WO2004046145A1 - Imidazo[1, 5a]pyridine derivatives and methods for treating aldosterone mediated diseases - Google Patents
Imidazo[1, 5a]pyridine derivatives and methods for treating aldosterone mediated diseases Download PDFInfo
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- WO2004046145A1 WO2004046145A1 PCT/EP2003/012851 EP0312851W WO2004046145A1 WO 2004046145 A1 WO2004046145 A1 WO 2004046145A1 EP 0312851 W EP0312851 W EP 0312851W WO 2004046145 A1 WO2004046145 A1 WO 2004046145A1
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- WIPO (PCT)
- Prior art keywords
- hydrogen
- optionally substituted
- compound
- trifluoromethyl
- alkoxy
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 38
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 title abstract description 6
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 title abstract description 6
- 229960002478 aldosterone Drugs 0.000 title abstract description 6
- 230000001404 mediated effect Effects 0.000 title abstract description 5
- 201000010099 disease Diseases 0.000 title description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title description 3
- MLXWMEFKFOSOCP-UHFFFAOYSA-N imidazo[1,5-a]pyridine Chemical class C1=CC=CC2=C=N[CH]N21 MLXWMEFKFOSOCP-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 108
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- 238000000265 homogenisation Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
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- 238000002513 implantation Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 description 1
- 239000011630 iodine Chemical group 0.000 description 1
- 229910052740 iodine Chemical group 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 229960002198 irbesartan Drugs 0.000 description 1
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 125000003971 isoxazolinyl group Chemical group 0.000 description 1
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- 239000008101 lactose Substances 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
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- CZRQXSDBMCMPNJ-ZUIPZQNBSA-N lisinopril dihydrate Chemical compound O.O.C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 CZRQXSDBMCMPNJ-ZUIPZQNBSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000002171 loop diuretic Substances 0.000 description 1
- 229960004773 losartan Drugs 0.000 description 1
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 1
- 229960004844 lovastatin Drugs 0.000 description 1
- 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 description 1
- 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 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
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- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- VKQFCGNPDRICFG-UHFFFAOYSA-N methyl 2-methylpropyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)C)C1C1=CC=CC=C1[N+]([O-])=O VKQFCGNPDRICFG-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
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- 229960002237 metoprolol Drugs 0.000 description 1
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 229950009116 mevastatin Drugs 0.000 description 1
- 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 description 1
- 238000004452 microanalysis Methods 0.000 description 1
- 230000003228 microsomal effect Effects 0.000 description 1
- PZRHRDRVRGEVNW-UHFFFAOYSA-N milrinone Chemical compound N1C(=O)C(C#N)=CC(C=2C=CN=CC=2)=C1C PZRHRDRVRGEVNW-UHFFFAOYSA-N 0.000 description 1
- 229960003574 milrinone Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229960005170 moexipril Drugs 0.000 description 1
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 230000003680 myocardial damage Effects 0.000 description 1
- 210000000107 myocyte Anatomy 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- VWPOSFSPZNDTMJ-UCWKZMIHSA-N nadolol Chemical compound C1[C@@H](O)[C@@H](O)CC2=C1C=CC=C2OCC(O)CNC(C)(C)C VWPOSFSPZNDTMJ-UCWKZMIHSA-N 0.000 description 1
- 229960004255 nadolol Drugs 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 229960001783 nicardipine Drugs 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
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- 229960000227 nisoldipine Drugs 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- LVRLSYPNFFBYCZ-VGWMRTNUSA-N omapatrilat Chemical compound C([C@H](S)C(=O)N[C@H]1CCS[C@H]2CCC[C@H](N2C1=O)C(=O)O)C1=CC=CC=C1 LVRLSYPNFFBYCZ-VGWMRTNUSA-N 0.000 description 1
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- AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical compound CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 description 1
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- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
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- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
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- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229960002797 pitavastatin Drugs 0.000 description 1
- VGYFMXBACGZSIL-MCBHFWOFSA-N pitavastatin Chemical compound OC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 VGYFMXBACGZSIL-MCBHFWOFSA-N 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- 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 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridine hydrochloride Substances [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 1
- FFWJHVGUAKWTKW-UHFFFAOYSA-N pyridine-3-thiol Chemical compound SC1=CC=CN=C1 FFWJHVGUAKWTKW-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000006085 pyrrolopyridyl group Chemical group 0.000 description 1
- 229960001455 quinapril Drugs 0.000 description 1
- JSDRRTOADPPCHY-HSQYWUDLSA-N quinapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)CC1=CC=CC=C1 JSDRRTOADPPCHY-HSQYWUDLSA-N 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 229960003401 ramipril Drugs 0.000 description 1
- HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 210000005241 right ventricle Anatomy 0.000 description 1
- 229960000672 rosuvastatin Drugs 0.000 description 1
- 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 description 1
- 229950001780 sampatrilat Drugs 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002370 sotalol Drugs 0.000 description 1
- ZBMZVLHSJCTVON-UHFFFAOYSA-N sotalol Chemical compound CC(C)NCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 ZBMZVLHSJCTVON-UHFFFAOYSA-N 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229960005187 telmisartan Drugs 0.000 description 1
- 125000006092 tetrahydro-1,1-dioxothienyl group Chemical group 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000006090 thiamorpholinyl sulfone group Chemical group 0.000 description 1
- 125000006089 thiamorpholinyl sulfoxide group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- RSPCKAHMRANGJZ-UHFFFAOYSA-N thiohydroxylamine Chemical compound SN RSPCKAHMRANGJZ-UHFFFAOYSA-N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- 229960005461 torasemide Drugs 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 229960002051 trandolapril Drugs 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- BPLUKJNHPBNVQL-UHFFFAOYSA-N triphenylarsine Chemical compound C1=CC=CC=C1[As](C=1C=CC=CC=1)C1=CC=CC=C1 BPLUKJNHPBNVQL-UHFFFAOYSA-N 0.000 description 1
- DRDCQJADRSJFFD-UHFFFAOYSA-N tris-hydroxymethyl-methyl-ammonium Chemical class OC[N+](C)(CO)CO DRDCQJADRSJFFD-UHFFFAOYSA-N 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 210000003368 zona glomerulosa Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the present invention provides compounds of the formula (I)
- Ri is cycloalkyl, heterocyclyl or an aryl radical of the formula in which
- R 4 is cycloalkyl, aryl or heterocyclyl
- R 4 is optionally substituted alkyl, alkoxy, hydroxy, halogen or trifluoromethyl provided that both R 5 and R 6 are not hydrogen;
- R 5 is hydrogen, halogen, cyano, alkoxy or trifluoromethyl; or
- R 5 are attached to carbon atoms adjacent to each other;
- R 6 is hydrogen, halogen, cyano, nitro, trifluoromethyl, optionally substituted lower alkyl, optionally substituted amino, alkoxy, carboxy, alkoxycarbonyl, sulfonyl or carbamoyi;
- R 2 and R 3 are, independently, hydrogen, trifluoromethyl or alkoxy; or
- R 2 and R 3 combined together with the carbon atoms to which they are attached form an optionally substituted aromatic or heteroaromatic 5- or 6-membered ring;
- R 2 and R 3 combined are alkylene which taken together with the carbon atoms to which they are attached form a 4- to 7-membered ring; or a pharmaceutically acceptable salt thereof.
