ZA200304266B - Chemical compounds. - Google Patents
Chemical compounds. Download PDFInfo
- Publication number
- ZA200304266B ZA200304266B ZA200304266A ZA200304266A ZA200304266B ZA 200304266 B ZA200304266 B ZA 200304266B ZA 200304266 A ZA200304266 A ZA 200304266A ZA 200304266 A ZA200304266 A ZA 200304266A ZA 200304266 B ZA200304266 B ZA 200304266B
- Authority
- ZA
- South Africa
- Prior art keywords
- solvate
- formula
- pharmaceutically acceptable
- salt
- compound
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims description 115
- -1 nitro, cyano, hydroxy, amino, carboxy, carbamoyl Chemical group 0.000 claims description 170
- 150000003839 salts Chemical class 0.000 claims description 170
- 239000012453 solvate Substances 0.000 claims description 156
- 239000001257 hydrogen Substances 0.000 claims description 94
- 229910052739 hydrogen Inorganic materials 0.000 claims description 94
- 229940002612 prodrug Drugs 0.000 claims description 81
- 239000000651 prodrug Substances 0.000 claims description 81
- 238000000034 method Methods 0.000 claims description 53
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 51
- 239000000126 substance Substances 0.000 claims description 51
- 125000000217 alkyl group Chemical group 0.000 claims description 48
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 43
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 41
- 150000002431 hydrogen Chemical class 0.000 claims description 39
- 125000001424 substituent group Chemical group 0.000 claims description 36
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 35
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 33
- 229910052799 carbon Inorganic materials 0.000 claims description 33
- 241001465754 Metazoa Species 0.000 claims description 31
- 125000000623 heterocyclic group Chemical group 0.000 claims description 25
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 23
- 239000003613 bile acid Substances 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 238000004519 manufacturing process Methods 0.000 claims description 21
- 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 claims description 19
- 239000011230 binding agent Substances 0.000 claims description 17
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 17
- 230000003516 hyperlipidaemic effect Effects 0.000 claims description 17
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 11
- 230000002401 inhibitory effect Effects 0.000 claims description 10
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 9
- 230000002265 prevention Effects 0.000 claims description 9
- 230000002792 vascular Effects 0.000 claims description 8
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 125000001041 indolyl group Chemical group 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 6
- 206010021024 Hypolipidaemia Diseases 0.000 claims description 6
- 208000029078 coronary artery disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 5
- 206010002383 Angina Pectoris Diseases 0.000 claims description 5
- 201000001320 Atherosclerosis Diseases 0.000 claims description 5
- 208000018262 Peripheral vascular disease Diseases 0.000 claims description 5
- 208000006011 Stroke Diseases 0.000 claims description 5
- 208000032109 Transient ischaemic attack Diseases 0.000 claims description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 5
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 5
- 208000010125 myocardial infarction Diseases 0.000 claims description 5
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 4
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 4
- 125000001589 carboacyl group Chemical group 0.000 claims description 4
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 3
- 229920001268 Cholestyramine Polymers 0.000 claims description 3
- 229920002911 Colestipol Polymers 0.000 claims description 3
- 206010048554 Endothelial dysfunction Diseases 0.000 claims description 3
- 206010019280 Heart failures Diseases 0.000 claims description 3
- 208000035150 Hypercholesterolemia Diseases 0.000 claims description 3
- 206010020606 Hyperchylomicronaemia Diseases 0.000 claims description 3
- 208000000563 Hyperlipoproteinemia Type II Diseases 0.000 claims description 3
- 206010061218 Inflammation Diseases 0.000 claims description 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 description 3
- 208000007536 Thrombosis Diseases 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 230000006793 arrhythmia Effects 0.000 claims description 3
- 206010003119 arrhythmia Diseases 0.000 claims description 3
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 3
- 208000035475 disorder Diseases 0.000 claims description 3
- 230000001258 dyslipidemic effect Effects 0.000 claims description 3
- 230000008694 endothelial dysfunction Effects 0.000 claims description 3
- 201000001386 familial hypercholesterolemia Diseases 0.000 claims description 3
- 201000011110 familial lipoprotein lipase deficiency Diseases 0.000 claims description 3
- 208000020346 hyperlipoproteinemia Diseases 0.000 claims description 3
- 208000000522 hyperlipoproteinemia type IV Diseases 0.000 claims description 3
- 208000029498 hypoalphalipoproteinemia Diseases 0.000 claims description 3
- 208000026621 hypolipoproteinemia Diseases 0.000 claims description 3
- 208000015181 infectious disease Diseases 0.000 claims description 3
- 230000002458 infectious effect Effects 0.000 claims description 3
- 230000004054 inflammatory process Effects 0.000 claims description 3
- 208000014674 injury Diseases 0.000 claims description 3
- 210000000265 leukocyte Anatomy 0.000 claims description 3
- 210000002540 macrophage Anatomy 0.000 claims description 3
- 210000001616 monocyte Anatomy 0.000 claims description 3
- 239000011347 resin Substances 0.000 claims description 3
- 229920005989 resin Polymers 0.000 claims description 3
- 229960002855 simvastatin Drugs 0.000 claims description 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 description 3
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 230000008719 thickening Effects 0.000 claims description 3
- 230000008733 trauma Effects 0.000 claims description 3
- 230000006492 vascular dysfunction Effects 0.000 claims description 3
- 125000003143 4-hydroxybenzyl group Chemical group [H]C([*])([H])C1=C([H])C([H])=C(O[H])C([H])=C1[H] 0.000 claims description 2
- 208000031481 Pathologic Constriction Diseases 0.000 claims description 2
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 210000001367 artery Anatomy 0.000 claims description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 2
- 208000037803 restenosis Diseases 0.000 claims description 2
- 230000036262 stenosis Effects 0.000 claims description 2
- 208000037804 stenosis Diseases 0.000 claims description 2
- 210000005166 vasculature Anatomy 0.000 claims description 2
- 210000003462 vein Anatomy 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims 55
- 229940123934 Reductase inhibitor Drugs 0.000 claims 15
- 239000005557 antagonist Substances 0.000 claims 12
- 239000003085 diluting agent Substances 0.000 claims 12
- 125000001475 halogen functional group Chemical group 0.000 claims 12
- 239000000556 agonist Substances 0.000 claims 9
- 230000001906 cholesterol absorption Effects 0.000 claims 9
- 102000023984 PPAR alpha Human genes 0.000 claims 8
- 108010028924 PPAR alpha Proteins 0.000 claims 8
- 102000000536 PPAR gamma Human genes 0.000 claims 8
- 108010016731 PPAR gamma Proteins 0.000 claims 8
- 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
- 102100021711 Ileal sodium/bile acid cotransporter Human genes 0.000 claims 3
- 101710156096 Ileal sodium/bile acid cotransporter Proteins 0.000 claims 3
- 229960005370 atorvastatin Drugs 0.000 claims 3
- 230000000069 prophylactic effect Effects 0.000 claims 3
- 229960000672 rosuvastatin Drugs 0.000 claims 3
- 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 3
- 230000001225 therapeutic effect Effects 0.000 claims 3
- VDSBXXDKCUBMQC-HNGSOEQISA-N (4r,6s)-6-[(e)-2-[2-(4-fluoro-3-methylphenyl)-4,4,6,6-tetramethylcyclohexen-1-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C1=C(F)C(C)=CC(C=2CC(C)(C)CC(C)(C)C=2\C=C\[C@H]2OC(=O)C[C@H](O)C2)=C1 VDSBXXDKCUBMQC-HNGSOEQISA-N 0.000 claims 2
- 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 2
- 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 2
- AJLFOPYRIVGYMJ-UHFFFAOYSA-N SJ000287055 Natural products C12C(OC(=O)C(C)CC)CCC=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 AJLFOPYRIVGYMJ-UHFFFAOYSA-N 0.000 claims 2
- 150000001412 amines Chemical class 0.000 claims 2
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical group O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 claims 2
- 229950005357 bervastatin Drugs 0.000 claims 2
- 229960005110 cerivastatin Drugs 0.000 claims 2
- SEERZIQQUAZTOL-ANMDKAQQSA-N cerivastatin Chemical compound COCC1=C(C(C)C)N=C(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)=C1C1=CC=C(F)C=C1 SEERZIQQUAZTOL-ANMDKAQQSA-N 0.000 claims 2
- 229950003040 dalvastatin Drugs 0.000 claims 2
- ZADJRRFMOOACHL-WQICJITCSA-N ethyl (e,3s,5r)-7-[4-(4-fluorophenyl)spiro[chromene-2,1'-cyclopentane]-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound C12=CC=CC=C2OC2(CCCC2)C(/C=C/[C@H](O)C[C@H](O)CC(=O)OCC)=C1C1=CC=C(F)C=C1 ZADJRRFMOOACHL-WQICJITCSA-N 0.000 claims 2
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical group N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 claims 2
- 229960000815 ezetimibe Drugs 0.000 claims 2
- 229960004844 lovastatin Drugs 0.000 claims 2
- 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 2
- 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 2
- AJLFOPYRIVGYMJ-INTXDZFKSA-N mevastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=CCC[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 AJLFOPYRIVGYMJ-INTXDZFKSA-N 0.000 claims 2
- 229950009116 mevastatin Drugs 0.000 claims 2
- BOZILQFLQYBIIY-UHFFFAOYSA-N mevastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CCC=C21 BOZILQFLQYBIIY-UHFFFAOYSA-N 0.000 claims 2
- 229960002965 pravastatin Drugs 0.000 claims 2
- 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 2
- 230000001732 thrombotic effect Effects 0.000 claims 2
- FHGWEHGZBUBQKL-UHFFFAOYSA-N 1,2-benzothiazepine Chemical compound S1N=CC=CC2=CC=CC=C12 FHGWEHGZBUBQKL-UHFFFAOYSA-N 0.000 claims 1
- ZEZPDHKACVMMCD-UHFFFAOYSA-N 5,6-dihydroimidazo[2,1-b][1,3]thiazol-3-ylmethyl n,n'-dicyclohexylcarbamimidothioate Chemical compound C=1SC2=NCCN2C=1CSC(=NC1CCCCC1)NC1CCCCC1 ZEZPDHKACVMMCD-UHFFFAOYSA-N 0.000 claims 1
