EA013567B1 - Хинолиноновые соединения в качестве агонистов рецептора 5-ht - Google Patents

Info

Publication number

EA013567B1

EA013567B1 EA200701867A EA200701867A EA013567B1 EA 013567 B1 EA013567 B1 EA 013567B1 EA 200701867 A EA200701867 A EA 200701867A EA 200701867 A EA200701867 A EA 200701867A EA 013567 B1 EA013567 B1 EA 013567B1

Authority

EA

Eurasian Patent Office

Prior art keywords

isopropyl

oct

dihydroquinoline

formula

oxo

Prior art date

2005-03-02

Links

• Espacenet
• Global Dossier
• Discuss

• LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims description 260
• -1 quinoline carboxamide compound Chemical class 0.000 claims description 152
• QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 108
• 238000000034 method Methods 0.000 claims description 89
• UUCJNYSXZJNSLE-UHFFFAOYSA-N 2-oxo-1-propan-2-ylquinoline-3-carboxylic acid Chemical compound C1=CC=C2C=C(C(O)=O)C(=O)N(C(C)C)C2=C1 UUCJNYSXZJNSLE-UHFFFAOYSA-N 0.000 claims description 53
• 150000003839 salts Chemical class 0.000 claims description 47
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 46
• 125000000217 alkyl group Chemical group 0.000 claims description 43
• 102000005962 receptors Human genes 0.000 claims description 39
• 108020003175 receptors Proteins 0.000 claims description 39
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 38
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 38
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 36
• 229910052739 hydrogen Inorganic materials 0.000 claims description 34
• 239000008194 pharmaceutical composition Substances 0.000 claims description 34
• KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 33
• KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 claims description 33
• 150000001408 amides Chemical class 0.000 claims description 31
• 239000001257 hydrogen Substances 0.000 claims description 31
• 229910052799 carbon Inorganic materials 0.000 claims description 27
• 230000000694 effects Effects 0.000 claims description 27
• 150000004702 methyl esters Chemical class 0.000 claims description 24
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 23
• 241000124008 Mammalia Species 0.000 claims description 20
• 239000012453 solvate Substances 0.000 claims description 20
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 19
• 230000002829 reductive effect Effects 0.000 claims description 19
• 229910052757 nitrogen Inorganic materials 0.000 claims description 18
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 18
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
• 239000000018 receptor agonist Substances 0.000 claims description 17
• 229940044601 receptor agonist Drugs 0.000 claims description 17
• 150000002431 hydrogen Chemical class 0.000 claims description 14
• 206010010774 Constipation Diseases 0.000 claims description 13
• 201000010099 disease Diseases 0.000 claims description 13
• 239000003814 drug Substances 0.000 claims description 13
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 13
• 108091005482 5-HT4 receptors Proteins 0.000 claims description 12
• YEHGFLMAQOJVPH-UHFFFAOYSA-N 2-oxo-1-propan-2-ylquinoline-3-carboxamide Chemical compound C1=CC=C2C=C(C(N)=O)C(=O)N(C(C)C)C2=C1 YEHGFLMAQOJVPH-UHFFFAOYSA-N 0.000 claims description 11
• 239000003937 drug carrier Substances 0.000 claims description 11
• 210000001035 gastrointestinal tract Anatomy 0.000 claims description 11
• 208000002551 irritable bowel syndrome Diseases 0.000 claims description 9
• 230000004899 motility Effects 0.000 claims description 9
• 206010021518 Impaired gastric emptying Diseases 0.000 claims description 8
• 125000003545 alkoxy group Chemical group 0.000 claims description 8
• 230000001684 chronic effect Effects 0.000 claims description 8
• 201000006549 dyspepsia Diseases 0.000 claims description 8
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 7
• 229910052736 halogen Inorganic materials 0.000 claims description 7
• 150000002367 halogens Chemical class 0.000 claims description 7
• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 6
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
• 125000004076 pyridyl group Chemical group 0.000 claims description 6
• 206010051153 Diabetic gastroparesis Diseases 0.000 claims description 5
• 150000001721 carbon Chemical group 0.000 claims description 5
• 230000003247 decreasing effect Effects 0.000 claims description 5
• 229940079593 drug Drugs 0.000 claims description 5
• 238000004519 manufacturing process Methods 0.000 claims description 5
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 5
• 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 4
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
• 150000002148 esters Chemical class 0.000 claims description 4
• 206010052105 Gastrointestinal hypomotility Diseases 0.000 claims description 3
• 201000005081 Intestinal Pseudo-Obstruction Diseases 0.000 claims description 3
• 208000021302 gastroesophageal reflux disease Diseases 0.000 claims description 3
• 208000001288 gastroparesis Diseases 0.000 claims description 3
• 208000003243 intestinal obstruction Diseases 0.000 claims description 3
• 239000012948 isocyanate Substances 0.000 claims description 3
• 230000002980 postoperative effect Effects 0.000 claims description 3
• 125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 claims description 2
• BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 claims description 2
