CN1142184A - 抗心律失常的苯并二氮杂䓬 - Google Patents
抗心律失常的苯并二氮杂䓬 Download PDFInfo
- Publication number
- CN1142184A CN1142184A CN94194856A CN94194856A CN1142184A CN 1142184 A CN1142184 A CN 1142184A CN 94194856 A CN94194856 A CN 94194856A CN 94194856 A CN94194856 A CN 94194856A CN 1142184 A CN1142184 A CN 1142184A
- Authority
- CN
- China
- Prior art keywords
- phenyl
- group
- dihydro
- methyl
- dichlorophenyl
- 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.)
- Granted
Links
- 239000003416 antiarrhythmic agent Substances 0.000 title description 10
- 229940049706 benzodiazepine Drugs 0.000 title description 4
- 230000003288 anthiarrhythmic effect Effects 0.000 title description 3
- 150000001557 benzodiazepines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 85
- 206010003119 arrhythmia Diseases 0.000 claims abstract description 13
- 239000000203 mixture Substances 0.000 claims description 135
- -1 5-methylisoxazol-3-yl Chemical group 0.000 claims description 70
- 238000000034 method Methods 0.000 claims description 39
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 31
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 30
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 125000005605 benzo group Chemical group 0.000 claims description 15
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 11
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 239000001301 oxygen Substances 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 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
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- PDQRQJVPEFGVRK-UHFFFAOYSA-N 2,1,3-benzothiadiazole Chemical compound C1=CC=CC2=NSN=C21 PDQRQJVPEFGVRK-UHFFFAOYSA-N 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 150000003254 radicals Chemical class 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 claims description 2
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 claims 1
- JUXAVSAMVBLDKO-UHFFFAOYSA-N 1-(1-azabicyclo[2.2.2]octan-3-yl)-3-[3-(1h-indol-3-yl)-1-oxo-1-spiro[1,2-dihydroindene-3,4'-piperidine]-1'-ylpropan-2-yl]urea Chemical group C1N(CC2)CCC2C1NC(=O)NC(C(=O)N1CCC2(C3=CC=CC=C3CC2)CC1)CC1=CNC2=CC=CC=C12 JUXAVSAMVBLDKO-UHFFFAOYSA-N 0.000 claims 1
- OCBFFGCSTGGPSQ-UHFFFAOYSA-N [CH2]CC Chemical compound [CH2]CC OCBFFGCSTGGPSQ-UHFFFAOYSA-N 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 230000006793 arrhythmia Effects 0.000 abstract description 8
- 150000001408 amides Chemical class 0.000 abstract description 2
- ZVAPWJGRRUHKGP-UHFFFAOYSA-N 1h-1,5-benzodiazepine Chemical class N1C=CC=NC2=CC=CC=C12 ZVAPWJGRRUHKGP-UHFFFAOYSA-N 0.000 abstract 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 212
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 207
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 137
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 109
- 238000000921 elemental analysis Methods 0.000 description 106
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 92
- 235000019439 ethyl acetate Nutrition 0.000 description 68
- 239000000243 solution Substances 0.000 description 68
- 229910001868 water Inorganic materials 0.000 description 68
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 64
- 239000002904 solvent Substances 0.000 description 63
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 59
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 59
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 56
- 239000007787 solid Substances 0.000 description 55
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 49
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 42
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 42
- 239000000741 silica gel Substances 0.000 description 41
- 229910002027 silica gel Inorganic materials 0.000 description 41
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 38
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 35
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 34
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 28
- 239000011541 reaction mixture Substances 0.000 description 28
- 239000000047 product Substances 0.000 description 27
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 25
- 239000003921 oil Substances 0.000 description 23
- 239000012267 brine Substances 0.000 description 22
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 22
- 235000017557 sodium bicarbonate Nutrition 0.000 description 22
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 22
- 238000003818 flash chromatography Methods 0.000 description 21
- 229910052938 sodium sulfate Inorganic materials 0.000 description 20
- 239000007832 Na2SO4 Substances 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 229920006395 saturated elastomer Polymers 0.000 description 18
- 239000006260 foam Substances 0.000 description 17
- 238000010992 reflux Methods 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 13
- 229940080818 propionamide Drugs 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 238000001704 evaporation Methods 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Substances [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 230000005484 gravity Effects 0.000 description 10
- 235000019341 magnesium sulphate Nutrition 0.000 description 10
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 10
- YSGXGPPBXAAFTC-OAHLLOKOSA-N (3r)-1-methyl-5-phenyl-2,3-dihydro-1,4-benzodiazepin-3-amine Chemical compound N([C@@H](N)CN(C1=CC=CC=C11)C)=C1C1=CC=CC=C1 YSGXGPPBXAAFTC-OAHLLOKOSA-N 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- APRBAQZYHRCFJI-OAHLLOKOSA-N N[C@@H]1N(C2=C(C(=NC1)C1=CC=CC=C1)C=CC=C2)C Chemical compound N[C@@H]1N(C2=C(C(=NC1)C1=CC=CC=C1)C=CC=C2)C APRBAQZYHRCFJI-OAHLLOKOSA-N 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 7
- HJZLEGIHUQOJBA-UHFFFAOYSA-N cyclohexane propionic acid Chemical compound OC(=O)CCC1CCCCC1 HJZLEGIHUQOJBA-UHFFFAOYSA-N 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical group SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 6
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 5
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 5
- 101100391174 Dictyostelium discoideum forC gene Proteins 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- PUJDIJCNWFYVJX-UHFFFAOYSA-N benzyl carbamate Chemical compound NC(=O)OCC1=CC=CC=C1 PUJDIJCNWFYVJX-UHFFFAOYSA-N 0.000 description 5
- 238000010828 elution Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical compound N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 description 4
- PLZWYQYDWCXHTF-UHFFFAOYSA-N 1-methyl-5-phenyl-3h-1,4-benzodiazepin-2-one Chemical compound N=1CC(=O)N(C)C2=CC=CC=C2C=1C1=CC=CC=C1 PLZWYQYDWCXHTF-UHFFFAOYSA-N 0.000 description 4
- XUZGZTXIPRIZMH-UHFFFAOYSA-N 3-(2,4-dichlorophenyl)propanamide Chemical compound NC(=O)CCC1=CC=C(Cl)C=C1Cl XUZGZTXIPRIZMH-UHFFFAOYSA-N 0.000 description 4
- LQFCAVZOCFSRBM-UHFFFAOYSA-N 3-(2,4-dichlorophenyl)propanoyl chloride Chemical compound ClC(=O)CCC1=CC=C(Cl)C=C1Cl LQFCAVZOCFSRBM-UHFFFAOYSA-N 0.000 description 4
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 239000007868 Raney catalyst Substances 0.000 description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 4
- 229910000564 Raney nickel Inorganic materials 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 description 4
- 239000002480 mineral oil Substances 0.000 description 4
- 235000010446 mineral oil Nutrition 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 208000003663 ventricular fibrillation Diseases 0.000 description 4
- VXIMIQNIBMDZCM-UHFFFAOYSA-N (2-aminothiophen-3-yl)-phenylmethanone Chemical class S1C=CC(C(=O)C=2C=CC=CC=2)=C1N VXIMIQNIBMDZCM-UHFFFAOYSA-N 0.000 description 3
- JUIKUQOUMZUFQT-UHFFFAOYSA-N 2-bromoacetamide Chemical compound NC(=O)CBr JUIKUQOUMZUFQT-UHFFFAOYSA-N 0.000 description 3
- HLNPVFSCAMKIOD-UHFFFAOYSA-N 3-(2,4-dichlorophenyl)propanoic acid Chemical compound OC(=O)CCC1=CC=C(Cl)C=C1Cl HLNPVFSCAMKIOD-UHFFFAOYSA-N 0.000 description 3
- IHQPPUHOUDNMEL-UHFFFAOYSA-N 5-cyclohexyl-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound C12=CC=CC=C2NC(=O)CN=C1C1CCCCC1 IHQPPUHOUDNMEL-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- ITPDYQOUSLNIHG-UHFFFAOYSA-N Amiodarone hydrochloride Chemical compound [Cl-].CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(OCC[NH+](CC)CC)C(I)=C1 ITPDYQOUSLNIHG-UHFFFAOYSA-N 0.000 description 3
- ZMFWCURQXGZQRH-UHFFFAOYSA-N CN(CCN1CC(N=C(C2=C1C=CC=C2)C2=CC=CC=C2)=NO)C Chemical compound CN(CCN1CC(N=C(C2=C1C=CC=C2)C2=CC=CC=C2)=NO)C ZMFWCURQXGZQRH-UHFFFAOYSA-N 0.000 description 3
- KUDQAEHNHRZPBJ-UHFFFAOYSA-N N,N-dimethyl-2-(5-phenyl-2,3-dihydro-1,4-benzodiazepin-1-yl)ethanamine Chemical compound CN(CCN1CCN=C(C2=C1C=CC=C2)C2=CC=CC=C2)C KUDQAEHNHRZPBJ-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 229960005260 amiodarone Drugs 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 235000015165 citric acid Nutrition 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- YWGHUJQYGPDNKT-UHFFFAOYSA-N hexanoyl chloride Chemical compound CCCCCC(Cl)=O YWGHUJQYGPDNKT-UHFFFAOYSA-N 0.000 description 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- ZYECOAILUNWEAL-NUDFZHEQSA-N (4z)-4-[[2-methoxy-5-(phenylcarbamoyl)phenyl]hydrazinylidene]-n-(3-nitrophenyl)-3-oxonaphthalene-2-carboxamide Chemical compound COC1=CC=C(C(=O)NC=2C=CC=CC=2)C=C1N\N=C(C1=CC=CC=C1C=1)/C(=O)C=1C(=O)NC1=CC=CC([N+]([O-])=O)=C1 ZYECOAILUNWEAL-NUDFZHEQSA-N 0.000 description 2
- WULCMEBFNHGYFB-UHFFFAOYSA-N (5-phenyl-3h-1,4-benzodiazepin-2-yl)hydrazine Chemical compound N=1CC(NN)=NC2=CC=CC=C2C=1C1=CC=CC=C1 WULCMEBFNHGYFB-UHFFFAOYSA-N 0.000 description 2
- WOGITNXCNOTRLK-VOTSOKGWSA-N (e)-3-phenylprop-2-enoyl chloride Chemical compound ClC(=O)\C=C\C1=CC=CC=C1 WOGITNXCNOTRLK-VOTSOKGWSA-N 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- CLZRDHUBODXICN-OWOJBTEDSA-N 1-chloro-4-[(e)-3-chloroprop-1-enyl]benzene Chemical compound ClC\C=C\C1=CC=C(Cl)C=C1 CLZRDHUBODXICN-OWOJBTEDSA-N 0.000 description 2
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Classifications
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
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- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
-
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
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Abstract
在3-位上具有酰胺或脲官能的苯并-(1,5)-二氮杂䓬衍生物可用于治疗心律失常。这类化合物具有通式(I)和(II)的结构。
Description
发明概述
本发明还涉及含有一种或多种该新型化合物作为活性成分的药物配方,这些活性成分可以单独使用或与一种或多种类I、类II或类IV抗心律失常药剂组合使用。
发明背景
心律失常通常作为心脏疾病,如心肌梗死和心力衰竭的并发症发生。在严重的情况下,心律失常会引起心室纤维性颤动,从而会导致猝死。
虽然目前市场上已有各种抗心律失常药剂出售,但是既具有满意效果又有高度安全的这类药剂至今还未出现。例如,按照Vaughan-Williams分类的抗心律失常药类I,对动作电位上升的最大速度(Vmax)会产生选择性抑制,因此不能有效防止心室纤维颤动。此外,这类药剂还有安全问题,即会抑制心肌的收缩力,因而具有诱发由于博动传导受到抑制而产生的心律失常的倾向。分别属于类II和类IV的β-肾上腺受体阻滞剂和钙拮抗药的缺点是其效果或是局限于某种类型的心律失常,或是被禁忌,因为这两类药剂对某些心血管病患者具有心抑制药性能。但是,其安全性比类I的抗心律失常药剂高。
类III的抗心律失常药剂是能导致动作电位持续时间选择性延长而不会明显抑制Vmax值的药物。这类药物是受限制的。例如心得恰(Sotalol)和乙胺碘呋酮(amiodarone)已显示出具有类III的性能。心得怡还具有类II的效果,即对某些易感患者会导致心抑郁,因而被禁忌。同样,乙胺碘呋酮由于副作用大而受到严格限制。这类药物期望能有效预防心室纤维性颤动。纯的类III药剂,从定义上讲,不认为会引起心肌衰退或诱发由于动作电位传导受到抑制而产生心律失常,如使用类I的心律失常药剂时所见到情形那样。
发明的详述
可用于本发明的新型治疗方法的化合物具有下面的结构式:或其药物上可接受的盐,其中:
A是
1)噻吩并,
2)吡啶并,或
3)苯并,可以是未取代的或被-NH2、-NHSO2(C1-3烷基)、C1-3烷基或C1-3烷氧基取代的;
X是
1)=O,
2)=S,
3)=N-NH2
4)=N-OH或
5)=H2
Y是
1)=O,
2)=N-CN或
3)=H2
Z是
1)C1-5亚烷基,可为直链或支链,且可以是未取代的或被苯基或螺哌啶取代的,
2)C2-4亚链烯基,可为直链或支链,
3)-(CH2)m-W-(CH2)n-,其中m和n独立地是0、1、2、3或4,W是-O-、-S-或-NH-,
4)4-(5-甲基异噁唑-3-基),
5)C3-6亚环烷基,或
6)单键:
p是0或1:
R1是
1)苯基,可以是未取代的或被1个或2个选自下列的取代基取代的:
a)-NO2
b)-Cl、Br、F、或I,
c)-CF3,
d)-C1-3烷基,
e)-C1-3烷氧基,
f)-CN,
g)亚甲二氧基,
2)C5-7环烷基
4)5-10元的单或双杂环基,其中有1个或2个元素是硫,氮或氧,其余为碳,例如2-噻吩基、2-呋喃基、2-吲哚基、2-喹喔啉基或2-(2,3-二氢苯并呋喃基),
5)C1-3烷基,或
6)2,3-二氢化茚-5-基:
R2是
1)苯基,可以是未取代的或被C1-3烷氧基或4,4-二甲基噁唑啉-2-基取代的,
2)C1-5烷基,可为直链或支链,且可以是未取代的或被C1-3烷氧基或C1-3烷氧基-C1-3烷氧基取代,
3)C5-7环烷基,
4)2-或3-呋喃基,
5)1-甲基哌啶-2-基,或
6)如果R2是苯基,则苯基的2-位可以通过一个羰基连接到该二氮杂环的4-位氮上,且4-氮和5-碳之间的双键变成单健;
R3是
1)氢或
2)C1-3烷基,可以是未取代的或被-N(CH3)2、OH、-CF3取代的,或
3)-CF3;
R4是
1)氢,
2)C1-5烷基,其碳原子链可被1个或2个不相邻的氧原子隔开,且可以是未取代的或被C1-3烷氧羧基、-OH或取代的,或
3)四唑-5-基;
R5是氢或氧,或连接到R2上形成下面的部分结构:和
1)当p是0时,或当p是1,且R5是氧时,表示双键,或
2)当R5是氢,或R5连接到R2上形成下面的部分结构时,表示单键:
本发明意在包括所存在的各个非对映体及其混合物和对映体及对映体的混合物。
式I化合物的药物上可接受的盐包括例如由无毒的无机酸或有机酸形成的式I化合物的习用无毒盐或季铵盐。例如,这类习用无毒盐包括由无机酸如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等衍生出来的那些盐;以及由有机酸如乙酸、丙酸、乙醇酸、硬酯酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、pamoic酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、磺胺酸、2-乙酰氧基苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙磺酸等制备的盐。
本发明的药物上可接受的盐可用常规化学方法从含有碱或酸部分的式I化合物合成。通常,这类盐可通过让游离的碱或酸与化学计量的或过量的所要的成盐无机或有机的酸或碱在适当的溶剂或各种混合溶剂中进行反应来制备。
本发明的一个具体方案是可用于本发明的新治疗方法的新型化合物,其中:
A是苯并:
X是Y是氧;
R3是甲基;
R4是氢;和
R2是C1-6烷基。
本具体方案的特定新型化合物的代表是具有如下结构的列于表I中的那些化合物:
表I
R1 R2
2,4-二氯苯基 -CH3
