CN114716384A - 一种含有3,4-二氢嘧啶或嘧啶侧链的截短侧耳素类衍生物及其制备与应用 - Google Patents

一种含有3,4-二氢嘧啶或嘧啶侧链的截短侧耳素类衍生物及其制备与应用 Download PDF

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CN114716384A
CN114716384A CN202210234067.6A CN202210234067A CN114716384A CN 114716384 A CN114716384 A CN 114716384A CN 202210234067 A CN202210234067 A CN 202210234067A CN 114716384 A CN114716384 A CN 114716384A
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pleuromutilin derivative
pleuromutilin
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尚若锋
周宇航
刘宇
刘勤勤
王学红
郝宝成
蒲万霞
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Lanzhou Institute of Animal Husbandry and Veterinary Medicine CAAS
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Abstract

本发明属于抗菌活性化合物技术领域，尤其涉及一种含有3,4‑二氢嘧啶和嘧啶侧链的截短侧耳素类衍生物及其应用。本发明公开了一种含有3,4‑二氢嘧啶侧链或嘧啶侧链的截短侧耳素类衍生物，所述含有3,4‑二氢嘧啶或嘧啶侧链的截短侧耳素类衍生物对多种阳性菌，如金黄色葡萄球菌、耐甲氧西林的表皮球菌、耐甲氧西林的金黄色葡萄球菌、化脓链球菌等具有非常显著的抑制作用，可应用于制备耐药菌药物。

Description

一种含有3,4-二氢嘧啶或嘧啶侧链的截短侧耳素类衍生物及 其制备与应用
技术领域
本发明属于抗菌活性化合物技术领域，尤其涉及一种含有3,4-二氢嘧啶或嘧啶侧链的截短侧耳素类衍生物及其应用。
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中分离出的一种具有抗菌活性的双萜类化合物。尽管截短侧耳素抑菌活性较低，但通过对该化合物经过结构改造，尤其在C-14位酯基上连接一个硫醚基的侧链，可显著提高该类化合物的抑菌活性。截短侧耳素及其衍生物是在核糖体水平上抑制细菌蛋白质的合成，该类化合物结合在核糖体肽基转移酶(PTC)的V结构域，其中，三元母核结合于A位点的活性口袋中，而侧链部分覆盖了tRNA与核糖体结合的P位点，通过抑制细菌蛋白质的合成而达到抑菌目的。正是由于这种特殊的作用机制，截短侧耳素及其衍生物在体内和体外均有着良好的抗阳性耐药菌的活性，以及较好的药代动力学性质和较低的耐药性。
通过对截短侧耳素结构改造，已研发出泰妙菌素、沃尼妙林、瑞他莫林和Lefamulin四种药物。其中，前两种作为兽用药物用于治疗或预防由Brachyspirahyodysenteriae和Mycoplasma spp.引起的疾病。后两种作为人用药物，分别治疗由葡萄球菌和链状球菌引起的伤口感染皮肤感染和社区获得性细菌性肺炎。而开发抑菌活性更好的截短侧耳素衍生物，对于抗菌药物的研发及其重要。
发明内容
本发明的目的在于提供一种含有3,4-二氢嘧啶或嘧啶侧链的截短侧耳素类衍生物及其应用，所提供的截短侧耳素类衍生物具有显著的抑菌活性。
为实现上述目的，本发明采用的技术方案是：
第一方面，本发明提供了一种截短侧耳素类衍生物或其药学上可接受的盐，所述截短侧耳素类衍生物为式(I)所示的含有取代3,4-二氢嘧啶侧链的截短侧耳素类衍生物，或式(II)所示的含有取代嘧啶侧链的截短侧耳素类衍生物：
Figure BDA0003541110690000021
其中，R1选自烷基或烷氧基；R2选自直链或支链烷基。
优选地，所述R1选自-CH3、-OCH3、-OCH2CH3、-OCH2CH2CH3、-OCH2CH＝CH2；R2选自-CH3、-CH2CH3、-CH2CH2CH3、-CH2CH2CH2CH3、-CHCH(CH3)2、或-CH(CH2CH3)2。
优选地，所述截短侧耳素类衍生物为式(II)所示的含有取代嘧啶侧链的截短侧耳素类衍生物。
优选地，所述R1为-OCH3，R2为-CH3。
优选地，所述R1为-CH3，R2为-CH3。
优选地，所述R1为-OCH2CH3，R2为-CH3。
第二方面，本发明提供了上述第一方面所述的截短侧耳素类衍生物或其药学上可接受的盐在制备抗菌药物中的应用。
优选地，所述抗菌药物为抗耐药菌的药物。
优选地，所述耐药菌包括金黄色葡萄球菌、耐甲氧西林的表皮球菌、耐甲氧西林的金黄色葡萄球菌、化脓链球菌。
第三方面，本发明提供了上述第一方面所述的截短侧耳素类衍生物或其药学上可接受的盐加入药学上可接受的载体或辅料制成药学上可接受的任一剂型。
相比于现有技术的缺点和不足，本发明具有以下有益效果：
相较于已有的截短侧耳素类衍生物，本发明提供的含有3,4-二氢嘧啶或嘧啶侧链的截短侧耳素类衍生物，对多种阳性菌，如金黄色葡萄球菌、耐甲氧西林的表皮球菌、耐甲氧西林的金黄色葡萄球菌、化脓链球菌等，具有显著的抑制作用，因此，本发明的截短侧耳素衍生物可以进一步研发为抗菌药物，尤其是抗耐药菌药物；本发明涉及到的截短侧耳素类衍生物的制备原料主要是乙酰乙酸乙酯、醛和硫脲，与泰妙菌素、沃尼妙林、瑞他莫林和利发姆林等截短侧耳素类药物相比，具有原料易得、成本低廉，工艺简单，绿色环保等优点；而且相较于现有已知的泰妙菌素、沃尼妙林、瑞他莫林和利发姆林等截短侧耳素类衍生物，本发明所述的截短侧耳素类衍生物5a、5g和5h对MRSA、MRSE和S.aureus的MIC均小于或等于0.0313μg/mL，对化脓链球菌也有中等的抑菌活性，抑菌效果更显著。
附图说明
图1化合物5a、5g和5h的1×和6×MIC浓度进行了杀菌动力学结果；
图2化合物5h治疗感染MRSA小鼠的死亡率及ED50，其中A为死亡率；B为ED50。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合具体实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
本发明所述的含有3,4-二氢嘧啶和嘧啶侧链的截短侧耳素类衍生物，通过以下技术路线实施制备：
