RU2247579C2 - Комбинированное лечение с применением бензотиепинов, ингибирующих транспорт желчной кислоты в подвздошной кишке, и ингибиторов hmg co-а редуктазы - Google Patents

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Publication number

RU2247579C2

RU2247579C2 RU99121514/15A RU99121514A RU2247579C2 RU 2247579 C2 RU2247579 C2 RU 2247579C2 RU 99121514/15 A RU99121514/15 A RU 99121514/15A RU 99121514 A RU99121514 A RU 99121514A RU 2247579 C2 RU2247579 C2 RU 2247579C2

Authority

RU

Russia

Prior art keywords

heteroaryl

heterocycle

quaternized

alkyl

aryl

Prior art date

1997-03-11

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• 239000003112 inhibitor Substances 0.000 title claims abstract description 39
• 239000003613 bile acid Substances 0.000 title claims abstract description 35
• 238000011282 treatment Methods 0.000 title claims abstract description 22
• HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 title claims abstract description 19
• 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 title abstract description 5
• 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 title abstract description 5
• 210000001630 jejunum Anatomy 0.000 title abstract 2
• 230000002401 inhibitory effect Effects 0.000 title description 6
• 239000000203 mixture Substances 0.000 claims abstract description 151
• 238000000034 method Methods 0.000 claims abstract description 100
• 238000002648 combination therapy Methods 0.000 claims abstract description 6
• 230000002402 anti-lipaemic effect Effects 0.000 claims abstract 3
• 125000000623 heterocyclic group Chemical group 0.000 claims description 182
• 125000001072 heteroaryl group Chemical group 0.000 claims description 173
• 150000001875 compounds Chemical class 0.000 claims description 163
• 125000000217 alkyl group Chemical group 0.000 claims description 129
• 125000003118 aryl group Chemical group 0.000 claims description 115
• 125000003342 alkenyl group Chemical group 0.000 claims description 106
• 125000000304 alkynyl group Chemical group 0.000 claims description 105
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 97
• -1 carboalkoxyalkyl Chemical group 0.000 claims description 95
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 69
• 229910052739 hydrogen Inorganic materials 0.000 claims description 63
• 125000001424 substituent group Chemical group 0.000 claims description 57
• 125000001188 haloalkyl group Chemical group 0.000 claims description 55
• 229920000728 polyester Polymers 0.000 claims description 51
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 48
• 108090000765 processed proteins & peptides Proteins 0.000 claims description 44
• 229910052736 halogen Inorganic materials 0.000 claims description 42
• 150000002367 halogens Chemical class 0.000 claims description 42
• 229910052757 nitrogen Inorganic materials 0.000 claims description 38
• 125000004043 oxo group Chemical group O=* 0.000 claims description 38
• 239000001257 hydrogen Substances 0.000 claims description 33
• 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 32
• 150000001413 amino acids Chemical class 0.000 claims description 27
• 150000001720 carbohydrates Chemical class 0.000 claims description 23
• 229920001184 polypeptide Polymers 0.000 claims description 22
• 102000004196 processed proteins & peptides Human genes 0.000 claims description 22
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
• 229910052799 carbon Inorganic materials 0.000 claims description 21
• 150000003839 salts Chemical class 0.000 claims description 21
• 239000008194 pharmaceutical composition Substances 0.000 claims description 19
• 229910052760 oxygen Inorganic materials 0.000 claims description 17
• 125000003545 alkoxy group Chemical group 0.000 claims description 16
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 14
• 125000004122 cyclic group Chemical group 0.000 claims description 14
• 210000003405 ileum Anatomy 0.000 claims description 14
• 229940123934 Reductase inhibitor Drugs 0.000 claims description 13
• 125000002252 acyl group Chemical group 0.000 claims description 12
• 125000004423 acyloxy group Chemical group 0.000 claims description 12
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 12
• 150000002431 hydrogen Chemical class 0.000 claims description 10
• 229940077672 Ileal bile acid transport inhibitor Drugs 0.000 claims description 9
• 125000004414 alkyl thio group Chemical group 0.000 claims description 9
• 238000011284 combination treatment Methods 0.000 claims description 9
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
• 150000001450 anions Chemical class 0.000 claims description 8
• 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims description 8
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 8
• 102000004316 Oxidoreductases Human genes 0.000 claims description 5
• 108090000854 Oxidoreductases Proteins 0.000 claims description 5
• 150000001768 cations Chemical class 0.000 claims description 5
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
• 239000000651 prodrug Substances 0.000 claims description 5
• 229940002612 prodrug Drugs 0.000 claims description 5
• 239000012453 solvate Substances 0.000 claims description 5
• 125000004964 sulfoalkyl group Chemical group 0.000 claims description 5
• 241000124008 Mammalia Species 0.000 claims description 4
• 125000004946 alkenylalkyl group Chemical group 0.000 claims description 4
• 125000005038 alkynylalkyl group Chemical group 0.000 claims description 4
• 125000003705 anilinocarbonyl group Chemical group O=C([*])N([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
• 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 claims description 4
• 150000001721 carbon Chemical group 0.000 claims description 4
• 125000004181 carboxyalkyl group Chemical group 0.000 claims description 4
• 125000004966 cyanoalkyl group Chemical group 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 4
• 125000001624 naphthyl group Chemical group 0.000 claims description 4
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
• 125000005504 styryl group Chemical group 0.000 claims description 4
• 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
• 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
• 125000002541 furyl group Chemical group 0.000 claims description 3
• 125000002883 imidazolyl group Chemical group 0.000 claims description 3
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 3
• 125000004193 piperazinyl group Chemical group 0.000 claims description 3
• 229960005235 piperonyl butoxide Drugs 0.000 claims description 3