2,4-二氯苯基 -C2H5
2,4-二氯苯基 -t-Bu
4-CF3Ph i-C3H7
环己基 i-C3H7
2,4-二氯苯基 i-C3H7
可用于本发明的新治疗方法的化合物的另一种具体方案在于其中:
X和Y是氧;
R3是甲基;
R4是氢;和
R2是苯基。
本方案中的一类新型化合物是具有如下结构式的化合物:式中Z是C1-5亚烷基或一个键,R1是苯基、被-Cl、-Br、-I、-F、或-CF3取代的苯基,或者R1是环己基。
这类特定新型化合物的代表是下面表II中所列的那些化合物:
表II
Z R1
-(CH2)2- 2,4-二氯苯基
-(CH2)2- 4-ClPh
-(CH2)2- 2,4-二氟苯基
-(CH2)2- 2-ClPh
-(CH2)2- 4-CF3Ph
-CH2- 4-CF3Ph
-(CH2)2- 3-CF3Ph
-(CH2)2- 2-CF3Ph
-(CH2)2- 环己基
- 环己基
-(CH2)3- 环己基
-CH2- 环己基
-(CH2)2- Ph
-CH2- Ph
-(CH2)2- 4-CNPh
-(CH2)2- 3-ClPh
-(CH2)3- Ph
-(CH2)2- 3-CNPh
-(CH2)3 2-噻吩基
这类特定新型化合物的代表是下面表III中所列那些化合物:
表III
Z R1
-CH=CH- 4-NO2Ph
-CH=CH- 2,4-二氯苯基
-CH=CH- 3-ClPh
-CH=CH- 2-ClPh
-CH=CH- 2,4-二氟苯基
-CH=CH- 2,6-二氯苯基
-CH=CH- 4-CF3Ph
-CH=CH- 2-BrPh
-CH=CH- 4-IPh
-CH=CH- 4-BrPh
Z R1
-CH=CH- Ph*
-CH=CH- 3,4-二氯苯基
-CH=CH- 4-CH3Ph
-CH=CH- 4-CH3OPh
-CH=CH- 3,4-亚甲二氧基苯基
-CH=CH- 3-BrPh
*该化合物是已知的,见美国专利4,820,834。
可用于本发明的新治疗方法的化合物的第三种具体方案在于其中Z是-NH-:
包括在最广的种类内,但不包括在前述各方案之一中的其它特定化合物如表V所示。
A Z R1 R2 R3 R4 X Y
-(CH2) 2-2,4-二氯苯基 Ph CH3 H O O
-(CH2) 2-环己基 Ph CH3 H O O
苯并 -CH2O- 4-NO2Ph Ph
O H2表V(续)A Z R1 R2 R3 R4 X Y苯并 -CH2O- 4-NO2Ph Ph OH3 H O H2苯并 -(CH2)2- 2-CH3OPh Ph CH3 CH3 O H2苯并 -CH=CH- 4-ClPh Ph CH3 H O H2苯并 -(CH2)2- 4-ClPh Ph CH3 H O H2苯并
4-ClPh Ph CH3 H O O表V(续)A Z R1 R2 R3 R4 X Y苯并 —
Ph CH3 H O O苯并
Ph Ph CH3 H O O苯并
2·ClPh Ph CH3 H O O苯并 —
Ph CH3 H O O苯并
Ph Ph CH3 H O O表V(续)A Z R1 R2 R3 R4 X Y苯并 — Ph Ph CH3 H O O苯并
Ph Ph CH3 H O O苯并
Ph Ph CH3 H O O苯并
2,4-二氯苯基 Ph CH3 H O O苯并
Ph Ph CH3 H O O表V(续)A Z R1 R2 R3 R4 X Y苯并
Ph Ph CH3 H O O苯并
Ph Ph CH3 H S O苯并 -(CH2)4- -CH3 Ph -CH3 O O苯并 -(CH2)4- -CH3 Ph -CH3 -(CH2)5OH O O苯并 -(CH2)3- -CH3 Ph CH3 H O O表V(续)A Z R1 R2 R3 R4 X Y苯并 -(CH2)4- -CH3 Ph CH3 H O O苯并 -(CH2)5- -CH3 Ph CH3 H O O苯并 -(CH2)2- -CH-(CH3)2 Ph CH3 H O O苯并 -(CH2)2- 环己基 Ph CH3 (四唑-1-基) O O-甲基苯并 -(CH2)2- 环己基 Ph H H
O表V(续)A Z R1 R2 R3 R4 X Y苯并 -(CH2)2- 2,4-二氯苯基
CH3 H O O苯并 -(CH2)4S- -CH3 Ph CH3 H O O苯并 -(CH2)2- 环己基 Ph CH3 H S O苯并 -(CH2)-2 环己基 Ph CH3 H H2 O苯并
Ph Ph CH3 H O O表V(续)A Z R1 R2 R3 R4 X Y苯并 —
Ph CH3 H O O苯并 -(CH2)2-
Ph CH3 H O O苯并 -(CH2)2- 2,4-二氯苯基
CH3 H O O苯并 -(CH2)2- 环己基
CH3 H O O苯并 -(CH2)2- 4-CF3Ph
CH3 H O O表V(续)A Z R1 R2 R3 R4 X Y苯并 -(CH2)2- 2,4-二氯苯基
CH3 H O O苯并
Ph 环己基 CH3 H O O苯并
Ph Ph CH3 H O O苯并
2,4-二氯苯基 Ph CH3 H O O苯并 —
Ph CH3 H O O表V(续)A Z R1 R2 R3 R4 X Y苯并
4-CF3Ph Ph CH3 H O O苯并
Ph Ph CH3 H O O苯并
Ph Ph CH3 H O O苯并
2,4-二氯苯基 Ph
H O O苯并
环己基 Ph H H S O表V(续)A Z R1 R2 R3 R4 X Y苯并
环己基 Ph CH3
O O苯并 -(CH2)4- CH3 Ph CH3 O O -(CH2)2- 2,4-二氯 Ph CH3 H O O苯基 -(CH2)2- 环己基 Ph CH3 H O O表V(续)A Z R1 R2 R3 R4 X Y苯并 -(CH2)2- 环己基 Ph H H =N-NH2 O苯并 -(CH2)2- 环己基 Ph CH3 (四唑-2-基) O O-甲基苯并 -(CH2)2- 4-CF3Ph
CH3 H O O苯并 -(CH2)2- 环己基 环己基 CH3 H O O-(CH2)2- 4-CF3Ph Ph CH3 H O O苯并 -(CH2)2- 环己基 3-呋喃基 CH3 H O O苯并 -(CH2)2- 环己基 Ph CH3 CH2CO2Et O O苯并 -(CH2)4- CH3 Ph CH3 CH2CO2Et O O苯并 -(CH2)4- CH3 Ph CH3 -CH2OH O O其中p是1的化合物的代表是结构式如下的化合物其中4位和5位之间的键是单键的化合物的代表是结构式如下的化合物:其中
代表单键,且R5连接到R2上的化合物的代表是结构式如下的化合物:
可用于本发明的新治疗方法的化合物具有类III的抗心律失常药剂所要求的药理性能,即能延长体内心肌动作电位,而不会明显抑制Vmax值,并能延长麻醉了的狗中的QTc-internal。
这些化合物能有效治疗和预防所有类型的心律失常,包括心室和动脉(室上)心律失常。本发明的化合物特别可用来控制再进入心律失常并预防由于心室纤维性颤动而发生的猝死。这些化合物在治疗和预防心的泵功能减弱方面也是有效的。
在本发明的治疗心律失常的新方法中,可用一种本发明的化合物或其药物上可接受的盐投药,其用量为约0,0001-约20mg/kg体重/每天,优选为约0.001-约10mg/kg/体重/每天,可以以单剂量或以2-4分剂量形式投药。
这些化合物可以以单一活性成分形式投药,或与其它抗心律失常药剂或其它心血管药剂组合一起投药。
这些化合物或其药物上可接受的盐,可按上述剂量,经口服、腹膜内,皮下、肌内、经皮、舌下或静脉注射等方式投药。较好是经静脉注射或口服给药,其形式例如可为通过技术上公知的方法制得的片剂、锭剂、胶囊、酏剂、悬浮剂、糖浆、糯米纸囊剂、口香糖等。在这种可用于治疗的组合物或制剂中活性化合物的含量为能得到合适的剂量的量。
这里所述的化合物作为抗心律失常药剂的活性是通过其阻滞IKs和IKr的能力测定的,IKs和IKr是通过下列实验方法测定的。
向外钾电流是用其它文献(Sanguinetti和Jurkiewicz,1990,TwoComponents of cardiac delayed actifier K+current:differentialsensitivity to block by Class III antiarrhythmic agent.J.Gen.Physiol.96:195-215)详细叙述的全细胞电压箝位技术(whole-cellvoltage clamp technique)在单个豚鼠心室肌细胞中测定的。肌细胞是通过Langandorf灌注心脏的酶(胶原酶和蛋白酶)催消化法分离的。然后用填充有0.5M葡糖酸钾、25mM KCl、5mM K2 ATP的口径为1毫米见方的移液管对这些单细胞进行电压箝位。将这些细胞浸泡在pH=7.2,温度为35℃的含有132NaCl、4KCl、1.2MgCl2、10HEPES和10葡萄糖(单位均为mN)的溶液中。
使每个细胞保持在-50mV的固定电位。当电压从-85mV上升到-50mV,以及当达到-10mV(0.5秒)和+50mV(1.0秒)时进行去极化试验。I[KI]测定为电压上升期间的峰值向外电流。I[Kr]测定为从-10mV到-50mV重新极化时的拖尾电流。I[KS]测定为脉冲到+50mV期间随时间而变化的电流。上述电流是在空白对照期间,然后在暴露于两种不同浓度的药物后测定的。
用上述试验测得,这里所述的化合物作为IKs和/或IKr阻滞剂,其IC50值小于1000nM。
可用于本发明的新治疗方法的化合物或是本技术中公知的,或是在结构上与本技术中已知的化合物相似,且已知具有CCK-B拮抗药活性。请参见例如Evans等人的专利4,820,834和5,004,741。因此这些命名的化合物的制备方法对于本技术的专业人员来说是显而易见的。下面用图解法列出制备本发明化合物时所采用的典型合成方案。方案1方案2方案3方案4方案5方案6方案7方案8方案9方案10方案11方案12方案13方案14方案15
(E)-(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-
苯基-1H-1,4-苯并二氮杂-3-基]-3-苯基-2-丙烯酰胺
将(E)-3-苯基-2-丙烯酰氯(367mg,2.2mmol)在二氯甲烷(1ml)中的溶液加入到3(R)-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮(J.Org.Chem.1987,52,3232-3239)(531mg,2.0mmol)和三乙胺(307μl,225mg,2.2mmol)在二氯甲烷(10ml)中的溶液中。该混合物在室温下搅拌25分钟,在减压下蒸发掉溶剂。残留物在硅胶上用快速柱色谱法提纯,用CH2Cl2/Et2O(95∶5)洗脱,残留物用Et2O研制。收集固体物,在70℃进行真空干燥,得到无色固体状的(E)-(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-苯基-2-丙烯酰胺(170mg,21%),mp:140-142℃。[α]D=+86.7°(c=0.173,CH2Cl2)。δH(CDCl3)7.70-7.26(16H,m),6.63(1H,d,J 15.6 Hz),5.68(1H,d,J8.3 Hz),和3.50(3H,s).元素分析:C25H21N3O2.0.15(C2H5)2O:计算值:C,75.63;H,5.58;N,10.33.实测值:C,75.29;H,5.57;N,10.33%.
采用基本上如上述的程序,但用适当的酰氯代替(E)-3-苯基-2-丙烯酰氯,制得了下述化合物:
实例2
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]苯甲酰胺m.p.224-225℃,[α]D+89.2°(c=0.141,CH2Cl2).δH(CDCl3)8.04(1H,d,J 8.1 Hz),7.96(2H,d,J 6.8 Hz),7.64-7.36(10H,m),7.27(2H,t,J 7.6 Hz),5.74(1H,d,J 7.8 Hz),和3.51(3H,s).元素分析:C23H19N3O2.0.20H2O:计算值:C,74.06;H,5.24;N,11.26.实测值:C,74.13;H,5.12;N,11.16%.
洗出的第一种非对映异构体:
(-)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基](反-2-苯基-1-环丙烷)碳酰胺m.p.180-181℃,[α]D-155.8°(c=0.434,CH2Cl2).δH(CDCl3)7.62-7.09(15H,m),5.59(1H,d,J 8.1 Hz),3.47(3H,s),2.52-2.45(1H,m),1.90-1.84(1H,m),1.69-1.56(1H,m),和138-1.32(1H,m).元素分析:C26H23N3O2.0.25H2O:计算值:C,75.43;H,5.72;N,10.15.实测值:C,75.38;H,5.64;N,9.94%.
洗出的第二种非对映异构体:
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基](反-2-苯基-1-环丙烷)碳酰胺m.p.104-107℃,[α]D+328.2°(c=0.098,CH2Cl2).δH(CDCl3)7.62-7.13(15H,m),5.60(1H,d,J 8.3 Hz),3.48(3H,s),2.59-2.54(1H,m),1.93-1.87(1H,m),1.62-1.56(1H,m,与水重叠),1.33-1.25(1H,m)。元素分析:C26H23N3O2.0.50H2O.0.45PhCH3:计算值:C,76.13;H,5.95;N,9.14.实测值:C,76.10;H,5.94;N,9.17%.
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-1H-吲哚-2-碳酰胺m.p.167-177℃,[α]D+113°(c=1.103,CH2Cl2).δH(CDCl3)9.15(1H,brs),8.10(1H,d,J 9.0 Hz),7.75-7.10(14H,m),5.75(1H,d,J 9.0 Hz),和3.50(3H,s).元素分析:C25H20NO2:计算值:C,73.51;H,4.94;N,13.72.实测值:C,73.31;H,4.80;N,13.62%.实例5
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]庚酰胺mp:49-54℃,[α]D+69.5°(c=1.000,MeOH)。元素分析:C23H27N3O2.0.40H2O:计算值:C,71.81;H,7.28;N,10.92.实测值:C,71.90;H,7.09;N,10.85%.
实例6
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]己酰胺[α]D+72.6°(c=0.920,MeOH)元素分析:C22H25N3O2:计算值:C,72.70;H,6.93;N,11.56.实测值:C,72.44;H,6.75;N,11.25%.实例7
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]戊酰胺[α]D+68.2°(c=1.310,MeOH)元素分析:C21H23N3O2.0.25CHCl3:计算值:C,68.21;H,6.26;N,11.26.实测值:C,68.2;H,6.29;N,11.17%.
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-苯基丙酰胺
将草酰氯(158μl,230mg,1.81mmol)加入到3-苯基丙酸(249mg,1.66mmol)和DMF(1滴)在THF(10ml)中的混合物中,将该混合物在室温下搅拌40分钟。加入3(R)-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮(J.Org.Chem.1987,52,3232-3239)(400mg,1.51mmol)和三乙胺(252μl,183mg,1.81mmol),在室温下将该混合物搅拌18小时。将该混合物倒入到饱和碳酸氢钠水溶液(20ml)中,然后用乙酸乙酯(3×20ml)萃取。将合并的有机级分干燥(Na2SO4),在减压下蒸发掉溶剂。残留物在硅胶上用快速柱色谱法提纯,用CH2Cl2/Et2O(95∶5)洗脱,残留物从甲苯/己烷中重结晶得到无色固体状的(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-苯基丙酰胺(380mg,63%),m.p:179℃。[α]D+100.4°(c=0.225,CH2Cl2).δH(CDCl3)7.62-7.57(2H,m),7.47-7.21(13H,m),5.54(1H,d,J8.1Hz),3.47(3H,s),3.03(2H,t,J7.8 Hz),和2.73-2.67(2H,m).元素分析:C25H23N3O2.0.15H2O:计算值:C,75.04;H,5.87;N,10.50.实测值:C,75.06;H,5.78;N,10.55%.
采用基本上如上述的程序,但用适当羧酸代替3-苯基丙酸,制得下述化合物:
E-(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(3,4-二氯苯基)-2-丙烯酰胺m.p.145-147℃,[α]D+77.8°(c=0.126,CH2Cl2).δH(CDCl3)7.64-7.25(14H,m),6.61(1H,d,J 15.6 Hz),5.65(1H,d,J8.0 Hz),和3.50(3H,s).元素分析:C25H19N3O2Cl2:计算值:C,64.67;H,4.12;N,9.05.实测值:C,64.57;H,4.25;N,9.01%.实例10
E-(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(4-硝基苯基)-2-丙烯酰胺m.p.165-166℃,[α]D+80.5°(c=0.126,CH2Cl2).δH(CDCl3)8.26(1H,d,J 8.8 Hz),7.74-7.28(13H,m),6.76(1H,d,J15.6 Hz),5.66(1H,d,J 8.0 Hz),和3.51(3H,s).元素分析:C25H19N4O4:计算值:C,68.17;H,4.58;N,12.72.实测值:C,68.25;H,4.65;N,12.57%.
实例11
E-(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(2,4-二氯苯基)-2-丙烯酰胺m.p.137-139℃,[α]D+66.0°(c=0.144,CH2Cl2).δH(CDCl3)8.02(1H,d,J 15.6 Hz),7.73-7.26(13H,m),6.66(1H,d,J15.6 Hz),5.81(1H,d,J 8.8 Hz),和3.53(3H,s).元素分析:C25H19Cl2N3O2:计算值:C,64.67;H,4.12;N,9.05.实测值:C,64.28;H,4.24;N,8.83%.
E-(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(4-甲基苯基)-2-丙烯酰胺m.p.133-135℃,[α]D+90.4°(c=0.125,CH2Cl2).δH(CDCl3)7.68-7.19(15H.m),6.59(1H,d,J 15.6 Hz),5.70(1H,d,J8.0 Hz),3.50(3H,s),和2.38(3H,s).元素分析:C26H23N3O2:计算值:C,76.26;H,5.66;N,10.26.实测值:C,75.93;H,5.82;N,10.10%.
E-(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(4-甲氧基苯基)-2-丙烯酰胺m.p.129-133℃,[α]D+89.9°(c0.188,CH2Cl2).δH(CDCl3)7.65-7.24(14H,m),6.92(1H,d,J 8.8 Hz),6.50(1H,d,J15.6 Hz),5.69(1H,d,J 8.0 Hz),3.84(3H,s),和3.50(3H,s)..元素分析:C26H23N3O3.0.30H2O:计算值:C,72.48;H,5.52;N,9.75.实测值:C,72.75;H,5.60;N,9.36%.
实例14
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(2,4-二氯苯基)丙酰胺m.p.92-95℃,[α]D 90.5°(c=0.196,CH2Cl2)δH(CDCl3)7.62-7.15(13H,m),5.52(1H,d,J 8.1 Hz),3.47(3H,s),3.10(2H,t,J 7.6 Hz),和d2.68(2H,dd,J 7.6,2.8Hz).元素分析:C25H21Cl2N3O2.0.20H2O:计算值:C,63.89;H,4.59;N,8.94.实测值:C,63.86;H,4.62;N,8.87%.
实例15
E-(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(3-氯苯基)-2-丙烯酰胺m.p.229-231℃,[α]D+86.2°(c=0.225,CH2Cl2).δH(CDCl3)7.64-7.26(15H,m),6.62(1H,d,J 15.6 Hz),5.66(1H,d,J8.1Hz),和3.50(3H,s).元素分析:C25H20ClN3O2:计算值:C,69.85;H,4.69;N,9.77.实测值:C,70.20;H,4.83;N,9.41%.
E-(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(2-氯苯基)-2-丙烯酰胺m.p.128-131℃,[α]D=+61.7°(c=0.196,CH2Cl2).δH(CDCl3)8.06(1H,d,J 15.6 Hz),7.65-7.28(14H,m),6.62,(1H,d,J15.6 Hz),5.68(1H,d,J 8.3 Hz),和3.50(3H,s).元素分析:C25H20ClN3O2.0.20H2O:计算值:C,69.27;H,4.74;N,9.69.实测值:C,69.21;H,4.68;N,9.45%.
E-(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(2,4-二氟苯基)-2-丙烯酰胺m.p.121-123℃,[α]D+76.8°(c=0.111,CH2Cl2).δH(CDCl3)7.71(1H,d,J 15.9 Hz),7.64-7.24(11H,m),6.92-6.84(2H,m),6.69(1H,d,J 15.9 Hz),5.67(1H,d,J 8.1 Hz),and3.50(3H,s).元素分析:C25H19F2N3O2.0.10H2O:计算值:C,69.31;H,4.47;N,9.70.实测值:C,69.28;H,4.57;N,9.31%.
实例18
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(4-氯苯基)丙酰胺m.p.203-205℃,[α]D+99.2°(c=0.300,CH2Cl2).δH(CDCl3)7.62-7.16(14H,m),5.52(1H,d,J 8.1 Hz),3.47(3H,s),2.99(2H,t,J 7.7 Hz),和2.67(2H,t,J 7.7 Hz).元素分析:C25H22ClN3O2:计算值:C,69.52;H,5.13;N,9.73.实测值:C,69.50;H,5.15;N,9.72%.
E(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(2,6-二氯苯基)-2-丙烯酰胺m.p.121-124℃,[α]D+69.0°(c=0.342,CH2Cl2).δH(CDCl3)7.79(1H,d,J 16.1 Hz),7.64-7.15(13H,m),6.78(1H,d,J15.8 Hz),5.69(1H,d,J 8.1 Hz),和3.50(3H,s).元素分析:C25H19Cl2N3O2.0.15PhCH3:计算值:C,65.44;H,4.23;N,8.79.实测值:C,65.40;H,4.38;N,8.85%.
E-(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-[4-(三氟甲基)苯基]-2-丙烯酰胺m.p.133-137℃,[α]D+68.7°(c=0.115,CH2Cl2).δH(CDCl3)7.72-7.25(15H,m),6.71(1H,d,J 15.6 Hz),5.67(1H,d,J8.1 Hz),和3.51(3H,s).元素分析:C26H20F3N3O2:计算值:C,67.38;H,4.35;N,9.07.实测值:C,67.38;H,4.45;N,8.95%.
实例21
(+)-5-氯-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-吲哚-2-碳酰胺m.p.160-164℃,[α]D+103.8°(c=0.160,CH2Cl2).δH(CDCl3)9.71(1H,brs),8.13(1H,d,J 7.8 Hz),7.68-7.09(13H,m),5.75(1H,d,J 7.8 Hz),和d 3.53(3H,s).元素分析:C25H19ClN4O2.0.25H2O.0.15PhCH3:计算值:C,67.84;H,4.49;N,12.15.实测值:C,67.80;H,4.41;N,12.07%.
实例22
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-2,2-二苯基乙酰胺m.p.200-201℃,[α]D+97.0°(c=0.168,CH2Cl2).δH(CDCl3)7.60-7.22(20H,m),5.58(1H,d,J 8.1 Hz),5.08(1H,s),和3.44(3H,s).元素分析:C30H25N3O2.0.15PhCH3:计算值:C,78.79;H,5.55;N,8.88.实测值:C,78.81;H,5.63;N,9.07%.
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(2,4-二氟苯基)丙酰胺m.p.79-81℃,[α]D+92.9°(c=0.105,CH2Cl2).δH(CDCl3)7.62-7.56(3H,m),7.50-7.19(8H,m),6.82-6.76(2H,m),5.52(1H,d,J 8.1 Hz),3.47(3H,s),3.01(2H,t,J 7.6 Hz),和2.69(2H,m).元素分析:C25H21FN3O2:计算值:C,69.27;H,4.88;N,9.69.实测值:C,68.96;H,4.99;N,9.47%.
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-2-苯基乙酰胺m.p.241-242℃(dec.),[α]D+85.5°(c=0.159,CH2Cl2).δH(CDCl3)7.59-7.55(3H,m),7.46-7.22(12H,m),5.51(1H,d,J8.1Hz),3.72(2H,s),和3.44(3H,s).元素分析:C24H21N3O2.0.55H2O:计算值:C,73.28;H,5.66;N,10.68.实测值:C,73.25;H,5.38;N,10.47%.
实例25
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(2-氯苯基)丙酰胺m.p.158.5-159.5℃,[α]D+95.8°(c=0.224,CH2Cl2).δH(CDCl3)7.62-7.57(3H,m),7.47-7.16(11H,m),5.55(1H,d,J 8.1Hz),3.47(3H,s),3.14(2H,t,J 7.9 Hz),和2.75-2.69(2H,m).元素分析:C25H22ClN3O2.0.15H2O:计算值:C,69.09;H,5.17;N,9.67.实测值:C,69.05;H,5.12;N,9.63%.
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-[4-(三氟甲基)苯基]丙酰胺m.p.175-176℃,[α]D+86.5°(c=0.141,CH2Cl2).δH(CDCl3)7.62-7.54(5H,m),7.47-7.22(9H,m),5.52(1H,d,J 8.1Hz),3.47(3H,m),3.08(2H,t,J 7.6Hz),和2.72(2H,m).元素分析:C26H22F3N3O2.0.80H2O:计算值:C,65.08;H,4.93;N,8.76.实测值:C,65.03;H,4.63;N,8.72%.
