CN108484424A - 侧链含有季铵盐基团的截短侧耳素类衍生物及其用途 - Google Patents

侧链含有季铵盐基团的截短侧耳素类衍生物及其用途 Download PDF

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CN108484424A
CN108484424A CN201810307924.4A CN201810307924A CN108484424A CN 108484424 A CN108484424 A CN 108484424A CN 201810307924 A CN201810307924 A CN 201810307924A CN 108484424 A CN108484424 A CN 108484424A
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analog derivative
pleuromutilin
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pleuromutilin analog
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尚若锋
刘宇
衣云鹏
杨珍
付运星
梁剑平
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Lanzhou Institute of Animal Husbandry and Veterinary Medicine CAAS
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Abstract

本发明公开了一种侧链含有季铵盐基团的截短侧耳素类衍生物，具体如下结构式： 其中，R、R1和R2各自独立的为C1‑C4的烷基；R3为H、C1‑C4的烷基、羟基、羟甲基、羟乙基、氨基、一烷基氨基、二烷基氨基、环烷基或环烯基；X为卤素；Y为C、N、O或S；n＝1～3，该截短侧耳素类衍生物具有较强的抑菌活性，部分达到或优于延胡索酸泰妙菌素。

Description

侧链含有季铵盐基团的截短侧耳素类衍生物及其用途
技术领域
本发明属于医药领域，具体涉及一种侧链含有季铵盐基团的截短侧耳素类衍生物及其在制备抗菌药物中的应用。
背景技术
截短侧耳素是上世纪50年代首次从高等真菌Pleurotus multilus(Fr.)Sacc.和Pleurotus Passecke-rianus Pilat中分离了一种具有抗菌活性的双萜类化合物。该化合物及其衍生物作用于细菌核糖体50S亚基的23SRNA上，结合位点在肽基转移酶(PTC)的V结构域，通过抑制细菌蛋白质的合成而达到抑菌目的。由于截短侧耳素及其衍生物的抑菌作用是通过抑制肽基转移酶的活性而使蛋白质合成受阻，从而在核糖体水平上抑制细菌生长，与目前市场上普遍使用的抗菌药物作用靶点不同，而与其他药物之间不会出现交叉耐药性，尤其对耐药的金黄色葡萄球菌、肺炎链球菌和结核分枝杆菌等有良好的抑制作用。
截短侧耳素：
截短侧耳素C14的酯基结构侧链是进行化学修饰的主要位点，国内外对截短侧耳素C14的侧链的结构修饰研究一般是在保留酯基结构的前提下，在C22位进行改造，这样能够显著提高其抑菌活性和生物利用度。
现有的化学修饰大多是通过在C22位引入巯基来保证较高的活性，如泰妙菌素、沃尼妙林、瑞他莫林、CN102924350A、CN104803926A、CN105622524A、CN102229580A。
Kinoshita研究组(Bioorganic&Medicinal Chemistry Letters，2009，19(1)，p175-179)公开了一种的化合物。
发明内容
本发明的目的在于提供了一种侧链含有季铵盐基团的截短侧耳素类衍生物。
侧链含有季铵盐基团的截短侧耳素类衍生物，具体如下结构式：
其中，R、R1和R2各自独立的为C1-C4的烷基，例如甲基、乙基、正丙基，异丙基、正丁基、异丁基、叔丁基；
R3为H、C1-C4的烷基、羟基、羟甲基、羟乙基、氨基、一烷基氨基、二烷基氨基、环烷基或环烯基；
X为卤素；
Y为C、N、O或S；
n＝1～3，如1、2、3。
上述截短侧耳素类衍生物可通过如下方法制备得到：
与反应得到中间物1所述中间物1再与R-X反应即得到
或者，与反应得到中间物2所述中间物2再与R-X反应即得到
或者，与反应得到
上述各反应可在甲醇、乙醇、丙醇、异丙醇、乙二醇、丙酮、乙酸乙酯、乙酸甲酯、乙腈、四氢呋喃、甲基叔丁基醚、甲基异丁基酮的一种或一种以上的溶剂中进行，反应温度为20～80℃。
具体实施方式
以下对本发明的优选实施例进行说明，应当理解，此处所描述的优选实施例仅用于说明和解释本发明，并不用于限定本发明。
实施例1:14-O-[(二甲氨基)-乙酰基]姆体林：
式(IV)为已知物质，按已报道的方法制备，大致过程为：由截短侧耳素先与对甲苯磺酰氯在碱性条件下反应制备出截短侧耳素对甲苯磺酸酯，该中间体再与NaI经亲核反应制获得。
