CN1787997A - 用于拮抗5-ht2a受体的4-芳基磺酰基哌啶衍生物 - Google Patents
用于拮抗5-ht2a受体的4-芳基磺酰基哌啶衍生物 Download PDFInfo
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- CN1787997A CN1787997A CNA2004800131464A CN200480013146A CN1787997A CN 1787997 A CN1787997 A CN 1787997A CN A2004800131464 A CNA2004800131464 A CN A2004800131464A CN 200480013146 A CN200480013146 A CN 200480013146A CN 1787997 A CN1787997 A CN 1787997A
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- 102000049773 5-HT2A Serotonin Receptor Human genes 0.000 title abstract 2
- 108010072564 5-HT2A Serotonin Receptor Proteins 0.000 title abstract 2
- 230000008485 antagonism Effects 0.000 title description 2
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- 229910052731 fluorine Inorganic materials 0.000 claims description 70
- 229910052739 hydrogen Inorganic materials 0.000 claims description 58
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- 239000011737 fluorine Substances 0.000 claims description 49
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 48
- 239000001257 hydrogen Substances 0.000 claims description 34
- -1 methoxyl group Chemical group 0.000 claims description 33
- 239000000460 chlorine Substances 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 29
- 239000000203 mixture Substances 0.000 claims description 29
- 229910052801 chlorine Inorganic materials 0.000 claims description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 16
- 125000001153 fluoro group Chemical group F* 0.000 claims description 16
- 150000002431 hydrogen Chemical class 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 229910052794 bromium Inorganic materials 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 125000004429 atom Chemical group 0.000 claims description 7
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Classifications
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- 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
- C07D401/12—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 chain containing hetero atoms as chain links
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Abstract
式(I)化合物为选择性5-HT2A受体拮抗剂,因此适用于治疗中枢神经系统疾病如睡眠障碍和精神分裂症。
Description
本发明涉及一类作用于血清素受体(也称为5-羟色胺或5-HT受体)的磺酰基衍生物。更具体地讲,本发明涉及4-位氟取代的4-芳基磺酰基哌啶衍生物。这些化合物为有效的和选择性的人5-HT2A受体拮抗剂,因此可用作药物,尤其是在治疗和/或预防中枢神经系统障碍,包括睡眠障碍如失眠;精神障碍,如精神分裂症和精神病如焦虑症上的药物。
本发明的化合物典型地显现出对人类5-HT2A受体的结合比对其它人类受体如D2、5-HT2C和Ikr受体的结合更有效。因此可以期望这些化合物比与此类受体之间的结合能力不突出的化合物表现出更小的副反应。尤其是,这些化合物对于IKr受体作用较弱,因此,所期望的作用与心脏作用这类副作用相分离。
由于它们具有很强的人5-HT2A受体拮抗剂活性,本发明的化合物有效治疗神经病学疾病,包括睡眠障碍如失眠;精神障碍如精神分裂症以及抑郁症、焦虑症、恐慌症、强迫症、疼痛、饮食障碍如神经性厌食症和与麻醉剂如LSD或MDMA有关的依赖性或急性毒性;此外,还有效控制与服用抗精神病药有关的锥体外系综合征。更进一步地,这些化合物有效降低眼内压,并且还可有效治疗绝经综合征,尤其是热潮红(见Waldinger等,Maturitas,2000,36,165-8)。
在专利WO 00/43362、WO 96/35666、EP-A-0261688、EP-0304888、美国专利4,218,455和4,128,552、DE-A-3901735以及Fletcher等,J Med.Chem.,2002,45,492-503中描述了各类除别的以外还含有磺酰基的化合物。然而,所有这些出版物并未公开或指明本发明所提供的特定类的化合物。
本发明的化合物是强效的、选择性的5-HT2A受体拮抗剂,典型地具有对人5-HT2A受体(Ki)为100nM或更低的结合亲合力,典型地为50nM或更低,优选地为10nM或更低。本发明的化合物对于人5-HT2A受体相对于人体多巴胺D2受体,具有至少为10倍的选择性亲合力,合适地至少为20倍的选择性亲合力,优选地至少为50-倍的选择性亲合力。本发明的化合物对于人5-HT2A受体相对于IKr,可具有至少为10倍的选择性亲合力,合适地具有至少为20倍选择性亲合力,优选地具有至少为50倍的选择性亲合力。本发明的化合物对于人5-HT2A受体相对于人体5-HT2C受体,可具有至少为10倍的选择性亲合力,合适地具有至少为20倍选择性亲合力,优选地具有至少为50倍的选择性亲合力。优选的化合物相对于人5-HT2C受体显示出至少100倍的选择性。
