CN1152873C - 新的二苯基哌啶衍生物 - Google Patents
新的二苯基哌啶衍生物 Download PDFInfo
- Publication number
- CN1152873C CN1152873C CNB008106703A CN00810670A CN1152873C CN 1152873 C CN1152873 C CN 1152873C CN B008106703 A CNB008106703 A CN B008106703A CN 00810670 A CN00810670 A CN 00810670A CN 1152873 C CN1152873 C CN 1152873C
- Authority
- CN
- China
- Prior art keywords
- methyl
- phenylbenzene
- piperidino
- benzyl chloride
- chloride base
- 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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- BTVVEKSXUOEVAY-UHFFFAOYSA-N 4,4-diphenylpiperidine Chemical compound C1CNCCC1(C=1C=CC=CC=1)C1=CC=CC=C1 BTVVEKSXUOEVAY-UHFFFAOYSA-N 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 98
- 238000000034 method Methods 0.000 claims abstract description 42
- 229910052720 vanadium Inorganic materials 0.000 claims abstract description 19
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 230000008569 process Effects 0.000 claims abstract description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 283
- 229940073608 benzyl chloride Drugs 0.000 claims description 242
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 80
- 150000003839 salts Chemical class 0.000 claims description 31
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 27
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 22
- -1 methylene-dioxy Chemical group 0.000 claims description 21
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 15
- 239000012453 solvate Substances 0.000 claims description 15
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- 150000001721 carbon Chemical group 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 13
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical group 0.000 claims description 11
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 claims description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 6
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 5
- 229910052770 Uranium Inorganic materials 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- NDGRWYRVNANFNB-UHFFFAOYSA-N pyrazolidin-3-one Chemical compound O=C1CCNN1 NDGRWYRVNANFNB-UHFFFAOYSA-N 0.000 claims description 5
- 238000006268 reductive amination reaction Methods 0.000 claims description 5
- 229910052721 tungsten Inorganic materials 0.000 claims description 5
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 125000001118 alkylidene group Chemical group 0.000 claims description 4
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- AIDLAEPHWROGFI-UHFFFAOYSA-N 2-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=C(C(O)=O)C=CC=C1C(O)=O AIDLAEPHWROGFI-UHFFFAOYSA-N 0.000 claims description 3
- WNWVKZTYMQWFHE-UHFFFAOYSA-N 4-ethylmorpholine Chemical group [CH2]CN1CCOCC1 WNWVKZTYMQWFHE-UHFFFAOYSA-N 0.000 claims description 3
- PNWSHHILERSSLF-UHFFFAOYSA-N 4-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=CC=C(C(O)=O)C=C1C(O)=O PNWSHHILERSSLF-UHFFFAOYSA-N 0.000 claims description 3
- FUFZNHHSSMCXCZ-UHFFFAOYSA-N 5-piperidin-4-yl-3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole Chemical compound FC(F)(F)C1=CC=CC(C=2N=C(ON=2)C2CCNCC2)=C1 FUFZNHHSSMCXCZ-UHFFFAOYSA-N 0.000 claims description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 3
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 3
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 claims description 3
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 claims description 3
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 claims description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 3
- XIWBSOUNZWSFKU-UHFFFAOYSA-N ethyl piperidine-3-carboxylate Chemical compound CCOC(=O)C1CCCNC1 XIWBSOUNZWSFKU-UHFFFAOYSA-N 0.000 claims description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 3
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 229940017219 methyl propionate Drugs 0.000 claims description 3
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 3
- AJFDBNQQDYLMJN-UHFFFAOYSA-N n,n-diethylacetamide Chemical compound CCN(CC)C(C)=O AJFDBNQQDYLMJN-UHFFFAOYSA-N 0.000 claims description 3
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 125000004417 unsaturated alkyl group Chemical group 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 19
- 201000010099 disease Diseases 0.000 abstract description 18
- 238000002560 therapeutic procedure Methods 0.000 abstract description 2
- 239000005482 chemotactic factor Substances 0.000 abstract 1
- 239000002585 base Substances 0.000 description 286
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- 239000000243 solution Substances 0.000 description 44
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 239000000047 product Substances 0.000 description 31
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 29
- 239000012265 solid product Substances 0.000 description 26
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- 239000000203 mixture Substances 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 15
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 14
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- 210000003979 eosinophil Anatomy 0.000 description 7
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 6
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
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- JELQZSVKOONUKD-UHFFFAOYSA-N phenol dihydrochloride Chemical compound Cl.Cl.OC1=CC=CC=C1.OC1=CC=CC=C1 JELQZSVKOONUKD-UHFFFAOYSA-N 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
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- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
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- DFEYYRMXOJXZRJ-UHFFFAOYSA-N sevoflurane Chemical compound FCOC(C(F)(F)F)C(F)(F)F DFEYYRMXOJXZRJ-UHFFFAOYSA-N 0.000 description 1
- 229960002078 sevoflurane Drugs 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
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- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
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- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
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- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- 229960000344 thiamine hydrochloride Drugs 0.000 description 1
- 235000019190 thiamine hydrochloride Nutrition 0.000 description 1
