CN116396259A - 一种苯并吡喃类衍生物、制备方法及其在制备治疗慢性结肠炎药物中的应用 - Google Patents
一种苯并吡喃类衍生物、制备方法及其在制备治疗慢性结肠炎药物中的应用 Download PDFInfo
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Abstract
本发明提供一种苯并吡喃类衍生物、制备方法及其在制备治疗慢性结肠炎药物中的应用,该类化合物具有通式(I)的结构;本发明提供了所述苯并吡喃类衍生物的制备方法以及应用,本发明制备的苯并吡喃类衍生物对LPS刺激RAW264.7细胞后IL‑6的分泌量有抑制作用,对LPS刺激RAW264.7细胞后TNF‑α的分泌量都有一定的抑制作用,对于慢性结肠炎的小鼠,可以降低其腹泻程度,增加皮毛光泽度;可以抑制小鼠结肠慢性炎症的作用。
Description
技术领域
本发明属于药物领域,涉及一种苯并吡喃类衍生物、制备方法及其在制备治疗慢性结肠炎药物中的应用。
背景技术
慢性结肠炎是临床常见病与多发病,目前没有有效药物。更重要的是慢性结肠炎还与慢性炎症相关性的结直肠癌的发病密切相关,西方国家尤其高发,近20年来我国呈现较快上升趋势,中老年群体高发。由于慢性结肠炎易发展成为结直肠癌,对该病的积极治疗已经引起国内外关注,制备新型抗慢性结肠炎的药物极其重要,从临床考虑,除降低慢性结肠炎本身的发病外,主要是间接地预防了结直肠癌的发生与发展。从社会效益方面考虑,该病为多发病,尤其西方国家特别注重慢性肠炎与结直肠癌预防治疗,研发特色新抗炎药物将会创造较大的经济价值。目前,临床对慢性结肠炎治疗缺乏有效药物,主要以氨基水杨酸类、糖皮质激素类和免抑制剂等为主,这些药物疗效低,长期使用毒副作用大,复发率很高。近年来,单抗药物成为目前最为有效的缓解慢性结肠炎症状的药物,但该类药物均需注射给药,患者顺应性差,治疗成本高,长期使用易产生耐药性及不良反应。因此,制备可以口服、药效更好和低成本的药物成为慢性结肠炎临床治疗亟待解决的难题。
发明内容
针对现有技术存在的不足,本发明提供一种苯并吡喃类衍生物、制备方法及其在制备治疗慢性结肠炎药物中的应用,实现以下发明目的:制备一种可以口服、对慢性结肠炎的药效更好、低成本的苯并吡喃类衍生物。
为实现上述发明目的,本发明的技术方案如下:
本发明提供了一种苯并吡喃类衍生物,其具有通式(I)所示结构:
式中:
R1、R2、R3、R4和R5为氢;
R6为甘氨酸、丙氨酸、亮氨酸、异亮氨酸、缬氨酸、脯氨酸、苯丙氨酸、蛋氨酸、色氨酸、丝氨酸、谷氨酰胺、苏氨酸、半胱氨酸、天冬酰胺、络氨酸、赖氨酸、精氨酸、组氨酸中的一种;
进一步的,所述苯并吡喃类衍生物具体为ZT-1、ZT-2、ZT-3、ZT-4、ZT-5和ZT-6,其结构式分别为:
进一步的,所述的苯并吡喃类衍生物的制备方法包括以下步骤:
(1)以杨梅苷M1为起始原料,对杨梅苷的7位、3’位、4’位、5’位酚羟基进行保护,形成苄基保护的杨梅苷M2;
(2)脱除苄基保护的杨梅苷M2的3位鼠李糖,形成苄基保护的M3;
(3)苄基保护的M3与各种氨基酸在缩合剂作用下进行缩合反应制得苄基保护的各种氨基酸衍生物M4;
(4)M4在钯碳催化作用下脱除苄基制得苯并吡喃类衍生物(I);
其中,M1-M4的结构式如下所示:
其中R为氨基酸。
进一步的,所述苯并吡喃类衍生物的制备方法步骤(3)中所用缩合剂为N,N'-二环己基碳二亚胺(DCC)、1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDCI)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)中的一种。
本发明还提供了所述的苯并吡喃类衍生物在制备治疗慢性结肠炎药物中的应用。
与现有技术相比,本发明取得以下有益效果:
