CN101128455A - 杂环基酰胺-取代的咪唑类 - Google Patents
杂环基酰胺-取代的咪唑类 Download PDFInfo
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- CN101128455A CN101128455A CNA2006800056123A CN200680005612A CN101128455A CN 101128455 A CN101128455 A CN 101128455A CN A2006800056123 A CNA2006800056123 A CN A2006800056123A CN 200680005612 A CN200680005612 A CN 200680005612A CN 101128455 A CN101128455 A CN 101128455A
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- Prior art keywords
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- phenyl
- compound
- expression
- alkyl
- Prior art date
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- 150000002460 imidazoles Chemical class 0.000 title abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 68
- 238000011282 treatment Methods 0.000 claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 15
- 201000010099 disease Diseases 0.000 claims abstract description 14
- 238000011321 prophylaxis Methods 0.000 claims abstract 4
- -1 trifluoromethoxy, difluoro-methoxy Chemical group 0.000 claims description 93
- 150000001875 compounds Chemical class 0.000 claims description 85
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 43
- 238000002360 preparation method Methods 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 24
- 229910052731 fluorine Inorganic materials 0.000 claims description 23
- 239000011737 fluorine Substances 0.000 claims description 23
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 21
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 19
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 239000012453 solvate Substances 0.000 claims description 18
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 17
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims description 17
- 125000005034 trifluormethylthio group Chemical group FC(S*)(F)F 0.000 claims description 17
- 230000009385 viral infection Effects 0.000 claims description 15
- 241000700605 Viruses Species 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 13
- 239000003513 alkali Substances 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 206010011831 Cytomegalovirus infection Diseases 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 10
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 10
- 208000015181 infectious disease Diseases 0.000 claims description 10
- 125000004043 oxo group Chemical group O=* 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 230000000840 anti-viral effect Effects 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 230000002829 reductive effect Effects 0.000 claims description 6
- 241001465754 Metazoa Species 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 208000036142 Viral infection Diseases 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 241000282412 Homo Species 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 229940124531 pharmaceutical excipient Drugs 0.000 claims 1
- 241000701022 Cytomegalovirus Species 0.000 abstract description 4
- 239000003443 antiviral agent Substances 0.000 abstract description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
- 239000000203 mixture Substances 0.000 description 38
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 36
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 36
- 238000005160 1H NMR spectroscopy Methods 0.000 description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 238000004128 high performance liquid chromatography Methods 0.000 description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 22
- 239000002904 solvent Substances 0.000 description 21
- 125000004494 ethyl ester group Chemical group 0.000 description 20
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 18
- 239000003480 eluent Substances 0.000 description 18
- 235000019253 formic acid Nutrition 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 10
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 239000012442 inert solvent Substances 0.000 description 9
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- PFKFTWBEEFSNDU-UHFFFAOYSA-N 1,1'-Carbonyldiimidazole Substances C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 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
- 239000000706 filtrate Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000004215 Carbon black (E152) Substances 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 5
- 239000007868 Raney catalyst Substances 0.000 description 5
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 5
- 229910000564 Raney nickel Inorganic materials 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 229930195733 hydrocarbon Natural products 0.000 description 5
- 150000002430 hydrocarbons Chemical class 0.000 description 5
- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 5
- 235000015320 potassium carbonate Nutrition 0.000 description 5
- 238000004007 reversed phase HPLC Methods 0.000 description 5
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
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- 229910052786 argon Inorganic materials 0.000 description 4
- 229960001701 chloroform Drugs 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
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- 150000005826 halohydrocarbons Chemical class 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
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- 238000012360 testing method Methods 0.000 description 4
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- 239000012317 TBTU Substances 0.000 description 3
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- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
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- 238000004587 chromatography analysis Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- 230000002265 prevention Effects 0.000 description 3
