CN1260797A - 3－取代的3,4－二氢噻吩并[2,3－d]嘧啶衍生物及其制备和用途 - Google Patents
3－取代的3,4－二氢噻吩并[2,3－d]嘧啶衍生物及其制备和用途 Download PDFInfo
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- CN1260797A CN1260797A CN98806146A CN98806146A CN1260797A CN 1260797 A CN1260797 A CN 1260797A CN 98806146 A CN98806146 A CN 98806146A CN 98806146 A CN98806146 A CN 98806146A CN 1260797 A CN1260797 A CN 1260797A
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- methyl
- dihydro
- thieno
- dimethylamino
- piperazine
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- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 title claims description 6
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Abstract
本发明涉及通式Ⅰ的3－取代的3,4－二氢噻吩并[2,3－d]－嘧啶衍生物,其中R1和R2是氢原子或C1－C4－烷基,R3是未取代的或被卤素原子、C1－C4－烷基、三氟甲基、三氟甲氧基、羟基、C1－C4－烷氧基、氨基、一甲基氨基、二甲基氨基、氰基或硝基一或二取代的苯基、吡啶基、嘧啶基或吡嗪基,这些基团可以任选地与一个未取代的或被卤素原子、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的并可任选含有1个氮原子的苯核稠合,或与可含有1－2个氧原子的5－或6－员环稠合,A是NH或氧原子,Y是CH2、CH2－CH2、CH2－CH2－CH2或CH2－CH,Z是氮原子、碳原子或CH,Y和Z之间的键也可以是双键,和n是2、3或4。本发明还涉及发明的3－取代的3,4－二氢噻吩并[2,3－d]－嘧啶衍生物的生理学可接受的盐。
Description
本发明涉及新的3，4-二氢噻吩并[2，3-d]-嘧啶衍生物、其制备和生产用于药物的活性组分的用途。
传统的抗抑郁剂和较新的选择性血清素再吸收抑制剂(SSRIs)尤其是通过抑制突触前神经末梢对传递质的有效再吸收显示其抗抑郁剂的作用。不幸的是，其抗抑郁剂作用直到治疗进行至少3周才开始出现，并且，约30％的患者对治疗有耐受性。
通过消除隐性偶合，突触前的血清素自受体的阻断增加血清素释放并因此在突触裂缝中聚集现时的传递质。这种传递质聚集的增加被认为是抗抑郁剂作用的原理。该作用机理与以前所知的抗抑郁剂不同，以前的抗抑郁剂作用于突触前和体树状自受体并因此只有在这些自受体脱敏后才产生延迟的作用。直接的自受体阻断绕过了这个效应。
根据已有知识，突触前血清素自受体是5-HT1B亚型(Fink等人，Arch.Pharmacol.352(1995)，p.451)。其通过5-HT1B/D拮抗剂的选择性阻断增加了血清素在大脑的释放(G.W.Price等人，大脑行为研究(Behavioural Brain Research)73(1996)，p79-82；P.H.Hutson等人，神经药理学(Neuropharmacology)Vol.34，No.4(1995)，p.383-392)。
但是，令人惊奇的是，在全身给药后，选择性5-HT1B拮抗剂GR 127935降低了血清素在皮层的释放。一种解释可能是由于释放的血清素刺激了在缝区域中的体树状5-HT1A受体，这抑制了血清素能神经元的释放速率，并因此抑制了血清素的释放(M.Skingle等人，神经药理学(Neuropharmacology)Vol.34，No.4(1995)，p377-382，p393-402)。
因此，一种用于在起端的血清素能区域避开自抑制作用的的方法是瞄准阻断突触前的5-HT1B受体。氟苯哌苯醚对大鼠背侧缝核中血清素释放的作用通过5-HT1B受体拮抗剂GR 127 935得到加强(Davidson和Stamford，Neuroscience Letts.，188(1995)，41)，这一观察结果支持了该假说。