实例 27
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-2-[4-(三氟甲基)苯基]乙酰胺m.p.224-226℃,[α]D+68.0°(c=0.153,CH2Cl2).δH(CDCl3)7.63-7.55(4H,m),7.51-7.33(8H,m),7.26-7.23(2H,m),5.51(1H,d,J 8.1 Hz),3.77(2H,s),和3.46(3H,s).元素分析:C25H20F3N3O2:计算值:C,66.51;H,4.47;N,9.31.实测值:C,66.46;H,4.36;N,9.10%.
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-[3-(三氟甲基)苯基]丙酰胺m.p.135-136℃,[α]D+78.8°(c=0.134,CH2Cl2).δH(CDCl3)7.62-7.56(3H,m),7.49-7.22(11H,m),5.53(1H,d,J 8.1Hz),3.47(3H,s),3.08(2H,t,J 7.3 Hz),和2.72(2H,m).元素分析:C26H22F3N3O2:计算值:C,67.09;H,4.76;N,9.03.实测值:C,67.03;H,4.73;N,9.13%.
(+)-3-环己基-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]丙酰胺m.p.144.5-145.5℃,[α]D+83.1°(c=0.116,CH2Cl2).δH(CDCl3)7.62-7.56(3H,m),7.46-7.21(7H,m),5.55(1H,d,J 8.3Hz),3.48(3H,s),2.41-2.36(2H,m),1.77-1.58(7H,m),1.31-1.16(4H,m),和0.98-0.90(2H,m).元素分析:C25H29N3O2:计算值:C,74.41;H,7.24;N,10.41.实测值:C,74.46;H,7.27;N,10.58%.
实例30
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-[2-(三氟甲基)苯基]丙酰胺m.p.110-113℃,[α]D+79.2°(c=0.376,CH2Cl2).δH(CDCl3)7.65-7.57(4H,m),7.50-7.22(10H,m),5.55(1H,d,J8.0Hz),3.47(3H,s),3.20(2H,t,J 7.9 Hz),和2.70(2H,dt,J 7.9,3.3Hz).元素分析:C26H22F3N3O2:计算值:C,67.09;H,4.76;N,9.03.实测值:C,66.97;H,4.76;N,8.93%.
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(4-氰基苯基)丙酰胺m.p.81-85℃,[α]D+91.0°(c=0.111,CH2Cl2).δH(CDCl3)7.64-7.55(4H,m),7.48-7.16(10H,m),5.50(1H,d,J 8.3Hz),3.47(3H,s),3.08(2H,t,J 7.6 Hz),和2.74-2.69(2H,m).元素分析:forC26H22N4O2.0.60H2O.0.50PhCH3:计算值:C,73.93;H,5.62;N,11.69.实测值:C,73.98;H,5.61;N,11.71%.
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(3-氯苯基)丙酰胺m.p.157-159℃,[α]D+90.7°(c=0.134,CH2Cl2).δH(CDCl3)7.62-7.57(3H,m),7.47-7.12(11H,m),5.53(1H,d,J 8.1Hz),3.47(3H,s),3.00(2H,t,J 7.3 Hz),和2.71-2.66(2H,m).元素分析:C25H22ClN3O2.0.55H2O:计算值:C,67.96;H,5.27;N,9.51.实测值:C,67.99;H,5.18;N,9.26%.
E-(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(2-溴苯基)-2-丙烯酰胺m.p.113-116℃,[α]D+44.2°(c=0.113,CH2Cl2).δH(CDCl3)8.03(1H,d,J 15.6 Hz),7.64-7.16(14H,m),6.57(1H,d,J15.6 Hz),5.68(1H,d,J 8.1 Hz),和3.50(3H,s).元素分析:C25H20BrN3O2.0.60H2O.0.30PhCH3:计算值:C,63.48;H,4.58;N,8.19.实测值:C,63.49;H,4.38;N,8.19%.
实例34
E-(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(3-溴苯基)-2-丙烯酰胺m.p.221-223d℃,[α]D+65.5°(c=0.206,CH2Cl2).δH(CDCl3)7.69(1H,brs),7.64-7.57(4H,m),7.51-7.37(6H,m),7.29-7.19(4H,m),6.62(1H,d,J 15.6 Hz),5.66(1H,d,J 8.1 Hz),和3.50(3H,s).元素分析:C25H20BrN3O2.0.35H2O.0.20PhCH3:计算值:C,63.54;H,4.46;N,8.42.实测值:C,63.50;H,4.39;N,8.42%.实例35
E-(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(4-碘苯基)-2-丙烯酰胺m.p.137-140℃,[α]D+67.9°(c=0.268,CH2Cl2).δH(CDCl3)7.75-7.72(2H,m),7.64-7.36(8H,m),7.29-7.16(5H,m),6.63(1H,d,J 15.6 Hz),5.66(1H,d,J 8.1 Hz),和3.50(3H,m).元素分析:C25H20IN3O2.0.30PhCH3:计算值:C,59.29;H,4.06;N,7.65.实测值:C,59.29;H,3.90;N,7.40%.
E-(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(4-溴苯基)-2-丙烯酰胺m.p.121-124℃,[α]D+75.6°(c=0.201,CH2Cl2).δH(CDCl3)7.64-7.57(3H,m),7.55-7.35(11H,m),7.28-7.24(1H,m),6.62(1H,d,J 15.6 Hz),5.66(1H,d,J 8.1 Hz),和3.50(3H,s).元素分析:C25H20BrN3O2:计算值:C,63.30;H,4.25;N,8.86.实测值:C,63.50;H,4.20;N,8.78%.
实例37
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-4-苯基丁酰胺m.p.65-74℃,[α]D+77.4°(c=0.155,CH2Cl2).δH(CDCl3)7.62-7.56(3H,m),7.46-7.19(12H,m),5.55(1H,d,J 8.1Hz),3.47(3H,s),2.71(2H,t,J 7.6 Hz),2.42-2.37(2H,m),和2.09-2.01(2H,m).元素分析:C26H25N3O2.0.30H2O:计算值:C,74.91;H,6.19;N,10.08.实测值:C,74.93;H,6.05;N,10.07%.
实例38
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-5-甲基-3-苯基异噁唑-4-碳酰胺m.p.123-126℃,[α]D+122.0°(c=0.199,CH2Cl2).δH(CDCl3)7.79-7.76(2H,m),7.62-7.32(11H,m),7.26-7.21(2H,m),5.61(1H,d,J 7.9 Hz),3.42(3H,s),和2.76(3H,s).元素分析:C27H20N4O3.0.40H2O:计算值:C,70.85;H,5.02;N,12.24.实测值:C,70.84;H,4.91;N,11.92%.
实例39
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(3-氰基苯基)丙酰胺m.p.110-112℃,[α]D+84.2°(c=0.202,CH2Cl2).δH(CDCl3)7.63-7.22(14H,m),5.51(1H,d,J 8.1 Hz),3.47(3H,s),3.06(2H,t,J 7.8 Hz),和2.74-2.68(2H,m).元素分析:C26H22N4O2.0.50H2O:计算值:C,72.37;H,5.37;N,12.98.实测值:C,72.52;H,5.12;N,12.59%.
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-环己烷乙酰胺m.p:144-146℃,[α]D+72.1°(c=1.000,MeOH)。元素分析:C24H27N3O2.0.20H2O:计算值:C,73.33;H,7.03;N,10.69.实测值:C,73.27;H,7.02;N,10.76%.实例41
(+)-4-环己基-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]丁酰胺[α]D+57.7°(c=0.440,MeOH)元素分析:C26H31N3O2:计算值:C,74.79;H,7.48;N,10.06.实测值:C,74.8;H,7.78;N,10.05%.
实例42
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-4-甲基戊酰胺m.p:123-125℃,[α]D+66.8°(c=0.500,MeOH)。元素分析:C22H25N3O2.0.45H2O:计算值:C,71.12;H,7.03;N,11.31.实测值:C,71.08;H,6.81;N,11.42%.实例43
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-2,3-二氢苯并呋喃-2-碳酰胺
将二异丙基乙基胺(0.3ml,223mg,1.72mmol)加入到3(R)-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮(J.Org.Chem.1987,52,3232-3239)(400mg,1.5mmol)、2,3-二氢苯并呋喃-2-羧酸(274mg,1.7mmol)、1-(3-二甲氨基丙基)-3-乙基碳二酰亚胺盐酸盐(583mg,3.0mmol),和1-羟基苯并三唑(479mg,3.1mmol)在DMF(4.5ml)中的搅拌着的冷却(0℃)溶液中。在室温下将该混合物搅拌18小时,然后将其倒入到盐酸水溶液(3M,12ml)中,并用乙酸乙酯(3×20ml)萃取。合并的有机级分用饱和碳酸氢钠水溶液(20ml)和盐水(20ml)洗涤,干燥(MgSO4),然后在减压下蒸发,残留物从2-氯-2-甲基丙烷/己烷中重结晶,得到(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-2,3-二氢苯并呋喃-2-碳酰胺,呈无色固体(156mg,25%),m.p.141-180℃,[α]D+127.1°(c=0.425,CHCl3)。δH(CDCl3)(3∶1非对映异构体混合物)8.44(1H,m),7.65-6.91(13H,m),5.52(1H,m,),5.28(1H,m),和3.70-3.40(5H,m)。元素分析:C25H21N3O3·0.25己烷计算值:C,73.50;H,5.70;N,9.71.实测值:C,74.12;H,5.57;N,9.71%.
实例44
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-1′-(1,1-二甲基乙氧羰基)螺(环己烷-4,4′-哌啶)-1-碳酰胺步骤A:
1-苄基哌啶-4,4-二乙酸二乙酯
将乙醇(120ml)在冰中冷却,鼓入氨气,得到饱和溶液。加入1-苄基-4-哌啶酮(40.0g,211mmol)和氰基乙酸乙酯(47.8g,423mmol),将反应容器塞紧,在0℃贮存过夜。收集固体物,用乙醇和乙醚洗涤,经真空干燥后得到黄色固体(68.86g)。将该固体(58.86g)溶于硫酸(70ml,98%)和水(60ml)的混合物中,加热回流3天,将混合物冷却,蒸发掉大部分水。残留物与乙醇(4×750ml)共沸,再加入乙醇(500ml),将混合物加热回流20小时,在冰中冷却,在猛烈搅拌下慢慢加入碳酸钠(100g)。在减压下将乙醇蒸发掉,加水(800ml),混合物用二氯甲烷萃取(3×400ml)。将合并的有机萃取物干燥(Na2SO4)、蒸发掉溶剂后得到1-苄基哌啶-4,4-二乙酸二乙酯(37.51g),取少部分该化合物进行快速柱色谱提纯。NMR(300MHz,CDCl3)δ:7.2-7.4(m,5H),4.11(q,J=7.3Hz,4H),3.50(s,2H),2.56(s,4H),2.4(m,4H),1.7(m,4H),1.24(t,J=7.3Hz,6H).步骤B:1-苄基哌啶-4,4-二乙醇
在氩气保护下将该二酯(12.2g,35mmol)的乙醚(25ml)溶液加入到LiAlH4(2.1g,55mmol)在乙醚(400ml)中的冷却(-30℃)和搅拌的悬浮液中。加入THF(60ml),让反应混合物温热到室温。重新冷却到0℃后,依次加入水(2.2ml)、1MNaOH(4.4ml)和水(5ml),将反应混合物猛烈搅拌30分钟,滤出固体物,用乙醚充分洗涤。合并的滤液经蒸发后得到一种白色固体,将其用乙醚研制后得到1-苄基哌啶-4,4-二乙醇。m.p.75-78℃NMR(300MHz,CDCl3)δ:7.2-7.4(m,5H),3.7(t,J=6.8Hz,4H),3.52(s,2H),2.7(brs,2H),2.43(m,4H),1.66(t,J=6.8 Hz,4H),1.5(m,4H).
1-叔丁氧羰基哌啶-4,4-二乙醇
将苄胺(2.07g,7.9mmol)溶于甲醇(60ml)中,加入BOC2O(1.72g,7.9mmol),混合物在50psi(磅/平方英寸)压力下用10%氢氧化钯/木炭(200mg)进行加氢18小时。将反应混合物通过硅藻土过滤,用甲醇洗涤,滤液蒸发后得到1-叔丁氧羰基哌啶-4.4-二乙醇(2.0g)。NMR(300MHz,CDCl3)δ:3.7(m,4H),d3.3(m,6H),1.65(t,J=6.8Hz,4H),1.41(s,9H).
1-叔丁氧羰基哌啶-4,4-二乙醇,双(甲磺酸盐)
将该二醇(2.41g,8.9mmol)溶于二氯甲烷(50ml)中,在氩气保护下将该溶液冷却到-20℃,然后加入三乙胺(3.7mg,26mmol)和甲磺酰氯(1.6ml,20mmol)。30分钟后,将反应混合物倒入到冰冷的10%柠檬酸中,用乙醚萃取三次。合并的萃取物用水、饱和NaHCO3和盐水洗涤、干燥(MgSO4)、将溶剂蒸发,得到1-叔丁氧羰基哌啶-4,4-二乙醇,双(甲磺酸盐)(3.2g)。NMR(300MHz,CDCl3)δ:4.32(t,J=7.1Hz,4H),3.4(m,4H),3.04(s,6H),1.89(t,J=7.1Hz,4H).步骤E:
3-叔丁氧羰基-3-氮杂螺[5.5]十一烷-9.9-二羧酸二乙酯
在氩气保护下将苹果酸二乙酯(3.72ml,24.3mmol)慢慢加入到60%NaH(2.04g,0.51mole)在甲苯(160ml)中的浆液中。将该混合物冷却到0℃,加入固体双甲磺酸盐1(7.0g,16.3mmol),将混合物加热回流18小时。然后,倒入到10%柠檬酸(100ml)中,以终止反应,产物用CH2Cl2(2×150ml)萃取。将萃取物干燥(Na2SO4)、浓缩成油,在硅胶上进行色谱提纯,得到3.83g(60%)3-叔丁氧羰基-3-氮杂螺[5.5]十一烷-9.9-二羧酸二乙酯。1H NMR(CDCl3)δ:1.22(t,6H),1.4(s,9H),2.0(m,4H),3.35(m,4H),4.2(q,4H).
3-叔丁氧羰基-3-氮杂螺[5.5]十一烷-9-羧酸
将1N LiOH(47ml)加入到该二酯2(3.69g,0.0093m)在THF(50ml)中的溶液中。在搅拌下于25℃反应3天,用水(50ml)稀释,用KHSO4将pH值调到2.2。产物萃取到乙酸乙酯(2×75ml)中,用Na2SO4干燥,浓缩成泡沫(3.5g)。让该固体在烧瓶中于140℃熔融2小时,然后冷却,同时将该油溶解在THF(15ml)中,加入1N LiOH(10ml),混合物在30℃搅拌过夜。将反应混合物浓缩,除去THF,用水(20ml)稀释,用二乙基醚(10ml)洗涤。用KHSO4将pH值调节到2.5,产物用乙酸乙酯萃取(3×50ml)。萃取物用Na2SO4干燥、过滤和浓缩,得到3-叔丁氧羰基-3-氮杂螺[5.5]十一烷-9-羧酸,呈泡沫状(2.48g,90%)。1H NMR(CDCl3,partial)δ:1.45(s,9H),3.4(m,4H).
采用基本上如实例43所述程序,但用适当的酸代替2,3-二氢苯并呋喃-2-羧酸,制备了下述化合物:
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-1′-(1,1-二甲基乙氧羰基)螺(环己烷-4,4′-哌啶)-1-碳酰胺m.p.135-138℃,[α]D+58.8°(C=0.925,CHCl3).δH(CDCl3)7.61-7.23(10H,m),5.54(1H,d,J 9.0 Hz),3.47(3H,s),3.37(4H,m),2.28(1H,m),和1.81-1.18(21H,s).元素分析:C32H40N4O4:计算值:C,70.56;H,7.40;N,10.29.实测值:C,70.21;H,7.40;N,10.16%.
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(呋喃-2-基)丙酰胺m.p.115-118℃,[α]D+65.8°(c=0.800,CHCl3).δH(CDCl3)7.62-7.26(11H,m),6.28(1H,dd,J3.2,2.0Hz),6.08(1H,dd,J3.2,0.7Hz),5.58(1H,d,J 8.1 Hz),3.48(3H,s),3.04(2H,t,J 7.6Hz),和2.75(2H,m).元素分析:C23H21N3O3.0.3己烷:计算值:C,72.07;H,6.15;N,10.17.实测值:C,71.78;H,6.30;N,9.77%.
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-H-1,4-苯并二氮杂-3-基]-4-(2-噻吩基)丁酰胺m.p:170-180℃,[α]D+63.5°(c=1.000,MeOH)。元素分析:C24H23N3O2S.0.95H2O:计算值:C,66.32;H,5.77;N,9.67.实测值:C,66.32;H,5.34;N,9.40%.
实例47
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]环己基碳酰胺m.p:213-214℃,[α]D+62.4°(c=1.000,MeOH)。元素分析:C23H24N3O2:计算值:C,73.77;H,6.46;N,11.22.实测值:C,73.86;H,6.81;N,11.15%.
E-(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(3,4-亚甲二氧基苯基)2-丙烯酰胺m.p:143-145℃,[α]D+62.3°(c=0.960,MeOH)。元素分析:C25H21N3O4.0.10H2O.0.20Et2O:计算值:C,69.78;H,5.27;N,9.46.实测值:C,69.78;H,4.98;N,9.28%.
实例49
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-2-喹喔啉碳酰胺[α]D+85.8°(c=1.360,MeOH)。元素分析:C25H19N5O2:计算值:C,69.96;H,4.90;N,15.33.实测值:C,69.95;H,4.72;N,15.25%.
实例50
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-2-(苯基氨基)乙酰胺
步骤A:
N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-2-溴乙酰胺
将溴乙酰溴(165μl,383mg,1.9mmol)加入到冰冷却的3(R)-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮(J.Org.Chem.1987,52,3232-3239)(500mg,1.88mmol)和三乙胺(264μl,192mg,1.9mmol)在二氯甲烷(10ml)中的溶液中,混合物在室温下搅拌1小时。将混合物水洗(3×10ml)、干燥(MgSO4)及减压下蒸出溶剂,得到N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-2-溴乙酰胺,呈无色泡沫状(760mg,100%)。δH(CDCl3)8.24(1H,d,J 7.8 Hz),7.64-7.24(9H,m),5.48(1H,d,J7.8 Hz),4.00(2H,m),和3.50(3H,s).
步骤B:
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-2-(苯基氨基)乙酰胺
将苯胺(297μl,304mg,3.26mmol)加入到N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-2-溴乙酰胺(600mg,1.55mmol)的乙醇(25ml)溶液中,混合物在回流下加热24小时。将该混合物冷却,收集固体物,用乙醇(20ml)重结晶,得到(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-2-(苯基氨基)乙酰胺,呈无色固体(500mg,81%)。m.p:245-246℃,[α]D+119°(c=0.850,CHCl3)。δH(CDCl3)8.26(1H,d,J 8.3 Hz),7.63-7.20(12H,m),6.81(1H,t,J7.3Hz),6.72(2H,d,J 7.6 Hz),5.56(1H,d,J 8.3 Hz),3.95(2H,d,J 1.5Hz),和3.45(3H,s).元素分析:C24H22N4O2:计算值:C,72.34;H,5.57;N,14.06.实测值:C,72.37;H,5.59;N,14.32%.
采用基本上如上述的程序,但用2-氯苯胺或4-(三氟甲基)苯胺代替苯胺,制得了下列化合物:
实例51
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-2-(2-氯苯基氨基)乙酰胺m.p.222-224℃,[α]D+111°(c=0.973,CHCl3).δH(CDCl3)8.15(1H,d,J 8.3 Hz),7.60-7.16(12H,m),6.71(2H,m),5.57(1H,d,J 8.3 Hz),4.01(2H,d,J 2.7 Hz),和3.45(3H,s).元素分析:C24H21ClN4O2:计算值:C,66.59;H,4.89;N,12.94.实测值:C,66.40;H,4.94;N,12.92%.实例52
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-2-[4-(三氟甲基)苯基氨基]乙酰胺m.p.218-219℃,[α]D+91.9°(c=0.419,CHCl3).δH(CDCl3)8.13(1H,d,J 9.0 Hz),7.70-7.25(12H,m),6.72(2H,d,J8.7 Hz),5.60(1H,d,J 9.0 Hz),4.05(2H,m),和3.50(3H,s).元素分析:C25H21F3N4O2.0.7H2O:计算值:C,62.68;H,4.71;N,11.69.实测值:C,62.47;H,4.32;N,11.44%.