(1)本发明制备的苯并吡喃类衍生物对LPS刺激RAW264.7细胞后IL-6的分泌量有抑制作用,药物的作用浓度为0.02μM时,抑制率为55.24-74.12%;药物的作用浓度为0.2μM时,抑制率为56.71-78.34%;药物的作用浓度为2μM时,抑制率为63.54-86.29%;药物的作用浓度为20μM时,抑制率为68.78-96.73%。
(2)本发明制备的苯并吡喃类衍生物对LPS刺激RAW264.7细胞后TNF-α的分泌量都有一定的抑制作用,药物的作用浓度为0.02μM时,抑制率为41.36-61.12%;药物的作用浓度为0.2μM时,抑制率为45.28-62.34%;药物的作用浓度为2μM时,抑制率为37.91-66.29%;药物的作用浓度为20μM时,抑制率为21.79-74.73%。
(3)本发明制备的苯并吡喃类衍生物,对于慢性结肠炎的小鼠,可以降低其腹泻程度,增加皮毛光泽度;可以抑制小鼠结肠慢性炎症的作用。
附图说明
图1为实施例10中小鼠结肠长度的柱状图;
图2为实施例10中小鼠结肠的病理学检查结果。
具体实施方式
下面结合实施例对本发明做进一步的说明。
下述实施例中DCC为N,N'-二环己基碳二亚胺;EDCI为1-(3-二甲胺基丙基)-3-乙基碳二亚胺;HATU为2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯。
实施例1
M2的合成路线如下:
将杨梅苷(100 g, 0.22 mol)溶入N,N-二甲基甲酰胺(1 L)中,然后加入碳酸钾(300 g, 2.16 mol),室温反应2小时后滴加溴化苄(370 g, 12.16 mol),加毕,加热至80℃反应60小时。反应完毕后,冷至室温,向反应体系中加入3L的水,搅拌下析出固体,过滤,将固体加入3 L体积比为1:1的水/二氯甲烷混合溶液中,用2N(2mol/L)盐酸调pH值至酸性(pH为6),分出有机相,水相用二氯甲烷萃取3次,合并有机相,干燥浓缩得200g M2,不经纯化直接用于下步反应。
实施例2
M3的合成路线如下:
将实施例1所得M2(200 g)溶入四氢呋喃(1 L)中,然后加入3 N (3mol/L)盐酸(1L),加热至回流反应12小时,反应完全后,冷至室温,析出固体,过滤,将所得固体加入0.8L体积比1:1的乙醇/二氯甲烷混合溶液,加热至回流打浆4小时,冷至室温,过滤得67 g黄色固体M3,收率45%。
1H NMR (500 MHz, DMSO-d 6) δ = 12.35 (s, 1H), 9.85 (s, 1H), 7.67 (s,2H), 7.50 (t, J = 6.7 Hz, 6H), 7.39 (m,12H), 7.29 (d, J = 1.5 Hz, 2H), 6.90(d, J = 2.2 Hz, 1H), 6.48 (d, J = 2.2 Hz, 1H), 5.26 (s, 2H), 5.20 (s, 4H),5.05 (s, 2H) ppm. ESI-MS: (m/z, %) = 677 [M-H]-。
实施例3
ZT-1的合成路线如下:
将苄基保护的M3(3.0 g, 4.42 mmol)加入二氯甲烷(50 mL)中,然后依次加入甘氨酸(0.33 g, 4.42 mmol)和DCC(1.1 g, 5.3 mmol),室温下反应24小时,过滤去白色固体,母液浓缩干,柱层析得1.9 g M4-1。将M4-1加入无水甲醇(25 mL)中,然后加入10%钯碳(200 mg), 加氢(氢气的通入速度为1mL/min),25℃下反应24小时后,过滤,母液浓缩蒸干得ZT-1(0.9 g,两步收率55%)。1H NMR (500 MHz, DMSO-d 6) δ 12.61 (s, 1H), 10.81 (s,1H), 9.16 (s, 2H), 8.89 (s, 1H), 8.32 (s, 2H), 7.15 (s, 2H), 6.35 (d, J =2.0Hz, 1H), 6.18 (d, J = 2.0 Hz, 1H), 4.03 (s, 1H).13C NMR (125 MHz, DMSO-d 6) δ177.34, 167.01, 164.04, 161.25, 156.27, 156.25, 145.36(2C), 136.66, 133.24,119.99, 108.54(2C), 103.86, 100.62, 98.70,98.45, 93.35, 40.28。
