CN1474693A - 噻吩并嘧啶的应用 - Google Patents
噻吩并嘧啶的应用 Download PDFInfo
- Publication number
- CN1474693A CN1474693A CNA018191800A CN01819180A CN1474693A CN 1474693 A CN1474693 A CN 1474693A CN A018191800 A CNA018191800 A CN A018191800A CN 01819180 A CN01819180 A CN 01819180A CN 1474693 A CN1474693 A CN 1474693A
- Authority
- CN
- China
- Prior art keywords
- pyrimidine
- base
- chloro
- benzyl amino
- benzothiophene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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Abstract
式I的化合物及其生理上可接受的盐供制备治疗咽痛、高血压、高肺压、充血性心力衰竭、动脉粥样硬化、心血管开放减少的情况、外周血管疾病、中风、支气管炎、变应性哮喘、慢性哮喘、变应性鼻炎、青光眼、过敏性肠综合征、瘤、肾功能不全、肝硬化的药物以及治疗雌性动物性病的药物的应用,其中R1、R2、R3、X和n的含义如权利要求1中所定义。
Description
R1和R2各自彼此独立地是H、A或Hal,其中R1或R2中基团之一总是≠H,
R1和R2或者一起是具有3-5个碳原子的亚烷基,
R3和R4各自彼此独立地是H、A、OA、OH或Hal,
R3和R4或者一起是具有3-5个碳原子的亚烷基、-O-CH2-CH2-、-O-CH2-O-或-O-CH2-CH2-O-,
X是R5或R6,其可以被R7所单取代,
R5是具有1-10个碳原子的直链或支链亚烷基,其中一个或两个CH2基团可以被-CH=CH-基团所取代,或可以是-C6H4-(CH2)m-,
R6是具有6-12个碳原子的环烷基亚烷基,
R7是COOH、COOA、CONH2、CONHA、CON(A)2或CN,
A是具有1至6个碳原子的烷基,
Hal是F、Cl、Br或I,
m是1或2,
和
n是0、1、2或3,
其中所说的药物是用于治疗咽痛、高血压、高肺压、充血性心力衰竭、动脉粥样硬化、心血管开放减少的情况、外周血管疾病、中风、支气管炎、变应性哮喘、慢性哮喘、变应性鼻炎、青光眼、过敏性肠综合征、瘤、肾功能不全、肝硬化的药物和用于治疗雌性动物性病的药物。
嘧啶衍生物已经被公开,例如在EP 201 188或WO 93/06104中。其它PDE-V抑制剂的应用在例如WO 94/28902中进行了描述。
本发明的目的是发现具有有价值性质的新型化合物,尤其是可用于制备药物的这些新型化合物。
已经发现式I的化合物以及它们的盐具有非常有价值的药理学性质并且具有良好的耐受性。
它们特别是对cGMP磷酸二酯酶(PDE V)表现出了特定的抑制作用。
具有cGMP-磷酸二酯酶抑制活性的喹唑啉类在例如J.Med.Chem.36,3765(1993)和ibid.
37,2106(1994)中进行了描述。
式I的化合物的生理活性可以用例如WO 93/06104中所描述的方法测定。本发明的化合物与cGMP和cAMP磷酸二酯酶的亲合力是通过测定它们的IC50值(酶的活性被抑制50%时所需抑制剂的浓度)来测定的。
这种测定可以使用用已知方法所分离出来的酶进行(例如W.J.Thompson等人,Biochem.1971,
10,311)。该实验可以用经过一些修改的W.J.Thompson和M.M.Appleman的间歇法来进行(Biochem.1979,
18,5228)。
因此,该化合物适于治疗心血管系统的疾病,尤其是心肌机能不全,并且还适用于阳痿(勃起机能障碍)的处理和/或治疗。
已经描述了取代的吡唑并嘧啶酮用于治疗雌性动物性病的应用,例如在WO 94/28902中。
该化合物可以有效地作为兔海绵体(corpus cavernosum)制剂中脱羟肾上腺素-诱导的挛缩的抑制剂。这种生物学作用可以通过例如F.Holmquist等人在J.Urol.,
150,1310-1315(1993)中所描述的方法来证明。
这种对萎缩的抑制作用证明了本发明的化合物在治疗和/或处理阳痿方面的有效性。
本发明涉及式I的化合物以及它们生理上可接受的盐和/或溶剂化物在制备治疗咽痛、高血压、高肺压、充血性心力衰竭、动脉粥样硬化、心血管开放减少的情况、外周血管疾病、中风、支气管炎、变应性哮喘、慢性哮喘、变应性鼻炎、青光眼、过敏性肠综合征、瘤、肾功能不全、肝硬化的药物以及治疗雌性动物性病的药物中的应用。
本发明特别涉及式I的化合物以及它们生理上可接受的盐和/或溶剂化物用于制备治疗高肺压药物的应用。
本发明优选地涉及5-[4-(3-氯-4-甲氧基-苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]戊酸及其生理上可接受的盐和/或溶剂化物用于制备治疗高肺压药物的应用。特别优选其乙醇胺盐或钠盐。
式I的化合物可被用作人和兽医药物中的药物活性成分。它们还可以被用作制备另外的药物活性成分的中间体。
因此,本发明涉及如权利要求1所述的式I的化合物及其盐以及制备式I的化合物及其盐的方法,其特征在于
a)将一种式II的化合物与式III的化合物进行反应,其中式
其中
R1、R2和X的定义同上,
并且L是Cl、Br、OH、SCH3或一种反应性的酯化的OH基团。
其中
R3、R4和n的定义同上,
或
b)将式I的化合物中的基团X转化成另一种基团X,例如可以通过将一个酯基水解成COOH基团或将一个COOH基团转化成酰胺或氰基,和/或将式I的化合物转化成它的一种盐。
除非另有明确说明,在上文和下文中,基团R1、R2、R3、R4、R5、R6、R7、X、L和n如式I、II和III中所定义。
A是具有1-6个碳原子的烷基。
在上式中,烷基优选的是直链烷基并且具有1、2、3、4、5或6个碳原子并且优选地是甲基、乙基或丙基,此外还优选异丙基、丁基、异丁基、仲-丁基或叔-丁基,但也可以是正-戊基、新戊基、异戊基或己基。
X是被R7单取代的R5或R6基团。
R5是具有1-10个碳原子,优选1-8个碳原子的直链或支链亚烷基,其中所说的亚烷基优选例如亚甲基、亚乙基、亚丙基、异亚丙基、亚丁基、异亚丁基、仲-亚丁基、亚戊基、1-、2-或3-甲基亚丁基、1,1-、1,2-或2,2-二甲基亚丙基、1-乙基亚丙基、亚己基、1-、2-、3-或4-甲基亚戊基、1,1-、1,2-、1,3-、2,2-、2,3-或3,3-二甲基亚丁基、1-或2-乙基亚丁基、1-乙基-1-甲基亚丙基、1-乙基-2-甲基亚丙基、1,1,2-或1,2,2-三甲基亚丙基、直链或支链亚庚基、亚辛基、亚壬基或亚癸基。
R5还可以是例如亚丁-2-烯基或亚己-3-烯基。
R6是具有6-12个碳原子的环烷基亚烷基,优选例如,环戊基亚甲基、环己基亚甲基、环己基亚乙基,环己基亚丙基或环己基亚丁基。
R1和R2基团中的一个优选地是H,而另一个优选地是丙基或丁基,但是特别优选乙基或甲基。此外,R1和R2还优选地一起是亚丙基、亚丁基或亚戊基。
Hal优选F、Cl或Br,但是也可以是I。
R3和R4可以是相同或不同的基团,并且优选位于该苯环的3-或4-位上。它们在每种情况中彼此独立是例如H、烷基、F、Cl、Br或I或一起是亚烷基,如,例如亚丙基、亚丁基或亚戊基,还可以是乙烯氧基、亚甲二氧基或亚乙二氧基。它们在各种情况中还优选烷氧基,例如甲氧基、乙氧基或丙氧基,此外还可以是羟基。
R7优选例如COOH、COOCH3、COOC2H5,CONH2,CON(CH3)2,CONHCH3或CN。
对于整个本发明而言,出现一次以上的所有基团可以是相同或不同的,即是彼此独立的。
