CN100400523C - 作为组胺h1和/或h3拮抗剂或组胺h3反向拮抗剂的取代的哌嗪类、(1,4)二氮杂䓬类和2,5-二氮杂双环(2.2.1)庚烷类 - Google Patents
作为组胺h1和/或h3拮抗剂或组胺h3反向拮抗剂的取代的哌嗪类、(1,4)二氮杂䓬类和2,5-二氮杂双环(2.2.1)庚烷类 Download PDFInfo
- Publication number
- CN100400523C CN100400523C CNB2003801060141A CN200380106014A CN100400523C CN 100400523 C CN100400523 C CN 100400523C CN B2003801060141 A CNB2003801060141 A CN B2003801060141A CN 200380106014 A CN200380106014 A CN 200380106014A CN 100400523 C CN100400523 C CN 100400523C
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- CN
- China
- Prior art keywords
- phenyl
- piperazine
- oxygen base
- carbonyl
- piperidino
- 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.)
- Expired - Fee Related
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- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 title description 42
- 229960001340 histamine Drugs 0.000 title description 21
- 239000005557 antagonist Substances 0.000 title description 11
- 150000004885 piperazines Chemical class 0.000 title description 3
- 230000002441 reversible effect Effects 0.000 title description 3
- UXAWXZDXVOYLII-UHFFFAOYSA-N tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Chemical compound C1C2N(C(=O)OC(C)(C)C)CC1NC2 UXAWXZDXVOYLII-UHFFFAOYSA-N 0.000 title 1
- 239000000203 mixture Substances 0.000 claims abstract description 192
- 238000002360 preparation method Methods 0.000 claims abstract description 70
- 229910052760 oxygen Inorganic materials 0.000 claims description 331
- 150000001875 compounds Chemical class 0.000 claims description 287
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 233
- -1 Pyrrolidyl Chemical group 0.000 claims description 136
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 114
- 238000013519 translation Methods 0.000 claims description 53
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 47
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 41
- 150000003839 salts Chemical class 0.000 claims description 36
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 32
- 125000003118 aryl group Chemical group 0.000 claims description 19
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 11
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 11
- 229910052794 bromium Inorganic materials 0.000 claims description 11
- 125000005936 piperidyl group Chemical group 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 4
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000005493 quinolyl group Chemical group 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 125000004434 sulfur atom Chemical group 0.000 claims description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
- 229920002554 vinyl polymer Polymers 0.000 claims description 3
- 208000018569 Respiratory Tract disease Diseases 0.000 claims description 2
- 239000003981 vehicle Substances 0.000 claims description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 abstract description 395
- 238000000034 method Methods 0.000 abstract description 150
- 230000008569 process Effects 0.000 abstract description 7
- 208000015122 neurodegenerative disease Diseases 0.000 abstract description 4
- 208000024827 Alzheimer disease Diseases 0.000 abstract description 2
- 150000001538 azepines Chemical class 0.000 abstract description 2
- 230000000144 pharmacologic effect Effects 0.000 abstract 1
- 239000002585 base Substances 0.000 description 421
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 342
- 239000001301 oxygen Substances 0.000 description 328
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 325
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 306
- 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 202
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 171
- 239000000243 solution Substances 0.000 description 139
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 115
- 239000000047 product Substances 0.000 description 101
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 75
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 72
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 67
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 67
- 238000001704 evaporation Methods 0.000 description 64
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 56
- 230000008020 evaporation Effects 0.000 description 50
- 230000014616 translation Effects 0.000 description 49
- 235000011114 ammonium hydroxide Nutrition 0.000 description 48
- 239000011541 reaction mixture Substances 0.000 description 48
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 46
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 45
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 42
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 41
- 239000002253 acid Substances 0.000 description 41
- 235000019439 ethyl acetate Nutrition 0.000 description 40
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 38
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 36
- 239000000741 silica gel Substances 0.000 description 36
- 229910002027 silica gel Inorganic materials 0.000 description 36
- 229960001866 silicon dioxide Drugs 0.000 description 36
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 34
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 34
- 238000005406 washing Methods 0.000 description 34
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 33
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 30
- 239000012044 organic layer Substances 0.000 description 29
- 235000015320 potassium carbonate Nutrition 0.000 description 29
- 238000003756 stirring Methods 0.000 description 29
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- 238000001819 mass spectrum Methods 0.000 description 25
- 238000010898 silica gel chromatography Methods 0.000 description 25
- 239000002904 solvent Substances 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- 150000003053 piperidines Chemical class 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 21
- 238000010438 heat treatment Methods 0.000 description 21
- 210000004027 cell Anatomy 0.000 description 20
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 19
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- 229910052786 argon Inorganic materials 0.000 description 19
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 19
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Natural products C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- KVYAHWOXPUTNIL-UHFFFAOYSA-N carbonyl dichloride;piperazine Chemical compound ClC(Cl)=O.C1CNCCN1 KVYAHWOXPUTNIL-UHFFFAOYSA-N 0.000 description 18
- 238000001914 filtration Methods 0.000 description 18
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 17
- 201000010099 disease Diseases 0.000 description 17
- 238000005342 ion exchange Methods 0.000 description 17
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 16
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 15
- 229910052757 nitrogen Inorganic materials 0.000 description 15
- 235000007715 potassium iodide Nutrition 0.000 description 15
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- 238000010992 reflux Methods 0.000 description 15
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- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 14
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- 239000003395 histamine H3 receptor antagonist Substances 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 13
- ADCUEPOHPCPMCE-UHFFFAOYSA-N 4-cyanobenzoic acid Chemical compound OC(=O)C1=CC=C(C#N)C=C1 ADCUEPOHPCPMCE-UHFFFAOYSA-N 0.000 description 12
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 12
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
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- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 12
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
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- RHWLIPUKNHPPJJ-UHFFFAOYSA-N 4-(pyrrolidine-1-carbonyl)benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C(=O)N1CCCC1 RHWLIPUKNHPPJJ-UHFFFAOYSA-N 0.000 description 6
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- LNETULKMXZVUST-UHFFFAOYSA-N 1-naphthoic acid Chemical compound C1=CC=C2C(C(=O)O)=CC=CC2=C1 LNETULKMXZVUST-UHFFFAOYSA-N 0.000 description 4
- BZFGKBQHQJVAHS-UHFFFAOYSA-N 2-(trifluoromethyl)pyridine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC(C(F)(F)F)=C1 BZFGKBQHQJVAHS-UHFFFAOYSA-N 0.000 description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
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Abstract
本发明涉及具有药理活性的新的哌嗪和氮杂䓬衍生物、制备它们的方法、含有它们的组合物以及它们在治疗包括阿尔茨海默氏病的神经变性性疾病中的用途。
Description
本发明涉及具有药理活性的新的哌嗪和氮杂衍生物、制备它们的方法、含有它们的组合物以及它们在治疗包括阿尔茨海默氏病的神经变性性疾病中的用途。
WO 02/76925(Eli Lilly)公开了作为组胺H3拮抗剂要求保护的一系列化合物。WO 02/055496(GlaxoSmithKline)叙述了作为LDL-受体表达诱导剂作的一系列哌啶和哌嗪衍生物。WO 02/12214(OrthoMcNeil Pharmaceutical Inc)描述了作为组胺H3拮抗剂要求保护的一系列取代的芳氧基烷基胺化合物。
组胺H3受体在哺乳类动物的中枢神经系统(CNS)以及外周组织中表达(Leurs等(1998),Trends Pharmacol.Sci.19,177-183)。经选择性兴奋剂或组胺引起的H3受体激活导致从各种不同神经群包括组胺能、肾上腺素能和胆碱能神经元中释放神经递质的抑制(Schlicker等,(1994),Fundam.Clin.Pharmacol.8,128-137)。另外,体外和体内的研究已表明H3拮抗剂可以促进神经递质在与认知有关的脑区域例如大脑皮层和海马中的释放(Onodera等,(1998),组胺H3受体,由Leurs和Timmerman编著,第255-267页,Elsevier Science B.V.)。此外,在该文献中的许多报道已说明在啮齿类动物模型包括五种选择性任务、物体识别、高架十字迷宫、新任务的获得以及被动回避中H3拮抗剂(例如噻普酰胺、clobenpropit、环丙沙芬和GT-2331)的认知增强特性(Giovanni等,(1999),Behav.Brain Res.104,147-155)。这些数据提示新的H3拮抗剂和/或反相兴奋剂例如目前所使用的这类药物可能对于神经性疾病中认知损害例如阿尔茨海默氏病以及有关的神经退行性疾病的治疗有效。
在第一个方面,本发明提供式(I)的化合物或其药学上可接受的盐:
其中:
R1代表氢、-C1-6烷基、-C1-6烷氧基、-C3-8环烷基、-C1-6烷基-C3-8环烷基、芳基、杂环基、杂芳基、-C1-6烷基-芳基、-C1-6烷基-杂芳基、-C1-6烷基-杂环基、-芳基-芳基、-芳基-杂芳基、-芳基-杂环基、-杂芳基-芳基、-杂芳基-杂芳基、杂芳基-杂环基、-杂环基-芳基、-杂环基-杂芳基、-杂环基-杂环基,
其中R1可以任选由一个或更多个取代基取代,所述取代基可以相同或不相同,选自卤素、羟基、COOR15、氰基、-C1-6烷基-氰基、硝基、氧代基、三氟甲基、三氟代甲氧基、氟代甲氧基、二氟代甲氧基、C1-6烷基(任选由COOR15基团取代)、C2-6链烯基(任选由COOR15基团取代)、C2-6炔基(任选由COOR15基团取代)、C1-6烷氧基(任选由COOR15基团取代)、五氟乙基、C1-6烷氧基、C2-6链烯氧基、芳基、芳基C1-6烷基、-CO-芳基(任选由卤原子取代)、-CO-杂芳基、-C1-6烷基-CO-芳基、芳基C1-6烷氧基、C1-6烷硫基、C1-6烷氧基C1-6烷基、C3-7环烷基、C3-7环烷基C1-6烷氧基、C1-6烷氧基羰基、C1-6烷基磺酰基、C1-6烷基亚磺酰基、C1-6烷基磺酰氧基、C1-6烷基磺酰基C1-6烷基、磺酰基、芳基磺酰基、芳基磺酰氧基、芳基磺酰基C1-6烷基、芳氧基、C1-6烷基亚磺酰氨基、C1-6烷基酰胺基、C1-6烷基亚磺酰氨基C1-6烷基、C1-6烷基酰胺基C1-6烷基、芳基亚磺酰氨基、芳基甲酰胺基、芳基亚磺酰氨基C1-6烷基、芳基甲酰胺基C1-6烷基、芳酰基、芳酰基C1-6烷基、芳基C1-6烷酰基或基团-COR15、-NR15R16、-CONR15R16、-NR15COR16、-NR15SO2R16或-SO2NR15R16,其中R15和R16独立代表氢、C1-6烷基或C3-8环烷基或一起可以稠合形成5-至7-元非-芳香杂环,该杂环任选被O或S原子间断并且任选由卤素、C1-6烷基或-C1-6烷基C1-6烷氧基取代;
Z代表键、CO、N(R10)CO或SO2,因此,当R1代表氢时,Z代表NR10CO;
P是1或2
m、n和r独立代表0、1或2;
R2代表卤素、C1-6烷基、C1-6烷氧基、氰基、氨基或三氟甲基,因此,当n代表2时,两个R2可以连接形成苯环;
R4代表C1-6烷基,或者当r代表2时,两个R4可以一起形成桥连CH2、(CH2)2或(CH2)3基团;
R10代表氢或C1-6烷基,或者R10与它所连接的氮原子和R1一起形成含氮杂环基团;
R3代表-(CH2)q-NR11R12或式(i)的基团:
其中q是2、3或4;
R11和R12独立代表C1-6烷基或C3-8环烷基或与它们所连接的氮原子一起代表含有N-连接的氮的杂环基团,所述杂环基团任选由一个或更多个R17基团取代;
R13代表氢、C1-6烷基、-C1-6烷基-C1-6烷氧基、C3-8环烷基、-C1-6烷基-C3-8环烷基、-C1-6烷基-芳基或杂环基;
R14和R17独立代表卤素、C1-6烷基、卤烷基、OH、二C1-6烷基氨基、C1-6烷氧基或杂环基;
f和k独立代表0、1或2;
g是0、1或2和h是0、1、2或3,此时g和h不能都是0;
条件是当m代表1,n和r都代表0且R3代表-(CH2)3-N-哌啶或(CH2)3-N(乙基)2时,R1-Z-代表除甲基、-CO-O-C(CH3)3或苄基以外的基团;
以及条件是当m、n和r都代表0,p代表1,R3代表-(CH2)3-N-吡咯烷或-(CH2)3-N-哌啶,R1代表苄基时,Z代表除键以外的基团;
以及条件是当m、n和r都代表0,p代表1,R3代表-(CH2)3-N-哌啶,R1代表异丙基时,Z代表除键以外的基团;
以及条件是当m代表1,n和r都代表0,p代表1,R3代表-(CH2)3-N-哌啶,R1代表甲基、异丙基、芳基或苄基时,Z代表除键以外的基团;
以及条件是当m和n都代表0,R3代表-(CH2)3-N(乙基)2,p代表1,r代表2以及R1和R4都代表甲基时,Z代表除键以外的基团。
在本发明的一个具体的方面,提供如上所定义的式(I)化合物,
其中:
R1代表除氢、-C1-6烷氧基或-C1-6烷基-C3-8环烷基的基团;且R1任选由一个或更多个除以下基团外的取代基取代:COOR15、-C1-6烷基-氰基、由COOR15基团取代的C1-6烷基、C2-6链烯基(任选由COOR15基团取代)、C2-6炔基(任选由COOR15基团取代)、C1-6烷氧基(任选由COOR15基团取代)、C2-6链烯氧基、芳基、芳基C1-6烷基、-CO-芳基(任选由卤原子取代)、-CO-杂芳基、-C1-6烷基-CO-芳基或C3-7环烷基;
以及
R15和R16独立代表除了C3-8环烷基以外的基团或可一起稠合形成任选由O或S原子间断的未取代的5-到7-元非芳香杂环;和
r代表0;和
两个R2基团不连接形成苯环;和
R11和R12独立代表除C3-8环烷基外的基团;和
R13代表除-C1-6烷基-C3-8环烷基外的基团。
在本发明的第二个具体的方面,提供如上定义的式(I)化合物,
其中m代表0或2。
在本发明的另一具体的方面,提供如上定义的式(I)化合物,其中Z代表CO、CONR10或SO2。
烷基,当单独存在或作为其它基团的部分时,可以是直链或支链以及基团烷氧基和烷酰基将被类似地说明。烷基部分更优选是C1-4烷基例如甲基或乙基。本文中所使用的术语“卤素”,除另外说明外表示选自氟、氯、溴或碘的基团。
术语“芳基”包括单环和稠合环,其中至少一个环是芳族的例如苯基、萘基、四氢萘基、2,3-二氢化茚基或芴基。
术语“杂环基”表示4-7元单环饱和或部分不饱和环或与苯环稠合的含有1-3个选自氧、氮或硫的杂原子的4-7元饱和或部分不饱和的环。这样单环的合适的实例包括吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、四氢呋喃基、二氮杂庚环基、吖庚烷基和吖辛烷基。苯并稠合的杂环的合适实例包括二氢吲哚基、异二氢吲哚基、苯并间二氧杂环戊烯基和二氢异喹啉基。
术语“含氮杂环基”表示任何如上定义的含氮杂环基团。
术语“杂芳基”表示含有1-3个选自氧、氮和硫的杂原子的5-7元单环芳族或稠合的8-11元二环芳族的环。所述单环的芳族环的实例包括噻吩基、呋喃基、吡咯基、三唑基、咪唑基、噁唑基、噻唑基、噁二唑基、异噻唑基、异噁唑基、噻二唑基、吡唑基、嘧啶基、哒嗪基、吡嗪基和吡啶基。所述稠合的芳族环的合适的实例包括呋喃并吡啶基和苯并稠合的芳族环例如喹啉基、异喹啉基、喹唑啉基、喹喔啉基、噌啉基、1,5-二氮杂萘基、吲哚基、吲唑基、吡咯并吡啶基、苯并呋喃基、苯并噻吩基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并噁二唑基、苯并噻二唑基等。
式(I)的化合物和它们的药学上可接受的盐对于组胺H3受体具有亲和力并且为组胺H3受体的拮抗剂和/或反相兴奋剂,相信可能用于治疗神经性疾病包括阿尔茨海默氏病、痴呆、与年龄有关的记忆功能障碍、轻度识别损害、认知障碍、癫痫、神经性疼痛、炎性疼痛、偏头痛、帕金森氏病、多发性硬化、中风和包括嗜眠症的睡眠障碍;精神病包括精神分裂症、注意涣散多动症、抑郁症和成瘾症;以及其它疾病包括肥胖、哮喘、变应性鼻炎、鼻充血、慢性阻塞性肺疾病和胃肠疾病。