实施例4
ZT-2的合成路线如下:
将苄基保护的M3(3.0 g, 4.42 mmol)加入二氯甲烷(50 mL)中,然后依次加入丙氨酸(0.39 g, 4.42 mmol)和DCC(1.1 g, 5.3 mmol),室温下反应24小时,过滤去白色固体,母液浓缩,柱层析得2.1 g M4-2。将M4-2加入无水甲醇(25mL)中,然后加入10%钯碳(200mg), 加氢(氢气的通入速度为1mL/min),25℃下反应24小时后,过滤,母液浓缩蒸干得ZT-2(1.1 g,两步收率64%)。
1H NMR (500 MHz, DMSO-d 6) δ 12.60 (s, 1H), 10.82 (s, 1H), 9.15 (s,2H), 8.76 (s, 1H), 8.32 (s, 2H), 7.16(s, 2H), 6.33 (d, J = 2.0 Hz, 1H), 6.17(d, J = 2.0 Hz, 1H), 3.55 (m, 1H) , 1.21 (d, 3H).13C NMR (125 MHz, DMSO-d 6) δ177.31, 167.11, 164.04, 161.21, 156.17, 156.25, 145.21(2C), 136.63, 133.34,119.91, 108.32(2C),103.81, 100.63, 98.72, 98.43, 93.31, 49.48, 17.76。
实施例5
ZT-3的合成路线如下:
将苄基保护的M3(3.0 g, 4.42 mmol)加入二氯甲烷(50 mL)中,然后依次加入脯氨酸(0.51 g, 4.42 mmol)和EDCI(1.0 g, 5.3 mmol),室温下反应24小时,过滤去白色固体,母液浓缩干,柱层析得2.9 g M4-3。将M4-3加入无水甲醇(25 mL)中,然后加入10%钯碳(200 mg), 加氢(氢气的通入速度为1mL/min),25℃下反应24小时后,过滤,母液浓缩蒸干得ZT-3(1.2 g,两步收率64%)。
1H NMR (500 MHz, DMSO-d 6) δ 12.58 (s, 1H), 10.81 (s, 1H), 9.13 (s,2H), 8.73 (s, 1H), 8.31 (s, 2H), 7.13(s, 2H), 6.32 (d, J = 2.0 Hz, 1H), 6.19(d, J = 2.0 Hz, 1H), 3.56 (m, 1H) , 2.78 (m, 2H) , 1.96 (m, 2H) , 1.56 (m,2H).13C NMR (125 MHz, DMSO-d 6) δ 177.31, 167.06, 164.01, 161.15, 156.37,156.23, 145.31(2C), 136.61, 133.14,119.95, 108.54(2C), 103.83, 100.62, 98.71,98.42, 93.32, 61.53, 46.28, 30.21, 25.23。
实施例6
ZT-4的合成路线如下:
将苄基保护的M3(3.0 g, 4.42 mmol)加入二氯甲烷(50 mL)中,然后依次加入谷氨酰胺(0.65 g, 4.42 mmol)和HATU(2.0 g, 5.3 mmol),室温下反应24小时,过滤去白色固体,母液浓缩干,柱层析得2.2 g M4-4。将M4-4加入无水甲醇(25 mL)中,然后加入10%钯碳(200 mg), 加氢(氢气的通入速度为1mL/min),25℃下反应24小时后,过滤,母液浓缩蒸干得ZT-4(1.3g,两步收率65%)。
