CN107365338B - 一类红霉素a-6,9-9,12-螺缩酮衍生物及其制备方法和应用 - Google Patents
一类红霉素a-6,9-9,12-螺缩酮衍生物及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及医药技术领域,特别涉及一类红霉素A‑6,9‑9,12‑螺缩酮衍生物、其制备方法及其在促进人体胃肠动力、降低人体血糖治疗糖尿病中的应用。本发明提供的红霉素A‑6,9‑9,12‑螺缩酮衍生物结构新颖,且具有良好的促胃肠动力与降低人体血糖的生物活性。
Description
技术领域
本发明涉及医药技术领域,特别涉及一类红霉素A-6,9-9,12-螺缩酮衍生物、其制备方法及其在促进人体胃肠动力、降低人体血糖治疗糖尿病中的应用。
背景技术
随着民众生活水平的普遍改善与提高、饮食文化的影响、食物结构的改变、生活节奏的加快以及人体应激状态的增加,全世界代谢类疾病的发病率也随之上升,且呈年轻化趋势,尤以高血糖为显著特征的糖尿病的发病率迅速上升。糖尿病是严重威胁人类健康的常见疾病,以高血糖为显著特征,它可以诱发心脏病、视网膜病、肾病及神经系统疾病等多种并发症,严重影响了糖尿病患者的生活质量且引起了病人的致死、致残等。目前,临床上常用的降糖药主要有胰岛素及其类似物、胰淀素类似物、磺酰脲类、格列奈类、双胍类、噻唑烷二酮类、葡萄糖苷酶抑制剂等,这些降糖药大多在控制血糖上取得了良好的治疗效果,但其各自又存在着不同的副作用,如耐受性、疗效低、肝肾毒性、容易发生低血糖反应等。因此疗效好且副作用小的降糖药的研发越来越受到重视。另外,社会生活节奏的加快、饮食结构的改变,胃动力障碍发病率也日益增高。临床迫切需要开发出新的高效低毒的促胃肠动力与降血糖药物。
红霉素A-6,9-9,12-螺缩酮衍生物与红霉素等大环内酯类抗生素结构相近。作为临床常用的抗生素,红霉素用作治疗某种慢性疾病而长期服用会导致抗生素的滥用,而红霉素A-6,9-9,12-螺缩酮衍生物则完全不具备抗菌活性,较大环内酯类抗生素使用更安全。
发明内容
本发明的目的在于提供一类结构新颖的红霉素A-6,9-9,12-螺缩酮衍生物;本发明的另一个目的是提供该类化合物的制备方法;本发明的再一目的是提供该类化合物在促胃肠动力与降低人体血糖治疗糖尿病中的应用。
本发明的具体技术方案如下:
在本发明的第一方面,发明人在促胃肠动力与降低人体血糖治疗糖尿病药物研制过程中,发现了一类如式I所示的红霉素A-6,9-9,12-螺缩酮衍生物,或其各光学异构体、各晶型、药学上可接受的无机或有机盐、水合物、溶剂合物或前药,具有治疗促胃肠动力与糖尿病作用。其结构通式I为:
其中R选自C1-12烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6羰基、C1-6烷氧羰基、羰基氨基、C1-6烷基单取代或双取代的氨基、磺酰基氨基、C1-6烷基单取代或双取代的磺酰基氨基、苯基、取代苯基、苄基、取代苄基、环烷基、取代环烷基、杂环烷基、取代杂环烷基、杂芳基或取代杂芳基。
所述的“烷基”,除非另有说明,是指含有1-10个碳原子。烷基包括但不限于甲基,乙基,正丙基,异丙基,正丁基,异丁基,叔丁基。所述的“烷氧基”指的是含氧的烷基。所述的烷氧基、烷硫基、烷羰基、烷氧基羰基等中涉及的烷基定义如上述。
所述的“烯基”是指含有一个或多个碳碳双键的2-6个碳原子的直链或支链烃基;包括但不限于乙烯基、丙烯基和丁烯基。
所述的“芳基”,除非另有说明,是指含有6个碳原子的单环芳烃,10个碳原子的双环芳烃,14个碳原子的三环芳烃,且每个环上可以有1-4个取代基。芳基包括但不限于苯基,萘基,蒽基。
所述的“环烷基”,除非另有说明,是指含有3-8个碳原子的饱和或者部分不饱和的环状烃。环烷基包括但不限于环丙基,环丁基,环戊基,环戊烯基,环己基,环己烯基。
所述的“杂芳基”,是指5-8个原子的单环芳烃、8-12个原子的双环芳烃或11-14个原子的三环芳烃,并且含有1个或多个杂原子(例如N,O,S)。杂芳基包括吡啶基,呋喃基,咪唑基,苯并咪唑基,嘧啶基,噻吩基,喹啉基,吲哚基。
所述的“杂环烷基”,是指含有3-8个原子的单环非芳烃烷基、8-12个原子的双环或11-14个原子的三环烃基,并且含有1个或多个杂原子(例如N、O、S);所述杂环烷基包括吗啉基、哌啶基或四氢呋喃基。
本发明还包括上述化合物的相应的所有药学上可以接受的盐、水合物或前药。这些盐可以由化合物中带正电荷的部分与具有相反电性的带负电荷形成;或者由化合物中带负电荷的部分与正电荷形成。
优选的,所述红霉素A-6,9-9,12-螺缩酮衍生物的结构如式Ⅱ所示:
其中,R1~R5分别独立的选自H、C1~6烷基、卤素、氰基或硝基;所述卤素为氟、氯或溴;
优选的,式I中的R基团还可以选自下列结构单元:
或选自下列结构单元:
其中,R7和R8各自独立的为H、C1-6烷基、C1-6烷氧基、卤素、氰基、硝基或三氟甲基。
本发明所列的化合物,如结构式与命名相冲突的,以化学结构式为准。具体红霉素A-6,9-9,12-螺缩酮衍生物(RL-553)代号、命名、结构式、分子式与分子量见表1。
表1 红霉素A-6,9-9,12-螺缩酮衍生物(RL-553)代号、命名、结构式、分子式与分子量
表1中列出了本发明的优选结构:
本发明的化合物可按照常规方法制备为药用盐的形式;包括其有机酸盐及无机酸盐:无机酸包括(但不限于)盐酸、硫酸、磷酸、二磷酸、氢溴酸、硝酸等,有机酸包括(但不限于)乙酸、马来酸、富马酸、酒石酸、琥珀酸、乳酸、对甲苯磺酸、水杨酸、草酸等。
作为本发明的第二方面,提供了上述化合物的制备方法:
(1)红霉素A-6,9-9,12-螺缩酮与卤代烷化合物或取代芳环苄卤或各酰卤化合物在碱、催化剂的存在下反应生成红霉素A-6,9-9,12-螺缩酮衍生物(I);
(2)按照常规方法制备为药学上可接受的盐的形式。
本发明还提供了一种药物组合物,其含有药学上可接受的赋形剂或载体,以及上述的化合物或其药学上可接受的无机或有机盐、水合物、溶剂合物或前药。
本发明还提供了本发明所述的化合物、或其药学上可接受的无机或有机盐、水合物、溶剂合物或前药的用途,它被用于制备治疗降低人体血糖治疗糖尿病以及促人体胃肠动力的应用。
本发明还提供了本发明所述的化合物、或其各晶型、药学上可接受的无机或有机盐、水合物、溶剂合物或前药的用途,它被用于制备降低人体血糖或治疗糖尿病以及促人体胃肠动力的相关疾病的药物。
为评价本发明合成的化合物及其药物组合物的治疗降低人体血糖治疗糖尿病以及促人体胃动力相关疾病,对本发明中的化合物进行了整体动物药理活性测试,结果显示该类化合物普遍具有较好的动物治疗效果。
附图说明
图1为糖尿病模型小鼠血糖含量结果图;
图2为RL-553系列化合物对离体小肠蠕动功能的影响结果图;
图3为RL-553对大鼠在体小肠蠕动的影响结果图。
具体实施方式
以下结合具体实施例,对本发明作进一步说明。应理解,以下实施例仅用于说明本发明而非用于限定本发明的范围。
实施例1.中间体红霉素A-6,9-9,12-螺缩酮的制备
于250ml三颈瓶中加入水90ml,称入红霉素A3.5g(4.77mmol),磁力搅拌,慢慢滴加浓盐酸至pH2-3,20-35℃反应4-5小时。停止反应,取10%碳酸钠溶液将反应液调至pH 8~9,二氯甲烷15m×3萃取,合并二氯甲烷层以无水硫酸镁干燥,过滤,残渣无水硫酸镁弃去,滤液蒸干,得中间体红霉素A-6,9-9,12-螺缩酮粗品2.9g。粗品以二氯甲烷5ml溶解,溶解后趁热向二氯甲烷溶液中加入环己烷适量,放置,慢慢析岀结晶,过滤,得纯品2.3g,产率67.5%
1H NMR(600MHz,DMSO)δ5.19(d,J=5.5Hz,1H),4.96(d,J=4.6Hz,1H),4.80(dd,J=11.9,2.6Hz,1H),4.24(d,J=9.1Hz,1H),4.20(s,1H),4.13(d,J=7.4Hz,1H),4.07–4.01(m,2H),3.30(d,J=6.4Hz,2H),3.18(s,3H),3.11–3.07(m,1H),3.06–3.02(m,2H),3.00(d,J=7.2Hz,1H),2.87(t,J=9.2Hz,1H),2.33(t,J=13.4Hz,1H),2.23(s,6H),2.19(s,1H),2.14–2.08(m,2H),2.08–2.04(m,1H),2.00(dd,J=13.2,6.6Hz,1H),1.64(d,J=12.0Hz,1H),1.53–1.50(m,1H),1.47(dd,J=14.9,4.5Hz,1H),1.39(dd,J=12.6,6.5Hz,1H),1.30(s,3H),1.26(dd,J=15.6,5.8Hz,1H),1.16(s,3H),1.12(d,J=3.2Hz,3H),1.11(d,J=1.7Hz,3H),1.11(s,3H),1.08(d,J=6.3Hz,3H),1.06(d,J=7.3Hz,3H),0.99(d,J=14.8Hz,6H),0.70(t,J=7.4Hz,3H).
HRMS[M+H]716.46
13C NMR(151MHz,)δ178.33,115.24,103.83,94.88,85.91,84.63,81.18,80.89,80.64,77.83,75.72,72.84,69.50,68.28,64.59,64.41,48.80,48.53,46.04,43.52,41.24,40.98,40.34,40.05,34.48,30.09,28.46,24.85,23.34,21.10,21.04,17.74,14.80,14.22,13.25,12.09,10.92.
实施例2.化合物RL-55302的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮1.44g(2mmol),加入二氯甲烷10ml,溶解澄清,再加入氢氧化钾0.06g(1mmol)、碳酸钠0.11g(1mmol)、TBAB(四丁基溴化铵)0.32g(1mmol),室温搅拌15-20分钟,将溴化苄0.43g(2.5mmol)加入到反应瓶中,45-50℃下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤液以饱和碳酸氢钠溶液洗涤,水洗涤,蒸干溶液得粗品,中压制备柱分离,流动相为甲醇与水,得目标物0.6g。二氯甲烷/正已烷重结晶,过滤,固体50℃干燥,得目标物纯品0.46g,产率28.8%。
1H NMR(600MHz,DMSO)δ7.59(d,J=7.1Hz,2H),7.50(p,J=6.7Hz,3H),6.12(s,1H),5.19(s,1H),4.93(d,J=4.6Hz,1H),4.79(dd,J=20.0,7.6Hz,2H),4.68(d,J=12.4Hz,1H),4.25(d,J=7.8Hz,1H),4.22(d,J=6.9Hz,1H),4.05–3.99(m,2H),3.83–3.77(m,1H),3.72(dd,J=9.7,7.4Hz,1H),3.54(dq,J=12.5,6.3Hz,1H),3.35–3.32(m,2H),3.16(s,3H),3.05(dq,J=14.9,7.4Hz,1H),3.00(s,3H),2.95(s,3H),2.93(dd,J=9.6,5.2Hz,1H),2.88(d,J=9.3Hz,1H),2.21(dd,J=19.5,9.0Hz,2H),2.12(dt,J=21.9,7.4Hz,1H),2.08–2.02(m,1H),2.00(dd,J=13.5,6.7Hz,1H),1.72–1.64(m,1H),1.53–1.48(m,1H),1.46(dd,J=15.0,4.7Hz,1H),1.42(dd,J=12.5,6.3Hz,1H),1.29(s,3H),1.19(d,J=6.0Hz,3H),1.14(s,3H),1.13(d,J=7.4Hz,3H),1.09(s,3H),1.06(d,J=7.9Hz,6H),0.99(d,J=7.0Hz,6H),0.68(t,J=7.4Hz,3H).HRMS[M+H]807.41
13C NMR(151MHz,)δ178.20,133.43,133.43,130.22,128.85,128.85,128.18,115.20,102.88,95.16,86.65,84.61,81.28,80.98,80.72,77.72,75.92,72.83,72.25,69.41,66.99,65.41,64.49,49.62,48.85,48.56,48.30,46.37,43.75,41.33,41.04,34.52,32.52,28.74,24.89,23.33,21.03,20.67,17.75,14.40,14.35,13.24,12.11,10.93.