本发明提供了式I化合物:
或其药学上可接受的盐,其中,
Ar为苯基、苯并异噻唑-3-基或苯并噻吩-3-基,各自带有R1、R2和R3取代基;
R1为氢、氟、氯、溴、C1-6烷基、C3-6环烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C2-6烯氧基、C2-6炔氧基或最多被5个氟原子取代的C1-6烷基;
R2为氢、氟、氯、C1-4烷基、C1-4烷氧基、最多被5个氟原子取代的C1-4烷基或最多被5个氟原子取代的C1-4烷氧基;
R3为氢、氟、氯、甲基、甲氧基、三氟甲基、二氟甲基、三氟甲氧基或二氟甲氧基;
Q1为氢;氟;氯;溴;C1-6烷基;C3-6环烷基;C2-6烯基;C2-6炔基;C1-6烷氧基;C2-6烯氧基;C2-6炔氧基;最多被5个氟原子取代的C1-6烷基;腈;COQ4或CO2Q4,其中Q4为氢或C1-6烷基;NQ5Q6、CONQ5Q6或SO2NQ5Q6,其中Q5为氢或C1-6烷基并且Q6为氢或C1-6烷基,或Q5和Q6连接形成4-7元杂环,该杂环还可以包含一个氧原子或一个另外的氮环原子,所述杂环可任选被最多3个氟原子或被CF3、甲基、乙基或羟基取代;羟基;硝基;SOQ7或SO2Q7,其中Q7为C1-4烷基;NQ8COQ9、NQ8CO2Q9或NQ8SO2Q9,其中Q8为氢或C1-4烷基并且Q9为氢或C1-4烷基或与Q8连接形成5-7元环;其中1、2、3或4个原子为氮原子,或其中1或2个为氮原子并且其中1个为氧或硫原子,或其中1个为氧或硫原子的5元杂芳环,该杂芳环任选被甲基、乙基或羟基取代;或者含有1或2个氮环原子的6元杂芳环或者苯基基团,两种基团都任选被下列基团取代:1或2个氟或氯原子或C1-4烷基、C1-4烷氧基或三氟甲基;
Q2为氢、氟、氯、腈、羟基、C1-4烷基、C1-4烷氧基、最多被5个氟原子取代的C1-4烷基或最多被5个氟原子取代的C1-4烷氧基;
Q3为氢、氟、氯、甲基、甲氧基、三氟甲基、二氟甲基、三氟甲氧基或二氟甲氧基;
或者Q2和Q3连接形成5、6或7元碳环残基;
R4为H或C1-4烷基,
m为0或1;
n为0、1或2;并且
W为CH2、CHF、CH(OH)或CO。
在一个式I化合物的子集中,R4为H,m为1,n为0,W为CH2,Ar为带有R1、R2和R3取代基的苯基,NQ5Q6代表的杂环任选被甲基、乙基或羟基取代。
适合的C1-6烷基可以为直链或支链。因此这些基团包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、直链和支链的戊基和己基。
有利的C1-6烷基包括甲基、乙基、正丙基等。
优选的C1-6烷基为甲基。
合适的和有利的烯基和炔基与合适的和有利的烷基类似。
本文所用的表述“C3-6环烷基”指含有3-6个环原子的非芳香单环烃环系统。实例包括环丙基、环丁基、环戊基、环己基和环庚基。
就医药用途而言,式I化合物可以以药学上可接受的盐形式出现。然而,其它盐也适用于制备式I化合物或它们的药学上可接受的盐。本发明化合物合适的药学上可接受的盐包括酸加成盐,这些盐例如可以通过将本发明化合物的溶液与药学上可接受的酸溶液混合进行制备,例如盐酸、硫酸、甲磺酸、苯甲磺酸、富马酸、马来酸、琥珀酸、乙酸、苯甲酸、草酸、柠檬酸、酒石酸、碳酸或磷酸。此外,本发明化合物带有酸性部分的,则式I化合物可以以两性离子存在,或者可以通过用合适的碱中和酸性部分形成药学上可接受的盐。由此所形成的药学上可接受的盐的实例包括碱金属盐如钠或钾盐;铵盐;碱土金属盐如钙或镁盐;以及与合适的有机碱所形成的盐如胺盐(包括吡啶鎓盐)和季铵盐。式I化合物典型地以游离碱、盐酸盐或甲磺酸盐形式出现。
当本发明化合物具有一个或多个不对称中心时,它们可相应地以对映体存在。当本发明化合物具有两个以上不对称中心时,它们可另外以非对映异构体存在。可以认为所有的这类异构体及其任何比例的混合物都包括在本发明的发明范围内。
在式I化合物中,R4代表H或C1-4烷基(如甲基、乙基或丙基),优选为H或甲基,最优选为H。
n代表0、1或2,优选为0或1,最优选为0。
m代表0或1,典型地为1,除当Ar代表苯并异噻唑或苯并噻唑残基时,该情况下n和m均优选为0。
W代表CH2、CHF、CH(OH)或CO,优选为CH2、CHF或CO。在一特定实例中,m为1,w代表CH2,n=0并且R4为H。
Q1优选位于SO2基团的对位。优选的Q1等价基团(identities)包括H、F、Cl、Br、CN、甲酰胺、5-元杂芳基和NQ5Q6,其中的Q5和Q6优选形成如前所定义的杂环。Q1代表的5-元杂芳环包括吡咯、吡唑、咪唑、三唑、四唑、噁唑和噻唑。这类环可以通过碳键合,或者在吡咯、吡唑、咪唑、三唑和四唑的情况下可通过氮键合。由NQ5Q6代表的杂环基实例包括氮杂环丁基、吡咯烷基、哌啶基、吗啉基、4-三氟甲基哌啶-1-基和4,4-二氟哌啶-1-基。
Q2优选为H、F、Cl、CF3、甲基或甲氧基,特别为H、F或Cl,最优选为H或F。
Q3优选为H或F,最优选为H。
当Ar代表苯基残基时,R1优选连在4-位。优选的R1等价基团包括H、F、Cl、Br、C1-6烷基(如甲基)、甲氧基和CF3,尤其是H、F、甲基和CF3。
当Ar代表苯基残基时,R2优选地连在2位。优选的R2等价基团包括H、F、Cl、C1-4烷基(如甲基)和CF3,尤其是H、F、甲基和CF3。
R3优选为H或F,最优选为H。
本发明的某些优选化合物包括式(II)化合物:
及其药学上可接受的盐,其中:
R1′为氢、氟、氯、甲基、三氟甲基或甲氧基;
R2′为氢、氟或氯;
R3′为氢或氟;
Q1′为氢、氟、氯、溴、甲基、三氟甲基、甲氧基、甲酰胺基、腈或1,2,3-三唑烷基;
Q2′为氢、氟或氯;
Q3′为氢或氟;
在某些优选的式(II)化合物中,R1′为氢或氟,R2′为氢或氟并且R3′为氢。
在某些优选的式(II)化合物中,Q1’在4-位并且为氢、氟、甲酰胺、腈或1,2,3-三唑基,Q2′为氢或氟并且Q3′为氢。
本发明的化合物优选子集包含式IIA化合物:
及其药学上可接受的盐,其中,
R13代表H,R14代表H、F或OH,或者R13和R14一起代表酮;
并且Q1、Q2、R1、R2和R4具有如前所定义的相同含义和优选等价基团。
在本实施方案中,R1和R2均适宜地独立选自H和F。
在本实施方案中,Q2优选为H或F。
在本实施方案中,优选的Q1等价基团包括H、F、Cl、Br、CN、CONH2、吗啉-1-基、1,2,3-三唑-1-基、1,2,4-三唑-1-基、吡唑-1-基、咪唑-1-基、吡咯-1-基、1-甲基吡唑-5-基、1-甲基咪唑-2-基、2-甲基四唑-5-基、噁唑-2-基、三唑-2-基、氮杂环丁-1-基、吡咯烷-1-基、哌啶-1-基、4,4-二氟-哌啶-1-基和4-(三氟甲基)哌啶-1-基。
本发明的特定化合物包括下文示例的化合物和它们药学上可接受的盐。
本发明的化合物具有人5-HT2A受体拮抗剂活性并且因此有治疗或预防由5-HT2A受体活性介导的疾病的用途。