Figure BDA0003541110690000031
本发明制得的侧链含有3,4-二氢嘧啶和嘧啶的截短侧耳素类衍生物采用IR、NMR和HRMS对其进行结构表征。
实施例1 14-O-[(5-甲氧羰基-4,6-二甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成4a所示的化合物，即14-O-[(5-甲氧羰基-4,6-二甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3175,3111,2964,1933,2874,1714,1653,1587,1479,1435,1375,1332,1267,1183,1133,1110,1081,785,760cm-1；1H NMR(400MHz,Chloroform-d)δ6.49–6.36(m,1H),5.79–5.64(m,1H),5.31–5.26(m,1H),5.23–5.11(m,1H),4.48(d,J＝6.5Hz,1H),3.79–3.59(m,5H),3.34(dd,J＝10.3,6.4Hz,1H),2.34–2.24(m,2H),2.22(s,3H),2.12–2.03(m,2H),1.78–1.70(m,1H),1.67–1.60(m,2H),1.54(d,J＝11.1Hz,2H),1.43(s,4H),1.37–1.32(m,2H),1.24(d,J＝7.1Hz,1H),1.20–1.13(m,3H),1.11–1.00(m,4H),0.85(d,J＝6.9Hz,3H),0.71(t,J＝5.9Hz,3H)；13C NMR(101MHz,Chloroform-d)δ217.02,168.07,167.99,167.14,138.92,138.90,117.16,74.58,70.12,60.38,58.13,50.97,45.45,44.43,43.97,41.88,36.77,36.74,36.02,34.46,33.74,33.70,30.42,26.86,26.39,24.83,22.24,16.77,14.89,11.45；HRMS(ES)calcd[M+H]+for C30H44N2O6S 561.2993,found 561.3056.
实施例2 14-O-[(5-甲氧羰基-4-乙基-6-甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成4b所示的化合物，即14-O-[(5-甲氧羰基-4-乙基-6-甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3489,3311,2956,2877,1731,1655,1458,1375,1341,1277,1246,1184,1117,1012,917cm-1；1H NMR(400MHz,Chloroform-d)δ6.39(ddd,J＝17.6,11.1,6.9Hz,1H),5.74–5.60(m,1H),5.31–5.21(m,1H),5.21–5.07(m,1H),4.35(s,1H),3.74–3.66(m,1H),3.63(s,3H),3.29(dd,J＝10.6,6.4Hz,1H),2.24(s,1H),2.18(s,3H),2.15(s,1H),2.01(d,J＝25.7Hz,3H),1.70(dd,J＝14.7,3.2Hz,1H),1.64–1.54(m,2H),1.52–1.46(m,1H),1.46–1.42(m,2H),1.39(s,3H),1.37(d,J＝7.5Hz,2H),1.30(d,J＝15.8Hz,2H),1.19(t,J＝7.2Hz,2H),1.09(d,J＝6.1Hz,3H),1.05(d,J＝10.1Hz,1H),0.87–0.72(m,6H),0.67(dd,J＝7.0,3.4Hz,3H)；13C NMR(101MHz,Chloroform-d)δ217.01,168.12,168.03,167.38,138.90,138.86,117.20,74.59,70.12,60.39,58.13,50.95,45.45,44.49,44.39,43.96,41.87,36.74,36.02,34.47,33.74,30.42,26.87,26.36,24.83,14.88,11.47；HRMS(ES)calcd[M+H]+for C31H46N2O6S 575.3149,found 575.3173.
实施例3 14-O-[(5-甲氧羰基-4-丙基-6-甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成4c所示的化合物，即14-O-[(5-甲氧羰基-4-丙基-6-甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3363,2953,2871,1701,1652,1491,1436,1422,1381,1299,1214,1141,1083,1052,1012cm-1；1H NMR(400MHz,Chloroform-d)δ6.38(ddd,J＝17.2,11.0,3.7Hz,1H),5.67(dd,J＝8.4,4.3Hz,1H),5.26–5.19(m,1H),5.12(dd,J＝17.5,4.3Hz,1H),4.41(s,1H),3.71(d,J＝10.7Hz,2H),3.63(d,J＝5.1Hz,3H),3.28(d,J＝7.0Hz,1H),2.31–2.22(m,2H),2.17(d,J＝6.8Hz,3H),2.03(s,2H),1.73–1.66(m,1H),1.58(dt,J＝12.3,4.8Hz,2H),1.53–1.44(m,2H),1.39(s,4H),1.35–1.31(m,2H),1.26–1.15(m,3H),1.09(d,J＝6.4Hz,4H),0.85(d,J＝6.7Hz,5H),0.80(s,3H),0.66(dd,J＝7.0,4.0Hz,3H)；13C NMR(101MHz,Chloroform-d)δ216.97,168.58,168.04,167.22,139.54,138.93,117.16,74.58,70.25,59.11,58.12,50.87,45.44,44.41,43.98,41.87,39.24,36.73,36.03,34.45,33.80,32.84,30.41,26.86,26.42,24.83,22.51,19.31,16.78,14.86,13.95,11.45；HRMS(ES)calcd[M+H]+for C32H48N2O6S 589.3306,found 589.3368.
