CN112759546B - 3-(二甲氨基甲基)哌啶-4-醇衍生物及其制备方法和药物用途 - Google Patents
3-(二甲氨基甲基)哌啶-4-醇衍生物及其制备方法和药物用途 Download PDFInfo
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- CN112759546B CN112759546B CN201911076330.8A CN201911076330A CN112759546B CN 112759546 B CN112759546 B CN 112759546B CN 201911076330 A CN201911076330 A CN 201911076330A CN 112759546 B CN112759546 B CN 112759546B
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- Prior art keywords
- methyl
- piperidin
- dimethylamino
- methoxyphenyl
- sulfonyl
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- 238000002360 preparation method Methods 0.000 title abstract description 11
- CAJTZENXFRGKHX-UHFFFAOYSA-N 3-[(dimethylamino)methyl]piperidin-4-ol Chemical class CN(C)CC1CNCCC1O CAJTZENXFRGKHX-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 34
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- -1 1- (1- (benzylsulfonyl) -4- (difluoromethoxy) -4- (3-methoxyphenyl) piperidin-3-yl) -N, N-dimethylaminomethyl amine Chemical class 0.000 claims description 41
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- 208000002193 Pain Diseases 0.000 claims description 17
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 15
- 230000036407 pain Effects 0.000 claims description 14
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 claims description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical group 0.000 claims description 9
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 8
- 108090000137 Opioid Receptors Proteins 0.000 claims description 7
- 102000003840 Opioid Receptors Human genes 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
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- 239000003814 drug Substances 0.000 claims description 4
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- 206010012335 Dependence Diseases 0.000 claims description 3
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- OBWBAIVWLKBMQS-UHFFFAOYSA-N C(S(=O)(=O)N1CCC(C2=CC(OC)=CC=C2)(O)C(CN(C)C)C1)CC1=CC=CC=C1 Chemical compound C(S(=O)(=O)N1CCC(C2=CC(OC)=CC=C2)(O)C(CN(C)C)C1)CC1=CC=CC=C1 OBWBAIVWLKBMQS-UHFFFAOYSA-N 0.000 claims description 2
- JUKOQNIFESKMAX-HMKHSRINSA-N CC(C)([C@@H](CC1)C2)[C@@]1(CS(N(CC1)CC(CN(C)C)C1(C1=CC(OC)=CC=C1)O)(=O)=O)C2=O Chemical compound CC(C)([C@@H](CC1)C2)[C@@]1(CS(N(CC1)CC(CN(C)C)C1(C1=CC(OC)=CC=C1)O)(=O)=O)C2=O JUKOQNIFESKMAX-HMKHSRINSA-N 0.000 claims description 2
- JUKOQNIFESKMAX-YGNMWTRNSA-N CC(C)([C@H](CC1)C2)[C@]1(CS(N(CC1)CC(CN(C)C)C1(C1=CC(OC)=CC=C1)O)(=O)=O)C2=O Chemical compound CC(C)([C@H](CC1)C2)[C@]1(CS(N(CC1)CC(CN(C)C)C1(C1=CC(OC)=CC=C1)O)(=O)=O)C2=O JUKOQNIFESKMAX-YGNMWTRNSA-N 0.000 claims description 2
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Abstract
本发明提供式(FWBH)化合物或其药学上可接受的盐，及其制备方法和药物用途，
Description
技术领域
本发明属于制药领域，涉及具有通式(FWBH)的3-(二甲氨基甲基)哌啶-4-醇哌啶衍生物或其盐类与制备方法，并涉及所述化合物在治疗阿片受体介导的疾病中的用途。
背景技术
疼痛是多种疾病进程中所出现的常见症状，是困扰患者的主要问题之一，已被列为继体温、脉搏、呼吸、血压之后的第五大生命体征。目前，阿片类镇痛药物在疼痛治疗中有着不可替代的作用，如吗啡、芬太尼等。但长期使用会出现耐药性，成瘾性，戒断反应，呼吸抑制等不良反应。曲马多是Grünenthal公司1977年开发的一种人工合成的阿片类中枢系统镇痛剂，商品名为tramal。它是相对较弱的μ阿片受体激动剂(对μ阿片受体的Ki＝2400nM，EC50＞1000nM)，并且可以抑制5-羟色胺和去甲肾上腺素的再摄取。它主要经肝脏代谢，且几乎完全经肾脏排泄。曲马多作为一种不典型的阿片类药物，不同于其他传统的阿片类药物，有其独特的药理学特点，不仅有较强的镇痛效果，而且不良反应少，现已经被广泛应用于疼痛的治疗。然而，临床上的应用显示，曲马多的镇痛效果略低于吗啡、芬太尼等镇痛药。此外，曲马多还存在呼吸抑制、成瘾性、恶心、腹泻、头痛、头晕、嗜睡和便秘等副作用。长期服药还可以出现出汗、焦虑、睡眠不良、疼痛和身体颤抖等戒断反应。另外，有研究表明，曲马多的使用与需要住院治疗的低钠血症和低血糖风险增加有关。因此，有必要开发镇痛作用更强、副作用更低的镇痛药。
