EP1999123A1 - Substituted chromanol derivatives and their use - Google Patents
Substituted chromanol derivatives and their useInfo
- Publication number
- EP1999123A1 EP1999123A1 EP07711808A EP07711808A EP1999123A1 EP 1999123 A1 EP1999123 A1 EP 1999123A1 EP 07711808 A EP07711808 A EP 07711808A EP 07711808 A EP07711808 A EP 07711808A EP 1999123 A1 EP1999123 A1 EP 1999123A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- compound
- mmol
- phenyl
- ethyl acetate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- SEBPXHSZHLFWRL-UHFFFAOYSA-N 3,4-dihydro-2,2,5,7,8-pentamethyl-2h-1-benzopyran-6-ol Chemical class O1C(C)(C)CCC2=C1C(C)=C(C)C(O)=C2C SEBPXHSZHLFWRL-UHFFFAOYSA-N 0.000 title abstract description 4
- 238000000034 method Methods 0.000 claims abstract description 150
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- 230000002265 prevention Effects 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 11
- 230000006806 disease prevention Effects 0.000 claims abstract description 8
- 230000008569 process Effects 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 242
- -1 methoxy, mercapto Chemical class 0.000 claims description 56
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 50
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 50
- 239000002904 solvent Substances 0.000 claims description 45
- 239000000126 substance Substances 0.000 claims description 37
- 150000003839 salts Chemical class 0.000 claims description 33
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 32
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 31
- 239000003112 inhibitor Substances 0.000 claims description 28
- 239000012453 solvate Substances 0.000 claims description 27
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 26
- 239000001257 hydrogen Substances 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- 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 claims description 23
- 239000011737 fluorine Substances 0.000 claims description 20
- 229910052731 fluorine Inorganic materials 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 18
- 239000000460 chlorine Chemical group 0.000 claims description 17
- 241001465754 Metazoa Species 0.000 claims description 16
- 239000003054 catalyst Substances 0.000 claims description 16
- 239000012442 inert solvent Substances 0.000 claims description 16
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 15
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 15
- 239000002585 base Substances 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 208000008589 Obesity Diseases 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 230000009467 reduction Effects 0.000 claims description 12
- 235000020824 obesity Nutrition 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 10
- 125000001153 fluoro group Chemical group F* 0.000 claims description 10
- 229910052763 palladium Inorganic materials 0.000 claims description 10
- 206010012601 diabetes mellitus Diseases 0.000 claims description 9
- 125000003003 spiro group Chemical group 0.000 claims description 9
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 7
- 208000029078 coronary artery disease Diseases 0.000 claims description 7
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 7
- 239000003146 anticoagulant agent Substances 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 235000012000 cholesterol Nutrition 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- 208000024827 Alzheimer disease Diseases 0.000 claims description 5
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 5
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 5
- 208000035150 Hypercholesterolemia Diseases 0.000 claims description 5
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 5
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 5
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 5
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 5
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical group 0.000 claims description 5
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims description 5
- 208000006575 hypertriglyceridemia Diseases 0.000 claims description 5
- 208000026621 hypolipoproteinemia Diseases 0.000 claims description 5
- 230000009862 primary prevention Effects 0.000 claims description 5
- 208000037803 restenosis Diseases 0.000 claims description 5
- 230000009863 secondary prevention Effects 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 239000003472 antidiabetic agent Substances 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 150000001642 boronic acid derivatives Chemical class 0.000 claims description 4
- 150000002902 organometallic compounds Chemical class 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 238000010168 coupling process Methods 0.000 claims description 3
- 238000005859 coupling reaction Methods 0.000 claims description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 231100000252 nontoxic Toxicity 0.000 claims description 3
- 230000003000 nontoxic effect Effects 0.000 claims description 3
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 claims description 3
- 230000000087 stabilizing effect Effects 0.000 claims description 3
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
- 125000006529 (C3-C6) alkyl group Chemical group 0.000 claims description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 2
- 125000006554 (C4-C8) cycloalkenyl group Chemical group 0.000 claims description 2
- 125000006564 (C4-C8) cycloalkyl group Chemical group 0.000 claims description 2
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims description 2
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 claims description 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 description 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 description 2
- 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 2
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 2
- 230000002785 anti-thrombosis Effects 0.000 claims description 2
- 239000002220 antihypertensive agent Substances 0.000 claims description 2
- 229960005370 atorvastatin Drugs 0.000 claims description 2
- 230000008878 coupling Effects 0.000 claims description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 2
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound 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 description 2
- 229960000815 ezetimibe Drugs 0.000 claims description 2
- 239000012025 fluorinating agent Substances 0.000 claims description 2
- 229960003765 fluvastatin Drugs 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 229960004844 lovastatin Drugs 0.000 claims description 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 description 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 description 2
- 229960002797 pitavastatin Drugs 0.000 claims description 2
- 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 claims description 2
- 229960002965 pravastatin Drugs 0.000 claims description 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 description 2
- 229960000672 rosuvastatin Drugs 0.000 claims description 2
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 claims description 2
- 229960002855 simvastatin Drugs 0.000 claims description 2
- 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 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 2
- 208000023516 stroke disease Diseases 0.000 claims 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 2
- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 claims 1
- 229940125708 antidiabetic agent Drugs 0.000 claims 1
- 230000037356 lipid metabolism Effects 0.000 claims 1
- 208000024172 Cardiovascular disease Diseases 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 452
- 239000000243 solution Substances 0.000 description 246
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 202
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 154
- 235000019439 ethyl acetate Nutrition 0.000 description 151
- 239000000203 mixture Substances 0.000 description 138
- 238000005160 1H NMR spectroscopy Methods 0.000 description 100
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 100
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 98
- 239000012074 organic phase Substances 0.000 description 88
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 88
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 87
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 83
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 82
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 76
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 73
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 72
- 239000000741 silica gel Substances 0.000 description 72
- 229910002027 silica gel Inorganic materials 0.000 description 72
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 67
- 239000012071 phase Substances 0.000 description 64
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 55
- 229910052938 sodium sulfate Inorganic materials 0.000 description 55
- 235000011152 sodium sulphate Nutrition 0.000 description 55
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 54
- 239000003480 eluent Substances 0.000 description 47
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 46
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 42
- 229910052786 argon Inorganic materials 0.000 description 41
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 37
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- 238000001035 drying Methods 0.000 description 33
