WO2019062661A1 - 含脲基的神经氨酸酶抑制剂及其医药用途 - Google Patents
含脲基的神经氨酸酶抑制剂及其医药用途 Download PDFInfo
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- the invention relates to the field of medicinal chemistry, in particular to a class of urea group-containing neuraminidase inhibitor oseltamivir derivatives, a preparation method thereof and a medical use thereof, and the medical use is mainly used for treating an infectious disease caused by a virus.
- Influenza is an acute respiratory infection caused by influenza virus.
- influenza A is highly spread, and has a high morbidity and mortality, which is easy to cause a pandemic or a large outbreak.
- M2 protein inhibitors There are two main anti-influenza drugs, M2 protein inhibitors and neuraminidase inhibitors.
- M2 protein inhibitors mainly include amantadine hydrochloride and rimantadine hydrochloride. After the oral absorption of amantadine hydrochloride, it can penetrate the blood brain. Barriers, causing central nervous system toxic side effects, and are prone to drug resistance, the United States Centers for Disease Control has not recommended these two drugs for the prevention and treatment of influenza A (Recommendations and Reports, 2007, 56, RR- 6, 1-54).
- Neuraminidase can promote the release of progeny virus from host cells, so neuraminidase inhibitors can inhibit the release of the virus and block the transmission pathway, thus playing a role in the treatment of influenza.
- the structure of the neuraminidase active center is relatively conservative, so it is an ideal target for the treatment of influenza.
- the drugs used worldwide are zanamivir and oseltamivir phosphate. Among them, oseltamivir phosphate is the only oral drug, which can be used in the body to be hydrolyzed by esterase to free acid (GS4071).
- the active ingredient is distributed to all influenza virus infection sites, including lung, trachea, nasal mucosa and The middle ear, which greatly reduces the occurrence of complications, is recognized as one of the specific drugs against influenza A and avian influenza.
- some drug-resistant strains inevitably appear in the clinic.
- a series of modified amine-modified derivatives of oseltamivir are provided.
- the pharmacological activity test results showed that the derivative of the present invention has an enzyme inhibitory activity against neuraminidase A/Anhui/1/2005 (H5N1), and some of the compounds exhibited strong enzyme inhibitory activity.
- the present invention provides a derivative represented by the formula (I) and a pharmaceutically acceptable salt or isomer thereof:
- R 1 and R 2 independently represent a hydrogen atom, an amino group, a hydroxyl group, a methyl group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted 5-10 membered aromatic ring, and the substituent is: C1-C6 Alkyl, halogen;
- R 3 represents a hydrogen atom or a C1-C6 alkyl group.
- R 3 is not an ethyl group.
- the present invention is preferably a derivative of the formula (I) and a pharmaceutically acceptable salt or isomer thereof:
- R 1 and R 2 independently represent a hydrogen atom, an amino group, a hydroxyl group, a methyl group, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted 5-6 membered aromatic ring, and the substituent is C1- C4 alkyl, halogen.
- R 1 and R 2 independently represent a hydrogen atom, an amino group, a hydroxyl group, a methyl group, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted benzene ring, and the substituent is a C1-C4 alkyl group.
- R 1 represents an amino group, a hydroxyl group, a C1-C4 alkyl group, or a halogen-substituted benzene ring; and R 2 represents a hydrogen atom or a C1-C4 alkyl group.
- the compounds of the invention are prepared as follows:
- the compounds of the present invention were tested for inhibitory activity of neuraminidase.
- the positive control drug is oseltamivir carboxylic acid (Oseltamivir acid).
- the test principle is that MUNANA (2'-(4-methylumbelliferyl)- ⁇ -N-acetylneuraminic acid) is a specific substrate for neuraminidase, and the substance produced by the metabolism of neuraminidase is excited by 355 nm light.
- the activity test results are:
- I-1 and I-2 exhibit strong neuraminidase inhibitory activity, which is superior to Duffy's active ingredient, oseltamivir carboxylic acid, and has further development value.
- oseltamivir phosphate 500 mg, 1.218 mmol
- cesium hydroxide 355 mg, 2.071 mmol
- urea 146 mg, 2.436 mmol
- Example 5 The same procedure as in Example 5 was carried out as 280 mg of (3R,4R,5S)-4-acetamido-5-(1-(imidazolyl)-aminocarboxamido)-2-oxoethylamino)-3-
- the starting material of ethyl (II)ethyl (1-ethylpropoxy)-1-cyclohexene-1-carboxylate was treated to give 231 mg of a white solid (yield: 65.7%).
