CN1332168A - 3-取代的吡啶并[4′,3′∶4,5]噻吩并[2,3-d]嘧啶衍生物,它们的制备和应用 - Google Patents
3-取代的吡啶并[4′,3′∶4,5]噻吩并[2,3-d]嘧啶衍生物,它们的制备和应用 Download PDFInfo
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- CN1332168A CN1332168A CN01116979A CN01116979A CN1332168A CN 1332168 A CN1332168 A CN 1332168A CN 01116979 A CN01116979 A CN 01116979A CN 01116979 A CN01116979 A CN 01116979A CN 1332168 A CN1332168 A CN 1332168A
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- Prior art keywords
- thieno
- hydrogen
- piperazine
- pyrido
- methyl
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- -1 3-substituted pyrido-[4',3':4,5] thieno-[2,3-d] pyrimidine Chemical class 0.000 title claims description 58
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- 229940076279 serotonin Drugs 0.000 claims abstract description 18
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- 201000010099 disease Diseases 0.000 claims abstract description 7
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- 150000003839 salts Chemical class 0.000 claims abstract description 6
- DDWBRNXDKNIQDY-UHFFFAOYSA-N thieno[2,3-d]pyrimidine Chemical class N1=CN=C2SC=CC2=C1 DDWBRNXDKNIQDY-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 85
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 72
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 150000002431 hydrogen Chemical class 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 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
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- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
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- 125000000217 alkyl group Chemical group 0.000 claims description 2
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- MMLLKVQSPFYOFR-UHFFFAOYSA-N 3h-pyrido[2,3]thieno[2,4-d]pyrimidin-4-one Chemical compound S1C2=CN=CC=C2C2=C1N=CNC2=O MMLLKVQSPFYOFR-UHFFFAOYSA-N 0.000 description 76
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Abstract
本发明涉及式(Ⅰ)3-取代的3,4,5,6,7,8-六氢-吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶衍生物及其生理上耐受的盐,其中各取代基具有如说明书中所述的定义。这些化合物适宜用作治疗下述疾病的药物,其中5-羟色胺浓度被降低以及其中在治疗中突触前受体5-HT1B、5-HT1A和5-HT1D活性被阻滞而对其他受体不会产生较大影响。此类疾病包括例如抑郁症。
Description
本申请是申请号为97197765.8、申请日为1997年8月22日、发明名称为“3-取代的吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶衍生物,它们的制备和应用”的发明专利申请的分案申请。
本发明涉及新的3-取代的吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶衍生物以及它们的制备和在制备药物活性物质上的应用。
典型的抗抑郁药和新的选择性5-羟色胺再摄入抑制剂(SSRI)除了其他作用以外,通过在突触前神经末梢中抑制介质的主动摄入起到抗抑郁作用。遗憾的是,在这种情况下,除了大约30%的患者对治疗产生耐药以外,所述抗抑郁作用只有在治疗至少3周后才开始起作用。
通过消除负偶联,突触前5-羟色胺自体受体的阻滞作用可提高5-羟色胺释放并因此提高突触间隙中存在的介质浓度。这种介质浓度的提高被认为是抗抑郁作用的原理所在。该作用机理不同于以前公知的抗抑郁药,它们可激活突触前和躯体树突自体受体,因而只有在这些自体受体脱敏后才使作用延迟发生。直接的自体受体阻滞避开了该作用。
根据现有技术可知,所述突触前5-羟色胺自体受体是5-HT1B亚型(Fink等人,Arch.Pharmacol.352(1995),451)。通过用5-HT1B/D拮抗剂对其进行-选择性阻滞可提高大脑中5-羟色胺的释放:
G.W.Price等人Behavioural Brain Research 73(1996),
S.79-82;P.H.Hutson等人,Neuropharmacology vol.34,No.4
(1995),S.383-392。
但是,令人惊奇的是,选择性5-HT1B拮抗剂GR127935在***用药后可降低皮质中5-羟色胺的释放。一种解释可能是,释放的5-羟色胺激活了缝隙区中躯体树突5-HT1A受体,其抑制了含5-羟色胺神经元的释放速度,并因此抑制了5-羟色胺的释放(M.Skingle等人,Neuropharmacology Vol.34 No.4(1 995),377-382和393-402)。
避免含5-羟色胺源区中自体抑制作用的一种方法是设法阻滞突触前5-HT1B受体。该假说得到了被5-HT1B受体拮抗剂GR127935强化的鼠基底神经节中帕若喜停对5-羟色胺释放的影响观测结果的支持(Davidson and Stamford,Neuroscience Letts.,188(1995),41)。
第二种方法包括阻滞两种自体受体,即为了提高神经元的释放,阻滞5-HT1A受体,以及为了提高末端5-羟色胺的释放,阻滞5-HT1B受体(Starkey and Skingle,Neuropharmacology 33(3-4)(1994),393)。
因此,单独的5-HT1B/D拮抗剂或者与5-HT1A受体拮抗组份结合应当能提高脑中5-羟色胺的释放,并因此可用于治疗抑郁症及有关的心理疾病。
现已发现,下列式I3-取代的3,4,5,6,7,8-六氢吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶衍生物及其与生理上耐受的酸形成的盐具有有价值的药理学性质:其中R1是氢、C1-C4-烷基、乙酰基或苯甲酰基,苯基烷基C1-C4基团,所述芳环可未被取代或者被卤素、C1-C4-烷基、三氟甲基、羟基、C1-C4-烷氧基、氨基、氰基或硝基取代,或者是萘基烷基C1-C3基团、苯基链烷酮C2-C3基团或苯基氨基甲酰基烷基C2基团,所述苯基也可以被卤素取代,R2是苯基、吡啶基、嘧啶基或吡嗪基,每个基团可未被取代或者被卤原子、C1-C4-烷基、三氟甲基、三氟甲氧基、羟基、C1-C4-烷氧基、氨基、一甲氨基、二甲氨基、氰基或硝基一-、二-或三-取代,并且每个基团可以与未被取代的或被卤原子、C1-C4-烷基、羟基、三氟甲基、C1-C4-烷氧基、氨基、氰基或硝基一-或二-取代,并可含有一个氮原子的苯环稠合,或者与可含有1-2个氧原子的5-或6-元环稠合,或者可以被苯基-C1-C2-烷基或-烷氧基基团取代,所述苯基也可以被卤素、甲基、三氟甲基或甲氧基取代,A是NH或氧原子,B是氢或甲基,C是氢、甲基或羟基,X是氮原子,Y是CH2、CH2-CH2、CH2-CH2-CH2或CH2-CH,Z是氮原子、碳原子或CH,Y和Z之间的连接键也可以是双键,和n是2、3或4。
特别优选的是下述化合物,其中R1是甲基、乙基、异丙基、苄基、取代的苄基、苯乙基、取代的苯乙基,R2是邻甲氧基苯基、1-萘基、嘧啶-2-基、2-甲氧基-1-萘基、2-甲基-1-萘基,A是NH或氧原子,X是氮原子,Y是CH2-CH2、CH2-CH,Z是氮原子、碳原子或CH,和n是2和3。
本发明式I化合物可通过下述方法制备,即将下列式II化合物与下列式III伯胺反应,其中R1如上定义,R3是氰基或C1-C3-烷基羧酸酯基,R4是C1-C3-烷基和C是氢、甲基或羟基,其中R2和B如上定义,并且如果需要,可用生理上耐受的酸将所得化合物转变成加成盐。
所述反应较有利地是在惰性有机溶剂,特别是在低级链烷醇如甲醇或乙醇中,或者在环状饱和醚,特别是四氢呋喃或二噁烷中,或者在无溶剂条件下进行。
通常,所述反应在20-190℃,特别是60-90℃下进行并且通常在1-10小时内完成。
或者,在60-120℃下,在惰性溶剂,优选醇例如乙醇中,将下列式II化合物与下列式IV伯胺反应,其中R1如上定义,R3是氰基或C1-C3-烷基羧酸酯基,R4是C1-C3-烷基和C是氢、甲基或羟基,其中B如上定义,得到环合产物V(D=OH)随后,在室温至100℃下,于有机溶剂例如卤代烃中或者无溶剂下,用卤化剂例如亚硫酰氯或氢溴酸将其转变成相应的卤代衍生物V(D=Cl、Br)。最后,将所述式V卤代衍生物(D=C1、Br)与下列式VI胺反应,其中,X、Y、Z和R2如上定义,得到本发明所述式I终产物。此反应最好在60-150℃下,在碱例如碳酸钾或氢氧化钾存在下,于隋性有机溶剂,优选甲苯或二甲苯中进行。
