CN107540627A - 一类具有抗菌活性的脱氢枞酸噁二嗪杂环衍生物及其制备方法和用途 - Google Patents
一类具有抗菌活性的脱氢枞酸噁二嗪杂环衍生物及其制备方法和用途 Download PDFInfo
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- 239000001257 hydrogen Substances 0.000 title claims abstract description 32
- 229910052739 hydrogen Inorganic materials 0.000 title claims abstract description 32
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 230000000844 anti-bacterial effect Effects 0.000 title claims abstract description 17
- 238000004519 manufacturing process Methods 0.000 title abstract description 3
- 238000006356 dehydrogenation reaction Methods 0.000 claims abstract description 53
- JOVOSQBPPZZESK-UHFFFAOYSA-N phenylhydrazine hydrochloride Chemical compound Cl.NNC1=CC=CC=C1 JOVOSQBPPZZESK-UHFFFAOYSA-N 0.000 claims abstract description 48
- 125000001424 substituent group Chemical group 0.000 claims abstract description 34
- NFWKVWVWBFBAOV-MISYRCLQSA-N dehydroabietic acid Chemical compound OC(=O)[C@]1(C)CCC[C@]2(C)C3=CC=C(C(C)C)C=C3CC[C@H]21 NFWKVWVWBFBAOV-MISYRCLQSA-N 0.000 claims abstract description 28
- -1 thionyl chloride acyl chloride Chemical class 0.000 claims abstract description 27
- QUUCYKKMFLJLFS-UHFFFAOYSA-N Dehydroabietan Natural products CC1(C)CCCC2(C)C3=CC=C(C(C)C)C=C3CCC21 QUUCYKKMFLJLFS-UHFFFAOYSA-N 0.000 claims abstract description 26
- NFWKVWVWBFBAOV-UHFFFAOYSA-N Dehydroabietic acid Natural products OC(=O)C1(C)CCCC2(C)C3=CC=C(C(C)C)C=C3CCC21 NFWKVWVWBFBAOV-UHFFFAOYSA-N 0.000 claims abstract description 26
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- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
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- 229940067157 phenylhydrazine Drugs 0.000 claims abstract description 13
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims abstract description 11
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Abstract
本发明公开了一种一类具有抗菌活性的脱氢枞酸噁二嗪杂环衍生物及其制备方法和用途。本发明的具有通式(I)所示结构的脱氢枞酸噁二嗪类杂环衍生物及其在药学上可接受的盐:本发明所述的通式(I)所示结构的脱氢枞酸噁二嗪类杂环衍生物I‑a1至I‑a9,I‑b1至I‑b2的制备方法,包括如下步骤:(1)脱氢枞酸经过氯化亚砜酰氯化反应得到脱氢枞酰氯;(2)脱氢枞酰氯与含有不同取代基的苯肼盐酸盐反应得到相对应取代基的脱氢枞酰苯肼衍生物;(3)脱氢枞酰苯肼衍生物与氯乙酰氯反应环化,得到相对应取代基的脱氢枞酸噁二嗪类杂环衍生物。本发明的脱氢枞酸噁二嗪类杂环衍生物对细菌有较强抑制作用,具有开发抗菌药物的价值。