- 239000011747 thiamine hydrochloride Substances 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 208000001319 vasomotor rhinitis Diseases 0.000 description 1
- 201000005539 vernal conjunctivitis Diseases 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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Abstract
本发明提供通式(I)化合物、其制备方法、含有这些化合物的药物组合物及其在治疗上的应用,特别是用于治疗趋化因子受体相关性疾病和病症。其中R1、R2、R3、R4、A、Q、U、V、W、X、Y和n如说明书所述。
Description
发明领域
本发明涉及新化合物、其制备方法、含有这些化合物的药物组合物及其在治疗中的应用。
发明背景
趋化因子对各种疾病和障碍的免疫炎症反应(例如哮喘和过敏性疾病)以及自免疫病症(例如类风湿性关节炎和动脉粥样硬化)起重要作用。这些小分泌型分子为8-14KDa蛋白质的一总类,其成员日益增加,其特征在于保守的(conserved)四个半胱氨酸基元。可以把趋化因子总类分为显示不同结构基元的两种主要类型:Cys-X-Cys(C-X-C)和Cys-Cys(C-C)类。这些类型是基于在半胱氨酸残基NH-邻近对之间的单个氨基酸插入和序列相似性而区分的。
C-X-C趋化因子包括若干强效的化学引诱剂和嗜中性白细胞活化剂例如白介素-8(IL-8)和嗜中性白细胞活化肽2(NAP-2)。
C-C趋化因子包括强效的单核细胞和淋巴细胞化学引诱剂但不包括嗜中性白细胞化学引诱剂,其例子如人单核细胞趋化蛋白1-3(MCP-1、MCP-2和MCP-3)、RANTES(对激活进行调控,正常T表达和分泌)、eotaxin和巨噬细胞炎症蛋白1α和1β(MIP-1α和MIP-1β)。
有研究表明:趋化因子的作用通过G蛋白-偶联受体亚类介导,这些受体被定义为CCR1、CCR2、CCR2A、CCR2B、CCR3、CCR4、CCR5、CCR6、CCR7、CXCR1、CXCR2、CXCR3和CXCR4。这些受体是药物开发的良好靶点,因为调控这些受体的试剂能够用于治疗例如上述疾病和障碍。
发明的公开
按照本发明,提供式(I)化合物或其可药用盐或溶剂化物
其中:
R1和R2独立地代表任选被卤素、C1-6烷基、硝基、氰基、羟基、亚甲二氧基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基或C1-6烷基磺酰基所取代的苯基;
各个R3独立地代表卤素、硝基、C1-6烷基、氰基、C1-6卤代烷基、羟基或C1-6烷氧基;各个烷氧基可任选地被卤素、NR5R6、CO2R7、CONR8R9、吡唑烷酮或含有1-3个独立选自N、O和S作为杂原子的五元杂芳环;所述杂芳环可以任选地进一步被1个或多个C1-4烷基所取代。
n代表整数0-3;
R4代表氢、羟基或NR10R11;
A代表-CO-、-CH2-或一个键;
Q代表C1-4亚烷基;
U、W和X独立地代表任选被C1-4烷基取代的碳原子或代表氮原子;
V代表任选被C1-4烷基取代的氮原子或代表氧原子;
Y代表C1-4亚烷基或-CO-;
R5、R6、R7、R8、R9独立地代表氢原子或C1-6烷基;
R10和R11独立地代表氢原子、C2-6不饱和烷基或C1-6烷基;各个烷基任选地被CO2R12、羟基、C1-6烷氧基、CONH2、NR13R14、OCH2CH2OH或含有一个或两个选自N、O和S作为杂原子的五元或六元饱和或不饱和杂环所取代;所述环任选地含有一个形成羰基的环碳原子;所述环任选地进一步被C1-4烷基所取代;
或者基团NR10R11一起代表4-8元饱和氮杂环系统,所述环任选地含有选自N、O和S的另一个环杂原子;所述环任选地含有一个组成羰基的环碳原子,所述环任选地还被C1-6烷基、C1-6羟基烷基、羟基、CO2R15、CONH2、CHO或COCH3所取代;
R12和R15独立地代表氢或C1-4烷基;和
R13和R14独立地代表氢、C1-4烷基或C1-4烷酰基。
在一个优选实施方案中,V代表氮原子。
优选地,R3代表卤素;更优选地,R3代表氯。
术语“C1-6烷基”在此处指具有1-6个碳原子的直链或支链烷基和/或具有3-6个碳原子的环烷基。这样基团的例子包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、环戊基、甲基环戊基和环己基。
术语“C1-4烷基”解释与上面类似。
术语“C2-6不饱和烷基”在此指具有2-6个碳原子并且包括一个双键或一个三键的直链或支链烷基或者指具有3-6个碳原子并且包括1个双键的环烷基。这样基团的例子包括乙烯基、乙炔基、1-和2-丙烯基、1和2-丙炔基、2-甲基-2-丙烯基、2-丁烯基、2-丁炔基、环戊烯基和环己烯基。
术语“C1-6烷氧基”在此指由一个氧原子键合于具有1-6个碳原子的直链或支链烷基所形成的基团或者由一个氧原子键合于具有3-6个碳原子的环烷基所形成的基团。这样的基团例子包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、环丙氧基和环己氧基。
术语“卤素”在此指氟、氯、溴和碘。
术语“C1-6卤代烷基”(例如氯甲基、2-氟乙基和三氟甲基)、“C1-6卤代烷氧基”(例如三氟甲氧基)和“C1-6羟烷基”(例如羟甲基、1-羟基乙基或2-羟基乙基)作类似解释。
类似地,术语“C1-6烷基磺酰基”代表的基团例如甲基磺酰基、叔丁基磺酰基和环己基磺酰基。
术语“C1-4烷酰基”在此指由一个羰基键合于具有1-3个碳原子的支链或直链烷基所形成的基团。这样基团的例子包括乙酰基或丙酰基。
“含有1-3个独立选自N、O和S作为杂原子的五元杂芳环”的例子包括呋喃、噻吩、咪唑、异噁唑、噻唑和三唑。
“含有一个或两个选自N、O和S作为杂原子的五元或六元饱和或不饱和杂环;所述环任选地含有一个形成羰基的环碳原子”的例子包括吗啉、吡咯烷、吡啶、四氢呋喃、咪唑、吡咯烷酮、哌啶酮和哌嗪。
“任选含有选自N、O和S作为另一个杂原子的4-8元饱和氮杂环系统”包括吡咯烷、吡啶、吗啉、哌嗪、吡唑烷、咪唑烷和全氢氮杂。
本发明包括盐形式特别是酸加成盐形式的式(I)化合物。合适的盐包括那些与有机酸或无机酸形成的盐。这样的酸加成盐通常为可药用盐,尽管非药用酸的盐可能对所述化合物的制备和纯化是有用的。因此,优选的盐包括那些与下列酸形成的盐:盐酸、氢溴酸、硫酸、硫酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、琥珀酸、富马酸、马来酸、甲磺酸和苯磺酸。
本发明化合物的具体例子包括:
1-[(1-苄基-1H-吡唑-3-基)甲基]-4,4-二苯基哌啶;
1-{[1-(3-氯苄基)-1H-吡唑-3-基]甲基}-4,4-二苯基哌啶;
1-{[1-(3,4-二甲基苄基)-1H-吡唑-3-基]甲基}-4,4-二苯基哌啶;
1-{[1-(4-甲基苄基)-1H-吡唑-3-基]甲基}-4,4-二苯基哌啶;
4,4-二苯基-1-({1-[4-三氟甲基)苄基]-1H-吡唑-3-基}甲基)-哌啶;
1-{[1-(2,4-二氯苄基)-1H-吡唑-3-基]甲基}-4,4-二苯基哌啶;
1-{[1-(3,4-二氯苄基)-1H-吡唑-3-基]甲基}-4,4-二苯基哌啶;
1-{[1-(3,4-二氟苄基)-1H-吡唑-3-基]甲基}-4,4-二苯基哌啶;
1-{[1-(4-氯苄基)-1H-吡唑-3-基]甲基}-4,4-二苯基哌啶;
1-{[1-(4-氟苄基)-1H-吡唑-3-基]甲基}-4,4-二苯基哌啶;
1-{[1-(4-氯-2-甲氧基苄基)-1H-吡唑-3-基]甲基}-4,4-二苯基哌啶;
5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲基)苯酚;
2-[5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲基)苯氧基]-N,N-二甲基乙酰胺;
1-{[1-(4-氯苄基)-1H-咪唑-4-基]甲基}-4,4-二苯基哌啶;
1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-4-甲醛;
{1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-4-基}甲醇;
1-{[1-(4-氯苄基)-1H-1,2,3-三唑-5-基]甲基}-4,4-二苯基哌啶;
1-{[1-(4-氯苄基)-1H-1,2,3-三唑-4-基]甲基}-4,4-二苯基哌啶;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-甲酸;
1-(4-氯苄基)-4-[(4,4-二苯基-哌啶基)甲基]-1H-咪唑-5-甲酰胺;
1-{[2-(4-氯苄基)-1H-咪唑-5-基]甲基}-4,4-二苯基哌啶;
1-{[2-(4-氯苄基)-1-甲基-1H-咪唑-5-基]甲基}-4,4-二苯基哌啶;
1-{[2-(4-氯苄基)-3-甲基-3H-咪唑-5-基]甲基}-4,4-二苯基哌啶;
[2-(4-氯苄基)-1H-咪唑-5-基](4,4-二苯基-1-哌啶基)甲酮;
2-[4-({1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-4-基}甲基)-1-哌嗪基]-1-乙醇;
4-({1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-4-基}甲基)-1-哌嗪甲醛;
1-[4-({1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-4-基}甲基)-1-哌嗪基]-1-乙酮;
N1-({1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-4-基}甲基)-N1,N2,N2-三甲基-1,2-乙二胺;
N-({1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-4-基}-甲基)-2-(4-吗啉基)-1-乙胺;
1-{[4-(1-氮杂环丁烷基甲基)-1-(4-氯苄基)-1H-吡唑-3-基]甲基}-4,4-二苯基哌啶;
N-({1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-4-基}-甲基)-2-(1-吡咯烷基)-1-乙胺;
N-({1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-4-基}-甲基)-β-丙氨酸;
2-[({1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-4-基}-甲基)氨基]乙酸;
N-({1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-4-基}甲基)-2-(2-吡啶基)-1-乙胺;
{1-(4-氯苄基)-3-[(4,4-二苯基-1-吡啶基)甲基]-1H-吡唑-4-基}-N-(4-吡啶基甲基)甲胺;
2-[1-({1-(4-氯苄基)-3-[(4,4-二苯基-1-吡啶基)甲基]-1H-吡唑-4-基}甲基)-4-哌啶基]-1-乙醇;
1-({1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-4-基}甲基)-4-甲基-1,4-二氮杂环庚烷;
3-[5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲基)苯氧基]-N,N-二甲基-1-丙胺;
2-[5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲基)苯氧基]乙酸;
2-[5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲基)苯氧基]乙酰胺;
2-[5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲基)苯氧基]-N,N-二甲基乙酰胺;
2-[5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲基)苯氧基]-N,N-二乙基乙酰胺;
2-[5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲基)苯氧基]丙酰胺;
2-[5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲基)苯氧基]-N-甲基乙酰胺;
1-{2-[5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲基)苯氧基]乙酰基}-3-吡唑烷酮;
1-[(1-{4-氯-2-[(3,5-二甲基-4-异噁唑基)甲氧基]苄基}-1H-吡唑-3-基)甲基]-4,4-二苯基哌啶;
5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲基)苯基(1-甲基-1H-咪唑-2-基)甲基醚;
5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲基)苯基(2-甲基-1,3-噻唑-4-基)甲基醚;
{1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-基}(4-吗啉基)甲酮;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N,N-二甲基-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(2-甲氧基乙基)-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(4-羟基环己基)-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基-]-N-[1-(羟甲基)丙基]-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(四氢-2-呋喃基甲基)-1H-咪唑-5-甲酰胺;
{1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-基}[2-(羟甲基)-1-哌啶基]甲酮;
1-(4-氯苄基)-N-[3-(二乙胺基)丙基]-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-甲酰胺;
