CN112851583B - 新型苯并氮杂䓬类化合物、组合物及其用途 - Google Patents
新型苯并氮杂䓬类化合物、组合物及其用途 Download PDFInfo
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- 239000003380 propellant Substances 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
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- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
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- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
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- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/06—Antiabortive agents; Labour repressants
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- A—HUMAN NECESSITIES
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
本发明涉及一种新型苯并氮杂类化合物,包括其药学上可接受的盐,本发明还提供包含所述化合物及其药学可接受的盐的药物组合物,本发明还涉及所述化合物和所述组合物在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***或肾素‑血管紧张素‑醛固酮***相关的疾病中的用途。
Description
技术领域
本发明涉及新型苯并氮杂类化合物、组合物及其用途。
背景技术
精氨酸加压素(AVP)是一种自然产生的神经激素,在大脑和血液中释放。AVP在调节水分、血压和垂体促肾上腺皮质激素(ACTH)的分泌方面具有重要作用,并通过与中枢神经***和某些外周部位或组织中特定的G蛋白偶联受体结合,发挥其对生理和行为的作用。在大脑中,AVP调节昼夜节律,促进海马的学习和记忆,并通过边缘回路中的作用在神经行为失调症中发挥调节社会行为的重要作用。
三种不同的AVP受体亚型已经在药理学和功能学的基础上确定:V1a、V1b和V2。这些受***于肝、血管(冠状动脉,肾血管,脑血管)、血小板、肾脏、子宫、肾上腺、胰腺、中枢神经***或垂体。AVP参与调控多种功能,如心血管、肝脏、胰腺、抗利尿的功能和血小板聚集效应,以及在中枢和外周神经***和子宫球上的作用。AVP受体产生的效应取决于其所处位置。V1a受体遍布大脑边缘***和皮层,并在血管的平滑肌、子宫和心肌上有分布。V1b族受体也分布在边缘***和脑垂体。V2受***于肾脏中肾单位的集合管,已成为心血管疾病治疗方法的一个靶点。抑制精氨酸加压素受体,可以产生一系列生理作用。
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。这类化合物具有对精氨酸加压素受体的拮抗活性,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中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-stagerenal disease,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。
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。基于ADPKD的发病机制,目前其药物靶点的研究一般集中在可调控细胞增殖和液体分泌的通路上,如水通道蛋白2(Aquaporin-2,AQP2)、V2受体(vasopressin-2receptor,V2R)、生长激素抑制激素受体(SSTR)、ErbB-2、整合素连接激酶(Integrin-linked kinase,ILK)等。抑制AQP2可显著抑制液体分泌导致的囊泡扩大,但对ADPKD所诱导的细胞增殖抑制效果并不明显,且可能会导致囊肿肿瘤性病变。SSTR作用于Gi信号通路,奥曲肽等生长激素抑制素类似物可激活该受体并抑制囊泡的生成,然而该类药物的应用会导致机体激素分泌失调且副作用较大,临床应用困难。ErbB-2和ILK介导的信号通路均可调控细胞的增殖,因此ErbB-2和ILK是潜在的作用靶点,对ADPKD的治疗作用仍需验证。灵芝三萜、槲皮素等中药提取物对ADPKD也有一定的治疗作用,但具体作用机制和不良反应需进一步研究。
在药物临床研究方面,目前临床上唯一被FDA(美国食品药品监督管理局)认证的ADPKD有效治疗药物是托伐普坦(Tolvaptan,OPC41061)。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。应用前瞻性研究分析30位ADPKD病人,发现在使用托伐普坦(V2R拮抗剂)后增加了钠和尿素的***率,说明V2R拮抗剂在维持ADPKD水钠平衡上起到重要作用。此外托伐普坦还能够通过抑制肾脏体积的增加和肾损伤,来减缓ADPKD发展成为终末期肾病的时间,意味着V2R拮抗剂对ADPKD的进程产生了缓解作用。但在临床试验中,托伐普坦减缓患者肾功能下降的同时,部分患者血清肝转氨酶上升至正常水平三倍以上,这表明托伐普坦的使用会引起肝损伤,因此FAD建议托伐普坦使用期间应每月对患者进行肝功能检查,在出现异常时应立即停用。