实施例4.化合物RL-55304的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮1.44g(2mmol),加入二氯甲烷10ml,溶解澄清,再加入氢氧化钾0.06g(1mmol)、碳酸钠0.11g(1mmol)、TBAB(四丁基溴化铵)0.32g(1mmol),室温搅拌15-20分钟,将对甲基氯苄0.35g(2.5mmol)加入到反应瓶中,45-50℃下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤液以饱和碳酸氢钠溶液洗涤,水洗涤,蒸干溶液得粗品,中压制备柱分离,流动相为甲醇与水,得目标物0.9g,产率54.9%。
1H NMR(600MHz,CDCl3)δ7.71(dd,J=25.4,2.2Hz,2H),7.30(dd,J=7.4,1.5Hz,2H),5.26–5.21(m,1H),5.14(dd,J=11.5,3.1Hz,1H),5.06(d,J=4.7Hz,1H),4.56(d,J=7.1Hz,1H),4.25(dd,J=6.8,3.2Hz,1H),3.93(dd,J=9.4,6.4Hz,1H),3.64(dd,J=11.3,5.8Hz,1H),3.53(d,J=10.8Hz,1H),3.48(d,J=5.1Hz,1H),3.40(s,1H),3.19(s,3H),2.98(d,J=9.3Hz,1H),2.77(s,1H),2.55(s,6H),2.47(d,J=12.7Hz,1H),2.31(s,3H),2.16(s,1H),2.14(s,1H),2.06(d,J=7.0Hz,2H),2.04–2.02(m,2H),1.89(d,J=7.6Hz,1H),1.87(d,J=7.4Hz,1H),1.66(ddd,J=13.9,7.4,3.0Hz,2H),1.53(d,J=12.9Hz,1H),1.49(d,J=6.8Hz,1H),1.48(s,1H),1.45(d,J=4.9Hz,1H),1.41(s,3H),1.39(d,J=7.2Hz,3H),1.32(d,J=6.1Hz,3H),1.30(s,3H),1.19(s,3H),1.18(d,J=2.4Hz,3H),1.09(d,J=7.2Hz,3H),0.97(d,J=7.4Hz,3H),0.80(t,J=7.4Hz,3H),0.56(d,J=7.4Hz,3H).HRMS[M+H]821.63
实施例5.化合物RL-55305的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮1.44g(2mmol),加入二氯甲烷10ml,溶解澄清,再加入氢氧化钾0.06g(1mmol)、碳酸钠0.11g(1mmol)、TBAB(四丁基溴化铵)0.32g(1mmol),室温搅拌15-20分钟,将4-乙基苄氯0.39g(2.5mmol)加入到反应瓶中,45-50℃下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤液以饱和碳酸氢钠溶液洗涤,水洗涤,蒸干溶液得粗品,中压制备柱分离,流动相为甲醇与水,得目标物0.18g,产率10.8%。
1H NMR(600MHz,CDCl3)δ7.26(dd,J=25.4,2.2Hz,2H),7.09(dd,J=7.4,1.5Hz,2H),5.25–5.23(m,1H),5.13(dd,J=11.5,3.1Hz,1H),5.08(d,J=4.7Hz,1H),4.51(d,J=7.1Hz,1H),4.24(dd,J=6.8,3.2Hz,1H),3.85(dd,J=9.4,6.4Hz,1H),3.66(dd,J=11.3,5.8Hz,1H),3.54(d,J=10.8Hz,1H),3.47(d,J=5.1Hz,1H),3.42(s,1H),3.19(s,3H),2.95(d,J=9.3Hz,1H),2.71(s,1H),2.53–5.51(m,2H),2.43(s,6H),2.45(d,J=12.7Hz,1H),2.33(s,3H),2.21(s,1H),2.11(s,1H),2.03(d,J=7.0Hz,2H),2.04–2.02(m,2H),1.89(d,J=7.6Hz,1H),1.86(d,J=7.4Hz,1H),1.64(ddd,J=13.9,7.4,3.0Hz,2H),1.55(d,J=12.9Hz,1H),1.50(d,J=6.8Hz,1H),1.49(s,1H),1.46(d,J=4.9Hz,1H),1.41(s,3H),1.40(d,J=7.2Hz,3H),1.34(d,J=6.1Hz,3H),1.31(s,3H),1.20(s,3H),1.19(d,J=2.4Hz,3H),1.10(d,J=7.2Hz,3H),1.05(d,J=7.4Hz,3H),0.89(t,J=7.4Hz,3H),0.73(d,J=7.4Hz,3H).HRMS[M+H]835.21
实施例6.化合物RL-55306的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮1.44g(2mmol),加入二氯甲烷10ml,溶解澄清,再加入氢氧化钾0.06g(1mmol)、碳酸钠0.11g(1mmol)、TBAB(四丁基溴化铵)0.32g(1mmol),室温搅拌15-20分钟,将3,5-二甲基苄溴0.50g(2.5mmol)加入到反应瓶中,45-50℃下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤液以饱和碳酸氢钠溶液洗涤,水洗涤,蒸干溶液得粗品,中压制备柱分离,流动相为甲醇与水,得目标物0.85g,产率50.9%。
1H NMR(600MHz,DMSO)δ7.24(s,2H),7.17(s,1H),5.15(s,1H),4.98(d,J=4.5Hz,1H),4.84–4.76(m,2H),4.65(d,J=12.4Hz,1H),4.23(d,J=7.0Hz,1H),4.04(dt,J=13.1,5.3Hz,2H),3.85–3.78(m,1H),3.76–3.71(m,1H),3.59–3.52(m,1H),3.38–3.35(m,2H),3.28(d,J=25.5Hz,1H),3.19(s,3H),3.10(tt,J=13.7,6.7Hz,1H),3.03(s,3H),2.99(s,3H),2.90(d,J=9.3Hz,1H),2.36(d,J=13.7Hz,1H),2.32(s,6H),2.26(d,J=12.0Hz,1H),2.23(s,1H),2.21(s,1H),2.18–2.12(m,1H),2.09(dd,J=12.7,6.7Hz,1H),2.07–2.01(m,1H),1.69(q,J=11.9Hz,1H),1.60–1.50(m,1H),1.50–1.47(m,1H),1.44(dd,J=12.4,6.3Hz,1H),1.32(s,3H),1.21(d,J=6.1Hz,3H),1.17(s,3H),1.15(d,J=10.6Hz,3H),1.12(s,3H),1.10(d,J=6.7Hz,6H),1.03(d,J=7.7Hz,3H),1.01(d,J=7.4Hz,3H),0.71(t,J=7.3Hz,3H).HRMS[M+H]834.92
实施例7.化合物RL-55307的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮1.44g(2mmol),加入二氯甲烷10ml,溶解澄清,再加入氢氧化钾0.06g(1mmol)、碳酸钠0.11g(1mmol)、TBAB(四丁基溴化铵)0.32g(1mmol),室温搅拌15-20分钟,将2-氟苄氯0.36g(2.5mmol)加入到反应瓶中,45-50℃下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤液以饱和碳酸氢钠溶液洗涤,水洗涤,蒸干溶液得粗品,中压制备柱分离,流动相为甲醇与水,得目标物0.62g,产率37.6%。
1H NMR(600MHz,DMSO)δ7.77(t,J=7.3Hz,1H),7.63(td,J=7.5,1.6Hz,1H),7.40(d,J=9.5Hz,1H),7.36(d,J=7.5Hz,1H),5.21(d,J=6.3Hz,1H),5.05(d,J=13.0Hz,1H),4.98(d,J=4.8Hz,1H),4.81(dd,J=11.7,2.6Hz,1H),4.72(d,J=13.1Hz,1H),4.27(dd,J=10.7,7.9Hz,2H),4.08–4.02(m,2H),3.95(td,J=12.0,4.5Hz,1H),3.79(dt,J=10.2,7.1Hz,1H),3.58(dq,J=12.2,5.9Hz,1H),3.36(dd,J=6.2,2.6Hz,2H),3.19(s,3H),3.17–3.11(m,1H),3.07–3.05(m,1H),3.03(s,3H),3.03(s,3H),2.90(t,J=9.0Hz,1H),2.35(t,J=13.4Hz,1H),2.27(dd,J=10.9,3.9Hz,1H),2.22(d,J=15.1Hz,1H),2.17–2.12(m,1H),2.09(ddd,J=14.0,8.0,4.6Hz,1H),2.06–2.01(m,1H),1.72(q,J=12.0Hz,1H),1.55–1.47(m,2H),1.44(dd,J=12.5,6.3Hz,1H),1.32(s,3H),1.23(d,J=6.1Hz,3H),1.18(d,J=7.3Hz,3H),1.16(s,3H),1.12(s,3H),1.09(d,J=15.2Hz,6H),1.02(d,J=16.4Hz,6H),0.71(t,J=7.4Hz,3H).HRMS[M+H]825.66
13C NMR(151MHz,)δ178.33,160.97,135.82,133.23,124.97,116.35,115.61,115.33,102.63,94.98,86.47,84.97,81.44,80.79,80.60,77.73,75.79,72.99,72.83,69.27,66.98,64.47,59.38,49.73,48.84,48.59,47.54,46.07,43.33,41.23,41.02,34.51,32.61,28.50,24.90,23.35,21.03,20.69,17.78,14.80,14.24,13.56,12.11,10.93.
实施例8.化合物RL-55308的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮1.44g(2mmol),加入二氯甲烷10ml,溶解澄清,再加入氢氧化钾0.06g(1mmol)、碳酸钠0.11g(1mmol)、TBAB(四丁基溴化铵)0.32g(1mmol),室温搅拌15-20分钟,将3-氟苄溴0.47g(2.5mmol)加入到反应瓶中,45-50℃下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤液以饱和碳酸氢钠溶液洗涤,水洗涤,蒸干溶液得粗品,中压制备柱分离,流动相为甲醇与水,得目标物0.71g,产率43.0%。
1H NMR(600MHz,CDCl3)δ7.55(d,J=15.4Hz,2H),7.40(s,1H),7.16(t,J=8.4Hz,1H),5.39(d,J=4.8Hz,1H),5.17(s,1H),5.09(dd,J=11.4,3.0Hz,1H),4.57(d,J=11.3Hz,1H),4.38(d,J=7.1Hz,1H),4.07(s,1H),3.99(dd,J=8.8,6.5Hz,1H),3.63(d,J=7.3Hz,1H),3.61(s,1H),3.57(d,J=10.1Hz,1H),3.51(d,J=5.1Hz,2H),3.49(s,3H),3.46(d,J=10.9Hz,1H),3.30(s,3H),3.16(s,3H),2.99(d,J=9.3Hz,1H),2.47–2.40(m,1H),2.30(d,J=6.8Hz,1H),2.27(s,1H),2.25(s,1H),2.17(dt,J=25.7,7.7Hz,2H),2.01(d,J=12.9Hz,1H),1.78(s,2H),1.66–1.62(m,1H),1.62–1.58(m,1H),1.55(dd,J=15.3,4.9Hz,1H),1.47(dd,J=11.9,6.6Hz,1H),1.40(d,J=7.3Hz,3H),1.39(s,3H),1.33(d,J=5.6Hz,3H),1.26(s,3H),1.21(d,J=8.5Hz,6H),1.19(s,3H),1.18(d,J=3.9Hz,3H),1.06(d,J=7.2Hz,3H),0.85(t,J=7.4Hz,3H).HRMS[M+H]825.29
实施例9.化合物RL-55309的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮1.44g(2mmol),加入二氯甲烷10ml,溶解澄清,再加入氢氧化钾0.06g(1mmol)、碳酸钠0.11g(1mmol)、TBAB(四丁基溴化铵)0.32g(1mmol),室温搅拌15-20分钟,将4-氟苄溴0.47g(2.5mmol)加入到反应瓶中,45-50℃下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤液以饱和碳酸氢钠溶液洗涤,水洗涤,蒸干溶液得粗品,中压制备柱分离,流动相为甲醇与水,得目标物0.16g,产率9.7%。
1H NMR(600MHz,DMSO)δ7.43(d,J=15.4Hz,2H),7.21(dd,J=25.4,2.2Hz,2H),5.19(d,J=5.9Hz,1H),5.02(d,J=4.8Hz,1H),4.87(d,J=12.6Hz,1H),4.83–4.76(m,2H),4.31(d,J=8.2Hz,2H),4.11–4.02(m,2H),3.85–3.81(m,1H),3.77(dt,J=10.0,7.0Hz,1H),3.60–3.56(m,1H),3.41(dd,J=12.1,5.2Hz,2H),3.22(s,3H),3.17–3.14(m,1H),3.12(s,3H),3.05(s,3H),3.01–2.99(m,1H),2.76(t,J=8.9Hz,1H),2.41(t,J=13.5Hz,1H),2.28(s,1H),2.22(s,1H),2.17(dt,J=21.6,7.3Hz,1H),2.10–2.06(m,1H),2.04–2.00(m,1H),1.72(dd,J=23.3,12.1Hz,1H),1.57–1.52(m,1H),1.50–1.46(m,1H),1.44(dd,J=12.5,6.4Hz,1H),1.33(s,3H),1.23(d,J=6.1Hz,3H),1.18(s,3H),1.17(d,J=7.6Hz,3H),1.13(s,3H),1.11(d,J=2.7Hz,3H),1.10(d,J=3.8Hz,3H),1.04(d,J=7.6Hz,3H),1.02(d,J=7.3Hz,3H),0.81(t,J=7.4Hz,3H).HRMS[M+H]825.12
实施例11.化合物RL-55311的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮1.44g(2mmol),加入二氯甲烷10ml,溶解澄清,再加入氢氧化钾0.06g(1mmol)、碳酸钠0.11g(1mmol)、TBAB(四丁基溴化铵)0.32g(1mmol),室温搅拌15-20分钟,将间三氟甲基溴苄0.60g(2.5mmol)加入到反应瓶中,45-50℃下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤液以饱和碳酸氢钠溶液洗涤,水洗涤,蒸干溶液得粗品,中压制备柱分离,流动相为甲醇与水,得目标物0.78g,产率44.6%。
1H NMR(600MHz,DMSO)δ8.11(s,1H),7.96(d,J=7.5Hz,1H),7.92(d,J=8.5Hz,1H),7.61(t,J=7.4Hz,1H),5.17(d,J=6.2Hz,1H),5.03(s,1H),4.96(dd,J=12.5,4.2Hz,1H),4.89(d,J=12.7Hz,2H),4.81(dd,J=11.8,2.8Hz,1H),4.59(d,J=5.8Hz,1H),4.25(d,J=5.7Hz,1H),4.20(d,J=8.6Hz,1H),4.11(dt,J=6.6,3.4Hz,1H),4.05(dq,J=12.2,6.2Hz,1H),3.82–3.75(m,2H),3.56(dq,J=12.6,6.5Hz,1H),3.20(s,3H),3.18–3.14(m,1H),3.06(s,3H),3.05(s,3H),2.90(t,J=9.0Hz,1H),2.35(t,J=13.4Hz,1H),2.21(t,J=14.2Hz,2H),2.16–2.10(m,2H),2.10–2.03(m,2H),1.69(dd,J=22.9,11.8Hz,1H),1.55–1.50(m,1H),1.50–1.46(m,1H),1.44(dd,J=12.4,6.5Hz,1H),1.31(s,3H),1.21(d,J=6.1Hz,3H),1.19(d,J=6.8Hz,3H),1.16(s,3H),1.12(s,3H),1.09(d,J=6.2Hz,6H),1.02(dd,J=13.4,7.3Hz,6H),0.72(t,J=7.4Hz,3H).
