CN1564686A - 8-氨基-[1,2,4]三唑并[1,5-a]吡啶-6-甲酰胺 - Google Patents
8-氨基-[1,2,4]三唑并[1,5-a]吡啶-6-甲酰胺 Download PDFInfo
- Publication number
- CN1564686A CN1564686A CNA02819912XA CN02819912A CN1564686A CN 1564686 A CN1564686 A CN 1564686A CN A02819912X A CNA02819912X A CN A02819912XA CN 02819912 A CN02819912 A CN 02819912A CN 1564686 A CN1564686 A CN 1564686A
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- Prior art keywords
- pyridine
- furan
- amino
- triazol
- chemical compound
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- 150000001875 compounds Chemical class 0.000 claims abstract description 84
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- OFSIFPKVGDAWIV-UHFFFAOYSA-N n,n-dibenzylpyridine-2-carboxamide Chemical compound C=1C=CC=NC=1C(=O)N(CC=1C=CC=CC=1)CC1=CC=CC=C1 OFSIFPKVGDAWIV-UHFFFAOYSA-N 0.000 claims description 4
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Abstract
本发明涉及通式(I)化合物或其可药用盐,其中R1是-NR′R″,其中R′和R″彼此独立地是低级烷基、-(CH2) n-C(O)NRaRb、-(CH2) n-杂芳基、-(CH2) n-芳基、-(CH2) n-CN、-(CH2) n-O-低级烷基或-(CH2) n-环烷基,或者R ′和R″与N原子一起形成5或6元非芳族环,该环可包含一个另外的O或S杂原子,并且该环可以是未取代的或者被一或两个选自低级烷基、-C(O)NRaRb或-(CH2) n-O-低级烷基的取代基取代,其中Ra和Rb彼此独立地是氢或低级烷基;R2是未取代的或被低级烷基或卤素取代的芳基或杂芳基;n是0、1、2或3。所述化合物可用于治疗与腺苷A2受体有关的疾病。
Description
本发明涉及通式I的化合物及其可药用盐,
其中
R1是-NR′R″,其中R′和R″彼此独立地是低级烷基、-(CH2)n-C(O)NRaRb、-(CH2)n-杂芳基、-(CH2)n-芳基、-(CH2)n-CN、-(CH2)n-O-低级烷基或-(CH2)n-环烷基,
或者R′和R″与N原子一起形成5或6元非芳族环,该环可包含一个另外的O或S杂原子,并且该环可以是未取代的或者被一或两个选自低级烷基、-C(O)NRaRb或-(CH2)n-O-低级烷基的取代基取代,其中Ra和Rb彼此独立地是氢或低级烷基;
R2是未取代的或被低级烷基或卤素取代的芳基或杂芳基;
n是0、1、2或3。
现出人意料地发现通式I化合物是腺苷受体的配体。
腺苷通过与特定的细胞表面受体相互作用来调节多种生理学功能。在1982年首次提出了腺苷受体作为药物靶点的可能性。腺苷同时在结构学和代谢方面与生物活性的核苷三磷酸腺苷(ATP)、二磷酸腺苷(ADP)、一磷酸腺苷(AMP)和环腺苷一磷酸(cAMP)有关;并且同时在结构学和代谢方面与生物化学甲基化试剂S-腺苷-L-甲硫氨酸(SAM)有关;其在结构上与辅酶NAD、FAD和辅酶A有关;并且与RNA有关。腺苷和这些相关的化合物一起对于调节细胞代谢的许多方面以及调节不同的中枢神经系统活性具有重要意义。
腺苷受体被分类成A1、A2A、A2B和A3受体,属于G蛋白偶联的受体家族。腺苷激活腺苷受体引发信号传导机制。这些机制依赖于与G蛋白结合的受体。每一种腺苷受体亚型均通过腺苷酸环化酶效应器系统进行分类表征,该系统使用cAMP作为第二信使。与Gi蛋白偶联的A1和A3受体抑制腺苷酸环化酶,导致细胞cAMP水平降低;而A2A和A2B受体与Gs蛋白偶联并激活腺苷酸环化酶,导致细胞cAMP水平升高。已知A1受体系统包括磷脂酶C的激活以及钾和钙离子通道的调节。A3亚型除了与腺苷酸环化酶结合外,还可以刺激磷脂酶C,从而激活钙离子通道。
由各种物种(犬、人、大鼠、狗、鸡、牛、豚鼠)克隆了A1受体(326-328个氨基酸),在哺乳动物物种之间该受体具有90-95%的序列同一性。由犬、大鼠、人、豚鼠和小鼠克隆了A2A受体(409-412个氨基酸)。由人和小鼠克隆了A2B受体(332个氨基酸),人A2B与人A1和A2A受体具有45%的同源性。由人、大鼠、狗、兔子和绵羊克隆了A3受体(317-320个氨基酸)。
有人提出A1和A2A受体亚型在腺苷对能量供给的调节中起补充作用。腺苷是一种ATP的代谢产物,它从细胞扩散并局部地产生作用而激活腺苷受体,以降低氧的需求(A1)或增加氧供给(A2A),从而恢复组织内能量的供需平衡。两种亚型的作用都是增加组织可以利用的氧的量,并使细胞免受因短时间的氧失衡所引起的损伤。内源性腺苷的一个重要功能是防止创伤例如组织缺氧、局部缺血、低血压和癫痫发作过程中的损伤。
此外,已知腺苷受体激动剂与表达大鼠A3受体的肥大细胞的结合导致三磷酸肌醇和胞内钙浓度增高,这增强了抗原诱导的炎性介质的分泌。因此,A3受体在介导哮喘发作和其它过敏反应中起作用。