综上,虽然V2R拮抗剂可以通过抑制cAMP(环磷酸腺苷)进而缓解ADPKD的发病进程,但临床上可用的药物仍十分稀少,因此需要基于V2R拮抗剂化合物构效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。
作为上述疾病的治疗药物,苯并氮杂类化合物无论是在活性、副作用方面还是物化特性方面都还存在一定的不足。本发明提出新型的苯并氮杂/>类化合物,具有较长的受体停留时间,减小其副作用,并且对PKD疾病中的囊泡的发展的抑制作用优于Tolvaptan,因此可以更好地用于此类疾病的治疗和预防。
发明内容
本发明涉及一种作为精氨酸加压素受体拮抗剂的新型苯并氮杂类化合物,本发明中的化合物具有式(I)的通式结构。本发明提供式(I)的化合物或其药学上可接受的盐,
其中,
X选自NH、O或S;
Y选自N、CH、O或S;
R1、R2和R3各自独立地选自氢、卤素、氰基、硝基、羟基、氨基、C1-6烷基、C1-6烷氧基、或C3-8环烷基;
R4和R5各自独立地选自氢、卤素、氰基、硝基、羟基、氨基、C1-6烷基、C1-6烷氧基、C3-8环烷基、芳基、杂芳基、杂环基、杂环基-(CH2)n-、芳基-C1-6烷基-、杂芳基-C1-6烷基-、芳基-(CH2)n-O-、杂芳基-(CH2)n-O-、C3-8环烷基-C(O)-、杂环基-C(O)-、芳基-C(O)-、或杂芳基-C(O),其中C1-6烷基、C1-6烷氧基、C3-8环烷基、芳基、杂芳基、杂环基、杂环基-(CH2)n-、芳基-C1-6烷基-、杂芳基-C1-6烷基-、芳基-(CH2)n-O-、杂芳基-(CH2)n-O-、C3-8环烷基-C(O)-、杂环基-C(O)-、芳基-C(O)-、或杂芳基-C(O)是各自未取代或者至少被一个选自卤素、C1-6烷基、C1-6环烷基或杂环基的取代基取代;
m为0、1、2、3或4;
n为0、1、2、3或4;
优选的,R1和R2各自独立的选自C1-6烷基,R3为卤素;
优选的,R1和R2均为甲基,R3为氯。
一些实施方式中,式(I)中的X为NH;优选的,Y选自N或CH。
一些实施方式中,式(I)中的R4为氢或C1-6烷基,R5选自C1-6烷基、杂芳基、杂环基、杂环基-(CH2)n-、杂芳基-C1-6烷基-、芳基-(CH2)n-O-、或杂环基-C(O)-,其中杂环基、或杂环基-(CH2)n-被C1-6烷基取代;
优选的,R4为氢,R5选自5-6元杂环基、5-6元杂芳基、5-6元杂芳基-C1-6烷基-、5-10元芳基-(CH2)n-O-、或5-6元杂环基-C(O)-,其中5-6元杂环基、或5-6元杂环基-(CH2)n-被C1-3烷基取代;
优选的,R4为氢,R5选自6元杂环基、6元杂芳基、6元杂芳基-C1-6烷基-、苯基-(CH2)n-O-、或6元杂环基-C(O)-,其中6元杂环基被C1-3烷基取代,其中n为0。
一些实施方式中,式(I)中的R4为氢,R5选自6元杂环基、6元杂环基-C(O)-或被甲基取代的6元杂环基;
优选的,所述杂环基含有一个或两个N或O的杂原子作为环原子;
优选的,R4为氢,R5为
一些实施方式中,式(I)中的R4为氢,R5选自6元杂芳基、6元杂芳基-C1-6烷基-、或苯-(CH2)n-O-;
优选的,所述杂芳基含有一个N或O的杂原子作为环原子;
优选的,R4为氢,R5为
一些实施方式中,式(I)中的R4为C1-6烷基,R5为C1-6烷基;优选的,R4为C1-3烷基,R5为C1-3烷基;优选的,R4和R5均为乙基。
本发明进一步提供了一些关于式(I)所示化合物的优选的技术方案,所述化合物是:
1)N-(4-(7-氯-5-((3-吗啉丙基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺;
2)N-(4-(7-氯-5-((4-吗啉丁基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺;
3)N-(4-(7-氯-5-((5-吗啉戊基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺;
4)N-(4-(7-氯-5-((2-吗啉乙基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺;
5)N-(4-(7-氯-5-((3-(吡啶-4-基)丙基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺;
6)N-(4-(7-氯-5-((2-(吡啶-4-基)乙基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺;
7)N-(4-(7-氯-5-((4-(吡啶-4-基)丁基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺;
8)N-(4-(7-氯-5-((5-(吡啶-4-基)戊基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺;
9)N-(4-(7-氯-5-((3-(哌啶-1-基)丙基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺;
10)N-(4-(7-氯-5-((2-(哌啶-1-基)乙基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺;
11)N-(4-(7-氯-5-((4-(哌啶-1-基)丁基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺;