第二种方法包括阻断两种自受体，即，阻断5-HT1A受体，从而强化神经元的释放，和阻断5-HT1B受体，从而增加末端血清素释放(Starkey和Skingle，神经药理学(Neuropharmacology)Vol.33，No.(3-4)(1994)，393)。
因此，5-HT1B/D受体拮抗剂，单独地或与5-HT1A受体拮抗剂成分联合，能导致在大脑中血清素释放的较大增加，从而可能带来在治疗抑郁症和相关的心理失调方面的益处。
现已发现，通式I的3-取代的3，4-二氢噻吩并[2，3-d]-嘧啶衍生物和其生理学可接受的酸的盐，其具有有价值的药理性能，
其中
R1和R2 是氢原子或C1-C4-烷基，
R3 是未取代的或被卤素原子、C1-C4-烷基、三氟甲基、三氟甲氧基、羟基、C1-C4-烷氧基、氨基、一甲基氨基、二甲基氨基、氰基或硝基一或二取代的苯基、吡啶基、嘧啶基或吡嗪基，这些基团可以任选地与一个未取代的或被卤素原子、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的并任选地可含有1个氮原子的苯核稠合，或与含有1-2个氧原子的5-或6-员环稠合，
A 是NH或氧原子，
Y 是CH2、CH2-CH2、CH2-CH2-CH2或CH2-CH，
Z 是氮原子、碳原子或CH，Y和Z之间的键也可以是双键，
和
n 是2、3或4。
特别优选的化合物是那些其中基团定义如下的化合物：
R1和R2 是甲基，
R3 是邻甲氧基苯基、1-萘基、2-甲氧基-1-萘基、2-甲基-1-萘基，
A 是氧原子，
Y 是CH2-CH2，
Z 是氮原子，
和
n 是2和3。
本发明的式I的化合物可如下制备，即，使式II化合物
其中
R1具有上述的定义，
R3是氰基或C1-3-烷基羧酸酯基，
R4是C1-3-烷基，
与式III的伯胺反应，
其中
R3具有上述定义，
以及，适当的话，将用该方法得到的化合物转化成生理学可接受的酸的加成盐。
该反应方便地在惰性有机溶剂中，特别是在低级醇例如甲醇或乙醇中，或在饱和环醚，特别是四氢呋喃或二噁烷中进行。
该反应通常在20-110℃进行，尤其是60-90℃，一般在1-10小时期间完成。
或者，使式II的化合物
其中
R1具有上述的定义，
R3是氰基或C1-3-烷基羧酸酯基，
R4是C1-3-烷基，
与式IV的伯氨基醇
在惰性溶剂，特别是诸如乙醇的醇类中在60-120℃反应，得到结晶产物V(X＝OH)，
随后用卤化试剂例如亚硫酰氯或氢溴酸在诸如卤代烃的有机溶剂中或在无溶剂条件下在室温到100℃的温度将其转化为相应的卤代衍生物V(X＝Cl，Br)。最后式V的卤代衍生物(X＝Cl，Br)与式VI的胺反应，
其中
Y、Z和R2定义如上，
得到本发明的式I最终产物。该反应最好在惰性有机溶剂，优选甲苯或二甲苯中在例如碳酸钾或氢氧化钾的碱的存在下在60-150℃进行。
本发明的式I化合物可从常规的有机溶剂，优选诸如乙醇的低级醇中重结晶，或用柱色谱纯化。
游离的式I的3-取代的吡啶[3’，4’：4，5]噻吩并[2，3-d]嘧啶衍生物可以常规的方法用化学计量量的适当的酸溶液转化成酸的加成盐。药物学可接受酸的例子是盐酸、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。
本发明因此还涉及一种治疗组合物，除了常规的载体和稀释剂，还含有式I化合物或其药物学可接受的酸加成盐作为活性成分，本发明还涉及将该新的化合物用于防治疾病的用途。
用常规的方法可将本发明化合物通过口服或非经胃肠道、静脉内或肌内给药。
剂量由患者的年龄、状况和体重以及给药方式确定。一般地，活性成分的口服日剂量为每千克体重约1-100毫克，非经胃肠道给药的日剂量为每千克体重0.1-10毫克。
可以常规的固体或液体药物剂型使用该新化合物，例如未包衣的或(薄膜)包衣的片剂、胶囊、粉末、颗粒、糖锭剂、栓剂、溶液、软膏、霜剂或喷剂。这些可用常规方法制备。为此可将活性成分与常规的药物助剂例如片剂粘合剂、膨胀剂、防腐剂、片剂崩解剂、流体调节剂、成型剂、湿润剂、分散剂、乳化剂、溶剂、缓释剂、抗氧化剂和/或抛射气体一起加工(参考H.Sucker等人：Pharmazeutische Technologie，Thieme-Verlag，Stuttgart，1978)。用这种方法获得的药剂通常含有1-99％重量的活性成分。
合成新化合物所需的起始物质式II-VI化合物是已知的，可用文献中描述的方法从类似的起始原料合成(F.Sauter和P.Stanetty，Monatsh，Chem.106(5)，(1975)，1111-1116；K.Gewald等人，Chem.Ber.99，(1966)94-100，德国专利申请196 36769.7)。