- GZRKXKUVVPSREJ-UHFFFAOYSA-N pyridinylpiperazine Chemical compound C1CNCCN1C1=CC=CC=N1 GZRKXKUVVPSREJ-UHFFFAOYSA-N 0.000 description 3
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- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 description 2
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- VWFCHDSQECPREK-LURJTMIESA-N Cidofovir Chemical compound NC=1C=CN(C[C@@H](CO)OCP(O)(O)=O)C(=O)N=1 VWFCHDSQECPREK-LURJTMIESA-N 0.000 description 2
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- 239000007821 HATU Substances 0.000 description 2
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- JRFWBYGYYILWPW-UHFFFAOYSA-N NC=1C=CC(CC1C(=O)O)(C(=O)O)C Chemical compound NC=1C=CC(CC1C(=O)O)(C(=O)O)C JRFWBYGYYILWPW-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
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- 206010035664 Pneumonia Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
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- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 2
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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
- C07D401/06—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 carbon chain containing only aliphatic carbon atoms
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
本发明涉及杂环基酰胺-取代的咪唑类和制备它们的方法,将它们用于治疗和/或预防疾病的应用,以及将它们用于制备治疗和/或预防疾病的药物、特别是用作抗病毒药剂的应用,所述抗病毒药剂特别地针对巨细胞病毒。
Description
本发明涉及杂环基酰胺-取代的咪唑类和制备它们的方法,将它们用于治疗和/或预防疾病的应用,以及将它们用于制备治疗和/或预防疾病的药物、特别是用作抗病毒药剂的应用,所述抗病毒药剂特别地针对巨细胞病毒。
WO 99/23091描述了作为抗炎药剂的芳族杂环化合物,其特别地还可以适合于病毒感染的治疗。
尽管具有抗病毒活性的不同结构的药剂可以在市场上获得,但是目前使用更昔洛韦、缬更昔洛韦、膦甲酸和西多福韦进行的治疗与严重的副作用,例如中毒性肾损害、中性白细胞减少症或血小板减少症相关。而且,始终可能发展抗性。因此,期望用于有效治疗的新的药剂。
因此本发明的一个目标是提供用于治疗人和动物中的病毒性感染疾病的新的化合物,其具有相同或改善的抗病毒活性。
已经令人惊奇地发现本发明中所述的取代的咪唑类具有高抗病毒活性。
本发明涉及下式的化合物:
其中
R1表示下式的基团
其中
*表示与羰基基团的连接位点,
R4表示苯基或5-或6-元杂芳基,
其中苯基和杂芳基可以由1-3个取代基所取代,其中所述取代基彼此独立地选自由下列各项组成的组:卤素,羟基,氧代,硝基,氰基,三氟甲基,二氟甲基,三氟甲氧基,二氟甲氧基,单氟甲氧基,三氟甲硫基,C1-C6-烷基,C1-C6-烷氧基,羟基羰基,C1-C6-烷氧基羰基,氨基,C1-C6-烷基氨基,氨基羰基和C1-C6-烷基氨基羰基,
R5表示苯基或5-或6-元杂芳基,
其中苯基和杂芳基可以由1-3个取代基所取代,其中所述取代基彼此独立地选自由下列各项组成的组:卤素,羟基,氧代,硝基,氰基,三氟甲基,二氟甲基,三氟甲氧基,二氟甲氧基,单氟甲氧基,三氟甲硫基,C1-C6-烷基,C1-C6-烷氧基,羟基羰基,C1-C6-烷氧基羰基,氨基,C1-C6-烷基氨基,氨基羰基和C1-C6-烷基氨基羰基,
并且
R6和R7彼此独立地表示氢,甲基或乙基,
R2表示C1-C6-烷基,
其中烷基可以由取代基所取代,其中所述取代基选自由下列各项组成的组:C3-C6-环烷基,C6-C10-芳基和5-或6-元杂芳基,
其中环烷基,芳基和杂芳基可以由1-3个取代基所取代,其中所述取代基彼此独立地选自由下列各项组成的组:卤素,羟基,氧代,硝基,氰基,三氟甲基,二氟甲基,三氟甲氧基,二氟甲氧基,单氟甲氧基,三氟甲硫基,C1-C6-烷基,C1-C6-烷氧基,羟基羰基,C1-C6-烷氧基羰基,氨基,C1-C6-烷基氨基,氨基羰基和C1-C6-烷基氨基羰基,
R3表示苯基,
其中苯基可以由1-3个取代基所取代,其中所述取代基彼此独立地选自由下列各项组成的组:卤素,羟基,三氟甲基,二氟甲基,三氟甲氧基,二氟甲氧基,单氟甲氧基,三氟甲硫基,C1-C6-烷基和C1-C6-烷氧基,和它们的盐、它们的溶剂合物和它们盐的溶剂合物
本发明的化合物是式(I)的化合物及其盐、其溶剂合物及其盐的溶剂合物;下面提及的式的式(I)所涵盖的化合物和它们的盐,溶剂合物和它们盐的溶剂合物,以及由式(I)涵盖并作为例示性实施方案的下文提及的化合物及其盐、溶剂合物及其盐的溶剂合物,如果在下文提及并且由式(I)所涵盖的化合物还不是盐、溶剂合物和所述盐的溶剂合物。
根据它们的结构,本发明的化合物可以以立体异构型(对映异构体,非对映异构体)存在。因此,本发明涉及对映异构体或非对映异构体及其各自的混合物。立体异构纯的组分可以以已知方式从对映异构体和/或非对映异构体的这样的混合物中分离出来。
如果本发明的化合物可以以互变异构形式存在,本发明包括所有的互变异构形式。
优选用于本发明的目的的盐是本发明的化合物的生理可接受的盐。然而,本身不适合于药用但是可以用于例如分离或纯化本发明的化合物的盐也被包括在内。
本发明的化合物的生理可接受的盐包括无机酸、羧酸和磺酸的酸加成盐,例如盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、甲苯磺酸、苯磺酸、萘二磺酸、乙酸、三氟乙酸、丙酸、乳酸、酒石酸、苹果酸、柠檬酸、富马酸、马来酸和苯甲酸的盐。
本发明的化合物的生理可接受的盐还包括常用的碱的盐,诸如,作为实例,并且优选地碱金属盐(例如,钠和钾盐),碱土金属盐(例如钙和镁盐)和衍生自氨或具有1-16个碳原子的有机胺的铵盐,所述有机胺诸如作为实例,并且优选地,乙胺、二乙胺、三乙胺、乙基二异丙胺、单乙醇胺、二乙醇胺、三乙醇胺、二环己胺、二甲基氨基乙醇、普鲁卡因、二苄基胺、N-甲基吗啉、精氨酸、赖氨酸、乙二胺和N-甲基哌啶。
对于本发明的目的而言,溶剂合物指通过与溶剂分子的配位作用形成固体或液体状态的复合物的本发明的化合物的那些形式。水合物是溶剂合物的特殊形式,其中配位作用与水发生。
此外,本发明还包括本发明化合物的前药。术语“前药”包括这样的化合物,所述化合物本身可以是具有生物学活性或不具有生物学活性,但是在它们在体内停留期间,被转化为本发明的化合物(例如通过代谢或水解作用)。
对于本发明的目的而言,除非另外指出,取代基具有下列含义:
烷基本身和烷氧基、烷基氨基、烷基羰基和烷基氨基羰基中的“烷基 (alk)”和“烷基(alkyl)”表示直链或支链烷基原子团,其通常具有1-6(“C1-C6-烷基”),优选地1-4,特别优选地1-3个碳原子,作为实例并且优选地是甲基、乙基、正丙基、异丙基、叔丁基、正戊基和正己基。
烷氧基表示,作为实例并且优选地,甲氧基、乙氧基、正丙氧基、异丙氧基、叔丁氧基、正戊氧基和正己氧基。
烷基氨基表示具有一个或两个烷基取代基(彼此独立地选择)的烷基氨基原子团,作为实例并且优选地,甲基氨基、乙基氨基、正丙基氨基、异丙基氨基、叔丁基氨基、正戊基氨基、正己基氨基、N,N-二甲基氨基、N,N-二乙基氨基、N-乙基-N-甲基氨基、N-甲基-N-正丙基氨基、N-异丙基-N-正丙基氨基、N-叔-丁基-N-甲基氨基、N-乙基-N-正戊基氨基和N-正己基-N-甲基氨基。C1-C3-烷基氨基表示例如具有1-3个碳原子的单烷基氨基原子团或每个取代基具有1-3个碳原子的二烷基氨基原子团。
烷氧羰基表示,作为实例,并且优选地,甲氧基羰基、乙氧基羰基、正丙氧基羰基、异丙氧基羰基、叔丁氧基羰基、正戊氧基羰基和正己氧基羰基。
烷基氨基羰基表示具有1或2个烷基取代基(彼此独立地选择)的原子团,作为实例并且优选地甲基氨基羰基,乙基氨基羰基,正丙基氨基羰基,异丙基氨基羰基,叔丁基氨基羰基,正戊基氨基羰基,正己基氨基羰基,N,N-二甲基氨基羰基,N,N-二乙基氨基羰基,N-乙基-N-甲基氨基羰基,N-甲基-N-正丙基氨基羰基,N-异丙基-N-正丙基-氨基羰基,N-叔丁基-N-甲基氨基羰基,N-乙基-N-正戊基氨基羰基和N-正己基-N-甲基氨基羰基。C1-C3-烷基氨基羰基表示例如具有1-3个碳原子的单烷基氨基羰基原子团或每个烷基取代基具有1-3个碳原子的二烷基氨基羰基原子团。
芳基表示通常具有6-10个碳原子的单或双环芳香碳环原子团,作为实例和优选地是苯基和萘基。
出于本发明的目的,5-或6-元杂芳基通常表示具有5或6个环原子和至多4个杂原子的芳香单环原子团,所述杂原子来自由S,O和/或N组成的组。所述杂芳基原子团可以通过碳原子或杂原子连接。作为实例和优选地可以提及下列原子团:噻吩基,呋喃基,吡咯基,噻唑基,噁唑基,吡唑基,咪唑基,吡啶基,嘧啶基和哒嗪基。
环烷基表示通常具有3-8个,优选地3-6个碳原子的环烷基基团,作为实例并且优选地,环丙基,环丁基,环戊基,环己基和环庚基。
卤素表示氟,氯,溴和碘。
出于本发明的目的,优选式(I)的化合物,
其中
R1表示下式的基团
其中
*表示与羰基基团的连接位点,
R4表示苯基或5-或6-元杂芳基,
其中苯基和杂芳基可以由1-3个取代基所取代,其中所述取代基彼此独立地选自由下列各项组成的组:卤素,羟基,氧代,硝基,氰基,三氟甲基,二氟甲基,三氟甲氧基,二氟甲氧基,单氟甲氧基,三氟甲硫基,C1-C6-烷基,C1-C6-烷氧基,羟基羰基,C1-C6-烷氧基羰基,氨基,C1-C6-烷基氨基,氨基羰基和C1-C6-烷基氨基羰基,
R2表示C1-C6-烷基,
其中烷基可由取代基所取代,其中所述取代基选自由C3-C6-环烷基和苯基组成的组,
其中环烷基和苯基可以由1-3个取代基所取代,其中所述取代基彼此独立地选自由下列各项组成的组:卤素,羟基,氧代,硝基,氰基,三氟甲基,二氟甲基,三氟甲氧基,二氟甲氧基,单氟甲氧基,三氟甲硫基,C1-C6-烷基,C1-C6-烷氧基,羟基羰基,C1-C6-烷氧基羰基,氨基,C1-C6-烷基-氨基,氨基羰基和C1-C6-烷基氨基羰基,
R3表示苯基,
其中苯基可以由1-3个取代基所取代,其中所述取代基彼此独立地选自由下列各项组成的组:卤素,羟基,三氟甲基,二氟甲基,三氟甲氧基,二氟甲氧基,单氟甲氧基,三氟甲硫基,C1-C6-烷基和C1-C6-烷氧基,和它们的盐,它们的溶剂合物和它们盐的溶剂合物
出于本发明的目的,优选式(I)的化合物,
其中
R1表示下式的基团
其中
*表示与羰基基团的连接位点,
R4表示苯基或吡啶基,
其中苯基和吡啶基可以由1-3个取代基所取代,其中所述取代基彼此独立地选自由下列各项组成的组:卤素,硝基,氰基,三氟甲基,二氟甲基,三氟甲氧基,二氟甲氧基,单氟甲氧基,C1-C4-烷基和C1-C4-烷氧基,
R2表示甲基,乙基或正丁基,
其中甲基,乙基和正丁基可以由取代基所取代,其中所述取代基选自由环丙基和苯基组成的组,
其中苯基可以由三氟甲基取代基所取代,
R3表示苯基,
其中苯基可以由1-3个取代基所取代,其中所述取代基彼此独立地选自由下列各项组成的组:氟,氯,三氟甲氧基,二氟甲氧基,三氟甲硫基和甲基,
和它们的盐,它们的溶剂合物和它们盐的溶剂合物出于本发明的目的,优选式(I)的化合物其中R1表示下式的基团
其中
*表示与羰基基团的连接位点,和
R4表示苯基或吡啶基,
其中苯基和吡啶基可以由1-3个取代基所取代,其中所述取代基彼此独立地选自由下列各项组成的组:卤素,硝基,氰基,三氟甲基,二氟甲基,三氟甲氧基,二氟甲氧基,单氟甲氧基,C1-C4-烷基和C1-C4-烷氧基.
出于本发明的目的,优选式(I)的化合物其中R3表示苯基,其中苯基可以由1-3个取代基所取代,其中所述取代基彼此独立地选自由下列各项组成的组:氟,氯,三氟甲氧基,二氟甲氧基,三氟甲硫基和甲基。
本发明还涉及制备式(I)的化合物的方法,其中按照方法[A],其中R1和R2具有上面指定含义的下式的化合物
在第一个步骤中与还原剂反应,并且在第二个步骤中,在碳酸衍生物存在的情况下,与其中R3具有上面指定含义的下式的化合物反应,
H2N-R3(III),
或
按照方法[B],式(II)的化合物在第一个步骤中与还原剂反应,在第二个步骤中,与其中R3具有上面指定含义的下式的化合物反应,