- the compounds of the present invention are inhibitors of the P450 enzyme, aldosterone synthase, and thus may be employed for the treatment of aldosterone mediated conditions.
- the compounds of formula (I) may be employed for prevention, delay of progression, or treatment of hypokalemia, hypertension, congestive heart failure, renal failure, in particular, chronic renal failure, restenosis, atherosclerosis, syndrome X, obesity, nephropathy, post-myocardial infarction, coronary heart diseases, increased formation of collagen, fibrosis and remodeling following hypertension and endothelial dysfunction.
- the compounds of formula (I) which are selective inhibitors of aldosterone synthase devoid of undesirable side effects due to general inhibition of cytochrome P450 enzymes.
- optionally substituted alkyl refers to unsubstituted or substituted straight- or branched-chain hydrocarbon groups having 1-20 carbon atoms, preferably 1-7 carbon atoms.
- exemplary unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, f-butyl, isobutyl, pentyi, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl and the like.
- Substituted alkyl groups include, but are not limited to, alkyl groups substituted by one or more of the following groups: halo, hydroxy, cycloalkyl, acyl, alkoxy, alkyloxyalkoxy, alkanoyloxy, amino, alkylamino, dialkylamino, acylamino, carbamoyl, thiol, alkylthio, alkylthiono, sulfonyl, sulfonamido, sulfamoyl, nitro, cyano, carboxy, alkoxycarbonyl, alkenyl, alkynyl, aryloxy, aralkoxy, guanidino, heterocyclyl including indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, piperidyl, morpholinyl and the like.
- lower alkyl refers to those optionally substituted alkyl groups as described above having 1-7, preferably 1-4 carbon atoms.
- halogen refers to fluorine, chlorine, bromine and iodine.
- alkenyl refers to any of the above alkyl groups having at least two carbon atoms and further containing a carbon to carbon double bond at the point of attachment. Groups having 2-4 carbon atoms are preferred.
- alkynyl refers to any of the above alkyl groups having at least two carbon atoms and further containing a carbon to carbon triple bond at the point of attachment. Groups having 2-4 carbon atoms are preferred.
- alkylene refers to a straight-chain bridge of 2-5 carbon atoms connected by single bonds, e.g., -(CH ) X -, wherein x is 2-5, which may be interrupted with one or more heteroatoms selected from O, S, S(O), S(O) 2 or NR, wherein R may be hydrogen, alkyl, cycloalkyl, aryl, acyl, carbamoyl, sulfonyl, sulfamoyl, alkoxycarbonyl, aryloxycarbonyl or aralkoxycarbonyl, and the alkylene may be substituted with one or more substituents selected from alkyl, cycloalkyl, oxo, halogen, hydroxy, carboxy, alkoxy, alkoxycarbonyl and the like.
- cycloalkyl refers to optionally substituted monocyclic, bicyclic or tricyclic hydrocarbon groups of 3-12 carbon atoms, each of which may be substituted by one or more substituents, such as alkyl, halo, oxo, hydroxy, alkoxy, alkanoyl, acylamino, carbamoyl, alkylamino, dialkylamino, thiol, alkylthio, nitro, cyano, carboxy, alkoxycarbonyl, sulfonyl, sulfonamido, sulfamoyl, heterocyclyl and the like.
- substituents such as alkyl, halo, oxo, hydroxy, alkoxy, alkanoyl, acylamino, carbamoyl, alkylamino, dialkylamino, thiol, alkylthio, nitro, cyano, carboxy, alkoxycarbonyl, sulfon
- Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl and the like.
- bicyclic hydrocarbon groups include bornyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl and the like.
- Exemplary tricyclic hydrocarbon groups include adamantyl and the like.
- alkoxy refers to alkyl-O-.
- alkanoyl refers to alkyl-C(O)-.
- alkanoyloxy refers to alkyl-G(O)-O-.
- alkylamino and “dialkylamino” refer to alkyl-NH- and (alkyl) 2 N-, respectively.
- alkanoylamino refers to a!kyl-C(O)-NH-.
- alkylthio refers to alkyl-S-.
- alkylthiono refers to alkyl-S(O)-.
- alkylsulfonyl refers to alkyl-S(O) 2 -.
- alkoxycarbonyl refers to alkyl-O-C(O)-.
- alkoxycarbonyloxy refers to alkyl-O-C(O)O-.
- carbamoyl refers to H 2 NC(O)-, aikyl-NHC(O)-, (alkyl) 2 NC(O)-, aryi-NHC(O)-, alkyl(aryl)-NC(O)-, heteroaryl-NHC(O)-, alkyl(heteroaryl)-NC(O)-, aralkyl-NHC(O)-, alkyl(aralkyl)-NC(O)- and the like.