{1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-基}[3-(羟甲基)-1-哌啶基]甲酮;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(2-羟基乙基)-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(2-羟基乙基)-N-甲基-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[3-(1H-咪唑-1-基)丙基]-1H-咪唑-5-甲酰胺;
{1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-基}(1-吡咯烷基)甲酮;
{1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-基}(3-羟基-1-吡咯烷基)甲酮;
1-[4-({1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-基}羰基)-1-哌嗪基]-1-乙酮;
{1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-基}(1-哌啶基)甲酮;
1-(4-氯苄基)-N-[2-(二乙胺基)乙基]-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(2-羟基乙基)-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[2-(4-吗啉基)乙基]-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-乙基-N-(2-羟基乙基)-1H-咪唑-5-甲酰胺;
{1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-基}(4-乙基-1-哌嗪基)甲酮;
N-(2-氨基-2-氧代乙基)-1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[2-(1-吡咯烷基)乙基]-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[2-(1H-咪唑-4-基)乙基]-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-甲基-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-N-(2,3-二羟基丙基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[(1-乙基-2-吡咯烷基)甲基]-1H-咪唑-5-甲酰胺;
1-({1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-基}羰基)-4-哌啶甲酸乙酯;
1-({1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-基}羰基)-3-哌啶甲酸乙酯;
3-[({1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-基}羰基)氨基]丙酸甲酯;
2-[({1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-基}羰基)氨基]乙酸甲酯;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(2-吡啶基甲基)-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[2-(2-吡啶基)乙基]-1H-咪唑-5-甲酰胺
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(3-吡啶基甲基)-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(2-羟基-1,1-二甲基乙基)-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(2-羟基-1-甲基乙基)-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[3-(2-氧代-1-吡咯烷基)丙基]-1H-咪唑-5-甲酰胺;
N-[2-(乙酰氨基)乙基]-1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[2-(2-羟基乙氧基)乙基]-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[1-(羟基甲基)环戊基]-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[2-羟基-1-(羟甲基)乙基]-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(3-甲氧基丙基)-1H-咪唑-5-甲酰胺;
1-({1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-基}-羰基)-2-吡咯烷甲酰胺;
1-({1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-基}-羰基)-2-吡咯烷甲酰胺;
{1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-基}[4-(2-羟乙基)-1-哌啶基]甲酮;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(2-丙炔基)-1H-咪唑-5-甲酰胺;
4-({1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-基}羰基)-2-哌嗪酮;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[1-(羟甲基)丙基]-1H-咪唑-5-甲酰胺;
1-{3-(4-氯苄基)-[1,2,4]-噁二唑-5-基甲基}-4,4-二苯基哌啶;
和上述化合物的可药用盐及其溶剂化物。
本发明还提供式(I)化合物的制备方法,包括:
(i)当Y代表CH2时,让式(III)化合物
其中R1和R2如式(I)所定义,
对通式(II)化合物
其中R3、R4、A、Q、U、V、W、X和n如式(I)所定义,进行还原胺化反应;或
(ii)当Y代表C1-4烷基时,让通式(IV)化合物
其中R3、R4、A、Q、U、V、W、X和n如式(I)所定义,L1为离去基团,与式(III)化合物反应;或
(iii)当Y代表CO时,
让通式(V)化合物
其中R3、R4、A、Q、U、V、W、X和n如式(I)所定义,L2为离去基团,
与式(III)化合物反应;或
(iv)当在式(I)中至少一个R3基团代表任选取代的C1-6烷氧基时,
让式(VI)化合物
其中R1、R2、R3、R4、A、Q、U、V、W、X、Y和n如式(I)所定义,
与式(VII)化合物进行反应
R-L3 (VII)
其中R是这样的基团:其能使所得基团OR代表如式(I)中定义R3所述的任选被取代的C1-6烷氧基,L3为离去基团;
(v)当A代表CO并且R4代表NR10R11时,
让式(VIII)化合物
其中R1、R2、R3、A、Q、U、V、W、X和n如式(I)所定义,L4为离去基团,
和式(IX)化合物反应
HNR10R11 (IX)
其中R10和R11如式(I)定义;或
(vi)当A代表CH2并且R4代表NR10R11时,
让式(IX)化合物
HNR10R11 (IX)
其中R10和R11如式(I)所定义
对式(X)化合物进行还原胺化反应
其中R1、R2、R3、Q、U、V、W、X、Y和n如式(I)所定义;或
(vii)当Q键合于V并且V代表氮原子时,
让式(XI)化合物
其中R1、R2、R4、A、U、W、X和Y如式(I)所定义,
与式(XII)化合物反应
其中R3、Q和n如式(I)所定义,L5为离去基团;
和任选地在(i)、(ii)、(iii)、(iv)、(V)、(vi)或(vii)后,把式(I)化合物转换成其它的式(I)化合物,和/或形成式(I)化合物的可药用盐或溶剂化物。
式(I)化合物的盐可以通过该化合物的游离碱或其另一个盐与1个当量或多个当量的合适酸反应得到。可以在盐不溶性溶剂中或者在盐可溶性溶剂中进行该反应,然后真空除去溶剂或冷冻干燥。合适的溶剂包括:例如水、二氧六环、乙醇、2-丙醇、四氢呋喃或乙醚或这些溶剂的混合物。还可以在离子交换树脂中进行该反应。
在方法(i)和(vi)中,还原胺化反应通常在本领域技术人员已知的条件下进行。例如,在惰性溶剂中在还原剂的存在下,用胺和醛反应。合适的还原系统包括催化氢化或硼烷及其衍生物。这样试剂的部分名单可参见:“Advanced Organic Chemistry”,J.March(1985)第3版,第799页。
在方法(ii)和(vii)中,在惰性溶剂中,用通式(IV)或(XII)的亲电试剂分别处理通式(III)或(XI)来进行反应。合适的离去基团L1和L5包括:磺酸根、三氟磺酸根、甲磺酸根、甲苯磺酸根和卤素(选自氯、溴或碘)。通常在碱存在下进行反应。该碱可以是过量胺亲核试剂或者可以另外加入到反应混合物中的碱。另外加入到反应混合物中的碱可以是金属碳酸盐(特别是碱金属碳酸盐例如碳酸铯)、金属氧化物和金属氢氧化物和叔胺碱。合适的有机溶剂的例子为乙腈、二氧六环、N,N-二甲基甲酰胺、N-甲基-2-吡咯烷酮、四氢呋喃、二甲基亚砜、环丁砜和C1-4醇类。在优选的实施方案中,离去基团为氯。
在上述方法(iii)和(v)中,反应进行条件如下:在合适的温度下,通常为0℃-溶剂沸点温度下,在合适的有机溶剂中搅拌反应混合物。反应时间尤其取决于所用的溶剂、反应温度和离去基团的特性。可以通过加入碱对反应进行催化;可以应用的碱包括有机胺(例如三乙胺或吡啶)和碱金属的氢氧化物、烷氧化物、碳酸盐或氢化物。合适的离去基团L2和L4包括卤素(尤其是氯)和羟基。当离去基团为OH时,还可以应用合适的偶联试剂例如CDI(1,1′-羰基二咪唑)、DCC(1,3-二环己基碳化二亚胺)或HOBt(1-羟基苯并三唑)使式(V)和(III)化合物之间或式(VIII)和式(IX)化合物之间进行反应。
在方法(iv)中,通常采用类似于上述方法(ii)和(vii)记载的条件进行。
通常来说,可以应用上述类似于式(I)化合物的反应类型制备式(II)、(IV)、(V)、(VI)、(VIII)、(X)和(XI)化合物。
当Q键合到V上并且V代表氮原子时的式(II)化合物可以制备如下:在类似于上述方法(ii)和(vii)记载的条件下,把式(XII)化合物和式(XIII)化合物反应
其中A、U、W、X和R4如式(I)所定义。
L1、L2和L4分别为离去基团时的式(IV)、(V)或(VIII)化合物可以制备如下:应用本领域技术人员熟知的反应条件,从L1、L2和L4为OH的相应化合物制备得到。因此,例如在合适的碱例如三乙胺的存在下,应用亚硫酰氯或甲磺酰氯进行反应。
当L1和L2为羟基并且Q键合至V同时V为氮原子时,式(IV)或(V)化合物可以通过类似于上述式(II)化合物的方法制备得到。
式(VI)化合物可以通过应用例如三溴化硼对相应的式(XIV)化合物进行脱甲基化反应得到
其中R1、R2、R3、R4、A、Q、U、V、W、X、Y和n如式(I)所定义。
式(X)化合物可以通过在N,N-二甲基甲酰胺中应用三氯氧化磷对相应的式(XV)化合物进行甲酰化反应得到:
其中R1、R2、R3、Q、U、V、W、X、Y和n如式(I)所定义。
类似地,式(II)化合物可以通过对相应的式(XVI)化合物甲酰化反应制备得到。
某些新中间体式(II)、(IV)、(V)、(VI)、(VIII)、(X)、(XI)、(XV)和(XVI)构成本发明的另一方面。
式(III)、(VII)、(IX)、(XII)和(XIII)可以市售得到或者被文献中所公开或者可以按照已知技术制备得到。
本领域技术人员明白:在本发明方法中,在起始反应试剂中或中间体中的某些官能团例如羟基或氨基需要用保护基团进行保护。因此,式(I)化合物的制备可以包括:在合适的阶段,加入和随后除去一个或多个保护基团。
官能团的保护和脱保护记载于:“Protective Groups in OrganicChemistry”,J.W.F.McOmie编,Plenum Press出版(1973年)和“Protective Groups in Organic Synthesis”第2版,T.W.Greene和P.G.M.Wuts,Wiley-Interscience(1991)。
某些式(I)化合物能够以立体异构体形式存在。容易理解:本发明包括应用所有式(I)化合物的几何异构体和光学异构体以及包括外消旋体的混合物。互变异构体及其混合物的应用也构成本发明的一个方面。
可以从反应混合物中分离得到本发明的化合物和中间体,如果需要,可以应用标准技术进行纯化。
式(I)化合物具有药学活性,特别是能够作为趋化因子受体活性的调控物质。更具体地说,这些化合物可以用作趋化因子受体CCR1和/或CCR3的活性调控剂。
本发明还有一个方面包括式(I)化合物在治疗那些受益于调控趋化因子受体活性的疾病或病症中的应用。
因此,式(I)化合物可以用于治疗自免疫性疾病、炎症、增生性和过度增生性疾病以及免疫学介导的疾病,包括器官或组织移植排斥和获得性免疫缺陷综合症(AIDS)。
这些疾病的例子包括:
(1)(呼吸道)阻塞性气道疾病包括慢性阻塞性肺疾病(COPD);哮喘例如支气管性哮喘、变应性气喘、内因性气喘、外因性气喘和尘埃性气喘,特别是慢性或顽固性气喘(例如晚期哮喘和气道或高反应性气喘);支气管炎;急性、变应性、萎缩性鼻炎和慢性鼻炎包括:干酪性鼻炎、肥厚性鼻炎、脓性鼻炎、干性鼻炎和药物性鼻炎;膜性鼻炎包括格鲁布性鼻炎、纤维蛋白性鼻炎和假膜性鼻炎和scrofoulous鼻炎;季节性鼻炎包括神经性鼻炎(枯草热)和血管舒缩性鼻炎;肉状瘤病、农民肺和相关疾病,纤维化肺和原发性间质性肺炎;
(2)(骨和关节)类风湿性关节炎、骨关节炎、血清反应阴性脊柱关节病(包括关节僵硬性脊椎炎、牛皮癣性关节病和莱特尔氏病)、贝切特氏病、斯耶格伦氏综合征和全身硬化;
(3)(皮肤)牛皮癣、特应性皮炎、接触性皮炎和其他湿疹性皮炎、皮脂溢性皮炎、扁平苔癣、天疱疮、大疱天疱疮、大疱性表皮松解、荨麻疹、angiodermas、vasculitides、erythrma、皮肤嗜曙红细胞增多、眼色素层炎、斑秃、春季结膜炎;