发明内容
本发明提供了式(FWBH)所示的化合物，或其药学上可接受的盐：
其中，
R1选自氢、C1-6烷基、氟代烷基、环烷基、链状烯基、环烯基、取代或未取代芳基C1-6烷基；
R2选自C1-6烷基，环烷基，取代或未取代桥环烷基，取代或未取代芳基，取代或未取代杂芳基，其取代基可选自芳基、卤素、C1-6烷基、氰基、烷氧基、氨基、硝基、烷磺酰基、酯基、三氟甲基、三氟甲氧基、二氟甲氧基、甲氧基、氟、硝基、酚羟基；
n＝0，1，2，或3；
R3选自氢、C1-6烷基、氟代烷基、环烷基、链状烯基、环烯基、芳基C1-6烷基。优选实施方式中，R1选自甲基、三氟甲基。
优选实施方式中，R2选自甲基、乙基、异丙基、烯丙基、取代或未取代苯基、取代或未取代桥环烷基。其中取代苯基中的取代基优选为单取代，取代基优选自卤素、甲基、三氟甲基、硝基，取代位点可为邻位、间位、对位。取代桥环烷基选自以下基团：
优选实施方式中，R3选自氢、氟代烷基。更优选实施方式中，R3选自氢、氟代甲基。
优选实施方式中，式(FWBH)化合物选自：
1-(苄基磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇；
1-((3-氯苄基)磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇；
3-((二甲氨基)甲基)-4-(3-甲氧基苯基)-1-((4-甲基苄基)磺酰基)哌啶-4-醇；
3-((二甲氨基)甲基)-4-(3-甲氧基苯基)-1-(苯乙基磺酰基)哌啶-4-醇；
3-((二甲氨基)甲基)-4-(3-甲氧基苯基)-1-((3-(三氟甲基)苄基)磺酰基)哌啶-4-醇；
1-((4-氯苄基)磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇；
3-((二甲氨基)甲基)-1-((4-氟苄基)磺酰基)-4-(3-甲氧基苯基)哌啶-4-醇；
1-((3-溴苄基)磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇；
3-((二甲氨基)甲基)-1-((2-氟苄基)磺酰基)-4-(3-甲氧基苯基)哌啶-4-醇；
1-(丁基磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇；
3-((二甲氨基)甲基)-4-(3-甲氧基苯基)-1-((3-硝基苄基)磺酰基)哌啶-4-醇；
3-((二甲氨基)甲基)-4-(3-甲氧基苯基)-1-(苯基磺酰基)哌啶-4-醇；
3-((二甲氨基)甲基)-4-(3-甲氧基苯基)-1-((4-(三氟甲基)苄基)磺酰基)哌啶-4-醇；
3-((二甲氨基)甲基)-1-(乙基磺酰基)-4-(3-甲氧基苯基)哌啶-4-醇；
3-((二甲氨基)甲基)-4-(3-甲氧基苯基)-1-(丙基磺酰基)哌啶-4-醇；
3-((二甲氨基)甲基)-1-(异丙基磺酰基)-4-(3-甲氧基苯基)哌啶-4-醇；
1-(烯丙基磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇；
(1R,4S)-1-(((3-((二甲氨基)甲基)-4-羟基-4-(3-甲氧基苯基)哌啶-1-基)磺酰基)甲基)-7,7-二甲双环[2.2.1]庚-2-酮；
3-((二甲氨基)甲基)-1-((((1R,4S)-2-羟基-7,7-二甲基双环[2.2.1]庚-1-基)甲基)磺酰基)-4-(3-甲氧基苯基)哌啶-4-醇；
3-((二甲氨基)甲基)-4-(3-甲氧基苯基)-1-(甲磺酰基)哌啶-4-醇；
(1S,4R)-1-(((3-((二甲氨基)甲基)-4-羟基-4-(3-甲氧基苯基)哌啶-1-基)磺酰基)甲基)-7,7-二甲基双环[2.2.1]庚-2-酮；
3-((二甲氨基)甲基)-1-((((1S,4R)-2-羟基-7,7-二甲基双环[2.2.1]庚-1-基)甲基)磺酰基)-4-(3-甲氧基苯基)哌啶-4-醇；
1-(苄基磺酰基)-3-((二甲氨基)甲基)-4-(3-(三氟甲氧基)苯基)哌啶-4-醇；
1-(1-(苄基磺酰基)-4-(二氟甲氧基)-4-(3-甲氧基苯基)哌啶-3-基)-N,N-二甲氨基甲胺。
本发明还提供了式(FWBH)化合物药学上可接受的盐类，可是与无机酸或有机酸形成的盐，如盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐或硫酸氢盐、磷酸盐或磷酸氢盐、乙酸盐、苯甲酸盐、酒石酸盐、琥珀酸盐、马来酸盐、富马酸盐、乳酸盐、柠檬酸盐、葡糖酸盐、甲磺酸盐、苯磺酸盐或对甲苯磺酸盐，优选盐酸盐。
本发明还提供了式(FWBH)化合物药学上可接受的溶剂化物或水合物。
本发明还提供了一种药物组合物，其包括：式(FWBH)化合物或其药学上可接受的盐、溶剂化物或水合物；以及药学上可接受的载体。
上述化合物制备的药物可用于治疗或改善与阿片受体有关的疾病。所述疾病可选自但不限于疼痛、胃肠道疾病和抑郁症。例如，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。
这种方法可以通过给予对象有效治疗量的式(FWBH)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。
本发明还提供了合成通式(FWBH)化合物的方法，包括Mannich反应、格式试剂亲核加成、脱保护基Boc、上保护基TES、与磺酰氯缩合、脱保护基、成盐等步骤。
反应路线中的取代基和基团的定义如上所述。
具体实施方式
如本申请全文，包括权利要求书中所使用，除非另外特别表明，否则以下术语具有下文定义的含义如本文中所使用。
术语“C1-C6烷基”指含有1至6个碳原子的饱和的支链或直链烷基，诸如(但不限于)甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、新戊基及正己基。
术语“C1-6单取代或多取代烷基”指如上文所定义的C1-C6烷基中的一个或多个氢原子被选自下列的取代基代替：OH、卤素、烷氧基、二烷基氨基或杂环基，例如吗啉基、哌啶基等。
术语“C1-6单取代或多取代烷基酰基”指上文所定义的“C1-6单取代或多取代烷基”通过羰基与连接于母体分子部分。
术语“环烷基”是指碳原子的环状饱和单价单环或双环碳氢基团，例如环丙基、环丁基、环戊基、环己基，或类似基团。所述环烷基可任选地被一个、两个或三个取代基所取代，所述取代基选自卤原子、羟基、芳基。
术语“链状烯基”指具有至少一个碳-碳双键的脂族烃基，包括具有至少一个碳-碳双键的直链或支链基团。其例如具有2至6个碳原子。代表性实例包括(但不限于)乙烯基、1-丙烯基、2-丙烯基(烯丙基)、异丙烯基、2-甲基-1-丙烯基、1-丁烯基、2-丁烯基等。当本发明的化合物含有C2-C6链状烯基时，所述化合物可以纯E(entgegen)形式、纯Z(zusammen)形式或其任何混合物形式存在。