本发明还提供了包含一种或多种本发明化合物和药学上可接受的载体的药用组合物。这些组合物优选地以单位剂量形式存在,如片剂、丸剂、胶囊剂、散剂、颗粒剂、无菌胃肠外溶液或悬浮液、定量气雾剂或液体喷雾剂、滴剂、安瓿剂、透皮贴剂、自动注射装置或栓剂;用于口服、胃肠外、鼻内、舌下或直肠给药,或者通过吸入或吹入给药。主要活性成分典型地与药用载体混合,例如常规的片剂成分如玉米淀粉、乳糖、蔗糖、山梨醇、滑石粉、硬脂酸、硬脂酸镁和磷酸二钙或树胶、分散剂、悬浮剂或表面活性剂如一油酸脱水山梨醇酯和聚乙二醇,以及其它药用稀释剂如水,以形成包含本发明化合物或其药学上可接受的盐的均一的制剂确定前组合物。当称这些制剂确定前组合物为均一时,指所述的活性成分是均匀地分散在该组合物中,因此所述组合物可以容易地细分为等效的单位剂型,如片剂、丸剂和胶囊剂。这种制剂确定前组合物随后细分成上述类型的单位剂型,各剂型包含有0.1至约500mg的本发明的活性成分。典型的单位剂型含有1-100mg,例如含1、2、5、10、25、50或100mg活性成分。新型组合物的片剂或丸剂可以进行包衣或复合以提供具有延长作用优点的剂型。例如,片剂或丸剂可以包含内部剂量和外部剂量组分,后者以包被形式包住前者。两种组分可以通过肠溶层隔开,该层可以抵抗在胃中的崩解作用而使内部组分完整地到达十二指肠或延缓释放。这类肠溶层或衣可以使用各种材料,这些材料包括多种聚合酸以及聚合酸与这些材料的混合物,如虫胶、鲸蜡醇和醋酸纤维素。
本发明新型组合物可以加入其中并用于口服或注射给药的液体形式包括:水溶液剂、液体或凝胶填充的胶囊剂、适宜的调味糖浆、水或油混悬剂以及含如棉籽油、芝麻油或椰子油等食用油的调味乳剂、酏剂和类似的药用溶媒。水混悬液适宜的分散剂或悬浮剂包括合成的和天然的树胶,如黄芪胶、阿拉伯胶、藻酸盐、葡聚糖、羧甲基纤维素钠、甲基纤维素、聚(乙二醇)、聚(乙烯基吡咯烷酮)或明胶。
本发明还提供了式I化合物或其药学上可接受的盐,其在治疗人体的方法中使用。优选的治疗是针对由5-HT2A受体活性介导病症的治疗。
本发明进一步提供式I化合物或其药学上可接受的盐在生产治疗或预防由5-HT2A受体活性介导病症的药物上的用途。
本发明还公开了对患有或易患5-HT2A受体活性介导病症的受试者的治疗方法,该方法包括给予该受试者有效量的式I化合物或其药学上可接受的盐。
本发明的一个方面中,5-HT2A受体活性介导的病症指睡眠障碍,尤其是失眠症。本发明的另一方面,5-HT2A受体活性介导的病症选自精神障碍(如精神分裂症)、抑郁症、焦虑症、恐慌症、强迫症、疼痛、饮食障碍(如神经性厌食症)、与麻醉剂如LSD或MDMA有关的依赖性或急性毒性以及与绝经有关的热潮红。
在本文所面对的治疗中,例如对于失眠或精神分裂症的治疗,适宜的剂量水平大约为每日0.01-250mg/kg,优选约每日0.05-100mg/kg,特别地约为每日0.05-5mg/kg。所述化合物可以按每日1-4次的方案给药,但优选地为每日一次,例如临睡前。
如果需要,本发明化合物可以与其它睡眠诱导剂、抗精神分裂药或抗焦虑药合并给药。这类合并给药可以在患者已经建立涉及其它常规药物的睡眠诱导、抗精神分裂或抗焦虑治疗方案的基础上进行。
式(I)化合物可以通过使式(III)和式(IV)化合物进行反应制备:
其中,X为离去基团(尤其为卤素,如Br)并且所有其它变量具有上述相同含义。该反应在常规的烷基化反应条件下进行,例如采用溶剂如四氢呋喃或乙腈,在碱如K2CO3、AgO或CsCO3存在下于如80℃-90℃温度下进行。可以常规方式应用催化量的NaI。
另外,式(III)化合物可以与式(IVA)化合物进行还原烷基化反应:
其中,Ar、m、n、W和R4如前所定义(但W优选为CH2)。该反应在硼氢化钠和四异丙醇钛(titanium tetraisopropoxide)存在下在乙醇中进行。
式(III)化合物另外还可以与环氧化物(IVB)反应:
其中,Ar如前所定义以提供式(I)化合物,其中R4为H,n为0,m为1,W为CH(OH)。
式(III)化合物可以通过从式(Va)化合物去除保护基在原位产生,
其中Prt为保护基,例如叔丁氧基羰基基团,该基团可以通过用三氟醋酸或盐酸/乙醇处理除去。
式(Va)化合物可以从相应的式(Vb)化合物,通过与强碱如正丁基锂和氟化试剂如(PhSO2)2NF反应制得。该反应通常在溶剂如四氢呋喃中在-78℃-25℃温度下进行。
可以通过式(VI)硫醇与式(VII)哌啶反应并氧化所得的硫醚获得化合物(Vb):
其中,Y为离去基团(优选地为甲磺酰酯或类似的磺酰酯)并且所有其它变量如前所定义。硫醚的形成在回流乙腈中在碱如K2CO3存在下进行,所述的氧化可以通过常规方法进行(如采用间氯过氧苯甲酸或通过与过硫酸钾制剂和湿氧化铝在氯仿中回流)。这些过程在专利WO 00/43362和文献J Med.Chem.,2002,45,492-503中有详细描述。
如果需要,上述的氧化可以经由相应的亚砜中间体分为两个阶段进行(如在室温采用过硫酸钾制剂方法作为第一步反应)。通过用氟化试剂,如三氟化二乙氨基硫(DAST)处理,所得亚砜可以在哌啶环的4-位进行氟代(典型地在三氟化锑存在下在惰性溶剂如二氯甲烷中于室温反应)。将所得化合物用氧化剂,如间氯过氧苯甲酸(例如在惰性溶剂如二氯甲烷中于室温反应)处理得到化合物(Va)。
式(I)化合物还可以通过对相应化合物进行氟化制备,该相应化合物具有氢原子而不是式(I)化合物中的氟原子。该反应采用氟化剂如(PhSO2)2NF和强碱如NaHMDS在-78℃-25℃下在惰性溶剂如四氢呋喃中进行。
式VI和式VII的原料无法商业获得时,它们可以通过与所附实施例中所描述的类似方法制备,或者通过本领域内熟知的标准方法制备。
适当时,可以认识到,根据上述方法最初获得的任何式(I)化合物随后都可以采用本领域所熟知的技术进一步加工为所需的式I化合物。例如,最初得到的式I化合物(其中的Q1代表溴),可以转化为相应的式I化合物(其中Q1代表氰基),方法为通过将该化合物用氰化铜(I)在1-甲基-2-吡咯烷酮(NMP)存在下,或用氰化锌在四(三苯基膦)合钯(O)存在下处理得到。所得的其中Q1代表氰基的式I化合物,可依次转化为相应的其中Q1代表酰胺基的式I化合物,方法为通过在无机酸,如85%硫酸中在100℃下加热得到,或者通过用三甲基硅烷醇(trimethylsilanolate)钾处理,典型地在四氢呋喃中回流得到。另外,最初得到的式I化合物(其中Q1代表溴),可以在一氧化碳气流下在1,1,1,3,3,3-六甲基二硅氮烷(hexamethyldisilazane)、二异丙胺、醋酸钯(II)和1,3-双(二苯基膦基)丙烷存在下加热,直接转化为相应的式I化合物(其中的Q1代表酰胺基)。例如,当式I化合物中的Q1代表任选取代的N-连接的杂环基如咪唑-1-基、吡唑-1-基、1,2,3-三唑-1-基、1,2,4-三唑-1-基、吡咯烷-1-基、哌啶-1-基或氮杂环丁-1-基,这些化合物可以通过将相应的式I化合物(其中的Q1代表氟)用适当的任选取代的N-杂环处理,典型地在DMSO中加热得到。例如,式I化合物中的Q1代表任选取代的碳连接的5元杂芳环如2-甲基四唑-5-基或1-甲基-1,2,4-三唑-5-基时,这些化合物可以通过使相应的式I化合物(其中的Q1代表溴)与合适的杂芳基化合物的三丁基锡基(tributylstannyl)衍生物,如2-甲基-5-三丁基锡基四唑或1-甲基-5-三丁基锡基-1,2,4-三唑,在过渡金属催化剂如四(三苯基膦)合钯(O)存在下反应,典型地在溶剂如N,N-二甲基甲酰胺中加热得到。
类似地,其中的W为CO的化合物可以被还原得到相应的W为CH(OH)的化合物。所得化合物接着用DAST处理得到W为CHF的化合物。