因此,本发明特别涉及其中至少一个所说的基团具有一种上述优选含义的式I的化合物。化合物的一些优选基团可以用如下的子式Ia至Id来表示,这些化合物与式I相符并且其中没有更详细的指定的基团的含义同式I中的定义相同,只是其中在Ia中X 是被COOH或COOA取代的R5或R6;在Ib中R1和R2 彼此独立地各自是H、A或Hal,其中R1或R2
中的至少一个总是≠H,
R3和R4 一起是具有3-5个碳原子的亚烷基、-O-CH2-CH2-
、-O-CH2-O-或-O-CH2-CH2-O,
X 是被COOH或COOA取代的R5或R6;在Ic中R1和R2 彼此独立地各自是H、A或Hal,其中R1或R2
中的至少一个总是≠H,
R3和R4 彼此独立地各自是H、A、OA或Hal,
R3和R4 一起是具有3-5个碳原子的亚烷基、-O-CH2-CH2-
、-O-CH2-O-或-O-CH2-CH2-O,
X 是被COOH或COOA取代的R5或R6,
n 是1或2;在Id中R1和R2 彼此独立地各自是H、A或Hal,其中R1和R2
中的至少一个总是≠H,
R1和R2 一起是具有3-5个碳原子的亚烷基,
R3和R4 彼此独立地各自是H、A、OA、OH或Hal,
R3和R4 一起选择性地是-O-CH2-O-,
X 是被R7取代的R5,
R5 是具有1-10个碳原子的直链或支链亚烷基、
或-C6H4-CH2-,
R7 是COOH或COOA,
A 是具有1至6个碳原子的烷基,
Hal 是F、Cl、Br或I,
m 是1,和
n 是1或2。
此外,式I的化合物以及用于其制备的起始材料可以用已知的方法制备,如用在文献中所描述的方法制备(例如在权威著作中的方法,如Houben-Weyl,Methoden der organischen Chemie[有机化学的方法],Georg-Thieme-Verlag,Stuttgart),确切地讲是在已知的并适用于所说反应的反应条件下来完成的。还可以对其进行一些本身已知的改变来进行应用,但是在这里不对其进行详细的说明。
在式II或III的化合物中,R1、R2、R3、R4、X和n具有已经表明的定义,特别是具有已经指出的优选的含义。
如果L是活性的酯化的OH基团,则其优选地是具有1-6个碳原子的烷基磺酰氧(优选甲基磺酰氧)或具有6-10个碳原子的芳基磺酰氧(优选苯基-或对-甲苯基磺酰氧,此外还可以是2-萘磺酰氧)。
式I的化合物优选地可以通过将式II的化合物与式III的化合物反应来获得。
如果需要的话,还可就地形成起始物质,不需要将其从该反应混合物中分离出来,而是可以立即将其进一步转化成式I的化合物。
另一方面,可逐步进行该反应。
式II和III的起始化合物一般是已知的。如果它们是未知的,则它们可以用本身已知的方法来制备。例如,可以由噻吩衍生物和CN-取代的亚烷基羧酸酯生成的化合物通过与POCl3反应来获得式II的化合物(Eur.J.Med.Chem.
23,453(1988))。
详细地说,式II的化合物与式III的化合物的反应可以在存或不存在惰性溶剂的条件下,在约-20至约150°,优选20至100°的温度下来进行。
可以优选地加入酸结合剂或有机碱或过量的胺组分,其中所说的酸结合剂例如碱金属或碱土金属氢氧化物、碳酸盐或碳酸氢盐或碱金属或碱土金属的弱酸的另外的盐,其中所说的碱金属或碱土金属优选钾、钠或钙,其中所说的有机碱如三乙胺、二甲胺、吡啶或喹啉。
适宜的惰性溶剂的实例有烃类,如己烷、石油醚、苯、甲苯或二甲苯;氯化烃,如三氯乙烯、1,2-二氯乙烷、四氯化碳、氯仿或二氯甲烷;醇,如甲醇、乙醇、异丙醇、正-丙醇、正-丁醇或叔-丁醇;醚,如乙醚、二异丙醚、四氢呋喃(THF)或二噁烷;乙二醇醚,如乙二醇一甲醚或一乙醚或乙二醇二甲醚(二甘醇二甲醚);酮,如丙酮或丁酮;酰胺,如乙酰胺、二甲基乙酰胺、N-甲基吡咯烷酮或二甲基甲酰胺(DMF);腈,如乙腈;亚砜,如二甲基亚砜(DMSO);硝基化合物,如硝基甲烷或硝基苯;酯,如乙酸乙酯,或所说溶剂的混合物。
此外,还可将式I的化合物中的基团X转化成另一种基团X,例如通过将酯或氰基水解而得到COOH基团。
酯基可以被皂化,例如用NaOH或KOH,在水、水/THF或水/二噁烷中,在0至100°之间的温度下进行皂化。
羧酸可以被转化成相应的羧酸氯化物,例如可用亚硫酰氯来进行转化,并且其可被转化成酰胺。从其中以已知的方法消除水就得到了腈。
可以用碱将式I的酸转化成缔合的酸加成盐,例如可通过在惰性溶剂如乙醇中将等当量的该酸与碱反应,然后进行蒸发来进行。用于这种反应的适宜的碱特别是那些能形成生理上可接受的盐的碱。
因此,式I的酸可以被转化成相应的金属盐,特别是碱金属或碱土金属盐,或可用碱(例如氢氧化钠、氢氧化钾、碳酸钠或碳酸钾)将式I的酸转化成相应的铵盐。
适用于这种反应的碱还特别是可给出生理上可接受盐的有机碱,例如乙醇胺。
另一方面,可以用酸将式I的碱转化成缔合的酸加成盐,例如可通过在惰性溶剂如乙醇中将等当量的碱与酸反应,然后蒸发来进行。可用于这种反应的适宜的酸特别是那些能给出生理上可接受的盐的酸。因此,可使用无机酸,例如硫酸、硝酸、氢卤酸如盐酸或氢溴酸、磷酸如正磷酸、或氨基磺酸,此外,还可以使用有机酸,特别是脂肪族、脂环族、芳基脂肪族(araliphatic)、芳香族或杂环族一元或多元羧酸、磺酸或硫酸,例如甲酸、醋酸、丙酸、新戊酸、二乙基乙酸、丙二酸、丁二酸、庚二酸、富马酸、马来酸、乳酸、酒石酸、苹果酸、枸橼酸、葡萄糖酸、抗坏血酸、烟酸、异烟酸、甲磺酸或乙烷磺酸、乙烷二磺酸、2-羟基乙烷磺酸、苯磺酸、对-甲苯磺酸、萘单-和二-磺酸、或十二烷基硫酸。生理上可接受的酸的盐,例如苦味酸盐可被用于式I化合物的分离和/或纯化。
本发明还涉及式I的化合物和/或其生理上可接受的盐用于制备药物制剂的应用,特别是通过非化学的方法制备药物制剂的应用。它们可以被转化成适宜的剂量形式,在所说的剂量形式中同时有至少一种固态、液态和/或半液态的赋形剂或助剂并且可与一种或多种另外的活性组分相结合或不与之相结合。
本发明还涉及作为磷酸二酯酶V抑制剂的式I的化合物及其生理上可接受的盐的药物。
此外,本发明还涉及包含至少一种式I的化合物和/或一种其生理上可接受的盐的药物制剂。
这些制剂可被用作人或兽医药中的药物。适宜的赋形剂是适于肠内给药(例如口服)、非肠道给药或局部给药并且不与该新型化合物起反应的有机或无机物质,例如水、植物油、苯甲醇、烷撑二醇、聚乙二醇、甘油三醋酸酯、明胶、碳水化合物,如乳糖或淀粉、硬脂酸镁、滑石粉或凡士林。适于口服的特别是片剂、丸剂、包衣的片剂、胶囊、粉末、颗粒、糖浆、汁或滴剂,适于直肠给药的有栓剂,适于非肠道给药的有溶液,优选以油为基础的溶液或水溶液,此外还可以是混悬液、乳剂或植入物,适于局部应用的有软膏、乳膏或粉末。该新型的化合物还可以被冷冻干燥,所得的冷冻干燥物可用于例如制备注射剂。所说的制剂可是无菌的和/或可包含助剂,如润滑剂、防腐剂、稳定剂和/或润湿剂、乳化剂、用于改变渗透压的盐、缓冲物质、着色剂和调味剂和/或一些其它活性成分,例如一种或多种维生素。
可以使用式I的化合物及其生理上可接受的盐来抵抗疾病,在这类应用中cGMP(环鸟苷一磷酸)的水平增加从而可抑制或预防炎症并且还可产生肌肉松弛作用。本发明的化合物特别可用于治疗心血管系统的疾病以及用于阳痿的处理和/或治疗。
一般而言,该物质的给药剂量一般在约1至500mg之间,特别是每剂量单位在5至100mg之间。日剂量优选地为约0.02至10mg/kg体重。但是,各个病人的特定剂量取决于许多因素,例如所用特定化合物的效力、患者的年龄、体重、健康的一般状况、性别、饮食、给药的时间和方法、排泄速率、药物结合以及所治疗特定疾病的严重程度。优选口服给药。
在上文和下文中,所给出的所有温度的单位都是℃。在下面的实施例中,“常规处理”指的是如果需要的话加入水,然后根据最终产物的组成,将pH设定为2至10,如果需要的话,将该混合物用乙酸乙酯或二氯甲烷萃取,将各相分离,将有机相在硫酸钠上干燥,然后蒸发,将产物用硅胶色谱法或通过结晶来进行纯化。
质谱法(MS):EI(电子碰撞离子化)M+
FAB(快原子轰击)(M+H)+
实施例1