14-O-[(二甲氨基)-乙酰基]姆体林的制备：在50mL的烧瓶中加入0.488g(1mmol)式(IV)所示化合物，0.338g含量为40％的二甲胺水溶液(3mmol)和10mL的甲醇，混合物在室温搅拌反应6h后，蒸干溶剂，获得的粗产品溶于30mL的乙酸乙酯中，用10ml的水萃取两次，有机相再加入10mL饱和的NaHCO3溶液洗涤一次，分离有机相，无水硫酸钠干燥过夜，蒸干溶剂后获得的粗产品用柱层析分离(石油醚：乙酸乙酯＝1:5)，获得0.315g的产品(收率78％)。IR(KBr):3254,2986,2928,2880,2859,2827,1736,1471,1448,1283,1205,1165,1151,1120,1062,1041cm-1.1H NMR(400MHz,DMSO)δ6.18(dd,J＝18.2,10.7Hz,1H),5.60(d,J＝8.1Hz,1H),5.07(d,J＝3.8Hz,1H),5.04(s,1H),4.51(d,J＝6.1Hz,1H),3.43(t,J＝6.0Hz,1H),3.04(d,J＝59.9Hz,2H),2.41(s,1H),2.21(s,6H),2.11(d,J＝7.6Hz,4H),1.77–1.57(m,2H),1.48(t,J＝9.4Hz,1H),1.44(d,J＝13.3Hz,1H),1.35(s,3H),1.30–1.21(m,3H),1.06(s,4H),0.83(d,J＝6.9Hz,3H),0.62(d,J＝6.5Hz,3H).13C NMR(101MHz,DMSO)δ217.71,169.36,141.48,115.54,73.11,68.59,60.68,57.80,45.46,45.02,44.60,44.52,41.89,36.92,36.82,34.47,30.63,28.99,27.04,24.99,16.38,15.08,12.03.HRMS(ESI)calcd[M+H]+for C24H39NO4 406.2951,found406.2959.
实施例2:14-O-[(二乙氨基)-乙酰基]姆体林：
以二乙胺替代实施例1的二甲胺，制备过程与实施例1相同，获得0.398g的产品(收率91％)。IR(KBr):3448,2980,2955,2881,2863,1734,1459,1215,1195,1121cm-1.1H NMR(400MHz,DMSO)δ6.18(dd,J＝17.4,11.5Hz,1H),5.59(d,J＝8.1Hz,1H),5.07(d,J＝6.3Hz,1H),5.03(s,1H),4.51(d,J＝5.7Hz,1H),3.43(t,J＝5.9Hz,1H),3.18(d,J＝28.3Hz,2H),2.56(dd,J＝7.1,4.0Hz,4H),2.40(s,1H),2.11(d,J＝8.8Hz,4H),1.65(dd,J＝20.7,11.8Hz,2H),1.55–1.44(m,2H),1.44–1.38(m,1H),1.36(s,3H),1.27(d,J＝15.4Hz,3H),1.06(s,3H),0.99(s,1H),0.93(t,J＝7.1Hz,5H),0.83(d,J＝6.9Hz,3H),0.63(d,J＝6.4Hz,3H).13C NMR(101MHz,DMSO)δ217.67,170.14,141.52,115.47,73.13,68.57,57.84,54.49,47.31,45.46,44.65,44.50,41.90,36.94,36.85,34.47,30.64,29.04,27.02,25.00,16.37,15.09,12.88,12.03.HRMS(ESI)calcd[M+H]+for C26H43NO4 434.3264,found 434.3268.
实施例3:14-O-[(吡咯烷-1-基)-乙酰基]姆体林：
以吡咯烷替代实施例1的二甲胺，制备过程与实施例1相同，获得0.354g的产品(收率82％)。IR(KBr):3240,2982,2954,2927,2881,2859,1737,1466,1452,1427,1237,1211,1188,1152,1117,1040,977,951,939,925,913,880,867cm-1.1H NMR(400MHz,DMSO)δ6.26–6.09(m,1H),5.60(d,J＝8.1Hz,1H),5.11–5.06(m,1H),5.03(s,1H),4.51(d,J＝6.1Hz,1H),3.43(s,1H),3.18(dd,J＝93.4,16.9Hz,2H),2.49(dd,J＝7.1,5.0Hz,3H),2.40(s,1H),2.11(d,J＝8.2Hz,4H),1.67(s,6H),1.49(d,J＝4.2Hz,3H),1.35(s,3H),1.30–1.20(m,3H),1.06(s,4H),0.83(d,J＝6.9Hz,3H),0.62(d,J＝6.5Hz,3H).13C NMR(101MHz,DMSO)δ217.64,169.36,141.43,115.53,73.12,68.62,57.81,57.23,53.48,45.46,44.51,41.89,40.63,36.93,36.82,34.47,30.64,28.99,27.03,24.99,23.91,16.37,15.05,12.02.HRMS(ESI)calcd[M+H]+for C26H41NO4 432.3108,found432.3115.