术语“环烯基”是指通过在环烷基移除额外的氢原子形成双键基团而得到相应的环烯基。
术语“桥环烷基”指任意两个碳环共用两不直接相连的碳原子的环烃基。
术语“取代或未取代桥环烷基”是指桥环烷基上的0个或至少一个氢原子被选自下列的取代基代替：羟基、氧代、卤素、C1-6烷基、腈基、烷氧基、氨基、硝基、烷磺酰基、酯基、三氟甲基、三氟甲氧基、二氟甲氧基、甲氧基、氟、硝基。
术语“芳基”指含有6至10个碳原子且具有共轭π电子系统的所有碳单环或稠环多环芳族基团，诸如苯基或萘基。
术语“取代或未取代芳基”是指芳基上的0至3个氢原子被选自下列的取代基代替：芳基、卤素、C1-6烷基、腈基、烷氧基、氨基、硝基、烷磺酰基、酯基、三氟甲基、三氟甲氧基、二氟甲氧基、甲氧基、氟、硝基、酚羟基。
术语“卤代”或“卤素”指氯、氟、溴或碘原子。
术语“取代或未取代芳基酰基”指上文所定义的“取代或未取代芳基”通过羰基与连接于母体分子部分。
术语“取代或未取代芳基烷基”是指如上文所定义的C1-C6烷基中的一个或多个氢原子被如上文所定义的“取代或未取代芳基”所取代。
术语“杂芳基”指单环或稠环多环芳族杂环基团，其中至少一个环中的一个或多个杂原子环成员(成环原子)各自独立地选自氧(O)、硫(S)及氮(N)。杂芳基的实例包括(但不限于)6元环取代基，诸如吡啶基、吡嗪基、嘧啶基及哒嗪基；5元杂芳基，诸如三唑基、咪唑基、呋喃基、异噁唑基、异噻唑基、1,2,3-、1,2,4、1,2,5-或1,3,4-噁二唑基、噁唑基、噻吩基、噻唑基、异噻唑基及吡唑基；6/5元稠环取代基，诸如吲哚基、吲唑基、苯并呋喃基、苯并咪唑基、苯并噻吩基、苯并噁二唑基、苯并噻唑基、异苯并噻吩基、苯并噻吩基、苯并异噁唑基、苯并噁唑基、苯并间二氧杂环戊烯基、呋喃并吡啶基、嘌呤基、咪唑并吡啶基、咪唑并嘧啶基、吡咯并吡啶基、吡唑并吡啶基、吡唑并嘧啶基、噻吩并吡啶基、三唑并嘧啶基、三唑并吡啶基(例如5,6,7,8-四氢[1,2,4]三唑并[1,5-a]吡啶-2-基)及邻氨基苯甲酰基；及6/6元稠环取代基，诸如喹啉基、异喹啉基、噌啉基、喹唑啉基、氧代色烷基及1,4-苯并噁嗪基。
术语“取代或未取代杂芳基”是指杂芳基上的0至3个氢原子被选自下列的取代基代替：芳基、卤素、C1-6烷基、氰基、烷氧基、氨基、硝基、烷磺酰基、酯基、三氟甲基、三氟甲氧基、二氟甲氧基、甲氧基、氟、硝基、酚羟基。
除非特别说明，本发明中，所有出现的化合物均意在包括所有可能的异构体，例如互变异构体、对映异构体、非对映异构体、及其混合物形式。
“有效治疗量”指在某种程度上减轻所治疗病症中一种或多种症状的化合物的给药量。
术语“药学上可接受的载体”表示能用于制备药物组合物的载体，它们一般是安全的、无毒性的，不是生物上或其他方面不期待的，且包括能被动物和人类药学上接受的载体。在说明书和权利要求书中使用的“药学上可接受的载体”包括一种或一种以上的这类载体。
本发明所述的药物组合物可以是液体、半液体或固体形式，按照适合于所用的给药途径的方式配制。本发明所述的药物组合物可以按照下列给药方式给药：口服、肠胃外、腹膜内、静脉内、透皮、舌下、肌内、直肠、口腔、鼻内、脂质体等方式。
口服药物组合物可以是固体、凝胶或液体。固体制剂的实例包括但不限于片剂、胶囊剂、颗粒剂和散装粉剂。这些制剂可以选择地含有粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂和矫味剂等。粘合剂的实例包括但不限于微晶纤维素、葡萄糖溶液、阿拉伯胶浆、明胶溶液、蔗糖和淀粉糊；润滑剂的实例包括但不限于滑石、淀粉、硬脂酸镁、硬脂酸钙、硬脂酸；稀释剂的实例包括但不限于乳糖、蔗糖、淀粉、甘露糖醇、磷酸二钙；助流剂的实例包括但不限于二氧化硅；崩解剂的实例包括但不限于交联羧甲基纤维素钠、淀粉羟乙酸钠、藻酸、玉米淀粉、马铃薯淀粉、甲基纤维素、琼脂和羧甲基纤维素。
以肠胃外给予本发明药物组合物，一般以注射为主，包括皮下、肌内或静脉内注射。注射剂可以被制成任何常规形式，如液体溶液或悬液、适合于在注射之前溶解或悬浮在液体中的固体形式或者乳剂。可用于本发明注射剂的药学上可接受的载体的实例包括但不限于水性载体、非水性载体、抗微生物剂、等渗剂、缓冲剂、抗氧剂、悬浮与分散剂、乳化剂、螯合剂和其它药学上可接受的物质。水性载体的实例包括氯化钠注射液、林格式注射液、等渗葡萄糖注射液、无菌水注射液、葡萄糖与乳酸化林格氏注射液；非水性载体的实例包括植物来源的固定油、棉籽油、玉米油、芝麻油和花生油；抗微生物剂的实例包括间甲酚、苄醇、氯丁醇、苯扎氯铵等；等渗剂的实例包括氯化钠和葡萄糖；缓冲剂包括磷酸盐和柠檬酸盐。
本发明药物组合物还可以制备成无菌的冻干粉针剂，将化合物溶于磷酸钠缓冲溶液，其中含有葡萄糖或其他适合的赋形剂，随后在本领域技术人员已知的标准条件下将溶液无菌过滤，继之以冷冻干燥，得到所需的制剂。
术语“式(FWBH)”或“式(FWBH)化合物”可称作“本发明的化合物”。这样的术语还被定义为包括本发明的化合物的所有形式，包括水合物、溶剂合物、异构体、结晶及非结晶形式、同晶型体、多晶型物及其代谢物。
本发明的化合物一般按照IUPAC或CAS命名体系命名。可以使用本领域技术人员公知的缩写(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)。
本发明通过以下实施例阐述，这些实施仅用于说明，不限制本发明的范围。式FWBH化合物可如下面的通用合成路线和实施例描述而制备。
实施例1
中间体2的制备
伴有氮气气球、温度计和恒压滴液漏斗的1L三口瓶加N,N,N',N'-四甲基甲烷二胺(60g，587.2mmol,1eq.)、甲基叔丁基醚(500ml)，冷却至0℃，30℃下滴加乙酰氯(46.1g，587.2mmol，1eq.，约20min)。滴加完毕，搅拌30分钟，抽滤，滤饼加乙腈(100ml)和MTBE(25ml)搅拌10min，抽滤，滤饼减压蒸干(55℃)，得46g类白色固体(极易吸潮)，收率83.7％。
实施例2
中间体3的制备：
伴有温度计、氮气球的1L单口瓶加Boc-哌啶酮(35g，175.66mmol，1eq.)、乙腈(350ml)，搅拌溶解，加中间体2(19.72g，210.8mmol，1.2eq.)。内温30～35℃反应24h，24h后TLC显示基本反应完全。将乙腈减压蒸除，加DCM(300ml)，再加饱和碳酸氢钠(250ml)，混合、静置、分层、分液。水相DCM(200+100ml)萃取。有机相合并，水洗(50ml)，无水硫酸镁干燥，抽滤，滤液减压蒸除，得43.3g红棕色粘稠液体，收率93.5％。
实施例3
中间体5的制备：