- 125000005281 alkyl ureido group Chemical group 0.000 claims 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 claims 1
- 125000006239 protecting group Chemical group 0.000 claims 1
- CXGTZJYQWSUFET-IBGZPJMESA-N tesaglitazar Chemical group C1=CC(C[C@H](OCC)C(O)=O)=CC=C1OCCC1=CC=C(OS(C)(=O)=O)C=C1 CXGTZJYQWSUFET-IBGZPJMESA-N 0.000 claims 1
- 125000003396 thiol group Chemical class [H]S* 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- 125000004429 atom Chemical group 0.000 description 18
- 229910052757 nitrogen Inorganic materials 0.000 description 13
- 150000002148 esters Chemical class 0.000 description 10
- 125000002619 bicyclic group Chemical group 0.000 description 9
- 125000002950 monocyclic group Chemical group 0.000 description 9
- 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 8
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 150000007657 benzothiazepines Chemical class 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
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- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 4
- 235000012000 cholesterol Nutrition 0.000 description 4
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 3
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- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
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- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 3
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- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
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- 150000001408 amides Chemical class 0.000 description 2
- 229940085242 benzothiazepine derivative selective calcium channel blockers with direct cardiac effects Drugs 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Natural products OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000001786 isothiazolyl group Chemical group 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 125000005493 quinolyl group Chemical group 0.000 description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- UNPBSZUDTFBULK-CZCKBYKRSA-N (2s)-2-[[(2r)-2-[[(3s)-3-amino-2-oxopentanoyl]amino]-4-methylpentanoyl]-[(2s,6s)-2,6-diamino-3,7-dimethyl-5-oxooctanoyl]amino]-3-methylbutanoic acid Chemical compound CC[C@H](N)C(=O)C(=O)N[C@H](CC(C)C)C(=O)N([C@@H](C(C)C)C(O)=O)C(=O)[C@@H](N)C(C)CC(=O)[C@@H](N)C(C)C UNPBSZUDTFBULK-CZCKBYKRSA-N 0.000 description 1
- 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 description 1
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 description 1
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- 125000005871 1,3-benzodioxolyl group Chemical group 0.000 description 1
- JPRPJUMQRZTTED-UHFFFAOYSA-N 1,3-dioxolanyl Chemical group [CH]1OCCO1 JPRPJUMQRZTTED-UHFFFAOYSA-N 0.000 description 1
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- 125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 108010028554 LDL Cholesterol Proteins 0.000 description 1
- 108010007622 LDL Lipoproteins Proteins 0.000 description 1
- 102000007330 LDL Lipoproteins Human genes 0.000 description 1
- LRXVQHCIMZSTJH-UHFFFAOYSA-N Poststatin Natural products CC(C)C(N)C(=O)NC(C(C)C)C(=O)NC(CC)C(=O)C(=O)NC(CC(C)C)C(=O)NC(C(C)C)C(O)=O LRXVQHCIMZSTJH-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 125000001721 carboxyacetyl group Chemical group 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 125000005117 dialkylcarbamoyl group Chemical group 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000006627 ethoxycarbonylamino group Chemical group 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 125000006260 ethylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 229960003765 fluvastatin Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- RCCPEORTSYDPMB-UHFFFAOYSA-N hydroxy benzenecarboximidothioate Chemical compound OSC(=N)C1=CC=CC=C1 RCCPEORTSYDPMB-UHFFFAOYSA-N 0.000 description 1
- 230000000871 hypocholesterolemic effect Effects 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000002485 inorganic esters Chemical class 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 108010022197 lipoprotein cholesterol Proteins 0.000 description 1
- 230000008604 lipoprotein metabolism Effects 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 125000005633 phthalidyl group Chemical group 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 description 1
- 108010080180 poststatin Proteins 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 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
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005329 tetralinyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000005505 thiomorpholino group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Description
1,5 BENZOTHIAZEPINES AND THEIR USE AS ANTIHHYPERLIPIDEMICS
This invention relates to benzothiazepine derivatives, or pharmaceutically acceptable ) salts, solvates, solvates of such salts and prodrugs thereof. These benzothiazepines possess . 5 ileal bile acid transport (IBAT) inhibitory activity and accordingly have value in the treatment of disease states associated with hyperlipidaemic conditions and they are useful in methods of -treatment of a warm-blooded animal, such as man. The invention also relates to processes for the manufacture of said benzothiazepine derivatives, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments to inhibit IBAT in a warm-blooded animal, such as man.
It is well-known that hyperlipidaemic conditions associated with elevated concentrations of total cholesterol and low-density lipoprotein cholesterol are major risk factors for cardiovascular atherosclerotic disease (for instance “Coronary Heart Disease:
Reducing the Risk; a Worldwide View” Assman G., Carmena R. Cullen P. et al; Circulation 1999, 100, 1930-1938 and “Diabetes and Cardiovascular Disease: A Statement for Healthcare
Professionals from the American Heart Association” Grundy S, Benjamin I., Burke G., et al;
Circulation, 1999, 100, 1134-46). Interfering with the circulation of bile acids within the lumen of the intestinal tracts is found to reduce the level of cholesterol. Previous established therapies to reduce the concentration of cholesterol involve, for instance, treatment with :
HMG-CoA reductase inhibitors, preferably statins such as simvastatin and fluvastatin, or treatment with bile acid binders, such as resins. Frequently used bile acid binders are for instance cholestyramine and cholestipol. One recently proposed therapy (“Bile Acids and
Lipoprotein Metabolism: a Renaissance for Bile Acids in the Post Statin Era” Angelin B,
Eriksson M, Rudling M; Current Opinion on Lipidology, 1999, 10, 269-74) involved the treatment with substances with an IBAT inhibitory effect.
Re-absorption of bile acid from the gastro-intestinal tract is a normal physiological process which mainly takes place in the ileum by the IBAT mechanism. Inhibitors of IBAT - can be used in the treatment of hypercholesterolaemia (see for instance “Interaction of bile ) acids and cholesterol with nonsystemic agents having hypocholesterolaemic properties”,
Biochemica et Biophysica Acta, 1210 (1994) 255- 287). Thus, suitable compounds having such inhibitory IBAT activity are also useful in the treatment of hyperlipidaemic conditions.
Compounds possessing such IBAT inhibitory activity have been described, see for instance compounds described in WO 93/16055, WO 94/18183, WO 94/18184, WO 96/05188, WO
96/08484, WO 96/16051, WO 97/33882, WO 98/38182, WO 99/35135, WO 98/40375, WO 99/35153, WO 99/64409, WO 99/64410, WO 00/01687, WO 00/47568, WO 00/61568, WO 01/68906, DE 19825804, WO 00/38725, WO 00/38726, WO 00/38727, WO 00/38728, WO 100/38729, WO 01/68906, and EP 0 864 582. . 5 A further aspect of this invention relates to the use of the compounds of the invention in the treatment of dyslipidemic conditions and disorders such as hyperlipidaemia, hypertrigliceridemia, hyperbetalipoproteinemia (high LDL), hyperprebetalipoproteinemia (high VLDL), hyperchylomicronemia, hypolipoproteinemia, hypercholesterolemia, hyperlipoproteinemia and hypoalphalipoproteinemia (low HDL). In addition, these compounds are expected to be useful for the prevention and treatment of different clinical conditions such as atherosclerosis, arteriosclerosis, arrhythmia, hyper-thrombotic conditions, vascular dysfunction, endothelial dysfunction, heart failure, coronary heart diseases, cardiovascular diseases, myocardial infarction, angina pectoris, peripheral vascular diseases, inflammation of cardiovascular tissues such as heart, valves, vasculature, arteries and veins, aneurisms, stenosis, restenosis, vascular plaques, vascular fatty streaks, leukocyte, monocytes and/or macrophage infiltrate, intimital thickening, medial thinning, infectious and surgical trauma and vascular thrombosis, stroke and transient ischaemic attacks.
The present invention is based on the discovery that certain benzothiazepine compounds surprisingly inhibit IBAT. Such properties are expected to be of value in the treatment of disease states associated with hyperlipidaemic conditions.
Accordingly, the present invention provides a compound of formula (I):
RS 0 Rr’
RS Ox” ay
R * ie Oh ] ®R?), ® ? wherein: :
R" and R" are independently selected from hydrogen or C;.galkyl;
R! and R? are independently selected from C,.salkyl;
R* and R? are independently selected from hydrogen or Cysalkyl, or one of R* and R’ is hydrogen or Cjsalkyl and the other is hydroxy or C;_salkoxy;
R? is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, ) sulphamoyl, Crsalkyl, Cz. 6alkenyl, Cs.salkynyl, Ci.¢alkoxy, Cygalkanoyl, C;.¢alkanoyloxy, . 5 N-(Ci.galkyl)amino, N,N-(C;.salkyl),amino, Cysalkanoylamino, N-(C.salkyl)carbamoyl,
N,N-(Ci.¢alkyl),carbamoyl, C¢alkylS(O). wherein a is 0 to 2, C,.salkoxycarbonyl,
C,.salkoxycarbonylamino, ureido, N'-(Csalkyl)ureido, N-(C;.¢alkyl)ureido,
N' N'-(C;.¢alkyl)ureido, N'-(C;.salkyl)-N-(Cisalkyl)ureido,
N'N'-(C1salkyl),-N-(Cisalkyl)ureido, N-(C;.salkyl)sulphamoyl and
N,N-(C,.salkyl);sulphamoyl; v is 0-5; one of R? and R® is a group of formula (IA): : R10 rR’ y iy .
R
IA)
R® and R and the other of R* and R® are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cy4alkyl,
Caalkenyl, Ca4alkynyl, Cy4alkoxy, C1 4alkanoyl, Cyalkanoyloxy, N~(Ci4alkyl)amino,
N,N-(Ci.4alkyl),amino, C;-4alkanoylamino, N-(C;.4alkyl)carbamoyl, .