• 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 claims description 3
• 238000011321 prophylaxis Methods 0.000 claims description 3
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
• 125000004076 pyridyl group Chemical group 0.000 claims description 3
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
• 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 3
• 125000001544 thienyl group Chemical group 0.000 claims description 3
• VCHLHEVUAZQAJZ-UHFFFAOYSA-N 2-(1h-pyrrol-2-yl)-1,3-oxazole Chemical compound C1=CNC(C=2OC=CN=2)=C1 VCHLHEVUAZQAJZ-UHFFFAOYSA-N 0.000 claims description 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 3
• XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims 3
• XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 claims 3
• TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 claims 3
• RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 claims 3
• 229960005370 atorvastatin Drugs 0.000 claims 3
• 229960003765 fluvastatin Drugs 0.000 claims 3
• 229960002965 pravastatin Drugs 0.000 claims 3
• TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 claims 3
• 229960002855 simvastatin Drugs 0.000 claims 3
• RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 claims 3
• 125000001151 peptidyl group Chemical group 0.000 claims 1
• 239000000126 substance Substances 0.000 abstract description 23
• 239000003814 drug Substances 0.000 abstract description 10
• 230000000694 effects Effects 0.000 abstract description 9
• 230000007721 medicinal effect Effects 0.000 abstract 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 238
• RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 201
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 158
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 156
• 239000000243 solution Substances 0.000 description 148
• 239000011541 reaction mixture Substances 0.000 description 112
• 239000000047 product Substances 0.000 description 106
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 102
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 90
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 75
• 238000006243 chemical reaction Methods 0.000 description 74
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 70
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 61
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 60
• 238000001819 mass spectrum Methods 0.000 description 58
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 57
• 239000007787 solid Substances 0.000 description 57
• 235000019439 ethyl acetate Nutrition 0.000 description 55
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 51
• 239000003921 oil Substances 0.000 description 47
• 235000019198 oils Nutrition 0.000 description 47
• 238000005481 NMR spectroscopy Methods 0.000 description 44
• HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 41
• 239000010410 layer Substances 0.000 description 40
• 239000012044 organic layer Substances 0.000 description 40
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 39
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 39
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 38
• 238000004128 high performance liquid chromatography Methods 0.000 description 37
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 33
• 239000012267 brine Substances 0.000 description 33
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 33
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 32
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
• 238000003756 stirring Methods 0.000 description 28
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 26
• OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 25
• 239000000741 silica gel Substances 0.000 description 25
• 229910002027 silica gel Inorganic materials 0.000 description 25
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 24
• 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 24
• 238000010992 reflux Methods 0.000 description 24
• RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 24
• 238000000746 purification Methods 0.000 description 23
• LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 22
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• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 22
• 239000000460 chlorine Substances 0.000 description 21
• LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 21
• 238000004809 thin layer chromatography Methods 0.000 description 20
• NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 18
• ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 18
• 239000007858 starting material Substances 0.000 description 18
• AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 18
• 235000012000 cholesterol Nutrition 0.000 description 17
• 239000000706 filtrate Substances 0.000 description 17
• 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 17
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• 238000007792 addition Methods 0.000 description 16
• 229910000027 potassium carbonate Inorganic materials 0.000 description 16
• NIGNBCLEMMGDQP-UHFFFAOYSA-N 1-benzothiepine Chemical class S1C=CC=CC2=CC=CC=C12 NIGNBCLEMMGDQP-UHFFFAOYSA-N 0.000 description 15
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• 239000003054 catalyst Substances 0.000 description 14
• 229920000642 polymer Polymers 0.000 description 14
• UOLPWQTZNSRMCK-UHFFFAOYSA-N 3-butyl-3-ethyl-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound OC1C(CCCC)(CC)CS(=O)(=O)C2=CC=CC=C2C1C1=CC=CC=C1 UOLPWQTZNSRMCK-UHFFFAOYSA-N 0.000 description 13
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 13
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• LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 12
• 238000002390 rotary evaporation Methods 0.000 description 12
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• GDVUGFJXFFCXMX-UHFFFAOYSA-N (2-ethyl-2-formylhexyl) methanesulfonate Chemical compound CCCCC(CC)(C=O)COS(C)(=O)=O GDVUGFJXFFCXMX-UHFFFAOYSA-N 0.000 description 11
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• ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 11
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• QLGASNJOKSCXCB-UHFFFAOYSA-N 3-butyl-3-ethyl-7-(hydroxyamino)-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound OC1C(CCCC)(CC)CS(=O)(=O)C2=CC=C(NO)C=C2C1C1=CC=CC=C1 QLGASNJOKSCXCB-UHFFFAOYSA-N 0.000 description 10
• 201000001320 Atherosclerosis Diseases 0.000 description 10
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• ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 9
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