Description
技术领域
本发明涉及有机合成和药物化学领域,具体涉及一类具有抗菌活性的脱氢枞酸噁二嗪类杂环衍生物的制备方法,含有它们的药物组合物及其抗菌用途。
背景技术
脱氢枞酸衍生物具有多种生物活性,如抗菌、细胞毒、抗溃疡、抗病毒、抗炎、免疫抑制、抗氧化等,已引起了国内外研究者的关注。特别是在抗细菌活性实验中,一些天然或半合成的脱氢枞酸衍生物表现出了优良的活性,说明脱氢枞酸作为一个前体化合物,在寻找新型抗细菌药物的研究中具有较大的开发潜力;另外,脱氢枞酸作为一种廉价、易得、无毒、资源丰富的天然产物,可进行多种衍生化反应。以之作为起始原料,综合运用化学和生物学的技术手段,对其分子进行结构修饰,结合深入的构效关系研究,有望合成活性更强、效果更好、副作用更低的衍生物,并从中筛选出具有开发潜力的药物先导物。
脱氢枞酸的化学结构式为:
噁二嗪类(oxadiazine)化合物是一类重要的杂环化合物,最早是作为杀虫剂来开发的,但许多噁二嗪类化合物也具有较强的抗菌活性,具有开发抗菌药物的潜力。例如K.M.Khan等人合成了一系列2-取代的5,6-二氢-5-羰基-4氢-1,3,4-噁二嗪-4-丙腈化合物,并对所有化合物进行了体外抗菌活性测试和抗真菌活性测试,部分化合物的测试结果表现出了一定的杀菌和杀真菌活性;S.M.Sicardi等人合成的5,6-二氢-2-巯苯基-4-氢-1,3,4-噁二嗪-5-酮经体外抗菌活性测试,其对多种细菌菌株具有抑制作用。
为了更深入研究脱氢枞酸噁二嗪类杂环衍生物的构效关系,本发明提供一种具有抗菌活性的脱氢枞酸噁二嗪类杂环衍生物的制备方法,对羧酸酰氯化,再与不同取代基的苯肼反应,生成系列酰肼衍生物,然后进行环化和还原反应获得目标产物,衍生物的结构较为新颖,国内外未见报道。
发明内容
为了克服上述现有技术中的不足之处,本发明的目的是提供一种一类具有抗菌活性的脱氢枞酸噁二嗪杂环衍生物及其制备方法和用途。
为了实现上述技术目的,本发明采用的技术方案如下:本发明的一种具有通式(I)所示结构的脱氢枞酸噁二嗪类杂环衍生物及其在药学上可接受的盐:
其中,脱氢枞酸噁二嗪类杂环衍生物I-a1至I-a9,I-b1至I-b2、I-a10对应的R1和R2分别为:
I-a1:R1为H,R2为H;I-a2:R1为H,R2为Me;
I-a3:R1为H,R2为Et;I-a4:R1为H,R2为F;
I-a5:R1为H,R2为Cl;I-a6:R1为H,R2为Br;
I-a7:R1为H,R2为NO2;I-a8:R1为H,R2为CN;
I-a9:R1为H,R2为CF3;I-b1:R1为Me,R2为H;
I-b2:R1为Cl,R2为H;I-a10:R1为NH2,R2为H。
本发明所述的通式(I)所示结构的脱氢枞酸噁二嗪类杂环衍生物I-a1至I-a9,I-b1至I-b2的制备方法,包括如下步骤:
(1)脱氢枞酸经过氯化亚砜酰氯化反应得到脱氢枞酰氯,其结构如下:
(2)脱氢枞酰氯与含有不同取代基的苯肼盐酸盐反应得到相对应取代基的脱氢枞酰苯肼衍生物,结构式如式II所示:
(3)脱氢枞酰苯肼衍生物与氯乙酰氯反应环化,得到相对应取代基的脱氢枞酸噁二嗪类杂环衍生物,结构式如式Ⅰ所示:
进一步地,在步骤(1)中,将脱氢枞酸溶于环己烷,缓慢滴加SOCl2后85℃回流2小时,后减压浓缩去除溶剂;所述脱氢枞酸与SOCl2的摩尔比为6.6:13.3;所述脱氢枞酸与环己烷的质量体积比为1g/10ml;
在步骤(2)中,再加入环己烷,加入苯肼盐酸盐,在冰浴条件下缓慢滴加三乙胺,在冰浴条件下反应1小时,室温下反应3小时,反应结束后将对反应液进行抽滤取溶液,用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩去除溶剂,用甲醇重结晶,得黄色固体的脱氢枞酰苯肼Ⅱ-a1;所述苯肼盐酸盐与三乙胺的摩尔比为1:2;所述环己烷与三乙胺的体积比为20:3;
在步骤(3)中,取脱氢枞酰苯肼Ⅱ-a1溶于10ml的2-丁酮(无水),缓慢滴加氯乙酰氯,85℃回流1小时,冷却至室温,加入K2CO3,回流3小时,反应结束后减压浓缩去除溶剂,加入乙酸乙酯溶解,饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩去除溶剂,所述脱氢枞酰苯肼Ⅱ-a1、氯乙酰氯与K2CO3的摩尔比为0.26:0.26:3;所述2-丁酮(无水)与氯乙酰氯的体积比为10ml:21μL;产物用硅胶柱层析纯化,所述石油醚/丙酮的体积比为200:1,得到化合物I-a1的淡黄色固体。
进一步地,所述含有不同取代基的苯肼盐酸盐为对甲基苯肼盐酸盐时,则步骤(2)中,相同条件下,制得化合物I-a2;
所述含有不同取代基的苯肼盐酸盐为对乙基苯肼盐酸盐3时,则步骤(2)中,相同条件下,制得化合物I-a3;