12)N-(4-(7-氯-5-((5-(哌啶-1-基)戊基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺;
13)N-(4-(7-氯-5-((3-吗啉-3-氧代丙基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺;
14)N-(4-(7-氯-5-((4-吗啉-4-氧代丁基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺;
15)N-(4-(7-氯-5-((5-吗啉-5-氧代戊基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺;
16)N-(4-(7-氯-5-((6-吗啉-6-氧代己基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺;
17)N-(4-(7-氯-5-((3-(4-甲基哌嗪-1-基)丙基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺;
18)N-(4-(7-氯-5-((2-(4-甲基哌嗪-1-基)乙基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺;
19)N-(4-(7-氯-5-((4-(4-甲基哌嗪-1-基)丁基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺;
20)N-(4-(7-氯-5-((5-(4-甲基哌嗪-1-基)戊基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺;
21)N-(4-(7-氯-5-((2-苯氧基乙基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺;
22)N-(4-(7-氯-5-((3-苯氧基丙基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺;
23)N-(4-(7-氯-5-((4-苯氧基丁基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺;
24)N-(4-(7-氯-5-((5-苯氧基戊基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺;
25)N-(4-(7-氯-5-((3-(二乙基氨基)丙基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺;
26)N-(4-(7-氯-5-((2-(二乙基氨基)乙基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺;
27)N-(4-(7-氯-5-((4-(二乙基氨基)丁基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺;或
28)N-(4-(7-氯-5-((5-(二乙基氨基)戊基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺。
一些实施方式中,其中所述药学上可接受的盐是式(I)化合物与无机酸或有机酸形成的盐;优选的,所述无机酸为盐酸、氢溴酸、硫酸或磷酸,所述有机酸为柠檬酸、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。
另一方面,本发明还提供药物组合物,其包含治疗有效剂量的式(I)化合物或其药学可接受的盐,和一种或多种药学可接受的载体。
本发明进一步还提供了本发明的化合物或其药学上可接受的盐或以上提及的药物组合物在制备药物中的应用;
优选的,所述药物用于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***或肾素-血管紧张素-醛固酮***相关的疾病。
优选的,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***或肾素-血管紧张素-醛固酮***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。
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,“C1-6烷基”中的“C1-6”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。取代的烷基是含有一个或多个取代基代替氢的烷基,例如1,2或3个取代基,最多达未取代烷基上的存在的氢的数目。如果没有另外说明,烷基的合适取代基可以选自卤素、CN、氧代、羟基、C1-4烷氧基、取代或未取代的C3-6环烷基、取代或未取代的苯基、氨基、(C1-4烷基)氨基、二(C1-4烷基)氨基、C1-4烷硫基、C1-4烷基磺酰基、-C(=O)-C1-4烷基、COOH、COO(C1-4烷基)、-O(C=O)-C1-4烷基,-NHC(=O)C1-4烷基和-NHC(=O)OC1-4烷基;其中,对于取代的环烷基或苯基,取代基是最多三个选自Me、Et、-OMe、-OEt、CF3、卤素、CN、OH和NH2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。
类似地,其他基团的各杂环基部分如“杂环基氧基”、“杂环基氧基烷基”、“杂环基氧基羰基”应具有与上述“杂环基”定义中所述相同的含义。