OCN-R3(IV),
或
按照方法[C]
其中R2和R3具有上面指定含义,且R8表示甲基或乙基的下式的化合物
在第一个步骤中与碱反应,并且在第二个步骤与其中R1具有上面指定含义的式R1-H(VI)在存在脱水剂的情况下反应。
式(III),(IV)和(VI)的化合物是已知的,或可以通过已知方法从相应的原材料进行合成。
对于方法[A]和[B],步骤1,应用下列:
反应通常在惰性试剂中发生,优选地在从0℃到溶剂的回流温度的温度范围内,并在3巴的大气压下。
还原剂是例如,披钯碳和氢,甲酸/三乙胺/披钯碳,锌,锌/盐酸,铁,铁/盐酸,硫酸亚铁/盐酸,硫化钠,二硫化二钠,连亚硫酸钠,多硫化铵,硼氢化钠/氯化镍,二氯化锡,三氯化钛或阮内镍和肼水溶液;优选阮内镍和肼水溶液,披钯碳和氢或甲酸/三乙胺/披钯碳。
惰性溶剂是例如醚诸如二乙醚、甲基叔丁醚、1,2-二甲氧基乙烷、二噁烷、四氢呋喃、乙二醇二甲醚或二乙二醇二甲基醚,醇诸如甲醇,乙醇,正丙醇,异丙醇,正丁醇或叔丁醇,烃诸如苯、二甲苯、甲苯、己烷、环己烷或石油级分,或其它溶剂诸如二甲基甲酰胺,二甲基乙酰胺,乙腈或吡啶,至于水混溶性溶剂,还包括其与水的混合物;优选的溶剂是甲醇,乙醇,异丙醇,或对于阮内镍和肼水溶液,优选四氢呋喃。
对于方法[A],步骤2,应用下列:
反应通常发生在惰性溶剂中,优选地在从室温到40℃的温度范围,在大气压下进行。
碳酸衍生物是,例如,N,N-羰二咪唑,光气,双光气,三光气,氯甲酸苯酯或4-硝基苯基氯甲酸酯;优选N,N-羰二咪唑。
惰性溶剂是例如卤代烃诸如二氯甲烷、三氯甲烷、四氯化碳、三氯乙烷、四氯乙烷、1,2-二氯乙烷或三氯乙烯,醚诸如二乙醚、甲基叔丁醚、1,2-二甲氧基乙烷、二噁烷、四氢呋喃、乙二醇二甲醚或二乙二醇二甲基醚,烃诸如苯、二甲苯、甲苯、己烷、环己烷或石油级分,或其它溶剂诸如乙酸乙酯、丙酮、二甲基甲酰胺、二甲基乙酰胺、2-丁酮、二甲亚砜、乙腈或吡啶,对于水混溶性溶剂,还包括其与水的混合物;其中优选二甲亚砜。
对于方法[B],步骤2,应用下列:
反应通常发生在惰性溶剂中,任选地在碱存在的情况下,优选地在从室温到溶剂的回流温度的温度范围中,在大气压下进行。
惰性溶剂是,例如,卤代烃诸如二氯甲烷、三氯甲烷、四氯化碳、三氯乙烷、四氯乙烷、1,2-二氯乙烷或三氯乙烯,醚诸如二乙醚、甲基叔丁醚、1,2-二甲氧基乙烷、二噁烷、四氢呋喃、乙二醇二甲醚或二乙二醇二甲醚、烃诸如苯、二甲苯、甲苯、己烷、环己烷或石油级分,或其它溶剂诸如乙酸乙酯、丙酮、二甲基甲酰胺、二甲基乙酰胺、2-丁酮、二甲亚砜、乙腈或吡啶;其中优选四氢呋喃或二氯甲烷。
碱是,例如碱金属碳酸盐,诸如碳酸铯,碳酸钠或碳酸钾或叔丁醇钾,或其它碱,诸如氢化钠,DBU,三乙胺或二异丙基乙胺,优选三乙胺。
对于方法[C],步骤1,应用下列:
反应通常发生在惰性溶剂中,优选地在从0℃到溶剂的回流温度的温度范围内,在大气压下进行。
碱是,例如碱金属氢氧化物,诸如氢氧化钠,氢氧化锂或氢氧化钾,或碱金属碳酸盐,诸如碳酸铯,碳酸钠或碳酸钾,优选氢氧化钠。
惰性溶剂是,例如卤代烃,诸如二氯甲烷,三氯甲烷,四氯化碳,三氯乙烷,四氯乙烷,1,2-二氯乙烷或三氯乙烯,醚诸如二乙醚,甲基叔丁醚,1,2-二甲氧基乙烷,二噁烷,四氢呋喃,乙二醇二甲醚或二乙二醇二甲醚、醇诸如甲醇,乙醇,正丙醇,异丙醇,正丁醇或叔丁醇,烃诸如苯,二甲苯,甲苯,己烷,环己烷或石油级分,或其它溶剂诸如二甲基甲酰胺,二甲基乙酰胺,二甲亚砜,乙腈或吡啶,或溶剂与水的混合物;优选的溶剂是乙醇和水的混合物。
对于方法[C],步骤2,应用下列:
反应通常发生在惰性溶剂中,任选地在存在碱,优选地在从-70℃到40℃的温度范围内,在大气压下进行。
本文的适合的脱水剂包括例如碳二亚胺诸如,例如N,N′-二乙基-,N,N,′-二丙基-,N,N′-二异丙基-,N,N′-二环己基碳二亚胺,N-(3-二甲基氨基异丙基)-N′-乙基碳二亚胺盐酸盐(EDC),N-环己基碳二亚胺-N‘-丙基氧基甲基-聚苯乙烯(PS-碳二亚胺)或羰基化合物诸如羰二咪唑,或1,2-噁唑鎓(oxazolium)化合物诸如2-乙基-5-苯基-1,2-噁唑鎓-3-硫酸盐或2-叔-丁基-5-甲基异噁唑鎓高氯酸盐,或酰基氨基化合物诸如2-乙氧基-1-乙氧基羰基-1,2-二氢喹啉,或丙烷膦酸酐,或氯甲酸异丁酯,或二(2-氧代-3-噁唑烷基)磷酰氯,或苯并三唑基氧基三(二甲基氨基)磷鎓六氟磷酸盐,或O-(苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓六氟磷酸盐(HBTU),2-(2-氧代-1-(2H)-吡啶基)-1,1,3,3-四甲基脲鎓四氟硼酸盐(TPTU)或O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓六氟磷酸盐(HATU),或1-羟基苯并三唑(HOBt)或苯并三唑-1-基氧基三(二甲基氨基)六氟膦酸鏻(BOP),或这些与碱的混合物。
碱是,例如碱金属碳酸盐,诸如例如,碳酸钠或碳酸钾,或碳酸氢钠或碳酸氢钾或有机碱,诸如三烷基胺,例如三乙胺,N-甲基吗啉,N-甲基哌啶,4-二甲基氨基吡啶或二异丙基乙胺,或DBU,DBN,吡啶;优选三乙胺。
缩合优选地羰二咪唑进行。
惰性溶剂是例如卤代烃,诸如二氯甲烷,三氯甲烷,四氯化碳,三氯乙烷,四氯乙烷,1,2-二氯乙烷或三氯乙烯,醚诸如二乙醚,甲基叔丁醚,1,2-二甲氧基乙烷,二噁烷,四氢呋喃,乙二醇二甲醚或二乙二醇二甲醚、烃诸如苯,二甲苯,甲苯,己烷,环己烷或石油级分,或其它溶剂诸如诸如乙酸乙酯、丙酮、二甲基甲酰胺、二甲基乙酰胺、2-丁酮、二甲亚砜、乙腈或吡啶;至于水混溶性溶剂,还包括其与水的混合物;优选二甲基甲酰胺。
式(II)的化合物是已知的或可以通过使其中R2具有上面指定含义且R8表示甲基或乙基的下式的化合物
在第一个步骤与碱反应,并且在第二个步骤中,在脱水剂存在的情况下与式(VI)的化合物反应。
反应如在方法[C]中所述。
式(VII)的化合物是已知的或可以通过使其中R2具有上面指定含义且R8表示甲基或乙基的下式的化合物
与发烟硝酸,浓缩的硝酸,硝化酸或其它混合比率的硫酸和硝酸,任选地在作为溶剂的乙酸酐中,优选地在从室温到60℃的温度范围内,在大气压下进行反应。
式(V)的化合物是已知的,或可以通过使式(VII)的化合物在第一个步骤中与还原剂反应并且在第二个步骤中在碳酸衍生物存在的情况下与式(III)的化合物反应,或在第二个步骤中与式(IV)的化合物反应。
反应如在方法[A]和[B]中所述发生。
式(III),(IV),(VI)和(VIII)的化合物是已知的或可以通过已知方法从相应的原材料进行制备。
合成方案1:
合成方案2:
本发明的通式(I)化合物显示了不可预期的,令人惊奇的活性谱。它们具有对疱疹病毒科类的代表(疱疹病毒),特别是对巨细胞病毒(CMV),尤其是对人巨细胞病毒(HCMV)的抗病毒活性。因此它们适合于治疗和预防疾病,特别是病毒尤其是上述病毒的感染,以及由其导致的感染性疾病。病毒感染在下文意味着病毒的感染和由病毒感染所导致的疾病两者。
由于它们特定的性质,通式(I)的化合物可以用于制备适合于预防和/或治疗疾病,特别是病毒感染的的药物。
可以提及的作为实例的适应症的范围是:
1)在AIDS患者中治疗和预防HCMV感染(视网膜炎、肺炎、肠胃传染)。
2)在骨髓和器官移植患者中治疗和预防巨细胞病毒感染,所述患者经常发展威胁生命的HCMV肺炎或脑炎,和胃肠道和全身性HCMV感染。
3)在新生儿和婴幼儿中治疗和预防HCMV感染。
4)在怀孕妇女中治疗急性HCMV感染。
5)在与癌症和癌症治疗相关的免疫抑制患者中治疗HCMV感染。
6)治疗HCMV-阳性的癌症患者,目的是减少HCMV介导的肿瘤进展(参见,J.Cinatl,等,FEMS Microbiology Reviews 2004,28,59-77)。
本发明的化合物优选地用于制备药物,所述药物适合于预防和/或治疗疱疹病毒科类的代表的感染,特别是巨细胞病毒感染,尤其是人巨细胞病毒的感染。
由于它们的药物代谢动力学性质,本发明的化合物可以单独使用并且如果需要,还组合以其它的活性化合物,尤其是抗病毒活性化合物,诸如,例如更昔洛韦或阿昔洛韦以治疗和/或预防病毒感染,尤其是HCMV感染。
本发明还涉及将本发明的化合物用于治疗和/或预防疾病,特别是病毒感染,尤其是人巨细胞病毒(HCMV)或疱疹病毒科类的另一个代表的感染。
本发明还涉及将本发明的化合物用于治疗和/或预防疾病,尤其是前述疾病的应用。
本发明还涉及将本发明的化合物用于制备药物的应用,所述药物用于治疗和/或预防疾病,尤其是前述疾病。
本发明还涉及通过使用抗病毒有效量的本发明的化合物,治疗和/或预防疾病,尤其是前述疾病的方法。
本发明的化合物可以具有全身性和/或局部效果。出于该目的,它们可以以适合的方式进行施用,所述方式诸如,例如通过口服的、肠胃外的、肺的、鼻的、舌下的、舌的、颊的、直肠的、皮肤的、透皮的、结膜的、或耳的途径,或作为植入物或斯滕特固定模。
对于这些给药途径而言,本发明的化合物以适合的给药形式进行施用是可能的。
适合于口服给药的是这样的给药形式,其按照现有技术发挥功能并且快速地和/或以改进的方式释放本发明的化合物,并且其包括晶体形式和/或非晶形形式和/或溶解形式的本发明的化合物,诸如,例如片剂(未包被和包被的片剂,例如具有肠溶包衣或这样的包衣,所述包衣延缓溶解或是不溶的并且控制本发明的化合物的释放),快速在口腔中崩解的片剂或薄膜/糯米纸囊剂,薄膜/冻干物(lyophilisates),胶囊(例如硬或软明胶胶囊),糖包被的片剂,颗粒剂,微型药片,粉末,乳剂,混悬液,气溶胶或溶液。
肠胃外给药的发生可以避免吸收步骤(例如,静脉内、动脉内、心脏内、脊髓内或腰椎内),或包含吸收(例如,肌内、皮下、皮内、经皮或腹膜内)。适合于肠胃外给药的给药形式特别是,用于注射和输注的,以溶液、混悬液、乳剂、冻干物或无菌粉末存在的制剂。
适合于其它给药途径的实例是用于吸入的药物形式(特别是粉末吸气器,喷雾器),滴鼻剂,溶液,喷雾剂;可以通过舌、舌下或颊施用的片剂,薄膜/糯米纸囊剂或胶囊;栓剂,用于耳或眼的制剂,阴道胶囊,水性混悬液(洗剂,振摇混合物),亲脂性混悬液,软膏剂,乳膏剂,透皮治疗系统,乳,糊剂,泡沫,扑粉,植入物或斯滕特固定模。
可以将本发明的化合物转化成为列出的给药形式。其可以以本身已知的方式通过混合以惰性、非毒性的药用的赋形剂来进行。这些赋形剂包括,特别是,载体(例如微晶纤维素,乳糖,甘露醇),溶剂(例如液体聚乙二醇),乳化剂和分散剂或湿润剂(例如十二烷基硫酸钠,聚氧基失水山梨糖醇油酸酯),粘合剂(例如聚乙烯吡咯烷酮),合成的和天然的聚合物(例如白蛋白),稳定剂(例如抗氧化剂诸如,例如抗坏血酸),颜料(例如无机颜料诸如,例如氧化铁)或味道和/或气味矫正剂。
本发明还涉及这样的药物和将其用于前述目的的应用,所述药物包括至少一种本发明的化合物,以及通常地一种或多种惰性、非毒性药用的赋形剂。
以约0.001到10mg/kg,优选地约0.01到5mg/kg体重的静脉内给药量施用从而获得有效效果通常被证明有利的,并且口服给药所用的剂量是约0.01到25mg/kg,优选地0.1到10mg/kg体重。
然而,可能需要的是,当需要时偏离提及的量,其具体地取决于体重、给药途径、对活性化合物的个体反应、制备的方式和在施用发生过程中的时间或间隔。因此,在某些情形中以少于前述最少量进行的施用可以是充分的,而在其它情形中,必须超过提及的上限。在更大量的施用的情形中,可以推荐将这些分成一天内的多个单独剂量。
在下述测试和实施例中的百分比数据是重量百分比,除非另外指出;份是重量份。液体/液体溶液的溶剂比率、稀释比率和浓度数据在每种情形中基于体积。
A.实施例
所用的缩写:
aqu. 水性
BINAP 2,2’-双(二苯膦)-1,1’-联萘基
CD3CN 含氚乙腈
conc. 浓缩的
DCI 直接化学电离(在MS中)
DCM 二氯甲烷
DIEA N,N-二异丙基乙胺(Hünig′s碱)
dil. 稀释的
DMAP 4-N,N-二甲基氨基吡啶
DMF N,N-二甲基甲酰胺
DMSO 二甲亚砜
EA 乙酸乙酯
EDCI x HCl N’-(3-二甲基氨基丙基)-N-乙基碳二亚胺盐酸盐
EI 电子碰撞电离(在MS中)
ESI 电雾化电离(在MS中)
Ex. 实施例
h 小时
HATU O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓六氟磷酸盐
HBTU O-(苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓六氟磷酸盐
HPLC 高压、高效液相色谱
LC-MS 偶联液相色谱法-质谱法
LDA 二异丙基氨基化锂
lit. 参考文献(参考文献)
m.p. 熔点
MS 质谱法
NMR 核磁共振波谱法
RP-HPLC 反相HPLC
RT 室温
Rt 保留时间(在HPLC中)
sat. 饱和的
sol. 溶液
TBTU O-(苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓四氟硼酸盐
THF 四氢呋喃
TLC 薄层色谱法
HPLC和LC-MS方法:
方法1(LC-MS):仪器:具有HPLC Agilent series 1100的MicromassPlatform LCZ;柱:Thermo HyPURITY Aquastar 3μ 50mm×2.1mm;洗脱剂A:11水+0.5ml的50%甲酸,洗脱剂B:11乙腈+0.5ml的50%甲酸;梯度:0.0min 100%A→0.2min 100%A→2.9min 30%A→3.1min10%A→5.5min 10%A;烘箱:50℃;流速:0.8ml/min;UV检测:210nm.
