CA2283575A1 - Combination therapy employing ileal bile acid transport inhibiting benzothiepines and hmg co-a reductase inhibitors - Google Patents
Combination therapy employing ileal bile acid transport inhibiting benzothiepines and hmg co-a reductase inhibitors Download PDFInfo
- Publication number
- CA2283575A1 CA2283575A1 CA002283575A CA2283575A CA2283575A1 CA 2283575 A1 CA2283575 A1 CA 2283575A1 CA 002283575 A CA002283575 A CA 002283575A CA 2283575 A CA2283575 A CA 2283575A CA 2283575 A1 CA2283575 A1 CA 2283575A1
- Authority
- CA
- Canada
- Prior art keywords
- iso
- butyl
- propyl
- pentyl
- ethyl
- 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
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- 239000003112 inhibitor Substances 0.000 title claims abstract description 35
- 238000002648 combination therapy Methods 0.000 title claims abstract description 16
- NIGNBCLEMMGDQP-UHFFFAOYSA-N 1-benzothiepine Chemical class S1C=CC=CC2=CC=CC=C12 NIGNBCLEMMGDQP-UHFFFAOYSA-N 0.000 title abstract description 24
- 239000003613 bile acid Substances 0.000 title description 30
- 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 20
- 230000002401 inhibitory effect Effects 0.000 title description 4
- 239000000203 mixture Substances 0.000 claims abstract description 141
- 238000000034 method Methods 0.000 claims abstract description 86
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 19
- 238000011282 treatment Methods 0.000 claims abstract description 18
- 229940077672 Ileal bile acid transport inhibitor Drugs 0.000 claims abstract description 13
- 238000011321 prophylaxis Methods 0.000 claims abstract description 8
- 241000124008 Mammalia Species 0.000 claims abstract description 6
- 229940123934 Reductase inhibitor Drugs 0.000 claims description 12
- 230000001315 anti-hyperlipaemic effect Effects 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 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
- 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 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 3
- 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 3
- 229960003765 fluvastatin Drugs 0.000 claims 3
- 229960004844 lovastatin Drugs 0.000 claims 3
- 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 3
- 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 3
- 229960002965 pravastatin Drugs 0.000 claims 3
- 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 3
- 229960002855 simvastatin Drugs 0.000 claims 3
- 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 3
- 150000001875 compounds Chemical class 0.000 abstract description 174
- 201000001320 Atherosclerosis Diseases 0.000 abstract description 11
- 239000003814 drug Substances 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 220
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 207
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 152
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 151
- 239000000243 solution Substances 0.000 description 149
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 146
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 108
- 239000000047 product Substances 0.000 description 104
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 description 103
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 102
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 101
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 97
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 95
- 238000006243 chemical reaction Methods 0.000 description 93
- 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 92
- 229910001868 water Inorganic materials 0.000 description 88
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 87
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 83
- -1 Benzothiazepine Compounds Chemical class 0.000 description 82
- 239000011541 reaction mixture Substances 0.000 description 81
- 229940073584 methylene chloride Drugs 0.000 description 73
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 72
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 71
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 64
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 63
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 60
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 57
- 125000000623 heterocyclic group Chemical group 0.000 description 55
