CN103848788A - 氮杂环庚烷类化合物及其制备方法和用途 - Google Patents
氮杂环庚烷类化合物及其制备方法和用途 Download PDFInfo
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- CN103848788A CN103848788A CN201210500628.9A CN201210500628A CN103848788A CN 103848788 A CN103848788 A CN 103848788A CN 201210500628 A CN201210500628 A CN 201210500628A CN 103848788 A CN103848788 A CN 103848788A
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- compound
- pain
- azepane
- alkyl
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- -1 Azacycloheptane compound Chemical class 0.000 title claims abstract description 78
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 208000002193 Pain Diseases 0.000 claims abstract description 29
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 23
- 230000036407 pain Effects 0.000 claims abstract description 23
- 230000001404 mediated effect Effects 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 10
- 102000003840 Opioid Receptors Human genes 0.000 claims abstract description 9
- 108090000137 Opioid Receptors Proteins 0.000 claims abstract description 9
- 208000000094 Chronic Pain Diseases 0.000 claims abstract description 3
- 208000018522 Gastrointestinal disease Diseases 0.000 claims abstract description 3
- 206010061218 Inflammation Diseases 0.000 claims abstract description 3
- 208000005298 acute pain Diseases 0.000 claims abstract description 3
- 230000004054 inflammatory process Effects 0.000 claims abstract description 3
- 208000004296 neuralgia Diseases 0.000 claims abstract description 3
- 208000021722 neuropathic pain Diseases 0.000 claims abstract description 3
- 208000037821 progressive disease Diseases 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 62
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 claims description 5
- 208000035475 disorder Diseases 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 150000005840 aryl radicals Chemical class 0.000 claims description 3
- 150000001537 azepanes Chemical class 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000004946 alkenylalkyl group Chemical group 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 208000026137 Soft tissue injury Diseases 0.000 claims 1
- 125000003725 azepanyl group Chemical group 0.000 claims 1
- 201000010099 disease Diseases 0.000 abstract description 18
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000003446 ligand Substances 0.000 abstract description 3
- 230000000451 tissue damage Effects 0.000 abstract description 2
- 231100000827 tissue damage Toxicity 0.000 abstract description 2
- 208000020401 Depressive disease Diseases 0.000 abstract 1
- 230000002093 peripheral effect Effects 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 50
- 238000005160 1H NMR spectroscopy Methods 0.000 description 29
- 238000001308 synthesis method Methods 0.000 description 28
- 239000002994 raw material Substances 0.000 description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 238000001035 drying Methods 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 13
- 101100244562 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) oprD gene Proteins 0.000 description 12
- 108700023159 delta Opioid Receptors Proteins 0.000 description 12
- 102000048124 delta Opioid Receptors Human genes 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- 150000003839 salts Chemical class 0.000 description 11
- 102000051367 mu Opioid Receptors Human genes 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- 108020001612 μ-opioid receptors Proteins 0.000 description 10
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
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- 239000000203 mixture Substances 0.000 description 8
- 239000007832 Na2SO4 Substances 0.000 description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
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- 125000001424 substituent group Chemical group 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
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- 238000000034 method Methods 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
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- 229910052736 halogen Inorganic materials 0.000 description 4
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- JLICHNCFTLFZJN-HNNXBMFYSA-N meptazinol Chemical compound C=1C=CC(O)=CC=1[C@@]1(CC)CCCCN(C)C1 JLICHNCFTLFZJN-HNNXBMFYSA-N 0.000 description 4
- 229960000365 meptazinol Drugs 0.000 description 4
