disease |
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| CN106659726A (zh) | 2014-06-25 | 2017-05-10 | Ea制药株式会社 | 固体制剂及其着色防止或着色减少方法 |
| EP3197459B1 (en) * | 2014-09-28 | 2025-02-12 | Huahui Health Ltd. | Polymeric bile acid derivatives inhibit hepatitis b and d virus and ntcp transport |
| EP3012252A1 (en) | 2014-10-24 | 2016-04-27 | Ferring BV | Crystal modifications of elobixibat |
| WO2017138878A1 (en) | 2016-02-09 | 2017-08-17 | Albireo Ab | Oral cholestyramine formulation and use thereof |
| ES2874669T3 (es) | 2016-02-09 | 2021-11-05 | Albireo Ab | Formulación oral de colestiramina y uso de la misma |
| CN108601739B (zh) | 2016-02-09 | 2022-01-04 | 阿尔比里奥公司 | 考来烯胺丸剂及其制备方法 |
| EP3664782B1 (en) | 2017-08-09 | 2025-01-29 | Albireo AB | Cholestyramine pellets, oral cholestyramine formulations and medical use thereof |
| CN111032019B (zh) | 2017-08-09 | 2022-07-05 | 阿尔比里奥公司 | 考来烯胺颗粒、口服考来烯胺制剂及其用途 |
| SG11202001685TA (en) | 2017-08-28 | 2020-03-30 | Enanta Pharm Inc | Hepatitis b antiviral agents |
| CN112449637B (zh) | 2018-06-05 | 2024-03-19 | 阿尔比里奥公司 | 苯并硫杂(二)氮杂环庚三烯化合物及其作为胆汁酸调节剂的用途 |
| PL3810581T3 (pl) | 2018-06-20 | 2025-04-28 | Albireo Ab | Modyfikacje kryształu odewiksibatu |
| US11801226B2 (en) | 2018-06-20 | 2023-10-31 | Albireo Ab | Pharmaceutical formulation of odevixibat |
| US10722457B2 (en) | 2018-08-09 | 2020-07-28 | Albireo Ab | Oral cholestyramine formulation and use thereof |
| US11007142B2 (en) | 2018-08-09 | 2021-05-18 | Albireo Ab | Oral cholestyramine formulation and use thereof |
| US11549878B2 (en) | 2018-08-09 | 2023-01-10 | Albireo Ab | In vitro method for determining the adsorbing capacity of an insoluble adsorbant |
| IL283190B2 (en) | 2018-11-21 | 2025-08-01 | Enanta Pharm Inc | Functionalized heterocycles as antiviral agents |
| TWI835997B (zh) | 2019-02-06 | 2024-03-21 | 瑞典商艾爾比瑞歐公司 | 苯并噻氮呯化合物及其用作膽酸調節劑之用途 |
| CN118852054A (zh) | 2019-02-06 | 2024-10-29 | 阿尔比里奥公司 | 苯并硫杂二氮杂环庚三烯化合物及其用作胆汁酸调节剂的用途 |
| EP3923943B1 (en) | 2019-02-12 | 2024-07-31 | Mirum Pharmaceuticals, Inc. | Genotype and dose-dependent response to an asbti in patients with bile salt export pump deficiency |
| WO2021110883A1 (en) | 2019-12-04 | 2021-06-10 | Albireo Ab | Benzothia(di)azepine compounds and their use as bile acid modulators |
| JP7696898B2 (ja) | 2019-12-04 | 2025-06-23 | アルビレオ・アクチボラグ | ベンゾチア（ジ）アゼピン化合物及び胆汁酸モジュレータとしてのそれらの使用 |
| EP4069247B1 (en) | 2019-12-04 | 2025-03-26 | Albireo AB | Benzothiadiazepine compounds and their use as bile acid modulators |
| IL293379B2 (en) | 2019-12-04 | 2026-04-01 | Albireo Ab | Benzothia(dia)azepine compounds and their use as bile acid modulators |
| AR120676A1 (es) | 2019-12-04 | 2022-03-09 | Albireo Ab | Compuestos de benzoti(di)azepina y su uso como ácido biliar |
| WO2021110884A1 (en) | 2019-12-04 | 2021-06-10 | Albireo Ab | Benzothia(di)azepine compounds and their use as bile acid modulators |
| US11014898B1 (en) | 2020-12-04 | 2021-05-25 | Albireo Ab | Benzothiazepine compounds and their use as bile acid modulators |
| WO2021110887A1 (en) | 2019-12-04 | 2021-06-10 | Albireo Ab | Benzothiazepine compounds and their use as bile acid modulators |
| TWI877263B (zh) | 2019-12-04 | 2025-03-21 | 瑞典商艾爾比瑞歐公司 | 苯并噻二氮呯化合物及其作為膽酸調節劑之用途 |
| ES2973355T3 (es) | 2019-12-04 | 2024-06-19 | Albireo Ab | Compuestos de benzotia(di)azepina y su uso como moduladores del ácido biliar |