N,N-(C1alkyl),carbamoyl, C;.4alkylS(O)s wherein a is 0 to 2, C;4alkoxycarbonyl,
N-(Ci4alkyl)sulphamoyl and N,N-(Csalkyl);sulphamoyl; wherein R® and R® and the other of
R* and R® may be optionally substituted on carbon by one or more R'S;
D is -O-, -N(RY-, -S(O)p- or -CH[R®)-; wherein R* is hydrogen or C;.salkyl and b is 0-2;
Ring A is aryl or heteroaryl; wherein Ring A is optionally substituted by one or more substituents selected from R'7; ) R'is hydrogen, C.4alkyl, carbocyclyl or heterocyclyl; wherein Ris optionally \ substituted by one or more substituents selected from RIS;
R® is hydrogen or C;_4alkyl;
R’ is hydrogen or C;4alkyl;
RY is hydrogen, C;alkyl, carbocyclyl or heterocyclyl; wherein R'® is optionally substituted by one or more substituents selected from R'’;
RY is carboxy, sulpho, sulphino, phosphono, tetrazolyl, -P(O)(OR®)(ORY), -P(O)(OH)(OR®), -P(O)}(OH)(RY) or -P(O)(OR°)(R?) wherein R° and R? are independently i 5 selected from Cy alkyl; or R!! is a group of formula (IB): 14 13 15 bf 1 pi (IB) wherein:
X is -NRY-, -NRHC(O)-, -O-, and -S(0),-; wherein a is 0-2 and RY is hydrogen or
Cj4alkyl;
Ris hydrogen or C.salkyl; .R® and R™ are independently selected from hydrogen, C;.4alkyl, carbocyclyl, heterocyclyl or R*; wherein said C;.4alkyl, carbocyclyl or heterocyclyl may be independently optionally substituted by one or more substituents selected from R?%;
R is carboxy, sulpho, sulphino, phosphono, tetrazolyl, -P(O)(OR®)(OR5, -P(O)(OH)(OR®), -P(0)(OH)(R®) or -P(O)(OR®)(RY) wherein R® and Rf are independently selected from C; alkyl; or RP¥isa group of formula (IC):
R® o 2th rR? ac wherein:
R* is selected from hydrogen or C; alkyl; :
R? is selected from hydrogen, C;.4alkyl, carbocyclyl, heterocyclyl or R?; wherein said C;4alkyl, carbocyclyl or heterocyclyl may be independently optionally substituted by one or more substituents selected from R%; . 25 R is selected from carboxy, sulpho, sulphino, phosphono, tetrazolyl, -P(O)(ORE)Y(OR™), -P(O)(OH)(ORS), -P(O)(OH)(RE) or -P(O)(ORE)(R™) wherein RE and R" are independently selected from C; galkyl; p is 1-3; wherein the values of R!> may be the same or different;
q is 0-1; r is 0-3; wherein the values of RM may be the same or different; m is 0-2; wherein the values of R' may be the same or different; ) n is 1-3; wherein the values of R’ may be the same or different; . 5 z is 0-3; wherein the values of R% may be the same or different;
R¢, RY and R*® are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C;4alkyl, C; 4alkenyl, C;4alkynyl, Ci4alkoxy,
Cj.4alkanoyl, C;.4alkanoyloxy, N-(Ci4alkyl)amino, N,N-(C;4alkyl),amino,
Cj4alkanoylamino, N-(Calkyl)carbamoyl, N,N-(C;4alkyl),carbamoyl, C;4alkylS(O), | wherein a is 0 to 2, C;4alkoxycarbonyl, N-(Ci4alkyl)sulphamoyl and
N,N-(C,_salkyl);sulphamoyl; wherein RS, R'” and R'® may be independently optionally substituted on carbon by one or more R?!;
RY, R®, R® R? and R® are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C;.4alkyl, C,4alkenyl, C,4alkynyl,
C,4alkoxy, Cj4alkanoyl, Cj4alkanoyloxy, N-(C;4alkyl)amino, N,N-(C1alkyl)amino,
Ci4alkanoylamino, N-(C;4alkyl)carbamoyl, N,N-(C,.salkyl),carbamoyl, C;4alkylS(O), wherein a is 0 to 2, C;4alkoxycarbonyl, N-(C;.salkyl)sulphamoyl,
N,N-(C;.4alkyl);sulphamoyl, carbocyclyl, heterocyclyl, sulpho, sulphino, amidino, phosphono, ~P(O)(OR*(OR"), -P(O)(OH)(OR?), -P(O)(OH)(R®) or -P(O)(OR*(R"), wherein R* and R® are independently selected from C;_galkyl; wherein R', R?, R%, R?” and R® may be independently optionally substituted on carbon by one or more RZ,
R?! and R? are independently selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl,
N,N-dimethylcarbamoyl, methylthio, methylsulphinyl, mesyl, N-methylsulphamoyl and
N,N-dimethylsulphamoyl; or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof. ’ According to a further aspect of the present invention there is provided a compound of formula (I'):
R3 ond R! . he
N
: R? pp a wherein:
R! and R? are independently selected from C,_salkyl; one of R* and R® is a group of formula (IA): op : ds rR R’ da"
R? and R® and the other of R* and R® are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C;.alkyl,
Caalkenyl, Ca4alkynyl, Ci4alkoxy, Ci4alkanoyl, C;4alkanoyloxy, N-(Cy4alkyl)amino,
N,N-(C;.4alkyl),amino, C;4alkanoylamino, N-(C;-salkyl)carbamoyl,
N,N-(C4alkyl),carbamoyl, C;4alkylS(O), wherein a is 0 to 2, Cy 4alkoxycarbonyl,
N-(C4alkyl)sulphamoyl and N,N-(C;_salkyl),sulphamoyl; wherein R? and R® and the other of
R* and R® may be optionally substituted on carbon by one or more R'%;
Ring A is aryl or heteroaryl; wherein Ring A is optionally substituted by one or more substituents selected from R'3;
R’ is hydrogen, C14alkyl, carbocyclyl or heterocyclyl; wherein R’ is optionally substituted by one or more substituents selected from R}
Ris hydrogen, C; alkyl, carbocyclyl or heterocyclyl; wherein R® is optionally substituted by one or more substituents selected from R®;
R’ is carboxy, sulpho, sulphino, phosphono, -P(O)(OR°)(ORY), -P(O)(OH)(OR®), -P(O)OH)R®) or -P(O)(OR°)(R*) wherein R® and R? are independently selected from « Ci.¢alkyl; or Risa group of formula (IB"):
<7 -
RY Oo hy (B") . wherein:
R" is hydrogen, C;.salkyl, carbocyclyl or heterocyclyl; wherein R'® is optionally substituted by one or more substituents selected from RS;
RYis carboxy, sulpho, sulphino, phosphono, -P(O)(OR®)(ORD), -P(O)(OH)(OR®), -P(O)(OH)(R®) or -P(0)(OR®)(RY) wherein R® and R are independently selected from
C.ealkyl; p is 1-3; wherein the values of RY may be the same or different; m is 0-2; wherein the values of R® may be the same or different; n is 1-3; wherein the values of R” may be the same or different;
RY R® and R™ are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci4alkyl, C;.4alkenyl, Cz 4alkynyl, C;salkoxy,
Ci4alkanoyl, C,.salkanoyloxy, N-(C;salkyl)amino, N,N-(C;4alkyl),amino,
Cj.4alkanoylamino, N-(C;4alkyl)carbamoyl, N,N-(C;.4alkyl);carbamoyl, C;4alkylS(O), wherein a is 0 to 2, C;4alkoxycarbonyl, N-(C;.4alkyl)sulphamoyl and
N,N~(Cialkyl),sulphamoyl; wherein R'2, R*® and R!* may be independently optionally substituted on carbon by one or more R';
R" and R* are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C;4alkyl, C;4alkenyl, Cs 4alkynyl, C4alkoxy,
Ci.salkanoyl, C;4alkanoyloxy, N-(C,4alkyl)amino, N,N-(C;.salkyl);amino,
Ci4alkanoylamino, N-(C14alkyl)carbamoyl, N,N-(C;.4alkyl),carbamoyl, C;4alkylS(O), wherein a is 0 to 2, C;4alkoxycarbonyl, N-(Ci4alkyl)sulphamoyl and
N,N-(C,4alkyl);sulphamoyl, sulpho, sulphino, amidino, phosphono, -P(O)(OR*)(ORD), -P(O)(OH)(OR®), -P(O)(OH)(R®) or -P(O)(OR*(R®), wherein R® and R® are independently selected from Cj.¢alkyl; wherein R' and R'® may be independently optionally substituted on carbon by one or more R'S, ’ . . RY and R® are independently selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, :
N,N-dimethylcarbamoyl, methylthio, methylsulphinyl, mesyl, N-methylsulphamoyl and
N,N-dimethylsulphamoyl; ora pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
According to a further aspect of the present invention there is provided a compound of . 5 formula (I""): 6
RS oss rl =<
N
R® ph a wherein:
R! and R? are independently selected from Cj.galkyl; oneof R*and R¥is a group of formula (XA"):
R o-
R10. rR YY dA")
R? and R® and the other of R* and R® are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cy.4alkyl,
Cjqalkenyl, Co 4alkynyl, C;4alkoxy, Cj4alkanoyl, Ci4alkanoyloxy, N-(C;4alkyl)amino,
N,N-(C;.4alkyl);amino, C;4alkanoylamino, N-(C;4alkyl)carbamoyl,
N,N=(C;.alkyl),carbamoyl, C;.4alkylS(O), wherein a is 0 to 2, C;4alkoxycarbonyl,
N-(Cj4alkyl)sulphamoyl and N,N-(C,4alkyl);sulphamoyl; wherein R3 and RS and the other of
R* and R® may be optionally substituted on carbon by one or more RS,
Ring A is aryl or heteroaryl; wherein Ring A is optionally substituted by one or more . substituents selected from R'7;
R’ is hydrogen, C;.alkyl, carbocyclyl or heterocyclyl; wherein R is optionally . substituted by one or more substituents selected from R!8;
R® is hydrogen or C;.4alkyl;
R’ is hydrogen or C; alkyl;
R" is hydrogen, Cy.4alkyl, carbocyclyl or heterocyclyl; wherein R'is optionally substituted by one or more substituents selected from R'%;
RM is carboxy, sulpho, sulphino, phosphono, -P(O)(OR°}OR"), -P(O)(OH)(OR"), -P(O)(OH)RY) or -P(O)(OR®)RY wherein R° and RY are independently selected from . 5 Cpealkyl; or R is a group of formula (IB"): 14 3g pip,
R12 dB") wherein:
X is -NRY)-, -NRYHC(0)-, -O-, and -S(0),-; wherein a is 0-2 and R? is hydrogen or
Cjsalkyl;
R* is hydrogen or C;alkyl;
R™ and RM are independently selected from hydrogen, C; alkyl, carbocyclyl or heterocyclyl; wherein R'® and R* may be independently optionally substituted by one or more substituents selected from R*;
RY is carboxy, sulpho, sulphino, phosphono, -P(O)(OR®)(ORY), -P(O)(OH)(OR®), -P(O)(OH)(R®) or -P(O)(OR°)(RY) wherein R® and Rf are independently selected from
Ci-salkyl; p is 1-3; wherein the values of R'®> may be the same or different; qis 0-1; r is 0-3; wherein the values of R™ may be the same or different; m is 0-2; wherein the values of R! may be the same or different; n is 1-3; wherein the values of R” may be the same or different;
R', R! and R® are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cy4alkyl, C,_4alkenyl, Co4alkynyl, C;4alkoxy,
Cj.aalkanoyl, C;.4alkanoyloxy, N-(Ci4alkyl)amino, N,N-(C;4alkyl),amino, . Cialkanoylamino, N-(C;.4alkyl)carbamoyl, N,N-(C;_4alkyl),carbamoyl, C;4alkylS(0), wherein a is 0 to 2, Cj4alkoxycarbonyl, N-(C;4alkyl)sulphamoyl and : N,N-(C;.4alkyl);sulphamoyl; wherein R'®, R" and R'® may be independently optionally substituted on carbon by one or more R*;
R* and R® are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cy.4alkyl, C;.salkenyl, Cs 4alkynyl, C;_salkoxy,
Ci4alkanoyl, Cj.4alkanoyloxy, N-(C;4alkyl)amino, N,N-(C;.4alkyl),amino,
C;4alkanoylamino, N-(C;alkyl)carbamoyl, N,N-(C;.4alkyl),carbamoyl, C;.4alkylS(O), wherein a is 0 to 2, Cy 4alkoxycarbonyl, N-(C;4alkyl)sulphamoyl,
N,N-(Cy.4alkyl),sulphamoyl, carbocyclyl, heterocyclyl, sulpho, sulphino, amidino, phosphono, -P(O)(OR*(OR), -P(O)(OH)(OR?®), -P(O)(OH)(R®) or -P(O)OR*(R®), wherein R® and R® are independently selected from C;galkyl; wherein R'® and R* may be independently optionally substituted on carbon by one or more R%;
R? and RZ are independently selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl,
N,N-dimethylcarbamoyl, methylthio, methylsulphinyl, mesyl, N-methylsulphamoyl and
N,N-dimethylsulphamoyl; or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In the following paragraphs of the description, and in the claims, where a compound of formula (I) is referred to, it is to be understood that this aspect also relates to compounds of formula (I') and compounds of formula (I'').