实例53
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-2-(苯氧基)乙酰胺
将苯酚(104mg,1.1mmol)加入到氢化钠(在矿物油中的60%分散液,44mg,1.1mmol)的甲苯(10ml)悬浮液中。当氢气停止放出时加入N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-2-溴乙酰胺(400mg,1.04mmol),混合物在室温下搅拌18小时。将该混合物水洗(3×15ml)、干燥(MgSO4),在减压下蒸出溶剂。残留物用2-丙醇调制,收集固体物、用2-丙醇(5ml)重结晶,得到无色固体状的(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-2-(苯氧基)乙酰胺(112mg,27%)。m.p:126-128℃,[α]D+81.6°(c=0.692,CHCl3)。δH(CDCl3)8.49(1H,d,J 8.2 Hz),7.64-7.01(14H,m),5.61(1H,d,J8.2 Hz),4.65(1H,d,J 14.6 Hz),4.58(1H,d,J 14.6 Hz),和3.50(3H,s).元素分析:C24H21N3O3:计算值:C,72.17;H,5.30;N,10.52.实测值:C,71.84;H,5.25;N,10.41%.
采用基本上如上述的程序,但用2,4-二氯苯酚、苯硫酚或2,4-二氯苯硫酚代替苯酚,制得了下列化合物:
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-2-(2,4-二氯苯氧基)-乙酰胺m.p.206℃,[α]D+31.1°(c=0.289,CHCl3).δH(CDCl3)8.75(1H,d,J 9.0 Hz),7.65-7.20(11H,m),6.90(1H,d,J8.7 Hz),5.60(1H,d,J 9.0 Hz),4.65(2H,m),和3.50(3H,s).元素分析:C24H19Cl2N3O3.0.3H2O:计算值:C,60.85;H,4.17;N,8.87.实测值:C,60.80;H,4.04;N,8.87%.实例55
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-2-(苯硫基)乙酰胺[α]D+104.9°(c=0.316,CHCl3).δH(CDCl3)8.50(1H,d,J 9.0 Hz),7.60-7.20(14H,m),5.50(1H,d,J9.0 Hz),3.75(2H,m),和3.45(3H,s).元素分析:C24H21N3O2S:计算值:C,69.37;H,5.10;N,10.1 1.实测值:C,68.98;H,5.06;N,9.76%.
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基1H-1,4-苯并二氮杂-3-基]-2-(2,4-二氯苯硫基)乙酰胺[α]D+97.4°(c=0.286,CHCl3).δH(CDCl3)8.35(1H,d,J 9.0 Hz),7.70-7.20(12H,m),5.50(1H,d,J9.0 Hz),3.70(2H,m),和3.50(3H,s).元素分析:forC24H19Cl2N3O2S:计算值:C,59.51;H,3.95;N.8.67.实测值:C,59.32;H,3.95;N,8.65%.实例57
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(苯基氨基)丙酰胺
将3-溴丙酰氯(2.01ml,3.428g,20mmol)加入到冰冷却的3(R)-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮(J.0rg.Chem.1987,52,3232-3239)(5.0g,18.8mmol)和三乙胺(2.79ml,2.02mg,20mmol)在二氯甲烷(85ml)中的溶液中,混合物在室温下搅拌18小时,混合物用饱和碳酸氢钠水溶液(85ml)、水(2×85ml)和盐水(85ml)洗涤,干燥(MgSO4),在减压下蒸出溶剂。样品(0.5g,1.25mmol)溶于乙醇(25ml)中,加入苯胺(230μl,233mg,2.5mmol),混合物在回流下加热70小时。将混合物冷却,收集固体物,用乙醇重结晶,得到(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(苯基氨基)丙酰胺,呈无色固体状。mp:218-221℃,[α]D+58.2°(c=0.585,CHCl3).δH(CDCl3)7.60-6.71(16H,m),5.54(1H,d,J 8.1 Hz),3.54(2H,t,J6.1 Hz),3.52(3H,s),和2.70(2H,m).元素分析:C25H24N4O2.0.5EtOH:计算值:C,71.70;H,6.25;N,12.87.实测值:C,71.42;H,5.98;N,12.84%.
实例58
(+)-1-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(2,4-二氯苯基)脲
将2,4-二氯苯基异氰酸酯(188mg,1.0mmol)加入到3(R)-氨基1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮(J.0rg.Chem.1987,52,3232-3239)(265mg,1.0mmol)的四氢呋喃(20ml)溶液中。混合物在室温搅拌18小时,减压蒸出溶剂。残留物用快速柱色谱在硅胶上提纯,用CH2Cl2/MeOH(99.5:0.5)洗脱,残留物用CH2Cl2/己烷重结晶,得到无色固体状(+)-1-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(2,4-二氯苯基)脲,m.p:215-216℃;[α]D+76.2°(c=0.261,CHCl3).δH(CDCl3)8.10(1H,d,J 9.0 Hz),7.65-6.95(13H,m),5.50(1H,d,J9.0 Hz),和3.50(3H,s).元素分析:C23H18Cl2N4O2.0.3H2O:计算值:C,60.22;H,4.09;N,12.21.实测值:C,60.28;H,3.89;N,12.10%.
(-)-3-环己基-N-[(3R)-2,3-二氢-1-甲基-2-氧代-4-氧-5-苯基-1H-1,4-苯并二氮杂-3-基]丙酰胺
将3-氯过苯甲酸(80%,0.32g,1.5mmol)加入到(+)-3-环己基-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]丙酰胺(0.60g,1.5mmol)的二氯甲烷(25ml)溶液中,混合物在室温下搅拌18小时。再加入3-氯过苯甲酸(80%,0.1g,0.5mmol),再将混合物搅拌24小时。混合物用饱和碳酸氢钠水溶液(4×25ml)、水(2×25ml)和盐水(25ml)洗涤,干燥(MgSO4),减压蒸出溶剂。残留物用甲苯/己烷(65:35)重结晶,得到无色棱晶状(-)-3-环己基-N-[(3R)-2,3-二氢-1-甲基-2-氧代-4-氧-5-苯基-1H-1,4-苯并二氮杂-3-基]丙酰胺,m.p:222-224℃,[α]D-80.7°(c=1.15,CHCl3).δH(CDCl3)7.71-7.23(10H,m),6.01(1H,d,J 9.3 Hz),3.54(3H,s),2.48(2H,m),和1.76-0.89(13H,m).元素分析:C25H29N3O3.0.5H2O:计算值:C,70.06;H,7.06;N,9.81.实测值:C,70.10;H,6.80;N,9.79%.
实例60
N-[2,3-二氢-1-(2-二甲氨基乙基)-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(2,4-二氯苯基)丙酰胺
2,3-二氢-1-(2-二甲氨基乙基)-5-苯基-1H-1,4-苯并二氮杂-2-酮
将2,3-二氢-5-苯基-1H-1,4-苯并二氮杂-2-酮(1.00g,4.23mmol)加入到在DMF(5ml)中的己烷洗过的氢化钠(在矿物油中的60%分散液,186mg,4.65mmol)中。再加入DMF(10ml),混合物在室温下搅拌。将2-(二甲氨基)乙基氯盐酸盐(0.73g,5mmol)加入到在DMF(5ml)中的己烷洗过的氢化钠(在矿物油中的60%分散液,200mg,5.0mmol)中,然后将上述两种混合物合并,加入碘化钾(1个晶粒),混合物在110℃搅拌30分钟。减压蒸出溶剂,加水,用乙酸乙酯萃取该混合物。合并的有机级分用水洗涤(2次)、干燥(MgSO4),减压蒸出溶剂,得到2,3-二氢-1-(2-二甲氨基乙基)-5-苯基-1H-1,4-苯并二氮杂-2-酮(1.21g,93%)。δH(CDCl3)7.63-7.16(9H,m),4.77(1H,d,J 10.6 Hz),4.41(1H,m),3.80(1H,m),3.78(1H,d,J 10.6 Hz),2.49(2H,m),和2.13(6H,s).步骤B:
2,3-二氢-1-(2-二甲氨基乙基)-3-肟基-5-苯基-1H-1,4-苯并二氮杂-2-酮
将2,3-二氢-1-(2-二甲氨基乙基)-5-苯基-1H-1,4-苯并二氮杂-2-酮(1.21g,3.9mmol)溶解在甲苯(20ml)中。将混合物冷却至-78℃,加入叔丁醇钾(在权丁醇中的1.0M溶液,4.72ml,4.72mmol)。混合物在-78℃搅拌20分钟,然后加入亚硝酸异戊酯(0.63ml,0.55g,4.72mmol)混合物在-78℃搅拌90分钟,然后让其温热至室温,倒入到柠檬酸水溶液中(1M,10ml)。用氢氧化钠水溶液将pH调节到5.0,再用饱和碳酸氢钠水溶液调节到7.0。混合物用乙酸乙酯(50ml)萃取,有机层在室温下陈化。收集所形成的固体物,经真空干燥后得到2,3-二氢-1-(2-二甲氨基乙基)-3-肟基-5-苯基-1H-1,4-苯并二氮杂-2-酮(0.876g,66%)呈固体,m.p:232-234℃。δH(d6-DMSO)10.90(1H,s),7.72-7.25(9H,m),4.40(1H,m),3.80(1H,m),2.50(2H,m),和1.85(6H,s).
步骤C:
3-氨基-2,3-二氢-1-(2-二甲氨基乙基)-5-苯基-1H-1,4-苯并二氮杂-2-酮
将异氰酸乙酯(320μl,287mg,4.0mmol)加入到2,3-二氢-1-(2-二甲氨基乙基)-3-肟基-5-苯基-1H-1,4-苯并二氮杂-2-酮(0.91g,2.7mmol)和三乙胺(0.56ml,0.41g,4.0mmol)的THF(30ml)溶液中。将混合物回流加热7小时,再加入异氰酸乙酯(167μl,150mg,2.1mmol),再将混合物回流加热12小时,然后将混合物冷却,减压蒸出溶剂,加入乙酸乙酯(75ml)和水(25ml)。将有机相水洗(4×25ml)、干燥(MgSO4)、减压蒸发。残留物溶解在乙醇(100ml)中,加入披钯炭(10%,100mg),在氢压(50p.s.i.)下将混合物振动4.5小时。再加入披钯炭(10%,100mg),混合物再次在氢压下(50p.s.i.)下振动1.5小时。将混合物过滤,减压蒸出溶剂。残留物在硅胶上用快速柱色谱提纯,用CH2Cl2/MeOH洗脱,得到3-氨基-2,3-二氢-1-(2-二甲氨基乙基)-5-苯基-1H-1,4-苯并二氮杂-2-酮(180mg,17%)。δH(CDCl3)7.75-7.17(9H,m),4.45(1H,s),4.40(1H,m),3.82(1H,m),2.47(4H,m),和2.08(6H,s).
N-[2,3-二氢-1-(2-二甲氨基乙基)-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(2,4-二氯苯基)丙酰胺
将三乙胺加入到3-氨基-2,3-二氢-1-(2-二甲氨基乙基)-5-苯基-1H-1,4-苯并二氮杂-2-酮(180mg,0.6mmol)、3-(2,4-二氯苯基)丙酸(131mg,0.6mmol)、1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐(115mg,0.6mmol)和1-羟基苯并三唑(81mg,0.6mmol)在DMF(15ml)中的混合物中,直到pH为9.0。混合物在室温下搅拌72小时。减压蒸出溶剂,加入乙酸乙酯。将混合物用水、饱和碳酸氢钠水溶液及水洗涤,干燥(MgSO4),减压蒸发。残留物用丙酮调制,用异丙醇/甲醇重结晶,得到N-[2,3-二氢-1-(2-二甲氨基乙基)-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(2,4-二氯苯基)丙酰胺,呈固体状,m.p:199-201℃。δH(CDCl3)7.60-7.15(13H,m),5.50(1H,d,J 8.0 Hz),4.40(1H,m),3.80(1H,m),3.10(2H,t,J 7.5 Hz),2.70(2H,t,J 7.5 Hz),2.40(2H,m),和2.05(6H,s).元素分析:C28H28Cl2N4O2:计算值:C,64.25;H,5.39;N,10.70.实测值:C,64.23;H,5.40;N,10.61%.
(+)-3(R)-{N-[3-(4-氯苯基)丙-1-烯-3-基]氨基}-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮盐酸盐
3(R)-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮(J.Org.Chem.1987,52,3232-3239)(265mg,1mmol)、E-1-氯-4-(3-氯-1-丙烯基)苯(281mg,1.5mmol)、碳酸钾(276mg,2mmol)和碘化钾(25mg,0.15mmol)在乙腈(2ml)中的混合物回流加热4小时。混合物冷却后倒入到乙酸乙酯(10ml)和水(5ml)中。将两层分离,水层用乙酸乙酯(5ml)萃取。合并后的有机级分用盐水洗涤,干燥(Na2SO4),减压蒸出溶剂。残留物在硅胶上用快速柱色谱提纯,用乙酸乙酯/己烷(65∶35升至100∶0)洗脱。先洗出的化合物悬浮于乙醇(1ml)中,加入乙醇盐酸(6M,0.11ml)。将混合物搅拌,减压蒸出溶剂。残留物用乙醚调制,收集固体物。经真空干燥后得到(+)-3(R)-{N,N-二[1-(4-氯苯基)-丙烯-3-基]-氨基}-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮盐酸盐(235mg,39%)呈固体状。m.p.138-145℃,[α]D+9.2°(c=0.500,MeOH).δH(d6-DMSO)11.2(1H,brs),7.77-7.31(17H,m),6.85(2H,brm),6.54(2H,m),5.20(1H,brs),4.60-4.00(4H,m),and3.46(3H,s).元素分析:C34H29Cl2N3O.HCl.0.10EtOH:计算值:C,67.60;H,5.08;N,6.92.实测值:C,67.60;H,5.03;N,7.03%.
后洗出的化合物悬浮于乙醇(0.5ml)中,加入乙醇HCl(6M,0.035ml)。将混合物搅拌,减压蒸出溶剂。残留物用乙醚调制,收集固体物,经真空干燥后得到(+)-3(R)-{N-[3-(4-氯苯基)丙烯-3-基]氨基}-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮盐酸盐(56mg,12%),呈黄色固体,m.p:156-162℃,[α]D+35°(c=0.100,MeOH)。δH(d6-DMSO)10.3(1H,brs),10.0(1H,brs),7.79-7.34(13H,m),6.78(1H,d,J 15.9 Hz),6.40(1H,dt,Jd 15.9,Jt 9.0 Hz),5.13(1H,s),4.00(2H,m),和3.46(3H,s).元素分析:C25H22CN3O.HCl.0.10EtOH.0.40H2O:计算值:C,65.20;H,5.30;N,9.05.实测值:C,65.14;H,5.09;N,9.33%.
采用基本上如上所述的程序,但用1-(2-溴乙氧基)-4-硝基苯或4-氯苯-丙醇甲磺酸盐代替E-1-氯-4-(3-氯-1-丙烯基)-苯,制得了下列化合物:
实例62
(+)-3(S)-{N,N-二[2-(4-硝基苯氧基)乙基]氨基}-1,3-二氢-1-甲基-5-苯基-2H-4,4-苯并二氮杂-2-酮盐酸盐m.D.126-145℃.[α]D+5.0°(0.100.CHCl3).δH(d6-DMSO)8.20(4H,d,J 9.2 Hz),7.75-7.36(9H,m),7.08(4H,d,J9.2 Hz),4.90(1H,brs),4.50(4H,brs),4.30-3.60(5H,brm),和3.34(3H,s).元素分析:C32H29N5O7.HCl.0.15EtOH:计算值:C,60.71;H,4.87;N,10.96.实测值:C,60.70;H,4.87;N,10.70%.
实例63
(+)-3(R)-{N-[3-(4-硝基苯氧基)乙基]氨基}-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮盐酸盐m.p.154-160℃,[α]D+84.6°(0.500,MeOH).δH(d6-DMSO)10.2(1H,brs),8.25(2H,d,J 9.0 Hz),7.83-7.41(9H,m),7.09(2H,d,J 9.0 Hz),5.21(1H,s),4.57(2H,m),3.70(2H,m),3.47(3H,s),和3.40(1H,m).元素分析:forC24H22N4O4.HCl.0.15EtOH.0.20H2O:计算值:C,61.13;H,5.13;N,11.74.实测值:C,61.12;H,4.92;N,11.64%.
实例64
(+)-3(R)-{N-[3-(4-氯苯基)丙-1-基]氨基}-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮盐酸盐m.p.167-168C,[α]D+20.8°(c=0.500,MeOH).δH(d6-DMSO)9.9(2H,brm),7.78-7.26(13H,m),5.08(1H,s),3.45(3H,s),3.20(1H,m),3.00(1H,m),2.70(2H,t,J 7.4 Hz),和2.05(2H,m).元素分析:C25H24ClN3O.HCl:计算值:C,66.08;H,5.55;N,9.25.实测值:C,65.81;H,5.49;N,9.30%.
(+)-N-[(3R)-2,3-二氢-1-甲基-5-苯基-2-硫代-1H-1,4-苯并二氮杂-3-基]氨基甲酸苯甲酯
将(+)-N-[(3R)-2,3-二氢-1-甲基-5-苯基-2-氧代-1H-1,4-苯并二氮杂-3-基]氨基甲酸苯甲酯(4.0g,10mmol)和2,4-二(4-甲氧基苯基)-1,3-二噻-2,4-二磷烷(diphosphetane)2,4-二硫化物(4.5g,11mmol)在甲苯(100ml)中的混合物加热回流75分钟。将混合物冷却,在减压下蒸发使体积减少到30ml。残留物用硅胶柱闪急色谱提纯,用乙酸乙酯/己烷(75∶25)洗脱,得到(+)-N-[(3R)-2,3-二氢-1-甲基-5-苯基-2-硫代-1H-1,4-苯并二氮杂-3-基]氨基甲酸苯甲酯。呈固体状,
m.p.128-131℃,[α]D+22.5°(c=0.656,CHCl3).δH(CDCl3)7.65-7.26(15H,m),5.50(1H,d,J 8.8 Hz),5.14(2H,s),和3.86(3H,s).元素分析:C24H21N3O2S.0.25H2O:计算值:C,68.63;H,5.16;N,10.01.实测值:C,68.28;H,5.21;N,10.06%.
采用基本上如上面所述程序,但用N-[2,3-二氢-5-苯基-2-氧代-1 H-1,4-苯并二氮杂-3-基]氨基甲酸苯甲酯代替(+)-N-[(3R)-2,3-二氢-1-甲基-5-苯基-2-氧代-1H-1,4-苯并二氮杂-3-基]氨基甲酸苯甲酯,制得下列化合物:
实例66
N-[2,3-二氢-5-苯基-2-硫代-1H-1,4-苯并二氮杂-3-基]氨基甲酸苯甲酯δH(d6-DMSO)10.85(1H,s),8.42(1H,d,J 8.6 Hz),7.65-7.10(14H,m),5.10(2H,s),和5.05(1H,d,J 8.6 Hz).
3-环己基-N-(2,3-二氢-1-甲基-5-苯基-2-硫代-1H-1,4-苯并二氮杂-3-基)丙酰胺
在室温下将溴化氢鼓泡通过(+)-N-[(3R)-2,3-二氢-1-甲基-5-苯基-2-硫代-1H-1,4-苯并二氮杂-3-基]氨基甲酸苯甲酯(0.9g,2.1mmol)、乙酸(5ml)和二氯甲烷(5ml)的溶液中。2小时后,在减压下蒸出溶剂,加入乙醚,收集固体物,进行真空干燥。将样品(0.58g,1.8mmol)悬浮于THF(10ml)中,加入三乙胺(0.24ml,0.18g,1.8mmol),混合物在室温下搅拌3小时。在另-个烧瓶中,将草酰氯(0.20ml,0.29g,2.3mmol)加入到环己烷丙酸(0.33ml,0.30g,1.9mmol)和DMF(1滴)在THF(10ml)的溶液中。将上述两种混合物合并,加入三乙胺(0.32ml,0.23g,2.3mmol),混合物在室温下搅拌2.5小时。减压蒸出溶剂,加水,混合物用乙酸乙酯萃取,合并的有机级分用水、饱和碳酸氢钠水溶液、水(2次)和盐水洗涤,干燥(Na2SO4),在减压下蒸出溶剂。残留物用硅胶柱闪急色谱提纯,用CH2Cl2/MeOH(99.5:0.5)洗脱,残留物用乙酸乙酯,/己烷重结晶,得到3-环己基-N-(2,3-二氢-1-甲基-5-苯基-2-硫代-1H-1,4-苯并二氮杂-3-基)丙酰胺,呈固体状,m.p:219-221℃。δH(CDCl3)7.95(1H,brd,J 8.6 Hz),7.65-7.30(9H,m),5.72(1H,d,J8.6 Hz),3.87(3H,s),2.41(2H,t,J 7.6 Hz),和1.80-0.85(13H,m).元素分析:C25H29N3OS.0.25H2O:计算值:C,70.81;H,7.01;N,9.91.实测值:C,70.80;H,6.91;N,9.95%.