因此,本发明也提供式(I)的化合物或其药学上可接受的盐,用作治疗或预防以上疾病、特别是识别损害疾病例如阿尔茨海默氏病和有关的神经变性性疾病的治疗药物。
优选R1代表:
氢;
C1-6烷基(例如甲基、甲基丁基或丙基);
C1-6烷氧基(例如-OC(CH3)3);
芳基(例如苯基、萘基、四氢萘基、2,3-二氢化茚基或芴基);
杂芳基(例如苯并呋喃基、吲哚基、吡嗪基、苯并噁二唑基、噻二唑基、噻吩基、吡唑并嘧啶基、吡唑并吡啶基、苯并噻唑基、呋喃并吡啶基、吡啶基、喹啉基、异喹啉基、喹喔啉基、噌啉基、噻唑基、三唑基、异噁唑基、嘧啶基、1,5-二氮杂萘基、苯并异噁唑基或苯并异噻唑基);
杂环基(例如苯并间二氧杂环戊烯基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、四氢噻喃基、噻喃基、四氢吡喃基、二氢苯并呋喃基、二氢苯并吡喃基和呫吨基);
C3-8环烷基(例如环丙基、环戊基或环己基);
-C1-6烷基-芳基(例如苄基);
-C1-6烷基-C3-8环烷基(例如-CH2-环丙基);
-C1-6烷基-杂芳基(例如-CH2-吡啶基、-CH2-四唑基、-CH2-三唑基、-CH2-异噻唑基、-CH2-噻吩基或-CH2-呋喃基);
-芳基-杂环基(例如-苯基-吡咯烷基);
-芳基-芳基(例如联苯基);
-芳基-杂芳基(例如-苯基-吡啶基、-苯基-吡咯基或-苯基-四唑基);或
-杂芳基-芳基(例如-吡啶基-苯基)。
更优选,R1代表未取代的苯基。
此外,更优选R1代表:
芳基(例如苯基);或
杂环基(例如哌啶基、哌嗪基、吗啉基、硫代吗啉基或四氢吡喃基)。
优选R1由一个或更多个(例如1、2或3个)以下取代基任选取代:卤素(例如氯、氟或溴);三氟甲基;-C1-6烷基(例如甲基、乙基、异丙基、丙基或叔-丁基),任选由COOR15(例如COOH、COOMe或COOEt)取代;-C1-6烷氧基(例如甲氧基、丁氧基、-OCH(Me)2或-OC(Me)3),任选由COOR15(例如COOH或COOMe)取代;羟基;氧代基;氰基;-C1-6烷基-氰基(例如-CH2-CN);C1-6链烯基(例如乙烯基),任选由COOR15(例如COOMe)取代;C3-7环烷基(例如环戊基);C1-6烷基磺酰基(例如-SO2Me);C1-6链烯氧基(例如-OCH2CH=CH2);C1-6烷硫基(例如-S-乙基);NR15R16(例如N(Me)2);-C1-6烷基-芳基(例如苄基);芳基(例如苯基);-CO-芳基(例如-CO-苯基),任选由卤素(例如氯)取代;-CO-杂芳基(例如-CO-氮杂环丁烷基);-CO-杂环基(例如-CO-四氢吡喃基);-COOR15(例如COOH、COOMe或COO叔-丁基);-COR15(例如-CO-甲基、-CO-乙基、-CO-异丙基、-CO-环丙基、-CO-环丁基、-CO-环戊基或-CO-环己基);-CONR15R16(例如-CONH2、-CO-吡咯烷基、-CO-吗啉基、-CO-哌嗪基、-CO-哌啶基、-CO-硫代吗啉基),任选由C1-6烷基(例如甲基)、卤素(例如氟)或-C1-6烷基C1-6烷氧基(例如-CH2-OMe)取代;或-C1-6烷基-CO-芳基(例如-CH2CO苯基)。
更优选,R1任选由一个或更多个(例如1、2或3)以下基团取代:卤素(例如氟);氧代基;氰基;-CONR15R16(例如-CO-吡咯烷基),或-COR15(例如-CO-异丙基、-CO-环丙基或-CO-环丁基)。
优选Z代表键、CO或CONR10,更优选Z代表键或CO,特别是CO。
优选R10代表氢或C1-6烷基。
优选m是0或2,更优选m是0。
优选n是0或1,更优选n是0。
当n代表1时,R2优选为卤素(例如氯、溴或氟)、三氟甲基、氰基或C1-6烷基(例如甲基)。
优选r是0。
当r代表1或2时,R2优选是C1-6烷基(例如甲基)或两个R4基团一起形成桥连CH2基团。
优选p是1。
优选R3代表-(CH2)q-NR11R12。
当R3代表式(i)基团时,优选f是0或1,g是2,h是1,k是0以及R13代表氢、任选取代的C1-6烷基(例如乙基、甲基丙基、异丙基或甲氧基乙基)、C3-8环烷基(例如环丙基、环丁基或环戊基)或-C1-6烷基-C3-8环烷基(例如-CH2-环丙基)。
当R3代表式(i)基团时,更优选f是0,g是2,h是1,k是0以及R13代表C1-6烷基(例如异丙基)或C3-8环烷基(例如环丙基或环丁基)。
优选q是2或3,更优选q是3。
优选R11和R12独立代表C1-6烷基(例如甲基)或C3-8环烷基(例如环戊基)或NR11R12代表杂环基(例如哌啶基、吡咯烷基、硫代吗啉基、吖庚烷基或吖辛烷基,任选由一个或更多个卤素(例如氟)或C1-6烷基(例如甲基或乙基)取代。
更优选NR11R12代表任选由一个或更多个C1-6烷基(例如甲基或乙基)取代的吡咯烷基、哌啶基、吖庚烷基或吖辛烷基,特别是代表未取代的哌啶基。
优选-O-R3存在于苯基的相对所述化合物其它部分的对位。
根据本发明的优选化合物包括如下所示的实例E1-E503,或其药学上可接受的盐。
式(I)的化合物可以与酸例如常规的药学上可接受的酸如马来酸、盐酸、氢溴酸、磷酸、乙酸、富马酸、水杨酸、硫酸、柠檬酸、乳酸、扁桃酸、酒石酸和甲磺酸形成酸加成盐。因而式(I)化合物的盐类、溶剂合物和水合物组成本发明的一个方面。
一些式(I)的化合物能够以立体异构的形式存在。可以理解,本发明包括这些化合物的所有几何和光学异构体以及包括外消旋物的混合物。互变异构体也形成本发明的一方面。例如,当R3代表(CH2)qNR11R12以及NR11R12代表由一个或更多个C1-6烷基取代的含氮杂环基时,本发明延伸至包括非对映异构体和对映体化合物是可以理解的。
本发明也提供制备式(I)化合物或其药学上可接受的盐的方法,所述方法包括:
(a)使式(II)的化合物
其中R1、Z、R4、p、m、r、R2和n如上所定义,与式R3’-L1的化合物反应,其中R3’如以上对于R3的定义或可以转化的基团以及L1代表合适的离去基团如卤原子(例如溴或氯)或任选活化的羟基;或
(b)通过使式(III)化合物
或其保护的衍生物,其中R4、r、p、m、R2、n和R3如上所定义,与式R1-COX的化合物反应,其中R1如上所定义和X代表合适的离去基团如活化的羟基、合适的卤原子或苯并三唑基,制备其中Z代表CO的式(I)化合物;或
(c)通过使如上所定义的式(III)的化合物与式R1-SO2Cl的化合物(其中R1如上所定义)反应,制备其中Z代表SO2的式(I)的化合物;或
(d)通过使如上所定义的式(III)的化合物与式R1-N=C=O(其中R1如上所定义的化合物)反应,制备其中Z代表NR10CO的式(I)化合物;或
(e)通过使如上所定义的式(III)的化合物在溶剂如甲苯中先与光气反应,随后在溶剂如二氯甲烷中与式R10R1-NH的化合物反应,其中R1和R10如上所定义,制备其中Z代表CONR10的式(I)化合物;或
(f)通过使式(IV)的化合物
与式(XI)的化合物
或其任选保护的衍生物(其中R4、r、R2、n、R3、R1、Z和p如上所定义)在还原条件下反应,制备式(I)的化合物,其中m代表1;
或
(g)将保护的式(I)的化合物脱保护;以及
(h)互变成其它的式(I)化合物。
当R3代表-(CH2)q-NR11R12时,方法(a)通常包括在合适的溶剂例如2-丁酮中,任选在活化剂例如碘化钾存在下,在合适的温度例如回流下,使用合适的碱例如碳酸钾。
当由R3’转变为R3的基团代表例如L2-(CH2)q-时,方法(a)通常包括使用与以上所述类似的条件的烷基化反应。
当R3代表式(i)的基团和L1代表任选活化的羟基时,方法(a)通常包括在合适的溶剂例如四氢呋喃中使用膦例如三苯膦,随后在合适的温度如室温下加入偶氮二羧酸酯例如偶氮二羧酸二乙基酯。
方法(b)通常包括任选在有机或无机碱例如碳酸钾存在下或在合适的偶合剂例如1,3-二环己基碳二亚胺和1-羟基苯并三唑存在下,使用合适的溶剂例如二氯甲烷。
方法(c)和(d)通常包括使用合适的溶剂如2-丁酮。
方法(e)通常包括使用合适的碱如三乙胺。
方法(f)包括任选在酸如乙酸存在下使用还原条件(例如用硼氢化物如三乙酰氧基硼氢化钠),随后在式(XI)化合物为保护的衍生物的情况下任选脱保护。
在方法(g)中,保护基团的实例以及除去其的方法可以在文献T.W.Greene‘Protective Groups in Organic Synthesis’(J.Wiley and Sons,1991)中发现。合适的胺保护基团包括磺酰基(例如甲苯磺酰基)、酰基(例如乙酰基、2’,2’,2’-三氯代乙氧基羰基、苄氧基羰基或叔-丁氧基羰基)和芳烷基(例如苄基),它们合适时可以经水解(例如使用酸如溶于二噁烷中的盐酸或溶于二氯甲烷中的三氟乙酸)或还原(例如苄基的氢解或在乙酸中使用锌还原去除2’,2’,2’-三氯代乙氧基羰基)除去。其它合适的胺保护基团包括三氟乙酰基(-COCF3),所述保护基团可以经碱催化水解除去或固相树脂结合的苄基如Merrifleld树脂结合的2,6-二甲氧基苄基(Ellman linker)除去,所述保护基团可以经酸催化水解例如使用三氟乙酸除去。
方法(h)可以使用常规互变方法例如差向异构化、氧化、还原、烷基化、亲核或亲电芳族取代、酯水解或酰胺键形成进行。例如,式(I)的化合物,其中R3代表式(i)基团,可以在R13位通过与烷基卤例如1-氯代-2-甲氧基乙烷在碱如碳酸钾存在下、在合适的溶剂如2-丁酮中、任选在转移剂如碘化钾存在下相互转变。所述转变也可以通过还原胺化进行,例如使用丙酮在硼氢化物如三乙酰氧基硼氢化钠以及任选在酸如乙酸存在下,在合适的溶剂如二氯甲烷中进行。
式(II)和(III)的化合物,其中m是1或2,可以按照以下流程制备:
其中R4、r、R2、n、R3、p如上所定义以及式(V)的化合物可以任选被保护。
步骤(i)可以以与以上方法(f)所述相似的方法进行。
式(III)的化合物,其中m是0,可以按照以下流程制备:
其中R4、r、p、R2、n和R3如上所定义以及P1代表合适的保护基团(例如Boc)。
当P1代表Boc时,步骤(i)可以通过使式(IX)的化合物与碳酸二-叔-丁基酯,在合适的碱(例如三乙胺)存在下,在合适的溶剂(例如二氯甲烷)中,在合适的温度(例如室温)下进行。
步骤(ii)可以按以下用于制备式(IV)化合物所示的方法相似的方法进行。
步骤(iii)通常包括脱保护反应,例如,当P1代表Boc时,脱保护通常可包括使式(III)P1的化合物与盐酸在二噁烷中或与三氟乙酸在二氯甲烷中反应。
式(III)的化合物,其中m是2,可以按照以下流程制备:
其中R2、R3、R4、n、p、r如上所定义,P2代表合适的保护基团如Boc以及L5代表合适的离去基团如卤原子(例如溴)。
步骤(i)通常包括使式(XII)的化合物与式(XIII)的化合物在惰性溶剂例如二甲基甲酰胺或乙腈中反应。
步骤(ii)通常包括脱保护反应,例如当P2代表Boc时,脱保护通常可包括使式(III)P11的化合物与盐酸在二噁烷中或与三氟乙酸在二氯甲烷中反应。
式(IV)的化合物,其中R3代表-(CH2)q-NR11R12可以按照以下流程制备:
其中R2、n、q、R11、R12如上所定义,L1、L2、L3和L4代表合适的离去基团(例如卤原子如溴或氯)。
步骤(i)、(ii)和(iii)可以使用根据以上方法(a)所述的相似的条件进行。
式(IV)的化合物,其中R3代表如上所定义的式(i)的基团,可以按照以下流程制备:
其中R2、n、f、g、h、k如上所定义,L4代表合适的离去基团例如卤原子或羟基以及R13a如上对于R13的定义或是保护基团如叔-丁氧基羰基,随后任选脱保护。
步骤(i)可以使用根据以上对于方法(a)所述类似的条件进行。
式(II)的化合物,其中m是0,可以通过以上所定义的式(IX)化合物的脱保护反应制备,随后通过与以上方法(b)、(c)、(d)和(e)中所述的类似方法,任选随后经水解处理以再生式(II)的游离羟基。
式(II)的化合物,其中m是1或2,可以由以上所定义的式(IV)的化合物,按以上制备式(III)a的化合物限定的类似的方法,随后按以上方法(b)、(c)、(d)和(e)中所述类似的方法,任选随后经水解处理再生式(II)的游离羟基制备。
式(XI)的化合物可以由相应的哌嗪或二吖庚烷,按以上方法(b)、(c)、(d)和(e)类似的方法制备。
式(XI)的化合物,其中Z代表键,可以根据Buchwald,OrganicLetters,2002,4,2885-2888的方法,通过使式R1-L6(其中R1如上所定义和L6代表合适的离去基团例如溴原子)与式(XII)的化合物例如1-BOC-哌嗪,在钯催化剂如三(二亚苄基丙酮)二钯和配体如2-环己基膦基-2’-(N,N-二甲基氨基)联苯存在下,在惰性溶剂如四氢呋喃中,在碱如二(三甲基甲硅烷基)氨化锂存在下,在惰性气氛(氮气)中,在升高的温度如80℃下制备。
式(V)、(VI)、(VIII)、(IX)、(XII)和(XIII)的化合物是已知的或者可以根据已知的方法制备。
也已经发现一些式(I)的化合物和它们药学上可接受的盐对于组胺H1受体具有亲合力。
组胺H1受体广泛分布在整个CNS和外周神经中并参与失眠和急性炎症过程[Hill等,Pharmacol.Rev.49:253-278(1997)]。季节性变应性鼻炎和其它变应性疾病与组胺从肥大细胞中释放有关。激活血管中和神经末稍的H1受体引起许多变应性鼻炎的症状(包括鼻痒、打喷嚏以及产生水样鼻涕)。抗组胺化合物即为选择性H1受体拮抗剂的药物如氯苯那敏和西替利嗪对治疗与变应性鼻炎有关的鼻痒、打喷嚏和流鼻涕有效,但是对于治疗鼻充血症状不是十分有效[Aaronson,Ann.Allergy,67:541-547,(1991)]。
已知H3受体激动剂可以在猪鼻粘膜中抑制交感神经对血管紧张度的激活作用[Varty & Hey.Eur.J.Pharmacol.452:339-345,(2002)]。在体内,H3受体激动剂抑制通过交感神经的激活导致鼻气流阻力降低[Hey等,Arzneim-Forsch Drug Res.48:881-888(1998)]。另外,H3受体拮抗剂与组胺H1受体拮抗剂联合使肥大细胞激活对鼻气流阻力和鼻腔体积、鼻充血指数的影响逆转[McLeod等,Am.J.Rhinol.13:391-399,(1999)]。联合的组胺H1和H3受体拮抗剂例如本文中所述的系列在治疗与季节性和全年性变性性鼻炎有关的鼻充血和打喷嚏、鼻痒和流青涕都有效。
因此,其中二元组胺H1和H3拮抗剂对其具有潜在有益抗炎效应的疾病的实例包括呼吸道疾病如哮喘(包括变应性或非变应性哮喘)、变应性鼻炎、鼻窦炎、支气管炎(包括慢性支气管炎)、支气管扩张、慢性阻塞性肺疾病(COPD)和囊性纤维化。
其中二元组胺H1和H3拮抗剂对其具有潜在有益效应的疾病的其它实例包括胃肠道的疾病例如肠炎性疾病包括炎性肠疾病(例如局限性回肠炎或溃疡性结肠炎)以及继发于辐射暴露或过敏源暴露的肠炎性疾病。
本发明的二元组胺H1和H3拮抗剂也可以用于治疗睡眠/唤醒障碍、觉醒/失眠症、偏头痛、痴呆症、轻度认知损害(早老性痴呆)、认知功能障碍、阿尔茨海默氏病、癫痫、嗜眠症、进食障碍、晕动病、眩晕、注意涣散多动症、认识障碍、记忆保持障碍、精神分裂症、抑郁症、噪狂症、双极情感性精神病和糖尿病。
对于二元组胺H1和H3拮抗剂主要敏感的疾病包括哮喘、COPD和包括季节性和全年性变应性鼻炎的上呼吸道炎性疾病、非变应性鼻炎和与这些疾病有关的特殊症状包括鼻充血、流青涕、打喷嚏、咳嗽和眼、耳、鼻和喉发痒(瘙痒)。主要敏感的其它疾病包括咳嗽、慢性荨麻疹、变应性结膜炎、鼻息肉、鼻窦炎、银屑病、湿疹和变应性皮肤病(包括荨麻疹、特应性皮炎、接触性皮炎、药物性皮疹和昆虫咬伤)。
主要敏感的疾病包括哮喘、COPD、认知障碍以及包括季节性和全年性变应性鼻炎的上呼吸道炎性疾病。
主要敏感的优选疾病包括哮喘、认知障碍以及包括季节性和全年性变应性鼻炎的上呼吸道炎性疾病。
也是主要敏感的其它疾病包括胃肠道炎性疾病例如炎性肠疾病。
因此本发明也提供式(I)的二元组胺H1和H3拮抗剂化合物或其药学上可接受的盐,作为治疗物质在治疗或预防以上所述疾病、特别是变应性鼻炎中的用途。
优选的式(I)的二元组胺H1和H3拮抗剂化合物为这样一些化合物:
其中:
R1代表芳基(例如苯基、萘基或四氢萘基)或杂芳基(例如苯并呋喃基、吲哚基或喹啉基);
R1任选由一个或更多个(例如1、2或3个)以下取代基取代: 卤素(例如氯、氟或溴);三氟甲基;任选由COOR15(例如COOEt)取代的-C1-6烷基(例如甲基、乙基、异丙基、丙基或叔-丁基);任选由COOR15(例如COOMe)取代的-C1-6烷氧基(例如甲氧基);C1-6链烯基(例如乙烯基);NR15R16(例如N(Me)2);或C1-6烷硫基(例如-S-乙基)基团;
Z是键或CO;
m是0或2;
n是0;
r是0;
p是1;
R3代表-(CH2)q-NR11R12;
q代表3;和
NR11R12代表任选由一个或者多个C1-6烷基(例如甲基或乙基)取代的吡咯烷基、哌啶基、吖庚烷基或吖辛烷基,更优选由一个或两个甲基或乙基取代的哌啶基。
本发明还提供在哺乳动物包括人中治疗或预防以上所述疾病的方法,该方法包括给予患者治疗有效量的式(I)的化合物或其药学上可接受的盐。
另一方面,本发明提供式(I)的化合物或其药学上可接受的盐在制备用于治疗以上所述疾病的药物中的用途。
当用于治疗时,式(I)的化合物通常配制成标准的药用组合物。可以使用标准方法制备所述组合物。
因此,本发明还提供用于治疗以上所述疾病的药用组合物,该组合物包含式(I)的化合物或其药学上可接受的盐和药学上可接受的载体。
本发明还提供包含式(I)的化合物或其药学上可接受的盐和药学上可接受的载体的药用组合物。
根据本发明的药用组合物也可以与其它治疗药物联合使用,所述其它治疗药物例如是抗炎药(例如皮质类固醇类(例如丙酸氟替卡松、丙酸倍氯米松、莫米松糠酸酯、曲安奈德或布地奈德)或NSAIDs(例如色甘酸钠、奈多罗米钠、PDE-4抑制剂、白三烯拮抗剂、脂氧合酶抑制剂、趋化因子拮抗剂(例如CCR3、CCR1、CCR2、CXCR1、CXCR2)、iNOS抑制剂、类胰蛋白酶和弹性蛋白酶抑制剂、β-2整联蛋白拮抗剂和腺苷2a激动剂))或β肾上腺素能药(例如沙美特罗、沙丁胺醇、福莫特罗、非诺特罗或特布他林和其盐),或拟交感神经药(例如伪麻黄碱或羟甲唑啉),或其它对于组胺受体(例如H4)的拮抗剂,或胆碱能酶抑制剂,胆碱能拮抗剂或抗感染药(例如抗生素、抗病毒药)。
本发明的药用组合物,可以通过在室温和常压下适当地混合制备,通常适合于口服、局部、胃肠外或直肠给药,因此,可以是片剂、胶囊、口服液体制剂、散剂、颗粒剂、锭剂、可重新配制的粉末剂、可以注射或输注的液体或悬浮液或栓剂的形式。一般优选口服给药的组合物。
用于口服的片剂和胶囊可以是单位剂量形式并可以含有常用的赋形剂如粘合剂、填充剂、压片润滑剂、崩解剂和可接受的甜味剂。可以根据常规制药实践熟知的方法将片剂包衣。
口服液体制剂可以例如是水性或油性悬浮液、溶液剂、乳剂、糖浆或酏剂的形式,或者可以是在使用前与水和其它合适的溶媒重新配制的干燥产物的形式。所述液体制剂可以含有常规的添加剂如悬浮剂、乳化剂、非水溶性溶媒(其可以包含可食用的油)、防腐剂,以及如果需要可以含有常规调味剂或着色剂。
用于胃肠外给药,可以利用本发明化合物或其药学上可接受的盐和无菌溶媒制备成液体的单位剂量形式。根据所用溶媒和化合物的浓度,所述化合物可以悬浮或溶解于溶媒中。在制备溶液中,可以将化合物溶解用于注射并在注入到合适的小瓶或安瓿前过滤除菌并密封。将辅助剂如局部麻醉剂、防腐剂和缓冲剂溶于溶媒中是有益的。为了增加稳定性,在填充到小瓶中以后,可以将所述组合物冷冻并在真空中除去水份。除了将所述化合物悬浮在溶媒中代替溶解以及不能经过滤进行灭菌外,可以以大体上相同的方法制备胃肠外给药的悬浮液。可以在悬浮在无菌溶媒中之前,通过将化合物暴露在环氧乙烷下灭菌。将表面活性剂或湿润剂包括在组合物中,有益于促使所述化合物均匀地分布。
根据给药的方法,所述组合物可以含有0.1%-99%重量,优选10-60%重量的活性物质。用于治疗上述疾病所用化合物的剂量通常根据所治疗疾病的严重程度、患者的体重以及其它类似因素而变化。但是,一般指导性的合适的单位剂量可以为0.05-1000mg,更合适为1.0-200mg,该单位剂量按每天一次以上、例如一天两次或三次给予。所述治疗可以持续数周或数月。
以下说明和实施例说明本发明化合物的制备。
说明1
4-[4-(3-哌啶-1-基-丙氧基)-苄基]-哌嗪-1-羧酸叔-丁基酯(D1)
向4-(3-(哌啶-1-基)丙氧基)苯甲醛(WO 02/12214 A2)(1.90g、7.68mmol)的二氯甲烷(25ml)溶液中加入1-N叔丁氧基羰基哌嗪(1.57g,8.45mmol),随后加入乙酸(1ml),将反应物在室温下搅拌1小时,然后用三乙酰氧基硼氢化钠(2g,9.61mmol)处理,在室温下搅拌16小时。然后用饱和碳酸氢钠溶液稀释反应物并用二氯甲烷萃取。然后顺序用水和盐水洗涤二氯甲烷,经无水硫酸钠干燥并在真空中蒸发,得到残余物,使用0.880氨水∶甲醇∶二氯甲烷(0.5∶4.5∶95)的混合物洗脱的硅胶层析纯化,得到标题化合物(1.586g,50%);MS(ES+)m/e418[M+H]+。
说明2
1-[4-(3-哌啶-1-基-丙氧基)-苄基]-哌嗪三盐酸盐(D2)
向4-[4-(3-哌啶-1-基-丙氧基)-苄基]-哌嗪-1-羧酸叔-丁基酯(D1)(1.576g,3.76mmol)的二氯甲烷和甲醇(1∶1)混合物(20ml)中的溶液中加入1M氯化氢的乙醚溶液(20ml)并将反应物在室温下搅拌5小时。然后在真空中蒸发溶剂并用乙醚研磨得到的残余物,得到标题化合物(1.5g,93%);MS(ES+)m/e 318[M+H]+。
说明3
4-[4-(3-哌啶-1-基-丙氧基)-苄基]-[1,4]二吖庚烷-1-羧酸叔-丁基酯(D3)
使用说明1(D1)的方法,由[1,4]二吖庚烷-1-羧酸叔-丁基酯制备标题化合物(D3)。
MS(ES+)m/e 432[M+H]+。
说明4
1-[4-(3-哌啶-1-基-丙氧基)-苄基]-[1,4]二吖庚烷(D4)
将4-[4-(3-哌啶-1-基-丙氧基)-苄基]-[1,4]二吖庚烷-1-羧酸叔-丁基酯(D3)(2.27g,5.27mmol)溶于二氯甲烷(10ml)中,用三氟乙酸(5ml)处理并在室温、氩气氛下搅拌2小时。在真空中蒸发溶剂并将残余物溶于甲醇中,使其通过用甲醇、随后用0.88氨水/甲醇(1∶9)洗脱的SCX柱(10g)。合并碱性部分并在真空中浓缩,得到标题化合物(1.57g)。
MS(ES+)m/e 332[M+H]+。
说明5
4-(4-甲酰基-苯氧基)-哌啶-1-羧酸叔-丁基酯(D5)
将4-羟基苯甲醛(2.0g,16.4mmol)溶于四氢呋喃(20ml)中并用4-羟基-哌啶-1-羧酸叔-丁基酯(4.1g,20.5mmol)和三苯膦(5.4g,20.5mmol)处理。将混合物在冰浴中冷却,用偶氮二羧酸二乙基酯(3.2ml,20.5mmol)处理,并且在室温下搅拌36小时。用乙酸乙酯稀释该反应混合物,用氢氧化钠溶液(2M)、碳酸氢钠溶液和盐水洗涤。经硫酸镁干燥有机层,过滤并在真空中除去溶剂。经用乙酸乙酯/己烷(1∶4)洗脱的柱层析,得到标题化合物(1.85g)。
1H NMR(CDCl3)δ9.88(1H,s),7.85-7.82(2H,d),7.02-6.99(2H,d),4.65-4.59(1H,m),3.74-3.65(2H,m),3.43-3.33(2H,m),2.04-1.92(2H,m),1.82-1.77(2H,m),1.47(9H,s).
说明6
4-(4-哌嗪-1-基甲基-苯氧基)-哌啶-1-羧酸叔-丁基酯(D6)
使用说明1(D1)的方法,由4-(4-甲酰基-苯氧基)-哌啶-1-羧酸叔-丁基酯(D5)和哌嗪制备标题化合物(D6)。MS(ES+)m/e 376[M+H]+。
说明7
4-{4-[4-(1-苯基-甲酰基)-哌嗪-1-基甲基]-苯氧基}-哌啶-1-羧酸叔-丁基酯(D7)
使用在实施例24(E24)中所述的方法,由4-(4-哌嗪-1-基甲基-苯氧基)-哌啶-1-羧酸叔-丁基酯(D6)和苯甲酰氯制备标题化合物(D7)。MS(ES+)m/e 480[M+H]+。
说明8
4-(4-羟基-苯基)-哌嗪-1-羧酸叔-丁酯(D8)
将二碳酸二-叔-丁基酯(10.1g,1.1当量)分批加入到4-哌嗪-1-基-苯酚(Chem.Pharm.Bull.49(10),1314(2001))(7.5g,42.1mM)和三乙胺(6.4ml,1.1当量)的二氯甲烷(150ml)溶液中。将得到的混合物在室温下搅拌18小时。
将反应物用水(2×100ml)洗涤,干燥(硫酸钠)并经真空蒸发除去溶剂。经用4-1己烷-乙酸乙酯洗脱的硅胶柱层析纯化残余物,得到标题化合物为灰白色固体(4.71g)。
MS(ES+)m/e 279[M+H]+。
说明9
4-[4-(3-氯代-丙氧基)-苯基]-哌嗪-1-羧酸叔-丁酯(D9)
将4-(4-羟基-苯基)-哌嗪-1-羧酸叔-丁酯(D8)(4.0g,14.4mM)、1-溴代-3-氯代丙烷(1.70ml,1.2当量)和碳酸钾(4.0g,2当量)的丁-2-酮(100ml)混合物在回流下加热18小时。将混合物冷却至室温,过滤并蒸发。经用4-1己烷-乙酸乙酯洗脱的硅胶柱层析纯化残余物,得到标题化合物为无色粘性油状物(3.8g)
MS(ES+)m/e 355[M+H]+。
说明10
4-[4-(3-哌啶-1-基-丙氧基)-苯基]-哌嗪-1-羧酸叔-丁酯(D10)
将4-[4-(3-氯代-丙氧基)-苯基]-哌嗪-1-羧酸叔-丁酯(D9)(4.0g,11.3mM)、哌啶(2.23ml,2当量)、碳酸钾(3.73g,2.4当量)和碘化钾(3.74g,2当量)的丁-2-酮(100ml)混合物在回流下加热3天。将混合物冷却至室温,过滤并蒸发,得到标题化合物为浅黄色固体(4.6g)
MS(ES+)m/e 404[M+H]+。
说明11
1-[4-(3-哌啶-1-基-丙氧基)-苯基]-哌嗪(D11)
将4-[4-(3-哌啶-1-基-丙氧基)-苯基]-哌嗪-1-羧酸叔-丁酯(D10)(1.0g,2.48mM)和三氟乙酸(5ml)溶液在室温下搅拌60分钟。将反应混合物在SCX离子交换柱体中纯化,得到标题化合物为无色结晶固体(0.76g)
MS(ES+)m/e 304[M+H]+。
说明12
4-(3-羟基-苯基)-哌嗪-1-羧酸叔-丁基酯(D12)
使用与说明8(D8)中所述相同的方法,由3-哌嗪-1-基-苯酚(Chem.Pharm.Bull.49(10),1314(2001))制备。
MS(ES+)m/e 279[M+H]+。
说明13
4-[3-(3-氯代-丙氧基)-苯基]-哌嗪-1-羧酸叔-丁基酯(D13)
使用与说明9(D9)中所述相同的方法,由4-(3-羟基-苯基)-哌嗪-1-羧酸叔-丁基酯(D12)制备。
MS(ES+)m/e 355[M+H]+。
说明14
4-[3-(3-哌啶-1-基-丙氧基)-苯基]-哌嗪-1-羧酸叔-丁基酯(D14)
使用与说明10(D10)中所述相同的方法,由4-[3-(3-氯代-丙氧基)-苯基]-哌嗪-1-羧酸叔-丁基酯(D13)制备。
MS(ES+)m/e 404[M+H]+。
说明15
1-[3-(3-哌啶-1-基-丙氧基)-苯基]-哌嗪(D15)
使用与说明11(D11)中所述相同的方法,由4-[3-(3-哌啶-1-基-丙氧基)-苯基]-哌嗪-1-羧酸叔-丁基酯(D14)制备。
MS(ES+)m/e 304[M+H]+。
说明16
4-溴代-1-甲基-1H-吲哚(D16)
将4-溴代-1H-吲哚(6.7g)的四氢呋喃(75ml)溶液用氢化钠(1.24g)处理并在室温下搅拌0.5小时。将得到的悬浮液用碘代甲烷(2.34ml)的四氢呋喃(35ml)溶液在0℃下处理并用1小时加热至室温,同时搅拌。将反应混合物倒在水上面并分配在二氯甲烷和水之间。干燥(MgSO4)有机层并在真空中浓缩,得到标题化合物(7.2g)。TLC硅胶(环己烷-乙酸乙酯[1∶1]),Rf=0.55。
说明17
4-溴代-1-甲基-1H-吲哚-3-羧酸(D17)
将4-溴代-1-甲基-1H-吲哚(D16)(7.0g)的四氢呋喃(50ml)溶液在0℃下用三氟乙酸酐(5.65ml)的四氢呋喃(20ml)溶液处理。经6小时将反应混合物加热至室温,同时搅拌。在真空中浓缩反应混合物,然后重悬浮在乙醇(25ml)中。用5N氢氧化钠溶液(50ml)处理该溶液并在回流下加热18小时。用乙醚洗涤反应混合物并用5N盐酸溶液酸化含水层。过滤沉淀物,用水洗涤并在真空中浓缩,得到标题化合物(4.88g)。TLC,硅胶(环己烷-乙酸乙酯-乙酸[3∶1∶0.1]),Rf=0.35。
说明18-23
使用以与实施例76b相似的方法,用合适的胺代替2-甲基哌啶制备说明18-23的化合物。
说明24-32
经与下表中所示相似的方法制备说明24-32化合物。
说明 | 名称 | 类似于下列方法制备 | RT(分钟) |
24 | 4-(2-萘基)-1-哌嗪羧酸1,1-二甲基乙基酯 | E229a来自已知的原料 | 3.74 |
25 | 4-(4-喹啉基)-1-哌嗪羧酸1,1-二甲基乙基酯和4-(3-喹啉基)-1-哌嗪羧酸1,1-二甲基乙基酯(1∶1) | E229a来自已知的原料 | 2.18&3.02 |