HRMS[M+H]875.16
实施例15.化合物RL-55315的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮1.44g(2mmol),加入二氯甲烷10ml,溶解澄清,再加入氢氧化钾0.06g(1mmol)、碳酸钠0.11g(1mmol)、TBAB(四丁基溴化铵)0.32g(1mmol),室温搅拌15-20分钟,将4-氯氯苄0.32g(2.5mmol)加入到反应瓶中,45-50℃下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤液以饱和碳酸氢钠溶液洗涤,水洗涤,蒸干溶液得粗品,中压制备柱分离,流动相为甲醇与水,得目标物0.26g,产率15.5%。
1H NMR(600MHz,DMSO)δ7.51(d,J=8.5Hz,2H),7.28(d,J=8.5Hz,2H),6.25(d,J=6.8Hz,1H),5.36(d,J=5.9Hz,1H),4.96–4.92(m,2H),4.88(d,J=12.4Hz,1H),4.79(dd,J=11.7,2.4Hz,1H),4.51(d,J=8.5Hz,1H),4.41(d,J=6.9Hz,1H),4.20(dt,J=9.7,5.4Hz,2H),3.84–3.80(m,1H),3.77–3.73(m,1H),3.61(dq,J=12.2,6.2Hz,1H),3.41–3.38(m,1H),3.24(s,3H),3.11–3.07(m,1H),2.97(td,J=11.4,7.3Hz,1H),2.87(d,J=8.5Hz,1H),2.33(d,J=6.8Hz,1H),2.67(s,6H),2.29(d,J=14.7Hz,2H),2.21(dt,J=21.5,7.2Hz,1H),2.18(dd,J=12.3,6.7Hz,1H),2.10–2.06(m,1H),1.83(q,J=11.9Hz,1H),1.60–1.57(m,1H),1.55(dd,J=14.9,4.3Hz,1H),1.47(dd,J=12.5,6.3Hz,1H),1.36(s,3H),1.27(d,J=6.1Hz,3H),1.23(d,J=9.0Hz,6H),1.18(s,3H),1.16(s,3H),1.10(d,J=3.5Hz,3H),0.97(d,J=16.5Hz,6H),0.73(t,J=7.4Hz,3H).HRMS[M+H]841.69
实施例16.化合物RL-55316的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮1.44g(2mmol),加入二氯甲烷10ml,溶解澄清,再加入氢氧化钾0.06g(1mmol)、碳酸钠0.11g(1mmol)、TBAB(四丁基溴化铵)0.32g(1mmol),室温搅拌15-20分钟,将2,3-二氯氯苄0.49g(2.5mmol)加入到反应瓶中,45-50℃下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤液以饱和碳酸氢钠溶液洗涤,水洗涤,蒸干溶液得粗品,中压制备柱分离,流动相为甲醇与水,得目标物0.16g,产率9.1%。
1H NMR(600MHz,DMSO)δ7.80(d,J=8.2Hz,1H),7.66(d,J=8.2Hz,1H),7.64–7.60(m,1H),5.16(s,1H),5.02(s,1H),4.91–4.84(m,1H),4.83–4.81(m,1H),4.80(d,J=2.9Hz,1H),4.78(s,1H),4.26(d,J=6.1Hz,1H),4.19(dd,J=21.0,8.2Hz,1H),4.04(dq,J=12.4,6.3Hz,1H),3.58(s,2H),3.39(d,J=2.4Hz,1H),3.37(d,J=6.0Hz,2H),3.19(s,3H),3.17(d,J=4.2Hz,1H),3.05(s,3H),3.04(s,3H),3.01(s,1H),2.90(d,J=9.1Hz,1H),2.34(dd,J=23.5,10.4Hz,1H),2.25–2.19(m,1H),2.20–2.16(m,1H),2.12(dd,J=14.2,7.1Hz,1H),2.06(dd,J=13.1,7.4Hz,1H),2.04–1.99(m,1H),1.74–1.60(m,2H),1.44(dd,J=12.4,6.6Hz,1H),1.34(s,1H),1.31(s,3H),1.22(s,3H),1.18(d,J=7.1Hz,3H),1.16(d,J=5.4Hz,3H),1.12(s,3H),1.10(d,J=4.7Hz,3H),1.09(d,J=3.9Hz,3H),1.03(d,J=7.1Hz,3H),1.01(d,J=7.4Hz,3H),0.71(t,J=7.6Hz,3H).
HRMS[M+H]875.59
实施例17.化合物RL-55317的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮1.44g(2mmol),加入二氯甲烷10ml,溶解澄清,再加入氢氧化钾0.06g(1mmol)、碳酸钠0.11g(1mmol)、TBAB(四丁基溴化铵)0.32g(1mmol),室温搅拌15-20分钟,将2,4-二氯氯苄0.49g(2.5mmol)加入到反应瓶中,45-50℃下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤液以饱和碳酸氢钠溶液洗涤,水洗涤,蒸干溶液得粗品,中压制备柱分离,流动相为甲醇与水,得目标物1.2g,产率68.6%。
1H NMR(600MHz,CDCl3)δ7.86(s,1H),7.52(d,J=5.3Hz,1H),7.50(d,J=4.9Hz,1H),5.58–5.54(m,1H),5.37(d,J=13.1Hz,1H),5.10(ddd,J=11.2,5.1,1.5Hz,1H),5.01(dd,J=11.7,2.5Hz,1H),4.91(d,J=4.3Hz,1H),4.59(dd,J=12.1,4.2Hz,1H),4.33–4.29(m,1H),4.01(d,J=6.2Hz,1H),3.67–3.64(m,1H),3.29(s,3H),3.02(d,J=9.3Hz,1H),2.76–2.72(m,1H),2.57–2.54(m,2H),2.50(d,J=6.6Hz,1H),2.31(d,J=5.3Hz,1H),2.25(d,J=5.9Hz,1H),2.20(dd,J=7.7,2.4Hz,1H),1.90(d,J=1.1Hz,1H),1.80(s,1H),1.68(s,6H),1.64–1.63(m,1H),1.63–1.61(m,1H),1.60(dd,J=6.1,3.1Hz,1H),1.58(s,1H),1.58–1.56(m,1H),1.51(d,J=4.8Hz,1H),1.50–1.48(m,1H),1.45(s,1H),1.42(s,3H),1.33(d,J=7.3Hz,3H),1.31(s,3H),1.20(d,J=7.3Hz,3H),1.18(d,J=2.6Hz,3H),1.11(d,J=10.1Hz,3H),1.06(d,J=6.9Hz,3H),1.02(d,J=5.9Hz,3H),0.96(d,J=7.0Hz,3H),0.85(t,J=3.5Hz,3H).HRMS[M+H]875.72
实施例18.化合物RL-55318的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮1.44g(2mmol),加入二氯甲烷10ml,溶解澄清,再加入氢氧化钾0.06g(1mmol)、碳酸钠0.11g(1mmol)、TBAB(四丁基溴化铵)0.32g(1mmol),室温搅拌15-20分钟,将3,4-二氯氯苄0.49g(2.5mmol)加入到反应瓶中,45-50℃下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤液以饱和碳酸氢钠溶液洗涤,水洗涤,蒸干溶液得粗品,中压制备柱分离,流动相为甲醇与水,得目标物1.1g,产率62.9%。
1H NMR(600MHz,CDCl3)δ8.15(d,J=7.7Hz,1H),7.58(d,J=8.0Hz,1H),7.32(s,1H),5.53(d,J=11.5Hz,1H),5.40(d,J=4.8Hz,1H),5.19(d,J=12.7Hz,1H),5.06(dd,J=11.5,3.0Hz,1H),4.75(s,1H),4.57(d,J=11.2Hz,1H),4.47(d,J=6.0Hz,1H),4.12(s,2H),4.00(dq,J=12.6,6.2Hz,1H),3.76–3.66(m,2H),3.59(dq,J=13.9,7.0Hz,1H),3.49(s,1H),3.43(d,J=10.9Hz,1H),3.34(s,1H),3.28(s,3H),3.23(d,J=18.9Hz,1H),2.97(d,J=8.8Hz,1H),2.46(t,J=13.1Hz,1H),2.36(d,J=10.4Hz,1H),2.26(d,J=5.1Hz,1H),2.24(s,1H),2.21(d,J=4.1Hz,1H),2.19(d,J=7.0Hz,1H),2.13(s,1H),1.67(s,3H),1.66(s,3H),1.52(dd,J=15.1,4.9Hz,1H),1.42(s,1H),1.37(s,3H),1.25(s,3H),1.19(s,3H),1.17(d,J=3.8Hz,3H),1.16(d,J=5.0Hz,3H),1.06(d,J=7.2Hz,3H),1.02(d,J=7.2Hz,6H),0.99(d,J=13.2Hz,3H),0.82(t,J=7.4Hz,3H).HRMS[M+H]875.83
实施例19.化合物RL-55319的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮1.44g(2mmol),加入二氯甲烷10ml,溶解澄清,再加入氢氧化钾0.06g(1mmol)、碳酸钠0.11g(1mmol)、TBAB(四丁基溴化铵)0.32g(1mmol),室温搅拌15-20分钟,将邻溴溴苄0.62g(2.5mmol)加入到反应瓶中,45-50℃下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤液以饱和碳酸氢钠溶液洗涤,水洗涤,蒸干溶液得粗品,中压制备柱分离,流动相为甲醇与水,得目标物0.82g,产率46.3%。
1H NMR(600MHz,DMSO)δ7.83(d,J=8.0Hz,1H),7.78(d,J=7.6Hz,1H),7.56(t,J=7.5Hz,1H),7.50(t,J=7.7Hz,1H),5.24(s,1H),5.14(d,J=13.1Hz,1H),4.91(d,J=4.1Hz,1H),4.83(dd,J=11.8,1.9Hz,1H),4.75(d,J=13.1Hz,1H),4.30(s,1H),4.24(d,J=7.0Hz,1H),4.09–4.05(m,1H),4.02(dd,J=14.1,5.9Hz,1H),3.98(s,1H),3.79(dd,J=9.6,7.4Hz,1H),3.60(dq,J=12.3,6.1Hz,1H),3.40–3.35(m,2H),3.19(s,3H),3.06(dd,J=11.6,7.5Hz,1H),3.03(s,6H),2.92(d,J=9.4Hz,1H),2.89(s,1H),2.33(dd,J=16.3,10.1Hz,2H),2.24(d,J=14.8Hz,1H),2.16(td,J=14.2,7.1Hz,1H),2.13–2.05(m,1H),2.02(dt,J=14.7,7.3Hz,1H),1.72(dt,J=30.1,15.1Hz,1H),1.56–1.51(m,1H),1.52–1.49(m,1H),1.46(dd,J=12.9,6.5Hz,1H),1.34(s,3H),1.24(d,J=6.1Hz,3H),1.17(s,3H),1.15(d,J=7.3Hz,3H),1.12(d,J=5.4Hz,6H),1.07(s,3H),1.03(d,J=4.1Hz,3H),1.02(d,J=3.9Hz,3H),0.71(t,J=7.4Hz,3H).HRMS[M+H]885.69
实施例21.化合物RL-55321的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮1.44g(2mmol),加入二氯甲烷10ml,溶解澄清,再加入氢氧化钾0.06g(1mmol)、碳酸钠0.11g(1mmol)、TBAB(四丁基溴化铵)0.32g(1mmol),室温搅拌15-20分钟,将对溴溴苄0.62g(2.5mmol)加入到反应瓶中,45-50℃下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤液以饱和碳酸氢钠溶液洗涤,水洗涤,蒸干溶液得粗品,中压制备柱分离,流动相为甲醇与水,得目标物1.15g,产率65.0%。
1H NMR(600MHz,CDCl3)δ7.67(dd,J=34.2,7.8Hz,1H),7.58(d,J=12.0Hz,2H),7.50(d,J=8.1Hz,1H),5.45–5.36(m,1H),5.25(s,1H),5.12–5.04(m,1H),5.04–4.97(m,1H),4.93(ddd,J=9.4,8.4,4.5Hz,1H),4.60(dt,J=21.8,10.5Hz,1H),4.38–4.29(m,1H),4.08–4.03(m,1H),4.03–3.97(m,1H),3.84(dd,J=25.0,11.0Hz,1H),3.48(s,1H),3.45–3.41(m,1H),3.38(s,1H),3.31(s,1H),3.29(s,3H),3.19(s,3H),3.16(s,3H),2.99(dd,J=22.1,9.4Hz,1H),2.79–2.72(m,1H),2.71–2.63(m,1H),2.53–2.50(m,1H),2.34(dd,J=14.4,2.1Hz,1H),2.28(t,J=9.1Hz,1H),2.17(dd,J=9.7,7.0Hz,1H),2.04(d,J=7.5Hz,1H),1.87(d,J=25.1Hz,1H),1.55(s,1H),1.43(d,J=10.2Hz,1H),1.38(s,1H),1.36–1.34(m,1H),1.31(s,3H),1.27(d,J=3.2Hz,3H),1.26(d,J=2.0Hz,3H),1.25(s,3H),1.24(d,J=10.6Hz,3H),1.22(s,3H),1.21(d,J=3.8Hz,3H),1.19(d,J=6.0Hz,3H),1.06(d,J=12.3Hz,3H),0.85(t,J=7.8Hz,3H).HRMS[M+H]885.53
