CN115504902A - 5-氯水杨酰胺类衍生物、其制备方法及其作为药物的用途 - Google Patents
5-氯水杨酰胺类衍生物、其制备方法及其作为药物的用途 Download PDFInfo
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- CN115504902A CN115504902A CN202110694688.8A CN202110694688A CN115504902A CN 115504902 A CN115504902 A CN 115504902A CN 202110694688 A CN202110694688 A CN 202110694688A CN 115504902 A CN115504902 A CN 115504902A
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- chloro
- trifluoromethyl
- biphenyl
- hydroxybenzamide
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
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Abstract
本发明涉及一类通式(I)所示的新型5‑氯水杨酰胺类衍生物、其制备方法及含有该衍生物的药物组合物作为制备预防或/和治疗脑水肿相关疾病的药物用途。所述的衍生物具有优异的体内抗脑水肿效果,明显提高水毒性模型的存活率,具有广阔的药物开发前景。
Description
技术领域
本发明涉及与脑水肿相关的药物学领域,具体涉及一种新的5-氯水杨酰胺类衍生物、其制备方法及含有该衍生物的药物组合物作为制备治疗脑水肿相关药物中的应用。本发明中涉及的衍生物结构在该领域中具有独特性和新颖性。
背景技术
脑水肿主要表现为脑组织中水含量的增加引发组织肿胀,是脑卒中、创伤性脑损伤、脑肿瘤和脑部炎症等疾病的常见并发症。由于脑组织处于封闭刚性的颅骨中,脑水肿引起的脑组织体积增加会直接导致血液灌注减少,从而引发缺血事件和颅内压增加。大多数情况下,颅内压的增加会加重脑部疾病继发性损伤。目前,脑水肿的治疗主要是调节颅内压、维持脑灌注压和限制脑缺血时间,这些干预措施有助于减轻和缓解脑部损伤,但没能从根本上抑制脑水肿,因此开发直接针对脑水肿形成机制的药物是必要的。
脑水肿分为细胞毒性脑水肿、离子源性脑水肿和血管源性脑水肿。细胞毒性水肿的特征是细胞内水积聚,但血脑屏障没有被破坏,其主要表现为星形胶质细胞和神经元树突的肿胀。通常是因为缺血缺氧和中毒引起细胞损伤,Na+-k+-ATP酶活性丧失,导致细胞内水钠潴留。离子源性水肿是缺血和缺血后再灌注引起的脑毛细血管功能障碍的早期阶段,此时血脑屏障通透性发生改变但还未被破坏,主要涉及脑毛细血管内皮细胞钠通量增加,进入脑组织间液引起脑部水肿。血管源性脑水肿是脑毛细血管功能障碍的第二个阶段,血脑屏障分解,水、血蛋白和血液等物质泄漏到脑组织间液引起脑部肿胀,此时为血管源性脑水肿。
水通道蛋白(aquaporins,AQPs)是一类的跨膜转运蛋白,双向渗透介导水的流动。至今已经发现了13种水通道蛋白(AQP0-AQP12)。目前在脑部发现的水通道蛋白有:AQP1、AQP3、AQP4、AQP5、AQP6、AQP7、AQP8、AQP9和AQP11。许多研究表明,AQP1、AQP4、AQP9在中枢神经系统与多种疾病相关,如脑水肿、脑卒中和脑肿瘤等。其中AQP4是哺乳动物大脑主要的水通道蛋白,大量表达于位于脑实质和主要液室的交界处的星形胶质细胞脚板,参与脑水平衡。动物模型表明,在细胞毒性脑水肿中,AQP-4的缺失减缓了水进入大脑的速度,而在血管源性水肿中,AQP4的缺失降低了水从脑实质流出的速度。证明了AQP4在细胞毒性脑水肿的发展和血管源性脑水肿的清除中起着重要作用。这也表明AQP4可能成为治疗和预防细胞毒性脑水肿的靶点。相关研究发现AER-270是AQP4的抑制剂,能够降低AQP4介导的水渗透作用,改善小鼠水毒性实验小鼠的脑水肿和生存率。此外,AER-270的磷酸酯二钠盐AER-271能够改善大鼠大脑中动脉闭塞模型的缺血性卒中(George W.Farr et al.Neuroscience,2019,404,484-498)。然而,AER-270和AER-271改善脑水肿的疗效极为有限,仅使小鼠水毒性模型脑水肿减轻11.2%至15.9%。