26 | 1-(2-萘基)哌嗪 | E229b来自已知的原料 | 2.00 |
27 | 4-(1-哌嗪基)喹啉和3-(1-哌嗪基)喹啉(1∶1) | E229b来自D25 | 1.18 |
28 | 3-{[4-(2-萘基)-1-哌嗪基]甲基}苯酚 | E229c来自D24 | 2.39 |
29 | 3-{[4-(1-萘基)-1-哌嗪基]甲基}苯酚 | E229c来自D26 | 2.41 |
30 | 4-{[4-(8-喹啉基)-1-哌嗪基]甲基}苯酚 | E229c来自E229b | 1.78 |
31 | 4-{[4-(4-喹啉基)-1-哌嗪基]甲基}苯酚和3-{[4-(3-喹啉基)-1-哌嗪基]甲基}苯酚(1∶1) | E229c来自D27 | 1.91 |
32 | 4-{[4-(1-萘基)-1-哌嗪基]甲基}苯酚 | E229c来自D26 | 2.46 |
说明33-42
以与下表中所示相似的方法制备说明33-42的化合物。
说明 | 名称 | 类似于下列方法制备 | RT(分钟) |
33 | 2-甲基-4-[4-(2-{4-[(苯基甲基)氧基]苯基}乙基)-1-哌嗪基]喹啉 | E237a来自已知的原料 | 2.20 |
34 | 2-甲基-4-[4-(2-{3-[(苯基甲基)氧基]苯基}乙基)-1-哌嗪基]喹啉 | E237a来自已知的原料 | 2.11 |
35 | 1-(1-萘基)-4-(2-{4-[(苯基甲基)氧基]苯基}乙基)哌嗪 | E237a来自已知的原料 | 2.91 |
36 | 1-(1-萘基)-4-(2-{3-[(苯基甲基)氧基]苯基}乙基)哌嗪 | E237a来自已知的原料 | 2.82 |
37 | 1-苯基-4-(2-{4-[(苯基甲基)氧基]苯基}乙基)哌嗪 | E237a来自已知的原料 | 2.55 |
38 | 4-{2-[4-(2-甲基-4-喹啉基)-1-哌嗪基]乙基}苯酚 | E237b来自D33 | 1.69 |
39 | 3-{2-[4-(2-甲基-4-喹啉基)-1-哌嗪基]乙基}苯酚 | E237b来自D34 | 4.56 |
40 | 4-{2-[4-(1-萘基)-1-哌嗪基]乙基}苯酚 | E237b来自D35 | 2.28 |
41 | 3-{2-[4-(1-萘基)-1-哌嗪基]乙基}苯酚 | E237b来自D36 | 2.32 |
42 | 4-[2-(4-苯基-1-哌嗪基)乙基]苯酚 | E237b来自D37 | 2.02 |
说明43
3-溴代-4-乙基-苯甲酸(D43)
向浓NHO3(66mL)、冰AcOH(300mL)和水(50mL)混合物中加入4-乙基-苯甲酸(15g),剧烈搅拌,以后用溴(5.67mL)处理。然后滴加入AgNO3(16.97g)的水(50mL)溶液并将混合物剧烈搅拌2小时。经过滤收集沉淀物,用水很好地洗涤,然后用热的饱和K2CO3溶液萃取,再用木碳处理。将该热溶液经硅藻土过滤并使用浓HCl酸化该溶液至pH为1。经过滤收集得到的白色沉淀物并在60℃下在真空干燥箱中过夜,得到标题化合物(19.46g)。
NMR(CDCl3)δ1.26(3H,t),2.83(2H,q),7.34(1H,d),7.97(1H,dd),8.27(1H,dd)。
说明44
3-溴代-4-乙基-苯甲酸甲酯(D44)
将3-溴代-4-乙基-苯甲酸(D43)(19.40g)溶于MeOH(200mL)中,然后用浓H2SO4(1mL)处理。将混合物在回流下加热过夜,然后在减压下浓缩。将残余物分配在EtOAc和饱和NaHCO3水溶液之间,再用EtOAc萃取一次。然后用盐水洗涤合并的萃取液,干燥(MgSO4)。在真空中蒸发溶剂,得到标题化合物(15.8g)。1H NMR(CDCl3)δ1.24(3H,t),2.79(2H,q),3.91(3H,s),7.29(1H,d),7.89(1H,dd),8.19(1H,d)。
说明45
3-氰基-4-乙基-苯甲酸甲酯(D45)
将3-溴代-4-乙基-苯甲酸甲酯(D44)(5g)的NMP(180mL)溶液用氰化铜(I)(3.69)处理。然后将混合物在氩气氛、回流下加热5小时。冷却至20℃后,将反应混合物用水稀释,然后通过硅藻土过滤,用水和EtOAc很好地洗涤。用水、盐水洗涤有机层并经硫酸镁干燥。在真空中将溶剂蒸发至干并将残余物经用EtOAc-己烷(1∶9)洗脱的硅胶层析纯化,得到标题化合物(1.9g)。1H NMR(CDCl3)δ1.33(3H,t),2.94(2H,q),3.94(3H,s),7.43(1H,d),8.17(1H,dd),8.28(1H,d)。
说明46
3-氰基-4-乙基苯甲酸(D46)
将3-氰基-4-乙基-苯甲酸甲酯(D45)(1.92g)溶于MeOH(50mL)中,然后加入1M NaOH溶液(15.24mL)并将得到的混合物在室温、氩气氛下搅拌过夜。将反应混合物用水稀释,用EtOAc萃取。使用2M HCl使含水层酸化至pH1,然后用EtOAc萃取。用盐水洗涤合并的萃取液,经硫酸镁干燥,在真空中将溶剂蒸发至干,得到标题化合物(1.63g)。1H NMR(CDCl3)δ1.35(3H,t),2.97(2H,q),7.49(1H,d),8.24(1H,dd),8.36(1H,d)。
如下进行实施例的分析:
在Supelcosil LCABZ+PLUS柱(3.3cm×4.6mm ID)上进行LCMS。用0.1%甲酸和0.01M乙酸铵的水溶液(溶剂A)和0.05%甲酸和5%水的乙腈溶液(溶剂B)洗脱,随后用下列洗脱梯度、以0.0-7分钟0%B、0.7-4.2分钟100%B、4.2-5.3分钟0%B、5.3-5.5分钟0%B,以3mL/分的流速洗脱。使用电喷雾正性和负性方式(ES+ve和ES-ve),在Fisons VG Platform分光计上记录质谱。在包括具有延伸的泵头的Waters 600泵、Waters 2700自动进样器、Waters 996二极管列阵和在10cm×2.54cm ID ABZ+柱上的GiLson 202流分收集器的Waters FractionLynx系统上进行制备质谱导向的HPLC。用0.1%甲酸的水溶液(溶剂A)和0.1%甲酸的乙腈溶液(溶剂B)洗脱,使用合适的洗脱梯度,流速为20ml/分,在200-320nm、室温下检测。使用电喷雾正性和负性方式,交替扫描,在Micromass ZMD质谱分光计上记录质谱。所用的软件为具有OpenLynx和FractionLynx备选样机的MassLynx 3.5。
实施例1
1-苯基-1-{4-[4-(3-哌啶-1-基-丙氧基)-苄基]-哌嗪-1-基}-甲酮(E1)
将N-环己基碳二亚胺、N-甲基聚苯乙烯HL(200-400目)1.8mMol/g(650mg,1.172mmol)悬浮在二氯甲烷和二甲基甲酰胺(1∶1)的混合物中并用苯甲酸(72mg,0.58mmol)、1-羟基苯并三唑水合物(80mg,0.58mmol)顺序处理,在室温下搅拌10分钟。将1-[4-(3-哌啶-1-基-丙氧基)-苄基]-哌嗪三盐酸化物(D2)(125mg,0.29mmol)的二氯甲烷(1ml)溶液和三乙胺(0.13ml,0.87mmol)加入到该反应物中并在室温下搅拌16小时。过滤后,将滤液加入到Mega Bond elute SCX离子交换柱上,顺序用水和甲醇洗涤,随后用0.880氨水/甲醇(1∶10)洗脱粗制反应混合物。经硅胶层析纯化,用0.880氨水∶甲醇∶二氯甲烷(0.5∶4.5∶95)的混合物洗脱,得到标题产物(95mg,77%);MS(ES+)m/e422[M+H]+。
实施例2-11
使用与实施例1(E1)中所述类似的方法,用以下表中所示合适的酸代替苯甲酸,由说明2(D2)制备实施例2-11(E2-E11)。
实施例 | 酸 | 质谱 |
1-苯并[1,3]间二氧杂环戊烯-5-基-1-{4-[4-(3-哌啶-1-基-丙氧基)-苄基]-哌嗪-1-基}-甲酮(E2) | 胡椒基酸 | MS(ES+)m/e 466[M+H]+ |
1-萘-2-基-1-{4-[4-(3-哌啶-1-基-丙氧基)-苄基]-哌嗪-1-基}-甲酮(E3) | 2-萘甲酸 | MS(ES+)m/e 472[M+H]+ |
1-(3,5-二氯代-苯基)-1-{4-[4-(3-哌啶-1-基-丙氧基)-苄基]-哌嗪-1-基}-甲酮(E4) | 3,5-二氯代苯甲酸 | MS(ES+)m/e491/493[M+H]+ |
1-(4-溴代-3-甲基-苯基)-1-{4-[4-(3-哌啶-1-基-丙氧基)-苄基]-哌嗪-1-基}-甲酮(E5) | 3-甲基,4-溴代苯甲酸 | MS(ES+)m/e515/517[M+H]+ |
1-(2-甲氧基-苯基)-1-{4-[4-(3-哌啶-1-基-丙氧基)-苄基]-哌嗪-1-基}-甲酮(E6) | 2-甲氧基苯甲酸 | MS(ES+)m/e452[M+H]+ |
1-(3,4-二氯代-苯基)-1-{4-[4-(3-哌啶-1-基-丙氧基)-苄基]-哌嗪-1-基}-甲酮(E7) | 3,4-二氯代苯甲酸 | MS(ES+)m/e491/493/495[M+H]+ |
4-(1-{4-[4-(3-哌啶-1-基-丙氧基)-苄基]-哌嗪-1-基}-甲酰基)-苄腈(E8) | 4-氰基苯甲酸 | MS(ES+)m/e447[M+H]+ |
1-(4-氟代-苯基)-1-{4-[4-(3-哌啶-1-基-丙氧基)-苄基]-哌嗪-1-基}-甲酮(E9) | 4-氟代苯甲酸 | MS(ES+)m/e440[M+H]+ |
1-(4-溴代-苯基)-1-{4-[4-(3-哌啶-1-基-丙氧基)-苄基]-哌嗪-1-基}-甲酮(E10) | 4-溴代苯甲酸 | MS(ES+)m/e500/502[M+H]+ |
1-苯并呋喃-2-基-1-{4-[4-(3-哌啶-1-基-丙氧基)-苄基]-哌嗪-1-基}-甲酮(E11) | 2-苯并呋喃羧酸 | MS(ES+)m/e462[M+H]+ |
实施例12
1-苯并[1,3]间二氧杂环戊烯-5-基-1-{4-[4-(3-哌啶-1-基-丙氧基)-苄基]-[1,4]二吖庚烷-1-基}-甲酮(E12)
将1-[4-(3-哌啶-1-基-丙氧基)-苄基]-[1,4]二吖庚烷(D4)(100mg,0.30mmol)溶于二氯甲烷(5ml)中并顺序用苯并[1,3]间二氧杂环戊烯-5-羧酸(125mg,0.75mmol)、1,3-二环己基碳二亚胺(155mg,0.75mmol)和1-羟基苯并三唑水合物(101mg,0.75mmol)处理。将混合物在室温、氩气氛下搅拌12小时,用甲醇稀释并通过SCX离子交换柱(2g),用甲醇、随后用0.880氨水/甲醇(1∶9)洗脱。合并碱性部分并在真空中浓缩,得到标题化合物(127mg)。MS(ES+)m/e 480[M+H]+。
实施例13-15
使用与实施例12(E12)类似的方法,通过以下表中所示合适的酸代替苯并[1,3]间二氧杂环戊烯-5-羧酸,由说明4(D4)制备实施例13-15(E13-E15)。
实施例 | 羧酸 | 质谱 |
1-苯基-1-{4-[4-(3-哌啶-1-基-丙氧基)-苄基]-[1,4]二吖庚烷-1-基}-甲酮(E13) | 苯甲酸 | MS(ES+)m/e436[M+H]+。 |
1-萘-2-基-1-{4-[4-(3-哌啶-1-基-丙氧基)-苄基]-[1,4]二吖庚烷-1-基}-甲酮(E14) | 萘-2-羧酸 | MS(ES+)m/e486[M+H]+。 |
1-(3,5-二氯代-苯基)-1-{4-[4-(3-哌啶-1-基-丙氧基)-苄基]-[1,4]二吖庚烷-1-基}-甲酮(E15) | 3,5-二氯代-苯甲酸 | MS(ES+)m/e505[M+H]+。 |
实施例16-23
使用与实施例12(E12)类似的方法,通过以下表中所示合适的酸代替苯并[1,3]间二氧杂环戊烯-5-羧酸,由说明4(D4)制备实施例16-23(E16-E23),随后再经0.880氨水/甲醇/二氯甲烷(0.5∶4.5∶95)混合物洗脱的硅胶柱层析纯化。
实施例 | 羧酸 | 质谱 |
1-(4-溴代-3-甲基-苯基)-1-{4-[4-(3-哌啶-1-基-丙氧基)-苄基]-[1,4]二吖庚烷-1-基}-甲酮(E16) | 4-溴代-3-甲基-苯甲酸 | MS(ES+)m/e529[M+H]+。 |
1-(2-甲氧基-苯基)-1-{4-[4-(3-哌啶-1-基-丙氧基)-苄基]-[1,4]二吖庚烷-1-基}-甲酮(E17) | 2-甲氧基-苯甲酸 | MS(ES+)m/e466[M+H]+。 |
4-(1-{4-[4-(3-哌啶-1-基-丙氧基)-苄基]-[1,4]二吖庚烷-1-基}-甲酰基)-苄腈(E18) | 4-氰基-苯甲酸 | MS(ES+)m/e461[M+H]+。 |
1-(4-氟代-苯基)-1-{4-[4-(3-哌啶-1-基-丙氧基)-苄基]-[1,4]二吖庚烷-1-基}-甲酮(E19) | 4-氟代-苯甲酸 | MS(ES+)m/e454[M+H]+。 |
1-(4-溴代-苯基)-1-{4-[4-(3-哌啶-1-基-丙氧基)-苄基]-[1,4]二吖庚烷-1-基}-甲酮(E20) | 4-溴代-苯甲酸 | MS(ES+)m/e515[M+H]+。 |
1-苯并呋喃-2-基-1-{4-[4-(3-哌啶-1-基-丙氧基)-苄基]-[1,4]二吖庚烷-1-基}-甲酮(E21) | 苯并呋喃-2-羧酸 | MS(ES+)m/e476[M+H]+。 |
1-(3,4-二氯代-苯基)-1-{4-[4-(3-哌啶-1-基-丙氧基)-苄基]-[1,4]二吖庚烷-1-基}-甲酮(E22) | 3,4-二氯代-苯甲酸 | MS(ES+)m/e505[M+H]+。 |
1-环丙基-1-{4-[4-(3-哌啶-1-基-丙氧基)-苄基]-[1,4]二吖庚烷-1-基}-甲酮(E23) | 环丙烷羧酸 | MS(ES+)m/e400[M+H]+。 |
实施例24
1-环戊基-1-{4-[4-(3-哌啶-1-基-丙氧基)-苄基]-[1,4]二吖庚烷-1-基}-甲酮(E24)
将1-[4-(3-哌啶-1-基-丙氧基)-苄基]-[1,4]二吖庚烷(D4)(100mg,0.30mmol)溶于二氯甲烷(5ml)中,用环戊基酰氯(80mg,0.60mmol)、碳酸钾(83mg,0.60mmol)处理并在室温、氩气氛下搅拌12小时。用甲醇稀释反应混合物并通过SCX柱(2g),用甲醇、随后用氨水/甲醇(1∶9)洗脱。合并碱性部分并在真空中浓缩,得到标题化合物(56mg)。MS(ES+)m/e 428[M+H]+。
实施例25
1-苯磺酰基-4-[4-(3-哌啶-1-基-丙氧基)-苄基]-[1,4]二吖庚烷(E25)
将1-[4-(3-哌啶-1-基-丙氧基)-苄基]-[1,4]二吖庚烷(D4)(100mg,0.30mmol)溶于2-丁酮(5ml)中,用苯磺酰氯(57mg,0.32mmol)处理并在室温、氩气氛下搅拌2小时。用甲醇稀释反应混合物并通过SCX柱(2g),用甲醇、随后用氨水/甲醇(1∶9)洗脱。合并碱性部分并在真空中浓缩,得到标题化合物(91mg)。MS(ES+)m/e 472[M+H]+。
实施包例26-28
使用与实施例25(E25)类似的方法,通过以下表中所示的合适的磺酰氯代替苯磺酰氯,由说明4(D4)制备实施例26-28(E26-E28)。
实施例 | 磺酰氯 | 质谱 |
1-(萘-2-磺酰基)-4-[4-(3-哌啶-1-基-丙氧基)-苄基]-[1,4]二吖庚烷(E26) | 萘-2-磺酰氯 | MS(ES+)m/e522[M+H]+。 |
1-(4-氟代-苯磺酰基)-4-[4-(3-哌啶-1-基-丙氧基)-苄基]-[1,4]二吖庚烷(E27) | 4-氟代-苯磺酰氯 | MS(ES+)m/e490[M+H]+。 |
1-(4-溴代-苯磺酰基)-4-[4-(3-哌啶-1-基-丙氧基)-苄基]-[1,4]二吖庚烷(E28) | 4-溴代-苯磺酰氯 | MS(ES+)m/e552[M+H]+。 |
实施例29-31
使用与实施例25(E25)类似的方法,通过以下表中所示的合适的磺酰氯代替苯磺酰氯,随后再经0.880氨水/甲醇/二氯甲烷(0.5∶4.5∶95)混合物洗脱的硅胶柱层析纯化,由说明4(D4)制备实施例29-31(E29-E31)。
实施例 | 磺酰氯 | 质谱 |
1-(3,5-二氯代-苯磺酰基)-4-[4-(3-哌啶-1-基-丙氧基)-苄基]-[1,4]二吖庚烷(E29) | 3,5-二氯代-苯磺酰氯 | MS(ES+)m/e540[M+H]+。 |
1-(3,4-二氯代-苯磺酰基)-4-[4-(3-哌啶-1-基-丙氧基)-苄基]-[1,4]二吖庚烷(E30) | 3,4-二氯代-苯磺酰氯 | MS(ES+)m/e540[M+H]+。 |
4-{4-[4-(3-哌啶-1-基-丙氧基)-苄基]-[1,4]二吖庚烷-1-磺酰基}-苄腈(E31) | 4-氰基-苯磺酰氯 | MS(ES+)m/e497[M+H]+。 |
实施例32
1-苯基-1-{4-[4-(哌啶-4-基氧基)-苄基]-哌嗪-1-基}-甲酮(E32)
使用在说明4(D4)中所述的方法,由4-{4-[4-(1-苯基-甲酰基)-哌嗪-1-基甲基]-苯氧基}-哌啶-1-羧酸叔-丁基酯(D7)制备标题化合物(E32)。MS(ES+)m/e 380[M+H]+。
实施例33
1-{4-[4-(1-异丙基-哌啶-4-基氧基)-苄基]-哌嗪-1-基}-1-苯基-甲酮(E33)
使用在说明1(D1)中所述的方法,由1-苯基-1-{4-[4-(哌啶-4-基氧基)-苄基]-哌嗪-1-基}-甲酮(E32)制备标题化合物(E33)。MS(ES+)m/e422[M+H]+。
实施例34
1-(4-{4-[1-(2-甲氧基-乙基)-哌啶-4-基氧基]-苄基}-哌嗪-1-基)-1-苯基-甲酮(E34)
将1-苯基-1-{4-[4-(哌啶-4-基氧基)-苄基]-哌嗪-1-基}-甲酮(E32)(150mg,0.40mmol)溶于2-丁酮中并用1-氯代-2-甲氧基-乙烷(0.08ml,0.80mmol)、碳酸钾(132mg,0.96mmol)和碘化钾(159mg,0.96mmol)处理。将反应混合物在回流下加热24小时。将混合物冷却至室温,以加入冰乙酸使其酸化并通过用甲醇、随后通过氨水/甲醇(1∶9)洗脱的SCX离子交换柱(2g)。合并碱性部分并在真空中浓缩,得到标题化合物(76mg)。MS(ES+)m/e 438[M+H]+。
实施例35-37
根据以下通用合成方法制备实施例35-37(E35-37):
将合适的酰基氯(1.1当量)加入到1-[4-(3-哌啶-1-基丙氧基)-苯基]-哌嗪(D11)(100mg,0.33mM)和碳酸钾(55mg,1.5当量)的丁-2-酮(2ml)混合物中。将得到的混合物在室温下搅拌3小时,然后在SCX离子交换柱体上纯化,得到标题化合物。
实施例 | 酰基氯 | 质谱 |
1-环丙基-1-{4-[4-(3-哌啶-1-基丙氧基)-苯基]-哌嗪-1-基}-甲酮(E35) | 环丙烷碳酰氯 | MS(ES+)m/e372[M+H]+ |
1-苯基-1-{4-[4-(3-哌啶-1-基丙氧基)-苯基]-哌嗪-1-基}-甲酮(E36) | 苯甲酰氯 | MS(ES+)m/e408[M+H]+ |
1-(3,4-二氯代-苯基)-1-{4-[4-(3-哌啶-1-基-丙氧基)-苯基]-哌嗪-1-基}-甲酮(E37) | 3,4-二氯代苯甲酰氯 | MS(ES+)m/e477[M+H]+ |
实施例38-39
分别使用在实施例36和37中所述相同的方法,由1-[3-(3-哌啶-1-基-丙氧基)-苯基]哌嗪(D15)制备实施例38-39(E38-E38)。
实施例 | 质谱 |
1-苯基-1-{4-[3-(3-哌啶-1-基-丙氧基)-苯基]-哌嗪-1-基}-甲酮(E38) | MS(ES+)m/e 408[M+H]+ |
1-(3,4-二氯代-苯基)-1-{4-[3-(3-哌啶-1-基-丙氧基)-苯基]-哌嗪-1-基}-甲酮(E39) | MS(ES+)m/e 477[M+H]+ |
实施例40-42
根据以下通用合成法制备实施例40-42(E40-E42):
将合适的酰基氯(1.1当量)加入到1-[4-(3-哌啶-1-基丙氧基)-苯基]-哌嗪(D11)(100mg,0.33mM)和碳酸钾(55mg,1.5当量)的丁-2-酮(2ml)混合物中。将得到的混合物在室温下搅拌3小时,然后在SCX离子交换柱体上纯化,得到标题化合物。
实施例 | 磺酰氯 | 质谱 |
1-甲磺酰基-4-[4-(3-哌啶-1-基-丙氧基)-苯基]-哌嗪(E40) | 甲磺酰氯 | MS(ES+)m/e382[M+H]+ |
1-苯磺酰基-4-[4-(3-哌啶-1-基丙氧基)-苯基]-哌嗪(E41) | 苯磺酰氯 | MS(ES+)m/e444[M+H]+ |
1-(3,4-二氯代-苯磺酰基)-4-[4-(3-哌啶-1-基丙氧基)-苯基]-哌嗪(E42) | 3,4-二氯代苯磺酰氯 | MS(ES+)m/e513[M+H]+ |
实施例43-45
分别使用在实施例40、41和42中所述相同的方法,由1-[3-(3-哌啶-1-基-丙氧基)-苯基]哌嗪(D15)制备实施例43-45(E43-E45)。
实施例 | 质谱 |
1-甲磺酰基-4-[3-(3-哌啶-1-基-丙氧基)-苯基]哌嗪(E43) | MS(ES+)m/e382[M+H]+ |
1-苯磺酰基-4-[3-(3-哌啶-1-基-丙氧基)-苯基]哌嗪(E44) | MS(ES+)m/e444[M+H]+ |
1-(3,4-二氯代-苯磺酰基)-4-[3-(3-哌啶-1-基-丙氧基)-苯基]-哌嗪(E45) | MS(ES+)m/e513[M+H]+ |
实施例46-47
根据以下通用合成法制备实施例46-47(E46-E47):
将合适的异氰酸酯(1.1当量)加入到1-[4-(3-哌啶-1-基丙氧基)-苯基]-哌嗪(D11)(100mg,0.33mM)的丁-2-酮(2ml)溶液中。将得到的混合物在室温下搅拌3小时,然后在SCX离子交换柱体上纯化,得到标题化合物。
实施例 | 异氰酸酯 | 质谱 |
4-[4-(3-哌啶-1-基-丙氧基)-苯基]-哌嗪-1-羧酸苯基酰胺(E46) | 异氰酸根合苯 | MS(ES+)m/e423[M+H]+ |
4-[4-(3-哌啶-1-基-丙氧基)-苯基]-哌嗪-1-羧酸(3,4-二氯代-苯基)-酰胺(E47) | 3,4-二氯代异氰酸根合苯 | MS(ES+)m/e492[M+H]+ |
实施例48
4-[4-(3-哌啶-1-基丙氧基)-苯基]-哌嗪-1-羧酸环丙基酰胺(E48)
向1-[4-(3-哌啶-1-基丙氧基)-苯基]-哌嗪(D11)(150mg,0.49mM)的干燥二氯甲烷(3ml)溶液中滴加入20%的光气的甲苯溶液(0.5ml,大约2当量)并将得到的混合物搅拌1小时。经蒸发去除溶剂,将得到的白色粉未溶于干燥的二氯甲烷(4ml)中。加入三乙胺(0.14ml,2当量)随后加入环丙胺(0.1ml,3当量),将混合物搅拌18小时。在真空中蒸发去除溶剂并将残余物在用3%甲醇的二氯甲烷洗脱的硅胶柱上纯化,得到标题化合物为白色固体(155mg)。MS(ES+)m/e 387[M+H]+。
实施例49-50
分别使用在实施例46和47中所述相同的方法,由1-[3-(3-哌啶-1-基-丙氧基)-苯基]哌嗪(D15)制备实施例49-50(E49-E50)。
实施例 | 质谱 |
4-[3-(3-哌啶-1-基-丙氧基)-苯基]哌嗪-1-羧酸苯基酰胺(E49) | MS(ES+)m/e423[M+H]+ |
4-[3-(3-哌啶-1-基-丙氧基)-苯基]哌嗪-1-羧酸(3,4-二氯代-苯基)-酰胺(E50) | MS(ES+)m/e492[M+H]+ |
实施例51
1-(3,4-二氯代-苯基)-4-[4-(3-哌啶-1-基-丙氧基)-苯基]-哌嗪(E51)
将三(二亚苄基丙酮)二钯(0)(5mol%,23mg)加入到1-[4-(3-哌啶-1-基-丙氧基)-苯基]-哌嗪(D11)(150mg,0.49mmol)、3,4-二氯代溴苯(160mg,1.2当量)、叔-丁醇钠(71mg,1.1当量)和外消旋2,2’-二(二苯基膦)-1,1’-联苯(7.5mol%,24mg)的干燥甲苯(3ml)混合物中。将反应混合物在回流、氩气氛下加热18小时。将反应物冷却至室温并用乙酸乙酯(10ml)稀释。经过滤除去得到的固体并在真空中蒸发滤液。将残余物在3%甲醇的二氯甲烷洗脱的硅胶上层析纯化,得到标题化合物为米黄色固体(45mg)MS(ES+)m/e 448[M+H]+。
实施例52
1-(3,4-二氯代-苯基)-4-[3-(3-哌啶-1-基-丙氧基)-苯基]-哌嗪(E52)
使用与在实施例51(E51)中所述相同的方法,由1-[3-(3-哌啶-1-基-丙氧基)-苯基]-哌嗪(D15)制备标题化合物(E52)。
实施例53
5-氟代-1-甲基-3-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}-1H-吲哚(E53)
将5-氟代-1-甲基-1H-吲哚-3-羧酸[WO 0071537 A1](35mg)和1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(D11)(50mg)的二氯甲烷(1ml)溶液用苯并三唑-1-基氧基三吡咯烷基鏻六氟磷酸盐(94.4mg)处理并在微波炉(CEMTM Discover microwave)上、120℃下加热5分钟。将反应混合物在真空中浓缩并在甲醇-氨水溶液(10∶1)洗脱的SCX柱(2g)上纯化,随后经质谱导向的自动制备性HPLC纯化,得到标题化合物(12mg)。LCMS RT=2.49分钟,478(M+H)+。
实施例54-61
以与在E53中所述类似的方法,由D11和已知合适的酸制备以下化合物,而实施例57由D11和D17制备。
实施例62
(1-甲基-3-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}-1H-吲哚-2-基)乙酸(E62)
将(1-甲基-3-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}-1H-吲哚-2-基)乙酸乙酯(E60)(54mg)的甲醇(6ml)和水(0.8ml)中的溶液用2N氢氧化钠(0.46ml)处理并在回流下加热2小时。在室温下用盐酸(10ml)猝灭反应混合物。将反应混合物在真空中浓缩并分配在乙酸乙酯和水之间。干燥有机层并在真空中浓缩,得到标题化合物(20mg)。LCMS RT=2.35分,518(M+H)+。
实施例63
1-(1-萘甲酰基)-4-[4-(3-哌啶-1-基丙氧基)苯基]哌嗪三氟乙酸盐(E63)
E63a:4-[4-(1-萘甲酰基)哌嗪-1-基]苯酚
向搅拌的4-(1-哌嗪基)苯酚(5.54g)和三乙胺(10.83ml)的二氯甲烷(140ml)混合物中滴加入1-萘碳酰氯(9.83ml)。将得到的反应混合物在氮气氛下搅拌3小时。将混合物分配在二氯甲烷和水之间并用饱和盐水洗涤有机层,干燥(MgSO4)并蒸发至干燥。将残余物悬浮在6∶4四氢呋喃-甲醇(370ml)中并用碳酸钾的甲醇饱和溶液(45ml)处理。将混合物在室温、氮气氛下搅拌20小时。蒸发溶剂并将残余物分配在二氯甲烷和水之间。用饱和盐水洗涤有机层,干燥(MgSO4)并蒸发得到油状物(15.5g),将其中部分(14.5g)用10%-80%乙酸乙酯-环己烷梯度洗脱的硅胶SPE结合洗脱柱层析纯化,得到标题化合物(8.9g)。LCMS RT=2.97分钟。
E63b:1-[4-(3-氯代丙氧基)苯基]-4-(1-萘甲酰基)哌嗪
使用与在说明9中所述相同的方法,由4-[4-(1-萘甲酰基)哌嗪-1-基]苯酚(E63a)和1-溴代-3-氯丙烷制备。LCMS RT=3.59分钟。
E63c:1-(1-萘甲酰基)-4-[4-(3-哌啶-1-基丙氧基)苯基]哌嗪三氟乙酸盐
将1-[4-(3-氯代丙氧基)苯基]-4-(1-萘甲酰基)哌嗪(E63b)(27mg)、哌啶(0.033ml)、碳酸钾(46mg)、碘化钾(56mg)的2-丁酮(2ml)溶液加热至回流36小时。在室温下经氮气流动除去溶剂。将残余物溶于水和二氯甲烷中。分离有机层,浓缩并经质谱导向的制备性HPLC纯化,得到标题化合物(23mg)。LCMS RT=2.15分钟,ES+ve m/z 458(M+H)+。
实施例64-75
以阵列程序,使用在实施例63c中所述相同的方法,由1-[4-(3-氯代丙氧基)苯基]-4-(1-萘甲酰基)哌嗪(0.067mmol)、合适的仲胺(5.0当量)、碳酸钾(5.0当量)和碘化钾(5.0当量)的2-丁酮(2ml)溶液制备实施例64-75。将产物经质谱导向的自动制备性HPLC纯化,得到为TFA盐的化合物。
实施例76
5-氟代-1-甲基-3-[(4-{4-[3-(2-甲基哌啶-1-基)丙氧基]苯基}哌嗪-1-基)羰基]-1H-吲哚(E76)
E76a:4-(4-{[3-(2-甲基-1-哌啶基)丙基]氧基}苯基)-1-哌嗪羧酸1,1-二甲基乙基酯