对于5-HT1B、5-HT1D和5-HT1A血清素受体本发明化合物具有高亲和力。此外，对于这些受体的亲和力大体相同，至少是同样的数量级。此外，一些新化合物表现出好的血清素再吸收抑制性，这是一个对于大多数抗抑郁剂都实现了的原则。
这些化合物适合作为药物用于治疗其中血清素浓度降低了的病症，作为治疗的一部分，希望特定地阻断突触前的5-HT1B、5-HT1D和5-HT1A受体的活性，同时对其它受体没有很大影响。这类病症的一个例子是抑郁症。
本发明的化合物还可用于治疗中枢神经原因的心境失调，诸如季节性情感性精神病和心境恶劣。还包括诸如一般化的焦虑、恐慌发作、反社会症、强迫性神经机能症和创伤后应激症状的焦虑状态，包括痴呆、健忘症和与年龄有关的记忆损失的记忆障碍，以及诸如厌食症和食欲过盛症的心理性的饮食失调。
该新化合物还可用于治疗内分泌失调，诸如血促性腺激素过多，治疗血管痉挛(特别是脑脉管)、高血压和与能动性和分泌紊乱相关的胃肠失调。另一个应用领域是治疗性欲失调。
下列实施例用于详细说明本发明：
A制备起始原料
a)2-氨基-3-乙氧基羰基-5-甲基-5-二甲基氨基甲酰基噻吩
将82.8ml(775mM)氰基乙酸乙酯和24.8g(755mM)硫粉加入到在400ml乙醇中的100g(775mM)N，N-二甲基乙酰胺中，然后在剧烈搅拌和氮气气氛下，滴加90ml(647mM)三乙基胺。1小时后，将混合物回流8小时，然后在室温搅拌过夜。减压浓缩混合物，残余物溶于2升水中，将pH调节到9，用二氯甲烷萃取2次。干燥并浓缩有机相，然后将粗产物(70g)溶于200ml沸腾的乙酸乙酯中提纯。搅拌过夜沉淀的固体在冰浴冷却后进行吸滤，用冷的乙酸乙酯洗涤几次。分离到灰色固体产物39.0g(20％)，熔点122-124℃。
b)2-乙氧基亚甲基氨基-3-乙氧羰基-4-甲基-5-二甲基氨基甲酰基噻吩
将2.0ml乙酸酐加入到在150ml原甲酸三乙酯中的30.6g(119mM)2-氨基-3-乙氧羰基-4-甲基-5-二甲基氨基甲酰基噻吩中，在氮气气氛下回流2小时。然后将该混合物在旋转蒸发器上在80℃完全蒸发。分离到深色油粗产物35.6g(96％)，其纯度足以进行下一步反应。
c)3-(2-羟基乙基)-5-甲基-6-二甲基氨基甲酰基噻吩并[2，3-d]嘧啶-4-酮
将8.0ml(133mM)乙醇胺加入到在200ml乙醇中的35.6g(114mM)2-乙氧基亚甲基氨基-3-乙氧羰基-5-甲基-5-二甲基氨基甲酰基噻吩中，回流2小时。然后减压浓缩混合物。分离到29.9g(93％)深色粘性油。
d)3-(2-氯乙基)-5-甲基-6-二甲基氨基甲酰基噻吩并[2，3-d]嘧啶-4-酮
将在200ml 1，2-二氯乙烷中的29.9g(106mM)3-(2-羟基乙基)-5-甲基-6-二甲基氨基甲酰基噻吩并[2，3-d]嘧啶-4-酮加热到回流(缓慢溶解)，然后滴加在20ml 1，2-二氯乙烷中的12.7ml(175mM)亚硫酰氯。回流1小时后，冷却反应混合物并浓缩。在二氯甲烷和水之间在pH＝9分配粗产物。干燥并浓缩有机相，分离得到44.1g(83％)深色油产物，用柱色谱提纯(硅胶，乙酸乙酯洗脱)。分离得到23.8g(76％)产物，熔点120-122℃。
用a)-d)方法可制备其它式II和V的C1-C4-单或二烷基氨基甲酰基衍生物。
e)N-(1-萘基)哌嗪
在5.4g(24.2mM)乙酸钯和14.7g(48.3mM)三邻甲苯基膦在500ml二甲苯中的混合物中加入83.2g(966mM)哌嗪、38.0g(339mM)叔丁醇钾和50.0g(241mM)1-溴萘，在剧烈搅拌和氮气气氛下回流混合物10小时。然后用二氯甲烷稀释混合物，滤除不溶的残余物，浓缩滤液。用柱色谱提纯粗产物(硅胶，THF/甲醇/氨85/13/2洗脱)。分离到21.5g(42％)产物，熔点84-86℃。
f)N-(2-甲基-1-萘基)哌嗪
在100ml氯苯中的13.0g(82.7mM)1-氨基-2-甲基萘中加入14.7g(82.7mM)二(2-氯乙基)胺×HCl，在氮气气氛下回流90小时。然后浓缩混合物，在二氯甲烷和水之间在pH＝9分配粗产物，干燥并浓缩有机相。用柱色谱提纯粗产物(硅胶，THF/甲醇/氨85/13/2洗脱)。分离得到11.6g(62％)产物。
g)4-哌嗪-1-基异喹啉