实施例4 14-O-[(5-甲氧羰基-4-丁基-6-甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成4d所示的化合物，即14-O-[(5-甲氧羰基-4-丁基-6-甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3369,2954,2867,1734,1701,1491,1459,1434,1375,1274,1220,1171,1118,1088,1015,954,917,776cm-1；1H NMR(400MHz,Chloroform-d)δ6.47–6.28(m,1H),5.75–5.59(m,1H),5.30–5.22(m,1H),5.12(dd,J＝16.5,4.1Hz,1H),4.41(s,1H),3.64(s,2H),3.63(s,3H),3.34–3.24(m,1H),2.23(d,J＝9.6Hz,2H),2.17(d,J＝6.1Hz,3H),2.04(d,J＝8.4Hz,2H),1.71–1.67(m,1H),1.60(s,2H),1.56(d,J＝6.8Hz,2H),1.42–1.38(m,4H),1.36–1.26(m,5H),1.19(dd,J＝16.4,10.6Hz,6H),1.09(d,J＝5.9Hz,4H),0.90(d,J＝7.1Hz,1H),0.85(d,J＝6.7Hz,3H),0.79(d,J＝6.3Hz,3H),0.67(dd,J＝7.1,4.6Hz,3H)；13CNMR(101MHz,Chloroform-d)δ216.58,167.54,167.10,166.27,138.42,137.83,116.21,74.10,73.58,58.09,57.12,49.89,44.43,44.05,42.96,40.85,35.81,35.56,35.01,33.45,31.85,29.38,25.82,25.32,23.82,21.52,18.42,17.17,15.80,13.86,13.05,12.41,10.46；HRMS(ES)calcd[M+H]+for C33H50N2O6S 603.3462,found 603.3455.
实施例5 14-O-[(5-甲氧羰基-4-异丁基-6-甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成4e所示的化合物，即14-O-[(5-甲氧羰基-4-异丁基-6-甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3315,2953,2867,1733,1655,1458,1437,1375,1285,1224,1176,1118,1089,1017,981,917,775cm-1；1H NMR(400MHz,Chloroform-d)δ6.43–6.32(m,1H),5.67(dd,J＝8.4,3.2Hz,1H),5.31–5.20(m,1H),5.18–5.06(m,1H),4.41(s,1H),3.66(s,2H),3.63(d,J＝5.7Hz,3H),3.28(d,J＝7.2Hz,1H),2.29–2.18(m,2H),2.16(d,J＝10.7Hz,3H),2.05–1.95(m,2H),1.72–1.67(m,1H),1.59(dd,J＝7.0,3.5Hz,2H),1.41(d,J＝2.7Hz,2H),1.39(s,4H),1.30(d,J＝7.6Hz,2H),1.22–1.14(m,3H),1.09(d,J＝6.6Hz,4H),0.84(ddd,J＝12.9,5.6,2.2Hz,7H),0.79(d,J＝5.8Hz,3H),0.66(dd,J＝7.0,4.1Hz,3H)；13C NMR(101MHz,Chloroform-d)δ217.05,168.24,168.09,167.23,138.89,138.85,117.20,74.59,70.11,65.04,58.14,50.94,45.45,44.51,43.98,41.87,36.76,36.73,36.02,34.47,33.82,30.41,26.91,26.86,26.38,24.83,23.53,18.43,16.79,14.88,11.48；HRMS(ES)calcd[M+H]+for C33H50N2O6S 603.3462,found 603.3457.
实施例6 14-O-[(5-甲氧羰基-4-(戊烷-3-基)-6-甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成4f所示的化合物，即14-O-[(5-甲氧羰基-4-(戊烷-3-基)-6-甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3313,2957,2936,2873,1733,1663,1491,1458,1376,1270,1168,1114,1082,1016,981,917cm-1；1H NMR(400MHz,Chloroform-d)δ6.42(td,J＝11.3,5.5Hz,1H),5.71(d,J＝8.5Hz,1H),5.33–5.25(m,1H),5.22–5.11(m,1H),4.58(s,1H),3.70(d,J＝4.2Hz,2H),3.67(s,3H),3.37–3.28(m,1H),2.29(t,J＝6.6Hz,1H),2.22(s,3H),2.18(d,J＝9.4Hz,1H),2.09–1.99(m,2H),1.75(dd,J＝14.5,3.2Hz,1H),1.63(dd,J＝7.4,3.5Hz,2H),1.56–1.49(m,2H),1.42(d,J＝14.2Hz,4H),1.33(d,J＝5.5Hz,2H),1.23(t,J＝6.0Hz,2H),1.14(d,J＝6.2Hz,4H),0.91(td,J＝7.6,7.1,2.9Hz,4H),0.83(dt,J＝13.5,7.1Hz,9H),0.70(dd,J＝7.0,4.2Hz,3H)；13C NMR(101MHz,Chloroform-d)217.00,168.21,168.01,167.69,138.97,138.92,117.15,74.59,70.05,60.37,58.15,50.83,45.44,44.53,43.96,41.87,36.75,36.73,36.02,34.45,33.51,30.41,26.90,26.86,26.41,24.83,22.63,16.77,14.86,11.73,11.67,11.45；HRMS(ES)calcd[M+H]+for C34H52N2O6S 617.3619,found617.3752.