将4-{4-[(3-氯代丙基)氧基]苯基}-1-哌嗪羧酸1,1-二甲基乙基酯(D9)(1.6g)溶于2-丁酮(10ml)中。加入碳酸钾(1.38g)和催化量的碘化钾,随后加入2-甲基哌啶(0.99g)。将混合物在回流、氮气氛下加热72小时。将反应混合物用水稀释并用二氯甲烷萃取。使用疏水玻璃料分离有机层,合并并在真空中蒸发。将残余物在0%-20%[0.880氨水-甲醇(1∶9)]-二氯甲烷混合物梯度洗脱的100g硅胶SPE结合洗脱柱上纯化,得到标题化合物(1.66g)。LCMS RT=2.48分钟。
E76b:1-(4-{[3-(2-甲基-1-哌啶基)丙基]氧基}苯基)哌嗪
将4-(4-{[3-(2-甲基-1-哌啶基)丙基]氧基}苯基)-1-哌嗪羧酸1,1-二甲基乙基酯(E76a)(1.66g)溶于干燥二氯甲烷(25ml)中并在氮气氛下搅拌。加入50%三氟乙酸的二氯甲烷(5ml),将该混合物在室温下搅拌4小时。然后加入饱和的碳酸氢钠溶液并将混合物用二氯甲烷萃取。使用疏水玻璃料分离有机层并在真空中蒸发,然而,大部分产物在含水层中。使用OASIS萃取柱将产物从含水层中移出,用水洗涤并用甲醇洗脱,再使用氨丙基粘合体洗脱柱进一步纯化,用二氯甲烷、然后用SCX萃取柱洗脱,用50%[0.880氨水-甲醇(1∶9)]-二氯甲烷洗脱,得到标题化合物(0.94g)。LCMS RT=1.10分钟,ES+ve m/z=318(M+H)+。
E76c:5-氟代-1-甲基-3-[(4-{4-[3-(2-甲基哌啶-1-基)丙氧基]苯基}哌嗪-1-基)羰基]-1H-吲哚
将5-氟代-1-甲基-1H-吲哚-3-羧酸(19.3mg)和O-(1H-苯并三唑-1-基)-N,N,N’,N’,-四甲基脲鎓四氟硼酸盐(TBTU)(56mg)的DMF(1ml)和二异丙基乙胺(0.035ml)溶液搅拌10分钟,然后加入1-{4-[3-(2-甲基哌啶-1-基)丙氧基]苯基}哌嗪(E76b)(21.3mg)的DMF(0.5ml)。将混合物搅拌18小时,然后在减压下浓缩。将残余物经在SCX-2柱(1g)上的SPE离子交换层析纯化。用甲醇(3ml)洗涤柱体并用2M氨水的甲醇溶液(2.5ml)洗脱产物,得到标题化合物(15mg)LCMS RT=2.42分钟,ES+ve m/z=493(M+H)+。
实施例77-224
以阵列程序,在管形瓶中使用合适羧酸(0.1mmol)的DMF(0.5ml)溶液和O-(1H-苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓四氟硼酸盐(TBTU)(0.15mmol)的DMF(0.5ml)和二异丙基乙胺(0.2mmol)溶液制备实施例77-224。在将合适的哌嗪(选自D18-D23或在实施例99中选自D46)(0.067mmol)的DMF(0.5ml)溶液加入到每一反应混合物中之前,将每一个管形瓶手动摇动并放置10分钟。在室温下将管形瓶放置过夜大约18小时。然后将每一种溶液加入到预稳定的SCX-2 SPE柱体(1g)中。将该柱体用甲醇(3ml)洗涤,用2M氨水的甲醇(2.5ml)溶液洗脱产物,放入预称重的管形瓶中。将溶液在genevac上蒸发至干燥得到产物(实施例77-222)。将实施例151、154、162-171和206-222经质谱导向的自动制备性HPLC再纯化,得到产物为三氟乙酸盐。
实施例225
1-[3-氯代-4-(3-哌啶-1-基丙氧基)苯基]-4-(1-萘甲酰基)哌嗪甲酸盐(E225)
E225a:4-(1-萘甲酰基)哌嗪-1-羧酸叔-丁基酯
在0℃下,将1-萘甲酰氯(2.15ml)加入到哌嗪-1-羧酸叔丁基酯(3.28g)和二异丙基乙胺(3.44ml)的二氯甲烷(100ml)溶液中。当混合物搅拌2小时后,将其分配在二氯甲烷和2M盐酸之间。用饱和碳酸氢钠水溶液洗涤有机层,干燥(MgSO4)并蒸发至干燥,得到标题化合物(4.9g)。LCMS RT=3.16分钟。
E225b:1-(1-萘甲酰基)哌嗪
在20℃下,将4-(1-萘甲酰基)哌嗪-1-羧酸叔-丁基酯(E225a)(4.2g)溶于二氯甲烷(80ml)并用三氟乙酸(10ml)处理4.5小时。在减压下除去溶剂并将残余物分配在二氯甲烷和2M氢氧化钠之间。干燥(MgSO4)有机层并蒸发至干燥,得到标题化合物(3.19g)LCMS RT=1.50分钟。
E225c:2-氯代-4-[4-(1-萘甲酰基)哌嗪-1-基]苯酚
将1-(1-萘甲酰基)哌嗪(E225b)(143.7mg)、4-溴代-2-氯代苯酚(207mg)、三(二亚苄基丙酮)二钯(4.75mg)、2-二环己基膦基-2’-(N,N-二甲基氨基)联苯(4.91mg)混合物溶于四氢呋喃(3ml)中,然后在0℃、氮气氛下用1M二(三甲基甲硅烷基)氨基化锂溶液(1.1ml)处理。将混合物在70℃下加热18小时,然后分配在水和二氯甲烷之间。使用疏水玻璃料分离有机层,用氨水溶液-甲醇-二氯甲烷(1∶2∶98)洗脱的硅胶SPE结合洗脱柱纯化,得到标题化合物(81mg)。LCMS RT=3.16分钟。
E225d:1-[3-氯代-4-(3-哌啶-1-基丙氧基)苯基]-4-(1-萘甲酰基)哌嗪甲酸盐
将2-氯代-4-[4-(1-萘甲酰基)哌嗪-1-基]苯酚(E225c)(37mg)、碳酸(81mg)、碘化钠(2.3mg)、1-(3-氯代丙基)哌啶(22mg)的DMF(2.5ml)溶液在微波炉中、160℃下加热10分钟并在170℃下加热20分钟。将反应混合物倒入水中并用乙酸乙酯萃取。用盐水洗涤有机层,干燥(MgSO4)并经质谱导向的自动制备性HPLC纯化,得到标题化合物(30mg)LCMS RT=2.60分钟,ES+ve m/z 492和494。
实施例226
1-(2-溴代-4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-(1-萘基羰基)哌嗪(E226)
E226a:4-(4-乙酰基哌嗪-1-基)-3-溴代苯基乙酸酯
将4-(4-乙酰基哌嗪-1-基)苯酚(38.5g)的二氯甲烷(875ml)溶液用三乙胺(35ml)处理并将该溶液在冰中冷冻。搅拌着、保持温度在18和20℃之间滴加入乙酰氯(15.05ml)的二氯甲烷(87ml)溶液。30分钟后,用水洗涤溶液,干燥并蒸发,得到4-(4-乙酰基哌嗪-1-基)苯基乙酸盐(44.2g)。将其一部分(31.4g)溶于乙酸(720ml)和乙酸钠(19.7g)中。将该溶液冷却至15℃,搅拌着用15分钟、保持温度在15℃下滴加入溴(6.2ml)的乙酸(72ml)溶液。30分钟后,加入焦亚硫酸钠水溶液(4.6g溶于60ml水中)并将混合物经蒸发浓缩至大约200ml。加入二氯甲烷(500ml),随后加入碳酸氢钠直至含水层的pH为5。将二氯甲烷层稀释(1L)并分离,用等体积的水洗涤,干燥,蒸发并用乙酸乙酯-己烷(3∶1)洗脱的Biotage(800g柱体)上纯化,得到标题化合物(34.8g)mp 75℃。
E226b:4-(4-乙酰基哌嗪-1-基)-3-溴代苯酚
将4-(4-乙酰基哌嗪-1-基)-3-溴代苯基乙酸酯(E226a)(29.5g)的甲醇(300ml)溶液在冰浴中冷却至15℃并用2N NaOH水溶液(87ml)滴加处理。30分钟后,将该溶液倒入冰水(1.7L)中并将混合物酸化至pH6。经过滤收集白色沉淀物并用水(0.5L)洗涤。在真空中干燥,得到标题化合物(22.8g),mp 212-4℃。
E226c:1-(2-溴代-4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪
将4-(4-乙酰基-1-哌嗪基)-3-溴代苯酚(E226b)(1g)的DMF(10ml)和氯代丙基哌啶盐酸盐(0.72g)、Cs2CO3(2.99g)和NaI(75mg)混合物在80℃下加热24小时。将该混合物冷却至室温并用水(10ml)猝灭,然后用乙酸乙酯萃取并蒸发。将残余物用5ml浓HCl和5ml水的混合物处理并加热至回流。将反应混合物冷却至20℃并用水(10ml)稀释,用碳酸钾碱化并用DCM萃取。将残余物在DCM-EtOH-NH3(45∶5∶1)洗脱的biotage(40g柱体)上层析纯化,得到标题化合物(0.86g)LCMSRT=1.68分钟,ES+ve m/z 382、384(M+H)+。
E226d:1-(2-溴代-4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-(1-萘基羰基)哌嗪
将1-(2-溴代-4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E226c)(0.86g)的无水DCM(10ml)和三乙胺(0.34ml)溶液冷却至0℃并加入萘甲酰氯(0.37ml)。将混合物在氮气氛下搅拌48小时,蒸发至干燥并分配在饱和碳酸氢钠溶液和DCM之间。分离有机层,浓缩并将残余物在DCM-MeOH-含水NH3(200∶8∶1)洗脱的biotage(40g柱体)上层析纯化,得到标题化合物(1.2g)。LCMS RT=2.71分钟,ES+ve m/z 536、538(M+H)+。
实施例227
1-(2-甲基-4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-(1-萘基羰基)哌嗪(E227)
将1-(2-溴代-4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-(1-萘基羰基)哌嗪(E226)(50mg)、四(三苯膦)钯(0)(10mg)、碳酸钾(38mg)和三甲基环硼氧烷(23mg)的DMF(1ml)溶液在150℃下的微波炉中加热10分钟,冷却,蒸发至干燥并在DCM-MeOH-含水NH3(200∶8∶1)洗脱的biotage柱体上层析纯化,得到标题化合物(21mg)。LCMS RT=2.63分钟,472(M+H)+。
实施例228
1-{[5-甲基-2-(甲氧基)苯基]甲基}-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-哌嗪甲酸盐(E228)
将5-甲基-2-(甲氧基)苯甲醛(40mg)和1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-哌嗪[D11](40mg)的二氯甲烷(2ml)溶液用乙酸(7.9μl)和三乙酰氧基硼氢化钠(56mg)处理。将得到的悬浮液在22℃下搅拌24小时。将反应混合物浓缩并经质谱导向的自动制备性HPLC纯化,得到标题化合物(4.8mg)。LCMS RT=1.99分钟,438(M+H)+。
实施例229
8-{4-[(3-{[3-(1-哌啶基)丙基]氧基}苯基)甲基]-1-哌嗪基}喹啉三氟乙酸盐(E229)
E229a:4-(8-喹啉基)-1-哌嗪羧酸1,1-二甲基乙基酯
将8-溴代喹啉(28.6mg)的干燥THF(1ml)溶液用1-哌嗪羧酸1,1-二甲基乙基酯(30.7mg)、三(二亚苄基丙酮)二钯(0)(1.5mg)和2-二环己基膦基-2’-(N,N-二甲基氨基)联苯(1.6mg)处理。将反应混合物用二(三甲基甲硅烷基)氨化锂(1M THF,0.27ml)处理,然后在75℃下加热4小时。将反应混合物冷却至室温并在真空中浓缩。将残余物经层析(硅胶SPE结合洗脱柱体)纯化,在环己烷和EtOAc之间梯度洗脱,得到标题化合物(29mg)。LCMS RT=2.86分钟。
E229b:8-(1-哌嗪基)喹啉
将4-(8-喹啉基)-1-哌嗪羧酸1,1-二甲基乙基酯(E229a)(2.5g)的DCM(60mL)溶液用TFA(20mL)处理并在室温下搅拌4小时,然后倒入DCM中,用饱和碳酸氢钠(Aq)洗涤。用水洗涤有机层,干燥(MgSO4)并在真空中浓缩。将残余物经层析(硅胶SPE柱体)纯化,在DCM和100∶10∶1DCM-MeOH-含水NH3梯度之间洗脱,得到标题化合物(643mg)。LCMS RT=0.68分钟。
E229c:3-{[4-(8-喹啉基)-1-哌嗪基]甲基}苯酚
将8-(1-哌嗪基)喹啉(E229b)(126mg)的干燥DCM(2mL)溶液用AcOH(500μL)处理。加入3-羟基苯甲醛(88mg)的干燥DCM(3mL)溶液,随后加入硼氢化钠(191mg)。将反应混合物搅拌16小时,然后加入水。将含水层用2N NaOH中和。用DCM萃取有机层两次并在真空中浓缩合并的有机层。将残余物经层析(硅胶SPE,用DCM和100∶10∶1DCM-MeOH-含水NH3梯度洗脱)纯化,得到标题化合物(133mg)。LCMS RT=1.96分钟。
E229d:8-{4-[(3-{[3-(1-哌啶基)丙基]氧基}苯基)甲基]-1-哌嗪基}喹啉三氟乙酸盐
将1-(3-氯代丙基)哌啶盐酸盐(46mg)的干燥DMF溶液用3-{[4-(8-喹啉基)-1-哌嗪基]甲基}苯酚(E229c)(43mg)的溶液处理。将得到的溶液用氢化钠(60%分散在油中,11mg)处理并在室温下搅拌16小时。将反应混合物用水(1滴)猝灭并分配在水和DCM之间。在真空中浓缩有机层。将残余物经质谱导向的自动制备性HPLC纯化,得到标题化合物(5.7mg)。LCMS RT=1.83分钟,ES+ve m/z 445(MH)+。
实施例230-236
以与E229d所述类似的方法,由已知的和以下表中所示的原料制备实施例230-236:
实施例237
8-{4-[2-(4-{[3-(1-哌啶基)丙基]氧基}苯基)乙基]-1-哌嗪基}喹啉三氟乙酸盐(E237)
E237a:8-[4-(2-{4-[(苯基甲基)氧基]苯基}乙基)-1-哌嗪基]喹啉
将8-(1-哌嗪基)喹啉(E229b)(126mg)的干燥DMF(2mL)溶液用二异丙基乙胺(176μL)处理,随后经1-(2-溴代乙基)-4-[(苯基甲基)氧基]苯(277mg)的干燥DMF(1mL)处理。将得到的反应混合物在氮气氛下搅拌18小时,然后用水猝灭。将反应混合物分配在水和DCM之间并干燥(MgSO4)有机层,在真空中浓缩。将残余物经硅胶SPE层析纯化,用DCM和100∶10∶1的DCM-MeOH-含水NH3之间梯度洗脱,得到标题化合物(51mg)。LCMS RT=2.54分钟。
E237b:4-{2-[4-(8-喹啉基)-1-哌嗪基]乙基}苯酚
将8-[4-(2-{4-[(苯基甲基)氧基]苯基}乙基)-1-哌嗪基]喹啉(E237a)(107mg)的干燥DCM(5mL)溶液冷却至-20℃并用三溴化硼(1M溶于DCM中,250μL)处理。将反应混合物在-20℃下搅拌30分钟并在室温下搅拌12小时。将反应混合物在真空中浓缩。将残余物在硅胶SPE上层析纯化,用DCM和100∶10∶1的DCM-MeOH-含水NH3之间的梯度洗脱,得到标题化合物(51mg)。LCMS RT=1.73分钟。
E237c:8-{4-[2-(4-{[3-(1-哌啶基)丙基]氧基}苯基)乙基]-1-哌嗪基}喹啉三氟乙酸盐
使用E228d中所述的方法制备。LCMS RT=2.32分钟,ES+vem/z 460[M+H]+。
实施例238-244
以与E229d类似的方法,由已知的和在下表中所示的原料制备实施例238-244:
实施例245
1-二苯基乙酰基-4-[4-(3-哌啶-1-基丙氧基)苯基]哌嗪(E245)
将二苯基乙酸(11mg,50μmol)的DMF(1ml)溶液用1-[4-(3-哌啶-1-基丙氧基)苯基]哌嗪(D11)(15mg)的DMF(1ml)溶液处理,随后用三乙胺(20μl)和HBTU(19mg)处理。将混合物摇动5分钟,然后在室温中放置过夜。加入聚苯乙烯-三甲醇氨基甲烷(100μmol)和聚苯乙烯-异氰酸盐(50μmol)并将混合物再摇动20小时。然后将混合物过滤并将滤液倒在固相阳离子交换(SCX)柱体上。用80%MeOH-DCM洗涤后,将产物用NH3的MeOH(0.5M)溶液洗脱。将洗脱部分在真空下浓缩至干燥,得到标题化合物(17.5mg)。LCMS RT=3.36分钟,ES+vem/z 498[M+H]+。
实施例246
1-(萘-1-基磺酰基)-4-[4-(3-哌啶-1-基丙氧基)苯基]哌嗪(E246)
将1-[4-(3-哌啶-1-基丙氧基)苯基]哌嗪(D11)(30mg)的DCM(3ml)溶液用萘-1-磺酰氯(27mg)的DCM(1ml)溶液处理。加入聚苯乙烯-甲基吗啉(200μmol)并将混合物在室温下摇动24小时。将混合物上样到SCX柱体上,然后用50%MeOH-DCM洗涤,将粗制产物用NH3的MeOH(0.5M)溶液洗脱。将洗脱部分在真空下浓缩至干燥并用快速硅胶层析,用5%MeOH-DCM洗脱,得到标题化合物(22mg)。LCMSRT=3.30分钟,ES+ve m/z 394[M+H]+。
实施例247
1-(9H-呫吨-9-基羰基)-4-[4-(3-哌啶-1-基丙氧基)苯基]哌嗪(E247)
将聚苯乙烯-碳二亚胺(450μmol)用9H-呫吨-9-羧酸(34mg)的DMF(2ml)溶液处理并摇动5分钟,然后用1-[4-(3-哌啶-1-基丙氧基)苯基]哌嗪(D11)(30mg)的DMF(1ml)溶液处理并在室温下摇动20小时。加入聚苯乙烯-异氰酸盐(100μmol)并将混合物再摇动24小时。然后将混合物过滤并将滤液倒在SCX柱体上。用80%MeOH-DCM洗涤后,将粗制产物用NH3的MeOH(0.5M)溶液洗脱。将洗脱部分在真空下浓缩至干燥并经快速硅胶层析纯化,用5-10%MeOH-DCM梯度洗脱,得到标题化合物(5.7mg)。LCMS RT=3.16分钟,ES+vem/z 512[M+H]+。
实施例248-251
根据实施例247的方法制备实施例248-251。
实施例252
1-(4-羧基-1-萘甲酰基)-4-[4-(3-哌啶-1-基丙氧基)苯基]哌嗪二(三氟乙酸盐)(E252)
将1,4-二萘甲酸(50mg)的DMF(2ml)溶液用1-[4-(3-哌啶-1-基丙氧基)苯基]哌嗪(D11)(70mg)的DCM(1.5ml)溶液处理,随后经HBTU(88mg)处理。将混合物摇动5分钟,然后在室温下摇动过夜。加入水(100μl),然后将混合物在真空下浓缩至干燥并用反相HPLC纯化,得到标题化合物(80mg)。LCMS RT=2.36分钟,ES+ve m/z 502[M+H]+。
实施例253
1-[4-(甲氧基羰基甲氧基)萘-1-甲酰基]-4-[4-(3-哌啶-1-基丙氧基)苯基]哌嗪(E253)
E253a:4-(甲氧基羰基甲氧基)萘-1-羧酸
在0℃下,向(4-甲酰基萘-1-基氧基)乙酸甲酯(J.Med.Chem.2002,45,5755)(2.35g)的叔-BuOH(10ml)、丙酮(10ml)和H2O(5ml)溶液中加入固体NaClO2(1.3g)和NaH2PO4·H2O(1.99g)并将混合物在室温、氮气氛下搅拌过夜。再加入溶于H2O(3ml)中的NaClO2(1.73g)和Na3PO4(2.66g)并使反应持续24小时。然后将混合物在真空中浓缩并用H2O处理。经过滤收集得到的沉淀物,用H2O洗涤并在真空中干燥,得到标题化合物(2.2g)。1H-NMRδ(DMSO-d6,400MHz)12.74(br,s,1H),8.97(d,1H),8.27(d,1H),8.13(d,1H),7.63(m,1H),7.58(m,1H),6.95(d,1H),5.07(s,2H),3.70(s,3H)。
E253b:1-[4-(甲氧基羰基甲氧基)萘-1-甲酰基]-4-[4-(3-哌啶-1-基丙氧基)苯基]哌嗪
根据用于实施例252的方法,由4-(甲氧基羰基甲氧基)萘-1-羧酸(E253a)(50mg)和1-[4-(3-哌啶-1-基丙氧基)苯基]哌嗪(D11)(58mg)制备标题化合物(76mg)。LCMS RT=2.79分钟, ES+ve m/z 545[M+H]+。
实施例254
1-[4-(羧基甲氧基)萘-1-甲酰基]-4-[4-(3-哌啶-1-基丙氧基)苯基]哌嗪(E254)
将搅拌着的1-[4-(甲氧基羰基甲氧基)萘-1-甲酰基]-4-[4-(3-哌啶-1-基丙氧基)苯基]哌嗪(E253b)(38mg)的THF(2ml)溶液用KOH(6mg)的H2O(1ml)溶液处理。1.5小时后将混合物用2M HCl的Et2O(50μl)溶液处理并在真空中浓缩至干燥。将残余物用EtOH处理,然后过滤并在真空中将滤液浓缩至干燥,得到标题化合物(29mg)。LCMS RT=2.42分钟,ES+ve m/z 532[M+H]+。
实施例255
1-[(4-氟代苯基)羰基]-4-(4-{[1-(1-甲基乙基)-4-哌啶基]氧基}苯基)哌嗪(E255)
步骤1:4-{4-[(4-氟代苯基)羰基]-1-哌嗪基}苯酚
将4-氟代苯甲酰氯(1.59ml,18.5mmol)的二氯甲烷(15ml)溶液加入到冰冷的4-(1-哌嗪基)苯酚(3g,16.8ml)和三乙胺(2.8ml,20.2mmol)的混合物中。将得到的混合物在室温下搅拌18小时。经蒸发除去溶剂并将残余物溶于甲醇(30ml)中。将其用碳酸钾(5g)处理30分钟并过滤。蒸发滤液并溶于乙酸乙酯中。用饱和碳酸氢钠溶液洗涤,干燥(硫酸钠)并蒸发,得到粉色固体(2.58g,51%)MS(ES+)m/e 301[M+H]+。
步骤2:4-[(4-{4-[(4-氟代苯基)羰基]-1-哌嗪基}苯基)氧基]-1-哌啶羧酸1,1-二甲基乙基酯
将偶氮二羧酸二-叔-丁基酯(2.4g,10.3mmol)加入到4-{4-[(4-氟代苯基)羰基]-1-哌嗪基}苯酚(2.57g,8.6mmol)、三苯膦(2.7g,10.3mmol)和4-羟基-1-哌啶羧酸1,1-二甲基乙基酯(2g,10.3mmol)的四氢呋喃(30ml)混合物中。将该混合物在室温下搅拌18小时。用乙酸乙酯稀释反应物并用2摩尔氢氧化钠溶液洗涤。干燥(硫酸钠)有机部分并蒸发。将残余物在用己烷∶乙酸乙酯(1∶1)混合物洗脱的硅胶柱上纯化,得到标题化合物(2.75g,67%)。MS(ES+)m/e 484[M+H]+。
步骤3:1-[(4-氟代苯基)羰基]-4-[4-(4-哌啶基氧基)苯基]哌嗪
将4-[(4-{4-[(4-氟代苯基)羰基]-1-哌嗪基}苯基)氧基]-1-哌啶羧酸1,1-二甲基乙基酯(2.75g,5.7mmol)的三氟乙酸(10ml)溶液在室温下搅拌30分钟。经蒸发除去溶剂并将残余物在SCX离子交换树脂上纯化,用甲醇、然后用0.88氨水∶甲醇(1∶9)混合物洗脱,得到标题化合物(2.1g,95%)。MS(ES+)m/e 384[M+H]+。
步骤4:1-[(4-氟代苯基)羰基]-4-(4-{[1-(1-甲基乙基)-4-哌啶基]氧基}苯基)哌嗪
将三乙酰氧基硼氢化钠(360mg,1.72mmol)加入到1-[(4-氟代苯基)羰基]-4-[4-(4-哌啶基氧基)苯基]哌嗪(330mg,0.86mmol)和丙酮(126μl,1.72mmol)的二氯甲烷(5ml)溶液中。在室温下搅拌18小时后,加入2摩尔氢氧化钠溶液并将混合物用乙酸乙酯萃取。干燥(硫酸钠)萃取液并蒸发。将残余物在硅胶柱上纯化,用甲醇∶0.88氨水∶甲醇∶二氯甲烷(0.5∶4.56∶95)的混合物洗脱,得到标题化合物(191mg,52%)。MS(ES+)m/e 426[M+H]+。
实施例256-259
以与实施例255相同的方法,使用下表所示合适的酮或醛制备
实施例256-259:
化合物 | 酮/醛 | MS(ES+)m/e[M+H]+ |
1-(4-{[1-(环丙基甲基)-4-哌啶基]氧基}苯基)-4-[(4-氟代苯基)羰基]哌嗪(E256) | 环丙烷甲醛 | 475 |
1-[(4-氟代苯基)羰基]-4-(4-{[1-(2-甲基丙基)-4-哌啶基]氧基}苯基)哌嗪(E257) | 2-甲基丙醛 | 440 |
1-{4-[(1-环戊基-4-哌啶基)氧基]苯基}-4-[(4-氟代苯基)羰基]哌嗪(E258) | 环戊酮 | 452 |
1-{4-[(1-环丁基-4-哌啶基)氧基]苯基}-4-[(4-氟代苯基)羰基]哌嗪(E259) | 环丁酮 | 438 |
实施例260
1-{4-[(1-环丙基-4-哌啶基)氧基]苯基}-4-[(4-氟代苯基)羰基]哌嗪(E260)
将{[1-(乙氧基)环丙基]氧基}(三甲基)硅烷(524μl,2.6mmol)加入到实施例255步骤3的产物(1-[(4-氟代苯基)羰基]-4-[4-(4-哌啶基氧基)苯基]哌嗪)(250mg,0.65mmol)和聚合物结合的氰基硼氢化物(4mmol/g的650mg树脂)的甲醇(10ml)和乙酸(250μl)搅拌的混合物中。将混合物在50℃下加热18小时。将混合物过滤并蒸发滤液。将残余物在硅胶柱上纯化,用0.88氨水∶甲醇∶二氯甲烷(0.5∶4.5∶95)的混合物洗脱,得到标题化合物(155mg,56%)。MS(ES+)m/e 424[M+H]+。
实施例261-262
以与实施例255步骤4所述类似的方法,由戊-3-酮和实施例255步骤3的产物制备实施例261-262。
实施例263
1-(4-{[1-(1-甲基乙基)-4-哌啶基]氧基}苯基)-4-(四氢-2H-吡喃-4-基羰基)哌嗪(E263)
步骤1:4-[(4-碘代苯基)氧基]-1-哌啶羧酸1,1-二甲基乙基酯
将偶氮二羧酸二-叔-丁基酯(5.9g,25.8mmol)加入到4-碘代苯酚(4.72g,21.5mmol)、三苯膦(6.8g,25.8mmol)和4-羟基-1-哌啶羧酸1,1-二甲基乙基酯(5.18g,25.8mmol)的四氢呋喃(100ml)混合物中。将混合物在室温下搅拌18小时。将反应物用乙酸乙酯稀释并用2摩尔氢氧化钠溶液洗涤。干燥(硫酸钠)有机部分并蒸发。将残余物在硅胶柱上纯化,用9-1己烷-乙酸乙酯洗脱,得到标题化合物(5.5g,64%)。MS(ES+)m/e 304[M+H]+-BOC。
步骤2:4-[(4-碘代苯基)氧基]哌啶
将步骤1的产物4-{(4-碘代苯基)氧基}-1-哌啶羧酸1,1-二甲基乙基酯(5.5g,13.6mmol)的三氟乙酸(10ml)溶液在室温下搅拌30分钟。经蒸发除去溶剂并将残余物用2M氢氧化钠溶液碱化。将其萃取到二氯甲烷中,干燥(硫酸钠)萃取液并蒸发,得到标题化合物(3.4g,82%)。MS(ES+)m/e 304[M+H]+。
步骤3:4-[(4-碘代苯基)氧基]-1-(1-甲基乙基)哌啶
将三乙酰氧基硼氢化钠(4.75mg,22.4mmol)加入到步骤2的产物(4-[(4-碘代苯基)氧基]哌啶)(3.4g,11.2mmol)和丙酮(1.65ml,22.4mmol)的二氯甲烷(70ml)溶液中。在室温下搅拌18小时后,加入2摩尔的氢氧化钠溶液并将混合物用乙酸乙酯萃取。干燥(硫酸钠)萃取液并蒸发,得到标题化合物(3.63mg,94%)。MS(ES+)m/e 346[M+H]+。
步骤4:4-(4-{[1-(1-甲基乙基)-4-哌啶基]氧基}苯基)-1-哌啶羧酸1,1-二甲基乙基酯
将乙酸钯(32mg,5mol%)和2,2’-二(二苯基膦基)-1,1-联萘(135mg,7.5mol%)的甲苯混合物在100℃下加热10分钟。加入步骤3的产物(4-[(4-碘代苯基)氧基]-1-(1-甲基乙基)哌啶)(1g,2.9mmol)和1-哌嗪羧酸1,1-二甲基乙基酯(647mg,3.5mmol)的甲苯(10ml)溶液,随后加入叔-丁醇钠(390mg,4.4mmol)。将混合物在100℃下加热3小时并通过硅藻土过滤。蒸发滤液并在硅胶上纯化,用0.88氨水溶液∶甲醇∶二氯甲烷(0.3∶2.7∶97)的混合物洗脱,得到标题化合物(770mg,66%)。MS(ES+)m/e 404[M+H]+。
步骤5:1-(4-{[1-(1-甲基乙基)-4-哌啶基]氧基}苯基)哌嗪
将步骤5的产物(4-(4-{[1-(1-甲基乙基)-4-哌啶基]氧基}苯基)-1-哌啶羧酸1,1-二甲基乙基酯)(750mg,1.86mmol)的三氟乙酸(4ml)溶液在室温下搅拌30分钟。经蒸发除去溶剂并将残余物在SCX离子交换树脂上纯化,用甲醇、然后用10%的0.88氨水溶液洗脱,得到标题化合物(514mg,91%)。MS(ES+)m/e 304[M+H]+。
步骤6:1-(4-{[1-(1-甲基乙基)-4-哌啶基]氧基}苯基)-4-(四氢-2H-吡喃-4-基羰基)哌嗪
将聚合物结合的环己基碳二亚胺(460mg 1.9mmol/g树脂)、四氢-2H-吡喃-4-羧酸(111mg,0.86mmol)和1H-1,2,3-苯并三唑-1-醇(116mg,0.86mmol)在二氯甲烷(10ml)中混合。20分钟后,加入步骤5的产物(1-(4-{[1-(1-甲基乙基)-4-哌啶基]氧基}苯基)哌啶)(128mg,0.46mmol),将混合物搅拌60分钟,将混合物蒸发并将残余物在硅胶上纯化,用0.88氨水溶液∶甲醇∶二氯甲烷(0.3∶2.7∶97)的混合物洗脱,得到标题化合物(134mg,75%)。MS(ES+)m/e 416[M+H]+。
实施例264-268
以与实施例263相同的方法,使用下表所示合适的酸制备实施例264-268:
化合物 | 酸 | MS(ES+)m/e[M+H]+。 |
4-{[4-(4-{[1-(1-甲基乙基)-4-哌啶基]氧基}苯基)-1-哌嗪基]羰基}苄腈(E264) | 4-氰基苯甲酸 | 433 |
1-(4-{[1-(1-甲基乙基)-4-哌啶基]氧基}苯基)-4-(4-吡啶基羰基)哌嗪(E265) | 哌啶-4-羧酸 | 409 |