(4)(胃肠道)腹腔疾病、直肠炎、eosinopilic胃肠炎、mastocytosis、节段性回肠炎、肠炎、应激性肠综合症、溃疡性结肠炎、影响离肠较远部位的室温相关性变态反应例如偏头痛、鼻炎和湿疹;
(5)(其它组织和全身性疾病)多发性硬化、动脉粥样硬化、获得性免疫缺陷综合症(AIDS)、红斑狼疮、全身性狼疮、红斑慢性甲状腺炎、Hashimoto’s disease、肌无力、I型糖尿病、肾病综合症、嗜曙红细胞增多筋膜炎、高IgE综合症、结节性麻风、sezary综合症和特发性血小板减少性紫癜;和
(6)(同种移植排斥)例如肾、心脏、肝、肺、骨髓、皮肤和角膜移植后急性和慢性疾病;和抗宿主慢性移植病。
因此,本发明提供用于上述治疗的式(I)化合物或其可药用盐或溶剂化物。
另一方面,本发明提供式(I)化合物或其可药用盐或溶剂化物在制备用于上述治疗的药物中的应用。
在本说明书上下文中,除非另有说明,术语“治疗”还指“预防”。术语“治疗学(的)”、“治疗性(的)”或“治疗上(的)”应该作相应地理解。
预防被特别认为与治疗那些曾经患有所述疾病或者被认为具有患所述疾病高度危险性的病人非常相关。具有患某种疾病或病症危险性的病人通常包括那些具有疾病或病症家族史、或那些经基因测试或筛选被特别怀疑具有发展出该疾病或病症的人。
本发明还提供治疗病人炎症的方法,所述病人患有所述疾病或者具有患所述疾病的危险性,该方法包括:把治疗有效量的上述式(I)化合物或其可药用盐或溶剂化物给药于受治疗者。
对于上述应用,显然,给药剂量将发生变化,其决定因素包括所应用的化合物、给药方式、所期望的治疗和适用症。
可以把式(I)化合物或其可药用盐或溶剂化物单独应用,但通常将其以药物组合物形式应用,在药物组合物中,式(I)化合物/盐/溶剂化物(活性成分)和可药用辅料、稀释剂或载体混在一起。根据给药方式的不同,该药物组合物优选含有0.05-99%w(重量百分比)、更优选0.05-80%w、还更优选0.10-70%w和甚至更优选0.10-50%w的活性成分,所有百分比是基于组合物总重量来计算的。
本发明还提供含有在上面定义的式(I)化合物、或其可药用盐或溶剂化物和可药用辅料、稀释剂或载体的药物组合物。
本发明还提供制备本发明药物组合物的方法,包括:把上面所述的式(I)化合物或其可药用盐或溶剂化物和可药用辅料、稀释剂或载体混合。
该组合物可以局部给药(例如给药至肺和/或气管或皮肤),其剂型为溶液剂、混悬剂、七氟烷气雾剂和干粉剂型;或者可以全身给药,例如以片剂、胶囊、糖浆剂、粉剂或粒剂口服,或者以溶液剂或混悬剂胃肠外(注射)给药,或者皮下给药或以栓剂形式直肠给药或透皮给药。
现在将通过下列实施例举例说明本发明。
实施例1
1-[(1-苄基-1H-吡唑-3-基)甲基]-4,4-二苯基哌啶
(a)1-苄基-1H-吡唑-3-甲醛
把1H-吡唑-3-甲醛(0.15g)和碳酸钾(0.24g)加入到溴苯(0.29g)的N,N-二甲基甲酰胺(9ml)溶液中,室温下搅拌化合物24小时,加入硅胶,蒸发除去溶剂,用色谱纯化粗产物(洗脱剂∶异己烷-乙醚,2∶1)得到油状产物(0.18g)。
1H NMRδ(CDCl3)10.0(s,1H)、7.5-7.2(m,5H)、6.8(d,1H)、5.4(s,2H)。
(b)[(1-苄基)-1H-吡唑-3-基)甲基]-4,4-二苯基哌啶
把步骤(a)得到的产品(0.17g)溶解于乙醇(3ml)中,加入4,4-二苯基哌啶(0.118g)的乙醇(1ml)溶液。加入氰基硼氢化钠(1.0M的四氢呋喃溶液,0.3ml),室温下搅拌该溶液16小时。加入硅胶,蒸发除去溶剂,用色谱纯化粗产物(二氯甲烷∶甲醇,从100∶0至95∶5)得到油状产物。用超临界流体色谱法进行进一步纯化得到固体产物(0.010g),m.p.167-168℃。
MS:APCI(+ve)400(M+H);
1H NMRδ(CDCl3)7.4-7.0(m,16H)、6.64(d,1H)、5.25(s,2H)、4.0(s,2H)、3.6-2.6(m,8H)。
实施例2
1-{[3-(3-氯苄基)-1H-吡唑-3-基]甲基}-4,4-二苯基哌啶
通过实施例1的方法在步骤(a)中应用3-氯苄基溴制备得到固体产物(0.011g),熔点:136-137℃。
MS:APCI(+ve)442/44(M+H);
1H NMRδ(CDCl3)7.42(d,1H),7.4-7.0(m,14H),6.6(d,1H),5.2(s,2H),4.0(s,2H),3.4-2.6(m,8H)。
实施例3
1-{[1-(3,4-二甲基苄基)-1H-吡唑-3-基]甲基}-4,4-二苯基哌啶
通过实施例1的方法,在步骤(a)中应用3,4-二甲基苄基氯制备得到固体产物(0.015g),熔点:139-140℃。
MS:APCI(+ve)436(M+H);
1H NMRδ(CDCl3)7.45-6.8(m,14H),6.6(d,1H),5.16(s,2H),4.0(s,2H),3.4-2.6(m,8H),2.2(m,6H)。
实施例4
1-{[1-(4-甲基苄基)-1H-吡唑-3-基]甲基}-4,4-二苯基哌啶二盐酸
盐
按照实施例1的方法,在步骤(a)中应用4-甲基苄基溴制备得到油状产物。用1.0M氯化氢乙醚溶液处理得到固体产物(0.010g),熔点:147-148℃。
MS:APCI(+ve)422(M+H);
1H NMRδ(CDCl3)7.4-6.8(m,16H),5.2(s,2H),4.1(s,2H),3.6-2.6(m,8H),2.0(s,3H)。
实施例5
4,4-二苯基-1-({1-[4-三氟甲基)苄基]-1H-吡唑-3-基}甲基)-哌啶
二盐酸盐
按照实施例1的方法,在步骤(a)中应用4-三氟甲基苄基氯制备得到油状产物。用1.0M氯化氢乙醚溶液处理得到固体产物(0.022g),熔点:66-67℃。
MS:APCI(+ve)476/78(M+H);
1H NMRδ(CDCl3)7.6(d,2H),7.5-7.1(m,13H),6.9(bs,1H),5.3(s,2H),4.1(s,2H),3.6-2.6(m,8H)。
实施例6
1-{[1-(2,4-二氯苄基)-1H-吡唑-3-基]甲基}-4,4-二苯基哌啶二盐
酸盐
按照实施例1的方法,在步骤(a)中应用2,4-二氯苄基氯得到油状产物。用1.0M氯化氢乙醚溶液处理得到固体产物(0.022g),熔点:101-102℃。
MS:APCI(+ve)476/78(M+H);
1H NMRδ(CDCl3)7.6-6.8(m,15H),5.3(bs,2H),4.1(bs,2H),3.6-2.4(m,8H)。
实施例7
1-{[1-(3,4-二氯苄基)-1H-吡唑-3-基]甲基}-4,4-二苯基哌啶二盐
酸盐
按照实施例1的方法,在步骤(a)中应用3,4-二氯苄基氯制备得到油状产物。用1.0M氯化氢乙醚溶液处理得到固体产物(0.022g),熔点:191-192℃。
MS:APCI(+ve)476/78(M+H);
1H NMRδ(CDCl3)7.5-6.9(m,15H),5.2(s,2H),4.1(s,2H),3.0-2.6(m,8H)。
实施例8
1-{[1-(3,4-二氟苄基)-1H-吡唑-3-基]甲基}-4,4-二苯基哌啶
(a)1-(3,4-二氟苄基)-1H-吡唑-3-甲醛
按照实施例1的方法,在步骤(a)中应用3,4-二氟苄基溴制备得到油状产物(1.2g)。
1H NMRδ(CDCl3)10.0(s,1H),7.46(d,1H),7.3-6.9(m,3H),6.82(d,1H),5.35(s,2H)。
(b)1-{[1-(3,4-二氟苄基)-1H-吡唑-3-基]甲基}-4,4-二苯基哌啶
盐酸盐
把步骤(a)中产物(0.23g)溶解于乙醚(10ml)中,加入4,4-二苯基哌啶(0.25g),将溶液冷却到0℃。加入四丙氧化钛(0.34ml),将溶液搅拌1小时,加入四氯化钛(0.13ml)。在0℃下经30分钟后,加入BH3·SMe2(2.0M的四氢呋喃溶液,0.5ml),然后将该化合物温热至室温20小时。加入2.0M氢氧化钠水溶液,然后加入乙酸乙酯。搅拌混合物1小时,经Kiesselgur凝胶过滤除去不溶性固体。分离水相滤液,加入乙酸乙酯,合并有机相,用盐水洗涤,干燥,除去溶剂得到树胶状物质。用色谱纯化(二氯甲烷∶甲醇,10∶1)得到油状产物。用1.0M氯化氢乙醚溶液处理得到固体产物(0.20g),熔点:236-237℃。
MS:APCI(+ve)476/78(M+H);
1H NMRδ(d6-DMSO)10.6(bs,1H),7.91(d,1H),7.5-7.0(m,13H),6.5(d,1H),5.3(s,2H),4.2(d,2H),3.5-2.3(m,8H)。
实施例9
1-{[1-(4-氯苄基)-1H-吡唑-3-基]甲基}-4,4-二苯基哌啶二盐酸盐
按照实施例8的方法,在步骤(a)中应用4-氯苄基氯得到油状产物。用1.0M氯化氢乙醚溶液处理得到固体产物(0.09g),熔点:137-138℃。
MS:APCI(+ve)442/44(M+H);
1H NMRδ(d6-DMSO)7.88(d,1H),7.5-7.1(m,14H),6.5(d,1H),5.3(s,2H),4.2(d,2H),3.5-2.5(m,8H)。
实施例10
1-{[1-(4-氟苄基)-1H-吡唑-3-基]甲基}-4,4-二苯基哌啶盐酸盐
按照实施例8的方法,在步骤(a)中应用4-氟苄基氯得到油状产物。用1.0M氯化氢乙醚溶液处理得到固体产物(0.085g),熔点:192-193℃。
MS:APCI(+ve)426(M+H);
1H NMRδ(d6-DMSO)11.0(bs,1H),7.85(d,1H),7.5-7.1(m,14H),6.5(d,1H),53(s,2H),4.2(d,2H),3.5-2.4(m,8H)。
实施例11
1-{[1-(4-氯-2-甲氧基苄基)-1H-吡唑-3-基]甲基}-4,4-二苯基哌
啶盐酸盐
按照实施例8的方法,在步骤(a)中应用4-氯-2-甲氧基苄基氯得到油状产物。用1.0M氯化氢乙醚溶液处理得到固体产物(0.025g),熔点:73-74℃。
MS:ESI(+ve)472.21(M+H);
1H NMRδ(d6-DMSO)12.6(bs,1H),7.4-6.8(m,15H),5.2(s,2H),4.0(s,2H),3.8(s,3H),3.6-2.4(m,8H)
实施例12
5-氯-2-({3-[4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲基)
苯酚二盐酸盐
把实施例11的产物(0.4g)溶解于二氯甲烷(8.5ml)中,冷却至0℃。加入三溴化硼(1.0M的二氯甲烷溶液,8.5ml)。24小时后蒸发除去溶剂得到残余物,将其溶解于甲醇中,除去溶剂,将残余物溶解于2.0M氯化氢水溶液中。24小时后得到固体产物(0.39g),熔点:260-261℃。
MS:ESI(+ve)458.19(M+H);
1H NMRδ(d6-DMSO)10.4(bs,2H),7.8(d,1H),7.5-6.8(m,13H),6.42(d,1H),5.2(s,2H),4.2(d,2H),3.5-2.2(m,8H)。
实施例13
2-[5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲
基)苯氧基]-N,N-二甲基乙酰胺盐酸盐
在10ml Wheaton小瓶中,把实施例12产物(0.1g)溶解于N,N-二甲基甲酰胺(5ml)中,加入碳酸铯(0.2g)和2-氯-N,N-二甲基乙酰胺(0.05g),将混合物在70℃下加热2小时。冷却混合物,加入水和乙酸乙酯,分离有机相,干燥并浓缩成残余物。色谱纯化(二氯甲烷∶甲醇∶0.880氨水,90∶10∶1)得到树胶状物质。用1.0M氯化氢乙醚溶液处理得到固体(0.016g),熔点:181-182℃。
MS:ESI(+ve)543.25(M+H);
1H NMRδ(CDCl3)7.7-6.8(m,15H),5.26(s,2H),4.7(s,2H),4.0(s,2H),3.6-2.4(m,14H)。
实施例14
1-{[1-(4-氯苄基)-1H-咪唑-4-基]甲基}-4,4-二苯基哌啶二盐酸盐
(a)[1-(4-氯苄基)-1H-咪唑-4-基]甲醇
把4-氯苄基氯(1.2g)溶解于N,N-二甲基甲酰胺(20ml)中,加入4(5)-羟甲基咪唑盐酸盐(1.0g)和碳酸钾(4g),将混合物在90℃下加热20小时。加入水和乙酸乙酯,分离有机相,用盐水洗涤,干燥,蒸发除去溶剂。残余物用色谱纯化(二氯甲烷∶甲醇=9∶1)得到区域异构体混合物产品(0.5g)。在下一步骤中应用该产物不需进行进一步纯化。
(b)1-{[1-(4-氯苄基)-1H-咪唑-4-基]甲基}-4,4-二苯基哌啶
把步骤(a)产物(0.39g)溶解于甲苯(10ml)中,加入三乙胺(0.26ml)和亚硫酰氯(0.13ml),将混合物在室温下搅拌20小时。蒸发除去溶剂,加入4,4-二苯基哌啶盐酸盐(0.478g)的二甲亚砜(10ml)和三乙胺(0.65ml)溶液。经2小时后加入水和乙酸乙酯,分离有机相,用盐水洗涤,干燥,除去溶剂得到树胶状物质。用超临界流体色谱法纯化得到固体,用1.0M氯化氢乙醚溶液处理得到固体产物(0.02g),熔点254-255℃。
MS:APCI(+ve)442/44(M+H);
1H NMRδ(d6-DMSO)9.2(bs,1H),8.05(s,1H),7.7-7.0(m,15H),5.4(s,2H),4.4(s,2H),3.6-2.6(m,8H)。
实施例15
1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-4-甲醛
把实施例9产物(0.11g)溶解于N,N-二甲基甲酰胺(1ml)中,加入三氯氧化磷(0.023ml),把溶液在70℃下加热16小时,然后在100℃下加热20小时。冷却溶液,加入冰、水和乙酸乙酯,分离有机相并干燥。蒸发除去溶剂得到残余物,将其用色谱纯化(二氯甲烷∶甲醇=8∶2)得到固体产物(0.03g),熔点:133-134℃。
MS:APCI(+ve)470(M+H);
1H NMRδ(CDCl3)10.0(s,1H),7.8(s,1H),7.4-7.0(m,14H),5.2(s,2H),3.7(s,2H),2.7-2.4(m,8H)。
实施例16
{1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-4-基]
甲醇
把实施例15(0.05g)产物溶解于二氯甲烷(5ml)中,加入三乙酰氧硼氢化钠(0.068g)。经室温20小时后,加入盐水和二氯甲烷,分离有机相,干燥,蒸发除去溶剂得到残余物。用乙醚研碎得到固体产物(0.028g),熔点104-105℃。
MS:ESI(+ve)472.21(M+H);