腺苷还是一种神经调质,它通过介导中枢抑制作用对生理学脑功能的许多方面所涉及的分子机制的调节具有整体重要性。在创伤例如组织缺氧、局部缺血和癫痫发作后会出现神经递质释放的增加。这些神经递质最终与神经变性和神经死亡有关,而神经变性和神经死亡会引起大脑损伤或个体的死亡。因此,模拟腺苷的中枢抑制作用的腺苷A1激动剂可用作神经保护剂。有人提出腺苷是一种内源性抗惊厥剂,可以抑制兴奋性神经元释放谷氨酸并抑制神经元放电。因此,腺苷激动剂可用作抗癫痫剂。腺苷拮抗剂可以刺激CNS的活性,并且已证实其可用作认知促进剂。选择性的A2a-拮抗剂在治疗各种形式的痴呆例如早老性痴呆中具有潜在治疗作用并且可用作神经保护剂。腺苷A2a-受体拮抗剂可以抑制中枢突触末梢释放多巴胺并降低运动活性,从而改善帕金森氏病的症状。腺苷的中枢活性还与镇静、催眠状态、精神分裂症、焦虑、疼痛、呼吸、抑郁症和药物滥用所涉及的分子机制有关。因此,作用于腺苷受体的药物具有作为镇静剂、肌肉松弛剂、抗精神病药、抗焦虑药、镇痛药、呼吸兴奋药和抗抑郁药的潜在治疗价值。
腺苷在心血管系统中的一个重要作用是作为心脏保护剂。内源性腺苷水平会在局部缺血和组织缺氧时增加,并在创伤期间和之后(预适应)保护心脏组织。因此,腺苷激动剂是潜在的心脏保护剂。
腺苷调节肾功能的许多方面,包括肾素释放、肾小球滤过率和肾脏血流。拮抗腺苷的肾脏作用的化合物是潜在的肾脏保护剂。此外,腺苷A3和/或A2B拮抗剂可以用于治疗哮喘和其它过敏反应。
许多文献描述了关于腺苷受体的现有知识,例如下列出版物:
Bioorganic & Medicinal Chemistry,6,(1998),619-641,
Bioorganic & Medicinal Chemistry,6,(1998),707-719,
J.Med.Chem.,(1998),41,2835-2845,
J.Med.Chem.,(1998),41,3186-3201,
J.Med.Chem.,(1998),41,2126-2133,
J.Med.Chem.,(1999),42,706-721,
J.Med.Chem.,(1996),39,1164-1171,
Arch.Pharm.Med.Chem.,(1999),332,39-41。
本发明的目的是式I化合物及其可药用盐本身和作为药物活性物质的这些化合物、它们的生产方法,基于本发明化合物的药物及它们的生产方法,以及式I化合物在控制或预防基于腺苷系统的调节作用的疾病中的应用,这些疾病是例如早老性痴呆、帕金森氏病、神经保护、精神分裂症、焦虑、疼痛、呼吸不足、抑郁、哮喘、过敏反应、组织缺氧、局部缺血、癫痫发作和药物滥用。此外,本发明的化合物可用作镇静剂、肌肉松弛剂、抗精神病药、抗癫痫药、抗惊厥药和心脏保护剂。本发明最优选的适应症是基于A2A受体拮抗活性的那些,包括中枢神经系统病症,例如某些抑郁症、神经保护和帕金森氏病的预防或治疗。
本文中所用的术语“低级烷基”是指含有1-6个碳原子的饱和的直链或支链的烷基,例如甲基、乙基、丙基、异丙基、正丁基、异丁基、2-丁基、叔丁基等。优选的低级烷基是具有1-4个碳原子的基团。
术语“环烷基”是指含有3-8个碳原子的饱和碳环基团。优选的环烷基是环己基。
术语“卤素”是指氯、碘、氟和溴。
术语“低级烷氧基”是指其中的烷基是如上定义的并且通过氧原子连接的基团。
术语“芳基”是指苯基或萘基。优选的芳基是苯基。
术语“杂芳基”是指具有杂原子,如O、N或S的5或6元环,例如吡啶基、噻吩基、呋喃基和噻唑基。
术语“5或6元非芳族环”是指除N原子外,还可包含一个另外的杂原子,如O或S的环,例如吗啉基、硫代吗啉基、哌啶基、吡咯烷基或3,6-二氢-2H-吡啶-1-基。
术语“可药用酸加成盐”包括与无机酸和有机酸形成的盐,所述酸是例如盐酸、硝酸、硫酸、磷酸、柠檬酸、甲酸、富马酸、马来酸、乙酸、琥珀酸、酒石酸、甲磺酸、对甲苯磺酸等。
优选其中R2是被溴取代的杂芳基、例如呋喃-2-基的本发明式I化合物。例如下列化合物:
[8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-基]-哌啶-1-基-甲酮,
[8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-基]-吡咯烷-1-基-甲酮,
[8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-基]-(2-甲基-吡咯烷-1-基)-甲酮,
1-[8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-羰基]-哌啶-3-甲酸二乙基酰胺,
[8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-基]-(3,5-二甲基-哌啶-1-基)-甲酮,
[8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-基]-(2-甲基-哌啶-1-基)-甲酮,
[8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-基]-(2-甲氧基甲基-吡咯烷-1-基)-甲酮,
[8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-基]-((S)-2-甲氧基甲基-吡咯烷-1-基)-甲酮,
1-[8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-羰基]-吡咯烷-2-甲酸(S)-二甲基酰胺,
8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-甲酸二甲基氨基甲酰基甲基-甲基-酰胺,
[8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-基]-(3-甲基-哌啶-1-基)-甲酮,