当上述在本发明中使用的化合物的制备方法产生了立体异构体混合物时,这些异构体可以采用常规技术如制备色谱进行分离。所述化合物可以制备为外消旋形式,或通过对映体专一合成或拆分得到单一对映异构体。例如,该化合物可以通过标准技术如制备HPLC或通过与光学活性酸如二-对甲苯酰基-D-酒石酸和/或二-对甲苯酰基-L-酒石酸成盐形成非对映异构体对,然后再通过分部结晶、再生为游离碱,从而拆分为它们的组分对映体。所述化合物还可以通过先形成非对映异构的酯或酰胺,然后通过色谱分离并除去手性辅助物拆分。
在上述任何的合成顺序中,都可能有必要和/或需要保护所涉及的任一分子上的敏感或反应性基团。这可以通过常规的保护基,如“Protective Groups in Organic Chemistry,ed.J.F.W.McOmie,PlenumPress,1973;和T.W.Greene&P.G.M.Wuts,Protective Groups inOrganic Synthesis,John Wiley&Sons,1991中所描述的获得。所述的保护基可以采用本领域熟知的方法在后面的适当阶段除去。采用Fletcher等,在J.Med.Chem.,2002,45,492-503中所述的方法检测化合物与5-HT2A受体和其它受体如5-HT2C和IKr的结合。
实施例1
4-(4-溴苯磺酰基)-1-[2-(2,4-二氟苯基)乙基]-4-氟哌啶
在悬浮有湿氧化铝(10%水,13g)的氯仿(60ml)中先加入N-BOC4-(4-溴苯硫基)哌啶(根据Fletcher,S.R.等.,J.Med.Chem.2002,45,492-503的方法制备),随后加入Oxone(24g)。所得反应物搅拌3小时,过滤,硅胶层析,用50%EtOAc/异己烷洗脱得到N-BOC 4-(4-溴苯基亚磺酰基)哌啶(3.5g,69%):δH(400MHz,CDCl3)1.44(9H,s),1.55-1.8(4H,m),2.6-2.75(3H,m),4.25(2H,m),7.47(2H,d),7.67(2H,d)。
将N-BOC 4-(4-溴苯基亚磺酰基)哌啶(3.17g,8.5mmol)溶于二氯甲烷(50ml)中,依次加入三氯化锑(194mg,0.85mmol)和三氟化二乙胺基硫(2.8mL,0.022mol)。反应混合物于室温搅拌16小时后用冷的饱和碳酸氢钠溶液淬灭,所得产物用乙酸乙酯萃取。所得有机相用饱和食盐水洗涤,MgSO4干燥后蒸干。所得残留物溶解于二氯甲烷(50mL)中并将其加入含mCPBA(50-55%;7.3g,0.021mol)的二氯甲烷溶液(30mL)中,该溶液已预先用MgSO4干燥并过滤。所得反应混合物于25℃中搅拌2小时后用饱和的焦亚硫酸钠淬灭。所得产物用二氯甲烷萃取,用饱和碳酸氢钠溶液和饱和食盐水洗涤所得有机相。用MgSO4干燥后,真空除去溶剂,所得残留物用硅胶层析,用10%EtOAc/异己烷洗脱得到N-BOC 4-(4-溴苯磺酰基)-4-氟哌啶的白色固体(2.3g,70%):δH(360MHz,CDCl3)1.46(9H,s)1.9(2H,m),2.02-2.3(2H,m),2.9(2H,m),4.2(2H,m),7.8(4H,dd)。
将N-BOC 4-(4-溴苯磺酰基)-4-氟哌啶(2.3g,5.5mmol)溶于6NHCl(30mL)中,加入乙醇直到混浊溶液变澄清(约20mL)。所得反应混合物加热至85℃并在该温度下搅拌16小时。所得反应混合物冷却,蒸去乙醇,通过加入5N NaOH将所得的酸性溶液碱化。所得产物用EtOAc萃取,所得有机相用饱和食盐水洗涤后用MgSO4干燥,真空蒸去溶剂后得到4-(4-溴苯磺酰基)-4-氟哌啶盐酸盐的白色固体(1.4g,80%):δH(360MHz,CDCl3)1.84(2H,dt),2.04-2.22(2H,m),2.82(2H,dt),3.09(2H,dt),7.75(4H,m)。m/z(ES+)322,324(M+1)。
将4-(4-溴苯磺酰基)-4-氟哌啶盐酸盐(1.4g,4mmol)溶于乙腈中,依次加入碳酸钾(1.4g,0.01mol)和2,4-二氟苯乙基溴(按WO 00/43362所述方法制备,1.3g,6mmol)。所得反应物加热回流16小时。冷却后,反应混合物在EtOAc和水之间分配,有机相用饱和食盐水洗涤,用MgSO4干燥后蒸发。所得残留物用硅胶层析,用30%EtOAc/异己烷洗脱得到标题化合物的白色固体(0.950g,51%):δH(360MHz,CDCl3)1.86(2H,t),2.22-2.39(4H,m),2.57(2H,t),2.76(2H,t),2.93(2H,m),6.76(2H,m),7.13(1H,m),7.74(4H,m).m/z(ES+)462,464(M+1)。
实施例2
1-[2-(2,4-二氟苯基)乙基]-4-氟-4-(4-氟苯基磺酰基)哌啶
方法1
于-78℃,将双(三甲基硅烷基)酰胺钠(Sodium bis(trimethylsilyl)amide)(1.0M/THF;0.3mL,0.3mmol)滴加到搅拌的1-[2-(2,4-二氟苯基)乙基]-4-(4-氟苯基磺酰基)哌啶(95.8mg,0.25mmol)(根据Fletcher,S.R.等,J.Med.Chem.2002,45,492-503中所述方法制备)的THF(0.5mL)溶液中。所得溶液温热至0℃,搅拌5分钟,再次冷却至-78℃。加入N-氟代双(苯基磺酰基)胺(80.8mg,0.38mmol)的THF(0.25mL)溶液,使所得混合物达到室温,继续搅拌15分钟。通过加入饱和NH4Cl水溶液(1mL)淬灭该反应,然后在水(20mL)和EtOAc(20mL)之间分配。所得有机部分用Na2SO4干燥,过滤后真空浓缩,所得粗品通过硅胶层析(硅胶,30%EtOAc/异己烷)得到标题化合物的白色固体(19mg):
δH(500MHz,DMSO)1.79-1.83(2H,m),2.20-2.19(4H,m),2.52-2.55(2H,m),2.73-2.76(2H,m),2.95-2.97(2H,m),7.00-7.04(1H,m),7.14-7.19(1H,m),7.36-7.41(1H,m),7.56-7.61(2H,m),7.96-7.99(2H,m).m/z(ES+)402(100%,[MH]+).
方法2
-78℃,将正丁基锂(1.6M/异己烷;13ml,20.8mmol)滴加到搅拌的N-BOC 4-(4-氟苯磺酰基)哌啶(6g,17.4mmol)的THF(70mL)溶液中。1小时后,滴加N-氟代双(苯基磺酰基)胺(6.04g,19mmol)的THF(17mL)溶液,将所得混合物升至室温,搅拌1小时后加入水(1mL)淬灭,在饱和NH4Cl水溶液(80mL)和EtOAc(80mL)之间分配。所得有机相用饱和食盐水(30mL)洗涤,Na2SO4干燥,过滤后真空浓缩。柱层析纯化(硅胶,20%EtOAc/异己烷)得到N-BOC 4-氟-4-(4-氟苯磺酰基)哌啶的类白色固体(4.8g):
δH(360MHz,CDCl3)1.46(9H,s),1.80-1.95(2H,m),2.05-2.30(H,m),2.90-3.00(2H,m),4.12-4.22(2H,m),7.28(2H,t,J8.5Hz),7.93-7.96(2H,m).m/z(ES+)261[(M-BOC)H]+.