方法2(LC-MS):仪器:具有HPLC Agilent series 1100的MicromassQuattro LCZ;柱:Phenomenex Synergi 2μHydro-RP Mercury 20mm×4mm;洗脱剂A:11水+0.5ml 50%甲酸,洗脱剂B:11乙腈+0.5ml 50%甲酸;梯度:0.0min 90%A→2.5min 30%A→3.0min 5%A→4.5min 5%A;流速:0.0min 1ml/min,2.5min/3.0min/4.5min 2ml/min;烘箱:50℃;UV检测:208-400nm.
方法3(LC-MS):仪器:具有HPLC Agilent series 1100的MicromassPlatform LCZ;柱:Phenomenex Synergi 2μHydro-RP Mercury 20mm×4mm;洗脱剂A:11水+0.5ml 50%甲酸,洗脱剂B:11乙腈+0.5ml50%甲酸;梯度:0.0min 90%A→2.5min 30%A→3.0min 5%A→4.5min 5%A;流速:0.0min 1ml/min,2.5min/3.0min/4.5min 2ml/min;烘箱:50℃;UV检测:210nm.
方法4(LC-MS):MS仪器类型:Micromass ZQ;HPLC仪器类型:WatersAlliance 2795;柱:Phenomenex Synergi 2μHydro-RP Mercury 20mm×4mm;洗脱剂A:11水+0.5ml 50%甲酸,洗脱剂B:11乙腈+0.5ml50%甲酸;梯度:0.0min 90%A→2.5min 30%A→3.0min 5%A→4.5min 5%A;流速:0.0min 1ml/min,2.5min/3.0min/4.5min 2ml/min;烘箱:50℃;UV检测:210nm.
方法5(LC-MS):MS仪器类型:Micromass ZQ;HPLC仪器类型:HP 1100系列;UV DAD;柱:Phenomenex Synegi 2μHydro-RP Mercury 20mm×4mm;洗脱剂A:11水+0.5ml 50%甲酸,洗脱剂B:11乙腈+0.5ml50%甲酸;梯度:0.0min 90%A→2.5min 30%A→3.0min 5%A→4.5min 5%A;流速:0.0min 1ml/min,2.5min/3.0min/4.5min.2ml/min;烘箱:50℃;UV检测:210nm.
方法6(LC-MS):MS仪器类型:Micromass ZQ;HPLC仪器类型:HP1100系列;UV DAD;柱:Grom-Sil 120ODS-4HE 50mm×2mm,3.0μm;洗脱剂A:水+500μl 50%甲酸/l,洗脱剂B:乙腈+500μl 50%甲酸/l;梯度:0.0min 0%B→2.9min 70%B→3.1min 90%B→4.5min 90%B;烘箱:50℃;流速:0.8ml/min;UV检测:210nm.
方法7(LC-MS):MS仪器类型:Micromass ZQ;HPLC仪器类型:WatersAlliance 2795;柱:Merck Chromolith SpeedROD RP-18e 50mm×4.6mm;洗脱剂A:水+500μl 50%甲酸/l;洗脱剂B:乙腈+500μl 50%甲酸/l;梯度:0.0min 10%B→3.0min 95%B→4.0min 95%B;烘箱:35℃;流速:0.0min 1.0ml/min→3.0min 3.0ml/min→4.0min 3.0ml/min;UV检测:210nm.
方法8(LC-MS):仪器:具有HPLC Agilent系列1100的MicromassQuattro LCZ;柱:Grom-SIL120ODS-4HE,50mm×2.0mm,3μm;洗脱剂A:11水+1ml 50%甲酸,洗脱剂B:11乙腈+1ml 50%甲酸;梯度:0.0min 100%A→0.2min 100%A→2.9min 30%A→3.1min 10%A→4.5min 10%A;烘箱:55℃;流速:0.8ml/min;UV检测:208-400nm.
方法9(GC-MS):仪器:Micromass GCT, GC6890;柱:Restek RTX-35MS,30m×250μm×0.25μm;持续的氦流速:0.88ml/min;烘箱:60℃;入口:250℃;梯度:60℃(维持0.30min),50℃/min→120℃,16℃/min→250℃,30℃/min→300℃(维持1.7min).
方法10(分析HPLC):柱:Kromasil 100 RP-18.60mm×2.1mm,3.5μm;洗脱剂A:水+0.5%高氯酸(70%),洗脱剂B:乙腈;梯度:0min 2%B,0.5min 2%B,4.5min 90%B,9min 90%B,9.2min 2%B,10min 2%B;流速:0.75ml/min;柱温:30℃;检测:UV 210nm.
起始化合物
实施例1A
1-苄基-1H-咪唑-2-羧酸乙酯
将148g(936rmmol)的1-苄基-1H-咪唑悬浮在480ml乙腈中,并且在-20℃,加入120ml(87.1g;860mmol)的三乙胺。在15分钟阶段中,接着逐滴加入211.2ml(239g;2208mmol)的氯甲酸乙酯。将所述反应混合物在-20℃搅拌10分钟。在加温到15到20℃后,将所述反应混合物搅拌18小时,接着在真空中浓缩。将水,饱和的氯化钠溶液和饱和的碳酸氢钠溶液加入所述残余物,并用乙酸乙酯将所述混合物提取三次。用饱和的氯化钠溶液洗涤所述合并的有机相,并在用硫酸镁干燥后,在真空中浓缩。将所述残余物在高真空下进行分馏(沸点=173-181℃,压力=1.7-1.2毫巴)。
产率:122.6g(理论值的46%)
LC-MS(方法4):Rt=1.71min.
MS(ESI+):m/z=231[M+H]+
1H-NMR(300MHz,DMSO-d6):δ=7.6(s,1H),7.4-7.1(m,6H),5.2(s,2H),4.25(q,2H),1.25(tr,3H)ppm.
实施例2A
咪唑-2-羧酸乙酯
将34.7g(150.9mmol)的1-苄基-1H-咪唑-2-羧酸乙酯溶解于1005ml的乙醇,并将34g的甲酸铵加入。将所述反应混合物在回流下加热约6小时。由此,将总共8g的10%披钯碳和18g的甲酸铵以小份加入。在冷却后,将催化剂滤去,并在真空中浓缩滤液。将在该操作过程中结晶出来的产物用80ml的冰水研磨,并通过吸滤来收集。
产率:15.9g(理论值的75%)
MS(ESI+):m/z=141[M+H]+
1H-NMR(200MHz,DMSO-d6):δ=13.3(s宽,1H),7.4(s,1H),7.15(s,1H),4.3(q,2H),1.3(tr,3H)ppm.
实施例3A
4-硝基-1H-咪唑-2-羧酸乙酯
在冰上冷却过程中,将16.08g(114.7mmol)咪唑-2-羧酸乙酯溶解于71.7ml的浓缩的硫酸中。接着逐滴加入71.7ml的100%发烟硝酸。将所述反应溶液在50-60℃搅拌3小时,并在冷却后,注入800ml的冰/水混合物。通过吸滤收集沉淀的晶体,并用1500ml的冰-水进行洗涤。
产率:15g(理论值的70%)
MS(ESI+):m/z=186[M+H]+
1H-NMR(300MHz,DMSO-d6):δ=14.5(s宽,1H),8.5(s,1H),4.4(q,2H),1.35(tr,3H),ppm.