在50ml甲苯中混合4.51g(21.7mM)4-溴异喹啉、4.65g(25.0mM)哌嗪-N-羧酸叔丁酯、0.1g(0.11mM)三(二苯亚甲基丙酮)二钯、0.11g(0.18mM)2，2’-二(二苯基膦)-1，1’-联萘和2.92g(30.4mM)叔丁醇钠，在75℃搅拌2小时。将反应混合物加入冰/氯化钠中，用乙酸乙酯萃取，用硫酸钠干燥，用旋转蒸发器除去溶剂。抽滤结晶出的产物，用戊烷洗涤。得到5.5g(81％)Boc保护的哌嗪(熔点：111℃)。将5.2g(16.6mM)该物质溶于17ml二氯甲烷中，在0℃缓慢溶于17ml二氯甲烷，在0℃缓慢加入17ml(0.22mM)三氟乙酸。混合物在0℃搅拌4小时，倾入冰水中，用二氯甲烷萃取。过滤水相，使呈碱性，用二氯甲烷萃取。用硫酸钠干燥，随后除去溶剂，然后用乙醚稀释，用盐酸乙醚溶液得到盐酸盐沉淀。得到3.2g(67％)产物，熔点293-294℃。
文献(参考德国专利申请19636769.7)中没有公开的其它哌嗪衍生物(参见实施例)可如e)、f)和g)制备。
B制备最终产物
实施例1
3，4-二氢-5-甲基-6-二甲基氨基甲酰基-3-[2-(4-(2-甲氧基苯基)哌嗪-1-基)乙基]噻吩并[2，3-d]嘧啶-4-酮
将1.9g(8.0mM)1-(2-氨基乙基)-4-(2-甲氧基苯基)-哌嗪加入到在30ml乙醇中的2.4g(7.8mM)2-乙氧基亚甲基氨基-3-乙氧羰基-4-甲基-5-二甲基氨基甲酰基噻吩中，回流2小时。静置过夜后结晶出产物，抽滤并用少量乙醇洗涤。分离得到2.2g(62％)产物，熔点188-190℃。
实施例2
3，4-二氢-5-甲基-6-二甲基氨基甲酰基-3-[2-(4-(2，3-二甲基苯基)哌嗪-1-基)乙基]噻吩并[2，3-d]嘧啶-4-酮
将1.1g(5.0mM)1-(2，3-二甲基苯基)哌嗪盐酸盐和1.54ml(11mM)三乙基胺加入到在15ml二甲基甲酰胺中的1.5g(5.0mM)3-(2-氯乙基)-5-甲基-6-二甲基氨基甲酰基噻吩并[2，3-d]嘧啶-4-酮中，在氮气气氛下加热到125℃共3小时。倾如水中，然后用乙酸乙酯萃取，用稀盐酸在pH＝2萃取有机相，由此得到的水相用稀氢氧化钠溶液调节呈碱性。用二氯甲烷萃取粗产物，用硫酸钠干燥后，减压除去溶剂。将油状残留物从少量甲醇中结晶，抽滤。由此可得到0.7g(31％)产物，熔点160-161℃。
如实施例1和2可制备下列化合物：
3. 3，4-二氢-5-甲基-6-二甲基氨基甲酰基-3-[2-(4-(1-萘基)哌
嗪-1-基)乙基]噻吩并[2，3-d]嘧啶-4-酮，熔点190-191℃
4. 3，4-二氢-5-甲基-6-二甲基氨基甲酰基-3-[2-(4-(2-甲基-1-
萘基)哌嗪-1-基)乙基]噻吩并[2，3-d]嘧啶-4-酮，熔点178-180
℃5. 3，4-二氢-5-甲基-6-二甲基氨基甲酰基-3-[2-(4-(2-甲氧基-1-
萘基)哌嗪-1-基)乙基]噻吩并[2，3-d]嘧啶-4-酮×H2O，熔点
153-155℃(分解)6. 3，4-二氢-5-甲基-6-二甲基氨基甲酰基-3-[2-(4-(2-甲基-苯
基)哌嗪-1-基)乙基]噻吩并[2，3-d]嘧啶-4-酮7. 3，4-二氢-5-甲基-6-二甲基氨基甲酰基-3-[2-(4-(3-三氟甲基
苯基)哌嗪-1-基)乙基]噻吩并[2，3-d]嘧啶-4-酮，熔点146℃8. 3，4-二氢-5-甲基-6-二甲基氨基甲酰基-3-[2-(4-(2-氯苯基)
哌嗪-1-基)乙基]噻吩并[2，3-d]嘧啶-4-酮9. 3，4-二氢-5-甲基-6-二甲基氨基甲酰基-3-[2-(4-嘧啶-2-基哌
嗪-1-基)乙基]噻吩并[2，3-d]嘧啶-4-酮×2HCl×4H2O，熔点
180-182℃(分解)10. 3，4-二氢-5-甲基-6-二甲基氨基甲酰基-3-[2-(4-吡啶-2-基哌
嗪-1-基)乙基]噻吩并[2，3-d]嘧啶-4-酮11. 3，4-二氢-5-甲基-6-二甲基氨基甲酰基-3-[2-(4-喹啉-2-基哌
嗪-1-基)乙基]噻吩并[2，3-d]嘧啶-4-酮12. 3，4-二氢-5-甲基-6-二甲基氨基甲酰基-3-[2-(4-(3，5-二氯
苯基)哌嗪-1-基)乙基]噻吩并[2，3-d]嘧啶-4-酮13. 3，4-二氢-5-甲基-6-二甲基氨基甲酰基-3-[2-(4-四氢化萘-5-
基哌嗪-1-基)乙基]噻吩并[2，3-d]嘧啶-4-酮，熔点174℃14. 3，4-二氢-5-甲基-6-二甲基氨基甲酰基-3-[2-(4-(2，3-二氢
茚)-4-基哌嗪-1-基)乙基]噻吩并[2，3-d]嘧啶-4-酮，熔点153
℃15. 3，4-二氢-5-甲基-6-二甲基氨基甲酰基-3-[2-(4-(2-氰基苯基)
哌嗪-1-基)乙基]噻吩并[2，3-d]嘧啶-4-酮，熔点210℃(盐酸
盐)16. 3，4-二氢-5-甲基-6-二甲基氨基甲酰基-3-[2-(4-异喹啉-4-基
哌嗪-1-基)乙基]噻吩并[2，3-d]嘧啶-4-酮17. 3，4-二氢-5-甲基-6-二甲基氨基甲酰基-3-[3-(4-嘧啶-2-基哌