- sulfamoyl refers to H 2 NS(O) 2 -, alkyl-NHS(O) 2 -, (alkyl) 2 NS(O) 2 -, aryl-NHS(O) 2 -, alkyl(aryl)-NS(O) 2 -, (aryl) 2 NS(O) 2 -, heteroaryl-NHS(O) 2 -, aralkyl-NHS(O) 2 -, heteroaralkyl- NHS(O) 2 - and the like.
- sulfonamido refers to alkyl-S(O) 2 -NH-, aryl-S(O) 2 -NH-, aralkyl-S(O) 2 -NH-, heteroaryl-S(O)a-NH-, heteroaralkyl-S(O) 2 -NH-, alkyl-S(O) 2 -N(alkyl)-, aryl-S(O) 2 -N(alkyl)-, aralkyl-S(O) 2 -N(alkyl)-, heteroaryl-S(O) 2 -N(alkyl)-, heteroaralkyl-S(O) 2 -N(alkyl)- and the like.
- sulfonyl refers to alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl and the like.
- optionally substituted amino refers to a primary or secondary amino group which may optionally be substituted by a substituent, such as acyl, sulfonyl, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, carbamoyl and the like.
- aryl refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6-12 carbon atoms in the ring portion, such as phenyl, biphenyl, naphthyl or tetrahydronaphthyl, each of which may optionally be substituted by 1-4 substituents, such as optionally substituted alkyl, trifluoromethyl, cycloalkyl, halo, hydroxy, alkoxy, acyl, alkanoyloxy, aryloxy, optionally substituted amino, thiol, alkylthio, arylthio, nitro, cyano, carboxy, alkoxycarbonyl, carbamoyl, alkylthiono, sulfonyl, sulfonamido, heterocyclyl and the like.
- aryl refers to optionally substituted phenyl as described under aryl.
- aralkyl refers to an aryl group bonded directly through an alkyl group, such as benzyl and phenethyl.
- aralkanoyl refers to aralkyl-C(O)-.
- aralkylthio refers to aralkyl-S-.
- alkoxy refers to an aryl group bonded directly through an alkoxy group.
- arylsulfonyl refers to aryl-S(O) 2 -.
- arylthio refers to aryl-S-.
- aroyl refers to aryl-C(O)-.
- aroyloxy refers to aryl-C(O)-O-.
- aroylamino refers to aryl-C(O)-NH-.
- aryloxycarbonyl refers to aryl-O-C(O)-.
- heterocyclyl refers to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, e.g., which is a 4- to 7-membered monocyclic, 7- to 12-membered bicyclic or 10- to 15-membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom containing ring.
- Each ring of the heterocyclic group containing a heteroatom may have 1 , 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also be optionally oxidized.
- the heterocyclic group may be attached at a carbon atom, or it may be attached through a nitrogen atom provided that an appropriately hybridized nitrogen atom constitutes part of the structure.
- the point of attachment is always at the ring containing at least one heteroatom as defined herein above.
- Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, triazolyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl
- bicyclic heterocyclic groups include indolyl, dihydroindolyl, benzothiazolyl, benzoxazinyl, benzoxazolyl, benzothienyl, benzothiazinyl, quinolinyl, tetrahydroquinolinyl, decahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl, e.g., furo[2,3-c]pyridinyl, furo[3,2-b]-pyridinyl and furo[2,3-b]pyridinyl,
- Exemplary tricyclic heterocyclic groups include carbazolyl, dibenzoazepinyl, dithienoazepinyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, phenoxazinyl, phenothiazinyl, xanthenyl, carbolinyl and the like.
- heterocyclyl includes substituted heterocyclic groups.
- Substituted heterocyclic groups refer to heterocyclic groups substituted with 1 , 2 or 3 substitutents selected from the group consisting of the following:
- alkoxycarbonyl such as unsubstituted lower alkoxycarbonyl
- heterocyclooxy denotes a heterocyclic group bonded through an oxygen bridge.
- heteroaryl refers to an aromatic heterocycle, e.g., monocyclic or bicyclic aryl, such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzofuryl and the like, optionally substituted by, e.g., lower alkyl, lower alkoxy or halo.
- heteroarylsulfonyl refers to heteroaryl-S(O) 2 -.
- heteroaroyl refers to heteroaryl-C(O)-.
- heteroaroyiamino refers to heteroaryl-C(O)NH-.
- heteroaryl refers to a heteroaryl group bonded through an alkyl group.
- heteroaralkanoyl refers to heteroaralkyl-C(O)-.
- heteroaralkanoylamino refers to heteroaralkyl-C(O)NH-.
- acyl refers to alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl and the like.
- acylamino refers to alkanoylamino, aroylamino, heteroaroyiamino, araikanoylamino, heteroaralkanoylamino and the like.
- compositions of any compound of the present invention refer, in particular, to salts formed with acids, namely acid addition salts with the imidazolyl moiety of the structure.
- the acid addition salts may be formed with mineral acids, organic carboxylic acids or organic sulfonic acids, e.g., hydrochloric acid, maleic acid and methanesulfonic acid, respectively.
- salts formed with bases e.g., cationic salts, such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethylammonium, diethylammonium and tris(hydroxymethyl)methylammonium salts and salts with amino acids, are possible if an acidic group constitutes part of the structure.
- bases e.g., cationic salts, such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium
- ammonium salts such as ammonium, trimethylammonium, diethylammonium and tris(hydroxymethyl)methylammonium salts and salts with amino acids
- the present invention provides bicyclic imidazole derivatives of formula (I), pharmaceutical compositions containing them, methods for preparing said compounds, and methods of treating aldosterone mediated conditions by administration of a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
- R-i is heterocyclyl
- R 2 and R 3 are hydrogen; or pharmaceutically acceptable salt thereof.