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- 239000000014 opioid analgesic Substances 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- YVPSEIUDVQNJDC-JKSUJKDBSA-N (3S,4S)-3-ethyl-3-(3-methoxyphenyl)-1-methylazepan-4-ol Chemical compound CC[C@@]1(CN(C)CCC[C@@H]1O)c1cccc(OC)c1 YVPSEIUDVQNJDC-JKSUJKDBSA-N 0.000 description 3
- WMPPDTMATNBGJN-UHFFFAOYSA-N 2-phenylethylbromide Chemical compound BrCCC1=CC=CC=C1 WMPPDTMATNBGJN-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 206010012335 Dependence Diseases 0.000 description 3
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 3
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- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
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- XOFLBQFBSOEHOG-UUOKFMHZSA-N γS-GTP Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=S)[C@@H](O)[C@H]1O XOFLBQFBSOEHOG-UUOKFMHZSA-N 0.000 description 3
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
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- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 description 2
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- QCTOLMMTYSGTDA-UHFFFAOYSA-N CN(C)CCCCO Chemical compound CN(C)CCCCO QCTOLMMTYSGTDA-UHFFFAOYSA-N 0.000 description 2
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- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
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- 239000000651 prodrug Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
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- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
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- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
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- 125000000168 pyrrolyl group Chemical group 0.000 description 1
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- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
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- 238000011069 regeneration method Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
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- 235000011152 sodium sulphate Nutrition 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D223/04—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with only hydrogen atoms, halogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings 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
- C07D223/08—Oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属药物化学领域，涉及式(I)结构的氮杂环庚烷类化合物；所述的氮杂环庚烷类化合物可作为新型阿片受体配基。本发明所述的化合物可用于制备治疗其可通过调节阿片受体改善或治疗的疾病中的药物；其中，所述疾病选自但不限于疼痛、胃肠道疾病和抑郁症，所述疼痛可选自但不限于中枢介导的疼痛、外周介导的疼痛、与结构或软组织损伤有关的疼痛、与炎症有关的疼痛、与进行性疾病有关的疼痛、神经病疼痛、急性疼痛和慢性疼痛。
Description
技术领域
本发明属药物化学领域，涉及氮杂环庚烷类化合物，具体涉及氮杂环庚烷类化合物及制备方法和它们在治疗阿片受体介导的疾病中的用途；所述的氮杂环庚烷类化合物为可用作阿片受体的化合物。
背景技术
目前，随着非阿片镇类痛药如乙酰氨基酚、阿司匹林的发现，为轻、中度疼痛提供了更为适宜的药物，但在缓解中重度疼痛上，阿片类镇痛药仍然是目前最为有效的治疗手段。所述阿片类镇痛药可作用于体内μ、δ和κ三种阿片亚型受体，其中，强效型镇痛药，如吗啡、芬太尼等多为μ受体激动剂，存在严重的呼吸抑制和成瘾性副作用，使其临床应用受到很多限制。近年研究发现，虽然δ受体自身的活化不能产生强效镇痛的生理效应，但其对μ受体介导的生理效应存在着调节作用，可减少呼吸抑制和成瘾性等副作用的产生；因此，对μ和δ受体具有混合作用的配基已成为寻找新型强效低毒镇痛药的一个重要研究方向。
此外，对δ阿片受体的研究也发现，δ阿片受体可介导多种中枢调控的疾病，如抑郁症和帕金森病等，因此，具有δ阿片受体活性的化合物除镇痛外，也可能拥有其他潜在的临床应用。
在已公开的研究中，如Bishop,M.J.et al.Journal ofMedicinal Chemistry，2003,46(4),623-633中报道了如下结构表示二芳基甲基哌嗪类化合物，具有对μ和δ阿片受体的混合作用。
此外，Cheng,K.et al.Organic & Biomolecular Chemistry，2007,5(8),1177-1190.和Hiebel,A.C.et al.Journal of Medicinal Chemistry，2007,50(16),3765-3776中报道如下结构表示的苯基哌啶类化合物，也同样具有对μ和δ阿片受体的混合作用。
美普他酚是一个上市的阿片类镇痛药，其结构属于3-芳基氮杂环庚烷；由于其具有区别于传统六元环结构如哌嗪和哌啶的结构特征，因此有成瘾性低，呼吸抑制作用小的特点。对美普他酚的早期机理研究证明，不同于传统μ阿片受体激动剂，美普他酚的特殊作用可能通过μl亚型受体发挥。近年的研究中，CN200610147585报道的基于美普他酚的双配基化合物证明具有镇痛的作用。
目前，研究同时作用于μ和δ阿片受体的新型化合物成为本领域一个重要研究方向。
发明内容
本发明的目的是提供氮杂环庚烷类化合物，具体涉及一类新型的3-芳基氮杂环庚烷类化合物或其药学上可接受的盐；所述化合物可同时作用于μ和δ阿片受体。
本发明中，所述的氮杂环庚烷类化合物，具有式（I）的结构，
其中，
R1为H、C1-6烷基、环烷基、链烯基、芳基C1-6烷基、杂环基C1-6烷基或杂芳基C1-6烷基；
R2为H或OR4，当R2为OR4时，R4为氢、C1-6烷基、环烷基、链烯烷基、芳基C1-6烷基、杂环基C1-6烷基、杂芳基C1-6烷基、取代或非取代的酰基；其中当R2为H时，R1选自芳基C1-6烷基、杂环基C1-6烷基或杂芳基C1-6烷基；
R3为H或CH3。
本发明中，优选地，氮杂环庚烷的3位的手性中心为R构型，如氮杂环庚烷的手性中心为（3R，4R）构型，或者氮杂环庚烷的手性中心为（3R，4S）构型；
或，R3优选为H；R2优选为H或OH；R1优选为芳基C1-6烷基。
本发明提供下述特别优选的化合物：
具体的，本发明提供了包含具有式（I）的化合物，或者是其药学上可接受的盐、前药、溶剂化物或其水合物，以及药学上可接受的载体、赋形剂和稀释液的药剂或者药物组合物。
本发明的另一个目的是，提供上述化合物在制备治疗阿片受体介导的疾病的药物中的用途；所述的药物为治疗其可通过调节阿片受体改善或治疗的疾病中的药物；所述疾病可选自但不限于疼痛、胃肠道疾病和抑郁症，所述疼痛可选自但不限于中枢介导的疼痛、外周介导的疼痛、与结构或软组织损伤有关的疼痛、与炎症有关的疼痛、与进行性疾病有关的疼痛、神经病疼痛、急性疼痛和慢性疼痛。
本发明所述化合物制备的药物可用于治疗有需要的患者中治疗或改善μ或δ阿片受体介导的疾病，可通过对需要对象给予有效治疗量的式（I）化合物或其药学上可接受的盐、溶剂化物或其水合物来实现治疗的目的；如，式（I）所示的化合物可通过口服、肠胃外、经皮、局部、经直肠或鼻内给药。
本发明中，除非另有说明，使用的以下术语具有以下的指定含义：
各种含烃部分的碳原子数含量由前缀表示，标示出该部分中碳原子的最小数和最大数，即前缀Ci-j表示整数“i”至整数“j”个碳原子的部分，包括端点；因此，如，C1-6烷基指1至6个碳原子的羰基，包括1个和6个碳原子；