将1.9g的3-(4-氯-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)丙酸甲酯[由2-氨基-4,5,6,7-四氢苯并噻吩-3-羧酸甲酯与3-氰基丙酸甲酯环化,然后用磷酰氯/二甲胺氯化来获得]和2.3g的3-氯-4-甲氧基苄胺(“A”)在20ml N-甲基吡咯烷酮中在110°下搅拌5小时。除去溶剂,然后将混合物进行常规处理,得到2.6g无色油状的3-[4-(3-氯-4-甲氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丙酸甲酯。
“A”的类似反应
与3-(4-氯-5,6-环戊烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)丙酸甲酯反应,得到
3-[4-(3-氯-4-甲氧基苄基氨基)-5,6-环戊烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丙酸甲酯;
与3-(4-氯-5,6-环庚烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)丙酸甲酯反应,得到
3-[4-(3-氯-4-甲氧基苄基氨基)-5,6-环庚烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丙酸甲酯;
与3-(4-氯-6-甲基噻吩并-[2,3-d]-嘧啶-2-基)丙酸甲酯反应,得到
3-[4-(3-氯-4-甲氧基苄基氨基)-6-甲基噻吩并-[2,3-d]-嘧啶-2-基]丙酸甲酯;
与3-(4-氯-5,6-二甲基噻吩并-[2,3-d]-嘧啶-2-基)丙酸甲酯反应,得到
3-[4-(3-氯-4-甲氧基苄基氨基)-5,6-二甲基噻吩并-[2,3-d]-嘧啶-2-基]丙酸甲酯;
与3-(4-氯-6-乙基噻吩并-[2,3-d]-嘧啶-2-基)丙酸甲酯反应,得到
3-[4-(3-氯-4-甲氧基苄基氨基)-6-乙基噻吩并-[2,3-d]-嘧啶-2-基]丙酸甲酯;
与3-(4,6-二氯噻吩并-[2,3-d]-嘧啶-2-基)丙酸甲酯反应,得到
3-[4-(3-氯-4-甲氧基苄基氨基)-6-氯噻吩并-[2,3-d]-嘧啶-2-基]丙酸甲酯;
与2-(4-氯-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)醋酸甲酯反应,得到
2-[4-(3-氯-4-甲氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]醋酸甲酯。
3,4-亚甲二氧基苄胺的类似反应
与3-(4-氯-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)丙酸甲酯反应,得到
3-[4-(3,4-亚甲二氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丙酸甲酯;
与3-(4-氯-5,6-环戊烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)丙酸甲酯反应,得到
3-[4-(3,4-亚甲二氧基苄基氨基)-5,6-环戊烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丙酸甲酯;
与3-(4-氯-5,6-环庚烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)丙酸甲酯反应,得到
3-[4-(3,4-亚甲二氧基苄基氨基)-5,6-环庚烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丙酸甲酯;
与3-(4-氯-6-甲基噻吩并-[2,3-d]-嘧啶-2-基)丙酸甲酯反应,得到
3-[4-(3,4-亚甲二氧基苄基氨基)-6-甲基噻吩并-[2,3-d]-嘧啶-2-基]丙酸甲酯;
与3-(4-氯-5,6-二甲基噻吩并-[2,3-d]-嘧啶-2-基)丙酸甲酯反应,得到
3-[4-(3,4-亚甲二氧基苄基氨基)-5,6-二甲基噻吩并-[2,3-d]-嘧啶-2-基]丙酸甲酯;
与3-(4-氯-6-乙基噻吩并-[2,3-d]-嘧啶-2-基)丙酸甲酯反应,得到
3-[4-(3,4-亚甲二氧基苄基氨基)-6-乙基噻吩并-[2,3-d]-嘧啶-2-基]丙酸甲酯;
与3-(4,6-二氯噻吩并-[2,3-d]-嘧啶-2-基)丙酸甲酯反应,得到
3-[4-(3,4-亚甲二氧基苄基氨基)-6-氯噻吩并-[2,3-d]-嘧啶-2-基]丙酸甲酯。
“A”的类似反应
与4-(4-氯-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)丁酸甲酯反应,得到
4-[4-(3-氯-4-甲氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丁酸甲酯;
与4-(4-氯-5,6-环戊烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)丁酸甲酯反应,得到
4-[4-(3-氯-4-甲氧基苄基氨基)-5,6-环戊烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丁酸甲酯;
与4-(4-氯-5,6-环庚烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)丁酸甲酯反应,得到
4-[4-(3-氯-4-甲氧基苄基氨基)-5,6-环庚烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丁酸甲酯;
与4-(4-氯-6-甲基噻吩并-[2,3-d]-嘧啶-2-基)丁酸甲酯反应,得到
4-[4-(3-氯-4-甲氧基苄基氨基)-6-甲基噻吩并-[2,3-d]-嘧啶-2-基]丁酸甲酯;
与4-(4-氯-5,6-二甲基噻吩并-[2,3-d]-嘧啶-2-基)丁酸甲酯反应,得到
4-[4-(3-氯-4-甲氧基苄基氨基)-5,6-二甲基噻吩并-[2,3-d]-嘧啶-2-基]丁酸甲酯;
与4-(4-氯-6-乙基噻吩并-[2,3-d]-嘧啶-2-基)丁酸甲酯反应,得到
4-[4-(3-氯-4-甲氧基苄基氨基)-6-乙基噻吩并-[2,3-d]-嘧啶-2-基]丁酸甲酯;
与4-(4,6-氯-6-氯噻吩并-[2,3-d]-嘧啶-2-基)丁酸甲酯反应,得到
4-[4-(3-氯-4-甲氧基苄基氨基)-6-氯噻吩并-[2,3-d]-嘧啶-2-基]丁酸甲酯。
3,4-亚甲二氧基苄胺的类似反应
与4-(4-氯-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)丁酸甲酯反应,得到
4-[4-(3,4-亚甲二氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丁酸甲酯;
与4-(4-氯-5,6-环戊烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)丁酸甲酯反应,得到
4-[4-(3,4-亚甲二氧基苄基氨基)-5,6-环戊烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丁酸甲酯;
与4-(4-氯-5,6-环庚烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)丁酸甲酯反应,得到
4-[4-(3,4-亚甲二氧基苄基氨基)-5,6-环庚烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丁酸甲酯;
与4-(4-氯-6-甲基噻吩并-[2,3-d]-嘧啶-2-基)丁酸甲酯反应,得到
4-[4-(3,4-亚甲二氧基苄基氨基)-6-甲基噻吩并-[2,3-d]-嘧啶-2-基]丁酸甲酯;
与4-(4-氯-5,6-二甲基噻吩并-[2,3-d]-嘧啶-2-基)丁酸甲酯反应,得到
4-[4-(3,4-亚甲二氧基苄基氨基)-5,6-二甲基噻吩并-[2,3-d]-嘧啶-2-基]丁酸甲酯;
与4-(4-氯-6-乙基噻吩并-[2,3-d]-嘧啶-2-基)丁酸甲酯反应,得到
4-[4-(3,4-亚甲二氧基苄基氨基)-6-乙基噻吩并-[2,3-d]-嘧啶-2-基]丁酸甲酯;