为进一步改善AER-270和AER-271抗脑水肿效果,发明人对AER-270进行了系统的结构优化,发现了一系列结构新颖、疗效更优的5-氯水杨酰胺类抗脑水肿化合物,本发明所述5-氯水杨酰胺类衍生物及其可药用盐可以潜在的用于治疗或者预防脑水肿,具有广阔的药物开发前景。
发明内容
针对现有技术存在的上述问题和未满足的临床需求,本发明的目的是提供一类疗效更优的抗脑水肿化合物,为预防或/和治疗脑水肿提供一类新的潜在药物。
本发明所述的5-氯水杨酰胺类化合物,是含有有效量的通式(I)所示的化合物或其可药用的盐:
其中:
R1选自氢、卤素、三氟甲基;
R2选自氢、氨甲酰基;
R3选自C3-C6环烷基、吗啉基、苯基,其中所述苯基任选进一步被一个或多个选自氢、卤素、三氟甲基、羧基、C1-C3的烷基所取代。
更优选的通式(I)所示的化合物或其可药用的盐:
R1选自氢、氯、三氟甲基;
R2选自氢、氨甲酰基;
R3选自环丙基、吗啉基、苯基,其中所述苯基任选进一步被一个或多个选自氢、卤素、三氟甲基、羧基、甲基所取代。
更优选的本发明化合物包括,但不限于:
N-(4-氨基甲酰基-3-氯苯基)-5-氯-2-羟基苯甲酰胺(I-1);
5-氯-N-(3-环丙基-5-(三氟甲基)苯基)-2-羟基苯甲酰胺(I-2);
5-氯-2-羟基-N-(5-(三氟甲基)-[1,1′-联苯]-3-基)苯甲酰胺(I-3);
N-(4′,5-双(三氟甲基)-[1,1′-联苯]-3-基)-5-氯-2-羟基苯甲酰胺(I-4);
3′-(5-氯-2-羟基苯甲酰胺基)-5′-(三氟甲基)-[1,1′-联苯]-3-羧酸(I-5);
3′-(5-氯-2-羟基苯甲酰胺基)-5′-(三氟甲基)-[1,1′-联苯]-4-羧酸(I-6);
5-氯-2-羟基-N-(3-吗啉代-5-(三氟甲基)苯基)苯甲酰胺(I-7);
5-氯-2-羟基-N-(4′-甲基-5-(三氟甲基)-[1,1′-联苯]-3-基)苯甲酰胺(I-8);
5-氯-2-羟基-N-(2′-甲基-5-(三氟甲基)-[1,1′-联苯]-3-基)苯甲酰胺(I-9);
5-氯-N-(4′-氟-5-(三氟甲基)-[1,1′-联苯]-3-基)-2-羟基苯甲酰胺(I-10);
5-氯-N-(4′-氯-5-(三氟甲基)-[1,1′-联苯]-3-基)-2-羟基苯甲酰胺(I-11);
N-(2′,5-双(三氟甲基)-[1,1′-联苯]-3-基)-5-氯-2-羟基苯甲酰胺(I-12);
5-氯-N-(2′-氯-5-(三氟甲基)-[1,1′-联苯]-3-基)-2-羟基苯甲酰胺(I-13);
5-氯-N-(4′-氟-2′-甲基-5-(三氟甲基)-[1,1′-联苯]-3-基)-2-羟基苯甲酰胺(I-14);
5-氯-N-(2′,6′-二甲基-5-(三氟甲基)-[1,1′-联苯]-3-基)-2-羟基苯甲酰胺(I-15);
3′-(5-氯-2-羟基苯甲酰胺基)-2-甲基-5′-(三氟甲基)-[1,1′-联苯]-4-羧酸(I-16)。
本发明还涉及通式(II)所示的前药或其可药用的盐:
其中,R1、R2、R3定义与通式(I)所述一致。
本发明的另一方面涉及一种药物组合物,其含有治疗有效剂量的所述化合物、前药或其可药用的盐及适当的载体、稀释剂或赋形剂。
本发明同时涉及所述化合物、前药或其可药用的盐或其药物组合物在制备预防或/和治疗脑水肿相关疾病的药物中的用途。
具体实施方式