“独立”选择的取代基指其中所述取代基可以是不同的取代基；因此，指定数目的碳原子（如C1-7）应独立地指烷基或环烷基部分中的碳原子数或指其中烷基作为其前缀词根出现的较大取代基的烷基部分；
“烷基”表示具有1-8个碳原子或在此范围内任何数目的直链和支链的基团，但是对单独基团例如“丙基”则只包括直链基团，支链异构体例如“异丙基”将明确表示；烷基可任意被一个、两个或三个选自下组的取代基所取代：卤素、芳基、杂芳基。代表性的例子包括但不限于：二氟甲基、2-氟乙基、3-氟丙基、4-氟丁基、3-氰基丁基，-CH=CH-芳基等；
“链烯基”和“链炔基”指具有2-8个碳原子或在此范围内任何数目的直链和支链的基团，其中链烯基链在所述链上具有至少一个双键和链炔基链在所述链上具有至少一个三键；
“环烷基”表示3-14个碳原子的饱和或部分饱和的、单环或多环烃环；所述的环包括但不限于环丙基、环丁基、环己基等；环烷基可任选被选自下组的一个、两个或三个取代基取代：卤素、芳基或杂芳基，或者，所述环烷基可稠合于苯环（苯并稠合的环烷基）5或6元杂芳基环形成杂芳基环稠和的环烷基；
“杂环基”指5-7元的其中1-2元为N的非芳族环或5-7元的其中0、1或2元为氮和至多2元为氧或硫的非芳族环，其中任选地，所述环包含0-1个不饱和键，并且任选地当所述环具有6或7个成员时，其包含至多2个不饱和键；杂环基的实例包括但不限于吡咯啉基（包括2H-吡咯、2-吡咯啉基或3-吡咯啉基）、吡咯烷基、2-咪唑啉基、咪唑烷基、2-吡唑啉基、吡唑烷基、哌啶基、吗啉基、硫吗啉基和哌嗪基；
“芳基”指不饱和的6个碳原子的芳族单环或指不饱和的10-14个碳原子的芳族多环；所述芳基环的实例包括但不限于苯基、萘基、或蒽基；
“杂芳基”指其中所述环由碳原子组成并具有至少一个杂原子成员的5或6元的芳族环；合适的杂原子包括氮、硫或氧；杂芳基的实例包括但不限于呋喃基、噻吩基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基、吡啶基、哒嗪基、嘧啶基或吡嗪基；稠合的杂芳基包括吲哚基、异吲哚基、二氢吲哚基、苯并呋喃基、苯并噻吩基、吲唑基、苯并咪唑基、苯并噻唑基、苯并噁唑基、苯并异噁唑基、苯并噻二唑基、苯并三唑基、喹嗪基、喹啉基、异喹啉基或喹唑啉基；
“芳基烷基”指用芳基取代的烷基（例如苄基、苯乙基）；类似地，“芳烷氧基”指用芳基取代的烷氧基（例如苄氧基）；
“卤素”是氟、氯、溴和碘；用多个卤素取代的取代基以提供稳定的化合物的方式被取代；
具有相同分子式但是特性或其原子间的连接顺序或原子在空间的排列不同的化合物被称作“异构体”；原子在空间排列不同的异构体被称作“立体异构体”；
与另一个异构体不成镜像的立体异构体称作“非对映异构体”，而彼此是非叠加镜像的那些异构体称作“对映体”；当化合物具有不对称中心时，如与四个不同基团连接时，就可能成是一对对映体；上述对映体的特征在于其不对称中心的绝对构型，并用Cahn和Prelog的R-和S-排序规则表示，或者用分子旋转偏振光的平面的方式描述并指定为右旋或左旋性(即分别为(+)或(-)异构体)；手性化合物可单独对映体或者以对映体混合物存在；含有相等比例的对映体的混合物称作“外消旋混合物”。
本发明中所述的化合物可具有至少两个不对称中心，其可作为对映体存在，也可作为非对映体存在；当用于制备本发明所述化合物的方法产生立体异构体的混合物，所述异构体可通过常规技术例如制备性色谱法得到分离；所述化合物可以外消息形式或作为各对映体或非对映体通过立体定向合成或拆分制备；所述化合物例如可通过例如光学活性酸如(-)-二-对甲苯甲酰-D-酒石酸和/或(+)-二-对甲苯甲酰-L-酒石酸形成盐，随后经分级结晶并再生游离碱形成立体异构体；所述化合物也可通过形成立体异构酯或酰胺，随后层析分离并除去所述手性助剂被拆分，或者，所述化合物可采用手性HPLC柱进行拆分；本发明的范围包括所有的立体异构体、它们的外消旋混合物、非对映体和对映体；
“药学上可接受的载体”表示能用于制备药物组合物的载体；其一般是安全、无毒性的，无论生物上和其他方面的不良作用，包括能被用于兽用和人用药剂的载体；本发明中“药学上可以接受的载体”可包括一种或者一种以上的该类载体；
化合物的“药物上可接受的盐”是药学上可接受的盐，并具有母体化合物的药理活性，该类盐包括：
(1)酸加成盐，与无机酸，例如盐酸、氢溴酸、硫酸、硝酸、磷酸等形成；或与以下有机酸形成，例如乙酸、丙酸、己酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、3-(4-羟基苯甲酰基)苯甲酸、肉桂酸、苯乙醇酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、4-氯苯磺酸、2-萘磺酸、4-甲苯磺酸、樟脑磺酸、4-甲基二环[2.2.2]辛-2-烯-1-羧酸、葡糖庚酸（glucoheptonic acid）、4,4'-亚甲基二-(3-羟基-2-烯-1-羧酸)、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、月桂基磺酸、葡糖酸、谷氨酸、羟萘甲酸、水杨酸、硬脂酸、粘康酸等；或者
(2)母体化合物中的酸性质子被金属离子，如碱金属离子、碱土金属离子或铵离子取代形成的盐，或与有机碱如乙醇胺、二乙醇胺、三乙醇胺、氨基丁三醇、N-甲基葡萄糖胺等配位所形成的盐。
疾病的“处理”和“治疗”包括：
(1)预防疾病，即，使某种疾病的临床症状不在接触该疾病或易感染该疾病但尚未经历或者显示该疾病症状的哺乳动物上发生；
(2)抑制疾病，即，阻止或减轻该疾病或其临床症状的发展，或
(3)缓解疾病，即，使疾病及其临床症状消退。
“治疗有效量”是指给予哺乳动物以治疗疾病时足以实现对这种疾病的治疗的化合物量；“治疗有效量”随化合物、疾病和其严重程度以及待治疗哺乳动物的年龄和体重等而变。
本发明所述的化合物通常按IUPAC或CAS命名法进行命名，可使用本领域的普通技术人员公知的缩写形式（例如，“Ph”表示苯基，“Me”表示甲基，“Et”表示乙基，“h”表示小时，“r.t.”表示室温)。
具体实施方式
具有式（I）结构的化合物可如下面的通用合成路线和实施例描述而制备；用于合成本发明化合物起始原料的化合物是公知的，即使无法商业购得，也可使用所提供的具体参考或通过本领域技术人员通常应用的和/或记载于一般性参考文献中的标准方法方便地合成。
具体而言，本发明所述化合物根据下面详细描述的通用合成路线或本领域技术人员已知的类似方法制备；上述反应通常根据已知的工艺、方法或类似方法进行：
通用合成路线
Scheme 1.a:1)ClCOOAlk,DCM;2)MeOH;b:AlkCl,AlkBr or AlkOMs;c:AlkCOCl or AlkCOOH,缩合剂（如EDC，HATU，ClCOOAlk等）;d:BBr3,DCM
通用合成方法1：
将化合物1(1.69mmol)溶于30mL二氯乙烷中，搅拌下加入(5.1mmol)碳酸钠，升温至回流，回流状态下滴加α-氯代氯甲酸乙酯(8.5mmol)，反应4h。加入20mL水洗涤使白色固体全部溶解，分液，水相用20mL二氯甲烷回提，合并有机相，经饱和食盐水洗涤，无水Na2SO4干燥，过滤，浓缩；将该粗品溶于20mL甲醇，回流12h，冷却，加压蒸干溶剂，得浅黄色油状物，直接用于下步反应；
通用合成方法2：
将化合物2（0.46mmol）溶于2ml乙腈，加入三乙胺280μl（2mmol）及1.2摩尔当量的卤代烃，加热回流反应6小时；减压蒸除溶剂，加入饱和NaHCO3溶液，用氯仿提取；合并有机层，饱和食盐水洗涤；氯仿层用无水Na2SO4干燥。过滤，浓缩，干燥得粗品。经硅胶柱层析分离后得产物3；
通用合成方法3：
将化合物3（0.38mmol）溶于10ml二氯甲烷，加入三乙胺60μl（0.43mmol），在并水浴冷却下，缓慢加入酰氯（0.42mmol）；继续搅拌反应1小时；停止反应后，加入10ml水洗涤，用10ml二氯甲烷回提两次；合并有机层，饱和食盐水洗涤。二氯甲烷层用无水Na2SO4干燥；过滤，浓缩，干燥得粗品；经硅胶柱层析分离后得产物4；
通用合成方法4：
在25ml的三口圆底瓶中，加入10ml无水二氯甲烷，冰盐浴冷却到-20°C，将约200ul的BBr3加至液面下，机械强力搅拌。缓慢滴加含有化合物4（0.38mmol）的二氯甲烷溶液；搅拌反应1小时，将反应液缓慢倒入冷却的饱和碳酸氢钠溶液；水层用二氯甲烷提取，合并有机层饱和食盐水洗涤；乙醚层用无水Na2SO4干燥；过滤，浓缩，干燥；粗品经硅胶柱层析分离得产物5。
下面通过实施例详细地说明本发明。本发明又不受这些实施例的限制。
实施例1
(±)-cis-3-乙基-3-(3'-甲氧基苯基)-4-羟基-1-甲基-氮杂环庚烷-2-酮（A-2）和(±)-trans-3-乙基-3-(3'-甲氧基苯基)-4-羟基-1-甲基-氮杂环庚烷-2-酮（A-3）
在50ml圆底烧瓶中加入4g（14.5mmol）化合物A-1（按中国专利200410017499.3报道的方法合成）和20ml甲醇，缓慢加入0.78g（14.5mmol）KBH4，室温下，搅拌反应2小时；滴加1N HCl至pH为4，蒸除溶剂，加入30ml水及60ml乙酸乙酯，水层用乙酸乙酯回提，合并有机层，饱和食盐水洗涤，无水NaSO4干燥。过滤，浓缩，干燥后得4.5g白色固体；经柱层析分离得A-21.56g。1H NMR（CDCl3）δ7.21(t,3H,J=7.9Hz),7.09(s,1H),6.97(d,1H,J=8.1Hz),6.76(dd,1H,J=2.5,8.2Hz),4.09(dt,1H,J=3.7,11.5Hz),3.79(s,3H),3.15(m,1H),3.06(s,3H),2.82(m,1H),2.28(m,1H),2.10(q,1H,J=7.1Hz),2.05(d,1H,J=3.3Hz),2.02(m,1H),1.94(q,1H,J=7.2Hz),1.67-1.54(m,2H),1.00(t,3H,J=7.1Hz。得A-31.7g。1H NMR（CDCl3）δ7.23(t,3H,J=8.1Hz),6.77(dd,1H,J=2.0,7.9Hz),6.66(d,1H,J=7.9Hz),6.62(m,1H),4.43(m,1H),3.79(s,3H),3.19(m,1H),3.10(s,3H),2.83(m,1H),2.39(q,1H,J=7.2Hz),2.24(m,1H),1.97(m,1H),1.82(m,1H),1.81(d,1H,J=3.9Hz),1.73(q,1H,J=7.3Hz),1.38(m,1H),0.67(t,3H,J=7.3Hz).