本发明所述式I化合物可经常规有机溶剂,优选低级链烷醇例如乙醇中重结晶法重结晶,或者经柱色谱法纯化。
式I所述游离的3-取代的吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶衍生物可以按照常规方法在含有化学计算量的适宜酸溶液中转变成酸加成盐。药物上适宜的酸的实例有盐酸、磷酸、硫酸、甲磺酸、氨基磺酸、马来酸、富马酸、草酸、酒石酸或柠檬酸。
本发明还涉及药物组合物,该组合物除了常规赋形剂和稀释剂以外含有作为活性物质的式I化合物或其药物上适宜的酸加成盐,并且本发明还涉及所述新的的化合物在控制疾病方面的应用。
本发明所述化合物可经口服、非肠道、静脉内或肌内等常规方式施用。
剂量将根据患者的年龄、身体状况和体重以及用药方式而定。通常,口服施用时,所述活性物质的日剂量约为1-100mg/kg体重,非肠道施用时,约为0.1-10mg/kg体重。
所述新的化合物可以常规固体或液体药物剂型使用,例如未包衣的或(膜)包衣的片剂、胶囊剂、粉剂、颗粒剂、糖衣丸、栓剂、溶液、软膏剂、乳膏或喷雾剂。这些制剂可按常规方法制得。为此,可将所述活性物质与常规药物辅剂一起进行加工,所述辅剂例如有粘合剂、填充剂、防腐剂、片剂崩解剂、流动调节剂、增塑剂、润湿剂、分散剂、乳化剂、溶剂、缓释剂、抗氧化剂和/或推进剂(参考H.Sucker等人的:Pharmazeutische Technologie,Thieme-Verlag,Stuttgart,1978)。按此方法获得的施用剂型通常含有1-99%(重量比)的活性物质。
作为合成所述新化合物所需原料的式II和III化合物是已知的或者可以经文献中所述制备方法由适宜原料合成得到(F.Sauter und P.Stanetty,Monatsh.Chem.(1975),106(5),1111-1116;K.Gewald et al,Chem.Ber.99,94-100(1966))。
本发明所述化合物对5-HT1B、5-HT1D和5-HT1A 5-羟色胺受体具有较高的亲合性。对于每种受体,亲合性基本相同,至少在数量级上相同。另外,本发明某些化合物对5-羟色胺的再摄入表现出良好的抑制作用,这是绝大多数抗抑郁药具有的特性。
这些化合物可适宜用作药物以治疗这样的病理学疾病,其中5-羟色胺浓度被降低以及希望出于特定的治疗目的阻滞突触前5-HT1B、5-HT1A和5-HT1D受体而对其他受体没有较大影响。此类病理学疾病的一个实例就是抑郁症。
本发明所述化合物还可用于治疗中枢神经性心境障碍例如季节性情感疾病和精神抑郁症。它们还包括焦虑症例如综合性焦虑、恐慌发作、社会恐怖症、强迫性神经病和脑外伤后紧张症,记忆障碍包括痴呆、遗忘症和与年龄有关的记忆力丧失,以及精神性饮食紊乱例如神经性厌食症和神经性贪食症。
另外,本发明所述化合物还可用于治疗内分泌紊乱例如高催乳激素血症,并且还可用于治疗血管痉挛(特别是脑血管)、高血压和与运动有关的肠胃功能紊乱及分泌紊乱。另一个应用领域还包括性障碍。
下列实施例用于说明本发明:
A式II、V和VI原料的制备可用作原料的在6位上带有甲基、苄基、乙酰基或苯甲酰基或者6位未被取代的2-氨基-3-乙酯基(氰基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶已被公开于所述文献中(K.Gewald等人)。a)2-乙氧基亚甲基氨基-3-氰基-6-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶
于250ml原甲酸三乙酯中,将46.0g(238mM)2-氨基-3-氰基-6-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶与3.5ml乙酸酐混合并于氮气氛下回流蒸煮4小时。然后将混合物趁热吸滤过滤,滤液在旋转蒸发仪上于80℃下完全蒸发。残余物用300ml甲基叔丁基醚处理并加热至沸腾。经吸滤过滤除去不溶固体后,于冰浴中搅拌下结晶,得到45.4g(77%)产物。作为第二级馏份由母液中得到1.7g(3%)产物。熔点为88-89℃。b)2-乙氧基亚甲基氨基-3-乙酯基-6-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶
于250ml原甲酸三乙酯中,将40.0g(167mM)2-氨基-3-乙酯基-6-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶与3.2ml乙酸酐混合并于氮气氛下回流蒸煮3小时。然后将混合物在旋转蒸发仪上于80℃下完全蒸发。分离得到48.0g(97%)黑色油状粗产物,其纯度足以进行下步反应。c)2-氨基-3-乙酯基-6-(4-氯)苄基-4,5,6,7-四氢噻吩并[2,3-c]吡啶
于250ml四氢呋喃中,将20.4g(90.2mM)2-氨基-3-乙酯基-6-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶与25.6g(204mM)4-氯代苄基氯和12.4g(90mM)碳酸钾精细粉末混合并回流蒸煮3小时。然后将混合物在旋转蒸发仪上完全蒸发。残余物于甲基叔丁基醚和水之间分配,并用氢氧化钠溶液调至碱性后,有机相用水洗涤并浓缩。将粗产物溶于100ml热乙醇并令其于搅拌下结晶。分离得到20.5g(65%)产物,熔点为134-135℃。
d)2-乙氧基亚甲基氨基-3-乙酯基-6-(4-氯)苄基-4,5,6,7-四氢噻吩并[2,3-c]吡啶
于125ml原甲酸三乙酯中,将19.3g(55.0mM)2-氨基-3-乙酯基-6-(4-氯苄基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶与2.0ml乙酸酐混合并于氮气氛下回流蒸煮1小时。然后将混合物在旋转蒸发仪上于80℃下完全蒸发。分离得到21.9g(98%)黑色油状粗产物,其纯度足以进行下步反应。e)2-氨基-3-乙酯基-6-(3-苯基)丙基-4,5,6,7-四氢噻吩并[2,3-c]吡啶
于100ml二甲苯中,将10.0g(44.2mM)2-氨基-3-乙酯基-4,5,6,7-四氢噻吩并[2,3-c]吡啶与9.0g(45mM)1-苯基-3-溴代丙烷、400mg碘化钾和6.1g(44.2mM)碳酸钾精细粉末混合并回流蒸煮6小时。将于旋转蒸发仪上浓缩后的残余物用水处理,调至pH=10并用二氯甲烷萃取两次。将有机相干燥并浓缩后,粗产物在搅拌下用50ml异丙醇萃取。吸滤滤出灰色固体并用异丙醇洗涤。分离得到7.8g(51%)产物,熔点为108-110℃。
类似于c)和e)所述制得其他6位取代的4,5,6,7-四氢噻吩并[2,3-c]吡啶衍生物,例如:
2-氨基-3-乙酯基-6-乙基-4,5,6,7-四氢噻吩并[2,3-c]吡啶,熔点为74-76℃2-氨基-3-乙酯基-6-异丙基-4,5,6,7-四氢噻吩并[2,3-c]吡啶
2-氨基-3-乙酯基-6-苄基-4,5,6,7-四氢噻吩并[2,3-c]吡啶,熔点为116-118℃
2-氨基-3-乙酯基-6-(4-甲基)苄基-4,5,6,7-四氢噻吩并[2,3-c]吡啶
2-氨基-3-乙酯基-6-(4-硝基)苄基-4,5,6,7-四氢噻吩并[2,3-c]吡啶,熔点为170-172℃
2-氨基-3-乙酯基-6-(4-甲氧基)苄基-4,5,6,7-四氢噻吩并[2,3-c]吡啶,熔点为154-156℃
2-氨基-3-乙酯基-6-(2-苯基)乙基-4,5,6,7-四氢噻吩并[2,3-c]吡啶,熔点为80-83℃
2-氨基-3-乙酯基-6-(2-(4-甲氧基苯基)乙基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶,熔点为76-78℃
2-氨基-3-乙酯基-6-(2-(4-氯苯基)乙基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶,熔点为102-105℃
2-氨基-3-乙酯基-6-(3-(4-氯)苯基)丙基-4,5,6,7-四氢噻吩并[2,3-c]吡啶
2-氨基-3-乙酯基-6-(4-苯基)丁基-4,5,6,7-四氢噻吩并[2,3-c]吡啶
2-氨基-3-乙酯基-6-(3-苯甲酰基)丙基-4,5,6,7-四氢噻吩并[2,3-c]吡啶
2-氨基-3-乙酯基-6-(2-苯甲酰氨基)乙基-4,5,6,7-四氢噻吩并[2,3-c]吡啶,熔点为190-192℃
2-氨基-3-乙酯基-6-(3-苯甲酰氨基)丙基-4,5,6,7-四氢噻吩并[2,3-c]吡啶f)N-(3-乙酯基-6-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶-2-基)乙亚氨酸乙酯
于25ml原甲酸三乙酯中,将3.0g(12.5mM)2-氨基-3-乙酯基-4,5,6,7-四氢噻吩并[2,3-c]吡啶与0.8ml乙酸酐混合并于氮气氛下回流蒸煮2小时。然后将混合物在旋转蒸发仪上于80℃下完全蒸发。分离得到3.6g(93%)黑色油状粗产物,其纯度足以进行下步反应。g)2-乙酯基氨基-3-乙酯基-6-乙酰基-4,5,6,7-四氢噻吩并[2,3-c]吡啶
于50ml甲苯中,将5.0g(18.6mM)2-氨基-3-乙酯基-6-乙酰基-4,5,6,7-四氢噻吩并[2,3-c]吡啶与3.0g(28mM)氯代甲酸乙酯和2.6g(18.6mM)碳酸钾精细粉末混合并回流蒸煮2小时。然后将反应混合物用冰/水处理,分离甲苯相,水相用甲苯反萃取。将合并有机相干燥,然后浓缩。分离得到5.8g(92%)油状产物,其略微有点缓慢结晶。h)3,4,5,6,7,8-六氢-3-(2-羟基)乙基-7-甲基吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮
于200ml乙醇中,将86.4g(292mM)2-乙氧基亚甲基氨基-3-乙酯基-6-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶与17.6ml(292mM)乙醇胺混合并回流蒸煮2小时。然后将混合物在真空下浓缩,残余物于搅拌下用30ml乙酸乙酯处理,吸滤滤出过夜沉淀出的残余物并用少量乙酸乙酯洗涤。于乙醇中重结晶后,分离得到48.0g(62%)产物,熔点为163-165℃。i)3,4,5,6,7,8-六氢-3-(2-氯)乙基-7-甲基吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮
于240ml1,2-二氯乙烷中,将42.0g(158mM)3,4,5,6,7,8-六氢-3-(2-羟基)乙基-7-甲基吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮加热至回流,然后滴加12.7ml(175mM)亚硫酰氯的20ml 1,2-二氯乙烷溶液。回流蒸煮2小时后,令混合物冷却并倾入冰/水中。于pH=10下在二氯甲烷和水之间分配后,水相用二氯甲烷反萃取。将合并的有机相干燥并浓缩,粗产物(40g)于400ml异丙醇中重结晶,分离得到30.5g(68%)产物,熔点为159-161℃。
类似于h)和i)所述制得下列化合物:
3,4,5,6,7,8-六氢-3-(1-羟基)丙-2-基-7-甲基吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮
3,4,5,6,7,8-六氢-3-(1-氯)丙-2-基-7-甲基吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮
3,4,5,6,7,8-六氢-3-(2-羟基)丙基-7-甲基吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮,m.p.158-160℃
3,4,5,6,7,8-六氢-3-(2-氯)丙基-7-甲基吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮k)N-(1-萘基)哌嗪
将83.2g(966mM)哌嗪、38.0g(339mM)叔丁醇钾和50.0g(241mM)1-溴萘加入到于500ml二甲苯中的5.4g(24.2mM)乙酸钯和14.7g(48.3mM)三邻甲苯基膦混合物中,并将混合物于氮气氛充分搅拌下加热回流10小时。然后将混合物用二氯甲烷稀释,滤除不溶残余物并将滤液浓缩。粗产物经柱色谱法(硅胶,移动相为THF/甲醇/氨85/13/2)纯化,分离得到21.5g(42%)产物,熔点为84-86℃。1)N-(2-甲基-1-萘基)哌嗪
于100ml氯苯中,将13.0g(82.7mM)1-氨基-2-甲基萘与14.7g(82.7mM)二(2-氯乙基)胺×HCl混合并于氮气氛下回流蒸煮90小时。然后将混合物浓缩并在pH=9下于二氯甲烷和水之间分配,将有机相干燥并浓缩。粗产物经柱色谱法(硅胶,移动相/THF/甲醇/氨85/13/2)纯化,分离得到11.6g(62%)产物。m)4-哌嗪-1-基-异喹啉
于50ml甲苯中,将4.51g(21.7mM)4-溴异喹啉、4.65g(25.0mM)哌嗪-N-羧酸叔丁基酯、0.1g(0.11mM)三(二亚苄基丙酮)二钯、0.11g(0.18mM)2,2’-二(二苯膦基)-1,1’-联萘和2.92g(30.4mM)叔丁醇钠混合,并于75℃下搅拌2小时。将混合物加入到冰/氯化钠中并用乙酸乙酯萃取,有机相用硫酸钠干燥,并于旋转蒸发仪上除去溶剂。结晶出产物,吸滤过滤并用戊烷洗涤。得到5.5g(81%)Boc-保护的哌嗪(熔点为111℃)。将5.2g(16.6mM)此产物用17ml二氯甲烷处理,并于0℃下缓慢地用17ml二氯甲烷处理,于0℃下缓慢地加入17ml(0.22mM)三氟乙酸。混合物于0℃下搅拌4小时,倾入冰-水中并用二氯甲烷萃取。将水相过滤,调至碱性并用二氯甲烷萃取。用硫酸钠干燥后,基本上除去溶剂,然后用***稀释,用醚盐酸沉淀出盐酸盐。得到3.2g(67%)所述产物,熔点为293-294℃。
类似于k)、l)和m)所述可制备文献(参见德国专利申请19636769.7)中未曾公开的其他哌嗪衍生物(参见实施例)。
B最终产物的制备
实施例1
3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(2-甲氧基苯基)-哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-亚胺×3HCl
于60ml乙醇中,将3.0g(12.1mM)2-乙氧基亚甲基氨基-3-氰基-6-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶与3.3g(12.1mM)1-(2-氨基乙基)-4-(2-甲氧基苯基)哌嗪混合并回流蒸煮3小时。然后将混合物于旋转蒸发仪上蒸发,残余物用100ml乙酸乙酯处理。搅拌下加入醚盐酸,沉淀出三盐酸盐,于氮气氛下吸滤滤出所述产物并用乙酸乙酯洗涤。于50℃真空烘箱中干燥,分离得到3.6g(55%)产物,该产物于282-284℃下分解。
实施例23,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(2-甲氧基苯基)-哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×3HCl
于50ml乙醇中,将3.0g(12.1mM)2-乙氧基亚甲基氨基-3-乙酯基-6-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶与2.4g(10.2mM)1-(2-氨基乙基)-4-(2-甲氧基苯基)哌嗪混合并回流蒸煮3小时。然后将混合物于旋转蒸发仪上蒸发,粗产物经柱色谱法(硅胶,移动相为二氯甲烷/甲醇93/7)纯化。如上所述,将游离碱转变成所述三盐酸盐(3.2g,48%),该产物于288-290℃下分解。
实施例33,4,5,6,7,8-六氢-7-(4-氯苄基)-3-[2-(4-(2-甲氧基苯基)-哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×3HCl
于60ml乙醇中,将3.5g(8.6mM)2-乙氧基亚甲基氨基-3-乙酯基-6-(4-氯苄基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶与2.0g(8.6mM)1-(2-氨基乙基)-4-(2-甲氧基苯基)哌嗪混合并回流蒸煮4小时。然后将混合物于旋转蒸发仪上蒸发,粗产物经柱色谱法(硅胶,移动相为二氯甲烷/甲醇95/5)纯化。如上所述,将游离碱转变成所述三盐酸盐(3.2g,57%),该产物于290-293℃下分解。
实施例43,4,5,6,7,8-六氢-7-甲基-3-[3-(4-(2-甲氧基苯基)-哌嗪-1-基)丙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×3HCl×2H2O
于40ml乙醇中,将3.5g(11.8mM)2-乙氧基亚甲基氨基-3-乙酯基-6-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶与3.0g(11.8mM)1-(3-氨基丙基)-4-(2-甲氧基苯基)哌嗪混合并回流蒸煮2小时。然后将混合物于旋转蒸发仪上蒸发,粗产物经柱色谱法(硅胶,移动相为二氯甲烷/甲醇93/7)纯化。如上所述,将游离碱转变成所述三盐酸盐(3.1g,44%),该产物于122-124℃下分解。
实施例53,4,5,6,7,8-六氢-7-甲基-3-[3-(4-吡啶-2-基)-哌嗪-1-基)丙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-亚胺×4HCl×H2O
于60ml乙醇中,将3.0g(12.1mM)2-乙氧基亚甲基氨基-3-乙酯基-6-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶与2.65g(12.1mM)1-(3-氨基丙基)-4-(2-吡啶基)哌嗪混合并回流蒸煮6小时。然后将混合物于旋转蒸发仪上蒸发,粗产物用100ml乙酸乙酯处理。如上所述,将过夜结晶出的固体转变成所述四盐酸盐。分离得到2.7g(38%)产物,该产物于261-264℃下分解。
实施例63,4,5,6,7,8-六氢-7-甲基-3-[3-(4-(2-甲硫基苯基)-哌嗪-1-基)丙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-亚胺×3HCl
于50ml乙醇中,将3.0g(12.1mM)2-乙氧基亚甲基氨基-3-乙酯基-6-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶与3.2g(12.1mM)1-(3-氨基丙基)-4-(2-甲硫基苯基)哌嗪混合并回流蒸煮4小时。然后将混合物于旋转蒸发仪上蒸发,粗产物用100ml沸腾的乙酸乙酯处理。冷却后,滤除不溶物,搅拌下加入醚盐酸盐,由滤液中沉淀出所述三盐酸盐,与氮气氛下吸滤滤出所述产物并用乙酸乙酯洗涤。随后将粗产物(5.1g)于甲醇中重结晶,分离得到3.8g(54%)产物,熔点为306-307℃。
实施例73,4,5,6,7,8-六氢-7-甲基-3-[2-(4-吡啶基-2-哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×3HCl×2H2O
于50ml二甲苯中,将2.2g(7.8mM)3,4,5,6,7,8-六氢-3-(2-氯)乙基-7-甲基吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮与1.6g(10.0mM)1-(2-吡啶基)哌嗪、1.4g(10.0mM)碳酸钾精细粉末和400mg碘化钾混合并回流蒸煮24小时。然后将混合物于旋转蒸发仪上浓缩,在pH=10下残余物于二氯甲烷和水之间配分。水相用二氯甲烷再萃取一次,将合并的有机相干燥,然后浓缩。粗产物经柱色谱法(硅胶,移动相为丙酮)纯化,分离得到2.3g(72%)产物,将其溶于100ml乙酸乙酯并用HCl/乙酸乙酯溶液将其转变成所述盐酸盐,熔点为233-235℃。
实施例83,4,5,6,7,8-六氢-7-甲基-3-[1-(4-(1-萘基)-哌嗪-1-基)丙-2-基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×3HCl×2H2O
于50ml二甲苯中,将2.7g(9.0mM)3,4,5,6,7,8-六氢-3-(1-氯)-2-丙基-7-甲基吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮与2.1g(10.0mM)1-(1-萘基)哌嗪、1.4g(10.0mM)碳酸钾精细粉末和250mg碘化钾混合并回流蒸煮70小时。然后将混合物于旋转蒸发仪上浓缩,在pH=10下残余物于二氯甲烷和水之间分配。水相用二氯甲烷再萃取一次,将合并的有机相干燥,然后浓缩。粗产物经柱色谱法(硅胶,移动相为丙酮)纯化,分离得到1.6g(38%)产物,将其溶于乙酸乙酯并用HCl/乙酸乙酯溶液将其转变成所述盐酸盐,熔点为242-244℃。实施例93,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(2-甲氧基苯基)-哌嗪-1-基)丙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×3HCl