与4-(4,6-二氯噻吩并-[2,3-d]-嘧啶-2-基)丁酸甲酯反应,得到
4-[4-(3,4-亚甲二氧基苄基氨基)-6-氯噻吩并-[2,3-d]-嘧啶-2-基]丁酸甲酯。
“A”的类似反应
与5-(4-氯-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)戊酸甲酯反应,得到
5-[4-(3-氯-4-甲氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]戊酸甲酯;
与5-(4-氯-5,6-环戊烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)戊酸甲酯反应,得到
5-[4-(3-氯-4-甲氧基苄基氨基)-5,6-环戊烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]戊酸甲酯;
与5-(4-氯-5,6-环庚烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)戊酸甲酯反应,得到
5-[4-(3-氯-4-甲氧基苄基氨基)-5,6-环庚烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]戊酸甲酯;
与5-(4-氯-6-甲基噻吩并-[2,3-d]-嘧啶-2-基)戊酸甲酯反应,得到
5-[4-(3-氯-4-甲氧基苄基氨基)-6-甲基噻吩并-[2,3-d]-嘧啶-2-基]戊酸甲酯;
与5-(4-氯-5,6-二甲基噻吩并-[2,3-d]-嘧啶-2-基)戊酸甲酯反应,得到
5-[4-(3-氯-4-甲氧基苄基氨基)-5,6-二甲基噻吩并-[2,3-d]-嘧啶-2-基]戊酸甲酯;
与5-(4-氯-6-乙基噻吩并-[2,3-d]-嘧啶-2-基)戊酸甲酯反应,得到
5-[4-(3-氯-4-甲氧基苄基氨基)-6-乙基噻吩并-[2,3-d]-嘧啶-2-基]戊酸甲酯;
与5-(4,6-二氯噻吩并-[2,3-d]-嘧啶-2-基)戊酸甲酯反应,得到
5-[4-(3-氯-4-甲氧基苄基氨基)-6-氯噻吩并-[2,3-d]-嘧啶-2-基]戊酸甲酯。
3,4-亚甲二氧基苄胺的类似反应
与5-(4-氯-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)戊酸甲酯反应,得到
5-[4-(3,4-亚甲二氧基-苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]戊酸甲酯;
与5-(4-氯-5,6-环戊烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)戊酸甲酯反应,得到
5-[4-(3,4-亚甲二氧基-苄基氨基)-5,6-环戊烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]戊酸甲酯;
与5-(4-氯-5,6-环庚烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)戊酸甲酯反应,得到
5-[4-(3,4-亚甲二氧基-苄基氨基)-5,6-环庚烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]戊酸甲酯;
与5-(4-氯-6-甲基噻吩并-[2,3-d]-嘧啶-2-基)戊酸甲酯反应,得到
5-[4-(3,4-亚甲二氧基苄基氨基)-6-甲基噻吩并-[2,3-d]-嘧啶-2-基]戊酸甲酯;
与5-(4-氯-5,6-二甲基噻吩并-[2,3-d]-嘧啶-2-基)戊酸甲酯反应,得到
5-[4-(3,4-亚甲二氧基苄基氨基)-5,6-二甲基噻吩并-[2,3-d]-嘧啶-2-基]戊酸甲酯;
与5-(4-氯-6-乙基噻吩并-[2,3-d]-嘧啶-2-基)戊酸甲酯反应,得到
5-[4-(3,4-亚甲二氧基苄基氨基)-6-乙基噻吩并-[2,3-d]-嘧啶-2-基]戊酸甲酯;
与5-(4,6-二氯噻吩并-[2,3-d]-嘧啶-2-基)戊酸甲酯反应,得到
5-[4-(3,4-亚甲二氧基苄基氨基)-6-氯噻吩并-[2,3-d]-嘧啶-2-基]戊酸甲酯。
“A”的类似反应
与7-(4-氯-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)庚酸甲酯反应,得到
7-[4-(3-氯-4-甲氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]庚酸甲酯;
与7-(4-氯-5,6-环戊烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)庚酸甲酯反应,得到
7-[4-(3-氯-4-甲氧基苄基氨基)-5,6-环戊烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]庚酸甲酯;
与7-(4-氯-5,6-环庚烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)庚酸甲酯反应,得到
7-[4-(3-氯-4-甲氧基苄基氨基)-5,6-环庚烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]庚酸甲酯;
与7-(4-氯-6-甲基噻吩并-[2,3-d]-嘧啶-2-基)庚酸甲酯反应,得到
7-[4-(3-氯-4-甲氧基苄基氨基)-6-甲基噻吩并-[2,3-d]-嘧啶-2-基]庚酸甲酯;
与7-(4-氯-5,6-二甲基噻吩并-[2,3-d]-嘧啶-2-基)庚酸甲酯反应,得到
7-[4-(3-氯-4-甲氧基苄基氨基)-5,6-二甲基噻吩并-[2,3-d]-嘧啶-2-基]庚酸甲酯;
与7-(4-氯-6-乙基噻吩并-[2,3-d]-嘧啶-2-基)庚酸甲酯反应,得到
7-[4-(3-氯-4-甲氧基苄基氨基)-6-乙基噻吩并-[2,3-d]-嘧啶-2-基]庚酸甲酯;
与7-(4-氯-6-氯噻吩并-[2,3-d]-嘧啶-2-基)庚酸甲酯反应,得到
7-[4-(3-氯-4-甲氧基苄基氨基)-6-氯噻吩并-[2,3-d]-嘧啶-2-基]庚酸甲酯。
3,4-亚甲二氧基苄胺的类似反应
与7-(4-氯-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)庚酸甲酯反应,得到
7-[4-(3,4-亚甲二氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]庚酸甲酯;
与7-(4-氯-5,6-环戊烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)庚酸甲酯反应,得到
7-[4-(3,4-亚甲二氧基苄基氨基)-5,6-环戊烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]庚酸甲酯;
与7-(4-氯-5,6-环庚烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)庚酸甲酯反应,得到
7-[4-(3,4-亚甲二氧基-苄基氨基)-5,6-环庚烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]庚酸甲酯;
与7-(4-氯-6-甲基噻吩并-[2,3-d]-嘧啶-2-基)庚酸甲酯反应,得到
7-[4-(3,4-亚甲二氧基苄基氨基)-6-甲基噻吩并-[2,3-d]-嘧啶-2-基]戊酸甲酯;
与7-(4-氯-5,6-二甲基噻吩并-[2,3-d]-嘧啶-2-基)庚酸甲酯反应,得到
7-[4-(3,4-亚甲二氧基苄基氨基)-5,6-二甲基噻吩并-[2,3-d]-嘧啶-2-基]庚酸甲酯;
与7-(4-氯-6-乙基噻吩并-[2,3-d]-嘧啶-2-基)-庚酸甲酯反应,得到
7-[4-(3,4-亚甲二氧基苄基氨基)-6-乙基噻吩并-[2,3-d]-嘧啶-2-基]庚酸甲酯;
与7-(4,6-二氯噻吩并-[2,3-d]-嘧啶-2-基)庚酸甲酯反应,得到