1H NMR (500 MHz, DMSO-d 6) δ 12.61 (s, 1H), 10.85 (s, 1H), 9.11 (s,2H), 8.76 (s, 2H), 8.32 (s, 2H), 7.12(s, 2H), 7.03 (s, 2H), 6.32 (d, J = 2.0Hz, 1H), 6.18 (d, J = 2.0 Hz, 1H), 3.33 (m, 1H), 2.06 (m, 4H).13C NMR (125MHz, DMSO-d 6) δ 177.34, 173.06, 168.78, 167.02, 164.04, 161.21, 156.37,156.22, 145.33(2C),136.64, 133.24, 119.92, 108.52(2C), 103.83, 100.63, 98.70,98.42, 93.35, 52.28, 33.05, 28.12。
实施例7
ZT-5的合成路线如下:
将苄基保护的M3(3.0 g, 4.42 mmol)加入二氯甲烷(50 mL)中,然后依次加入苯丙氨酸(0.73 g, 4.42 mmol)和HATU(2.0 g, 5.3 mmol),室温下反应24小时,过滤去白色固体,母液浓缩干,柱层析得2.5 g M4-5。将M4-5加入无水甲醇(25mL)中,然后加入10%钯碳(200 mg), 加氢(氢气的通入速度为1mL/min),25℃下反应24小时,过滤,母液浓缩蒸干得ZT-5(1.2g,两步收率60%)。
1H NMR (500 MHz, DMSO-d 6) δ 12.60 (s, 1H), 10.85 (s, 1H), 9.11 (s,2H), 8.71 (s, 2H), 7.19 (m, 1H), 7.14 (m,4H), 7.12 (s, 2H), 7.03 (s, 2H),6.32 (d, J = 2.0 Hz, 1H), 6.18 (d, J = 2.0 Hz, 1H), 4.13 (m, 1H), 3.46 (m,2H).13C NMR (125 MHz, DMSO-d 6) δ 177.31, 168.78, 167.03, 164.04, 161.22,156.37, 156.23, 145.33(2C), 140.87, 136.61,133.24, 128.67(2C), 127.77(2C),125.89, 119.92, 108.52(2C), 103.82, 100.63, 98.72, 98.42, 93.36, 54.28,37.75。
实施例8
ZT-6的合成路线如下:
将苄基保护的M3(3.0 g, 4.42 mmol)加入二氯甲烷(50 mL)中,然后依次加入赖氨酸(0.65 g, 4.42 mmol)和HATU(2.0 g, 5.3 mmol),室温下反应24小时,过滤去白色固体,母液浓缩干,柱层析得1.9 g M4-6。将M4-6加入无水甲醇(25 mL)中,然后加入10%钯碳(200 mg), 加氢(氢气的通入速度为1mL/min),25℃下反应24小时后,过滤,母液浓缩蒸干得ZT-6(1.1 g,两步收率55%)。
1H NMR (500 MHz, DMSO-d 6) δ 12.62 (s, 1H), 10.82 (s, 1H), 9.16 (s,2H), 8.79 (s, 1H), 8.72 (s, 2H), 7.15(s, 2H), 6.35 (d, J = 2.0 Hz, 1H), 6.18(d, J = 2.0 Hz, 1H), 3.36 (m, 1H) , 2.67 (m, 2H) , 1.76 (m, 4H) , 1.26 (m,2H).13C NMR (125 MHz, DMSO-d 6) δ 177.34, 167.03, 164.02, 161.25, 156.25,156.23, 145.35(2C), 136.66, 133.23,119.98, 108.55(2C), 103.86, 100.64, 98.71,98.46, 93.35, 53.27, 42.03, 31.11, 29.05, 22.76。