嗪-1-基)丙基]噻吩并[2，3-d]嘧啶-4-酮×2HCl×2H2O，熔点
209-211℃(分解)18. 3，4-二氢-5-甲基-6-二甲基氨基甲酰基-3-[2-(4-(2-甲氧基苯
基)哌啶-1-基)乙基]噻吩并[2，3-d]嘧啶-4-酮19. 3，4-二氢-5-甲基-6-二甲基氨基甲酰基-3-[2-(4-(2-甲氧基苯
基)-3，4-二氢哌啶-1-基)乙基]噻吩并[2，3-d]嘧啶-4-酮20. 3，4-二氢-5-甲基-6-二甲基氨基甲酰基-3-[2-(4-萘-1-基哌啶
-1-基)乙基]噻吩并[2，3-d]嘧啶-4-酮21. 3，4-二氢-5-甲基-6-二甲基氨基甲酰基-3-[2-(4-(2-甲氧基萘
-1-基)-3，4-脱氢哌啶-1-基)乙基]噻吩并[2，3-d]嘧啶-4-酮22. 3，4-二氢-5-甲基-6-二甲基氨基甲酰基-3-[2-(4-萘-1-基-1，
4-六氢-1，4-二氮杂-1-基)乙基]噻吩并[2，3-d]嘧啶-4-酮，
熔点225-230℃(盐酸盐)23. 3，4-二氢-5-甲基-6-氨基甲酰基-3-[2-(4-(1-萘基)哌嗪-1-基)
乙基]噻吩并[2，3-d]嘧啶-4-酮24. 3，4-二氢-5-甲基-6-氨基甲酰基-3-[2-(4-嘧啶-2-基哌嗪-1-
基)乙基]噻吩并[2，3-d]嘧啶-4-酮25. 3，4-二氢-5-甲基-6-二乙基氨基甲酰基-3-[2-(4-(2-甲氧基苯
基)哌嗪-1-基)乙基]噻吩并[2，3-d]嘧啶-4-酮26. 3，4-二氢-5-甲基-6-二乙基氨基甲酰基-3-[2-(4-(1-萘基)哌
嗪-1-基)乙基]噻吩并[2，3-d]嘧啶-4-酮27. 3，4-二氢-5-甲基-6-二乙基氨基甲酰基-3-[2-(4-嘧啶-2-基哌
嗪-1-基)乙基]噻吩并[2，3-d]嘧啶-4-酮28. 3，4-二氢-5-甲基-6-二甲基氨基甲酰基-3-[2-(4-喹唑啉-4-基
哌嗪-1-基)乙基]噻吩并[2，3-d]嘧啶-4-酮，熔点295-300℃(盐
酸盐)29. 3，4-二氢-5-甲基-6-二甲基氨基甲酰基-3-[2-(4-(2，4-二甲
氧基苯基)哌嗪-1-基)乙基]噻吩并[2，3-d]嘧啶-4-酮，熔点
170-171℃30. 3，4-二氢-5-甲基-6-二甲基氨基甲酰基-3-[2-(4-(2，5-二甲
基苯基)哌嗪-1-基)乙基]噻吩并[2，3-d]嘧啶-4-酮，熔点90-
91℃31. 3，4-二氢-5-甲基-6-二甲基氨基甲酰基-3-[2-(4-萘-1-基-3，4-
脱氢哌啶-1-基)乙基]噻吩并[2，3-d]嘧啶-4-酮，MS：m+＝509.1。
Claims (6)
1.通式I的3-取代的3，4-二氢噻吩并[2，3-d]-嘧啶衍生物和其生理学可接受的盐，
其中
R1和R2 是氢原子或C1-C4-烷基，
R3 是未取代的或被卤素原子、C1-C4-烷基、三氟甲基、三氟甲氧基、羟基、C1-C4-烷氧基、氨基、一甲基氨基、二甲基氨基、氰基或硝基一或二取代的苯基、吡啶基、嘧啶基或吡嗪基，这些基团可以任选地与一个未取代的或被卤素原子、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的并可任选地含有1个氮原子的苯核稠合，或与含有1-2个氧原子的5-或6-员环稠合，
A 是NH或氧原子，
Y 是CH2、CH2-CH2、CH2-CH2-CH2或CH2-CH，
Z 是氮原子、碳原子或CH，Y和Z之间的键也可以是双键，
和
n 是2、3或4。
2.权利要求1的化合物，其中
R1和R2 是甲基，
R3 是邻甲氧基苯基、1-萘基、2-甲氧基-1-萘基、2-甲基-1-萘基，
A 是氧原子，
Y 是CH2-CH2，
Z 是氮原子，
和
n 是2和3。
3.权利要求1-2的化合物用于制备药品的用途。
4.权利要求3的用途，用于治疗抑郁症和相关失调。
5.权利要求1-2的化合物作为5HT1B和5HT1A选择性拮抗剂的用途。
6.权利要求5的用途，其中选择性血清素拮抗作用通过抑制血清素再吸收来实现。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19724980.9 | 1997-06-13 | ||
| DE19724980A DE19724980A1 (de) | 1997-06-13 | 1997-06-13 | 3-Substituierte 3,4-Dihydro-thieno[2,3-d]pyrimidin-Derivate, ihre Herstellung und Verwendung |