- R 2 and R 3 are, independently, hydrogen, trifluoromethyl or alkoxy; or
- R 2 and R 3 combined together with the carbon atoms to which they are attached form an optionally substituted aromatic or heteroaromatic 5- or 6-membered ring;
- R 2 and R 3 combined are alkylene which taken together with the carbon atoms to which they are attached form a 4- to 7-membered ring;
- R is cycloalkyl, aryl or heterocyclyl; or
- R 4 is optionally substituted alkyl, alkoxy, hydroxy, halogen or trifluoromethyl provided that both R 5 and R 6 are not hydrogen;
- R 5 is hydrogen, halogen, cyano, alkoxy or trifluoromethyl
- R and R 5 combined together with the carbon atoms to which they are attached form an optionally substituted aromatic or heteroaromatic 5- or 6-membered ring provided that R and R 5 are attached to carbon atoms adjacent to each other;
- R 6 is hydrogen, halogen, cyano, nitro, trifluoromethyl, optionally substituted lower alkyl, optionally substituted amino, alkoxy, carboxy, alkoxycarbonyl, sulfonyl or carbamoyl; or a pharmaceutically acceptable salt thereof.
- R 2 and R 3 are, independently, hydrogen, trifluoromethyl or alkoxy; or
- R 2 and R 3 combined together with the carbon atoms to which they are attached form aromatic or heteroaromatic 5- to 6-membered ring;
- R 4 is cycloalkyl, aryl or heterocyclyl
- R 4 is hydroxy, halogen or trifluoromethyl provided that both R 5 and R 6 are not hydrogen;
- R 5 is hydrogen, halogen, cyano, alkoxy or trifluoromethyl
- R 4 and R 5 combined together with the carbon atoms to which they are attached form an optionally substituted aromatic or heteroaromatic 5- or 6-membered ring;
- R 6 is hydrogen, halogen, cyano, nitro, trifluoromethyl, optionally substituted lower alkyl, optionally substituted amino, alkoxy, carboxy, alkoxycarbonyl, sulfonyl or carbamoyl; or a pharmaceutically acceptable salt thereof.
- R 6 is hydrogen, halogen, cyano, nitro, trifluoromethyl, optionally substituted lower alkyl, optionally substituted amino, alkoxy, carboxy, alkoxycarbonyl, sulfonyl or carbamoyl; or a pharmaceutically acceptable salt thereof.
- R 2 and R 3 are hydrogen; or a pharmaceutically acceptable salt thereof.
- R 4 is monocyclic aryl or heteroaryl
- R 5 is hydrogen
- R 6 is hydrogen, halogen, cyano, trifluoromethyl or alkoxy; or a pharmaceutically acceptable salt thereof.
- R 4 and R 5 combined together with the carbon atoms to which they are attached form an optionally substituted aromatic or heteroaromatic 5- or 6-membered ring;
- R 6 is hydrogen, halogen, cyano, trifluoromethyl or alkoxy; or a pharmaceutically acceptable salt thereof.
- the compounds of the invention depending on the nature of the substituents, may possess one or more asymmetric centers.
- the resulting diastereoisomers, enantiomers and geometric isomers, and mixtures thereof, are encompassed by the instant invention.
- compounds of formula (I), wherein R-- is attached through a carbon atom may be prepared by condensing amines of the formula (III)
- R 2 and R 3 have meanings as defined herein above, with an isothiocyanate, such as phenylisothiocyanate, in an organic solvent, such as toluene or xylenes to afford thiols of the formula (IV)
- R 2 and R 3 have meanings as defined for formula (III).
- Amines of formula (III) are known, or if they are novel, they may be prepared according to methods well-known in the art, e.g., as described by Browne et al., supra and Ahmad et al., supra, or modifications thereof.
- the alkylation reaction may be conducted at a temperature ranging from room temperature (RT) to a temperature near the boiling point of the solvent.
- R 2 , R 3 and R 7 have meanings as defined for formula (VI); and R 8 represents lower alkyl, such as methyl, ethyl or ⁇ -butyl, preferably n-butyl, by treating thioethers of formula (VI) with a base, such as n-butyllithium to form an anion, and then reacting the resulting anion with a tin reagent of the formula (VIII) r
- the reaction may be conducted in an inert organic solvent, such as pentane, hexane, tetrahydrofuran (THF) or ethyl ether, or in a mixture of solvents thereof, at a temperature ranging from about -45°C to about -100°C.
- THF tetrahydrofuran
- ethyl ether ethyl ether
- compounds of formula (X) may be obtained by reacting compounds of formula (VII) with a compound of formula (IX) in the presence of a palladium(O) catalyst such as fr.s(dibenzylidineacetone)dipalladium(0) and a ligand, such as tri-t-butylphosphine or triphenylarsine in an organic solvent, such as THF, 1 ,4-dioxane, N,N- dimethylformamide (DMF) or ⁇ /-methylpyrrolidine (NMP).
- a palladium(O) catalyst such as fr.s(dibenzylidineacetone)dipalladium(0)
- a ligand such as tri-t-butylphosphine or triphenylarsine
- organic solvent such as THF, 1 ,4-dioxane, N,N- dimethylformamide (DMF) or ⁇ /-methylpyrrolidine (NMP).
- NMP ⁇ /-methylpyrrolidine
- Ri', R 2 and R 3 have meanings as defined for formula (X), by desulfurization, e.g., in the presence of Raney nickel in a polar organic solvent, such as a lower alcohol.
- a polar organic solvent such as a lower alcohol.
- the lower alcohol is ethanol, and the reaction is conducted at a temperature near the boiling point of the solvent.
- protecting groups are to protect the functional groups from undesired reactions with reaction components under the conditions used for carrying out a desired chemical transformation.
- the need and choice of protecting groups for a particular reaction is known to those skilled in the art and depends on the nature of the functional group to be protected (hydroxyl group, amino group, etc.), the structure and stability of the molecule of which the substituent is a part and the reaction conditions.
- the above-mentioned reactions are carried out according to standard methods, in the presence or absence of diluent, preferably, such as are inert to the reagents and are solvents thereof, of catalysts, condensing or said other agents, respectively and/or inert atmospheres, at low temperatures, RT or elevated temperatures, preferably at or near the boiling point of the solvents used, and at atmospheric or super-atmospheric pressure.