伴有氮气球、恒压滴液漏斗、冷凝管和温度计的1L四口瓶加镁屑(11g，451.68mmol，3eq.)、THF(300ml)、3粒碘，少量间溴苯甲醚(84.5g，451.68mmol，3eq.)的THF(70ml)溶液，升温回流引发。待黄色褪去，停止加热。缓慢滴加间溴苯甲醚的THF溶液(约1h)，直至滴加完全。滴加完毕，搅拌自然降至室温。30min后，25℃下滴加中间体3(37.76g，1eq.)的THF(100ml)溶液。滴加完毕，撤冰水浴搅拌，室温过夜(18h)。将反应液倒入氯化铵的水溶液中(200ml)和冰(约100g)的混合液中，搅拌5min，将THF减压蒸除(30℃)。加乙酸乙酯(300ml)，搅拌、静置、分层、分液。水相乙酸乙酯萃取(300ml)。有机相合并，水洗(100ml)，无水硫酸镁干燥，抽滤，滤液减压蒸除，得76.5g黄色液体，柱层析纯化，得21.4g浅黄色粘稠状液体，收率38.9％(两步，以boc-哌啶酮计)。1H NMR(400MHz,CD3OD),δ7.26(t,J＝8Hz,1H),7.04～7.05(m,1H),6.98(d,J＝8Hz,1H),6.81(dd,J＝8Hz,J＝4Hz,1H),4.20～4.25(m,1H),3.96～4.00(m,1H),3.79(s,3H),3.35(s,1H),3.03～3.22(m,2H),2.31～2.37(m,1H),2.07～2.11(m,1H),2.04(s,6H),1.94～2.01(m,1H),1.78～1.81(m,1H),1.58～1.62(m,1H),1.50(s,9H).。
实施例4
中间体6的制备：
250ml单口瓶加Boc-氨基醇(9.5g,26.06mmol，1eq.))、甲醇(76ml)，搅拌，滴加HCl/1,4-二氧六环溶液(16.3ml，65.15mmol，2.5eq.)，内温升至约36℃。搅拌2小时后，TLC显示有大量原料。升温至50℃搅拌，2小时后TLC显示基本反应完全。加MTBE(150ml)搅拌，逐渐析出固体，搅拌过夜(24h)。抽滤，滤饼MTBE(20ml)淋洗，旋蒸减压旋干，得8.63g类白色固体，收率98.3％。1H NMR(400MHz,CD3OD),δ7.38(t,J＝8Hz,1H),7.15～7.16(m,1H),7.12(d,J＝8Hz,1H),6.92(dd,J1＝8Hz,J2＝4Hz,1H),3.83(s,3H),3.75(dd,J1＝12Hz,J2＝4Hz,1H),3.41～3.43(m,3H),3.09～3.15(m,1H),2.85～2.92(m,1H),2.75(s,3H),2.75～2.78(m,1H),2.57(s,3H),2.54～2.62(m,1H),1.89～1.94(m,1H).。
实施例5
中间体7的制备：
伴有氮气气球、恒压滴液漏斗和温度计的250ml三口瓶加氨基醇盐酸盐(10g,33.22mmol,1eq.)、咪唑(20.35g,298.98mmol,9eq.)、DCM(100ml)，搅拌溶解。冷却，10℃下滴加三乙基氯硅烷(35.06g,232.6mmol,7eq.)。滴加完毕，搅拌5min，撤冰水浴搅拌过夜(26h)。TLC(DCM:MeOH＝10:1和4：1)显示反应完全。冰水浴下，将反应液缓慢倒入饱和碳酸氢钠水溶液中(100ml)，搅拌10分钟，加二氯甲烷(25ml)萃取。水相二氯甲烷萃取。有机相合并，水洗(20ml)，无水硫酸镁干燥，抽滤，滤液减压蒸除，得36.72g浅黄色液体，三氧化二铝柱层析纯化，得10.2g浅黄色液体，收率81％。LC-MS：ESI+[M+H]+379.1。
实施例6
中间体7与磺酰氯缩合通用方法：
100ml单口瓶加中间体7(1eq.)、DCM(10ml)、TEA(2eq.)，冰水浴下搅拌，加磺酰氯(1eq.)。30℃下搅拌一定时间。加水(30ml)，DCM，混合、静置、分层、分液。水相DCM(20ml)萃取。有机相合并，水洗。减压蒸除，得浅黄色液体。未经进一步纯化，直接用于下一步。
实施例7
脱TES通用方法：
50ml单口瓶加原料(1eq.)，THF，搅拌溶解，加TBAF(1.5eq.)。室温搅拌，LC-MS监测直至反应完全。将THF减压蒸除，加碳酸氢钠溶液(30ml)，DCM萃取。有机相合并，水洗，无水硫酸镁干燥，抽滤，滤液减压蒸除，得液体。柱层析纯化得目标产物。
实施例8
成盐通用方法：
50ml单口瓶加原料(1eq.)，加二氯甲烷，搅拌溶解，加甲基叔丁基醚.。加HCl的1,4-二氧六环溶液(1.2eq.)，析出固体，搅拌一定时间，抽滤，滤饼甲基叔丁基醚淋洗，油泵抽干，得目标产物。
实施例9
1-(苄基磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇盐酸盐(FWBH6)
由1-(苄基磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇成盐得到，收率:95.8％.1H NMR(400MHz,CDOD),δ7.50(dd,J1＝8Hz,J2＝4Hz,1H),7.36～7.44(m,3H),7.33(t,J＝8Hz,1H),7.07(s,1H),70.03(d,J＝8Hz,1H),6.85～6.87(m,1H),4.45(s,2H),3.79～3.83(m,4H),3.52～3.57(m,1H),3.12～3.20(m,2H),2.95～3.01(m,1H),2.60～2.69(m,1H),2.60(s,6H),2.29～2.35(m,1H),2.13～2.21(m,1H),1.65～1.70(m,1H).LC-MS-ESI+:[M+H]+419.3.。
实施例10
1-((3-氯苄基)磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇盐酸盐(FWBH7)
由1-((3-氯苄基)磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇成盐得到，收率:92.1％.1H NMR(400MHz,CDOD),δ7.56～7.57(m,1H),7.41～7.47(m,3H),7.34(t,J＝8Hz,1H),7.10～7.11(m,1H),7.05(d,J＝12Hz,1H),6.88(dd,J1＝8Hz,J2＝4Hz,H),4.49(t,2H),3.89(dd,J1＝12Hz,J2＝4Hz,1H),3.82(s,3H),3.56～3.61(m,1H),3.18～3.25(m,2H),2.99～3.05(m,1H),2.71(s,6H),2.69～2.73(m,1H),2.53(s,3H),2.34～2.41(m,1H),2.15～2.23(m,1H),1.68～1.73(m,1H).LC-MS-ESI+:[M+H]+453.2.。
实施例11
3-((二甲氨基)甲基)-4-(3-甲氧基苯基)-1-((4-甲基苄基)磺酰基)哌啶-4-醇盐酸盐(FWBH8)
由3-((二甲氨基)甲基)-4-(3-甲氧基苯基)-1-((4-甲基苄基)磺酰基)哌啶-4-醇成盐得到，收率:96.8％.1H NMR(400MHz,CD3OD),δ7.31～7.38(m,3H),7.23～7.26(m,2H),7.02～7.07(m,2H),6.87(dd,J＝8Hz,J＝4Hz,1H),4.40(s,2H),3.81(s,3H),3.75～3.82(m,1H),3.51～3.56(m,1H),3.12～3.21(m,3H),2.95～3.01(m,1H),2.66～2.70(m,1H),2.60(s,6H),2.35(s,3H),2.28～2.37(m,1H),2.13～2.21(m,1H),1.65～1.70(m,1H).LC-MS-ESI+:[M+H]+433.3.。
实施例12
3-((二甲氨基)甲基)-4-(3-甲氧基苯基)-1-(苯乙基磺酰基)哌啶-4-醇盐酸盐(FWBH9)