- 239000012043 crude product Substances 0.000 description 31
- 238000004128 high performance liquid chromatography Methods 0.000 description 28
- 238000004440 column chromatography Methods 0.000 description 27
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 26
- 102000012336 Cholesterol Ester Transfer Proteins Human genes 0.000 description 25
- 108010061846 Cholesterol Ester Transfer Proteins Proteins 0.000 description 25
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical group CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 25
- 238000002953 preparative HPLC Methods 0.000 description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 23
- 238000001514 detection method Methods 0.000 description 23
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- KHYAFFAGZNCWPT-UHFFFAOYSA-N boron;n,n-diethylaniline Chemical compound [B].CCN(CC)C1=CC=CC=C1 KHYAFFAGZNCWPT-UHFFFAOYSA-N 0.000 description 21
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 21
- 235000019341 magnesium sulphate Nutrition 0.000 description 21
- 239000000047 product Substances 0.000 description 21
- 238000000746 purification Methods 0.000 description 21
- 229960004592 isopropanol Drugs 0.000 description 20
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 19
- 238000012360 testing method Methods 0.000 description 19
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 17
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 16
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 16
- 239000005557 antagonist Substances 0.000 description 16
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 238000004587 chromatography analysis Methods 0.000 description 14
- 230000000694 effects Effects 0.000 description 14
- 235000019253 formic acid Nutrition 0.000 description 13
- 108010010234 HDL Lipoproteins Proteins 0.000 description 12
- 102000015779 HDL Lipoproteins Human genes 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 11
- 238000000825 ultraviolet detection Methods 0.000 description 11
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 10
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
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- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000004059 squalene synthase inhibitor Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 108091008672 sterol hormone receptors Proteins 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical compound OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 229950007367 tanogitran Drugs 0.000 description 1
- 239000011975 tartaric acid Chemical class 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960000651 tasosartan Drugs 0.000 description 1
- ADXGNEYLLLSOAR-UHFFFAOYSA-N tasosartan Chemical compound C12=NC(C)=NC(C)=C2CCC(=O)N1CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 ADXGNEYLLLSOAR-UHFFFAOYSA-N 0.000 description 1
- 229960005187 telmisartan Drugs 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical class N1(CCCC2=CC=CC=C12)* 0.000 description 1
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical class C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- 229960005001 ticlopidine Drugs 0.000 description 1
- PHWBOXQYWZNQIN-UHFFFAOYSA-N ticlopidine Chemical compound ClC1=CC=CC=C1CN1CC(C=CS2)=C2CC1 PHWBOXQYWZNQIN-UHFFFAOYSA-N 0.000 description 1
- 229950004437 tiqueside Drugs 0.000 description 1
- COKMIXFXJJXBQG-NRFANRHFSA-N tirofiban Chemical compound C1=CC(C[C@H](NS(=O)(=O)CCCC)C(O)=O)=CC=C1OCCCCC1CCNCC1 COKMIXFXJJXBQG-NRFANRHFSA-N 0.000 description 1
- 229960003425 tirofiban Drugs 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 229960002051 trandolapril Drugs 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- UFXIRMVZNARBDL-UHFFFAOYSA-N trifluoro(morpholin-4-yl)-$l^{4}-sulfane Chemical compound FS(F)(F)N1CCOCC1 UFXIRMVZNARBDL-UHFFFAOYSA-N 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- 229910000406 trisodium phosphate Inorganic materials 0.000 description 1
- 235000019801 trisodium phosphate Nutrition 0.000 description 1
- SOBHUZYZLFQYFK-UHFFFAOYSA-K trisodium;hydroxy-[[phosphonatomethyl(phosphonomethyl)amino]methyl]phosphinate Chemical compound [Na+].[Na+].[Na+].OP(O)(=O)CN(CP(O)([O-])=O)CP([O-])([O-])=O SOBHUZYZLFQYFK-UHFFFAOYSA-K 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 229960004699 valsartan Drugs 0.000 description 1
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 229940019333 vitamin k antagonists Drugs 0.000 description 1
- 229960001729 voglibose Drugs 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- ZXIBCJHYVWYIKI-PZJWPPBQSA-N ximelagatran Chemical compound C1([C@@H](NCC(=O)OCC)C(=O)N2[C@@H](CC2)C(=O)NCC=2C=CC(=CC=2)C(\N)=N\O)CCCCC1 ZXIBCJHYVWYIKI-PZJWPPBQSA-N 0.000 description 1
- 229960001522 ximelagatran Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- GTJUPSNUGOBNMF-UHFFFAOYSA-M zinc;cyclopentane;bromide Chemical compound Br[Zn+].C1CC[CH-]C1 GTJUPSNUGOBNMF-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- 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
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
- A61P9/10—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/96—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings spiro-condensed with carbocyclic rings or ring systems
Definitions
- the present application relates to substituted chromanol derivatives, processes for their preparation, their use alone or in combinations for the treatment and / or prevention of diseases and their use for the preparation of medicaments for the treatment and / or prevention of diseases, in particular for the treatment and / or Prevention of cardiovascular diseases.
- HDL high-density lipoprotein
- LDL low-density lipoprotein
- VLDL very low-density lipoprotein
- High LDL cholesterol levels (> 160 mg / dl) and low HDL cholesterol levels ( ⁇ 40 mg / dl) contribute significantly to the development of arteriosclerosis [ATP HI Guidelines, Report of the NCEP Expert Panel].
- peripheral vascular disease and stroke are also promoted by unfavorable HDL / LDL ratios.
- New methods for increasing HDL cholesterol in the plasma therefore represent a therapeutically useful enrichment in the prevention and treatment of arteriosclerosis and the associated diseases.
- CETP Cholesterol ester transfer protein
- the present invention relates to compounds of the general formula (I)
- R 6 represents a substituent chosen from the series halogen, cyano, (C r C6) alkyl and (C r C6) alkoxy, wherein alkyl and alkoxy in turn can be substituted up to five times by fluorine,
- D is (C 3 -C 6) -AlkVl, (C 4 -C 8 ) -cycloalkyl, (C 4 -C 8 ) -cycloalkenyl, (C 6 -C 10 ) -aryl, 5- or 6-membered heteroaryl, tetrahydrofuranyl or tetrahydropyranyl, wherein
- Aryl and heteroaryl in turn with halogen, cyano, (C r C 6 ) alkyl, (C r C 6 ) alkoxy, trifluoromethyl or trifluoromethoxy
- Cycloalkyl and cycloalkenyl in turn may be substituted by fluorine or (C 1 -Ce) -AlkVl,
- R 1 is hydrogen, fluorine, hydroxyl, methoxy, mercapto or methyl
- R 2 is hydrogen
- R 1 and R 2 together with the carbon atom to which they are attached form a carbonyl group
- R 3 is (C 1 -C 6 ) alkyl or (C 3 -C 7 ) cycloalkyl
- R 4 and R 5 independently of one another represent hydrogen or (C 1 -C 4 ) -alkyl or together with the carbon atom to which they are attached form a spiro-linked 3- to 5-membered cycloalkyl ring,
- Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.
- the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers).
- the present invention includes therefore the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.
- the present invention encompasses all tautomeric forms.
- Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention.
- Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
- salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid acetic acid, trifluoroacetic acid, propionic acid
- Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, trisethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
- customary bases such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salt
- solvates are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
- the present invention also includes prodrugs of the compounds of the invention.
- prodrugs includes compounds which may themselves be biologically active or inactive, but during their residence time in the body are converted to compounds of the invention (for example metabolically or hydrolytically). Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:
- Alkyl radical having 1 to 4 carbon atoms is preferred.
- Alkyl radical having 1 to 4 carbon atoms is preferred.
- (C 1 -Cs) -alkoxy and (C 1 -Ca) -alkoxy are a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms. Preference is given to a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned by way of example include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert. Butoxy, n-pentoxy and n-hexoxy.
- (C 1 -C 4 -cycloalkyl) C 1 -C 4 -cycloalkyl and (C 1 -C 4 -cycloalkyl represent a monocyclic, saturated cycloalkyl group having 4 to 8, 3 to 7 or 3 to 6 carbon atoms
- (C4-CR) -cycloalkenyl in the context of the invention is a monocyclic cycloalkyl group having 4 to 8 carbon atoms and one double bond.
- Preferred is a cycloalkenyl radical having 5 or 6 carbon atoms. Examples which may be mentioned are cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
- (Cfi-C j n) -aryl is in the context of the invention an aromatic carbocycle having 6 or 10 ring carbon atoms.