In addition, the skilled person will appreciate that the numbering system differs between compounds of formula (I) and compounds of formula (I'). The numbering system used hereinbelow refers to compounds of formula (I), but it is to be understood that these statements also apply to the corresponding values in formula (I').
In this specification the term “alkyl” includes both straight and branched chain alkyl groups but references to individual alkyl groups such as “propyl” are specific for the straight chain version only. For example, “Ci.salkyl” includes C,4alkyl, C;.alkyl, propyl, isopropyl and #-butyl. However, references to individual alkyl groups such as ‘propyl’ are specific for the straight chained version only and references to individual branched chain alkyl groups such as ‘isopropyl’ are specific for the branched chain version only. A similar convention applies to other radicals, for example “phenylCi alkyl” would include phenylC, 4alkyl, benzyl, 1-phenylethyl and 2-phenylethyl. The term “halo” refers to fluoro, chloro, bromo and iodo. ‘Where optional substituents are chosen from “one or more” groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups,
“Heteroaryl” is a totally unsaturated, mono or bicyclic ring containing 3-12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked. Preferably “heteroaryl” refers to a totally unsaturated, monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 ) 5 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked. In another aspect of the invention, “heteroaryl” refers to a totally unsaturated, monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 8, 9 or 10 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked.
Examples and suitable values of the term “heteroaryl” are thienyl, isoxazolyl, imidazolyl, . pyrrolyl, thiadiazolyl, isothiazolyl, triazolyl, pyranyl, indolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyridyl and quinolyl. Preferably the term “heteroaryl” refers to thienyl or indolyl. “Aryl” is a totally unsaturated, mono or bicyclic carbon ring that contains 3-12 atoms.
Preferably “aryl” is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms. Suitable values for “aryl” include phenyl or naphthyl. Particularly “aryl” is phenyl.
A “heterocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 3-12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH,- group can optionally be replaced by a -C(O)- or a ring sulphur atom may be optionally oxidised to form the S-oxides. Preferably a “heterocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 5 or 6 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH;,- group can optionally be replaced by a -C(O)- or a ring sulphur atom may be optionally oxidised to form S-oxide(s). Examples and suitable values of the term “heterocyclyl” are thiazolidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2,5-dioxopyrrolidinyl, 2-benzoxazolinonyl, 1,1-dioxotetrahydrothienyl, 2 4-dioxoimidazolidinyl, 2-oxo-1,3,4-(4-triazolinyl), 2-oxazolidinonyl, 5,6-dihydrouracilyl, 1,3-benzodioxolyl, 1,2,4-oxadiazolyl, 2-azabicyclo[2.2.1]heptyl, 4-thiazolidonyl, morpholino, . 30 2-oxotetrahydrofuranyl, tetrahydrofuranyl, 2,3-dihydrobenzofuranyl, benzothienyl, tetrahydropyranyl, piperidyl, 1-oxo-1,3-dihydroisoindolyl, piperazinyl, thiomorpholino, 1,1-dioxothiomorpholino, tetrahydropyranyl, 1,3-dioxolanyl, homopiperazinyl, thienyl, isoxazolyl, imidazolyl, pyrrolyl, thiadiazolyl, isothiazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl,
pyranyl, indolyl, pyrimidyl, thiazolyl, pyrazinyl, pyridazinyl, pyridyl, 4-pyridonyl, quinolyl and 1-isoquinolonyl.
A “carbocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic carbon ring that contains 3-12 atoms; wherein a ~CH,- group can optionally be replaced by a ] 5 -C(O)-. Preferably “carbocyclyl” is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms. Suitable values for “carbocyclyl” include cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl. Particularly “carbocyclyl” is cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl or 1-oxoindanyl.
An example of “Cj.¢alkanoyloxy” and “Cj.salkanoyloxy” is acetoxy. Examples of “Crsalkoxycarbonyl” and “C;.salkoxycarbonyl” include methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl. Examples of “C;salkoxy” and “C;4alkoxy” include methoxy, ethoxy and propoxy. Examples of “Cj.¢alkanoylamino” and “Cj 4alkanoylamino” include formamido, acetamido and propionylamino. Examples of “C;.alkylS(O), wherein a is 0 to 2” and “C14alkylS(O), wherein a is 0 to 2” include methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl. Examples of “C.¢alkanoyl” and “C;.4alkanoyl” include C;.salkanoyl, propionyl and acetyl. Examples of “N-(C;.salkyl)amino” and “N-(Cj.4alkyl)amino” include methylamino and ethylamino. Examples of “N,N-(C;¢alkyl);amino” and “N,N-(C;.salkyl);amino” include di-N-methylamino, di-(N-ethyl)amino and N-ethyl-N-methylamino. Examples of “C, ¢alkenyl” and “C,.4alkenyl” are vinyl, allyl and 1-propenyl. Examples of “C,.¢alkynyl” and “C,4alkynyl” are ethynyl, 1-propynyl and 2-propynyl. Examples of “N-(C;.salkyl)sulphamoyl” and “N-(C1-qalkyl)sulphamoyl” are N-(C;.3alkyl)sulphamoyl, N-(methyl)sulphamoyl and
N-(ethyl)sulphamoyl. Examples of “N-(C;.galkyl);sulphamoyl” and “N-(Cy.4alkyl),sulphamoyl” are N,N-(dimethyl)sulphamoyl and
N-(methyl)-N-(ethyl)sulphamoyl. Examples of “N-(C;alkyl)carbamoyl” and “N-(Ci4alkylcarbamoyl” are methylaminocarbonyl and ethylaminocarbonyl. Examples of ’ “N,N-(C1.alkyl),carbamoyl” and “N,N-(Cialkyl),carbamoyl” are dimethylaminocarbonyl and methylethylaminocarbonyl. Examples of “C;.salkoxycarbonylamino” are ethoxycarbonylamino and z-butoxycarbonylamino. Examples of “N'~(C,.salkyl)ureido” are
N'-methylureido and N'-ethylureido. Examples of “N-(Cy.salkyl)ureido are N-methylureido and N-ethylureido. Examples of “N',N'-(C,.alkyl);ureido are N',N'-dimethylureido and N'-
methyl-N'-ethylureido. Examples of “N'-(C;.salkyl)-N-(C,_salkyl)ureido are . N'-methyl-N-methylureido and N'-propyl-N-methylureido. Examples of “N',N'<(C;.¢alkyl),-N-(C;.¢alkyl)ureido are N',N'-dimethyl-N-methylureido and
N'-methyl-N"-ethyl-N-propylureido. . 5 A suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid. In addition a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
The compounds of the formula (I) may be administered in the form of a pro-drug which is broken down in the human or animal body to give a compound of the formula (I).
Examples of pro-drugs include in vivo hydrolysable esters and in vivo hydrolysable amides of a compound of the formula (I).
An in vivo hydrolysable ester of a compound of the formula (I) containing carboxy or hydroxy group is, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include Cj salkoxymethyl esters for example methoxymethyl,
C).salkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters,
Cs.scycloalkoxycarbonyloxyCi alkyl esters for example 1-cyclohexylcarbonyloxyethyl: 1,3-dioxolen-2-onylmethyl esters for example 5-methyl-1,3-dioxolen-2-onylmethyl; and
C)-salkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention.
An in vivo hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and a-acyloxyalkyl ethers and i 30 related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group. Examples of o-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and
N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl. Examples of substituents on benzoyl include morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3- or 4- position of the benzoyl ring. ) 5 A suitable value for an in vivo hydrolysable amide of a compound of the formula (I) containing a carboxy group is, for example, a N-C_galkyl or N,N-di-C;.¢alkyl amide such as
N-methyl, N-ethyl, N-propyl, N,N-dimethyl, N-ethyl-N-methyl or N,N-diethyl amide.
Some compounds of the formula (I) may have chiral centres and/or geometric isomeric centres (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers that possess IBAT inhibitory activity.
The invention relates to any and all tautomeric forms of the compounds of the formula (I) that possess IBAT inhibitory activity.
It is also to be understood that certain compounds of the formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which possess IBAT inhibitory activity.
Preferred values of R!, R% R?, R*, R® and RS are as follows. Such values may be used where appropriate with any of the definitions, claims or embodiments defined hereinbefore or hereinafter.
Preferably RY and RY are both hydrogen.
Preferably R! and R? are independently selected from C;4alkyl.
More preferably R' and R? are independently selected from ethyl or butyl.
More preferably R and R? are independently selected from ethyl, propyl or butyl.
In one aspect of the invention particularly R' and R? are both butyl.
In a further aspect of the invention particularly R' and R? are both propyl.
In another aspect of the invention particularly one of R! and R? is ethyl and the other is butyl. ’ Preferably R* and R” are independently selected from hydrogen or Cgalkyl.