实施例22.化合物RL-55322的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮1.44g(2mmol),加入二氯甲烷10ml,溶解澄清,再加入氢氧化钾0.06g(1mmol)、碳酸钠0.11g(1mmol)、TBAB(四丁基溴化铵)0.32g(1mmol),室温搅拌15-20分钟,将邻氰基氯苄0.38g(2.5mmol)加入到反应瓶中,45-50℃下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤液以饱和碳酸氢钠溶液洗涤,水洗涤,蒸干溶液得粗品,中压制备柱分离,流动相为甲醇与水,得目标物1.3g,产率78.3%。
1H NMR(600MHz,CDCl3)δ8.48(d,J=7.7Hz,1H),7.82(d,J=7.8Hz,1H),7.76(t,J=7.4Hz,1H),7.67(t,J=7.7Hz,1H),5.77(s,1H),5.40(d,J=4.6Hz,1H),5.09(dd,J=11.5,3.1Hz,1H),5.04(d,J=12.5Hz,1H),4.58(d,J=11.0Hz,1H),4.47(d,J=7.3Hz,1H),4.23–4.18(m,1H),4.01–3.95(m,1H),3.81–3.73(m,1H),3.69(dq,J=11.1,5.7Hz,1H),3.63(dd,J=15.5,8.0Hz,1H),3.60–3.54(m,1H),3.51(s,1H),3.45(d,J=11.1Hz,1H),3.37(s,3H),3.27(s,3H),3.25(s,3H),2.98(d,J=9.6Hz,1H),2.49–2.42(m,1H),2.32–2.26(m,1H),2.24(d,J=14.9Hz,2H),2.21–2.13(m,2H),1.77(dd,J=23.2,11.7Hz,2H),1.60–1.57(m,1H),1.55(d,J=5.2Hz,1H),1.53(d,J=5.0Hz,1H),1.49(dd,J=12.0,6.6Hz,1H),1.43(d,J=6.9Hz,3H),1.41(d,J=6.2Hz,3H),1.40(s,3H),1.26(s,3H),1.20(d,J=8.7Hz,6H),1.17(s,3H),1.16(d,J=7.7Hz,3H),1.07(d,J=7.2Hz,3H),0.83(t,J=7.4Hz,3H).HRMS[M+H]831.50
实施例23.化合物RL-55323的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮1.44g(2mmol),加入二氯甲烷10ml,溶解澄清,再加入氢氧化钾0.06g(1mmol)、碳酸钠0.11g(1mmol)、TBAB(四丁基溴化铵)0.32g(1mmol),室温搅拌15-20分钟,将间氰基氯苄0.38g(2.5mmol)加入到反应瓶中,45-50℃下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤液以饱和碳酸氢钠溶液洗涤,水洗涤,蒸干溶液得粗品,中压制备柱分离,流动相为甲醇与水,得目标物0.43g,产率25.9%。
1H NMR(600MHz,DMSO)δ8.42(s,1H),8.31(d,J=8.0Hz,1H),7.63(d,J=2.0Hz,1H),7.62–7.60(m,1H),5.18(d,J=64.5Hz,1H),4.95(d,J=5.4Hz,1H),4.87(d,J=12.3Hz,2H),4.74(s,2H),4.72–4.65(m,1H),4.25(d,J=5.0Hz,1H),4.22(d,J=7.1Hz,1H),4.00(d,J=13.2Hz,1H),3.92(d,J=7.4Hz,1H),3.86–3.81(m,2H),3.74(s,1H),3.19(s,3H),2.33(dd,J=17.4,9.5Hz,1H),2.15(s,6H),2.02(t,J=3.6Hz,1H),1.98–1.92(m,1H),1.88(d,J=15.6Hz,1H),1.81(s,1H),1.71(s,1H),1.67(d,J=11.9Hz,2H),1.51(s,1H),1.45–1.42(m,1H),1.41(d,J=4.0Hz,1H),1.37(d,J=12.3Hz,2H),1.23(d,J=5.5Hz,3H),1.22(s,3H),1.19(d,J=2.8Hz,3H),1.15(d,J=7.5Hz,3H),1.12(s,3H),1.09(d,J=7.5Hz,3H),1.02(s,3H),0.99(d,J=7.1Hz,3H),0.89(d,J=5.9Hz,3H),0.75(t,J=7.0Hz,3H).HRMS[M+H]832.15
实施例24.化合物RL-55324的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮1.44g(2mmol),加入二氯甲烷10ml,溶解澄清,再加入氢氧化钾0.06g(1mmol)、碳酸钠0.11g(1mmol)、TBAB(四丁基溴化铵)0.32g(1mmol),室温搅拌15-20分钟,将对氰基氯苄0.38g(2.5mmol)加入到反应瓶中,45-50℃下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤液以饱和碳酸氢钠溶液洗涤,水洗涤,蒸干溶液得粗品,中压制备柱分离,流动相为甲醇与水,得目标物0.63g,产率38.0%。
1H NMR(600MHz,DMSO)δ8.03(d,J=7.8Hz,1H),7.97(d,J=8.0Hz,1H),7.75(d,J=7.8Hz,1H),7.73(d,J=7.8Hz,1H),5.17(d,J=5.9Hz,1H),4.97(d,J=4.8Hz,1H),4.88(d,J=12.6Hz,1H),4.84–4.76(m,2H),4.26(d,J=8.2Hz,2H),4.08–4.02(m,2H),3.86–3.80(m,1H),3.75(dt,J=10.0,7.0Hz,1H),3.61–3.55(m,1H),3.36(dd,J=12.1,5.2Hz,2H),3.19(s,3H),3.13–3.08(m,1H),3.06(s,3H),3.01(s,3H),3.00–2.97(m,1H),2.91(t,J=8.9Hz,1H),2.34(t,J=13.5Hz,1H),2.24(s,1H),2.21(s,1H),2.15(dt,J=21.6,7.3Hz,1H),2.11–2.07(m,1H),2.06–2.01(m,1H),1.70(dd,J=23.3,12.1Hz,1H),1.56–1.51(m,1H),1.51–1.47(m,1H),1.45(dd,J=12.5,6.4Hz,1H),1.32(s,3H),1.22(d,J=6.1Hz,3H),1.17(s,3H),1.16(d,J=7.6Hz,3H),1.12(s,3H),1.10(d,J=2.7Hz,3H),1.09(d,J=3.8Hz,3H),1.03(d,J=7.6Hz,3H),1.01(d,J=7.3Hz,3H),0.71(t,J=7.4Hz,3H).HRMS[M+H]831.68
13C NMR(151MHz,DMSO)δ178.22,138.18,136.96,133.82,130.07,129.71,118.29,115.22,111.99,102.66,99.50,95.06,86.55,84.69,81.30,80.89,80.68,77.70,75.81,72.80,69.30,66.90,64.47,63.92,50.10,48.84,48.56,48.29,46.26,43.61,41.28,41.02,34.49,32.47,28.62,24.87,23.32,21.02,20.66,17.75,14.54,14.31,13.31,12.09,10.92.
实施例25.化合物RL-55325的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮1.44g(2mmol),加入二氯甲烷10ml,溶解澄清,再加入氢氧化钾0.06g(1mmol)、碳酸钠0.11g(1mmol)、TBAB(四丁基溴化铵)0.32g(1mmol),室温搅拌15-20分钟,将2-硝基苄基溴0.54g(2.5mmol)加入到反应瓶中,45-50℃下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤液以饱和碳酸氢钠溶液洗涤,水洗涤,蒸干溶液得粗品,中压制备柱分离,流动相为甲醇与水,得目标物0.61g,产率35.9%。
1H NMR(600MHz,DMSO)δ7.62(d,J=7.4Hz,2H),7.46(t,J=7.5Hz,2H),5.34(d,J=5.4Hz,1H),4.97(d,J=4.6Hz,1H),4.83(d,J=4.8Hz,1H),4.73(s,1H),4.52(d,J=12.5Hz,1H),4.40(d,J=6.9Hz,1H),4.35–4.32(m,1H),4.25(d,J=7.0Hz,1H),3.94–3.91(m,1H),3.83(dd,J=11.0,7.2Hz,1H),3.78–3.74(m,1H),3.58(dd,J=9.3,6.1Hz,1H),3.42(t,J=5.7Hz,1H),3.19(s,3H),3.17(s,1H),3.16(d,J=3.2Hz,1H),3.00(d,J=4.0Hz,1H),2.95(s,3H),2.92(s,3H),2.90–2.86(m,1H),2.60(d,J=13.5Hz,1H),2.46(d,J=13.6Hz,1H),2.21(s,1H),2.12(dd,J=7.1,4.4Hz,1H),2.07(dd,J=6.7,5.2Hz,1H),2.00(dd,J=16.4,6.7Hz,1H),1.82(dd,J=23.4,12.0Hz,1H),1.71(d,J=11.7Hz,1H),1.56–1.54(m,1H),1.45(dd,J=12.5,6.4Hz,1H),1.32(s,3H),1.23(d,J=6.1Hz,3H),1.19(s,3H),1.16(d,J=5.9Hz,6H),1.12(s,3H),1.01(d,J=7.5Hz,3H),0.97(d,J=7.3Hz,3H),0.94(d,J=7.3Hz,3H),0.71(t,J=6.1Hz,3H).HRMS[M+H]851.92
13C NMR(151MHz,)δ178.28,137.18,133.46,133.28,128.85,128.72,127.70,115.27,103.76,96.45,95.07,86.56,84.78,81.35,80.89,80.68,77.63,75.84,72.76,69.30,66.97,64.64,64.48,49.68,48.86,48.80,48.48,46.22,43.54,41.77,41.29,34.52,32.71,28.61,24.89,23.07,21.04,20.37,19.21,17.52,14.32,13.49,12.13,10.94.
实施例26.化合物RL-55326的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮1.44g(2mmol),加入二氯甲烷10ml,溶解澄清,再加入氢氧化钾0.06g(1mmol)、碳酸钠0.11g(1mmol)、TBAB(四丁基溴化铵)0.32g(1mmol),室温搅拌15-20分钟,将4-硝基苄基溴0.54g(2.5mmol)加入到反应瓶中,45-50℃下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤液以饱和碳酸氢钠溶液洗涤,水洗涤,蒸干溶液得粗品,中压制备柱分离,流动相为甲醇与水,得目标物0.71g,产率41.8%。
1H NMR(600MHz,DMSO)δ8.37(d,J=8.5Hz,2H),7.93(d,J=8.5Hz,2H),6.25(d,J=6.8Hz,1H),5.21(d,J=5.9Hz,1H),4.98–4.93(m,2H),4.88(d,J=12.4Hz,1H),4.82(dd,J=11.7,2.4Hz,1H),4.32(d,J=8.5Hz,1H),4.25(d,J=6.9Hz,1H),4.05(dt,J=9.7,5.4Hz,2H),3.88–3.81(m,1H),3.79–3.74(m,1H),3.57(dq,J=12.2,6.2Hz,1H),3.42–3.37(m,1H),3.20(s,3H),3.13–3.08(m,1H),3.07(s,3H),3.04(s,3H),2.99(td,J=11.4,7.3Hz,1H),2.91(t,J=9.0Hz,1H),2.33(t,J=13.5Hz,1H),2.22(d,J=14.7Hz,2H),2.15(dt,J=21.5,7.2Hz,1H),2.09(dd,J=12.3,6.7Hz,1H),2.06–2.00(m,1H),1.72(q,J=11.9Hz,1H),1.56–1.51(m,1H),1.50(dd,J=14.9,4.3Hz,1H),1.45(dd,J=12.5,6.3Hz,1H),1.32(s,3H),1.22(d,J=6.1Hz,3H),1.16(d,J=9.0Hz,6H),1.12(s,3H),1.10(s,3H),1.09(d,J=3.5Hz,3H),1.02(d,J=16.5Hz,6H),0.71(t,J=7.4Hz,3H).HRMS[M+H]852.13.