- Preferred aryl radicals are phenyl and naphthyl.
- 5- or 6-membered heteroaryl is in the context of the invention for an aromatic heterocycle (heteroaromatic) with a total of 5 or 6 ring atoms containing one or two ring heteroatoms from the series N, O and / or S and a Ring carbon atom or optionally a ring nitrogen atom is linked.
- aromatic heterocycle heterocycle
- pyrrolyl thienyl
- pyrazolyl imidazolyl
- thiazolyl oxazolyl
- isoxazolyl isoxazolyl
- isothiazolyl pyridyl, pyrimidinyl, pyridazinyl and Pyrazinyl.
- Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine and fluorine.
- radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. Substitution with one, two or three identical or different substituents is preferred. Very particular preference is given to the substitution with a substituent.
- A is a group of the formula
- R 6 is a substituent selected from the group fluorine, chlorine, cyano, (Ci-C 4 ) -
- Alkyl and (C r C 4 ) alkoxy wherein alkyl and alkoxy in turn may be substituted up to five times with fluorine,
- n is the number 0, 1, 2 or 3
- D is phenyl, thienyl, furyl, cyclopentyl, cyclohexyl, cyclopentenyl or cyclohexenyl, wherein
- Phenyl, thienyl and furyl in turn with fluorine, chlorine, cyano, (Ci-C 4 ) alkyl, (C 1 -C 4 ) - alkoxy, trifluoromethyl or trifluoromethoxy - T - and
- Cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl may in turn be substituted by fluorine or (C 1 -C 4 ) -alkyl,
- R 1 is hydrogen, fluorine, hydroxy or methyl
- R 2 is hydrogen
- R 1 and R 2 together with the carbon atom to which they are attached form a carbonyl group
- R 3 is (C 3 -C 6 ) alkyl or (C 3 -C 6 ) cycloalkyl
- R 4 and R 5 independently of one another represent hydrogen or methyl or together with the carbon atom to which they are attached form a spiro-linked 3- to 5-membered cycloalkyl ring,
- A is a group of the formula
- R 6 is trifluoromethyl, trifluoromethoxy or tert-butyl
- D is phenyl, 4-fluorophenyl, cyclopentyl, cyclohexyl, cyclopent-1-en-1-yl or cyclohex-1-en-1-yl
- R 1 is hydrogen, fluorine or hydroxy
- R 2 is hydrogen
- R 1 and R 2 together with the carbon atom to which they are attached form a carbonyl group
- R 3 is isopropyl or cyclopentyl
- R 4 and R 5 are methyl or together with the carbon atom to which they are attached form a spiro-linked cyclopropyl or cyclobutyl ring,
- Another object of the invention is a process for the preparation of the inventive compounds of formula (I), characterized in that either
- R 7 is hydrogen, methyl or a conventional hydroxy protecting group such as AHyI, benzyl, tetrahydropyranyl or trialkylsilyl,
- Q is Li, -MgBr, -ZnBr or -B (OH) 2 ,
- X represents a leaving group such as, for example, chlorine, bromine, iodine, tosylate, mesylate or triflate,
- R 8 is hydrogen or (C r C 4) -alkyl or together are a -C (CH 3) 2 -C (CH 3) 2 bridge form two radicals,
- the chromanol hydroxy group may be temporarily protected by a conventional hydroxy-protecting group in these transformations, if necessary or convenient.
- a trialkylsilyl group is used for this purpose; particularly preferred is tert-butyldimethylsilyl.
- the introduction and removal of such protecting groups is carried out by known methods [see, e.g. T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999].
- tert-butyldimethylsilyl group preference is given to using tert-butyldimethylsilyl chloride or tert-butyldimethylsilyl trifluoromethanesulfonate in conjunction with triethylamine, N, N-diisopropylethylamine, pyridine, 2,6-lutidine or 4-N, N-dimethylaminopyridine as base ,
- the Cleavage of the tert.-butyldimethylsilyl group is preferably carried out with the aid of tetra-n-butylammonium fluoride (TBAP).
- TBAP tetra-n-butylammonium fluoride
- Suitable reducing agents for the reduction of ketones to secondary alcohols are, for example, complex aluminum or boron hydrides such as lithium, sodium, potassium, zinc borohydride, lithium aluminum hydride, diisobutylaluminum hydride (DIBAL-H), sodium bis (2-methoxyethoxy ) aluminum dihydride, Lithiumtrialkylborhydride or Lithiumtrialkoxyaluminium- hydride, or borane complexes such as borane-tetrahydrofuran, borane-dimethyl sulfide or borane-NN-diethylaniline complex.
- complex aluminum or boron hydrides such as lithium, sodium, potassium, zinc borohydride, lithium aluminum hydride, diisobutylaluminum hydride (DIBAL-H), sodium bis (2-methoxyethoxy ) aluminum dihydride, Lithiumtrialkylborhydride or Lithiumtrialkoxyaluminium- hydr
- Inert solvents for process steps (U) + (Iu) ⁇ (TV) and (X) + (UT) ⁇ (XI) are, for example, ethers, such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or hydrocarbons such as benzene, xylene, toluene, pentane, hexane, cyclohexane or petroleum fractions. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to tetrahydrofuran.
- the reactions (U) + (UT) ⁇ (IV) and (X) + (UI) ⁇ (XI) may optionally be advantageously carried out with the addition of dialkylzinc compounds or palladium or rhodium-phosphine complexes as catalysts [cf. e.g. M. Ueda and ⁇ . Miyaura, J. Org. Chem. 65, 4450-4452 (2000) and literature cited therein].
- the reactions are generally carried out in a temperature range of -80 0 C to +50 0 C, preferably at -80 0 C to 0 0 C.
- Suitable oxidizing agents in process step (IV) -> (V) are manganese (IV) oxide, pyridinium chlorochromate (PCC), N-methylmorpholine N-oxide, 2,2,6,6-tetramethylpiperidin-1-yloxy Radical (TEMPO) or Dess-Martin periodinane (1,1-dihydro-1,1,2-triacetoxy-1,2-benziodoxol-3 (1H) -On).
- Manganese (IV) oxide or Dess-Martin periodinan are preferably used.
- a trifiato group (trifluoromethylsulfonate) is preferably used.
- the phenol derivative (Va) or (Ha) in an inert solvent such as dichloromethane or dimethylformamide with trifluoromethanesulfonic anhydride or preferably reacted with N, N-bis (trifluoromethanesulphonyl) aniline in the presence of a base such as potassium carbonate, pyridine, 2,6-lutidine, 4-N, N-dimethylaminopyridine (DMAP), triethylamine or N, N-diisopropylethylamine.
- a base such as potassium carbonate, pyridine, 2,6-lutidine, 4-N, N-dimethylaminopyridine (DMAP), triethylamine or N, N-diisopropylethylamine.
- Inert solvents for process steps (VI) + (VII) ⁇ (VTfl) and (DC) + (VU) ⁇ (X) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol , Ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene Glykoldimethylether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethyl sulfoxide, N, N-dimethylpropyleneurea (DMPU), N-methylpyrrolidone ( ⁇ MP), pyridine, acetonitrile or water. It is likewise possible to use mixtures of the solvents mentioned. Dioxane is preferred.