下面结合实施例对本发明作进一步说明。需要说明的是,下述实施例仅是用于说明,而并非用于限制本发明。本领域技术人员根据本发明的教导所做出各种变化均应在本申请权利要求的保护范围之内。
实施例1
N-(4-氨基甲酰基-3-氯苯基)-5-氯-2-羟基苯甲酰胺(I-1)
将2-氯-4-硝基苯甲酸(1当量)溶于适量的二氯甲烷,向体系中加入二氯亚砜(2当量)和N,N-二甲基甲酰胺(1至2滴),于室温反应2小时,薄层色谱监控反应完全后,浓缩掉溶剂,得到中间体2-氯-4-硝基苯甲酰氯。将4-二甲氨基吡啶(0.05当量)加入至适量的氨水中,将2-氯-4-硝基苯甲酰氯(1当量)溶于适量二氯甲烷于-5℃缓慢滴加入体系,滴加完后于室温反应2小时,用水洗涤有机层多次,无水硫酸钠于燥有机层,经柱层析得到2-氯-4-硝基苯甲酰胺。将2-氯-4-硝基苯甲酰胺溶于二氯甲烷与甲醇1∶1∶的混合溶剂中,向其中加入底物质量10%的10%钯碳,于氢气氛围中反应12小时,抽滤,浓缩掉溶剂,得到中间体4-氨基-2-氯苯甲酰胺。将4-氨基-3-氯苯甲酰胺(0.5当量)溶于适量二氯甲烷中,向体系中加入三乙胺(3当量)和4-二甲氨基吡啶(0.05当量),将5-氯-2-羟基苯甲酰氯(1当量)溶于适量二氯甲烷于-5℃缓慢滴加入体系,滴加完后于室温反应2小时,用10%的稀盐酸洗涤有机层多次,无水硫酸钠干燥有机层,经柱层析得到N-(4-氨基甲酰基-3-氯苯基)-5-氯-2-羟基苯甲酰胺0.5g,收率36%。1H NMR(300MHz,DMSO-d6)δ11.69(s,1H),10.64(s,1H),8.02(s,1H),7.96(d,J=2.2Hz,1H),7.93-7.88(m,1H),7.73(d,J=8.4Hz,1H),7.66-7.61(m,1H),7.56(d,J=8.1Hz,2H),7.11(d,J=8.8Hz,1H).13C NMR(75MHz,DMSO-d6)δ168.19,165.52,156.83,140.34,133.58,132.67,130.52,129.81,129.01,123.24,121.32,120.56,119.50,119.06.ESI-MS m/z:325.1[M+H]+.
实施例2
5-氯-N-(3-环丙基-5-(三氟甲基)苯基)-2-羟基苯甲酰胺(I-2)
将3-溴-5-(三氟甲基)苯胺、环丙基硼酸、磷酸钾、三环己基磷和醋酸钯溶于甲苯/水(4∶1)的混合溶剂中,在氮气氛围下100℃反应两小时,向其中加入适量水,用乙酸乙酯萃取三次,合并有机层,无水硫酸钠干燥有机层,经柱层析得到3-环丙基-5-(三氟甲基)苯胺。将3-环丙基-5-(三氟甲基)苯胺(0.5当量)溶于适量的二氯甲烷中,向体系中加入三乙胺(3当量)和4-二甲氨基吡啶(0.05当量),将5-氯-2-羟甚苯甲酰氯(1当量)溶于适量二氯甲烷于-5℃缓慢滴加入体系,滴加完后于室温反应2小时,用10%的稀盐酸洗涤有机层多次,无水硫酸钠干燥有机层,经柱层析得到5-氯-N-(3-环丙基-5-(三氟甲基)苯基)-2-羟基苯甲酰胺0.67g,收率62%。1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),10.51(s,1H),7.97(s,1H),7.92-7.87(m,1H),7.59(s,1H),7.53-7.39(m,1H),7.20(s,1H),7.02(d,J=8.8Hz,1H),2.05-2.01(m,1H),1.08-0.64(m,4H).13C NMR(101MHz,DMSO-d6)δ165.73,157.07,146.73,129.94(q,J=31.3Hz),130.09,129.78,128.86,125.90,123.21,121.15,120.19,119.52,118.27(d,J=4.0Hz),114.39(d,J=4.0Hz),15.48,10.30.ESI-MS m/z:356.1[M+H]+.