实施例9
苯并吡喃类衍生物的体外抗炎活性研究
材料:
待测药品:苯并吡喃类衍生物ZT-1、ZT-2、ZT-3、ZT-4、ZT-5和ZT-6,室温保存。实验前将上述样品用DMSO溶解并稀释。
RAW264.7小鼠腹腔巨噬细胞:由中国医学科学院基础医学研究所提供,细胞在DMEM+10Vol%胎牛血清培养基中生长与传代。
IL-6检测试剂盒:由北京达科为生物技术有限公司提供;TNF-α检测试剂盒:由北京达科为生物技术有限公司提供。
LPS(美国Sigma公司提供):将1μg LPS溶解至100μL PBS中,充分搅拌,配成1mg/mL的LPS母液,以0.22μm微孔滤膜除菌,0.2mL EP管分装,-20℃保存。
检测设备:Softmax pro6 software SMP6多功能酶标仪(美国Molecular Devices公司产品)。
实验方法:
取生长状态处于80%融合度的RAW264.7小鼠腹腔巨噬细胞,以吹打管直接吹打成为单个细胞后计数,接种于含培养基的96孔培养板中,3000细胞/孔,培养24小时后,分别加入不同浓度苯并吡喃类衍生物ZT-1~ZT-6,每种药物每个浓度设5个复孔(在该剂量下药物对RAW264.7细胞生长无明显影响),药物的终浓度见表1。1小时后加入LPS母液,终浓度为1ug/mL,培养板置37℃ (5% CO2-95% air)培养箱中24小时。培养结束,取上清液,置于IL-6和TNF-α酶联免疫试剂盒(ELISA)下检测IL-6和TNF-α。
实验结果如表1所示:
(1)苯并吡喃类衍生物对LPS刺激RAW264.7细胞分泌IL-6的抑制作用实验结果如表1所示。
表1、苯并吡喃类衍生物对LPS刺激RAW264.7细胞分泌IL-6的抑制作用
从表1可以看出ZT-1、ZT-2、ZT-3、ZT-4、ZT-5和ZT-6对LPS刺激RAW264.7细胞后IL-6的分泌量都有一定的抑制作用,药物的作用浓度为0.02μM时,抑制率为55.24-74.12%;药物的作用浓度为0.2μM时,抑制率为56.71-78.34%;药物的作用浓度为2μM时,抑制率为63.54-86.29%;药物的作用浓度为20μM时,抑制率为68.78-96.73%;其中ZT-2、ZT-5和ZT-6对IL-6具有更好的抑制作用。
(2)苯并吡喃类衍生物对LPS刺激RAW264.7细胞分泌TNF-α的抑制作用实验结果如表2所示。
表2、苯并吡喃类衍生物对LPS刺激RAW264.7细胞分泌TNF-α的抑制作用
从表2可以看出ZT-1、ZT-2、ZT-3、ZT-4、ZT-5和ZT-6对LPS刺激RAW264.7细胞后TNF-α的分泌量都有一定的抑制作用,药物的作用浓度为0.02μM时,抑制率为41.36-61.12%;药物的作用浓度为0.2μM时,抑制率为45.28-62.34%;药物的作用浓度为2μM时,抑制率为37.91-66.29%;药物的作用浓度为20μM时,抑制率为21.79-74.73%;其中ZT-2和ZT-5对TNF-α具有更好的抑制作用。
实施例10
测定苯并吡喃类衍生物对葡聚糖硫酸钠盐(DSS)诱导小鼠慢性结肠炎的治疗作用
实验材料与方法
1. 实验材料:
受试化合物与对照药物:苯并吡喃类衍生物,动物实验阳性对照药物美沙拉嗪,Sigma公司;
实验动物:C57BL/6小鼠,20-22g,雌雄兼用,SPF级。
2. DSS诱导小鼠慢性结肠炎模型:取C57BL/6小鼠36只,随机分组,每组6只备用。精密称取DSS 0.5 g溶解于50 mL纯净水中,供6只小鼠一天饮用,每日更换新鲜配置DSS水,固定时间更换新鲜配置DSS水,连续饮用含DSS水七天,各组均采取同样的处理方法,制作小鼠慢性结肠炎模型。DSS给药7天后,更换新鲜纯净水,连续14天。上述过程连续进行3个周期。
3. 药物配置方法:
3.1. 溶剂对照组:将0.5 mL DMSO溶解于10 mL 0.5%(质量百分比) CMC-Na。
