CN117105872A - 苯并二氮杂䓬类化合物及其制备方法与用途 - Google Patents
苯并二氮杂䓬类化合物及其制备方法与用途 Download PDFInfo
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- CN117105872A CN117105872A CN202310301331.8A CN202310301331A CN117105872A CN 117105872 A CN117105872 A CN 117105872A CN 202310301331 A CN202310301331 A CN 202310301331A CN 117105872 A CN117105872 A CN 117105872A
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- Prior art keywords
- benzo
- tetrahydro
- dinitrogen
- carbonyl
- phenyl
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 37
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 claims abstract description 33
- 125000003118 aryl group Chemical group 0.000 claims abstract description 30
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 15
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- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 11
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
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- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 117
- ZWLPBLYKEWSWPD-UHFFFAOYSA-N o-toluic acid Chemical compound CC1=CC=CC=C1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 0.000 claims description 56
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 54
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- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 claims description 4
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Abstract
本发明公开了一种苯并二氮杂类化合物及其制备方法与用途。所述苯并二氮杂类化合物具有如下式所示的结构:其中,R1、R2各自独立地选自氢、卤素、氰基、硝基、羟基、氨基、C1‑C6烷基、C1‑C6烷氧基、C3‑C8环烷基、芳基、杂芳基、杂环基中的任一者;n选自1、2、3或4。本发明从构动关系的新角度提供了一种新的苯并二氮杂类化合物,其对V2R的亲和力略低于托伐普坦,但其停留时间更长,可用于诊断、预防和/或治疗与血管加压素受体相关的疾病,为此类疾病的治疗和预防提供了一类新型先导化合物。
Description
技术领域
本发明属于医药化合物技术领域,具体涉及一种苯并二氮杂类化合物及其制备方法,本发明还涉及包含苯并氮杂/>并环衍生物及其盐作为活性成分的药物,可用于诊断、预防和/或治疗与血管加压素受体相关的疾病。
背景技术
精氨酸加压素(AVP)又称后叶加压素、抗利尿激素,是由下丘脑产生和垂体释放的一种9肽环状激素,它与人体水钠代谢的调节密切相关。精氨酸加压素(AVP)的代谢紊乱可引起低钠血症、抗利尿激素分泌异常综合征、充血性心力衰竭、肝硬化、肾脏疾病、高血压以及浮肿等多种疾病。
研究表明,精氨酸加压素受体拮抗剂在预防和治疗高血压,雷氏综合征,痛经,早产,促肾上腺皮质激素分泌紊乱,肾上腺增生,抑郁症,慢性充血性心力衰竭,肝硬化,抗力尿激素分泌紊乱综合征或者慢性心力衰竭、肝硬化、抗利尿激素分泌紊乱引起的低钠血症以及常染色体显性多囊肾病中有积极作用。苯并氮杂类化合物考尼伐坦、托伐普坦等的开发已成为上述疾病治疗药物研发的热点方向。这类化合物具有拮抗精氨酸加压素受体的活性,并因此可应用于治疗上述疾病。
常染色体显性多囊肾病(Autosomal dominant polycystic kidney disease,ADPKD)是一种常见的遗传性肾脏疾病,其患病率在1/1000与1/2500之间。ADPKD可于胚胎期发病,其特征是肾小管和集合管形成充满液体的肾囊肿并不断增殖扩大,损害正常肾实质,这种由囊肿导致的肾功能不全会持续数十年,并最终导致终末期肾病(End-stage renaldisease,ESRD)。此外,ADPKD还可诱发一系列并发症,例如:高血压、急/慢性疼痛、血尿、囊肿感染和肾结石等,给患者的日常生活带来极大痛苦。因此探究ADPKD的发病机制,寻找抑制ADPKD发病进程的有效手段日益成为热点研究课题。
ADPKD是由基因突变而产生的疾病,PKD1、PKD2和GANAB等基因的功能异常被认为是诱发ADPKD的主要原因。PKD1和PKD2编码的初级纤毛多囊蛋白1(polycystin-1,PC1)和多囊蛋白2(polycystin-2,PC2)对疾病的发生发展有着极大的影响。在正常生理状态下,PC1和PC2通过协成作用,促进质膜Ca2+内流,调节肾脏及其他器官的小管发育。当PC1或者PC2功能丧失后,胞内Ca2+浓度降低可导致腺苷环化酶活性增加,磷酸二酯酶-1活性降低,环磷酸腺苷(cAMP)浓度上升,进而诱导细胞过度增殖且液体异常分泌,从而促进了囊泡的形成,使得囊肿和整体肾脏不断增大。
由于ADPKD是一种基因缺陷疾病,其药物靶点的选择十分困难,因此当前市面上可用且有效的治疗药物十分稀少,相关研究尚处于起步阶段。其中,V2R是目前研究最充分,在ADPKD治疗方面潜力最大的靶点。V2R下游的cAMP活性抑制被认为是其拮抗剂调控ADPKD的核心机制。通过拮抗V2R可以有效缓解囊泡的生成与扩大,减缓ADPKD的病程发展,而且其效果稳定,副作用相对较小。
在药物临床研究方面,托伐普坦(Tolvaptan,OPC41061)是目前临床上唯一被FDA(美国食品药品监督管理局)批准认证的ADPKD有效治疗药物。Tolvaptan是一种选择性的V2R拮抗剂,可延迟肾脏体积的增加(疾病进展的替代标记)、并减慢肾功能的下降、缓解ADPKD患者的疼痛。但是,该类药物在临床使用中,往往需要患者进行严格的血钠浓度监测、尿酸浓度监测以及肝功能监测等在内的长达数月的用药监测,同时,患者在治疗过程中可能出现电解质失调、尿酸分泌增加以及肝功能损伤等严重不良反应。这些问题大大限制了Tolvaptan的临床应用,降低了患者用药依从性。
近期,结合动力学在先导化合物筛选中的应用逐渐受到关注。研究提示,药物药效的发挥取决于药物与靶点的结合,当药物分子与其药物靶点结合形成二元复合物时,才能发挥药效。目前,在传统药物研发中,常以亲和力(affinity)作为筛选先导化合物的指标,但是基于传统评价体系中亲和力等评价指标筛选出的先导化合物,尽管会表现出较高的亲和力,但在后期的药效学评价中,可能会产生较低功效,甚至没有功效。产生这一现象的主要原因为:体内外的评价体系不同。传统亲和力的评价,主要是在体外封闭体系中进行。但是,人体环境处于时刻动态变化中,药物进入人体后经历吸收、分布、代谢和排泄等药物代谢过程,药物以及受体浓度很难达到体外封闭评价体系中的相对不变状态。因此,采用亲和力为评价指标的传统先导化合物筛选,具有一定局限性。而结合动力学参数RT(ResidenceTime)关注于药物与受体结合形成药物-受体二元复合物的存在时间,决定了药物药效的持续时间。由此,在以亲和力为评价指标的基础上,将结合动力学参数RT纳入药物评价体系,或许有利于筛选出功效高、不良反应少的先导化合物。
综上,虽然V2R拮抗剂可以通过抑制cAMP进而缓解ADPKD的发病进程,但临床上可用的药物仍十分稀少,因此将药物结合动力学参数纳入药物评价体系中,基于V2R拮抗剂化合物构效关系和构动关系对托伐普坦等已有的化合物进行结构修饰,研发出治疗效果更好、毒副作用更小的药物来缓解ADPKD的发生是亟待解决的问题。
发明内容
本发明的主要目的在于提供一种苯并二氮杂类化合物及其制备方法与用途,以克服现有技术的不足。
为实现前述发明目的,本发明采用的技术方案包括:
本发明实施例提供了一种苯并二氮杂类化合物,所述苯并二氮杂/>类化合物具有如式(I)所示的结构:
其中,R1、R2各自独立地选自氢、卤素、氰基、硝基、羟基、氨基、C1-C6烷基、C1-C6烷氧基、C3-C8环烷基、芳基、杂芳基、杂环基中的任一者,其中芳基、杂芳基或杂环基是未取代或者至少被一个选自C1-6烷基的取代基取代;n选自1、2、3或4。
本发明实施例还提供了前述的苯并二氮杂类化合物的制备方法,其包括:
使1,3,4,5-四氢-2H-苯并[b][1,4]二氮杂-2-酮与溴代酚氧烷基类化合物反应,获得第一中间体;
对所述第一中间体进行还原处理,制得第二中间体;
使所述第二中间体与硝基苯甲酰氯反应,之后进行氢化还原处理,制得第三中间体;
以及,使所述第三中间体与苯甲酸类化合物反应,制得所述苯并二氮杂类化合物。
本发明实施例还提供了前述的苯并二氮杂类化合物、其立体异构体或其药学可接受的盐在制备用于预防和/或治疗与精氨酸加压素V1a受体、精氨酸加压素V1b受体、精氨酸加压素V2受体、交感神经系统或肾素-血管紧张素-醛固酮系统相关的疾病的药物中的用途。
本发明实施例还提供了一种药物组合物,其包括前述的苯并二氮杂类化合物、其立体异构体或其药学可接受的盐,以及药学上可接受的载体。
与现有技术相比,本发明的有益效果在于:本发明提供了一种新的苯并二氮杂类化合物,其对V2R的亲和力与托伐普坦相当,且对PKD疾病中的囊泡发展有很好的抑制作用,同时本申请中的苯并二氮杂/>类化合物具有更长的靶点停留时间,为疾病的治疗和预防提供了一类新型先导化合物。
具体实施方式
鉴于现有技术的缺陷,本案发明人经长期研究和大量实践,得以提出本发明的技术方案,下面将对本发明的技术方案进行清楚、完整地描述,显然,所描述的实施例是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
具体的,作为本发明技术方案的一个方面,其所涉及的一种苯并二氮杂类化合物具有如式(I)所示的结构:
其中,R1、R2各自独立地选自氢、卤素、氰基、硝基、羟基、氨基、C1-C6烷基、C1-C6烷氧基、C3-C8环烷基、芳基、杂芳基、杂环基中的任一者,其中芳基、杂芳基或杂环基是未取代或者至少被一个选自C1-6烷基的取代基取代;n选自1、2、3或4。
在一些优选实施方案中,所述R1选自C1-C6烷基或芳基,R2选自C1-C6烷基、C1-C6烷氧基或卤素。
进一步地,所述R1选自甲基或芳基,R2选自甲基、甲氧基或卤素。
更进一步地,所述R1为芳基,R2选自氯。
在一些优选实施方案中,所述R1为芳基,R2选自C1-C6烷基、C1-C6烷氧基或卤素。
进一步地,所述R1为芳基,R2为3-氯基。
在一些优选实施方案中,所述R1为芳基,R2选自2-氟基、4-甲基、4-甲氧基中的任一者。