13C NMR(151MHz,DMSO)δ178.24,148.57,135.35,135.00,135.00,123.70,123.70,115.24,102.78,95.12,86.67,84.71,81.33,80.93,80.69,77.71,75.87,72.85,72.76,69.32,66.94,64.50,63.79,50.14,48.87,48.58,48.53,46.29,43.64,41.31,41.04,34.52,32.49,28.70,24.90,23.35,21.04,20.69,17.78,14.49,14.38,13.35,12.13,10.95.
实施例27.化合物RL-55327的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮1.44g(2mmol),加入二氯甲烷10ml,溶解澄清,再加入氢氧化钾0.06g(1mmol)、碳酸钠0.11g(1mmol)、TBAB(四丁基溴化铵)0.32g(1mmol),室温搅拌15-20分钟,将3-苄氧基溴苄0.69g(2.5mmol)加入到反应瓶中,45-50℃下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤液以饱和碳酸氢钠溶液洗涤,水洗涤,蒸干溶液得粗品,中压制备柱分离,流动相为甲醇与水,得目标物0.47g,产率25.8%。
1H NMR(600MHz,DMSO)δ8.08(s,1H),7.96–7.91(m,3H),7.90(d,J=3.9Hz,1H),7.80(d,J=10.0Hz,1H),7.77(t,J=7.8Hz,1H),7.71(dd,J=12.4,5.6Hz,1H),6.24(d,J=6.2Hz,1H),5.17(d,J=6.0Hz,1H),4.99(d,J=4.7Hz,1H),4.89(q,J=12.6Hz,2H),4.82(dd,J=11.7,2.6Hz,1H),4.24(d,J=6.6Hz,1H),4.20(d,J=8.6Hz,1H),4.08–4.05(m,1H),4.04(dd,J=6.3,3.0Hz,1H),4.00(ddd,J=16.3,9.7,4.9Hz,1H),3.82–3.73(m,2H),3.58–3.52(m,1H),3.36(dd,J=9.6,6.4Hz,2H),3.20(s,3H),3.11(dd,J=11.4,7.3Hz,1H),3.06(s,3H),3.04(s,3H),3.02(s,2H),2.91(t,J=9.0Hz,1H),2.23(d,J=15.0Hz,2H),2.19(s,1H),2.07–2.03(m,1H),1.70(q,J=11.5Hz,1H),1.55–1.52(m,1H),1.50(dd,J=15.0,4.8Hz,2H),1.44(dd,J=12.4,6.4Hz,1H),1.38(t,J=9.0Hz,1H),1.32(s,3H),1.21(d,J=6.1Hz,3H),1.17(s,3H),1.15(d,J=8.0Hz,3H),1.12(s,3H),1.10(d,J=6.6Hz,6H),1.03(d,J=7.5Hz,3H),1.01(d,J=7.3Hz,3H),0.71(t,J=7.4Hz,3H).
HRMS[M+H]913.07
13C NMR(151MHz,)δ178.26,158.65,137.51,131.13,130.15,130.00,129.74,129.54,126.94,125.51,124.80,123.88,123.00,120.63,115.25,102.65,94.98,86.54,84.75,81.32,80.82,80.69,77.68,75.73,72.78,72.04,69.33,67.00,64.47,64.38,50.14,48.78,48.57,48.20,46.19,43.50,41.26,41.01,34.47,32.45,28.52,24.86,23.32,21.02,20.65,17.76,14.71,14.22,13.37,12.09,10.92.
实施例28.化合物RL-55362的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮2g(2.79mmol),加入二氯甲烷30ml,溶解澄清,无水碳酸钠0.33g(3.07mmol),室温搅拌15-20分钟,将正戊酰氯0.37g(3.07mmol)加入到反应瓶中,室温下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤饼以少许二氯甲烷洗涤,滤液在25℃下浓缩至干,浓缩物搅拌下加入乙醚至固体析出,固体过滤,烘干得粗品1.8g,粗品以二氯甲烷/正已烷重结晶2次,得纯品目标物0.61g,产率27.4%。
1H NMR(600MHz,CDCl3)δ5.17(d,J=9.4Hz,1H),5.13(d,J=4.3Hz,1H),4.85(dd,J=10.3,7.9Hz,1H),4.35(d,J=7.6Hz,1H),4.29(s,1H),3.98(dd,J=9.1,6.5Hz,1H),3.51(d,J=11.1Hz,1H),3.44(d,J=5.8Hz,1H),3.28(s,3H),3.00(d,J=9.4Hz,1H),2.98–2.95(m,1H),2.95–2.91(m,1H),2.74(s,1H),2.48–2.43(m,1H),2.38(d,J=8.0Hz,1H),2.35(d,J=7.8Hz,1H),2.32(d,J=7.5Hz,2H),2.26(s,6H),2.05(ddd,J=21.4,14.7,7.6Hz,2H),1.93(dd,J=13.1,6.4Hz,1H),1.77(d,J=12.5Hz,1H),1.68(dd,J=15.9,7.8Hz,1H),1.64(d,J=7.6Hz,1H),1.61(d,J=7.6Hz,1H),1.60–1.56(m,1H),1.53(dd,J=15.0,4.8Hz,1H),1.46(dd,J=12.7,6.3Hz,1H),1.43(s,3H),1.39–1.36(m,2H),1.35(d,J=8.1Hz,2H),1.31(d,J=7.5Hz,3H),1.30(s,3H),1.24(d,J=6.1Hz,3H),1.21(d,J=9.6Hz,6H),1.07(s,3H),1.06(d,J=5.1Hz,6H),0.91(t,J=5.6Hz,3H),0.83(t,J=7.4Hz,3H).HRMS[M+H]800.86.
实施例29.化合物RL-55365的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮2g(2.79mmol),加入二氯甲烷30ml,溶解澄清,无水碳酸钠0.34g(3.07mmol),室温搅拌15-20分钟,将月桂酰氯0.67g(3.07mmol)加入到反应瓶中,室温下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤饼以少许二氯甲烷洗涤,滤液在25℃下浓缩至干,浓缩物搅拌下加入乙醚至固体析出,固体过滤,烘干得粗品1.5g粗品以二氯甲烷/正已烷重结晶2次,得纯品目标物0.36g,产率14.3%。
1H NMR(600MHz,DMSO)δ5.75(s,1H),5.24–5.24(m,1H),5.18(d,J=5.3Hz,1H),4.82(dd,J=11.8,2.2Hz,1H),4.74(d,J=4.5Hz,1H),4.64(dd,J=10.4,8.2Hz,1H),4.29(d,J=7.6Hz,1H),4.25(d,J=9.4Hz,1H),4.05–4.02(m,1H),3.83(d,J=5.9Hz,1H),3.50(td,J=12.9,6.8Hz,1H),3.35(dd,J=11.8,5.5Hz,2H),3.32–3.25(m,1H),3.19(s,3H),2.91(dd,J=13.4,9.2Hz,1H),2.87(t,J=7.6Hz,1H),2.76(s,1H),2.64–2.58(m,1H),2.32(d,J=12.7Hz,1H),2.26(dd,J=20.9,11.1Hz,2H),2.22(d,J=9.2Hz,1H),2.20–2.13(m,6H),1.99(s,1H),1.87(p,J=9.1Hz,1H),1.74(d,J=11.3Hz,1H),1.55(dd,J=13.9,7.5Hz,1H),1.52–1.50(m,1H),1.49(d,J=3.6Hz,1H),1.47(d,J=4.4Hz,1H),1.38(dd,J=12.9,6.4Hz,1H),1.32(s,3H),1.30–1.27(m,4H),1.26–1.24(m,10H),1.18(d,J=7.1Hz,1H),1.16(s,3H),1.14(d,J=6.1Hz,3H),1.12(s,3H),1.11(d,J=4.1Hz,3H),1.02(d,J=7.4Hz,3H),1.00(d,J=7.2Hz,6H),0.95(d,J=7.1Hz,3H),0.85(t,J=6.4Hz,3H),0.68(t,J=7.4Hz,3H).HRMS[M+H]899.82.
实施例30.化合物RL-55370的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮2g(2.79mmol),加入二氯甲烷30ml,溶解澄清,无水碳酸钠0.34g(3.07mmol),室温搅拌15-20分钟,将苯甲酰氯0.43g(3.07mmol)加入到反应瓶中,室温下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤饼以少许二氯甲烷洗涤,滤液在25℃下浓缩至干,浓缩物搅拌下加入乙醚至固体析出,固体过滤,烘干得粗品1.7g粗品以二氯甲烷/正已烷重结晶2次,得纯品目标物0.86g,产率37.6%。
1H NMR(600MHz,DMSO)δ7.96–7.95(m,1H),7.64(dt,J=14.8,7.4Hz,2H),7.51(d,J=7.7Hz,2H),5.14(d,J=5.1Hz,1H),4.94–4.89(m,1H),4.78(d,J=11.9Hz,1H),4.74(d,J=4.3Hz,1H),4.48(d,J=7.2Hz,1H),4.27(d,J=9.0Hz,1H),4.06–4.00(m,1H),3.83(s,1H),3.60(dt,J=12.7,6.7Hz,2H),3.10(s,3H),2.99(s,1H),2.87(t,J=9.0Hz,2H),2.57–2.52(m,1H),2.39(t,J=13.7Hz,1H),2.19(s,6H),2.13(d,J=14.9Hz,1H),2.09(dd,J=14.4,6.9Hz,1H),2.06–1.99(m,1H),1.82(d,J=8.9Hz,1H),1.79–1.73(m,1H),1.47(ddd,J=14.2,7.6,2.4Hz,1H),1.44(d,J=4.3Hz,1H),1.42(d,J=5.1Hz,1H),1.39(d,J=6.3Hz,1H),1.30(s,3H),1.24(s,1H),1.18(d,J=6.0Hz,3H),1.15(s,3H),1.11(d,J=6.2Hz,3H),1.10(s,3H),1.06(d,J=7.3Hz,3H),1.01(d,J=7.2Hz,3H),0.80(d,J=7.1Hz,3H),0.72(d,J=7.2Hz,3H),0.64(t,J=7.3Hz,3H).
HRMS[M+H]821.11
13C NMR(151MHz,)δ177.59,167.35,164.69,133.15,132.87,130.81,130.12,129.27,129.27,128.58,128.58,115.03,101.83,95.72,85.81,84.18,81.14,81.09,80.68,77.79,76.23,72.79,68.46,64.52,62.43,48.73,48.43,46.74,44.75,41.45,40.75,40.31,34.35,30.34,29.70,24.97,23.30,20.98,20.76,17.61,14.64,12.63,12.03,10.88.
实施例31.化合物RL-55371的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮2g(2.79mmol),加入二氯甲烷30ml,溶解澄清,无水碳酸钠0.34g(3.07mmol),室温搅拌15-20分钟,将4-甲基苯甲酰氯0.48g(3.07mmol)加入到反应瓶中,室温下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤饼以少许二氯甲烷洗涤,滤液在25℃下浓缩至干,浓缩物搅拌下加入乙醚至固体析出,固体过滤,烘干得粗品1.5g粗品以二氯甲烷/正已烷重结晶2次,得纯品目标物0.38g,产率16.3%。
1H NMR(600MHz,DMSO)δ7.85(d,J=8.2Hz,2H),7.32(d,J=8.0Hz,2H),5.11(d,J=5.5Hz,1H),4.89(dd,J=10.1,7.8Hz,1H),4.79(dd,J=11.8,2.5Hz,1H),4.73(d,J=4.6Hz,1H),4.46(d,J=7.5Hz,1H),4.23(d,J=9.2Hz,1H),4.03(dq,J=12.7,6.3Hz,1H),3.82(dd,J=5.3,3.1Hz,1H),3.59(ddd,J=11.1,6.1,1.7Hz,1H),3.37–3.32(m,2H),3.28(s,1H),3.11(s,3H),2.95(s,1H),2.90–2.83(m,2H),2.57–2.51(m,1H),2.38(s,3H),2.18(s,6H),2.14(d,J=15.0Hz,1H),2.10(dd,J=14.2,7.1Hz,1H),2.05–2.00(m,1H),1.80(dd,J=12.1,3.6Hz,1H),1.78–1.71(m,1H),1.51–1.46(m,1H),1.45(d,J=4.8Hz,1H),1.44–1.41(m,1H),1.41–1.37(m,1H),1.31(s,3H),1.18(d,J=6.1Hz,3H),1.15(s,3H),1.12(d,J=6.3Hz,3H),1.10(s,3H),1.05(d,J=7.4Hz,3H),1.01(d,J=7.3Hz,3H),0.80(d,J=7.2Hz,3H),0.76(d,J=7.3Hz,3H),0.65(t,J=7.4Hz,3H).HRMS[M+H]834.87.