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Abstract
本发明涉及药物化学领域,具体是一类含脲基的神经氨酸酶抑制剂奥司他韦衍生物、其制备方法及其医药用途,医药用途主要用于治疗由病毒引起的感染性疾病。本发明的化合物为具有如下通式(I)所示的衍生物及其药学上可接受的盐或异构体,其中,R1、R2、R3如权利要求书和说明书所述。
Description
本发明涉及药物化学领域,具体是一类含脲基的神经氨酸酶抑制剂奥司他韦衍生物、其制备方法及其医药用途,医药用途主要用于治疗由病毒引起的感染性疾病。
流行性感冒(简称流感)是由流感病毒引起的急性呼吸道感染病,其中甲型流感具有很强的传播性,并且有较高的致病率和致死率,容易造成大流行或大暴发。
抗流感病毒药物主要有两种,M2蛋白抑制剂和神经氨酸酶抑制剂,M2蛋白抑制剂主要有盐酸金刚烷胺和盐酸金刚乙胺,盐酸金刚烷胺口服吸收后,能穿透血脑屏障,引起中枢神经系统毒副反应,并且很容易产生耐药性,美国Centers for Disease Control已经不推荐这两种药物用于甲型流感的预防和治疗(Recommendations and Reports,2007,56,RR-6,1-54)。
神经氨酸酶能促进宿主细胞释放子代病毒,故神经氨酸酶抑制剂能抑制病毒释放,阻断传播途径,从而起到治疗流感的作用。神经氨酸酶活性中心的结构相对比较保守,所以它是一个比较理想的治疗流感的靶点。全世界范围内使用的这一类药物有扎那米韦和磷酸奥司他韦。其中磷酸奥司他韦是唯一的口服用药,它在体内经酯酶水解成为游离酸(GS4071)后才能发挥药效,活性成分分布至所有流感病毒感染的部位,包括肺、气管、鼻黏膜和中耳,从而大大减少并发症的发生,是公认的抗甲型流感、禽流感的特效药之一。但是,临床上不可避免地出现了一些耐药株。
发明内容
本发明中为了克服现有技术的缺陷,提供了一系列奥司他韦的伯胺基团修饰改造的衍生物。药理活性测试结果表明,本发明的衍生物对神经氨酸酶A/Anhui/1/2005(H5N1)有酶抑制活性,部分化合物表现了较强的酶抑制活性。
本发明提供具有通式(I)所示的衍生物及其药学上可接受的盐或异构体:
其中:
R
1、R
2独立的表示氢原子、氨基、羟基、甲基、取代或未取代的C1-C6烷基、取代或未取代的5-10元芳香环,所述取代基为:C1-C6烷基,卤素;
R
3表示氢原子、C1-C6烷基。
R
1、R
2同时为氢时,R
3为不能为乙基。
本发明优选通式(I)所示的衍生物及其药学上可接受的盐或异构体:
其中,R
1、R
2独立的表示氢原子、氨基、羟基、甲基、取代或未取代的C1-C4烷基、取代或未取代的5-6元芳香环,所述取代基为C1-C4烷基、卤素。
本发明优选通式(I)所示的化合物及其药学上可接受的盐或异构体:
其中,R
1、R
2独立的表示氢原子、氨基、羟基、甲基、取代或未取代的C1-C4烷基、取代或未取代的苯环,所述取代基为C1-C4烷基,F、Cl、Br。
本发明优选通式(I)所示的化合物及其药学上可接受的盐和异构体:
其中,R
1表示氨基、羟基、C1-C4烷基、卤素取代的苯环;R
2表示氢原子、C1-C4烷基。
本发明优选如下化合物及其药学上可接受的盐和异构体:
(3R,4R,5S)-4-乙酰胺基-5-(3-酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸(I-1)
(3R,4R,5S)-4-乙酰胺基-5-(3-胺基酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸(I-2)
(3R,4R,5S)-4-乙酰胺基-5-(3,3-二甲基酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸(I-3)
(3R,4R,5S)-4-乙酰胺基-5-(3,3-二异丙基酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸(I-4)
(3R,4R,5S)-4-乙酰胺基-5-(3-(3-溴苯基)酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸(I-5)
本发明中的化合物制备如下:
当R
1、R
2同时表示氢原子时,合成方法如下:
当R
1和R
2不同时表示氢原子时,合成方法如下:
本发明中的化合物进行了神经氨酸酶的抑制活性测试。其中阳性对照药为奥司他韦羧酸(Oseltamivir acid)。测试原理为MUNANA(2’-(4-methylumbelliferyl)-α-N-acetylneuraminic acid)是神经氨酸酶的特异性底物,经神经氨酸酶代谢所生成的物质,在355nm的光照激发下,能够产生460nm的荧光,当测试的化合物与神经氨酸酶作用时,导致该特异性底物的结合率发生变化,从而产生荧光强度的变化,通过荧光强度变化反映神经氨酸酶的活性,从而计算出化合物在特定浓度下对神经氨酸酶的抑制率,根据不同浓度的抑制率得到相应的IC