1-(4-{[1-(1-甲基乙基)-4-哌啶基]氧基}苯基)-4-{[4-(甲基磺酰基)苯基]羰基}哌嗪(E266) | 4-(甲基磺酰基)苯甲酸 | 486 |
1-[(1,1-二氧代四氢-2H-噻喃-4-基)羰基]-4-(4-{[1-(1-甲基乙基)-4-哌啶基]氧基}苯基}哌嗪(E267) | 四氢-2H-噻喃-4-羧酸1,1-二氧化物 | 464 |
1-(4-{[1-(1-甲基乙基)-4-哌啶基]氧基}苯基)-4-{[4-(1-吡咯烷基羰基)苯基]羰基}哌嗪(E268) | 4-(1-吡咯烷基羰基)苯甲酸(J.Med.Chem.46(10),1845-1857,2003) | 505 |
实施例269
4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}吗啉(E269)
步骤1:4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪羰基氯盐酸盐
将1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(D11)(524mg,1.73mmol)的二氯甲烷(10ml)溶液滴加入到2M光气的甲苯(1.8ml)溶液中。将混合物在室温下搅拌60分钟并经蒸发除去溶剂,得到白色粉末(680mg),NMR(DMSO)δ1.4(2H,m),1.75(4H,m),2.2(2H,m),2.88(2H,m),3.1-3.9(12H,m),4.06(2H,m),6.89(2H,m),7.01(2H,m),9.97(H,m)。
步骤2:4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}吗啉
将吗啉(75μl,1.1mmol)加入到步骤1的产物(4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪羰基氯盐酸盐)(170mg,0.42mmol)和三乙胺(126μl,0.88mmol)的二氯甲烷(5ml)混合物中。60分钟后将混合物蒸发并在硅胶上纯化,用甲醇∶0.88氨水∶甲醇∶二氯甲烷(0.2∶2.8∶98)混合液洗脱,得到白色固体(141mg,81%)MS(ES+)m/e 417[M+H]+。
实施例270-282
以与实施例269相同的方法,使用下表中所示合适的胺制备实施例270-282。
化合物 | 胺 | MS(ES+)m/e[M+H]+ | |
1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-(1-吡咯烷基羰基)哌嗪(E270) | 吡咯烷 | 401 | |
1-(1-哌啶基羰基)-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E271) | 哌啶 | 415 | |
4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪甲酰胺(E272) | 氨水 | 347 | |
4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}硫代吗啉(E273) | 硫代吗啉 | 433 | |
4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}硫代吗啉1,1-二氧化物(E274) | 1,1-二氧化硫代吗啉 | 465 | |
4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-N-(四氢-2H-吡喃-4-基)-1-哌嗪甲酰胺(E275) | 四氢-2H-吡喃-4-胺 | 431 | |
1-{[(2R,6S)-2,6-二甲基-1-哌啶基]羰基}-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E276) | (2R,6S)-2,6-二甲基哌啶 | 443 | |
1-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}-4-哌啶甲酰胺(E277) | 4-哌啶甲酰胺 | 458 | |
1-{[(2R,5S)-2,5-二甲基-1-吡咯烷基]羰基}-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E278) | (2R,5S)-2,5-二甲基吡咯烷 | 429 | |
1-[(2-苯基-1-吡咯烷基)羰基]-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E279) | 2-苯基吡咯烷 | 477 | |
1-[(3-苯基-1-吡咯烷基)羰基]-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E280) | 3-苯基吡咯烷 | 477 | |
4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-N-6-喹啉基-1-哌嗪甲酰胺(E281) | 6-喹啉胺 | 474 | |
N-(4-氰基苯基)-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪甲酰胺(E282) | 4-氨基苄腈 | 448 |
实施例283
4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}-1-哌嗪羧酸1,1-二甲基乙基酯(E283)
将1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(D11)(1.8g,5.94mmol)的二氯甲烷(15ml)溶液加入到2M光气的甲苯(6ml)溶液中并搅拌60分钟。经蒸发除去溶剂并将残余物溶于二氯甲烷(30ml)中。加入三乙胺(1.7ml,11.9mmol),随后加入1-哌嗪羧酸1,1-二甲基乙基酯(1.2g,6.5mmol)并将混合物搅拌90分钟。经蒸发除去溶剂并将残余物在硅胶上纯化,用0.88氨溶液∶甲醇∶二氯甲烷(0.5∶4.5∶95)混合物洗脱,得到标题化合物(1.13g,37%)MS(ES+)m/e 516[M+H]+。
实施例284
1-(1-哌嗪基羰基)-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E284)
将4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}-1-哌嗪羧酸1,1-二甲基乙基酯(E283)(1.13g,2.19mmol)的三氟乙酸(5ml)和二氯甲烷(5ml)溶液在室温下搅拌90分钟。经蒸发除去溶剂并将残余物在SCX离子交换树脂上纯化,用甲醇,然后用0.88氨溶液∶甲醇(1∶9)混合物洗脱,得到标题化合物(854mg,94%)MS(ES+)m/e416[M+H]+。
实施例285
1-(2-甲基丙酰基)-4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}哌嗪(E285)
将2-甲基丙酰氯(30μl,1.2mmol)加入到搅拌着的1-(1-哌嗪基羰基)-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E284)(100mg,0.24mmol)的三乙胺(37μl,0.26mmol)的二氯甲烷(2ml)混合物中。将得到的混合物在室温下搅拌60分钟。蒸发并通过SCX离子交换树脂,用甲醇、然后用0.88氨溶液∶甲醇(1∶9)混合物洗脱。蒸发碱性部分并将残余物在硅胶上纯化,用0.88氨溶液∶甲醇∶二氯甲烷(0.5∶4.5∶95)混合物洗脱,得到标题化合物(50mg,43%)MS(ES+)m/e 486[M+H]+。
实施例286-291
以与实施例285相同的方法,使用合适的酰基氯制备实施例286-291:
化合物 | 酰基氯 | MS(ES+)m/e[M+H]+ |
1-(环丙基羰基)-4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}哌嗪(E286) | 环丙烷碳酰氯 | 484 |
1-(环丁基羰基)-4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}哌嗪(E287) | 环丁烷碳酰氯 | 497 |
1-(环戊基羰基)-4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}哌嗪(E288) | 环戊烷碳酰氯 | 512 |
1-(环己基羰基)-4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}哌嗪(E289) | 环己烷碳酰氯 | 526 |
1-[4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-{[4-(四氢-2H-吡喃-4-基羰基)-1-哌嗪基]羰基}哌嗪(E290) | 四氢-2H-吡喃-4-碳酰氯 | 528 |
1-[(4-氯代苯基)羰基]-4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}哌嗪(E291) | 4-氯代苯甲酰氯 | 555 |
实施例292
4-[(4-{4-[(1-环丁基-4-哌啶基)氧基]苯基}-1-哌嗪基)羰基]吗啉(E292)
步骤1:4-{4-[(1-{[(1,1-二甲基乙基)氧基]羰基}-4-哌啶基)氧基]苯基}-1-哌嗪羧酸苯基甲酯
将乙酸钯(300mg,5mol%)和2,2’-二(二苯基膦)-1,1’-联苯(1.3g,7.5mol%)的甲苯混合物在100℃下加热10分钟。加入实施例263、步骤1的产物(4-[(4-碘代苯基)氧基]-1-哌啶羧酸1,1-二甲基乙基酯)(13g,59.5mmol)的1-哌嗪羧酸苯基甲酯(20g,49.6mmol)的甲苯(120ml)溶液,随后加入叔-丁基醇钠(7.1g,64.5mmol)。将混合物在100℃下加热15分钟并通过硅藻土过滤。蒸发滤液并在硅胶上纯化,用己烷∶乙酸乙酯(2∶1)混合物洗脱,得到标题化合物(6.4g,26%)MS(ES+)m/e496[M+H]+。
步骤2:4-[4-(4-哌啶基氧基)苯基]-1-哌嗪羧酸苯基甲酯
将步骤1的产物(4-{4-[(1-{[(1,1-二甲基乙基)氧基]羰基}-4-哌啶基)氧基]苯基}-1-哌嗪羧酸苯基甲酯)(2g,4mmol)的三氟乙酸(5ml)和二氯甲烷(5ml)溶液在室温下搅拌45分钟。经蒸发除去溶剂并将残余物经SCX离子交换树脂纯化,用甲醇、然后用0.88氨溶液∶甲醇(1∶9)混合物、甲醇洗脱。然后将碱性部分在真空中还原,得到标题化合物(1.53mg,97%)MS(ES+)m/e 396[M+H]+。
步骤3:4-{4-[(1-环丁基-4-哌啶基)氧基]苯基}-1-哌嗪羧酸苯基甲酯
将三乙酰氧基硼氢化钠(1.64g,7.74mmol)加入到步骤2的产物(4-[4-(4-哌啶基氧基)苯基]-1-哌嗪羧酸苯基甲酯)(1.53g,3.87mmol)和环丁酮(578μl,7.74mmol)的二氯甲烷(15ml)溶液中。2小时后,加入甲醇并蒸发混合物。将残余物通过SCX离子交换树脂,用甲醇、然后用0.88氨溶液∶甲醇(1∶9)混合物洗脱。蒸发碱性部分并将残余物在硅胶上纯化,用0.88氨溶液∶甲醇∶二氯甲烷(0.5∶4.5∶95)混合物洗脱,得到标题化合物(1.35g,78%)MS(ES+)m/e 450[M+H]+。
步骤4:1-{4-[(1-环丁基-4-哌啶基)氧基]苯基}哌嗪
将4-{4-[(1-环丁基-4-哌啶基)氧基]苯基}-1-哌嗪羧酸苯基甲酯(1.35g,3mmol)的无水乙醇20ml溶液在室温下氢化并压入10%铍钯碳(500mg)的50%糊浆。18小时后,经过滤除去催化剂并蒸发滤液,得到标题化合物(889mg,94%)MS(ES+)m/e 316[M+H]+。
步骤5:4-[(4-{4-[(1-环丁基-4-哌啶基)氧基]苯基}-1-哌嗪基)羰基]吗啉
将4-吗啉碳酰氯(78mg,0.53mmool)加入到步骤4产物(1-{4-[(1-环丁基-4-哌啶基)氧基]苯基}哌嗪)(150mg,0.48mmol)和聚合物结合的二乙胺树脂(300mg,3.2mmol/g)的二氯甲烷(5ml)混合物中。2小时后,过滤混合物并蒸发滤液。将残余物在硅胶上纯化,用0.88氨溶液∶甲醇∶二氯甲烷(0.5∶4.5∶95)混合物洗脱,得到标题化合物(121mg,58%)MS(ES+)m/e 429[M+H]+。
实施例293
4-{[4-(4-{[1-(1-甲基乙基)-4-哌啶基]氧基}苯基)-1-哌嗪基]羰基}吗啉(E293)
将实施例263、步骤5的产物(1-(4-{[1-(1-甲基乙基)-4-哌啶基]氧基}苯基)哌嗪)(200mg,0.66mmol)的溶液加入到2M光气的甲苯(1.3ml)溶液中并将混合物搅拌30分钟。蒸发除去溶剂并将残余物溶于二氯甲烷(5ml)中。加入吗啉(75μl,1.1mmol),随后加入三乙胺(126μl,0.88mmol)。60分钟后,蒸发混合物并在硅胶上纯化,用0.88氨溶液∶甲醇∶二氯甲烷(0.3∶2.7∶97)混合物洗脱,得到标题化合物(177mg,65%)MS(ES+)m/e 417[M+H]+。
实施例294
1-(4-{[1-(1-甲基乙基)-4-哌啶基]氧基}苯基)-4-(1-哌啶基羰基)哌嗪(E294)
以与实施例293相同的方法,由哌啶制备实施例294。MS(ES+)m/e 415[M+H]+。
实施例295
1-[4-({[1-(1-甲基乙基)-4-哌啶基]甲基}氧基)苯基]-4-(苯基羰基)哌嗪(E295)
步骤1:4-(羟基甲基)-1-哌嗪羧酸1,1-二甲基乙基酯
将1-{[(1,1-二甲基乙基)氧基]羰基}-4-哌啶羧酸(2.0g,8.73mmol)溶于干燥的四氢呋喃(20ml)中,在冰浴中冷却并在氩气氛下用1M硼烷-四氢呋喃溶液(17.46ml,17.46mmol)处理。将混合物加热至室温并在氩气氛下搅拌4小时。加入甲醇(5ml)的四氢呋喃(10ml)溶液,随后加入甲醇(4ml)和水(2ml)。在真空中除去溶剂并将残余物溶于乙酸乙酯中,用饱和碳酸氢钠溶液洗涤(x2)。分离有机层,经硫酸镁干燥并在真空中蒸发,得到标题化合物(1.83g)。1H NMR(CDCl3)δ4.18-4.10(2H,m),3.51-3.50(2H,m),2.72-2.68(2H,m),1.75-1.69(2H,m),1.62(1H,m),1.46(9H,s),1.20-1.10(2H,m)。
步骤2:4-(碘代甲基)-1-哌啶羧酸1,1-二甲基乙基酯
将三苯膦(2.79g,10.6mmol)加入到碘(2.59g,10.2mmol)的甲苯(90ml)混合物中。5分钟后,加入吡啶(1.65ml,20.4mmol),随后加入步骤1的产物。将得到的混合物在回流下加热3小时。将冷的反应混合物过滤并用饱和硫代硫酸钠和盐水洗涤滤液,经硫酸镁干燥,过滤并在真空中浓缩。将残余物经硅胶层析,用乙酸乙酯∶己烷(1∶9)的混合物洗脱,得到标题化合物(1.83g)。1H NMR(CDCl3)δ4.18-4.10(2H,m),3.11-3.09(2H,d),2.72-2.65(2H,m),1.88-1.82(2H,m),1.62(1H,m),1.46(9H,s),1.20-1.11(2H,m)。
步骤3:4-[4-(苯基羰基)-1-哌嗪基]苯酚
将4-(1-哌嗪基)苯酚(4.0g,22.5mmol)溶于干燥二氯甲烷(50ml)中,用三乙胺(3.4ml,24.8mmol)和苯甲酰氯(2.6ml,22.5mmol)处理,在室温、氩气氛下搅拌2小时。在真空中除去溶剂并将残余物溶于乙酸乙酯中。用饱和碳酸氢钠溶液洗涤乙酸乙酯层,经硫酸镁干燥并在真空中蒸发。将粗制产物溶于甲醇中,用碳酸钾(2当量)处理并在室温下搅拌30分钟。将碳酸钾滤出并在真空中蒸发滤液。将残余物溶于乙酸乙酯中,用饱和碳酸氢钠溶液洗涤,经硫酸镁干燥并在真空中蒸发,得到标题化合物(5.27g)。MS(ES+)m/e 283[M+H]+。
步骤4:4-[({4-[4-(苯基羰基)-1-哌嗪基]苯基}氧基)甲基]-1-哌啶羧酸1,1-二甲基乙基酯
将步骤2的产物(1.83g,5.63mmol)、步骤3的产物(1.59g,5.63mmol)、碳酸钾(1.86g,13.5mmol)和碘化钾(2.24g,13.5mmol)一起加入到2-丁酮(70ml)中并将混合物在回流下加热24小时。将混合物冷却至室温,用硫代硫酸钠(1M,15ml)处理并用乙酸乙酯萃取。分离有机层,用水和盐水洗涤,经硫酸镁干燥并在真空中蒸发。经硅胶层析,用乙酸乙酯∶己烷(1∶1)混合物洗脱,得到标题化合物(0.30g)。MS(ES+)m/e 480[M+H]+。
步骤5:1-(苯基羰基)-4-{4-[(4-哌啶基甲基)氧基]苯基}哌嗪
将步骤4的产物(0.30g,0.63mmol)溶于二氯甲烷(3ml)中,用三氟乙酸(2ml)处理并在室温、氩气氛下搅拌2小时。在真空中除去溶剂并将残余物溶于甲醇中并通过SCX离子交换柱(5g),用甲醇、随后用0.880氨水∶甲醇(1∶9)混合物洗脱。合并碱性部分并在真空中浓缩,得到标题化合物(0.1g)MS(ES+)m/e 380[M+H]+。
步骤6:1-[4-({[1-(1-甲基乙基)-4-哌啶基]甲基}氧基)苯基]-4-(苯基羰基)哌嗪
将步骤5的产物(90mg,0.24mmol)的干燥二氯甲烷(4ml)溶液用丙酮(0.06ml,0.72mmol)和冰醋酸(1滴)处理并在室温下搅拌15分钟。加入三乙酰氧基硼氢化钠(152mg,0.72mmol)并将反应混合物在室温、氩气氛下搅拌36小时。用甲醇稀释反应混合物并通过SCX离子交换柱(5g),用甲醇、随后用0.880氨水∶甲醇(1∶9)混合物洗脱。合并碱性部分并在真空中浓缩,得到标题化合物(98mg)MS(ES+)m/e422[M+H]+。
实施例296
1-[4-({[(3S)-1-(甲基乙基)-3-哌啶基]甲基}氧基)苯基]-4-(苯基羰基)哌嗪(E296)
步骤1:(3S)-3-(羟基甲基)-1-哌啶羧酸1,1-二甲基乙基酯
使用实施例295步骤1的方法,由(3S)-1-{[(1,1-二甲基乙基)氧基]羰基}-3-哌啶羧酸制备标题化合物。1H NMR(CDCl3)δ3.99-3.58(3H,m),3.50(1H,m),3.22-2.95(1H,m),2.80-2.52(1H,m),1.87-1.52(3H,m),1.46(9H,s),1.32-1.12(1H,m),0.95-0.92(1H,q)。
步骤2:(3S)-3-(碘代甲基)-1-哌啶羧酸1,1-二甲基乙基酯
使用实施例295步骤2的方法,由步骤1的产物制备标题化合物。1H NMR(CDCl3)δ4.11-3.98(1H,m),3.87-3.82(1H,m),3.09-2.08(2H,d),2.85-2.78(2H,m),1.93-1.91(1H,m),1.66-1.62(2H,m),1.47(10H,s),1.30-1.22(1H,m)。
步骤3:(3S)-3-[({4-[4-(苯基羰基)-1-哌嗪基]苯基}氧基)甲基]-1-哌啶羧酸1,1-二甲基乙基酯
使用实施例295步骤4的方法,由步骤2的产物和实施例295步骤3的产物制备标题化合物。MS(ES+)m/e 480[M+H]+。
步骤4:1-(苯基羰基)-4-(4-{[(3S)-3-哌啶基甲基]氧基}苯基)哌嗪
使用实施例295步骤5的方法,由步骤3的产物制备标题化合物。MS(ES+)m/e 380[M+H]+。
步骤5:1-[4-({[(3S)-1-(1-甲基乙基)-3-哌啶基]甲基}氧基)苯基]-4-(苯基羰基)哌嗪
使用实施例295步骤6的方法,由步骤4的产物和丙酮制备标题化合物。MS(ES+)m/e 422[M+H]+。
实施例297-299
使用实施例295步骤6的方法,由实施例296步骤4的产物与下表所示合适的酮或醛制备以下实施例。
实施例 | 酮或醛 | MS(ES+)m/e[M+H]+ |
1-[4-({[(3S)-1-环戊基-3-哌啶基]甲基}氧基)苯基]-4-(苯基羰基)哌嗪(E297) | 环戊酮 | 448 |
1-[4-({[(3S)-1-(环丙基甲基)-3-哌啶基]甲基}氧基)苯基]-4-(苯基羰基)哌嗪(E298) | 环丙烷甲醛 | 434 |
1-[4-({[(3S)-1-乙基-3-哌啶基]甲基}氧基)苯基]-4-(苯基羰基)哌嗪(E299) | 乙醛 | 408 |
实施例300
1-[4-({[(3R)-1-(1-甲基乙基)-3-哌啶基]甲基}氧基)苯基]-4-(苯基羰基)哌嗪(E300)
步骤1:(3R)-3-(羟基甲基)-1-哌啶羧酸1,1-二甲基乙基酯
使用实施例295步骤1的方法,由(3R)-1-{[(1,1-二甲基乙基)氧基]羰基}-3-哌啶羧酸制备标题化合物。1H NMR(CDCl3)δ3.99-3.58(3H,m),3.50(1H,m),3.22-2.95(1H,m),2.80-2.52(1H,m),1.87-1.52(3H,m),1.46(9H,s),1.32-1.12(1H,m),0.95-0.92(1H,q)。
步骤2:(3R)-3-(碘代甲基)-1-哌啶羧酸1,1-二甲基乙基酯
使用实施例295步骤2的方法,由步骤1的产物制备标题化合物。1H NMR(CDCl3)δ4.11-3.98(1H,m),3.87-3.82(1H,m),3.09-2.08(2H,),2.85-2.78(2H,m),1.93-1.91(1H,m),1.66-1.62(2H,m),1.47(10H,s),1.30-1.22(1H,m)。
步骤3:(3R)-3-[({4-[4-(苯基羰基)-1-哌嗪基]苯基}氧基)甲基]-1-哌啶羧酸1,1-二甲基乙基酯
使用实施例295步骤4的方法,由步骤2和实施例295步骤3的产物制备标题化合物。MS(ES+)m/e 480[M+H]+。
步骤4:1-(苯基羰基)-4-(4-{[(3R)-3-哌啶基甲基]氧基}苯基)哌嗪
使用实施例295步骤5的方法,由步骤3的产物制备标题化合物。MS(ES+)m/e 380[M+H]+。
步骤5:1-[4-({[(3R)-1-(1-甲基乙基)-3-哌啶基]甲基}氧基)苯基]-4-(苯基羰基)哌嗪
使用实施例295步骤6的方法,由步骤4的产物和丙酮制备标题化合物。MS(ES+)m/e 422[M+H]+。
实施例301-302
使用实施例295步骤6的方法,使用下表所示合适的醛或酮,由实施例300步骤4的产物制备以下实施例。
实施例 | 酮或醛 | MS(ES+)m/e[M+H]+ |
1-[4-({[(3R)-1-环戊基-3-哌啶基]甲基}氧基)苯基]-4-(苯基羰基)哌嗪(E301) | 环戊酮 | 448 |
1-[4-({[(3R)-1-(环丙基甲基)-3-哌啶基]甲基}氧基)苯基]-4-(苯基羰基)哌嗪(E302) | 环丙烷甲醛 | 434 |
实施例303
4-({4-[4-({[(3S)-1-环戊基-3-哌啶基]甲基}氧基)苯基]-1-哌嗪基}羰基)苄腈(E303)
步骤1:4-{[4-(4-羟基苯基)-1-哌嗪基]羰基}苄腈
将4-氰基苯甲酸(6.2g,42.2mmol)、1,3-二环己基碳二亚胺(8.7g,42.2mmol)和1-羟基苯并三唑水合物(5.7g,42.2mmol)加入到4-(1-哌啶基)苯酚(5.0g,28.1mmol)的干燥二氯甲烷(50ml)悬浮液中。将混合物在室温下搅拌2小时,用二氯甲烷稀释并用饱和碳酸氢钠溶液洗涤。分离有机层,经硫酸镁干燥并在真空中蒸发。将残余物经柱层析纯化,用乙酸乙酯∶己烷(1∶1)混合物洗脱,得到标题化合物(2.2g)。MS(ES+)m/e 308[M+H]+。
步骤2:(3S)-3-{[(4-{4-[(4-氰基苯基)羰基]-1-哌嗪基}苯基)氧基]甲基}-1-哌啶羧酸1,1-二甲基乙基酯
使用实施例295步骤4的方法,由步骤1和实施例296步骤2的产物制备标题化合物。MS(ES+)m/e 505[M+H]+。
步骤3:4-{[4-(4-{[(3S)-3-哌啶基甲基]氧基}苯基)-1-哌嗪基]羰基}苄腈
使用实施例295步骤5的方法,由步骤2产物制备标题化合物。MS(ES+)m/e 405[M+H]+。
步骤4:4-({4-[4-({[(3S)-1-环戊基-3-哌啶基]甲基}氧基)苯基]-1-哌嗪基}羰基)苄腈
使用实施例295步骤6的方法,由步骤3产物和环戊酮制备标题化合物。MS(ES+)m/e 473[M+H]+。
实施例304
1-(苯基羰基)-4-(4-{[2-(1-哌啶基)乙基]氧基}苯基)哌嗪(E304)
步骤1:1-{4-[(2-溴代乙基)氧基]苯基}-4-(苯基羰基)哌嗪
将实施例295步骤3的产物(1.0g,3.55mmol)溶于2-丁酮(20ml)中,用1,2-二溴代乙烷(0.46ml,5.32mmol)和碳酸钾(0.73g,5.32mmol)处理,将得到的混合物在回流下加热18小时。将反应混合物冷却至室温,用水稀释,经加入含水的氢氧化钠溶液(2M)使其成碱性并用乙酸乙酯萃取。分离乙酸乙酯层,经硫酸镁干燥并在真空中蒸发。将残余物经硅胶层析纯化,用乙酸乙酯∶己烷(1∶1)混合物洗脱,得到标题化合物(0.40g)。MS(ES+)m/e 390[M+H]+。
步骤2:1-(苯基羰基)-4-(4-{[2-(1-哌啶基)乙基]氧基}苯基)哌嗪
使用实施例295步骤4的方法,由步骤1的产物和哌啶制备标题化合物。MS(ES+)m/e 394[M+H]+。
实施例305
4-({4-[4-{[3-(1-哌啶基)丙基]氧基}-2-(三氟甲基)苯基]-1-哌嗪基}羰基)苄腈(E305)
步骤1:4-溴代-3-(三氟甲基)苯酚
将3-(三氟甲基)苯酚(1.88ml,15.4mmol)溶于乙酸(4ml)中并通过滴加溴(2.7g,16.9mmol)处理。将得到的混合物在室温下搅拌2小时,倒入水(15ml)中并用二氯甲烷萃取(x3)。合并二氯甲烷层,用饱和碳酸氢钠溶液洗涤,经硫酸镁干燥并在真空中蒸发。将残余物经硅胶层析纯化,用己烷∶二氯甲烷的(1∶4)混合物洗脱,得到标题化合物(0.73g)。1H NMR(CDCl3)δ7.55-7.53(1H,d),7.19-7.18(1H,d),6.89-6.86(1H,dd),5.51(1H,s)。
步骤2:1-(3-{[4-溴代-3-(三氟甲基)苯基]氧基}丙基)哌啶
将步骤1的产物溶于2-丁酮(30ml)中,用1-(3-氯代丙基)哌啶盐酸盐(0.72g,3.63mmol)、碳酸钾(1.17g,8.48mmol)和碘化钠(0.15g,0.91mmol)处理并在回流下加热18小时。将混合物冷却至室温,用乙酸乙酯稀释并用水洗涤。分离有机层,经硫酸镁干燥并在真空中蒸发。将残余物经硅胶层析纯化,用0.880氨水∶甲醇∶二氯甲烷(0.5∶4.5∶95)混合物洗脱,得到标题化合物(0.76g)。MS(ES+)m/e 367[M+H]+。
步骤3:4-[4-{[3-(1-哌啶基)丙基]氧基}-2-(三氟甲基)苯基]-1-哌嗪羧酸1,1-二甲基乙基酯
将乙酸钯(23mg,0.10mmol)、外消旋-2,2’-二(二苯膦)-1,1’-联苯(97mg,0.16mmol)和干燥甲苯(4ml)上料到烘干的50ml圆底烧瓶中。将混合物在氩气氛、100℃下加热3分钟,得到暗红紫色的溶液。加入步骤2的产物(0.76g,2.08mmol)的甲苯(2ml)、1-哌嗪羧酸1,1-二甲基乙基酯(0.46g,2.49mmol)的甲苯(2ml)溶液和叔丁醇钠(0.30g,3.12mmol)并将混合物在100℃下加热5小时。将反应混合物冷却,用乙酸酸化并通过SCX离子交换柱(10g),用0.880氨水∶甲醇(1∶9)混合物洗脱。合并碱化部分并在真空中蒸发。将残余物经硅胶层析纯化,用0.880氨水/甲醇/二氯甲烷(0.7∶6.3∶93)纯化,得到标题化合物(0.49g)。MS(ES+)m/e 472[M+H]+。
步骤4:1-[4-{[3-(1-哌啶基)丙基]氧基}-2-(三氟甲基)苯基]哌嗪
使用实施例295步骤5的方法,由步骤3的产物制备标题化合物。MS(ES+)m/e 372[M+H]+。
步骤5:4-({4-[4-{[3-(1-哌啶基)丙基]氧基}-2-(三氟甲基)苯基]-1-哌嗪基}羰基)苄腈
将4-氰基苯甲酸(123mg,0.84mmol)、聚合物结合的1,3-二环己基碳二亚胺(1.9mmol/g,442mg,0.84mmol)和1-羟基苯并三唑水合物(113mg,0.84mmol)在干燥二氯甲烷(5ml)溶液中搅拌30分钟。加入步骤4的产物(154mg,0.42mmol)并将混合物在室温下搅拌2小时。将反应混合物用甲醇稀释并通过SCX离子交换柱(5g),用甲醇、随后用0.880氨水∶甲醇(1∶9)混合物洗脱。合并碱性部分并在真空中蒸发,得到标题化合物(0.199g)。MS(ES+)m/e 501[M+H]+。
实施例306
2-[4-(苯基羰基)-1-哌嗪基]-5-{[3-(1-哌啶基)丙基]氧基}苄腈(E306)
