SK287059B6 - 1,5-Benzotiazepíny, farmaceutická kompozícia a kombinácia, ktorá ich obsahuje, a ich použitie - Google Patents

Info

Publication number

SK287059B6

SK287059B6 SK776-2003A SK7762003A SK287059B6 SK 287059 B6 SK287059 B6 SK 287059B6 SK 7762003 A SK7762003 A SK 7762003A SK 287059 B6 SK287059 B6 SK 287059B6

Authority

SK

Slovakia

Prior art keywords

alkyl

group

phenyl

solvate

formula

Prior art date

2000-12-21

Links

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• KJFRSZASZNLCDF-UHFFFAOYSA-N 1,5-benzothiazepine Chemical class S1C=CC=NC2=CC=CC=C12 KJFRSZASZNLCDF-UHFFFAOYSA-N 0.000 title claims 2
• 239000008194 pharmaceutical composition Substances 0.000 title abstract description 12
• 150000001875 compounds Chemical class 0.000 claims abstract description 371
• 150000003839 salts Chemical class 0.000 claims abstract description 281
• 239000012453 solvate Substances 0.000 claims abstract description 275
• 238000000034 method Methods 0.000 claims abstract description 255
• 150000002148 esters Chemical class 0.000 claims abstract description 28
• 238000001727 in vivo Methods 0.000 claims abstract description 25
• 230000008569 process Effects 0.000 claims abstract description 15
• -1 nitro, cyano, hydroxy, amino, carboxy, carbamoyl Chemical group 0.000 claims description 260
• 125000000217 alkyl group Chemical group 0.000 claims description 159
• 229910052739 hydrogen Inorganic materials 0.000 claims description 132
• 125000004432 carbon atom Chemical group C* 0.000 claims description 126
• 239000001257 hydrogen Substances 0.000 claims description 126
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 93
• 229910052757 nitrogen Inorganic materials 0.000 claims description 84
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 72
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 61
• 150000002431 hydrogen Chemical class 0.000 claims description 58
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 57
• 229910052799 carbon Inorganic materials 0.000 claims description 57
• 125000001424 substituent group Chemical group 0.000 claims description 54
• 125000004452 carbocyclyl group Chemical group 0.000 claims description 49
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 46
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 43
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 42
• PIGFYZPCRLYGLF-UHFFFAOYSA-N Aluminum nitride Chemical compound [Al]#N PIGFYZPCRLYGLF-UHFFFAOYSA-N 0.000 claims description 41
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 41
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 37
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 37
• 229910052736 halogen Inorganic materials 0.000 claims description 36
• 150000002367 halogens Chemical class 0.000 claims description 36
• 125000000623 heterocyclic group Chemical group 0.000 claims description 29
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 26
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 25
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 24
• GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 20
• 125000004429 atom Chemical group 0.000 claims description 18
• 125000001072 heteroaryl group Chemical group 0.000 claims description 18
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 17
• 125000003545 alkoxy group Chemical group 0.000 claims description 17
• 150000001408 amides Chemical class 0.000 claims description 17
• 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 17
• 125000003118 aryl group Chemical group 0.000 claims description 17
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 15
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 15
• 238000002360 preparation method Methods 0.000 claims description 15
• 229920006395 saturated elastomer Polymers 0.000 claims description 15
• 125000005843 halogen group Chemical group 0.000 claims description 14
• 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 13
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 13
• 125000002619 bicyclic group Chemical group 0.000 claims description 13
• 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 13
• 125000004423 acyloxy group Chemical group 0.000 claims description 12
• 125000002950 monocyclic group Chemical group 0.000 claims description 12
• 125000003342 alkenyl group Chemical group 0.000 claims description 11
• 150000001721 carbon Chemical group 0.000 claims description 11
• 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 11
• 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 10
• 229910052717 sulfur Inorganic materials 0.000 claims description 10
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 9
• 125000001041 indolyl group Chemical group 0.000 claims description 9
• 229910052760 oxygen Inorganic materials 0.000 claims description 9
• 125000001544 thienyl group Chemical group 0.000 claims description 9
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
• ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 8
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
• 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 8
• 239000011593 sulfur Substances 0.000 claims description 8
• 125000005236 alkanoylamino group Chemical group 0.000 claims description 7
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
• 239000001301 oxygen Substances 0.000 claims description 7
• 125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 claims description 6
• 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 6
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 6
• 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 claims description 6
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 5
• HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 5
• 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 5
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 5
• 229920002554 vinyl polymer Polymers 0.000 claims description 5
• 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
• 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 3
• 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 3
• 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 3
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
• 125000005862 (C1-C6)alkanoyl group Chemical group 0.000 claims description 2
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
• 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 2
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
• 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 claims description 2
• PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims 2
• 125000006624 (C1-C6) alkoxycarbonylamino group Chemical group 0.000 claims 1
• XSLBWZNMWUEVMS-UHFFFAOYSA-N 2,3,4,5-tetrahydro-1,5-benzothiazepine Chemical compound S1CCCNC2=CC=CC=C21 XSLBWZNMWUEVMS-UHFFFAOYSA-N 0.000 claims 1
• 125000005281 alkyl ureido group Chemical group 0.000 claims 1
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
• 238000011282 treatment Methods 0.000 abstract description 51
• 239000003613 bile acid Substances 0.000 abstract description 40
• 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 abstract description 33
• 239000003814 drug Substances 0.000 abstract description 19
• 238000004519 manufacturing process Methods 0.000 abstract description 9
• 239000003112 inhibitor Substances 0.000 abstract description 8
• 208000031226 Hyperlipidaemia Diseases 0.000 abstract description 7
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 286
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 134
• 229940002612 prodrug Drugs 0.000 description 124
• 239000000651 prodrug Substances 0.000 description 124
• 230000002829 reductive effect Effects 0.000 description 100
• 239000002904 solvent Substances 0.000 description 89
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 88
• 239000011541 reaction mixture Substances 0.000 description 86
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 86
• 239000000203 mixture Substances 0.000 description 81
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 76
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 69
• 235000019439 ethyl acetate Nutrition 0.000 description 67
• 239000000243 solution Substances 0.000 description 64
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
• 241001465754 Metazoa Species 0.000 description 59
• 239000007858 starting material Substances 0.000 description 57
• 239000003480 eluent Substances 0.000 description 56
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 52
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 48
• 238000002953 preparative HPLC Methods 0.000 description 48
• 239000000872 buffer Substances 0.000 description 45
• USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 44
• 239000005695 Ammonium acetate Substances 0.000 description 44
• 229940043376 ammonium acetate Drugs 0.000 description 44
• 235000019257 ammonium acetate Nutrition 0.000 description 44
• 241000282414 Homo sapiens Species 0.000 description 40
• CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 40
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 39
• 239000012317 TBTU Substances 0.000 description 39
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 38
• 239000012044 organic layer Substances 0.000 description 36
• OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 35
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 35
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 34
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 34
• 102100021711 Ileal sodium/bile acid cotransporter Human genes 0.000 description 30
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• 230000002401 inhibitory effect Effects 0.000 description 24
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 23
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 23
• 239000012267 brine Substances 0.000 description 22
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 22
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• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 19
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
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• 150000001412 amines Chemical class 0.000 description 13
• 238000004440 column chromatography Methods 0.000 description 13
• 125000006239 protecting group Chemical group 0.000 description 12
• JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 12
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