7-[4-(3,4-亚甲二氧基苄基氨基)-6-氯噻吩并-[2,3-d]-嘧啶-2-基]庚酸甲酯。
“A”的类似反应
与2-[4-(4-氯-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)-环己基-]-基]醋酸甲酯反应,得到
2-{4-[4-(3-氯-4-甲氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]-环己基-]-基}醋酸甲酯;
与2-[4-(4-氯-6-乙基噻吩并-[2,3-d]-嘧啶-2-基)-环己基-1-基]醋酸甲酯反应,得到
2-{4-[4-(3-氯-4-甲氧基苄基氨基)-6-乙基噻吩并-[2,3-d]-嘧啶-2-基]-环己基-1-基}醋酸甲酯。
3,4-亚甲二氧基苄胺的类似反应
与2-[4-(4-氯-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)-环己基-1-基]醋酸甲酯反应,得到
2-{4-[4-(3,4-亚甲二氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]-环己基-1-基}醋酸甲酯。
苄胺的类似反应
与3-(4-氯-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)丙酸甲酯反应,得到
3-(4-苄基氨基-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)丙酸甲酯;
与4-(4-氯-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)丁酸甲酯反应,得到
4-(4-苄基氨基-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)丁酸甲酯;
与5-(4-氯-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)戊酸甲酯反应,得到
5-(4-苄基氨基-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)戊酸甲酯;
与4-(4-氯-6-甲基噻吩并-[2,3-d]-嘧啶-2-基)丁酸甲酯反应,得到
4-[4-苄基氨基-6-甲基噻吩并-[2,3-d]-嘧啶-2-基]丁酸甲酯;
与5-(4-氯-6-乙基噻吩并-[2,3-d]-嘧啶-2-基)戊酸甲酯反应,得到
5-[4-苄基氨基-6-乙基噻吩并-[2,3-d]-嘧啶-2-基]戊酸甲酯。实施例2
将2.2g的3-[4-(3-氯-4-甲氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丙酸甲酯溶解于20ml的乙二醇一甲醚中,向其中加入10ml 32%的NaOH,然后将该混合物在110°下搅拌5小时。向其中加入20%的HCl,然后用二氯甲烷萃取该混合物。加入石油醚,得到2.0g 3-[4-(3-氯-4-甲氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丙酸,熔点为229°。
将沉淀出来的晶体溶解于30ml异丙醇中,并且向其中加入0.5g乙醇胺。结晶,得到1.35g 3-[4-(3-氯-4-甲氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丙酸盐,乙醇胺盐,熔点135°。
在实施例1中所列酯的类似反应可给出如下的羧酸:
3-[4-(3-氯-4-甲氧基苄基氨基)-5,6-环戊烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丙酸;
3-[4-(3-氯-4-甲氧基苄基氨基)-5,6-环庚烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丙酸;
3-[4-(3-氯-4-甲氧基苄基氨基)-6-甲基噻吩并-[2,3-d]-嘧啶-2-基]丙酸;
3-[4-(3-氯-4-甲氧基苄基氨基)-5,6-甲基噻吩并-[2,3-d]-嘧啶-2-基]丙酸;
3-[4-(3-氯-4-甲氧基苄基氨基)-6-乙基噻吩并-[2,3-d]-嘧啶-2-基]丙酸;
3-[4-(3-氯-4-甲氧基苄基氨基)-6-氯噻吩并-[2,3-d]-嘧啶-2-基]丙酸;
2-[4-(3-氯-4-甲氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]醋酸,乙醇胺盐,熔点126°;
3-[4-(3,4-亚甲二氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丙酸;
3-[4-(3,4-亚甲二氧基苄基氨基)-5,6-环戊烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丙酸;
3-[4-(3,4-亚甲二氧基苄基氨基)-5,6-环庚烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丙酸;
3-[4-(3,4-亚甲二氧基苄基氨基)-6-甲基噻吩并-[2,3-d]-嘧啶-2-基]丙酸;
3-[4-(3,4-亚甲二氧基苄基氨基)-5,6-二甲基噻吩并-[2,3-d]-嘧啶-2-基]丙酸;
3-[4-(3,4-亚甲二氧基苄基氨基)-6-乙基噻吩并-[2,3-d]-嘧啶-2-基]丙酸;
3-[4-(3,4-亚甲二氧基苄基氨基)-6-氯噻吩并-[2,3-d]-嘧啶-2-基]丙酸;
4-[4-(3-氯-4-甲氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丁酸;
4-[4-(3-氯-4-甲氧基苄基氨基)-5,6-环戊烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丁酸;
4-[4-(3-氯-4-甲氧基苄基氨基)-5,6-环庚烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丁酸;
4-[4-(3-氯-4-甲氧基苄基氨基)-6-甲基噻吩并-[2,3-d]-嘧啶-2-基]丁酸,乙醇胺盐,熔点142°;
4-[4-(3-氯-4-甲氧基苄基氨基)-5,6-甲基噻吩并-[2,3-d]-嘧啶-2-基]丁酸;
4-[4-(3-氯-4-甲氧基苄基氨基)-6-乙基噻吩并-[2,3-d]-嘧啶-2-基]丁酸,乙醇胺盐,熔点170°;
4-[4-(3-氯-4-甲氧基苄基氨基)-6-氯噻吩并-[2,3-d]-嘧啶-2-基]丁酸;
4-[4-(3,4-亚甲二氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丁酸,乙醇胺盐,熔点114°;
4-[4-(3,4-亚甲二氧基苄基氨基)-5,6-环戊烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丁酸;
4-[4-(3,4-亚甲二氧基苄基氨基)-5,6-环庚烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丁酸;
4-[4-(3,4-亚甲二氧基苄基氨基)-6-甲基噻吩并-[2,3-d]-嘧啶-2-基]丁酸,乙醇胺盐,熔点170°;
4-[4-(3,4-亚甲二氧基苄基氨基)-5,6-二甲基噻吩并-[2,3-d]-嘧啶-2-基]丁酸;
4-[4-(3,4-亚甲二氧基苄基氨基)-6-乙基噻吩并-[2,3-d]-嘧啶-2-基]丁酸;
4-[4-(3,4-亚甲二氧基苄基氨基)-6-氯噻吩并-[2,3-d]-嘧啶-2-基]丁酸;
5-[4-(3-氯-4-甲氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]戊酸,熔点165°;乙醇胺盐,熔点112°;
5-[4-(3-氯-4-甲氧基苄基氨基)-5,6-环戊烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]戊酸;