(±)-cis-3-乙基-3-(3'-甲氧基苯基)-4-羟基-1-甲基-氮杂环庚烷(A-4)
在250ml干燥的三口烧瓶中，加入8.3g（29.9mmol）化合物A-2及80ml无水THF，分批缓慢加入LiAlH43.4g（89.5mmol）。升温回流反应1h；冷至室温，缓慢滴加8mL H2O/10mLTHF混合液，再滴加15％NaOH溶液8ml，产生白色固体，最后再加入8mLH2O，过滤得到无色透明溶液，滤饼用THF提取，合并滤液后浓干，加入10％NaHCO3溶液30mL，用氯仿提取；合并有机层，饱和食盐水洗涤，无水Na2SO4干燥；过滤，浓缩；经柱层析分离得浅黄色油状物6.7g；1H NMR(CDCl3)δ7.28(t,1H,J=8.0Hz,Ar-H),6.95(d,1H,J=7.9Hz,Ar-H),6.91(m,1H,Ar-H),6.78(dd,1H,J=2.0,8.2Hz,Ar-H),3.86(m,1H,CH),3.81(s,3H,OCH3),6.47(d,1H,J=14.3Hz,CH2),2.68(m,1H,CH2),5.12(d,1H,J=14.3Hz,CH2),2.52(m,1H,CH2),2.47(s,3H,NCH3),2.10-1.91(m,4H,CH2),1.65(q,1H,J=7.3Hz,CH2),1.54(m,1H,CH2),0.57(t,3H,J=7.3Hz,CH2 CH 3 )。MS(ESI)m/z264.2(M+H)+。
(3S，4R)-3-乙基-3-(3'-甲氧基苯基)-4-羟基-1-甲基-氮杂环庚烷-L-二苯甲酰酒石酸盐(A-5)
在25ml圆底烧瓶中将730mg（2.78mmol）A-4溶于30ml乙醇中，加热回流至完全溶解。滴加含L-二苯甲酰酒石酸（L-DBTA）1g（2.79mmol）的20ml无水乙醇溶液，滴加完毕后，即析出白色固体。继续回流搅拌1小时，缓慢放冷，置冰箱过夜。过滤，干燥得白色固体0.63g，收率72.8%。经甲醇重结晶得白色粉末A-5。[α]20 D-85.5°(c=0.13,MeOH)。1H NMR(Methanol-d4)δ8.13(d,4H,J＝7.0Hz,Ar-H),7.61(t,2H,J＝7.4Hz,Ar-H),7.48(t,4H,J＝7.8,7.4Hz,Ar-H),7.29(t,1H,J＝8.2,7.8Hz,Ar-H),6.98-6.82(m,3H,Ar-H),5.91(s,2H,CHCOOH),4.21(m,1H,OCHCH2),3.95(d,1H,J＝4.1Hz,NCH 2 C),3.79(s,3H,OCH3),3.51(d,1H,J=4.1Hz,NCH 2 C),3.42-2.32(m,2H,NCH 2 CH2),2.98(s,3H,NCH3),2.14-1.84(m,6H,3CH2),0.62(t,3H,J＝7.4Hz,CH2 CH 3 )。
(3S，4R)-3-乙基-3-(3'-甲氧基苯基)-4-羟基-1-甲基-氮杂环庚烷(A-6)
将290mg A-5盐溶于水20ml和乙醚20ml中，用氨水调节pH至9，分液，水层用乙醚提取，合并乙醚层，饱和食盐水洗涤；乙醚层用无水Na2SO4干燥；过滤，浓缩，干燥，得无色透明油状物A-6；1H NMR(Methnol-d4)δ7.24-6.73(m,4H,Ar-H),3.88(d,1H,J＝7.0Hz,-OCHCH2),3.78(s,3H,OCH3),3.20-2.58(m,4H,2CH2),1.99-1.56(m,6H,3CH2),0.58(t,3H,J＝7.4Hz,CH2 CH 3 ).MS(ESI)m/z264.2(M+H)+。
(3S，4R)-3-乙基-3-(3'-羟基苯基)-4-羟基-1-甲基-氮杂环庚烷(A)
按通用合成方法4，以A-6为原料，得到化合物A。1H NMR(CDCl3)δ7.14(t,1H,J=7.8Hz,Ar-H),6.83(d,1H,J=8.2Hz,Ar-H),6.77(s,1H,Ar-H),6.55(dd,J=8.2,2.0Hz,Ar-H),4.79(brs,2H,2OH),3.93(d,1H,J=5.9Hz,CH),3.27(d,1H,J=14.1Hz,NCH2),2.74(m,1H,NCH2),2.56(d,1H,J=14.5Hz,NCH2),2.48(m,1H,NCH2),2.45(s,3H,NCH3),2.11-1.53(m,6H,3CH2),0.55(t,3H,J=7.4Hz,CH2 CH 3 )。MS(ESI)m/z250.1(M+H)+。
实施例2
(3R，4S)-3-乙基-3-(3'-甲氧基苯基)-4-羟基-1-甲基-氮杂环庚烷-D-二苯甲酰酒石酸盐(B-1)
按实施例1中A-5的合成方法，以A-4为原料，经D-DBTA手性拆分，得化合物B-1.[α]20 D+89.03°(c=0.12,MeOH)，mp 181-182°C；1H NMR(Methnol-d4)δ8.13(d,4H,J＝7.0Hz,Ar-H),7.61(t,2H,J＝7.4Hz,Ar-H),7.48(t,4H,J＝7.8,7.4Hz,Ar-H),7.29(t,1H,J＝8.2,7.8Hz,Ar-H),6.98-6.82(m,3H,Ar-H),5.91(s,2H,CHCOOH),4.21(m,1H,CH),3.93(d,1H,J=4.1Hz,NCH2),3.79(s,3H,OCH3),3.50(d,1H,J＝4.1Hz,NCH2),3.42-2.32(m,2H,NCH2),2.98(s,3H,NCH3),2.14-1.84(m,6H,3CH2),0.62(t,3H,J＝7.4Hz,CH2 CH 3 )。
(3R,4S)-3-乙基-3-(3'-甲氧基苯基)-4-羟基-1-甲基-氮杂环庚烷(B-2)
按实施例1中A-6的合成方法，以B-1为原料，得化合物B-2。1H NMR(CDCl3)δ7.29-6.74(m,4H,Ar-H),3.86(m,1H,OCHCH2),3.81(s,3H,-OCH3),3.23(d,1H,J＝4.1Hz,NCH 2 C),2.70-2.50(m,2H,NCH 2 CH2),2.55(d,1H,J＝4.9Hz,NCH 2 C),2.46(s,3H,NCH3),2.10-1.51(m,6H,3CH2),0.57(t,3H,J＝7.4Hz,CH2 CH 3 )；MS(ESI)m/z264.2(M+H)+。