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| EP (1) | EP0988306B1 (zh) |
| JP (1) | JP2002504103A (zh) |
| KR (1) | KR20010013696A (zh) |
| CN (1) | CN1260797A (zh) |
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| AT (1) | ATE244720T1 (zh) |
| AU (1) | AU749320B2 (zh) |
| BG (1) | BG103900A (zh) |
| BR (1) | BR9810017A (zh) |
| CA (1) | CA2293816A1 (zh) |
| CO (1) | CO4940507A1 (zh) |
| CZ (1) | CZ290464B6 (zh) |
| DE (2) | DE19724980A1 (zh) |
| HR (1) | HRP980319A2 (zh) |
| HU (1) | HUP0002902A3 (zh) |
| ID (1) | ID23421A (zh) |
| IL (1) | IL132967A0 (zh) |
| NO (1) | NO996043D0 (zh) |
| NZ (1) | NZ502238A (zh) |
| PL (1) | PL337453A1 (zh) |
| SK (1) | SK168499A3 (zh) |
| TR (1) | TR199903062T2 (zh) |
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| BR9813279B1 (pt) * | 1997-10-27 | 2010-11-16 | derivado de homopiperazina, composição farmacêutica, e, uso do derivado de homopiperazina. | |
| DE19900545A1 (de) | 1999-01-11 | 2000-07-13 | Basf Ag | Verwendung von Pyrimidinderivaten zur Prophylaxe und Therapie der zerebralen Ischämie |
| WO2001064683A1 (fr) * | 2000-02-29 | 2001-09-07 | Takeda Chemical Industries, Ltd. | Procedes de production de derives de thienopyramidine |
| DE10031389A1 (de) * | 2000-07-03 | 2002-01-17 | Knoll Ag | Pyrimidinderivate und ihre Verwendung zur Prophylaxe und Therapie der zerebralen Ischämie |
| 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 |
| US7612078B2 (en) * | 2003-03-31 | 2009-11-03 | Epix Delaware, Inc. | Piperidinylamino-thieno[2,3-D] pyrimidine compounds |
| US20050222175A1 (en) * | 2004-03-31 | 2005-10-06 | Dhanoa Dale S | New piperidinylamino-thieno[2,3-D] pyrimidine compounds |
| CN1777612A (zh) * | 2003-03-31 | 2006-05-24 | 普雷迪克医药品控股公司 | 新的哌啶基氨基－噻吩并[2,3－d]嘧啶化合物 |
| 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 |
| US8349850B2 (en) | 2006-03-28 | 2013-01-08 | Atir Holding S.A. | Heterocyclic compounds and uses thereof in the treatment of sexual disorders |