- 239000007787 solid Substances 0.000 description 55
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 53
- 235000019439 ethyl acetate Nutrition 0.000 description 51
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 50
- 238000003756 stirring Methods 0.000 description 50
- 125000000217 alkyl group Chemical group 0.000 description 49
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 45
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 45
- 239000003921 oil Substances 0.000 description 45
- 235000019198 oils Nutrition 0.000 description 45
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 44
- 125000003118 aryl group Chemical group 0.000 description 44
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 43
- 238000001819 mass spectrum Methods 0.000 description 42
- 238000002360 preparation method Methods 0.000 description 42
- 238000007792 addition Methods 0.000 description 40
- 239000012044 organic layer Substances 0.000 description 40
- 239000010410 layer Substances 0.000 description 39
- 238000004128 high performance liquid chromatography Methods 0.000 description 36
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 36
- 125000003342 alkenyl group Chemical group 0.000 description 35
- 238000010992 reflux Methods 0.000 description 35
- 125000000304 alkynyl group Chemical group 0.000 description 34
- 239000012267 brine Substances 0.000 description 34
- 125000001072 heteroaryl group Chemical group 0.000 description 34
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 34
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 32
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 32
- 125000000753 cycloalkyl group Chemical group 0.000 description 32
- 229910052757 nitrogen Inorganic materials 0.000 description 32
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 31
- 125000001424 substituent group Chemical group 0.000 description 31
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 30
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
- 229910052739 hydrogen Inorganic materials 0.000 description 27
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 26
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 26
- 239000000284 extract Substances 0.000 description 26
- 238000005481 NMR spectroscopy Methods 0.000 description 25
- 239000004721 Polyphenylene oxide Substances 0.000 description 25
- 229920000570 polyether Polymers 0.000 description 25
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 24
- 229910052799 carbon Inorganic materials 0.000 description 24
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 23
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 23
- 239000000463 material Substances 0.000 description 22
- 108090000765 processed proteins & peptides Proteins 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 21
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 21
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 21
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 21
- 239000007789 gas Substances 0.000 description 20
- 125000001188 haloalkyl group Chemical group 0.000 description 20
- 238000000746 purification Methods 0.000 description 19
- 238000004809 thin layer chromatography Methods 0.000 description 19
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 18
- 235000012000 cholesterol Nutrition 0.000 description 18
- 239000001257 hydrogen Substances 0.000 description 18
- 229910000027 potassium carbonate Inorganic materials 0.000 description 18
- 229910000104 sodium hydride Inorganic materials 0.000 description 18
- 239000007858 starting material Substances 0.000 description 18
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 18
- 150000001413 amino acids Chemical class 0.000 description 17
- 239000000706 filtrate Substances 0.000 description 17
- 238000010898 silica gel chromatography Methods 0.000 description 17
- 125000003710 aryl alkyl group Chemical group 0.000 description 16
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 15
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 15
- 238000004949 mass spectrometry Methods 0.000 description 15
- 229910052760 oxygen Inorganic materials 0.000 description 15
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 15
- 150000003839 salts Chemical class 0.000 description 15
- 229910052717 sulfur Inorganic materials 0.000 description 15