将N-BOC 4-氟-4-(4-氟苯磺酰基)哌啶(2g,5.5mmol)悬浮于乙醇(50mL)和6N HCl(25mL)混合物中,将混合物加热至80℃直到完全溶解。该溶液真空浓缩后所得残留物用10∶1的Et2O和EtOAc(50mL)混合液洗涤后得到4-氟-4-(4-氟苯磺酰基)哌啶盐酸盐的白色固体。
如实施例1中所描述,将4-氟-4-(4-氟苯磺酰基)哌啶盐酸盐用二氟苯基乙基溴烷基化,在50%EtOAc/异己烷中重结晶得到标题化合物,经分析与先前数据一致。
实施例3
4-({1-[2-(2,4-二氟苯基)乙基]-4-氟哌啶-4-基}磺酰基)苯基氰
方法1:
将4-(4-溴苯基磺酰基)-1-[2-(2,4-二氟苯基)乙基]-4-氟哌啶(0.350g,0.758mmol)溶于无水DMF(10mL)中并加入氰化锌(0.090g,0.758mmol)。所得溶液用氮气脱气5分钟后加入四(三苯基膦)合钯(O)(100mg)。将反应物加热到85℃反应两小时,加入另外的100mg四(三苯基磷)钯(O),半小时后再加入另外的100mg。再加入另外的100mg钯催化剂后将反应物在95℃加热72小时。所得反应混合物在EtOAc和水之间分配,合并有机相后依次用水(x3)和饱和食盐水洗涤,MgSO4干燥。真空除去溶剂,所得残留物用硅胶层析,用10-25%EtOAc/异己烷洗脱得到固体,将该固体在EtOAc/异己烷中重结晶得到标题化合物的白色固体(0.153g):
δH(400MHz,CDCl3)1.87(2H,m),233(4H,m),2.58(2H,m),2.76(2H,m),2.94(2H,m),6.78(2H,m),7.13(1H,m),7.88(2H,d),8.04(2H,d).
方法2
将1-[2-(2,4-二氟苯基)乙基]-4-氟-4-(4-氟苯基磺酰基)哌啶(25mg,0.062mmol)、氰化钠(20mg,0.41mmol)和DMSO(0.5mL)合并后在120℃加热18小时。冷却过程中,加入水(5mL),过滤分离所析出晶体。所得残余物用水洗涤(10mL)并用连续的空气流干燥后得到标题化合物(10mg),经分析与前面数据一致。
方法3
将N-BOC 4-(4-溴苯基磺酰基)哌啶(25g,62mmol)(根据Fletcher,S.R.等,J Med.Chem.2002,45,492-503所描述的方法制备)、氰化锌(8.73g,74mmol)和四(三苯基磷化)钯(O)(3.58g,3.1mmol)在N-甲基吡咯烷(250mL)中合并,所得混合物在160℃加热30分钟。冷却过程中,将反应混合物在EtOAc(250mL)和饱和NaHCO3水溶液(200mL)之间分配。所得有机相用水(2×150mL)和饱和食盐水(150mL)洗涤,用MgSO4干燥后真空浓缩至约100mL,此时结晶开始析出。加入Et2O(500mL)并将所得结晶滤出,用另外的Et2O(200mL)洗涤后在真空干燥箱中干燥得到N-BOC 4-(哌啶-4-基磺酰基)苯甲腈(9.9g)。
δH(500MHz,DMSO)1.30-1.40(2H,m),1.37(9H,s),1.80-1.85(2H,m),2.65-79(2H,m),3.60-3.68(1H,m),3.95-4.05(2H,m),8.04(2H,d,J8.5Hz),8.17(2H,d,J8.5Hz).
于-78℃下将正丁基锂(1.6M异己烷;18.3mL,29mmol)加入搅拌的2,2,6,6,-四甲基哌啶(5.4mL,32mmol)的THF(50mL)溶液中,5分钟后,加入N-BOC 4-(哌啶-4-基磺酰基)苯甲腈(9.9g,29.3mmol)的THF(100mL)溶液中。所得溶液温热至-10℃,搅拌90分钟后再加入N-氟代双(苯磺酰基)胺(10.1g,32mmol)的THF(40mL)溶液。所得反应混合物温热至室温,搅拌30分钟后于EtOAc(150mL)和饱和NH4Cl(150mL)水溶液之间分配。所得有机相用MgSO4干燥,过滤,真空浓缩后所得粗品用柱层析纯化(硅胶,20%EtOAc/异己烷)得到N-BOC 4-(4-氟哌啶-4-基磺酰基)苯甲腈(6g):
:δH(500MHz,DMSO)1.41(9H,s),1.82-1.90(2H,m),1.96-1.11(2H,m),2.82-2.93(2H,m),3.95-4.05(2H,m),8.09(2H,d,J8.2Hz),8.22(2H,d,J8.5Hz).
分别采用实施例2和1中所述的方法对N-BOC 4-(4-氟哌啶-4-基磺酰基)苯甲腈进行脱保护和烷基化,得到标题化合物,经分析与先前的数据一致。
实施例4
4-({1-[2-(2,4-二氟苯基)乙基]-4-氟哌啶-4-基}磺酰基)苯甲酰胺
将水(0.5mL)、K2CO3(9mg,0.065mmol)和过氧化氢水溶液(约50%,0.05mL,约0.7mmol)依次加入剧烈搅拌的4-({1-[2-(2,4-二氟苯基)乙基]-4-氟哌啶-4-基}磺酰基}苯甲腈(53mg,0.13mmol)的DMSO(1mL)溶液中。30分钟后,所得反应混合物在EtOAc(20mL)和饱和食盐水(20mL)之间分配,所得有机相用Na2SO4干燥,过滤并真空浓缩。柱层析纯化(硅胶,10%EtOH/EtOAc)得到标题产物的白色固体(8mg):
δH(500MHz,DMSO)1.75-1.85(2H,m),2.02-2.20(4H,m),2.50-2.55(2H,m),2.70-2.78(2H,m),2.91-2.99(2H,m),6.98-7.02(1H,m),7.11-7.18(1H,m),7.31-7.41(1H,m),7.81(1H,s),7.97(2H,dJ8.4Hz),8.13(2H,dJ8.3Hz),8.25(1H,s).m/z(ES+)427[MH]+
实施例5
4-({4-氟-1-[2-(2-氟苯基)乙基]哌啶-4-基}磺酰基)苯甲酰胺
将N-BOC 4-(4-氟哌啶-4-基磺酰基)苯甲腈(1g,2.7mmol)和三甲基硅烷醇钾(346mg,2.7mmol)的甲苯(12mL)溶液加热回流2小时。冷却后,反应混合物在饱和NH4Cl(20mL)和EtOAc(20mL)之间分配,所得水相再用EtOAc(2×20mL)萃取。合并有机相,用MgSO4干燥,过滤后浓缩,所得残留物用柱层析纯化(硅胶,30-80%EtOAc/异己烷)得到N-BOC 4-(4-氟哌啶-4-基磺酰基)苯甲酰胺(350mg):
δH(500MHz,DMSO)1.47(9H,s),1.82-1.94(2H,m),2.12-2.28(2H,m),2.89-2.99(2H,m),4.10-4.20(2H,m),5.90-6.00(1H,m),6.18-6.28(1H,m),8.02(4H,s).
分别采用实施例2和1中所述的方法对N-BOC 4-(4-氟哌啶-4-基磺酰基)苯甲酰胺进行脱保护和烷基化,得到标题化合物的白色固体。
δH(500MHz,DMSO)1.78-1.83(2H,m),2.05-2.20(4H-,m),2.53-2.56(2H,m),2.74-2.77(2H,m),2.96-2.97(2H,m),7.10-7.14(2H,m),7.22-7.26(1H,m),7.30-7.34(1H,m),7.70(1H,s),7.97(2H,dJ8.3Hz),8.12-8.14(2H,m),8.25(1H,s).m/z(ES+)409[MH]+.