(3R，4S)-3-乙基-3-(3'-羟基苯基)-4-羟基-1-甲基-氮杂环庚烷(B)
按通用合成方法4，以B-2为原料，得到化合物B；1H NMR(CDCl3)δ7.14(t,1H,J=7.9Hz,Ar-H),6.83(d,1H,J=7.9Hz,Ar-H),6.77(s,1H,Ar-H),6.56(dd,J=7.9,2.0Hz,Ar-H),4.51(brs,2H,2OH),3.93(d,1H,J=6.1Hz,CH),3.28(d,1H,J=14.1Hz,NCH2),2.75(m,1H,NCH2),2.57(d,1H,J=14.3Hz,NCH2),2.49(m,1H,NCH2),2.46(s,3H,NCH3),2.12-1.91(m,3H,CH2),1.80(q,1H,J=7.3Hz,CH2),1.63(q,1H,J=7.3Hz,CH2),1.57(m,1H,CH2),0.55(t,3H,J=7.3Hz,CH2 CH 3 );MS(ESI)m/z250.1(M+H)+。
实施例3
(±)-trans-3-乙基-3-(3'-甲氧基苯基)-4-羟基-1-甲基-氮杂环庚烷(C-1)
在50ml干燥的三口烧瓶中，加入无水THF 20ml，冰浴冷却下，分批缓慢加入AlCl3 4.2g（30.6mmol）及LiAlH4 1.2g（31.6mmol）。升温至回流反应0.5h后，滴加含2.9g（10.4mmol）A-3的THF溶液10ml；滴加完毕后，继续回流反应1h；冷至室温，加冰浴冷却，缓慢滴加含3ml H2O的THF溶液，再滴加15％NaOH溶液至pH为9，产生白色固体，过滤得到无色透明溶液，滤饼用THF提取，合并滤液后浓干；加入10％NaHCO3溶液30ml，用氯仿提取，合并有机层，饱和食盐水洗涤，无水Na2SO4干燥。过滤，浓缩，干燥得C-1；1H NMR(CDCl3)δ7.23(t,1H,J=8.2Hz,Ar-H),6.81(m,2H,Ar-H),6.73(dd,1H,J=2.0,8.2Hz,Ar-H),4.44(brs,1H,OH),4.30(d,1H,J=7.4Hz,CH),3.80(s,3H,OCH3),2.99(d,1H,J=13.7Hz,NCH2),2.83(d,1H,J=14.0Hz,NCH2),2.72(m,1H,NCH2),2.41(s,3H,NCH3),2.35(m,1H,NCH2),2.17(q,1H,J=7.4Hz,CH2),1.99(m,2H,CH2),1.64(m,2H,CH2),1.47(m,1H,CH2),0.66(t,3H,J=7.4Hz,CH2 CH 3 )δ;MS(ESI)m/z264.2(M+H)+。
(3R,4R)-3-乙基-3-(3'-甲氧基苯基)-4-羟基-1-甲基-氮杂环庚烷-L-酒石酸盐(C-2)
在50ml圆底烧瓶中，将5g（19.0mmol）C-1溶于15ml 90%乙醇，加热回流至完全溶解，滴加含2.85g（19.0mmol）L-酒石酸（L-TA）的15ml 80%乙醇溶液，滴加完毕，继续搅拌1小时；缓慢冷却，置冰箱过夜。过滤，干燥，得白色固体3.48g，收率88.7%；经四氢呋喃水溶液重结晶后，得C-2；[α]20 D+10.6°(c=0.12,MeOH)，mp 110-112°C。1H NMR(Methanol-d4)δ7.40-6.90(m,4H,Ar-H),4.55(m,1H,OCHCH2),4.38(s,2H,CHCOOH),3.82(s,3H,OCH3),3.70(m,2H,CH2),3.25-3.04(m,2H,CH2),2.93(s,3H,NCH3),2.20-1.55(m,6H,3CH2),0.60(t,3H,J＝7.4Hz,CH2 CH 3 )。
(3R，4R)-3-乙基-3-(3'-甲氧基苯基)-4-羟基-1-甲基-氮杂环庚烷(C-3)
按实施例1中A-6的合成方法，以C-2为原料，得化合物C-3；1H NMR(CDCl3)δ7.23(t,1H,J=7.9Hz,Ar-H),6.80(m,2H,Ar-H),6.73(dd,1H,J=2.4,8.2Hz,Ar-H),4.45(brs,1H,OH),4.30(d,1H,J=7.6Hz,CH),3.80(s,3H,OCH3),2.99(d,1H,J=14.1Hz,NCH2),2.83(d,1H,J=14.0Hz,NCH2),2.72(m,1H,NCH2),2.41(s,3H,NCH3),2.35(m,1H,NCH2),2.18(q,1H,J=7.3Hz,CH2),2.00(m,2H,CH2),1.63(m,2H,CH2),1.44(m,1H,CH2),0.66(t,3H,J=7.3Hz,CH2 CH 3 );MS(ESI)m/z264.2(M+H)+
(3R，4R)-3-乙基-3-(3'-羟基苯基)-4-羟基-1-甲基-氮杂环庚烷(C)
按通用合成方法4，以C-3为原料，得到化合物C；1H NMR(CDCl3)δ7.16(t,1H,J=8.0Hz,Ar-H),6.72(m,3H,Ar-H),5.61(brs,2H,2OH),4.48(d,1H,J=7.3Hz,NCH),3.07(d,1H,J=14.1Hz,NCH2),2.90(d,1H,J=13.8Hz,CH2),2.78(m,1H,NCH2),2.42(s,3H,NCH3),2.35(m,1H,NCH2),2.12(q,1H,J=7.0Hz,CH2),2.04-1.92(m,2H,CH2),1.73(m,2H,CH2),1.51-1.44(m,1H,CH2),0.65(t,3H,J=7.3Hz,CH2 CH 3 );MS(ESI)m/z250.1(M+H)+。
实施例4
(3S,4S)-3-乙基-3-(3'-甲氧基苯基)-4-羟基-1-甲基-氮杂环庚烷-D-酒石酸盐(D-1)
按实施例3中C-2的方法，以C-1为原料，经D-酒石酸（D-TA）拆分得D-1；[α]20 D-10.4°(c=0.13,MeOH)，mp 108-110°C；1H NMR(Methanol-d4)δ7.40-6.89(m,4H,Ar-H),4.55(m,1H,-OCHCH2),4.39(s,2H,CHCOOH),3.82(s,3H,OCH3),3.70(m,2H,CH2),3.25-3.04(m,2H,CH2),2.93(s,3H,NCH3),2.20-1.55(m,6H,CH2),0.60(t,3H,J＝7.4Hz,CH2 CH 3 )。