所述含有不同取代基的苯肼盐酸盐的苯肼盐酸盐为对氟苯肼盐酸盐4时,则步骤(2)中,相同条件下,制得化合物I-a4;
所述含有不同取代基的苯肼盐酸盐的苯肼盐酸盐为对氯苯肼盐酸盐5时,则步骤(2)中,相同条件下,制得化合物I-a5;
所述含有不同取代基的苯肼盐酸盐的苯肼盐酸盐为对溴苯肼盐酸盐时,则步骤(2)中,相同条件下,制得化合物I-a6;
所述含有不同取代基的苯肼盐酸盐的苯肼盐酸盐为对硝基苯肼盐酸盐7时,则步骤(2)中,相同条件下,制得化合物I-a7;
所述含有不同取代基的苯肼盐酸盐的苯肼盐酸盐为对氰基苯肼盐酸盐8时,则步骤(2)中,相同条件下,制得化合物I-a8;
所述含有不同取代基的苯肼盐酸盐的苯肼盐酸盐为对三氟甲基苯肼盐酸9时,则步骤(2)中,相同条件下,制得化合物I-a9;
所述含有不同取代基的苯肼盐酸盐的苯肼盐酸盐为邻甲基苯肼盐酸盐b1时,则步骤(2)中,相同条件下,制得化合物I-b1;
所述含有不同取代基的苯肼盐酸盐的苯肼盐酸盐为邻氯苯肼盐酸盐b2时,则步骤(2)中,相同条件下,制得化合物I-b2。
进一步地,所述不同取代基苯肼盐酸盐是由对应的取代基苯胺经过亚硝酸钠重氮盐后再用氯化亚锡还原制得。
进一步地,本发明所述的通式(I)所示结构的脱氢枞酸噁二嗪类杂环衍生物I-a10的制备方法,包括如下步骤:
(1)脱氢枞酸经过氯化亚砜酰氯化反应得到脱氢枞酰氯,其结构如下:
(2)脱氢枞酰氯与含有对硝基的苯肼盐酸盐反应得到相对应取代基的脱氢枞酰苯肼衍生物,结构式如式Ⅱ-a7所示:
(3)脱氢枞酰对硝基苯肼与氯乙酰氯反应环化,得到相对应取代基的脱氢枞酸噁二嗪类杂环衍生物,结构式如式Ⅰ-a7所示:
(4)2-脱氢枞基-4-对硝苯基-1,3,4-噁二嗪-5-酮被铁粉还原,得到2-脱氢枞基-4-对胺苯基-1,3,4-噁二嗪-5-酮,结构式如式Ⅰ-a10所示:
本发明所述的一种具有通式(I)所示结构的脱氢枞酸噁二嗪类杂环衍生物及其药学上可接受的盐在制备抗菌药物中应用。
进一步地,所述菌类为细菌。
有益效果:本发明的优点在于,本发明对天然产物脱氢枞酸进行结构改造,得到一系列结构新颖的脱氢枞酸噁二嗪类杂环衍生物;体外抑菌试验表明,它们对四种细菌菌株具有明显的抑制作用。其中化合物I-a8和Ⅰ-a10的抑菌效果最好。
具体实施方式
以下通过本发明的具体实施例进一步说明本发明,但不作为对本发明的限制。
实施例1
2-脱氢枞基-4-苯基-1,3,4-噁二嗪-5-酮(Ⅰ-a1)的合成
将脱氢枞酸(2g,6.6mol)溶于20ml的环己烷,缓慢滴加SOCl2(1ml,13.3mol)后85℃回流2小时,后减压浓缩去除溶剂,再加入20ml环己烷,加入苯肼盐酸盐(1.44g,0.01mol),在冰浴条件下缓慢滴加三乙胺(3ml,0.02mol),在冰浴条件下反应1小时,室温下反应3小时,反应结束后将对反应液进行抽滤取溶液,用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩去除溶剂,用甲醇重结晶,得黄色固体的脱氢枞酰苯肼(Ⅱ-a1)(2.18g,56%)。
取Ⅱ-a1(0.1g,0.26mmol)溶于10ml的2-丁酮(无水),缓慢滴加氯乙酰氯(21μL,0.26mmol),85℃回流1小时,冷却至室温,加入K2CO3(0.415g,3mmol),回流3小时,反应结束后减压浓缩去除溶剂,加入乙酸乙酯溶解,饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩去除溶剂。产物用硅胶柱层析纯化(石油醚/丙酮200:1,v/v),得到化合物I-a1的淡黄色固体(35.5mg,32%)。
M.p.130~133℃;1H NMR(600MHz,CDCl3):δ1.23(d,J=7.0Hz,6H),1.25(s,3H),1.32(s,3H),1.51(dt,J=12.8,3.6Hz,1H),1.60~1.90(m,6H),2.20(dd,J=12.5,2.0Hz,1H),2.33(brd,J=13.2Hz,1H),2.83(m,1H),2.87~2.92(m,2H),4.56(d,J=15.1Hz,1H),4.61(d,J=15.1Hz,1H),6.90(d,J=1.1Hz,1H),7.02(dd,J=8.1,1.7Hz,1H),7.19(d,J=8.2Hz,1H),7.25(t,J=7.4Hz,1H),7.41(t,J=7.6Hz,2H),7.70(d,J=7.7Hz,2H);IR(KBr,cm-1):2954,2925,2867,1694,1646,1595,1493,1374,1309,1274,1052,817,758,685;MS(ESI):m/z[M+H]+:431.3;Anal.Calcd.for C28H34N2O2:C 78.10;H 7.96;N 6.51;found:C78.16;H 7.91;N 6.58.