在一些优选实施方案中,所述苯并二氮杂类化合物包括2-甲基-N-(4-(5-(2-苯氧乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)苯甲酰胺、2-甲基-N-(4-(5-(3-苯氧丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)苯甲酰胺、2-甲基-N-(4-(5-(4-苯氧丁基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)苯甲酰胺、2-甲基-N-(4-(5-(5-苯氧戊基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)苯甲酰胺、N-(4-(5-(2-苯氧乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(3-苯氧丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(4-苯氧丁基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(5-苯氧戊基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(2-(2-氯苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(2-(3-氯苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(2-(4-氯苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(2-(2-氟苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(2-(3-氟苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(2-(4-氟苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(2-(邻甲苯基氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(2-(间甲苯基氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(2-(对甲苯基氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(2-(2-甲氧基苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(2-(3-甲氧基苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(2-(4-甲氧基苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(3-(2-氯苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(3-(3-氯苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(3-(4-氯苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(3-(2-氟苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(3-(3-氟苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(3-(4-氟苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(3-(邻甲苯基氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(3-(间甲苯基氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(3-(对甲苯基氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(3-(2-甲氧基苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(3-(3-甲氧基苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(3-(4-甲氧基苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺中的任意一种或两种以上的组合,且不限于此。
在一些优选实施方案中,所述苯并二氮杂类化合物包括:
1)2-甲基-N-(4-(5-(2-苯氧乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)苯甲酰胺;
2)2-甲基-N-(4-(5-(3-苯氧丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)苯甲酰胺;
3)2-甲基-N-(4-(5-(4-苯氧丁基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)苯甲酰胺;
4)2-甲基-N-(4-(5-(5-苯氧戊基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)苯甲酰胺;
5)N-(4-(5-(2-苯氧乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺;
6)N-(4-(5-(3-苯氧丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺;
7)N-(4-(5-(4-苯氧丁基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺;
8)N-(4-(5-(5-苯氧戊基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺;
9)N-(4-(5-(2-(2-氯苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺;
10)N-(4-(5-(2-(3-氯苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺;
11)N-(4-(5-(2-(4-氯苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺;
12)N-(4-(5-(2-(2-氟苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺;
13)N-(4-(5-(2-(3-氟苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺;
14)N-(4-(5-(2-(4-氟苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺;
15)N-(4-(5-(2-(邻甲苯基氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺;
16)N-(4-(5-(2-(间甲苯基氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺;
17)N-(4-(5-(2-(对甲苯基氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺;
18)N-(4-(5-(2-(2-甲氧基苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺;
19)N-(4-(5-(2-(3-甲氧基苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺;
20)N-(4-(5-(2-(4-甲氧基苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺;
21)N-(4-(5-(3-(2-氯苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺;
22)N-(4-(5-(3-(3-氯苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺;
23)N-(4-(5-(3-(4-氯苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺;
24)N-(4-(5-(3-(2-氟苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺;
25)N-(4-(5-(3-(3-氟苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺;
26)N-(4-(5-(3-(4-氟苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺;
27)N-(4-(5-(3-(邻甲苯基氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺;
28)N-(4-(5-(3-(间甲苯基氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺;
29)N-(4-(5-(3-(对甲苯基氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺;
30)N-(4-(5-(3-(2-甲氧基苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺;
31)N-(4-(5-(3-(3-甲氧基苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺;或
32)N-(4-(5-(3-(4-甲氧基苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺。
本发明实施例的另一个方面还提供了前述的苯并二氮杂类化合物的制备方法,其包括:
使1,3,4,5-四氢-2H-苯并[b][1,4]二氮杂-2-酮与溴代酚氧烷基类化合物反应,获得第一中间体;
对所述第一中间体进行还原处理,制得第二中间体;
使所述第二中间体与硝基苯甲酰氯反应,之后进行氢化还原处理,制得第三中间体;
以及,使所述第三中间体与苯甲酸类化合物反应,制得所述苯并二氮杂类化合物。
在一些优选实施方案中,所述溴代酚氧烷基类化合物包括2-溴乙氧基苯、3-溴丙氧基苯、4-溴丁氧基苯、5-溴戊氧基苯、1-(2-溴乙氧基)-2-氯苯、1-(2-溴乙氧基)-3-氯苯、1-(2-溴乙氧基)-4-氯苯、1-(2-溴乙氧基)-2-氟苯、1-(2-溴乙氧基)-3-氟苯、1-(2-溴乙氧基)-4-氟苯、1-(2-溴乙氧基)-2-甲基苯、1-(2-溴乙氧基)-3-甲基苯、1-(2-溴乙氧基)-4-甲基苯、1-(2-溴乙氧基)-2-甲氧基苯、1-(2-溴乙氧基)-3-甲氧基苯、1-(2-溴乙氧基)-4-甲氧基苯、1-(3-溴丙氧基)-2-氯苯、1-(3-溴丙氧基)-3-氯苯、1-(3-溴丙氧基)-4-氯苯、1-(3-溴丙氧基)-2-氟苯、1-(3-溴丙氧基)-3-氟苯、1-(3-溴丙氧基)-4-氟苯、1-(3-溴丙氧基)-2-甲基苯、1-(3-溴丙氧基)-3-甲基苯、1-(3-溴丙氧基)-4-甲基苯、1-(3-溴丙氧基)-2-甲氧基苯、1-(3-溴丙氧基)-3-甲氧基苯、1-(3-溴丙氧基)-4-甲氧基苯中的任意一种或两种以上的组合,且不限于此。
在一些优选实施方案中,所述苯并二氮杂类化合物具有下式结构中的任一者:
在一些优选实施方案中,所述制备方法包括:采用硼烷-二甲硫醚、四氢铝锂或硼氢化钠-路易斯酸体系对所述第一中间体进行还原处理,制得第二中间体。
进一步地,采用四氢铝锂对所述第一中间体进行还原处理。
在一些优选实施方案中,所述制备方法包括:采用雷尼镍、Pd/C或Fe/HCl进行所述氢化还原处理。
进一步地,采用Pd/C或Fe/HCl进行所述氢化还原处理。
在一些优选实施方案中,所述苯甲酸类化合物包括2-甲基苯甲酸和/或2-苯基苯甲酸,且不限于此。
本发明实施例的另一个方面还提供了前述的苯并二氮杂类化合物、其立体异构体或其药学可接受的盐在制备用于预防和/或治疗与精氨酸加压素V1a受体、精氨酸加压素V1b受体、精氨酸加压素V2受体、交感神经系统或肾素-血管紧张素-醛固酮系统相关的疾病的药物中的用途。