下列化合物(实施例6-22)采用实施例1-5的类似方法制备:
6)4-氟-4-(4-氟苯磺酰基)-1-[2-(4-氟苯基)乙基]哌啶
m/z(ES+)384[MH]+。
7)4-氟-4-(4-氟苯磺酰基)-1-[2-(2-氟苯基)乙基]哌啶
m/z(ES+)384[MH]+。
8)4-氟-4-(4-氟苯基磺酰基)-1-(2-苯基乙基)哌啶
m/z(ES+)366[MH]+。
9)4-({4-氟-1-[2-(4-氟苯基)乙基]哌啶-4-基}磺酰基)苯甲腈
m/z(ES+)391[MH]+。
10)
4-({4-氟-1-[2-(2-氟苯基)乙基]哌啶-4-基}磺酰基)苯甲腈
m/z(ES+)391[MH]+。
11)4-{[4-氟-1-(2-苯基乙基)哌啶-4-基]磺酰基}苯甲腈
m/z(ES+)373[MH]+。
12)4-({4-氟-1-[2-(4-氟苯基)乙基]哌啶-4-基}磺酰基)苯甲酰胺
m/z(ES+)409[MH]+。
13)4-{[4-氟-1-(2-苯乙基)哌啶-4-基]磺酰基}苯甲酰胺
m/z(ES+)391[MH]+。
14)1-[2-(2,4-二氟苯基)乙基]-4-氟-4-(苯磺酰基)哌啶
m/z(ES+)384[MH]+。
15)4-氟-1-(2-(2-氟苯基)乙基)-4-(苯磺酰基)哌啶
m/z(ES+)366[MH]+。
16)4-氟-1-(2-(4-氟苯基)乙基)-4-(苯磺酰基)哌啶
m/z(ES+)366[MH]+。
17)4-氟-1-(2-苯基乙基)-4-(苯磺酰基)哌啶
m/z(ES+)348[MH]+。
18)1-[2-(2,4-二氟苯基)乙基]-4-氟-4-(2-氟苯磺酰基)哌啶
m/z(ES+)402[MH]+。
19)1-[2-(2,4-二氟苯基)乙基]-4-氟-4-(3-氟苯磺酰基)哌啶
m/z(ES+)402[MH]+。
20)4-(4-氯苯磺酰基)-1-[2-(2,4-二氟苯基)乙基]-4-氟哌啶
m/z(ES+)419[MH]+。
21)4-({4-氟-1-[(6-氟-1,2-苯并异噻唑-3-基)甲基]哌啶-4-基}磺酰基)苯
基氰
m/z(ES+)434[MH]+。
22)6-氟-3-({4-氟-4-[(4-氟苯基)磺酰基]哌啶-1-基}甲基)-1,2-苯并异噻
唑
m/z(ES+)427[MH]+。
实施例23
4-[4-({1-[2-(2,4-二氟苯基)乙基]-4-氟哌啶-4-基}磺酰基)苯基]吗啉
将4-(4-溴苯磺酰基)-1-[2-(2,4-二氟苯基)乙基]-4-氟哌啶(25mg,0.054mmol)溶于无水甲苯(1.5mL)中,加入吗啉(0.01mL,0.108mmol)和外消旋(rac)-2,2′-双(二苯基膦)-1,1’-联二萘基(2.7mg;5mol%)。所得溶液用氮气脱气5分钟后加入醋酸钯(1.1mg;2mol%)和碳酸铯(26mg,0.082mmol)。所得反应物在90℃加热16小时。该反应混合物在二氟甲烷和水之间分配,收集有机相,用水和饱和食盐水洗涤,Na2SO4干燥。真空除去溶剂,所得残留物用硅胶层析,用70%EtOAc/异己烷洗脱得到标题化合物的白色固体(16mg):
δH(400MHz,DMSO)1.75(2H,m),1.97(2H,m),2.09(2H,m),2.71(2H,m),2.92(2H,m),3.34(4H,m),3.72(4H,m),6.97(1H,m),7.08(3H,m),7.35(1H,m),7.61(2H,m).m/z(ES+)469[MH]+.
实施例24
1-[2-(2,4-二氟苯基)乙基]-4-氟-4-[4-(吡咯烷-1-基)苯磺酰基]哌啶
将4-(4-氟苯磺酰基)-1-[2-(2,4-二氟苯基)乙基]-4-氟哌啶(100mg,2.44mmol)溶于DMSO(5ml)中,加入吡咯烷(0.61mL,7.32mmol),将所得溶液在微波反应器中于150℃加热10分钟。冷却,反应混合物在EtOAc(30mL)和饱和NaHCO3水溶液(30mL)之间分配。所得有机相用水洗涤后用Na2SO4干燥,过滤后真空浓缩得到标题化合物的白色固体(102mg):
δH(400MHz,DMSO)1.75(2H,m)2.0(4H,m)2.1(2H,m)2.5(2H,m)2.7(2H,m)2.95(2H,m)3.35(4H,m)6.7(2H,d)7.0(1H,m)7.15(1H,m)7.4(1H,m)7.6(2H,d).m/z(ES+)453[MH]+.
下列化合物(实施例25-31)采用实施例23-24的类似方法制备:
25)1-[2-(2,4-二氟苯基)乙基]-4-氟-4-[4-(哌啶-1-基)苯磺酰基]哌啶
m/z(ES+)467[MH]+。
26)1-[2-(2,4-二氟苯基)乙基]-4-氟-4-{4-[4-(三氟甲基)哌啶-1-基]苯磺
酰基}哌啶
m/z(ES+)535[MH]+。
27)4-[4-(氮杂环丁-1-基)苯磺酰基]-1-[2-(2,4-二氟苯基)乙基]-4-氟哌
啶
m/z(ES+)439[MH]+。
28)1-[2-(2,4-二氟苯基)乙基]-4-[4-(4,4-二氟哌啶-1-基)苯磺酰基]-4-
氟哌啶
m/z(ES+)503[MH]+。
29)1-[2-(2,4-二氟苯基)乙基]-4-氟-4-[4-([1,2,3]三唑-1-基)苯磺酰基]哌啶
m/z(ES+)451[MH]+。
30)1-[2-(2,4-二氟苯基)乙基]-4-氟-4-[4-(吡咯-1-基)苯磺酰基]哌啶
m/z(ES+)449[MH]+。
31)1-[2-(2,4-二氟苯基)乙基]-4-氟-4-[4-(吡唑-1-基)苯磺酰基]哌啶
m/z(ES+)450[MH]+。
下列化合物(实施例32-35)是通过实施例24的类似方法从4-(3,4-二氟苯磺酰基)-1-[2-(2,4-二氟苯基)乙基]-4-氟哌啶)制备得到。
32)1-[2-(2,4-二氟苯基)乙基]-4-氟-4-{[3-氟-4-(吡唑-1-基)苯基]磺酰
基}哌啶
m/z(ES+)468[MH]+。
33)1-[2-(2,4-二氟苯基)乙基]-4-氟-4-{[3-氟-4-(咪唑-1-基)苯基]磺酰
基}哌啶
m/z(ES+)468[MH]+。
34)1-[2-(2,4-二氟苯基)乙基]-4-氟-4-{[3-氟-4-(1,2,3-三唑-1-基)苯基]
磺酰基}哌啶
m/z(ES+)469[MH]+。
35)1-[2-(2,4-二氟苯基)乙基]-4-氟-4-{[3-氟-4-(1,2,4-三唑-1-基)苯基]
磺酰基}哌啶
m/z(ES+)469[MH]+。
实施例36
1-[2-(2,4-二氟苯基)乙基]-4-氟-4-[4-(1,3-噁唑-2-基)苯磺酰基]哌啶
将4-(4-溴苯磺酰基)-1-[2-(2,4-二氟苯基)乙基]-4-氟哌啶(50mg,0.108mmol)和2-(三丁基锡基)噁唑(0.04mL,0.119mmol)溶于无水THF(0.25mL)中,所得溶液用氮气脱气5分钟后加入双(三苯基膦)氯化钯(II)(3.8mg,5mol%)。所得反应混合物在80℃加热72小时后在DCM(20mL))和水(20mL)之间分配,所得有机相用Na2SO4干燥,过滤,真空浓缩。所得残留物用DCM(0.5mL)稀释后过SCX柱,所得吸附物用另外的DCM(10mL)洗涤。所得产物用含氨的甲醇(2M,10mL)洗脱。合并洗脱液,蒸除易挥发物,所得残留物用柱层析纯化(硅胶,65%EtOAc/异己烷)得到标题化合物的白色固体(28mg):
δH(400MHz,DMSO)1.8(2H,m)2.1(4H,m)2.55(2H,m)2.7(2H,m)2.95(2H,m)7.0(1H,m)7.15(1H,m)7.4(1H,m)7.55(1H,s)8.05(2H,d)8.29(2H,d)8.35(1H,s).m/z(ES+)451[MH]+.