13C NMR(151MHz,)δ177.45,164.56,143.27,129.25,129.25,129.02,129.02,127.38,114.91,101.90,95.75,85.73,84.10,81.13,81.00,80.61,77.74,76.27,72.72,71.16,68.37,64.46,62.38,54.82,48.63,48.37,46.78,44.80,41.41,40.69,40.25,40.05,34.32,30.48,29.74,24.91,23.25,21.06,20.92,20.92,20.67,17.51,14.67,12.28,10.79.
实施例32.化合物RL-55375的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮2g(2.79mmol),加入二氯甲烷30ml,溶解澄清,无水碳酸钠0.34g(3.07mmol),室温搅拌15-20分钟,将4-甲氧基苯甲酰氯0.52g(3.07mmol)加入到反应瓶中,室温下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤饼以少许二氯甲烷洗涤,滤液在25℃下浓缩至干,浓缩物搅拌下加入乙醚至固体析出,固体过滤,烘干得粗品1.3g粗品以二氯甲烷/正已烷重结晶,得目标物0.7g,产率29.5%。
1H NMR(600MHz,CDCl3)δ7.45(d,J=8.2Hz,2H),6.92(d,J=8.4Hz,2H),5.34(s,1H),5.15(d,J=11.3Hz,2H),4.97(d,J=4.2Hz,1H),4.55(s,1H),4.14–4.11(m,1H),4.00(s,1H),3.89(s,3H),3.54(d,J=10.9Hz,1H),3.49(t,J=3.7Hz,1H),3.44(d,J=6.5Hz,1H),3.23(s,3H),3.21–3.18(m,1H),3.16(s,1H),3.02–2.97(m,2H),2.96(s,1H),2.92(s,3H),2.87(s,3H),2.31(d,J=7.7Hz,1H),2.15(s,1H),2.11(s,1H),2.04(d,J=7.6Hz,1H),1.98(d,J=5.1Hz,1H),1.76(d,J=3.6Hz,1H),1.53–1.52(m,1H),1.45(d,J=1.4Hz,1H),1.45–1.44(m,1H),1.41–1.40(m,1H),1.34(d,J=5.5Hz,3H),1.28(s,3H),1.21(d,J=5.0Hz,3H),1.19(s,3H),1.09(s,3H),1.07(d,J=10.1Hz,3H),0.87(d,J=7.2Hz,3H),0.83(d,J=6.9Hz,3H),0.77(t,J=7.4Hz,3H),0.63(d,J=7.3Hz,3H).HRMS[M+H]851.23
实施例33.化合物RL-55378的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮2g(2.79mmol),加入二氯甲烷30ml,溶解澄清,无水碳酸钠0.34g(3.07mmol),室温搅拌15-20分钟,将4-氟苯甲酰氯g(3.07mmol)加入到反应瓶中,室温下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤饼以少许二氯甲烷洗涤,滤液在25℃下浓缩至干,浓缩物搅拌下加入乙醚至固体析出,固体过滤,烘干得粗品1.8g粗品以二氯甲烷/正已烷重结晶2次,得纯品目标物0.61g,产率26.1%。
1H NMR(600MHz,CDCl3)δ8.04(d,J=3.3Hz,1H),7.88(d,J=3.2Hz,1H),7.04(d,J=8.6Hz,1H),6.99(d,J=8.5Hz,1H),5.21–5.16(m,1H),5.13(dd,J=11.7,3.0Hz,1H),5.02(d,J=4.5Hz,1H),4.51(d,J=7.4Hz,1H),4.21(dd,J=6.1,4.1Hz,1H),3.94(dq,J=12.8,6.4Hz,1H),3.64–3.58(m,1H),3.53(d,J=10.8Hz,1H),3.49(s,1H),3.46(d,J=5.6Hz,1H),3.20(s,3H),2.98(d,J=9.4Hz,1H),2.95(dd,J=10.6,7.3Hz,1H),2.69(dt,J=11.5,7.3Hz,2H),2.49(d,J=13.3Hz,1H),2.40(s,6H),2.33–2.24(m,2H),2.17(d,J=15.2Hz,1H),2.05–2.00(m,1H),1.96(s,1H),1.83–1.77(m,1H),1.69–1.61(m,1H),1.48(d,J=6.3Hz,1H),1.47(s,1H),1.46–1.44(m,1H),1.41(s,3H),1.34(d,J=7.3Hz,3H),1.30(d,J=6.2Hz,3H),1.29(s,3H),1.19(d,J=6.8Hz,6H),1.09(d,J=7.2Hz,3H),0.93(d,J=7.4Hz,3H),0.76(t,J=7.4Hz,3H),0.52(d,J=7.4Hz,3H).HRMS[M+H]838.79.
13C NMR(151MHz,)δ177.63,164.24,163.80,132.13,132.07,115.86,115.72,115.62,115.48,115.08,101.82,99.57,95.75,85.89,84.21,81.15,80.72,77.80,76.27,72.81,71.58,71.52,68.52,64.55,62.44,48.72,48.45,46.73,44.74,41.46,40.78,40.32,34.37,30.26,29.67,24.98,23.33,21.01,20.78,17.65,14.67,12.71,12.05,10.90.
实施例34.化合物RL-55380的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮2g(2.79mmol),加入二氯甲烷30ml,溶解澄清,无水碳酸钠0.34g(3.07mmol),室温搅拌15-20分钟,将3-(三氟甲基)苯甲酰氯0.64g(3.07mmol)加入到反应瓶中,室温下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤饼以少许二氯甲烷洗涤,滤液在25℃下浓缩至干,浓缩物搅拌下加入乙醚至固体析出,固体过滤,烘干得粗品1.9g粗品以二氯甲烷/正已烷重结晶2次,得纯品目标物0.51g,产率20.1%。
1H NMR(600MHz,CDCl3)δ8.25(s,1H),8.22(d,J=7.9Hz,1H),7.86(d,J=7.8Hz,1H),7.41(t,J=7.7Hz,1H),5.26(dd,J=10.3,7.8Hz,1H),5.13(dd,J=11.8,2.9Hz,1H),4.97(d,J=4.6Hz,1H),4.57(d,J=7.4Hz,1H),4.14(t,J=4.9Hz,1H),3.97–3.91(m,1H),3.66(ddd,J=10.8,6.1,1.6Hz,1H),3.52(d,J=10.9Hz,1H),3.49(s,2H),3.45(d,J=6.6Hz,1H),3.42(s,1H),3.18(s,3H),2.98(d,J=9.4Hz,1H),2.92–2.84(m,1H),2.60(dd,J=7.4,4.5Hz,1H),2.50(s,6H),2.46(d,J=13.2Hz,1H),2.30(tt,J=14.2,7.2Hz,1H),2.17(d,J=15.1Hz,1H),2.05(s,1H),2.02–1.96(m,1H),1.78(dd,J=12.8,6.8Hz,1H),1.64(ddd,J=14.2,7.4,3.0Hz,1H),1.53(t,J=11.9Hz,1H),1.50–1.47(m,1H),1.47–1.45(m,1H),1.43(s,3H),1.33(d,J=6.1Hz,3H),1.29(d,J=4.1Hz,3H),1.29(d,J=3.1Hz,3H),1.21(d,J=6.4Hz,3H),1.19(s,3H),1.09(d,J=7.2Hz,3H),0.89(d,J=7.4Hz,3H),0.74(t,J=7.4Hz,3H),0.54(d,J=7.3Hz,3H).HRMS[M+H]889.21
实施例35.化合物RL-55381的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮2g(2.79mmol),加入二氯甲烷30ml,溶解澄清,无水碳酸钠0.34g(3.07mmol),室温搅拌15-20分钟,将2-氯苯甲酰氯0.54g(3.07mmol)加入到反应瓶中,室温下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤饼以少许二氯甲烷洗涤,滤液在25℃下浓缩至干,浓缩物搅拌下加入乙醚至固体析出,固体过滤,烘干得粗品1.4g粗品以乙醚/石油醚重结晶2次,得纯品目标物0.52g,产率21.9%。
1H NMR(600MHz,CDCl3)δ7.77(d,J=1.6Hz,1H),7.76(d,J=1.6Hz,1H),7.38–7.35(m,2H),5.47(s,1H),5.30(s,1H),5.27(dd,J=10.4,7.3Hz,1H),5.00(dd,J=11.6,2.6Hz,1H),4.86(dd,J=15.7,4.6Hz,1H),4.44(d,J=7.3Hz,1H),3.64(dt,J=14.5,8.4Hz,2H),3.49(s,1H),3.37(d,J=11.1Hz,1H),3.22(s,3H),3.19(s,1H),3.02(d,J=9.4Hz,1H),3.00–2.95(m,1H),2.77–2.70(m,1H),2.67(s,6H),2.56(s,2H),2.49(dd,J=13.6,6.9Hz,1H),2.39(d,J=7.3Hz,1H),2.28(s,1H),2.26–2.21(m,1H),2.02(dd,J=8.8,4.5Hz,1H),1.73(d,J=1.2Hz,1H),1.67(d,J=1.3Hz,1H),1.63(dd,J=13.1,6.5Hz,2H),1.54(s,3H),1.40(dd,J=12.3,5.8Hz,3H),1.29(d,J=2.8Hz,3H),1.27(d,J=12.4Hz,3H),1.25(s,3H),1.21(s,3H),1.16(dd,J=11.1,6.5Hz,3H),1.01(d,J=7.3Hz,3H),0.97(d,J=6.9Hz,3H),0.81(t,J=7.2Hz,3H).HRMS[M+H]855.61
实施例36.化合物RL-55382的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮2g(2.79mmol),加入二氯甲烷30ml,溶解澄清,无水碳酸钠0.34g(3.07mmol),室温搅拌15-20分钟,将3-氯苯甲酰氯0.54g(3.07mmol)加入到反应瓶中,室温下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤饼以少许二氯甲烷洗涤,滤液在25℃下浓缩至干,浓缩物搅拌下加入乙醚至固体析出,固体过滤,烘干得粗品1.8g粗品以乙醚/石油醚重结晶2次,得纯品目标物0.36g,产率15.1%。
1H NMR(600MHz,CDCl3)δ7.96(s,1H),7.84(d,J=7.8Hz,2H),7.20(t,J=7.8Hz,1H),5.26(dd,J=10.3,7.6Hz,1H),5.14(dd,J=11.8,2.9Hz,1H),4.97(d,J=4.6Hz,1H),4.55(d,J=7.3Hz,1H),4.15(t,J=4.9Hz,1H),3.95(dd,J=11.1,4.7Hz,1H),3.93(s,1H),3.66(ddd,J=10.8,6.1,1.7Hz,1H),3.53(d,J=10.8Hz,1H),3.45(d,J=6.4Hz,1H),3.20(s,3H),2.99(d,J=9.4Hz,1H),2.89(dd,J=10.9,7.4Hz,1H),2.87(s,1H),2.59(dd,J=7.5,4.5Hz,1H),2.55(s,6H),2.50–2.44(m,1H),2.33–2.26(m,1H),2.18(d,J=15.2Hz,1H),2.10(s,1H),2.01(ddd,J=14.2,11.9,7.3Hz,1H),1.78(dd,J=13.1,6.5Hz,1H),1.64(ddd,J=14.2,7.3,3.1Hz,1H),1.56–1.51(m,1H),1.50–1.47(m,1H),1.47–1.45(m,1H),1.44(d,J=4.8Hz,1H),1.42(s,3H),1.33(d,J=6.1Hz,3H),1.30(d,J=7.9Hz,6H),1.21(s,3H),1.19(s,3H),1.09(d,J=7.2Hz,3H),0.90(d,J=7.4Hz,3H),0.76(t,J=7.4Hz,3H),0.56(d,J=7.4Hz,3H).HRMS[M+H]855.28
实施例37.化合物RL-55384的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮2g(2.79mmol),加入二氯甲烷30ml,溶解澄清,无水碳酸钠0.34g(3.07mmol),室温搅拌15-20分钟,将2,4-二氯苯甲酰氯0.64g(3.07mmol)加入到反应瓶中,室温下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤饼以少许二氯甲烷洗涤,滤液在25℃下浓缩至干,浓缩物搅拌下加入乙醚至固体析出,固体过滤,烘干得粗品1.35g粗品以二氯甲烷/正已烷重结晶2次,得纯品目标物0.43g,产率17.3%。
1H NMR(600MHz,CDCl3)δ7.96(d,J=8.4Hz,1H),7.48(d,J=2.0Hz,1H),7.31–7.28(m,1H),5.14(d,J=4.1Hz,1H),5.12(d,J=3.1Hz,1H),5.07(dd,J=10.6,7.8Hz,1H),4.53(d,J=7.6Hz,1H),4.35(dd,J=8.3,2.3Hz,1H),3.97(ddd,J=13.1,10.4,4.3Hz,1H),3.93(s,1H),3.57(td,J=11.9,6.4Hz,2H),3.51(d,J=3.8Hz,1H),3.46(dd,J=10.1,7.6Hz,1H),3.26(s,1H),3.20(s,3H),3.03(dd,J=10.6,7.2Hz,1H),3.00(d,J=9.5Hz,1H),2.96(s,1H),2.89(s,1H),2.51–2.45(m,1H),2.33–2.29(m,1H),2.27(s,6H),2.16(d,J=15.2Hz,1H),2.03–1.98(m,1H),1.91–1.87(m,1H),1.67(ddd,J=14.3,7.3,3.1Hz,2H),1.46(d,J=5.4Hz,1H),1.41(s,1H),1.40(s,3H),1.31(d,J=7.7Hz,3H),1.30(s,3H),1.29(d,J=2.3Hz,3H),1.20(d,J=8.2Hz,3H),1.17(s,3H),1.09(d,J=7.1Hz,3H),1.04(d,J=7.5Hz,3H),0.81(t,J=7.4Hz,3H),0.56(d,J=7.5Hz,3H).