1H NMRδ(CDCl3)7.5-7.0(m,15H),5.34(bs,1H),5.18(s,2H),4.7(s,2H),4.1(s,2H),3.8-2.6(m,8H)。
实施例17
1-{[1-(4-氯苄基)-1H-1,2,3-三唑-5-基]甲基}-4,4-二苯基哌啶
(a)[1-(4-氯苄基)-1H-1,2,3-三唑-5-基]甲醇和[1-(4-氯苄基)-
1H-1,2,3-三唑-4-基]甲醇
把1-叠氮甲基-4-氯苯(5.6g)溶解于二氧六环(100ml)中,加入炔丙基醇(1.67g),将溶液回流加热72小时。冷却溶液,加入水和乙酸乙酯,分离有机相,浓缩至油状物。色谱纯化(二氯甲烷∶乙酸乙酯=1∶1至0∶1)得到油状产物:首先洗脱出的异构体:[1-(4-氯苄基)-1H-1,2,3-三唑-5-基]甲醇(1.66g);
1H NMRδ(d6-DMSO)7.68(s,1H)、7.4-7.2(dd,4H)、5.59(s,2H)、5.52(s,1H)、4.53(d,2H)。
随后洗脱的异构体:[1-(4-氯苄基)-1H-1,2,3-三唑-4-基]甲醇(1.76g);
1H NMRδ(d6-DMSO)8.0(s,1H)、7.46-7.34(dd,4H)、5.57(s,2H)、5.15(t,1H)、4.51(d,2H)。
(b)1-{1-(4-氯苄基)-1H-1,2,3-三唑-5-基]甲基}-4,4-二苯基哌
啶
把(a)步骤中首先洗脱出的异构体(0.1g)溶解于二氯甲烷(2ml)中,加入甲磺酰氯(0.035ml)和三乙胺(0.062ml),在室温下搅拌该混合物16小时。加入4,4-二苯基哌啶盐酸盐(0.122g)在N,N-二甲基甲酰胺(1ml)和三乙胺(0.062ml)中的溶液,搅拌混合物48小时。加入乙酸乙酯和盐水,分离有机相,浓缩成树胶状物,用色谱纯化(二氯甲烷∶乙酸乙酯,4∶1)得到固体产物,用乙腈重结晶得到固体产物(0.060g),熔点195℃。
MS:APCI(+ve)443/5(M+H);
1H NMRδ(CDCl3)7.6(s,1H),7.35-7.1(m,14H),5.65(s,2H),3.2(s,2H),2.36(bs,8H)。
实施例18
1-{[1-(4-氯苄基)-1H-1,2,3-三唑-4-基]甲基}-4,4-二苯基哌啶
按照实施例17(b)的方法,应用实施例17步骤(a)中随后洗脱得到的异构体制备。用HPLC纯化得到固体产物(0.036g),熔点148℃。
MS:ESI(+ve)443.19(M+H);
1H NMRδ(CDCl3)7.4-7.1(m,15H),5.46(s,2H),3.59(s,2H),2.6(m,4H),2.42(m,4H)。
实施例19
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-甲酸
(a)1-(4-氯苄基)-4-(羟甲基)-1H-咪唑-5-甲酸甲酯
按照实施例14步骤(a)的方法,应用4-羟甲基-1H-咪唑甲酸甲酯(3.69g)制备得到区域异构体混合物产物(1.8g)。将混合物不进行纯化直接用于下一步骤。
(b)1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-甲
酸甲酯
按照实施例14步骤(b)的方法制备得到油状物,将其用色谱纯化(乙酸乙酯∶三乙胺=95∶5)得到固体产物(0.9g)。
1H NMRδ(CDCl3)7.6(s,1H),7.35-7.0(m,14H),5.4(s,2H),3.94(s,3H),3.7(s,2H),2.62(bm,4H),2.45(m,4H)。
(c)1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-甲
酸
把步骤(b)(0.5g)中产物溶解于甲醇(20ml)中,加入2N氢氧化钠水溶液(10ml)。经16小时后,加入2M盐酸水溶液,加入碳酸氢钠水溶液将pH值调节至6。加入乙酸乙酯,分离有机相,干燥,蒸发除去溶剂得到固体产物(0.35g),熔点:135-136℃。
MS:APCI(+ve)486/88(M+H);
1H NMRδ(CDCl3)7.5-7.0(m,15H),5.65(s,2H),3.9(s,2H),3.3(d,2H),2.8(m,4H),2.5(m,2H)。
实施例20
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-甲酰
胺
把实施例19产物(0.03g)溶解于N,N-二甲基甲酰胺(2ml)中,加入N,N-羰基二咪唑(0.020g),将该溶液在60℃下加热2小时,然后冷却。加入氨水溶液(1ml),室温下搅拌混合物16小时。加入盐水和乙酸乙酯,分离有机相,干燥蒸发除去溶剂得到固体,用乙醚研碎得到固体产物(0.014g),熔点:227-228℃。
MS:APCI(+ve)485/87(M+H);
1H NMRδ(d6-DMSO)10.4(bs,1H),7.4(s,1H),7.39-7.1(m,14H),5.5(s,2H),5.4(bs,2H),3.6(s,2H),2.7-2.2(bm,8H)。
实施例21
1-{[2-(4-氯苄基)-1H-咪唑-5-基]甲基}-4,4-二苯基哌啶二盐酸盐
按照实施例14的方法,应用2-(4-氯苄基)-4-(羟甲基)咪唑(1.0g)和4,4-二苯基哌啶(1.23g)得到残余物,用色谱纯化(乙酸乙酯∶甲醇=95∶5)得到固体。用色谱进一步纯化该物质(二氯甲烷∶甲醇∶氨水溶液=95∶3∶0.1)得到固体,用1.0M氯化氢乙醚溶液处理得到固体产物(0.07g),熔点:186-187℃。
MS:ESI(+ve)442.2(M+H);
1H NMRδ(CDCl3)7.6-7.0(m,15H),4.4(bs,2H),3.6-1.6(bm,10H)。
实施例22
1-{[2-(4-氯苄基)-1-甲基-1H-咪唑-5-基]甲基}-4,4-二苯基哌啶
二盐酸盐和1-{[2-(4-氯苄基)-3-甲基-3H-咪唑-5-基]甲基}-4,4-
二苯基哌啶二盐酸盐
(a)[2-(4-氯苄基)-1-甲基-1H-咪唑-5-基]甲醇和[2-(4-氯苄基)-
1-甲基-1H-咪唑-4-基]甲醇
把2-(4-氯苄基)-4-(羟甲基)咪唑(1.0g)溶解于N,N-二甲基甲酰胺(20ml)中,加入氢化钠(60%的油分散体,0.18g)。经室温1小时后加入碘甲烷(0.28ml),室温下搅拌该溶液2小时。加入水和乙酸乙酯,分离有机相,除去溶剂得到树胶状物质。用色谱纯化(二氯甲烷∶甲醇=97∶3)得到区域异构体固体混合物产物(0.5g)。该混合物不需再进行纯化可以直接应用于下一步骤。
(b)1-{[2-(4-氯苄基)-1-甲基-1H-咪唑-5-基]甲基}-4,4-二苯基哌
啶和1-{[2-(4-氯苄基)-3-甲基-3H-咪唑-5-基]甲基}-4,4-二苯基
哌啶
按照实施例14步骤(b)的方法制备得到区域异构体的混合物产物。用超临界流体色谱法纯化得到分离的产物,呈油状。用1.0M氯化氢乙醚溶液处理第一种被洗脱出的油得到固体产物(0.01g),熔点:252-253℃。
MS:APCI(+ve)456(M+H);
1H NMRδ(CDCl3)7.3-7.0(m,14H),6.75(s,1H),4.0(s,2H),3.4(s,3H),3.3(s,2H),2.4(m,8H)。
用1.0M氯化氢乙醚溶液处理第二种被洗脱出的油的固体产物(0.01g),熔点:248-249℃。
MS:APCI(+ve)456(M+H);
1H NMRδ(CDCl3)7.3-7.0(m,14H),6.70(s,1H),4.05(s,2H),3.38(s,2H),3.35(s,3H),2.7-2.4(m,8H)。
实施例23
[2-(4-氯苄基)-1H-咪唑-5-基](4,4-二苯基-1-哌啶基)甲酮
(a)2-(4-氯苄基)-1H-咪唑-5-甲酸乙酯
把4-氯-N-羟基-苯ethanimidamide(1.0g)和丙炔酸乙酯(0.53g)溶解于甲醇(20ml)中,回流加热20小时,冷却至室温。将残余物溶解于二苯醚中,回流加热1小时。冷却至室温,加入异己烷(300ml)。过滤收集得到的固体,用乙醚研碎,干燥得到固体产物(0.1g)。
1H NMRδ(CDCl3)7.65(s,1H),7.3(d,2H),7.15(d,2H),4.3(q,2H),4.05(s,2H),1.4(t,3H)。
(b)[2-(4-氯苄基)-1H-咪唑-5-基](4,4-二苯基-1-哌啶)甲酮
把步骤(a)中产物(0.07g)溶解于甲醇(5ml)中,加入2N氢氧化钠水溶液,室温下搅拌该溶液20小时。蒸发除去溶剂,加入2N盐酸水溶液,除去溶剂。把残余物溶解于亚硫酰氯(10ml)中,回流加热溶液2小时,冷却并蒸发。把残余物溶解于二氯甲烷(5ml)中,加入4,4-二苯基哌啶(0.073g)和三乙胺(1ml),室温下搅拌该溶液2小时。加入盐水,分离有机相,除去溶剂得到残余物,用超临界流体色谱法纯化得到固体产物(0.03g),熔点:105-106℃。
MS:ESI 456.18(M+H);
1H NMRδ(CDCl3)7.47.0(m,15H),4.05(s,2H),3.9(bm,3H),2.95(bt,1H),2.45(m,4H),1.6(m,4H)。
实施例24
2-[4-({1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-
4-基}甲基)-1-哌嗪基]-1-乙醇
把实施例15产物(0.001g)溶解于N,N-二甲基甲酰胺(0.2ml)中,加入N-(2-羟乙基)哌嗪(0.0008g)和1滴乙酸。经1小时后加入三乙酰氧硼氢化钠(0.0013g)的N,N-二甲基甲酰胺(0.1ml)溶液,室温下搅拌该溶液24小时。除去溶剂得到油状产物。
MS:APCI(+ve)基峰583。
按照实施例24的通用方法,应用合适的胺,制备25-36的化合物。
实施例25
4-({1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-4-
基}甲基)-1-哌嗪甲醛
MS:APCI(+ve)基峰568。
实施例26
1-[4-({1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-
4-基}甲基)-1-哌嗪基]-1-乙酮
MS:APCI(+ve)基峰582。
实施例27
N 1 -({1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-4- 基}甲基)-N 1,
N 2,
N 2 -三甲基-1,2-乙二胺
MS:APCI(+ve)基峰556。
实施例28
N-({4-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-4-
基}-甲基)-2-(4-吗啉基)-1-乙胺
MS:APCI(+ve)基峰584。
实施例29
1-{[4-(1-氮杂环丁烷基甲基)-1-(4-氯苄基)-1H-吡唑-3-基]甲
基}-4,4-二苯基哌啶
MS:APCI(+ve)基峰511。
实施例30
N-({1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-4-
基}-甲基)-2-(1-吡咯烷基)-1-乙胺
MS:APCI(+ve)基峰568。
实施例31
N-({1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-4-
基}-甲基)-β-丙氨酸
MS:APCI(+ve)基峰543。
实施例32
2-[({1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-4-
基}-甲基)氨基]乙酸
MS:APCI(+ve)基峰529。
实施例33
N-({1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-4-
基}甲基)-2-(2-吡啶基)-1-乙胺
MS:APCI(+ve)基峰576。
实施例34
{1-(4-氯苄基)-3-[(4,4-二苯基-1-吡啶基)甲基]-1H-吡唑-4-基}-
N-(4-吡啶基甲基)甲胺
MS:APCI(+ve)基峰562。
实施例35
2-[1-({1-(4-氯苄基)-3-[(4,4-二苯基-1-吡啶基)甲基]-1H-吡唑-
4-基}甲基)-4-哌啶基]-1-乙醇
MS:APCI(+ve)基峰583。
实施例36
1-({1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-4-
基}甲基)-4-甲基-1,4-二氮杂环庚烷
MS:APCI(+ve)基峰568。
按照实施例13的通法制备实施例37-47的化合物。
实施例37
3-[5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲
基)苯氧基]-N,N-二甲基-1-丙胺
MS:APCI(+ve)基峰543。
实施例38
2-[5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲
基)苯氧基]乙酸
MS:APCI(+ve)基峰516。
实施例39
2-[5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲
基)苯氧基]乙酰胺
MS:APCI(+ve)基峰515。
实施例40
2-[5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲
基)苯氧基]-N,N-二甲基乙酰胺
MS:APCI(+ve)基峰543。
实施例41
2-[5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲
基)苯氧基]-N,N-二乙基乙酰胺
MS:APCI(+ve)基峰571。
实施例42
2-[5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲
基)苯氧基]丙酰胺
MS:APCI(+ve)基峰529。
实施例43
2-[5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲
基)苯氧基]-N-甲基乙酰胺
MS:APCI(+ve)基峰529。
实施例44
1-{2-[5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基-]-1H-吡唑-1-基}
甲基)苯氧基]乙酰基}-3-吡唑烷酮
MS:APCI(+ve)基峰584。
实施例45
1-[(1-{4-氯-2-[(3,5-二甲基-4-异噁唑基)甲氧基]苄基}-1H-吡唑-
3-基)甲基]-4,4-二苯基哌啶
MS:APCI(+ve)基峰567。
