CN1440407A - 新的bispidine化合物及其在治疗心律失常中的应用 - Google Patents

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Publication number

CN1440407A

CN1440407A CN01812475A CN01812475A CN1440407A CN 1440407 A CN1440407 A CN 1440407A CN 01812475 A CN01812475 A CN 01812475A CN 01812475 A CN01812475 A CN 01812475A CN 1440407 A CN1440407 A CN 1440407A

Authority

CN

China

Prior art keywords

formula

compound

alkyl

het

optionally substituted

Prior art date

2000-07-07

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.)

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• 206010003119 arrhythmia Diseases 0.000 title claims abstract description 25
• 238000011282 treatment Methods 0.000 title claims abstract description 14
• PTPQJKANBKHDPM-UHFFFAOYSA-N 3,7-diazabicyclo[3.3.1]nonane Chemical class C1NCC2CNCC1C2 PTPQJKANBKHDPM-UHFFFAOYSA-N 0.000 title claims description 17
• 150000001875 compounds Chemical class 0.000 claims abstract description 365
• 230000006793 arrhythmia Effects 0.000 claims abstract description 11
• 230000001746 atrial effect Effects 0.000 claims abstract description 5
• 206010047281 Ventricular arrhythmia Diseases 0.000 claims abstract description 4
• 238000011321 prophylaxis Methods 0.000 claims abstract description 4
• 206010003130 Arrhythmia supraventricular Diseases 0.000 claims abstract description 3
• 125000000217 alkyl group Chemical group 0.000 claims description 84
• -1 -OH Chemical group 0.000 claims description 75
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 71
• 125000003118 aryl group Chemical group 0.000 claims description 65
• 125000001424 substituent group Chemical group 0.000 claims description 64
• 229910052736 halogen Inorganic materials 0.000 claims description 53
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 52
• 150000002367 halogens Chemical class 0.000 claims description 39
• 125000002947 alkylene group Chemical group 0.000 claims description 34
• 238000006243 chemical reaction Methods 0.000 claims description 33
• 238000000034 method Methods 0.000 claims description 33
• 229910052757 nitrogen Inorganic materials 0.000 claims description 28
• 239000012634 fragment Substances 0.000 claims description 27
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 24
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 16
• 239000003814 drug Substances 0.000 claims description 14
• 229910052799 carbon Inorganic materials 0.000 claims description 13
• 125000005843 halogen group Chemical group 0.000 claims description 13
• 229910052760 oxygen Inorganic materials 0.000 claims description 12
• 150000001721 carbon Chemical group 0.000 claims description 10
• 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 9
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
• 125000000623 heterocyclic group Chemical group 0.000 claims description 9
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• 230000008569 process Effects 0.000 claims description 6
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
• 125000005842 heteroatom Chemical group 0.000 claims description 5
• 239000007800 oxidant agent Substances 0.000 claims description 5
• 229910052739 hydrogen Inorganic materials 0.000 claims description 4
• 229910052740 iodine Inorganic materials 0.000 claims description 4
• 238000002360 preparation method Methods 0.000 claims description 4
• LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
• IVRMZWNICZWHMI-UHFFFAOYSA-N Azide Chemical compound [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 claims description 3
• YIKSCQDJHCMVMK-UHFFFAOYSA-N Oxamide Chemical compound NC(=O)C(N)=O YIKSCQDJHCMVMK-UHFFFAOYSA-N 0.000 claims description 3
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• 239000004480 active ingredient Substances 0.000 claims description 2
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• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
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• 230000002265 prevention Effects 0.000 claims description 2
• 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 claims description 2
• ASVNRQFCHFLEPS-UHFFFAOYSA-N 4-[3-(7-benzyl-2,4-dimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)-2-hydroxypropoxy]benzonitrile Chemical compound CC1N(CC(O)COC=2C=CC(=CC=2)C#N)C(C)C(C2)CC1CN2CC1=CC=CC=C1 ASVNRQFCHFLEPS-UHFFFAOYSA-N 0.000 claims 1
• SEOQYNBBMGIYOF-UHFFFAOYSA-N 4-[3-(7-benzyl-4-methyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)-2-hydroxypropoxy]benzonitrile Chemical compound C1N(CC(O)COC=2C=CC(=CC=2)C#N)C(C)C(C2)CC1CN2CC1=CC=CC=C1 SEOQYNBBMGIYOF-UHFFFAOYSA-N 0.000 claims 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
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• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical class CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 34
• 239000000203 mixture Substances 0.000 description 33
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• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
• 239000002904 solvent Substances 0.000 description 27
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 23
• 239000003960 organic solvent Substances 0.000 description 23
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
• 238000012360 testing method Methods 0.000 description 21
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• 239000002585 base Substances 0.000 description 20
• 238000010992 reflux Methods 0.000 description 19
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 17
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
• 150000003254 radicals Chemical class 0.000 description 15
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
• 230000000694 effects Effects 0.000 description 14
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
• 235000019439 ethyl acetate Nutrition 0.000 description 12
• 238000002474 experimental method Methods 0.000 description 12
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 10
• 239000003054 catalyst Substances 0.000 description 10
• 239000003638 chemical reducing agent Substances 0.000 description 10
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
• 239000011541 reaction mixture Substances 0.000 description 10
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• 238000005481 NMR spectroscopy Methods 0.000 description 9
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
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• 229940079593 drug Drugs 0.000 description 8
• 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 7
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• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
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• 241001465754 Metazoa Species 0.000 description 6
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
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• 238000004128 high performance liquid chromatography Methods 0.000 description 6
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
• BKIMMITUMNQMOS-UHFFFAOYSA-N normal nonane Natural products CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 6
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• 125000003545 alkoxy group Chemical group 0.000 description 5
• 125000005233 alkylalcohol group Chemical group 0.000 description 5
• 125000003277 amino group Chemical group 0.000 description 5
• 125000004429 atom Chemical group 0.000 description 5
• LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 5
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• 125000004665 trialkylsilyl group Chemical group 0.000 description 1
• 125000001425 triazolyl group Chemical group 0.000 description 1
• TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
• 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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