8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-甲酸甲基-丙基-酰胺,
8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-甲酸乙基-(2-吡啶-2-基-乙基)-酰胺,
[8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-基]-硫代吗啉-4-基-甲酮,或
8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-甲酸甲基-苯乙基-酰胺。
其它优选的是其中R2是未取代的杂芳基,例如呋喃-2-基的化合物。该组的实例是下列化合物:
(8-氨基-2-呋喃-2-基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-吡咯烷-1-基-甲酮,
(8-氨基-2-呋喃-2-基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-(2-R-甲氧基甲基-吡咯烷-1-基)-甲酮,
(8-氨基-2-呋喃-2-基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-(2-S-甲氧基甲基-吡咯烷-1-基)-甲酮或
8-氨基-2-呋喃-2-基-[1,2,4]三唑并[1,5-a]吡啶-6-甲酸二苄基酰胺。
还优选其中R2是杂芳基、例如噻吩-2-基的本发明式I化合物。例如下列化合物:
8-氨基-2-噻吩-2-基-[1,2,4]三唑并[1,5-a]吡啶-6-甲酸二苄基酰胺。
其它优选的化合物是其中R2是被甲基取代的杂芳基、例如呋喃-2-基的化合物。该组的实例是下列化合物:
[8-氨基-2-(5-甲基-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-基]-吡咯烷-1-基-甲酮,
[8-氨基-2-(5-甲基-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-基]-哌啶-1-基-甲酮,
[8-氨基-2-(5-甲基-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-基]-(2-甲基-吡咯烷-1-基)-甲酮或
8-氨基-2-(5-甲基-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-甲酸甲基-丙基-酰胺。
式I化合物及其可药用盐可通过本领域已知的方法制备,例如采用下述方法制备,该方法包括
将式II化合物
与式III的胺反应
HNR′R″ III
得到式I化合物
其中R′、R″和R2具有上面给出的含义,并且
如果需要,将所得化合物转化为可药用酸加成盐。
按照上述方法的改变方法,为获得式I化合物(8-氨基-2-(芳基或杂芳基)-[1,2,4]三唑并[1,5-a]吡啶-6-基)-哌啶-1-基-甲酮),将式III的胺(HNR′R″)的二噁烷溶液用三甲基铝的甲苯液处理并在室温搅拌1小时。加入8-氨基-2-(芳基或杂芳基)-[1,2,4]三唑并[1,5-a]吡啶-6-甲酸甲酯(II)在1ml二噁烷中的溶液并将该混合物在90℃加热72小时。加入盐酸并除去挥发物。将残余物加到甲酸和甲醇中并经反相制备型HPLC纯化,用乙腈和水梯度洗脱。
按照先前已知的和本领域技术人员熟悉的方法在室温下形成盐。与无机酸形成的盐以及与有机酸形成的盐均包括在内。所述盐的例子为盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、柠檬酸盐、乙酸盐、马来酸盐、琥珀酸盐、甲磺酸盐、对甲苯磺酸盐等。
在实施例9-108和下面的反应方案1中详细描述了式I化合物的制备。
反应方案1
按照反应方案1,如下所述获得式V化合物(6-羟基-5-硝基-烟酸):在低于20℃下,向式IV化合物(6-羟基-烟酸)的浓硫酸溶液中加入浓硫酸和浓硝酸的混合物并在室温搅拌1小时,之后将该溶液在80℃加热4小时。将该混合物倾倒在冰上,收集沉淀并使之干燥。然后将所得式V化合物与POCl3混合并在130℃加热5小时,之后减压蒸除过量的POCl3。使残余物冷却到0℃并缓慢地加入150ml甲醇。该混合物在0℃搅拌2小时。加入25%氨水溶液后,将该混合物在室温搅拌4小时。过滤沉淀,用乙醚洗涤一次并真空干燥,得到6-氨基-5-硝基-烟酸甲酯(VI)。形成6-氨基-5-硝基-烟酸甲酯的甲醇悬浮液,然后加入Pd/C(10%)催化剂并在室温下氢化14小时。滤除催化剂,将溶液浓缩,得到5,6-二氨基-烟酸甲酯(VII)。将(VII)在二噁烷中的混合物用O-均三甲苯磺酰基羟胺(由O-均三甲苯磺酰基乙酰氧肟酸乙酯和HClO4制备)在室温处理1小时。向噻吩-2-甲醛或另一种式R2CHO的醛中(其中R2是如说明书中所述的芳基或杂芳基)加入4分子筛并在100℃加热4小时,之后加入KOH的甲醇溶液。将该混合物在70℃加热2小时并在室温搅拌14小时。减压除去挥发物,残余物经快速柱色谱纯化,得到8-氨基-2-(芳基或杂芳基)-[1,2,4]三唑并[1,5-a]吡啶-6-甲酸甲酯(II)。为获得式I化合物(8-氨基-2-(芳基或杂芳基)-[1,2,4]三唑并[1,5-a]吡啶-6-基)-哌啶-1-基-甲酮),将式III的胺(HNR′R″)的二噁烷溶液用三甲基铝的甲苯溶液处理并在室温搅拌1小时。加入8-氨基-2-(芳基或杂芳基)-[1,2,4]三唑并[1,5-a]吡啶-6-甲酸甲酯(II)在1ml二噁烷中的溶液并将该混合物在90℃加热72小时。加入HCl水溶液并除去挥发物。将残余物加到甲酸和甲醇中并经反相制备型HPLC纯化,用乙腈和水梯度洗脱。
式I化合物及其可药用加成盐具有有价值的药理学特性。具体而言,发现本发明化合物是腺苷受体配体。
按照下文中给出的试验对化合物进行研究。
