PT1427423E - Derivados de benzotiazepina e benzotiadiazepina com actividade inibidora do transporte ileal de ácidos biliáres (ibat) para o tratamento de hiperlipidemia - Google Patents

Info

Publication number

PT1427423E

PT1427423E PT02765013T PT02765013T PT1427423E PT 1427423 E PT1427423 E PT 1427423E PT 02765013 T PT02765013 T PT 02765013T PT 02765013 T PT02765013 T PT 02765013T PT 1427423 E PT1427423 E PT 1427423E

Authority

PT

Portugal

Prior art keywords

solvate

carbamoyl

formula

pharmaceutically acceptable

carbamoylmethoxy

Prior art date

2001-09-08

Links

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• 238000011282 treatment Methods 0.000 title claims abstract description 63
• 239000003613 bile acid Substances 0.000 title claims abstract description 48
• 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 claims abstract description 37
• 208000031226 Hyperlipidaemia Diseases 0.000 title claims abstract description 11
• 230000002401 inhibitory effect Effects 0.000 title claims description 59
• KAOYLRLQZXRRBD-UHFFFAOYSA-N 1,2,3-benzothiadiazepine Chemical class S1N=NC=CC2=CC=CC=C12 KAOYLRLQZXRRBD-UHFFFAOYSA-N 0.000 title description 6
• FHGWEHGZBUBQKL-UHFFFAOYSA-N 1,2-benzothiazepine Chemical compound S1N=CC=CC2=CC=CC=C12 FHGWEHGZBUBQKL-UHFFFAOYSA-N 0.000 title description 4
• 239000012453 solvate Substances 0.000 claims abstract description 328
• 150000001875 compounds Chemical class 0.000 claims abstract description 277
• 150000003839 salts Chemical class 0.000 claims abstract description 201
• 238000000034 method Methods 0.000 claims abstract description 129
• 239000000651 prodrug Substances 0.000 claims abstract description 125
• 229940002612 prodrug Drugs 0.000 claims abstract description 125
• 230000008569 process Effects 0.000 claims abstract description 24
• 238000004519 manufacturing process Methods 0.000 claims abstract description 15
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
• 239000003112 inhibitor Substances 0.000 claims abstract description 13
• -1 hydroxy, amino, mercapto Chemical group 0.000 claims description 295
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 161
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 103
• 239000001257 hydrogen Substances 0.000 claims description 101
• 229910052739 hydrogen Inorganic materials 0.000 claims description 101
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 87
• 238000001727 in vivo Methods 0.000 claims description 85
• 229910052757 nitrogen Inorganic materials 0.000 claims description 85
• 125000000217 alkyl group Chemical group 0.000 claims description 84
• 241001465754 Metazoa Species 0.000 claims description 70
• 239000000203 mixture Substances 0.000 claims description 69
• 150000002148 esters Chemical class 0.000 claims description 59
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 47
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 42
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 42
• 150000001408 amides Chemical class 0.000 claims description 41
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 41
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 38
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 35
• 239000011230 binding agent Substances 0.000 claims description 33
• 229910052799 carbon Inorganic materials 0.000 claims description 33
• 125000001424 substituent group Chemical group 0.000 claims description 32
• 239000003814 drug Substances 0.000 claims description 31
• 125000000623 heterocyclic group Chemical group 0.000 claims description 30
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 30
• 238000002360 preparation method Methods 0.000 claims description 30
• 239000003085 diluting agent Substances 0.000 claims description 26
• 229940123934 Reductase inhibitor Drugs 0.000 claims description 24
• 150000002431 hydrogen Chemical class 0.000 claims description 22
• GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 21
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 20
• 125000004452 carbocyclyl group Chemical group 0.000 claims description 19
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 18
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 15
• 239000000556 agonist Substances 0.000 claims description 15
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 15
• 239000002253 acid Substances 0.000 claims description 14
• 125000004423 acyloxy group Chemical group 0.000 claims description 14
• 125000006239 protecting group Chemical group 0.000 claims description 14
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 13
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 12
• 230000002792 vascular Effects 0.000 claims description 12
• 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 11
• 230000001225 therapeutic effect Effects 0.000 claims description 11
• 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 10
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 10
• 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 claims description 10
• 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 claims description 10
• 125000005236 alkanoylamino group Chemical group 0.000 claims description 10
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
• 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 9
• 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 9
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 9
• 206010021024 Hypolipidaemia Diseases 0.000 claims description 9
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 9
• 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 9
• PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical group FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 9
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
• 208000006011 Stroke Diseases 0.000 claims description 8
• 150000001412 amines Chemical class 0.000 claims description 8
• 125000003118 aryl group Chemical group 0.000 claims description 8
• 238000011284 combination treatment Methods 0.000 claims description 8
• 208000029078 coronary artery disease Diseases 0.000 claims description 8
• 125000001072 heteroaryl group Chemical group 0.000 claims description 8
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 8
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 8
• 206010002383 Angina Pectoris Diseases 0.000 claims description 7
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• 108090000854 Oxidoreductases Proteins 0.000 claims description 7
• 102000004316 Oxidoreductases Human genes 0.000 claims description 7
• 208000018262 Peripheral vascular disease Diseases 0.000 claims description 7
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 7
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
• 230000003516 hyperlipidaemic effect Effects 0.000 claims description 7
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
• 125000003282 alkyl amino group Chemical group 0.000 claims description 6
• 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 6
• 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 6
• 208000010125 myocardial infarction Diseases 0.000 claims description 6
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 5
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 5
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 5
• 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 description 5
• 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 description 5
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 5
• 208000024172 Cardiovascular disease Diseases 0.000 claims description 5
• 208000035150 Hypercholesterolemia Diseases 0.000 claims description 5
• 208000032109 Transient ischaemic attack Diseases 0.000 claims description 5
• 125000003545 alkoxy group Chemical group 0.000 claims description 5
• HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 5
• 229960005370 atorvastatin Drugs 0.000 claims description 5
• 230000002526 effect on cardiovascular system Effects 0.000 claims description 5
• 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 5
• 208000026621 hypolipoproteinemia Diseases 0.000 claims description 5
• 150000002632 lipids Chemical class 0.000 claims description 5
• 229960000672 rosuvastatin Drugs 0.000 claims description 5
• BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 claims description 5
• 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 5
• 201000010875 transient cerebral ischemia Diseases 0.000 claims description 5
• 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 4
• 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 4
• MQEZYLMJQKBGHE-UHFFFAOYSA-N 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine Chemical compound S1NCCNC2=CC=CC=C21 MQEZYLMJQKBGHE-UHFFFAOYSA-N 0.000 claims description 4
• 206010002329 Aneurysm Diseases 0.000 claims description 4
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• 206010019280 Heart failures Diseases 0.000 claims description 4
• 208000000563 Hyperlipoproteinemia Type II Diseases 0.000 claims description 4
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• 102000023984 PPAR alpha Human genes 0.000 claims description 4
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• 210000001367 artery Anatomy 0.000 claims description 4
• FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 claims description 4
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• 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
• 208000000522 hyperlipoproteinemia type IV Diseases 0.000 claims description 4
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• 208000029498 hypoalphalipoproteinemia Diseases 0.000 claims description 4
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• UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 4
• 208000037803 restenosis Diseases 0.000 claims description 4
• 229910052701 rubidium Inorganic materials 0.000 claims description 4
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• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
• 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
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• 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 description 3
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