于60ml二甲苯中,将2.9g(8.9mM)3,4,5,6,7,8-六氢-3-(2-氯)丙基-7-甲基吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮与3.5g(18.0mM)1-(2-甲氧基苯基)哌嗪、1.4g(10.0mM)碳酸钾精细粉末和400mg碘化钾混合并回流蒸煮100小时。然后将混合物于旋转蒸发仪上浓缩,在pH=10下残余物于二氯甲烷和水之间分配。水相用二氯甲烷再萃取一次,将合并的有机相干燥,然后浓缩。粗产物经柱色谱法(硅胶,移动相为丙酮)纯化,分离得到1.0g(25%)产物,将其溶于100ml乙酸乙酯并用HCl/乙酸乙酯溶液将其转变成所述盐酸盐,熔点为190-192℃(分解)。
实施例103,4,5,6,7,8-六氢-2,7-二甲基-3-[2-(4-(2-甲氧基苯基)-哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮
于30ml乙醇中,将1.9g(6.2mM)N-(3-乙酯基-6-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶-2-基)乙亚氨酸与1.5g(6.2mM)1-(2-氨基乙基)-4-(2-甲氧基苯基)哌嗪混合并回流蒸煮7小时。然后将混合物于旋转蒸发仪上浓缩,残余物用20ml乙酸乙酯处理。过夜结晶出2.1g粗产物,吸滤过滤并经柱色谱法(硅胶,移动相为二氯甲烷/甲醇92/8)纯化,分离得到0.8g(29%)产物。
实施例113,4,5,6,7,8-六氢-2-羟基-7-乙酰基-3-[2-(4-(2-甲氧基苯基)-哌嗪-1-基)乙基]吡啶并[4’,3’:-4,5]噻吩并[2,3-d]嘧啶-4-酮
于180℃氮气氛下,将2.5g(7.3mM)2-乙酯基氨基-3-乙酯基-6-乙酰基-4,5,6,7-四氢噻吩并[2,3-c]吡啶与1.7g(7.3mM)1-(2-氨基乙基)-4-(2-甲氧基苯基)哌嗪加热2小时,同时充分搅拌所述熔融物。冷却后,粗产物经柱色谱法(硅胶,移动相为二氯甲烷/甲醇95\5)纯化,分离得到0.7g(20%)产物,熔点为135-137℃。实施例123,4,5,6,7,8-六氢-7-乙酰基-3-[2-(4-(2-甲氧基苯基)-哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮
于50ml乙醇中,将5.8g(23.4mM)2-乙氧基亚甲基氨基-3-乙酯基-6-乙酰基-4,5,6,7-四氢噻吩并[2,3-c]吡啶与5.5g(23.4mM)1-(2-氨基乙基)-4-(2-甲氧基苯基)哌嗪混合并回流蒸煮2小时。然后将混合物于旋转蒸发仪上浓缩,残余物用30ml乙酸乙酯处理,加热至沸腾并于搅拌下令其冷却。于冰浴中冷却后,吸滤过滤结晶出的固体并用乙酸乙酯洗涤。分离得到8.7g(80%)产物,熔点为170-172℃。
实施例133,4,5,6,7,8-六氢-3-[2-(4-(2-甲氧基苯基)-哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮
将4.0g(8.6mM)3,4,5,6,7,8-六氢-7-乙酰基-3-[2-(4-(2-甲氧基苯基)-哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮溶于80ml 10%盐酸中并于加热浴温度为100℃下搅拌2小时。然后将混合物倾入冰水中,用浓氢氧化钠溶液调至碱性并用二氯甲烷萃取两次。将合并的有机相干燥并浓缩,分离得到3.7g粗产物,将其于50ml异丙醇中重结晶,得到2.4g(66%)产物,熔点为168-170℃。
实施例143,4,5,6,7,8-六氢-7-(2-(1-萘基)乙基)-3-[2-(4-(2-甲氧基苯基)-哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×3HCl
于35ml二甲苯中,将1.0g(2.3mM)3,4,5,6,7,8-六氢-3-[2-(4-(2-甲氧基苯基)-哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮与0.8g(3.4mM)2-溴-1-1-萘基-乙烷和0.3g(2.4mM)碳酸钾精细粉末混合并回流蒸煮12小时。然后将混合物于旋转蒸发仪上浓缩,在pH=10下残余物于二氯甲烷和水之间分配。水相用二氯甲烷再萃取一次,将合并的有机相干燥,然后浓缩。经柱色谱法(硅胶,移动相为二氯甲烷/丙酮7/3)纯化,得到2.7g黑色油状粗产物。于乙酸乙酯中转变成所述盐酸盐后,分离得到1.0g(63%)产物,熔点为293-295℃(分解)。
按照实施例l-14所述相似方法可制备下列化合物:15. 3,4,5,6,7,8-六氢-7-甲基-3-[3-(4-(2-甲氧基苯基)-哌嗪-1-
基)丙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-亚胺,熔点
为112-114℃16. 3,4,5,6,7,8-六氢-7-苄基-3-[3-(4-(2-甲氧基苯基)-哌嗪-1-
基)丙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-亚胺×
2HCl,熔点为258-281℃(分解)17. 3,4,5,6,7,8-六氢-7-苄基-3-[2-(4-苯基-哌嗪-1-基)乙基]吡
啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-亚胺,熔点为168-170
℃18. 3,4,5,6,7,8-六氢-7-苄基-3-[3-(4-(2-甲氧基苯基)-哌嗪-1-
基)丙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮,熔点为
66-67℃19. 3,4,5,6,7,8-六氢-7-苄基-3-[2-(4-苯基-哌嗪-1-基)乙基]吡
啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮,熔点为70-71℃20. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-嘧啶基-2-哌嗪-1-基)乙基]
吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-亚胺酒石酸盐,熔点
为112-114℃(分解)21. 3,4,5,6,7,8-六氢-7-甲基-3-[3-(4-(3-甲氧基苯基)-哌嗪-1-
基)丙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-亚胺×
3HCl×2H2O,熔点为268-270℃(分解)22. 3,4,5,6,7,8-六氢-7-甲基-3-[3-(4-萘基-1-哌嗪-1-基)丙基]
吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-亚胺×3HCl,熔点为
250-253℃(分解)23. 3,4,5,6,7,8-六氢-7-甲基-3-[3-(4-(2-硝基苯基)-哌嗪-1-基)
丙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-亚胺×3HCl×
2H2O,熔点为271-273℃(分解)24. 3,4,5,6,7,8-六氢-7-甲基-3-[3-(4-(2-甲基)-哌嗪-1-基)丙基]
吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-亚胺×3HCl,熔点为
280-282℃(分解)25. 3,4,5,6,7,8-六氢-7-甲基-3-[3-(4-(2-氨基苯基)-哌嗪-1-基)
丙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-亚胺×HCl×
4H2O,熔点为113-115℃(分解)26. 3,4,5,6,7,8-六氢-7-甲基-3-[3-(4-(2-氯苯基)-哌嗪-1-基)丙
基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-亚胺×3HCl,熔
点为261-263℃(分解)27. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-嘧啶基-2-哌嗪-1-基)乙基]
吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮,熔点为146-148
℃(分解)28. 3,4,5,6,7,8-六氢-7-甲基-3-[3-(4-苄基-哌嗪-1-基)丙基]吡
啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-亚胺×3HCl,熔点为
295-297℃(分解)29. 3,4,5,6,7,8-六氢-7-甲基-3-[3-(4-(2-羟基苯基)-哌嗪-1-基)
丙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-亚胺,熔点为
164-166℃30. 3,4,5,6,7,8-六氢-7-甲基-3-[4-(4-(2-甲氧基苯基)-哌嗪-1-
基)丁基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-亚胺×HCl
×3H2O,熔点为272-274℃(分解)31. 3,4,5,6,7,8-六氢-7-甲基-3-[3-(4-(2-乙氧基苯基)-哌嗪-1-
基)丙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-亚胺×
3HCl×3H2O,熔点为284-286℃(分解)32. 3,4,5,6,7,8-六氢-7-甲基-3-[3-(4-(2-乙基苯基)-哌嗪-1-基)
丙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-亚胺×3HCl,
熔点为303-305℃(分解)33. 3,4,5,6,7,8-六氢-7-甲基-3-[3-(4-(2-氰基苯基)-哌嗪-1-基)
丙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×2HCl×
2H2O,熔点为136-138℃(分解)34. 3,4,5,6,7,8-六氢-7-甲基-3-[3-(4-苯基-哌嗪-1-基)丙基]吡
啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-亚胺×3HCl,熔点为
280-282℃(分解)35. 3,4,5,6,7,8-六氢-7-甲基-3-[3-(4-吡嗪基-2-哌嗪-1-基)丙基]
吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-亚胺×4HCl×H2O,
熔点为284-286℃(分解)36. 3,4,5,6,7,8-六氢-7-甲基-3-[3-(4-2-嘧啶基-哌嗪-1-基)丙基]
吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-亚胺,熔点为161-
163℃37. 3,4,5,6,7,8-六氢-7-甲基-3-[3-(4-(2-氰基苯基)-哌嗪-1-基)
丙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-亚胺,熔点为
148-150℃(分解)38. 3,4,5,6,7,8-六氢-7-苄基-3-[2-(4-(2-甲氧基苯基)-哌嗪-1-
基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×3HCl
×H2O,熔点为288-290℃(分解)39. 3,4,5,6,7,8-六氢-7-甲基-3-[3-(4-(3,4-亚甲二氧基苯基)-哌
嗪-1-基)丙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-亚胺
×3HCl,熔点为288-290℃(分解)40. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(2-甲基苯基)-哌嗪-1-基)
乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×2HCl×
H2O,熔点>300℃41. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(2-氯苯基)-哌嗪-1-基)乙
基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×2HCl×
H2O,熔点>30042. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(3,4-二甲基苯基)-哌嗪-
1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×
2HCl,熔点为307-310℃43. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(2,6-二甲基苯基)-哌嗪-
1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×
2HCl,熔点为297-300℃44. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(2,3-二甲基苯基)-哌嗪-
1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮,熔点
为163-167℃45. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(2,4-二甲基苯基)-哌嗪-
1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×
2HCl,熔点为300-303℃46. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(3,5-二氯苯基)-哌嗪-1-
基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮,熔点为
97-100℃47. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(2,4-二甲氧基苯基)-哌嗪
-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×
2HCl,熔点为287-290℃48. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(3-三氟甲基苯基)-哌嗪-
1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×
2HCl,熔点为309-312℃49. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-萘-1-基-哌嗪-1-基)乙基]
吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×2HCl×H2O,熔
点为298-300℃(分解)50. 3,4,5,6,7,8-六氢-7-甲基-3-[3-(4-(3-羟基苯基)-哌嗪-1-基)
丙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-亚胺×2HCl×
2H2O,熔点为182-184℃(分解)51. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(2-甲氧基-5-氯苯基)-哌
嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×
3HCl,熔点为170-172℃(分解)52. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(2,5-二甲氧基苯基)-哌嗪
-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×
3HCl×H2O,熔点为176-178℃(分解)53. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(2-甲氧基-5-苯基-苯基)-
哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮
×H2O,熔点为79-80℃54. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(2-甲氧基苯基)-3,4-二氢
哌啶-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮
×2HCl×2H2O,熔点为182-185℃(分解)55. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(2-羟基苯基)-哌嗪-1-基)
乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×2HCl×
H2O,熔点为281-283℃(分解)56. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(7-甲氧基萘-1-基)-哌嗪
-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×
2HCl×H2O,熔点为272-274℃(分解)57. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-萘-1-基-哌嗪-1-基)乙基]
吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-亚-胺×3HCl,熔点为
288-289℃(分解)58. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(4,5-亚甲二氧基苄基)-哌
嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-亚胺
×4HCl×2H2O,熔点为249-251℃(分解)59. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(6-异丙基嘧啶-4-基)-哌
嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-亚胺
×3HCl×2H2O,熔点为250-253℃(分解)60. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(2-甲氧基萘-1-基)-哌嗪
-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×
2HCl×2H2O,熔点为241-243℃(分解)61. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(2-甲氧基苯基)-哌嗪-1-
基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×2HCl
×2H2O,熔点为299-301℃(分解)62. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(3,4-二甲氧基苯基)-哌嗪
-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮,熔点
为153-154℃63. 3,4,5,6,7,8-六氢-7-甲基-3-[3-(4-萘-1-基-哌嗪-1-基)丙基]
吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×3HCl×2H2O,
熔点为206-208℃(分解)64. 3,4,5,6,7,8-六氢-7-甲基-3-[3-(4-嘧啶-2-基-哌嗪-1-基)丙
基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮,熔点为161-
163℃65. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-喹啉-2-基-哌嗪-1-基)乙
基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮,熔点为143-
145℃66. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(2-甲基萘-1-基)乙基]吡
啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×2HCl×2H2O,熔
点为295-297℃(分解)67. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(2-甲氧基-3,5-二氯苯
基)-哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-