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***,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、***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***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)、C1-8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、C1-6烷基、C1-6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***)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》(Design of 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***或肾素-血管紧张素-醛固酮***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、***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***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***的疾病和不适、中枢神经***(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、***率、药物联用的情况和接受治疗的特定疾病的严重程度。
具体实施方式
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
MnO2二氧化锰
DCM二氯甲烷
MeOH甲醇
NaBH4硼氢化钠
N-CBZ-beta-丙氨酸苯甲氧羰基-beta-丙氨酸
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
DIPEA N,N-二异丙基乙胺
Pd钯
CDCl3氘代氯仿
DMSO二甲基亚砜
CO2二氧化碳
NaOH氢氧化钠Tween吐温
PEG聚乙二醇
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
PKD多囊肾病
本发明具体实施例中的化合物1-28是托伐普坦的衍生物,在这些化合物质中,其中通式中的X为NH,化合物1-28的制备方法是以托伐普坦为起始原料,经二氧化锰氧化得的相应的中间体IV,中间体IV再与相应的胺经烯胺还原得到目标产物(化合物1-28)。
实施例1
N-(4-(7-氯-5-((3-吗啉丙基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺(化合物1)的制备
步骤1:N-(4-(7-氯-5-氧代-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺(中间体IV)的制备:
将托伐普坦(1.0g,2.23mmol)溶于二氯甲烷(30mL)中,加入活性二氧化锰(1.0g),回流搅拌过夜。减压蒸干溶剂,固体残留物经硅胶柱层析纯化(洗脱剂:100%EA),得淡黄色油状中间体IV(0.90g,收率:90.4%)
HRMS(ESI)calculated for C26H24 Cl N2O3 +[M+H]+447.1470;Found:447.1473
步骤2:N-(4-(7-氯-5-((3-吗啉丙基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺(化合物1)的制备:
将中间体IV(0.80g,1.79mmol)与N-(3-氨丙基)吗啉(0.52g,3.61mmol)溶于无水四氢呋喃(40mL)中。逐滴加入冰醋酸调至反应液pH值约为6,在氮气保护下回流2小时。向反应液中加入甲醇(20mL),然后加入硼氢化钠(0.20g,5.29mmol)继续回流搅拌40分钟。减压蒸干溶剂,固体残留物经硅胶柱层析纯化(洗脱剂:MeOH/DCM=1:10),得白色泡沫状化合物1(0.50g,收率:48.6%)。
1H NMR(800MHz,CDCl3)δ7.83–6.41(m,10H),4.54–3.98(m,1H),3.92–3.55(m,5H),3.22–2.91(m,1H),2.90–2.67(m,2H),2.67–2.37(m,12H),2.11–1.43(m,6H).HRMS(ESI)calculated for C33H40ClN4O3 +[M+H]+575.2783;Found:575.2781。
实施例2
N-(4-(7-氯-5-((4-吗啉丁基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺(化合物2)的制备
步骤1:4-吗啉基丁腈(中间体V)的制备:
将4-氯丁腈(0.90g,8.69mmol)溶于吗啉(4.0mL)中,室温搅拌过夜。硅胶柱层析(洗脱剂:MeOH/DCM=1:20)分离得淡黄色透明液体中间体V(0.85g,收率:63%)。1H NMR(800MHz,CDCl3)δ3.75–3.65(m,4H),2.54–2.33(m,8H),1.87–1.78(m,2H).HRMS(ESI)calculated for C8H15N2O+[M+H]+155.1179;Found:155.1178。
步骤2:4-吗啉基-1-丁胺(中间体VI)的制备:
将中间体V(0.31g,2mmol)溶于甲醇(10mL)中,加入钯/碳催化剂(10%Pd,300mg)及浓盐酸(0.5mL)。在氢气环境下45℃搅拌2小时。滤掉钯/碳催化剂,减压蒸干溶剂。固体残留物重新用甲醇溶解,向溶液中加入甲醇钠(216mg,4mmol)。再次蒸干甲醇,固体残留物用二氯甲烷溶解,过滤除去固体氯化钠,减压蒸干二氯甲烷,得淡黄色液体中间体VI粗品(219mg,未进一步纯化直接用于下一步反应)。HRMS(ESI)calculated for C8H19N2O+[M+H]+159.1492;Found:159.1495。
步骤3:N-(4-(7-氯-5-((4-吗啉丁基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺(化合物2)的制备:
将实施例1步骤2中的N-(3-氨丙基)吗啉替换成中间体VI,其余所需原料,试剂及制备方法同实施例1步骤2,得白色泡沫状化合物2。1H NMR(800MHz,CDCl3)δ7.70–6.45(m,10H),4.55–3.99(m,1H),3.96–3.46(m,5H),3.24–3.04(m,1H),2.75–2.42(m,14H),2.12–1.98(m,2H),1.82–1.44(m,6H).HRMS(ESI)calculated for C34H42ClN4O3 +[M+H]+589.2940;Found:589.2942。
实施例3
N-(4-(7-氯-5-((5-吗啉戊基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺(化合物3)的制备:
将实施例2步骤1中的4-氯丁腈替换成5-溴戊腈,其余所需原料,试剂及制备方法同实施例2,得白色泡沫状化合物(I-3).1H NMR(800MHz,CDCl3)δ7.70–6.45(m,10H),4.57–4.01(m,1H),3.87–3.64(m,5H),3.21–3.05(m,1H),2.71–2.39(m,14H),2.11–1.97(m,2H),1.81–1.32(m,8H).HRMS(ESI)calculated for C35H44ClN4O3 +[M+H]+603.3096;Found:603.3098。
实施例4
N-(4-(7-氯-5-((2-吗啉乙基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺(化合物4)的制备:
将实施例1步骤2中的N-(3-氨丙基)吗啉替换成N-(2-氨乙基)吗啉,其余所需原料,试剂及制备方法同实施例1步骤2,得白色泡沫状化合物4。1H NMR(800MHz,DMSO-d6)δ10.41–10.16(m,1H),7.79–6.47(m,10H),4.44–3.92(m,1H),3.89–3.41(m,5H),3.08–2.87(m,1H),2.77–2.57(m,2H),2.46–2.26(m,12H),2.06–1.61(m,2H),1.55–1.27(m,2H).HRMS(ESI)calculated for C32H38ClN4O3 +[M+H]+561.2627;Found:561.2624。
实施例5
N-(4-(7-氯-5-((3-(吡啶-4-基)丙基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺(化合物5)的制备:/>
将实施例1步骤2中的N-(3-氨丙基)吗啉替换成3-(4-吡啶基)丙胺,其余所需原料,试剂及制备方法同实施例1步骤2,得白色泡沫状化合物5。1H NMR(800MHz,CDCl3)δ8.54–8.34(m,2H),8.01–6.39(m,12H),4.50–3.94(m,1H),3.83–3.07(m,2H),2.84–2.34(m,10H),2.05–1.41(m,6H).HRMS(ESI)calculated for C34H36ClN4O2 +[M+H]+567.2521;Found:567.2518。
基本按照实施例5所述的方法,使用相应的中间体制备如表1所示的化合物6-8。
表1
实施例6
N-(4-(7-氯-5-((3-(哌啶-1-基)丙基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺(化合物9)的制备:
将实施例1步骤2中的N-(3-氨丙基)吗啉替换成1-(3-氨基丙基)哌啶,其余所需原料,试剂及制备方法同实施例1步骤2,得白色泡沫状化合物9。1H NMR(800MHz,CDCl3)δ7.79–6.31(m,10H),4.51–3.11(m,3H),2.90–2.34(m,14H),2.08–1.37(m,12H).HRMS(ESI)calculated for C34H42ClN4O2 +[M+H]+573.2991;Found:573.2984。
基本按照实施例6所述的方法,使用相应的中间体制备如表2所示的化合物10-12。
表2
实施例7
N-(4-(7-氯-5-((3-吗啉-3-氧代丙基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺(化合物13)的制备:
步骤1:(3-吗啉基-3-氧代丙基)氨基甲酸苄酯(中间体VII)的制备:
将N-CBZ-beta-丙氨酸(2.23g,10mmol)溶于无水DMF(30mL)中,加入HATU(7.6g,20mmol),室温搅拌20分钟,再加入吗啉(0.87g,10mmol)及DIPEA(3.87g,30mmol),室温搅拌过夜。反应液加水稀释,以乙酸乙酯萃取三次,合并有机相,减压蒸除溶剂,剩余固体用硅胶柱层析分离纯化,得中间体VII(1.31g,收率45%)。1H NMR(800MHz,CDCl3)δ7.38–7.28(m,5H),5.61(s,1H),5.08(s,2H),3.68–3.63(m,4H),3.62–3.56(m,2H),3.53–3.46(m,2H),3.44–3.38(m,2H),2.52(t,J=5.6Hz,2H).HRMS(ESI)calculated for C15H21N2O4 +[M+H]+293.1496,Found:293.1491。