实施例4:14-O-[(3-羟基吡咯-1-基)-乙酰基]姆体林：
以3-羟基吡咯替代实施例1的二甲胺，制备过程与实施例1相同，获得0.356g的产品(收率80％)。IR(KBr):3483,2987,2935,2860,1735,1458,1203,1156,1117cm-1.1H NMR(400MHz,DMSO)δ6.18(dd,J＝17.5,11.4Hz,1H),5.58(d,J＝8.0Hz,1H),5.08(d,J＝7.6Hz,1H),5.05(s,1H),4.59(d,J＝4.9Hz,1H),4.51(d,J＝6.0Hz,1H),3.42(d,J＝5.0Hz,2H),3.19(dd,J＝17.0,7.2Hz,1H),3.00(dd,J＝17.0,7.6Hz,1H),2.89–2.73(m,1H),2.61(dd,J＝19.2,10.9Hz,1H),2.40(s,1H),2.09(d,J＝8.7Hz,5H),1.93(d,J＝14.6Hz,1H),1.77(d,J＝9.1Hz,1H),1.66(s,1H),1.59(s,2H),1.48(s,2H),1.35(s,3H),1.28(s,3H),1.06(s,4H),0.83(d,J＝6.8Hz,3H),0.63(d,J＝5.9Hz,3H).13C NMR(101MHz,DMSO)δ217.67,169.29,141.46,115.63,73.12,68.62,66.43,60.97,59.77,57.79,52.56,45.46,44.50,41.89,36.90,36.83,34.48,33.50,30.63,28.98,27.04,24.98,23.71,16.46,15.08,12.02.HRMS(ESI)calcd[M+H]+for C26H41NO5448.3057,found 448.3063.
实施例5:14-O-[(哌啶-1-基)-乙酰基]姆体林：
以哌啶替代实施例1的二甲胺，制备过程与实施例1相同，获得0.369g的产品(收率83％)。IR(KBr):3448,2988,2955,2936,2860,1736,1205cm-1.1H NMR(400MHz,DMSO)δ6.18(dd,J＝17.4,11.4Hz,1H),5.58(d,J＝8.1Hz,1H),5.08(d,J＝6.3Hz,1H),5.04(s,1H),4.51(d,J＝6.1Hz,1H),3.43(t,J＝5.9Hz,1H),3.04(dd,J＝75.4,16.8Hz,2H),2.48–2.33(m,5H),2.11(d,J＝7.8Hz,4H),1.65(d,J＝6.7Hz,2H),1.46(d,J＝5.7Hz,5H),1.39(d,J＝21.1Hz,2H),1.35(s,3H),1.31(d,J＝7.2Hz,1H),1.25(d,J＝15.6Hz,3H),1.06(s,4H),0.83(d,J＝6.9Hz,3H),0.62(d,J＝6.5Hz,3H).13C NMR(101MHz,DMSO)δ217.69,169.29,141.49,115.58,73.12,68.58,60.53,57.79,53.74,45.46,44.61,44.48,41.89,36.89,36.83,34.48,30.63,28.96,27.03,25.95,24.97,24.09,16.44,15.06,12.02.HRMS(ESI)calcd[M+H]+for C27H43NO4 446.3264,found 446.3268.
实施例6:14-O-[(3-羟乙基哌啶-1-基)-乙酰基]姆体林：
以3-羟基乙基哌啶替代实施例1的二甲胺，制备过程与实施例1相同，获得0.323g的产品(收率68％)。IR(KBr):3414,2951,1731,1655,1637,1459,1420,1370,1239,1181,1155,1119,1021,941,911cm-1.1H NMR(400MHz,DMSO)δ6.12(dd,J＝17.7,11.3Hz,1H),5.56(dd,J＝55.0,5.3Hz,2H),5.10(d,J＝4.6Hz,2H),4.57(dd,J＝58.5,16.9Hz,3H),4.01(s,1H),3.69–3.48(m,2H),3.31(s,5H),3.17(s,1H),2.47(s,1H),2.16(dd,J＝24.5,9.2Hz,2H),2.05(d,J＝7.6Hz,2H),1.83(d,J＝42.3Hz,2H),1.66(s,2H),1.56(d,J＝29.9Hz,1H),1.49(d,J＝15.8Hz,3H),1.38(s,3H),1.29(d,J＝11.4Hz,2H),1.09(s,4H),0.86(d,J＝6.6Hz,3H),0.66(d,J＝6.3Hz,3H).13C NMR(101MHz,DMSO)δ217.44,164.14,141.51,115.78,72.87,71.79,64.62,61.60,61.29,57.58,51.09,49.07,45.39,44.93,43.56,42.02,37.24,36.65,34.44,30.57,29.84,29.55,26.99,24.96,16.92,16.48,14.94,12.13.HRMS(ESI)calcd[M+H]+for C28H45NO5 476.3770,found476.3765.