人腺苷A2A受体
用塞姆利基森林病毒表达系统在中国仓鼠卵巢(CHO)细胞中重组表达人腺苷A2A受体。收获细胞,通过离心洗涤两次,匀化并再次通过离心进行洗涤。将最后洗涤的膜沉积物悬浮在Tris(50mM)缓冲液中,所述缓冲液中含有120mM NaCl、5mM KCl、2mM CaCl2和10mM MgCl2(pH 7.4)(缓冲液A)。在96孔培养板中进行[3H]-SCH-58261(Dionisotti等,1997,Br.J.Pharmacol.121,353)结合试验,试验在2.5μg膜蛋白、0.5mg Ysi-聚-L-赖氨酸SPA珠和0.1U腺苷脱氨酶的存在下、在最终体积为200μl的缓冲液A中进行。用黄嘌呤胺同类物(XAC;2μM)测定非特异性结合。在10μM至0.3nM的10种浓度下对化合物进行测定。所有试验均一式两份地进行并且重复至少两次。将测定培养板在室温下保温1小时,然后离心并用Packard Topcount闪烁计数器测定结合的配体。用非线性曲线拟合程序计算IC50值并用Cheng-Prussoff方程计算Ki值。
根据本发明,证实式I化合物对A2A受体具有高度亲和性。下表中描述了所制备的化合物的具体值。优选的化合物是对hA2a的Ki值小于100nM的化合物,例如下列的那些:
实施例号 | hA2a Ki(nm) |
11 | 35.2 |
12 | 26.8 |
13 | 40.5 |
14 | 37.2 |
15 | 62.4 |
16 | 16.4 |
17 | 61.2 |
18 | 67.0 |
19 | 23.2 |
20 | 15.5 |
21 | 44.6 |
22 | 76.2 |
25 | 50.0 |
34 | 56.8 |
37 | 34.9 |
41 | 77.6 |
42 | 69.4 |
64 | 83.0 |
83 | 75.6 |
84 | 56.8 |
85 | 75.2 |
88 | 56.2 |
式I化合物及式I化合物的可药用盐可,例如以药物制剂的形式用作药物。药物制剂可例如以片剂、包衣片、糖衣丸、硬和软明胶胶囊、溶液、乳液或混悬液的形式经口服给药。但也可例如以栓剂的形式直肠给药,或者以注射液的形式胃肠外给药。
式I化合物可用药物惰性的、无机或有机载体加工以生产药物制剂。乳糖、玉米淀粉或其衍生物、滑石、硬脂酸或其盐等,可用作例如制备片剂、包衣片、糖衣丸和硬明胶胶囊的载体。用于软明胶胶囊的适宜载体是,例如植物油、蜡、脂肪、半固体和液体的多元醇等。根据活性物质的性质,在软明胶胶囊的情况下通常不需要载体。用于制备溶液和糖浆的适宜载体是,例如水、多元醇、甘油、植物油等。用于栓剂的适宜载体是,例如天然的或硬化的油、蜡、脂肪、半液体或者液体多元醇等。
此外,药物制剂还可包含防腐剂、增溶剂、稳定剂、润湿剂、乳化剂、甜味剂、着色剂、矫味剂、用于改变渗透压的盐、缓冲剂、掩蔽剂或抗氧剂。它们还可包含其它治疗学上有益的物质。
含有式I化合物或其可药用盐以及治疗惰性的载体的药物及其生产方法也是本发明的目的,所述生产方法包括,将一种或多种式I化合物和/或可药用酸加成盐以及,如果需要的话,一种或多种其它治疗学上有益的物质与一种或多种治疗学惰性的载体一起制成盖仑给药形式。
根据本发明,式I化合物及其可药用盐可用于控制或预防基于腺苷受体拮抗活性的疾病,例如早老性痴呆、帕金森氏病、神经保护、精神分裂症、焦虑、疼痛、呼吸不足、抑郁、哮喘、过敏反应、组织缺氧、局部缺血、癫痫发作和药物滥用。此外,本发明的化合物还可用作镇静剂、肌肉松弛剂、抗精神病药、抗癫痫药、抗惊厥药和心脏保护剂以及用于生产相应的药物。
根据本发明,首选的适应症包括中枢神经系统疾病,例如某些抑郁症、神经保护和帕金森氏病的治疗或预防。
剂量可在较宽的限度内变化,但在每个具体病例中,当然应根据个体需求进行调整。在口服给药的情况下,对于成人的日剂量可以为约0.01mg-约1000mg通式I化合物或相应量的其可药用盐。该日剂量可以以单次剂量给药,或者以划分的剂量给药,此外,当需要时,剂量也可超过上限。
中间体
实施例1
8-氨基-2-噻吩-2-基-[1,2,4]三唑并[1,5-a]吡啶-6-甲酸甲酯
a)6-羟基-5-硝基-烟酸
在低于20℃下,向30g(0.217mol)6-羟基-烟酸在50ml浓硫酸中的溶液中加入60ml 1∶1浓硫酸与浓硝酸的混合物并在室温下搅拌1小时,之后在80℃加热4小时。将该混合物倾入冰中,收集形成的沉淀并干燥,得到14.2g(36%)黄色非晶固体状标题化合物。
MS m/e(%):184(MH+,100)
1H-NMR(300MHz,DMSO-d6):δ=13.3(s,br,2H,COOH/OH),8.65(d,J=2.5Hz,1H,H-4),8.38(d,J=2.5Hz,1H,H-2)。
b)6-氨基-5-硝基-烟酸甲酯
将14.2g(78mmol)6-羟基-5-硝基-烟酸在50ml POCl3中的混合物在130℃加热5小时,之后减压蒸馏过量的POCl3。使残余物冷却到0℃并缓慢地加入150ml甲醇。该混合物在0℃搅拌2小时。加入300ml 25%NH3水溶液后,该混合物在室温搅拌4小时。过滤沉淀,用乙醚洗涤一次,真空干燥,得到5.97g(39%)黄色固体状标题化合物。
MS m/e(%):197(MH+,100)
1H-NMR(300MHz,DMSO-d6):δ=8.83(d,J=2.1Hz,1H,H-4),8.72(d,J=2.1Hz,1H,H-2),8.38(s,br,2H,NH2),3.85(s,3H,OCH3)。
c)5,6-二氨基-烟酸甲酯
形成5.97g(30mmol)6-氨基-5-硝基-烟酸甲酯在30ml甲醇中的悬浮液,加入600mg Pd/C(10%)催化剂并在室温氢化14小时。滤除催化剂并将溶液浓缩,得到4.74g(94%)白色非晶固体状标题化合物。
MS m/e(%):167(MH+,100)