More preferably R* and RY are both hydrogen.
Preferably R* is selected from halo, amino, Cj.alkyl, C;_¢alkoxycarbonylamino or
N'-(Cy¢alkyl)ureido.
More preferably R” is selected from chloro, amino, #-butyl, -butoxycarbonylamino or
N'-(¢t-butyl)ureido.
Preferably vis O or 1.
In one aspect of the invention, more preferably v is 0.
In one aspect of the invention, more preferably vis 1.
In one aspect of the invention preferably R* is a group of formula (IA) (as depicted above).
In another aspect of the invention preferably R’ is a group of formula (IA) (as depicted above).
Preferably R> and RS are hydrogen.
Preferably the other of R* and R® that is not the group of formula (IA) is selected from halo, C;.salkoxy or C;4alkylS(O), wherein a is 0 to 2; wherein that R* or R® may be optionally substituted on carbon by one or more R'®; wherein R!® is independently selected from hydroxy and N,N-(C;.4alkyl),amino.
More preferably the other of R* and R’ that is not the group of formula (IA) is selected from bromo, methoxy, isopropoxy, methylthio, ethylthio, isopropylthio or mesyl; wherein that
R*orR® may be optionally substituted on carbon by one or more R*S; wherein R® is independently selected from hydroxy and N,N-dimethylamino.
Particularly the other of R* and R® that is not the group of formula (IA) is selected from bromo, methoxy, isopropoxy, methylthio, ethylthio, isopropylthio, 2-hydroxyethylthio, 2-(N,N-dimethylamino)ethylthio or mesyl.
More particularly the other of R* and R° that is not the group of formula (IA) is methylthio.
Preferably the other of R* and R® that is not the group of formula (IA) is selected from hydrogen, halo, Cyalkoxy or C,.4alkylS(O), wherein a is 0 to 2; wherein that R* or R® may be optionally substituted on carbon by one or more R*®; wherein R'® is independently selected from hydroxy, carboxy and N,N-(C;4alkyl),amino.
More preferably the other of R* and R® that is not the group of formula (IA) is selected from hydrogen, bromo, methoxy, isopropoxy, methylthio, ethylthio, isopropylthio or mesyl; wherein that R* or R® may be optionally substituted on carbon by one or more R®; wherein
R'S is independently selected from hydroxy, carboxy and N,N-dimethylamino.
Particularly the other of R* and R’ that is not the group of formula (IA) is selected from hydrogen, bromo, methoxy, isopropoxy, methylthio, carboxymethylthio, ethylthio, isopropylthio, 2-hydroxyethylthio, 2-(N,N-dimethylamino)ethylthio or mesyl.
In another aspect of the invention, more preferably the other of R* and R’ that is not } 5 the group of formula (IA) is selected from hydrogen, chloro, bromo, methoxy, isopropoxy, methylthio, ethylthio or isopropylthio; wherein that R* or RS may be optionally substituted on carbon by one or more R!®; wherein RS is independently selected from hydroxy, carboxy and
N,N-dimethylamino.
In another aspect of the invention, particularly the other of R* and R® that is not the group of formula (TA) is selected from hydrogen, chloro, bromo, methoxy, isopropoxy, methylthio, carboxymethylthio, ethylthio, isopropylthio, 2-hydroxyethylthio or 2-(N,N-dimethylamino)ethylthio.
In another aspect of the invention, more particularly the other of R* and R that is not the group of formula (IA) is bromo or chloro.
In another aspect of the invention, more particularly the other of R* and R that is not the group of formula (IA) is methoxy.
In one aspect of the invention, preferably Ring A is aryl.
In another aspect of the invention, preferably Ring A is heteroaryl.
When Ring A is aryl, preferably Ring A is phenyl.
When Ring A is heteroaryl, preferably Ring A is thienyl or indolyl.
Preferably Ring A is aryl or heteroaryl; wherein Ring A is optionally substituted by one or more substituents selected from R'’; wherein
R'” is selected from halo, hydroxy or Cj4alkyl; wherein R!7 may be optionally substituted on carbon by one or more R?'; wherein
R?! is selected from halo.
Preferably D is -O- or -S-.
In one aspect of the invention, more preferably D is -O-.
In one aspect of the invention, more preferably D is -S-.
More preferably Ring A is phenyl, thienyl or indolyl; wherein Ring A is optionally : 30 substituted by one or more substituents selected from halo, hydroxy or trifluoromethyl.
Particularly Ring A is selected from phenyl, 4-hydroxyphenyl, thien-2-y], 4-trifluoromethylphenyl, 3-hydroxyphenyl, 2-fluorophenyl, 2,3-dihydroxyphenyl or indol-3-yl.
More particularly Ring A is phenyl.
In another aspect of the invention, preferably Ring A is aryl or heteroaryl; wherein
Ring A is optionally substituted by one or more substituents selected from R'”; wherein
RY is selected from halo, hydroxy, Ci4alkyl or C;4alkoxy; wherein RY may be } 5 optionally substituted on carbon by one or more R*'; wherein :
R? is selected from halo.
In another aspect of the invention, more preferably Ring A is phenyl, thienyl or indolyl; wherein Ring A is optionally substituted by one or more substituents selected from halo, hydroxy, methoxy or trifluoromethyl.
In another aspect of the invention, particularly Ring A is selected from phenyl, 4-hydroxyphenyl, 4-methoxyphenyl, thien-2-yl, 4-trifluoromethylphenyl, 3-hydroxyphenyl, 2-fluorophenyl, 2,3-dihydroxyphenyl or indol-3-yl.
In a further aspect of the invention, particularly Ring A is selected from phenyl, 4-hydroxyphenyl, 4-methoxyphenyl, thien-2-yl, 4-trifluoromethylphenyl, 3-hydroxyphenyl, 2-fluorophenyl, 4-fluorophenyl, 2,3-dihydroxyphenyl or indol-3-yl.
Preferably R’ is hydrogen, C;alkyl or carbocyclyl.
More preferably Ris hydrogen, methyl or phenyl.
Particularly R’ is hydrogen.
In one aspect of the invention, preferably Riis hydrogen.
In another aspect of the invention, preferably R® is C; 4alkyl.
In anothér aspect of the invention, more preferably R® is hydrogen or methyl.
In one aspect of the invention, preferably R is hydrogen.
In another aspect of the invention, preferably R° is C;4alkyl.
In another aspect of the invention, more preferably R® is hydrogen or methyl.
Preferably R'° is hydrogen.
In one aspect of the invention, preferably R!! is carboxy, sulpho, sulphino, phosphono, -P(O)(OR°)(OR?), -P(O)(OH)(OR®), -P(O)OH)(R?) or -P(O)(OR®)(R®) wherein R® and R¢ are independently selected from C.galkyl.
In another aspect of the invention, preferably R!! is a group of formula (IB) (as depicted above).
Preferably R'! is carboxy, -P(O)(OH)(OR®) or a group of formula (IB) (as depicted above).
Mote preferably R!! is carboxy, -P(O)(OH)(OE) or a group of formula (IB) (as depicted above).
In another aspect of the invention, preferably Ris carboxy, sulpho, -P(O)(OH)(OR®) wherein R° is selected from C;4alkyl or a group of formula (IB) (as depicted above).
Preferably X is -NH- or -NHC(O)-.
More preferably X is -NHC(O)-.
In one aspect of the invention, preferably R' is hydrogen.
In another aspect of the invention, preferably R'? is Cy4alkyl.
In another aspect of the invention, more preferably R'2 is hydrogen or methyl. :
Preferably R™ is hydrogen, C;.4alkyl or carbocyclyl; wherein R™ is optionally substituted by one or more substituents selected from R?%; wherein
R? is hydroxy.
More preferably R™ is hydrogen, methyl or phenyl; wherein RPis optionally substituted by one or more substituents selected from R%; wherein
R? is hydroxy.
Particularly R'* is hydrogen, hydroxymethyl or phenyl.
More particularly R™ is hydrogen or hydroxymethyl.
In another aspect of the invention, preferably RP" is hydrogen, Cj._salkyl or carbocyclyl; wherein RBis optionally substituted by one or more substituents selected from
R®; wherein
R? js hydroxy, carboxy, carbocyclyl or amino; wherein R? may be optionally substituted on carbon by one or more R%;
R* is hydroxy. :
In another aspect of the invention, more preferably R!? is hydrogen, methyl, ethyl, butyl or phenyl; wherein R™ is optionally substituted by one or more substituents selected from R?®; wherein
R? is hydroxy, carboxy, phenyl or amino; wherein R? may be optionally substituted on carbon by one or more RZ,
RZ is hydroxy.
In another aspect of the invention, particularly R" is hydrogen, hydroxymethyl, 4-aminobutyl, 2-carboxyethyl, 4-hydroxybenzyl or phenyl.