实施例7:14-O-[(吗啉-1-基)-乙酰基]姆体林：
以吗啉替代实施例1的二甲胺，制备过程与实施例1相同，获得0.379g的产品(收率85％)。IR(KBr):3449,2957,2931,2869,1735,1452,1298,1285,1215,1163,1117,1034,1018,915,871cm-1.1H NMR(400MHz,DMSO)δ5.93(dd,J＝17.1,11.7Hz,1H),5.35(d,J＝8.1Hz,1H),4.89–4.82(m,1H),4.80(s,1H),4.26(d,J＝6.0Hz,1H),3.31(t,J＝4.5Hz,4H),3.18(s,1H),2.96(d,J＝17.0Hz,1H),2.76(d,J＝17.0Hz,1H),2.27–2.15(m,5H),1.96–1.71(m,4H),1.51–1.32(m,2H),1.24(dd,J＝12.6,7.5Hz,2H),1.11(s,3H),1.02(d,J＝15.9Hz,3H),0.82(s,4H),0.59(d,J＝6.9Hz,3H),0.38(d,J＝6.6Hz,3H).13C NMR(101MHz,DMSO)δ217.62,168.92,141.44,115.60,73.11,68.76,66.58,59.81,57.77,52.93,45.45,44.55,44.51,41.89,36.90,36.81,34.47,30.62,28.96,27.04,24.97,16.46,15.04,12.02.HRMS(ESI)calcd[M+H]+for C26H41NO5 448.3057,found448.3051.
实施例8:N,N,N,N-三甲基[乙酰基姆体林基]碘盐：
在50mL的烧瓶中加入0.406g(1mmol)由实施例1制备的化合物0.170g碘代甲烷(1.2mmol，CH3I)和10mL的甲醇，混合物在50℃搅拌反应4h后，反应体系冷至0至-20℃，过滤，获得的粗产品丙酮重结晶，获得0.256g的产品(收率47％)。IR(KBr):3448,2991,2948,1733,1460,1446,1407,1387,1369,1259,1224,1212,1157,1140,1123,1063,1002,973cm- 1.1H NMR(400MHz,DMSO)δ6.13(dd,J＝17.4,11.6Hz,1H),5.64(d,J＝8.0Hz,1H),5.11(s,1H),5.07(d,J＝6.8Hz,1H),4.65–4.43(m,3H),3.45(t,J＝5.8Hz,1H),3.24(s,9H),2.48(s,1H),2.24–1.99(m,4H),1.73–1.59(m,2H),1.52(dd,J＝7.1,3.2Hz,1H),1.49–1.39(m,2H),1.35(d,J＝14.0Hz,3H),1.29(d,J＝11.4Hz,2H),1.13–0.96(m,4H),0.85(d,J＝6.8Hz,3H),0.65(d,J＝6.9Hz,3H).13C NMR(101MHz,DMSO)δ217.40,164.26,141.44,115.84,72.86,71.67,63.17,57.55,53.46,45.39,44.90,43.64,41.99,37.20,36.61,34.44,30.57,29.48,27.00,24.94,16.55,14.86,12.11.HRMS(ESI)calcd[M]+for C25H42NO4420.3108,found 420.3101.