实施例3
5-氯-2-羟基-N-(5-(三氟甲基)-[1,1′-联苯]-3-基)苯甲酰胺(I-3)
将3-溴-5-(三氟甲基)苯胺(1当量)、苯硼酸(1当量)、碳酸钠(3当量)和四(三苯基)磷钯(5%)溶于甲苯/乙醇/水(3∶1∶3)的混合溶剂中,在氮气氛围下80℃反应24小时,冷却,过滤,向滤液中加适量水萃取,无水硫酸钠干燥有机相,经柱层析得到5-(三氟甲基)-[1,1′-联苯]-3-胺。将其溶于适量的二氯甲烷中,向体系中加入三乙胺(3当量)和4-二甲氨基吡啶(0.05当量),将5-氯-2-羟基苯甲酰氯(1当量)溶于适量二氯甲烷于-5℃缓慢滴加入上述体系,滴加完后于室温反应2小时,用10%的稀盐酸洗涤有机层多次,无水硫酸钠干燥有机层,经柱层析得到5-氯-2-羟基-N-(5-(三氟甲基)-[1,1′-联苯]-3-基)苯甲酰胺0.73g,收率29%。1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),10.69(s,1H),8.23(d,J=16.1Hz,2H),7.94(d,J=2.7Hz,1H),7.74(d,J=1.3Hz,1H),7.72(s,2H),7.56-7.42(m,4H),7.04(d,J=8.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ165.88,157.10,142.45,140.05,138.90,133.66,130.68(q,J=31.3Hz),129.63,128.93,128.90,127.40,124.49(d,J=272.6Hz),123.23,122.83,120.29,119.55,119.08(d,J=3.5Hz),116.16(d,J=3.9Hz).ESI-MS m/z:392.1[M+H]+.
实施例4
N-(4′,5-双(三氟甲基)-[1,1′-联苯]-3-基)-5-氯-2-羟基苯甲酰胺(I-4)
采用I-3相同的制备方法得到目标化合物0.71g,收率35%。1H NMR(400MHz,DMSO-d6)δ11.66(s,1H),10.72(s,1H),8.28-8.21(m,2H),7.99-7.90(m,3H),7.86(d,J=8.4Hz,2H),7.79(s,1H),7.48-7.40(m,1H),7.04(d,J=8.8Hz,1H).13C NMR(101MHz,DMSO-d6)13CNMR(101MHz,DMSO-d6)δ165.86,157.08,142.82,140.83,140.19,133.69,130.87(q,J=32.3Hz),129.2(q,J=31.3Hz),128.95,128.28,126.43,126.39,125.87(q,J=31.3Hz),123.27,123.09,120.19,119.55,117.06.ESI-MS m/z:460.1[M+H]+.
实施例5
3′-(5-氯-2-羟基苯甲酰胺基)-5′-(三氟甲基)-[1,1′-联苯]-3-羧酸(I-5)
采用I-3相同的制备方法得到目标化合物0.52g,收率27%。1H NMR(400MHz,DMSO-d6)δ15.65(s,1H),8.26-8.22(m,2H),8.12(s,1H),7.97(d,J=7.6Hz,1H),7.69(d,J=7.7Hz,1H),7.66(d,J=3.1Hz,1H),7.52(s,1H),7.44(t,J=7.6Hz,1H),6.99(dd,J=8.9,3.1Hz,1H),6.51(d,J=8.9Hz,1H).13C NMR(101MHz,DMSO-d6)δ170.36,169.74,166.83,142.70,142.40,140.90,138.30,132.36,130.65(q,J=31.3Hz),129.49,128.60,128.48,128.06,128.01,124.8(q,J=273.7Hz),124.41,121.32,119.00,116.68,114.64,113.45.ESI-MS m/z:434.1[M-H]-.