- diluent preferably, such as are inert to the reagents and are solvents thereof, of catalysts, condensing or said other agents, respectively and/or inert atmospheres, at low temperatures, RT or elevated temperatures, preferably at or near the boiling point of the solvents used, and at atmospheric or super-atmospheric pressure.
- the invention further includes any variant of the present processes, in which an intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or in which the starting materials are formed in situ under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure antipodes.
- the new compounds may be in the form of one of the possible isomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.
- the aforesaid possible isomers or mixtures thereof are within the purview of this invention.
- Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
- any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
- the imidazolyl moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-0,0'-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid.
- Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
- HPLC high pressure liquid chromatography
- Compounds of the invention may be converted into acid addition salts thereof, in particular, acid addition salts with the imidazolyl moiety of the structure, preferably pharmaceutically acceptable salts thereof.
- inorganic acids such as mineral acids, e.g., sulfuric acid, a phosphoric or hydrohalic acid
- organic carboxylic acids such as (C ⁇ -C 4 )alkanecarboxylic acids which, for example, are unsubstituted or substituted by halogen, e.g., acetic acid, such as saturated or unsaturated dicarboxylic acids, e.g., oxalic, succinic, maleic or fumaric acid, such as hydroxycarboxylic acids, e.g., glycolic, lactic, malic, tartaric or citric acid, such as amino acids, e.g., aspartic or glutamic acid, or with organic suifonic acids, such as (C C 4 )alkyls
- salts may be converted into salts with pharmaceutically acceptable bases.
- Such salts include alkali metal salts, like sodium, lithium and potassium salts; alkaline earth metal salts, like calcium and magnesium salts; ammonium salts with organic bases, e.g., trimethylamine salts, diethylamine salts, fr/s(hydroxymethyl)methylamine salts, dicyclohexylamine salts and ⁇ /-methyl-D-glucamine salts; salts with amino acids like arginine, lysine and the like.
- Salts may be formed using conventional methods, advantageously in the presence of an ethereal or alcoholic solvent, such as a lower alkanol.
- the salts may be precipitated with ethers, e.g., diethyl ether. Resulting salts may be converted into the free compounds by treatment with acids. These or other salts can also be used for purification of the compounds obtained.
- Prodrug derivatives of any compound of the invention are derivatives of said compounds which following administration release the parent compound in vivo via some chemical or physiological process, e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the parent compound.
- exemplary prodrug derivatives are, e.g., esters of free carboxylic acids and S-acyl and O-acyl derivatives of thiols, alcohols or phenols, wherein acyl has a meaning as defined herein.
- ester derivatives convertible by solvolysis under physiological conditions to the parent carboxylic acid, e.g., lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or di-substituted lower alkyl esters, such as the ⁇ -(amino, mono- or di-lower alkylamino, carboxy, lower alkoxycarbonyl)-lower alkyl esters, the ⁇ -(lower alkanoyloxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters, such as the pivaloyloxymethyl ester and the like conventionally used in the art.
- lower alkyl esters e.g., lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or di-substituted lower alkyl esters, such as the ⁇ -(
- prodrug derivatives In view of the close relationship between the free compounds, the prodrug derivatives and the compounds in the form of their salts, whenever a compound is referred to in this context, a prodrug derivative and a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.
- the compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
- the pharmaceutical compositions according to the invention are those suitable for enteral, such as oral or rectal, transdermal and parenteral administration to mammals, including man, to inhibit aldosterone synthase, and for the treatment of conditions associated with aldosterone synthase activity. Such conditions include hypokalemia, hypertension, congestive heart failure, renal failure, in particular chronic renal failure, restenosis, atherosclerosis, syndrome X, obesity, nephropathy, post-myocardial infarction, coronary heart diseases, increased formation of collagen, fibrosis and remodeling following hypertension and endothelial dysfunction.
- the said pharmaceutical compositions comprise a therapeutically effective amount of a pharmacologically active compound of the instant invention, alone or in combination with one or more pharmaceutically acceptable carriers.
- the pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions comprising a therapeutically effective amount thereof in conjunction or admixture with excipients or carriers suitable for either enteral or parenteral application.
- Preferred are tablets and gelatin capsules comprising the active ingredient together with diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or
- compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions.
- Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
- Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, preferably about 1-50%, of the active ingredient.
- transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
- the pharmaceutical formulations contain a therapeutically effective amount of a compound of the invention as defined above, either alone or in a combination with another therapeutic agent, e.g., each at an effective therapeutic dose as reported in the art.
- therapeutic agents include anti-obesity agents, such as orlistat, anti-hypertensive agents, inotropic agents and hypolipidemic agents, e.g., loop diuretics, such as ethacrynic acid, furosemide and torsemide; angiotensin converting enzyme (ACE) inhibitors, such as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perinodopril, quinapril, ramipril and trandolapril; inhibitors of the Na-K-ATPase membrane pump, such as digoxin; neutralendopeptidase (NEP) inhibitors; ACE/NEP inhibitors, such as
- the present invention concerns a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention in combination with one or more pharmaceutically acceptable carriers.
- a combination such as a combined preparation or pharmaceutical composition, respectively, comprising a compound of the invention and another therapeutic agent as described above preferably an anti-obesity agent, anti-hypertensive agent, inotropic agent or hypolipidemic agent.
- the present invention concerns a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention in combination with a therapeutically effective amount of another therapeutic agent as described above preferably an anti-obesity agent, anti-hypertensive agent, inotropic agent or hypolipidemic agent.
- the invention concerns furthermore;
- a pharmaceutical composition or combination as described above for the preparation of a medicament for the treatment of conditions associated with aldosterone synthase activity preferably hypokalemia, hypertension, congestive heart failure, renal failure, in particular, chronic renal failure, restenosis, atherosclerosis, syndrome X, obesity, nephropathy, post-myocardial infarction, coronary heart diseases, increased formation of collagen, fibrosis and remodeling following hypertension and endothelial dysfunction.