5-[4-(3-氯-4-甲氧基苄基氨基)-5,6-环庚烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]戊酸;
5-[4-(3-氨-4-甲氧基苄基氨基)-6-甲基噻吩并-[2,3-d]-嘧啶-2-基]戊酸,乙醇胺盐,熔点156°;
5-[4-(3-氯-4-甲氧基苄基氨基)-5,6-二甲基噻吩并-[2,3-d]-嘧啶-2-基]戊酸;
5-[4-(3-氯-4-甲氧基苄基氨基)-6-乙基噻吩并-[2,3-d]-嘧啶-2-基]戊酸,乙醇胺盐,熔点156°;
5-[4-(3-氯-4-甲氧基苄基氨基)-6-氯噻吩并-[2,3-d]-嘧啶-2-基]戊酸;
5-[4-(3,4-亚甲二氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]戊酸;
5-[4-(3,4-亚甲二氧基苄基氨基)-5,6-环戊烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]戊酸;
5-[4-(3,4-亚甲二氧基苄基氨基)-5,6-环庚烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]戊酸;
5-[4-(3,4-亚甲二氧基苄基氨基)-6-甲基噻吩并-[2,3-d]-嘧啶-2-基]戊酸,乙醇胺盐,熔点167°;
5-[4-(3,4-亚甲二氧基苄基氨基)-5,6-二甲基噻吩并-[2,3-d]-嘧啶-2-基]戊酸;
5-[4-(3,4-亚甲二氧基苄基氨基)-6-乙基噻吩并-[2,3-d]-嘧啶-2-基]戊酸;
5-[4-(3,4-亚甲二氧基苄基氨基)-6-氯噻吩并-[2,3-d]-嘧啶-2-基]戊酸;
7-[4-(3-氯-4-甲氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]庚酸,乙醇胺盐,熔点130°;
7-[4-(3-氯-4-甲氧基苄基氨基)-5,6-环戊烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]庚酸;
7-[4-(3-氯-4-甲氧基苄基氨基)-5,6-环庚烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]庚酸;
7-[4-(3-氯-4-甲氧基苄基氨基)-6-甲基噻吩并-[2,3-d]-嘧啶-2-基]庚酸;
7-[4-(3-氯-4-甲氧基苄基氨基)-5,6-二甲基噻吩并-[2,3-d]-嘧啶-2-基]庚酸;
7-[4-(3-氯-4-甲氧基苄基氨基)-6-乙基噻吩并-[2,3-d]-嘧啶-2-基]庚酸;
7-[4-(3-氯-4-甲氧基苄基氨基)-6-氯噻吩并-[2,3-d]-嘧啶-2-基]庚酸;
7-[4-(3,4-亚甲二氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]庚酸,乙醇胺盐,熔点137°;
7-[4-(3,4-亚甲二氧基苄基氨基)-5,6-环戊烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]庚酸;
7-[4-(3,4-亚甲二氧基苄基氨基)-5,6-环庚烯-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]庚酸;
7-[4-(3,4-亚甲二氧基苄基氨基)-6-甲基噻吩并-[2,3-d]-嘧啶-2-基]戊酸;
7-[4-(3,4-亚甲二氧基苄基氨基)-5,6-二甲基噻吩并-[2,3-d]-嘧啶-2-基]庚酸;
7-[4-(3,4-亚甲二氧基苄基氨基)-6-乙基噻吩并-[2,3-d]-嘧啶-2-基]庚酸;
7-[4-(3,4-亚甲二氧基苄基氨基)-6-氯噻吩并-[2,3-d]-嘧啶-2-基]庚酸;
2-{4-[4-(3-氯-4-甲氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]-环己基}醋酸;
2-{4-[4-(3-氯-4-甲氧基苄基氨基)-6-乙基噻吩并-[2,3-d]-嘧啶-2-基]-环己基}醋酸;
2-{4-[4-(3,4-亚甲二氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]-环己基}醋酸;
3-(4-苄基氨基-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)丙酸,乙醇胺盐,熔点126°;
4-(4-苄基氨基-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)丁酸,乙醇胺盐,熔点133°;
5-(4-苄基氨基-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)戊酸,乙醇胺盐,熔点135°;
4-[4-苄基氨基-6-甲基噻吩并-[2,3-d]-嘧啶-2-基]丁酸,乙醇胺盐,熔点165°;
5-[4-苄基氨基-6-乙基噻吩并-[2,3-d]-嘧啶-2-基]戊酸,乙醇胺盐,熔点162°。实施例3
将1当量的3-[4-(3-氯-4-甲氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丙酸和1.2当量的亚硫酰氯在二氯甲烷中搅拌2小时。除去溶剂,得到3-[4-(3-氯-4-甲氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]-丙酰氯。
将该产物转移到氨水中,将该混合物搅拌1小时,然后对其进行常规处理,得到3-[4-(3-氯-4-甲氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丙酰胺。实施例4
将1当量的DMF和1当量的乙二酰氯在0°下溶解于乙腈中。然后向其中加入1当量的3-[4-(3-氯-4-甲氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丙酰胺。将该混合物再搅拌1小时。进行常规处理,得到3-[4-(3-氯-4-甲氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丙腈。实施例5
与实施例1和2类似,获得如下的化合物
6-[4-(3-氯-4-甲氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]己酸,熔点165°;
2-[4-(3-氯-4-甲氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丙酸,乙醇胺盐,熔点150°;
4-[4-(3-氯-4-甲氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]-2,2-二甲基丁酸,乙醇胺盐,熔点130°;
4-[4-(3,4-亚甲二氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]-2,2-二甲基丁酸,乙醇胺盐,熔点126°;
5-[4-(3-氯-4-羟基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]戊酸,熔点179°;
5-[4-(3,4-二氯苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]戊酸,乙醇胺盐,熔点136°;
5-[4-(3-氯-4-异丙氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]戊酸,乙醇胺盐,熔点118°;
2-[4-(4-(3-氯-4-甲氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)-苯基]醋酸,乙醇胺盐,熔点119°;
2-[4-(4-(3,4-亚甲二氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基)-苯基]醋酸,熔点214°。