50值。
试验方法:
往96孔板中每孔加入10μL含有酶的溶液,70μL缓冲液(33mM吗啉乙磺酸,4mM CaCl
2),10μL一定浓度的待测化合物,37°条件下孵育十分钟,然后加入100μM的荧光底物10μL,在37°条件下孵育30分钟,加150μL终止液(14mM NaOH的83%乙醇溶液)测定荧光强度,其中激发波长355nm,发射波长460nm。
活性测试结果为:
化合物名称 | I-1 | I-2 | I-3 | I-4 | I-5 |
IC 50/μM | 0.254 | 0.072 | 4.832 | 30.8 | 16.98 |
实验结果表明I-1和I-2表现了较强的神经氨酸酶抑制活性,优于达菲活性成分——奥司他韦羧酸,有进一步开发的价值。
实施实例1
(3R,4R,5S)-4-乙酰胺基-5-(3-酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸(I-1)
往50mL圆底烧瓶中加入磷酸奥司他韦(500mg,1.218mmol)、氢氧化钡(355mg,2.071mmol)和尿素(146mg,2.436mmol),加入10mL去离子水,回流反应。反应结束后,反应液冷却至室温,过滤,滤液的pH值调节至1-2,过滤,干燥得白色固体262mg,收率为65.7%。
1H NMR(400MHz,DMSO-d
6)δ12.50(br s,1H),7.80(d,J=8.8Hz,1H),6.60(s,1H),5.69(d,J=8.2Hz,1H),5.54 (s,2H),4.01(d,J=7.4Hz,1H),3.78–3.57(m,2H),3.40–3.35(m,1H),2.63-2.53(m,1H),2.05–1.92(m,1H),1.80(s,3H),1.49-1.32(m,4H),0.83(t,J=7.4Hz,3H),0.77(t,J=7.4Hz,3H);LC-MS(ESI):350.3[M+Na]
+,326.0[M-H]
-。
实施实例2
(3R,4R,5S)-4-乙酰胺基-5-(1-(咪唑)-胺基甲酰胺基)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸乙酯(Ⅱ)
往100mL圆底烧瓶中加入500mg(1.60mmol)奥司他韦,加入30mL二氯甲烷溶解,冰水浴下,分批加入260mg(1.60mmol)羰基二咪唑,搅拌。反应结束后,有机相用饱和的氯化铵溶液和饱和氯化钠溶液洗涤,无水硫酸钠干燥,浓缩得粗品530mg,不经纯化直接投入下一步反应。
实施实例3
(3R,4R,5S)-4-乙酰胺基-5-(3-胺基酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸乙酯(Ⅱ-2)
取(3R,4R,5S)-4-乙酰胺基-5-(1-(咪唑)-胺基甲酰胺基)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸乙酯(Ⅱ)(600mg,1.477mmol)和2.00g无水Na
2SO
4加入到圆底烧瓶中,接着加入30mL干燥CHCl
3和0.5mL水合肼溶液,室温搅拌0.5h,升温至35℃,随后补加0.3mL水合肼溶液。反应结束后,往反应液中加入适量的饱和氯化钠溶液,搅拌5min,分液,有机相用饱和氯化钠水溶液洗涤,无水Na
2SO
4干燥,过滤,浓缩,粗产品经柱层析纯化得白色固体334mg,收率61.1%。
实施实例4
(3R,4R,5S)-4-乙酰胺基-5-(3-胺基酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸乙酯(I-2)
取上一步产物(3R,4R,5S)-4-乙酰胺基-5-(3-胺基酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸乙酯(Ⅱ-2)(334mg,0.902mmol),加入10mL甲醇和1.13mL 2N NaOH水溶液,补加0.83mL去离子水,使V
甲醇:V
水=5:1,室温搅拌反应。反应结束后,用离子交换树脂(Amberlite IR120,H form)调节反应液pH至6.0–7.0,过滤,纯化得白色固体96mg,收率30.2%。
1H NMR(600MHz,Methanol-d
4)δ6.79(s,1H),4.13(d,J=7.3Hz,1H),4.04–3.94(m,2H),3.44(p,J=5.7Hz,1H),2.82–2.75(m,1H),2.37–2.30(m,1H),2.00(s,2H),1.94(s,3H),1.87(s,2H),1.58–1.46(m,4H),0.93(t,J=7.4Hz,3H),0.90(t,J=7.4Hz,3H);LC-MS(ESI):340.9[M-H]
-.