在一些优选实施方案中,所述与精氨酸加压素V1a受体、精氨酸加压素V1b受体、精氨酸加压素V2受体、交感神经系统或肾素-血管紧张素-醛固酮系统相关的疾病包括高血压、雷氏综合征、痛经、早产、促肾上腺皮质激素释放激素分泌紊乱、肾上腺增生、抑郁症、慢性充血性心力衰竭、肝硬化、抗利尿激素分泌紊乱综合征、慢性心力衰竭/肝硬化/抗利尿激素分泌紊乱引起的低钠血症或多囊肾疾病。
在一些优选实施方案中,所述药学可接受的盐是由所述苯并二氮杂类化合物与无机酸和/或有机酸形成的盐。
进一步地,所述无机酸包括盐酸、氢溴酸、硫酸或磷酸中的任意一种或两种以上的组合,且不限于此。
进一步地,所述有机酸包括柠檬酸、乳酸、苹果酸、葡糖酸、酒石酸、己二酸、醋酸、琥珀酸、富马酸、抗败血酸、衣康酸、甲磺酸或苯磺酸中的任意一种或两种以上的组合,且不限于此。
本发明实施例的另一个方面还提供了一种药物组合物,其包括前述的苯并二氮杂类化合物、其立体异构体或其药学可接受的盐,以及药学上可接受的载体。
除非另有说明,上述结构通式中使用的化学属于具有通常的含义。
例如,除非另有说明,本发明所用的属于“卤素”是指氟、氯、溴或碘。优选的,“卤素”为氟、氯或溴。
在本发明中,除非另有说明,“烷基”是指具有至多10个碳原子的直链或支链的一价饱和烃基。烷基的代表性的实例包括但不限于包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、正己基、2-己基、2-甲基戊基、3-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、正庚基、正辛基、正壬基、正癸基等。类似的,“C1-C6烷基”中的“C1-C6”是指包含有1、2、3、4、5或6个碳原子的直链或支链形式排列的基团。
在本发明中,除非另有说明,术语“烷氧基”是指烷基-O-,其中烷基如上定义。烷氧基的代表性实例包括但不限于甲氧基、乙氧基、丙氧基、2-丙氧基、丁氧基、叔丁氧基、戊氧基、己氧基等。通常,烷氧基具有1-6个碳,更通常1-4个碳原子。
在本发明中,除非另有说明,术语“环烷基”是指3-12个碳原子的饱和或不饱和的非芳族单环、双环、三环或螺环烃基:环烷基可以是不饱和的,并且可以与另一个可以是饱和的、不饱和的或芳族的环稠合,条件是与目标分子式连接的环烷基的环原子不是芳环碳。除非另有说明,否则环烷基是指具有3至9个环碳原子或3至7个环碳原子的环状烃基。优选地,除非另有说明,环烷基是具有3-7个环原子的饱和单环,例如环丙基、环丁基、环戊基和环己基,。
在本发明中,除非另有说明,术语“杂环基”是指饱和或部分不饱和但不是芳香族的杂环基,并且可以是单环或多环(在多环的情况下,特别是双环、三环或螺环);并且具有3至14个、更常见的是4至10个、最优选5或6个环原子;其中一个或多个、优选一至四个、尤其是一个或两个环原子是独立地选自O、S和N的杂原子(其余的环原子是碳)。即使被描述为例如C5-6原子环,则杂环含有至少一个杂原子作为环原子,其它环原子是碳,并且具有所述的环原子数,例如在此示例中是5-6。优选地,杂环基具有一个或两个这样的杂原子作为环原子,并且优选地,杂原子不直接彼此连接。除非另有说明,键合环(即连接到目标式的环)优选具有4-12个、特别是5-7个环原子。杂环基团可以稠合到芳环上,条件是与目标化学式连接的杂环基团的原子不是芳香性的。杂环基团可以通过杂原子(通常为氮)或杂环基团上的碳原子与目标式连接。杂环基可以包括稠环或桥环以及螺环,并且只要多环杂环基团的一个环含有杂原子作为环原子。该杂环基可以被连接到任何的杂原子或碳原子上以形成稳定的结构。这些杂环基的实例包括但不限于四氢呋喃(THF)基、二氢呋喃基、1,4-二氧六环基、吗啉基、1,4-二噻烷基、哌嗪基、哌啶基、1,3-二氧戊环基、咪唑烷基、咪唑啉基、吡咯啉基、吡咯烷基、四氢吡喃基、二氢吡喃基、氧硫杂环戊烷基、二硫杂环戊烷基、1,3-二氧六环基、1,3-二噻烷基、氧硫杂环己烷基、硫代吗啉基等。
在本发明中,除非另有说明,术语“芳基”是指环部分中具有6-14个碳原子的芳族烃基。通常,芳基是具有6-14个碳原子、通常为6-10个碳原子的单环、双环或三环芳基,例如苯基或萘基。此外,如本文所用的术语“芳基”是指芳族取代基,其可以是单个芳族环,或稠合在一起的多个芳族环。非限制性实例包括苯基、萘基和1,2,3,4-四氢萘基,条件是四氢萘基通过四氢萘基的芳环的碳与与目标分子式连接。除非另有说明,优选的芳基是苯基。
在本发明中,除非另有说明,术语“杂芳基”是指5-14元单环-或双环-或三环-芳族环系统,具有1至8个杂原子作为环原子,其余环原子为碳,并且杂原子选自N、O和S。通常,杂芳基是5-10元环系,特别是5-6元单环或8-10元双环基团。杂芳基可以连接在任何杂原子或碳原子上以形成稳定的结构。杂芳基的实例包括但不限于噻吩基、呋喃基、咪唑基、异恶唑基、恶唑基、吡唑基、吡咯基、噻唑基、噻二唑基、三唑基、吡啶基、哒嗪基、吲哚基、氮杂吲哚基、吲唑基、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并异恶唑基、苯并噻唑基、苯并噻唑基、苯并噻二唑基、苯并三唑基腺嘌呤、喹啉基或异喹啉基。
术语“取代的”或“取代”是指基团中的一个或多个氢原子分别被相同的或者不同的取代基所取代。典型的取代基包括但不限于卤素(F、Cl、Br或I)、C1-C8烷基、C3-12环烷基、-OR1、-SR1、=O、=S、-C(O)R1、-C(S)R1、=NR1、-C(O)OR1、-C(S)OR1、-NR1R1、-C(O)NR1R1、氰基、硝基、-S(O)2R1、-O-S(O2)OR1、-O-S(O)2R1、-OP(O)(OR1)(OR2);其中R1和R2独立地选自-H、C1-C6烷基、C1-C6卤代烷基。在一些实施例中,取代基独立地选自包含-F、-Cl、-Br、-I、-OH、三氟甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、-SCH3、-SC2H5、甲醛基、-C(OCH3)、氰基、硝基、-CF3、-OCF3、氨基、二甲基氨基、甲硫基、磺酰基和乙酰基的基团。
本发明化合物能由于存在氨基和/或羧基或类似基团而形成酸和/或碱盐。如本文所用,术语“盐”或“盐类”是指本发明化合物的酸加成盐或碱加成盐。“盐”特别包括“药学上可接受的盐”。术语“药学上可接受的盐”是指保留本发明化合物的生物有效性和性质并且通常是生物学上或其他方面符合需要的盐。尤其是,从药学上可接受的无毒的碱或酸制备的盐。当本发明提供的化合物是酸时,可以从药学上可接受的无毒的碱,包括无机碱和有机碱,方便地制得其相应的盐。从无机碱衍生的盐包括铝、铵、钙、铜(高价和低价)、三价铁、亚铁、锂、镁、锰(高价和低价)、钾、钠、锌之类的盐。特别优选铵、钙、镁、钾和钠的盐。药学上可接受的能够衍生成盐的无毒有机碱包括伯胺、仲胺和叔胺,也包括环胺及含有取代基的胺,如天然存在的和合成的含取代基的胺。能够成盐的其他药学上可接受的无毒有机碱,包括离子交换树脂以及精氨酸、甜菜碱、咖啡因、胆碱、N′,N′-二苄乙二胺、二乙胺、2-二乙氨基乙醇、2-二甲胺基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、还原葡萄糖胺、氨基葡萄糖、组氨酸、哈胺、异丙胺、赖氨酸,甲基葡萄糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。
当本发明提供的化合物是碱时,可以从药学上可接受的无毒的酸,包括无机酸和有机酸,方便制得其相应的盐。这样的酸包括无机酸和有机酸,例如,醋酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、甲酸、富马酸、葡萄糖酸、谷氨酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、黏酸、硝酸、扑酸、泛酸、磷酸、琥珀酸、硫酸、酒石酸和对甲苯磺酸等。优选的,无机酸为盐酸、氢溴酸、硫酸或磷酸等,有机酸为柠檬酸、乳酸、苹果酸、葡糖酸、酒石酸、己二酸、醋酸、琥珀酸、富马酸、抗败血酸、衣康酸、甲磺酸或苯磺酸等。由于式(I)所示化合物将作为药物应用,较优地,使用一定纯度,例如,至少为60%纯度,比较合适的纯度为至少75%,特别合适地纯度为至少98%(%是重量比)。
本发明的药学上可接受的盐可以通过常规化学方法由碱性或酸性部分合成。通常,这些盐可以通过使这些化合物的游离酸形式与化学计量量的适当碱(例如Na、Ca、Mg或K,氢氧化物、碳酸盐、碳酸氢盐等)反应来制备,或者通过使这些化合物的游离碱形式与化学计算量的合适的酸反应。这样的反应通常在水中或在有机溶剂中或在两者的混合物中进行。通常,在可行的情况下,使用非水介质如醚、乙酸乙酯、四氢呋喃、甲苯、氯仿、二氯甲烷、甲醇、乙醇、异丙醇或乙腈是较为理想的。
本发明化合物的药物前体包含在本发明的保护范围内。通常,所述药物前体是指很容易在体内转化成所需化合物的功能性衍生物。例如,本申请化合物的任何药学上可接受的盐、酯、酯的盐或其它衍生物,其在向受体施用后能够直接或间接地提供本申请的化合物或其具有药学活性的代谢物或残基。特别优选的衍生物或前药是在施用于患者时可以提高本申请化合物生物利用度的那些化合物(例如,可以使口服的化合物更易于被吸收到血液中),或者促进母体化合物向生物器官或作用位点(例如脑部或淋巴系统)递送的那些化合物。因此,本发明提供的治疗方法中的术语“给药”是指施用能治疗不同疾病的本发明公开的化合物,或虽未明确公开但对受试者给药后能够在体内转化为本发明公开的化合物。有关选择和制备合适药物前体衍生物的常规方法,已记载在例如《药物前体设计》(Designof Prodrugs,ed.H.Bundgaard,Elsevier,1985)这类书中。
本发明所述化合物可能含有一个或多个不对称中心,并可能由此产生非对映异构体和光学异构体。本发明包括所有可能的非对映异构体及其外消旋混合物、其基本上纯的拆分对映异构体、所有可能的几何异构体及其药学上可接受的盐。
以上所述式(I)没有确切定义该化合物某一位置的立体结构。本发明包括式(I)所示化合物的所有立体异构体及其药学上可接受的盐。进一步地,立体异构体的混合物及分离出的特定的立体异构体也包括在本发明中。制备此类化合物的合成过程中,或使用本领域技术人员公知的外消旋化或差向异构化的过程中,制得的产品可以是立体异构体的混合物。当式(I)所示化合物存在互变异构体时,除非特别声明,本发明包括任何可能的互变异构体和其药学上可接受的盐,及它们的混合物。
当式(I)所示化合物及其药学上可接受的盐存在溶剂化物或多晶型时,本发明包括任何可能的溶剂化物和多晶型。形成溶剂化物的溶剂类型没有特别的限定,只要该溶剂是药学上可以接受的。例如,水、乙醇、丙醇、丙酮等类似的溶剂都可以采用。
因此,本发明的药物组合物包括药学上可接受的载体和式(I)所示化合物或其立体异构体、互变异构体,多晶型物、溶剂化物、其药学上可接受的盐、其药物前体。式(I)所示化合物或其药学上可接受的盐,与其他一种或多种具有治疗活性的化合物的联合用药也包括在本发明的药物组合物中。
本发明中,术语“组合物”,是指包括包含指定量的各指定成分的产品,以及直接或间接地由指定量的各指定成分的组合生产的任何产品。因此,含有本发明的化合物作为活性成分的药物组合物以及制备本发明化合物的方法也是本发明的一部分。此外,化合物的一些结晶形式可以多晶型存在,并且此多晶型包括在本发明中。另外,一些化合物可以与水(即水合物)或常见的有机溶剂形成溶剂化物,并且此类溶剂化物也落入本发明的范围内。
本发明提供的药物组合物包括作为活性组分的式(I)所示化合物(或其药学上可接受的盐)、一种药学上可接受的赋形剂及其他可选的治疗组分或辅料。尽管任何给定的情况下,最适合的活性组分给药方式取决于接受给药的特定的主体、主体性质和病情严重程度,但是本发明的药物组合物包括适于口腔、直肠、局部和不经肠道(包括皮下给药、肌肉注射、静脉给药)给药的药物组合物。本发明的药物组合物可以方便地以本领域公知的单位剂型存在和药学领域公知的任何制备方法制备。