(3S，4S)-3-乙基-3-(3'-甲氧基苯基)-4-羟基-1-甲基-氮杂环庚烷(D-2)
按实施例1中A-6的合成方法，以D-1为原料，得化合物D-2。1H NMR(CDCl3)δ7.23(t,1H,J=7.9Hz,Ar-H),6.80(m,2H,Ar-H),6.73(dd,1H,J=2.4,8.2Hz,Ar-H),4.44(brs,1H,OH),4.30(d,1H,J=7.6Hz,CH),3.80(s,3H,OCH3),2.99(d,1H,J=14.1Hz,NCH2),2.83(d,1H,J=13.8Hz,NCH2),2.72(m,1H,NCH2),2.41(s,3H,NCH3),2.35(m,1H,NCH2),2.18(q,1H,J=7.3Hz,CH2),2.01(m,2H,CH2),1.64(m,2H,CH2),1.44(m,1H,CH2),0.66(t,3H,J=7.3Hz,CH2 CH 3 );MS(ESI)m/z264.2(M+H)+。
(3S，4S)-3-乙基-3-(3'-羟基苯基)-4-羟基-1-甲基-氮杂环庚烷(D)
按通用合成方法4，以D-2为原料，得到化合物D；1H NMR(CDCl3)δ7.16(t,1H,J=8.2Hz,Ar-H),6.71(m,3H,Ar-H),5.74(brs,2H,2OH),4.48(d,1H,J=7.4Hz,CH),3.07(d,1H,J=14.7Hz,NCH2),2.89(d,1H,J=14.1Hz,NCH2),2.78(m,1H,NCH2),2.42(s,3H,NCH3),2.38-2.32(m,1H,NCH2),2.18-1.92(m,3H,CH2),1.73-1.62(m,2H,CH2),1.49-1.45(m,1H,CH2),0.65(t,3H,J=7.4Hz,CH2 CH 3 );13CNMR(CDCl3)δ156.4,146.6,129.3,118.3,113.7,113.1,73.6,68.0,60.9,49.1,48.2,32.1,28.7,23.0,8.7。MS(ESI)m/z250.1(M+H)+。
实施例5
(3R，4R)-3-乙基-3-(3`-甲氧基苯基)-4-羟基-氮杂环庚烷(E-1)
按通用合成方法1，以C-3为原料，得到化合物E-1；1H NMR(CDCl3)δ7.25(t,1H,J=7.8Hz,Ar-H),6.84(d,1H,J=7.8Hz,Ar-H),6.81(s,1H,Ar-H),6.75(dd,1H,J=2.4,8.2Hz,Ar-H),4.37(d,1H,J=8.2Hz,CH),3.81(s,3H,OCH3),3.32(d,1H,J=14.1Hz,NCH2),3.14(d,1H,J=14.1Hz,NCH2),3.11(m,1H,NCH2),2.64(m,1H,NCH2),2.17(q,1H,J=7.4Hz,CH2),2.02(m,2H,CH2),1.69-1.50(m,3H,CH2),0.67(t,3H,J=7.4Hz,CH2 CH 3 )。
(3R，4R)-3-乙基-3-(3`-甲氧基苯基)-4-羟基-1-苄基氮杂环庚烷(E-2)
按通用合成方法2，以E-1和苄基溴为原料，得到化合物E-2。
(3R，4R)-3-乙基-3-(3`-羟基苯基)-4-羟基-1-苄基氮杂环庚烷(E)
按通用合成方法4，以E-2为原料，得到化合物E；1H NMR(CDCl3)δ7.27-7.37(m,5H,Ar-H),7.14-7.18(m,1H,Ar-H),6.67-6.73(m,3H,Ar-H),4.46(d,1H,J=6.8Hz,CH),3.70(dd,2H,J=12.0Hz,CH2Ph),3.08(dd,2H,J=12.0Hz,NCH2),2.96-2.98(m,1H,NCH2),1.98-2.38(m,1H,NCH2),1.93-1.97(m,2H,CH2),1.86-1.87(m,1H,CH2),1.63-1.70(m,1H,CH2),1.27-1.48(m,2H,CH2),0.41-0.44(m,3H,CH2CH3);MS(ESI)m/z326.2(M+H)+.
实施例6
(3R，4R)-3-乙基-3-(3`-甲氧基苯基)-4-羟基-1-苯乙基氮杂环庚烷(F-1)
按通用合成方法2，以E-1和苯乙基溴为原料，得到化合物F-1。
(3R，4R)-3-乙基-3-(3'-羟基苯基)-4-羟基-1-苯乙基-氮杂环庚烷(F)
按通用合成方法4，以F-1为原料，得到化合物F；1H NMR(CDCl3)δ7.28(m,2H,Ar-H),7.18(m,3H,Ar-H),7.10(t,1H,J=8.2Hz,Ar-H),6.75(m,2H,Ar-H),6.55(d,1H,J=8.6Hz,Ar-H),3.90(d,1H,J=6.1Hz,CH),3.40(d,1H,J=14.4Hz,CH2),3.01-2.60(m,7H,CH2),2.07-1.58(m,6H,CH2),0.52(t,3H,J=7.4Hz,CH2 CH 3 );MS(ESI)m/z340.3(M+H)+。
实施例7
(3R，4R)-3-乙基-3-(3`-甲氧基苯基)-4-羟基-1-环丙甲基-氮杂环庚烷(G-1)
按通用合成方法2，以E-1和环丙基甲基溴为原料，得到化合物G-1。
(3R，4R)-3-乙基-3-(3’-羟基苯基)-4-羟基-1-环丙甲基-氮杂环庚烷(G)
按通用合成方法4，以G-1为原料，得到化合物G；1H NMR(DMSO)δ8.52(s,H,ArOH),7.04(dd,H,Ar-H),6.8(m,2H,Ar-H),6.6(dd,1H,J=7.03Hz,Ar-H),4.52(s,H,OH),3.98(d,H,J=6.7Hz,CHO),2.92(d,1H,J=12Hz,NCH2),2.77(d,H,J=12Hz,NCH2),2.75(m,2H,NCH2),2.45(m,2H,NCH2),1.96-1.46(m,6H,CH2),0.94(m,H,CH2),0.56(t,3H,J=7.4Hz,CH3),0.24(m,2H,CH2),0.08(m,2H,CH2)。MS(ESI)m/z290.2(M+H)+.