由3-((二甲氨基)甲基)-4-(3-甲氧基苯基)-1-(苯乙基磺酰基)哌啶-4-醇成盐得到，收率:87.2％.1H NMR(400MHz,CD3OD),δ7.23～7.37(m,6H),7.11(s,1H),7.07(d,J＝8Hz,1H),6.88(dd,J1＝8Hz,J2＝4Hz,H),3.86～3.91(m,1H),3.82(s,3H),3.70(d,J＝12Hz,1H),3.39～3.43(m,2H),3.10～3.27(m,4H),3.01～3.06(m,1H),2.69～2.74(m,1H),2.65(s,6H),2.41～2.46(m,1H),2.21～2.29(m,1H),1.76(dd,J1＝12Hz,J2＝4Hz,H).LC-MS-ESI+:[M+H]+433.3.。
实施例13
3-((二甲氨基)甲基)-4-(3-甲氧基苯基)-1-((3-(三氟甲基)苄基)磺酰基)哌啶-4-醇盐酸盐(FWBH10)
由3-((二甲氨基)甲基)-4-(3-甲氧基苯基)-1-((3-(三氟甲基)苄基)磺酰基)哌啶-4-醇成盐得到，收率:90.6％.1H NMR(400MHz,CD3OD),δ7.70～7.81(m,3H),7.83(t,J＝8Hz,1H),7.33(t,J＝8Hz,1H),7.04～7.10(m,2H),6.87(d,J＝8Hz,1H),4.57(s,2H),3.82～3.87(m,1H),3.81(s,3H),3.58～3.61(m,1H),3.18～3.25(m,2H),2.96～3.04(m,1H),2.69～2.73(m,1H),2.62(s,6H),2.39(m,1H),2.18～2.26(m,1H),1.70～1.74(m,1H).LC-MS-ESI+:[M+H]+487.2.。
实施例14
1-((4-氯苄基)磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇盐酸盐(FWBH11)
由1-((4-氯苄基)磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇成盐得到，收率:68.4％.1H NMR(400MHz,CD3OD),δ7.41～7.50(m,4H),7.30～7.37(m,1H),7.04～7.09(m,2H),6.85～6.88(m,1H),4.44～4.46(m,2H),3.80～3.84(m,4H),3.59(m,1H),3.14～3.24(m,3H),2.96～3.03(m,1H),2.69～2.71(m,4H),2.54(s,3H),2.35(s,1H),2.16～2.23(m,1H),1.68～1.72(m,1H).LC-MS-ESI+:[M+H]+453.2.。
实施例15
3-((二甲氨基)甲基)-1-((4-氟苄基)磺酰基)-4-(3-甲氧基苯基)哌啶-4-醇盐酸盐(FWBH12)
由3-((二甲氨基)甲基)-1-((4-氟苄基)磺酰基)-4-(3-甲氧基苯基)哌啶-4-醇成盐得到，收率:98.33％.1H NMR(400MHz,CD3OD),δ7.50～7.54(m,2H),7.31～7.35(m,1H),7.14～7.19(m,2H),7.09(s,1H),7.05(d,J＝8Hz,1H),6.87(d,J＝8Hz,1H),4.45(s,2H),3.82～3.84(m,1H),3.81(s,3H),3.54～3.59(m,1H),3.15～3.21(m,1H),2.97～3.03(m,1H),2.68～2.72(m,1H),2.62(s,6H),2.34～2.40(m,1H),2.16～2.24(m,1H),1.67～1.72(m,1H).LC-MS-ESI+:[M+H]+437.2.。
实施例16
1-((3-溴苄基)磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇盐酸盐(FWBH13)
由1-((3-溴苄基)磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇成盐得到，收率:85％.1H NMR(400MHz,CD3OD),δ7.57～7.58(m,1H),7.43(d,J＝8Hz,1H),7.35(d,J＝8Hz,1H),7.18～7.24(m,2H),6.90～6.98(m,2H),6.72～6.76(m,1H),4.33(s,2H),3.68～3.75(m,1H),3.67(s,3H),3.45(dd,J1＝16Hz,J2＝8Hz,1H),3.03～3.11(m,2H),2.84～2.90(m,1H),2.54～2.59(m,1H),2.48(s,6H),2.19～2.24(m,1H),2.01～2.09(m,1H),1.55～1.59(m,1H).LC-MS-ESI+:[M+H]+497.2.。
实施例17
3-((二甲氨基)甲基)-1-((2-氟苄基)磺酰基)-4-(3-甲氧基苯基)哌啶-4-醇盐酸盐(FWBH14)
由3-((二甲氨基)甲基)-1-((2-氟苄基)磺酰基)-4-(3-甲氧基苯基)哌啶-4-醇成盐得到，收率:94％.1H NMR(400MHz,CD3OD),δ7.54～7.60(m,1H),7.41～7.49(m,1H),7.32～7.38(m,1H),7.19～7.29(m,2H),7.04～7.11(m,2H),6.86～6.91(m,1H),4.52(s,2H),3.82～3.87(m,1H),3.81(s,3H),3.54～3.57(m,1H),3.20～3.27(m,2H),2.99～3.06(m,1H),2.67～2.73(m,1H),2.62(s,6H),2.36～2.41(m,1H),2.15～2.25(m,1H),1.61～1.74(m,1H).LC-MS-ESI+:[M+H]+437.2.。
实施例18
1-(丁基磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇盐酸盐(FWBH15)
由1-(丁基磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇盐成盐得到，收率:88.6％.1H NMR(400MHz,CD3OD),δ7.32～7.39(m,1H),7.08～7.15(m,2H),6.86～6.92(m,1H),3.87～3.91(m,1H),3.81(s,3H),3.67～3.72(m,1H),3.20～3.27(m,1H),3.03～3.16(m,3H),2.70～2.77(m,1H),2.65(s,6H),2.45～2.50(m,1H),2.25～2.33(m,1H),1.76～1.84(m,3H),1.46～1.56(m,2H),0.91～1.04(m,3H).LC-MS-ESI+:[M+H]+385.2.。
实施例19
3-((二甲氨基)甲基)-4-(3-甲氧基苯基)-1-((3-硝基苄基)磺酰基)哌啶-4-醇盐酸盐(FWBH22)
由3-((二甲氨基)甲基)-4-(3-甲氧基苯基)-1-((3-硝基苄基)磺酰基)哌啶-4-醇成盐得到收率:98.4％.1H NMR(400MHz,CD3OD),δ8.28～8.34(m,2H),7.74～7.80(m,2H),7.32～7.40(m,1H),7.05～7.13(m,2H),6.86～6.92(m,1H),4.62～4.66(m,2H),3.81～3.88(m,4H),3.60～3.69(m,2H),3.18～3.27(m,3H),2.98～3.08(m,1H),2.64～2.74(m,7H),2.40～2.48(m,1H),2.19～2.28(m,1H),1.70～1.77(m,1H).LC-MS-ESI+:[M+H]+464.2.。