- Suitable bases for the process steps (VI) + (VII) ⁇ (Vffl) and (DC) + (VIT) ⁇ (X) are customary inorganic bases. These include in particular alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal bicarbonates such as sodium or potassium bicarbonate, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali metal hydrogen phosphates such as disodium or dipotassium hydrogen phosphate, or Alkaline phosphates such as trisodium or tripotassium phosphate. Preferably, tripotassium phosphate is used.
- alkali metal hydroxides such as lithium, sodium or potassium hydroxide
- alkali metal bicarbonates such as sodium or potassium bicarbonate
- alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate
- alkali metal hydrogen phosphates such as disodium or
- the reactions (VI) + (VTT) ⁇ (VTTT) and (DC) + (VIT) ⁇ (X) are generally in a temperature range of +20 0 C to +150 0 C, preferably at +60 0 C to + 120 0 C performed.
- the reaction is generally carried out in toluene or in an ether such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, preferably in tetrahydrofuran, in a temperature range of -80 0 C to +50 0 C, preferably from 0 0 C to +30 0 C, performed.
- an ether such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, preferably in tetrahydrofuran, in a temperature range of -80 0 C to +50 0 C, preferably from 0 0 C to +30 0 C, performed.
- the fluorination in process step (XT) -> (XTT) and analogous reactions is generally carried out in a hydrocarbon such as benzene, toluene, xylene, pentane, hexane or cyclohexane, or in a halohydrocarbon such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-di - Chloroethane, trichlorethylene or chlorobenzene carried out as a solvent. Preference is given to toluene or dichloromethane.
- the fluorination reagent is preferably diethylaminosulfur trifluoride (DAST) or Morpholinoschwefeltrifluorid used.
- the reaction is generally carried out in a temperature range of -80 0 C to +40 0 C, preferably at -60 0 C to +20 0 C.
- the compounds of the formula (Ha) can be prepared by reacting a compound of the formula (XIII)
- X 1 represents a leaving group such as mesylate, tosylate or in particular triflate
- a triflate group (trifluoromethylsulfonate) is preferably used.
- the phenol derivative (XHI) in an inert solvent such as dichloromethane or dimethylformamide with trifluoromethanesulfonic anhydride or preferably with NN-bis (trifluoromethanesulfonyl) aniline in the presence of a base such as potassium carbonate , Pyridine, 2,6-lutidine, 4-N, N-dimethylaminopyridine (DMAP), triethylamine or N, N-diisopropylethylamine.
- a base such as potassium carbonate , Pyridine, 2,6-lutidine, 4-N, N-dimethylaminopyridine (DMAP), triethylamine or N, N-diisopropylethylamine.
- Inert solvents for process step (XIV) + (XVa) or (XVb) ⁇ (XVI) are, for example, ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, Toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethyl sulfoxide, N, N'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidone (NMP). It is likewise possible to use mixtures of the solvents mentioned. Preference is given to using dimethylformamide.
- DMPU N, N'-dimethylpropyleneurea
- NMP N-methylpyrrolidone
- Suitable catalysts for process step (XIV) + (XVa) or (XVb) ⁇ (XVI) ["Negishi-Kumada coupling”] are bis (diphenylphosphino) ferrocene-palladium (II) chloride or palladium (II). acetate in conjunction with triphenylphosphine, with addition of co-catalysts such as copper (I) iodide or lithium chloride, suitable [see. e.g. A. Weichert et al., Synlett, Al.> (1996) and references cited therein].
- the reaction is generally carried out in a temperature range from -20 0 C to +120 0 C, preferably at 0 0 C to +60 0 C.
- the Lewis acid suitable is, for example, titanium (IV) chloride, titanium (IV) isopropylate, Zmn (II) chloride or magnesium chloride.
- titanium (IV) chloride is used.
- boron trifluoride is particularly suitable as the Lewis acid.
- agents such as methanesulfonic acid or phosphorus pentoxide can be used.
- the reaction can be carried out in a hydrocarbon such as benzene, toluene, xylene, hexane or cyclohexane, or in a halohydrocarbon such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichlorethylene or chlorobenzene solvent or else without solvent.
- R 5A is hydrogen or (C 1 -C 4 ) -alkyl
- R 5A has the abovementioned meaning
- X 2 represents a leaving group such as tosylate, mesylate or in particular triflate
- the leaving group X 2 is preferably a triflate group (trifluoromethylsulfonate).
- a triflate group trifluoromethylsulfonate
- the phenol derivative (XX) in an inert solvent such as dichloromethane or dimethylformamide with trifluoromethanesulfonic anhydride or preferably with NN-bis (trifluoromethanesulfbnyl) aniline in the presence of a base such as potassium carbonate, Pyridine, 2,6-lutidine, 4-N, N-dimethylaminopyridine (DMAP), triethylamine or N, N-diisopropylethylamine.
- a base such as potassium carbonate, Pyridine, 2,6-lutidine, 4-N, N-dimethylaminopyridine (DMAP), triethylamine or N, N-diisopropylethylamine.
- Inert solvents for process step (XXI) -> (XXII) are, for example, ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, toluene, xylene, hexane,
- Cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethyl sulfoxide, NN'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone ( ⁇ MP) or acetonitrile.
- Examples of catalysts for process step (XXI) ⁇ (XXS) ["Heck-coupling”] are palladium ( ⁇ ) -acetate or palladium ( ⁇ ) -trifluoroacetate, in combination with triphenyl- or tritolyl- phosphine, or bis (dibenzylideneacetone) palladium (0).
- the reaction is carried out with the addition of a base such as potassium carbonate or NN-diisopropylethylamine.
- the reaction is generally carried out in a temperature range from + 2O 0 C to +120 0 C, preferably at + 40 0 C to + 100 0 C.
- LiAlH 4 , THF, RT; d): (1 ⁇ , 25) -aminoindanol, borane-N, N-diethylaniline complex, THF, RT (when R 6 CF 3 )].
- the compounds according to the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.
- the compounds according to the invention open up a further treatment alternative and represent an enrichment of the pharmaceutical industry.
- the compounds according to the invention show an improved spectrum of activity. They are characterized by high specificity and good compatibility.
- An advantage of the compounds according to the invention is in particular their high activity in human plasma. At the same time they have as a further advantage a reduced deposition behavior in adipose tissue.
- the compounds of the invention are potent inhibitors of cholesterol ester transfer protein (CETP) and stimulate reverse cholesterol transport. They cause an increase in HDL cholesterol levels in the blood.
- CETP cholesterol ester transfer protein
- the compounds according to the invention can be used in particular for the treatment and primary or secondary prevention of coronary heart diseases, for example of myocardial infarction, angina pectoris, cardiac insufficiency, myocardial insufficiency, pulmonary hypertension and ischemia-related damage to the heart (acute coronary syndrome).
- coronary heart diseases for example of myocardial infarction, angina pectoris, cardiac insufficiency, myocardial insufficiency, pulmonary hypertension and ischemia-related damage to the heart (acute coronary syndrome).
- the compounds according to the invention can be used for the treatment and prevention of arteriosclerosis, peripheral vascular diseases, restenosis, strokes and Alzheimer's disease.
- the compounds according to the invention can also be used for the treatment and prevention of hypolipoproteinemias, dyslipidemias, hypertriglyceridemias, hyperlipidemias, hypercholesterolemias, obesity, obesity, pancreatitis, insulin-dependent and non-insulin-dependent diabetes, diabetic late effects such as Retinopathy, nephropathy and neuropathy, combined hyperlipidaemias and the metabolic syndrome.