3.2. 受试苯并吡喃类衍生物:称取苯并吡喃类衍生物各100 mg溶解于0.5 mLDMSO中,再以0.5% CMC-Na稀释至10 mL。
3.3. 美沙拉嗪:称取美沙拉嗪 100 mg溶解于10 mL生理盐水中。
4. 给药方法:先称量小鼠体重,根据体重每天给药,按0.01ml/g/次连续给药18天,每天给药1次。
5. 动物观察与处理方法:日常观察,体重、饮食、腹泻(或血便)等。实验结束,将小鼠处死解剖,取出结肠和小肠,肉眼观察拍照后分别做病理学分析。病理学检查方法与评价标准:将各组小鼠结肠以10%福尔马林(质量百分比)固定后,常规石蜡包埋、切片和HE染色,镜下观察,评价各组结肠炎症程度,主要根据结肠固有层的炎症细胞浸润程度,评级标准如下:0级,无明显炎症细胞浸润;+(1级),少量炎性细胞浸润;++(2级),中等量炎症细胞浸润;+++(3级),严重炎症细胞浸润并可能伴有粘膜层细胞坏死脱落等。
实验结果如下:
1、DSS诱导小鼠慢性结肠炎症状:各组小鼠造模后均表现(100%)腹泻,饮食量下降,体重下降,皮毛光泽度下降,表明造模成功。
2、各组小鼠一般症状:ZT-2组小鼠从5天开始腹泻程度明显减轻,其中4只小鼠腹泻程度不明显,皮毛光泽度增加;ZT-5组小鼠腹泻程度略有减轻,其中1-2只不明显;美沙拉嗪对照组小鼠的腹泻程度略有减轻。
3、各组小鼠结肠长度:实验结束截取结肠(由回盲端至肛门端)测量各组结肠的长度。实验结果如图1所示,与正常组比较,模型组小鼠明显缩短(P<0.05),而ZT-2组和阳性对照组小鼠平均长度接近空白对照组,明显长于模型组(P<0.05),说明具有良好的抑制慢性结肠炎症作用,ZT-5组小鼠与模型组无明显差异。
4、各组小鼠结肠的病理学检查:在模型组,显示结肠粘膜固有层与粘膜下层均有浸润大量的淋巴细胞,各层肠组织较松散,肌层组织也有较多的浸润淋巴细胞,并可见粘膜上皮细胞脱落现象。ZT-2治疗组慢性结肠炎症程度明显减轻,依据结肠慢性炎症的4级判断标准,发现苯并吡喃类衍生物ZT-2具有明显抑制小鼠结肠慢性炎症的作用,ZT-5和阳性对照组的效果相当,对小鼠结肠慢性炎症也有一定的抑制作用,见图2和表3。
表3. 各组小鼠结肠慢性炎症的病理学分级打分结果(n = 3)
注:每组检查3只小鼠,表格内数字为实际观察得到各组小鼠结肠的结肠炎症程度分级。
与模型组相比,ZT-5对于炎症反应具有一定的改善程度,与对照药物美沙拉嗪的药理学活性相当,但均弱于苯并吡喃类衍生物ZT-2。
由葡聚糖硫酸钠DSS方法诱导的小鼠慢性结肠炎是研究和评价抗慢性结肠炎及筛选药物的经典方法和基本动物模型,其中对结肠病理学分析是确定药物疗效的基本标准。在本申请中,苯并吡喃类衍生物ZT-2除具有明显地抑制小鼠慢性结肠炎一般临床症状外,还能够明显减轻结肠炎症程度,而其他各受试化合物及对照药物美沙拉嗪的药理学活性均弱于苯并吡喃类衍生物ZT-2,ZT-5与对照药物美沙拉嗪的药理学活性相当,对小鼠慢性结肠炎症具有一定的抑制作用。
以上实施例仅用以说明本发明的技术方案,而非对其进行限制;尽管参照前述实施例对本发明进行了详细的说明,对于本领域的普通技术人员来说,依然可以对前述实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换;而这些修改或替换,并不使相应技术方案的本质脱离本发明所要求保护的技术方案的精神和范围。
Claims (5)
4.根据权利要求3所述的苯并吡喃类衍生物的制备方法,其特征在于:所述步骤(3)中所述缩合剂为N,N'-二环己基碳二亚胺、1-(3-二甲胺基丙基)-3-乙基碳二亚胺、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯中的一种。
5.权利要求1所述苯并吡喃类衍生物在制备治疗慢性结肠炎药物中的应用。
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