Claims (81)
1. A compound of formula (I): . 6 0 RS Ox J / Ce, “ Be ie RY R R23), @ wherein: R’ and R" are independently selected from hydrogen or Ci.salkyl; R! and R? are independently selected from Cy.galkyl; R* and RY are independently selected from hydrogen or Ci.¢alkyl, or one of R* and R” is hydrogen or C;.¢alkyl and the other is hydroxy or C;.¢alkoxy; Ris selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cj.alkyl, Cz alkenyl, Cp ¢alkynyl, Cisalkoxy, Ci.¢alkanoyl, C;.¢alkanoyloxy, N=(C;.¢alkyl)amino, N,N-(C1.¢alkyl);amino, C;.¢alkanoylamino, N-(C;.salkyl)carbamoyl, N,N-(C;.¢alkyl),carbamoyl, Cy.6alkylS(O), wherein a is 0 to 2, Ci.¢alkoxycarbonyl,
C,.¢alkoxycarbonylamino, ureido, N'-(C,.salkyl)ureido, N-(C;.salkyl)ureido, N'N'-(Cyalkyl)sureido, N'-(Cj-galkyl)-N-(C;salkyl)ureido, N',N'«(C;.alkyl);-N-(C1.¢alkyDureido, N-(Cyalkyl)sulphamoyl and N,N-(C,-¢alkyl),sulphamoyl; v is 0-5; one of R* and R° is a group of formula (IA): RU 3 _ RIO rR’ hy : (Ia)
R? and RS and the other of R* and R® are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C;4alkyl,
C,.4alkenyl, Cz 4alkynyl, C;4alkoxy, C;alkanoyl, Cy 4alkanoyloxy, N-(C;.salkyl)amino, N,N-(Ci.4alkyl);amino, C, 4alkanoylamino, N-(C;salkyl)carbamoyl, N,N-(Ci4alkyl),carbamoyl, Ci4alkylS(O), wherein a is 0 to 2, C;salkoxycarbonyl, N-(C,.qalkyl)sulphamoyl and N,N-(Ci.4alkyl),sulphamoyl; wherein R® and R® and the other of R* and R® may be optionally substituted on carbon by one or more R'S; D is -O-, -N(R?)-, -S(O)p- or -CH(R®)-; wherein R* is hydrogen or Cy.¢alkyl and b is 0-2; Ring A is aryl or heteroaryl; wherein Ring A is optionally substituted by one or more substituents selected from R'"; R’ is hydrogen, C;.alkyl, carbocyclyl or heterocyclyl; wherein R’ is optionally substituted by one or more substituents selected from RS, R® is hydrogen or Cjalkyl; R?’ is hydrogen or C;.qalkyl; RY is hydrogen, C;4alkyl, carbocyclyl or heterocyclyl; wherein R is optionally substituted by one or more substituents selected from RY, R!! is carboxy, sulpho, sulphino, phosphono, tetrazolyl, -P(O)(OR®)(ORY), -P(O)(OH)(OR®), -P(O)(OH)RY) or -P(O)(OR®)(R*) wherein R® and R* are independently selected from C_salkyl; or R!! is a group of formula (IB): 14 13 ith, i (IB) wherein: X is -NRY-, -NRHC(O)-, -O-, and -S(0),-; wherein a is 0-2 and RY is hydrogen or Cjalkyl; RZis hydrogen or C;4alkyl; R® and R" are independently selected from hydrogen, Ci4alkyl, carbocyclyl, heterocyclyl or R%; wherein said C;4alkyl, carbocyclyl or heterocyclyl may be independently optionally substituted by one or more substituents selected from R%;
RY is carboxy, sulpho, sulphino, phosphono, tetrazolyl, -P(O)(OR®)(OR), -P(O)(OH)(OR®), -P(O}(OH)(R®) or -P(O)(OR®)(RY) wherein R® and Rf are independently selected from Cj ¢alkyl; or RYisa group of formula (IC): ® 0 or rR Ic wherein: R* is selected from hydrogen or Cy alkyl; R% is selected from hydrogen, C;4alkyl, carbocyclyl, heterocyclyl or R*; wherein said C,.4alkyl, carbocyclyl or heterocyclyl may be independently optionally substituted by one or more substituents selected from R%; R? is selected from carboxy, sulpho, sulphino, phosphono, tetrazolyl, -P(O)(ORE)(OR™), -P(O)(OH)(OR®), -P(0)(OH)(R®) or -P(O)(ORE)(R?) wherein RE and R® are independently selected from Ci.g¢alkyl; p is 1-3; wherein the values of R'? may be the same or different; q is 0-1; r is 0-3; wherein the values of R'* may be the same or different; m is 0-2; wherein the values of R'® may be the same or different; n is 1-3; wherein the values of R” may be the same or different; z is 0-3; wherein the values of R” may be the same or different; R, R" and R* are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C;.4alkyl, C;4alkenyl, Co 4alkynyl, C;.4alkoxy, Ci4alkanoyl, Ci4alkanoyloxy, N-(C;4alkyl)amino, N,N-(C;.salkyl),amino,
Ci.salkanoylamino, N-(C;4alkyl)carbamoyl, N,N-(C;4alkyl),carbamoyl, C;4alkylS(O), wherein a is 0 to 2, C;4alkoxycarbonyl, N-(C;.4alkyl)sulphamoyl and N,N-(Cy.4alkyl);sulphamoyl; wherein R'S, R!7 and R'® may be independently optionally substituted on carbon by one or more R%; R”, R*, R®, R¥ and R? are independently selected from halo, nitro, cyano, hydroxy, ) amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cjalkyl, Cz 4alkenyl, C;4alkynyl, Ci4alkoxy, Cjqalkanoyl, Cy 4alkanoyloxy, N-(C;.salkyl)amino, N,N-(C;.4alkyl);amino, Cj4alkanoylamino, N-(Ci4alkyl)carbamoyl, N,N-(C;4alkyl),carbamoyl, C;4alkylS(O), wherein a is 0 to 2, C,4alkoxycarbonyl, N-(C;.4alkyl)sulphamoyl,
N,N-(Cj.4alkyl);sulphamoyl, carbocyclyl, heterocyclyl, sulpho, sulphino, amidino, phosphono, -P(O)(OR*)(ORY), -P(O)(OH)(OR?), -P(O)(OH)(R®) or -P(O)(OR*)(R"), wherein R* and R® are independently selected from Cy.galkyl; wherein R'®, R%, R®, R¥ and R% may be independently optionally substituted on carbon by one or more R%,
. 5 R* and R? are independently selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulphinyl, mesyl, N-methylsulphamoyl and N,N-dimethylsulphamoyl; or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
2. A compound of formula (I) according to claim 1 wherein R' and R¥ are both hydrogen or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
3. A compound of formula (I) according to either of claims 1 or 2 wherein R! and R? are independently selected from ethyl, propyl or butyl or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
4. A compound of formula (I) according to any one of claims 1 to 3 wherein R* and R’ are both hydrogen or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
5. A compound of formula (I) according to any one of claims 1 to 4 wherein R" is selected from halo, amino, C1.salkyl, C;¢alkoxycarbonylamino or N'-(C; alkyl ureido or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
6. A compound of formula (I) according to any one of claims 1 to 5 wherein vis 0 or 1 or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
7. A compound of formula (I) according to any one of claims 1 to 6 wherein Riis hydrogen or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
8. A compound of formula (I) according to any one of claims 1 to 7 wherein the R* or R’ that is not the group of formula (IA) is selected from hydrogen, halo, C;4alkoxy or :
C,.4alkylS(O), wherein a is 0 to 2; wherein that R*or R’ may be optionally substituted on carbon by one or more RS; wherein R'¢ is independently selected from hydroxy, carboxy and N,N-(C;4alkyl),amino or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
9. A compound of formula (I) according to any one of claims 1 to 8 wherein Risa group of formula (IA) (as depicted in claim 1) and R* is methylthio or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
10. A compound of formula (I) according to any one of claims 1 to 9 wherein Ris hydrogen or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
11. A compound of formula (I) according to any one of claims 1 to 10 wherein in the group of formula (IA): Dis -O- or -S-; Ring A is phenyl, thienyl or indolyl; wherein Ring A is optionally substituted by one or more substituents selected from halo, hydroxy, methoxy or trifluoromethyl; R’ is hydrogen, methyl or phenyl; R® is hydrogen or methyl; R’ is hydrogen or methyl; RY is hydrogen; m is 0-2 wherein the values of R'° may be the same or different; and RY is carboxy, -P(O)(OH)(OE) or a group of formula (IB) (as depicted in claim 1); or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
12. A compound of formula (I) according to any one of claims 1 to 11 wherein in the group of formula (IB): RZ is hydrogen or methyl;
R" is hydrogen, methyl, ethyl, butyl or phenyl or R?%; wherein R" is optionally substituted by one or more substituents selected from R?’; R? is hydroxy, methylthio, methoxy, amino, imidazolyl or mercapto; wherein R% may be independently optionally substituted on carbon by one or more hydroxy; R? is carboxy; : 5 X is -NH- or -NHC(O)-; RY is selected from hydrogen, methyl or phenyl; wherein said methyl or phenyl may be optionally substituted by one or more substituents selected from hydroxy; RYis carboxy, sulpho, phosphono, -P(0)(OR®)(ORY), -P(O)(OH)(OR®), -P(O)(OH)(R®) or -P(O) (ORR wherein R® and Rf are independently selected from methyl or ethyl or R" is a group of formula (IC) (as depicted in claim 1); p is 1-3 wherein the values of R'3 may be the same or different; q is 0-1; and r is 0-3 wherein the values of R'* may be the same or different; or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
13. A compound of formula (I) according to any one of claims 1 to 12 wherein in the group of formula (IC): R* is hydrogen; R% is hydrogen; R¥ is carboxy; and zis 1; or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
14. A compound of formula (I) (as depicted in claim 1) wherein: R" and R" are both hydrogen; R! and R? are independently selected from C;.4alkyl; R* and RY are both hydrogen; RZ is selected from halo, amino, C;.¢alkyl, C;.¢alkoxycarbonylamino or N*-(Cy.salkyhureido; visOor1; R® and R® are hydrogen; one of R* and Ris a group of formula (IA) (as depicted in claim 1) and the other is selected from hydrogen, halo, C; alkoxy or C;.4alkylS(O). wherein a is 0 to 2; wherein that
R* or R® may be optionally substituted on carbon by one or more R'S; wherein RS is independently selected from hydroxy, carboxy and N,N-(C;.4alkyl),amino; Dis -O-or-S-; R’ is hydrogen, methyl or phenyl; } 5 R® is hydrogen or methyl; Ring A is aryl or heteroaryl; wherein Ring A is optionally substituted by one or more substituents selected from R!"; wherein R" is selected from halo, hydroxy, C;.4alkyl or Ci4alkoxy; wherein RY may be optionally substituted on carbon by one or more R?; wherein R?! is selected from halo; R? is hydrogen or methyl; RY is hydrogen; R" is carboxy, -P(O)(OH)(OR®) wherein R® is selected from C;.4alkyl or a group of formula (IB) (as depicted in claim 1); R* is hydrogen or methyl; X is -NH- or -NHC(O)-; RB is hydrogen, C;alkyl, carbocyclyl or R%,; wherein R" is optionally substituted by one or more substituents selected from R%, wherein R? is hydroxy, Ci-4alkylS(O), wherein a is 0, C;4alkoxy, amino, carbocyclyl, heterocyclyl or mercapto; wherein R?’ may be independently optionally substituted on carbon by one or more R%; RZ is selected from hydroxy; and R? is carboxy; RM is selected from hydrogen, C;.4alkyl or carbocyclyl; wherein said C;4alkyl or carbocyclyl may be optionally substituted by one or more substituents selected from R*; and R®is hydroxy; R' is carboxy, sulpho, phosphono, -P(O)OR®)(ORY), -P(O)(OH)(OR®), -P(O)OH)(R®) or -P(O)(OR®)(R’) wherein R® and Rf are independently selected from
C1.4alkyl or RY is a group of formula (IC) (as depicted in claim 1); R* is hydrogen; R% is hydrogen; - R* is carboxy; p is 1-3; wherein the values of R'? may be the same or different; Co qis 0-1; r is 0-3; wherein the values of RM" may be the same or different; m is 0-2; wherein the values of R'® may be the same or different;
n is 1-2; wherein the values of R” may be the same or different; : z is 0-1; wherein the values of R* may be the same or different; or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