实施例9:N,N,N,N-甲基二乙基[乙酰基姆体林基]碘盐:
用实施例8的方法，以实施例2制备的化合物为原料制备得到，获得0.472g的产品(收率82％)。IR(KBr):3447,2984,2945,1731,1458,1409,1238,1121,1023cm-1.1H NMR(400MHz,DMSO)δ6.20–6.06(m,1H),5.63(d,J＝8.0Hz,1H),5.11(s,1H),5.08(d,J＝2.8Hz,1H),4.63(d,J＝5.8Hz,1H),4.44(dd,J＝48.3,17.6Hz,2H),3.51(dd,J＝23.9,14.3Hz,5H),3.10(s,3H),2.48(s,1H),2.20(d,J＝9.3Hz,2H),2.14–1.99(m,2H),1.67(s,2H),1.48(d,J＝16.0Hz,2H),1.39(s,4H),1.29(d,J＝13.0Hz,2H),1.23(dd,J＝11.7,7.0Hz,6H),1.10(s,4H),0.86(d,J＝6.8Hz,3H),0.66(d,J＝6.9Hz,3H).13C NMR(101MHz,DMSO)δ217.40,164.25,141.55,115.78,72.89,71.76,58.20,57.54,57.39,47.97,45.38,44.85,43.81,41.99,37.13,36.62,34.44,30.57,29.40,27.02,24.92,16.54,14.92,12.10,8.15.HRMS(ESI)calcd[M]+for C27H46NO4448.3421,found 448.3426.
实施例10:N,N,N,N-甲基吡咯烷基[乙酰基姆体林基]碘盐：
用实施例8的方法，以实施例3制备的化合物为原料制备得到，获得0.368g的产品(收率64％)。IR(KBr)3530,2949,1742,1717,1458,1231,1209,1126,1013cm-1.1H NMR(400MHz,DMSO)δ6.12(dd,J＝18.1,10.9Hz,1H),5.63(d,J＝8.0Hz,1H),5.20–4.96(m,2H),4.74(dt,J＝21.6,10.9Hz,1H),4.59(d,J＝17.0Hz,2H),4.08–3.82(m,4H),3.68(dd,J＝18.8,13.4Hz,1H),3.56(dd,J＝29.4,15.8Hz,3H),3.45(d,J＝5.3Hz,1H),3.33(s,3H),2.48(s,1H),2.27–2.12(m,2H),2.12–2.06(m,1H),2.06–2.00(m,1H),1.73–1.59(m,2H),1.50(d,J＝15.9Hz,2H),1.48–1.40(m,1H),1.36(d,J＝21.5Hz,3H),1.33–1.26(m,2H),1.12–0.98(m,4H),0.85(d,J＝6.8Hz,3H),0.67(d,J＝6.9Hz,3H).13C NMR(101MHz,DMSO)δ217.41,163.97,141.48,115.86,72.87,71.93,61.78,60.51,60.10,57.53,47.53,45.39,44.93,43.55,42.02,37.21,36.63,34.44,30.55,29.52,27.01,24.94,16.56,14.91,12.12.HRMS(ESI)calcd[M]+for C27H44NO4 446.3215,found446.3221.
实施例11:N,N,N,N-甲基-3-羟基吡咯基[乙酰基姆体林基]碘盐：
用实施例8的方法，以实施例4制备的化合物为原料制备得到，获得0.326g的产品(收率55％)。IR(KBr):3630,3316,2985,2960,2920,2862,1732,1458,1422,1407,1259,1226,1171,1155,1124,1091,1053,1016,941,913cm-1.1H NMR(400MHz,DMSO)δ6.13(dd,J＝17.7,11.3Hz,1H),5.64(dd,J＝10.3,5.8Hz,2H),5.16–5.03(m,2H),4.66–4.61(m,1H),4.60–4.46(m,3H),3.90–3.80(m,1H),3.72(dd,J＝12.4,5.1Hz,1H),3.60(d,J＝12.1Hz,2H),3.49–3.37(m,2H),3.32(s,1H),2.47(s,2H),2.24–2.01(m,5H),1.64(d,J＝13.3Hz,2H),1.49(s,2H),1.45(s,1H),1.37(s,3H),1.30(t,J＝8.9Hz,2H),1.28(s,1H),1.09(s,4H),0.85(d,J＝6.8Hz,3H),0.65(d,J＝6.9Hz,3H).13CNMR(101MHz,DMSO)δ217.44,164.66,141.43,115.87,72.88,72.58,71.77,68.74,65.65,63.78,57.51,52.36,45.39,44.91,43.53,42.00,37.15,36.61,34.44,32.83,30.53,29.45,27.02,24.93,16.58,14.85,12.08.HRMS(ESI)calcd[M]+for C27H44NO5462.3214,found 462.3217.