实施实例5
(3R,4R,5S)-4-乙酰胺基-5-(3,3-二甲基酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸乙酯(Ⅱ-3)
往50mL圆底烧瓶中加入(3R,4R,5S)-4-乙酰胺基-5-(1-(咪唑)-胺基甲酰胺基)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸乙酯(Ⅱ)(200mg,0.492mmol)和10mL氯仿溶液,接着加入DIPEA(318mg,2.46mmol)和盐酸二甲胺(60mg,0.738mmol),室温搅拌0.5h,加热至回流。反应结束后,缓慢冷却至室温,反应液依次用3N HCl水溶液、1N NaOH水溶液和饱和氯化钠水溶液洗涤,无水Na
2SO
4干燥,过滤,浓缩,粗品经柱层析纯化得白色固体72mg,收率38.3%。
实施实例6
(3R,4R,5S)-4-乙酰胺基-5-(3,3-二甲基酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸(I-3)
取上一步产物(3R,4R,5S)-4-乙酰胺基-5-(3,3-二甲基酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸乙酯(Ⅱ-3)(72mg,0.188mmol)加到圆底烧瓶中,接着加入10mL甲醇溶液中和0.47mL 1N NaOH水溶液,补加1.53mL去离子水,使V
甲醇:V
水=5:1,室温搅拌反应。反应结束后,调节pH至1-2,减压蒸除甲醇,用2×10mL乙酸乙酯萃取水相,合并两次有机相,用饱和氯化钠水溶液洗涤有机相,无水MgSO
4干燥,过滤,浓缩得白色固体50mg,收率为74.4%。
1H NMR(400MHz,DMSO)δ9.02(s,1H),7.91(d,J=8.3Hz,1H),6.80(d,J=7.5Hz,1H),6.71(s,1H),4.15(q,J=7.0Hz,2H),4.07–4.00(m,1H),3.94–3.87(m,1H),3.86–3.76(m,1H),3.43(p,J=5.6Hz,1H),2.65(dd,J=17.8,4.6Hz,1H),2.32–2.19(m,1H),1.84(s,3H),1.80(s,3H),1.77(s,3H),1.52–1.35(m,4H),1.23(t,J=7.1Hz,3H),0.83(dt,J=11.3,7.4Hz,6H);LC-MS(ESI):356.3[M+H]
+,354.1[M-H]
-.