| EP2896624B1 (en) * | 2007-03-28 | 2016-07-13 | Atir Holding S.A. | Heterotricyclic compounds as serotonergic and/or dopaminergic agents and uses thereof |
| CA2685753A1 (en) * | 2007-05-09 | 2008-11-20 | Neuromed Pharmaceuticals Ltd. | Bicyclic pyrimidine derivatives as calcium channel blockers |
| EP2445877B1 (en) * | 2008-12-03 | 2014-07-23 | Nanotherapeutics, Inc. | Bicyclic compounds and methods of making and using same |
| JP5722781B2 (ja) * | 2009-08-26 | 2015-05-27 | 武田薬品工業株式会社 | 縮合複素環誘導体およびその用途 |
| WO2012140642A1 (en) | 2011-04-10 | 2012-10-18 | Atir Holding S.A. | Heterocyclic compounds and uses thereof in the treatment of sexual disorders |
| US9671052B2 (en) | 2015-10-27 | 2017-06-06 | Whirlpool Corporation | Collet securing device for joining two fluid lines and providing lateral support at the connection of the two fluid lines |
| US10557469B2 (en) | 2016-03-22 | 2020-02-11 | Whirlpool Corporation | Multi-outlet fluid flow system for an appliance incorporating a bi-directional motor |
| US10655266B2 (en) | 2016-11-30 | 2020-05-19 | Whirlpool Corporation | Lint processing fluid pump for a laundry appliance |
| US10662574B2 (en) | 2017-02-27 | 2020-05-26 | Whirlpool Corporation | Self cleaning heater exchanger plate |
| US10480117B2 (en) | 2017-02-27 | 2019-11-19 | Whirlpool Corporation | Self cleaning sump cover |
| US10619289B2 (en) | 2017-02-27 | 2020-04-14 | Whirlpool Corporation | Self cleaning diverter valve |
| US10634412B2 (en) | 2017-04-10 | 2020-04-28 | Whirlpool Corporation | Concealed upstream air tower guide vanes |
| WO2020183011A1 (en) | 2019-03-14 | 2020-09-17 | Institut Curie | Htr1d inhibitors and uses thereof in the treatment of cancer |
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| 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 |
| DE19636769A1 (de) * | 1996-09-10 | 1998-03-12 | Basf Ag | 3-Substituierte Pyrido [4',3':4,5]thieno[2,3-d]pyrimidin-Derivate, ihre Herstellung und Verwendung |
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- 1997-06-13 DE DE19724980A patent/DE19724980A1/de not_active Withdrawn