1H-NMR(300MHz,DMSO-d6):δ=7.95(d,J=1.5Hz,1H,H-4),7.16(d,J=1.5Hz,1H,H-2),6.25(s,br,2H,NH2),4.91(s,br,2H,NH2),3.74(s,3H,OCH3)。
d)8-氨基-2-噻吩-2-基-[1,2,4]三唑并[1,5-a]吡啶-6-甲酸甲酯
将1.114g(6.66mmol)5,6-二氨基-烟酸甲酯在40ml二噁烷中的混合物用1.578g(7.33mmol)O-均三甲苯磺酰基羟胺(由O-均三甲苯磺酰基乙酰氧肟酸乙酯和HClO4(70%)制备)在室温处理1小时。加入0.897g(8mmol)噻吩-2-甲醛和4分子筛并在100℃加热4小时,然后加入1.6ml 5M KOH的甲醇溶液。将该混合物在70℃加热2小时并在室温搅拌14小时。减压除去挥发物,残余物经快速硅胶柱色谱纯化,用乙酸乙酯和正己烷的混合液洗脱,蒸发后,得到0.88g(48%)标题化合物。
MS m/e(%):275.3(MH+,100)
1H-NMR(300MHz,DMSO-d6):δ=8.65(d,J=1.4Hz,1H,H-5),7.81(dd,J1=3.5Hz,J2=1Hz,1H,噻吩H-2),7.76(dd,J1=4.8Hz,J2=1Hz,1H,噻吩H-4),7.24(dd,J1=4.8Hz,J2=3.5Hz,1H,噻吩H-3),7.09(d,J=1.4Hz,1H,H-7),6.31(s,br,2H,NH2),3.88(s,3H,OCH3)。
实施例2
8-氨基-2-苯基-[1,2,4]三唑并[1,5-a]吡啶-6-甲酸甲酯
按照实施例1的一般方法,由5,6-二氨基-烟酸甲酯、O-均三甲苯-磺酰基羟胺和苯甲醛制备该标题化合物,M/S m/e(%):269(M+,100)。通过快速硅胶柱色谱纯化,用乙酸乙酯和正己烷的混合液洗脱。
实施例3
8-氨基-2-噻唑-2-基-[1,2,4]三唑并[1,5-a]吡啶-6-甲酸甲酯
按照实施例1的一般方法,由5,6-二氨基-烟酸甲酯、O-均三甲苯磺酰基羟胺和噻唑-2-甲醛制备该标题化合物,M/S m/e(%):276.1(M+,100)。通过快速硅胶柱色谱纯化,用乙酸乙酯和正己烷的混合液洗脱。
实施例4
8-氨基-2-(5-甲基-噻吩-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-甲酸甲酯
按照实施例1的一般方法,由5,6-二氨基-烟酸甲酯、O-均三甲苯磺酰基羟胺和5-甲基噻吩-2-甲醛制备该标题化合物,M/S m/e(%):289.2(M+,100)。通过快速硅胶柱色谱纯化,用乙酸乙酯和正己烷的混合液洗脱。
实施例5
8-氨基-2-呋喃-2-基-[1,2,4]三唑并[1,5-a]吡啶-6-甲酸甲酯
按照实施例1的一般方法,由5,6-二氨基-烟酸甲酯、O-均三甲苯磺酰基羟胺和呋喃-2-甲醛制备该标题化合物,M/S m/e(%):259.1(M+,100)。通过快速硅胶柱色谱纯化,用乙酸乙酯和正己烷的混合液洗脱。
1H-NMR(300MHz,DMSO-d6):δ=8.65(d,J=1.5Hz,1H,H-5),7.92(dd,J1=1.7Hz,J2=0.8Hz,1H,呋喃H-5),7.16(dd,J1=3.4Hz,J2=0.8Hz,1H,呋喃H-3),7.08(d,J=1.5Hz,1H,H-7),6.73(dd,J1=3.4Hz,J2=1.7Hz,1H,呋喃H-4),6.35(s,br,2H,NH2),3.89(s,3H,OCH3)。
实施例6
8-氨基-2-(5-甲基-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-甲酸甲酯
按照实施例1的一般方法,由5,6-二氨基-烟酸甲酯、O-均三甲苯磺酰基羟胺和5-甲基呋喃-2-甲醛制备该标题化合物,M/S m/e(%):273.2(M+,100)。通过快速硅胶柱色谱纯化,用乙酸乙酯和正己烷的混合液洗脱。
实施例7
8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-甲酸甲酯
按照实施例1的一般方法,由5,6-二氨基-烟酸甲酯、O-均三甲苯磺酰基羟胺和5-溴呋喃-2-甲醛制备该标题化合物,M/S m/e(%):338.2(M+,100)。通过快速硅胶柱色谱纯化,用乙酸乙酯和正己烷的混合液洗脱。
实施例8
8-氨基-2-吡啶-2-基-[1,2,4]三唑并[1,5-a]吡啶-6-甲酸甲酯
按照实施例1的一般方法,由5,6-二氨基-烟酸甲酯、O-均三甲苯磺酰基羟胺和吡啶-2-甲醛制备该标题化合物,M/S m/e(%):270.3(M+,100)。通过快速硅胶柱色谱纯化,用乙酸乙酯和正己烷的混合液洗脱。
1H-NMR(300MHz,DMSO-d6):δ=8.75(dd,J1=2Hz,J2=0.6Hz,1H,吡啶H-6),8.70(d,J=1.5Hz,1H,H-5),8.25(dd,J1=7.8Hz,J2=0.6Hz,1H,吡啶H-3),8.00(dd,J1=7.8Hz,J2=2Hz,1H,吡啶H-4),7.54(dd,J1=7.8Hz,J2=1.2Hz,1H,吡啶H-5),7.09(d,J=1.5Hz,1H,H-7),6.41(s,br,2H,NH2),3.89(s,3H,OCH3)。
药物活性化合物
实施例9
[8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-基]-哌啶-1-基-甲酮
将20mg(0.24mmol)哌啶在1ml二噁烷中的溶液用0.24ml(0.24mmol)三甲基铝的甲苯溶液处理并在室温搅拌1小时。加入20mg(0.06mmol)8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-甲酸甲酯在1ml二噁烷中的溶液并将该混合物在90℃加热72小时。加入0.5ml 1N HCl水溶液并除去挥发物。将残余物加到1.5ml甲酸和0.5ml甲醇中,并通过反相制备型HPLC纯化,用乙腈和水梯度洗脱。蒸发洗脱溶剂,获得7mg(29%)标题化合物。