15. A compound of formula (I) (as depicted in claim 1) selected from: 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{ (R)-1'-phenyl-1'-[N'-(carboxymethyl) carbamoyl]methyl }carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{ (R)-o-[N'-(carbox ymethyl)carbamoyl]-4- hydroxybenzyl }carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N"-(2- sulphoethyl)carbamoyl]methyl }carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{ (R)-1'-phenyl-1'-[N'-(2- sulphoethyl)carbamoyl]methyl }carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{ (R)-0-[N'-(2-sulphoethyl)carbamoyl]-4- hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{ (R)-o-[N'-(2-sulphoethyl) carbamoyl]4-hydroxybenzyl } carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{ (R)-0-[N"-(2- carboxyethyl)carbamoyl]benzyl }carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{ (R)-o.-[N"-(2-carboxyethyl)carbamoyl]-4- hydroxybenzyl }carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{ (R)-0-[N'-(5-carboxypentyl) carbamoyl]benzyl }carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{ (R)-0-[N'-(2-carboxyethyl)carbamoyl] benzyl }carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{ o--[N’-(2-sulphoethyl)carbamoyl]-2- fluorobenzyl }carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{ (R)-0-[N"-(R)-(2-hydroxy-1- carboxyethyl)carbamoyl]benzyl }carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; ‘ 30 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-0-[N'-(R)-(2-hydroxy-1- carboxyethyl)carbamoyl]benzyl }carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{ N-[(R)-a-(N'-{ R)-1-[N"-(R)-(2-hydroxy-1- carboxyethyl)carbamoyl]-2-hydroxyethyl }carbamoyl)benzyl]carbamoylmethoxy}-2,3,4,5- tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{ a-[N'-(carbox ymethyl)carbamoyl] benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{ o-[N'-((ethox y)(methyl)phosphoryl- methyl)carbamoyl]benzyl }carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-{ N-[(R)-0-(N"-{2- [(hydroxy)(methyl)phosphoryl]ethyl } carbamoyl)benzyl]carbamoylmethoxy}-2,3,4,5- tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{ (R)-a-[N'-(2-methylthio-1- carboxyethyl)carbamoyl]benzyl }carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{ N-[(R)-0-(N'-{ 2-[ (methyl)(ethyl) phosphoryljethyl }carbamoyl)-4-hydroxybenzyllcarbamoylmethoxy}-2,3,4,5-tetrahydro-1,5- benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{ N-[(R)-0-(V'-{ 2-[ (methyl) (hydroxy) phosphoryljethyl }carbamoyl)-4-hydroxybenzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5- benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{ (R)-0-[(R)-N'-(2-methylsulphinyl-1- carboxyethyl)carbamoyl]benzyl }carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; and 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methoxy-8-[N-{ (R)-0-[N"-(2-sulphoethyl)carbamoyl]-4- hydroxybenzyl }carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine; or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
16. A process for preparing a compound of the formula (I) as claimed in any one of claims 1 to 15 which comprises of:- Process 1): oxidising a benzothiazepine of formula (IX):
RS Y w RS S Re 4 R? R Ng R3 | RY R?), (am; Process 2): for compounds of formula (I) wherein D is -O-,-NR? or -S-; reacting a compound of formula (IT1a) or (IIIb): RE OR “0 OR ' Oa / w Ox /” w N 5 ~ R HD S py R S a. 4 R? R? R N Rx HD N R* R3 | rR’ R? - RY R?), R?, (Ilka) (IIIb) with a compound of formula (IV): RY L 5 fs RO RE R’ av) wherein L is a displaceable group; Process 3): reacting an acid of formula (Va) or (Vb):
6 (@) R' 6 (0) v [0 I Y/ D Ss) PW HO 2 R 7 R! R’ R? wo.
R2 N x D R R* R?), R?, (Va) (Vb) or an activated derivative thereof; with an amine of formula (VI): Rl ml, NH ro R as (VD; Process 4): for compounds of formula (I) wherein RM is a group of formula (IB); reacting a compound of formula (I) wherein R"! is carboxy with an amine of formula (VII): 14 13 ict R71 ka | INH R12 (VID Process 5): for compounds of formula (I) wherein R! is carboxy; deprotecting a compound of formula (VIIa): R® OR’ / RS Ox rR" R10 8 R’ R! . 0) N R: R 1) iD) N R Xx oo lo} (x) lo R3 : R’ R?, (VIIa) or (VIIIb):
6 v 0 0) R Os 2 Y RE, D S R . 0) mo } 1 R RIO RS R’ R? ’ N R* R3 | RY R?), (VIIIb) wherein RP is Cj 4alkyl; Process 6): for compounds of formula (I) wherein R is a group of formula (IB) and RY" is carboxy; deprotecting a compound of formula (IXa): 6 (0) R' RS Ox’ LR” 0 RY | RE R’ R' H ) N N.
R? ®0 el “Eo x R* RE © 0 R® RY R?), (IXa) or (IXb):
14 13 Q (a) 6 v RO (| XH? S pe T q P , 9 n O H id na rR’ R? R X ) R3 RY R?), (IXb) wherein RP? is Cy4alkyl; Process 7) for compounds of formula (I) wherein one of R* and R’ are independently selected from Cyalkylthio optionally substituted on carbon by one or more R'S; reacting a compound "of formula (Xa) or (Xb): RS OR’ 6 ORY RS Sd Lg” Og” [ro R! R! R? R? L NT p= N~| Rx R3 RY R3 | RY R2), R3, (Xa) (Xb) wherein L is a displaceable group; with a thiol of formula (XI): RY-H XT) wherein RY is C;.4alkylthio optionally substituted on carbon by one or more R'S; ] Process 8) for compounds of formula (I) wherein RPisa group of formula (IC) reacting a compound of formula (IXa) or (IXb) wherein RP is hydrogen with a compound of formula : XID):
RZ
Hh . R 24 (XI) Process 9): for compounds of formula (I) wherein R'is a group of formula (IB) and R” is a group of formula (IC) and R* is carboxy; deprotecting a compound of formula (XIIla): 6 v i Ni > R R R% 0 10 8 7 R! P H R® R 5 RO N N R AN NER ER iD ee oO R R* R* RB © 0 R® - RY 5 R?), (XIIIa) or (XIIIb): R2# Ru RI3 O 0 RS OR" P os R yin AHA 17 a Ng Re R2S 9 ne Y 0 H id LPI Y R? . N RX R® : R’ R3), (XIIIb) and RP is Cialkyl; Process 10): for compounds of formula (I) wherein X is -N(R*)C(O)-; reacting a compound of formula (XXVa):
6 (0) M / w RS Oxf’ | Rr 10 R 8 7 R! R® N N R? HO p m nD N Rx RB O 0] R? - RY R?, (XIVa) or (XIVb): 3 6 v R13 OQ 0 R Os LOR R 0 | HP Tr 9 n 0 H Rok RS R’ R? N R* R3 | RY R?), (XIVb) with a compound of formula (XV): R 14 sf, R r NH ie XV) and thereafter if necessary or desirable: i) converting a compound of the formula (I) into another compound of the formula (I); ii) removing any protecting groups; iif) forming a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug.
17. A compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1 to 15 for use as a medicament.
® | -156- PCT/GB01/05554
18. A compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1 to 15 for use in a method of prophylactic or therapeutic treatment of a warm-blooded animal, such as man.
19. The use of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1 to 15 in the manufacture of a medicament for use in the production of an IBAT inhibitory effect in a warm-blooded animal, such as man.
20. A method for producing an IBAT inhibitory effect in a warm-blooded animal, such as man, which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1 to 15.
21. A pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutically acceptable salt, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1 to 15, in association with a pharmaceutically-acceptable diluent or carrier.
22. A pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1 to 15, and an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate of such a salt or a prodrug thereof, in association with a pharmaceutically acceptable diluent or carrier.
23. A pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1 to 15, and a bile acid binder, in association with a pharmaceutically acceptable diluent or carrier. AMENDED SHEET
Py -167- PCT/GB01/05554
24. A pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1 to 15, and an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and a bile acid binder in association with a pharmaceutically acceptable diluent or carrier.
25. A composition according to claim 22 or claim 24 wherein the HMG Co-A reductase inhibitor is atorvastatin, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
26. A composition according to claim 22 or claim 24 wherein the HMG Co-A reductase inhibitor is rosuvastatin, or a pharmaceutically acceptable salt thereof.
27. A pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1 to 15 and a PPAR alpha and/or gamma agonist, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier. :
28. A composition according to claim 27 wherein the PPAR alpha and/or gamma agonist is (S)-2-ethoxy-3-[4-(2-{4-methanesulphonyloxyphenyl}ethoxy)phenyl]propanoic acid or a pharmaceutically acceptable salt thereof.
29. A compound of formula (VIIa), (VIIIb), (IXa), (IXb), (XIIIa) or (XIIIb) (as depicted in claim 16) or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
30. Use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1 to 15, in the manufacture of a preparation for use in a method of prophylactic or therapeutic treatment of a warm-blooded animal, such as man. AMENDED SHEET
Py -168- PCT/GB01/05554
31. A compound of formula (IXb) according to claim 29 which is 1,1-dioxo-3,3- dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1’-phenyl-1’-[N’ -(t-butoxycarbonylmethyl) carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine.
32. The use of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1-15, in the manufacture of a medicament for use in the treatment of hyperlipidaemic conditions in a warm-blooded animal, such as man.
33. The use of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1-15, in the manufacture of a medicament for use in the treatment of dyslipidemic conditions and disorders such as hyperlipidaemia, hypertrigliceridemia, hyperbetalipoproteinemia (high LDL), hyperprebetalipoproteinemia (high VLDL), hyperchylomicronemia, hypolipoproteinemia, hypercholesterolermia, hyperlipoproteinemia and hypoalphalipoproteinemia (low HDL) in a warm-blooded animal, such as man.
34. The use of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1-15, in the manufacture of a medicament for use in the treatment of different clinical conditions such as atherosclerosis, arteriosclerosis, arrhythmia, hyper- thrombotic conditions, vascular dysfunction, endothelial dysfunction, heart failure, coronary heart diseases, cardiovascular diseases, myocardial infarction, angina pectoris, peripheral vascular diseases, inflammation of cardiovascular tissues such as heart, valves, vasculature, arteries and veins, aneurisms, stenosis, restenosis, vascular plaques, vascular fatty streaks, leukocyte, monocytes and/or macrophage infiltrate, intimital thickening, medial thinning, infectious and surgical trauma and vascular thrombosis, stroke and transient ischaemic attacks in a warm-blooded animal, such as man. : AMENDED SHEET
Py -159- PCT/GBO1/05554
35. The use of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1-15, in the manufacture of a medicament for use in the treatment of atherosclerosis, coronary heart diseases, myocardial infarction, angina pectoris, peripheral vascular diseases, stroke and transient ischaemic attacks in a warm-blooded animal, such as man.