4-酮×2HCl×H2O,熔点为264-267℃(分解)68. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(2-氰基苯基)哌嗪-1-基)
乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮,熔点为
162-164℃69. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(2-氯苯基)-哌嗪-1-基)乙
基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮,熔点为165-
167℃70. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-吡啶-2-基-哌嗪-1-基)乙
基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×3HCl×
2H2O,熔点为232-234℃(分解)71. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-吡啶-4-基-哌嗪-1-基)乙
基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×3HCl×
2H2O,熔点为270-272℃(分解)72. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(5-甲氧基嘧啶-4-基)-哌
嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×
3HCl×4H2O,熔点为266-268℃(分解)73. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-萘-2-基-哌嗪-1-基)乙基]
吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮,熔点为140-141
℃74. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-吡嗪-2-基-哌嗪-1-基)乙
基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×3HCl×
3H2O,熔点为170-172℃(分解)75. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-四氢化萘-5-基-哌嗪-1-基)
乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×3HCl×
2H2O,熔点为285-287℃(分解)76. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-2,3-二氢化茚-1-基-哌嗪
-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×
3HCl×2H2O,熔点为300-301℃(分解)77. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(2-甲氧基-4-硝基-5-甲基
苯基)-哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶
-4-酮×2HCl×2H2O,熔点为210-212℃(分解)78. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-4-异喹啉基-哌嗪-1-基)乙
基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×3HCl×
3H2O,熔点为290-292℃(分解)79. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(2-甲氧基-4-氯-5-甲基苯
基)-哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-
4-酮×2HCl×2H2O,熔点为293-294℃(分解)80. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(2,4-二甲氧基苯基)-哌嗪
-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×
3HCl×3H2O,熔点为290-291℃(分解)81. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-4-喹唑啉基-哌嗪-1-基)乙
基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×3HCl×
4H2O,熔点为258-260℃(分解)82. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(3-三氟甲基-4-氯苯基)-
哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮
×2HCl×3H2O,熔点为311-312℃(分解)83. 3,4,5,6,7,8-六氢-7-(4-氯苄基)-3-[2-(4-(2-甲氧基苯基)-哌
嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×
3HCl×H2O,熔点为290-292℃(分解)84. 3,4,5,6,7,8-六氢-7-乙基-3-[2-(4-(2-甲氧基苯基)-哌嗪-1-
基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×3HCl
×H2O,熔点为295-297℃(分解)85. 3,4,5,6,7,8-六氢-7-异丙基-3-[2-(4-(2-甲氧基苯基)-哌嗪-
1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×
3HCl×H2O,熔点为300-302℃(分解)86. 3,4,5,6,7,8-六氢-7-(4-硝基)苄基-3-[2-(4-(2-甲氧基苯基)-
哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮
×3HCl×H2O,熔点为214-217℃(分解)87. 3,4,5,6,7,8-六氢-7-(4-甲氧基)苄基-3-[2-(4-(2-甲氧基苯
基)-哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-
4-酮×3HCl×H2O,熔点为278-281℃(分解)88. 3,4,5,6,7,8-六氢-7-(2-苯基)乙基-3-[2-(4-(2-甲氧基苯基)-
哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮
×3HCl×H2O,熔点为305-306℃(分解)89. 3,4,5,6,7,8-六氢-7-(3-苯甲酰基)丙基-3-[2-(4-(2-甲氧基苯
基)-哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-
4-酮×3HCl×H2O,熔点为124-126℃(分解)90. 3,4,5,6,7,8-六氢-7-(4-氨基)苄基-3-[2-(4-(2-甲氧基苯基)-
哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮
×HCl×3H2O,熔点为280-282℃(分解)91. 3,4,5,6,7,8-六氢-7-(3-苯基)丙基-3-[2-(4-(2-甲氧基苯基)-
哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮
×2HCl×3H2O,熔点为301-302℃(分解)92. 3,4,5,6,7,8-六氢-7-(3-苯基)丙基-3-[2-(4-萘-1-基)-哌嗪-
1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×
2HCl×2H2O,熔点为306-307℃(分解)93. 3,4,5,6,7,8-六氢-7-(2-(4-甲氧基)苯基)乙基-3-[2-(4-萘-1-
基)-哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-
4-酮×2HCl×3H2O,熔点为306-308℃(分解)94. 3,4,5,6,7,8-六氢-7-(2-(4-氯)苯基)乙基-3-[2-(4-萘-1-基)-
哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮
×2HCl×3H2O,熔点为300-303℃(分解)95. 3,4,5,6,7,8-六氢-7-(2-苯基)乙基-3-[2-(4-萘-1-基)-哌嗪-
1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×
2HCl×3H2O,熔点为295-298℃96. 3,4,5,6,7,8-六氢-7-(2-(4-羟基)苯基)乙基-3-[2-(4-萘-1-
基)-哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-
4-酮×2HCl×3H20,熔点为254-256℃97. 3,4,5,6,7,8-六氢-7-(2-(4-氯)苯基)乙基-3-[2-(4-(2-甲氧基
苯基)-哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶
-4-酮×2HCl×2H2O,熔点为304-306℃(分解)98. 3,4,5,6,7,8-六氢-7-(2-萘-1-基)乙基-3-[2-(4-(2-甲氧基苯
基)-哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-
4-酮×2HCl×2H2O,熔点为293-295℃(分解)99. 3,4,5,6,7,8-六氢-7-(2-苯甲酰氨基)乙基-3-[2-(4-萘-1-基)-
哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮
×2HCl×2H2O,熔点为292-294℃(分解)100. 3,4,5,6,7,8-六氢-7-(2-苯甲酰氨基)乙基-3-[2-(4-(2-甲氧
基苯基)-哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧
啶-4-酮×2HCl×3H2O,熔点为202-204℃(分解)101. 3,4,5,6,7,8-六氢-7-(3-苯甲酰氨基)丙基-3-[2-(4-(2-甲氧
基苯基)-哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧
啶-4-酮×3HCl×2H2O,熔点为182-183℃(分解)102. 3,4,5,6,7,8-六氢-7-(3-苯甲酰氨基)丙基-3-[2-(4-萘-1-
基)-哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-
4-酮×3HCl×H2O,熔点为128-130℃(分解)103. 3,4,5,6,7,8-六氢-7-(4-苯基)丁基-3-[2-(4-(2-甲氧基苯
基)-哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-
4-酮×3HCl×H2O,熔点为311-312℃(分解)104. 3,4,5,6,7,8-六氢-7-(4-苯基)丁基-3-[2-(4-萘-1-基)-哌嗪
-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×
3HCl×H2O,熔点为312-314℃(分解)105. 3,4,5,6,7,8-六氢-7-(4-甲氧基)苄基-3-[2-(4-萘-1-基)-哌
嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×
3HCl×H2O,熔点为275-277℃(分解)106. 3,4,5,6,7,8-六氢-7-(2-(4-甲氧基)苯基)乙基-3-[2-(4-(2-
甲氧基苯基)-哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-
d]嘧啶-4-酮×3HCl×3H2O,熔点为297-298℃(分解)107. 3,4,5,6,7,8-六氢-7-(2-苯基)乙基-3-[3-(4-萘-1-基)-哌嗪
-1-基)丙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮,熔点
为153-155℃108. 3,4,5,6,7,8-六氢-7-(2-苯基)乙基-3-[2-(4-嘧啶-2-基)-哌
嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×
2HCl×3H2O,熔点为304-305℃(分解)109. 3,4,5,6,7,8-六氢-7-(2-苯基)乙基-3-[3-(4-嘧啶-2-基)-哌
嗪-1-基)丙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×
3HCl×2H2O,熔点为302-303℃(分解)110. 3,4,5,6,7,8-六氢-7-(3-苯甲酰氨基)丙基-3-[2-(4-嘧啶-2-
基)-哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-
4-酮×3HCl×3H2O,熔点为125-127℃(分解)111. 3,4,5,6,7,8-六氢-7-(4-苯基)丁基-3-[2-(4-嘧啶-2-基)-哌
嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×
3HCl×3H2O,熔点为317-319℃(分解)112. 3,4,5,6,7,8-六氢-7-(2-(4-甲氧基)苯基)乙基-3-[2-(4-嘧啶
-2-基)-哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧
啶-4-,熔点为165-167℃113. 3,4,5,6,7,8-六氢-7-乙酰基-3-[3-(4-(2-甲氧基苯基)-哌嗪
-1-基)丙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-亚胺×
2HCl,熔点为265-268℃114. 3,4,5,6,7,8-六氢-7-乙酰基-3-[3-(4-(2-甲氧基苯基)-哌嗪
-1-基)丙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×
2HCl×2H2O,熔点为264-267℃115. 3,4,5,6,7,8-六氢-3-[2-(4-(2-甲氧基苯基)-哌嗪-1-基)乙基]
吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮,熔点为168-170
℃116. 3,4,5,6,7,8-六氢-7-乙酰基-3-[2-(4-(2-甲氧基苯基)-哌嗪
-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮,熔点
为170-172℃117. 3,4,5,6,7,8-六氢-7-苯甲酰基-3-[2-(4-(2-甲氧基苯基)-哌
嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×
2HCl×2H2O,熔点为185-1877℃(分解)118. 3,4,5,6,7,8-六氢-7-苯甲酰基-3-[2-(4-萘-1-基)-哌嗪-1-基)
乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮,熔点为
195-197℃119. 3,4,5,6,7,8-六氢-7-苯甲酰基-3-[2-(4-嘧啶-2-基)-哌嗪-1-
基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮,熔点为
130-132℃(分解)120. 3,4,5,6,7,8-六氢-2,7-二甲基-3-[2-(4-(2-甲氧基苯基)-哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮,熔
点为176-178℃121. 3,4,5,6,7,8-六氢-7-乙酰基-2-羟基-3-[2-(4-(2-甲氧基苯
基)-哌嗪-1-基)乙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-
4-酮,熔点为135-137℃122. 3,4,5,6,7,8-六氢-7-甲基-3-[1-(4-(2-甲氧基苯基)-哌嗪-1-
基)丙-2-基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮,熔点
为184-186℃123. 3,4,5,6,7,8-六氢-[1-(4-萘-1-基-哌嗪-1-基)丙-2-基]吡啶
并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×2HCl×4H2O,熔点
为242-244℃(分解)124. 3,4,5,6,7,8-六氢-7-甲基-3-[2-(4-(2-甲氧基苯基)-哌嗪-1-
基)丙基]吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮×3HCl
×3H2O,熔点为190-192℃
C受体结合作用的测定
带受体的细胞膜的制备
用膜制品进行受体结合试验,所述膜制品由人胚胎肾细胞系293(HEK 293)细胞培养物获得,每个细胞克隆特定的5-羟色胺受体亚型(h5HT1A、h5HT1B或h5HT1D)并永久表达。
所述细胞在另外含有10%牛胎血清(FCS)、2mmol/l L-谷氨酰胺和400mg/l Geneticin G 418的RPMI1640培养基(LifeTechnologies)中生长。在空气/5%CO2下,在保温箱中将所述细胞在37℃下于托盘中进行孵育,直至得到连续的单层细胞。然后用下列组份(每升中含有的量)的缓冲液将所述细胞由培养基容器中分离出:胰蛋白酶10mg;EDTA 4mg;EGTA 200mg;KCl 200mg;KH2PO4 200mg;Na2HPO41.15g;NaCl8.0g;pH7.4。将所述细胞制成片状,再悬浮于Dulbecco磷酸盐缓冲生理盐水(PBS)中并将细胞密度调至约108个细胞/ml。再度制备片状物后,用相同体积冰冷的溶解缓冲液(5mmol/ltris;10%甘油;pH7.4)代替PBS并于4℃下孵育30分钟。将溶解的细胞(=膜)以等分试样贮存于液氮中,直至用于受体结合试验。用每一制品的一个等分试样测定蛋白含量。
对于克隆细胞系表达的人5-HT1A、5-HT1B和5-HT1D受体亚型,本发明所述化合物表现出较强的亲合性(K;≤30nM)。
受体结合试验
在含有下列组份的1ml大孔试管中进行受体结合试验:—用50μl各种浓度的试验底物进行竞争试验或者用50μl试验缓冲液或50μl未标记的5-羟色胺(最终达到1μmol/l)测定总的结合对照或非特异性结合对照—200μl蛋白含量为200μg/管的适宜受体亚型膜悬浮液—250μl放射配位体溶液(对于h5HT1B和h5TH1D受体用[3H]5-甲酰胺基色胺(5-CT)或者对于h5HT1A受体用[3H]8-羟基二丙氨基-1,2,3,4-四氢化萘(8-OH-DPAT)。分别将所述放射配位体的最终浓度调至3nmol/l和0.3nmol/l。
所述试验缓冲液含有下列组份(每升):tris6.057g;CaCl2×2H2O=5.88g;抗坏血酸1g;巴吉林1.96mg。
将所述试验混合物于25℃下孵育30分钟,然后用细胞捕获器(Skatron)经纤维玻璃过滤器(Whatman GF/B)过滤,过滤器用5-9ml冷缓冲液洗涤。在每种情况中,于闪烁管中,将过滤器与5ml UltimaGold×R液体闪烁体(Packard)混合并振摇1小时,然后在β计数器(Wallac)中测定放射性。用统计分析***(SAS)对测定的数据进行迭代非线性回归分析,其与Munson和Rodbard所述LIGAND程序相似(Anal.Biochem:107,220(1980))。竞争常数(Ki)用nmol/l表示。
Claims (6)
1.下列式I3-取代的3,4,5,6,7,8-六氢吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶衍生物及其生理上耐受的盐:
其中
R1是氢、C1-C4-烷基、乙酰基或苯甲酰基,苯基烷基C1-C4基团,所述芳环可未被取代或者被卤素、C1-C4-烷基、羟基、C1-C4-烷氧基、氨基或硝基取代,或者是萘基烷基C1-C3基团或苯基氨基甲酰基烷基C2基团,
R2是苯基、吡啶基、嘧啶基或吡嗪基,每个基团可未被取代或者被卤原子、C1-C4-烷基、三氟甲基、三氟甲氧基、羟基、C1-C4-烷氧基、氨基、一甲氨基、二甲氨基、氰基或硝基一-、二-或三-取代,并且苯基可以与未被取代的或被C1-C4-烷基或C1-C4-烷氧基一-或二-取代的苯环稠合,
A是NH或氧原子,
B是氢或甲基,