实施例12:N,N,N,N-甲基哌啶基[乙酰基姆体林基]碘盐：
用实施例8的方法，以实施例5制备的化合物为原料制备得到，获得0.423g的产品(收率72％)。IR(KBr):3462,3393,3023,3001,2985,2974,2943,2874,1734,1474,1458,1227,1197,1121,1021,986,938,911cm-1.1H NMR(400MHz,DMSO)δ6.22–6.01(m,1H),5.63(d,J＝8.0Hz,1H),5.09(dd,J＝14.5,1.9Hz,2H),4.64(d,J＝17.1Hz,2H),4.45(d,J＝17.3Hz,1H),3.70–3.61(m,1H),3.54(d,J＝4.1Hz,2H),3.45(s,2H),3.21(s,3H),2.47(s,1H),2.26–2.01(m,4H),1.91–1.76(m,4H),1.66(s,2H),1.53(s,3H),1.48(d,J＝11.6Hz,1H),1.41(d,J＝9.7Hz,1H),1.39(s,3H),1.30(t,J＝10.4Hz,2H),1.09(s,4H),0.86(d,J＝6.8Hz,3H),0.66(d,J＝6.9Hz,3H).13C NMR(101MHz,DMSO)δ217.42,164.19,141.49,115.81,72.88,71.71,61.60,60.28,57.59,48.59,45.39,44.93,43.58,42.02,37.23,36.65,34.45,30.59,29.54,27.00,24.95,21.04,19.58,16.50,14.95,12.13.HRMS(ESI)calcd[M]+for C28H46NO4 460.3421,found 460.3428.
实施例13:N,N,N,N-甲基-3-羟乙基哌啶基[乙酰基姆体林基]碘盐：
用实施例8的方法，以实施例6制备的化合物为原料制备得到，获得0.361g的产品(收率59％)。IR(KBr):3422,2926,1730,1458,1240,1222,1022,912cm-1.1H NMR(400MHz,DMSO)δ6.11(dd,J＝17.3,11.2Hz,1H),5.62(d,J＝6.3Hz,1H),5.47(s,1H),5.09(d,J＝12.7Hz,2H),4.62(s,2H),4.47(d,J＝17.6Hz,1H),4.10–3.97(m,1H),3.53(s,3H),3.45(s,2H),3.35(s,2H),3.24(d,J＝7.4Hz,2H),3.16(d,J＝4.1Hz,1H),2.47(s,1H),2.28–1.94(m,5H),1.80(s,2H),1.66(s,2H),1.49(s,3H),1.37(s,3H),1.29(s,3H),1.08(s,4H),0.85(d,J＝5.4Hz,3H),0.65(s,3H).13C NMR(101MHz,DMSO)δ217.41,164.11,141.48,115.83,72.87,71.77,64.58,63.86,61.59,60.98,57.59,51.04,49.72,49.07,45.38,44.94,43.58,41.98,37.24,36.65,34.45,30.60,29.56,27.00,24.95,17.00,16.52,14.95,12.14.HRMS(ESI)calcd[M]+for C29H48NO5 490.3527,found 490.3529.
实施例14:N,N,N,N-甲基吗啉基[乙酰基姆体林基]碘盐：
用实施例8的方法，以实施例7制备的化合物为原料制备得到，获得0.412g的产品(收率70％)。IR(KBr):3537,2983,2960,2949,2876,1742,1717,1458,1406,1231,1209,1153,1126,1012,998cm-1.1H NMR(400MHz,DMSO)δ6.13(dd,J＝17.8,11.2Hz,1H),5.63(d,J＝8.1Hz,1H),5.22–4.98(m,2H),4.59(dd,J＝46.0,17.2Hz,3H),3.82–3.61(m,3H),3.48(dd,J＝19.8,8.2Hz,3H),3.17(d,J＝1.4Hz,3H),2.48(s,1H),2.31–2.05(m,7H),2.04(s,1H),1.66(s,2H),1.50(d,J＝15.9Hz,2H),1.37(s,3H),1.30(s,2H),1.09(s,4H),0.85(d,J＝6.8Hz,3H),0.66(d,J＝6.9Hz,3H).13C NMR(101MHz,DMSO)δ217.41,164.68,141.45,115.87,72.89,71.74,65.62,65.12,62.40,57.55,49.43,45.39,44.92,42.00,37.18,36.62,34.45,30.57,29.48,27.02,24.93,21.70,16.58,14.89,12.10.HRMS(ESI)calcd[M]+for C27H44NO5 434.3265,found 434.3274.