实施例46
5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲基)
苯基(1-甲基-1H-咪唑-2-基)甲基醚
MS:APCI(+ve)基峰552。
实施例47
5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲基)
苯基(2-甲基-1,3-噻唑-4-基)甲基醚
MS:APCI(+ve)基峰569。
按照实施例20的通法,应用合适的胺,制备实施例48-94的化合物。
实施例48
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-
基}(4-吗啉基)甲酮
MS:APCI(+ve)基峰555。
实施例49
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N,N-二甲基-1H-
咪唑-5-甲酰胺
MS:APCI(+ve)基峰513。
实施例50
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(2-甲氧基乙
基)-1H-咪唑-5-甲酰胺
MS:APCI(+ve)基峰552。
实施例51
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(4-羟基环己
基)-1H-咪唑-5-甲酰胺
MS:APCI(+ve)基峰543。
实施例52
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[1-(羟甲基)丙
基]-1H-咪唑-5-甲酰胺
MS:APCI(+ve)基峰557。
实施例53
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(四氢-2-呋喃
基甲基)-1H-咪唑-5-甲酰胺
MS:APCI(+ve)基峰569。
实施例54
{1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-
基}[2-(羟甲基)-1-哌啶基]甲酮
MS:APCI(+ve)基峰583。
实施例55
1-(4-氯苄基)-N-[3-(二乙胺基)丙基]-4-[(4,4-二苯基-1-哌啶基)
甲基]-1H-咪唑-5-甲酰胺
MS:APCI(+ve)基峰598。
实施例56
{1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-
基}[3-(羟甲基)-1-哌啶基]甲酮
MS:APCI(+ve)基峰583。
实施例57
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(2-羟基乙基)-
1H-咪唑-5-甲酰胺
MS:APCI(+ve)基峰529。
实施例58
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(2-羟基乙基)-
N-甲基-1H-咪唑-5-甲酰胺
MS:APCI(+ve)基峰543。
实施例59
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[3-(1H-咪唑-
1-基)丙基]-1H-咪唑-5-甲酰胺
MS:APCI(+ve)基峰593。
实施例60
{1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-
基}(1-吡咯烷基)甲酮
MS:APCI(+ve)基峰539。
实施例61
{1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-
基}(3-羟基-1-吡咯烷基)甲酮
MS:APCI(+ve)基峰555。
实施例62
1-[4-({1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-
5-基}羰基)-1-哌嗪基]-1-乙酮
MS:APCI(+ve)基峰596。
实施例63
{1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-
基}(1-哌啶基)甲酮
MS:APCI(+ve)基峰553。
实施例64
1-(4-氯苄基)-N-[2-(二乙氨基)乙基]-4-[(4,4-二苯基-1-哌啶基)
甲基]-N-(2-羟基乙基)-1H-咪唑-5-甲酰胺
MS:APCI(+ve)基峰628。
实施例65
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[2-(4-吗啉基)
乙基]-1H-咪唑-5-甲酰胺
MS:APCI(+ve)基峰598。
实施例66
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-乙基-N-(2-羟
基乙基)-1H-咪唑-5-甲酰胺
MS:APCI(+ve)基峰587。
实施例67
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-
基}(4-乙基-1-哌嗪基)甲酮
MS:APCI(+ve)基峰582。
实施例68
N-(2-氨基-2-氧代乙基)-1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)
甲基]-1H-咪唑-5-甲酰胺
MS:APCI(+ve)基峰542。
实施例69
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[2-(1-吡咯烷
基)乙基]-1H-咪唑-5-甲酰胺
MS:APCI(+ve)基峰582。
实施例70
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[2-(1H-咪唑-
4-基)乙基]-1H-咪唑-5-甲酰胺
MS:APCI(+ve)基峰579。
实施例71
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基-]-N-甲基-1H-咪唑-
5-甲酰胺
MS:APCI(+ve)基峰499。
实施例72
1-(4-氯苄基)-N-(2,3-二羟基丙基)-4-[(4,4-二苯基-1-哌啶基)甲
基]-1H-咪唑-5-甲酰胺
MS:APCI(+ve)基峰559。
实施例73
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[(1-乙基-2-吡
咯烷基)甲基]-1H-咪唑-5-甲酰胺
MS:APCI(+ve)基峰596。
实施例74
1-({1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-
基}羰基)-4-哌啶甲酸乙酯
MS:APCI(+ve)基峰625。
实施例75
1-({1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-
基}羰基)-3-哌啶甲酸乙酯
MS:APCI(+ve)基峰625。
实施例76
3-[({1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-
基}羰基)氨基]丙酸甲酯
MS:APCI(+ve)基峰571。
实施例77
2-[{1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-
基}羰基)氨基]乙酸甲酯
MS:APCI(+ve)基峰557。
实施例78
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(2-吡啶基甲
基)-1H-咪唑-5-甲酰胺
MS:APCI(+ve)基峰576。
实施例79
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[2-(2-吡啶基)
乙基]-1H-咪唑-5-甲酰胺
MS:APCI(+ve)基峰590。
实施例80
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(3-吡啶基甲
基)-1H-咪唑-5-甲酰胺
MS:APCI(+ve)基峰576。
实施例81
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(2-羟基-1,1-
二甲基乙基)-1H-咪唑-5-甲酰胺
MS:APCI(+ve)基峰557。
实施例82
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(2-羟基-1-甲
基乙基)-1H-咪唑-5-甲酰胺
MS:APCI(+ve)基峰543。
实施例83
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[3-(2-氧代-1-
吡咯烷基)丙基]-1H-咪唑-5-甲酰胺
MS:APCI(+ve)基峰610。
实施例84
N-[2-(乙酰氨基)乙基]-1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)
甲基]-1H-咪唑-5-甲酰胺
MS:APCI(+ve)基峰570。
实施例85
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[2-(2-羟基乙
氧基)乙基]-1H-咪唑-5-甲酰胺
MS:APCI(+ve)基峰573。
实施例86
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[1-(羟基甲基)
环戊基]-1H-咪唑-5-甲酰胺
MS:APCI(+ve)基峰583。
实施例87
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[2-羟基-1-(羟
甲基)乙基]-1H-咪唑-5-甲酰胺
MS:APCI(+ve)基峰559。
实施例88
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(3-甲氧基丙
基)-1H-咪唑-5-甲酰胺
MS:APCI(+ve)基峰557。
实施例89
1-({1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-
基}羰基)-2-吡咯烷甲酰胺
MS:APCI(+ve)基峰582。
实施例90
1-({1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基-]-1H-咪唑-5-
基}-羰基)-2-吡咯烷甲酰胺
MS:APCI(+ve)基峰582。
实施例91
{1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-
基}[4-(2-羟乙基)-1-哌啶基]甲酮
MS:APCI(+ve)基峰597。
实施例92
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(2-丙炔基)-
1H-咪唑-5-甲酰胺
MS:APCI(+ve)基峰523。
实施例93
4-({1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-
基}羰基)-2-哌嗪酮
MS:APCI(+ve)基峰513。
实施例94
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[1-(羟甲基)丙
基]-1H-咪唑-5-甲酰胺
MS:APCI(+ve)基峰557。
实施例95
1-{3-(4-氯苄基)-[1,2,4]-噁二唑-5-基甲基}-4,4-二苯基哌啶盐酸
盐
(a)3-(4-氯苄基)-[1,2,4]噁二唑-5-甲醇
在0℃和搅拌下,把乙酰氧乙酰氯溶液(1.75ml)加入到4-氯-N-羟基苯ethanimidamide(3.0g)和碳酸钾(2.46g)在丙酮(60ml)的悬浮液中。经2小时后,把溶液温热至室温,加入水和二氯甲烷,分离有机相,然后浓缩。把残余物溶解于甲苯(100ml)中,将溶液回流加热20小时,冷却后浓缩至油状物。色谱纯化(异己烷∶乙酸乙酯=6∶1)得到油状物(2.2g),将其溶解于甲醇(20ml),加入碳酸钾(1.15g)。室温下搅拌化合物16小时,加入水和乙酸乙酯。分离有机相,除去溶剂得到油状物(1.6g)。
MS:APCI(+ve)225/227(M+H);
1H NMRδ(CDCl3)7.3-7.2(m,4H)、4.8(s,2H)、4.04(s,2H)、2.9(s,1H)。
(b)1-{3-(4-氯苄基)-[1,2,4]-噁二唑-5-基甲基}-4,4-二苯基哌啶
盐酸盐
按照实施例17(b)的方法,应用实施例95(a)产物(0.5g)得到油状粗产物。用色谱纯化(异己烷∶乙酸乙酯=3∶1)得到泡沫状物质,用1.0M氯化氢乙醚溶液处理得到固体标题化合物(0.15g),熔点:161-162℃。
MS:ESI(+ve)448.18(M+H);
1H NMRδ(d6-DMSO)7.6-7.2(m,15H)、4.76(s,2H)、4.13(s,2H)、3.05(sb,4H)、2.5(sb,4H)。
药理学分析
钙流出[Ca2+]1分析
a)人嗜酸性细胞
根据现有技术(Hansel等.,J.Immunol.Methods,1991,145,105-110)从EDTA抗凝外周细胞分离出人嗜酸性细胞。将细胞重新悬浮(5×106ml-1),在室温下,以1小时的时间加入5μM FLUO-3/AM+Pluronic F127 2.2μl/ml(分子探针)的低钾溶液(LKS;NaCl118mM,硫酸镁0.8mM、葡萄糖5.5mM、碳酸钠8.5mM、氯化钾5mM、HEPES 20mM、氯化钙1.8mM、BSA0.1%,pH7.4)。加载后,将细胞在200g处离心5分钟,将其以2.5×106ml-1的浓度重新悬浮于LKS中。然后以100ml/孔的量将细胞转移至96孔FLIPr培养皿(聚-D-赖氨酸培养皿,来自Becton Dickinson,用5μM纤连蛋白预先培养2小时)。将该培养皿在200g处离心5分钟,用LKS洗涤细胞两次(200μl;室温)。
在二甲亚砜中预先溶解实施例中的化合物,使其浓度最终为0.1%(v/v)的二甲基亚砜。加入A50浓度的eotaxin开始分析,应用FLIPR(荧光成像板读数计,Molecular Devices,Sunnyvale,美国)监测fluo-3荧光(IEx=490nm和IEm=520nm)的瞬间增加。
b)人单核细胞