- 229910052736 halogen Inorganic materials 0.000 description 14
- 150000002367 halogens Chemical class 0.000 description 14
- 229920000642 polymer Polymers 0.000 description 14
- 238000010926 purge Methods 0.000 description 14
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 13
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 13
- 238000003556 assay Methods 0.000 description 13
- 150000001720 carbohydrates Chemical class 0.000 description 13
- 235000014633 carbohydrates Nutrition 0.000 description 13
- 235000019341 magnesium sulphate Nutrition 0.000 description 13
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 13
- 239000012312 sodium hydride Substances 0.000 description 13
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 12
- 125000003545 alkoxy group Chemical group 0.000 description 12
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 12
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
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- 230000029936 alkylation Effects 0.000 description 11
- 238000005804 alkylation reaction Methods 0.000 description 11
- 150000001412 amines Chemical class 0.000 description 11
- 235000001014 amino acid Nutrition 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 11
- 230000037396 body weight Effects 0.000 description 11
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- 229960001866 silicon dioxide Drugs 0.000 description 11
- 239000003826 tablet Substances 0.000 description 11
- GDVUGFJXFFCXMX-UHFFFAOYSA-N (2-ethyl-2-formylhexyl) methanesulfonate Chemical compound CCCCC(CC)(C=O)COS(C)(=O)=O GDVUGFJXFFCXMX-UHFFFAOYSA-N 0.000 description 10
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 10
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- 239000002585 base Substances 0.000 description 10
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- 239000003054 catalyst Substances 0.000 description 10
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 10
- 239000012043 crude product Substances 0.000 description 10
- 239000002552 dosage form Substances 0.000 description 10
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- 239000011780 sodium chloride Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
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- WGCYRFWNGRMRJA-UHFFFAOYSA-N 1-ethylpiperazine Chemical compound CCN1CCNCC1 WGCYRFWNGRMRJA-UHFFFAOYSA-N 0.000 description 7
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- TZSDMELQUACXIN-UHFFFAOYSA-N 2,3,4,5-tetrahydro-1$l^{6}-benzothiepine 1,1-dioxide Chemical class O=S1(=O)CCCCC2=CC=CC=C12 TZSDMELQUACXIN-UHFFFAOYSA-N 0.000 description 7
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- 150000001335 aliphatic alkanes Chemical class 0.000 description 6
- 150000001336 alkenes Chemical class 0.000 description 6
- 150000001345 alkine derivatives Chemical class 0.000 description 6
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- 125000005605 benzo group Chemical group 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 6
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
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Classifications
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- A—HUMAN NECESSITIES
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- 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
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- 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
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- 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
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- 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)
- Veterinary Medicine (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)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Emergency Medicine (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nitrogen Condensed Heterocyclic Rings (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 (1)
| Publication Number | Publication Date |
|---|---|
| CA2283575A1 true CA2283575A1 (en) | 1998-09-17 |
Family
ID=21912237
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002283575A Abandoned CA2283575A1 (en) | 1997-03-11 | 1998-03-10 | Combination therapy employing ileal bile acid transport inhibiting benzothiepines and hmg co-a reductase inhibitors |