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- 1998-05-28 ID IDW991496A patent/ID23421A/id unknown
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- 1998-05-29 US US09/445,222 patent/US6159962A/en not_active Expired - Lifetime
- 1998-05-29 CZ CZ19994431A patent/CZ290464B6/cs not_active IP Right Cessation
- 1998-05-29 WO PCT/EP1998/003230 patent/WO1998056792A1/de active IP Right Grant
- 1998-05-29 CN CN98806146A patent/CN1260797A/zh active Pending
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- 1998-05-29 KR KR1019997011711A patent/KR20010013696A/ko not_active Application Discontinuation
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- 1998-05-29 DE DE59808992T patent/DE59808992D1/de not_active Expired - Fee Related
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Also Published As
| Publication number | Publication date |
|---|---|
| CO4940507A1 (es) | 2000-07-24 |
| CA2293816A1 (en) | 1998-12-17 |
| EP0988306A1 (de) | 2000-03-29 |
| JP2002504103A (ja) | 2002-02-05 |
| PL337453A1 (en) | 2000-08-14 |
| AU7917698A (en) | 1998-12-30 |
| ATE244720T1 (de) | 2003-07-15 |
| HUP0002902A3 (en) | 2002-09-30 |
| BG103900A (en) | 2000-06-30 |
| SK168499A3 (en) | 2000-05-16 |
| ID23421A (id) | 2000-04-20 |
| CZ443199A3 (cs) | 2000-06-14 |
| DE19724980A1 (de) | 1998-12-17 |
| HRP980319A2 (en) | 1999-04-30 |
| AU749320B2 (en) | 2002-06-20 |
| NO996043L (no) | 1999-12-08 |
| DE59808992D1 (de) | 2003-08-14 |
| BR9810017A (pt) | 2000-09-19 |
| EP0988306B1 (de) | 2003-07-09 |
| HUP0002902A2 (hu) | 2001-02-28 |
| US6159962A (en) | 2000-12-12 |
| CZ290464B6 (cs) | 2002-07-17 |
| TR199903062T2 (xx) | 2000-06-21 |
| KR20010013696A (ko) | 2001-02-26 |
| NZ502238A (en) | 2001-02-23 |
| IL132967A0 (en) | 2001-03-19 |
| ZA985121B (en) | 1999-12-13 |
| WO1998056792A1 (de) | 1998-12-17 |
| NO996043D0 (no) | 1999-12-08 |
| AR015712A1 (es) | 2001-05-16 |
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