36. A combination, comprising a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1-15, and an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
37. A combination, comprising a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1-15, and a bile acid binder.
38. A combination, comprising a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1-15, and an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and a bile acid binder.
39. The use of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1-15, and an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment of hyperlipidaemic conditions in a warm-blooded animal, such as man.
40. The use of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of AMENDED SHEET
® -160- PCT/GB01/05554 claims 1-15, and a bile acid binder, in the manufacture of a medicament for use in the treatment of hyperlipidaemic conditions in a warm-blooded animal, such as man.
41. The use of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1-15, an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and a bile acid binder, in the manufacture of a medicament for use in the treatment of hyperlipidaemic conditions in a warm-blooded animal, such as man.
42. Use of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1- 15, in the manufacture of a medicament for use with at least one other agent in the treatment of hyperlipidaemic conditions in a warm-blooded animal, such as man, and said at least one other agent is an HMG Co-A reductase inhibitor and/or a bile acid binder.
43. The combination or use according to any one of claims 37 or 40 to 42, wherein the bile acid binder is a resin. y
44. The combination or use according to any one of claims 37 or 40 to 42, wherein the bile acid binder is cholestyramine or cholestipol.
45. Use of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1- 15, and a cholesterol absorption antagonist, optionally together with a pharmaceutically acceptable diluent or carrier, in the manufacture of a medicament for use in a method of treatment.
46. Use of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1- 15, optionally together with a pharmaceutically acceptable diluent or carrier, in the AMENDED SHEET
Py -161- PCT/GB01/05554 manufacture of a medicament for use with a cholesterol absorption antagonist in a method of treatment.
47. Use according to claim 46, wherein said compound and said antagonist are administrable simultaneously, sequentially or separately.
48. Use according to any one of claims 45 to 47, wherein the cholesterol absorption antagonist is an azetidinone.
49. Use according to any one of claims 45 to 47, wherein the cholesterol absorption antagonist is SCH 58235.
50. A combination or use according to any one of claims 36 to 39, 41 or 42, wherein the HMG Co-A reductase inhibitor is luvastatin, lovastatin, pravastatin, simvastatin, atorvastatin, cerivastatin, bervastatin, dalvastatin, mevastatin, and rosuvastatin, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
51. A eombination comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1-15 and a PPAR alpha and/or gamma agonist, or a pharmaceutically acceptable salt thereof.
52. The use of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1-15 and a PPAR alpha and/or gamma agonist, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment of hyperlipidaemic conditions in a warm-blooded animal, such as man.
53. Use of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1- AMENDED SHEET
Py -162- PCT/GB0O1/05554 15, in the manufacture of a medicament for use with a PPAR alpha and/or gamma agonist, or optionally together with a pharmaceutically acceptable diluent or carrier, in the treatment of hyperlipidaemic conditions in a warm-blooded animal, such as man.
54. A substance or composition for use in a method for the treatment of hyperlipidaemic conditions in a warm-blooded animal, such as man, said substance or composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1-15, and said method comprising administering said substance or composition.
55. A substance or composition for use in a method for the treatment of dyslipidemic conditions and disorders such as hyperlipidaemia, hypertrigliceridemia, hyperbetalipoproteinemia (high LDL), hyperprebetalipoproteinemia (high VLDL), hyperchylomicronemia, hypolipoproteinemia, hypercholesterolemia, hyperlipoproteinemia and hypoalphalipoproteinemia (low HDL) in a warm-blooded animal, such as man, said substance or composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1-15, and said method comprising administering said substance or composition.
56. A substance or composition for use in a method for the treatment of different clinical conditions such as atherosclerosis, arteriosclerosis, arrhythmia, hyper- thrombotic conditions, vascular dysfunction, endothelial dysfunction, heart failure, coronary heart diseases, cardiovascular diseases, myocardial infarction, angina pectoris, peripheral vascular diseases, inflammation of cardiovascular tissues such as heart, valves, vascular fatty streaks, leukocyte, monocytes and/or macrophage infiltrate, intimital thickening, medial thinning, infectious and surgical trauma and vascular thrombosis, stroke and transient ischaemic attacks in a warm-blooded animal, such as man, said substance or composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as AMENDED SHEET o -163- PCT/GB01/05554 claimed in any one of claims 1-15, and said method comprising administering said substance or composition.
57. A substance or composition for use in a method for the treatment of atherosclerosis, coronary heart diseases, myocardial infarction, angina pectoris, peripheral vascular diseases, stroke and transient ischaemic attacks in a warm-blooded animal, such as man, said substance or composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1-15, and said method comprising administering said substance or composition.
58. A substance or composition for use in a method for the treatment of hyperlipidaemic conditions in a warm-blooded animal, such as man, said substance or composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1-15, and an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and said method comprising administering said substance or composition.
59. A substance or composition for use in a method for the treatment of hyperlipidaemic conditions in a warm-blooded animal, such as man, said substance or composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1-15, and a bile acid binder, and said method comprising administering said substance or composition.
60. A substance or composition for use in a method for the treatment of hyperlipidaemic conditions in a warm-blooded animal, such as man, said substance or composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1-15, an HMG Co-A reductase inhibitor, or a pharmaceutically AMENDED SHEET
PY -164- PCT/GB01/05554 acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and a bile acid binder, and said method comprising administering said substance or composition.
61. A substance or composition for use with at least one other agent which is an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof and/or a bile acid binder, in a method of treatment of hyperlipidaemic conditions in a warm-blooded animal, such as man, said substance or composition comprising, a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1-15, optionally together with a pharmaceutically acceptable diluent or carrier, and said method comprising administering said substance or composition and said at least one other agent.
62. A substance or composition for use in a method of treatment or prevention according to any one of claims 59 to 61 wherein the bile acid binder is a resin.
63. A substance or composition for use in a method of treatment or prevention according to any one of claims 59 to 61 wherein the bile acid binder is cholestyramine or cholestipol.
64. A substance or composition for use in a method of treatment, said substance or composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1-15, and a cholesterol absorption antagonist, optionally together with a pharmaceutically acceptable diluent or carrier, and said method comprising administering said substance or composition.
65. A substance or composition for use with a cholesterol absorption antagonist in a method of treatment, said substance or composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1-15, optionally together with a AMENDED SHEET
® -165- PCT/GB01/05554 pharmaceutically acceptable diluent or carrier, and said method comprising administering said substance or composition and said antagonist.
66. A substance or composition for use in a method of treatment or prevention according to claim 65, wherein said compound and said antagonist are administered simultaneously, sequentially or separately.
67. A substance or composition for use in a method of treatment or prevention according to any one of claims 64 to 66 wherein the cholesterol absorption antagonist is an azetidinone.
68. A substance or composition for use in a method of treatment or prevention according to any one of claims 64 to 66 wherein the cholesterol absorption antagonist is SCH 58235.
69. A substance or composition for use in a method of treatment or prevention according to any one of claims 58 to 61 wherein the HMG Co-A reductase inhibitor is luvastatin, lovastatin, pravastatin, simvastatin, atorvastatin, cerivastatin, bervastatin, dalvastatin, mevastatin and rosuvastatin, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
70. A substance or composition for use in a method in the treatment of hyperlipidaemic conditions in a warm-blooded animal, such as man, said substance or composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1-15 and a PPAR alpha and/or gamma agonist, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and said method comprising administering said substance or composition.
71. A substance or composition for use with a PPAR alpha and/or gamma agonist, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug AMENDED SHEET
Py -166- PCT/GB01/05554 thereof, in a method of treatment of hyperlipiadaemic conditions in a warm-blooded animal, such as man, said substance or composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1-15, optionally together with a pharmaceutically acceptable diluent or carrier, and said method comprising administering said substance or composition and said agonist.
72. A substance or composition for use in a method of prophylactic or therapeutic treatment of a warm-blooded animal, such a man, said substance or composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1 to 15, and said method comprising administering said substance or composition.
73. A substance or composition for use in a method for the production of an IBAT inhibitory effect in a warm-blooded animal, such as man, said substance or composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1 to 15, and said method comprising administering said substance or composition.
74. A compound according to any one of claims 1 to 15, 17, 18, 29 or 31, substantially as herein described and illustrated.
75. A process according to claim 16, substantially as herein described and illustrated.
76. Use according to anyone of claims 19, 30, 32 to 35, 39 to 50, 52, or 53, substantially as herein described and illustrated.
77. A method according to claim 20, substantially as herein described and illustrated. AMENDED SHEET
® -167- PCT/GB01/05554
78. A composition according to any one of claims 21 to 28, substantially as herein described and illustrated.
79. A combination according to any one of claims 36 to 38, or 51, substantially as herein described and illustrated.
80. A substance or composition for use in a method of treatment or prevention, according to any one of claims 54 to 73, substantially as herein described and illustrated.
81. A new compound; a new process for preparing a compound; a new use of a compound as claimed in any one of claims 1 to 15; a new use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1 - 15 and/or an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and/or a bile acid binder, and/or a cholesterol absorption antagonist, and/or a PPAR alpha and/or gamma agonist, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof; a new non- therapeutic method of treatment; a new composition; a new combination; or a substance or composition for a new use in a method of treatment or prevention, substantially as herein described. AMENDED SHEET
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE0004811A SE0004811D0 (en) | 2000-12-21 | 2000-12-21 | Chemical compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200304266B true ZA200304266B (en) | 2004-08-30 |
Family
ID=20282391
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200304266A ZA200304266B (en) | 2000-12-21 | 2003-05-30 | Chemical compounds. |
Country Status (3)
| Country | Link |
|---|---|
| SE (1) | SE0004811D0 (en) |
| UA (1) | UA79085C2 (en) |
| ZA (1) | ZA200304266B (en) |
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2000
- 2000-12-21 SE SE0004811A patent/SE0004811D0/en unknown
-
2001
- 2001-12-17 UA UA2003076824A patent/UA79085C2/en unknown
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2003
- 2003-05-30 ZA ZA200304266A patent/ZA200304266B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| UA79085C2 (en) | 2007-05-25 |
| SE0004811D0 (en) | 2000-12-21 |
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