实施例20
3-((二甲氨基)甲基)-4-(3-甲氧基苯基)-1-(苯基磺酰基)哌啶-4-醇盐酸盐(FWBH16)
由3-((二甲氨基)甲基)-4-(3-甲氧基苯基)-1-(苯基磺酰基)哌啶-4-醇成盐得到，收率:92.3％.1H NMR(400MHz,CD3OD),δ7.89(d,J＝8Hz,1H),7.72～7.76(m,1H),7.65～7.69(m,2H),7.32(t,J＝8Hz,1H),7.02～7.06(m,2H),6.84～6.87(m,1H),3.98(dd,J1＝12Hz,J2＝4Hz,1H),3.79(s,3H),3.71～3.73(m,1H),2.95～3.01(m,1H),2.53～2.77(m,10H),2.29～2.36(m,1H),1.73～1.77(m,1H).LC-MS-ESI+:[M+H]+405.2.。
实施例21
3-((二甲氨基)甲基)-4-(3-甲氧基苯基)-1-((4-(三氟甲基)苄基)磺酰基)哌啶-4-醇盐酸盐(FWBH17)
由3-((二甲氨基)甲基)-4-(3-甲氧基苯基)-1-((4-(三氟甲基)苄基)磺酰基)哌啶-4-醇成盐得到，收率:98.5％.1H NMR(400MHz,CD3OD),δ7.69～7.75(m,4H),7.31～7.36(m,1H),7.04～7.10(m,2H),6.86～6.89(m,1H),4.56(s,2H),3.82～3.88(m,1H),3.81(s,3H),3.58～3.62(m,1H),3.22(t,J＝8Hz,2H),2.98～3.05(m,1H),2.69～2.74(m,1H),2.63(s,6H),2.35～2.41(m,1H),2.17～2.25(m,1H),1.69～1.74(m,1H).LC-MS-ESI+:[M+H]+487.2.。
实施例22
3-((二甲氨基)甲基)-1-(乙基磺酰基)-4-(3-甲氧基苯基)哌啶-4-醇盐酸盐(FWBH18)
由3-((二甲氨基)甲基)-1-(乙基磺酰基)-4-(3-甲氧基苯基)哌啶-4-醇成盐得到，收率:98.7％.1H NMR(400MHz,CD3OD),δ7.34(t,J＝8Hz,1H),7.13(s,1H),7.09(d,J＝8Hz,1H),6.88(dd,J1＝8Hz,J2＝4Hz,1H),3.91(dd,J1＝12Hz,J2＝8Hz,1H),3.82(s,3H),3.70(dd,J1＝12Hz,J2＝4Hz,1H),3.22～3.36(m,2H),3.13～3.18(m,2H),3.03～3.09(m,1H),2.74(s,3H),2.70～2.73(m,1H),2.58(s,3H),2.45～2.51(m,1H),2.25～2.33(m,1H),1.75～1.80(m,1H),1.37(t,J＝8Hz,3H).LC-MS-ESI+:[M+H]+357.3.。
实施例23
3-((二甲氨基)甲基)-4-(3-甲氧基苯基)-1-(丙基磺酰基)哌啶-4-醇盐酸盐(FWBH19)
由3-((二甲氨基)甲基)-4-(3-甲氧基苯基)-1-(丙基磺酰基)哌啶-4-醇成盐得到，收率:80％.1H NMR(400MHz,CD3OD),δ7.32～7.36(m,1H),7.08～7.13(m,2H),6.88(dd,J1＝8Hz,J2＝4Hz,1H),3.87～3.91(m,1H),3.81(s,3H),3.66～3.71(m,1H),3.19～3.33(m,2H),3.03～3.12(m,3H),2.61～2.75(m,7H),2.45～2.51(m,1H),2.25～2.33(m,1H),1.82～1.89(m,2H),1.76～1.81(m,1H),1.08～1.12(m,3H).LC-MS-ESI+:[M+H]+371.2.。
实施例24
3-((二甲氨基)甲基)-1-(异丙基磺酰基)-4-(3-甲氧基苯基)哌啶-4-醇盐酸盐(FWBH20)
由3-((二甲氨基)甲基)-1-(异丙基磺酰基)-4-(3-甲氧基苯基)哌啶-4-醇成盐得到，收率:85.5％.1H NMR(400MHz,CD3OD),δ7.34(t,J＝8Hz,1H),7.04～7.11(m,2H),6.88(dd,J1＝8Hz,J2＝4Hz,1H),3.89～3.93(m,1H),3.81(s,3H),3.70～3.75(m,1H),3.34～3.44(m,3H),3.03～3.09(m,1H),2.61～2.73(m,7H),2.41～2.45(m,1H),2.22～2.30(m,1H),1.71～1.76(m,1H),1.37(d,J＝4Hz,6H),.LC-MS-ESI+:[M+H]+371.3.。
实施例25
1-(烯丙基磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇盐酸盐(FWBH21)
由1-(烯丙基磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇成盐得到，收率:89％.1H NMR(400MHz,CD3OD),δ7.32～7.36(m,1H),7.07～7.12(m,2H),6.88(dd,J1＝8Hz,J2＝4Hz,1H),5.91～6.02(m,1H),5.45～5.53(m,2H),3.94(d,J＝8Hz,3H),3.82(s,3H),3.70～3.75(m,1H),3.25～3.39(m,3H),3.02～3.08(m,1H),2.74(s,3H),2.57(s,3H),2.42～2.47(m,1H),2.23～2.31(m,1H),1.77(dd,J1＝16Hz,J2＝4Hz,1H).LC-MS-ESI+:[M+H]+369.2.。
实施例26
(1R,4S)-1-(((3-((二甲氨基)甲基)-4-羟基-4-(3-甲氧基苯基)哌啶-1-基)磺酰基)甲基)-7,7-二甲双环[2.2.1]庚-2-酮盐酸盐(FWBH24)
由(1R,4S)-1-(((3-((二甲氨基)甲基)-4-羟基-4-(3-甲氧基苯基)哌啶-1-基)磺酰基)甲基)-7,7-二甲双环[2.2.1]庚-2-酮成盐得到，收率:84.4％.1H NMR(400MHz,CD3OD),δ7.32～7.37(m,1H),7.07～7.13(m,2H),6.88(dd,J1＝8Hz,J2＝4Hz,H),3.92～3.95(m,1H),3.82(s,3H),3.73～3.77(m,1H),3.46(t,J＝16Hz,1H),3.20～3.35(m,2H),2.96～3.12(m,2H),2.39～2.75(m,10H),2.24～2.35(m,1H),2.06～2.14(m,2H),1.98(dd,J1＝20Hz,J2＝4Hz,1H),1.80(dd,J1＝12Hz,J2＝4Hz,1H),1.62～1.70(m,1H),1.45～1.53(m,1H),1.15(d,J＝4Hz,3H),0.93(d,J＝4Hz,3H).LC-MS-ESI+:[M+H]+479.3.。
实施例27
3-((二甲氨基)甲基)-1-((((1R,4S)-2-羟基-7,7-二甲基双环[2.2.1]庚-1-基)甲基)磺酰基)-4-(3-甲氧基苯基)哌啶-4-醇盐酸盐(FWBH26)