Country Status (16)
| Country | Link |
|---|---|
| EP (1) | EP0971744A2 (enExample) |
| JP (1) | JP2002500628A (enExample) |
| CN (1) | CN1255864A (enExample) |
| AU (1) | AU730024C (enExample) |
| BG (1) | BG103793A (enExample) |
| BR (1) | BR9808013A (enExample) |
| CA (1) | CA2283575A1 (enExample) |
| HU (1) | HUP0002395A3 (enExample) |
| IL (1) | IL131872A0 (enExample) |
| MX (1) | MXPA99008417A (enExample) |
| NO (1) | NO994390L (enExample) |
| NZ (1) | NZ337830A (enExample) |
| PL (1) | PL336415A1 (enExample) |
| RU (1) | RU2247579C2 (enExample) |
| SK (1) | SK125099A3 (enExample) |
| WO (1) | WO1998040375A2 (enExample) |
Families Citing this family (66)
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|---|---|---|---|---|
| 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 |
| 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 |
| 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 |
| 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 |
| AU3103800A (en) | 1998-12-23 | 2000-07-31 | G.D. Searle Llc | Combinations of cholesteryl ester transfer protein inhibitors and nicotinic acidderivatives 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 |
| MY131995A (en) | 2001-09-08 | 2007-09-28 | Astrazeneca Ab | Benzothiazepine and benzothiadiazepine derivatives with illeal bile acid transport (ibat) inhibitory activity for the treatment hyperlipidaemia |
| CN1596240A (zh) | 2001-12-19 | 2005-03-16 | 阿特罗吉尼克斯公司 | 查耳酮衍生物及其治疗疾病的用途 |
| 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 |
| MXPA04006255A (es) | 2002-01-17 | 2004-09-27 | Pharmacia Corp | Compuestos novedosos de alquil/aril hidroxi o ceto tiepina como inhibidores del transporte del acido biliar codependiente del sodio apical y la captacion de taurocolato. |
| GB0209467D0 (en) | 2002-04-25 | 2002-06-05 | Astrazeneca Ab | Chemical compounds |
| GB0213669D0 (en) | 2002-06-14 | 2002-07-24 | Astrazeneca Ab | Chemical compounds |
| WO2004020421A1 (ja) * | 2002-08-28 | 2004-03-11 | Asahi Kasei Pharma Corporation | 新規な４級アンモニウム化合物 |
| GB0304194D0 (en) | 2003-02-25 | 2003-03-26 | Astrazeneca Ab | Chemical compounds |
| GB0307918D0 (en) | 2003-04-05 | 2003-05-14 | Astrazeneca Ab | Therapeutic use |
| AU2005217318B2 (en) | 2004-02-27 | 2010-07-01 | Asahi Kasei Pharma Corporation | Novel benzothiazepine and benzothiepine compounds |
| EP4137137A1 (en) | 2010-05-26 | 2023-02-22 | Satiogen Pharmaceuticals, Inc. | Bile acid recycling inhibitors and satiogens for treatment of diabetes, obesity, and inflammatory gastrointestinal conditions |
| MX366925B (es) | 2010-11-04 | 2019-07-31 | Albireo Ab | Inhibidores de ibat para el tratamiento de enfermedades hepaticas. |
| US20130236541A1 (en) | 2010-11-08 | 2013-09-12 | Albireo Ab | Pharmaceutical combination comprising an ibat inhibitor and a bile acid binder |
| EA038594B1 (ru) | 2011-10-28 | 2021-09-21 | Шайр Хьюман Дженетик Терапис, Инк. | Ингибиторы рециркуляции желчных кислот для лечения гиперхолемии и холестатического заболевания печени |
| JP6217938B2 (ja) | 2011-10-28 | 2017-10-25 | ルメナ ファーマシューティカルズ エルエルシー | 小児の胆汁うっ滞性肝疾患の処置のための胆汁酸再循環阻害剤 |
| KR20160002773A (ko) | 2013-03-15 | 2016-01-08 | 루메나 파마수티컬즈, 인코포레이티드 | 원발성 담관염 및 염증성 장 질환 치료용 담즙산 재순환 억제제 |
| 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 |
| JO3301B1 (ar) | 2013-04-26 | 2018-09-16 | Albireo Ab | تعديلات بلورية على إيلوبيكسيبات |
| CA2952406A1 (en) | 2014-06-25 | 2015-12-30 | Ea Pharma Co., Ltd. | Solid formulation and method for preventing or reducing coloration thereof |
| CN106794188B (zh) | 2014-09-28 | 2022-12-02 | 华辉安健（北京）生物科技有限公司 | 聚合胆汁酸衍生物抑制乙型肝炎病毒和丁型肝炎病毒和ntcp运输 |
| EP3012252A1 (en) | 2014-10-24 | 2016-04-27 | Ferring BV | Crystal modifications of elobixibat |
| CN108601744B (zh) | 2016-02-09 | 2022-01-04 | 阿尔比里奥公司 | 口服考来烯胺制剂及其用途 |
| JP6954927B2 (ja) | 2016-02-09 | 2021-10-27 | アルビレオ・アクチボラグ | 経口コレスチラミン製剤及びその使用 |
| CA3011595C (en) | 2016-02-09 | 2024-01-02 | Albireo Ab | Cholestyramine pellets and methods for preparation 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 |
| JP7328207B2 (ja) | 2017-08-09 | 2023-08-16 | アルビレオ・アクチボラグ | コレスチラミンペレット、経口コレスチラミン製剤、及びそれらの使用 |
| SG11202001685TA (en) | 2017-08-28 | 2020-03-30 | Enanta Pharm Inc | Hepatitis b antiviral agents |
| JP7391048B2 (ja) | 2018-06-05 | 2023-12-04 | 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 |