下列化合物(实施例37-40)采用实施例36的类似方法制备:
37)1-[2-(2,4-二氟苯基)乙基]-4-氟-4-[4-(1-甲基吡唑-5-基)苯磺酰基]哌
啶
m/z(ES+)464[MH]+。
38)1-[2-(2,4-二氟苯基)乙基]-4-氟-4-[4-(1-甲基咪唑-2-基)苯磺酰基哌
啶
m/z(ES+)464[MH]+。
39)1-[2-(2,4-二氟苯基)乙基]-4-氟-4-[4-(2-甲基四唑-5-基)苯磺酰基]哌
啶
m/z(ES+)466[MH]+。
40)1-[2-(2,4-二氟苯基)乙基]-4-氟-4-[4-(1,3-三唑-2-基)苯磺酰基]哌啶
m/z(ES+)467[MH]+。
实施例41
4-[(2-溴-4-氟苯基)磺酰基])-1-[2-(2,4-二氟苯基)乙基]-4-氟哌啶
于-78℃下,将正丁基锂(1.6N异己烷;1.0mL,1.6mmol)滴加到N-BOC 4-氟-4-(4-氟苯磺酰基)哌啶(500mg;1.4mmol)的乙醚(16mL)溶液中。1小时后,快速加入1,2-二溴四氟乙烷(0.54g,2.1mmol),搅拌5分钟后温热至0℃并在该温度再搅拌1.5小时。加入饱和的NH4Cl水溶液(1mL),
所得混合物在水(20mL)和EtOAc(20mL)之间分配。所得有机相用Na2SO4干燥,过滤,真空浓缩得到粗品,将该粗品分别采用实施例2和1中所述的方法进行脱保护和烷基化。终产物用50%Et2O/异己烷洗涤得到标题化合物的白色固体(117mg):δH(400MHz,DMSO)1.75-1.90(2H,m)2.04-2.22(4H,m)2.50-2.55(2H,m)2.70-2.75(2H,m)2.95-3.00(2H,m)6.98-7.02(1H,m)7.12-7.18(1H,m)7.35-7.40(1H,m)7.58-7.62(1H,m)7.98-8.00(1H,m)8.10-8.13(1H,m)。m/z(ES+)482,480[MH]+。所得材料还含有3.6%的杂质:1-[2-(2,4-二氟苯基)乙基]-4-氟-4-(4-氟苯磺酰基)哌啶,与实施例2中的数据一致。
实施例42
(RS)-1-[2-(2,4-二氟苯基)-2-氟乙基]-4-氟-4-(苯磺酰基)哌啶
将4-氟-4-(苯磺酰基)哌啶盐酸盐(300mg,mmol)用饱和碳酸氢钠水溶液处理,游离碱用EtOAc萃取。所得有机相用MgSO4干燥,真空除去溶剂后得到4-氟-4-(苯磺酰基)哌啶(187mg)的白色固体。
将2-(2,4-二氟苯基)环氧乙烷(0.17ml,1.08mmol)加入到4-氟-4-(苯磺酰基)哌啶(187mg,0.9mmol)的DMSO(5ml)溶液中,所得溶液在105℃加热10小时。冷却,将该反应液倾入饱和食盐水(10ml)中并用EtOAc萃取。所得有机相用水(3×10ml)洗涤,Na2SO4干燥,过滤并浓缩。所得残余物用柱层析纯化(硅胶,30%EtOAc/异己烷)得到(RS)-1-(2,4-二氟苯基)-2-[4-氟-4-(苯磺酰基)哌啶-1-基]乙醇的白色固体(108mg):
δH(400MHz,DMSO)1.75(2H,m)2.05(2H,m)2.2(2H,m)2.5(2H,m)2.95(2H,m)4.95(1H,m)5.39(1H,d)7.05(1H,m)7.15(1H,m)7.5(1H,m)7.72(2H,m)7.85(3H,m).m/z(ES+)399[MH]+.
向冷却(-78℃)的(RS)-1-(2,4-二氟苯基)-2-[4-氟-4-(苯磺酰基)哌啶-1-基]乙醇(40mg,0.10mmol)的无水DCM(0.5ml)溶液中,于氮气流下加入三氟化二乙胺基硫(0.02ml,0.15mmol)。所得溶液在-78℃搅拌10分钟后温热至室温并继续搅拌2小时。所得反应物用饱和碳酸氢钠水溶液(20ml)淬灭后用EtOAc(3×20ml)萃取。所得有机相用Na2SO4干燥,过滤后真空浓缩。所得残余物柱层析纯化(硅胶,25%EtOAc/异己烷)得到标题化合物的白色固体(29mg):
δH(400MHz,DMSO)1.8(2H,m)2.1(2H,m)2.2(2H,m)2.7(2H,m)2.95(3H,m)5.8-5.9(1H,ddd)7.15(1H,m)7.25(1H,m)7.55(1H,m)7.72(2H,m)7.85(3H,m).m/z(ES+)402[MH]+.