根据现有技术(Cunoosamy & Holbrook,J.Leukocyte Biology,1998,S2,13)从EDTA抗凝外周血液中分离人单核细胞。将细胞重新悬浮(5×106ml-1)于LKS,在室温下,以1小时的时间加入5μMFLUO-3/AM+Pluronic F127 2.2μl/ml(分子探针)。加载后,将细胞在200g处离心5分钟,将其以0.5×106ml-1的浓度重新悬浮于LKS中。然后将细胞转移至96孔FLIPr培养皿(Costar)。以0.5×106ml-1的浓度把100μl细胞加入到各个孔中。将该培养皿离心(200g;5分钟;室温)使细胞粘附。离心后用LKS洗涤细胞2次(200μl;室温)。
在二甲亚砜中预先溶解实施例中的化合物,使其浓度最终为0.1%(v/v)的二甲基亚砜。加入A50浓度的MIP-1α开始分析,应用FLIPR(荧光成像板读数计,Molecular Devices,Sunnyvale,美国)监测fluo-3荧光(IEx=490nm和IEm=520nm)的瞬间增加。
实施例中的化合物被发现为在人嗜酸性细胞中介导[Ca2+]i的eotaxin拮抗剂和/或在人单核细胞中介导[Ca2+]i的MIP-1α拮抗剂。
人嗜酸性细胞趋药性
根据现有技术(Hansel等.,J.Immunol.Methods,1991,145,105-110)从EDTA抗凝外周血液中分离人嗜酸性细胞。在室温下,将其以10×106ml-1的浓度重新悬浮于含有200IU/ml青霉素、200μg/ml硫酸链霉素并补充有10%HIFCS的RPMI中。
在37℃下用载体或化合物(100×所需要在10%二甲基亚砜中的最终浓度)预先培养嗜酸性细胞(700μl)15分钟。把28μl含实施例化合物或溶剂浓度的eotaxin浓度(0.1-100nM)加入到趋药性培养皿的较低孔中。然后将过滤器置于孔上,把25μl嗜酸性细胞悬浮液加入到过滤器顶部。在37℃下在湿润培养器中用95%空气/5%CO2气体培养该培养皿至趋药性。
把含有未移动细胞的基质小心地从过滤器上方吸出,然后弃去。用含有5mM EDTA的磷酸缓冲液(PBS)洗涤过滤器1次以除去所有粘附的细胞。把通过过滤器移动的细胞经离心(300×g室温下离心5分钟)沉淀,移开过滤器,将上清液转移至96-孔培养皿(Costar)的各个孔中。加入28μl含0.5%Triton×100的PBS溶解沉淀的细胞,然后进行两次冷冻/解冻步骤。然后把细胞溶解物加入到上清液中。按照Strath等.,J.Immunol.Methods,1985,
83,209中记载的方法,通过测定上清液中嗜酸性细胞过氧化物酶活性定量分析嗜酸性细胞转移的数目。
发现某些实施例化合物为介导人嗜酸性细胞趋药性的eotaxin的拮抗剂。
Claims (8)
1、式(I)化合物或其可药用盐或溶剂化物:
其中:
R1和R2独立地代表任选被卤素、C1-6烷基、硝基、氰基、羟基、亚甲二氧基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基或C1-6烷基磺酰基所取代的苯基;
各个R3独立地代表卤素、硝基、C1-6烷基、氰基、C1-6卤代烷基、羟基或C1-6烷氧基;各个烷氧基可任选地被卤素、NR5R6、CO2R7、CONR8R9、吡唑烷酮或含有1-3个独立选自N、O和S作为杂原子的五元杂芳环;所述杂芳环可以任选地进一步被1个或多个C1-4烷基所取代;
n代表整数0-3;
R4代表氢、羟基或NR10R11;
A代表-CO-、-CH2-或一个键;
Q代表C1-4亚烷基;
U、W和X独立地代表任选被C1-4烷基取代的碳原子或代表氮原子;
V代表任选被C1-4烷基取代的氮原子或代表氧原子;
Y代表C1-4亚烷基或-CO-;
R5、R6、R7、R8、R9独立地代表氢原子或C1-6烷基;
R10和R11独立地代表氢原子、C2-6不饱和烷基或C1-6烷基;各个烷基任选地被CO2R12、羟基、C1-6烷氧基、CONH2、NR13R14、OCH2CH2OH或含有一个或两个选自N、O和S作为杂原子的五元或六元饱和或不饱和杂环所取代;所述环任选地含有一个形成羰基的环碳原子;所述环任选地进一步被C1-4烷基所取代;
或者基团NR10R11一起代表4-8元饱和氮杂环系统,所述环任选地含有选自N、O和S的另一个环杂原子;所述环任选地含有一个组成羰基的环碳原子,所述环任选地还被C1-6烷基、C1-6羟基烷基、羟基、CO2R15、CONH2、CHO或COCH3所取代;
R12和R15独立地代表氢或C1-4烷基;和
R13和R14独立地代表氢、C1-4烷基或C1-4烷酰基。
2、权利要求1的化合物,其中V代表氮原子。
3、权利要求1或2的化合物,其中R3代表卤素。
4、权利要求3的化合物,其中R3代表氯。
5、权利要求1的式(I)化合物或其可药用盐或溶剂化物,其选自:
1-[(苄基-1H-吡唑-3-基)甲基-]-4,4-二苯基哌啶;
1-{[1-(3-氯苄基)-1H-吡唑-3-基]甲基}-4,4-二苯基哌啶;
1-{[1-(3,4-二甲基苄基)-1H-吡唑-3-基]甲基}-4,4-二苯基哌啶;
1-{[1-(4-甲基苄基)-1H-吡唑-3-基]甲基}-4,4-二苯基哌啶;
4,4-二苯基-1-({1-[4-三氟甲基)苄基]-1H-吡唑-3-基}甲基)-哌啶;
1-{[1-(2,4-二氯苄基)-1H-吡唑-3-基]甲基}-4,4-二苯基哌啶;
1-{[1-(3,4-二氯苄基)-1H-吡唑-3-基]甲基}-4,4-二苯基哌啶;
1-{[1-(3,4-二氟苄基)-1H-吡唑-3-基]甲基}-4,4-二苯基哌啶;
1-{[1-(4-氯苄基)-1H-吡唑-3-基]甲基}-4,4-二苯基哌啶;
1-{[1-(4-氟苄基)-1H-吡唑-3-基]甲基}-4,4-二苯基哌啶;
1-{[4-(4-氯-2-甲氧基苄基)-1H-吡唑-3-基]甲基}-4,4-二苯基哌啶;
5-氯-2-({3-[(4,4-二苯基-1-哌基)甲基]-1H-吡唑-1-基}甲基)苯酚;
2-[5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲基)苯氧基]-N,N-二甲基乙酰胺;
1-{[1-(4-氯苄基)-1H-咪唑-4-基]甲基}-4,4-二苯基哌啶;
1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基}-1H-吡唑-4-甲醛;
{1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基}-1H-吡唑-4-基]甲醇;
1-{[1-(4-氯苄基)-1H-1,2,3-三唑-5-基]甲基}-4,4-二苯基哌啶;
1-{[1-(4-氯苄基)-1H-1,2,3-三唑-4-基]甲基}-4,4-二苯基哌啶;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-甲酸;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-甲酰胺;
1-{[2-(4-氯苄基)-1H-咪唑-5-基]甲基}-4,4-二苯基哌啶;
1-{[2-(4-氯苄基)-1-甲基-1H-咪唑-5-基]甲基}-4,4-二苯基哌啶;
1-{[2-(4-氯苄基)-3-甲基-3H-咪唑-5-基]甲基}-4,4-二苯基哌啶;
[2-(4-氯苄基)-1H-咪唑-5-基](4,4-二苯基-1-哌啶基)甲酮;
2-[4-({1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-4-基}甲基)-1-哌嗪基]-1-乙醇;
4-({1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-4-基}甲基)-1-哌嗪甲醛;
1-[4-({1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-4-基}甲基)-1-哌嗪基]-1-乙酮;
N′-({1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-4-基}甲基)-N1,N2,N2-三甲基-1,2-乙二胺;
N-({1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-4-基}-甲基)-2-(4-吗啉基)-1-乙胺;
1-{[1-(4-氮杂环丁烷基甲基)-1-(4-氯苄基)-1H-吡唑-3-基]甲基}-4,4-二苯基哌啶;
N-({1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-4-基}-甲基)-2-(1-吡咯烷基)-1-乙胺;
N-({1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-4-基}-甲基)-β-丙氨酸;
2-[({1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-4-基}-甲基)氨基]乙酸;
N-({1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-4-基}甲基)-2-(2-吡啶基)-1-乙胺;
{1-(4-氯苄基)-3-[(4,4-二苯基-1-吡啶基)甲基]-1H-吡唑-4-基}-N-(4-吡啶基甲基)甲胺;
2-[1-({1-(4-氯苄基)-3-[(4,4-二苯基-1-吡啶基)甲基]-1H-吡唑-4-基}甲基)-4-哌啶基]-1-乙醇;
1-({1-(4-氯苄基)-3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-4-基}甲基)-4-甲基-1,4-二氮杂环庚烷;
3-[5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲基)苯氧基]-N,N-二甲基-1-丙胺;
2-[5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲基)苯氧基]乙酸;
2-[5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲基)苯氧基]乙酰胺;
2-[5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲基)苯氧基]-N,N-二甲基乙酰胺;
2-[5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲基)苯氧基]-N,N-二乙基乙酰胺;
2-[5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲基)苯氧基]丙酰胺;
2-[5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲基)苯氧基]-N-甲基乙酰胺;
1-{2-[5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲基)苯氧基]乙酰基}-3-吡唑烷酮;
1-[(1-{4-氯-2-[(3,5-二甲基-4-异噁唑基)甲氧基]苄基}-1H-吡唑-3-基)甲基]-4,4-二苯基哌啶;
5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲基)苯基(1-甲基-1H-咪唑-2-基)甲基醚;
5-氯-2-({3-[(4,4-二苯基-1-哌啶基)甲基]-1H-吡唑-1-基}甲基)苯基(2-甲基-1,3-噻唑-4-基)甲基醚;
{1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-基}(4-吗啉基)甲酮;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N,N-二甲基-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(2-甲氧基乙基)-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(4-羟基环己基)-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[1-(羟甲基)丙基]-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(四氢-2-呋喃基甲基)-1H-咪唑-5-甲酰胺;
{1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-基}[2-(羟甲基)-1-哌啶基]甲酮;
1-(4-氯苄基)-N-[3-(二乙基氨基)丙基]-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-甲酰胺;
{1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-基}[3-(羟甲基)-1-哌啶基]甲酮;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(2-羟基乙基)-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(2-羟基乙基)-N-甲基-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[3-(1H-咪唑-1-基)丙基]-1H-咪唑-5-甲酰胺;
{1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-基}(1-吡咯烷基)甲酮;
{1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-基}(3-羟基-1-吡咯烷基)甲酮;
1-[4-({1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-基}羰基)-1-哌嗪基]-1-乙酮;
{1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-基}(1-哌啶基)甲酮;
1-(4-氯苄基)-N-[2-(二乙基氨)乙基]-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(2-羟基乙基)-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[2-(4-吗啉基)乙基]-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-乙基-N-(2-羟基乙基)-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-基}(4-乙基-1-哌嗪基)甲酮;