实施例2
2-脱氢枞基-4-对甲苯基-1,3,4-噁二嗪-5-酮(Ⅰ-a2)的合成
参照实施例1的合成方法,以脱氢枞酸和对甲基苯肼盐酸盐为原料,在相同条件下反应得橙色油状物的脱氢枞酰对甲基苯肼(Ⅱ-a2)(1.89g,0.47%)。然后以化合物Ⅱ-a2为原料,在相同条件下反应,产物经硅胶柱层析纯化(石油醚/丙酮200:1,v/v),得到化合物I-a2的黄色油状物(32.1mg,29%)。
1H NMR(600MHz,CDCl3):δ1.23(d,J=6.9Hz,6H),1.25(s,3H),1.31(s,3H),1.50(dt,J=12.8,3.8Hz,1H),1.60~1.89(m,6H),2.20(dd,J=12.5,2.1Hz,1H),2.33(brd,J=13.1Hz,1H),2.36(s,3H),2.83(m,1H),2.87~2.92(m,2H),4.54(d,J=15.1Hz,1H),4.59(d,J=15.1Hz,1H),6.90(d,J=1.1Hz,1H),7.01(dd,J=8.2,1.7Hz,1H),7.18(d,J=8.2Hz,1H),7.20(d,J=8.3Hz,2H),7.55(d,J=8.4Hz,2H);IR(KBr,cm-1):2953,2927,2863,1727,1693,1648,1506,1460,1374,1300,1274,1210,1172,1116,1063,967,819,711,634;MS(ESI):m/z[M+H]+:445.3;Anal.Calcd.for C29H36N2O2:C 78.34;H 8.16;N 6.30;found:C78.39;H 8.10;N 6.24.
实施例3
2-脱氢枞基-4-对乙苯基-1,3,4-噁二嗪-5-酮(Ⅰ-a3)的合成
参照实施例1的合成方法,以脱氢枞酸和对乙基苯肼盐酸盐为原料,在相同条件下反应得红色固体的脱氢枞酰对乙基苯肼(Ⅱ-a3)。然后以化合物Ⅱ-a3为原料,在相同条件下反应,产物经硅胶柱层析纯化(石油醚/丙酮100:1,v/v),得到化合物I-a3的黄色油状物(18.6mg,17%)。
1H NMR(600MHz,CDCl3):δ1.23(d,J=6.9Hz,6H),1.24(t,J=7.6Hz,3H),1.25(s,3H),1.31(s,3H),1.50(dt,J=12.7,3.8Hz,1H),1.60~1.90(m,6H),2.20(dd,J=12.4,2.1Hz,1H),2.33(brd,J=13.2Hz,1H),2.66(q,J=7.6Hz,2H),2.83(m,1H),2.87~2.92(m,2H),4.55(d,J=15.1Hz,1H),4.59(d,J=15.1Hz,1H),6.90(d,J=1.2Hz,1H),7.01(dd,J=8.2,1.7Hz,1H),7.18(d,J=8.2Hz,1H),7.23(d,J=8.5Hz,2H),7.57(d,J=8.5Hz,2H);IR(KBr,cm-1):2958,2928,2866,1734,1693,1650,1507,1460,1375,1309,1288,1283,1209,1179,1118,1076,1057,968,899,829,706;MS(ESI):m/z[M+H]+:459.3;Anal.Calcd.forC30H38N2O2:C 78.56;H 8.35;N 6.11;found:C 78.61;H 8.39;N 6.18.
实施例4
2-脱氢枞基-4-对氟苯基-1,3,4-噁二嗪-5-酮(Ⅰ-a4)的合成
参照实施例1的合成方法,以脱氢枞酸和对氟苯肼盐酸盐为原料,在相同条件下反应得黄色固体的脱氢枞酰对氟苯肼(Ⅱ-a4)(1.95g,48%)。然后以化合物Ⅱ-a4为原料,在相同条件下反应,产物经硅胶柱层析纯化(石油醚/丙酮200:1,v/v),得到化合物I-a4的淡黄色油状物(26.7mg,24%)。
1H NMR(600MHz,CDCl3):δ1.23(d,J=7.0Hz,6H),1.25(s,3H),1.31(s,3H),1.50(dt,J=12.5,2.0Hz,1H),1.60~1.90(m,6H),2.20(dd,J=12.5,2.1Hz,1H),2.34(brd,J=12.8Hz,1H),2.83(m,1H),2.87~2.92(m,2H),4.55(d,J=15.2Hz,1H),4.60(d,J=15.2Hz,1H),6.90(brs,1H),7.02(dd,J=8.1,1.3Hz,1H),7.09(t,J=8.7Hz,2H),7.18(d,J=8.2,1H),7.67(dd,J=9.1,4.9Hz,2H);IR(KBr,cm-1):2949,2927,2862,1695,1649,1604,1504,1460,1375,1285,1229,1207,1180,1099,1059,969,833,723,694,633;MS(ESI):m/z[M+H]+:449.3;Anal.Calcd.for C28H33FN2O2:C 74.97;H 7.42;N 6.25;found:C 74.90;H 7.36;N 6.32.