采用基本上如上面所述程序,但用N-[2,3-二氢-5-苯基-2-硫代-1H-1,4-苯并二氮杂-3-基]氨基甲酸苯甲酯代替(+)-N-[(3R)-2,3-二氢-1-甲基-5-苯基-2-硫代-1H-1,4-苯并二氮杂-3-基]氨基甲酸苯甲酯和用适当的酸代替环己烷丙酸,制得了下列化合物:
3-环己基-N-(2,3-二氢-5-苯基-2-硫代-1H-1,4-苯并二氮杂-3-基]丙酰胺m.p.113-119℃.δH(CDCl3)9.8(1H,brs),7.75-7.25(10H,m),5.75(1H,d,J 8.1 Hz),2.41(2H,m),和1.80-0.85(13H,m).元素分析:C24H27N3OS.0.8CH2Cl2:计算值:C,62.91;H,6.09;N,8.87.实测值:C,62.88;H,5.70;N,9.12%.实例69
3-环己基-N-(2,3-二氢-2-亚肼基-5-苯基-1H-1,4-苯并二氮杂-3-基)丙酰胺
将肼(53μl,56mg,1.8mmol)加入到3-环己基-N-(2,3-二氢-1-甲基-5-苯基-2-硫代-1H-1,4-苯并二氮杂-3-基)丙酰胺(120mg,0.25mmol)的甲醇(3ml)溶液中。混合物在室温下搅拌3小时,减压蒸出溶剂。加入乙酸乙酯,混合物用水和盐水洗涤,干燥(MgSO4),在减压下蒸出溶剂,残留物用硅胶柱闪急色谱提纯,用CH2Cl2/MeOH(99.5∶0.5升至98∶2)洗脱,得到3-环己基-N-(2,3-二氢-2-亚肼基-5-苯基-1H-1,4-苯并二氮杂-3-基)丙酰胺,呈泡沫状。δH(CDCl3)7.55-7.00(11H,m),5.75(1H,d,J 7.6 Hz),3.50(2H,brs),2.37(2H,t,J 8.0 Hz),和1.80-0.85(13H,m).元素分析:C24H29N5O.0.8CH3OH.0.15CH2Cl2:计算值:C,67.82;H,7.41;N,15.85.实测值:C,67.79;H,7.46;N,16.05%.
实例70
(E)-和(Z)-3-环己基-N-(2,3-二氢-2-肟基-5-苯基-1H-1,4-苯并二氮杂-3-基)丙酰胺
将3-环己基-N-(2,3-二氢-1-甲基-5-苯基-2-硫代-1H-1,4-苯并二氮杂-3-基)丙酰胺(740mg,1.83mmol)、盐酸羟胺(140mg,2mmol)和三乙胺(280μl,203mg,2mmol)在甲醇(15ml)/THF(15ml)中的混合物在室温搅拌3小时。在减压下蒸出溶剂,用硅胶柱闪急色谱提纯,用CH2Cl2/MeOH(98∶2)洗脱。残留物用乙酸乙酯重结晶。先结晶出来的异构体用乙酸乙酯重结晶,得到(E)-3-环己基-N-(2,3-二氢-2-肟基-5-苯基-1H-1,4-苯并二氮杂-3-基)丙酰胺,呈固体状,m.p.196℃。δH(d6-DMSO)12.20(1H,s),9.00(1H,d,J 8.0 Hz),7.70-7.30(10H,m),5.45(1H,d,J 8.0 Hz),2.30(2H,m),和1.80-0.75(13H,m).
后结晶出来的异构体用甲醇重结晶,得到(Z)-3-环己基-N-(2,3-二氢-2-肟基-5-苯基-1H-1,4-苯并二氮杂-3-基)丙酰胺,呈固体状,m.p.219℃。δH(d6-DMSO)9.95(1H,s),8.95(1H,s),8.75(1H,d,J 8.0 Hz),7.50-7.00(9H,m),5.70(1H,d,J 8.0 Hz),2.25(2H,m),和1.75-0.75(13H,m).元素分析:C24H28N4O2:计算值:C,71.26;H,6.98;N,13.85.实测值:C,70.89;H,6.99;N,13.55%.
3-环己基-N-(2,3-二氢-1-甲基-5-苯基-1H-1,4-苯并二氮杂-3-基)丙酰胺
将新制备的阮内镍(400mg)加入到3-环己基-N-(2,3-二氢-1-甲基-5-苯基-2-硫代-1H-1,4-苯并二氮杂-3-基)丙酰胺(200mg,0.5mmol)的乙醇(20ml)溶液中,混合物在室温下搅拌2小时。将混合物过滤,在减压下蒸出溶剂。残留物用硅胶柱闪急色谱提纯,用CH2Cl2/MeOH(99.75:0.25)洗脱,得到泡沫状的3-环己基-N-(2,3-二氢-1-甲基-5-苯基-1H-1,4-苯并二氮杂-3-基)丙酰胺。δH(CDCl3)7.60-6.80(9H,m),6.37(1H,brd,J 6.6 Hz),5.53(1H,m),3.60(2H,m),2.77(3H,s),2.21(2H,t,J 8.0 Hz),和1.85-0.80(13H,m).元素分析:forC25H31N3O.0.2CH2Cl2:计算值:C,74.45;H,7.79;N,10.34.实测值:C,74.68;H,7.87;N,10.23%.
实例72
1-(2,3-二氢-1-甲基-2-氧代-5-苯基-1H-噻吩并[2,3-e]-1,4-二氮杂-3-基)-3-(3-甲基苯基)脲
(2-氨基-3-噻吩基)苯基甲酮
将三乙胺(6.8ml,4.94g,49mmol)加入到β-氧代苯丙腈(18.6g,128mmol)和1,2-二噻烷-2,5-二醇(9.8g,64mmol)在乙醇(120ml)中的加热(33℃)混合物中,混合物在50℃搅拌18小时。将混合物冷却,在减压下蒸出溶剂。加入二氯甲烷,混合物用盐酸水溶液(0.5M)、氢氧化钠水溶液(1M)及盐水洗涤,干燥(Na2SO4),在减压下蒸出溶剂。残留物用乙腈(150ml)重结晶,得到-种橙色固体状(2-氨基-3-噻吩基)苯基甲酮,(5.7g,44%)。δH(CDCl3)7.70-7.35(5H,m),6.95(2H,brs),6.90(1H,d,J 6.3 Hz),和6.15(1H,d,J 6.3 Hz).
步骤B:
2,3-二氢-5-苯基-1H-噻吩并[2,3-e]-1,4-二氮杂-2-酮
将1,3-二氢-1,3-二氧代-2H-异吲哚-2-乙酰氯(8.6g,38mmol)的二氯甲烷(20ml)溶液慢慢加入到(2-氨基-3-噻吩基)苯基甲酮(6.8g,33mmol)、吡啶(6.34ml,6.20g,78mmol)和4-二甲氨基吡啶(0.79g,6.5mmol)在二氯甲烷(130ml)中的冷却(0℃)混合物中。该混合物在0℃搅拌30分钟,用二氯甲烷(80ml)稀释,用盐酸水溶液(1M)、饱和碳酸氢钠水溶液及盐水洗涤,用硫酸钠干燥,在减压下蒸出溶剂,残留物用乙醇调制,收集固体物,经真空干燥后得到N-(3-苯甲酰基噻吩-2-基)1,3-二氢-1,3-二氧代-2H-异吲哚-2-乙酰胺,呈固体状(9.8g,76%)。
将N-(3-苯甲酰基噻吩-2-基)1,3-二氢-1,3-二氧代-2H-异吲哚-2-乙酰胺(10.9g,28mmol)和肼(1.9ml,1.94g,60mmol)在THF(500ml)中的混合物回流加热4小时。将混合物冷却、过滤,在减压下蒸出溶剂。加入饱和碳酸氢钠水溶液,混合物用乙酸乙酯萃取。合并的有机级分用盐水洗涤、干燥(Na2SO4),在减压下蒸出溶剂。加入乙酸(300ml),混合物在回流下加热15分钟。将混合物冷却,在减压下蒸出溶剂。加入碳酸氢钠水溶液,用乙酸乙酯萃取。合并的有机级分用盐水洗涤、干燥(Na2SO4),在减压下蒸出溶剂,得到2,3-二氢-5-苯基-1H-噻吩并[2,3-e]-1,4-二氮杂-2-酮(3.5g,52%),呈泡沫状。δH(CDCl3)9.75(1H,brs),7.90-7.30(5H,m),6.87(1H,d,J 6.0 Hz),6.82(1H,d,J 6.0 Hz),和4.45(2H,s).
2,3-二氢-1-甲基-5-苯基-1H-噻吩并[2,3-e]-1,4-二氮杂-2-酮
将氢化钠(在矿物油中的60%分散液,757mg,11.3mmol)加入到冷却的(0℃)2,3-二氢-5-苯基-1H-噻吩并[2,3-e]-1,4-二氮杂-2-酮(2.61g,10.8mmol)的DMF(7ml)溶液中。再加入DMF(10ml),将混合物搅拌30分钟。加入碘甲烷(0.67ml,1.53g,10.8mmol)的乙醚(20ml)溶液,搅拌1小时。将混合物倒入到水中,用乙酸乙酯萃取。合并的有机级分用盐水洗涤,干燥(Na2SO4),在减压下蒸发。残留物用硅胶柱闪急色谱提纯,用CH2Cl2/MeOH(95∶5)洗脱,得到2,3-二氢-1-甲基-5-苯基-1H-噻吩并[2,3-e]-1,4-二氮杂-2-酮(1.5g,54%)。δH(CDCl3)7.67-7.35(5H,m),7.00(1H,d,J 6.0 Hz),6.85(1H,d,J6.0 Hz),4.45(2H,br s),和3.50(3H,s).
3-氨基-2,3-二氢-1-甲基-5-苯基-1H-噻吩并[2,3-e]-1,4-二氮杂-2-酮
将2,3-二氢-1-甲基-5-苯基-1H-噻吩并[2,3-e]-1,4-二氮杂-2-酮(1.5g,5.8mmol)溶于甲苯(30ml)中。将混合物冷却到-10℃,加入叔丁醇钾(1.7g,15.1mmol)。混合物在-10℃搅拌15分钟,然后加入亚硝酸异戊酯(1.0ml,0.87g,7.4mmol)。混合物在-10℃搅拌1小时,令其温热至室温,然后倒入到水(50ml)和乙酸(3ml)中。混合物用乙酸乙酯萃取,合并的有机级分用盐水洗涤、干燥(Na2SO4),在减压下蒸出溶剂。残留物用硅胶柱闪急色谱提纯,用乙酸乙酯/己烷洗脱,得到2,3-二氢-1-甲基-3-肟基-5-苯基-1H-噻吩并[2,3-e]-1,4-二氮杂-2-酮(0.80g,48%)。
将2,3-二氢-1-甲基-3-肟基-5-苯基-1H-噻吩并[2,3-e]-1,4-二氮杂-2-酮(0.80,2.8mmol)溶于乙醇(40ml)中,加入阮内镍(2g)。将混合物在氢气(50p.s.i.)下振荡5天,再分批加入阮内镍(10g)。将混合物过滤,在减压下蒸出溶剂。残留物用硅胶柱闪急色谱提纯,用CH2Cl2/MeOH洗脱,得到3-氨基-2,3-二氢-1-甲基-5-苯基-1H-噻吩并[2,3-e]-1,4-二氮杂-2-酮(248mg,33%)。δH(CDCl3)7.50-7.30(5H,m),7.05(1H,d,J 6.0 Hz),6.85(1H,d,J6.0 Hz),4.57(1H,s),3.55(3H,s),和1.70(2H,brs).
1-(2,3-二氢-1-甲基-2-氧代-5-苯基-1H-噻吩并[2,3-e]-1,4-二氮杂-3-基)-3-(3-甲基苯基)脲
将异氰酸3-甲基苯酯(60μl,62mg,0.46mmol)加入到3-氨基-2,3-二氢-1-甲基-5-苯基-1H-噻吩并[2,3-e]-1,4-二氮杂-2-酮(124mg,0.46mmol)的THF(5ml)溶液中。混合物在室温下搅拌2小时,在减压下蒸出溶剂,残留物用乙酸乙酯(4ml)结晶,得到固体状的1-(2,3-二氢-1-甲基-2-氧代-5-苯基-1H-噻吩并[2,3-e]-1,4-二氮杂-3-基)-3-(3-甲基苯基)脲(94mg,50%)。m.p.128-130℃.δH(CDCl3)8.70(1H,s),7.65-6.75(12H,m),5.55(1H,d,J 9.0 Hz),3.55(3H,s),和2.30(3H,s).元素分析:C22H20N4O2S.0.25H2O:计算值:C,64.62;H,4.99;N,13.70.实测值:C,64.68;H,4.96;N,13.70%.实例73
3-环己基-N-(2,3-二氢-1-甲基-2-氧代-5-苯基-1H-噻吩并[2,3-e]-1,4-二氮杂-3-基)丙酰胺
将三乙胺(75μl,54mg,0.54mmol)加入到3-氨基-2,3-二氢-1-甲基-5-苯基-1H-噻吩并[2,3-e]-1,4-二氮杂-2-酮(82mg,0.3mmol)、环己烷丙酸(52μl,47mg,0.3mmol)、1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐(58mg,0.3mmol)和1-羟基苯并三唑(42mg,0.3mmol)在DMF(1.5ml)中的混合物中。该混合物在室温下搅拌18小时,加入乙酸乙酯(60ml)。混合物用柠檬酸水溶液(10%)、饱和碳酸氢钠水溶液和盐水洗涤,干燥(Na2SO4),在减压下蒸出溶剂。残留物用硅胶柱闪急色谱提纯,用乙酸乙酯/己烷洗脱,得到3-环己基-N-(2,3-二氢-1-甲基-2-氧代-5-苯基-1H-噻吩并[2,3-e]-1,4-二氮杂-3-基)丙酰胺(56mg,46%)。呈固体状。m.p.189-190℃.δH(CDCl3)7.65-6.85(8H,m),5.65(1H,d,J 8.0 Hz),3.55(3H,s),2.40(2H,t,J 7.0 Hz),和1.80-0.85(13H,m).元素分析:C23H27N3O2S.0.5H2O:计算值:C,66.00;H,6.74;N,10.04.实测值:C,66.25;H,6.76;N,9.83%.
实例74
3-环己基-N-(5-环己基-2,3-二氢-2-氧代-1H-1,4-苯并二氮杂-3-基)丙酰胺
将N-[5-环己基-2,3-二氢-2-氧代-1H-1,4-苯并二氮杂-3-基]氨基甲酸苯甲酯(150mg,0.38mmol)溶于在乙酸中的溴化氢(30%,0.5ml)中。2小时后加入乙醚,收集固体物,在真空下干燥。加入THF(3ml)和三乙胺(0.45μl,33mg,0.32mmol),混合物在室温下搅拌3小时。在另一个烧瓶中,将草酰氯(38μl,56mg,0.44mmol)加入到环己烷丙酸(61μl,56ml,0.36mmol)和DMF(1滴)在THF(2ml)中的溶液中,混合物在室温下搅拌3小时。将上述两种混合物合并,加入三乙胺(61μl,44mg,0.44mmol),在室温下搅拌3小时。减压蒸出溶剂,加入乙酸乙酯。混合物用水(2次)、饱和碳酸氢钠水溶液、水和盐水洗涤,干燥(Na2SO4),在减压下蒸出溶剂。残留物用异丙醇重结晶,得到固体状3-环己基-N-(5-环己基-2,3-二氢-2-氧代-1H-1,4-苯并二氮杂-3-基)丙酰胺,m.p.133-138℃。δH(CDCl3)7.85(1H,brs),7.62-6.95(5H,m),5.40(1H,d,J 8.7 Hz),2.77(1H,m),2.34(2H,m),和2.05-0.75(23H,m).元素分析:C24H33N3O2.0.7C3H7OH:计算值:C,71.64;H,8.89;N,9.60.实测值:C,71.28;H,8.70;N,9.82%.
(+)-N-[(3R)-7-氨基-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(2,4-二氯苯基)丙酰胺
步骤A:
将硝酸钾(2.12g,21.0mmol)的浓硫酸(6ml)溶液滴加到3(R)-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮(J.Org.Chem.1987,52,3232-3239)(3.98g,15.0mmol)在置于冰浴中冷却的浓硫酸(15ml)中的混合物中。在冷却下将混合物搅拌2小时,然后在环境温度下搅拌1.5小时。加入冰(80g),混合物用浓氢氧化铵碱化至pH9,用乙酸乙酯萃取(3×220ml)。合并的有机级分用盐水洗涤,干燥(Na2SO4),在减压下蒸出溶剂。残留物用硅胶柱闪急色谱提纯,用氯仿/甲醇(97∶3)洗脱。洗出的物质用硅胶柱闪急色谱进一步提纯,用乙酸乙酯/甲醇(95∶5)洗脱。洗出的物质在正丁基氯(30ml)中搅拌,在减压下蒸出溶剂后得到3(R)-氨基-1,3-二氢-1-甲基-7-硝基-5-苯基-2H-1,4-苯并二氮杂-2-酮和3(R)-氨基-1,3-二氢-1-甲基-7-硝基-5-(2-硝基苯基)-2H-1,4-苯并二氮杂-2-酮的3∶1不可分离的混合物(3.81g),呈黄色固体状。δH(CDCl3)(一硝基化合物)8.43(1H,dd,J 9,3 Hz),8.23(1H,d,J 3 Hz),7.59(2H,m),7.52(2H,m),7.44(2H,m),4.47(1H,s),3.53(3H,s),和2.42(2H,brs);(二硝基化合物)8.49(1H,dd,J 9,3),8.42(1H,m),8.18(1H,d,J 3 Hz),8.01(1H,m),7.67(1H,t,J 6 Hz),7.6-7.4(2H,m),4.52(1H,s),3.56(3H,s),和2.42(2H,brs).
步骤B:
将3-(2,4-二氯苯基)丙酸(482mg,2.2mmol)、DMF(0.017ml,0.22mmol),和亚硫酰氯(0.24mg,3.3mmol)在氯仿(2.5ml)中的溶液加热回流1小时。在减压下蒸出溶剂得到3-(2,4-二氯苯基)丙酰氯(520mg,100%)。将3-(2,4-二氯苯基)丙酰氯(520mg,2,2mmol)的二氯甲烷(1.5ml)溶液加入到3(R)-氨基-1,3-二氢-1-甲基-7-硝基-5-苯基-2H-1,4-苯并二氮杂-2-酮和3(R)-氨基-1,3-二氢-1-甲基-7-硝基-5-(2-硝基苯基)-2H-1,4-苯并二氮杂-2-酮(3∶1)的混合物(621mg,2mmol)和三乙胺(0.305ml,2.2mmol)在二氯甲烷(10ml)中的溶液中,将该混合物搅拌30分钟,在减压下蒸出部分溶剂,反应混合物用硅胶柱闪急色谱提纯,用二氯甲烷/乙醚(90∶10)洗脱,得到(+)-N-[(3R)-2,3-二氢-1-甲基-7-硝基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(2,4-二氯苯基)-丙酰胺和(+)-N-[(3R)-2,3-二氢-1-甲基-7-硝基-2-氧代-5-(2-硝基苯基)-1H-1,4-苯并二氮杂-3-基]-3-(2,4-二氯苯基)-丙酰胺(3∶1)的混合物(850mg,84%),呈固体白色泡沫。δH(CDCl3)(一硝基化合物)8.45(1H,dd,J 9,3 Hz),8.25(1H,d J 3 Hz),7.54(3H,m),7.45(2H,m),7.38(1H,d,J 2 Hz),7.26-7.18(4H,m),5.50(1H,d,J 8 Hz),3.52(3H,s),3.10(2H,m),和2.70(2H,m);(二硝基化合物)8.51(1H,dd,J 9,3 Hz),8.40(1H,m),8.21(1H,d J 3 Hz),7.98(1H,m),7.68(1H,t,J 6 Hz),7.60(1H,m),7.44(1H,m),7.26-7.15(4H,m),5.52(1H,d,J 8 Hz),3.55(3H,s),3.10(2H,m),和2.70(2H,m).