N-(2-氨基-2-氧代乙基)-1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[2-(1-吡咯烷基)乙基]-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[2-(1H-咪唑-4-基)乙基]-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-甲基-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-N-(2,3-二羟基丙基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[(1-乙基-2-吡咯烷基)甲基]-1H-咪唑-5-甲酰胺;
1-({1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-基}羰基)-4-哌啶甲酸乙酯;
1-({1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-基}羰基)-3-哌啶甲酸乙酯;
3-[({1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-基}羰基)氨基]丙酸甲酯;
2-[({1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-基}羰基)氨基]乙酸甲酯;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(2-吡啶基甲基)-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[2-(2-吡啶基)乙基]-1H-咪唑-5-甲酰胺
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(3-吡啶基甲基)-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(2-羟基-1,1-二甲基乙基)-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(2-羟基-1-甲基乙基)-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[3-(2-氧代-1-吡咯烷基)丙基]-1H-咪唑-5-甲酰胺;
N-[2-(乙酰氨基)乙基]-1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[2-(2-羟基乙氧基)乙基]-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[1-(羟基甲基)环戊基]-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[2-羟基-1-(羟甲基)乙基]-1H-咪唑-5-甲酰胺;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(3-甲氧基丙基)-1H-咪唑-5-甲酰胺;
1-({4-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-基}-羰基)-2-吡咯烷甲酰胺;
1-({1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-基}-羰基)-2-吡咯烷甲酰胺;
{1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-基}[4-(2-羟乙基)-1-哌啶基]甲酮;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-(2-丙炔基)-1H-咪唑-5-甲酰胺;
4-({1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-1H-咪唑-5-基}羰基)-2-哌嗪酮;
1-(4-氯苄基)-4-[(4,4-二苯基-1-哌啶基)甲基]-N-[1-(羟甲基)丙基]-1H-咪唑-5-甲酰胺;
1-{3-(4-氯苄基)-[1,2,4]-噁二唑-5-基甲基}-4,4-二苯基哌啶。
6、制备权利要求1所定义的式(I)化合物的方法,包括:
(i)当Y代表CH2时,让式(III)化合物
其中R1和R2如权利要求1所定义,
对通式(II)化合物
其中R3、R4、A、Q、U、V、W、X和n如权利要求1所定义,进行还原胺化反应;或
(ii)当Y代表C1-4烷基时,让通式(IV)化合物
其中R3、R4、A、Q、U、V、W、X和n如权利要求1所定义,L1为离去基团,
与式(III)化合物反应;或
(iii)当Y代表CO时,
让通式(V)化合物
其中R3、R4、A、Q、U、V、W、X和n如权利要求1所定义,L2为离去基团,
与式(III)化合物反应;或
(iv)当在式(I)中至少一个R3基团代表任选取代的C1-6烷氧基时,
让式(VI)化合物
其中R1、R2、R3、R4、A、Q、U、V、W、X、Y和n如式(I)所定义,与式(VII)化合物进行反应
R-L3 (VII)
其中R是这样的基团:其能使所得基团OR代表权利要求1中定义R3所述的任选被取代的C1-6烷氧基,L3为离去基团;
(v)当A代表CO并且R4代表NR10R11时,
让式(VIII)化合物
其中R1、R2、R3、Q、U、V、W、X、Y和n如权利要求1所定义,L4为离去基团,
和式(IX)化合物反应
HNR10R11 (IX)
其中R10和R11如权利要求1所定义;或
(vi)当A代表CH2并且R4代表NR10R11时,
让式(IX)化合物
HNR10R11 (IX)
其中R10和R11如权利要求1所述
对式(X)化合物进行还原胺化反应
其中R1、R2、R3、Q、U、V、W、X、Y和n如权利要求1所定义;或
(vii)当Q键合于V并且V代表氮原子时,
让式(XI)化合物
其中R1、R2、R4、A、U、W、X和Y如权利要求1所定义,
与式(XII)化合物反应
其中R3、Q和n如权利要求1所定义,L5为离去基团;
和任选地在(i)、(ii)、(iii)、(iv)、(v)、(vi)或(vii)后,把式(I)化合物转换成其它的式(I)化合物,和/或形成式(I)化合物的可药用盐或溶剂化物。
7、含有权利要求1-5任意一项所述的式(I)化合物或其可药用盐或溶剂化物和可药用辅料、稀释剂或载体的药物组合物。
8、制备权利要求7的药物组合物的方法,包括:把权利要求1-5任意一项所述的式(I)化合物或其可药用盐或溶剂化物和可药用辅料、稀释剂或载体相混合。
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PL2970132T3 (pl) | 2013-03-14 | 2021-04-06 | Epizyme, Inc. | Inhibitory metylotransferazy argininy i ich zastosowania |
PT3022202T (pt) | 2013-07-18 | 2019-09-03 | Novartis Ag | Inibidores da autotaxina compreendendo um núcleo beteroaromático anel-benzilo-amida-ciclo |
CN108299411B (zh) | 2017-01-13 | 2021-02-05 | 中国人民解放军军事医学科学院毒物药物研究所 | 4,4-二苯基哌啶类化合物或其可药用盐、药物组合物及用途 |
Family Cites Families (9)
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DE2139084C3 (de) | 1971-08-04 | 1979-03-01 | Byk Gulden Lomberg Chemische Fabrik Gmbh, 7750 Konstanz | Verfahren zur Herstellung von 4,4-Diphenyl-piperidinen |
IL90858A (en) | 1988-07-07 | 1994-08-26 | Rhone Poulenc Sante | History (Aza) Naftalensultam, their preparation and preparations containing them |
AU652747B2 (en) | 1990-04-10 | 1994-09-08 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Pyridines as medicaments |
DE4140542A1 (de) | 1991-12-09 | 1993-06-17 | Bayer Ag | Piperdylmethyl substituierte chormanderivate |
IL125658A0 (en) | 1997-08-18 | 1999-04-11 | Hoffmann La Roche | Ccr-3 receptor antagonists |
US6339087B1 (en) | 1997-08-18 | 2002-01-15 | Syntex (U.S.A.) Llc | Cyclic amine derivatives-CCR-3 receptor antagonists |
DE19756235A1 (de) * | 1997-12-17 | 1999-07-01 | Klinge Co Chem Pharm Fab | Neue piperidinylsubstituierte Pyridylalkan- alken- und -alkincarbonsäureamide |
HN1999000149A (es) * | 1998-09-09 | 2000-01-12 | Pfizer Prod Inc | Derivados de 4,4-biarilpiperidina |
US6046331A (en) | 1998-12-17 | 2000-04-04 | Synaptic Pharmaceutical Corporation | Imidazolones and their use in treating benign prostatic hyperplasia and other disorders |
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1999
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- 2000-07-18 DE DE60001586T patent/DE60001586T2/de not_active Expired - Fee Related
- 2000-07-18 AT AT00946134T patent/ATE233754T1/de not_active IP Right Cessation
- 2000-07-18 IL IL14714900A patent/IL147149A0/xx unknown
- 2000-07-18 KR KR1020027000797A patent/KR20020027498A/ko not_active Application Discontinuation
- 2000-07-18 BR BR0012610-1A patent/BR0012610A/pt not_active IP Right Cessation
- 2000-07-18 JP JP2001511441A patent/JP2003505383A/ja not_active Withdrawn
- 2000-07-18 EP EP00946134A patent/EP1202984B1/en not_active Expired - Lifetime
- 2000-07-18 NZ NZ516606A patent/NZ516606A/en unknown
- 2000-07-18 US US09/623,744 patent/US6566376B1/en not_active Expired - Fee Related
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- 2000-07-18 MX MXPA02000671A patent/MXPA02000671A/es active IP Right Grant
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2001
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WO2001005782A1 (en) | 2001-01-25 |
NO20020282D0 (no) | 2002-01-18 |
IL147149A0 (en) | 2002-08-14 |
CA2378084A1 (en) | 2001-01-25 |
ZA200110540B (en) | 2003-03-24 |
JP2003505383A (ja) | 2003-02-12 |
SE9902765D0 (sv) | 1999-07-21 |
ATE233754T1 (de) | 2003-03-15 |
MXPA02000671A (es) | 2002-07-02 |
DE60001586D1 (de) | 2003-04-10 |
DE60001586T2 (de) | 2004-02-12 |
NO20020282L (no) | 2002-03-21 |
EP1202984B1 (en) | 2003-03-05 |
AU6001600A (en) | 2001-02-05 |
NZ516606A (en) | 2003-09-26 |
US6566376B1 (en) | 2003-05-20 |
AU771344B2 (en) | 2004-03-18 |
CN1361775A (zh) | 2002-07-31 |
KR20020027498A (ko) | 2002-04-13 |
BR0012610A (pt) | 2002-04-09 |
EP1202984A1 (en) | 2002-05-08 |
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