实施例8
(3R，4R)-3-乙基-3-(3'-甲氧基苯基)-4-苯乙酰氧基-1-甲基氮杂环庚烷(H-1)
按通用合成方法3，以C-3和苯乙酰氯为原料，得化合物H-1；1H NMR (CDCl3)δ7.33-7.22(m,5H,Ar-H),7.18(t,1H,J=8.2Hz,Ar-H),7.00(s,1H,Ar-H),6.92(d,1H,J=7.8Hz,Ar-H),6.72(d,1H,J=8.2Hz,Ar-H),5.23(d,1H,J=7.4Hz,CH),3.78(s,3H,OCH3),3.60(s,2H,CH2Ar),2.80(m,1H,NCH2),2.67(m,1H,NCH2),2.46(d,1H,J=14.4Hz,NCH2),2.40(s,3H,NCH3),2.32(m,1H,NCH2),1.91-1.78(m,2H,CH2),1.67(m,2H,CH2),1.54(m,2H,CH2),0.58(t,3H,J=7.4Hz,CH2 CH 3 ).MS(ESI)m/z382.2(M+H)+。
(3R，4R)-3-乙基-3-(3'-羟基苯基)-4-苯乙酰氧基-1-甲基氮杂环庚烷(H)
按通用合成方法4，以H-1为原料，得到化合物H；1H NMR(CDCl3)δ7.33-7.24(m,5H,Ar-H),7.10(t,1H,J=7.8Hz,Ar-H),6.85(d,1H,J=7.8Hz,Ar-H),6.81(s,1H,Ar-H),6.62(d,1H,J=7.4Hz,Ar-H),5.22(d,1H,J=7.8hz,CH),4.38(brs,1H,OH),3.60(s,2H,CH2Ph),2.98(d,1H,J=14.1Hz,NCH2),2.66(m,1H,NCH2),2.45(d,1H,J=14.1Hz,NCH2),2.38(s,3H,NCH3),2.32(m,1H,NCH2),1.88(m,1H,CH2),1.79-1.26(m,5H,CH2),0.54(t,3H,J=7.4Hz,CH2 CH 3 ).MS(ESI)m/z368.2(M+H)+。
实施例9
(3R，4R)-3-乙基-3-(3’-甲氧基苯基)-4-苯基乙酰氧基-1-苯乙基-氮杂环庚烷(J-1)
按通用合成方法3，以F-1和苯乙酰氯为原料，得化合物J-1。
(3R，4R)-3-乙基-3-(3’-羟基苯基)-4-苯基乙酰氧基-1-苯乙基-氮杂环庚烷(J)
按通用合成方法4，以J-1为原料，得到化合物J；1H NMR(CDCl3)δ7.31-7.14(m,10H,Ar-H),7.02(t,1H,J=7.3Hz,Ar-H),6.84(d,1H,J=7.43Hz,Ar-H),6.77(m,1H,Ar-H),6.71(d,1H,J=7.4,Ar-H),5.18(d,1H,J=8.19Hz,CH),3.6(s,2H,COCH2Ph),3.1(d,1H,J=14.5Hz,NCH2),2.87-2.5(m,6H,NCH2),2.5(m,2H,PhCH2),1.87(m,2H,CH2CH2),1.67(q,2H,J=7.4Hz,CH2),0.57(t,3H,J=7.4Hz,CH3)。MS(ESI)m/z458.3(M+H)+.
实施例10
(3R，4S)-3-乙基-3-(3`-甲氧基苯基)-4-羟基-氮杂环庚烷(K-1)
按通用合成方法1，以B-2为原料，得到化合物K-1；MS(ESI)m/z250.3(M+H)+。
(3R，4S)-3-乙基-3-(3`-甲氧基苯基)-4-羟基-1-苯乙基氮杂环庚烷(K-2)
按通用合成方法2，以K-1和苯乙基溴为原料，得到化合物K-2；MS(ESI)m/z353.4(M+H)+。
(3R，4S)-3-乙基-3-(3'-羟基苯基)-4-羟基-1-苯乙基-氮杂环庚烷(K)
按通用合成方法4，以F-1为原料，得到化合物F；1H NMR(CDCl3)δ7.28(m,2H,Ar-H),7.18(m,3H,Ar-H),7.10(t,1H,J=8.2Hz,Ar-H),6.75(m,2H,Ar-H),6.55(d,1H,J=8.6Hz,Ar-H),3.90(d,1H,J=6.1Hz,CH),3.40(d,1H,J=14.4Hz,CH2),3.01-2.60(m,7H,CH2),2.07-1.58(m,6H,CH2),0.52(t,3H,J=7.4Hz,CH2 CH 3 );MS(ESI)m/z340.3(M+H)+。
实施例11
(3R，4R)-3-乙基-3-(3`-甲氧基苯基)-4-羟基-1-苯乙基氮杂环庚烷(L-1)
按通用合成方法2，以E-1和苯戊基溴为原料，得到化合物L-1；1H NMR(CDCl3)δ7.30-7.15(m,6H,Ar-H),6.80-6.72(m,3H,Ar-H),4.38(d,1H,J=7.0Hz,CH),3.80(s,3H,OCH3),3.06-2.88(m,3H,CH2),2.63(t,2H,J=7.8Hz,CH2Ph),2.61-1.98(m,6H,CH2),1.70-1.33(m,9H,CH2),0.64(t,3H,J=7.4Hz,CH2 CH 3 ).MS(ESI)m/z396.3(M+H)+。
(3R，4R)-3-乙基-3-(3'-羟基苯基)-4-羟基-1-苯乙基-氮杂环庚烷(L)
按通用合成方法4，以L-1为原料，得到化合物L；1H NMR(CDCl3)δ7.30-7.15(m,6H,Ar-H),7.00(brs,1H,OH),6.69(m,3H,Ar-H),5.71(brs,1H,OH),4.51(d,1H,J=6.7Hz,CH),3.02(s,2H,NCH2),2.89(m,1H,NCH2),2.63(t,2H,J=7.3Hz,CH2Ph),2.50(m,2H,NCH2),2.30(m,1H,NCH2),2.13(m,1H,NCH2),2.07-1.96(m,2H,CH2),1.69-1.25(m,9H,CH2),0.64(t,3H,J=7.3Hz,CH2 CH 3 );MS(ESI)m/z382.3(M+H)+。
实施例12
(R)-3-乙基-3-(3`-羟基苯基)-1-苯甲基氮杂环庚烷(M)
按通用合成方法2，以M-1（按CN200610147585中公开的方法制备）和苯甲基溴为原料，得到化合物M；1H NMR(CDCl3)δ7.36-7.25(m,5H,Ar-H),7.17(t,1H,J=7.8Hz,Ar-H),6.88(d,1H,J=7.8Hz,Ar-H),6.76(s,1H,Ar-H),6.66(d,1H,J=7.8Hz,Ar-H)),5.14(brs,1H,OH),3.70(q,2H,J=14.3Hz,CH2),2.95(d,1H,J=13.7Hz,CH2),2.79(d,1H,J=14.1Hz,CH2),2.64(m,1H,CH2),2.44(m,1H,CH2),2.17(m,1H,CH2),1.79-1.53(m,7H,CH2),0.55(t,3H,J=7.4Hz,CH2 CH 3 );MS(ESI)m/z310.1(M+H)+。
实施例13
(R)-3-乙基-3-(3`-羟基苯基)-1-苯乙基氮杂环庚烷(N)