步骤C:
在1.5小时内将15%三氯化钛在20-30%盐酸中的溶液(7.8ml,9.0mmol)分批滴加到(+)-N-[(3R)-2,3-二氢-1-甲基-7-硝基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(2,4-二氯苯基)-丙酰胺和(+)-N-[(3R)-2,3-二氢-1-甲基-7-硝基-2-氧代-5-(2-硝基苯基)-1H-1,4-苯并二氮杂-3-基]-3-(2,4-二氯苯基)-丙酰胺(3∶1)的混合物(770mg,1.5mmol)的乙酸(6ml)溶液中。将所得溶液搅拌30分钟,用20%NaOH溶液碱化(pH9),用水(80ml)稀释,用乙酸乙酯(3×100ml)萃取。合并的有机级分用盐水洗涤,干燥(Na2SO4),在减压下蒸出溶剂。残留物用硅胶柱闪急色谱提纯,用乙酸乙酯/己烷(75∶25升至100∶0)洗脱,洗出的第一种化合物用乙酸乙酯结晶得到(+)-N-[(3R)-7-氨基-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(2,4-二氯苯基)丙酰胺(413mg,57%),呈淡黄色固体,m.p.179-180℃,[α]D+60.2°(c=0.500,CHCl3).δH(CDCl3)7.60(2H,d,J 7 Hz),7.49-7.36(5H,m)7.24(1H,d,J 9Hz),7.17(2H,m),6.99(1H,dd,J 9,3 Hz),6.64(1H,d,J 3 Hz),5.54(1H,d,J 8 Hz),4.80-3.50(2H,brs),3.39(3H,s),3.09(2H,t,J 8 Hz),和2.68(2H,dt,Jd 3,Jt 8 Hz).元素分析:C25H22Cl2N4O2:计算值:C,62.38;H,4.61;N,11.64.实测值:C,62.58;H,4.68;N,11.65%.
洗出的第二种化合物用乙酸乙酯结晶得到(+)-N-[(3R)-7-氨基-2,3-二氢-1-甲基-2-氧代-5-(2-氨基苯基)-1H-1,4-苯并二氮杂-3-基]-3-(2,4-二氯苯基)-丙酰胺(114mg,15%),呈淡黄色固体,m.p.188-189℃,[α]D+50.0°(c=0.100,MeOH).δH(CDCl3)7.36(2H,m),7.25(1H,d,J 9 Hz),7.15(3H,m),7.00(1H,m),6.88(2H,m),6.79(1H,m),6.60(1H,bs),5.52(1H,d,J 8 Hz),4.10-2.80(4H brs),3.40(3H,m),3.09(2H,t,J 8 Hz),和2.69(2H,m).元素分析:C25H23Cl2N5O2.0.05EtOAc:计算值:C,60.43;H,4.71;N,13.99.实测值:C,60.79;H,4.74;N,13.83%.
(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-7-甲磺酰氨基-1H-1,4-苯并二氮杂-3-基]-3-(2,4-二氯苯基)-丙酰胺
将甲磺酰氯(0.040ml,0.52mmol)加入到(+)-N-[(3R)-7-氨基-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-3-(2,4-二氯苯基)丙酰胺(193mg,0.40mmol)和吡啶(0.0065ml,0.80mmol)的二氯甲烷(1.6ml)溶液中。将所得溶液搅拌2小时。该溶液用乙酸乙酯(12ml)稀释,用1N HCl、水、饱和碳酸氢钠溶液、水和盐水(各3ml)洗涤,干燥(Na2SO4),减压蒸出溶剂。残留物溶于温热的甲苯中,用活性炭处理,然后过滤。滤液用己烷稀释,将混合物冷却,收集所生成的沉淀物,经真空干燥后得到(+)-N-[(3R)-2,3-二氢-1-甲基-2-氧代-5-苯基-7-甲磺酰氨基-1H-1,4-苯并二氮杂-3-基]-3-(2,4-二氯苯基)-丙酰胺(152mg,68%),呈白色固体,m.p.130-148℃,[α]D+111.6°(c=0.500,CHCl3)。δH(CDCl3)7.55-7.32(9H,m),7.24(2H,dd,J 10,2 Hz),7.17(1H,dd,J 9,2 Hz),7.05(1H,d,J 3 Hz),5.49(1H,d,J 8 Hz),3.41(3H,s),3.08(2H,t,J 8 Hz),2.97(3H,s),和2.71(2H,dt,Jd 3,Jt 8 Hz).元素分析:C26H24Cl2N4O4S:计算值:C,55.82;H,4.32;N,10.01.实测值:C,56.12;H,4.47;N,9.89%.
实例77
N-(2,3-二氢-1-甲基-2-氧代-5-苯基-1H-吡啶并[4,3-e]-1,4-二氮杂-3-基)-3-(2,4-二氯苯基)丙酰胺盐酸盐
步骤A:
将叔丁醇钾(1.83g,16.3mmol)加入到2,3-二氢-1-甲基-5-苯基-1H-吡啶并[4,3-e]-1,4-二氮杂-2-酮(J.Med.Chem.1965,8,722-724)(1.63g,6.5mmol)在冷却到-20℃(冰/甲醇浴)和氩气保护下的甲苯(32ml)溶液中。在-20℃将所形成的红紫色悬浮液搅拌15分钟,然后加入亚硝酸异戊酯(1.05ml,7.8mmol)。混合物在-20℃搅拌30分钟,然后倒入到水(50ml)、乙酸(3ml),和乙酸乙酯(65ml)的混合物中。搅拌该混合物,使固体物全部溶解,然后分离各层。水层用乙酸乙酯(65ml)萃取。合并的有机级分用饱和碳酸氢钠溶液和盐水(各20ml)洗涤,干燥(Na2SO4),在减压下蒸出溶剂。残留物用冷甲苯调制,收集固体物,经真空干燥后得到2,3-二氢-3-肟基-1-甲基-5-苯基-1H-吡啶并[4,3-e]-1,4-二氮杂-2-酮(1.22g,67%),呈黄色固体,m.p.223-224℃。δH(CDCl3)8.92(1H,bs),8.73(1H,d,J 7 Hz),8.62(1H,s),7.80(2H,dd,J 7,1 Hz),7.59(1H,m),748(2H,m),7.26(1H,d,J 7 Hz),和3.50(3H,s).
步骤B:
将2,3-二氢-3-肟基-1-甲基-5-苯基-1H-吡啶并[4,3-e]-1,4-二氮杂-2-酮(1.77g,6.3mmol)和新制备的阮内镍(3.2g)在1∶1的乙醇/甲醇(190ml)中的混合物置于Parr氢化装置上在氢气(50psi)存在下振荡4小时。混合物通过助滤剂过滤,在减压下蒸出滤液。残留物用硅胶柱闪急色谱提纯,用甲醇/氯仿/乙酸(5∶95∶1升至10∶90∶1)洗脱,洗出的物质在氯仿(30ml)中与碳酸钾(0.3g)和水(0.2ml)-起搅拌5分钟。将混合物干燥(Na2SO4),在减压下蒸出溶剂后得到3-氨基-2,3-二氢-1-甲基-5-苯基-1H-吡啶并[4,3-e]-1,4-二氮杂-2-酮(276mg,16%),呈黄色固体,m.p.109-123℃。δH(CDCl3)8.72(1H,d,J 6 Hz),8.58(1H,s),7.61(2H,m),7.51(1H,m),7.43(2H,m),7.26(1H,m),4.47(1H,s),3.50(3H,s),和2.1(2H,bs).高分辨率质谱:C15H14N4O(M+1):理论质量:267.124586,实测质量:(M+1):267.123654。
步骤C:
在氩气保护下将二环己基碳化二亚胺(87mg,0.42mmol)的二氯甲烷(0.17ml)溶液加入到3-氨基-2,3-二氢-1-甲基-5-苯基-1H-吡啶并[4,3-e]-1,4-二氮杂-2-酮(93mg,0.35mmol)和3-(2,4-二氯苯基)丙酸(83mg,0.38mmol)的THF(0.5ml)溶液中。将所得混合物搅拌5小时,过滤,在减压下蒸出滤液。残留物在硅胶上用制备性板色谱提纯,用甲醇/氯仿/乙酸(5∶95∶1)洗脱。纯化后的物质在氯仿(5ml)中与碳酸钾(0.1g)和水(2滴)一起搅拌5分钟。将该混合物干燥(Na2SO4),在减压下蒸出溶剂。将残留物悬浮于乙醇(2ml)中,然后加入乙醇盐酸(6.8M,0.147ml )。搅拌混合物.收集所生成的沉淀物,经真空干燥后得到N-(2,3-二氢-1-甲基-2-氧代-5-苯基-1H-吡啶并[4,3-e]-1,4-二氮杂-3-基)-3-(2,4-二氯苯基)丙酰胺盐酸盐(32mg,18%),呈白色固体,m.p.218-219℃。δH(d6-DMSO)9.38(1H,d,J 8 Hz),8.86(1H,bs),8.59(1H bs),7.79(1H,d,J 6 Hz),7.56(3H,m),7.51(2H,m),7.39(2H,m),7.25(1H,m),7.16(1H,m),5.37(1H,d,J 8 Hz),3.44(3H,s)2.94(2H,t,J 7 Hz),和2.64(2H,t,J 7 Hz).元素分析:forC24H20Cl2N4O2.HCl:计算值:C,57.22;H,4.20;N,11.12.实测值:C,56.87;H,4.18;N,11.09%.实例78
N-(2,3-二氢-1-甲基-2-氧代-5-苯基-1H-吡啶并[4,3-e]-1,4-二氮杂-3-基)-3-(环己基)丙酰胺
在氩气保护下将二环己基碳化二亚胺(87mg,0.42mmol)的二氯甲烷(0.17ml)溶液加入到3-氨基-2,3-二氢-1-甲基-5-苯基-1H-吡啶并[4,3-e]-1,4-二氮杂-2-酮(93mg,0.35mmol)和环己烷丙酸(0.065ml,0.38mmol)的THF(0.5ml)溶液中。将所得混合物搅拌5小时,过滤,在减压下蒸出滤液。残留物在硅胶上用制备性板色谱提纯,用甲醇/氯仿/乙酸(5:95∶1)洗脱。纯化后的物质在氯仿(5ml)中与碳酸钾(0.1g)和水(2滴)一起搅拌5分钟。将该混合物干燥(Na2SO4),在减压下蒸出溶剂。残留物用甲苯结晶,得到N-(2,3-二氢-1-甲基-2-氧代-5-苯基-1H-吡啶并[4,3-e]-1,4-二氮杂-3-基)-3-(环己基)丙酰胺(47mg,33 %),呈白色结晶固体,m.p.170-173℃。δH(CDCl3)8.75(1H,d,J 6 Hz),8.61(1H,s),7.58(2H,m),7.52(1H,m),7.45(2H,m),7.31(1H,d,J 6 Hz),7.21(1H,d,J 8 Hz),5.54(1H,d,J 8 Hz),3.51(3H,s),2.39(2H,m),1.73(4H,m),1.63(3H,m),1.85-1.12(4H,m),和0.94(2H,m).元素分析:C24H28N4O2.0.10PhCH3:计算值:C,71.70;H,7.02;N,13.54.实测值:C,71.78;H,7.01;N,13.57%.
采用基本上如上面所述的程序,但用3-(4-三氟甲基苯基)-丙酸代替环己烷丙酸,制备了下列化合物:实例79
N-(2,3-二氢-1-甲基-2-氧代-5-苯基-1H-吡啶并[4,3-e]-1,4-二氮杂-3-基)-3-(4-三氟甲基苯基)丙酰胺m.p.191-192℃.δH(CDCl3)8.76(1H,d,J 6 Hz),8.61(1H,s),7.56(4H,m),7.52(1H,m),7.42(2H,d,J 7 Hz),7.38(2H,m),7.30(1H,d,J 6 Hz),7.22(1H,d,J 8 Hz),5.51(1H,d,J 8 Hz),3.50(3H,s),3.09(2H,t,J 8 Hz),和2.73(2H,t,J 8 Hz).元素分析:C25H21F3N4O2.0.20PhCH3:计算值:C,65.39;H,4.70;N,11.56.实测值:C,65.69;H,4.64;N,11.95%.
N-(2,3-二氢-1-甲基-2-氧代-5-苯基-1H-吡啶并[3,4-e]-1,4-二氮杂-3-基)-3-(2,4-二氯苯基)丙酰胺
步骤A:
将叔丁醇钾(1.59g,14.2mmol)加入到2,3-二氢-1-甲基-5-苯基-1H-吡啶并[3,4-e]-1,4-二氮杂-2-酮(Can.J.Chem.,1987,65,1158-1161)(1.43g,5.7mmol)在冷却到-20℃(冰/甲醇浴)和氩气保护下的甲苯(28ml)溶液中。在-20℃将所形成的红紫色悬浮液搅拌15分钟,然后加入亚硝酸异戊酯(0.92ml,6.8mmol)。混合物在-20℃搅拌30分钟,然后倒入到水(25ml)、乙酸(2.5ml)和乙酸乙酯(55ml)的混合物中。搅拌该混合物,使固体物全部溶解,然后分离各层,水层用乙酸乙酯(2×55ml)萃取。合并的有机级分用碳酸氢钠溶液和盐水(各20ml)洗涤,干燥(Na2SO4)在减压下蒸出溶剂。残留物用己烷调制,收集固体物,经真空干燥后得到2,3--二氢-3-肟基-1-甲基-5-苯基-1H-吡啶并[3,4-e]-1,4-二氮杂-2-酮(1.60g,100%),呈棕黄色泡沫。δH(CDCl3)8.77(1H,s),8.50(1H,d,J 4 Hz),7.81(2H,dd,J 8,1 Hz),7.60(1H,m),7.49(3H,m),7.32(1H,d,J 5 Hz),和3.55(3H,s).
步骤B:
将氯化锡二水合物(3.72g,16.5mmol)的浓盐酸(11ml)溶液滴加到在冰浴中冷却的2,3-二氢-3-肟基-1-甲基-5-苯基-1H-吡啶并[3,4-e]-1,4-二氮杂-2-酮(1.54g,5.5mmol)中。该溶液用水(20ml)稀释,用浓氢氧化铵(18ml)碱化,用乙醚(4×75ml)萃取。合并的有机级分用盐水(30ml)洗涤,干燥(Na2SO4),在减压下蒸出溶剂。残留物用硅胶柱闪急色谱提纯,用甲醇/氯仿乙醇(5∶95∶1升至10∶90∶1)洗脱。洗出的物质在氯仿(20ml)中与碳酸钾(0.3g)和水(2滴)一起搅拌5分钟。将混合物干燥(Na2SO4),在减压下蒸出溶剂。残留物在己烷中搅拌,收集所形成的固体物,得到3-氨基-2,3-二氢-1-甲基-5-苯基-1H-吡啶并[3,4-e]-1,4-二氮杂-2-酮(241mg,16%),呈黄色固体,m.p.94-118℃。δH(CDCl3)8.79(1H,s),8.48(1H,d,J 5 Hz),7.62(2H,dd,J 8,1Hz),7.51(1H,m),7.45(2H,m),7.24(1H,dd,J 5,1Hz),4.47(1H,s),3.55(3H,s),和2.2(2H,bs).元素分析:C15H14N4O.0.25(C2H5)2O:计算值:C,67.46;H,5.84;N,19.67.实测值:C,67.28;H,5.66;N,19.53%.高分辨率质谱:C15H14N4O(M+1):理论质量:267.124586,实测质量(M+1):267.123093。
步骤C:
将草酰氯(0.023ml,0.26mmol)的二氯甲烷(0.2ml)溶液滴加到3-(2,4-二氯苯基)丙酸(48mg,0.22mmol)和DMF(1滴)的冰浴冷却的二氯甲烷(O.5ml)溶液中。所得溶液在冷却下搅拌1小时。在减压下蒸出溶剂后得到3-(2,4-二氯苯基)-丙酰氯(52mg,100%)。将3-(2,4-二氯苯基)-丙酰氯(52mg,0.22mmol)的二氯甲烷(0.5ml)溶液加入到3-氨基-2,3-二氢-l-甲基-5-苯基-1H-吡啶并[3,4-e]-1,4-二氮杂-2-酮(53mg,0.20mmol)和吡啶(0.021ml,0.22mmol)的二氯甲烷(3ml)溶液中。将混合物搅拌1小时,在减压下蒸出部分溶剂,反应混合物用硅胶柱闪急色谱提纯,用甲醇/乙醚(5∶95升至7.5∶92.5)洗脱。洗出的物质用甲苯/己烷结晶,得到N-(2,3-二氢-l-甲基-2-氧代-5-苯基-1H-吡啶并[3,4-e]-1,4-二氮杂-3-基)-3-(2,4-二氯苯基)丙酰胺(38mg,38%),呈白色晶状固体,m.p.220-221℃。δH(CDCl3)8.81(1H,s),8.52(1H,d,J 5 Hz),7.56(2H,dd,J 7,2 Hz),7.51(1H,m),7.44(2H,d,J 6 Hz),7.40(1H,m),7.27(2H,m),7.18(2H,dd,J 8,2 Hz),5.48(1H,d,J 8 Hz),3.55(3H,s),3.10(2H,t,J 7Hz),和2.71(2H,dt,Jd 2 Jt 8 Hz).元素分析:C24H20Cl2N4aO2.0.25PhCH3:计算值:C,63.06:H,4.52:N,11.43.实测值:C,63.03:H,4.48:N,11.25%.
实例81
N-[2,3-二氢-1-甲基-2-氧代-5-异丙基-1H-1,4-苯并二氮杂-3-基]-3-(2,4-二氯苯基)丙酰胺
步骧A:
在氩气保护下的-78℃的苯并二氮杂(1.0g,5.3mmol)的THF(20ml)溶液中加入60%(NaH,252g,6.3mmol)Boc酐(1.27g,5.8mmol),混合物在-78℃搅拌
小时。然后让反应混合物温热至25℃,搅拌2小时,然后倒入到冷NH4Cl(10%)水溶液中使反应终止,将产物萃取到乙酸乙酯(3×50ml)中。用Na2SO4干燥后的萃取物浓缩,得到的油状物通过硅胶(乙酸乙酯/己烷),得到1.35g产物(89%)。1H NMR(CDCl3)δ:1.60(s,9H),3.40(s,3H),3.95(brd,1H),4.80(brd,1H),7.20(d,1H),7.30(q,1H),7.60(t,1H),7.92(d,1H).
步骤B:
将氯化异丙基镁(2.0M)的THF(7.66ml,15.3mmol)溶液迅速加入到氩气保护下的BOC-苯并二氮杂(4.0g,13.8mmol)的THF(80ml)溶液中,在搅拌下反应0.5小时,将反应混合物倒入到NH4Cl水溶液(50ml)中,使反应终止,然后用乙酸乙酯(2×200ml)萃取。将有机萃取物浓缩,在硅胶上进行色谱提纯(1∶1的乙酸乙酯/己烷),得到1.55g(34%)产物。1H NMR(CDCl3)δ:1.14(d,3H),1.19(d,3H),1.40(s,9H),3.13(s,3H),3.2-3.8(m,3H),5.45(brs,1H),7.28(dt,1H),7.48(dt,1H),7.56(dt,1H),7.72(dd,1H).
步骤C
在90分钟时间内将无水HCl加入到0℃的异苯基苯甲酮(1.55g)的乙酸乙酯溶液中。然后将反应混合物在真空下浓缩,所得固体物溶解于水(40ml)中,用1N LiOH将pH调至11.0。在PH=11.0经过30分钟后用1N HCl调至pH=7.0,将产物萃取到乙酸乙酯中。将有机萃取物干燥(Na2SO4)、过滤、经浓缩后得到1.22g固体物,100%。1H NMR(CDCl3)δ:0.95(d,3H),1.30(d,3H),3.16(七重峰,1H),3.36(s,3H),3.60(d,1H),4.60(d,1H),7.2-7.3(m,2H),7.45-7.55(m,2H).
步骤D:
按实例80步骤A所述方法将步骤C中制得的苯并二氮杂转化成肟。
步骤E:
将肟(2g)溶解在乙酸(150ml)中,加入10%Pd/C(1g)。混合物在氢气氛下快速搅拌90分钟,或直至HPLC分析表明反应完全为止。将反应混合物过滤,催化剂用二氯甲烷(200ml)洗涤,滤液在真空下浓缩,得到的油状物溶于饱和碳酸氢钠水溶液(100ml)中,产物用乙酸乙酯(3×150ml)萃取。干燥(Na2SO4)后的萃取物浓缩后得到2.60g(97%)。
步骤F:
按实例43所述方法使该胺与3-(2,4-二氯苯基)-丙酸进行偶联制得N-[2,3-二氢-1-甲基-2-氧代-5-异丙基-1H-1,4-苯并二氮杂-3-基]-3-(2,4-二氯苯基)丙酰胺。1H NMR(CDCl3)δ:0.92(d,3H),1.25(d,3H),2.65(dt,2H),3.05(t,2H),3.15(SepT,1H),3.40(s,3H),5.38(d,1H),7.0-7.6(m,8H).