实施例6
3′-(5-氯-2-羟基苯甲酰胺基)-5′-(三氟甲基)-[1,1′-联苯]-3-羧酸(I-6)
采用I-3相同的制备方法得到目标化合物0.58g,收率32%。1H NMR(400MHz,DMSO-d6)δ13.00(s,1H),11.64(s,1H),10.71(s,1H),8.27-8.22(m,2H),8.07(d,J=8.4Hz,2H),7.93(d,J=2.6Hz,1H),7.86(d,J=8.4Hz,2H),7.79(s,1H),7.48(dd,J=8.8,2.7Hz,1H),7.04(d,J=8.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ167.44,165.88,157.12,142.88,141.28,140.14,133.69,130.83(q,J=34.3Hz),130.56,128.94,127.58,124.4(q,J=273.7Hz),123.25,123.01,120.17,119.56,119.34,119.30,116.86.ESI-MS m/z:434.0[M-H]-.
实施例7
5-氯-2-羟基-N-(3-吗啉代-5-(三氟甲基)苯基)苯甲酰胺(I-7)
将1-溴-3-硝基-5-(三氟甲基)苯(1当量)、吗啡啉(3当量)、碘化亚铜(5%)和L-脯氨酸(10%)溶于DMSO中,于氮气氛围下120℃反应48小时,加水以乙酸乙酯萃取三次,无水硫酸钠干燥有机层,柱层析得到4-(3-硝基-5-(三氟甲基)苯基)吗啉。将4-(3-硝基-5-(三氟甲基)苯基)吗啉溶于二氯甲烷与甲醇1∶1的混合溶剂中,向其中加入底物质量10%的10%钯碳,于氢气氛围中反应12小时,抽滤,浓缩掉溶剂,得到中间体3-吗啉代-5-(三氟甲基)苯胺。将其溶于适量的二氯甲烷中,向体系中加入三乙胺(3当量)和4-二甲氨基吡啶(0.05当量),将5-氯-2-羟基苯甲酰氯(1当量)溶于适量二氯甲烷于-5℃缓慢滴加入上述体系,滴加完后于室温反应2小时,用10%的稀盐酸洗涤有机层多次,无水硫酸钠干燥有机层,经柱层析得到5-氯-2-羟基-N-(3-吗啉代-5-(三氟甲基)苯基)苯甲酰胺0.48g,收率21%。1H NMR(400MHz,DMSO-d6)δ11.66(s,1H),10.46(s,1H),7.92(d,J=2.6Hz,1H),7.61(s,1H),7.52(s,1H),7.47(dd,J=8.8,2.6Hz,1H),7.08-6.93(m,2H),3.76(t,4H),3.19(t,4H).13CNMR(101MHz,DMSO-d6)δ165.75,157.12,152.29,140.19,133.57,130.63(q,J=31.3Hz),128.83,124.7(q,J=273.7Hz),123.19,120.25,119.53,110.27,107.76,107.40,66.36,48.29.ESI-MS m/z:401.1[M+H]+.
实施例8
5-氯-2-羟基-N-(4′-甲基-5-(三氟甲基)-[1,1′-联苯]-3-基)苯甲酰胺(I-8)
采用I-3相同的制备方法得到目标化合物0.62g,收率41%。1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),10.67(s,1H),8.23(s,1H),8.18(s,1H),7.95(d,J=2.6Hz,1H),7.70(s,1H),7.63(d,J=8.1Hz,2H),7.49(dd,J=8.8,2.7Hz,1H),7.33(d,J=8.0Hz,2H),7.05(d,J=8.8Hz,1H),2.37(s,3H).ESI-MS m/z:406.1[M+H]+.
实施例9
5-氯-2-羟基-N-(2′-甲基-5-(三氟甲基)-[1,1′-联苯]-3-基)苯甲酰胺(I-9)
采用I-3相同的制备方法得到目标化合物0.53g,收率26%。1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),10.68(s,1H),8.22(s,1H),7.95(s,1H),7.93(d,J=2.6Hz,1H),7.50(s,1H),7.43(s,1H),7.38-7.24(m,4H),7.04(d,J=8.8Hz,1H),2.27(s,3H).ESI-MS m/z:406.1[M+H]+.