实施例15:N-吡啶基-N-(乙酰基姆体林基)碘盐：
在50mL的烧瓶中加入0.488g(1mmol)式(IV)所示化合物，0.095g吡啶(1.2mmol)和10mL的甲醇，混合物在50℃搅拌反应4h后，反应体系冷至0至-20℃，过滤，获得的粗产品丙酮重结晶，获得0.502g的产品(收率89％)。IR(KBr):3505,3012,2935,2858,1747,1721,1637,1485,1466,1371,1237,1211,1158,1123,1018,934,914,677cm-1.1H NMR(400MHz,DMSO)δ9.09(d,J＝5.7Hz,2H),8.77(t,J＝7.7Hz,1H),8.31(t,J＝7.0Hz,2H),6.11(dd,J＝17.7,11.3Hz,1H),5.86–5.67(m,2H),5.57(d,J＝8.0Hz,1H),5.12(dd,J＝59.5,14.5Hz,2H),4.55(s,1H),3.45(s,1H),2.46(s,1H),2.21(dd,J＝18.7,11.0Hz,1H),2.07(dt,J＝16.8,8.6Hz,2H),2.00(dd,J＝12.5,6.2Hz,1H),1.62(t,J＝10.6Hz,2H),1.56(d,J＝15.9Hz,1H),1.48(s,1H),1.38–1.23(m,3H),1.15(d,J＝15.9Hz,3H),1.08(d,J＝25.9Hz,3H),0.99(t,J＝11.1Hz,1H),0.81(d,J＝6.6Hz,3H),0.61(d,J＝6.8Hz,3H).13C NMR(101MHz,DMSO)δ217.34,164.81,147.40,146.55,141.25,128.62,116.10,72.91,72.71,61.30,57.41,45.36,44.81,43.30,41.96,36.90,36.61,34.46,30.50,29.15,27.01,24.83,17.03,14.52,12.03.HRMS(ESI)calcd[M]+forC27H38NO4,440.2795,found 440.2804.
实施例16:N-[(4-二甲氨基)吡啶基]-N-(乙酰基姆体林基)碘盐：
以4-二甲氨基吡啶替代实施例15的吡啶，制备过程与实施例15相同，获得0.439g的产品(收率72％)。IR(KBr):3387,2923,2860,1730,1655,1575,1457,1403,1369,1248,1211,1181,1153,1120,1032,903cm-1.1H NMR(400MHz,DMSO)δ8.20(d,J＝7.6Hz,2H),7.12(d,J＝7.6Hz,2H),6.11(dd,J＝17.8,11.2Hz,1H),5.56(d,J＝8.2Hz,1H),5.16(dd,J＝23.5,5.3Hz,3H),5.04(dd,J＝11.2,1.2Hz,1H),4.55(d,J＝5.9Hz,1H),3.50–3.37(m,1H),3.28(d,J＝44.5Hz,6H),3.16(d,J＝4.8Hz,1H),2.44(s,1H),2.26–1.92(m,4H),1.62(dd,J＝18.6,12.7Hz,2H),1.48(d,J＝15.6Hz,2H),1.27(s,2H),1.24(s,3H),1.09(s,4H),0.81(d,J＝6.8Hz,3H),0.61(d,J＝7.0Hz,3H).13CNMR(101MHz,DMSO)δ217.44,166.28,156.48,143.36,141.25,115.98,108.01,72.93,71.80,57.59,57.52,49.08,45.38,44.77,43.50,41.95,36.93,36.68,34.47,30.53,29.17,27.01,24.87,16.93,14.73,12.05.HRMS(ESI)calcd[M]+for C29H43N2O4 483.3217,found 483.3224.
实施例17:N-[(N-甲基)咪唑基]-N-(乙酰基姆体林基)碘盐：
以N-甲基咪唑替代实施例15的吡啶，制备过程与实施例15相同，获得0.461g的产品(收率81％)。IR(KBr):3512,3094,3041,1751,1723,1562,1459,1374,1271,1229,1202,1170,1123,1093,1035,1019,997,983,935,915,864,739,620cm-1.1H NMR(400MHz,DMSO)δ9.18(s,1H),7.99–7.46(m,2H),6.12(dd,J＝17.5,11.3Hz,1H),5.57(d,J＝7.0Hz,1H),5.38–4.93(m,4H),4.54(s,1H),4.02(d,J＝56.1Hz,3H),3.46(s,1H),3.17(s,1H),2.47(s,1H),2.26–1.96(m,4H),1.73–1.57(m,2H),1.48(d,J＝15.6Hz,2H),1.33(d,J＝27.7Hz,4H),1.13(s,1H),1.12–0.93(m,4H),0.82(d,J＝5.8Hz,3H),0.63(d,J＝6.2Hz,3H).13C NMR(101MHz,DMSO)δ217.42,165.63,141.23,138.07,124.11,124.02,116.01,72.92,71.89,57.51,50.56,49.07,45.38,44.74,43.52,41.98,36.92,36.65,34.47,30.55,29.13,27.02,24.88,16.87,14.68,12.05.HRMS(ESI)calcd[M]+for C26H39N2O4 443.2904,found 443.2912.