实际上,根据常规的药物混合技术,本发明式(I)所示化合物,或药物前体,或代谢物,或药学上可接受的盐,可以作为活性组分,与药物载体混合成药物组合物。所述药物载体可以采取各种各样的形式,这取决于期望采用的给药方式,例如,口服或注射(包括静脉注射)。因此,本发明的药物组合物可以采用适于口服给药的独立单元,如包含预定剂量的活性组分的胶囊剂、扁囊剂或片剂。进一步地,本发明的药物组合物可采用粉末、颗粒、溶液、水性悬浮液、非水液体、水包油型乳液,或油包水型乳液形式。另外,除了上述提到的常见的剂型,式(I)所示化合物或其药学上可接受的盐,也可以通过控释的方式和/或输送装置给药。本发明的药物组合物可以采用任何制药学上的方法制备。一般情况下,这种方法包括使活性组分和组成一个或多个必要成分的载体缔合的步骤。一般情况下,所述药物组合物经由活性组分与液体载体或精细分割的固体载体或两者的混合物经过统一的密切的混合制得。另外,该产品可以方便地制备成所需要的外观。
在本发明中,术语“药学可接受的载体”包括任何和所有溶剂、分散介质、包衣、表面活性剂、抗氧化剂、防腐剂(例如抗菌剂、抗真菌剂)、等渗剂、吸收延迟剂、盐、防腐剂、药物稳定剂、粘合剂、赋形剂、崩解剂、润滑剂、甜味剂、调味剂、染料等及其组合,如本领域技术人员已知(参见例如Remington:The Science and Practice of Pharmacy,第22版)。除了与活性成分不相容的任何常规载体之外,还考虑其在治疗或药物组合物中的用途。术语“治疗有效量”的本发明化合物是指在对象中引发生物或医学反应的本发明化合物的量,例如,足以减少一种或多种症状、缓解病症、减慢或延迟疾病进展或预防疾病等的量。在一个非限制性实施方式中,术语“治疗有效量”是指当施用于对象时,本发明化合物有效预防或治疗与精氨酸加压素V1a受体、精氨酸加压素V1b受体、精氨酸加压素V2受体、交感神经系统或肾素-血管紧张素-醛固酮系统相关的疾病的量。
具体来说,本发明采用的药物载体可以是,例如,固体载体、液体载体或气体载体。固体载体,包括但不限于乳糖、石膏粉、蔗糖、滑石粉、明胶、琼脂、果胶、阿拉伯胶、硬脂酸镁、硬脂酸。液体载体,包括但不限于糖浆、花生油、橄榄油和水。气体载体,包括但不限于二氧化碳和氮气。制备药物口服制剂时,可以使用任何制药学上方便的介质。例如,水、乙二醇、油类、醇类、增味剂、防腐剂、着色剂等可用于口服的液体制剂如悬浮剂、酏剂和溶液剂;而载体,如淀粉类、糖类、微晶纤维素、稀释剂、造粒剂、润滑剂、粘合剂、崩解剂等可用于口服的固体制剂如散剂、胶囊剂和片剂。考虑到易于施用,口服制剂首选片剂和胶囊,在此应用固体药学载体。可选地,片剂包衣可使用标准的水制剂或非水制剂技术。
含有本发明化合物或药物组合物的片剂可通过压缩或模塑成型,可选地,可以与一种或多种辅助组分或辅药一起制成片剂。活性组分以自由流动的形式如粉末或颗粒,与粘合剂、润滑剂、惰性稀释剂、表面活性剂或分散剂混合,在适当的机器中,通过压缩可以制得压缩片。用一种惰性液体稀释剂浸湿粉末状的化合物或药物组合物,然后在适当的机器中,通过模塑可以制得模塑片。根据本领域已知的方法,片剂可以是薄膜包衣或肠溶包衣。较优地,每个片剂含有大约0.05mg到5g的活性组分,每个扁囊剂或胶囊剂含有大约0.05mg到5g的活性组分。例如,拟用于人类口服给药的配方包含约0.5mg到约5g的活性组分,与合适且方便计量的辅助材料复合,该辅助材料约占药物组合物总量的5%至95%。单位剂型一般包含约1mg到约2g的活性组分,典型的是25mg、50mg、100mg、200mg、300mg、400mg、500mg、600mg、800mg或1000mg。
本发明中的药物组合物可以为某些可注射组合物是水性等渗溶液或悬浮液,且栓剂有利地由脂肪乳剂或混悬剂制备。所述组合物可以是灭菌的和/或含有佐剂,如防腐剂、稳定剂、润湿剂或乳化剂、溶液促进剂、调节渗透压的盐和/或缓冲剂。另外,它们也可能含有其他有治疗价值的物质。所述组合物分别根据常规的混合、制粒或包衣方法制备,并且含有约0.1-75%或含有约1-50%的活性成分。
本发明中的药物组合物可以为用于透皮施用的合适组合物包含有效量的本发明化合物与合适的载体。适合透皮递送的载体包括可吸收的药理学可接受的溶剂以帮助穿过宿主皮肤。例如,透皮装置为绷带形式,其包含背衬构件,含有化合物以及可选有载体的储库,可选地速率控制屏障来在长时间段以受控并预定的速率作宿主皮肤的化合物递送,以及将装置固定到皮肤的手段。
本发明中的药物组合物可以为用于局部施用(例如皮肤和眼睛)的合适组合物包括水溶液、混悬剂、软膏剂、乳膏剂、凝胶剂或可喷雾制剂,例如用于通过气雾剂递送等。这些局部递送系统可以涉及(例如)可适用于治疗流感的吸入或鼻内应用且可含有增溶剂、稳定剂、张力增强剂、缓冲剂和防腐剂。使用或不使用合适的推进剂,它们可以方便地以干粉(单独地,作为混合物,例如与乳糖的干混物,或混合组分颗粒,例如与磷脂)形式从干粉吸入器递送或以气溶胶喷雾剂形式递送自加压容器、泵、喷器、雾化器或喷雾器。
对于约50-70kg的人类对象,本发明的药物组合物或组合的单位剂量可含有约1-1000mg活性成分(一种或多种),或约1-500mg或约1-250mg或约1-150mg或约0.5-100mg,或约1-50mg活性成分。化合物、药物组合物或其组合的治疗有效剂量取决于对象的种类、体重、年龄和个体状况、所治疗的紊乱或疾病或其严重程度。普通技术的医师、临床医生或兽医可以容易地确定预防、治疗或抑制病症或疾病进展所必需的各活性成分的有效量。
一般情况下,治疗上述所示的状况或不适,药物的剂量水平约为每天0.01mg/kg体重到150mg/kg体重,或者每个病人每天0.5mg到7g。例如,炎症、癌症、牛皮癣、过敏/哮喘、免疫系统的疾病和不适、中枢神经系统(CNS)的疾病和不适,有效治疗的药物剂量水平为每天0.01mg/kg体重到50mg/kg体重,或者每个病人每天0.5mg到3.5g。但是,可以理解,可能需要比上述那些更低或更高的剂量。任何特定病人的具体剂量水平和治疗方案将取决于多种因素,包括所用具体化合物的活性、年龄、体重、综合健康状况、性别、饮食、给药时间、给药途径、排泄率、药物联用的情况和接受治疗的特定疾病的严重程度。
以下实施例旨在说明本发明,而不应被解释为对其限制。温度以摄氏度给出。如果没有另外提及,所有蒸发都在减压下进行,通常在约15mmHg和100mmHg(约20-133mbar)之间。最终产物、中间体和原料的结构通过标准分析方法例如微量分析和光谱学特征例如MS、IR、NMR来确认。本发明所有的部分和百分数均以重量计算,所有的温度均为摄氏度。本文所述的化合物可以从市售获得或可通过以下使用市售的原料和试剂的常规方法合成。本发明中所使用的缩写是本领域中常规的缩写。现列举本发明中的部分缩写如下:
缩写
MS 质谱法
IR 红外吸收光谱法
NMR 核磁共振波谱
HRMS 高分辨质谱法
ESI 电喷雾离子源
Tolvaptan 托伐普坦
EA 乙酸乙酯
PE 石油醚
DCM 二氯甲烷
MeOH 甲醇
EtOH 乙醇
LiAlH4 氢化铝锂
THF 四氢呋喃
NaH 氢化钠
DMF N,N-二甲基甲酰胺
HATU 2-(7-氮杂苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯
Et3N 三乙胺
Pd/C 钯碳催化剂
CDCl3 氘代氯仿
DMSO 二甲基亚砜
NaHCO3 碳酸氢钠
K2CO3 碳酸钾
HCl 盐酸
Fe 铁粉
g 克
kg 千克
mL 毫升
mmol 毫摩尔
nm 纳米
μm 微米
μM 纳摩尔每升(微摩尔每升)
nM 体积摩尔浓度(纳摩尔每升)
M 体积摩尔浓度(摩尔每升)
℃ 摄氏度
h 小时
min 分钟
V2R 血管加压素-2-受体
AC 酶真核细胞腺苷酸环化酶
Forskolin 腺苷酸环化酶激活剂
ADPKD 常染色体显性多囊肾病
本发明具体实施例中的化合物1-32是新型苯并二氮杂类化合物,化合物1-32的制备方法是以1,3,4,5-四氢-2H-苯并[b][1,4]二氮杂/>-2-酮为起始原料,在NaH的作用下得到相应的第一中间体,第一中间体经LiAlH4还原得到第二中间体,第二中间体与对硝基苯甲酰氯反应后经Pd/C和H2或Fe/HCl还原得到第三中间体,第三中间体再与相应的苯甲酸反应得到目标产物苯并二氮杂/>类化合物(化合物1-32),具体反应过程如下所示:/>
下面结合若干优选实施例对本发明的技术方案做进一步详细说明,本实施例在以发明技术方案为前提下进行实施,给出了详细的实施方式和具体的操作过程,但本发明的保护范围不限于下述的实施例。
下面所用的实施例中所采用的实验材料,如无特殊说明,均可由常规的生化试剂公司购买得到。
实施例1
2-甲基-N-(4-(5-(2-苯氧乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)苯甲酰胺(化合物1)的制备
步骤1:1-(2-苯氧乙基)-1,3,4,5-四氢-2H-苯并[b][1,4]二氮杂-2-酮(第一中间体)的制备:
将1,3,4,5-四氢-2H-苯并[b][1,4]二氮杂-2-酮(2.0g,12.35mmol)溶于N,N-二甲基甲酰胺(20mL)中,在冰浴条件下分批加入氢化钠(1.5g,37.04mmol)搅拌30分钟,然后逐滴加入2-苯氧乙基溴(2.5g,12.35mmol),室温搅拌过夜。反应液加水(200mL)稀释,以乙酸乙酯(200mL)萃取三次,合并有机相,减压蒸干溶剂。再加水稀释(200mL),用乙酸乙酯(200mL)萃取一次,保留有机相。减压蒸干溶剂,固体残留物经硅胶柱层析纯化(洗脱剂∶PE/EA=4∶1),得棕黄色油状第一中间体(2.8g,收率:80.5%)。
1H NMR(400MHz,CDCl3)δ7.51-7.45(m,1H),7.26-7.22(m,2H),7.14-7.04(m,2H),6.96-6.82(m,4H),4.27-4.11(m,4H),3.74(t,J=6.8Hz,2H),2.52(t,J=6.6Hz,2H)。
步骤2:1-(2-苯氧基乙基)-2,3,4,5-四氢苯并[b][1,4]二氮(第二中间体)的制备:
将第一中间体(2.5g,8.87mmol)溶于四氢呋喃(200mL)中,在冰浴条件下分批加入氢化铝锂(2.0g,53.19mmol)搅拌30分钟,70℃回流搅拌1.5小时。反应液加入10%NaOH(5.4mL)淬灭,过滤,保留滤液,减压蒸干溶剂,固体残留物经硅胶柱层析纯化(洗脱剂∶PE/EA=10∶1),得淡黄色油状第二中间体(1.0g,收率:52.6%)。
1H NMR(400MHz,CDCl3)δ7.34-7.27(m,2H),7.01-6.92(m,4H),6.87-6.78(m,2H),6.69(dd,J=7.4,1.8Hz,1H),4.18(t,J=6.2Hz,2H),3.64(t,J=6.2Hz,2H),3.34-3.29(m,2H),3.25-3.18(m,2H),1.88(p,J=5.8Hz,2H)。
步骤3:(4-氨基苯基)(5-(2-苯氧乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-1-基)甲酮(第三中间体)的制备:
将第二中间体(1.0g,3.73mmol)溶于二氯甲烷(100mL)中,加入三乙胺(1.0mL,7.46mmol)和对硝基苯甲酰氯(1.0g,5.60mmol),室温搅拌1小时。加入水100mL,萃取后保留有机相。减压蒸干溶剂,得黄色油状物。
将上述黄色油状物(1.5g,3.59mmol)不经处理,1)直接溶于甲醇(100mL)中,加入钯/碳催化剂(10%Pd,0.2g)。在氢气环境下室温搅拌4小时。滤掉钯/碳催化剂,减压蒸干溶剂,固体残留物经硅胶柱层析纯化(洗脱剂∶PE/EA=3∶1);2)溶于乙醇(60mL)和水(20mL)的混合溶液中,加入1N HCl(0.61mL)和和铁粉(0.9g,15.45mmol),85℃回流搅拌1小时。待反应也冷却至室温,用硅藻土抽滤,浓缩滤液。用饱和碳酸氢钠溶液调PH至中性,加入二氯甲烷(100mL)萃取1次,保留有机相。再用饱和食盐水洗1次,保留有机相,减压蒸干溶剂,固体残留物经硅胶柱层析纯化(洗脱剂∶PE/EA=3∶1),两种方法均得淡黄色油状第三中间体(1.1g,收率:76.2%)。
1H NMR(400MHz,CDCl3)δ7.31-7.23(m,2H),7.16-7.06(m,3H),7.04-6.91(m,2H),6.91-6.85(m,2H),6.66-6.59(m,2H),6.32-6.22(m,2H),4.68-4.53(m,1H),4.19(t,J=6.0Hz,2H),3.90-3.78(m,1H),3.71-3.51(m,2H),3.25-3.12(m,1H),3.07-2.95(m,1H),2.13-1.99(m,1H),1.91-1.79(m,1H)。