步骤2:3-氨基-1-吗啉丙烷-1-酮(中间体VIII)的制备:
将中间体VII(1.2g,4.1mmol)溶于甲醇(40mL)中,加入钯/碳催化剂(10%Pd,400mg)。在氢气环境下室温搅拌5小时。滤掉钯/碳催化剂,减压蒸干溶剂得中间体VIII粗品(0.57g,未进一步纯化直接用于下一步反应)。HRMS(ESI)calculated for C7H15N2O2 +[M+H]+159.1128;Found:159.1125。
步骤3:N-(4-(7-氯-5-((3-吗啉-3-氧代丙基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺(化合物13)的制备:
将实施例1步骤2中的N-(3-氨丙基)吗啉替换成中间体VIII,其余所需原料,试剂及制备方法同实施例1步骤2,得白色泡沫状化合物13。1H NMR(800MHz,CDCl3)δ7.82–6.28(m,10H),4.52–4.05(m,1H),3.81–3.32(m,9H),3.19–2.06(m,11H),2.06–1.40(m,4H).HRMS(ESI)calculated for C33H38ClN4O4 +[M+H]+589.2576;Found:589.2571。
基本按照实施例7所述的方法,使用相应的中间体制备如表3所示的化合物14-16。
表3
实施例8
N-(4-(7-氯-5-((3-(4-甲基哌嗪-1-基)丙基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺(化合物17)的制备:
将实施例1步骤2中的N-(3-氨丙基)吗啉替换成1-(3-氨丙基)-4-甲基哌嗪,其余所需原料,试剂及制备方法同实施例1步骤2,得白色泡沫状化合物(I-8)。1H NMR(800MHz,CDCl3)δ8.02–6.41(m,10H),4.50–3.14(m,3H),2.92–2.28(m,21H),2.11–1.36(m,6H).HRMS(ESI)calculated for C34H43ClN5O2 +[M+H]+588.3100;Found:588.3097。
基本按照实施例8所述的方法,使用相应的中间体制备如表4所示的化合物18-20。
表4
实施例9
N-(4-(7-氯-5-((2-苯氧基乙基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺(化合物21)的制备:
将实施例1步骤2中的N-(3-氨丙基)吗啉替换成2-苯氧基乙胺,其余所需原料,试剂及制备方法同实施例1步骤2,得白色泡沫状化合物21。1H NMR(800MHz,CDCl3)δ7.67–6.47(m,15H),4.52–4.15(m,3H),3.25–2.90(m,3H),2.75–2.20(m,7H),2.17–1.99(m,2H),1.67–1.46(m,2H).HRMS(ESI)calculated for C34H35ClN3O3 +[M+H]+568.2361;Found:568.2368。
基本按照实施例9所述的方法,使用相应的中间体制备如表5所示的化合物22-24。
表5
实施例10
N-(4-(7-氯-5-((3-(二乙基氨基)丙基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺(化合物25)的制备:
将实施例1步骤2中的N-(3-氨丙基)吗啉替换成3-二乙氨基丙胺,其余所需原料,试剂及制备方法同实施例1步骤2,得白色泡沫状化合物25。1H NMR(800MHz,CDCl3)δ8.41–6.33(m,10H),4.48–3.17(m,3H),3.16–2.32(m,14H),2.28–1.11(m,12H).HRMS(ESI)calculated for C33H42ClN4O2 +[M+H]+561.2991;Found:561.2990。
基本按照实施例10所述的方法,使用相应的中间体制备如表6所示的化合物26-28。
表6
实施例11
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时间点下,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V2R荧光配体的kon以及koff。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Association kinetics-One conc.of hot模型分析V2R荧光配体的kon和Dissociation-One phase exponential decay模型分析V2R荧光配体的koff,以及使用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7结果表明,化合物1,4,5,9,13对V2R表现出与Tolvaptan相当的亲和力,但是,化合物1,4比Tolvaptan显示出更长的受体停留时间,在PKD疾病中的囊泡的发展的抑制作用优于Tolvaptan,在延缓PKD病程进程中,比Tolvaptan具有明显优势。
表7 受体亲和性实验
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);kon:待测化合物与细胞的结合常数;koff:待测化合物与细胞的解离常数;RT:待测化合物在细胞上的停留时间。