实施例5
2-脱氢枞基-4-对氯苯基-1,3,4-噁二嗪-5-酮(Ⅰ-a5)的合成
参照实施例1的合成方法,以脱氢枞酸和对氯苯肼盐酸盐为原料,在相同条件下反应得黄色固体的脱氢枞酰对氯苯肼(Ⅱ-a5)(1.68g,40%)。然后以化合物Ⅱ-a5为原料,在相同条件下反应,产物经硅胶柱层析纯化(石油醚/丙酮200:1,v/v),得到化合物I-a5的橙色油状物(27.8mg,25%)。
1H NMR(600MHz,CDCl3):δ1.23(d,J=7.0Hz,6H),1.25(s,3H),1.32(s,3H),1.50(dt,J=12.7,3.5Hz,1H),1.59~1.90(m,6H),2.19(dd,J=12.6,2.1Hz,1H),2.34(brd,J=12.5Hz,1H),2.83(m,1H),2.87~2.92(m,2H),4.55(d,J=15.2Hz,1H),4.60(d,J=15.2Hz,1H),6.90(d,J=1.1Hz,1H),7.02(dd,J=8.2,1.7Hz,1H),7.18(d,J=8.2Hz,1H),7.36(d,J=8.9Hz,2H),7.69(d,J=8.9Hz,2H);IR(KBr,cm-1):2949,2927,2854,1696,1490,1461,1369,1282,1209,1179,1137,1089,1059,1012,968,826,753,708,631;MS(ESI):m/z[M+H]+:465.2;Anal.Calcd.for C28H33ClN2O2:C 72.32;H 7.15;N 6.02;found:C 72.37;H7.09;N 6.09.
实施例6
2-脱氢枞基-4-对溴苯基-1,3,4-噁二嗪-5-酮(Ⅰ-a6)的合成
参照实施例1的合成方法,以脱氢枞酸和对溴苯肼盐酸盐为原料,在相同条件下反应得黄色固体的脱氢枞酰对溴苯肼(Ⅱ-a6)(1.86g,40%)。然后以化合物Ⅱ-a6为原料,在相同条件下反应,产物经硅胶柱层析纯化(石油醚/丙酮200:1,v/v),得到化合物I-a6的黄色油状物(29.4mg,27%)。
1H NMR(600MHz,CDCl3):δ1.23(d,J=6.9Hz,6H),1.25(s,3H),1.32(s,3H),1.50(dt,J=13.0,3.5Hz,1H),1.59~1.90(m,6H),2.19(dd,J=12.5,2.0Hz,1H),2.33(brd,J=12.5Hz,1H),2.83(m,1H),2.87~2.92(m,2H),4.54(d,J=15.2Hz,1H),4.60(d,J=15.2Hz,1H),6.90(d,J=1.1Hz,1H),7.02(dd,J=8.2,1.6Hz,1H),7.18(d,J=8.2Hz,1H),7.51(d,J=8.9Hz,2H),7.64(d,J=8.9Hz,2H);IR(KBr,cm-1):2955,2926,2861,1696,1649,1488,1460,1369,1282,1210,1179,1110,1074,1010,969,877,823,783,719,621;MS(ESI):m/z[M+H]+:509.2;Anal.Calcd.for C28H33BrN2O2:C 66.01;H 6.53;N 5.50;found:C 66.07;H6.58;N 5.43.
实施例7
2-脱氢枞基-4-对硝苯基-1,3,4-噁二嗪-5-酮(Ⅰ-a7)的合成
参照实施例1的合成方法,以脱氢枞酸和对硝基苯肼盐酸盐为原料,在相同条件下反应得黄色固体的脱氢枞酰对硝基苯肼(Ⅱ-a7)(2.31g,53%)。然后以化合物Ⅱ-a7为原料,在相同条件下反应,产物经硅胶柱层析纯化(石油醚/丙酮100:1,v/v),得到化合物I-a7的黄色固体(41.2mg,38%)。
M.p.120~124℃;1H NMR(600MHz,CDCl3):δ1.23(d,J=6.9Hz,6H),1.27(s,3H),1.36(s,3H),1.52(dt,J=12.5,3.7Hz,1H),1.60~1.90(m,6H),2.21(dd,J=12.5,2.1Hz,1H),2.35(brd,J=12.1Hz,1H),2.84(m,1H),2.87~2.92(m,2H),4.59(d,J=15.4Hz,1H),4.64(d,J=15.5Hz,1H),6.91(d,J=1.0Hz,1H),7.03(dd,J=8.2,1.6Hz,1H),7.19(d,J=8.2Hz,1H),8.06(d,J=9.3Hz,2H),8.27(dd,J=9.3Hz,2H);IR(KBr,cm-1):2952,2924,2852,1704,1650,1591,1520,1493,1458,1335,1297,1110,1056,852,823,745,688;MS(ESI):m/z[M+H]+:476.3;Anal.Calcd.for C28H33N3O4:C 70.71;H 6.99;N 8.84;found:C70.78;H 6.96;N 8.80.