实施例7 14-O-[(5-乙酰基-4,6-二甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成4g所示的化合物，即14-O-[(5-乙酰基-4,6-二甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3279,2960,2865,1728,1616,1473,1375,1255,1192,1117,1080,1016,955,916cm-1；1H NMR(400MHz,Chloroform-d)δ6.39(ddd,J＝17.5,11.0,2.7Hz,1H),5.68(dd,J＝8.5,5.0Hz,1H),5.25(d,J＝9.3Hz,1H),5.13(dd,J＝17.5,1.6Hz,1H),4.52(q,J＝6.4Hz,1H),3.79(d,J＝16.4Hz,1H),3.61(dd,J＝16.3,7.0Hz,1H),3.31(dd,J＝10.2,6.3Hz,1H),2.24(d,J＝1.6Hz,3H),2.18(s,6H),2.07–1.95(m,3H),1.70(dd,J＝14.5,3.0Hz,1H),1.62–1.51(m,3H),1.46(dd,J＝13.9,3.3Hz,1H),1.39(s,3H),1.30(dd,J＝16.2,4.0Hz,2H),1.19(t,J＝6.2Hz,2H),1.10(d,J＝4.1Hz,3H),1.03(t,J＝6.1Hz,3H),0.81(d,J＝7.0Hz,3H),0.73–0.63(m,3H)；13C NMR(101MHz,Chloroform-d)δ217.11,175.45,168.08,167.97,142.12,138.96,117.20,74.56,70.30,60.43,58.11,48.36,45.45,44.42,43.97,41.87,36.71,36.01,34.48,33.89,30.40,26.86,26.45,24.83,22.77,22.02,16.82,14.89,14.19,11.50；HRMS(ES)calcd[M+H]+for C30H44N2O5S545.3044,found 545.3041.
实施例8 14-O-[(5-乙氧羰基-4,6-二甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成4h所示的化合物，即14-O-[(5-乙氧羰基-4,6-二甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3307,2958,2865,1733,1651,1602,1487,1374,1340,1260,1180,1116,1016,915,776cm-1；1H NMR(400MHz,Chloroform-d)δ6.38(td,J＝12.8,6.5Hz,1H),5.66(d,J＝7.1Hz,1H),5.23(d,J＝8.5Hz,1H),5.11(d,J＝17.3Hz,1H),4.44(s,1H),4.07(dtq,J＝14.6,7.4,4.1Hz,3H),3.72(d,J＝16.3Hz,1H),3.58(d,J＝16.2Hz,1H),3.30(d,J＝6.4Hz,1H),2.24(d,J＝6.6Hz,1H),2.17(d,J＝3.3Hz,4H),2.05(s,1H),1.97(d,J＝3.4Hz,3H),1.70(d,J＝14.7Hz,1H),1.59(d,J＝11.2Hz,2H),1.46(d,J＝13.0Hz,1H),1.41–1.37(m,3H),1.34–1.25(m,2H),1.19(dt,J＝11.3,6.5Hz,5H),1.13–1.07(m,3H),1.03(dt,J＝8.7,4.8Hz,3H),0.81(d,J＝6.9Hz,3H),0.66(dt,J＝7.2,3.8Hz,3H)；13C NMR(101MHz,Chloroform-d)δ216.27,170.25,167.00,165.82,137.97,137.93,116.14,73.56,69.04,59.45,58.68,57.15,44.47,43.38,42.97,40.88,35.75,35.03,33.50,32.69,29.42,25.86,25.48,23.84,21.24,20.06,15.78,13.91,13.37,13.19,10.50；HRMS(ES)calcd[M+H]+for C31H46N2O6S 575.3149,found 575.3161.
实施例9 14-O-[(5-丙氧羰基-4,6-二甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成4i所示的化合物，即14-O-[(5-丙氧羰基-4,6-二甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3307,3128,2962,2864,1732,1655,1459,1399,1336,1268,1174,1152,1116,1069,1016,980,781cm-1；1H NMR(400MHz,Chloroform-d)δ6.45–6.32(m,1H),5.72–5.62(m,1H),5.30–5.21(m,1H),5.12(d,J＝17.5Hz,1H),4.46(d,J＝7.1Hz,1H),4.00(dt,J＝6.5,3.3Hz,2H),3.71(s,1H),3.59(dd,J＝16.2,1.9Hz,1H),3.29(dd,J＝10.3,6.4Hz,1H),2.28–2.21(m,1H),2.21–2.13(m,4H),2.04(d,J＝2.7Hz,1H),1.97(d,J＝1.7Hz,2H),1.70(dd,J＝14.7,3.2Hz,1H),1.58(td,J＝12.9,11.9,5.6Hz,4H),1.52–1.45(m,1H),1.38(d,J＝15.2Hz,5H),1.34–1.27(m,2H),1.19(t,J＝7.2Hz,2H),1.09(d,J＝4.0Hz,3H),1.05(t,J＝5.5Hz,3H),0.92–0.87(m,3H),0.81(d,J＝6.9Hz,3H),0.67(dd,J＝7.1,4.9Hz,3H)；13C NMR(101MHz,Chloroform-d)δ217.05,168.12,168.05,166.74,138.88,138.86,117.25,74.58,70.12,65.47,60.41,58.13,45.45,44.53,44.41,43.96,41.87,36.74,36.01,34.47,33.79,33.73,30.42,26.91,26.86,26.35,24.83,22.11,16.91,16.82,14.90,14.20,11.49,10.68；HRMS(ES)calcd[M+H]+for C32H48N2O6S 589.3306,found589.3278.
实施例10 14-O-[(5-烯丙氧羰基-4,6-二甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成4j所示的化合物，即14-O-[(5-烯丙氧羰基-4,6-二甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3547,3313,3088,2933,2864,1732,1655,1599,1456,1375,1226,1176,1036,937,815,775cm-1；1H NMR(400MHz,Chloroform-d)δ6.44–6.29(m,1H),5.94–5.75(m,1H),5.73–5.62(m,1H),5.26(s,1H),5.23(s,2H),5.11(d,J＝16.4Hz,1H),4.56(d,J＝4.7Hz,1H),4.49(d,J＝7.0Hz,1H),4.41(s,1H),4.05(qd,J＝7.1,2.4Hz,1H),3.79–3.55(m,1H),3.29(s,1H),2.38(s,1H),2.21(dd,J＝12.5,5.1Hz,3H),2.15(d,J＝7.6Hz,1H),2.04–1.94(m,3H),1.71(s,1H),1.60–1.53(m,2H),1.47(s,1H),1.42–1.31(m,6H),1.18(td,J＝7.2,2.7Hz,3H),1.07(d,J＝8.7Hz,6H),0.80(d,J＝7.1Hz,3H),0.71–0.55(m,3H)；13C NMR(101MHz,Chloroform-d)δ216.83,167.93,166.11,164.87,138.71,132.62,129.92,128.09,117.36,74.55,70.30,65.05,64.50,60.40,58.10,53.46,45.44,44.50,43.97,41.84,36.54,36.03,34.46,30.40,26.77,26.39,24.82,21.69,16.53,14.88,14.19,11.49；HRMS(ES)calcd[M+H]+for C32H46N2O6S 587.3149,found 587.3146.