按通用合成方法2，以M-1和苯乙基溴为原料，得到化合物N；1H NMR(CDCl3)δ7.29(m,2H,Ar-H),7.20-7.14(m,4H,Ar-H),6.86(d,1H,J=7.8Hz,Ar-H),6.80(s,1H,Ar-H),6.64(d,1H,J=7.8Hz,Ar-H),4.58(brs,1H,OH),2.90(d,1H,J=14.7Hz,NCH2),2.84-2.74(m,6H,NCH2,CH2Ph),2.63(m,1H,NCH2),2.14(m,1H,CH2),1.76-1.55(m,6H,CH2),1.54(m,1H,,CH2),0.58(t,3H,J=7.4Hz,CH3)；13C NMR(CDCl3)δ155.4,149.3,140.7,129.0,128.9,128.3,125.9,119.2,114.4,112.3,67.5,62.7,58.0,45.5,37.0,34.3,33.8,30.9,22.5,8.6.MS(ESI)m/z324.5(M+H)+。
实施例14
(3R，4R)-3-乙基-3-(3`-甲氧基苯基)-4-羟基-1-烯丙基-氮杂环庚烷(Q-1)
按通用合成方法2，以E-1和烯丙基溴为原料，得到化合物Q-1。
(3R，4R)-3-乙基-3-(3’-羟基苯基)-4-羟基-1烯丙基-氮杂环庚烷(Q)
按通用合成方法4，以G-1为原料，得到化合物Q；1H NMR(CDCl3)δ7.08(d,H,J=7.81,Ar-H),6.77(m,3H,Ar-H),5.93(m,H,CH=),5.18(d,2H,J=12.5Hz,=CH2),4.5(d,H,J=7.4Hz,CHO),3.23(m,H,NCH2),3.05(d,1H,J=14.5Hz,NCH2),3.03(m,H,NCH2),2.97(d,H,J=14.5Hz,NCH2),2.95(m,H,NCH2),2.35(td,H,NCH2),2.06-1.96(m,3H,CH2),1.65(q,2H,CH2CH3),0.56(t,3H,J=7.4Hz,CH3)；MS(ESI)m/z276.2(M+H)+。
实施例15阿片受体亲和力实验
本实验分总结合管和非特异结合管，另设几组样品管加入待筛选的化合物；总结合管中加细胞悬液50uL，[3H]diprenorphine(终浓度为0.35nM）10uL；相对应的非特异管另加M99，使其终浓度为1uM；样品管加各浓度的药物10uL，用50mM Tris.HCl(pH7.4)调节至终体积100uL；在37℃温育30min，然后置冰浴中终止反应；在Millipore样品收集器上经GF/C(Whatman）玻璃纤维滤负压抽滤。用冰冷的50mM Tris.HCl(pH7.4)冲洗三次，每次4mL滤纸烘干后，置于0.5mLEppendorf管，加0.5mL亲脂闪烁液，Beckman LS-6500多功能液体闪烁计数仪测定放射性强度；表示受体结合率的Ki值通过下式进行计算：
结果如表1所示，
表1
实施例16[35S]GTPγS结合实验
在中华仓鼠卵巢细胞（CHO）中表达鼠源的μ和δ阿片受体，提取细胞膜后，于30°C下，在含0.1nM[35S]GTPγS(1,030Ci/mmol,Amersham Pharmacia)的缓存液（50mM Tris.HCl,pH 7.5,1mM EDTA,5mM MgCl2,100mM NaCl,and 40μMGDP）中处理1h，并加入各浓度的药物；通过快速过滤结束受体结合，BeckmanLS-6500多功能液体闪烁计数仪测定放射性强度；表示[35S]GTPγS激活结合强度的EC50值通过下式进行计算：
结果如表2所示，
表2
ND：代表not detectable，即在该模型中无活性。
Claims (10)
1.式（I）结构的氮杂环庚烷类化合物，
其中，
R1为H、C1-6烷基、环烷基、链烯基、芳基C1-6烷基、杂环基C1-6烷基或杂芳基C1-6烷基；
R2为H或OR4，当R2为OR4时，R4为氢、C1-6烷基、环烷基、链烯烷基、芳基C1-6烷基、杂环基C1-6烷基、杂芳基C1-6烷基、取代或非取代的酰基；其中当R2为H时，R1选自芳基C1-6烷基、杂环基C1-6烷基或杂芳基C1-6烷基；
R3为H或CH3。
2.按权利要求1所述的氮杂环庚烷类化合物，其特征在于，其中氮杂环庚烷的3位的手性中心为R构型。
3.按权利要求2所述的氮杂环庚烷类化合物，其特征在于，其中氮杂环庚烷的手性中心为（3R，4R）构型。
4.按权利要求2所述的氮杂环庚烷类化合物，其特征在于，其中氮杂环庚烷的手性中心为（3R，4S）构型。
5.按权利要求1～4中任一项所述的氮杂环庚烷类化合物，其特征在于，其中R3为H，R2为H或OH。
6.按权利要求1～4中任一项所述的氮杂环庚烷类化合物，其特征在于，其中R1为芳基C1-6烷基。
7.按权利要求1所述的氮杂环庚烷类化合物，其特征在于，所述化合物选自以下结构式：
8.权利要求1～7中任一项所述的氮杂环庚烷类化合物在制备治疗阿片受体介导的疾病的药物中的用途，所述的药物其通过调节阿片受体改善或治疗疾病。
9.按权利要求8的用途，其特征在于，所述疾病选自疼痛、胃肠道疾病或抑郁症。
10.按权利要求9的用途，其特征在于，所述疼痛选自中枢介导的疼痛、外周介导的疼痛、与结构或软组织损伤有关的疼痛、与炎症有关的疼痛、与进行性疾病有关的疼痛、神经病疼痛、急性疼痛或慢性疼痛。
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| CN105622509A (zh) * | 2014-11-06 | 2016-06-01 | 复旦大学 | 左旋美普他酚茚酮衍生物和/或其盐类及其制备方法和用途 |
| CN107759606A (zh) * | 2017-11-29 | 2018-03-06 | 河南龙湖生物技术有限公司 | 具有抗肿瘤活性的氮杂环庚烷并二氮卓类药物分子及其制备方法 |
-
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Non-Patent Citations (1)
| Title |
|---|
| 王星海: ""新型3-芳基氮杂环庚烷类配基的设计、合成和μ/δ阿片受体活性研究"", 《中国博士学位论文全文数据库 医药卫生科技辑》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105622509A (zh) * | 2014-11-06 | 2016-06-01 | 复旦大学 | 左旋美普他酚茚酮衍生物和/或其盐类及其制备方法和用途 |
| CN105622509B (zh) * | 2014-11-06 | 2017-12-29 | 复旦大学 | 左旋美普他酚茚酮衍生物和/或其盐类及其制备方法和用途 |
| CN107759606A (zh) * | 2017-11-29 | 2018-03-06 | 河南龙湖生物技术有限公司 | 具有抗肿瘤活性的氮杂环庚烷并二氮卓类药物分子及其制备方法 |
| CN107759606B (zh) * | 2017-11-29 | 2018-12-21 | 南京诺希生物科技有限公司 | 具有抗肿瘤活性的氮杂环烯烃并二氮卓药物分子及其制备方法 |
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