实施例8
2-脱氢枞基-4-对氰苯基-1,3,4-噁二嗪-5-酮(Ⅰ-a8)的合成
参照实施例1的合成方法,以脱氢枞酸和对氰基苯肼盐酸盐为原料,在相同条件下反应得黄色固体的脱氢枞酰对氰基苯肼(Ⅱ-a8)(1.52g,37%)。然后以化合物Ⅱ-a8为原料,在相同条件下反应,产物经硅胶柱层析纯化(石油醚/丙酮100:1,v/v),得到化合物I-a8的淡黄色油状物(23.1mg,21%)。
1H NMR(600MHz,CDCl3):δ1.23(s,J=6.9Hz,6H),1.26(s,3H),1.34(s,3H),1.51(dt,J=12.6,2.9Hz,1H),1.60~1.90(m,6H),2.20(dd,J=12.5,2.1Hz,1H),2.35(brd,J=12.3Hz,1H),2.83(m,1H),2.87~2.92(m,2H),4.57(d,J=15.4Hz,1H),4.62(d,J=15.4Hz,1H),6.90(d,J=1.1Hz,1H),7.02(dd,J=8.2,1.6Hz,1H),7.19(d,J=8.2Hz,1H),7.69(d,J=8.9Hz,2H),7.99(d,J=8.9Hz,2H);IR(KBr,cm-1):2948,2927,2853,2223,1703,1646,1601,1494,1458,1368,1343,1163,835,819;MS(ESI):m/z[M+H]+:456.3;Anal.Calcd.forC29H33N3O2:C 76.45;H 7.30;N 9.22;found:C 76.51;H 7.23;N 9.20.
实施例9
2-脱氢枞基-4-对三氟甲苯基-1,3,4-噁二嗪-5-酮(Ⅰ-a9)的合成
参照实施例1的合成方法,以脱氢枞酸和对三氟甲基苯肼盐酸盐为原料,在相同条件下反应得黄色固体的脱氢枞酰对三氟甲基苯肼(Ⅱ-a9)(2.13g,47%)。然后以化合物Ⅱ-a9为原料,在相同条件下反应,产物经硅胶柱层析纯化(石油醚/丙酮200:1,v/v),得到化合物I-a9的黄色油状物(34.3mg,32%)。
1H NMR(600MHz,CDCl3):δ1.23(d,J=6.9Hz,6H),1.26(s,3H),1.34(s,3H),1.51(dt,J=13.0,3.4Hz,1H),1.60~1.89(m,6H),2.21(dd,J=12.5,2.1Hz,1H),2.34(brd,J=12.6Hz,1H),2.83(m,1H),2.87~2.92(m,2H),4.57(d,J=15.3Hz,1H),4.62(d,J=15.3Hz,1H),6.91(d,J=1.2Hz,1H),7.02(dd,J=8.2,1.7Hz,1H),7.19(d,J=8.2Hz,1H),7.66(d,J=8.6,2H),7.92(d,J=8.5,2H);IR(KBr,cm-1):2958,2931,2867,1702,1648,1613,1514,1496,1461,1365,1349,1324,1312,1284,1213,1165,1125,1068,1015,968,843,822;MS(ESI):m/z[M+H]+:499.3;Anal.Calcd.for C29H33F3N2O2:C 69.86;H 6.67;N 5.62;found:C69.82;H6.70;N 5.68.
实施例10
2-脱氢枞基-4-对氨基苯基-1,3,4-噁二嗪-5-酮(Ⅰ-a10)的合成
参照实施例2的合成方法,合成出化合物Ⅰ-a2。将化合物Ⅰ-a7(0.06g,0.13mmol)溶于15ml乙醇,加入水(1.5ml)、还原铁粉(0.056g,1mmol),滴入浓HCl(12滴),85℃回流2小时,反应结束后将反应液倒入20ml冷水中,用二氯甲烷萃取三次,合并有机相,依次用水和饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩去除溶剂。产物经硅胶柱层析纯化(石油醚/丙酮5:1,v/v),得到化合物I-a10的深黄色油状物(51.2mg,91%)。
1H NMR(600MHz,CDCl3):δ1.24(d,J=7.0Hz,6H),1.27(s,3H),1.34(s,3H),1.49(dt,J=12.6,3.6Hz,1H),1.60~1.86(m,6H),2.18(dd,J=12.5,2.2Hz,1H),2.32(brd,J=12.9Hz,1H),2.83(m,1H),2.87~2.92(m,2H),4.53(d,J=15.1Hz,1H),4.58(d,J=15.1Hz,1H),5.30(s,2H),6.69(dt,J=8.8,2.1Hz,2H),6.89(d,J=1.6Hz,1H),7.00(dd,J=8.1,1.6Hz,1H),7.17(d,J=8.2Hz,1H),7.40(dd,J=8.8,2.1Hz,2H);IR(KBr,cm-1):3431,3368,2949,2925,2857,1731,1682,1629,1511,1460,1382,1283,1210,1184,1125,1084,1057,1021,969,884,825,750,712,685;MS(ESI):m/z[M+H]+:446.3;Anal.Calcd.for C28H35N3O2:C 75.47H 7.92;N9.43;found:C 75.51;H 7.86;N 9.38.