- the pharmacological activity of the compounds according to the invention can be determined by means of the CETP inhibition tests listed below.
- Another object of the present invention is the use of the compounds of the invention for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
- Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
- Another object of the present invention is a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.
- the compounds of the invention may be used alone or as needed in combination with other agents.
- Another object of the present invention are pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, for the treatment and / or prevention of the aforementioned Erkran- kung.
- suitable combination active ingredients may be mentioned by way of example and preferably:
- the compounds of the invention may preferably be with one or more
- Antithrombotic agents by way of example and preferably from the group of platelet aggregation inhibitors or anticoagulants,
- Hypertensive agents for example and preferably from the group of calcium antagonists, angiotensin AH antagonists, ACE inhibitors, renin inhibitors, beta-receptor blockers, alpha-receptor blockers, phosphodiesterase inhibitors, stimulators of the soluble guanylate cyclase, cGMP level enhancers, adenosine receptor agonists, aldosterone antagonists, mineralocorticoid receptor antagonists, endothelin antagonists, ECE inhibitors, vasopeptidase inhibitors and diuretics, and / or
- the fat metabolism-altering agents by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors, squalene synthase inhibitors, squalene epoxidase inhibitors or oxydosqualene cyclase inhibitors, the ACAT inhibitors, MTP Inhibitors, PPAR agonists, fibrates, lipase inhibitors, cholesterol absorption inhibitors, bile acid reabsorption inhibitors, polymeric bile acid adsorbers, lipoprotein (a) antagonists, RXR modulators, FXR modulators, LXR modulators, ATP citrate lyase inhibitors , Cannabinoid receptor 1 antagonists, leptin receptor agonists, bombesin receptor agonists, histamine receptor agonists, and antioxidants / radical scavengers
- cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors,
- Antidiabetics are understood by way of example and preferably as meaning insulin and insulin derivatives, as well as orally active hypoglycemic agents.
- Insulin and insulin derivatives here include both insulins of animal, human or biotechnological origin as well as mixtures thereof.
- the orally active hypoglycemic agents include, by way of example and by way of illustration, sulfonylureas, biguadins, meglitinide derivatives, oxadiazolidinones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-I agonists, DPPIV inhibitors, ghrelin receptor antagonists , CCK1 receptor agonists, leptin receptor agonists, insulin sensitizers, hepatic enzyme inhibitors involved in the stimulation of gluconeogenesis and / or glycogenolysis, modulators of glucose uptake and potassium channel openers, such as those described in WO 97/26265 and WO 99/03861.
- the compounds according to the invention are administered in combination with insulin.
- the compounds according to the invention are administered in combination with a sulphonylurea, such as, by way of example and by way of preference, tolbutamide, glibenclamide, glimepiride, glipizide or gliclazide.
- a sulphonylurea such as, by way of example and by way of preference, tolbutamide, glibenclamide, glimepiride, glipizide or gliclazide.
- the compounds according to the invention are administered in combination with a biguanide, such as by way of example and preferably metformin.
- the compounds according to the invention are administered in combination with a meglitinide derivative, such as by way of example and preferably repagolinide or nateglinide.
- a meglitinide derivative such as by way of example and preferably repagolinide or nateglinide.
- the compounds according to the invention are administered in combination with a PPARgamma agonist, for example from the class of thiazolidinediones, such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
- a PPARgamma agonist for example from the class of thiazolidinediones, such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
- the compounds according to the invention are used in combination with a mixed PPARalpha / gamma agonist such as, for example and preferably, GI-262570 (Farglitazar), GW 2331, GW 409544, AVE 8042, AVE 8134, AVE 0847, MK-0767 (KRP-297) or AZ-242.
- a mixed PPARalpha / gamma agonist such as, for example and preferably, GI-262570 (Farglitazar), GW 2331, GW 409544, AVE 8042, AVE 8134, AVE 0847, MK-0767 (KRP-297) or AZ-242.
- the compounds according to the invention are administered in combination with a glucosidase-inhibitor, such as, by way of example and by way of preference, acarbene, adiposin, voglibose or miglitol.
- a glucosidase-inhibitor such as, by way of example and by way of preference, acarbene, adiposin, voglibose or miglitol.
- the compounds according to the invention are administered in combination with a DPPIV inhibitor, such as, for example and preferably, vildaglipitin or sitaglipitin.
- a DPPIV inhibitor such as, for example and preferably, vildaglipitin or sitaglipitin.
- Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors, such as, for example and preferably, aspirin, clopidogrel, ticlopidine or dipyridamole, or anticoagulants.
- the compounds according to the invention are administered in combination with a thrombin inhibitor, such as by way of example and preferably ximelagatran, melagatran, dabigatran, tanogitran, bivalirudin or clexane.
- a thrombin inhibitor such as by way of example and preferably ximelagatran, melagatran, dabigatran, tanogitran, bivalirudin or clexane.
- the compounds according to the invention are administered in combination with a GPUb / IIIa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab.
- the compounds according to the invention are administered in combination with a factor Xa inhibitor, such as, by way of example and by way of preference, apixaban, razaxaban, otamixaban or rivaroxaban.
- a factor Xa inhibitor such as, by way of example and by way of preference, apixaban, razaxaban, otamixaban or rivaroxaban.
- the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
- LMW low molecular weight
- the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.
- antihypertensive agents are, by way of example and by way of example, compounds from the group of calcium antagonists, such as, for example, the compounds nifedipine, amlodipine, nitrendipine, nisoldipine, verapamil or diltiazem, the angiotensin Aü antagonists, ACE inhibitors, renin inhibitors, Beta-blockers, alpha-blockers and diuretics understood.
- compounds from the group of calcium antagonists such as, for example, the compounds nifedipine, amlodipine, nitrendipine, nisoldipine, verapamil or diltiazem, the angiotensin Aü antagonists, ACE inhibitors, renin inhibitors, Beta-blockers, alpha-blockers and diuretics understood.
- the compounds according to the invention are administered in combination with reserpine, minoxidil, diazoxide, dihydralazine, hydralazine or nitric oxide-releasing substances, such as, by way of example and by way of preference, glycerol nitrate or nitroprusside sodium.
- the compounds according to the invention are administered in combination with an angiotensin Aü antagonist, such as by way of example and preferably losartan, valsartan, candesartan, telmisartan, embusartan, irbesartan, olmesartan, tasosartan or saprisartan.
- an ACE inhibitor such as by way of example and preferably enalapril, captopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandolapril.
- the compounds according to the invention are administered in combination " with a renin inhibitor, such as by way of example and preferably aliskiren.
- the compounds according to the invention are administered in combination with a beta-blocker, such as, by way of example and by way of preference, propranolol or atenolol.
- a beta-blocker such as, by way of example and by way of preference, propranolol or atenolol.
- the compounds according to the invention are administered in combination with a diuretic, such as by way of example and preferably furosemide.
- lipid metabolizing agents are exemplified and preferably compounds from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR agonists, fibrates, Cholesterol absorption inhibitors, bile acid reabsorption inhibitors, lipase inhibitors, polymeric bile acid adsorber, lipoprotein antagonists and the cannabinoid receptor 1 antagonists understood.
- cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors
- ACAT inhibitors such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors
- MTP inhibitors MTP inhibitors
- PPAR agonists PPAR agonists
- fibrates Cholesterol absorption inhibitors
- bile acid reabsorption inhibitors bile acid reabsorption inhibitors
- the compounds according to the invention are administered in combination with a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronm (T3), CGS 23425 or axitirome (CGS 26214) ,
- a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronm (T3), CGS 23425 or axitirome (CGS 26214) ,
- the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK 475.
- a squalene synthesis inhibitor such as by way of example and preferably BMS-188494 or TAK 475.
- the compounds according to the invention are administered in combination with an ACAT inhibitor, such as by way of example and preferably avasimibe, eflucimibe or CS-505.
- an ACAT inhibitor such as by way of example and preferably avasimibe, eflucimibe or CS-505.
- the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
- a cholesterol absorption inhibitor such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
- the compounds according to the invention are administered in combination with a bile acid reabsorption inhibitor, such as by way of example and by way of preference barixibat, AZD 7508, SC 435, SC 635, S-8921, 264W94 or HM 1453.
- the compounds according to the invention are administered in combination with an MTP inhibitor, such as by way of example and preferably implitapide, BMS-201038 or R-103757.
- an MTP inhibitor such as by way of example and preferably implitapide, BMS-201038 or R-103757.
- the compounds of the invention are administered in combination with a PPARalpha agonist, e.g. the fibrates fenofibrate, clofibrate, bezafibrate, ciprofibrate or gemfibrozil, or as exemplified and preferably GW 9578, GW 7647, LY-518674 or NS-220.
- a PPARalpha agonist e.g. the fibrates fenofibrate, clofibrate, bezafibrate, ciprofibrate or gemfibrozil, or as exemplified and preferably GW 9578, GW 7647, LY-518674 or NS-220.
- the compounds according to the invention are administered in combination with a PPARdelta agonist, such as by way of example and preferably GW 501516.
- the compounds according to the invention are administered in combination with a mixed PPARalpha / gamma agonist such as, for example and preferably, GI-262570 (Farglitazar), GW 2331, GW 409544, AVE 8042, AVE 8134, AVE 0847, MK No. 0767 (KRP-297) or AZ-242.
- a mixed PPARalpha / gamma agonist such as, for example and preferably, GI-262570 (Farglitazar), GW 2331, GW 409544, AVE 8042, AVE 8134, AVE 0847, MK No. 0767 (KRP-297) or AZ-242.
- the compounds of the invention are administered in combination with a mixed PPARalpha / gamma / delta agonist, as exemplified and preferably MCC-555.
- the compounds according to the invention are used in combination with a lipase inhibitor from the group of endothelial lipase inhibitors, pancreatic lipase inhibitors, gastric lipase inhibitors, hormone-sensitive lipase inhibitors or hepatic lipase inhibitors. Administered inhibitors.
- the compounds according to the invention are administered in combination with an inhibitor of pancreatic lipase, preferably from the class of lipstins such as, for example, orlistat.
- the compounds according to the invention are administered in combination with a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
- a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
- the compounds according to the invention are administered in combination with a lipoprotein (a) antagonist, such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
- a lipoprotein (a) antagonist such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
- the compounds according to the invention are administered in combination with a cannabinoid receptor 1 antagonist, such as by way of example and preferably rimonabant.
- a cannabinoid receptor 1 antagonist such as by way of example and preferably rimonabant.
- the compounds according to the invention are administered in combination with an antagonist of the niacin receptor, such as by way of example and preferably Niaspan, Acipimox or Niceritrol.
- the compounds according to the invention are administered in combination with an antioxidant, such as, by way of example and by way of preference, probucol, AGI 1067 or Bo 653.
- an antioxidant such as, by way of example and by way of preference, probucol, AGI 1067 or Bo 653.
- the compounds according to the invention are administered in combination with an LDL receptor inducer, such as, for example, Lifibrol.
- an LDL receptor inducer such as, for example, Lifibrol.
- the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins such as, for example and preferably, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin.
- statins such as, for example and preferably, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin.
- Another object of the present invention are combinations of the compounds of the invention with substances that cause a reduction in HMG-CoA reductase gene expression.
- substances may, for example, be inhibitors of HMG-CoA reductase transcription or of HMG-CoA reductase translation.
- Inhibition of HMG-CoA reductase gene expression can be caused, for example, by inhibition of the SlP (site I) protease or by lowering the SREBP (sterol receptor binding protein) levels.
- Another object of the present invention are combinations of the compounds of the invention with substances which have anti-inflammatory and / or the atherosclerotic plaque stabilizing effect.
- substances may be, for example, agents from the class of NSAIDs, the Lp-PLA 2 antagonists or the chemokine receptor antagonists, such as IL-8 receptor antagonists or MCP-1 antagonists by way of example.
- the compounds according to the invention are administered in combination with an Lp-PLA 2 antagonist, such as by way of example and preferably darapladib or goxalapladib.
- the active compound combinations according to the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases.
- the active compound combinations according to the invention are in particular for the treatment and for the primary or secondary prevention of coronary heart diseases, e.g. Myocardial infarction, angina pectoris, heart failure, myocardial insufficiency, pulmonary hypertension and ischemia-related damage to the heart (acute coronary syndrome) can be used. They can also be used to treat and prevent atherosclerosis, peripheral vascular disease, restenosis, strokes and Alzheimer's disease.
- coronary heart diseases e.g. Myocardial infarction, angina pectoris, heart failure, myocardial insufficiency, pulmonary hypertension and ischemia-related damage to the heart (acute coronary syndrome) can be used. They can also be used to treat and prevent atherosclerosis, peripheral vascular disease, restenosis, strokes and Alzheimer's disease.
- the active substance combinations mentioned can also be used for the treatment and prevention of hypolipoproteinemias, dyslipidaemias, hypertriglyceridemias, hyperlipidemias, hypercholesterolemias, obesity (adipositas), obesity, pancreatitis, insulin-dependent and non-insulin-dependent diabetes, diabetic late effects, such as retinopathy, nephropathy and neuropathy, combined hyperlipidaemias and the metabolic syndrome.
- the active compound combinations according to the invention are suitable for the treatment of hypertension as well as of inflammatory diseases.
- compositions containing at least one compound of the invention usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
- the compounds according to the invention can act systemically and / or locally.
- they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.
- the compounds according to the invention can be administered in suitable administration forms.
- the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved
- Contain mold such as tablets (uncoated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings controlling the release of the compound of the invention), rapidly disintegrating tablets or films / wafers, films / lyophilisates, capsules (eg hard or soft gelatin capsules), dragees, granules, pellets, powders , Emulsions, suspensions, aerosols or solutions.
- Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
- a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
- absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
- parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
- Inhalation medicaments including powder inhalers, nebulizers
- nasal drops solutions or sprays
- lingual, sublingual or buccal tablets films / wafers or capsules
- suppositories ear or ophthalmic preparations
- vaginal capsules aqueous suspensions (lotions, shake mixtures)
- lipophilic suspensions ointments
- creams transdermal therapeutic systems (eg plasters)
- milk pastes, foams, powdered powders, implants or stents.
- the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
- excipients for example microcrystalline cellulose, lactose, mannitol
- solvents for example liquid polyethylene glycols
- emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitanoleate
- binders for example polyvinylpyrrolidone
- synthetic and natural polymers for example albumin
- Stabilizers eg, antioxidants such as ascorbic acid
- dyes eg, inorganic pigments such as iron oxides
- flavor and / or odoriferous include, among others.