实施实例7
(3R,4R,5S)-4-乙酰胺基-5-(3,3-二异丙基酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸乙酯(Ⅱ-4)
实施操作同实施实例5,以250mg(3R,4R,5S)-4-乙酰胺基-5-(1-(咪唑)-胺基甲酰胺基)-2-氧代乙基氨基)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸乙酯(Ⅱ)反应原料,得到白色固体214mg,收率为79.1%。
实施实例8
(3R,4R,5S)-4-乙酰胺基-5-(3,3-二异丙基酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸(I-4)
实施操作同实施实例6,以214mg(0.514mmol)(3R,4R,5S)-4-乙酰胺基-5-(3,3-二异丙基酰脲)-2-氧代乙基氨基)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸乙酯(Ⅱ-4)为反应原料,经处理得到白色固体154mg,收率为82.4%。
1H NMR(400MHz,DMSO-d
6)δ12.50(s,br 1H),7.86(d,J=8.4Hz,1H),6.60(s,1H),5.59(d,J=7.2Hz,1H),4.04(d,J=3.4Hz,1H),3.85–3.70(m,2H),3.64(dt,J= 13.4,6.7Hz,2H),3.43–3.38(m,1H),2.56–2.50(m,1H),2.29–2.14(m,1H),1.50–1.32(m,4H),1.14(d,J=6.6Hz,12H),0.83(t,J=7.4Hz,3H),0.78(t,J=7.4Hz,3H);LC-MS(ESI):412.4[M+H]
+,410.1[M-H]
-。
实施实例9
(3R,4R,5S)-4-乙酰胺基-5-(3-(3-溴苯基)酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸乙酯(Ⅱ-5)
实施操作同实施实例5,以280mg(3R,4R,5S)-4-乙酰胺基-5-(1-(咪唑)-胺基甲酰胺基)-2-氧代乙基氨基)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸乙酯(Ⅱ)反应原料,经处理得到白色固体231mg,收率为65.7%。
实施实例10
(3R,4R,5S)-4-乙酰胺基-5-(3-(3-溴苯基)酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸(I-5)
实施操作同实施实例6,以(3R,4R,5S)-4-乙酰胺基-5-(3-(3-溴苯基)酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸乙酯(Ⅱ-5)为反应原料,经处理得到白色固体160mg,收率为73.2%。
1H NMR(600MHz,DMSO-d
6)δ12.58(s,1H),8.92(s,1H),7.93(d,J=8.7Hz,1H),7.82(t,J=1.9Hz,1H),7.24–7.11(m,2H),7.08–7.01(m,1H),6.64(t,J=2.0Hz,1H),6.01(d,J=7.9Hz,1H),4.07(d,J=6.4Hz,1H),3.84-3.75(m,2H),3.41(p,J=5.6Hz,1H),2.68(dd,J=17.3,4.1Hz,1H),2.12-2.05(m,1H),1.79(s,3H),1.48-1.34(m,4H),0.85(t,J=7.4Hz,3H),0.78(t,J=7.4Hz,3H);LC-MS(ESI):480.0[M-H]
-。
Claims (10)
- 如权利要求1所述的衍生物及其药学上可接受的盐或异构体:其中:R 1、R 2独立的表示氢原子、氨基、羟基、甲基、取代或未取代的C1-C4烷基、取代或未取代的5-6元芳香环,所述取代基为C1-C4烷基,卤素。
- 如权利要求1或2所述的衍生物及其药学上可接受的盐或异构体:其中,R 1、R 2独立的表示氢原子、氨基、羟基、甲基、取代或未取代的C1-C4烷基、取代或未取代的5-6元苯环,所述取代基为C1-C4烷基,F、Cl、Br。
- 如权利要求1-3任何一项所述的衍生物及其药学上可接受的盐或异构体:其中,R 1表示氨基、羟基、C1-C4烷基、卤素取代的苯环;R 2表示氢原子、C1-C4烷基。
- 如下的化合物及其药学上可接受的盐或异构体:(3R,4R,5S)-4-乙酰胺基-5-(3-酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸(I-1)(3R,4R,5S)-4-乙酰胺基-5-(3-胺基酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸(I-2)(3R,4R,5S)-4-乙酰胺基-5-(3,3-二甲基酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸(I-3)(3R,4R,5S)-4-乙酰胺基-5-(3,3-二异丙基酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸(I-4)(3R,4R,5S)-4-乙酰胺基-5-(3-(3-溴苯基)酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸(I-5)。
- 权利要求1-5任何一项所述的衍生物或者药学上可接受的盐或异构体,其特征在于,还包括所述化合物的溶剂化物、多晶型体、对映体或外消旋混合物。
- 一种药物组合物,包含权利要求1-5中任何一项的衍生物及其药学上可接受的盐或异构体作为活性成分以及药学上可接受的赋型剂。
- 权利要求1-6任何一项的化合物及其药学上可接受的盐或异构体或权利要求7所述的药物组合物在制备神经氨酸酶抑制剂中的应用。
- 权利要求1-6任何一项所述的衍生物及其药学上可接受的盐或异构体或权利要求7所述的药物组合物在制备治疗流感病毒感染引起的疾病的药物中的应用。
- 权利要求1-6任何一项所述的衍生物及其药学上可接受的盐或异构体或权利要求7所述的药物组合物在制备治疗流感的药物中的应用。
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Title |
---|
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