按类似于实例81所述的方法,用适当的格氏试剂代替氯化异丙基镁,制备了下列化合物。
实例82
N-[2,3-二氢-1-甲基-2-氧代-5-异丙基-1H-1,4-苯并二氮杂-3-基]-3-环己基丙酰胺m.p.164-165℃CHN:元素分析:C22H31N3O2:计算值:C,71.51;H,8.46;N,11.37实测值:C,71.72;H,8.39;N,11.32
实例83
N-[2,3-二氢-1-甲基-2-氧代-5-异丙基-1H-1,4-苯并二氮杂-3-基]-3-(4-三氟甲基苯基)丙酰胺m.p.187-188℃1H NMR(CDCl3)δ:0.92(d,3H),1.25(d,3H),2.66(dt,2H),3.04(t,2H),3,15(SepT,1H),3.40(S,3H),5.38(d,1H),7.14(brd,1H),7.25-7.6(m,8H).
采用实例80中所述的基本上相同的方法,但用下面所述的还原方法代替步骤E,制备了下列化合物:
将连二亚硫酸钠(13.0g,0.075mole)加入到肟1(1.28g,0.0048mole)在H2O(130ml)和THF(65ml)中的溶液中。将混合物搅拌2小时,然后用饱和碳酸氢钠水溶液(50ml)稀释,将产物萃取到乙酸乙酯中(2×150ml)。将有机萃取物合并、用Na2SO4干燥、过滤和浓缩,得到一种油状物(约1.0g)。将该油进行硅胶色谱提纯,用乙酸乙酯洗脱,接着用10%甲醇/二氯甲烷,得到纯的胺0.778g(64%)。1H NMR(DMSO)δ3.32(s,3H),4.30(s,1H),6.64(d,d,1H),6.76(d,1H),7.35(dt,1H),7.58-7.74(m,3H),7.88(m,1H).
实例84
N-[2,3-二氢-1-甲基-2-氧代-5-(2-呋喃基)-1H-1,4-苯并二氮杂-3-基]-3-环己基丙酰胺m.p.168-169℃CHN:元素分析:C23H27N3O3:计算值:C,70.21;H,6.92;N,10.68实测值:C,70.15;H,6.67;N,10.64
实例85
N-[2,3-二氢-1-甲基-2-氧代-5-(2-呋喃基)-1H-1,4-苯并二氮杂-3-基]-3-(4-三氟甲基苯基)丙酰胺m.p.155-157℃CHN:元素分析:C24H20N3O3F3:计算值:C,63.29;H,4.432;N,9.23实测值:C,63.22;H,4.44;N,9.07
实施例86
N-[2,3-二氢-1-甲基-2-氧代-5-(2-呋喃基)-1H-1,4-苯并二氮杂-3-基]-3-(2,4-二氯苯基)丙酰胺m.p.132-133CCHN:元素分析:C23H19N3O3Cl2计算值:C,60.54;H,4.20;N,9.21实测值:C,60.62;H,4.07;N,9.07
实例87
N-[2,3-二氢-1-甲基-2-氧代-5-(3-呋喃基)-1H-1,4-苯并二氮杂-3-基]-3-环己基丙酰胺m.p.199-200℃1H NMR(CDCl3)δ:0.9-1.8(brm,3H),2.38(t,2H),3.42(S,3H),5.55(brd,1H),6.90(S,1H),7.2-7.77(m,7H)
实例88
N-[2,3-二氢-1-甲基-2-氧代-5-(3-呋喃基)-1H-1,4-苯并二氮杂-3-基]-3-(4-三氟甲基苯基)丙酰胺m.p.213-214℃1H NMR(CDCl3)δ:2.71(dt,2H),3.05(t,2H),3.42(S,3H),5.72(d,1H),6.82(brS,1H),7.2-7.7(m,11H)
实例89
N-[2,3-二氢-1-甲基-2-氧代-5-[2′-(4,4-二甲基-2-噁唑啉基)-苯基]-1H-1,4-苯并二氮杂-3-基]-3-(2,4-二氯苯基)-丙酰胺
该标题化合物基本上按实例81所述方法制备。m.p.194-195℃CHN:元素分析:C30H28N4O3Cl2计算值:C,63.95;H,5.01;N,9.94实测值:C,63.70;H,5.01;N,9.96
实例90
将含有10%Pd/C(50mg)的N-[2,3-二氢-1-甲基-2-氧代-5-异丙基-1H-1,4-苯并二氮杂-3-基]-3-环己基丙酰胺(50mg)甲醇(10ml)溶液在1大气压氢气中搅拌18小时。将反应混合物过滤、浓缩和用二乙醚结晶得到21mg N-[2,3,4,5-四氢-1-甲基-2-氧代-5-异丙基-1H-1,4-苯并二氮杂-3-基]-3-环己基丙酰胺。元素分析:C22H33N3O2计算值:C,71.12;H,8.95;N,11.31实测值:C,70.98;H,8.97;N,11.15m.p.114-115℃。
实例91
N-[2,3-二氢-1-甲基-2-氧代-5-甲基-1H-1,4-苯并二氮杂-3-基]-3-(2,4-二氯苯基)丙酰胺
将DMF二甲基缩醛(1.09ml)的甲苯(10ml)溶液滴加到CBZ-苯并二氮杂(250mg,0.776mmol)的甲苯(25ml)回流混合物中。将反应混合物回流5小时,然后冷却并浓缩成油状物。该油用乙醚调制得到白色固体(124mg)。1H NMR(CDCl3)δ:2.50(s,3H),3.42(s,3H),5.12-5.20(m,3H),6.62(d,1H),7.25-6.4(m,7H),7.5-7.6(m,2H).
在室温下用30%HBr/AcOH(0.8ml)处理上面得到的CBZ-胺-N-甲基酰胺(190mg)1小时。将反应混合物倒入到0℃乙醚(10ml)中,滤出固体。将固体物溶于10%NaOH水溶液(5ml)和CH2Cl2(10ml)中,将有机层分离、干燥(Na2SO4)、过滤和浓缩,得到一种油状物(172mg,110%)。1H NMR(CDCl3)δ:2.42(s,3H),3.05(brs,2H),3.40(s,3H),4.40 (s,
用类似于前面实例43所述方法制备了N-[2,3-二氢-1-甲基-2-氧代-5-甲基-1H-1,4-苯并二氮杂-3-基]-3-(2,4-二氯苯基)丙酰胺。m.p.194-195℃CHN:元素分析:C20H19N3O2Cl2计算值:C,59.42;H,4.74;N,10.39实测值:C,59.50;H,4.74;N,10.441H NMR(CDCl3)δ:2.49(brs,3H),2.65(dt,2H),3.05(t,2H),3.42(s,3H),5.35(d,1H),71-7.6(m,8H).
实例92
N-[2,3-二氢-1-甲基-2-氧代-[4,5-a]-(1-氧代-1,3-二氢-2H-异吲哚-1H-1,4-苯并二氮杂-3-基]-3-(2,4-二氯苯基)丙酰胺
将三氟甲磺酸甲酯(22ml,0.198mmol)慢慢加入到N-[2,3-二氢-1-甲基-2-氧代-5-[2′-(4,4-二甲基-2-噁唑啉基)-苯基]-1H-1,4-苯并二氮杂-3-基]-3-(2,4-二氯苯基)-丙酰胺(100mg,0.178mmol)的二氯甲烷溶液中。搅拌5分钟后,加入溶于绝对乙醇(0.5ml)中的硼氢化钠(7.6mg,0.20mmol),在搅拌下反应30分钟。将产物萃取到乙酸乙酯中,然后用硅胶柱色谱提纯(60%乙酸乙酯/己烷),得到30mg N-[2,3-二氢-1-甲基-2-氧代-[4,5-a]-(1-氧代-1,3-二氢-2H-异吲哚-1H-1,4-苯并二氮杂-3-基]-3-(2,4-二氯苯基)丙酰胺。1H NMR(CDCl3)δ:2.70(m,2H),3.12(t,2H),3.55(s,3H),5.68(s,1H),5.90(d,1H),6.85(dd,1H),7.05(brd,1H),7.1-7.5(m,9H),7.85(d,1H).MSM+1-494.
实例93
3R-(+)-3-(苯硫基)-N-[2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]丙酰胺
将K2CO3(1.8g,13mmol)和苯硫酚(0.72g,6.5mmol)加入到搅拌着的3-溴丙酸(1.0g,6.5mmol)的DMF(20ml)溶液中。将该混合物加热到50℃,保持1小时。混合物用200ml水稀释,用2×100ml乙酸乙酯萃取。合并的有机物用100ml水和盐水洗涤,用Ha2SO4干燥。经蒸发后得到1.52g无色油状物,收集1.18g,用于NMR分析残留DMF。
将上述的油状物加入到30mlDMF中,然后加入1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐(2.45g,12.8mmol)和1-羟基苯并三唑水合物(1.73g,12.8mmol)。该混合物在室温下搅拌5分钟,然后加入3-(R)-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮(0.66g,2.6mmol),在室温下搅拌,反应-夜。反应混合物用200ml水稀释,用2×150ml乙酸乙酯萃取。合并的有机物用1×100ml水洗涤,用Na2SO4干燥,然后蒸发。残留物用硅胶进行色谱提纯,用2%MeOH/CHCl3洗脱。收集纯级分,蒸发。蒸出乙醚后得到770mg白色泡沫。元素分析:C25H23N3O2S·0.05己烷计算值:C,70.04;H,5.51;N,9.69.实测值:C,69.91,H,5.40,N,9.78.实例94
3R-(+)-5-(甲硫基)-N-[2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]丙酰胺
往K2CO3(0.76g,5.5mmol)的水溶液中加入5-溴戊酸和甲硫醇钠。混合物在室温下搅拌过夜。反应混合物用50ml水稀释,用6N HCl酸化至pH=0。用2×50mlEtOAc萃取,用Na2SO4干燥,蒸发后得到0.55g黄色油状物。
将上面的油状物加入到10mlDMF中,然后加入1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐(1.30g,6.8mmol)和1-羟基苯并三唑水合物(0.92g,6.8mmol)。再加入3-(R)-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮(0.85g,3.4mmol),在室温下搅拌反应-夜。反应混合物用100ml水稀释,用2×50mlEtOAc萃取。合并的有机物用盐水洗涤,用Na2SO4干燥,蒸发后得到黄色油状物。残留物用硅胶进行色谱提纯,用50:50的乙酸乙酯/己烷至100%乙酸乙酯洗脱。收集纯级分,得到1.33g无色油状物,取其中0.4g进行硅胶色谱提纯,用2%MeOH/CH2Cl2洗脱。收集纯级分,蒸去乙醚/乙烷,得到白色粉末,m.p.61-65℃。元素分析:C22H25N3O2S·0.35H2O:计算值:C,65.76;H,6.45;N,10.46.实测值:C,65.81;H,6.21;N,10.57.
实例95
N-氰基-N′-环己基甲基-N″-(1,3-二氢-1-甲基-2-氧代-5-苯基-2H-1,4-苯并二氮杂-3-基)哌
用二苯基氰基carbonimidate(0.9g,3.7mmol)处理3-(R)-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮(1g,3.7mmol)的乙腈(20ml)溶液,然后在室温下搅拌30分钟。加入环己基甲基胺(0.84g,7.4mmol),在室温下搅拌反应2小时。将反应混合物倒入到100ml0.1N HCl中,用3×100ml乙酸乙酯萃取。将有机层合并、用饱和碳酸氢钠(50ml)溶液洗涤一次,用无水硫酸镁干燥,减压浓缩。残留物进行硅胶色谱提纯,用50%乙酸乙酯/己烷洗脱,得到0.875g产物。分析的样品用乙酸乙酯结晶。m.p.158-161℃。元素分析:C25H28N6O:计算值:C,70.07;H,6.59;N,19.61.实测值:C,70.05;H,6.59;N,19.64%.
N-(1,3-二氢-1-甲基-2-氧代-5-苯基-2H-1,4-苯并二氮杂-3-基)-4-(4-氯苄基)-4-哌啶甲酰胺二盐酸盐
步骤A:N-叔丁氧羰基-4-(4-氯苄基)-4-哌啶羧酸的制备
用双三甲基甲硅烷基酰胺锂溶液(220ml 1N THF溶液,220mmol)处理-60℃的N-Boc-3-异哌啶甲酸乙酯(51.4g,200mmol)的THF(1升)溶液。在-60℃搅拌5分钟后,加入4-氯苄基氯(33.8g,210mmol)的THF(200ml)溶液,使反应温热到室温。减压蒸发脱除大部分THF(约800ml)。剩余物倒入到1升1N HCl中,用乙酸乙酯萃取2次,每次用800ml。将有机层合并,用饱和碳酸氢钠(500ml)溶液洗涤一次,用无水硫酸镁干燥,减压浓缩。残留物进行硅胶色谱提纯,用10%-20%乙酸乙酯/己烷洗脱,得到的酯产物可直接使用。将这样得到的物质溶于THF(100ml)和IPA(100ml)中,用350ml 10N NaOH处理。将该混合物加热回流30小时。使反应混合物冷却至室温,然后倒在由碎冰(2升)、6N HCl(500ml)和饱和硫酸氢钾(1升)组成的混合物上。所得混合物用乙酸乙酯萃取2次,每次用1升。将有机层合并,用无水硫酸镁干燥,减压浓缩后得到52g产物。m.p.179-180℃,1H NMR CDCl3δ7.26(d,J=8Hz,2H),7.03(d,J=8Hz,2H),3.98(m,2H),3.0-2.8(m,2H),2.84(s,2H),2.10-2.00(m,2H),1.55-1.40(m,2H),1.45(s,9H)
步骤B:N-(1,3-二氢-1-甲基-2-氧代-5-苯基-2H-1,4-苯并二氮杂-3-基)-4-(4-氯苄基)-4-哌啶甲酰胺盐酸盐的制备
由N-叔丁氧羰基-4-(4-氯苄基)-4-哌啶羧酸(1.48g,4.18mmol)3-(R)-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮(1g,3.7mmol)、羟基苯并三唑(1.17g,8.66mmol)、1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐(1.49g,7.70mmol)、二异丙基乙基胺(0.53g,4.13mmol),和DMF(10ml)组成的混合物在室温下搅拌18小时。将反应混合物倒入到1N HCl中,用乙酸乙酯萃取(4×50ml)。合并有机层,用饱和碳酸氢钠(50ml)洗涤1次,用饱和氯化钠(50ml)洗涤1次,用无水硫酸镁干燥、过滤、和减压浓缩。残留物用硅胶色谱法提纯,用25%-50%乙酸乙酯/己烷洗脱,得到2.34g产物酰胺,可直接使用。如此得到的物质溶于乙酸乙酯(50ml)中,鼓入HCl(g)气,反应5分钟。将反应混合物减压浓缩,残留物用乙酸乙酯重结晶,得到1.13g淡黄色固体产物。m.p.190-195℃。元素分析:C29H29ClN4O2·2HCl:计算值:C,60.68;H,5.44;N,9.76.实测值:C,60.47;H,5.5;N,9.42%.
采用基本上如上面所述程序,但用N-Boc-3-哌啶甲酸乙酯代替N-Boc-3-异哌啶甲酸乙酯,制得下列化合物。
N-(1,3-二氢-1-甲基-2-氧代-5-苯基-2H-1,4-苯并二氮杂-3-基)-3-(4-氯苄基)-3-哌啶甲酰胺盐酸盐A+B异构体。异构体Am.p.205-210℃。元素分析:C29H28ClN4O2·HCl·0.5 CH3CH2OH·0.8H2O:计算值:C,62.67;H,6.07;N,9.75.实测值:C,62.69;H,5.94;N,9.42%.异构体Bm.p.200-205℃元素分析:C29H28ClN4O2·HCl.·0.1CH3CH2OCOCH3·1.6H2O:计算值:C,61.39;H,5.96;N,9.74.实测值:C,61.39;H,5.66;N,9.56%.
(+)-3-环己基-N-[2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-N-(乙氧羰基甲基)丙酰胺
在乙腈(100ml)中的3-(R)-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮(5.0g,18.8mmol)与溴乙酸乙酯(2.1ml,18.8mmol)混合,将碳酸氢钠(4.0g)悬浮于该混合物中。将混合物搅拌、加热回流2小时。然后让反应冷却至室温,用150ml水稀释,用乙酸乙酯萃取(3×100ml)。合并有机层,用硫酸镁干燥,重力过滤,真空脱除溶剂。所得油状物在硅胶上进行色谱提纯,用3∶1的乙酸乙酯/己烷洗脱,得到单烷基化产物(2.58g,39%)以及原料1,4-苯并二氮杂-2-酮和二烷基化产物。往3-环己基丙酸(1.0g,6.4mmol)的二氯甲烷(30ml)溶液中加入草酰氯(0.56ml,6.40mmol)和催化剂(N,N)-二甲基甲酰胺(2滴)。0.5小时后,加入该乙酸酯(2.25g,6.40mmol)的二氯甲烷(10ml)溶液,在搅拌下反应0.25小时。反应混合物用二氯甲烷(150ml)稀释,加入碳酸氢钠水溶液(150ml)。水相再用二氯甲烷(2×100ml)萃取,将有机物合并,用硫酸镁干燥,真空脱除溶剂。所得油状物在硅胶上进行色谱提纯,用1∶1的乙酸乙酯/己烷洗脱,得到的泡沫用乙醚结晶,制得2.0g(64%)产物。m.p.120-122C,[α]d+0.63°(c=0.79;MeOH)。元素分析:C29H35N3O4:计算值:C,71.14;H,7.21;N,8.58.实测值:C,71.13;H,7.13;N,8.75%.
用基本上如上面所述的方法,但用溴丁酸乙酯代替乙酸乙酯,制得了如下的化合物。
3-环己基-N-[2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-N-(乙氧羰基丙基)丙酰胺m,p.103-105℃,[α]d 0.00°:c=0.85:MeOH。元素分析:C31H39N3O4.·0.40molH2O:计算值:C,70.94;H,7.64;N,8.01.实测值:C,70.91;H,7.44;N,8.12%.实例100
N-[2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氨杂-3-基]-N-[2-(2-甲氧乙氧基)乙基]己酰胺
在N,N-二甲基甲酰胺(30ml)中的3-(R)-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮(1.33g,5.0mmol)与1-溴-2-(2-甲氧乙氧基)乙烷(1.35ml,5.0mmol)和三乙胺(1.0ml)混合。将该混合物搅拌、加热回流4小时。然后让反应混合物冷却至室温,用150ml水稀释,用乙酸乙酯萃取(3×100ml)。将有机层合并,用硫酸镁干燥,重力过滤,真空脱除溶剂。所得油状物在硅胶上进行色谱提纯,用1∶1的乙酸乙酯/己烷洗脱,得到单烷基化产物(1.2g,65%)以及原料1,4-苯并二氮杂-2-酮和二烷基化产物。往单烷基化产物(1.2g,3.27mmol)的二氯甲烷(20ml)溶液中加入己酰氯(0.96ml,3.27mmol),在搅拌下反应0.25小时。反应混合物用二氯甲烷(150ml)稀释,加入饱和碳酸氢钠水溶液(150ml)。水相再用二氯甲烷萃取(2×100ml),将有机相合并,用硫酸镁干燥,重力过滤,真空脱除溶剂。所得油状物在硅胶上进行色谱提纯,用1∶1的乙酸乙酯/己烷洗脱,得到一种油状物,给出580mg(38%)产物。[α]d0.00°;c=0.27;MeOH。元素分析:C27H35N3O4.·0.80 mol H2O:计算值:C,67.56;H,7.69;N,8.75.实测值:C,67.56;H,7.39;N,8.85%.
(+)-N-[2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-N-(5-羟基戊基)己酰胺
在乙腈(40ml)中的3-(R)-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮(1.33g,5.0mmol)与5-氯戊醇-1(0.61g,5.0mmol)混合,将碳酸氢钠(2.0g)悬浮于该混合物中。将混合物搅拌、加热回流12小时。然后让反应混合物冷却至室温,用100ml水稀释,用乙酸乙酯萃取(3×75ml)。将有机层合并,用硫酸镁干燥,重力过滤,真空脱除溶剂。所得油状物在硅胶上进行色谱提纯,用1∶49的甲醇/氯仿洗脱,得到单烷基化产物(1.1g,62%)以及原料1,4-苯并二氮杂-2-酮和二烷基化产物。往单烷基化产物(0.50g,1.42mmol)的二氯甲烷(30ml)溶液中加入己酰氯(0.20ml,1.42mmol),在搅拌下反应0.25小时。反应混合物用二氯甲烷(100ml)稀释,加入饱和碳酸氢钠水溶液(100ml)。水相用二氯甲烷萃取(2×75ml),将有机物合并,用硫酸镁干燥,重力过滤,真空脱除溶剂。所得油状物在硅胶上进行色谱提纯,用1∶1的乙酸乙酯/己烷洗脱,得到一种泡沫,给出360mg(64%)产物。泡沫,[α]d+8.36°(c=0.61;MeOH)元素分析:C27H35N3O2.·0.25molH2O:计算值:C,71.42;H,7.88;N,9.25.实测值:C,71.47;H,7.89;N,9.12%.