步骤1:2-溴代-5-羟基苄腈
将3-羟基苄腈(2.0g,16.8mmol)溶于乙腈(20ml)中并冷却至-20℃。加入四氟硼酸二乙基酯复合物(2.3ml,16.8mmol),随后加入N-溴丁二酰亚胺(3.0g,16.8mmol),将混合物加热至室温。将得到的混合物搅拌5小时,用含水硫酸氢钠溶液(38%,10ml)处理并用甲基2-甲基丙基醚萃取(x2)。合并有机层,用水(x2)和盐水洗涤,经硫酸镁干燥并在真空中蒸发。将残余物经硅胶层析纯化,用甲基2-甲基丙基醚/二氯甲烷(2∶98)混合物洗脱,得到标题化合物(1.58g)。MS(ES+)m/e 197[M-H]+。
步骤2:2-溴代-5-{[3-(1-哌啶基)丙基]氧基}苄腈
使用实施例305步骤2的方法,由步骤1的产物和1-(3-氯代丙基)哌啶盐酸盐制备标题化合物。MS(ES+)m/e 324[M+H]+。
步骤3:4-(2-氰基-4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪羧酸1,1-二甲基乙基酯
使用实施例305步骤3的方法,由步骤2的产物和1-哌啶羧酸1,1-二甲基乙基酯制备标题化合物。MS(ES+)m/e 429[M+H]+。
步骤4:2-(1-哌嗪基)-5-{[3-(1-哌啶基)丙基]氧基}苄腈
使用实施例295步骤5的方法,由步骤3的产物制备标题化合物。MS(ES+)m/e 329[M+H]+。
步骤5:2-[4-(苯基羰基)-1-哌嗪基]-5-{[3-(1-哌啶基)丙基]氧基}苄腈
使用实施例305步骤5的方法,由步骤4的产物和苯甲酸制备标题化合物。MS(ES+)m/e 433[M+H]+。
实施例307-309
使用实施例305步骤5的方法,由实施例306步骤4的产物和下表中所示合适的羧酸制备标题化合物。
实施例 | 羧酸 | MS(ES+)m/e[M+H]+ |
2-{4-[(4-氰基苯基)羰基]-1-哌嗪基}-5-{[3-(1-哌啶基)丙基]氧基}苄腈(E307) | 4-氰基苯甲酸 | 458 |
2-{4-[(4-氟代苯基)羰基]-1-哌嗪基}-5-{[3-(1-哌啶基)丙基]氧基}苄腈(E308) | 4-氟代苯甲酸 | 451 |
5-{[3-(1-哌啶基)丙基]氧基}-2-(4-{[4-(1-吡咯烷基羰基)苯基]羰基}-1-哌嗪基)苄腈(E309) | 4-(1-吡咯烷基羰基)苯甲酸(J.Med.Chem.46(10),1845-1857,2003) | 530 |
实施例310
1-(2-氟代-4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-(苯基羰基)哌嗪(E310)
步骤1:1-{3-[(4-溴代-3-氟代苯基)氧基]丙基}哌啶
使用实施例305步骤2的方法,由4-溴代-3-氟代苯酚和1-(3-氯代丙基)哌啶盐酸盐制备标题化合物。MS(ES+)m/e 317[M+H]+。
步骤2:4-(2-氟代-4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪羧酸1,1-二甲基乙基酯
使用实施例305步骤3的方法,由步骤1的产物和1-哌嗪羧酸1,1-二甲基乙基酯制备标题化合物。MS(ES+)m/e 422[M+H]+。
步骤3:1-(2-氟代-4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪
使用实施例295步骤5的方法,由步骤2的产物制备标题化合物。MS(ES+)m/e 322[M+H]+。
步骤4:1-(2-氟代-4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-(苯基羰基)哌嗪
使用实施例305步骤5的方法,由步骤3的产物和苯甲酸制备标题化合物。MS(ES+)m/e 426[M+H]+。
实施例311-313
使用实施例305步骤5的方法,由实施例310步骤3的产物和下表中所示合适的羧酸制备标题化合物。
实施例 | 羧酸 | MS(ES+)m/e[M+H]+ |
4-{[4-(2-氟代-4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}苄腈(E311) | 4-氰基苯甲酸 | 451 |
1-[(4-氟代苯基)羰基]-4-(2-氟代-4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E12) | 4-氟代苯甲酸 | 444 |
1-(2-氟代-4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-{[4-(1-吡咯烷基羰基)苯基]羰基}哌嗪(E313) | 4-(1-吡咯烷基羰基)苯甲酸(J.Med.hem.46(10),1845-1857,2003) | 523 |
实施例314
4-{[4-(2-氟代-4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}吗啉(E314)
将实施例310步骤3的产物(150mg,0.47mmol)溶于干燥的二氯甲烷(5ml)中,用二乙基氨基甲基聚苯乙烯(3.2mmol/g,294mg,0.94mmol)和吗啉碳酰氯(0.11ml,0.94mmol)处理,在室温、氩气氛下搅拌1小时。将反应混合物用甲醇稀释并通过SCX离子交换柱(5g),用甲醇、随后用0.880氨水∶甲醇(1∶9)混合物洗脱。合并碱性部分并在真空中蒸发。将残余物经柱层析纯化,用0.880氨水∶甲醇∶二氯甲烷(0.5∶4.5∶95)混合物洗脱,得到标题化合物(84mg)。MS(ES+)m/e 435[M+H]+。
实施例315
4-{[4-(2-氟代-4-{[1-(1-甲基乙基)-4-哌啶基]氧基}苯基)-1-哌嗪基]羰基}吗啉(E315)
步骤1:4-[(4-溴代-3-氟代苯基)氧基]-1-哌啶羧酸1,1-二甲基乙基酯
将4-溴代-3-氟代苯酚(5.0g,26.2mmol)溶于干燥的四氢呋喃(100ml)中并用4-羟基-1-哌啶羧酸1,1-二甲基乙基酯(6.3g,31.4mmol)、三苯膦(8.2g,31.4mmol)和偶氮二羧酸二-叔-丁基酯(7.2g,31.4mmol)处理。在室温、氩气氛下将得到的混合物搅拌18小时并在真空中除去溶剂。将残余物用乙酸乙酯/己烷(1∶9)混合物研磨,过滤白色固体并将滤液经硅胶层析纯化,用乙酸乙酸∶己烷(1∶9)洗脱,得到标题化合物(4.67g)。MS(ES+)m/e 375[M+H]+。
步骤2:4-[(4-溴代-3-氟代苯基)氧基]哌啶
将步骤1的产物(4.67g,12.5mmol)溶于干燥的二氯甲烷(30ml)中,用三氟乙酸(20ml)处理并在室温下搅拌2小时。在真空中除去溶剂并经加入含水氢氧化钠溶液(2M)使残余物呈碱性。将得到的混合物用二氯甲烷萃取(x2)。合并有机层,用盐水洗涤,经硫酸镁干燥并在真空中浓缩。将残余物柱层析纯化,用0.880氨水∶甲醇∶二氯甲烷(1∶9∶90)洗脱,得到标题化合物(2.13g)。MS(ES+)m/e 275[M+H]+。
步骤3:4-[(4-溴代-3-氟代苯基)氧基]-1-(1-甲基乙基)哌啶
将步骤2的产物(2.13g,7.77mmol)溶于干燥的二氯甲烷(20ml)中,用丙酮(0.86ml,11.7mmol)和乙酸(2滴)处理并在室温下搅拌15分钟。加入三乙酰氧基硼氢化钠(2.48g,11.7mmol)并将混合物在室温、氩气氛下搅拌18小时。将得到的混合物用二氯甲烷稀释并用饱和碳酸氢钠溶液和盐水洗涤。经硫酸镁干燥有机层并在真空中浓缩,得到标题化合物MS(ES+)m/e 317[M+H]+。
步骤4:4-(2-氟代-4-{[1-(1-甲基乙基)-4-哌啶基]氧基}苯基)-1-哌嗪羧酸1,1-二甲基乙基酯
使用实施例305步骤3的方法,由步骤3的产物和1-哌嗪羧酸1,1-二甲基乙基酯制备标题化合物。MS(ES+)m/e 422[M+H]+。
步骤5:1-(2-氟代-4-{[1-(1-甲基乙基)-4-哌啶基]氧基}苯基)哌嗪
使用实施例295步骤5的方法,由步骤4的产物制备标题化合物。MS(ES+)m/e 322[M+H]+。
步骤6:4-{[4-(2-氟代-4-{[1-(1-甲基乙基)-4-哌啶基]氧基}苯基)-1-哌嗪基]羰基}吗啉
使用实施例314的方法,由步骤5的产物和吗啉碳酰氯制备标题化合物。MS(ES+)m/e 435[M+H]+。
实施例316
4-{[2R,6S]-2,6-二甲基-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}苄腈(E316)
步骤1:1-{3-[(4-碘代苯基)氧基]丙基}哌啶
将1-(3-氯代丙基)哌啶盐酸盐(9.9g,50.0mmol)、碳酸钾(17.6g,127.4mmol)和碘化钾(1.1g,6.8mmol)加入到4-碘代苯酚(10g,45.5mmol)的二甲基甲酰胺(150ml)溶液中,将得到的反应混合物在90℃下加热18小时。将混合物冷却至室温,倒在水/冰(500ml)中并搅拌10分钟。将固体过滤并用冰水洗涤,得到标题化合物(13.5g)。MS(ES+)m/e 346 [M+H]+。
步骤2:(3R,5S)-3,5-二甲基-1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪
使用实施例305步骤3的方法,由步骤1的产物和(2R,6S)-2,6-二甲基哌嗪制备标题化合物。MS(ES+)m/e 332[M+H]+。
步骤3:4-{[(2R,6S)-2,6-二甲基-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}苄腈
将步骤2的产物(249mg,0.75mmol)溶于干燥二氯甲烷(5ml)中,用三乙胺(0.21ml,1.50mmol)和4-氰基苯甲酰氯(248mg,1.50mmol)处理,将得到的混合物在室温、氩气氛下搅拌2小时。加入甲醇并将混合物通过SCX离子交换柱(5g),用甲醇、随后用0.880氨水∶甲醇(1∶9)混合物洗脱。合并碱性部分并在真空中蒸发。将残余物经硅胶层析纯化,用氨水∶甲醇∶二氯甲烷(0.5∶4.5∶95)混合物洗脱,得到标题化合物(158mg)。MS(ES+)m/e 461[M+H]+。
实施例317
(2R,6S)-2,6-二甲基-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-(4-吡啶基羰基)哌嗪(E317)
将4-吡啶羧酸(116mg,0.94mmol)溶于干燥二氯甲烷(5ml)中,用草酰氯(0.08ml,0.96mmol)和二甲基甲酰胺(1滴)处理并在氩气氛、室温下搅拌2小时。在真空中除去溶剂并将残余物与甲苯共沸。将残余物再溶于干燥二氯甲烷(5ml)中,并用实施例316步骤2的产物(156mg,0.47mmol)和三乙胺(0.13ml,0.94mmol)处理。将得到的混合物在氩气氛、室温下搅拌1.5小时,用甲醇稀释并通过SCX离子交换柱(5g),用甲醇、随后用0.880氨水∶甲醇(1∶9)混合物洗脱。合并碱性部分并在真空中蒸发。将残余物经硅胶层析纯化,用氨水∶甲醇∶二氯甲烷(0.7∶6.3∶93)洗脱,得到标题化合物(110mg)。MS(ES+)m/e 437[M+H]+。
实施例318
4-{[(2S)-2-甲基-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}苄腈(E318)
步骤1:(3S)-3-甲基-1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪
使用实施例305步骤3的方法,由实施例316步骤1的产物和(2S)-2-甲基哌嗪制备标题化合物。MS(ES+)m/e 318[M+H]+。
步骤2:4-{[(2S)-2-甲基-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}苄腈
使用实施例305步骤5的方法,由步骤1的产物和4-氰基苯甲酸制备标题化合物。MS(ES+)m/e 447[M+H]+。
实施例319-324
使用实施例305步骤5的方法,由实施例318步骤1的产物与下表中所示合适的羧酸制备以下化合物。
实施例 | 羧酸 | MS(ES+)m/e[M+H]+ |
(2S)-2-甲基-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-{[4-(1-吡咯烷基羰基)苯基]羰基}哌嗪(E319) | 4-(1-吡咯烷基羰基)苯甲酸(J.Med.Chem.46(10)1845-1857,2003) | 519 |
(2S)-2-甲基-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-(4-吡啶基羰基)哌嗪(E320) | 4-吡啶羧酸 | 423 |
(2S)-1-[(4-氟代苯基)羰基]-2-甲基-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E321) | 4-氟代苯甲酸 | 440 |
(2S)-2-甲基-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-(四氢-2H-吡喃-4-基羰基)哌嗪(E322) | 四氢-2H-吡喃-4-羧酸 | 430 |
(2S)-2-甲基-1-{[4-(甲基磺酰基)苯基]羰基}-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E323) | 4-(甲基磺酰基)苯甲酸 | 500 |
1-(4-{[(2S)-2-甲基-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}苯基)乙酮(E324) | 4-乙酰基苯甲酸 | 464 |
实施例325
4-{[(3R)-3-甲基-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}苄腈(E325)
步骤1:(3R)-3-甲基-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪羧酸1,1-二甲基乙基酯
使用实施例305步骤3的方法,由实施例316步骤1的产物和(3R)-3-甲基-1-哌嗪羧酸1,1-二甲基乙基酯制备标题化合物。MS(ES+)m/e 418[M+H]+。
步骤2:(2R)-2-甲基-1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪
使用实施例295步骤5的方法,由步骤1的产物制备标题化合物。MS(ES+)m/e 318[M+H]+。
步骤3:4-{[(3R)-3-甲基-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}苄腈
使用实施例305步骤5的方法,由步骤2的产物和4-氰基苯甲酸制备标题化合物。MS(ES+)m/e 447[M+H]+。
实施例326-329
使用实施例305步骤5的方法,由实施例325步骤2的产物与下表中所示合适的羧酸制备以下化合物。
实施例 | 羧酸 | MS(ES+)m/e[M+H]+ |
(2R)-2-甲基-1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-{[4-(1-吡咯烷基羰基)苯基]羰基}哌嗪(E326) | 4-(1-吡咯烷基羰基)苯甲酸(J.Med.Chem.46(10)1845-1857,2003) | 519 |
(2R)-2-甲基-1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-(4-吡啶基羰基)哌嗪(E327) | 4-吡啶羧酸 | 423 |
(2R)-4-[(4-氟代苯基)羰基]-2-甲基-1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E328) | 4-氟代羧酸 | 440 |
(2R)-2-甲基-1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-(四氢-2H-吡喃-4-基羰基)哌嗪(E329) | 四氢-2H-吡喃-4-羧酸 | 430 |
实施例330
1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-{[4-(三氟甲基)苯基]羰基}哌嗪(E330)
将4-(三氟甲基)苯基[4-(三氟甲基)苯基]羰基甲酸酯(358g,1mmol)加入到搅拌着的1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-哌嗪(D11)(150mg,0.5mmol)的二氯甲烷(20ml)溶液中。3小时后,将混合物通过SCX离子交换柱,用甲醇、然后用0.880氨水∶甲醇(1∶9)混合物洗脱。将合并的碱性部分蒸发并将残余物在硅胶上纯化,用0.88氨溶液∶甲醇∶二氯甲烷(0.5∶4.5∶95)混合物洗脱,得到标题化合物(204mg,87%)。MS(ES+)m/e 476[M+H]+。
实施例331
1-(环己基羰基)-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E331)
将环己烷碳酰氯(79mg,0.55mmol)加入到1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-哌嗪(D11)(150mg,0.5mmol)和三乙胺(100μl,0.75mmol)的二氯甲烷(5ml)溶液中。5小时后,经蒸发除去溶剂并将残余物在硅胶上纯化,用0.88氨溶液∶甲醇∶二氯甲烷(0.5∶4.5∶95)混合物洗脱,得到标题化合物(150mg,89%)。MS(ES+)m/e 414[M+H]+。
实施例332-342
使用实施例331的方法,由1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-哌嗪(D11)与下表中所示合适的酰基氯制备E332-E342。
化合物 | 酰基氯 | MS(ES+)m/e[M+H]+ |
1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-(2-噻吩基羰基)哌嗪(E332) | 2-噻吩碳酰氯 | 414 |
3-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}苄腈(E333) | 4-氰基苯甲酰氯 | 433 |
1-{[4-(甲氧基)苯基]羰基}-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E334) | 4-(甲氧基)苯甲酰氯 | 438 |
1-(1,3-苯并间二氧杂环戊烯-5-基羰基)-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E335) | 1,3-苯并间二氧杂环戊烯-5-碳酰氯 | 452 |
1-{[3,5-二(三氟甲基)苯基]羰基}-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E336) | 3,5-二(三氟甲基)苯甲酰氯 | 544 |
1-[(3,5-二氯代苯基)羰基]-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E337) | 3,5-二氯代苯甲酰氯 | 477 |
1-[(4-溴代苯基)羰基]-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E338) | 4-溴代苯甲酰氯 | 486 |
1-[(3-溴代苯基)羰基]-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E339) | 3-溴代苯甲酰氯 | 486 |
1-[(2,6-二氯代苯基)羰基]-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E340) | 2,6-二氯代苯甲酰氯 | 477 |
1-(2-萘基羰基)-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E341) | 2-萘碳酰氯 | 458 |
1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-(3-吡啶基羰基)哌嗪(E343) | 2-吡啶基碳酰氯 | 409 |
实施例343
1-[(4-氯代苯基)羰基]-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E343)
将4-氯代苯甲酸(192mg,1.23mmol)用N,N’-二环己基碳二亚胺(0.25g,1.23mmol)和1-羟基苯并三唑水合物(165mg,1.23mmol)的二氯甲烷(5ml)溶液处理,2小时后,加入1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(D11)(150mg,0.5mmol)并连续搅拌18小时。经蒸发除去溶剂并将残余物在硅胶上纯化,用0.88氨溶液∶甲醇∶二氯甲烷(0.5∶4.5∶95)混合物洗脱,得到标题化合物(198mg,91%)。MS(ES+)m/e442[M+H]+。
实施例344-374
使用实施例343的方法,由1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(D11)与下表中所示合适的羧酸制备E344-E374。
化合物 | 酸 | MS(ES+)m/e[M+H]+ |
1-[(4-氟代苯基)羰基]-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E344) | 4-氟代苯甲酸 | 426 |
1-(4-联苯基羰基)-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E345) | 4-联苯羧酸 | 484 |
1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-(四氢-2H-吡喃-4-基羰基)哌嗪(E346) | 四氢-2H-吡喃-4-羧酸 | 416 |
1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-(2-吡啶基羰基)哌嗪(E347) | 2-吡啶羧酸 | 409 |
1-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}异喹啉(E348) | 1-异喹啉羧酸 | 459 |
2-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}喹啉(E349) | 2-喹啉羧酸 | 459 |
6-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}喹啉(E350) | 6-喹啉羧酸 | 459 |
1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-(4-吡啶基羰基)哌嗪(E351) | 4-吡啶羧酸 | 409 |
5-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}嘧啶(E352) | 5-嘧啶羧酸 | 410 |
1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-(3-噻吩基羰基)哌嗪(E353) | 3-噻吩羧酸 | 414 |
4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}苯甲酸甲酯(E354) | 4-[(甲氧基)羰基]苯甲酸 | 466 |
3-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}苯甲酸甲酯(E355) | 3-[(甲氧基)羰基]苯甲酸 | 466 |
1-(环丙基乙酰基)-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E356) | 环丙基乙酸 | 386 |
1-{[4-氟代-2-(三氟甲基)苯基]羰基}-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E357) | 4-氟代-2-(三氟代甲基)苯甲酸 | 494 |
1-[(4-溴代-2-甲基苯基)羰基]-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E358) | 4-溴代-2-甲基苯甲酸 | 501 |
1-[(4-氯代-3-氟代苯基)羰基]-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E359) | 4-氯代-3-氟代苯甲酸 | 460 |
1-{[4-(甲基磺酰基)苯基]羰基}-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E360) | 4-(甲基磺酰基)苯甲酸 | 486 |
1-{[2-氯代-4-(甲基磺酰基)苯基]羰基}-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E361) | 2-氯代-4-(甲基磺酰基)苯甲酸 | 521 |
1-[(2,4-二氟代苯基)羰基]-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E362) | 2,4-二氟代苯甲酸 | 444 |
1-(3-甲基丁酰基)-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E363) | 3-甲基丁酸 | 388 |
1-[(2,4-二氯代苯基)羰基]-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E364) | 2,4-二氯代苯甲酸 | 477 |
1-[(4-氯代-2-氟代苯基)羰基]-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E365) | 4-氯代-2-氟代苯甲酸 | 461 |
1-[(4-氟代-3-甲基苯基)羰基]-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E366) | 4-氟代-3-甲基苯甲酸 | 440 |
1-[(4-溴代-2-氟代苯基)羰基]-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E367) | 4-溴代-2-氟代苯甲酸 | 505 |
1-[(3,4-二氟代苯基)羰基]-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E368) | 3,4-二氟代苯甲基 | 444 |
1-[(4-氯代-3-甲基苯基)羰基]-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E369) | 4-氯代-3-甲基苯甲酸 | 457 |
1-[(4-溴代-3-甲基苯基)羰基]-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E370) | 4-溴代-3-甲基苯甲酸 | 501 |
1-[(2-溴代-4-氟代苯基)羰基]-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E371) | 2-溴代-4-氟代苯甲酸 | 505 |
N,N-二甲基-3-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}苯胺(E372) | 3-(二甲基氨基)苯甲酸 | 451 |
N,N-二甲基-4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}苯胺(E373) | 4-(二甲基氨基)苯甲酸 | 451 |
1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-{[4-(1-吡咯烷基羰基)苯基]羰基}哌嗪(E374) | 4-(1-吡咯烷基羰基)苯甲酸(Journal of.Medicinal Chemistry(2003)46(10),1845-1857) | 505 |
实施例375
8-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}喹啉(E375)