步骤4:2-甲基N-(4-(5-(2-苯氧乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)苯甲酰胺(化合物1)的制备:
将第三中间体(1.0g,2.58mmol)溶于二氯甲烷(50mL)中,按顺序加入三乙胺(0.81mL,5.81mmol)、HATU(1.47g,3.88mmol)和2-甲基苯甲酸(0.53g,3.88mmol),室温搅拌过夜。加入水100mL,萃取后保留有机相。减压蒸干溶剂,固体残留物经硅胶柱层析纯化(洗脱剂∶PE/EA=4∶1),得白色粉状化合物1(0.87g,收率:66.7%)。
1H NMR(400MHz,CDCl3)δ7.51(s,1H),7.43-7.32(m,2H),7.32-7.20(m,8H),7.16-7.09(m,1H),7.02(d,J=8.0Hz,1H),6.97-6.87(m,3H),6.68-6.59(m,2H),4.67-4.56(m,1H),4.21(t,J=5.8Hz,2H),3.90-3.80(m,1H),3.70-3.52(m,2H),3.24-3.13(m,1H),3.07-2.97(m,1H),2.46(s,3H),2.14-2.02(m,1H),1.92-1.80(m,1H).HRMS(m/z)(ESI):calcdfor C32H32N3O3 +[M+H]+:506.2438;found:506.2426。
基本按照实施例1所述的方法,使用相应的中间体制备如表1所示的化合物2-4。
表1化合物2-4
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实施例2
N-(4-(5-(2-苯氧乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺(化合物5)的制备/>
将实施例1步骤4中的2-甲基苯甲酸替换成2-苯基苯甲酸,其余所需原料,试剂及制备方法同实施例1,得白色粉状化合物5。1H NMR(400MHz,CDCl3)δ7.82(d,J=7.6Hz,1H),7.56-7.31(m,8H),7.31-7.26(m,2H),7.17-7.06(m,3H),7.01-6.73(m,7H),6.63-6.52(m,2H),4.66-4.56(m,1H),4.19(t,J=5.8Hz,2H),3.86-3.76(m,1H),3.67-3.51(m,2H),3.20-3.10(m,1H),3.05-2.96(m,1H),2.12-1.99(m,1H),1.91-1.78(m,1H).HRMS(m/z)(ESI):calcd for C37H34N3O3 +[M+H]+:568.2595;found:568.2579。
基本按照实施例1所述的方法,使用相应的中间体制备如表2所示的化合物6-8。
表2化合物6-8
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实施例3
N-(4-(5-(2-(2-氯苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺(化合物9)的制备:
将实施例1步骤l中的2-苯氧乙基溴替换成1-(2-溴乙氧基)-2-氯苯,将实施例1步骤4中的2-甲基苯甲酸替换成2-苯基苯甲酸,其余所需原料,试剂及制备方法同实施例1,得白色粉状化合物9。1H NMR(400MHz,CDCl3)δ7.83(d,J=7.4Hz,1H),7.57-7.29(m,9H),7.25-7.20(m,1H),7.14-7.01(m,4H),6.97-6.77(m,5H),6.62-6.51(m,2H),4.70-4.56(m,1H),4.25(t,J=5.6Hz,2H),3.92-3.80(m,1H),3.76-3.60(m,2H),3.22-3.02(m,2H),2.15-1.99(m,1H),1.95-1.81(m,1H).HRMS(m/z)(ESI):calcd for C37H33ClN3O3 +[M+H]+:602.2205;found:602.2189。
实施例4
N-(4-(5-(2-(3-氯苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺(化合物10)的制备:
将实施例1步骤1中的2-苯氧乙基溴替换成1-(2-溴乙氧基)-3-氯苯,将实施例1步骤4中的2-甲基苯甲酸替换成2-苯基苯甲酸,其余所需原料,试剂及制备方法同实施例1,得白色粉状化合物10。1H NMR(400MHz,CDCl3)δ7.82(d,J=7.6Hz,1H),7.55-7.29(m,8H),7.21-7.07(m,4H),7.01-6.73(m,7H),6.64-6.53(m,2H),4.67-4.55(m,1H),4.16(t,J=5.6Hz,2H),3.86-3.76(m,1H),3.66-3.50(m,2H),3.20-3.09(m,1H),3.04-2.95(m,1H),2.12-1.99(m,1H),1.90-1.78(m,1H).HRMS(m/z)(ESI):calcd for C37H33ClN3O3 +[M+H]+:602.2205;found:602.2198。
实施例5
N-(4-(5-(2-(4-氯苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-l-羰基)苯基)-[1,1′-联苯]-2-甲酰胺(化合物11)的制备:
将实施例1步骤1中的2-苯氧乙基溴替换成1-(2-溴乙氧基)-4-氯苯,将实施例1步骤4中的2-甲基苯甲酸替换成2-苯基苯甲酸,其余所需原料,试剂及制备方法同实施例1,得白色粉状化合物11。1H NMR(400MHz,CDCl3)δ7.83(d,J=7.6Hz,1H),7.57-7.29(m,8H),7.24-6.95(m,6H),6.84-6.75(m,5H),6.64-6.52(m,2H),4.65-4.53(m,1H),4.14(t,J=6.0Hz,2H),3.88-3.75(m,1H),3.66-3.48(m,2H),3.21-3.08(m,1H),3.03-2.93(m,1H),2.11-1.99(m,1H),1.90-1.76(m,1H).HRMS(m/z)(ESI):calcd for C37H33ClN3O3 +[M+H]+:602.2205;found:602.2183。
实施例6
N-(4-(5-(2-(2-氟苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺(化合物12)的制备:
将实施例1步骤1中的2-苯氧乙基溴替换成1-(2-溴乙氧基)-2-氟苯,将实施例1步骤4中的2-甲基苯甲酸替换成2-苯基苯甲酸,其余所需原料,试剂及制备方法同实施例1,得白色粉状化合物12。1H NMR(400MHz,CDCl3)δ7.83(d,J=7.6Hz,1H),7.57-7.30(m,8H),7.16-6.76(m,11H),6.63-6.52(m,2H),4.68-4.57(m,1H),4.25(t,J=6.2Hz,2H),3.90-3.79(m,1H),3.71-3.55(m,2H),3.23-2.96(m,2H),2.14-1.97(m,1H),1.94-1.78(m,1H).HRMS(m/z)(ESI):calcd for C37H33FN3O3 +[M+H]+:586.2500;found:586.2481。
实施例7
N-(4-(5-(2-(3-氟苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺(化合物13)的制备:
将实施例1步骤1中的2-苯氧乙基溴替换成1-(2-溴乙氧基)-3-氟苯,将实施例1步骤4中的2-甲基苯甲酸替换成2-苯基苯甲酸,其余所需原料,试剂及制备方法同实施例1,得白色粉状化合物13。1H NMR(400MHz,CDCl3)δ7.83(d,J=7.6Hz,1H),7.57-7.29(m,8H),7.25-7.07(m,4H),7.01-6.75(m,4H),6.69-6.52(m,5H),4.67-4.56(m,1H),4.16(t,J=5.8Hz,2H),3.87-3.76(m,1H),3.68-3.50(m,2H),3.21-3.10(m,1H),3.05-2.94(m,1H),2.13-1.99(m,1H),1.91-1.78(m,1H).HRMS(m/z)(ESI):calcd for C37H33FN3O3 +[M+H]+:586.2500;found:586.2483。
实施例8
N-(4-(5-(2-(4-氟苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺(化合物14)的制备:
将实施例1步骤1中的2-苯氧乙基溴替换成1-(2-溴乙氧基)-4-氟苯,将实施例1步骤4中的2-甲基苯甲酸替换成2-苯基苯甲酸,其余所需原料,试剂及制备方法同实施例1,得白色粉状化合物14。1H NMR(400MHz,CDCl3)δ7.83(d,J=7.6Hz,1H),7.57-7.43(m,2H),7.43-7.29(m,6H),7.17-7.06(m,3H),7.01-6.92(m,3H),6.86-6.73(m,5H),6.65-6.53(m,2H),4.66-4.55(m,1H),4.14(t,J=5.8Hz,2H),3.86-3.76(m,1H),3.66-3.48(m,2H),3.20-3.10(m,1H),3.04-2.94(m,1H),2.12-1.99(m,1H),1.91-1.78(m,1H).HRMS(m/z)(ESI):calcd for C37H33FN3O3 +[M+H]+:586.2500;found:586.2486。
实施例9
N-(4-(5-(2-(邻甲苯基氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺(化合物15)的制备:
将实施例1步骤1中的2-苯氧乙基溴替换成1-(2-溴乙氧基)-2-甲基苯,将实施例1步骤4中的2-甲基苯甲酸替换成2-苯基苯甲酸,其余所需原料,试剂及制备方法同实施例1,得白色粉状化合物15。1H NMR(400MHz,CDCl3)δ7.82(d,J=7.6Hz,1H),7.57-7.29(m,8H),7.20-6.98(m,6H),6.89-6.71(m,5H),6.63-6.50(m,2H),4.68-4.55(m,1H),4.20(t,J=5.8Hz,2H),3.91-3.80(m,1H),3.74-3.54(m,2H),3.24-3.13(m,1H),3.10-2.98(m,1H),2.17(s,3H),2.12-1.98(m,1H),1.93-1.79(m,1H).HRMS(m/z)(ESI):calcd for C38H36N3O3 +[M+H]+:582.2751;found:582.2731。
实施例10
N-(4-(5-(2-(间甲苯基氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺(化合物16)的制备:
将实施例1步骤1中的2-苯氧乙基溴替换成1-(2-溴乙氧基)-3-甲基苯,将实施例1步骤4中的2-甲基苯甲酸替换成2-苯基苯甲酸,其余所需原料,试剂及制备方法同实施例1,得白色粉状化合物16。1H NMR(400MHz,CDCl3)δ7.82(d,J=7.6Hz,1H),7.57-7.29(m,8H),7.20-6.96(m,5H),6.89-6.66(m,6H),6.63-6.50(m,2H),4.69-4.55(m,1H),4.17(t,J=6.0Hz,2H),3.86-3.75(m,1H),3.69-3.51(m,2H),3.21-3.10(m,1H),3.06-2.96(m,1H),2.31(s,3H),2.13-1.98(m,1H),1.92-1.78(m,1H).HRMS(m/z)(ESI):calcd for C38H36N3O3 +[M+H]+:582.2751;found:582.2726。
实施例11
N-(4-(5-(2-(对甲苯基氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺(化合物17)的制备:/>