C是氢、甲基或羟基,
X是氮原子,
Y是CH2、CH2-CH2、CH2-CH2-CH2或CH2-CH,
Z是氮原子、碳原子或CH,Y和Z之间的连接键也可以是双键,
和n是2、3或4。
2.权利要求1所述化合物,其中
R1是甲基、乙基、异丙基、苄基、取代的苄基、苯乙基、取代的苯乙基,
R2是邻甲氧基苯基、1-萘基、嘧啶-2-基、2-甲氧基-1-萘基、2-甲基-1-萘基,
A是NH或氧原子,
X是氮原子,
Y是CH2-CH2、CH2-CH,
Z是氮原子、碳原子或CH,
和n是2或3。
3.权利要求1或-2所述化合物在制备药物中的应用。
4.权利要求3所述的应用,所述药物用于治疗抑郁症及相关疾病。
5.权利要求1或2所述化合物在制备选择性5HT1B和5HT1A拮抗剂中的应用。
6.权利要求5所述的应用,其中除了所述选择性5-羟色胺拮抗作用外还具有抑制5-羟色胺再摄入作用。
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DE19636769.7 | 1996-09-10 | ||
DE19636769A DE19636769A1 (de) | 1996-09-10 | 1996-09-10 | 3-Substituierte Pyrido [4',3':4,5]thieno[2,3-d]pyrimidin-Derivate, ihre Herstellung und Verwendung |
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CN01116979A Pending CN1332168A (zh) | 1996-09-10 | 2001-05-18 | 3-取代的吡啶并[4′,3′∶4,5]噻吩并[2,3-d]嘧啶衍生物,它们的制备和应用 |
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DE19724980A1 (de) * | 1997-06-13 | 1998-12-17 | Basf Ag | 3-Substituierte 3,4-Dihydro-thieno[2,3-d]pyrimidin-Derivate, ihre Herstellung und Verwendung |
DE19724979A1 (de) * | 1997-06-13 | 1998-12-17 | Basf Ag | 3-substituierte Pyrido [3,4,5]thieno[2,3-d]pyrimidin-Derivate, ihre Herstellung und Verwendung |
DE19734444A1 (de) | 1997-08-08 | 1999-02-11 | Basf Ag | 3-Substituierte 3,4,5,7-Tetrahydro-pyrrolo(3',4':4,5) thieno (2,3-d) pyrimidin-Derivate, ihre Herstellung und Verwendung |
DE19900545A1 (de) | 1999-01-11 | 2000-07-13 | Basf Ag | Verwendung von Pyrimidinderivaten zur Prophylaxe und Therapie der zerebralen Ischämie |
DE19900673A1 (de) | 1999-01-11 | 2000-07-13 | Basf Ag | Verwendung von Bindungspartnern für 5-HT5-Rezeptoren zur Behandlung neurodegenerativer und neuropsychiatrischer Störungen |
FR2791980B1 (fr) * | 1999-04-09 | 2001-07-06 | Sod Conseils Rech Applic | Pyrido-thieno-diazepines, leur procede de preparation, et les compositions pharmaceutiques les contenant |
DE10031390A1 (de) * | 2000-07-03 | 2002-01-17 | Knoll Ag | Pyrimidinderivate und ihre Verwendung zur Prophylaxe und Therapie der zerebralen Ischämie |
DE10031389A1 (de) * | 2000-07-03 | 2002-01-17 | Knoll Ag | Pyrimidinderivate und ihre Verwendung zur Prophylaxe und Therapie der zerebralen Ischämie |
WO2002006231A1 (fr) * | 2000-07-18 | 2002-01-24 | Sumitomo Pharmaceuticals Co., Ltd. | Inhibiteurs de recaptage de la serotonine |
DE10259382A1 (de) * | 2002-12-18 | 2004-07-01 | Abbott Gmbh & Co. Kg | 3-Substituierte 3,4-Dihydro-thieno[2,3-d]pyrimidin-4-on-Derivate, ihre Herstellung und Verwendung |
US20050222175A1 (en) * | 2004-03-31 | 2005-10-06 | Dhanoa Dale S | New piperidinylamino-thieno[2,3-D] pyrimidine compounds |
US7030240B2 (en) * | 2003-03-31 | 2006-04-18 | Predix Pharmaceuticals Holdings, Inc. | Piperidinylamino-thieno[2,3-d] pyrimidine compounds |
US7612078B2 (en) * | 2003-03-31 | 2009-11-03 | Epix Delaware, Inc. | Piperidinylamino-thieno[2,3-D] pyrimidine compounds |
US20050165025A1 (en) * | 2004-01-22 | 2005-07-28 | Recordati Ireland Ltd. | Combination therapy with 5HT 1A and 5HT 1B-receptor antagonists |
US7488736B2 (en) * | 2004-05-17 | 2009-02-10 | Epix Delaware, Inc. | Thienopyridinone compounds and methods of treatment |
US7598265B2 (en) * | 2004-09-30 | 2009-10-06 | Epix Delaware, Inc. | Compositions and methods for treating CNS disorders |
US7407966B2 (en) * | 2004-10-07 | 2008-08-05 | Epix Delaware, Inc. | Thienopyridinone compounds and methods of treatment |
US7576211B2 (en) * | 2004-09-30 | 2009-08-18 | Epix Delaware, Inc. | Synthesis of thienopyridinone compounds and related intermediates |
US8114894B2 (en) * | 2008-12-03 | 2012-02-14 | Nanotherapeutics, Inc. | Bicyclic compounds and methods of making and using same |
JP5816262B2 (ja) * | 2010-04-14 | 2015-11-18 | バイエル・インテレクチュアル・プロパティ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツングBayer Intellectual Property GmbH | ジチインテトラカルボキシイミド類の製造方法 |
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US3823151A (en) * | 1968-08-02 | 1974-07-09 | Ciba Geigy Corp | 4,5,6,7-tetrahydrothieno(2,3-d)pyridines |
DE1937459A1 (de) * | 1968-08-02 | 1970-02-05 | Ciba Geigy | Neue Pyrimidinderivate und Verfahren zu ihrer Herstellung |
JPS60146891A (ja) * | 1984-01-05 | 1985-08-02 | Mitsubishi Chem Ind Ltd | 〔2,3−d〕チエノピリミジン誘導体およびその塩 |
DE3752141T2 (de) * | 1986-02-24 | 1998-03-26 | Mitsui Petrochemical Ind | Mittel zur behandlung von neuropathie |
US5001130A (en) * | 1988-02-18 | 1991-03-19 | Bristol-Myers Company | Psychotropic heterobicycloalkylpiperazine derivatives |
US4835157A (en) * | 1988-03-15 | 1989-05-30 | Ortho Pharmaceutical Corporation | Thieno- and furopyrimidine-2,4-dione piperidine derivatives as serotonin antagonists and alpha adrenergic blocking agents |
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