实施例11
2-脱氢枞基-4-邻甲苯基-1,3,4-噁二嗪-5-酮(Ⅰ-b1)的合成
参照实施例1的合成方法,以脱氢枞酸和邻甲基苯肼盐酸盐为原料,在相同条件下反应得黄色固体的脱氢枞酰邻甲基苯肼(Ⅱ-b1)(2.13g,53%)。然后以化合物Ⅱ-b1为原料,在相同条件下反应,产物经硅胶柱层析纯化(石油醚/丙酮100:1,v/v),得到化合物I-b1的黄绿色固体(26.1mg,24%)。
M.p.134~136℃;1H NMR(600MHz,CDCl3):δ1.22(d,J=7.0Hz,6H),1.23(s,6H),1.49(dt,J=13.0,3.8Hz,1H),1.60~1.89(m,6H),2.19(dd,J=12.5,2.2Hz,1H),2.25(s,3H),2.32(brd,J=13.1Hz,1H),2.83(m,1H),2.87~2.92(m,2H),4.59(d,J=15.1Hz,1H),4.64(d,J=15.1Hz,1H),6.89(d,J=1.7Hz,1H),7.01(dd,J=8.2,2.0Hz,1H),7.17(d,J=8.1Hz,1H),7.28(m,4H);IR(KBr,cm-1):2953,2928,2868,1695,1639,1495,1459,1385,1283,1219,1176,1131,1057,971,879,822,761,717,628;MS(ESI):m/z[M+H]+:445.3;Anal.Calcd.for C29H36N2O2:C 78.34;H 8.16;N 6.30;found:C 78.39;H 8.20;N 6.27.
实施例12
2-脱氢枞基-4-邻氯苯基-1,3,4-噁二嗪-5-酮(Ⅰ-b2)的合成
参照实施例1的合成方法,以脱氢枞酸和邻氯苯肼盐酸盐为原料,在相同条件下反应得白色固体的脱氢枞酰邻氯苯肼(Ⅱ-b2)(1.56g,37%)。然后以化合物Ⅱ-b2为原料,在相同条件下反应,产物经硅胶柱层析纯化(石油醚/丙酮100:1,v/v),得到化合物I-b2的微黄色固体(37.2mg,34%)。
M.p.166~168℃;1H NMR(600MHz,CDCl3):δ1.22(d,J=8.6Hz,6H),1.23(s,6H),1.49(dt,J=12.6,3.8Hz,1H),1.60~1.87(m,6H),2.19(dd,J=12.5,2.2Hz,1H),2.32(brd,J=13.1Hz,1H),2.83(m,1H),2.87~2.92(m,2H),4.61(d,J=15.2Hz,1H),4.66(d,J=15.1Hz,1H),6.90(d,J=2.0Hz,1H),7.01(dd,J=8.2,2.0Hz,1H),7.17(d,J=8.1Hz,1H),7.33(dt,J=7.4,2.0Hz,1H),7.37(dt,J=7.5,1.8Hz,1H),7.41(dd,J=7.4,2.0Hz,1H),7.50(dd,J=7.4,2.0Hz,1H);IR(KBr,cm-1):2953,2928,2867,1702,1639,1582,1481,1447,1386,1287,1219,1176,1137,1071,1031,821,763,751,736,722,621;MS(ESI):m/z[M+H]+:465.2;Anal.Calcd.for C28H33ClN2O2:C 72.32;H 7.15;N 6.02;found:C 72.34;H7.19;N 5.98.