实施例4A
4-({[(4-氯-2-甲基苯基)氨基]羰基}氨基)-1-(环丙基甲基)-1H-咪唑-2-羧酸
步骤1
1-(环丙基甲基)-4-硝基-1H-咪唑-2-羧酸乙酯
在氩气下,将15g(81mmol)的4-硝基-1H-咪唑-2-羧酸乙酯与13.13g(97.2mmol)的环丙基甲基溴和22.4g(162mmol)的碳酸钾在165ml的DMF中,在80℃一起搅拌1小时。冷却后,将所述反应混合物用水稀释,并用乙酸乙酯提取4次。合并的有机相用水来洗涤1次,并用饱和的氯化钠溶液洗涤3次,将其用硫酸镁进行干燥并在真空中浓缩。还将结晶的残余物直接用于下一个反应中。
产率:17.59g(理论值的70%)
LC-MS(方法2):Rt=2.02min.
MS(ESI+):m/z=240[M+H]+
1H-NMR(300MHz,DMSO-d6):δ=8.2(s,1H),4.4(q,2H),4.3(d,2H),1.4(m,4H),0.55(q,2H),0.45(q,2H)ppm.
步骤2
4-氨基-1-(环丙基甲基)-1H-咪唑-2-羧酸乙酯
将3.89g(16.26mmol)的1-(环丙基甲基)-4-硝基-1H-咪唑-2-羧酸乙酯溶解于50ml的THF,并且加入一刮勺尖的阮内镍。在氢化装置中,将所述反应混合物用氢在室温下进行氢化。将催化剂滤去,并在真空中浓缩滤液。将所述浓缩的残余物进一步直接用于下一步反应中。
产率:3.46g(理论值的100%)
LC-MS(方法3):Rt=1.21min.
MS(ESI+):m/z=210[M+H]+
1H-NMR(300MHz,DMSO-d6):δ=6.55(s,1H),4.55(s,2H),4.2(q,2H),4.1(d,2H),1.25(tr,3H),1.2(m,1H),0.5(q,2H),0.3(q,2H)ppm.
步骤3
4-({[(4-氯-2-甲基苯基)氨基]羰基}氨基)-1-(环丙基甲基)-1H-咪唑-2-羧酸乙酯
在氩气下,将6g(35.8mmol)的3-氯-4-苯基异氰酸酯加入在18ml的THF中的7.49g(35.8mmol)的4-氨基-1-(环丙基甲基)-1H-咪唑-2-羧酸乙酯,并将所述混合物在室温搅拌4小时。将所述反应混合物在真空中浓缩,将从所述混合物中结晶的产物与40ml的乙酸乙酯一起研磨,并通过吸滤进行收集。
产率:11.1g(理论值的82%)
LC-MS(方法2):Rt=2.66min.
MS(ESI+):m/z=376[M+H]+
1H-NMR(300MHz,DMSO-d6):δ=9.45(s,1H),8.0(d,1H),7.35(s,1H),7.3(d,1H),7.2(dd,1H),4.3(q,2H),4.25(d,2H),2.25(s,3H),1.3(tr,3H),1.25(m,1H),0.55(q,2H),0.35(q,2H)ppm.
步骤4
4-({[(4-氯-2-甲基苯基)氨基]羰基}氨基)-1-(环丙基甲基)-1H-咪唑-2-羧酸
将10.6g(28.1mmol)的4-({[(4-氯-2-甲基苯基)氨基]羰基}氨基)-1-(环丙基甲基)-1H-咪唑-2-羧酸乙酯悬浮于158ml的乙醇中。伴随着冰冷却,加入16.4ml水和6ml(112mmol)的50%氢氧化钠水溶液。将所述反应混合物在室温搅拌1小时,并接着在真空中进行浓缩。将所述残余物吸收在100ml的异丙醇中,加入100ml的1N盐酸,伴随冰冷却。通过吸滤收集所述晶体,并在真空中于40℃干燥。
产率:9.85g(理论值的100%)
LC-MS(方法4):Rt=1.74min.
MS(ESI+):m/z=349[M+H]+
1H-NMR(400MHz,DMSO-d6):δ=9.4(s,1H),8.0(d,1H),7.3(s,1H),7.25(d,1H),7.2(dd,1H),4.25(d,2H),2.25(s,3H),1.25(m,1H),0.55(q,2H),0.35(q,2H)ppm.
实施例5A
1-(环丙基甲基)-4-[({[4-(三氟甲氧基)苯基]氨基}羰基)氨基]-1H-咪唑-2-羧酸
制备以类似于实施例4A的方式进行。
产率:10.2g(理论值的93%)
LC-MS(方法4):Rt=1.87min.
MS(ESI+):m/z=385[M+H]+
1H-NMR(400MHz,DMSO-d6):δ=8.6(s,1H),8.4(s,1H),7.55(d,2H),7.4(s,1H),7.25(d,2H),4.25(d,2H),1.25(m,1H),0.55(q,2H),0.35(q,2H)ppm.
实施例6A
1-丁基-4-({[(4-氯-2-甲基苯基)氨基]羰基}氨基)-1H-咪唑-2-羧酸
制备以类似于实施例4A的方式进行。
产率:2.2g(理论值的93%)
LC-MS(方法4):Rt=1.83min.
MS(ESI+):m/z=351[M+H]+
1H-NMR(300MHz,DMSO-d6):δ=9.35(s,1H),8.0(d,1H),7.3(s,1H),7.25(d,1H),7.2(dd,1H),4.35(tr,2H),2.25(s,3H),1.7(五重峰,2H),1.25(六重峰,2H),0.9(tr,3H)ppm.
实施例7A
1-丁基-4-[({[4-(三氟甲氧基)苯基]氨基}羰基)氨基]-1H-咪唑-2-羧酸
制备以类似于实施例4A的方式进行。
产率:2.05g(理论值的96%)
LC-MS(方法4):Rt=1.96min.
MS(ESI+):m/z=387[M+H]+
1H-NMR(300MHz,DMSO-d6):δ=9.0(s,1H),8.9(s,1H),7.55(d,2H),7.3(s,1H),7.25(d,1H),4.35(tr,2H),1.7(五重峰,2H),1.25(六重峰,2H),0.9(tr,3H)ppm.
实施例8A
4-[({[4-(三氟甲氧基)苯基]氨基}羰基)氨基]-1-[4-(三氟甲基)苄基]-1H-咪唑-2-羧酸
制备以类似于实施例4A的方式进行。
产率:15.2g(理论值的100%)
LC-MS(方法2):Rt=2.46min.
MS(ESI+):m/z=489[M+H]+
1H-NMR(300MHz,DMSO-d6):δ=9.15(s,1H),9.05(s,1H),7.75(d,2H),7.55(d,2H),7.45(s,1H),7.35(d,2H),7.25(d,2H),5.7(s,2H)ppm.
实施例9A
4-({[(4-氯-2-甲基苯基)氨基]羰基}氨基)-1-[4-(三氟甲基)苄基]-1H-咪唑-2-羧酸
制备以类似于实施例4A的方式进行。
产率:15.6g(100%理论值的)
LC-MS(方法4):Rt=2.23min.
MS(ESI+):m/z=453[M+H]+
1H-NMR(300MHz,DMSO-d6):δ=9.5(s,1H),7.95(d,1H),7.75(d,2H),7.4(d,2H),7.35(s,1H),7.25(s,1H),7.15(d,1H),5.75(s,2H),2.25(s,3H)ppm.
实施例10A
1-甲基-4-硝基-1H-咪唑-2-羧酸乙酯
将6.80g(36.7mmol)的4-硝基-1H-咪唑-2-羧酸乙酯溶解于140ml的丙酮,并加入11.2g(80.8mmol)的碳酸钾和4.57ml(73.5mmol)的碘代甲烷。接着,将所述混合物在60℃搅拌4小时。按照TLC(环己烷/乙酸乙酯2∶1),原材料已经被完全转化。冷却后,将所述混合物进行过滤,用二氯甲烷洗涤所述残余物,去除滤液中的溶剂。在真空中干燥获得的固体。产率:7.0g(理论值的95%)
LC-MS(方法5):Rt=1.40min.
MS(ESI+):m/z=200[M+H]+
1H-NMR(400MHz,DMSO-d6):δ=8.64(s,1H),4.35(q,2H),3.99(s,3H),1.34(t,3H).
实施例11A
4-氨基-1-甲基-1H-咪唑-2-羧酸乙酯
将0.50g(2.5mmol)的1-甲基-4-硝基-1H-咪唑-2-羧酸乙酯溶解于7.5ml的乙醇,加入0.13g(0.13mmol)的披钯碳(10%)并将所述混合物在3巴下氢化12小时。接着,通过硅藻土过滤所述反应溶液,并浓缩滤液。将所述残余物在真空中进行干燥,并在没有进一步纯化的情况下进一步反应。
产率:0.42g(理论值的99%)
LC-MS(方法1):Rt=1.59min.
MS(ESI+):m/z=170[M+H]+
1H-NMR(400MHz,DMSO-d6):δ=6.47(s,1H),4.55(bs,2H),4.19(q,2H),3.80(s,3H),1.28(t,3H).
实施例12A
1-甲基-4-[({[4-(三氟甲氧基)苯基]氨基}羰基)氨基]-1H-咪唑-2-羧酸乙酯
在氩气下,将1.46g(7.21mmol)的4-(三氟甲氧基)苯基异氰酸酯加入在50ml的THF中的1.22g(3.61mmol)的4-氨基-1-甲基-1H-咪唑-2-羧酸乙酯(以类似于实施例4A步骤3的方式进行合成,或还按照TetrahedronLett.2003,44,1607及其引用的文献进行合成)并将所述混合物在室温搅拌过夜。过滤所述反应混合物并将所述滤液在真空中浓缩并通过色谱法进行纯化。
产率:860mg(理论值的62%)
LC-MS(方法5):Rt=2.41min.
MS(ESI+):m/z=373[M+H]+
1H-NMR(300MHz,DMSO-d6):δ=8.98(bs,2H),7.55(m,2H),7.36(s,1H),7.29(m,2H),4.28(q,2H),3.91(s,3H),1.30(t,3H).
实施例13A
1-甲基-4-[({[4-(三氟甲氧基)苯基]氨基}羰基)氨基]-1H-咪唑-2-羧酸
将835mg(2.13mmol)的1-甲基-4-[({[4-(三氟甲氧基)苯基]氨基}羰基)氨基]-1H-咪唑-2-羧酸乙酯悬浮于5ml的乙醇和12ml的四氢呋喃。伴随着冰冷却,加入2ml(25mmol)的50%氢氧化钠水溶液。将所述反应混合物在室温搅拌过夜,并接着,伴随着冰冷却,用1N盐酸进行酸化。用二氯甲烷提取所述溶液。将有机相在真空中浓缩。通过制备HPLC来纯化所述残余物。
产率:346mg(理论值的44%).
LC-MS(方法4):Rt=1.62min.