MS m/e(%):391.3(MH+,100)
1H-NMR(500MHz,DMSO):δ=8.21(s,1H,H-5),7.14(dd,J1=3.5Hz,1H,呋喃H-4),6.82(d,J=3.5Hz,1H,呋喃H-3),6.56(s,1H,H-7),6.26(s,br,2H,NH2),1.62(m,4H,NCH2),1.52(m,6H,CH2)。
根据实施例9,由实施例1-8所述的酯和相应的胺合成了其它[1,2,4]三唑并[1,5-a]吡啶-6-甲酰胺衍生物。下面包括实施例10-实施例108的表中汇总了结果。
片剂(湿法制粒)
项
成分
mg/片
5mg 25mg 100mg 500mg
1.式I化合物 5 25 100 500
2.无水乳糖DTG 125 105 30 150
3.Sta-Rx 1500 6 6 6 30
4.微晶纤维素 30 30 30 150
5.硬脂酸镁 1 1 1 1
总计
167
167
167
831
制备方法
1.混合1、2、3和4项并用纯水制粒。
2.在50℃下干燥该颗粒。
3.用适宜的研磨设备使该颗粒过筛。
4.加入第5项并混合3分钟;在适宜的压片机上压片。
胶囊制剂
项
成分
mg/胶囊
5mg 25mg 100mg 500mg
1.式I化合物 5 25 100 500
2.含水乳糖 159 123 148 ---
3.玉米淀粉 25 35 40 70
4.滑石粉 10 15 10 25
5.硬脂酸镁 1 2 2 5
总计
200
200
300
600
制备方法
1.将1、2和3项在适宜的混合器中混合30分钟。
2.加入第4和5项并混合3分钟。
3.填充到适合的胶囊中。
Claims (19)
1.通式I的化合物及其可药用盐,
其中
R1是-NR′R″,其中R′和R″彼此独立地是低级烷基、-(CH2)n-C(O)NRaRb、-(CH2)n-杂芳基、-(CH2)n-芳基、-(CH2)n-CN、-(CH2)n-O-低级烷基或-(CH2)n-环烷基,
或者R′和R″与N原子一起形成5或6元非芳族环,该环可包含一个另外的O或S杂原子,并且该环可以是未取代的或者被一或两个选自低级烷基、-C(O)NRaRb或-(CH2)n-O-低级烷基的取代基取代,其中Ra和Rb彼此独立地是氢或低级烷基;
R2是未取代的或被低级烷基或卤素取代的芳基或杂芳基;
n是0、1、2或3。
2.权利要求1的式I化合物,其中R2是杂芳基。
3.权利要求2的式I化合物,其中R2是被溴取代的呋喃-2-基。
4.权利要求3的式I化合物,其中该化合物是
[8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-基]-哌啶-1-基-甲酮,
[8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-基]-吡咯烷-1-基-甲酮,
[8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-基]-(2-甲基-吡咯烷-1-基)-甲酮,
1-[8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-羰基]-哌啶-3-甲酸二乙基酰胺,
[8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-基]-(3,5-二甲基-哌啶-1-基)-甲酮,
[8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-基]-(2-甲基-哌啶-1-基)-甲酮,
[8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-基]-(2-甲氧基甲基-吡咯烷-1-基)-甲酮,
[8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-基]-((S)-2-甲氧基甲基-吡咯烷-1-基)-甲酮,
1-[8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-羰基]-吡咯烷-2-甲酸(S)-二甲基酰胺,
8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-甲酸二甲基氨基甲酰基甲基-甲基-酰胺,
[8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-基]-(3-甲基-哌啶-1-基)-甲酮,
8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-甲酸甲基-丙基-酰胺,
8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-甲酸乙基-(2-吡啶-2-基-乙基)-酰胺,
[8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-基]-硫代吗啉-4-基-甲酮,或
8-氨基-2-(5-溴-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-甲酸甲基-苯乙基-酰胺。
5.权利要求2的式I化合物,其中R2是未取代的呋喃-2-基。
6.权利要求5的式I化合物,其中该化合物是
(8-氨基-2-呋喃-2-基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-吡咯烷-1-基-甲酮,
(8-氨基-2-呋喃-2-基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-(2-R-甲氧基甲基-吡咯烷-1-基)-甲酮,