- a pharmaceutical composition e.g. for use in any of the conditions described above comprising a compound of the invention in free form or pharmaceutically acceptable salt form in association with a pharmaceutically acceptable diluent or carrier therefore.
- a pharmaceutical composition as described above for the treatment of conditions associated with aldosterone synthase activity preferably hypokalemia, hypertension, congestive heart failure, renal failure, in particular, chronic renal failure, restenosis, atherosclerosis, syndrome X, obesity, nephropathy, post-myocardial infarction, coronary heart diseases, increased formation of collagen, fibrosis and remodeling following hypertension and endothelial dysfunction.
- a unit dosage for a mammal of about 50-70 kg may contain between about 1 -1000 mg, advantageously between about 5-500 mg of the active ingredient.
- the therapeutically effective dosage of a compound of formula (I) is dependent on the species of warm-blooded animal (mammal), the body weight, age and individual condition, on the form of administration and on the compound involved.
- the compounds of the present invention are inhibitors of aldosterone synthase, and thus may be employed for the treatment of conditions associated with aldosterone synthase activity, as described herein, e.g., hypokalemia, hypertension, congestive heart failure, renal failure, in particular, chronic renal failure, restenosis, atherosclerosis, syndrome X, obesity, nephropathy, post-myocardial infarction, coronary heart diseases, increased formation of collagen, fibrosis and remodeling following hypertension and endothelial dysfunction.
- hypokalemia e.g., hypokalemia, hypertension
- congestive heart failure renal failure
- renal failure in particular, chronic renal failure, restenosis, atherosclerosis, syndrome X
- obesity nephropathy, post-myocardial infarction
- coronary heart diseases increased formation of collagen, fibrosis and remodeling following hypertension and endothelial dysfunction.
- the present invention relates to
- a compound of the present invention for use as a medicament.
- a method for the prevention and/or treatment of conditions associated with with aldosterone synthase activity which comprises administering a therapeutically effective amount of a compound of the present invention.
- a therapeutic combination e.g. a kit, kit of parts e.g. for use in any method as defined herein, comprising a compound of the invention, in free form or in pharmaceutically acceptable salt form, to be used concomitantly or in sequence with at least one pharmaceutical composition comprising at least another therapeutic agent as described above, preferably an anti-obesity agent, anti-hypertensive agent, inotropic agent or hypolipidemic agent.
- the kit may comprise instructions for its administration.
- a pharmaceutical composition of the invention (i) a pharmaceutical composition of the invention, (ii ) a pharmaceutical composition comprising a compound selected from an another therapeutic agent as described above preferably an anti-obesity agent, anti-hypertensive agent, inotropic agent or hypolipidemic agent, or a pharmaceutically acceptable salt thereof, in the form of two separate units of the components (i) to (ii).
- a pharmaceutical composition comprising a compound selected from an another therapeutic agent as described above preferably an anti-obesity agent, anti-hypertensive agent, inotropic agent or hypolipidemic agent, or a pharmaceutically acceptable salt thereof, in the form of two separate units of the components (i) to (ii).
- a method as defined above comprising co-administration, e.g.
- a therapeutically effective amount of a compound of the invention in free form or in pharmaceutically acceptable salt form and a second therapeutic agent, said second therapeutic agent being selected from the other therapeutic agents described above preferably an anti-obesity agent, anti-hypertensive agent, inotropic agent or hypolipidemic agent.
- the compound of the invention is administered to a mammal in need thereof.
- the compound of the invention is used for the treatment of a disease which responds to activation of conditions associated with aldosterone synthase activity.
- the conditions associated with aldosterone synthase activity are selected from hypokalemia, hypertension, congestive heart failure, renal failure, in particular, chronic renal failure, restenosis, atherosclerosis, syndrome X, obesity, nephropathy, post-myocardial infarction, coronary heart diseases, increased formation of collagen, fibrosis and remodeling following hypertension and endothelial dysfunction.
- a method or use according to the invention which comprises administering said compound in combination with a therapeutically effective amount of another therapeutic agent as described above preferably an anti-obesity agent, anti-hypertensive agent, inotropic agent or hypolipidemic agent.
- the invention relates to; i) a use or method for the treatment of hypokalemia, hypertension, congestive heart failure, atherosclerosis, coronary heart diseases and post myocardial infarction, which method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of the invention; ii) a use or method for the treatment of restenosis, increased formation of collagen, fibrosis, and remodeling following hypertension and endothelial dysfunction, which method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of the invention; iii) a use or a method for the treatment of renal failure and nephropathy, which method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of the invention; iv) a use or a method for the treatment of syndrome X and obesity, which method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of the invention.
- treatmenf embraces all the different forms or modes of treatment as known to those of the pertinent art and in particular includes preventive, curative, delay of progression and palliative treatment.
- the above-cited properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof.
- Said compounds can be applied in vitro in the form of solutions, e.g., preferably aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g., as a suspension or in aqueous solution.
- the dosage in vitro may range between about 10 "3 molar and 10 "9 molar concentrations.
- a therapeutically effective amount in vivo may range depending on the route of administration, between about 0.1-500 mg/kg, preferably between about 1 -100 mg/kg.
- the aldosterone synthase inhibitory activity in vitro may be determined as follows:
- Rats Male male Sprague-Dawley rats weighing 125-150 g are obtained from Harlan Farms. All animals are caged in pairs and maintained under standard conditions of light and temperature. The animals are placed on a sodium depleted diet (0.01-0.02%) from Harland Teklad, Madison Wl (Cat. No. TD90228) and maintained on normal drinking water ad libitum. The animals are maintained on this diet for two to four weeks prior to harvesting the adrenal glomerulosa cells. The rats are killed by CO 2 inhalation, and the adrenals are immediately removed and placed in the same ice-cold buffer used during homogenization and assay of the enzyme preparation. The adrenals are de-capsulated to obtain the glomerulosa tissue.
- the tissue is homogenized in a glass homogenizer containing Tris assay buffer (8.5 mM MgCI 2 , 2.7 mM CaCI 2 , 3.13 mM KCI, 7.59 mM NaCI, 0.1% TEA and 50 mM Tris HCI adjusted to pH 7.4).