将8-喹啉羧酸(U.S.Pat.Appl.Publ.20020045225,18Apr2002)(173mg,1mmol)、聚合物结合的N-环己基碳二亚胺、N-甲基聚苯乙烯HL(200-400目)(1.9mmol/g树脂的526mg)和1-羟基苯并三唑水合物(135mg,1mmol)的二氯甲烷(5ml)混合物在室温下搅拌30分钟。加入1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-哌嗪(D11)(150mg,0.5mmol)并持续搅拌18小时。经蒸发除去溶剂并将残余物在硅胶上纯化,用0.88氨溶液∶甲醇∶二氯甲烷(0.5∶4.5∶95)混合物洗脱,得到标题化合物(93mg,41%)。MS(ES+)m/e 459[M+H]+。
实施例376-431
使用实施例375的方法,由1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(D11)与下表中所示合适的羧酸制备E376-E431。
化合物 | 酸 | MS(ES+)m/e[M+H]+ |
1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-(3-吡啶基乙酰基)哌嗪(E377) | 3-吡啶基乙酸 | 423 |
6-甲基-4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}-2(1H)-吡啶酮(E378) | 6-甲基-2-氧代-1,2-二氢-4-吡啶羧酸 | 439 |
1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-(1H-四唑-1-基乙酰基)哌嗪(E379) | 2H-四唑-2-基乙酸 | 414 |
1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-{[4-(1H-吡咯-1-基)苯基]羰基}哌嗪(E380) | 4-(1H-吡咯-1-基)苯甲酸 | 473 |
1-乙酰基-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E381) | 乙酸 | 346 |
1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-(1H-1,2,3-三唑-1-基乙酰基)哌嗪(E382) | 4-(1H-1,2,3-三唑-1-基)苯甲酸 | 413 |
1-{2-氧代-2-[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]乙基}-2(1H)-吡啶酮(E383) | (2-氧代-1(2H)-哌啶基)乙酸(Tetrahedron Letters(1998),39(34),6167-6170) | 439 |
6-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}喹喔啉(E384) | 6-喹喔啉羧酸 | 460 |
5-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}喹喔啉(E385) | 5-喹喔啉羧酸 | 460 |
1-(4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}苯基)乙酮(E386) | 4-乙酰基苯甲酸 | 450 |
1-[(甲基磺酰基)乙酰基]-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E387) | (甲基磺酰基)乙酸 | 424 |
1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-(1,3-噻唑-5-基羰基)哌嗪(E388) | 1,3-噻唑-5-羧酸(IzvestiyaAkademii Nauk SSSR,Seriya Khimicheskayk,(1),132-6;1976) | 415 |
1-(5-异噻唑基乙酰基)-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E389) | 5-异噻唑基乙酸(Journal ofMedicinal Chemisty(1967),11(1),70-3) | 429 |
3-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}-1,2-苯并异噁唑(E390) | 1,2-苯并异噁唑-3-羧酸 | 449 |
1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-{[3-(1-吡咯烷基羰基)苯基]羰基}哌嗪(E391) | 3-(1-吡咯烷基羰基)苯甲酸(WO 0304468) | 505 |
2-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}喹喔啉(E392) | 2-喹喔啉羧酸(OrganicProcess Research &Development,6(4),477-481;2002) | 460 |
4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}喹啉(E393) | 4-喹啉羧酸 | 459 |
4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}噌啉(E394) | 6-氰基-3-吡啶羧酸(J.Am.Chem.Soc.68,1310-13;1946) | 434 |
3-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}吡唑并[1,5-a]嘧啶(E395) | 吡唑并[1,5-a]吡嗪-3-羧酸 | 449 |
1-[(2-氯代-6-甲基-4-吡啶基)羰基]-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E396) | 2-氯代-6-甲基-4-吡啶羧酸 | 458 |
1-[(1-甲基-1H-1,2,3-三唑-4-基)羰基]-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E397) | 1-甲基-1H-1,2,3-三唑-4-羧酸(Jouranl of OrganicChemisty(1976),41(6),1041-51) | 413 | |
2-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}-1,8-二氮杂萘(E398) | 1,8-二氮杂萘-2-羧酸 | 460 | |
5-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}-1H-吲哚(E399) | 1H-吲哚-5-羧酸 | 447 | |
2-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}吡嗪(E400) | 4-嘧啶羧酸 | 410 | |
3-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}吡唑并[1,5-a]吡啶(E401) | 吡唑并[1,5-a]吡啶-3-羧酸 | 448 | |
1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-{[4-(1H-四唑-1-基)苯基]羰基}哌嗪(E402) | 4-(1H-四唑-1-基)苯甲酸 | 476 | |
1-(1-苯并呋喃-2-基羰基)-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E403) | 苯并呋喃-2-羧酸 | 448 | |
1-(3-异噁唑基羰基)-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E404) | 3-异噁唑羧酸 | 399 | |
5-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}-2,1,3-苯并噁二唑(E405) | 2,1,3-苯并噁二唑-5-羧酸 | 450 | |
1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-(3-噻吩基乙酰基)哌嗪(E406) | 3-噻吩乙酸 | 428 | |
1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-(1,2,3-噻二唑-4-基羰基)哌嗪(E407) | 1,2,3-噻二唑-4-羧酸 | 416 | |
4-{2-氧代-2-[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]乙基}苄腈(E408) | 4-氰基苯乙酸(WO0247762) | 447 | |
1-(2,3-二氢-1-苯并呋喃-7-基羰基)-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E409) | 2,3-二氢苯并呋喃-7-羧酸 | 450 | |
1-[(1,1-二氧代四氢-2H-噻喃-4-基)羰 | 1,1-二氧代六氢-1λ6-噻喃- | 464 |
基]-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E410) | 4-羧酸 | ||
1-(4-{2-氧代-2-[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]乙基}苯基)乙酮(E411) | 4-乙酰基苯基乙酸(Chemical Communications,2001,(20),2147-2148) | 464 | |
1-{[3,5-二(甲氧基)苯基]羰基}4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E412) | 3,5-二甲氧基苯甲酸 | 468 | |
1-(2-甲基-2-苯基丙酰基)-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E413) | 2-甲基-2-苯基丙酸 | 450 | |
1-[(4-甲基-1,2,3-噻二唑-5-基)羰基]-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E414) | 4-甲基-1,2,3-噻二唑-5-羧酸 | 430 | |
1-(5-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}-2-噻吩基)乙酮(E415) | 5-乙酰基噻吩-2-羧酸 | 456 | |
4-{3-氧代-3-[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]丙基}苄腈(E416) | 4-氰基苯丙酸(US5726159) | 461 | |
3-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}-1,2-苯并异噻唑(E417) | 1,2-苯并异噻唑-3-羧酸 | 465 | |
(4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}-1,3-噻唑-2-基)乙腈(E418) | 2-氰甲基-噻唑-4-羧酸(Bioorganic and MedicinalChemistry Letters,12;4;2002,561-566) | 454 | |
3-{2-氧代-2-[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]乙基}苄腈(E419) | 3-氰基苯乙酸(WO0351797)447 | 447 | |
(4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}苯基)乙腈(E420) | 4-(氰甲基)苯甲酸 | 447 | |
1-(3,4-二氢-2H-苯并吡喃-6-基羰基)-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E421) | 2H-1-苯并吡喃-6-羧酸,3,4-二氢-(Journal ofHeterocyclic Chemistry1994 31(2)457-79) | 464 | |
6-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯 | 苯并噻唑-6-羧酸 | 465 |
基)-1-哌嗪基]羰基}-1,3-苯并噻唑(E422) | ||
3,5-二氟代-4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}苄腈(E423) | 4-氰基-2,6-二氟代-苯甲酸(US 5914319) | 469 |
1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-[(2,4,6-三氟代苯基)羰基]哌嗪(E424) | 2,4,6-三氟代苯甲酸 | 462 |
1-[3-(甲氧基)丙酰基]-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E425) | 3-甲氧基丙酸 | 390 |
1-[3-(2-呋喃基)丙酰基]-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E426) | 3-(2-呋喃基)丙酸 | 426 |
1-[(甲氧基)乙酰基]-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E427) | 甲氧基乙酸 | 376 |
1-[(3,5-二甲基-1H-1,2,4-三唑-1-基)乙酰基]-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E428) | (3,5-二甲基-1H-1,2,4-三唑-1-基)乙酸 | 441 |
1-[(3,5-二甲基-4-异噁唑基)羰基]-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E429) | 3,5-二甲基异噁唑-4-羧酸 | 427 |
1-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-(四氢-2H-噻喃-4-基羰基)哌嗪(E430) | 四氢噻喃-4-羧酸(Helvetica.Chimica.Acta.1997,80(5)1528-1554) | 432 |
1-[(1-氧代四氢-2H-噻喃-4-基)羰基]-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E431) | 2H-噻喃-4-羧酸,四氢-,1-氧化物(Arkiv foer Kemi(1966),26(6),73-7) | 448 |
实施例432
4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}苯甲酸甲酯(E432)
将4-氯代羰基苯甲酸甲酯(3.6g,18.12mM)加入到1-[4-(3-哌啶基-1-基-丙氧基)-苯基]哌嗪(D11)(5g,16.48mmol)和三乙胺(2.53ml,18.12mM)的二氯甲烷(25ml)溶液中,并在室温下搅拌16小时。将碳酸氢钠饱和水溶液(25ml)加入到反应物中并搅拌1小时。分离有机层,用水洗涤,经无水硫酸钠干燥并在真空中蒸发,得到标题化合物(7.46g);MS(ES+)m/e 466[M+H]+。
实施例433
4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}苯甲酸(E433)
向4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}苯甲酸甲酯(E432)(6.45g,13.86mM)的甲醇∶水(5∶1)(90ml)混合物中加入氢氧化锂(365mg,15.24mM)并将反应物在室温下搅拌3天。加入乙酸(3.17ml,55.44mM)并将反应物再搅拌10分钟。在真空中蒸发溶剂并将得到的残余物溶于甲醇/二氯甲烷(1∶10)(20ml)混合物中并使用硅胶层析纯化,用0.880氨水∶甲醇∶二氯甲烷(2∶18∶80)混合物洗脱,得到标题化合物(6.21g);MS(ES+)m/e 452[M+H]+。
实施例434
1-{[4-(1-哌嗪基羰基)苯基]羰基}-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E434)
步骤1:4-[(4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}苯基)羰基]-1-哌嗪羧酸1,1-二甲基乙基酯
将N-环己基碳二亚胺、N-甲基聚苯乙烯HL(200-400目)1.9mmol/g(530mg,1mM)悬浮在二氯甲烷(10ml)中并连续用4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}苯甲酸(E433)(225mg,1mM)、1-羟基苯并三唑水合物(135mg,1mM)和1-哌嗪羧酸叔-丁基酯(93mg,0.5mM)处理,在室温下搅拌16小时。过滤后,将滤液上样到Mega Bond洗脱SCX离子交换柱上,顺序用水和甲醇、随后用0.880氨水∶甲醇(1∶10)洗涤以洗脱粗制反应混合物。经硅胶层析纯化,用0.880氨水∶甲醇∶二氯甲烷(0.5∶4.5∶95)洗脱,得到标题化合物(162mg);MS(ES+)m/e 620[M+H]+。
步骤2:1-{[4-(1-哌嗪基羰基)苯基]羰基}-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪
使用在D11所述方法,由步骤1的产物(162mg,0.26mM)制备标题化合物;MS(ES+)m/e 520[M+H]+。
实施例435-445
使用在实施例434步骤1中所述方法,由4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}苯甲酸(E433)与下表中所示合适的胺制备E435-E445。
化合物 | 胺 | MS(ES+)m/e[M+H]+ | |
1-{[4-(1-哌啶基羰基)苯基]羰基}-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E435) | 哌啶 | 519 | |
4-[(4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}苯基)羰基]吗啉(E436) | 吗啉 | 521 | |
4-[(4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}苯基)羰基]硫代吗啉(E437) | 硫代吗啉 | 537 | |
1-({4-[(4-甲基-1-哌啶基)羰基]苯基}羰基)-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E438) | 4-甲基哌啶 | 533 | |
N,N-二乙基-4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}苯甲酰胺(E439) | 二乙胺 | 507 | |
N,N-二甲基-4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}苯甲酰胺(E440) | 二甲基胺2M四氢呋喃溶液 | 479 | |
N-环戊基-4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}苯甲酰胺(E441) | 环戊基胺 | 519 | |
1-{[4-(1-氮杂环丁烷基羰基)苯基]羰基}-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E442) | 氮杂环丁烷 | 491 | |
1-[(4-{[(3S)-3-氟代-1-吡咯烷基]羰基}苯基)羰基]-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E443) | (S)-3-氟代吡咯烷(WO 9108206) | 523 | |
1-{[4-({(2R)-2-[(甲基氧基)甲基]-1-吡咯烷基}羰基)苯基]羰基}-4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪(E444) | (R)-2-(甲氧基甲基)吡咯烷 | 549 | |
(3R)-1-[(4-{[4-(4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪基]羰基}苯基)羰基]-3-吡咯烷醇(E445) | (R)-(+)-3-吡咯烷醇 | 521 |
实施例446
1-(3-氟代-4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-(苯基羰基)哌嗪(E446)
步骤1:1-{3-[(4-溴代-2-氟代苯基)氧基]丙基}哌啶
将2-氟代-4-溴代苯酚(4.20g,22mmol)、1-(3-氯代丙基)哌啶(3.96g,20mmol)、碳酸钾(8.26g,60mmol)和催化量的碘化钾在2-丁酮(100ml)中、在回流下加热24小时。过滤固体,用丙酮洗涤并在真空中浓缩得到粗制油状物。将残余物在硅胶上纯化,用乙酸乙酯∶己烷(0.7∶0.3)的混合物洗脱,然后用乙酸乙酯洗脱,得到标题化合物(5.71g,90%);MS(ES+)m/e 315/317[M+H]+。
步骤2:4-(3-氟代-4-{[3-(1-哌啶基)丙基]氧基}苯基)-1-哌嗪羧酸1,1-二甲基乙基酯
将步骤1的产物(632mg,2mmol)、叔-丁醇钠(538mg,5.6mmol)、1-哌嗪羧酸叔-丁基酯(894mg,4.8mmol)、三(二亚苄基丙酮)二钯(0)(18mg,0.01ml)和三(邻-甲苯基)膦(24mg,0.08mmol)在甲苯(10ml)中、在回流下加热16小时。将溶液直接上样到SCX离子交换树脂上,用甲醇、然后用0.88氨水溶液∶甲醇(1∶9)洗脱。蒸发碱性部分并将残余物经硅胶层析纯化,用0.880氨水∶乙醇∶二氯甲烷(1∶9∶190)混合物洗脱,得到标题化合物(468mg,54%);MS(ES+)m/e 422[M+H]+。
步骤3:1-(3-氟代-4-{[3-(1-哌啶基)丙基]氧基}苯基)哌嗪
在0℃下,将步骤2的产物(468mg,1.1mmol)溶于1∶1 TFA∶DCM(10ml)中并在室温下搅拌2小时以上。在真空中浓缩该溶液并与二氯甲烷一起重蒸发三次。将残余物通过SCX离子交换树脂,用甲醇、然后用0.88氨水溶液∶甲醇(1∶9)的混合物洗脱。蒸发碱性部分并将残余物经硅胶层析纯化,用0.880氨水∶乙醇∶二氯甲烷(1∶9∶90)混合物洗脱,得到标题化合物(320mg,90%);MS(ES+)m/e 322[M+H]+。
步骤4:1-(3-氟代-4-{[3-(1-哌啶基)丙基]氧基}苯基)-4-(苯基羰基)哌嗪
将步骤3的产物(320mg,1mmol)和三乙胺(140μl,1mmol)溶于二氯甲烷(5ml)中,经苯甲酰氯(115μl,1mmol)处理。在室温下搅拌该溶液过夜并在真空中浓缩成粗制固体。将该固体用硅胶层析纯化,用二氯甲烷、然后用0.880氨水∶乙醇∶二氯甲烷(1∶9∶90)混合物洗脱,得到标题化合物(354mg,83%);MS(ES+)m/e 426[M+H]+。
实施例447
4-[4-(3-哌啶-1-基-丙氧基)-萘-1-基]-哌嗪-1-羧酸叔-丁基酯(E447)
步骤1:4-溴代-萘-1-醇
将1-萘醇(1g,6.94mmol)的乙腈(25ml)溶液用N-溴丁二酰亚胺(1.6g,9.01mmol)处理并将该混合物在室温下搅拌3小时。在真空中除去溶剂并将残余物经硅胶层析纯化,用己烷∶乙酸乙酯(0.9∶1)混合物洗脱,得到标题化合物(0.85g,57%);MS(ES-)m/e 222[M-H]-。
步骤2:1-[3-(4-溴代-萘-1-基氧基)-丙基]-哌啶
将步骤1的产物(0.85g,3.83mmol)的2-丁酮(30ml)溶液用1-(3-氯代-丙基)-哌啶(0.74g,4.59mmol)、碳酸钾(1.2g,9.19mmol)处理,随后用碘化钾(1.5g,9.19mmol)处理并在回流下加热6小时。冷却至室温后,将反应混合物用硫代硫酸钠(1M,10ml)处理并将产物萃取到乙酸乙酯中,用水洗涤(x3),用盐水洗涤(x1),经硫酸镁干燥并在真空中浓缩。将残余物在硅胶上纯化,用0.88氨溶液∶甲醇∶二氯甲烷(0.5∶4.5∶95)混合物洗脱,得到标题化合物(0.88g,68%);MS(ES+)m/e350[M+H]+。
步骤3:4-[4-(3-哌啶-1-基-丙氧基)-萘-1-基]-哌嗪-1-羧酸叔-丁基酯
将二-叔-丁基膦钯(0.033g,0.064mmol)的邻-二甲苯(20ml)用步骤2的产物(0.45g,1.28mmol)、哌嗪-1-羧酸叔-丁基酯(1.47g,7.67mmol)处理,随后用叔-丁醇钠(0.17g,1.79mmol)处理并在120℃下加热2小时。冷却至室温后将反应混合物用乙酸乙酯稀释,用水洗涤(x3),用盐水洗涤(x1),经硫酸镁干燥并在真空中浓缩。将残余物在硅胶上纯化,用0.88氨溶液∶甲醇∶二氯甲烷(0.1∶0.9∶99)混合物洗脱,得到标题化合物(0.40g,56%);MS(ES+)m/e 454[M+H]+。
实施例448
4-(1-{4-[4-(3-哌啶-1-基-丙氧基)-萘-1-基]-哌嗪-1-基}-甲酰基)-苄腈(E448)
步骤1:1-[4-(3-哌啶-1-基-丙氧基)-萘-1-基]-哌嗪
将实施例447、步骤3的产物(0.40g,0.89mmol)的无水二氯甲烷(5ml)溶液用三氟乙酸(10ml)处理并在室温下搅拌1小时。在真空中除去溶剂,溶于甲醇中并上样到SCX离子交换柱上,用甲醇、然后用甲醇∶0.880氨水(9∶1)混合物洗脱。然后将碱性部分还原并将残余物在硅胶上纯化,用0.88氨溶液∶甲醇∶二氯甲烷(1∶9∶90)混合物洗脱,得到标题化合物(0.23g,73%);MS(ES+)m/e 354[M+H]+。
步骤2:4-(1-{4-[4-(3-哌啶-1-基-丙氧基)-萘-1-基]-哌嗪-1-基}-甲酰基)-苄腈
根据在实施例375中所述方法,由步骤1的产物(0.13g,0.37mmol)和4-氰基苯甲酸(0.11g,0.74mmol)制备标题化合物(0.17g,99%);MS(ES+)m/e 483[M+H]+。
实施例449
1-苯基-1-{4-[4-(3-哌啶-1-基-丙氧基)-苯基]-[1,4]二吖庚烷-1-基}-甲酮(E449)
步骤1:4-[4-(3-哌啶-1-基-丙氧基)-苯基]-[1,4]二吖庚烷-1-羧酸叔-丁基酯
将实施例316、步骤1的产物(1-[3-(4-碘代-苯氧基)-丙基]哌啶)(2g,5.8mmol)、[1,4]二吖庚烷-1-羧酸叔-丁基酯(2.7g,13.9mmol)、三(二亚苄基丙酮)二钯(0)(0.03g,0.03mmol)、三-邻-甲苯基-膦(0.04g,0.02mmol)的二噁烷(20ml)混合物在回流下加热20小时。冷却至室温后将反应混合物用乙酸乙酯稀释,用水洗涤(x3),用盐水洗涤(x1),经硫酸镁干燥并在真空中浓缩。将残余物经柱层析纯化,用0.88氨溶液∶甲醇∶二氯甲烷(0.1∶0.9∶99)混合物洗脱,得到标题化合物(0.61g,25%);MS(ES+)m/e 418[M+H]+。
步骤2:1-[4-(3-哌啶-1-基-丙氧基)-苯基]-[1,4]二吖庚烷
使用在D11中所详述的方法,由步骤1的产物(162mg,0.26mM)制备标题化合物;MS(ES+)m/e 318[M+H]+。
步骤3:1-苯基-1-{4-[4-(3-哌啶-1-基-丙氧基)-苯基]-[1,4]二吖庚烷-1-基}-甲酮
使用在实施例375中所详述的方法,由步骤2的产物(0.09g,0.29mmol)和苯甲酸(0.71g,0.58mmol)制备标题化合物(0.12g,95%);MS(ES+)m/e 422[M+H]+。
实施例450-453
使用在实施例375中所详述方法,由实施例449步骤2的产物与下表中所示合适的羧酸制备E450-E453。
化合物 | 羧酸 | MS(ES+)m/e[M+H]+ |