- Excipients for example microcrystalline cellulose, lactose, mannitol
- solvents for example liquid polyethylene glycols
- emulsifiers and dispersants or wetting agents for example sodium dodecy
- the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight.
- UV ultraviolet spectrometry v / v volume to volume ratio (of a solution) w / v weight to volume ratio (of a solution)
- Device Type Abimed Gilson 305; Column: YMC GEL ODS-AQS-5/15 ⁇ m, 250 mm x 30 mm; Mobile phase: gradient acetonitrile / water 50:50 ⁇ 80:20 (15 min) ⁇ 95: 5 (27 min); Flow: 40 ml / min; UV detection: 210 nm.
- Method 4 (analytical HPLC, chiral): Device type: HP 1100; Column: Chiralpak IA, 250 mm x 4.6 mm; Mobile phase: isopropanol / isohexane 3:97; Flow: 1.5 ml / min; Temperature: 24 ° C; UV detection: 254 nm.
- Device type MS Micromass ZQ
- Device type HPLC Waters Alliance 2795; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A -> 2.5 min 30% A ⁇ 3.0 min 5% A ⁇ 4.5 min 5% A; Flow: 0.0 min 1 ml / min ⁇ 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C .; UV detection: 210 nm.
- Method 8 (LC / MS): Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A - »2.5 min 30% A ⁇ 3.0 min 5% A ⁇ 4.5 min 5% A; Flow: 0.0 min 1 ml / min ⁇ 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C .; UV detection: 208-400 nm.
- Device type MS Micromass ZQ
- Device type HPLC HP 1100 Series
- UV DAD Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20 mm x 4 mm
- Eluent A 1 liter of water + 0.5 ml of 50% ant acid
- eluent B 1 liter acetonitrile + 0.5 ml 50% formic acid
- Flow 0.0 min 1 ml / min ⁇ 2.5 min / 3.0 min / 4.5 min 2 ml / min
- Oven 50 ° C .
- UV detection 210 nm.
- Method 10 Instrument: Micromass GCT, GC 6890; Column: Restek RTX-35MS, 30 m ⁇ 250 ⁇ m ⁇ 0.25 ⁇ m; constant flow with helium: 0.88 ml / min; Oven: 60 ° C; Inlet: 25O 0 C; Gradient: 60 0 C (0.30 keep min), 50 ° C min ⁇ 120 0 C, 16 ° C min ⁇ 250 0 C, 30 ° C (1.7 min hold) / / / min ⁇ 300 0C.
- Example 4A and Example 5A are Example 4A and Example 5A.
- Example 7A 100 mg (0.22 mmol) of 7-cyclopentyl-6- ⁇ hydroxy [4- (trifluoromethyl) phenyl] methyl ⁇ -5-methoxy-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 7A) are dissolved in 5 ml of dichloromethane, mixed with 194 mg (2.23 mmol) of manganese (IV) oxide and the mixture is stirred overnight at room temperature. It is filtered through a silica gel layer, washed well with ethyl acetate and the filtrate is concentrated to dryness.
- Example 14A [(45) -4 - ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ -7-cyclopentyl-5- (4-fluorophenyl) -2,2-dimethyl-3,4-dihydro-2H chromen-6-yl] [4- (trifluoromethyl) phenyl] methanol
- the crude product obtained is purified by preparative thick-layer chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 5: 1). There are obtained 47 mg (46% of theory) of the title compound, which is used without further characterization in the next stage.
- Example 15A tert. Butyl [((4S) -7-cyclopentyl-5- (4-fluoro-phenyl) -6-fluoro [4- (trifluoromethyl) -phenyl] -methyl ⁇ -2,2-dimethyl-3,4-dihydro-2H-chroma -4-yl) oxy] dimethylsilane
- Example 21 A rac-5- (4-fluorophenyl) -6- ⁇ hydroxy [4- (trifluoromethyl) phenyl] methyl ⁇ -7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromene-4- on
- Example 22A rac-5- (4-Fluoro-phenyl) -6- ⁇ fluoro [4- (trifluoromethyl) -phenyl] -methyl ⁇ -7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one
- the filtrate is concentrated and the residue is purified by column chromatography on silica gel (mobile phase: gradient cyclohexane ⁇ cyclohexane / ethyl acetate 20: 1 ⁇ 10: 1).
- the resulting product is combined with the crystals.
- the compound is in the form of two atropisomers (1: 1).
- Example 38A rac-5-cyclopent-1-yl-6- ⁇ - hydroxy [4- (trifluoromethyl) phenyl] methyl ⁇ -7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one
- the resulting product is treated with 230 ml (2.99 mol) of trifluoroacetic acid, heated to 75 ° C and stirred for 8 hours. It is then cooled, mixed with water and extracted several times with ethyl acetate. The combined organic phases are washed twice with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue is purified on silica gel (eluent: dichloromethane / methanol 100: 1 -> 100: 3). The product fractions are combined and concentrated. The resulting residue is treated with dichloromethane, stirred briefly and the precipitate is filtered off with suction and dried under high vacuum. This gives 2.25 g (5% of theory) of the target compound. The mother liquor is then purified again over a silica gel column (eluent: dichloromethane / methanol 100: 1). In this way, a further 3.41 g (7% of theory) of the title compound are obtained.
- the mixture After stirring for a total of 5 hours, the mixture is mixed with ammonium chloride solution. It is diluted with water and ethyl acetate, the organic phase separated and the aqueous phase extracted twice more with ethyl acetate. The combined organic phases are washed twice with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue is applied to silica gel and purified over a silica gel column (mobile phase: cyclohexane / ethyl acetate 30: 1). There are obtained 28 g (80% of theory) of the title compound.
- Example 44A The title compound is prepared analogously to Example 44A from 5.5 g of the compound from Example 43 A. 5.4 g (60% of theory) of the target product are obtained.
- Example 45A The title compound is prepared analogously to Example 46A from 5.4 g of 5-hydroxy-4-oxo-S ⁇ -dihydrospirofchromen ⁇ l-cyclopropan ⁇ -yl-irifluormethansulfonat (Example 45A). There are obtained 5.4 g (89% of theory) of the target product with a purity of about 87%.
- the main impurity is the propropylene isomer:
- the main impurity is the propropylene isomer:
- aqueous phase is extracted three times with ethyl acetate and the combined organic phases are washed twice with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated.
- the residue is applied to silica gel and purified over a silica gel column (mobile phase: cyclohexane / ethyl acetate 50: 1 ⁇ 20: 1). 1.42 g (42% of theory) of the title compound are obtained.
- a mixed fraction is purified again over silica gel as described above. In this way, a further 1.94 g (39% of theory) of the target compound having a purity of 65% are obtained.
- the main impurity is the propropylene isomer:
- the residue is taken up in 10 ml of ethanol, treated again with the same amount of rhodium on activated charcoal and hydrogenated for a further 18 hours under a hydrogen pressure of 60 bar at room temperature.
- the suspension is again filtered through kieselguhr, washed with ethyl acetate and the filtrate is concentrated under reduced pressure.
- the crude product is purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 15: 1).