(+)-N-[2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-N-(乙氧羰基戊基)己酰胺
在乙腈(40ml)中的3-(R)-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮(1.33g,5.0mmol)与6-溴己酸乙酯(0.89ml,5.0mmol)混合,将碳酸氢钠(2.0g)悬浮于该混合物中。将混合物搅拌、加热回流10小时。然后让反应混合物冷却至室温,用100ml水稀释,用乙酸乙酯萃取(3×75ml)。将有机层合并,用硫酸镁干燥,重力过滤,真空脱除溶剂。所得油状物进行色谱提纯,用1∶49甲醇/氯仿洗脱,得到单烷基化产物(0.56g,28%)以及原料1,4-苯并二氮杂-2-酮和二烷基化产物。往单烷基化产物(0.56g,1.37mmol)的二氯甲烷(20ml)溶液中加入己酰氯(0.19ml,1.37mmo),在搅拌下反应0.25小时。反应混合物用二氯甲烷(100ml)稀释,加入饱和碳酸氢钠水溶液(100ml)。水相再用二氯甲烷萃取(2×75ml),将有机物合并,用硫酸镁干燥,重力过滤,真空脱除溶剂,所得油状物在硅胶上进行色谱提纯,用1∶1的乙酸乙酯/己烷洗脱,得到一种泡沫,给出0.40g(58%)产物。m.p.59-65C,[α]d(+)52.7°(c=0.48:MeOH)元素分析:C30H39N3O4.·0.20molCH2Cl2:计算值:C,69.4;H,7.6;N,8.04.实测值:C,69.44;H,7.68;N,7.71%.
用基本上如上面所述的方法,但用溴乙酸乙酯代替6-溴己酸乙酯,制得了如下的化合物。
实例103
(+)-N-[2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-N-(乙氧羰基甲基)己酰胺泡沫,[α]d+2.04°(c=0.98:MeOH)。元素分析:C26H31N3O4:计算值:C,69.47;H,6.95;N,9.35.实测值:C,69.41;H,7.03;N,9.26%.实例104
(+)-3-环己基-N-[2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-N-(羟甲基)丙酰胺
将(+)-3-环己基-N-[2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]丙酰胺(2.0g,5.0mmol)溶于THF(30ml)中,冷却到0℃,加入氯化甲基镁(3M,2.0ml)。0.25小时后,加入多聚甲醛(0.1 5g,10mmol),让混合物温热至室温。反应混合物用乙酸乙酯(150ml)稀释,加入饱和碳酸氢钠水溶液(150ml)。水相再用乙酸乙酯萃取(2×100ml),将有机物合并,用硫酸镁干燥,重力过滤,真空脱除溶剂。所得油状物在硅胶上进行色谱提纯,用1∶1的乙酸乙酯/己烷洗脱,得到一种泡沫(0.80g,37%)。泡沫,[α]d+124°(c=0.69:MeOH)。元素分析:C26H31N3O3:计算值:C,72.03;H,7.21;N,9.69.实测值:C,71.66;H,7.08;N,9.78%.
用基本上如上面所述的方法,以(+)-N-[2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]己酰胺为起始原料制得了下面的化合物。
实例105
(+)-N-[2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-N-(羟甲基)己酰胺m.p.154-156℃,[α]d+190.8°(c=0.24;MeOH)。元素分析:C23H27N3O3·0.30 mol H2O:计算值:C,69.26;H,6.97;N,10.53.实测值:C,69.29;H,6.81;N,10.6%.
实例106
(+)-3-环己基-N-[2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-N-(四唑基甲基)丙酰胺
将(+)-3-环乙基-N-[2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基]-N-(羟甲基)丙酰胺(0.678,1.56mmol)溶解在二氯甲烷(100ml)中,然后加入四唑(0.338,4.7mmol)和N,N-二异丙基-二苄基-氨基磷酸酯(1.078,3.1mmol)。2小时后,混合物用二氯甲烷(150ml)稀释,用饱和碳酸氢钠水溶液萃取(3×100ml)。将有机层合并,用硫酸镁干燥,重力过滤,真空脱除溶剂。所得油状物在硅胶上进行色谱提纯,用1∶1的乙酸乙酯/己烷洗脱,得到两种成分的异构体a(65mg,9%)和b(56mg,7.5%)。异构体Am.p.96-98℃,[α]d+188.9°(c=0.19:MeOH)。元素分析:C27H31N7O2·0.30molTFA:计算值:C,63.78;H,6.07;N,18.86.实测值:C,63.7;H,6.12;N,18.76%.异构体Bm.p.92-95℃,[α]d+81.3°(c=0.31;MeOH)。元素分析:C27H31N7O20.35摩尔TFA:计算值:C,63.31;H,6.01;N,18.66.实测值:C,63.35;H,6.02;N,18.74%.实例107
3R-(+)-3-(苄氧羰基氨基)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂
将氯甲酸苄酯(1.2ml,8.3mmol)加入到3-(R)-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮(2.08,7.5mmol)在0℃的二氯甲烷(45ml)的搅拌着的溶液中,让反应温热到室温。反应混合物用二氯甲烷(150ml)稀释,用饱和碳酸氢钠水溶液(150ml)萃取。水相用二氯甲烷萃取(2×100ml),将有机物合并,用硫酸镁干燥,重力过滤,真空脱除溶剂。所得油状物在硅胶上进行色谱提纯,用1∶1的乙酸乙酯/己烷洗脱,得到白色泡沫(3.08,99.7%)。[α]d+57.5°(c=1.17:MeOH)。元素分析:C24H20N3O3·0.70摩尔H2O·0.15摩尔CHCl3:计算值:C,67.62;H,5.06;N,9.8.实测值:C,67.6;H,5.02;N,9.75%.
基本上按实例81所述的方法,制备了下列化合物。
实例108
N-[2,3-二氢-1-甲基-2-氧代-5-乙基-1H-1,4-苯并二氮杂-3-基]-3-(2,4-二氯苯基)丙酰胺m.p.156-158℃CHN:元素分析:C21H21Cl2N3O2·0.5H2O:计算值:C,59.02;H,5.19;N,9.83.实测值:C,58.99;H,4.89;N,9.88.
实例109
N-[2,3-二氢-1-甲基-2-氧代-5-权丁基-1H-1,4-苯并二氮杂-3-基]-3-(2,4-二氯苯基)丙酰胺m.p.170-171℃CHN:元素分析:C23H25Cl2N3O2·0.7H2O:计算值:C,60.18;H,5.80;N,9.16.实测值:C,60.17;H,5.30;N,9.30.
实例110
N-[2,3-二氢-1-甲基-2-氧代-[4′-(4,4-二甲基-2-噁唑啉基)苯基]-1H-1,4-苯并二氮杂-3-基]-3-(2,4-二氯苯基)丙酰胺m.p.188-190℃CHN:元素分析:C30H28N4O3Cl2:计算值:C,63.95;H,5.01;N,9.94.实测值:C,63.96;H,5.02;N,10.08.
实例111
N-[2,3-二氢-1-甲基-2-氧代-5-(4-甲氧基苯基)-1H-1,4-苯并二氮杂-3-基]-3-(2,4-二氯苯基)丙酰胺m.p.188-189℃CHN:元素分析:C26H23Cl2N3O3·0.45H2O:计算值:C,62.91;H,4.67;N,8.47.实测值:C,61.89;H,4.78;N,8.33.
Claims (21)
A是
1)噻吩并,
2)吡啶并,或
3)苯并,可以是未取代的或被-NH2、-NHSO2(C1-3烷基)、C1-3烷基或C1-3烷氧基取代的:
X是
1)=O,
2)=S,
3)=N-NH2
4)=N-OH或
5)=H2
Y是
1)=O,
2)=N-CN或
3)=H2
Z是
1)C1-6亚烷基,可为直链或支链,且可以是未取代的或被苯基或螺哌啶取代的,
2)C2-4亚链烯基,可为直链或支链,
3)-(CH2)m-W-(CH2)n-,其中m和n独立地是0、1、2、3或4,W是-O-、-S-或-NH-,
4)4-(5-甲基异噁唑-3-基),
5)C3-6亚环烷基,或
6)单键;
p是0或1:
R1是
1)苯基,可以是未取代的或被1个或2个选自下列的取代基取代的:
a)-NO2
b)-Cl、Br、F、或I,
c)-CF3,
d)-C1-3烷基,
e)-C1-3烷氧基,
f)-CN,
g)亚甲二氧基,
2)C5-7环烷基
4)5-10元的单或双杂环基,其中有1个或2个元素是硫,氮或氧,其余为碳,例如2-噻吩基、2-呋喃基、2-吲哚基、2-喹喔啉基或2-(2,3-二氢苯并呋喃基),
5)甲基,或
6)2,3-二氢化茚-5-基:
R2是
1)苯基,可以是未取代的或被C1-3烷氧基或4,4-二甲基噁唑啉-2-基取代的,
2)C1-4烷基,可为直链或支链,且可以是未取代的或被C1-3烷氧基或C1-3烷氧基-C1-3烷氧基取代,
3)C5-7环烷基,
4)2-或3-呋喃基,
5)1-甲基哌啶-2-基,或
6)如果R2是苯基,则苯基的2-位可以通过一个羰基连接到该二氮杂环的4-位氮上,且4-氮和5-碳之间的双键变成单健;
R3是
1)氢或
2)C1-3烷基,可以是未取代的或被-N(CH3)2、OH、-CF3取代的,或
3)-CF3:
R4是
1)氢,
3)四唑-5-基;
……所表示的键是:
1)当p是0时,或当p是1,且R5是氧时,表示双键,或
2.权利要求1的治疗方法,其中:
A是苯并;
X和Y是氧;
R3是甲基:
R4是氢;和
R2是C1-6烷基。
3.权利要求2的治疗方法,其中该化合物选自下表中所列的那些化合物:表
R1 R2
2,4-二氯苯基 -CH3
2,4-二氯苯基 -C2H3
2,4-二氯苯基 -t-Bu
4-CF3Ph i-C3H7
环己基 i-C3H7
2,4-二氯苯基 i-C3H7
4.权利要求1的治疗方法,其中:
A是苯并:
X和Y是氧:
R3是甲基:
R4是氢;和
R2是苯基。
6.权利要求5的方法,其中该化合物选自下表中所列的那些化合物:
Z R1
-(CH2)2- 2,4-二氯苯基
-(CH2)2- 4-ClPh
-(CH2)2- 2,4-二氟苯基
-(CH2)2- 2-ClPh
-(CH2)2- 4-CF3Ph
-CH2- 4-CF3Ph
-(CH2)2- 3-CF3Ph
-(CH2)2- 2-CF3Ph
-(CH2)2- 环己基
- 环己基
-(CH2)3- 环己基
-CH2- 环己基
-(CH2)2- Ph
-CH2- Ph
-(CH2)2- 4-NCPh
-(CH2)2- 3-ClPh
-(CH2)3- Ph
-(CH2)2- 3-NCPh
-(CH2)2- 2-噻吩基
7.权利要求4的方法,其中该化合物的结构式如下:
其中Z是C2-4亚链烯基,R1是苯基或被-Cl、-Br、-F、-I、-CF3、C1-3烷基、C1-3烷氧基、硝基或亚甲二氧基取代的苯基。
8.权利要求7的方法,其中该化合物选自下表中所列的那些化合物:
Z R1
-CH=CH- 4-NO2Ph
-CH=CH- 2,4-二氯苯基
Z R1
-CH=CH- 3-ClPh
-CH=CH- 2-ClPh
-CH=CH- 2,4-二氟苯基
-CH=CH- 2,6-二氯苯基
-CH=CH- 4-CF3Ph
-CH=CH- 2-BrPh
-CH=CH- 4-IPh
-CH=CH- 4-BrPh Ph
-CH=CH- Ph
-CH=CH- 3,4-二氯苯基
-CH=CH- 4-CH3Ph
-CH=CH- 4-CH3OPh
-CH=CH- 3,4-亚甲二氧基苯基
-CH=CH- 3-BrPh
9.权利要求1的方法,其中:Z是-NH-。
12.一种含有药物上可接受的载体和有效量的权利要求11的化合物的药物配方。
13.一种结构式如下的化合物:
其中Z是C1-6亚烷基或一个键,R1是苯基,被-Cl、-Br、-I、-F、-CN或-CF3取代的苯基,或R1是环己基。
14.权利要求13的化合物,其中该化合物选自下表中所列的那些化合物:
Z R1
-(CH2)2- 2,4-二氯苯基
-(CH2)2- 4-ClPh
-(CH2)2- 2,4-二氟苯基
-(CH2)2- 2-ClPh
-(CH2)2- 4-CF3Ph
-CH2- 4-CF3Ph
-(CH2)2- 3-CF3Ph
-(CH2)2- 2-CF3Ph
-(CH2)2- 环己基
- 环己基
-(CH2)3- 环己基
-CH2- 环己基
-(CH2)2- Ph
-CH2- Ph
-(CH2)2- 4-NCPh
-(CH2)2- 3-ClPh
-(CH2)3- Ph
-(CH2)2- 3-CNPh
-(CH2)2- 2-噻吩基
17.权利要求16的化合物,选自下表中所列的那些化合物:
L Z R1
735,801 -CH=CH- 4-NO2Ph
735,821 -CH=CH- 2,4′-二氯苯基
735,865 -CH=CH- 3-ClPh
735,868 -CH=CH- 2-ClPh
735,875 -CH=CH- 2,4-二氟苯基
735,894 -CH=CH- 2,6-二氯苯基
735,896 -CH=CH- 4-CF3Ph
L Z R1
738,048 -CH=CH- 2-BrPh
738,052 -CH=CH- 4-IPh
738,067 -CH=CH- 4-BrPh
735,800 -CH=CH- 3,4-二氯苯基
735,822 -CH=CH- 4-CH3Ph
735,826 -CH=CH- 4-CH3OPh
742,192 -CH=CH- 3,4-亚甲二氧基苯基
738,049 -CH=CH- 3-BrPh
l8.结构式如下的权利要求17的化合物:
l9.结构式如下的权利要求l7的化合物:
21.权利要求20的化合物,该化合物选自由下列表中所列的那些化合物构成的组:
R1 R2
2,4-二氯苯基 -CH3
2,4-二氯苯基 -C2H5
2,4-二氯苯基 -t-Bu
4-CF3Ph i-C3H7
环己基 i-C3H7
2,4-二氯苯基 i-C3H7
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IE904560A1 (en) * | 1989-12-18 | 1991-06-19 | Merck & Co Inc | New benzodiazepine analogs |
US4994258A (en) * | 1990-03-05 | 1991-02-19 | Merck & Co., Inc. | Gamma emitting, CCK-A antagonists for pancreatic imaging |
US5220018A (en) * | 1991-04-10 | 1993-06-15 | Merck & Co., Inc. | Cholecystokinin antagonists |
CA2068355A1 (en) * | 1991-05-14 | 1992-11-15 | Mark S. Chambers | Benzodiazephine derivatives, compositions containing them and their use in therapy |
GB9116113D0 (en) * | 1991-07-25 | 1991-09-11 | Merck Sharp & Dohme | Therapeutic agents |
KR970002640B1 (ko) * | 1991-09-30 | 1997-03-07 | 요시또미세이야꾸 가부시끼가이샤 | 티에노디아제핀 화합물 및 그의 용도 |
WO1993007131A1 (en) * | 1991-10-10 | 1993-04-15 | Merck Sharp & Dohme Limited | Benzodiazepine derivatives and their use as antagonists of cholecystokinin and/or gastrin receptors |
EP0539170A1 (en) * | 1991-10-24 | 1993-04-28 | Merck Sharp & Dohme Ltd. | Benzodiazepine derivatives and their use as antagonists of cholecystokinin and/or gastrin receptors |
AU2759692A (en) * | 1991-10-24 | 1993-05-21 | Glaxo Group Limited | Benzodiazepine derivatives as antagonists of gastrin and/or cholecystokinin |
EP0549039B1 (en) * | 1991-12-20 | 1995-08-09 | MERCK SHARP & DOHME LTD. | 3-Phenylureido-1,4-Benzodiazepinones and their use as cholecystokinin or gastrin antagonists |
GB9203790D0 (en) * | 1992-02-21 | 1992-04-08 | Merck Sharp & Dohme | Therapeutic agents |
JPH07504908A (ja) * | 1992-03-16 | 1995-06-01 | メルク シヤープ エンド ドーム リミテツド | ベンゾジアゼピン誘導体,該誘導体を含有する組成物及び治療におけるその使用 |
GB9209518D0 (en) * | 1992-05-01 | 1992-06-17 | Merck Sharp & Dohme | Therapeutic agents |
GB9218412D0 (en) * | 1992-08-28 | 1992-10-14 | Merck Sharp & Dohme | Therapeutic agents |
US5439906A (en) * | 1993-11-22 | 1995-08-08 | Merck & Co., Inc. | Antiarrhythmic benzodiazepines |
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US5438055A (en) * | 1993-11-22 | 1995-08-01 | Merck & Co., Inc. | Antiarrhythmic benzodiazepines |
US5426185A (en) * | 1993-11-22 | 1995-06-20 | Merck & Co., Inc. | Antiarrhythmic benzodiazepines |
-
1993
- 1993-11-22 US US08/156,331 patent/US5426185A/en not_active Expired - Fee Related
-
1994
- 1994-11-21 BR BR9408148A patent/BR9408148A/pt not_active Application Discontinuation
- 1994-11-21 PL PL94314592A patent/PL177810B1/pl unknown
- 1994-11-21 JP JP51516995A patent/JP3216136B2/ja not_active Expired - Fee Related
- 1994-11-21 WO PCT/US1994/013414 patent/WO1995014471A1/en not_active Application Discontinuation
- 1994-11-21 CA CA002176015A patent/CA2176015A1/en not_active Abandoned
- 1994-11-21 CZ CZ961477A patent/CZ147796A3/cs unknown
- 1994-11-21 CN CN94194856A patent/CN1074926C/zh not_active Expired - Fee Related
- 1994-11-21 RU RU96113042/14A patent/RU2155587C2/ru active
- 1994-11-21 AU AU11005/95A patent/AU695159B2/en not_active Ceased
- 1994-11-21 NZ NZ276649A patent/NZ276649A/en unknown
- 1994-11-21 EP EP95901955A patent/EP0730454A4/en not_active Withdrawn
- 1994-11-21 SK SK650-96A patent/SK281532B6/sk unknown
-
1995
- 1995-03-27 US US08/411,240 patent/US5595990A/en not_active Expired - Fee Related
-
1996
- 1996-05-20 BG BG100607A patent/BG62555B1/bg unknown
- 1996-05-21 FI FI962141A patent/FI962141A/fi unknown
- 1996-05-21 NO NO962059A patent/NO962059L/no not_active Application Discontinuation
- 1996-05-22 LV LVP-96-150A patent/LV11526B/en unknown
Also Published As
Publication number | Publication date |
---|---|
RU2155587C2 (ru) | 2000-09-10 |
FI962141A0 (fi) | 1996-05-21 |
CN1074926C (zh) | 2001-11-21 |
PL177810B1 (pl) | 2000-01-31 |
BR9408148A (pt) | 1997-08-12 |
NO962059D0 (no) | 1996-05-21 |
LV11526A (lv) | 1996-10-20 |
EP0730454A4 (en) | 2003-06-04 |
FI962141A (fi) | 1996-05-21 |
BG62555B1 (bg) | 2000-02-29 |
SK281532B6 (sk) | 2001-04-09 |
SK65096A3 (en) | 1997-03-05 |
AU695159B2 (en) | 1998-08-06 |
LV11526B (en) | 1997-02-20 |
JP3216136B2 (ja) | 2001-10-09 |
CA2176015A1 (en) | 1995-06-01 |
JPH09505598A (ja) | 1997-06-03 |
US5426185A (en) | 1995-06-20 |
WO1995014471A1 (en) | 1995-06-01 |
PL314592A1 (en) | 1996-09-16 |
BG100607A (bg) | 1996-11-29 |
NO962059L (no) | 1996-07-19 |
AU1100595A (en) | 1995-06-13 |
NZ276649A (en) | 1998-07-28 |
CZ147796A3 (en) | 1996-11-13 |
US5595990A (en) | 1997-01-21 |
EP0730454A1 (en) | 1996-09-11 |
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