实施例11 14-O-[(5-甲氧羰基-4,6-二甲基嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成5a所示的化合物，即14-O-[(5-甲氧羰基-4,6-二甲基嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3535,2973,2930,2870,1728,1545,1457,1446,1380,1295,1158,1118,1089,1018,978,914,886cm-1；1H NMR(400MHz,Chloroform-d)δ6.45(dd,J＝17.3,11.0Hz,1H),5.73(d,J＝8.5Hz,1H),5.28(d,J＝11.0Hz,1H),5.15(d,J＝17.4Hz,1H),3.90(d,J＝2.8Hz,3H),3.86(d,J＝2.3Hz,2H),3.32(s,1H),2.43(d,J＝2.9Hz,6H),2.28(d,J＝6.9Hz,1H),2.23–2.12(m,2H),2.07–1.97(m,2H),1.77–1.70(m,1H),1.62(dd,J＝11.1,3.2Hz,2H),1.49(d,J＝3.5Hz,2H),1.40(d,J＝3.0Hz,3H),1.34(s,1H),1.27(d,J＝15.8Hz,2H),1.12(d,J＝3.5Hz,3H),1.11–1.05(m,1H),0.84(d,J＝6.9Hz,3H),0.72(d,J＝6.8Hz,3H)；13C NMR(101MHz,Chloroform-d)δ216.98,170.21,167.65,165.33,138.99,121.75,117.16,74.54,69.70,58.12,52.44,45.43,44.58,43.93,41.86,36.75,35.99,34.45,34.02,30.41,26.85,26.35,24.81,23.14,16.88,14.86,11.44；HRMS(ES)calcd[M+H]+forC30H42N2O6S 559.2836,found 559.2824.
实施例12 14-O-[(5-甲氧羰基-4-乙基-6-甲基嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成5b所示的化合物，即14-O-[(5-甲氧羰基-4-乙基-6-甲基嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3539,2973,2931,2871,1728,1541,1458,1413,1377,1296,1229,1173,1117,1091,1018,978,916,888cm-1；1H NMR(400MHz,Chloroform-d)δ6.41(dd,J＝17.4,11.0Hz,1H),5.68(d,J＝8.4Hz,1H),5.24(dd,J＝11.0,1.6Hz,1H),5.10(dd,J＝17.4,1.6Hz,1H),3.85(s,4H),3.64(q,J＝7.0Hz,1H),3.27(d,J＝6.4Hz,1H),2.64(q,J＝7.5,7.0Hz,2H),2.36(s,3H),2.27–2.22(m,1H),2.19–2.10(m,2H),2.04–1.94(m,2H),1.69(dd,J＝14.7,3.1Hz,1H),1.61–1.54(m,2H),1.46(dd,J＝13.7,3.5Hz,2H),1.40(d,J＝3.3Hz,1H),1.36(s,3H),1.29(d,J＝3.5Hz,2H),1.18–1.14(m,3H),1.07(d,J＝4.5Hz,3H),1.02(d,J＝4.5Hz,1H),0.79(d,J＝7.0Hz,3H),0.67(d,J＝7.0Hz,3H)；13C NMR(101MHz,Chloroform-d)δ217.02,170.24,169.41,167.86,167.73,165.03,138.96,121.60,117.17,74.54,69.72,58.13,52.50,45.44,44.60,43.93,41.88,36.75,35.98,34.46,34.02,30.41,29.17,26.85,26.30,24.81,22.92,16.87,14.86,12.74,11.44；HRMS(ES)calcd[M+H]+for C31H44N2O6S 573.2993,found 573.2988.
实施例13 14-O-[(5-甲氧羰基-4-丙基-6-甲基嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成5c所示的化合物，即14-O-[(5-甲氧羰基-4-丙基-6-甲基嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3547,2956,2868,1732,1541,1497,1457,1375,1286,1223,1152,1116,1098,1017,980,917,814,554cm-1；1H NMR(400MHz,Chloroform-d)δ6.47(dd,J＝17.5,10.9Hz,1H),5.73(d,J＝8.5Hz,1H),5.33–5.26(m,1H),5.17(dd,J＝17.4,1.7Hz,1H),3.90(d,J＝7.8Hz,3H),3.33(d,J＝4.1Hz,1H),2.78–2.55(m,2H),2.43(d,J＝8.9Hz,3H),2.29(d,J＝6.8Hz,1H),2.25–2.18(m,2H),2.08–2.01(m,2H),1.73(s,1H),1.69–1.64(m,2H),1.55(d,J＝11.3Hz,2H),1.41(s,4H),1.35(s,2H),1.25(s,2H),1.14(d,J＝4.9Hz,4H),0.97–0.91(m,3H),0.85(d,J＝6.8Hz,3H),0.73(d,J＝6.8Hz,3H)；13C NMR(101MHz,Chloroform-d)δ217.00,170.12,168.35,167.89,167.74,167.01,138.96,121.98,117.18,74.55,69.72,58.13,52.48,45.44,44.61,43.94,41.88,36.76,35.99,34.46,34.01,30.42,26.91,26.86,26.30,24.82,22.95,21.96,16.88,14.86,13.98,11.45；HRMS(ES)calcd[M+H]+for C32H46N2O6S 587.3149,found 587.3143.