(8-氨基-2-呋喃-2-基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-(2-S-甲氧基甲基-吡咯烷-1-基)-甲酮或
8-氨基-2-呋喃-2-基-[1,2,4]三唑并[1,5-a]吡啶-6-甲酸二苄基酰胺。
7.权利要求2的式I化合物,其中R2是噻吩-2-基。
8.权利要求7的式I化合物,其中该化合物是8-氨基-2-噻吩-2-基-[1,2,4]三唑并[1,5-a]吡啶-6-甲酸二苄基酰胺。
9.权利要求2的式I化合物,其中R2是被甲基取代的呋喃-2-基。
10.权利要求9的式I化合物,其中该化合物是
[8-氨基-2-(5-甲基-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-基]-吡咯烷-1-基-甲酮,
[8-氨基-2-(5-甲基-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-基]-哌啶-1-基-甲酮,
[8-氨基-2-(5-甲基-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-基]-(2-甲基-吡咯烷-1-基)-甲酮或
8-氨基-2-(5-甲基-呋喃-2-基)-[1,2,4]三唑并[1,5-a]吡啶-6-甲酸甲基-丙基-酰胺。
11.权利要求1的式I化合物,其中R2是芳基。
12.权利要求11的式I化合物,其中R2是苯基。
13.一种药物,包含一种或多种权利要求1-12任一项所述的式I化合物和可药用赋形剂。
14.用于治疗与腺苷受体有关之疾病的权利要求13的药物。
16.通过权利要求15的方法或相当的方法制备的权利要求1-12任一项所述的化合物。
17.权利要求1-12任一项所述的化合物用于治疗疾病的用途。
18.权利要求1-12任一项所述的化合物在制备用于治疗与腺苷A2A受体有关之疾病的相应药物中的用途。
19.前述的本发明。
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EP01123948 | 2001-10-08 | ||
EP01123948.0 | 2001-10-08 |
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CN1564686A true CN1564686A (zh) | 2005-01-12 |
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US (1) | US6689790B2 (zh) |
EP (1) | EP1435952A1 (zh) |
JP (1) | JP4101755B2 (zh) |
KR (1) | KR100614486B1 (zh) |
CN (1) | CN1564686A (zh) |
AR (1) | AR036734A1 (zh) |
AU (1) | AU2002347055B2 (zh) |
BR (1) | BR0213172A (zh) |
CA (1) | CA2462806A1 (zh) |
MX (1) | MXPA04003277A (zh) |
PL (1) | PL370067A1 (zh) |
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WO (1) | WO2003030904A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102471337A (zh) * | 2009-07-17 | 2012-05-23 | 日本烟草产业株式会社 | 三唑并吡啶化合物及其作为脯氨酰基羟化酶抑制剂和红细胞生成素产生诱导剂的作用 |
CN104370807A (zh) * | 2014-11-13 | 2015-02-25 | 安徽星宇化工有限公司 | 一种6-羟基-5-硝基烟酸的合成方法及其分离提纯方法 |
Families Citing this family (9)
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RU2561104C2 (ru) * | 2008-06-20 | 2015-08-20 | Дженентек, Инк. | Триазолопиридиновые соединения-ингибиторы jak и способы |
RU2560153C2 (ru) * | 2008-06-20 | 2015-08-20 | Дженентек, Инк. | Триазолпиридиновые соединения, ингибирующие jak, и способы |
TWI453207B (zh) * | 2008-09-08 | 2014-09-21 | Signal Pharm Llc | 胺基三唑并吡啶,其組合物及使用其之治療方法 |
MX348447B (es) * | 2012-02-09 | 2017-06-13 | Hoffmann La Roche | Proceso para la preparacion de derivados de 2-fenil-[1,2,4]triazol o[1,5-a]piridina. |
US9048427B2 (en) * | 2013-03-06 | 2015-06-02 | National Tsing Hua University | Thin film fabrication of rubber material with piezoelectric characteristics |