由3-((二甲氨基)甲基)-1-((((1R,4S)-2-羟基-7,7-二甲基双环[2.2.1]庚-1-基)甲基)磺酰基)-4-(3-甲氧基苯基)哌啶-4-醇成盐得到，收率:84.2％.1H NMR(400MHz,CD3OD),δ7.32～7.39(m,1H),7.09～7.17(m,2H),6.87～6.93(m,1H),4.03～4.07(m,1H),3.92～3.97(m,1H),3.72～3.86(m,4H),3.46～3.52(m,1H),3.18～3.35(m,2H),3.05～3.10(m,1H),2.05～2.77(m,8H),2.28～2.36(m,1H),1.73～1.86(m,5H),1.43～1.48(m,1H),1.08～1.23(m,5H),0.99～1.00(m,1H),0.90～0.95(m,3H).LC-MS-ESI+:[M+H]+481.3.。
实施例28
3-((二甲氨基)甲基)-4-(3-甲氧基苯基)-1-(甲磺酰基)哌啶-4-醇盐酸盐(FWBH23)
由3-((二甲氨基)甲基)-4-(3-甲氧基苯基)-1-(甲磺酰基)哌啶-4-醇成盐得到，收率:94％.1H NMR(400MHz,CD3OD),δ7.34(t,J＝8Hz,1H),7.09～7.14(m,2H),6.86～6.89(m,1H),3.88(dd,J1＝8Hz,J2＝4Hz,1H),3.82(s,3H),3.65～3.70(m,1H),3.11～3.25(m,2H),3.03～3.09(m,1H),2.95(s,3H),2.72～2.78(m,1H),2.65(s,6H),2.49～2.55(m,1H),2.29～2.37(m,1H),1.79～1.84(m,1H).LC-MS-ESI+:[M+H]+343.2.。
实施例29
(1S,4R)-1-(((3-((二甲氨基)甲基)-4-羟基-4-(3-甲氧基苯基)哌啶-1-基)磺酰基)甲基)-7,7-二甲基双环[2.2.1]庚-2-酮盐酸盐(FWBH25)
由(1S,4R)-1-(((3-((二甲氨基)甲基)-4-羟基-4-(3-甲氧基苯基)哌啶-1-基)磺酰基)甲基)-7,7-二甲基双环[2.2.1]庚-2-酮成盐得到，收率:76.3％.1H NMR(400MHz,CD3OD),δ7.34(t,J＝8Hz,1H),7.07～7.13(m,2H),7.86～7.89(m,1H),3.95(d,J＝12Hz,1H),3.82(s,3H),3.74(t,J＝8Hz,1H),3.42～3.50(m,1H),3.20～3.35(m,2H),3.06～3.12(m,1H),2.97～3.03(m,1H),2.68～2.74(m,7H),2.39～2.57(m,3H),2.23～2.35(m,1H),2.06～2.15(m,2H),1.98(dd,J1＝20Hz,J2＝4Hz,1H),1.80(d,J＝16Hz,1H),1.62～1.70(m,1H),1.45～1.53(m,1H),1.14(d,J＝8Hz,3H),0.93(d,J＝8Hz,3H).LC-MS-ESI+:[M+H]+479.3.。
实施例30
3-((二甲氨基)甲基)-1-((((1S,4R)-2-羟基-7,7-二甲基双环[2.2.1]庚-1-基)甲基)磺酰基)-4-(3-甲氧基苯基)哌啶-4-醇盐酸盐(FWBH27)
由3-((二甲氨基)甲基)-1-((((1S,4R)-2-羟基-7,7-二甲基双环[2.2.1]庚-1-基)甲基)磺酰基)-4-(3-甲氧基苯基)哌啶-4-醇成盐得到，收率:88.6％.1H NMR(400MHz,CD3OD),δ7.32～7.38(m,1H),7.09～7.14(m,2H),6.89(dd,J1＝8Hz,J2＝4Hz,1H),4.02～4.07(m,1H),3.93～3.99(m,1H),3.82(s,3H),3.72～3.78(m,1H),3.46～3.52(m,1H),3.18～3.30(m,2H),3.05～3.11(m,1H),2.87～2.93(m,1H),2.50～2.75(m,8H),2.28～2.36(m,1H),1.73～1.86(m,5H),1.43～1.148(m,1H),0.91～1.20(m,8H).LC-MS-ESI+:[M+H]+481.3.。
实施例31
1-(苄基磺酰基)-3-((二甲氨基)甲基)-4-(3-(三氟甲氧基)苯基)哌啶-4-醇盐酸盐(FWBH29)
将实施例3中的3-(甲氧基)苯基溴化镁替换为3-(三氟甲氧基)苯基溴化镁，经与制备1-(苄基磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇相同的路线，可制得1-(苄基磺酰基)-3-((二甲氨基)甲基)-4-(3-(三氟甲氧基)苯基)哌啶-4-醇。由1-(苄基磺酰基)-3-((二甲氨基)甲基)-4-(3-(三氟甲氧基)苯基)哌啶-4-醇成盐得到，收率:91.4％.1H NMR(400MHz,CD3OD),δ7.49～7.55(m,4H),7.47(s,1H),7.39～7.44(m,3H),7.25(d,J＝8Hz,1H),4.46(s,2H),3.82(dd,J1＝12Hz,J2＝4Hz,1H),3.54～3.59(m,1H),3.12～3.21(m,2H),3.00～3.07(m,1H),2.58～2.63(m,7H),2.35～2.41(m,1H),2.13～2.22(m,1H),1.68～1.73(m,1H).LC-MS-ESI+:[M+H]+473.2.。
实施例32
1-(1-(苄基磺酰基)-4-(二氟甲氧基)-4-(3-甲氧基苯基)哌啶-3-基)-N,N-二甲氨基甲胺
25ml单口瓶加原料(100mg，0.24mmol，1eq.)、二氯甲烷(0.5ml)、水(0.5ml)、KOAc(188.43mmol，1.92mmol，8eq.)，加TMSCF2Br(195mg，0.96mmol，4eq.)。室温搅拌析出固体，补加二氯甲烷(0.5ml)、水(0.5ml)。LC-MS监测直至反应完全。抽滤，滤饼水洗，烘干，得约115mg类白色固体。甲醇和乙酸乙酯(0.4ml：0.6ml)结晶得90mg类白色固体，收率80.4％。
1-(1-(苄基磺酰基)-4-(二氟甲氧基)-4-(3-甲氧基苯基)哌啶-3-基)-N,N-二甲氨基甲胺盐酸盐(FWBH30)
由1-(1-(苄基磺酰基)-4-(二氟甲氧基)-4-(3-甲氧基苯基)哌啶-3-基)-N,N-二甲氨基甲胺成盐得到，收率84％。1H NMR(400MHz,CD3OD),δ7.485～7.501(m,2H),7.339～7.421(m,4H),7.107～7.148(m,2H),6.890～6.914(m,2H),6.838(s,J＝58.4Hz,1H),4.456(s,2H),3.823(s,3H),3.765(d,J＝13.2Hz,2H),3.564(d,J＝12.8Hz,1H),3.117～3.362(m,2H),2.977(s,3H),2.637(s,3H),2.482～2.504(m,1H),2.326～2.395(m,1H),1.715(d,J＝14.8Hz,1H).LC-MS-ESI+:
[M+H]+469.2.。
实施例33
膜受体的制备