实施例14 14-O-[(5-甲氧羰基-4-丁基-6-甲基嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成5d所示的化合物，即14-O-[(5-甲氧羰基-4-丁基-6-甲基嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3448,2956,2864,1732,1541,1458,1434,1376,1288,1233,1152,1116,1080,1017,980,916cm-1；1H NMR(400MHz,Chloroform-d)δ6.49(dd,J＝17.4,11.0Hz,1H),5.76(d,J＝8.5Hz,1H),5.33(dd,J＝11.0,1.6Hz,1H),5.19(dd,J＝17.4,1.6Hz,1H),3.93(s,3H),3.92–3.79(m,2H),3.35(s,1H),2.69(dd,J＝9.0,6.7Hz,2H),2.44(s,3H),2.32(d,J＝6.9Hz,1H),2.27–2.19(m,2H),2.11–2.02(m,2H),1.75(d,J＝2.8Hz,1H),1.65(dtd,J＝9.5,7.3,6.4,3.6Hz,4H),1.44(s,4H),1.37(dd,J＝8.7,6.3Hz,4H),1.28(d,J＝6.9Hz,2H),1.16(d,J＝4.6Hz,4H),0.94(d,J＝7.4Hz,3H),0.87(d,J＝5.0Hz,3H),0.75(d,J＝6.9Hz,3H)；13C NMR(101MHz,Chloroform-d)δ217.01,170.11,168.62,167.90,167.75,165.02,138.97,121.90,117.19,74.56,69.72,58.13,52.47,45.44,44.62,43.94,41.88,36.76,35.99,35.59,34.47,34.01,30.76,30.42,26.86,26.31,24.82,22.95,22.54,16.89,14.86,13.80,11.45；HRMS(ES)calcd[M+H]+for C33H48N2O6S 601.3306,found601.3288.
实施例15 14-O-[(5-甲氧羰基-4-异丁基-6-甲基嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成5e所示的化合物，即14-O-[(5-甲氧羰基-4-异丁基-6-甲基嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3554,2955,2870,1732,1639,1541,1456,1374,1288,1223,1177,1116,1018,980,916,786cm-1；1H NMR(400MHz,Chloroform-d)δ6.46(dd,J＝17.6,11.0Hz,1H),5.74(t,J＝8.2Hz,1H),5.30(ddd,J＝10.9,4.4,1.6Hz,1H),5.16(dt,J＝17.5,2.1Hz,1H),4.10(q,J＝7.1Hz,1H),3.90(s,3H),3.69(t,J＝7.0Hz,1H),3.33(d,J＝6.5Hz,1H),2.55(d,J＝7.2Hz,1H),2.42(d,J＝9.7Hz,3H),2.35–2.26(m,1H),2.24–2.14(m,2H),2.05(d,J＝17.0Hz,3H),1.79–1.71(m,1H),1.62(td,J＝11.0,10.2,6.0Hz,4H),1.55–1.48(m,1H),1.40(d,J＝7.8Hz,4H),1.37–1.28(m,2H),1.22(t,J＝7.2Hz,3H),1.16–1.10(m,4H),0.88(d,J＝6.6Hz,3H),0.84(d,J＝6.5Hz,3H),0.72(d,J＝6.8Hz,3H)；13C NMR(101MHz,Chloroform-d)δ217.03,169.97,167.75,167.68,164.95,164.87,138.96,122.53,117.18,74.54,69.72,58.13,52.46,45.44,44.60,43.94,41.87,36.76,35.98,34.46,34.00,30.41,28.38,26.85,26.31,24.81,22.95,22.46,18.42,16.88,14.85,14.19,11.45；HRMS(ES)calcd[M+H]+for C33H48N2O6S 601.3306,found 601.3295.
实施例16 14-O-[(5-甲氧羰基-4-(戊烷-3-基)-6-甲基嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成5f所示的化合物，即14-O-[(5-甲氧羰基-4-(戊烷-3-基)-6-甲基嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3567,2959,2928,2874,1735,1637,1541,1458,1403,1383,1286,1227,1151,1116,1016,917,781cm-1；1H NMR(400MHz,Chloroform-d)δ6.56–6.37(m,1H),5.73(d,J＝8.5Hz,1H),5.35–5.24(m,1H),5.18(d,J＝17.3Hz,1H),3.93(d,J＝6.6Hz,3H),3.90(s,1H),3.71(q,J＝7.0Hz,1H),3.35(d,J＝6.5Hz,1H),2.57–2.47(m,1H),2.41(s,2H),2.33–2.28(m,1H),2.24–2.14(m,2H),2.10–2.02(m,2H),1.79–1.73(m,2H),1.64(dtdd,J＝21.3,11.1,6.5,3.0Hz,6H),1.51(d,J＝3.4Hz,1H),1.43(s,3H),1.43–1.35(m,3H),1.33(d,J＝7.4Hz,1H),1.25(q,J＝8.1,7.1Hz,3H),1.15(d,J＝2.0Hz,3H),1.12(s,1H),0.86(d,J＝7.0Hz,3H),0.79–0.74(m,3H),0.72(dd,J＝4.9,2.6Hz,3H)；13C NMR(101MHz,Chloroform-d)δ217.01,171.04,170.12,168.09,167.83,164.30,138.95,123.81,117.16,74.54,69.76,58.12,52.45,47.92,45.44,44.65,43.95,41.89,36.76,35.97,34.46,33.96,30.41,27.59,26.84,26.28,24.80,22.74,16.92,14.85,12.05,11.45；HRMS(ES)calcd[M+H]+for C34H50N2O6S 615.3462,found 615.3463.