将实施例1步骤1中的2-苯氧乙基溴替换成1-(2-溴乙氧基)-4-甲基苯,将实施例1步骤4中的2-甲基苯甲酸替换成2-苯基苯甲酸,其余所需原料,试剂及制备方法同实施例1,得白色粉状化合物17。1H NMR(400MHz,CDCl3)δ7.82(d,J=7.6Hz,1H),7.56-7.29(m,8H),7.17-6.96(m,6H),6.87-6.75(m,5H),6.62-6.51(m,2H),4.67-4.54(m,1H),4.16(t,J=5.8Hz,2H),3.84-3.74(m,1H),3.67-3.50(m,2H),3.20-3.10(m,1H),3.05-2.95(m,1H),2.28(s,3H),2.10-1.99(m,1H),1.90-1.78(m,1H).HRMS(m/z)(ESI):calcd for C38H36N3O3 +[M+H]+:582.2751;found:582.2731.。
实施例12
N-(4-(5-(2-(2-甲氧基苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺(化合物18)的制备:
将实施例1步骤1中的2-苯氧乙基溴替换成1-(2-溴乙氧基)-2-甲氧基苯,将实施例1步骤4中的2-甲基苯甲酸替换成2-苯基苯甲酸,其余所需原料,试剂及制备方法同实施例1,得白色粉状化合物18。1H NMR(400MHz,CDCl3)δ7.82(dd,J=7.8,1.4Hz,1H),7.56-7.29(m,8H),7.14-6.98(m,4H),6.96-6.76(m,7H),6.61-6.50(m,2H),4.66-4.56(m,lH),4.24(t,J=6.2Hz,2H),3.89-3.82(m,1H),3.80(s,3H),3.70-3.59(m,2H),3.21-3.11(m,1H),3.06-2.97(m,1H),2.12-2.01(m,1H),1.93-1.81(m,1H).HRMS(m/z)(ESI):calcd forC38H36N3O4 +[M+H]+:598.2700;found:598.2682。
实施例13
N-(4-(5-(2-(3-甲氧基苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺(化合物19)的制备:
将实施例1步骤1中的2-苯氧乙基溴替换成1-(2-溴乙氧基)-3-甲氧基苯,将实施例1步骤4中的2-甲基苯甲酸替换成2-苯基苯甲酸,其余所需原料,试剂及制备方法同实施例1,得白色粉状化合物19。1H NMR(400MHz,CDCl3)δ7.82(d,J=7.6Hz,1H),7.57-7.29(m,8H),7.21-7.06(m,4H),7.01-6.76(m,4H),6.63-6.39(m,5H),4.67-4.55(m,1H),4.16(t,J=5.6Hz,2H),3.86-3.76(m,1H),3.72(s,3H),3.67-3.49(m,2H),3.21-3.09(m,1H),3.05-2.94(m,1H),2.12-1.97(m,1H),1.92-1.78(m,1H).HRMS(m/z)(ESI):calcd for C38H36N3O4 +[M+H]+:598.2700;found:598.2689。
实施例14
N-(4-(5-(2-(4-甲氧基苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺(化合物20)的制备:
将实施例1步骤1中的2-苯氧乙基溴替换成1-(2-溴乙氧基)-4-甲氧基苯,将实施例1步骤4中的2-甲基苯甲酸替换成2-苯基苯甲酸,其余所需原料,试剂及制备方法同实施例1,得白色粉状化合物20。1H NMR(400MHz,CDCl3)δ7.81(d,J=7.6Hz,1H),7.56-7.29(m,8H),7.18-7.06(m,3H),7.01-6.77(m,8H),6.63-6.52(m,2H),4.65-4.54(m,1H),4.14(t,J=5.8Hz,2H),3.84-3.76(m,1H),3.74(s,3H),3.66-3.48(m,2H),3.20-3.09(m,1H),3.04-2.93(m,1H),2.13-1.96(m,1H),1.91-1.78(m,1H).HRMS(m/z)(ESI):calcd for C38H36N3O4 +[M+H]+:598.2700;found:598.2680。
实施例15
N-(4-(5-(3-(2-氯苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺(化合物21)的制备:
将实施例1步骤1中的2-苯氧乙基溴替换成1-(3-溴丙氧基)-2-氯苯,将实施例1步骤4中的2-甲基苯甲酸替换成2-苯基苯甲酸,其余所需原料,试剂及制备方法同实施例1,得白色粉状化合物21。1H NMR(400MHz,CDCl3)δ7.82(d,J=7.6Hz,1H),7.57-7.30(m,9H),7.17-7.09(m,2H),7.08-7.00(m,3H),6.89-6.73(m,5H),6.65-6.52(m,2H),4.63-4.51(m,1H),4.19-4.08(m,2H),3.72-3.61(m,1H),3.55-3.44(m,1H),3.37-3.27(m,1H),3.19-3.09(m,1H),2.91-2.80(m,1H),2.22-2.09(m,2H),2.08-1.96(m,1H),1.86-1.72(m,1H).HRMS(m/z)(ESI):calcd for C38H35ClN3O3 +[M+H]+:616.2361;found:616.2341。
实施例16
N-(4-(5-(3-(3-氯苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺(化合物22)的制备:
将实施例1步骤l中的2-苯氧乙基溴替换成1-(3-溴丙氧基)-3-氯苯,将实施例1步骤4中的2-甲基苯甲酸替换成2-苯基苯甲酸,其余所需原料,试剂及制备方法同实施例1,得白色粉状化合物22。1H NMR(400MHz,CDCl3)δ7.82(d,J=7.6Hz,1H),7.56-7.32(m,8H),7.17-6.96(m,5H),6.90-6.71(m,6H),6.67-6.53(m,2H),4.63-4.52(m,1H),4.13-4.00(m,2H),3.62-3.43(m,2H),3.31-3.20(m,1H),3.18-3.07(m,1H),2.88-2.79(m,1H),2.19-1.96(m,3H),1.86-1.72(m,1H).HRMS(m/z)(ESI):calcd for C38H35ClN3O3 +[M+H]+:616.2361;found:616.2346。
实施例17
N-(4-(5-(3-(4-氯苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺(化合物23)的制备:
将实施例1步骤1中的2-苯氧乙基溴替换成1-(3-溴丙氧基)-4-氯苯,将实施例1步骤4中的2-甲基苯甲酸替换成2-苯基苯甲酸,其余所需原料,试剂及制备方法同实施例1,得白色粉状化合物23。1H NMR(400MHz,CDCl3)δ7.83(d,J=7.4Hz,1H),7.57-7.29(m,8H),7.19-7.08(m,3H),7.07-6.95(m,3H),6.84-6.72(m,5H),6.67-6.52(m,2H),4.64-4.52(m,1H),4.09-3.98(m,2H),3.63-3.41(m,2H),3.32-3.07(m,2H),2.87-2.76(m,1H),2.18-1.95(m,3H),1.86-1.71(m,1H).HRMS(m/z)(ESI):calcd for C38H35ClN3O3 +[M+H]+:616.2361;found:616.2340。
实施例18
N-(4-(5-(3-(2-氟苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-l-羰基)苯基)-[1,1′-联苯]-2-甲酰胺(化合物24)的制备:/>
将实施例1步骤1中的2-苯氧乙基溴替换成1-(3-溴丙氧基)-2-氟苯,将实施例1步骤4中的2-甲基苯甲酸替换成2-苯基苯甲酸,其余所需原料,试剂及制备方法同实施例1,得白色粉状化合物24。1H NMR(400MHz,CDCl3)δ7.82(d,J=7.6Hz,1H),7.57-7.30(m,8H),7.16-6.74(m,11H),6.65-6.52(m,2H),4.61-4.51(m,1H),4.20-4.09(m,2H),3.66-3.55(m,1H),3.53-3.43(m,1H),3.34-3.25(m,1H),3.19-3.09(m,1H),2.88-2.78(m,1H),2.23-1.96(m,3H),1.85-1.72(m,1H).HRMS(m/z)(ESI):calcd for C38H35FN3O3 +[M+H]+:600.2657;found:600.2643。
实施例19
N-(4-(5-(3-(3-氟苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺(化合物25)的制备:
将实施例1步骤l中的2-苯氧乙基溴替换成1-(3-溴丙氧基)-3-氟苯,将实施例1步骤4中的2-甲基苯甲酸替换成2-苯基苯甲酸,其余所需原料,试剂及制备方法同实施例1,得白色粉状化合物25。1H NMR(400MHz,CDCl3)δ7.81(dd,J=7.8,1.6Hz,1H),7.57-7.30(m,8H),7.25-6.75(m,9H),6.67-6.53(m,4H),4.63-4.51(m,1H),4.13-4.00(m,2H),3.62-3.43(m,2H),3.32-3.21(m,1H),3.18-3.08(m,1H),2.89-2.78(m,1H),2.19-1.96(m,3H),1.86-1.73(m,1H).HRMS(m/z)(ESI):calcd for C38H35FN3O3 +[M+H]+:600.2657;found:600.2637。
实施例20
N-(4-(5-(3-(4-氟苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺(化合物26)的制备:
将实施例1步骤1中的2-苯氧乙基溴替换成1-(3-溴丙氧基)-4-氟苯,将实施例1步骤4中的2-甲基苯甲酸替换成2-苯基苯甲酸,其余所需原料,试剂及制备方法同实施例1,得白色粉状化合物26。1H NMR(400MHz,CDCl3)δ7.82(d,J=7.6Hz,1H),7.57-7.30(m,8H),7.15-6.87(m,6H),6.83-6.73(m,5H),6.65-6.52(m,2H),4.62-4.51(m,1H),4.09-3.97(m,2H),3.62-3.43(m,2H),3.31-3.21(m,1H),3.18-3.08(m,1H),2.87-2.77(m,1H),2.16-1.97(m,3H),1.86-1.72(m,1H).HRMS(m/z)(ESI):calcd for C38H35FN3O3 +[M+H]+:600.2657;found:600.2647。
实施例21
N-(4-(5-(3-(邻甲苯基氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺(化合物27)的制备:
将实施例1步骤1中的2-苯氧乙基溴替换成1-(3-溴丙氧基)-2-甲基苯,将实施例1步骤4中的2-甲基苯甲酸替换成2-苯基苯甲酸,其余所需原料,试剂及制备方法同实施例1,得白色粉状化合物27。1H NMR(400MHz,CDCl3)δ7.82(d,J=7.6Hz,1H),7.57-7.30(m,8H),7.16-6.98(m,6H),6.84-6.71(m,5H),6.64-6.52(m,2H),4.65-4.53(m,1H),4.08(t,J=6.0Hz,2H),3.68-3.46(m,2H),3.34-3.25(m,1H),3.20-3.08(m,1H),2.90-2.81(m,1H),2.26(s,3H),2.19-1.98(m,3H),1.87-1.75(m,1H).HRMS(m/z)(ESI):calcd for C39H38N3O3 +[M+H]+:596.2908;found:596.2892。
实施例22