• 125000004432 carbon atom Chemical group C* 0.000 claims description 2
• 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 2
• 125000002541 furyl group Chemical group 0.000 claims description 2
• 230000005176 gastrointestinal motility Effects 0.000 claims description 2
• 208000013617 idiopathic gastroparesis Diseases 0.000 claims description 2
• 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 2
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims 5
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 2
• 239000003513 alkali Substances 0.000 claims 2
• 208000012895 Gastric disease Diseases 0.000 claims 1
• 235000018734 Sambucus australis Nutrition 0.000 claims 1
• 244000180577 Sambucus australis Species 0.000 claims 1
• 206010012601 diabetes mellitus Diseases 0.000 claims 1
• OGFXBIXJCWAUCH-UHFFFAOYSA-N meso-secoisolariciresinol Natural products C1=2C=C(O)C(OC)=CC=2CC(CO)C(CO)C1C1=CC=C(O)C(OC)=C1 OGFXBIXJCWAUCH-UHFFFAOYSA-N 0.000 claims 1
• 125000004433 nitrogen atom Chemical group N* 0.000 claims 1
• 208000018556 stomach disease Diseases 0.000 claims 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 102
• 239000000203 mixture Substances 0.000 description 70
• 239000000543 intermediate Substances 0.000 description 69
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 64
• 239000000243 solution Substances 0.000 description 61
• 238000006243 chemical reaction Methods 0.000 description 51
• 210000004027 cell Anatomy 0.000 description 48
• 230000015572 biosynthetic process Effects 0.000 description 39
• 238000003786 synthesis reaction Methods 0.000 description 39
• 238000004128 high performance liquid chromatography Methods 0.000 description 37
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 33
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 32
• 230000014759 maintenance of location Effects 0.000 description 28
• 238000002360 preparation method Methods 0.000 description 28
• 239000004615 ingredient Substances 0.000 description 22
• 125000006239 protecting group Chemical group 0.000 description 22
• 239000011541 reaction mixture Substances 0.000 description 22
• 238000012360 testing method Methods 0.000 description 22
• 238000003556 assay Methods 0.000 description 21
• 208000035475 disorder Diseases 0.000 description 21
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 19
• 239000007787 solid Substances 0.000 description 17
• 238000006467 substitution reaction Methods 0.000 description 17
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
• 238000009739 binding Methods 0.000 description 16
• 239000002775 capsule Substances 0.000 description 16
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 16
• 239000000047 product Substances 0.000 description 16
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 15
• ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
• 239000000725 suspension Substances 0.000 description 15
• 238000005160 1H NMR spectroscopy Methods 0.000 description 14
• 238000004458 analytical method Methods 0.000 description 14
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• 239000000460 chlorine Substances 0.000 description 14
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• 239000003826 tablet Substances 0.000 description 13
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
• 239000000872 buffer Substances 0.000 description 12
• FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 12
• 239000004480 active ingredient Substances 0.000 description 11
• 150000001412 amines Chemical class 0.000 description 11
• 239000003701 inert diluent Substances 0.000 description 11
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
• 238000005481 NMR spectroscopy Methods 0.000 description 10
• 229920002472 Starch Polymers 0.000 description 10
• 239000002585 base Substances 0.000 description 10
• 239000011575 calcium Substances 0.000 description 10
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 10
• XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 10
• 239000012044 organic layer Substances 0.000 description 10
• 239000000843 powder Substances 0.000 description 10
• 239000002904 solvent Substances 0.000 description 10
• 235000019698 starch Nutrition 0.000 description 10
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
• 108091003079 Bovine Serum Albumin Proteins 0.000 description 9
• DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
• 239000002609 medium Substances 0.000 description 9
• 239000003921 oil Substances 0.000 description 9
• 238000002953 preparative HPLC Methods 0.000 description 9
• 229930185107 quinolinone Natural products 0.000 description 9
• VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 8
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
• 229920000168 Microcrystalline cellulose Polymers 0.000 description 8
• 239000002253 acid Substances 0.000 description 8
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• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
• 239000008107 starch Substances 0.000 description 8
• DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 8
• ZZAKLGGGMWORRT-UHFFFAOYSA-N 1-methylsulfonylpiperazine Chemical compound CS(=O)(=O)N1CCNCC1 ZZAKLGGGMWORRT-UHFFFAOYSA-N 0.000 description 7
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• IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 7
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