HRMS[M+H]889.67
实施例38.化合物RL-55389的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮2g(2.79mmol),加入二氯甲烷30ml,溶解澄清,无水碳酸钠0.34g(3.07mmol),室温搅拌15-20分钟,将2-溴苯甲酰氯0.67g(3.07mmol)加入到反应瓶中,室温下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤饼以少许二氯甲烷洗涤,滤液在25℃下浓缩至干,浓缩物以中压制备柱分离,流动相为甲醇与石油醚,得纯品目标物0.37g,产率14.7%。
1H NMR(600MHz,DMSO)δ7.84(dd,J=5.8,3.1Hz,1H),7.75(dd,J=6.0,3.1Hz,1H),7.47(p,J=5.9Hz,2H),5.11(d,J=5.5Hz,1H),4.84(dd,J=10.0,8.1Hz,1H),4.80(s,1H),4.79–4.77(m,1H),4.47(d,J=7.6Hz,1H),4.17(d,J=9.2Hz,1H),4.03–3.97(m,1H),3.90(t,J=4.4Hz,1H),3.60(dq,J=12.4,6.1Hz,1H),3.39–3.33(m,2H),3.08(s,3H),2.99–2.94(m,1H),2.92(dd,J=13.2,6.0Hz,1H),2.85(t,J=9.3Hz,1H),2.66–2.60(m,1H),2.37(t,J=13.6Hz,1H),2.22(s,6H),2.15(s,1H),2.13(s,1H),2.12–2.03(m,2H),1.90–1.85(m,1H),1.83(d,J=13.0Hz,1H),1.54–1.46(m,1H),1.43(t,J=6.0Hz,1H),1.42–1.39(m,1H),1.31(s,3H),1.19(d,J=6.1Hz,3H),1.16(s,3H),1.12(d,J=7.4Hz,3H),1.09(d,J=6.3Hz,3H),1.08(s,3H),1.02(d,J=7.3Hz,3H),0.86(d,J=7.1Hz,3H),0.72(d,J=7.4Hz,3H),0.67(t,J=7.4Hz,3H).HRMS[M+H]899.73.
13C NMR(151MHz,)δ177.60,164.10,134.08,133.03,132.15,131.27,127.49,120.70,115.05,100.83,95.45,85.07,84.29,81.07,81.00,80.66,77.73,75.93,72.70,71.88,68.51,64.42,62.52,48.67,48.53,46.67,44.12,41.35,40.73,40.22,40.06,34.32,29.50,29.28,24.88,23.28,20.92,20.69,17.55,14.11,13.08,12.47,11.94,10.85.
实施例39.化合物RL-55390的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮2g(2.79mmol),加入二氯甲烷30ml,溶解澄清,无水碳酸钠0.34g(3.07mmol),室温搅拌15-20分钟,将苯乙酰氯0.48g(3.07mmol)加入到反应瓶中,室温下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤饼以少许二氯甲烷洗涤,滤液在25℃下浓缩至干,浓缩物搅拌下加入乙醚至固体析出,固体过滤,烘干得粗品1.75g粗品以二氯甲烷/正已烷重结晶2次,得纯品目标物0.69g,产率29.6%。
1H NMR(600MHz,DMSO)δ7.29(d,J=1.8Hz,2H),7.23(t,J=1.8Hz,2H),7.22–7.20(m,1H),4.97(d,J=4.3Hz,1H),4.80(dd,J=11.6,2.8Hz,1H),4.21(s,1H),4.13(d,J=7.4Hz,1H),4.06(d,J=5.5Hz,1H),4.05–4.02(m,1H),3.47(d,J=5.9Hz,1H),3.45(d,J=6.1Hz,1H),3.36(s,1H),3.34(s,1H),3.31(d,J=6.4Hz,1H),3.18(s,3H),3.10(dd,J=10.0,7.4Hz,1H),3.05–3.01(m,2H),2.87(d,J=9.4Hz,1H),2.37–2.30(m,1H),2.24(s,6H),2.21(d,J=14.8Hz,1H),2.14(s,1H),2.13–2.10(m,1H),2.10–2.06(m,1H),2.00(dd,J=13.7,6.5Hz,1H),1.65(dd,J=11.2,4.3Hz,1H),1.55–1.50(m,1H),1.49(d,J=4.9Hz,1H),1.46(d,J=5.0Hz,1H),1.40(dd,J=12.3,6.3Hz,1H),1.33(s,1H),1.30(s,3H),1.16(s,3H),1.13(d,J=3.7Hz,3H),1.11(d,J=2.3Hz,3H),1.11(s,3H),1.09(d,J=6.3Hz,3H),1.06(d,J=7.4Hz,3H),0.99(d,J=6.9Hz,3H),0.98(d,J=6.9Hz,3H),0.71(t,J=6.3Hz,3H).HRMS[M+H]835.25.
13C NMR(151MHz,)δ177.37,174.46,171.55,115.22,114.84,103.82,101.82,95.99,94.88,85.41,83.94,81.43,81.01,80.71,77.80,76.33,72.80,70.58,68.33,64.47,62.25,48.68,48.46,47.27,45.12,41.55,40.22,33.36,30.18,26.60,26.50,24.99,23.28,21.65,21.37,20.97,20.66,17.47,15.17,13.62,11.97,11.66,11.32,10.90,10.86.
实施例40.化合物RL-55396的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮2g(2.79mmol),加入二氯甲烷30ml,溶解澄清,无水碳酸钠0.34g(3.07mmol),室温搅拌15-20分钟,将5-氯-2-酰氯噻吩0.56g(3.07mmol)加入到反应瓶中,室温下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤饼以少许二氯甲烷洗涤,滤液在25℃下浓缩至干,浓缩物搅拌下加入乙醚至固体析出,固体过滤,烘干得粗品1.2g粗品以二氯甲烷/正已烷重结晶2次,得纯品目标物0.53g,产率21.7%。
1H NMR(600MHz,DMSO)δ7.67(d,J=4.1Hz,1H),7.28(d,J=4.1Hz,1H),5.16(d,J=5.4Hz,1H),4.80(d,J=2.4Hz,1H),4.78(d,J=2.6Hz,1H),4.77(d,J=4.7Hz,1H),4.44(d,J=7.6Hz,1H),4.26(d,J=9.1Hz,1H),4.03(dq,J=12.8,6.4Hz,1H),3.87(t,J=4.3Hz,1H),3.63–3.57(m,1H),3.38(q,J=7.0Hz,1H),3.36–3.33(m,1H),3.30(d,J=7.4Hz,1H),3.14(s,3H),2.89(d,J=7.6Hz,1H),2.86(d,J=9.2Hz,1H),2.66–2.60(m,1H),2.38(t,J=13.7Hz,1H),2.18(d,J=11.9Hz,6H),2.17(s,1H),2.14(s,1H),2.09(dd,J=14.2,7.2Hz,1H),2.04(ddd,J=13.9,9.6,4.9Hz,1H),1.81(dd,J=8.0,3.6Hz,2H),1.52–1.47(m,1H),1.45(dd,J=15.0,4.5Hz,1H),1.39(dd,J=12.8,6.5Hz,1H),1.29(s,3H),1.17(d,J=6.1Hz,3H),1.15(s,3H),1.11(s,3H),1.10(s,3H),1.05(d,J=7.4Hz,3H),0.99(d,J=7.3Hz,3H),0.89(d,J=7.2Hz,3H),0.79(d,J=7.3Hz,3H),0.66(t,J=7.4Hz,3H).HRMS[M+H]861.33
13C NMR(151MHz,)δ177.59,159.26,135.53,133.75,131.74,128.52,115.06,101.50,95.57,86.04,84.20,81.05,80.98,80.67,77.76,76.14,72.76,71.93,68.36,64.50,62.29,54.87,48.65,48.41,46.61,44.81,41.37,40.70,40.25,34.32,30.14,29.44,24.90,23.26,20.95,20.69,17.61,14.45,13.14,12.06,11.98,10.86.
实施例41.化合物RL-55397的制备
于100ml圆底烧瓶中,称入红霉素A-6,9-9,12-螺缩酮2g(2.79mmol),加入二氯甲烷30ml,溶解澄清,无水碳酸钠0.34g(3.07mmol),室温搅拌15-20分钟,将环己甲酰氯0.45g(3.07mmol)加入到反应瓶中,室温下搅拌反应,TCL检测红霉素A-6,9-9,12-螺缩酮点消失后停止反应,过滤,滤饼以少许二氯甲烷洗涤,滤液在25℃下浓缩至干,浓缩物以中压制备柱分离,流动相为甲醇与石油醚,得纯品目标物0.41g,产率17.8%。
1H NMR(600MHz,DMSO)δ5.76(s,1H),4.97(d,J=4.7Hz,1H),4.80(dd,J=11.9,2.6Hz,1H),4.19(s,1H),4.13(d,J=7.3Hz,1H),4.08–4.02(m,2H),3.45(ddd,J=11.0,6.1,1.6Hz,2H),3.35(d,J=11.5Hz,2H),3.30(d,J=6.4Hz,2H),3.18(s,3H),3.09(dd,J=10.0,7.4Hz,1H),3.03(dd,J=11.3,7.2Hz,2H),2.87(d,J=9.2Hz,1H),2.34(t,J=13.4Hz,1H),2.23(s,6H),2.19(s,1H),2.10(dt,J=12.3,6.8Hz,2H),2.00(dd,J=13.3,6.6Hz,2H),1.74(d,J=12.8Hz,2H),1.66–1.64(m,1H),1.62(dd,J=6.6,3.5Hz,2H),1.55(dd,J=11.2,4.2Hz,1H),1.53–1.49(m,1H),1.47(dd,J=15.0,4.9Hz,1H),1.39(dd,J=12.5,6.5Hz,1H),1.30(s,3H),1.28–1.23(m,2H),1.22–1.17(m,2H),1.16(s,3H),1.12(d,J=3.8Hz,3H),1.11(d,J=2.7Hz,3H),1.11(s,3H),1.08(d,J=6.3Hz,3H),1.06(d,J=7.4Hz,3H),0.99(d,J=7.2Hz,6H),0.70(t,J=7.4Hz,3H).