- Tris assay buffer 8.5 mM MgCI 2 , 2.7 mM CaCI 2 , 3.13 mM KCI, 7.59 mM NaCI, 0.1% TEA and 50 mM Tris HCI adjusted to pH 7.4
- the homogenate is diluted so that 37.5 mg of glomerulosa tissue is in each mL of buffer.
- the homogenate is centrifuged at 4°C at 900 x g for 10 min.
- the final corticosterone concentration consisted of 4 x 10 "6 M corticosterone (C-2505, Sigma Chemical Co, St. Louis, MO) and 1 x 10 "8 M [1,2,6,7- 3 H] corticosterone (70 Ci/mM; NET 399; NENTM Life Sciences Product, Inc., Boston, MA) and various concentrations of the putative aldosterone synthase inhibitor as indicated.
- the final volume of the incubation mixture is 0.5 mL.
- the mixture is incubated for 1 h at 25°C in a Dubnoff shaking incubator at 1 atm of 95% O 2 /5% CO 2 .
- the reaction is stopped by the addition of 7 mL EtOAc, and the steroids extracted after vortexing.
- the water phase is extracted again with 3 mL of EtOAc.
- the combined extracts are dried under nitrogen, reconstituted in EtOAc, and spotted on silica gel TLC plates (LK6F; Cat. No. 4866-820; Whatman, Inc. Clifton, NJ).
- the chromatograms are developed in a solvent system of toluene:acetone:water (120:80:0.87 V ) for 60 min.
- the plates are scanned for radioactivity with a Biosca ⁇ System 200 Imaging Scanner (Bioscan, Ish. DC).
- Bioscan, Ish. DC The two products of the aldosterone synthase, 18-OH-corticosterone and aldosterone are scraped and counted in a liquid scintillation counter (Beckman LS6000TA, Beckman Instr., Palo Alto, CA).
- the slope (Hill Coefficient) and x intercept (IC 50 ) are determined by linear regression of the experimental data.
- the aromatase inhibitory activity in vitro may be determined as follows:
- Human placental microsome fraction is prepared from freshly delivered human term placenta as previously described with minor modifications (see Steele et al., Steroids, Vol. 50, pp. 147-161 (1987)).
- the tissue is freed of membranes and large vessels and rinsed repeatedly with 0.15 M KCI (4°C). It is then minced in 0.25 M sucrose and homogenized. The homogenate is centrifuged at 20,000 x g for 30 min. The supernatant is then centrifuged at 148,000 x g for 60 min.
- the microsomal pellet obtained is re-suspended in 0.05 M potassium phosphate buffer pH 7.4 and centrifuged again at 148,000 x g for 60 min. The resulting pellet is re-suspended in phosphate buffer, divided into aliquots, and stored at
- Human placental aromatase assay is performed in a incubation mixture consisting of: 12.5 mM phosphate buffer (12.5 mM KH 2 PO 4 , 1 mM EDTA, 1.6 mM dithiothreitol and 1.0 g/L of albumin; pH 7.5), NADPH (2.4 x 10 "4 M), 1 ⁇ - 3 H androstenedione (1 x 10 "7 M) and the appropriate concentration of the desired inhibitor.
- the assay is started by pipetting the appropriate amount 50-500 ⁇ g of the human placental microsome preparation into the incubation mixture. The mixture is incubated at 37°C for 20 min and stopped by addition of 6 volumes of chloroform.
- the samples are immediately vortexed and centrifuged.
- the aqueous layer is carefully removed so as to avoid contamination with chloroform.
- the aqueous fraction is treated with an equal volume of a 5% aqueous suspension of charcoal to remove any substrate not extracted by the chloroform.
- After centrifugation an aliquot of the aqueous phase is counted in a liquid scintillation counter.
- the enzymatic activity for each concentration of inhibitor is calculated as a percent of the vehicle control, which is arbitrarily set at 100%. Therefore, the relative enzyme inhibition is expressed as a percentage: 100% minus % enzyme activity with inhibitor present.
- the aldosterone synthase inhibitory activity for reduction of cardiac damage in vivo may be evaluated as follows:
- the protocol is nearly identical to that previously described (see Rocha et al., Endocrinology, Vol. 141 , pp. 3871-3878 (2000)) with minor modifications.
- the rats are housed in individual cages and given 0.9% NaCI as drinking fluid ad libitum throughout the experiment. Three days later rats are placed on one of the three dosing protocols.
- Group 1 (control) receives L- NAME for 14 days, and on day 11 of L-NAME treatment, an osmotic mini-pump containing only saline is implanted in each animal subcutaneously (s.c).
- Group 2 (/L-NAME/Ang II) received L-NAME for 14 days, and on day 11 of L-NAME treatment, an osmotic mini-pump containing Ang II is implanted in each animal s.c.
- Group 3 (L-NAME/Ang 11/ test compound) is treated similarly to Group 2 but receives test compound (4 mg/kg/day) orally once a day. The test compound is dissolved in distilled water and given by gavage; whereas Groups 1 and 2 receive the vehicle. The experiment is concluded on day 14 of L-NAME treatment.
- the L-NAME Sigma Chemical Co., St.
- Ang II is administered in the 0.9% NaCI drinking water at a concentration of 60 mg/100 mL which results in a daily intake of approximately 60 mg/kg.
- Ang II is administered via Alzet osmotic mini-pumps (Model 2001 ; Alza Corp, Palo Alto, CA). The mini-pump is implanted s.c. at the nape of the neck.
- Ang II (human, 99% peptide purity) is purchased from Sigma Chemical Co., St. Louis, MO and administered at a dose of 225 ⁇ g/kg/day in saline.