N-(4-(5-(3-(间甲苯基氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺(化合物28)的制备:
将实施例1步骤1中的2-苯氧乙基溴替换成1-(3-溴丙氧基)-3-甲基苯,将实施例1步骤4中的2-甲基苯甲酸替换成2-苯基苯甲酸,其余所需原料,试剂及制备方法同实施例1,得白色粉状化合物28。1H NMR(400MHz,CDCl3)δ7.80(d,J=7.8Hz,1H),7.56-7.30(m,8H),7.15-7.02(m,4H),7.00-6.95(m,1H),6.83-6.73(m,3H),6.72-6.64(m,3H),6.63-6.52(m,2H),4.61-4.51(m,1H),4.05(t,J=6.0Hz,2H),3.62-3.42(m,2H),3.31-3.21(m,1H),3.19-3.07(m,1H),2.88-2.78(m,1H),2.25(s,3H),2.17-1.95(m,3H),1.86-1.71(m,1H).HRMS(m/z)(ESI):calcd for C39H38N3O3 +[M+H]+:596.2908;found:596.2891。
实施例23
N-(4-(5-(3-(对甲苯基氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺(化合物29)的制备:/>
将实施例1步骤1中的2-苯氧乙基溴替换成1-(3-溴丙氧基)-4-甲基苯,将实施例1步骤4中的2-甲基苯甲酸替换成2-苯基苯甲酸,其余所需原料,试剂及制备方法同实施例l,得白色粉状化合物29。1H NMR(400MHz,CDCl3)δ7.82(d,J=7.6Hz,1H),7.57-7.30(m,8H),7.15-6.95(m,6H),6.86-6.74(m,5H),6.64-6.52(m,2H),4.63-4.51(m,1H),4.05(t,J=5.8Hz,2H),3.63-3.44(m,2H),3.33-3.23(m,1H),3.19-3.09(m,1H),2.89-2.79(m,1H),2.24(s,3H),2.17-1.96(m,3H),1.85-1.73(m,1H).HRMS(m/z)(ESI):calcd for C39H38N3O3 +[M+H]+:596.2908;found:596.2891。
实施例24
N-(4-(5-(3-(2-甲氧基苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺(化合物30)的制备
将实施例1步骤1中的2-苯氧乙基溴替换成1-(3-溴丙氧基)-2-甲氧基苯,将实施例1步骤4中的2-甲基苯甲酸替换成2-苯基苯甲酸,其余所需原料,试剂及制备方法同实施例1,得白色粉状化合物30。1H NMR(400MHz,CDCl3)δ7.81(d,J=7.2Hz,1H),7.57-7.29(m,8H),7.14-6.97(m,4H),6.93-6.78(m,7H),6.63-6.52(m,2H),4.62-4.52(m,1H),4.14(q,J=6.0Hz,2H),3.86(s,3H),3.63-3.45(m,2H),3.37-3.27(m,1H),3.19-3.08(m,1H),2.89-2.79(m,1H),2.25-2.09(m,2H),2.08-1.97(m,1H),1.87-1.73(m,1H).HRMS(m/z)(ESI):calcd for C39H38N3O4 +[M+H]+:612.2857;found:612.2841。
实施例25
N-(4-(5-(3-(3-甲氧基苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺(化合物31)的制备:
将实施例1步骤1中的2-苯氧乙基溴替换成1-(3-溴丙氧基)-3-甲氧基苯,将实施例1步骤4中的2-甲基苯甲酸替换成2-苯基苯甲酸,其余所需原料,试剂及制备方法同实施例1,得白色粉状化合物31。1H NMR(400MHz,CDCl3)δ7.81(d,J=7.4Hz,1H),7.56-7.31(m,8H),7.17-6.95(m,5H),6.87-6.75(m,3H),6.64-6.54(m,2H),6.49-6.41(m,3H),4.63-4.52(m,1H),4.07(t,J=6.0Hz,2H),3.71(s,3H),3.63-3.44(m,2H),3.33-3.22(m,1H),3.19-3.08(m,1H),2.90-2.78(m,1H),2.17-1.97(m,3H),1.86-1.73(m,1H).HRMS(m/z)(ESI):calcd for C39H38N3O4 +[M+H]+:612.2857;found:612.2845。
实施例26
N-(4-(5-(3-(4-甲氧基苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺(化合物32)的制备:
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将实施例1步骤1中的2-苯氧乙基溴替换成1-(3-溴丙氧基)-4-甲氧基苯,将实施例1步骤4中的2-甲基苯甲酸替换成2-苯基苯甲酸,其余所需原料,试剂及制备方法同实施例1,得白色粉状化合物32。1H NMR(400MHz,CDCl3)δ7.82(d,J=7.6Hz,1H),7.57-7.30(m,8H),7.15-6.95(m,4H),6.84-6.72(m,7H),6.64-6.52(m,2H),4.62-4.52(m,1H),4.03(t,J=6.0Hz,2H),3.68(s,3H),3.63-3.43(m,2H),3.31-3.21(m,1H),3.18-3.08(m,1H),2.87-2.79(m,1H),2.16-1.96(m,3H),1.86-1.73(m,1H).HRMS(m/z)(ESI):calcd for C39H38N3O4 +[M+H]+:612.2857;found:612.2845。
实施例27 V2受体亲和性实验
本实验采用荧光的检测方法(fluorescence based methods),本实验通过检测在不同待测化合物的浓度下,终浓度为6.3nM的V2R荧光配体与细胞表达的V2R结合后的SB荧光强度,获得待测化合物的Ki和IC50。在本实验条件下,体系内V2R荧光配体与V2R的特异性结合无法直接测量,由总结合和非特异性结合间接获得:SB=TB-NSB。
具体做法如下:V2R荧光配体各浓度下的TB信号是由V2R荧光配体与SNAP-taggedHEK293-hV2R cell表达的V2R结合与解离达到平衡状态后,经多功能微孔板读数仪检测在620nm和665nm的条件下检测获得;V2R荧光配体各浓度下的NSB信号是由终浓度为100μM待测化合物与细胞表达的V2R结合与解离达到平衡状态后,即化合物充分拮抗体系内的V2R后,经多功能微孔板读数仪检测体系内V2R荧光配体与体系内除V2R外的非特异性结合在620nm和665nm条件下产生的荧光信号。
具体操作步骤如下:用Tag-lite assay buffer(1×)分别将待测化合物稀释成终浓度为1×10-6-1×10-12M的梯度浓度。依次将上述配制好的化合物、终浓度为100μM的待测化合物溶液、1%DMSO含量的Tag-lite assay buffer(1×)和终浓度为6.3nM的V2R荧光配体,转移到384孔板中,与已被标记的SNAP-tagged HEK293-hV2R cell混匀,置于37℃下,孵育2h。孵育时间到后,在多功能微孔板读数仪620nm和665nm处检测实验结果。检测结束后,运用公式“665nm处的荧光强度/620nm处的荧光强度·10000”计算SB荧光比率。以体系内待测化合物浓度最低时,终浓度为6.3nM的V2R荧光配体与细胞表达的V2R达到结合与解离平衡后,在620nm和665nm条件下测得SB荧光强度的比率作为100%,将各待测化合物在不同浓度下,终浓度为6.3nM的V2R荧光配体与V2R达到结合与解离平衡后的SB荧光比率进行归一化处理后。
分别使用Graphpad Prism 7.0中One site-Fit Ki和One site-Fit log IC50模型分析待测化合物的Ki值以及IC50值。表3结果表明,构效关系揭示化合物10,11,12,13,14,16,17,19和20对V2R具有良好的亲和力,但是构动关系显示这些化合物与V2R具有更长的结合时间,即表现出比Tolvaptan更长的靶点停留时间(RT,Residence Time),在药理活性方面,表现出与Tolvaptan相当或更优的活性。
表3 V2受体亲和性实验
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注:本实验使用的细胞系为高表达携带荧光基团人源V2R蛋白的人胚胎肾293细胞株(SNAP-tagged HEK293 V2R high expression cell,SNAP-tagged HEK293-hV2R cell)。
实施例28 V1a受体亲和性实验
本实验采用放射性配体取代实验的方法,通过检测在不同待测化合物的浓度下,终浓度为2.6nM的V1aR放射性配体与细胞表达的V1aR结合后的放射性强度,获得待测化合物的Ki和IC50。
将含有5μg蛋白质的CHOhV1aR细胞膜等分试样置于总体积为250μL的缓冲液(50mMTris-HCl,pH 7.4,100mM NaCl、10mM MgCl2、0.1mg/mL杆菌肽和1mg/mL BSA)中在37℃下孵育1h。在终浓度为2.6nM的[3H]-vasopressin存在下进行化合物10和Tolvaptan的取代实验。在10μM conivaptan的存在下测定非特异性结合。将细胞液加入96孔过滤板,使用细胞收集器,通过快速真空过滤终止孵育以分离结合的和游离的放射性配体。随后用冰Tris-HCl缓冲液(50mM,pH 7.4)洗涤过滤器3次。通过使用96孔过滤板的MicroBeta-2450闪烁计数器测定过滤结合的放射性。使用Graphpad Prism7.0分析待测化合物的Ki值以及IC50值。表4结果表明,与Tolvaptan相似,化合物10对V2R的亲和力远远高于对V1aR,即对V1aR具有一定的选择性。
表4 V1a受体亲和性实验
实施例29 V2受体配体功能性实验
本实验观察待测化合物是否有抑制V2R激动剂vasopressin所诱导的细胞内cAMP水平提升的作用。
在含有0.1%BSA和50μM PDE抑制剂(Rolipram和Cilostamide)的HEPES缓冲液中,测定化合物10对细胞cAMP积累的抑制作用。将CHOhV2R细胞(浓度为1000个细胞/孔)添加到含有化合物10和激动剂(0.8nM vasopressin)的混合物中,在37℃下孵育1h。随后在裂解液中连续加入5μL染料标记的cAMP和5μL荧光标记的抗cAMP抗体再孵育1h。按照试剂盒说明书的要求使用cAMP-Gi试剂盒进行cAMP的定量检测,使用Graphpad Prism 7.0分析cAMP水平得到量效曲线和IC50。
表5结果表明,化合物10能够抑制vasopressin诱导的cAMP的产生,即化合物10对V2R受体具有拮抗作用。
表5 V2受体配体功能性实验
实施例30组织胚胎肾实验
取13.5天的胚胎鼠肾脏置于transwell中,在8-Br-cAMP的刺激下形成类似PKD疾病中的囊泡,模拟疾病的发生发展并给予受试化合物,观察受试化合物对其影响。
1、胚胎肾的培养
将胚胎肾培养在37℃,5%CO2情况下,培养基采用DMEM F12培养基(康美可购买),
额外加入8-Br-cAMP、胰岛素、转铁蛋白、亚硒酸钠和双抗。并加入相应浓度的药物,分对照组。培育6天,每12h换液一次,并在2,4,6天拍照。
在第6天对比囊泡面积以评估受试化合物的作用效果。实验结果见表6。
表6组织胚胎肾实验
组织胚胎肾实验结果显示,与对照组相比,该类化合物可明显抑制PKD疾病中的囊泡的发展。
实施例31 PKD小鼠实验
此类化合物对精氨酸加压素受体具有拮抗作用,可以抑制体内cAMP作用,从而抑制PKD病程的发生发展。本实验利用PKD1基因敲除小鼠进行该类化合物的药效评价。
具体操作:
1.小鼠标号和基因鉴定:小鼠出生3天后,采用剪脚趾方法进行标记,并放入提前标记ep管,剪下脚趾煮沸后,pcr后用琼脂糖电泳进行基因鉴定。