实施例17 14-O-[(5-乙酰基-4,6-二甲基嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成5g所示的化合物，即14-O-[(5-乙酰基-4,6-二甲基嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3547,3084,2932,2864,1734,1698,1532,1455,1429,1353,1300,1215,1116,1017,980,915,774cm-1；1H NMR(400MHz,Chloroform-d)δ6.42(dd,J＝17.4,11.0Hz,1H),5.69(d,J＝8.5Hz,1H),5.26–5.21(m,1H),5.11(dd,J＝17.4,1.7Hz,1H),3.81(d,J＝2.0Hz,2H),3.28(d,J＝6.4Hz,1H),2.43(s,3H),2.29(s,6H),2.22(s,1H),2.15(dd,J＝6.4,2.8Hz,2H),2.03–1.96(m,2H),1.71–1.65(m,1H),1.58(d,J＝10.9Hz,2H),1.47(dd,J＝13.7,3.3Hz,2H),1.42–1.38(m,1H),1.38–1.35(m,3H),1.25(s,1H),1.20(d,J＝9.5Hz,2H),1.07(s,3H),0.79(d,J＝6.9Hz,3H),0.69(d,J＝7.0Hz,3H)；13C NMR(101MHz,Chloroform-d)δ216.99,203.49,169.43,167.72,162.25,139.03,130.41,117.16,74.53,69.67,58.12,45.43,44.59,43.92,41.85,36.74,35.98,34.45,33.95,32.12,30.40,26.85,26.32,24.80,22.33,16.90,14.86,11.43；HRMS(ES)calcd[M+H]+for C30H42N2O5S543.2887,found 543.2827.
实施例18 14-O-[(5-乙氧羰基-4,6-二甲基嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成5h所示的化合物，即14-O-[(5-乙氧羰基-4,6-二甲基嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3533,3085,2973,2871,1719,1541,1466,1445,1380,1358,1229,1158,1117,1084,977,861,785cm-1；1H NMR(400MHz,Chloroform-d)δ6.41(dd,J＝17.4,11.0Hz,1H),5.69(d,J＝8.5Hz,1H),5.28–5.19(m,1H),5.11(dd,J＝17.4,1.6Hz,1H),4.33(q,J＝7.1Hz,2H),3.82(d,J＝3.5Hz,2H),3.27(d,J＝6.4Hz,1H),2.39(s,6H),2.28–2.21(m,1H),2.18–2.08(m,2H),2.01(d,J＝2.6Hz,1H),1.99–1.92(m,1H),1.69(dd,J＝14.4,3.2Hz,1H),1.62–1.55(m,2H),1.47(dd,J＝13.7,3.4Hz,2H),1.40(d,J＝3.2Hz,1H),1.36(s,3H),1.34(s,1H),1.31(d,J＝7.1Hz,3H),1.22(d,J＝16.0Hz,2H),1.07(s,3H),0.79(d,J＝7.0Hz,3H),0.68(d,J＝7.0Hz,3H)；1313C NMR(101MHz,Chloroform-d)δ216.99,170.01,167.67,167.17,165.12,138.97,122.08,117.17,74.54,69.66,61.69,58.12,45.43,44.55,43.91,41.85,36.74,35.97,34.45,34.02,30.40,26.84,26.30,24.80,23.03,16.88,14.86,14.14,11.44；HRMS(ES)calcd[M+H]+for C31H44N2O6S 573.2993,found573.2948.
实施例19 14-O-[(5-丙氧羰基-4,6-二甲基嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成5i所示的化合物，即14-O-[(5-丙氧羰基-4,6-二甲基嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3547,3128,2934,2881,1728,1545,1457,1421,1386,1308,1228,1152,1116,1017,917,884cm-1；1H NMR(400MHz,Chloroform-d)δ6.41(dd,J＝17.4,11.0Hz,1H),5.69(d,J＝8.5Hz,1H),5.24(dd,J＝10.8,1.6Hz,1H),5.11(dd,J＝17.4,1.6Hz,1H),4.22(t,J＝6.7Hz,2H),3.81(d,J＝3.0Hz,2H),3.27(d,J＝6.4Hz,1H),2.39(s,6H),2.29–2.22(m,1H),2.19–2.11(m,2H),2.00(dd,J＝12.9,4.1Hz,2H),1.75–1.69(m,2H),1.68–1.64(m,1H),1.61–1.54(m,2H),1.52–1.43(m,2H),1.40(d,J＝3.0Hz,1H),1.36(s,3H),1.27(d,J＝19.5Hz,2H),1.20(s,1H),1.08(d,J＝5.5Hz,3H),0.95(t,J＝7.4Hz,3H),0.79(d,J＝7.0Hz,3H),0.68(d,J＝7.0Hz,3H)；13C NMR(101MHz,Chloroform-d)δ217.02,170.00,167.68,167.33,165.12,138.97,122.15,117.18,74.54,69.65,67.38,58.12,45.43,44.55,43.90,41.85,36.75,35.97,34.45,34.03,30.40,26.84,26.30,24.80,23.08,21.91,16.88,14.86,11.44,10.54；HRMS(ES)calcd[M+H]+for C32H46N2O6S 587.3149,found587.3087.
实施例20 14-O-[(5-烯丙氧羰基-4,6-二甲基嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成5j所示的化合物，即14-O-[(5-烯丙氧羰基-4,6-二甲基嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3553,3127,2934,2885,1731,1545,1456,1400,1374,1289,1177,1152,1117,1085,916,816cm-1；1H NMR(400MHz,Chloroform-d)δ6.43–6.33(m,1H),5.94(dd,J＝16.9,10.6Hz,1H),5.69(dd,J＝8.6,3.8Hz,1H),5.35(dd,J＝17.1,1.6Hz,1H),5.30–5.21(m,2H),5.16–5.09(m,1H),4.75(d,J＝5.8Hz,1H),4.41(s,1H),3.82(d,J＝3.3Hz,1H),3.27(d,J＝6.5Hz,1H),2.39(s,6H),2.23(dd,J＝6.8,4.2Hz,1H),2.19–2.13(m,2H),2.12(s,1H),2.02–1.97(m,2H),1.70–1.66(m,1H),1.58(dd,J＝10.7,3.2Hz,2H),1.48(dd,J＝13.8,10.6Hz,2H),1.41(s,1H),1.34(s,3H),1.24–1.17(m,2H),1.09(s,3H),1.03(d,J＝6.9Hz,1H),0.80(d,J＝6.5Hz,3H),0.68(d,J＝6.9Hz,2H),0.55(s,1H)；13C NMR(101MHz,Chloroform-d)δ217.00,170.19,167.65,166.89,165.27,164.87,138.95,129.90,128.08,117.19,74.53,69.67,66.32,65.02,58.12,45.42,44.56,43.91,41.82,36.74,35.97,34.39,30.40,26.84,26.29,24.80,23.12,16.88,14.86,11.44；HRMS(ES)calcd[M+H]+forC32H44N2O6S 585.2993,found 585.2925.