实施例43
2-[4-氟-4-(4-氟苯磺酰基)哌啶-1-基]-1-(4-氟苯基)乙基酮
将4-氟-2’-溴苯乙酮(55mg,0.25mmol)加入到含4-氟-4-(4-氟苯磺酰基)哌啶盐酸盐(60mg,0.23mmol)和三乙胺(0.064mL,0.50mmol)混合物的乙腈(1.2mL)中。所得溶液室温搅拌4小时后在水(20mL)和EtOAc(20mL)之间分配。所得有机相用Na2SO4干燥,过滤后真空浓缩得到粗品,通过柱层析纯化(硅胶,50%EtOAc/异己烷)得到标题化合物的白色固体(30mg):δH(500MHz,DMSO)1.95(2H,t,J11.6),2.20-2.35(2H,m),3.08(2H,d,J6.5),4.06(2H,s),7.48(2H,t,J8.9),7.71(2H,t,J8.8),8.11(2H,dd,J5.2和8.7),8.20(2H,dd,J5.6和8.9)。m/z(ES+)398[MH]+。
实施例44
(RS)-4-氟-1-[2-氟-2-(4-氟苯基)乙基]-4-(4-氟苯磺酰基)哌啶
将硼氢化钠(20mg,0.5mmol)加入到含有2-[4-氟-4-(4-氟苯磺酰基)哌啶-1-基]-1-(4-氟苯基)乙基酮(40mg,0.1mmol)的乙醇(5mL)悬浮液中,所得混合物在室温搅拌1小时。所得溶液真空浓缩,所得残留物在水(20mL)和EtOAc(20mL)之间分配。有机相用Na2SO4干燥,过滤后浓缩得(RS)-2-[4-氟-4-(4-氟苯磺酰基)哌啶-1-基]-1-(4-氟苯基)乙醇的白色固体:m/z(ES+)418[MH]+。
如实施例42中所述,将(RS)-2-[4-氟-4-(4-氟苯基磺酰基)哌啶-1-基]-1-(4-氟苯基)乙醇转化为标题化合物:
δH(500MHz,DMSO)1.78-1.82(2H,m),2.05-2.20(2H,m),2.25-2.32(2H,m),2.63-2.72(1H,m),2.88-3.04(3H,m),5.6-5.79(1H,m),7.21-7.25(2H,m),7.43-7.48(2H,m),7.56-7.60(2H,m),7.96-7.99(2H,m).m/z(ES+)402[MH]+.
下列化合物(实施例45-48)通过采用实施例42-44的类似方法制备:
45)4-{4-氟-1-[2-(4-氟苯基)-2-氧乙基]哌啶-4-基}磺酰基)苯甲腈
m/z(ES+)405[MH]+。
46)1-(4-氟苯基)-2-[4-氟-4-(苯磺酰基)哌啶-1-基]乙基酮
m/z(ES+)380[MH]+。
47)(RS)-4-({1-(2-(2,4-二氟苯基)-2-氟乙基)-4-氟哌啶-4-基}磺酰基)苯
甲酰胺
m/z(ES+)445[MH]+。
48)(RS)-4-({4-氟-[2-氟-2-(4-氟苯基)乙基]哌啶-4-基}磺酰基)苯甲
酰胺
m/z(ES+)427[MH]+。
实施例49
(RS)-1-[2-(2,4-二氟苯基)-1-甲基乙基]-4-氟-4-(4-氟苯磺酰基)哌啶
将四异丙醇钛(0.29mL,1.4mmol)加入4-氟-4-(4-氟苯磺酰基)哌啶(179mg,0.68mmol)和2,4-二氟苯基丙酮(116mg,0.68mmol)的乙醇(3.4mL)溶液中,所得混合物在室温搅拌16小时。加入硼氢化钠(41mg,1.0mmol)后继续搅拌2小时。加入水(20mL)和EtOAc(20mL),所得的两相混合物经过Hyflo过滤。将滤液分配,有机相用Na2SO4干燥,过滤,真空浓缩。柱层析纯化(硅胶,50%EtOAc/异己烷)得到半纯化的材料,该材料可进一步经过1N HCl的乙醚溶液纯化,再用另外的乙醚洗涤固体残留物得到标题化合物的盐酸盐:
δH(500MHz,DMSO)1.09-1.19(3H,m),2.14-2.21(2H,m),2.53-2.60(1H,m),2.68-2.85(3H,m),3.13-3.56(5H,m).7.08-7.14(1H,m),7.22-7.28(1H,m),7.41-7.48(1H,m),7.60-7.67(2H,m),8.00-8.07(2H,m),11.10-11.20(br s).m/z(ES+)416[MH]+.
Claims (9)
1.一种式I化合物或其药学上可接受的盐:
其中,
Ar为苯基、苯并异噻唑-3-基或苯并噻吩-3-基,各自带有R1、R2和R3取代基,
R1为氢、氟、氯、溴、C1-6烷基、C3-6环烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C2-6烯氧基、C2-6炔氧基或最多被5个氟原子取代的C1-6烷基;
R2为氢、氟、氯、C1-4烷基、C1-4烷氧基、最多被5个氟原子取代的C1-4烷基或最多被5个氟原子取代的C1-4烷氧基;
R3为氢、氟、氯、甲基、甲氧基、三氟甲基、二氟甲基、三氟甲氧基或二氟甲氧基;
Q1为氢;氟;氯;溴;C1-6烷基;C3-6环烷基;C2-6烯基;C2-6炔基;C1-6烷氧基;C2-6烯氧基;C2-6炔氧基;最多被5个氟原子取代的C1-6烷基;腈;COQ4或CO2Q4,其中Q4为氢或C1-6烷基;NQ5Q6、CONQ5Q6或SO2NQ5Q6,其中Q5为氢或C1-6烷基并且Q6为氢或C1-6烷基,或Q5和Q6连接形成4-7元杂环,该杂环还可以包含一个氧原子或一个另外的氮环原子,所述杂环可任选被最多3个氟原子或被CF3、甲基、乙基或羟基取代;羟基;硝基;SOQ7或SO2Q7,其中Q7为C1-4烷基;NQ8COQ9、NQ8CO2Q9或NQ8SO2Q9,其中Q8为氢或C1-4烷基并且Q9为氢或C1-4烷基或与Q8连接形成5-7元环;其中1、2、3或4个原子为氮原子,或其中1或2个为氮原子并且其中1个为氧或硫原子,或其中1个为氧或硫原子的5元杂芳环,该杂芳环任选被甲基、乙基或羟基取代;或者含有1或2个氮环原子的6元杂芳环或者苯基基团,两种基团都任选被下列基团取代:1或2个氟或氯原子或C1-4烷基、C1-4烷氧基或三氟甲基;
Q2为氢、氟、氯、腈、羟基、C1-4烷基、C1-4烷氧基、最多被5个氟原子取代的C1-4烷基或最多被5个氟原子取代的C1-4烷氧基;
Q3为氢、氟、氯、甲基、甲氧基、三氟甲基、二氟甲基、三氟甲氧基或二氟甲氧基;
或者Q2和Q3连接形成5、6或7元碳环残基;
R4为H或C1-4烷基,
m为0或1;
n为0、1或2;并且
W为CH2、CHF、CH(OH)或CO。
2.权利要求1化合物,其中Ar代表苯并异噻唑-3-基或苯并噻吩-3-基,各自带有R1、R2和R3取代基,并且m和n均为0。
3.权利要求1化合物,其中Ar代表带有R1、R2和R3取代基的苯基,m为1并且n为0。
4.权利要求1的化合物或其药学上可接受的盐,其具有式IIA:
其中,R13代表H并且R14代表H、F或OH,或者R13和R14一起代表酮基;
并且Q1、Q2、R1、R2和R4如权利要求1所定义。
5.上述权利要求中任一项的化合物,其中Q1选自H、F、Cl、Br、CN、甲酰胺、5-元杂芳基和NQ5Q6,其中Q5和Q6形成杂环;
Q2为H、F或Cl;
Q3为H或F;
R1为H、F、甲基或CF3;
R2为H、F、甲基或CF3;并且
R3为H。
6.一种药用组合物,该组合物包含权利要求1的化合物和药学上可接受的载体。
7.权利要求1化合物,该化合物在人体的治疗方法中使用。
8.权利要求1的化合物在生产治疗或预防由5-HT2A受体活性介导的病症的药物上的用途。
9.一种治疗患有或易患5-HT2A受体活性介导的病症的受试者的方法,该方法包括给予该受试者有效量的权利要求1的化合物。
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