实施例10
5-氯-N-(4′-氟-5-(三氟甲基)-[1,1′-联苯]-3-基)-2-羟基苯甲酰胺(I-10)
采用I-3相同的制备方法得到目标化合物0.73g,收率38%。1H NMR(300MHz,DMSO-d6)δ11.64(s,1H),10.73(s,1H),8.26-8.20(m,2H),7.96(d,J=2.7Hz,1H),7.86-7.78(m,2H),7.76(s,1H),7.53(dd,J=8.8,2.7Hz,1H),7.45-7.33(m,2H),7.08(d,J=8.8Hz,1H).13C NMR(126MHz,DMSO-d6)δ165.85,162.84,157.14,141.37,140.03,135.38,133.68,130.70(q,J=31.7Hz),129.56,129.49,128.92,124.45(q,J=272.2Hz),123.24,122.74,120.15,119.55,119.04,116.51,116.34,116.11.ESI-MS m/z:410.1[M+H]+.
实施例11
5-氯-N-(4′-氯-5-(三氟甲基)-[1,1′-联苯]-3-基)-2-羟基苯甲酰胺(I-11)
采用I-3相同的制备方法得到目标化合物0.61g,收率33%。1H NMR(300MHz,DMSO-d6)δ11.64(s,1H),10.84(s,1H),8.26-8.20(m,2H),7.95(d,J=2.7Hz,1H),7.83(s,1H),7.80-7.73(m,2H),7.62(d,J=8.6Hz,2H),7.52(dd,J=8.8,2.6Hz,1H),7.07(d,J=8.8Hz,1H).13C NMR(126MHz,DMSO-d6)δ165.85,157.15,141.06,140.09,137.66,133.83,133.68,130.76(q,J=31.8Hz),129.54,129.17,128.93,124.42(q,J=273.4Hz),123.24,122.69,120.12,119.56,119.02,116.42.ESI-MS m/z:426.1[M+H]+.
实施例12
N-(2′,5-双(三氟甲基)-[1,1′-联苯]-3-基)-5-氯-2-羟基苯甲酰胺(I-12)
采用I-3相同的制备方法得到目标化合物0.52g,收率18%。1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),10.71(s,1H),8.27(s,1H),8.00(s,1H),7.94-7.86(m,2H),7.79-7.73(m,1H),7.69-7.61(m,1H),7.52(d,J=7.6Hz,1H),7.48(dd,J=8.8,2.7Hz,1H),7.41(s,1H),7.04(d,J=8.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ165.86,156.86,141.31,139.28,133.54,133.00,132.46,129.67(q,J=31.9Hz),129.29,128.95,127.30(q,J=29.6Hz),126.66(q,J=5.0Hz),125.86,125.66,124.64,123.19,122.95,121.06,120.65,119.48,116.57(d,J=4.0Hz).ESI-MS m/z:460.1[M+H]+.
实施例13
5-氯-N-(2′-氯-5-(三氟甲基)-[1,1′-联苯]-3-基)-2-羟基苯甲酰胺(I-13)
采用I-3相同的制备方法得到目标化合物0.62g,收率25%。1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),10.71(s,1H),8.26(s,1H),8.07(s,1H),7.93(d,J=2.7Hz,1H),7.68-7.58(m,1H),7.56-7.43(m,5H),7.04(d,J=8.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ165.88,156.98,140.76,139.52,138.53,133.59,131.91,131.65,130.49,130.41,129.96(q,J=31.9Hz),128.93,128.18,125.29,124.36(q,J=272.7Hz),123.21,121.61,120.47,119.51,116.54(q,J=3.9Hz).ESI-MS m/z:426.1[M+H]+.
实施例14
5-氯-N-(4′-氟-2′-甲基-5-(三氟甲基)-[1,1′-联苯]-3-基)-2-羟基苯甲酰胺(I-14)
采用I-3相同的制备方法得到目标化合物0.53g,收率22%。1H NMR(400MHz,DMSO-d6)δ11.57(s,1H),10.67(s,1H),8.22(s,1H),7.97-7.89(m,2H),7.48(dd,J=8.8,2.7Hz,1H),7.42(s,1H),7.32(dd,J=8.4,6.1Hz,1H),7.21(dd,J=10.1,2.5Hz,1H),7.17-7.09(m,1H),7.04(d,J=8.8Hz,1H),2.28(s,3H).13C NMR(101MHz,DMSO-d6)δ165.87,162.16,157.03,142.32,139.46,138.26(d,J=8.2Hz),136.36,133.59,131.81(d,J=8.6Hz),130.05(q,J=31.7Hz),128.90,125.21,124.43(q,J=273.7Hz),123.21,121.38(d,J=3.4Hz),120.37,119.51,117.38(d,J=21.2Hz),115.96(d,J=4.0Hz),113.33(d,J=21.0Hz),20.50.ESI-MS m/z:424.1[M+H]+.