实施例21截短侧耳素衍生物的抑菌活性
本发明实施例1-20所制得的截短侧耳素衍生物采用琼脂稀释法测定其对金黄色葡萄球菌ATCC 25923(Staphylococcus aureus ATCC 25923，S.aureus)、耐甲氧西林的表皮球菌ATCC 51625(methicillin-resistant Staphylococcus epidermidis ATCC 51625，MRSE)、耐甲氧西林的金黄色葡萄球菌BNCC 337371(methicillin-resistantStaphylococcus aureus BNCC 337371，MRSA)、和化脓链球菌(Streptococcus pyogenes，S.pyogenes)的最小抑菌浓度(MIC)，结果如表1所示。结果表明，所制备的截短侧耳素类衍生物均具有良好的体外抑菌活性。除个别化合物外，多数化合物的MIC要低于对照药物泰妙菌素或瑞他莫林。其中侧链含嘧啶环的化合物的抑菌活性要优于侧链含3,4-二氢嘧啶类的化合物，尤其是化合物5a、5g和5h的活性最好，对MRSA、MRSE和S.aureus的MIC小于或等于0.0313μg/mL，对化脓链球菌也有中等的抑菌活性。
表1截短侧耳素类衍生物的体外最小抑菌浓度(μg/mL)
Figure BDA0003541110690000131
Figure BDA0003541110690000141
在MIC测定的基础上，进一步对化合物5a、5g和5h的1×和6×MIC浓度进行了杀菌动力学研究，结果如图1所示。结果表明，化合物5h的抑菌活性最好，6×MIC的5h能使MRSA和S.aureus的数量分别下降2.44和3.62个log10CFU，显著优于瑞他莫林。
对化合物5h进行了MRSA感染小鼠的治疗研究。昆明系小鼠射感染0.4mL的MRSA(108CFU/mL)后，应用不同剂量的化合物5h和对照药物泰妙菌素对小鼠进行腹腔注射，同时设阳性组和空白溶剂组。研究结果表明，与泰妙菌素相比，5h能显著提高感染了MRSA小鼠的死亡率(结果见图2中A)，其ED50为16.14mg/kg，显著低于对照药物泰妙菌素(图2中B，ED50为22.87mg/kg)。
本发明所述衍生物结构新颖，抑菌活性突出。尤其重要的是，本发明涉及到的截短侧耳素类衍生物的制备原料主要是乙酰乙酸乙酯、醛和硫脲；与泰妙菌素、沃尼妙林、瑞他莫林和利发姆林等截短侧耳素类药物相比，具有原料易得、成本低廉，工艺简单，绿色环保等优点。
上述测试说明，本发明制备的含有3,4-二氢嘧啶和嘧啶侧链的截短侧耳素类衍生物对多种阳性菌，如金黄色葡萄球菌、耐甲氧西林的表皮球菌、耐甲氧西林的金黄色葡萄球菌、化脓链球菌等，具有显著的抑制作用。因此，本发明的截短侧耳素衍生物可以在制备抗菌药物，尤其是抗耐药菌药物中应用。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。

Claims (10)

1.一种截短侧耳素类衍生物或其药学上可接受的盐，所述截短侧耳素类衍生物为式(I)所示的含有取代3,4-二氢嘧啶侧链的截短侧耳素类衍生物，或式(II)所示的含有取代嘧啶侧链的截短侧耳素类衍生物：
Figure FDA0003541110680000011
其中，R1选自烷基或烷氧基；R2选自直链或支链烷基。
2.如权利要求1所述的截短侧耳素类衍生物或其药学上可接受的盐，其特征在于，所述R1选自-CH3、-OCH3、-OCH2CH3、-OCH2CH2CH3、-OCH2CH＝CH2；R2选自-CH3、-CH2CH3、-CH2CH2CH3、-CH2CH2CH2CH3、-CHCH(CH3)2、或-CH(CH2CH3)2。
3.如权利要求2所述的截短侧耳素类衍生物或其药学上可接受的盐，其特征在于，所述截短侧耳素类衍生物为式(II)所示的含有取代嘧啶侧链的截短侧耳素类衍生物。
4.如权利要求3所述的截短侧耳素类衍生物或其药学上可接受的盐，其特征在于，所述R1为-OCH3，R2为-CH3。
5.如权利要求3所述的截短侧耳素类衍生物或其药学上可接受的盐，其特征在于，所述R1为-CH3，R2为-CH3。
6.如权利要求3所述的截短侧耳素类衍生物或其药学上可接受的盐，其特征在于，所述R1为-OCH2CH3，R2为-CH3。
7.如权利要求1-6任一所述的截短侧耳素类衍生物或其药学上可接受的盐在制备抗菌药物中的应用。
8.如权利要求7所述的应用，其特征在于，所述抗菌药物为抗耐药菌的药物。
9.如权利要求8所述的应用，其特征在于，所述耐药菌包括金黄色葡萄球菌、耐甲氧西林的表皮球菌、耐甲氧西林的金黄色葡萄球菌、化脓链球菌。
10.如权利要求1-6任一所述的截短侧耳素类衍生物或其药学上可接受的盐加入药学上可接受的载体或辅料制成药学上可接受的任一剂型。
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