BR112015029899B1 (pt) * | 2013-05-31 | 2020-07-21 | Nissan Chemical Corporation | composto de amida heterocíclica e sal do mesmo da formula (1), produto quimico agrícola e herbicida obtido |
EP3774813A4 (en) | 2018-04-08 | 2021-11-17 | BeiGene, Ltd. | PYRAZOLOTRIAZOLOPYRIMIDINE DERIVATIVES USED AS AN A2A RECEPTOR ANTAGONIST |
CN110742893B (zh) * | 2018-07-23 | 2024-04-05 | 百济神州(北京)生物科技有限公司 | A2a受体拮抗剂治疗癌症的方法 |
WO2020054712A1 (ja) * | 2018-09-12 | 2020-03-19 | 日本化薬株式会社 | 有害生物防除剤 |
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DE287263C (zh) * | ||||
AU743910B2 (en) * | 1997-03-24 | 2002-02-07 | Kyowa Hakko Kirin Co., Ltd. | {1,2,4}triazolo{1,5-c}pyrimidine derivatives |
US6355653B1 (en) * | 1999-09-06 | 2002-03-12 | Hoffmann-La Roche Inc. | Amino-triazolopyridine derivatives |
US6506772B1 (en) * | 2000-12-15 | 2003-01-14 | Hoffmann-La Roche Inc. | Substituted [1,2,4]triazolo[1,5a]pyridine derivatives with activity as adenosine receptor ligands |
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2002
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- 2002-10-04 PL PL02370067A patent/PL370067A1/xx not_active Application Discontinuation
- 2002-10-04 KR KR1020047005091A patent/KR100614486B1/ko not_active IP Right Cessation
- 2002-10-04 AR ARP020103749A patent/AR036734A1/es unknown
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- 2002-10-04 RU RU2004114278/04A patent/RU2296763C2/ru not_active IP Right Cessation
- 2002-10-04 BR BR0213172-2A patent/BR0213172A/pt not_active IP Right Cessation
- 2002-10-04 JP JP2003533936A patent/JP4101755B2/ja not_active Expired - Fee Related
- 2002-10-04 CN CNA02819912XA patent/CN1564686A/zh active Pending
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102471337A (zh) * | 2009-07-17 | 2012-05-23 | 日本烟草产业株式会社 | 三唑并吡啶化合物及其作为脯氨酰基羟化酶抑制剂和红细胞生成素产生诱导剂的作用 |
CN104370807A (zh) * | 2014-11-13 | 2015-02-25 | 安徽星宇化工有限公司 | 一种6-羟基-5-硝基烟酸的合成方法及其分离提纯方法 |
Also Published As
Publication number | Publication date |
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CA2462806A1 (en) | 2003-04-17 |
RU2296763C2 (ru) | 2007-04-10 |
AR036734A1 (es) | 2004-09-29 |
KR20040048940A (ko) | 2004-06-10 |
US20030207911A1 (en) | 2003-11-06 |
EP1435952A1 (en) | 2004-07-14 |
JP4101755B2 (ja) | 2008-06-18 |
PL370067A1 (en) | 2005-05-16 |
MXPA04003277A (es) | 2004-07-23 |
JP2005508942A (ja) | 2005-04-07 |
US6689790B2 (en) | 2004-02-10 |
RU2004114278A (ru) | 2005-10-27 |
KR100614486B1 (ko) | 2006-08-22 |
BR0213172A (pt) | 2004-09-14 |
WO2003030904A1 (en) | 2003-04-17 |
AU2002347055B2 (en) | 2006-10-12 |
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