MS(ESI+):m/z=345[M+H]+
1H-NMR(400MHz,DMSO-d6):δ=9.33(bs,1H),8.98(bs,1H),7.55(m,2H),7.30(s,1H),7.28(m,2H),3.90(s,3H),
实施例14A
1-(5-甲基吡啶-2-基)哌嗪
步骤1
1-(叔丁基氧基羰基)-4-(5-甲基吡啶-2-基)哌嗪
在氩气气氛下,将2.50g(19.6mmol)的2-甲基-5-氯吡啶和4.38g(23.5mmol)的N-(叔丁基氧基羰基)哌嗪溶解于50ml的无水甲苯中。将2.26g(23.5mmol)的叔丁醇钠,0.37g(0.59mmol)的BINAP和0.36g(0.39mmol)的三(二亚苄基丙酮)二钯接着加入,并将所述混合物在70℃加热12小时。冷却后,将二乙醚加入反应混合物中,用饱和的氯化钠溶液将所述混合物洗涤三次,并通过硫酸钠进行干燥,将所述溶剂在真空中去除。通过急骤色谱法(环己烷/乙酸乙酯9∶1)来纯化所述残余物。
产率:5.27g(理论值的97%).
LC-MS(方法4):Rt=1.26min.
MS(ESI+):m/z=278[M+H]+
1H-NMR(300MHz,CDCl3):δ=8.02(d,1H),7.34(dd,1H),6.59(d,1H),3.55(m,4H),3.45(m,4H),2.21(s,3H),1.49(s,9H).
步骤2
1-(5-甲基吡啶-2-基)哌嗪
将3.47g(12.5mmol)的1-(叔丁氧基羰基)-4-(5-甲基吡啶-2-基)哌嗪溶解于10ml的二噁烷,并加入在二噁烷(4molar)中的31ml(125mmol)的氯化氢。将所述混合物在室温搅拌2小时。接着,将所述混合物进行浓缩,并使用1M氢氧化钠水溶液使所述残余物呈碱性,用二氯甲烷提取数次。将合并的有机相通过硫酸钠进行干燥,浓缩并在真空中干燥。
产率:2.18g(理论值的98%).
LC-MS(方法5):Rt=0.38min.
MS(ESI+):m/z=177[M+H]+
1H-NMR(300MHz,CDCl3):δ=8.02(d,1H),7.32(dd,1H),6.59(d,1H),3.45(m,4H),3.00(m,4H),2.20(s,3H).
实施例15A
1-乙基-4-[({[4-(三氟甲氧基)苯基]氨基}羰基)氨基]-1H-咪唑-2-羧酸
制备以类似于实施例13A的方式进行。
产率:425mg(理论值的91%).
LC-MS(方法5):Rt=1.94min.
MS(ESI+):m/z=359[M+H]+
1H-NMR(300MHz,DMSO-d6):δ=10.3(bs,1H),7.67(m,2H),7.24(s,1H),7.20(m,2H),4.45(q,2H),1.33(t,3H).
实施例16A
1-丁基-4-[({[4-(三氟甲基)苯基]氨基}羰基)氨基]-1H-咪唑-2-羧酸
制备以类似于实施例13A的方式进行。
产率:1.71g(理论值的90%)
LC-MS(方法2):Rt=2.13min.
MS(ESI+):m/z=371[M+H]+
1H-NMR(300MHz,DMSO-d6):δ=9.30(bs,1H),9.03(bs,1H),7.64(m,4H),7.36(s,1H),4.35(t,2H),1.68(五重峰,2H),1.26(六重峰,2H),0.89(t,3H).
实施例17A
1-(5-氟吡啶-2-基)哌嗪
随着搅拌,将500mg(2.84mmol)的2-溴-5-氟吡啶和1.22g(14.2mmol)的哌嗪在150℃加热24小时。冷却后,将过量哌嗪在真空中蒸馏除去(库格尔若,1.5m巴,120℃)。所述残余物通过急骤色谱法(二氯甲烷/乙醇/浓缩的氨水溶液,30∶1∶0.1)进行纯化。
产率:267mg(理论值的52%).
LC-MS(方法9):Rt=8.07min.
MS(DCI):m/z=182[M+H]+
1H-NMR(400MHz,DMSO-d6):δ=8.07(d,1H),7.48(td,1H),6.82(dd,1H),3.32(t,4H),2.78(t,4H).
实施例18A
1-(5-溴吡啶-2-基)哌嗪
制备以类似于实施例17A的方式进行。
产率:827mg(理论值的81%).
LC-MS(方法1):Rt=2.02min.
MS(ESI+):m/z=242[M+H]+
1H-NMR(300MHz,DMSO-d6):δ=8.15(d,1H),7.65(dd,1H),6.79(d,1H),3.38(m,4H),2.74(m,4H).
实施例19A
1-(5-甲氧基吡啶-2-基)哌嗪
制备以类似于实施例14A的方式进行。
产率:91mg(理论值的90%)。
1H-NMR(400MHz,CDCl3):δ=7.94(d,1H),7.15(dd,1H),6.64(d,1H),3.80(s,3H),3.48(m,4H),3.00(m,4H).
实施例20A
4-[({[4-(二氟甲氧基)苯基]氨基}羰基)氨基]-1-甲基-1H-咪唑-2-羧酸
制备以类似于实施例13A的方式进行。
产率:964mg(理论值的81%).
HPLC(方法10):Rt=3.57min.
MS(ESI+):m/z=327[M+H]+
1H-NMR(400MHz,CDCl3):δ=8.9(s,1H),8.8(s,1H),7.5(d,2H),7.3(s,2H),7.1(t,1H),7.09(d,2H),3.9(s,3H).
实施例21A
1-[(1-乙基-4-硝基-1H-咪唑-2-基)羰基]-4-(吡啶-2-基)哌嗪
将1.23g(5.06mmol)的1-乙基-4-硝基-1H-咪唑-2-羧酸乙酯(以类似于实施例10A的方式进行制备)和2.48g(15.2mmol)的N-(吡啶-2-基)哌嗪在100℃搅拌过夜。结果,通过制备HPLC纯化获得的粗制混合物。获得0.724g(理论值的43%)的产物。
HPLC(方法10):Rt=3.19min.
MS(ESI+):m/z=331[M+H]+
1H-NMR(300MHz,DMSO-d6):δ=8.7(s,1H),8.1(m,1H),7.55(m,1H),6.9(d,1H),6.65(dd,1H),4.2(q,2H),3.8(m,4H),3.65(m,2H),3.55(m,2H),1.4(t,3H).
实施例22A
4-[({[4-(二氟甲氧基)苯基]氨基}羰基)氨基]-1-丁基-1H-咪唑-2-羧酸
制备以类似于实施例13A的方式进行。
产率:1.06g(理论值的71%).
HPLC(方法10):Rt=4.046min.
MS(ESI+):m/z=369[M+H]+
1H-NMR(400MHz,CDCl3):δ=11.1(s,1H),7.7(d,2H),7.1(t,1H),7.05(m,3H),4.5(t,2H),1.7(m,2H),1.3(m,2H),0.9(t,3H).
实施例23A
1-[(1-甲基-4-硝基-1H-咪唑-2-基)羰基]-4-(吡啶-2-基)哌嗪
制备以类似于实施例21A的方式进行。
产率:4g(理论值的72%)
HPLC(方法10):Rt=2.99min.
MS(ESI+):m/z=317[M+H]+
1H-NMR(300MHz,DMSO-d6):δ=8.6(s,1H),8.15(m,1H),7.55(m,1H),6.9(d,1H),6.7(dd,1H),3.9(m,5H),3.8(m,2H),3.7-3.5(m,4H).
实施例24A
1-甲基-4-[({[4-(三氟甲基)苯基]氨基}羰基)氨基]-1H-咪唑-2-羧酸
制备以类似于实施例13A的方式进行。
产率:168mg(理论值的99%).
HPLC(方法4):Rt=1.57min.
MS(ESI+):m/z=329[M+H]+
1H-NMR(400MHz,CDCl3):δ=9.80(bs,1H),9.18(bs,1H),7.65(m,4H),7.48(s,1H),3.92(s,3H).
例举性的实施方案
实施例1
N-{1-甲基-2-[(4-吡啶-2-基哌嗪-1-基)羰基]-1H-咪唑-4-基}-N’-[4-(三氟甲氧基)苯基]脲
将1.50g(4.36mmol)的实施例13A溶解于30ml的DMF,并将1.82g(5.66mmol)的O-(苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓四氟硼酸盐(TBTU)和266mg(2.18mmol)的4-二甲基氨基吡啶加入。在添加925mg(5.66mmol)的1-(吡啶-2-基)哌嗪后,将所述混合物在室温搅拌4小时。将所述反应混合物通过RP-HPLC进行纯化。
产率:1.79g(理论值的83%).
LC-MS(方法2):Rt=1.83min.
MS(ESI+):m/z=490[M+H]+
1H-NMR(400MHz,DMSO-d6):δ=8.89(bs,2H),8.12(d,1H),7.55(m,3H),7.29(m,2H),7.20(s,1H),6.88(d,1H),6.68(dd,1H),4.02(bs,2H),3.77(s,3H),3.71(bs,2H),3.58(bs,4H).
实施例2
N-(1-甲基-2-{[4-(5-甲基吡啶-2-基)哌嗪-1-基]羰基}-1H-咪唑-4-基)-N’-[4-(三氟甲氧基)苯基]脲
将100mg(0.29mmol)的实施例13A溶解于2ml的DMF,并加入139mg(0.44mmol)的O-(苯并三唑-1-基)-N,N,N’,N’-四甲基鎓四氟硼酸盐(TBTU)和53mg(0.44mmol)的4-二甲基氨基吡啶。在添加103mg(0.58mmol)的实施例14A后,将所述混合物在室温搅拌4小时。将所述所述混合物通过RP-HPLC进行纯化。
产率:103mg(理论值的70%).
LC-MS(方法5):Rt=2.01min.
MS(ESI+):m/z=504[M+H]+
1H-NMR(300MHz,DMSO-d6):δ=8.92(bs,2H),7.99(d,1H),7.54(m,2H),7.42(dd,1H),7.28(m,2H),7.20(s,1H),6.80(d,1H),4.00(bs,2H),3.77(s,3H),3.72(bs,2H),3.51(bs,4H),2.16(s,3H).
实施例3
N-(2-{[4-(5-氯吡啶-2-基)哌嗪-1-基]羰基}-1-乙基-1H-咪唑-4-基)-N’-[4-(三氟甲氧基)苯基]脲
制备以类似于实施例2的方式进行。
产率:55mg(理论值的68%).