- Example 5 and Example 6 (4S) -5- (4-Fluoro-phenyl) -6 - ⁇ (6) -hydroxy [4- (trifluoromethyl) -phenyl] -methyl ⁇ -7-isopropyl-2,2-dimethylchroman-4- ol (Example 5)
- Example 7 and Example 8 (4S) -5- (4-Fluoro-phenyl) -6 - ⁇ (S) -fluoro [4- (trifluoromethyl) -phenyl] -methyl ⁇ -7-isopropyl-2,2-dimethylchroman-4 ol ⁇ Example 7)
- the enantiomer of the target product is [(4i) -5- (4-fluorophenyl) -4-hydroxy-7-isopropyl-2,2-dimethyl-3,4-dihydro-2H-chromene -6-yl] [4- (trifluoromethoxy) phenyl] methanone, obtained:
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DE102006012548A DE102006012548A1 (en) | 2006-03-18 | 2006-03-18 | Substituted chromanol derivatives and their use |
PCT/EP2007/001930 WO2007107243A1 (en) | 2006-03-18 | 2007-03-07 | Substituted chromanol derivatives and their use |
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EP07711808A Withdrawn EP1999123A1 (en) | 2006-03-18 | 2007-03-07 | Substituted chromanol derivatives and their use |
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US (1) | US8227511B2 (en) |
EP (1) | EP1999123A1 (en) |
JP (1) | JP5285594B2 (en) |
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CR (1) | CR10305A (en) |
DE (1) | DE102006012548A1 (en) |
DO (1) | DOP2007000043A (en) |
EC (1) | ECSP088745A (en) |
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PE (1) | PE20080005A1 (en) |
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EP2025674A1 (en) | 2007-08-15 | 2009-02-18 | sanofi-aventis | Substituted tetra hydro naphthalines, method for their manufacture and their use as drugs |
GEP20125707B (en) * | 2007-12-18 | 2012-12-10 | Glenmark Pharmaceuticals Sa | Chromane derivatives as trpv3 modulators |
WO2011072064A1 (en) | 2009-12-08 | 2011-06-16 | Array Biopharma Inc. | S piro [chroman - 4, 4 ' - imidazol] ones as beta - secretase inhibitors |
US8933024B2 (en) | 2010-06-18 | 2015-01-13 | Sanofi | Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases |
WO2012120054A1 (en) | 2011-03-08 | 2012-09-13 | Sanofi | Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
WO2012120056A1 (en) | 2011-03-08 | 2012-09-13 | Sanofi | Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof |
US8901114B2 (en) | 2011-03-08 | 2014-12-02 | Sanofi | Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof |
WO2012120055A1 (en) | 2011-03-08 | 2012-09-13 | Sanofi | Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
WO2012120053A1 (en) | 2011-03-08 | 2012-09-13 | Sanofi | Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
US9938228B2 (en) * | 2014-09-09 | 2018-04-10 | Boehringer Ingelheim International Gmbh | Process for the preparation of spiro[2.5]octane-5,7-dione and spiro[3.5]nonane-6,8-dione |
CN105501108B (en) | 2014-10-08 | 2020-07-07 | 福特全球技术公司 | Vehicle lighting system with illuminated wheel assembly |
CN105546443B (en) | 2014-10-27 | 2019-10-18 | 福特全球技术公司 | The Vehicular illumination system of exhaust apparatus with illumination |
CN112326830A (en) * | 2020-11-03 | 2021-02-05 | 湖南迪诺制药股份有限公司 | Method for detecting atorvastatin calcium isomer |
WO2022238335A1 (en) | 2021-05-12 | 2022-11-17 | Boehringer Ingelheim International Gmbh | Pyridine derivatives with c-linked cyclic substituents as cgas inhibitors |
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DE19610932A1 (en) | 1996-03-20 | 1997-09-25 | Bayer Ag | 2-aryl substituted pyridines |
DE19619614A1 (en) * | 1996-05-15 | 1997-11-20 | Hoechst Ag | New sulphonamide derivatives of chroman |
DE19627431A1 (en) | 1996-07-08 | 1998-01-15 | Bayer Ag | Heterocyclically fused pyridines |
HRP970330B1 (en) | 1996-07-08 | 2004-06-30 | Bayer Ag | Cycloalkano pyridines |
US6207671B1 (en) | 1996-07-08 | 2001-03-27 | Bayer Aktiengesellschaft | Cycloalkano-pyridines |
DE19627430A1 (en) | 1996-07-08 | 1998-01-15 | Bayer Ag | Bicyclic condensed pyridines |
AR008789A1 (en) | 1996-07-31 | 2000-02-23 | Bayer Corp | PIRIDINES AND SUBSTITUTED BIPHENYLS |
DE19704244A1 (en) | 1997-02-05 | 1998-08-06 | Bayer Ag | 5-hydroxy-alkyl substituted phenyls |
DE19709125A1 (en) | 1997-03-06 | 1998-09-10 | Bayer Ag | Substituted quinolines |
MA24643A1 (en) * | 1997-09-18 | 1999-04-01 | Bayer Ag | SUBSTITUTED TETRAHYDRO-NAPHTHALENES AND SIMILAR COMPOUNDS |
DE19741051A1 (en) | 1997-09-18 | 1999-03-25 | Bayer Ag | New tetrahydroquinoline derivatives useful in treatment of raised lipid levels and arteriosclerosis |
DE19741399A1 (en) | 1997-09-19 | 1999-03-25 | Bayer Ag | New tetrahydroquinoline derivatives useful in treatment of elevated lipid levels and arteriosclerosis |
DE19935966A1 (en) | 1999-07-30 | 2001-02-01 | Bayer Ag | Process for the reduction of keto alcohols |
DE10148436A1 (en) | 2001-10-01 | 2003-04-17 | Bayer Ag | Tetrahydroquinolines |
DE10250687A1 (en) | 2002-10-31 | 2004-05-13 | Bayer Ag | 7H-Dibenzo (b, g) (1,5) dioxocin-5-one derivatives and their use |
SI1828137T1 (en) | 2004-12-18 | 2012-08-31 | Bayer Pharma AG | 4-cycloalkyl-substituted tetrahydrochinoline derivatives and use thereof as medicaments |
JP2008524137A (en) | 2004-12-18 | 2008-07-10 | バイエル・ヘルスケア・アクチェンゲゼルシャフト | (5S) -3-[(S) -Fluoro (4-trifluoromethylphenyl) methyl-5,6,7,8-tetrahydroquinolin-5-ol derivatives and their use as CETP inhibitors |
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AU2007229092A1 (en) | 2007-09-27 |
CN101443321A (en) | 2009-05-27 |
TW200812998A (en) | 2008-03-16 |
HK1132731A1 (en) | 2010-03-05 |
KR20090004997A (en) | 2009-01-12 |
CR10305A (en) | 2009-02-19 |
BRPI0708851A2 (en) | 2011-06-14 |
US8227511B2 (en) | 2012-07-24 |
JP5285594B2 (en) | 2013-09-11 |
KR101440633B1 (en) | 2014-09-22 |
DE102006012548A1 (en) | 2007-09-20 |
CN101443321B (en) | 2012-09-26 |
ZA200807809B (en) | 2009-11-25 |
MX2008011893A (en) | 2008-09-30 |
RU2459817C2 (en) | 2012-08-27 |
DOP2007000043A (en) | 2007-09-30 |
US20090306197A1 (en) | 2009-12-10 |
RU2008141240A (en) | 2010-04-27 |
JP2009530322A (en) | 2009-08-27 |
AR059831A1 (en) | 2008-04-30 |
UY30215A1 (en) | 2007-10-31 |
PE20080005A1 (en) | 2008-03-14 |
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