下面的实施例涉及药物制剂:
实施例A:注射管瓶
用2N HCl将100g式I的活性组分和5g磷酸氢二钠在31重蒸蒸馏水中的溶液调至pH6.5,无菌过滤,将其转移到数个注射管瓶中,在无菌的条件下冷冻干燥,然后在无菌的条件下密封。各注射管瓶包含5mg的活性成分。
实施例B:栓剂
将20g式I活性成分的混合物与100g大豆卵磷脂和1400g椰子油一起熔化,将其倒入到模具中并使之冷却。各栓剂包含20mg的活性成分。
实施例C:溶液
制备1g式I的活性成分、9.38g NaH2PO4·2H2O、28.48g Na2HPO4·12H2O和0.1g氯苄烷铵在940ml重蒸蒸馏水中的溶液。将其pH调至6.8,然后将该溶液配成11,然后辐射灭菌。
实施例D:软膏
将500mg式I的活性成分与99.5g凡士林在无菌的条件下混合。
实施例E:片剂
将1kg式I的活性成分、4kg的乳糖、1.2kg的马铃薯淀粉、0.2kg滑石粉和0.1kg硬脂酸镁的混合物用常规的方法进行压制来制备片剂,使用的方式要使各片剂包含10mg的活性成分。
实施例F:包衣片
用与实施例E类似的方法制备片剂,随后用常规的方法用蔗糖、马铃薯淀粉、滑石粉、黄蓍胶和染料的包衣来对其进行包衣。
实施例G:胶囊
将2kg式I的活性组分以常规的方式加入到硬胶囊中,通过一种方式使各胶囊包含20mg的活性组分。
实施例H:安瓿剂
将1kg式I的活性成分在601重蒸蒸馏水中的溶液无菌过滤,将其转移到安瓿中,在无菌的条件下冷冻干燥,然后在无菌的条件下密封。各安瓿包含10mg的活性成分。
实施例I:吸入喷雾剂
将14g式I的活性成分溶解于101的等渗NaCl溶液中,然后将该溶液转移到商业上可获得的带有泵装置的喷雾容器中。该溶液可被喷雾到嘴和鼻中。一次喷雾发射(约0.1ml)相当于约0.14mg的剂量。
Claims (5)
R1和R2各自彼此独立地是H、A或Hal,其中R1或R2基团之一总是≠H,
R1和R2或者一起是具有3-5个碳原子的亚烷基,
R3和R4各自彼此独立地是H、A、OA、OH或Hal,
R3和R4或者一起是具有3-5个碳原子的亚烷基、-O-CH2-CH2-、-O-CH2-O-或-O-CH2-CH2-O-,
X是被R7所单取代的R5或R6,
R5是具有1-10个碳原子的直链或支链亚烷基,其中一个或两个CH2基团可以被-CH=CH-基团所取代,或R5是-C6H4-(CH2)m-,
R6是具有6-12个碳原子的环烷基亚烷基,
R7是COOH、COOA、CONH2、CONHA、CON(A)2或CN,
A是具有1至6个碳原子的烷基,
Hal是F、Cl、Br或I,
m是1或2,
和
n是0、1、2或3,
其中所说的药物是用于治疗咽痛、高血压、高肺压、充血性心力衰竭、动脉粥样硬化、心血管开放减少的情况、外周血管疾病、中风、支气管炎、变应性哮喘、慢性哮喘、变应性鼻炎、青光眼、过敏性肠综合征、瘤、肾功能不全、肝硬化的药物和治疗雌性动物性病的药物。
2.权利要求1的式I的化合物及其生理上可接受的盐和/或溶剂化物
a)3-[4-(3-氯-4-甲氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丙酸;
b)4-(4-(3,4-亚甲二氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]丁酸;
c)7-[4-(3,4-亚甲二氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]庚酸;
d)7-[4-(3-氯-4-甲氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]庚酸;
e)5-[4-(3-氯-4-甲氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]戊酸;
f)5-[4-(3-氯-4-甲氧基苄基氨基)-6-甲基噻吩并-[2,3-d]-嘧啶-2-基]戊酸;
g)4-[4-(3-氯-4-甲氧基苄基氨基)-6-甲基噻吩并-[2,3-d]-嘧啶-2-基]丁酸;
h)4-[4-(3,4-亚甲二氧基苄基氨基)-6-甲基噻吩并-[2,3-d]-嘧啶-2-基]丁酸;
i)2-(4-[4-(3-氯-4-甲氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]-环己基-1-基}醋酸;
j)5-[4-(3,4-亚甲二氧基苄基氨基)-6-甲基噻吩并-[2,3-d]-嘧啶-2-基]戊酸;
用于制备治疗咽痛、高血压、高肺压、充血性心力衰竭、动脉粥样硬化、心血管开放减少的情况、外周血管疾病、中风、支气管炎、变应性哮喘、慢性哮喘、变应性鼻炎、青光眼、过敏性肠综合征、瘤、肾功能不全、肝硬化的药物以及治疗雌性动物性病的药物的应用。
3. 5-[4-(3-氯-4-甲氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]戊酸及其生理上可接受的盐和/或溶剂化物用于制备治疗高肺压的药物的应用。
4. 5-[4-(3-氯-4-甲氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]戊酸,乙醇胺盐用于制备治疗高肺压药物的应用。
5. 5-[4-(3-氯-4-甲氧基苄基氨基)-5,6,7,8-四氢-[1]-苯并噻吩并-[2,3-d]-嘧啶-2-基]戊酸钠盐用于制备治疗高肺压药物的应用。
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DE10058663A DE10058663A1 (de) | 2000-11-25 | 2000-11-25 | Verwendung von Thienopyrimidinen |
DE10058663.5 | 2000-11-25 |
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TW200845978A (en) | 2007-03-07 | 2008-12-01 | Janssen Pharmaceutica Nv | 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives |
TW200900065A (en) | 2007-03-07 | 2009-01-01 | Janssen Pharmaceutica Nv | 3-cyano-4-(4-pyridinyloxy-phenyl)-pyridin-2-one derivatives |
NZ584152A (en) | 2007-09-14 | 2011-11-25 | Ortho Mcneil Janssen Pharm | 1,3-disubstituted 4-(aryl-x-phenyl)-1h-pyridin-2-ones |
PT2203439E (pt) | 2007-09-14 | 2011-02-11 | Ortho Mcneil Janssen Pharm | 4-fenil-3,4,5,6-tetra-hidro-2h,1'h-[1,4']bipiridinil-2'- onas 1',3'-dissubstituídas |
JP5433579B2 (ja) | 2007-09-14 | 2014-03-05 | ジャンセン ファーマシューティカルズ, インコーポレイテッド. | 1,3−二置換−4−フェニル−1h−ピリジン−2−オン |
MX2010005110A (es) | 2007-11-14 | 2010-09-09 | Ortho Mcneil Janssen Pharm | Derivados de imidazo[1,2-a]piridina y su uso como moduladores alostericos positivos de los receptores de glutamato metabotropico 2. |