分别表达有μ阿片受体、δ阿片受体、κ阿片受体的CHO细胞种于10cm2培养皿中培养(F-12培养基+10％新生牛血清)数天，细胞长满皿底后吸去培养液；加PBS/EDTA溶液(0.1MNaCl，0.01M NaH2PO4,0.04％EDTA)3ml消化3-5min,用吸管吹打，使细胞完全脱落，收集细胞于40ml离心管，5000rpm离心5min,去上清液；加入冰冷的匀浆液(50mM HEPES PH 7.4，3mMMgCl,1mM EGTA)于离心管，将溶液和沉淀转移到匀浆器中匀浆；然后将匀浆液转移到离心管中，18000rpm离心15min，共离心2次；得到的沉淀加入适量的50mM Tris-HCl，pH 7.4的缓冲液匀浆并分装于离心管，-70℃冰箱保存待用。
竞争结合试验
总结合管加相当于20-30μg的表达的膜受体蛋白和[3H]标记的配体(1-2nM)，相对应的非特异性结合管另加1μM的相应配体，样品管加不同浓度的各种筛选的阿片配体类药物，终体积为100μl,30℃孵育30min，置冰水中终止反应。在Millipore样品收集器上经GF/C(whatman)玻璃纤维滤纸负压抽滤。用4ml 50mM Tris-HCl(pH 7.4)冲洗三次，滤纸烘干后，置于0.5ml Eppendorf管，加0.5ml亲脂闪烁液，PERKIN ELMER PRI-CARB 2910液体闪烁计数仪测定放射性强度，计算抑制率，实验重复三次以上，每组三复管。
抑制率(或称结合率)＝(总结合率dpm－样品管dpm)/(总结合管dpm－非特异性结合管dpm)×100％
用Graphpad Prism 5.0软件计算IC50。按下式计算Ki值，Ki＝IC50/(1+[L]/Kd)，[L]为所加标记配体的浓度，Kd为标记配体的平衡解离参数
表1为代表性化合物对阿片受体的亲和常数Ki值，采用三次独立的测量平均值±标准偏差表示。
表1化合物1μM浓度下阿片受体结合率或Ki
a.在0.1μM下抑制率或结合率。
表1的“结合率(％)或Ki(nM)”一栏中，用百分比表示的数值是指结合率，以nM为单位的数值是指Ki。
从表1可以看出，本发明化合物均表现出比曲马多更强或相当的阿片受体亲和力。
实施例34
体内热板法镇痛试验
将体重20g左右雌性小鼠放在预热至55℃热板仪上，以小鼠舔后足反应的潜伏期为痛阈指标。实验前筛选动物，将反应潜伏期小于5s或大于30s的动物剔除。为防止足部烫伤，最长观察时间设为60s。基础痛阈为2次测量值的平均值，两次测量之间相隔5min。各组小鼠痛阈值分别在腹腔给药后15分钟、30分钟、60分钟和120分钟进行测定。镇痛有效百分率(％MPE)根据以下公式计算：镇痛有效百分率(％MPE)。根据镇痛有效百分率用Graphpadprism 5.0软件计算ED50值。
表2 5mg/kg剂量下化合物热板最大镇痛有效百分比或ED50值
表2的“％MPE或ED50”一栏中，用百分比表示的数值是指％MPE，以mg/kg为单位的数值是指ED50。
从表2可以看出，本发明化合物均表现出比曲马多更强的体内镇痛作用。
Claims (9)
1.式(FWBH)所示的化合物，或其药学上可接受的盐：
其中，
R1选自氢、C1-6烷基、三氟甲基；
R2选自C1-6烷基，烯丙基，被卤素、C1-6烷基、硝基或三氟甲基取代或未取代苯基，
n＝0，1，2，或3；
R3选自氢、C1-6烷基、氟代甲基。
2.根据权利要求1所述的化合物，或其药学上可接受的盐，其特征在于，R1选自甲基、三氟甲基。
3.根据权利要求1或2所述的化合物，或其药学上可接受的盐，其特征在于，R2选自甲基、乙基、异丙基、烯丙基、被卤素、C1-6烷基、硝基或三氟甲基取代或未取代苯基，
4.根据权利要求1或2所述的化合物，或其药学上可接受的盐，其特征在于，R3选自氢、氟代甲基。
5.根据权利要求1或2所述的化合物，或其药学上可接受的盐，其特征在于，式(FWBH)化合物选自：
1-(苄基磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇；
1-((3-氯苄基)磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇；
3-((二甲氨基)甲基)-4-(3-甲氧基苯基)-1-((4-甲基苄基)磺酰基)哌啶-4-醇；
3-((二甲氨基)甲基)-4-(3-甲氧基苯基)-1-(苯乙基磺酰基)哌啶-4-醇；
3-((二甲氨基)甲基)-4-(3-甲氧基苯基)-1-((3-(三氟甲基)苄基)磺酰基)哌啶-4-醇；
1-((4-氯苄基)磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇；
3-((二甲氨基)甲基)-1-((4-氟苄基)磺酰基)-4-(3-甲氧基苯基)哌啶-4-醇；
1-((3-溴苄基)磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇；
3-((二甲氨基)甲基)-1-((2-氟苄基)磺酰基)-4-(3-甲氧基苯基)哌啶-4-醇；
1-(丁基磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇；
3-((二甲氨基)甲基)-4-(3-甲氧基苯基)-1-((3-硝基苄基)磺酰基)哌啶-4-醇；
3-((二甲氨基)甲基)-4-(3-甲氧基苯基)-1-(苯基磺酰基)哌啶-4-醇；
3-((二甲氨基)甲基)-4-(3-甲氧基苯基)-1-((4-(三氟甲基)苄基)磺酰基)哌啶-4-醇；
3-((二甲氨基)甲基)-1-(乙基磺酰基)-4-(3-甲氧基苯基)哌啶-4-醇；
3-((二甲氨基)甲基)-4-(3-甲氧基苯基)-1-(丙基磺酰基)哌啶-4-醇；
1-(烯丙基磺酰基)-3-((二甲氨基)甲基)-4-(3-甲氧基苯基)哌啶-4-醇；
(1R,4S)-1-(((3-((二甲氨基)甲基)-4-羟基-4-(3-甲氧基苯基)哌啶-1-基)磺酰基)甲基)-7,7-二甲双环[2.2.1]庚-2-酮；
3-((二甲氨基)甲基)-1-((((1R,4S)-2-羟基-7,7-二甲基双环[2.2.1]庚-1-基)甲基)磺酰基)-4-(3-甲氧基苯基)哌啶-4-醇；
3-((二甲氨基)甲基)-4-(3-甲氧基苯基)-1-(甲磺酰基)哌啶-4-醇；
(1S,4R)-1-(((3-((二甲氨基)甲基)-4-羟基-4-(3-甲氧基苯基)哌啶-1-基)磺酰基)甲基)-7,7-二甲基双环[2.2.1]庚-2-酮；
3-((二甲氨基)甲基)-1-((((1S,4R)-2-羟基-7,7-二甲基双环[2.2.1]庚-1-基)甲基)磺酰基)-4-(3-甲氧基苯基)哌啶-4-醇；
1-(苄基磺酰基)-3-((二甲氨基)甲基)-4-(3-(三氟甲氧基)苯基)哌啶-4-醇；
1-(1-(苄基磺酰基)-4-(二氟甲氧基)-4-(3-甲氧基苯基)哌啶-3-基)-N,N-二甲氨基甲胺。
6.一种药物组合物，其特征在于，包括：权利要求1至5中任一项所述的化合物或其药学上可接受的盐；以及药学上可接受的载体。
7.权利要求1-5中任一项所述的化合物或者其药学上可接受的盐类在制备治疗与阿片受体相关适应症的药物中的用途。
8.如权利要求7所述的用途，其特征在于，所述与阿片受体相关适应症为疼痛、肠易激综合征、瘙痒、成瘾、抑郁症。
9.如权利要求8所述的用途，其特征在于，所述的疼痛包括治疗或缓解手术期间的疼痛、慢性疼痛、神经性疼痛、癌性疼痛。
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