| KR20210024033A (ko) | 2018-06-20 | 2021-03-04 | 알비레오 에이비 | 오데빅시바트의 약학 제제 |
| US11801226B2 (en) | 2018-06-20 | 2023-10-31 | Albireo Ab | Pharmaceutical formulation of odevixibat |
| US11549878B2 (en) | 2018-08-09 | 2023-01-10 | Albireo Ab | In vitro method for determining the adsorbing capacity of an insoluble adsorbant |
| 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 |
| EP3883570A4 (en) | 2018-11-21 | 2022-07-13 | Enanta Pharmaceuticals, Inc. | FUNCTIONALIZED HETEROCYCLES AS ANTIVIRAL AGENTS |
| CN113453753B (zh) | 2019-02-06 | 2024-07-23 | 阿尔比里奥公司 | 苯并硫氮杂环庚三烯化合物及其用作胆汁酸调节剂的用途 |
| SG11202108566VA (en) | 2019-02-06 | 2021-09-29 | Albireo Ab | Benzothiadiazepine compounds and their use as bile acid modulators |
| EP4424363B1 (en) | 2019-02-12 | 2026-04-29 | Mirum Pharmaceuticals, Inc. | Methods for increasing growth in pediatric subjects having cholestatic liver disease |
| JP7665621B2 (ja) | 2019-12-04 | 2025-04-21 | アルビレオ・アクチボラグ | ベンゾチ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 |
| CA3158181A1 (en) | 2019-12-04 | 2021-06-10 | Albireo Ab | Benzothia(di)azepine compounds and their use as bile acid modulators |
| CA3158195A1 (en) | 2019-12-04 | 2021-06-10 | Per-Goran Gillberg | Benzothia(di)azepine compounds and their use as bile acid modulators |
| WO2021110885A1 (en) | 2019-12-04 | 2021-06-10 | Albireo Ab | Benzothiadiazepine compounds and their use as bile acid modulators |
| CN114786772B (zh) | 2019-12-04 | 2024-04-09 | 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 |
| ES3002777T3 (en) | 2020-08-03 | 2025-03-07 | Albireo Ab | Benzothia(di)azepine compounds and their use as bile acid modulators |
| AU2021379076A1 (en) | 2020-11-12 | 2023-06-08 | 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 |
| CN117412955A (zh) | 2021-06-03 | 2024-01-16 | 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 |
| EP4536232A1 (en) | 2022-06-09 | 2025-04-16 | Albireo AB | Treating hepatitis |
| 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 |
| WO2025146507A1 (en) | 2024-01-05 | 2025-07-10 | Albireo Ab | Benzothia(di)azepine compounds and their use as bile acid modulators |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4444784A (en) * | 1980-08-05 | 1984-04-24 | Merck & Co., Inc. | Antihypercholesterolemic compounds |
| FI108451B (fi) * | 1991-12-20 | 2002-01-31 | Hoechst Ag | Menetelmõ polymeeristen ja oligomeeristen sappihappojohdannaisten valmistamiseksi |
| GB9203347D0 (en) * | 1992-02-17 | 1992-04-01 | Wellcome Found | Hypolipidaemic compounds |
-
1998
- 1998-03-10 NZ NZ337830A patent/NZ337830A/en not_active Application Discontinuation
- 1998-03-10 MX MXPA99008417A patent/MXPA99008417A/es unknown
- 1998-03-10 JP JP53959498A patent/JP2002500628A/ja not_active Abandoned
- 1998-03-10 IL IL13187298A patent/IL131872A0/xx unknown
- 1998-03-10 PL PL98336415A patent/PL336415A1/xx unknown
- 1998-03-10 EP EP98910075A patent/EP0971744A2/en not_active Withdrawn
- 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 RU RU99121514/15A patent/RU2247579C2/ru not_active IP Right Cessation
- 1998-03-10 AU AU64408/98A patent/AU730024C/en not_active Ceased
- 1998-03-10 SK SK1250-99A patent/SK125099A3/sk unknown
- 1998-03-10 CA CA002283575A patent/CA2283575A1/en not_active Abandoned
- 1998-03-10 WO PCT/US1998/003792 patent/WO1998040375A2/en not_active Ceased
- 1998-03-10 HU HU0002395A patent/HUP0002395A3/hu unknown
-
1999
- 1999-09-10 NO NO994390A patent/NO994390L/no not_active Application Discontinuation
- 1999-10-11 BG BG103793A patent/BG103793A/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| MXPA99008417A (es) | 2005-02-03 |
| PL336415A1 (en) | 2000-06-19 |
| EP0971744A2 (en) | 2000-01-19 |
| NO994390L (no) | 1999-11-04 |
| SK125099A3 (en) | 2001-02-12 |
| BG103793A (en) | 2000-07-31 |
| NO994390D0 (no) | 1999-09-10 |
| AU6440898A (en) | 1998-09-29 |
| RU2247579C2 (ru) | 2005-03-10 |
| AU730024C (en) | 2004-08-05 |
| HUP0002395A2 (hu) | 2001-05-28 |
| NZ337830A (en) | 2001-07-27 |
| WO1998040375A3 (en) | 1998-12-03 |
| BR9808013A (pt) | 2001-09-25 |
| AU730024B2 (en) | 2001-02-22 |
| CN1255864A (zh) | 2000-06-07 |
| JP2002500628A (ja) | 2002-01-08 |
| HUP0002395A3 (en) | 2002-12-28 |
| WO1998040375A2 (en) | 1998-09-17 |
| IL131872A0 (en) | 2001-03-19 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued | ||
| FZDE | Discontinued |
Effective date: 20070312 |