实施例15
5-氯-N-(2′,6′-二甲基-5-(三氟甲基)-[1,1′-联苯]-3-基)-2-羟基苯甲酰胺(I-15)
采用I-3相同的制备方法得到目标化合物0.62g,收率17%。1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),10.65(s,1H),8.22(s,1H),7.93(d,J=2.7Hz,1H),7.77(s,1H),7.48(dd,J=8.8,2.7Hz,1H),7.27(s,1H),7.25-7.19(m,1H),7.16(d,J=7.3Hz,2H),7.04(d,J=8.8Hz,1H),2.02(s,6H).13C NMR(101MHz,DMSO-d6)δ165.84,157.00,142.51,139.98,139.78,135.56,133.56,130.34(q,J=31.9Hz),128.92,128.16,127.95,124.5(q,J=273.7Hz),125.09,123.19,121.29(d,J=4.0Hz),120.45,119.50,115.86(d,J=4.0Hz),20.86.ESI-MS m/z:420.1[M+H]+.
实施例16
3′-(5-氯-2-羟基苯甲酰胺基)-2-甲基-5′-(三氟甲基)-[1,1′-联苯]-4-羧酸(I-16)
采用I-3相同的制备方法得到目标化合物0.57g,收率22%。1H NMR(500MHz,DMSO-d6)δ11.67(s,1H),10.77(s,1H),8.25(s,1H),7.98(s,1H),7.94(d,J=2.6Hz,1H),7.92(d,J=1.2Hz,1H),7.85(dd,J=7.9,1.3Hz,1H),7.49-7.43(m,2H),7.40(d,J=7.9Hz,1H),7.08(d,J=8.8Hz,1H),2.31(s,3H).13C NMR(126MHz,DMSO-d6)δ167.52,165.86,157.01,144.18,142.42,139.57,135.83,133.54,131.82,130.84,130.28,129.00,127.52,124.94,124.4(q,J=273.4Hz),123.18,121.06,120.46,119.54,116.34,20.43.ESI-MS m/z:448.1[M-H]-.
实施例17
前药及其钠盐制备方法
将化合物I(1当量)和吡啶(21当量)溶于适量二氯甲烷,于0℃将三氯氧磷(10当量)滴加于上述溶液中。反应2h后,用丙酮/水(1∶1)混合溶剂淬灭反应,减压除去有机溶剂,用6M的NaOH水溶液调pH至9-10,用乙酸乙酯萃取两次除去杂质,水层用6M盐酸水溶液调pH至3-4,用乙酸乙酯萃取,减压除去有机溶剂,得到磷酸酯。将其溶于甲醇/水(1∶1)混合溶剂,加入氢氧化钠(2当量)搅拌30min后,减压除去溶剂,得到磷酸酯二钠盐,分别制备得到如下化合物I-2、I-11、I-13和I-15的二钠盐:
实施例18小鼠水毒性模型-脑含水量实验
水毒性模型是目前最经典、最常用的脑水肿模型,通过测量小鼠脑含水量来评估药物改善水毒性所致脑水肿的程度。25-30g雄性ICR小鼠,随机分组,每组6只。取4.0mg待测药物依次添加0.50mL DMSO、2.00mL PEG300、0.25mL Tween-80和2.25mL去离子水配制为溶液1备用;取待测药物0.20mg和加压素0.1μg溶于50ml的去离子水配制为溶液2备用。于0min时,溶液1以给药体积为0.01mL/g腹腔注射于小鼠(预防给药);20min时,溶液2以给药体积0.2mL/g腹腔注射(水毒性模型);50min时,处死小鼠取脑,即刻称取脑湿重。于电热恒温鼓风干燥箱105℃持续烘干36h至脑恒重,称取脑干重。计算小鼠脑水肿改善百分比,计算公式为:(1)脑含水量=(脑湿重-脑干重)/脑湿重×100%;(2)脑水肿改善百分比=(模型脑含水量-给药组脑含水量)/(模型脑含水量-正常脑含水量)×100%。结果如下表:
表1:小鼠水毒性模型-脑含水量实验结果
上述结果表明:本发明化合物对水毒性模型的脑水肿均表现出明显抑制作用,大部分化合物改善脑水肿的疗效明显优于在研药物AER270,其中化合物I-15疗效是AER270的两倍以上;此外,发明化合物的前药及盐也表现出明显抑制脑水肿的作用,且疗效优于AER271,显示出良好的药用前景。
实施例19 水中毒模型存活率实验
12周龄雄性ICR小鼠随机分组,每组15只,空白组腹腔注射生理盐水,给药组腹腔注射1mg/kg待测化合物,15分钟后,所有小鼠注射其体重20%的水,记录给水后3小时内小鼠的状态和存活情况。
表2:小鼠水毒性模型-存活率实验结果
上述结果表明:本发明化合物可通过抑制脑水肿,明显改善水毒性模型的生存率。
Claims (6)
2.权利要求1所定义的具有通式(I)的化合物或其可药用的盐:
R1选自氢、氯、三氟甲基;
R2选自氢、氨甲酰基;
R3选自环丙基、吗啉基、苯基,其中所述苯基任选进一步被一个或多个选自氢、卤素、三氟甲基、羧基、甲基所取代。
3.权利要求1-2任意一项所定义的通式(I)化合物或其可药用的盐,所述化合物选自:
N-(4-氨基甲酰基-3-氯苯基)-5-氯-2-羟基苯甲酰胺;
5-氯-N-(3-环丙基-5-(三氟甲基)苯基)-2-羟基苯甲酰胺;
5-氯-2-羟基-N-(5-(三氟甲基)-[1,1′-联苯]-3-基)苯甲酰胺;
N-(4′,5-双(三氟甲基)-[1,1′-联苯]-3-基)-5-氯-2-羟基苯甲酰胺;
3′-(5-氯-2-羟基苯甲酰胺基)-5′-(三氟甲基)-[1,1′-联苯]-3-羧酸;
3′-(5-氯-2-羟基苯甲酰胺基)-5′-(三氟甲基)-[1,1′-联苯]-4-羧酸;
5-氯-2-羟基-N-(3-吗啉代-5-(三氟甲基)苯基)苯甲酰胺;
5-氯-2-羟基-N-(4′-甲基-5-(三氟甲基)-[1,1′-联苯]-3-基)苯甲酰胺;
5-氯-2-羟基-N-(2′-甲基-5-(三氟甲基)-[1,1′-联苯]-3-基)苯甲酰胺;
5-氯-N-(4′-氟-5-(三氟甲基)-[1,1′-联苯]-3-基)-2-羟基苯甲酰胺;
5-氯-N-(4′-氯-5-(三氟甲基)-[1,1′-联苯]-3-基)-2-羟基苯甲酰胺;
N-(2′,5-双(三氟甲基)-[1,1′-联苯]-3-基)-5-氯-2-羟基苯甲酰胺;
5-氯-N-(2′-氯-5-(三氟甲基)-[1,1′-联苯]-3-基)-2-羟基苯甲酰胺;
5-氯-N-(4′-氟-2′-甲基-5-(三氟甲基)-[1,1′-联苯]-3-基)-2-羟基苯甲酰胺;
5-氯-N-(2′,6′-二甲基-5-(三氟甲基)-[1,1′-联苯]-3-基)-2-羟基苯甲酰胺;
3′-(5-氯-2-羟基苯甲酰胺基)-2-甲基-5′-(三氟甲基)-[1,1′-联苯]-4-羧酸。
5.一种药物组合物,含有权利要求1-4之一所述的化合物、前药或其可药用盐及适当的载体或赋形剂。
6.权利要求1-5任意一项所定义的化合物、前药或其可药用的盐或其药物组合物在制备预防或/和治疗脑水肿疾病的药物中的用途。
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CN112107568A (zh) * | 2019-06-19 | 2020-12-22 | 北京大学 | 二芳基酰胺类化合物及其应用 |
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