LC-MS(方法5):Rt=2.76min.
MS(ESI+):m/z=538[M+H]+
1H-NMR(300MHz,DMSO-d6):δ=8.97(bs,1H),8.92(bs,1H),8.14(d,1H),7.65(dd,1H),7.54(m,2H),7.28(m,2H),7.24(s,1H),6.92(d,1H),4.16(q,2H),3.97(bs,2H),3.72(bs,2H),3.59(bs,4H),1.32(t,3H).
实施例4
N-(2-{[4-(4-甲氧基苯基)哌嗪-1-基]羰基}-1-甲基-1H-咪唑-4-基)-N’-[4-(三氟甲氧基)苯基]脲
制备以类似于实施例2的方式进行。
产率:35mg(理论值的58%).
LC-MS(方法4):Rt=2.24min.
MS(ESI+):m/z=519[M+H]+
1H-NMR(400MHz,DMSO-d6):δ=8.89(bs,2H),7.53(m,2H),7.28(m,2H),7.19(s,1H),6.92(m,2H),6.84(m,2H),4.05(bs,2H),3.75(m,5H),3.69(s,3H),3.08(bs,4H).
实施例5
N-[4-(二氟甲氧基)苯基]-N’-(1-甲基-2-{[4-(5-甲基吡啶-2-基)哌嗪-1-基]-羰基}-1H-咪唑-4-基)脲
以类似于实施例2的方式从实施例20A进行制备。
产率:17mg(理论值的29%).
LC-MS(方法5):Rt=1.70min.
MS(ESI+):m/z=486[M+H]+
1H-NMR(400MHz,DMSO-d6):δ=8.84(bs,1H),8.77(bs,1H),7.98(d,1H),7.47(m,2H),7.42(dd,1H),7.18(s,1H),7.11(t,1H),7.10(m,2H),6.80(d,1H),4.01(bs,2H),3.77(s,3H),3.71(bs,2H),3.50(bs,4H),2.16(s,3H).
表1的实施例以类似于实施例2的方式进行。
表1:
实施例40
N-{1-(环丙基甲基)-2-[(4-吡啶-2-基哌嗪-1-基)羰基]-1H-咪唑-4-基}-N’-[4-(三氟甲氧基)苯基]脲
将57.6mg(0.15mmol)的实施例5A溶解于0.5ml的DMF,并将59.5mg(0.15mmol)的O-(苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓六氟磷酸盐(HBTU)和15mg(0.15mmol)的三乙胺加入。在加入49mg(0.3mmol)的N-(2-吡啶基)哌嗪后,将所述混合物在室温搅拌16小时。将所述反应混合物通过RP-HPLC进行纯化。
产率:46mg(理论值的58%).
LC-MS(方法5):Rt=2.08min.
MS(ESI+):m/z=530[M+H]+
1H-NMR(300MHz,DMSO-d6):δ=8.9(s,2H),8.15(d,1H),7.6-7.5(m,3H),7.25(m,3H),6.85(d,1H),6.7(dd,1H),4.05(d,2H),4.00(bs,2H),3.75(bs,2H),3.6-3.5(m,4H),1.75(m,1H),0.5(q,2H),0.35(q,2H).
表2中的实施例以类似于实施例40的方式进行制备。
表2:
实施例52
N-(3,5-二氟苯基)-N’-{1-乙基-2-[(4-吡啶-2-基哌嗪-1-基)羰基]-1H-咪唑-4-基}脲
首先,将一刮勺尖的阮内镍和接着11mg(0.23mmol)的水合肼加入50mg(0.15mmol)的1-[(1-乙基-4-硝基-1H-咪唑-2-基)羰基]-4-(吡啶-2-基)哌嗪在6ml的无水THF的溶液中,并将所述混合物接着搅拌1小时。将硫酸钠加入粗制溶液,其接着通过硅藻土进行过滤,并用二氯甲烷洗涤所述滤饼。将所述滤液在真空中进行浓缩,并再次置入6ml的THF中,加入28mg(0.18mmol)的二氟苯基异氰酸酯和2mg的1,4-二氮杂二环[2.2.2]辛烷,并将所述混合物在室温进行搅拌。1小时后,在旋转式汽化器上去除所述溶剂,并将所述残余物通过制备HPLC进行纯化。获得20mg(理论值的29%)的产物。
HPLC(方法10):Rt=3.94min.
MS(ESI+):m/z=456[M+H]+
1H-NMR(300MHz,DMSO-d6):δ=8.5(2s,2H),8.1(m,1H),7.55(m,1H),7.25(s,1H),/.15(m,2H),6.9-6.65(m,3H),4.2(q,2H),3.9(m,2H),3.7(m,2H),3.55(m,4H),1.3(t,3H).
表3的实施例以类似于实施例52的方式进行制备,除了实施例57以类似于实施例2的方式进行制备以外。
表3:
B.生理活性的评估
本发明的化合物的体外活性可以在下列测定中显示:
抗-HCMV(抗人巨细胞病毒)致细胞病性测试
将测试化合物作为在二甲亚砜(DMSO)中的50毫摩(mM)溶液使用。将更昔洛韦,膦甲酸和西多福韦用作参比化合物。在将2μl的50,5,0.5和0.05mM DMSO的贮存溶液分别加入在第2行A-H中的98μl的细胞培养基小份中以进行一式两份测定后,用50μl的培养基小份进行1∶2稀释,直到96孔板的第11行。在第1行和第12行中的每个孔包含50μl的培养基。接着将150μl的1×104细胞(人包皮成纤维细胞[NHDF])的混悬液吸移入每只孔中(第1行=细胞对照),在第2-12行中,加入HCMV感染和未感染的NHDF细胞的混合物(M.O.I.=0.001-0.002),即每1000个未感染细胞中1-2个感染细胞。第12行(不含物质)充当病毒对照。最终的测试浓度是250-0.0005μM。在37℃/5%CO2中对所述板温育6天,即直到在病毒对照中所有的细胞被感染(100%致细胞病性作用[CPE])。接着,通过加入甲醛和吉姆萨染液的混合物将孔进行固定和染色(30分钟),用双蒸水进行洗涤并于50℃在干燥烘箱中进行干燥。接着使用高架显微镜视觉评估所述板(来自Technomara的噬斑倍增器)。
可以从测试板中获得下列数据:
CC50(NHDF)=以μM表示的最大物质浓度,在该浓度上与未处理的细胞对照相比,没有观察到对细胞具有细胞抑制作用;
EC50(HCMV)=以μM表示的物质浓度,与未处理的病毒对照相比,其抑制CPE(细胞致病性作用)达50%;
SI(选择性指数)=CC50(NHDF)/EC50(HCMV)。
本发明化合物的代表性体外数据显示在表A中:
表A
实施例号 | NHDFCC50[nM] | HCMVEC50[nM] | SIHCMV |
1 | 43.5 | 3.0 | 14500 |
2 | 10.9 | 0.75 | 14530 |
25 | 12.5 | 4.8 | 2600 |
29 | 34.0 | 0.95 | 35790 |
32 | 5.3 | 0.85 | 6240 |
本发明的化合物用于治疗HCMV感染的适合性可以在下列动物模型中显示:
HCMV异种移植物Gelfoam模型
动物:
3-4周龄的雌性免疫缺陷小鼠(16-18g),Fox Chase SCID或Fox ChaseSCID-NOD或SCID米色(beige),购自商业饲种者(Bomholtgaard,Jackson)。在无菌条件(包括垫料和食物)下将动物隔离饲养。
病毒培养:
将人巨细胞病毒(HCMV),Davis毒株体外培养在人胚包皮成纤维细胞(NHDF细胞)上。在用0.01的感染复数(M.O.I)感染NHDF细胞后,5-7天后,收获病毒感染的细胞并且将其于-40℃在存在基本必需培养基(MEM)、具有10%DMSO的10%胎牛血清(FCS)的情况下进行贮存。在将病毒感染的细胞系列稀释10倍后,在用中性红进行活体染色或用甲醛/吉姆萨混合物(如上所述)固定和染色后,在汇合NHDF细胞的24孔板上测定滴度。
海绵的制备,移植,处理和评估:
将1×1×1cm大小的胶原海绵(Gelfoam;Peasel & Lorey,订单号407534;K.T.Chong等,Abstracts of 39th Interscience Conference on AntimicrobialAgents and Chemotherapy,1999,第439页;P.M.Kraemer等,CancerResearch 1983,(43):4822-4827)最初用磷酸缓冲盐溶液(PBS)湿润,通过排气来将捕获的气泡去除,接着贮存在MEM+10%FCS中。在感染后3小时,将1×106病毒感染的NHDF细胞(用HCMV Davis感染,M.O.I=0.01)进行脱附,并在20μl的MEM,10%FCS(v/v)中逐滴加入潮湿海绵中。12-13小时后,将在25μl的PBS/0.1%BSA/1mM DTT中的5ng/μl碱性成纤维细胞生长因子(bFGF)任选地加入海绵中并将所述海绵温育1小时。对于移植而言,用阿佛丁或azepromazine-赛拉嗪和氯胺酮的混合物对所述免疫缺陷小鼠进行麻醉,使用剃须刀将背部的毛皮去除,将表皮打开1-2cm,将未加载的和湿润的海绵移植在脊背部皮肤下。用组织胶粘剂闭合外科伤口。移植后24小时,在8天时期内进行一天3次(7.00h和14.00h和19.00h)、一天2次(8.00h和17.00h)或一天一次(14.00h)的物质的口服处理。剂量是3或10或30或100mg/kg体重,施用体积是10ml/kg体重。将物质以任选地包含2%DMSO的0.5%浓度的Tylose混悬液的形式进行配制。移植后9天和最后一次施用物质后约16小时,将动物无痛处死并且去除海绵。通过胶原酶(330U/1.5m1)消化,从海绵中释放病毒感染的细胞并且将其于-140℃在存在MEM,10%胎牛血清,10%DMSO的情况下贮存。在将病毒感染的细胞系列稀释10倍后,通过用中性红进行活体染色或在用甲醛/吉姆萨混合物固定和染色后,在汇合NHDF细胞的24孔板上测定滴度来进行评价(如上所述)。测定与安慰剂处理的对照组相比,在物质处理后,感染的病毒颗粒的数量。
C.药物组合物的例举性实施方案
可以将本发明的化合物以下列方式转化为药物制剂:
片剂:
组成:
100mg的实施例1的化合物,50mg的乳糖(一水合物),50mg的玉米淀粉(天然的),10mg的聚乙烯吡咯烷酮(PVP 25)(BASF,Ludwigshafen,德国)和2mg的硬脂酸镁。
片剂重量212mg。直径8mm,曲率半径12mm。
制备:
将活性化合物、乳糖和淀粉的混合物用PVP在水中的5%浓度的溶液(m/m)成粒。接着,干燥所述颗粒,并将其混合以硬脂酸镁达5分钟。使用常规的压片机(见上述关于片剂的形成)压缩该混合物。用于所述压缩的压缩力的指导是15kN。
可以口服施用的混悬剂:
组成:
1000mg的实施例1的化合物,1000mg的乙醇(96%),400mg的Rhodigel(来自FMC,宾夕法尼亚州,USA的黄原胶)和99g的水。
10ml的口服混悬剂等价于100mg的本发明化合物的单一剂量。
制备:
将Rhodigel悬浮在乙醇中,并将活性化合物加入混悬液中。在搅拌过程中,加入水。将所述混合物搅拌约6小时直到Rhodigel溶胀完全。
可以静脉内施用的溶液剂:
组成:
1mg的实施例1的化合物,15g的聚乙二醇400和250g的注射用水。
制备:
将本发明的化合物与聚乙二醇400一起溶解于水中,伴随搅拌。通过过滤(孔径0.22μm)来对溶液进行灭菌,并将其在无菌条件下分配到热灭菌的输液瓶中。用输注塞和卷曲帽来封闭后者。
Claims (10)
1.下式的化合物
其中
R1表示下式的基团
其中
*表示与羰基基团的连接位点,
R4表示苯基或5-或6-元杂芳基,
其中苯基和杂芳基可以由1-3个取代基所取代,其中所述取代基彼此独立地选自由下列各项组成的组:卤素,羟基,氧代,硝基,氰基,三氟甲基,二氟甲基,三氟甲氧基,二氟甲氧基,单氟甲氧基,三氟甲硫基,C1-C6-烷基,C1-C6-烷氧基,羟基羰基,C1-C6-烷氧基羰基,氨基,C1-C6-烷基氨基,氨基羰基和C1-C6-烷基氨基羰基,
R5表示苯基或5-或6-元杂芳基,
其中苯基和杂芳基可以由1-3个取代基所取代,其中所述取代基彼此独立地选自由下列各项组成的组:卤素,羟基,氧代,硝基,氰基,三氟甲基,二氟甲基,三氟甲氧基,二氟甲氧基,单氟甲氧基,三氟甲硫基,C1-C6-烷基,C1-C6-烷氧基,羟基羰基,C1-C6-烷氧基羰基,氨基,C1-C6-烷基氨基,氨基羰基和C1-C6-烷基氨基羰基,
和
R6和R7彼此独立地表示氢,甲基或乙基,
R2表示C1-C6-烷基,
其中烷基可以由取代基所取代,其中所述取代基选自由下列各项组成的组:C3-C6-环烷基,C6-C10-芳基和5-或6-元杂芳基,其中环烷基,芳基和杂芳基可以由1-3个取代基所取代,其中所述取代基彼此独立地选自由下列各项组成的组:卤素,羟基,氧代,硝基,氰基,三氟甲基,二氟甲基,三氟甲氧基,二氟甲氧基,单氟甲氧基,三氟甲硫基,C1-C6-烷基,C1-C6-烷氧基,羟基羰基,C1-C6-烷氧基羰基,氨基,C1-C6-烷基氨基,氨基羰基和C1-C6-烷基氨基羰基,
R3表示苯基,
其中苯基可以由1-3个取代基所取代,其中所述取代基彼此独立地选自由下列各项组成的组:卤素,羟基,三氟甲基,二氟甲基,三氟甲氧基,二氟甲氧基,单氟甲氧基,三氟甲硫基,C1-C6-烷基和C1-C6-烷氧基,
或其盐、其溶剂合物或其盐的溶剂合物其中之一。
2.按照权利要求1的化合物,其特征在于
R1表示下式的基团
其中
*表示与羰基基团的连接位点,
R4表示苯基或5-或6-元杂芳基,
其中苯基和杂芳基可以由1-3个取代基所取代,其中所述取代基彼此独立地选自由下列各项组成的组:卤素,羟基,氧代,硝基,氰基,三氟甲基,二氟甲基,三氟甲氧基,二氟甲氧基,单氟甲氧基,三氟甲硫基,C1-C6-烷基,C1-C6-烷氧基,羟基羰基,C1-C6-烷氧基羰基,氨基,C1-C6-烷基氨基,氨基羰基和C1-C6-烷基氨基羰基,
R2表示C1-C6-烷基,
其中烷基可以由取代基所取代,其中所述取代基选自由下列各项组成的组:C3-C6-环烷基和苯基,
其中环烷基和苯基可以由1-3个取代基所取代,其中所述取代基彼此独立地选自由下列各项组成的组:卤素,羟基,氧代,硝基,氰基,三氟甲基,二氟甲基,三氟甲氧基,二氟甲氧基,单氟甲氧基,三氟甲硫基,C1-C6-烷基,C1-C6-烷氧基,羟基羰基,C1-C6-烷氧基羰基,氨基,C1-C6-烷基氨基,氨基羰基和C1-C6-烷基氨基羰基,
R3表示苯基,
其中苯基可以由1-3个取代基所取代,其中所述取代基彼此独立地选自由下列各项组成的组:卤素,羟基,三氟甲基,二氟甲基,三氟甲氧基,二氟甲氧基,单氟甲氧基,三氟甲硫基,C1-C6-烷基和C1-C6-烷氧基。
3.按照权利要求1或2的化合物,其特征在于
R1表示下式的基团
其中
*表示与羰基基团的连接位点,
R4表示苯基或吡啶基,
其中苯基和吡啶基可以由1-3个取代基所取代,其中所述取代基彼此独立地选自由下列各项组成的组:卤素,硝基,氰基,三氟甲基,二氟甲基,三氟甲氧基,二氟甲氧基,单氟甲氧基,C1-C4-烷基和C1-C4-烷氧基,
R2表示甲基,乙基或正丁基,
其中甲基,乙基和正丁基可以由取代基所取代,其中所述取代基选自由环丙基和苯基组成的组,
其中苯基可以由三氟甲基取代基所取代,
R3表示苯基,
其中苯基可以由1-3个取代基所取代,其中所述取代基彼此独立地
选自由下列各项组成的组:氟,氯,三氟甲氧基,二氟甲氧基,三氟甲硫基和甲基。
4.制备按照权利要求1的式(I)的化合物的方法,其特征在于按照方法[A],其中R1和R2具有权利要求1指定的含义的下式的化合物
在第一个步骤中与还原剂反应,并且在第二个步骤中,在碳酸衍生物存在的情况下,与其中R3具有权利要求1指定含义的下式的化合物反应
H2N-R3(III)
或
按照方法[B],式(II)的化合物在第一个步骤中与还原剂反应,并且在第二个步骤中,与其中R3具有权利要求1指定含义的下式的化合物反应,
OCN-R3(IV),
或
按照方法[C]
其中R2和R3具有权利要求1指定含义且R8表示甲基或乙基的下式的化合物
在第一个步骤中与碱反应,并且在第二个步骤中与其中R1具有权利要求1指定含义的下式的化合物,
R1-H(VI)
在脱水剂存在的情况下反应。
5.按照权利要求1-3中任一项的化合物,其用于治疗和/或预防疾病。
6.药物,其包含按照权利要求1-3任一项的化合物和至少一种惰性的、非毒性的药用赋形剂。
7.按照权利要求1-3中任一项的化合物用于制备用于治疗和/或预防病毒感染的药物的应用。
8.按照权利要求7的应用,其特征在于所述病毒感染是由人巨细胞病毒(HCMV)或另一个疱疹病毒科类的代表所引起的感染。
9.按照权利要求6的药物,其用于治疗和/或预防病毒感染。
10.在人和动物中控制病毒感染的方法,其通过施用抗病毒有效量的按照权利要求1-3中任一项的至少一种化合物,按照权利要求6的药物,或按照权利要求7或8获得的药物来进行。
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US6342501B1 (en) | 1994-02-25 | 2002-01-29 | The Regents Of The University Of Michigan | Pyrrolo[2,3-d] pyrimidines as antiviral agents |
DE69826695T2 (de) * | 1997-05-23 | 2006-02-02 | Bayer Pharmaceuticals Corp., West Haven | Arylharnstoffderivate zur behandlung von inflammatorischen oder immunomodulatorischen erkrankungen |
WO1999023091A1 (en) | 1997-11-03 | 1999-05-14 | Boehringer Ingelheim Pharmaceuticals, Inc. | Aromatic heterocyclic compounds as anti-inflammatory agents |
KR20010086091A (ko) | 1998-12-09 | 2001-09-07 | 이곤 이 버그 | 치환된 페닐렌디아민 그룹을 함유하는 허프스 바이러스의헤테로사이클릭 카복사미드-함유 티오우레아 억제제 |
DE10257358A1 (de) | 2002-12-09 | 2004-07-08 | Bayer Healthcare Ag | Substituierte Pyrrole |
DE102004015007A1 (de) | 2004-03-26 | 2005-10-13 | Bayer Healthcare Ag | Substituierte Imidazole |
MXPA06013118A (es) * | 2004-05-12 | 2007-02-28 | Schering Corp | Antagonistas de cxcr1 y cxcr2 de quimocina. |
DE102005008183A1 (de) | 2005-02-23 | 2006-08-31 | Bayer Healthcare Ag | Heterocyclylamid-substituierte Imidazole |
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CN103889973A (zh) * | 2011-09-14 | 2014-06-25 | 爱库利斯有限两合公司 | 杂环基酰胺取代的咪唑的磺酸盐 |
CN103889973B (zh) * | 2011-09-14 | 2017-12-05 | 爱库利斯有限两合公司 | 杂环基酰胺取代的咪唑的磺酸盐 |
CN104610160A (zh) * | 2013-11-04 | 2015-05-13 | 南京大学 | 含哌嗪环的5-硝基咪唑类衍生物及其制备与在抗菌药物中的应用 |
CN104016925A (zh) * | 2014-06-17 | 2014-09-03 | 遵义医学院 | 4-烷基咪唑-2-羧酸的合成方法 |
CN104016925B (zh) * | 2014-06-17 | 2016-03-30 | 遵义医学院 | 4-烷基咪唑-2-羧酸的合成方法 |
CN116120238A (zh) * | 2023-03-01 | 2023-05-16 | 山东梅奥华卫科技有限公司 | 一种咪唑衍生物的制备方法 |
CN116120238B (zh) * | 2023-03-01 | 2023-09-22 | 山东梅奥华卫科技有限公司 | 一种咪唑衍生物的制备方法 |
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