实施例12囊泡实验
利用MDCK细胞在AC酶激动剂forskolin的作用下形成类似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。
具体操作:
1、细胞培养
将MDCK细胞培养在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10%胎牛血清和1%双抗。待细胞培养三天后,生长面积约在80-90%间便开始下一步实验。
2、按照下述配方配制基质胶(单孔)
3、消化细胞加入24孔板
在重新冷却基质胶的期间,消化MDCK细胞并计数。
配置好基质胶后将孔板放置培养箱内稳定90min,之后每孔加入1.5ml含10μMForsklin和相应浓度药物的细胞培养基,分对照组,AMPK激动剂(1μM)组,AMPK激动剂(3μM)组,AMPK激动剂(10μM)组。培育12天,每12h换液一次,并在4,6,8,10,12天拍照。选定拍照区域并追踪特定囊泡。
在第12天对比囊泡直径以评估受试化合物的作用效果。实验结果见表8。
表8 PKD囊泡实验
囊泡实验结果显示,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,并且该类化合物对PKD疾病中的囊泡的发展的抑制作用优于Tolvaptan。
实施例13PKD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2mg/kg化合物1为例,称取1mg化合物1,加入500μL 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***(拇指食指中间)中间***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9。
表9 PKD小鼠实验
动物实验结果显示,与对照组相比,该类化合物有明显延缓了PKD病程的发生发展,即该类化合物对PKD具有治疗作用,并优于Tolvaptan。
上述实验表明,这类化合物通过拮抗精氨酸加压素受体性,可有效抑制囊泡的发生发展,并减缓PKD疾病的病程发展。因此,该类化合物有治疗PKD的潜在用途。
实施例14
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10中的成分和用量制备硬明胶胶囊:
表10
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。
本发明已经描述了多个实施例,然而应当理解的是,在不脱离本发明的精神和范围的情况下,各种变化和修改对于本领域技术人员来说都是显而易见的。这样的变化和修改都应该包括在本发明所附权利要求的范围内。
Claims (9)
1.式(I)的化合物或其药学上可接受的盐,
(I)
其中,
X为NH;
Y为CH;
R1、R2各自独立地选自氢、氰基、硝基、羟基、氨基、C1-6烷基、C1-6烷氧基或C 3-8环烷基;
R3为卤素;
R4为氢,R5为;
m 为0或1 。
2.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于,R1和R2各自独立的选自C1-6烷基。
3.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于,R1和R2均为甲基,R3为氯。
4.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于,所述化合物是:
1)N-(4-(7-氯-5-((3-吗啉丙基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂䓬-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺;或
2)N-(4-(7-氯-5-((2-吗啉乙基)氨基)-2,3,4,5-四氢-1H-苯并[b]氮杂䓬-1-羰基)-3-甲基苯基)-2-甲基苯甲酰胺。
5.根据权利要求1-4中任一项所述的化合物或其药学上可接受的盐,其特征在于,所述的药学上的可接受的盐是所述化合物与无机酸或有机酸形成的盐。
6.根据权利要求5所述的化合物或其药学上可接受的盐,其特征在于,所述无机酸为盐酸、氢溴酸、硫酸或磷酸,所述有机酸为柠檬酸、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。
7.一种药物组合物,其特征在于,包含治疗有效量的权利要求1-6任一项所述的化合物、或其药学可接受的盐,和一种或多种药学可接受的载体。
8.根据权利要求1-6中任一项所述的化合物或其药学可接受的盐或权利要求7所述的药物组合物在制备药物中的应用,其中所述药物用于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***或肾素-血管紧张素-醛固酮***相关的疾病。
9.根据权利要求8所述的应用,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***或肾素-血管紧张素-醛固酮***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。
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CN1051038A (zh) * | 1989-10-20 | 1991-05-01 | 大塚制药株式会社 | 苯并杂环化合物 |
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