| EP4188541B1 (en) | 2020-08-03 | 2024-12-25 | Albireo AB | Benzothia(di)azepine compounds and their use as bile acid modulators |
| CA3196488A1 (en) | 2020-11-12 | 2022-05-19 | Albireo Ab | Odevixibat for treating progressive familial intrahepatic cholestasis (pfic) |
| CN112274648B (zh) * | 2020-11-23 | 2022-10-14 | 郑州大学 | 一种胆固醇氧化酶修饰的杂化金属有机框架肿瘤靶向纳米制剂的制备方法 |
| BR112023010799A2 (pt) | 2020-12-04 | 2023-10-03 | Albireo Ab | Compostos de benzotia(di)azepina e seus usos como moduladores de ácidos biliares |
| TW202313579A (zh) | 2021-06-03 | 2023-04-01 | 瑞典商艾爾比瑞歐公司 | 苯并噻(二)氮呯(benzothia(di)azepine)化合物及其作為膽酸調節劑之用途 |
| KR20250022025A (ko) | 2022-06-09 | 2025-02-14 | 알비레오 에이비 | 간염 치료 |
| TW202423921A (zh) * | 2022-08-22 | 2024-06-16 | 美商安塔製藥公司 | 稠合的雜雙環抗病毒劑 |
| WO2025146508A1 (en) | 2024-01-05 | 2025-07-10 | Albireo Ab | Benzothia(di)azepine compounds and their use as bile acid modulators |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4444784A (en) * | 1980-08-05 | 1984-04-24 | Merck & Co., Inc. | Antihypercholesterolemic compounds |
| EP0549967B1 (de) * | 1991-12-20 | 1996-03-13 | Hoechst Aktiengesellschaft | Polymere und Oligomere von Gallensäurederivaten, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
| GB9203347D0 (en) * | 1992-02-17 | 1992-04-01 | Wellcome Found | Hypolipidaemic compounds |
-
1998
- 1998-03-10 PL PL98336415A patent/PL336415A1/xx unknown
- 1998-03-10 CA CA002283575A patent/CA2283575A1/en not_active Abandoned
- 1998-03-10 HU HU0002395A patent/HUP0002395A3/hu unknown
- 1998-03-10 EP EP98910075A patent/EP0971744A2/en not_active Withdrawn
- 1998-03-10 WO PCT/US1998/003792 patent/WO1998040375A2/en not_active Ceased
- 1998-03-10 MX MXPA99008417A patent/MXPA99008417A/es unknown
- 1998-03-10 RU RU99121514/15A patent/RU2247579C2/ru not_active IP Right Cessation
- 1998-03-10 IL IL13187298A patent/IL131872A0/xx unknown
- 1998-03-10 NZ NZ337830A patent/NZ337830A/en not_active Application Discontinuation
- 1998-03-10 CN CN98804995A patent/CN1255864A/zh active Pending
- 1998-03-10 BR BR9808013-0A patent/BR9808013A/pt not_active IP Right Cessation
- 1998-03-10 AU AU64408/98A patent/AU730024C/en not_active Ceased
- 1998-03-10 JP JP53959498A patent/JP2002500628A/ja not_active Abandoned
- 1998-03-10 SK SK1250-99A patent/SK125099A3/sk unknown
-
1999
- 1999-09-10 NO NO994390A patent/NO994390L/no not_active Application Discontinuation
- 1999-10-11 BG BG103793A patent/BG103793A/xx unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPWO2004020421A1 (ja) * | 2002-08-28 | 2005-12-15 | 旭化成ファーマ株式会社 | 新規な４級アンモニウム化合物 |
Also Published As
| Publication number | Publication date |
|---|---|
| BG103793A (en) | 2000-07-31 |
| WO1998040375A2 (en) | 1998-09-17 |
| EP0971744A2 (en) | 2000-01-19 |
| RU2247579C2 (ru) | 2005-03-10 |
| NZ337830A (en) | 2001-07-27 |
| MXPA99008417A (es) | 2005-02-03 |
| HUP0002395A2 (hu) | 2001-05-28 |
| WO1998040375A3 (en) | 1998-12-03 |
| CA2283575A1 (en) | 1998-09-17 |
| HUP0002395A3 (en) | 2002-12-28 |
| NO994390D0 (no) | 1999-09-10 |
| AU6440898A (en) | 1998-09-29 |
| PL336415A1 (en) | 2000-06-19 |
| NO994390L (no) | 1999-11-04 |
| AU730024C (en) | 2004-08-05 |
| IL131872A0 (en) | 2001-03-19 |
| BR9808013A (pt) | 2001-09-25 |
| CN1255864A (zh) | 2000-06-07 |
| AU730024B2 (en) | 2001-02-22 |
| SK125099A3 (en) | 2001-02-12 |
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