- the concentration of Ang II used to fill the pumps is calculated based upon: (a) the mean pump rate provided by the manufacturer; (b) the body weight of the animals on the day before implantation of the pumps; and (c) dose planned. :
- the rats are sacrificed on day 14. Their hearts are removed and sliced through the ventricle/atrium in a "bread-loaf" manner, yielding three samples from the following gross cardiac regions: superior, middle and inferior. The samples are fixed in 10% buffered formalin. Paraffin sections are cut and stained with hematoxylin/eosin. A single investigator who is blinded to the experimental groups views slides. One slide from each of three gross cardiac sample regions is analyzed per rat. Cardiac sites (left and right ventricles and the . septum) are evaluated separately.
- the entire section is assessed histologicaily for the presence of myocardial damage (regardless of the severity) as evidenced by the presence of myocyte necrosis, inflammatory cells, hemorrhage and general tissue disruption. Evaluation of the histoiogical data is made by comparing Groups 2 and 3, i.e., ANG II with or without test compound.
- the compound of Example 1 inhibits the aldosterone synthase activity with an IC 50 value of about 50 nM.
- Our compounds exhibit high affinity, selectivity, improved potency as well as good oral bioavailability, pharmacokinetic profile and safety. Furthermore, they exhibit long duration of action, long-term tolerability.
- Phenyl Isothiocyanate (22 mL, 0.184 mol) is added slowly to a solution of 2-(aminomethyl)- pyridine (19 mL, 0.184 mol) in xylenes (180 mL) with cooling on ice. The resulting solution is heated at reflux for 3 h, and then allowed to cool to RT overnight. The resulting suspension is cooled to 0°C and the solid is collected by filtration.
- reaction is stirred at -78°C for 1 h further, and then allowed slowly to warm to RT overnight.
- the reaction is quenched by addition of saturated aqueous ammonium chloride (15 mL) and the mixture is extracted two times with ethyl acetate. The organic extracts are combined, washed with aqueous potassium fluoride solution (3 M, 20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated.
- Raney Nickel suspension (1 mL, Fluka Cat. No. 83440) is added to a solution of the title D compound, 3-ethylsulfanyl-5-naphthalen-1-yl-imidazo[1 ,5-a]pyridine (268 mg, 0.88 mmol) in ethanol (15 mL) and heated at reflux overnight. Additional Raney Nickel (1 mL) is added, and the reaction mixture is heated at reflux for three days further, until MS showed complete disappearance of the starting material. The catalyst is filtered off and washed with ethanol. The combined filtrates are concentrated under reduced pressure.
- the residue is purified by flash column chromatography on silica using ethyl ether as the eluant to yield 5-naphthalen- 1 -yl-imidazo[1 ,5-a]pyridine as an amber film.
- the hydrochloride salt is prepared in acetone by addition of an ethereal solution of HCI (1.2 eq.). The resulting precipitate is re-crystallized from acetonitrile to yield 5-naphthalen-1-yl-imidazo[1 ,5-a]pyridine hydrochloride (m.p.
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Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
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DE60321593T DE60321593D1 (en) | 2002-11-18 | 2003-11-17 | IMIDAZOÄ1,5ÜA PYRIDINE DERIVATIVES AND METHODS FOR THE TREATMENT OF DISEASES RELATED TO ALDOSTERONE |
US10/534,631 US7223866B2 (en) | 2002-11-18 | 2003-11-17 | Imidazo[1,5-a]pyridine derivatives and methods for treating aldosterone mediated diseases |
EP03767563A EP1565463B1 (en) | 2002-11-18 | 2003-11-17 | Imidazo[1,5a] pyridine derivatives and methods for treating aldosterone mediated diseases |
BR0316306-7A BR0316306A (en) | 2002-11-18 | 2003-11-17 | Organic compounds |
AU2003292039A AU2003292039A1 (en) | 2002-11-18 | 2003-11-17 | Imidazo(1, 5a)pyridine derivatives and methods for treating aldosterone mediated diseases |
CA002505752A CA2505752A1 (en) | 2002-11-18 | 2003-11-17 | Imidazo[1,5a]pyridine derivatives and methods for treating aldosterone mediated diseases |
JP2004552632A JP2006508970A (en) | 2002-11-18 | 2003-11-17 | Method for treating diseases mediated by imidazo [1,5A] pyridine derivatives and aldesterone |
HK06101571.9A HK1081540A1 (en) | 2002-11-18 | 2006-02-06 | Imidazo [1,5a]pyridine derivatives and methods for treating aldosterone mediated diseases |
US11/739,290 US7713991B2 (en) | 2002-11-18 | 2007-04-24 | Imidazo[[1, 5-A] pyridine derivatives and methods for treating aldosterone mediated diseases |
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US42732502P | 2002-11-18 | 2002-11-18 | |
US60/427,325 | 2002-11-18 |
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US (2) | US7223866B2 (en) |
EP (1) | EP1565463B1 (en) |
JP (1) | JP2006508970A (en) |
CN (1) | CN100447142C (en) |
AT (1) | ATE398124T1 (en) |
AU (1) | AU2003292039A1 (en) |
BR (1) | BR0316306A (en) |
CA (1) | CA2505752A1 (en) |
DE (1) | DE60321593D1 (en) |
ES (1) | ES2305520T3 (en) |
HK (1) | HK1081540A1 (en) |
PT (1) | PT1565463E (en) |
WO (1) | WO2004046145A1 (en) |
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ES2305520T3 (en) | 2008-11-01 |
PT1565463E (en) | 2008-09-10 |
EP1565463B1 (en) | 2008-06-11 |
US20060058342A1 (en) | 2006-03-16 |
ATE398124T1 (en) | 2008-07-15 |
BR0316306A (en) | 2005-09-27 |
AU2003292039A1 (en) | 2004-06-15 |
EP1565463A1 (en) | 2005-08-24 |
US7223866B2 (en) | 2007-05-29 |
DE60321593D1 (en) | 2008-07-24 |
US7713991B2 (en) | 2010-05-11 |
CN100447142C (en) | 2008-12-31 |
HK1081540A1 (en) | 2006-05-19 |
CA2505752A1 (en) | 2004-06-03 |
CN1711262A (en) | 2005-12-21 |
US20070197582A1 (en) | 2007-08-23 |
JP2006508970A (en) | 2006-03-16 |
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