2.制备相应药剂:用电子天平精密称取相应重量药物,乘放在全新ep管中。后用移液枪加入相应量hpmc以配制所需浓度药剂。(以5mg/kg化合物10为例,称取2.5mg化合物10,加入500uL hpmc后,先涡旋30s(混悬大部分药物),后超声15-20分钟以粉碎大块药物,再涡旋30s。)
3.小鼠给药:小鼠出生后第6或5天开始给药(小鼠体重过小则第6天给药,其余第5天给药),固定给药时间(例:上午9点)。用食指和拇指捏起目标小鼠(背部),称取重量后,用微量进样器吸取相应量药剂,从小鼠背部隆起(拇指食指中间)中间插入进样器,进行皮下注射。
4.小鼠组织提取:小鼠给药七天后处死后精密称取重量,剖腹,摘取左肾后精密称重,并将肾脏置于水平线正中进行拍照,完成后置编号ep管于冰上暂存。后摘取右肾,相同条件称重、拍照,存编号ep管于多聚甲醛中保存。摘取肝脏ep管于冰上暂存。操作完成后将肝脏和左肾保存于-80度冰箱。
5.数据处理:计算左右肾总重,肾脏比重等。实验结果见表7。
表7 PKD小鼠实验
动物实验结果显示,与对照组相比,在延缓PKD病程的发生发展上,该类化合物表现出比Tolvaptan更优的抑制活性,即该类化合物对PKD具有更明显的治疗作用。
实施例32体内药代动力学实验
根据上述实验结果,选择化合物10进行药代动力学研究。通过皮下注射给予雄性C57BL/6小鼠1mg/kg化合物10。取不同时间间隔的血样处理并用LC-MS分析血浆浓度随时间的变化。其中,以地塞米松(60.0ng/mL,溶于乙腈)为内标。在40℃,用3μm C18反相HPLC柱(FLM,美国)分离目标化合物,然后通过LC-MS光谱法进行分析。
在皮下给予C57BL/6小鼠1mg/kg Tolvaptan或化合物10后,在不同时间点对肾脏取样,并通过HPLC分析分离的肾脏组织以测定Tolvaptan或化合物10在肾脏和血浆中的药动学参数。
实验结果见表8。
表8体内药代动力学实验
综合上述实验结果,该类化合物通过拮抗精氨酸加压素V2受体,可有效抑制囊泡的发生发展,并减缓PKD疾病的病程发展,其中化合物10的亲和力仅为Tolvaptan的十分之一,但其7.7倍的停留时间使其在PKD体内模型中具有较好的抑制作用。因此,该类化合物有治疗PKD的潜在用途。
实施例33
为了更充分的说明本发明的药物组合物,下面提供制剂实施例,所述实施例仅用于说明,而不是用于限制本发明的范围。所述制剂可用于本发明化合物的任何活性化合物及其盐,以实施例1中所描述的化合物加以说明。按照表9中的成分和用量制备硬明胶胶囊:
表9
制备工艺:将原辅料预先干燥,过100目筛备用。按处方量将上述成分混匀后,填充入硬明胶胶囊。
此外,本案发明人还参照前述实施例,以本说明书述及的其它原料、工艺操作、工艺条件进行了试验,并均获得了较为理想的结果。
应当理解,本发明的技术方案不限于上述具体实施案例的限制,凡是在不脱离本发明宗旨和权利要求所保护的范围情况下,根据本发明的技术方案做出的技术变形,均落于本发明的保护范围之内。
Claims (10)
1.一种苯并二氮杂类化合物,其特征在于,所述苯并二氮杂/>类化合物具有如式(I)所示的结构:
其中,R1、R2各自独立地选自氢、卤素、氰基、硝基、羟基、氨基、C1-C6烷基、C1-C6烷氧基、C3-C8环烷基、芳基、杂芳基、杂环基中的任一者,其中芳基、杂芳基或杂环基是未取代或者至少被一个选自C1-6烷基的取代基取代;n选自1、2、3或4。
2.根据权利要求1所述的苯并二氮杂类化合物,其特征在于:所述R1选自C1-C6烷基或芳基,R2选自C1-C6烷基、C1-C6烷氧基或卤素;优选的,所述R1选自甲基或芳基,R2选自甲基、甲氧基或卤素;更为优选的,所述R1为芳基,R2选自氯;
和/或,所述R1为芳基,R2选自C1-C6烷基、C1-C6烷氧基或卤素;优选的,所述R1为芳基,R2为3-氯基;
和/或,所述R1为芳基,R2选自2-氟基、4-甲基、4-甲氧基中的任一者。
3.根据权利要求1所述的苯并二氮杂类化合物,其特征在于:所述苯并二氮杂/>类化合物包括2-甲基-N-(4-(5-(2-苯氧乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)苯甲酰胺、2-甲基-N-(4-(5-(3-苯氧丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮-1-羰基)苯基)苯甲酰胺、2-甲基-N-(4-(5-(4-苯氧丁基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)苯甲酰胺、2-甲基-N-(4-(5-(5-苯氧戊基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)苯甲酰胺、N-(4-(5-(2-苯氧乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(3-苯氧丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(4-苯氧丁基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(5-苯氧戊基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(2-(2-氯苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(2-(3-氯苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(2-(4-氯苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(2-(2-氟苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(2-(3-氟苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(2-(4-氟苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(2-(邻甲苯基氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(2-(间甲苯基氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(2-(对甲苯基氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(2-(2-甲氧基苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(2-(3-甲氧基苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(2-(4-甲氧基苯氧基)乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(3-(2-氯苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(3-(3-氯苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(3-(4-氯苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(3-(2-氟苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(3-(3-氟苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(3-(4-氟苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(3-(邻甲苯基氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(3-(间甲苯基氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(3-(对甲苯基氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(3-(2-甲氧基苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(3-(3-甲氧基苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺、N-(4-(5-(3-(4-甲氧基苯氧基)丙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮/>-1-羰基)苯基)-[1,1′-联苯]-2-甲酰胺中的任意一种或两种以上的组合;
和/或,所述苯并二氮杂类化合物具有下式结构中的任一者:
4.如权利要求1-3中任一项所述的苯并二氮杂类化合物的制备方法,其特征在于包括:
使1,3,4,5-四氢-2H-苯并[b][1,4]二氮杂-2-酮与溴代酚氧烷基类化合物反应,获得第一中间体;
对所述第一中间体进行还原处理,制得第二中间体;
使所述第二中间体与硝基苯甲酰氯反应,之后进行氢化还原处理,制得第三中间体;
以及,使所述第三中间体与苯甲酸类化合物反应,制得所述苯并二氮杂类化合物。
5.根据权利要求4所述的制备方法,其特征在于:所述溴代酚氧烷基类化合物包括2-溴乙氧基苯、3-溴丙氧基苯、4-溴丁氧基苯、5-溴戊氧基苯、1-(2-溴乙氧基)-2-氯苯、1-(2-溴乙氧基)-3-氯苯、1-(2-溴乙氧基)-4-氯苯、1-(2-溴乙氧基)-2-氟苯、1-(2-溴乙氧基)-3-氟苯、1-(2-溴乙氧基)-4-氟苯、1-(2-溴乙氧基)-2-甲基苯、1-(2-溴乙氧基)-3-甲基苯、1-(2-溴乙氧基)-4-甲基苯、1-(2-溴乙氧基)-2-甲氧基苯、1-(2-溴乙氧基)-3-甲氧基苯、1-(2-溴乙氧基)-4-甲氧基苯、1-(3-溴丙氧基)-2-氯苯、1-(3-溴丙氧基)-3-氯苯、1-(3-溴丙氧基)-4-氯苯、1-(3-溴丙氧基)-2-氟苯、1-(3-溴丙氧基)-3-氟苯、1-(3-溴丙氧基)-4-氟苯、1-(3-溴丙氧基)-2-甲基苯、1-(3-溴丙氧基)-3-甲基苯、1-(3-溴丙氧基)-4-甲基苯、1-(3-溴丙氧基)-2-甲氧基苯、1-(3-溴丙氧基)-3-甲氧基苯、1-(3-溴丙氧基)-4-甲氧基苯中的任意一种或两种以上的组合;
和/或,所述制备方法包括:采用硼烷-二甲硫醚、四氢铝锂或硼氢化钠-路易斯酸体系对所述第一中间体进行还原处理,制得第二中间体;优选的,采用四氢铝锂对所述第一中间体进行还原处理;
和/或,所述制备方法包括:采用雷尼镍、Pd/C或Fe/HCl进行所述氢化还原处理;优选的,采用Pd/C或Fe/HCl进行所述氢化还原处理;
和/或,所述苯甲酸类化合物包括2-甲基苯甲酸和/或2-苯基苯甲酸。
6.权利要求1-3中任一项所述的苯并二氮杂类化合物、其立体异构体或其药学可接受的盐在制备用于预防和/或治疗与精氨酸加压素V1a受体、精氨酸加压素V1b受体、精氨酸加压素V2受体、交感神经系统或肾素-血管紧张素-醛固酮系统相关的疾病的药物中的用途。
7.根据权利要求6所述的用途,其特征在于:所述与精氨酸加压素V1a受体、精氨酸加压素V1b受体、精氨酸加压素V2受体、交感神经系统或肾素-血管紧张素-醛固酮系统相关的疾病包括高血压、雷氏综合征、痛经、早产、促肾上腺皮质激素释放激素分泌紊乱、肾上腺增生、抑郁症、慢性充血性心力衰竭、肝硬化、抗利尿激素分泌紊乱综合征、慢性心力衰竭/肝硬化/抗利尿激素分泌紊乱引起的低钠血症或多囊肾疾病。
8.根据权利要求6所述的用途,其特征在于:所述药学可接受的盐是由所述苯并二氮杂类化合物与无机酸和/或有机酸形成的盐。
9.根据权利要求8所述的用途,其特征在于:所述无机酸包括盐酸、氢溴酸、硫酸或磷酸中的任意一种或两种以上的组合;
和/或,所述有机酸包括柠檬酸、乳酸、苹果酸、葡糖酸、酒石酸、己二酸、醋酸、琥珀酸、富马酸、抗败血酸、衣康酸、甲磺酸或苯磺酸中的任意一种或两种以上的组合。
10.一种药物组合物,其特征在于包括权利要求1-3中任一项所述的苯并二氮杂类化合物、其立体异构体或其药学可接受的盐,以及药学上可接受的载体。
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