3-(1-{4-[4-(3-哌啶-1-基丙氧基)-苯基]-[1,4]二吖庚烷-1-基}-甲酰基)-苄腈(E450) | 3-氰基-苯甲酸 | 447 |
1-环丙基-1-{4-[4-(3-哌啶-1-基丙氧基)-苯基]-[1,4]二吖庚烷-1-基}-甲酮(E451) | 环丙烷羧酸 | 386 |
1-(4-氟代-苯基)-1-{4-[4-(3-哌啶-1-基-丙氧基)-苯基]-[1,4]二吖庚烷-1-基}-甲酮(E452) | 4-氟代苯甲酸 | 440 |
1-{4-[4-(3-哌啶-1-基-丙氧基)-苯基]-[1,4]二吖庚烷-1-基}-1-噻吩-2-基-甲酮(E453) | 噻吩-2-羧酸 | 428 |
实施例454
4-(1-{(2S,5R)-2,5-二甲基-4-[4-(3-哌啶-1-基-丙氧基)-苯基]-哌嗪-1-基}-甲酰基)-苄腈(E454)
步骤1:(2R,5S)-2,5-二甲基-1-[4-(3-哌啶-1-基-丙氧基)-苯基]-哌嗪
将2,2’-二(二苯膦)-1,’-联萘(0.068g,0.109mmol)和乙酸钯(0.016g,0.072mmol)的甲苯(5ml)混合物加热至80℃。向其中加入预溶于甲苯(5ml)中的实施例316、步骤1的产物(1-[3-(4-碘代-苯氧基)-丙基]哌啶)(0.5g,1.45mmol)、预溶于甲苯(5ml)中的(2S,5R)-2,5-二甲基-哌嗪(0.20g,1.74mmol),随后加入叔-丁醇钠(0.20g,2.02mmol)。将该混合物在100℃下加热6小时。冷却至室温后并反应混合物用乙酸乙酯稀释,用水洗涤(x3),用盐水洗涤(x1),经硫酸镁干燥并在真空中浓缩。将残余物在硅胶上纯化,用0.880氨溶液∶甲醇∶二氯甲烷(0.5∶4.5∶95)混合物洗脱,得到标题化合物(0.98g,20%);MS(ES+)m/e332[M+H]+。
步骤2:4-(1-{(2S,5R)-2,5-二甲基-4-[4-(3-哌啶-1-基-丙氧基)-苯基]-哌嗪-1-基}-甲酰基)-苄腈
使用在实施例375中所详述的方法,由步骤1的产物(0.13g,0.38mmol)和4-氰基苯甲酸(0.11g,0.76mmol)制备标题化合物(0.097g,57%);MS(ES+)m/e 461[M+H]+。
实施例455-458
使用在实施例375中所述方法,由实施例454步骤1的产物与下表中所示合适的羧酸制备E455-E458。
化合物 | 羧酸 | MS(ES+)m/e[M+H]+ |
1-{(2R,5R)-2,5-二甲基-4-[4-(3-哌啶-1-基-丙氧基)-苯基]-哌嗪-1-基}-1-苯基-甲酮(E455) | 苯甲酸 | 436 |
1-{(2R,5R)-2,5-二甲基-4-[4-(3-哌啶-1-基-丙氧基)-苯基]-哌嗪-1-基}-1-吡啶-4-基-甲酮(E456) | 异烟酸 | 437 |
1-{(2R,5R)-2,5-二甲基-4-[4-(3-哌啶-1-基-丙氧基)-苯基]-哌嗪-1-基}-1-[4-(1-吡咯烷-1-基-甲酰基)-苯基]-甲酮(E457) | 4-(1-吡咯烷-1-基-甲酰基)-苯甲酸(J.Med.Chem.2003,46(10),1845-1857) | 534 |
1-{(2R,5R)-2,5-二甲基-4-[4-(3-哌啶-1-基-丙氧基)-苯基]-哌嗪-1-基}-1-(四氢-吡喃-4-基)-甲酮(E458) | 四氢-吡喃-4-羧酸 | 444 |
实施例459
1-{(2R,5R)-2,5-二甲基-4-[4-(3-哌啶-1-基-丙氧基)-苯基]-哌嗪-1-基}-1-吗啉-4-基甲酮(E459)
将实施例454步骤1的产物(0.20g,0.60mol)、4-吗啉碳酰氯(0.082g,0.55mol)、三乙胺(0.067g,0.66mol)的二氯甲烷(8ml)混合物在室温下搅拌18小时。将混合物通过am SCX柱,用甲醇、随后用0.880氨溶液∶甲醇(1∶9)洗脱,得到标题化合物(0.18g,66%);MS(ES+)m/e 445[M+H]+。
实施例460
4-(1-{5-[4-(3-哌啶-1-基-丙氧基)-苯基]-2,5-二氮杂-双环[2.2.1]庚-2-基}甲酰基)苄腈(E460)
步骤1:5-[4-(3-哌啶-1-基-丙氧基)-苯基]-2,5-二氮杂-双环[2.2.1]庚烷-羧酸叔-丁基酯
使用实施例454步骤1所述的方法,由实施例316、步骤1的产物(1-[3-(4-碘代-苯氧基)-丙基]哌啶)(0.25g,0.72mmol)和2,5-二氮杂-双环[2.2.1]庚烷-羧酸叔-丁基酯(0.17g,0.87mmol)制备标题化合物(0.313g,84%);MS(ES+)m/e 416[M+H]+。
步骤2:2-[4-(3-哌啶-1-基-丙氧基)-苯基]-2,5-二氮杂-双环[2.2.1]庚烷
使用在D11中所述的方法,由步骤1的产物(0.31g,0.75mmol)制备标题化合物;MS(ES+)m/e 316[M+H]+。
步骤3:4-(1-{5-[4-(3-哌啶-1-基-丙氧基)-苯基]-2,5-二氮杂-双环[2.2.1]庚-2-基}甲酰基)苄腈
使用在实施例375中所述的方法,由步骤2的产物(0.23g,0.73mmol)和4-氰基苯甲酸(0.21g,1.45mmol)制备标题化合物;MS(ES+)m/e 445[M+H]+。
实施例461
4-(1-{4-[2-氯代-4-(3-哌啶-1-基-丙氧基)-苯基]-哌嗪-1-基}-甲酰基)苄腈(E461)
步骤1:1-[3-(4-溴代-3-氯代-苯氧基)-丙基]-哌啶
使用在实施例305、步骤2中所述的方法,由1-(3-氯代丙基)哌啶盐酸盐(2.38g,12mmol)和4-溴代-3-氯代-苯酚(2.07g,10mmol)制备标题化合物(3.42g);MS(ES+)m/e 333[M+H]+。
步骤2:4-[2-氯代-4-(3-哌啶-1-基-丙氧基)-苯基]-哌嗪-1-羧酸叔-丁基酯
使用在实施例305步骤3中所述的方法,由步骤1的产物(0.6g,1.8mmol)和1-哌嗪羧酸1,1-二甲基乙基酯(0.40g,2.14mmol)制备标题化合物(0.46g);MS(ES+)m/e 439[M+H]+。
步骤3:1-[2-氯代-4-(3-哌啶-1-基-丙氧基)-苯基]-哌嗪
使用在实施例295步骤5中所述的方法,由步骤2的产物制备标题化合物(0.240g);MS(ES+)m/e 338[M+H]+。
步骤4:4-(1-{4-[2-氯代-4-(3-哌啶-1-基-丙氧基)-苯基]-哌嗪-1-基}-甲酰基)苄腈
使用在实施例305步骤5中所述的方法,由步骤3的产物(0.120g,0.36mmol)和4-氰基苯甲酸(105mg,0.712mmol)制备标题化合物(0.130g);MS(ES+)m/e 468[M+H]+。
实施例462
1-苯基-1-{4-[4-(3-吡咯烷-1-基-丙氧基)-苯基]-哌嗪-1-基}-甲酮(F462)
步骤1:1-{4-[4-(3-氯代-丙氧基)-苯基]-哌嗪-1-基}-1-苯基-甲酮
使用在说明9中所述的方法,由实施例295步骤3的产物(4-[4-(苯基羰基)-1-哌嗪基]苯酚)(1g,3.55mmol)和1-溴代-3-氯代丙烷(0.67g,4.25mmol)制备标题化合物(1.3g);MS(ES+)m/e 359[M+H]+。
步骤2:1-苯基-1-{4-[4-(3-吡咯烷-1-基-丙氧基)-苯基]-哌嗪-1-基}-甲酮
使用在说明10中所述的方法,由步骤1的产物(0.2g,0.56mmol)和吡咯烷(0.047g,0.67mmol)制备标题化合物(0.15g);MS(ES+)m/e394[M+H]+。
实施例463-464
使用在说明10中所述的方法,由实施例462步骤1的产物与下表中所示合适的胺制备E463-E464。
实施例 | 羧酸 | MS(ES+)m/e[M+H]+ |
1-(4-{4-[3-(3,3-二氟代-吡咯烷-1-基)-丙氧基]-苯基}-哌嗪-1-基)-1-苯基-甲酮(E463) | 3,3-二氟代-吡咯烷(Synlett,1995,1,55-57) | 430 |
1-(4-{4-[3-(4,4-二氟代-哌啶-1-基)-丙氧基]-苯基}-哌嗪-1-基)-1-苯基-甲酮(E464) | 4,4-二氟代-哌啶(Tetrahedron,1977,33(14),1707-1710) | 444 |
实施例465
1-(1-萘基羰基)-4-[2-(4-{[3-(1-哌啶基)丙基]氧基}苯基)乙基]哌嗪,甲酸盐(E465)
E465a:1-(1-萘基羰基)-4-(2-{4-[(苯基甲基)氧基]苯基}乙基)哌嗪
将1-(2-溴代乙基)-4-[(苯基甲基)氧基]苯(533mg)和1-(1-萘基羰基)哌嗪(440mg)部分溶于1-甲基-2-吡咯烷酮(2ml)中并用二异丙基乙胺(0.956ml)处理。将得到的反应混合物在微波炉中、在160℃下加热一固定的保持时间12分钟。将混合物分配在乙酸乙酯和水之间并将有机层用水和饱和盐水洗涤,干燥(MgSO4)并蒸发。将残余物上样到SCX-2 SPE柱体上,用甲醇、随后用2M甲醇氨洗脱。蒸发甲醇氨部分并将残余物再在硅胶SPE结合洗脱柱上层析,用3%甲醇-1%三乙胺-二氯甲烷洗脱,得到标题化合物(583mg)。LCMS RT=2.79分钟。
E465b:4-{2-[4-(1-萘基羰基)-1-哌嗪基]乙基}苯酚
将1-(1-萘基羰基)-4-(2-{4-[(苯基甲基)氧基]苯基}乙基)哌嗪(E465a)(2.33g)和20%披氢氧化钯碳(800mg)的乙醇(50ml)溶液在室温、氢大气压下搅拌。24小时后再加入钯催化剂(800mg)并再连续搅拌72小时。将反应混合物通过硅藻土过滤,用乙醇洗涤并合并滤液和洗涤液,在真空中蒸发,得到标题化合物(1.84g)。LCMS RT=2.20分钟。
E465c:1-(2-{4-[(3-氯代丙基)氧基]苯基}乙基)-4-(1-萘基羰基)哌嗪
将4-{2-[4-(1-萘基羰基)-1-哌嗪基]乙基}苯酚(E465b)(500mg)、1-溴代-3-氯代丙烷(0.165ml)和碳酸钾(481mg)的2-丁酮(25ml)溶液加热至回流18小时。加入更多的1-溴代-3-氯代丙烷(0.165ml)并连续加热6小时。将反应混合物分配在乙酸乙酯和水之间。将含水层用乙酸乙酯重萃取并将合并的有机层用饱和盐水洗涤,干燥(MgSO4)并蒸发。将粗制物在硅胶SPE结合的洗脱柱上层析纯化,用环己烷、随后用0-5%甲醇-二氯甲烷-1%三乙胺的梯度洗脱,得到标题化合物(582mg)。LCMS RT=2.67分钟。
E465d:1-(1-萘基羰基)-4-[2-(4-{[3-(1-哌啶基)丙基]氧基}苯基)乙基]哌嗪,甲酸盐
将1-(2-{4-[(3-氯代丙基)氧基]苯基}乙基)-4-(1-萘基羰基)哌嗪(E465c)(50mg)、碳酸钾(95mg)、碘化钾(95mg)和哌啶(0.067ml)的二丁酮(2ml)溶液加热至回流24小时。将反应混合物分配在二氯甲烷和水之间。重萃取含水层并将合并的有机萃取液浓缩,经质谱导向的制备性HPLC纯化,得到标题化合物(42mg)。LCMS RT=2.02分钟。ES+ve m/z 486(M+H)+。
实施例466-474
在列阵程序中,使用在实施例465d中所述方法,由1-(2-{4-[(3-氯代丙基)氧基]苯基}乙基)-4-(1-萘基羰基)哌嗪(0.114mmol)、合适的仲胺(6当量)、碳酸钾(6当量)和碘化钾(5当量)的2-丁酮(2ml)溶液制备实施例466-474。所述产物经质谱导向的自动-制备性HPLC纯化,得到为甲酸盐的化合物。
实施例475
1-(1-萘基羰基)-4-[2-(4-{[2-(1-哌啶基)乙基]氧基}苯基)乙基]哌嗪(E475)
E475a:1-(2-{4-[(2-氯代乙基)氧基]苯基}乙基)-4-(1-萘基羰基)哌嗪
使用如在实施例465c中所述相同的方法,由4-{2-[4-(1-萘基羰基)-1-哌嗪基]乙基}苯酚和1-溴代-2-氯代乙烷制备。
LCMS RT=2.52分钟
E475b:1-(1-萘基羰基)-4-[2-(4-{[2-(1-哌啶基)乙基]氧基}苯基)乙基]哌嗪
将1-(2-{4-[(2-氯代乙基)氧基]苯基}乙基)-4-(1-萘基羰基)哌嗪(E475a)(23mg)、碳酸钾(45mg)、碘化钾(45mg)和哌啶(0.032ml)的2-丁酮(2ml)溶液加热至回流48小时。将反应混合物分配在二氯甲烷和水之间。重萃取含水层并将合并的有机萃取液浓缩,经质谱导向的制备性HPLC纯化,得到标题化合物(9.9mg)。LCMS RT=1.97分钟。ES+ve m/z 472(M+H)+。
实施例476-479
在列阵程序中,使用在实施例465d中所述方法,由1-(2-{4-[(2-氯代乙基)氧基]苯基}乙基)-4-(1-萘基羰基)哌嗪(0.0544mmol)、合适的仲胺(6当量)、碳酸钾(6当量)和碘化钾(5当量)的2-丁酮(2ml)溶液制备实施例476-479。所述产物经质谱导向的自动-制备性HPLC纯化,得到为甲酸盐的化合物。
实施例480-499
以与实施例62中所述类似的方法制备实施例480-499。
实施例500
1-苯基-4-{2-[4-(3-哌啶-1-基丙氧基)苯基]乙基}哌嗪三氟乙酸盐(E500)
采用实施例229d中所述的方法1由D42制备标题化合物。
RT=1.86分钟,ES+ve m/z 408。
实施例501
1-(5-叔-丁基-2-甲氧基苯甲酰基)-4-[4-(3-哌啶-1-基丙氧基)苯基]哌嗪(E501)
使用实施例76c中所述方法,由D11制备标题化合物。
RT=2.61分钟,ES+ve m/z 494。
实施例502
1-(3-{4-[4-(5-异丙基-2-甲基苯甲酰基)哌嗪-1-基]苯氧基}丙基)吖庚烷(E502)
E502a:1-[3-(4-哌嗪-1-基苯氧基)丙基]吖庚烷
使用实施例76b中所述类似的方法制备标题化合物。
RT=1.42分钟,ES+ve m/z 318。
E502b:1-(3-{4-[4-(5-异丙基-2-甲基苯甲酰基)哌嗪-1-基]苯氧基}丙基)吖庚烷
使用实施例76c中所述的方法,由E502a制备标题化合物。
RT=2.65分钟,ES+ve m/z 478。
实施例503
1-(3-{4-[4-(5-乙基-2-甲基苯甲酰基)哌嗪-1-基]苯氧基}丙基)吖庚烷(E503)
使用实施例76c中所述的方法,由E502a制备标题化合物。
RT=2.57分钟,ES+ve m/z 464。
所有在本说明书中引用的出版物,包括但不限于专利和专利申请都结合在本文中作为参考,如同每一篇单独的出版物通过引用其全文特别地和分别地结合在本文中。
生物数据
根据以下方法可以制备含有组胺H3受体的膜制剂。
(i)组胺H3细胞系的增殖
将DNA编码的人组胺H3基因(Huvar,A.等.(1999)Mol.Pharmacol.55(6),1101-1107)克隆到结合的载体、pCDNA3.1TOPO(InVitrogen)中通过具有酶BamH1和Not-1的质粒DNA的限制酶切消化将它的cDNA从所述载体中分离并连接到用相同酶系消化的诱导型表达载体pGene(InVitrogen)上。如在US专利号5,364,791;5,874,534和5,935,934中所述使用GeneSwitchTM系统(一种在诱导物不存在时断电并在诱导物存在时通电的转基因表达系统)。将连接DNA转移到活性DH5αE.大肠杆菌宿主细菌细胞中并以50μg ml-1的浓度接种到含有ZeocinTM(一种抗菌素,其允许细胞表达sh ble基因的选择,所述基因存在于pGene和pSwitch上)的Luria Broth(LB)琼脂上。经限制酶切分析鉴定含有重配位质粒的菌落。从250ml含有pGeneH3质粒的宿主细菌的培养物中制备用于转移到哺乳动物细胞中的DNA并如每一制造商指导(Qiagen)的使用DNA制备试剂盒(Qiagen Midi-Prep)使其分离。
将早已用pSwitch调节质粒(InVitrogen)转染的CHO K1细胞在完全培养基中以2×10e6细胞/每T 75烧瓶的浓度接种,所述完全培养基含有Hams F12(GIBCOBRL,Life Technologies)培养基,其补加了10%v/v透析的胎牛血清、L-谷氨酰胺和潮霉素(100μg ml-1),24小时后使用。使用脂质转染胺并根据制造商的指导(InVitrogen),将质粒DNA转染到细胞中。48小时后将转染的细胞放置到补加500μgml-1ZeocinTM的完全培养基中。
10-14天后,将选择性10nM Mifepristone(InVitrogen)加入到培养基中以诱导受体的表达。18小时后,使用乙二胺四乙酸(EDTA;1∶5000;InVitrogen)使诱导的细胞从烧瓶中脱离,随后用pH 7.4的磷酸缓冲盐溶液洗涤数次并重悬浮在含有极限必需培养基(MEM)的分选培养基中,所述培养基没有酚红,并补加了Earles盐和3%FoetalClone II(Hyclone)。通过用兔多克隆抗体、4a染色,检查作为受体表达的近似1×10e7个细胞,高位阻止组胺H3受体的N-端结构域,在冰上温育60分钟,随后在分选培养基中洗涤两次。通过将所述细胞在带有山羊抗兔抗体的冰上培育60分钟检测受体结合的抗体,将受体结合的抗体与Alexa 488荧光标记(Molecoular Probes)结合。随后再用分选培养基洗涤两次,将细胞通过50μm FilconTM(BDBiosciences)过滤,然后在装备有自动细胞沉着部件的FACS VantageSE Fiow Cytometer上分析。对照细胞是以相同方法处理的非-诱导细胞。将阳性着色细胞作为单一细胞分选进96-孔平板中,该平板中含有含有500μg ml-1 ZeocinTM的完全培养基并充许在通过抗体和配体结合研究对于受体表达重分析前膨胀。一种克隆,3H3被选择用于膜制剂。
(ii)来自培养细胞的膜制剂
该方案的所有步骤都在4℃下并与预冷却的试剂一起进行。将细胞沉淀物重悬浮在10容积含有50mM N-2-羟基乙基哌嗪-N’-2-乙基磺酸(HEPES)(pH 7.40)的缓冲液A2中,其中补加了10e-4M亮抑酶肽(乙酰基-亮氨酰基-亮氨酰基精氨醛(arginal);Sigma L2884)、25μg/ml杆菌肽(Sigma B0125)、1mM乙二胺四乙酸(EDTA)、1mM苯基甲基磺酰氟化物(PMSF)和2×10e-6M抑胃酶肽A(Sigma)。然后在1升玻璃Waring搅拌器中经2×15秒裂解,随后在500g下离心20分钟使细胞均化。然后将上清液在48,000g下离心30分钟。经涡旋5秒钟将沉淀物重悬浮在4容积缓冲液A2中,随后在Dounce匀浆器(10-15振幅)中均化。此时将制备物等分试样放入聚丙烯管中并放置在-70℃下。
(iii)组胺H1细胞系的增殖
使用在文献[Biochem.Biophys.Res.Commun.1994,201(2),894]中所述已知的方法克隆人H1受体。根据在文献[Br.J.Pharmacol.1996,117(6),1071]中所述已知方法,使中国仓鼠卵巢细胞稳定表达的人H1受体增殖。
根据以下测试,可以试验本发明化合物的体外生物活性:
(I)组胺H3结合测试
向白色管壁透明底96孔平板中的每一种需测试的化合物中加入:-
(a)10μl试验化合物(或10μl iodophenpropit(一种已知的组受H3拮抗剂)终浓度为10mM),在10%DMSO中稀释成所需的浓度;
(b)10μl 125I 4-[3-(4-碘代苯基甲氧基)丙基]-1H-咪唑鎓(iodoproxyfan)(Amersham;1.85MBq/μl或50μCi/ml;SpecificActivity~2000 Ci/mmol),在测试缓冲液(50mM三(羟基甲基)氨基甲烷缓冲液(TRIS)pH 7.4,0.5mM乙二胺四乙酸(EDTA))中稀释为200pM,得到20pM终浓度;以及
(c)80μl珠粒/膜混合液,其经将闪烁亲近测定法(SPA)珠粒型WGA-PVT以100mg/ml悬浮在测试缓冲液中,随后与膜(根据以上所述方法制备)混合并以测试缓冲液稀释,得到含有7.5μg蛋白和0.25mg珠粒/每孔的80μl终容积,将混合物在室温下、在滚瓶中预混合60分钟制备。将平板振荡5分钟,然后放置在室温下3-4小时,在Wallac Microbeta计数器上、在1微型标准化氚计数流程上读数。使用4-参数逻辑斯谛方程分析数据。
(II)组胺H3功能拮抗物测试
向白色管壁透明底96孔平板中的每一种需测试的化合物中加入:-
(a)10μl试验化合物(或10μl鸟苷5’-三磷酸(GTP)(Sigma)作为非特异性结合对照),在测试缓冲液(20mM N-2-羟基乙基哌嗪-N’-2-乙基磺酸)(HEPES)+100Mm NaCl+10mM MgCl2,Ph 7.4 NaOH)中稀释成所需的浓度;
(b)60μl珠粒/膜/GDP混合液,其经将麦胚凝集素聚乙烯基甲苯(WGA-PVT)闪烁亲近测定法(SPA)珠粒以100mg/ml悬浮在测试缓冲液中,随后与膜(根据以上所述方法制备)混合并以测试缓冲液稀释,得到含有10μg蛋白和0.5mg珠粒/每孔的60μl终容积,将混合物在4℃下在滚瓶中预混合30分钟并马上加入到平板上,加入10μM终浓度的鸟苷5’-二磷酸(GDP)(Sigma;稀释到测试缓冲液中)制备。将平板在室温下培育成具有受体/珠粒的平衡拮抗物,振荡30分钟,随后加入:
(c)10μl组胺(Tocris),终浓度为0.3μM;和
(d)20μl鸟苷5’-[γ35-S]硫代三磷酸盐、三乙胺盐(Amersham;放射性浓度=37kBq/μl或1mCi/ml;比活性1160 Ci/mmol),在测试缓冲液中稀释为1.9nM得到0.38nM终浓度。
然后将平板在摇动器上、室温下温育30分钟,随后在1500rpm下离心5分钟。在离心机运行结束后,在Wallac Microbeta计数器上、在1微型标准化氚计数流程上将平板在3和6小时之间读数。使用4-参数逻辑斯谛方程分析数据。作为最低量的基础活性,即组胺不加入到孔中。
(III)组胺H1功能拮抗剂测试
在以10000细胞/孔的细胞接种的黑色管壁透明底384-孔平板中测试化合物。全部过程都使用Tyrodes缓冲液(NaCl 145mM、KCl2.5mM、HPPES 10mM、葡萄糖10mM、MgCl2 1.2mM、CaCl2 1.5mM、4-(二丙基氨磺酰基)苯甲酸2.5mM、用NaOH 1.0M将pH调至7.40)。每一个孔用10μl FLUO4AM(10μm在pH 7.4下溶于Tyrodes缓冲液中)处理,然后将平板在37℃下温育60分钟。然后用Tyrodes缓冲液、使用EMBLA细胞洗涤系统洗涤各孔,每一孔中留下40μ1缓冲液,然后用10μl试验化合物的Tyrodes缓冲液处理。将每一平板温育30分钟以使试验化合物与受体平衡化。然后将每一孔用10μl组胺溶液的Tyrodes缓冲液处理。
通过在荧光中抑制组胺诱导的增加显示功能拮抗作用,如经FLIPR系统(Molecular Devices)测定。根据浓度效应曲线使用标准药理数学分析确定功能效价。
结果
将实施例E1-260、263-479和E499-503的化合物进行组胺H3功能拮抗剂测试并显示拮抗作用>6.5pkb。特别是,实施例E1、E3、E10、E12-14、E16-20、E21、E23、E24、E31、E33、E35-37、E40-42、E46-48、E51、E255-256、E258-260、E263、E265-267、E268-271、E273-274、E277-280、E284-288、E290-293、E295、E309、E311、E314-315、E317、E319-329、E331、E333、E342、E344、E346-348、E350、E352、E354-355、E361-363、E368、E374、E378、E380、E384、E386、E389、E391-393、E396-E399、E405、E407、E410-411、E414-415、E420-421、E423-424、E429-431、E434-435、E436-445、E449、E452-453和E455-459的化合物显示拮抗作用>8.4pkb。更特别的是,实施例E255、E259、E263、E269、E271、E274、E285-287、E292-293、E333、E344、E346和E374的化合物显示拮抗作用>9.0pkb。
将实施例E53-254、E465-479和E499-503的化合物进行组胺H1功能拮抗剂测试并显示拮抗作用>6.5pkb。特别是,实施例E60、E64-65、E67、E70、E84、E87、E91、E93、E95、E98、E100、E108-110、E112、E114-115、E135-136、E162、E171、E188-189、E195、E199、E206-212、E214-219、E224、E229、E231、E235、E242、E244、E466、E468-474和E500-503显示拮抗作用>7.3pkb。
Claims (10)
1.一种式(I)的化合物或其药学上可接受的盐:
其中:
R1代表任选由1个或更多个以下取代基取代的芳基或杂芳基:卤素、三氟甲基、任选由COOR15取代的-C1-6烷基、任选由COOR15取代的-C1-6烷氧基、C1-6烯基、NR15R16、或C1-6烷硫基,其中R15和R16独立代表氢、C1-6烷基或C3-8环烷基或一起可以稠合形成5-至7-元非-芳香杂环,所述杂环任选被O或S原子间断并且任选由卤素、C1-6烷基或-C1-6烷基C1-6烷氧基取代;
Z代表化学键或CO;
m是0或2;
n是0;
r是0;
p是1;
R3代表-(CH2)q-NR11R12,其中q是3;以及
NR11R12代表任选由一个或更多个C1-6烷基取代的吡咯烷基、哌啶基、吖庚烷基或吖辛烷基。
2.一种根据权利要求1的化合物,其中R1代表任选取代的苯基、萘基或四氢萘基。
3.一种根据权利要求1的化合物,其中R1代表任选取代的苯并呋喃基、吲哚基或喹啉基。
4.一种根据权利要求1-3中任一项的化合物,其中R1由1、2或3个取代基任选取代,所述取代基选自氯;氟;溴;三氟甲基;甲基、乙基、异丙基、丙基或叔-丁基,任选由COOR15取代;任选由COOR15取代的甲氧基;乙烯基;-N(Me)2或-S-乙基。
5.一种根据权利要求1-4中任一项的化合物,其中NR11R12代表任选由一个或更多个甲基或乙基取代的吡咯烷基、哌啶基、吖庚烷基或吖辛烷基。
6.一种根据权利要求1-5中任一项的化合物,其中NR11R12代表由一个或两个甲基或乙基取代的哌啶基。
7.一种药用组合物,它包含如在权利要求1-6中任一项所定义的式(I)的化合物或其药学上可接受的盐和药学上可接受的载体或赋形剂。
8.权利要求1-6中任一项所定义的式(I)化合物或其药学上可接受的盐在制备用于治疗变应性鼻炎的药物中的用途。
9.一种用于治疗呼吸道疾病的药用组合物,它包含如权利要求1-6中任一项所定义的式(I)化合物或其药学上可接受的盐和药学上可接受的载体。
10.权利要求9所定义的药用组合物,其用于治疗变应性鼻炎。
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CN1726201A (zh) | 2006-01-25 |
KR20050049553A (ko) | 2005-05-25 |
NO20051689D0 (no) | 2005-04-05 |
CA2502249A1 (en) | 2004-04-29 |
RU2328494C2 (ru) | 2008-07-10 |
CN101070309A (zh) | 2007-11-14 |
US20100075953A1 (en) | 2010-03-25 |
NO20051689L (no) | 2005-07-07 |
EP1567511A1 (en) | 2005-08-31 |
ZA200603604B (en) | 2007-04-25 |
JP2006508935A (ja) | 2006-03-16 |
JP2007016041A (ja) | 2007-01-25 |
US20060025404A1 (en) | 2006-02-02 |
MA27482A1 (fr) | 2005-08-01 |
RU2005110061A (ru) | 2006-01-20 |
ZA200502873B (en) | 2006-07-26 |
NZ549963A (en) | 2008-03-28 |
WO2004035556A1 (en) | 2004-04-29 |
GB0224084D0 (en) | 2002-11-27 |
IS7782A (is) | 2005-03-31 |
MXPA05004078A (es) | 2005-06-08 |
AU2003280380A1 (en) | 2004-05-04 |
BR0315283A (pt) | 2005-08-30 |
NZ539446A (en) | 2006-11-30 |
US7615550B2 (en) | 2009-11-10 |
PL376477A1 (en) | 2005-12-27 |
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