HRMS[M+H]826.84
实施例42.红霉素A-6,9-9,12-螺缩酮衍生物(RL-553系列)对小鼠Ⅱ型糖尿病模型治疗试验
1、实验动物
KM小鼠216只,雄性,体重18~22g,购自上海斯莱克动物科技公司。实验期间,保持动物房室温在22℃左右,相对湿度70%左右,早8点至晚8点自动照明。动物自由进食,自由饮水。所有实验动物的使用,符合相关的管理准则。所有的动物都得到了人性化的对待。
2、主要试剂、受试化合物与仪器
生理盐水(北京双鹤药业),2-脱氧-2-[[(甲基亚硝基氨基)羰基]-氨基]-D-吡喃葡萄糖(STZ)(百灵威科技有限公司),羧甲基纤维素钠(上海生工生物科技有限公司),红霉素A-6,9-9,12-螺缩酮衍生物(RL-553系列衍生物)自行设计并合成,7600型日立全自动生化分析仪(株式会社日立高新技术),OneTouchUltra血糖检测仪(强生公司)。
3、KM小鼠Ⅱ型糖尿病模型制备
取KM小鼠216只,雄性,体重18~22g。随机选取6只小鼠作为正常对照组,喂以基础饲料,自由饮水,其余小鼠喂以高糖高脂饲料(含蔗糖10%、猪油10%、胆固醇5%)饲养4周,同时自由饮水。4周后,喂高糖高脂饲料小鼠腹腔注射150mg·kg-1体重的STZ溶液,分5次给予,并继续给予高糖高脂饲料1周后,测定各组小鼠空腹血糖,浓度≥11.1mmol/L者作为2型糖尿病小鼠模型。造模成功后,选取6只小鼠作为模型对照组。
4、动物分组情况
未给予高糖高脂饲料6只小鼠为正常对照组。对造模成功的小鼠随机分成35组,分别为模型对照组,红霉素A-6,9-9,12-螺缩酮衍生物(RL-553系列)组,均为造模成功动物,每组6只。
5、给药
以上各组动物分别给药,正常对照组和模型对照组小鼠每天给予蒸馏水,红霉素A-6,9-9,12-螺缩酮衍生物(RL-553系列)组,按每天150mg·kg-1给予红霉素A-6,9-9,12-螺缩酮衍生物(RL-553系列)溶液,给药体积10ml·kg-1,每天上午9点30分给药一次,连续给药5天。
6、血糖测定
分别在给药3d、5d后,禁食16~18h,小鼠尾静脉取血测血糖。
7、实验结果与结论
结果显示,红霉素A-6,9-9,12-螺缩酮衍生物(RL-553系列)组小鼠灌胃5d后,小鼠状态较好,从动物体重观察,给药5d后,各给药组和模型对照组小鼠的体重均在20.0~21.0g范围内。
给药5d后,红霉素A-6,9-9,12-螺缩酮衍生物(RL-553系列)组小鼠血糖明显下降,与模型对照组比较有显著差异。给药后小鼠血糖含量见表2与图1。
表2 糖尿病模型小鼠血糖含量的影响(X±S,mmol/L)
结论:本试验结果表明,红霉素A-6,9-9,12-螺缩酮衍生物(RL-553系列衍生物)均具显著降血糖活性。
实施例43.红霉素A-6,9-9,12-螺缩酮衍生物(RL-553系列)对大鼠离体小肠蠕动功能实验
1、实验目的
本实验对自行设计合成的34个RL-553系列化合物进行筛选,以期发现较好促进胃肠动力的化合物。
2、受试药物与试剂与实验仪器
红霉素A-6,9-9,12-螺缩酮衍生物(RL-553系列)34个,无色粉末状固体,溶于乙醇。生理盐水:安徽丰原药业股份有限公司涂山药厂生产。乙醇购于国药集团化学试剂有限公司。K-H液(mmol/L):NaC1 137.0、KC1 5.4、CaC12 1.8、MgC12 0.5、NaHCO3 23.8、NaH2PO40.4、葡萄糖11.0,用95%O2和5%CO2混合气体饱和,pH 7.4。张力换能传感器(上海奥尔科特生物科技有限公司)、离体组织器官恒温灌流系统(内置浴槽)(上海奥尔科特生物科技有限公司)、ALC-M Tissue-Organ Bath System(上海奥尔科特生物科技有限公司)、MPA2000生物信号采集系统(上海奥尔科特生物科技有限公司)、95﹪O2+5﹪CO2混合气钢瓶、蜡盘、手术器械。
3、剂量设置及分组
所有化合物剂量均设定为1mg/mL。分为溶剂对照组和RL-553系列化合物组。
4、给药途径及给药容积
红霉素A-6,9-9,12-螺缩酮衍生物系列用乙醇溶解,在体外直接加入浴槽中,体积为1mL。
5、离体肠管
离体肠管取自体重200g的SD大鼠。实验前动物禁食12h,自由饮水。脱臼处死后,迅速剖开腹部,取小肠1.5~2cm。在盛有K-H液的培养皿中漂洗,去除肠内容物,制成离体标本。
6、实验方法
将离体肠段的一端固定在“L形”支架底部,完全浸没在离体组织器官恒温灌流系统的浴槽中。另一端连接张力换能器,换能器与MPA2000生物电放大器连接,并用电脑实时显示张力曲线。持续向浴槽中充入95%O2和5%CO2混合气体,浴槽温度控制在37℃。调节离体组织器官恒温灌流系统上的微调旋钮,调节小肠初始张力为1g。平衡1-2h,期间每隔20min换一次K-H液。观察张力曲线,当曲线张力波动平稳后即可视为达到平衡状态。平衡后记录五分钟实验曲线,然后加入受试溶液,观察曲线变化情况并记录。实验采用分别加入的方法,即加入一种化合物并观察其效果后,用37-38℃K-H液反复灌洗,待肠段的活动基本恢复并稳定后(一般5min以上),再加入另一种化合物进行实验,每个离体肠管使用三次后废弃。
记录给药前后小肠平滑肌收缩的最大值,最小值和平均值,给药前5min内的平均值作为对照值,给药后5min内的平均值作为效应值,并换算成变化百分率:(效应值一对照值)/对照值×100%。
7、观察指标
1min收缩率:(效应值一对照值)/对照值×100%;5min收缩率。
8、实验结果与结论
34种红霉素A-6,9-9,12-螺缩酮衍生物(RL-553系列衍生物)对大鼠离体小肠蠕动功能见表3与图2。
表3 RL-553系列化合物对离体小肠蠕动功能的影响
结论:离体肠管筛选发现,35种红霉素A-6,9-9,12-螺缩酮衍生物(RL-553系列衍生物)均有较好的促进离体肠管收缩作用,其中多个化合物活性较強。
实施例43.高活性RL-553对促进大鼠在体小肠蠕动功能实验
1、实验目的:
观察红霉素A-6,9-9,12-螺缩酮衍生物对大鼠在体小肠蠕动功能的影响。
2、受试药物、试剂与实验仪器
阿拉伯树胶粉:国药集团化学试剂有限公司;木炭粉:购自超市,使用前用研钵研成粉末;生理盐水:安徽丰原药业股份有限公司涂山药厂生产;乙醇购于国药集团化学试剂有限公司;显色染料:将筛选后的木炭粉与阿拉伯胶粉1:1混合,加纯水制成悬液状混合染料;阳性药吗丁啉,西安杨森制药有限公司生产,每片10mg,使用前研成粉末后用生理盐水稀释;阳性药红霉素,粉末,使用前配制;RL-55302,RL-55309,RL-55316,RL-55317,RL-55324五个高活性化合物,无色粉状固体,溶于乙醇,使用前以乙醇溶解,溶解后按照乙醇与生理盐水比例为1:2的比例进行稀释。实验仪器有直尺、灌胃针、手术器械。
3、实验动物
雄性SD大鼠,清洁级,体重:200-250g;数量:48只。购自上海西普尔实验动物有限公司,大鼠实验前于动物房分笼适应性饲养三天,普通饲料喂养,自由饮水,光线12小时明暗自动转换,室内温度20-22℃。
4、分组与剂量设置
实验分空白对照组(溶剂组5ml/kg);吗丁啉组(3mg/kg)、红霉素组(5mg/kg);RL-55302,RL-55309,RL-55316,RL-55317,RL-55324五个高活性化合物组(每组5mg/kg),每组6只大鼠
5、给药途径及给药容积
灌胃给药,给药容积为5ml/kg。单次给药。
6、实验方法
大鼠称量体重,并记录。根据大鼠体重,按5ml/kg吸取给溶剂组、吗丁啉组、红霉素组、RL-55302,RL-55309,RL-55316,RL-55317,RL-55324五个高活性红霉素A-6,9-9,12-螺缩酮衍生物溶液给大鼠灌胃。半小时后,再给每只大鼠灌阿拉伯胶与木炭制成的混合染料,每只给1mL。40min后,脱臼处死大鼠。沿腹中线剪开大鼠腹部,分离出大鼠的小肠。小肠上端在幽门与十二指肠交界处剪断,下端在与升结肠交界的回盲部剪断。将小肠完整的取出,平放在洒水的桌面上,使其自然拉伸,十分钟后校正小肠的拉伸状态。用直尺测量小肠近端到染料最前端的小肠长度以及小肠的总长度,计算显色剂前进距离占小肠总长度的百分比,以此作为判断小肠蠕动功能的标准。
7、观察指标
显色剂运动百分率=染料最前端至小肠上端的长度/小肠总长度×100%,
8、实验结果。
RL-55302组、RL-55309组、RL-55316组、RL-55317组、RL-55324组五个高活性红霉素A-6,9-9,12-螺缩酮衍生物有促进胃肠蠕动的作用,在此剂量条件下RL-55324效果高于红霉素与吗丁啉。结果见表4与图3。
表4 RL-553对大鼠在体小肠蠕动的影响
组別 | 动物数(只) | 运动百分率(%) |
溶剂对照组 | 6 | 41.3±4.08 |
吗丁啉组 | 6 | 72.6±2.91 |
红霉素组 | 6 | 63.27±2.79 |
RL-55302组 | 6 | 65.6±1.97 |
RL-55309组 | 6 | 67.1±2.46 |
RL-55316组 | 6 | 71.5±3.27 |
RL-55317组 | 6 | 69.3±4.08 |
RL-55324组 | 6 | 77.2±2.79 |
9、结论:RL-55302、RL-55309、RL-55316、RL-55317、RL-55324对在体大鼠的小肠蠕动有显著促进作用,RL-55324其效果高于红霉素与吗丁啉。
实施例45.红霉素A-6,9-9,12-螺缩酮衍生物(RL-553系列)对大肠杆菌和金黄色葡萄球菌的抑菌作用
1、实验材料
RL-55302,RL-55309,RL-55316,RL-55317,RL-55324五个化合物为自行合成,红霉素市售,均溶于乙醇等有机溶剂。
2、实验菌种
金黄色葡萄球菌(S.a)、大肠埃希菌(E.coli)均购买于上海川翔生物科技有限公司。
3、实验试剂
蛋白胨:购于BD公司;琼脂粉:购于国药集团化学试剂有限公司;牛肉浸膏粉:购于国药集团化学试剂有限公司;氯化钠购于国药集团化学试剂有限公司;DMSO购于国药集团化学试剂有限公司;1×PBS:购于上海博光生物科技有限公司。
4、实验分组
实验分为:溶剂对照组、阳性对照组、RL-55302,RL-55309,RL-55316,RL-55317,RL-55324组。
5、实验器材
培养皿:购于Corning公司;MCO-15AC CO2恒温培养箱:SANYO公司;生物洁净工作台:购于苏州安泰空气技术有限公司;HYG-全温摇瓶柜:购于太仓市实验设备厂;XDS-200C倒置显微镜:购于上海蔡康光学仪器有限公司。
6、配制培养基
配制Mueller-Hinton培养基:将3g牛肉浸膏粉,蛋白胨10g,氯化钠5g,加入蒸馏水1L中,如需配制固体培养基,再加入琼脂粉12g。121℃高压灭菌15分钟移至生物洁净台内冷却备用。吸取20ml热培养基倒于培养皿中,冷却后成为M-H固体培养基平板,备用。
7、药敏纸片
用7mm打孔器从无菌吸水纸上打下圆形纸片。
8、溶液配制
用DMSO溶解受试化合物RL-55302,RL-55309,RL-55316,RL-55317,RL-55324与红霉素,制作成10mg/ml溶液,用1×PBS倍比稀释,备用。
9、细菌复苏
将购买回的细菌菌株接种于MH固体培养基上,放在37℃CO2恒温培养箱中培养24小时。取出培养皿,分离培养皿上单个典型细菌菌落,转种于MH液体培养基中,放于温度为37℃的摇床中混匀,作为试验菌液备用。
10、细菌计数
吸取部分菌液用生理盐水进行10倍顺序稀释,在倒置显微镜下计数,选择细菌数在1×107个/ml的稀释倍数,将剩余菌液按此倍数稀释,备用。
11、实验过程
将浓度为1×107个/ml的菌液吸取100uL,接种于固体培养基上,用直角玻璃棒将菌液涂抹均匀。用移液器吸取20uL受试溶液,滴加在圆形纸片上,完全吸收后将纸片贴在含菌培养基上,标记。将培养基放在37℃CO2恒温培养箱中培养24h后,观察药敏纸片周围细菌生长情况。
12、结果判读
药敏纸片周围有细菌生长,说明细菌未被抑制,以“-”表示;含药敏纸片周围无细菌生长,出现无色透明抑菌圈,说明细菌被抑制以“+”表示。
13、实验结果与结论
阳性对照药红霉素的滤纸,在对大肠杆菌和金黄色葡萄球菌药物敏感性试验中发现有非常明显的抑制这两种细菌生长的作用,表现为滤纸周围没有细菌生长,有非常明显的抑菌圈。
所有化合物RL-55302,RL-55309,RL-55316,RL-55317,RL-55324的滤纸周围,大肠杆菌和金黄色葡萄球菌生长良好,没有抑菌作用。见表5。
表5 RL-553 10mg/L时对大肠杆菌和金黄色葡萄球菌抑制状况
组別 | 大肠杆菌 | 金黄色葡萄球菌 |
溶剂对照组 | - | - |
红霉素组 | + | + |
RL-55302组 | - | - |
RL-55309组 | - | - |
RL-55316组 | - | - |
RL-55317组 | - | - |
RL-55324组 | - | - |
结论:在10mg/ml浓度时,化合物RL-55302,RL-55309,RL-55316,RL-55317,RL-55324对大肠杆菌和金黄色葡萄球菌没有抑制作用。
以上述依据本发明的理想实施例为启示,通过上述的说明内容,相关工作人员完全可以在不偏离本项发明技术思想的范围内,进行多样的变更以及修改。本项发明的技术性范围并不局限于说明书上的内容,必须要根据权利要求范围来确定其技术性范围。
Claims (7)
3.一种药物组合物,其含有如权利要求1所述的化合物及药学上可接受的赋形剂或载体,以及上述的化合物或其药学上可接受的无机或有机盐。
4.一种如权利要求1所述的化合物或其药学上可接受的无机或有机盐在制备治疗糖尿病药物中的应用。
6.根据权利要求4或5中任一项所述的应用,其特征在于,所述应用为在制备降低人体血糖药物中的应用。
7.根据权利要求5所述的应用,其特征在于,所述应用为化合物RL-55302、RL-55304、RL-55305、RL-55306、RL-55307、RL-55308、RL-55309,RL-55311、RL-55315、RL-55316、RL-55317、RL-55318、RL-55319,RL-55321、RL-55322、RL-55323、RL-55324、RL-55325、RL-55326或RL-55327之一或其药学上可接受的无机或有机盐在制备治疗糖尿病药物中的应用。
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