实施例18:N-2,3-环戊烯并吡啶基-N-(乙酰基姆体林基)碘盐：
以2,3-环戊烯并吡啶替代实施例15的吡啶，制备过程与实施例15相同，获得0.403g的产品(收率66％)。IR(KBr):3424,2986,2921,1724,1617,1457,1431,1363,1338,1280,1235,1150,1119,1016,978,911cm-1.1H NMR(400MHz,DMSO)δ8.86(d,J＝6.1Hz,1H),8.58(d,J＝7.7Hz,1H),8.05(t,J＝6.9Hz,1H),6.10(dd,J＝17.8,11.2Hz,1H),5.77(q,J＝17.5Hz,2H),5.60(d,J＝8.0Hz,1H),5.11(dd,J＝50.0,14.5Hz,2H),4.54(d,J＝5.9Hz,1H),3.49(t,J＝5.3Hz,1H),3.21(d,J＝6.9Hz,5H),2.33–2.14(m,4H),2.01(d,J＝6.6Hz,2H),1.73–1.61(m,2H),1.60–1.46(m,2H),1.32(s,4H),1.27(d,J＝11.0Hz,2H),1.13(s,4H),0.82(d,J＝6.7Hz,3H),0.65(d,J＝6.9Hz,3H).13C NMR(101MHz,DMSO)δ217.27,164.79,162.52,145.56,143.33,142.67,141.39,126.24,115.93,72.89,59.31,57.47,49.09,45.34,44.80,43.74,42.00,36.89,36.58,34.47,32.25,31.21,30.57,29.15,27.02,24.83,22.65,16.80,14.71,12.04.HRMS(ESI)calcd[M]+for C30H42NO4 480.3108,found 480.3116.
实施例19：体外抑菌试验
为研究本发明侧链含有季铵盐基团的截短侧耳素类衍生物体外对耐甲氧西林的金黄色葡萄球菌(methicillin-resistant Staphylococcus aureus，MRSA，ATCC 43300)、金黄色葡萄球菌(Staphylococcus aureus，S.aureus，ATCC 25923)、多杀性巴氏杆菌(Pasteurell amultocida，P.amultocida，CVCC 408)和鼠伤寒沙门氏杆菌(Salmonellatyphimurium，S.typhimurium，ATCC 14028)的抑菌活性，进行了MIC(琼脂稀释法)测定，结果见表1。从实验数据结果可看出这类衍生物均有不同程度的抗菌活性。
表1：受试衍生物的体外最小抑菌浓度
由实施例1-7与实施例8-14的比较可以看出，侧链的叔胺基团转化成季胺盐基团后，能明显提高相应衍生物的抑菌活性，而且以盐的形式存在还能提高化合物的水溶性。其中，实施例8的化合物的抑菌活性达到并部分优于对照药物延胡索酸泰妙菌素，且溶解性有明显的提高。
延胡索酸泰妙菌素：
最后应说明的是：以上所述仅为本发明的优选实施例而已，并不用于限制本发明，尽管参照前述实施例对本发明进行了详细的说明，对于本领域的技术人员来说，其依然可以对前述各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。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (6)

1.侧链含有季铵盐基团的截短侧耳素类衍生物，具体如下结构式：
其中，R、R1和R2各自独立的为C1-C4的烷基；
R3为H、C1-C4的烷基、羟基、羟甲基、羟乙基、氨基、一烷基氨基、二烷基氨基、环烷基或环烯基；
X为卤素；
Y为C、N、O或S；
n＝1～3。
2.根据权利要求1所述的截短侧耳素类衍生物，其特征在于：所述卤素为碘。
3.根据权利要求1所述的截短侧耳素类衍生物，其特征在于：所述截短侧耳素类衍生物为以下化合物之一：
4.权利要求1所述截短侧耳素类衍生物的制备方法，包括：
与反应得到中间物1所述中间物1再与R-X反应即得到
或者，与反应得到中间物2所述中间物2再与R-X反应即得到
或者，与反应得到
5.权利要求1所述截短侧耳素类衍生物的用途，其特征在于：所述截短侧耳素类衍生物在制备抗菌药物中的应用。
6.根据权利要求5所述的用途，其特征在于：所述抗菌药物为抗耐甲氧西林的金黄色葡萄球菌、非耐药的金黄色葡萄球菌、多杀性巴氏杆菌和/或鼠伤寒沙门氏杆菌的药物。
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