BRPI0918055A2 (pt) | 2008-09-02 | 2015-12-01 | Addex Pharmaceuticals Sa | derivados de 3-azabiciclo[3,1,0]hexila como moduladores de receptores metabotrópicos de glutamato. |
CA2738849C (en) | 2008-10-16 | 2016-06-28 | Addex Pharma S.A. | Indole and benzomorpholine derivatives as modulators of metabotropic glutamate receptors |
JP5690277B2 (ja) | 2008-11-28 | 2015-03-25 | ジャンセン ファーマシューティカルズ, インコーポレイテッド. | 代謝型グルタミン酸受容体の調節因子としてのインドールおよびベンゾオキサジン誘導体 |
CN102439015B (zh) | 2009-05-12 | 2015-05-13 | 杨森制药有限公司 | 1,2,4-三唑并[4,3-a]吡啶衍生物和其作为mGluR2受体的正向变构调节剂的用途 |
NZ596078A (en) | 2009-05-12 | 2013-06-28 | Janssen Pharmaceuticals Inc | 1,2,4-TRIAZOLO [4,3-a] PYRIDINE DERIVATIVES AND THEIR USE FOR THE TREATMENT OR PREVENTION OF NEUROLOGICAL AND PSYCHIATRIC DISORDERS |
MY153913A (en) | 2009-05-12 | 2015-04-15 | Janssen Pharmaceuticals Inc | 7-aryl-1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors |
CA2814998C (en) | 2010-11-08 | 2019-10-29 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors |
US9271967B2 (en) | 2010-11-08 | 2016-03-01 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors |
US8993591B2 (en) | 2010-11-08 | 2015-03-31 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo[4,3-a] pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors |
CA2842190A1 (en) | 2011-07-19 | 2013-01-24 | Infinity Pharmaceuticals Inc. | Heterocyclic compounds and uses thereof |
JO3368B1 (ar) | 2013-06-04 | 2019-03-13 | Janssen Pharmaceutica Nv | مركبات 6، 7- ثاني هيدرو بيرازولو [5،1-a] بيرازين- 4 (5 يد)- اون واستخدامها بصفة منظمات تفارغية سلبية لمستقبلات ميجلور 2 |
JO3367B1 (ar) | 2013-09-06 | 2019-03-13 | Janssen Pharmaceutica Nv | مركبات 2،1، 4- ثلاثي زولو [3،4-a] بيريدين واستخدامها بصفة منظمات تفارغية موجبة لمستقبلات ميجلور 2 |
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WO1998015530A1 (fr) * | 1996-10-08 | 1998-04-16 | Fujisawa Pharmaceutical Co., Ltd. | Derives d'indol |
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AU752072B2 (en) * | 1997-12-12 | 2002-09-05 | Osi Pharmaceuticals, Inc. | N-benzyl-3-indenylacetamides derivatives for treating neoplasia |
TR200003039T2 (tr) * | 1998-04-20 | 2001-01-22 | Pfizer Inc. | Seksüel fonksiyon bozukluklarının tedavisi için pirazolopirimidinon cGMP PDE5 inhibitörleri |
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JP2002524564A (ja) * | 1998-09-16 | 2002-08-06 | アイコス コーポレイション | cGMPホスホジエステラーゼ阻害剤としてのカルボリン誘導体 |
US6133271A (en) * | 1998-11-19 | 2000-10-17 | Cell Pathways, Inc. | Method for inhibiting neoplastic cells and related conditions by exposure thienopyrimidine derivatives |
FR2792635B1 (fr) * | 1999-04-20 | 2001-06-01 | Synthelabo | Derives de cyclobutene-3,4-dione leur preparation et leur application en therapeutique |
DE10042997A1 (de) * | 2000-09-01 | 2002-03-14 | Merck Patent Gmbh | Thienopyrimidine |
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ZA200304909B (en) | 2004-08-25 |
EP1337256A2 (de) | 2003-08-27 |
CA2429647A1 (en) | 2002-05-30 |
HUP0400818A2 (hu) | 2004-07-28 |
US20040034040A1 (en) | 2004-02-19 |
MXPA03004582A (es) | 2003-09-04 |
PL361277A1 (en) | 2004-10-04 |
KR20030051867A (ko) | 2003-06-25 |
BR0115247A (pt) | 2003-08-12 |
WO2002041896A3 (de) | 2002-10-31 |
SK7352003A3 (en) | 2003-11-04 |
AU2002224808A1 (en) | 2002-06-03 |
CZ20031618A3 (cs) | 2003-10-15 |
AR032482A1 (es) | 2003-11-12 |
RU2003117478A (ru) | 2004-11-27 |
JP2004513966A (ja) | 2004-05-13 |
DE10058663A1 (de) | 2002-05-29 |
WO2002041896A2 (de) | 2002-05-30 |
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