实施例13
体外抗菌活性筛选
筛选菌株为:细菌:大肠杆菌(Escherichia coli)、金黄色葡萄球菌(Staphylococcus aureus)、枯草芽孢杆菌(Bacillus subtilis)、荧光假单胞菌(Pseudomonas fluorescens);真菌:白色念珠菌(Candida albicans)、热带假丝酵母(Candida tropicalis)、桔青霉(Penicillium citrinum)。
实验方法:
最低抑菌浓度(MIC)采用二倍稀释法测定。将待测化合物分别用DMSO配成500μg/ml的溶液。将待测化合物在96孔板上连续稀释2倍,从第1到第12孔配成一系列的浓度梯度(250~0.122μg/ml),每孔含100μL该溶液。将预先培养的细菌和真菌制成菌悬液,向每孔中加入100μL的菌悬液,以不含样品的无菌水和菌悬液混合作为对照。将96孔板在28℃下培养。待细菌培养24h,真菌培养48h后观察,以不产生浑浊的最低浓度的孔对应的浓度作为该样品对该测试菌的最低抑菌浓度。每个样品对每种测试菌重复3次,结果取平均值。阿米卡星和酮康唑分别作为抗细菌和抗真菌活性的阳性对照。脱氢枞酸噁二嗪类杂环衍生物的体外抑菌作用的结果如表1所示。
表1
如表1结果所示,所合成的脱氢枞酸噁二嗪类杂环衍生物对四种细菌株分别具有明显的体外抑制作用。其中,化合物I-a8(对氰基)和I-a10(对胺基)对四株细菌的抑制效果最好,对其中一株或多株菌株表现出显著的抑制作用,如I-a10对枯草芽孢杆菌的MIC达到1.9μg/mL,接近阳性对照阿米卡星;另外,化合物I-a4、I-a5和I-b2对大肠杆菌或枯草芽孢杆菌表现出中等的抑制作用(MIC=15.6μg/mL),而化合物I-a1、I-a2、I-a3、I-a6、I-a7、I-a9和I-b1也对一株或多株细菌表现出一定的抑制作用(MIC=31.2μg/mL)。而对于三株真菌,除了化合物I-a7对白色念珠菌表现出较弱的抑制作用外(MIC=31.2μg/mL),其它化合物均未表现出显著的活性(MIC>50μg/mL)。以上结果表明,该系列化合物对细菌具有显著的抑制作用,具有开发新型抗细菌剂的潜力。
以上显示和描述了本发明的基本原理、主要特征和本发明的优点。本行业的技术人员应该了解,本发明不受上述实施例的限制,上述实施例和说明书中描述的只是说明本发明的原理,在不脱离本发明精神和范围的前提下,本发明还会有各种变化和改进,本发明要求保护范围由所附的权利要求书、说明书及其等效物界定。
Claims (8)
1.一种具有通式(I)所示结构的脱氢枞酸噁二嗪类杂环衍生物及其在药学上可接受的盐:
其中,脱氢枞酸噁二嗪类杂环衍生物I-a1至I-a9,I-b1至I-b2、I-a10对应的R1和R2分别为:
I-a1:R1为H,R2为H;I-a2:R1为H,R2为Me;
I-a3:R1为H,R2为Et;I-a4:R1为H,R2为F;
I-a5:R1为H,R2为Cl;I-a6:R1为H,R2为Br;
I-a7:R1为H,R2为NO2;I-a8:R1为H,R2为CN;
I-a9:R1为H,R2为CF3;I-b1:R1为Me,R2为H;
I-b2:R1为Cl,R2为H;I-a10:R1为NH2,R2为H。
2.权利要求1所述的通式(I)所示结构的脱氢枞酸噁二嗪类杂环衍生物I-a1至I-a9,I-b1至I-b2的制备方法,其特征在于包括如下步骤:
(1)脱氢枞酸经过氯化亚砜酰氯化反应得到脱氢枞酰氯,其结构如下:
(2)脱氢枞酰氯与含有不同取代基的苯肼盐酸盐反应得到相对应取代基的脱氢枞酰苯肼衍生物,结构式如式II所示:
(3)脱氢枞酰苯肼衍生物与氯乙酰氯反应环化,得到相对应取代基的脱氢枞酸噁二嗪类杂环衍生物,结构式如式Ⅰ所示:
3.根据权利要求2所述的通式(I)所示结构的脱氢枞酸噁二嗪类杂环衍生物I-a1至I-a9,I-b1至I-b2的制备方法,其特征在于:
在步骤(1)中,将脱氢枞酸溶于环己烷,缓慢滴加SOCl2后85℃回流2小时,后减压浓缩去除溶剂;所述脱氢枞酸与SOCl2的摩尔比为6.6:13.3;所述脱氢枞酸与环己烷的质量体积比为1g/10ml;
在步骤(2)中,再加入环己烷,加入苯肼盐酸盐,在冰浴条件下缓慢滴加三乙胺,在冰浴条件下反应1小时,室温下反应3小时,反应结束后将对反应液进行抽滤取溶液,用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩去除溶剂,用甲醇重结晶,得黄色固体的脱氢枞酰苯肼Ⅱ-a1;所述苯肼盐酸盐与三乙胺的摩尔比为1:2;所述环己烷与三乙胺的体积比为20:3;
在步骤(3)中,取脱氢枞酰苯肼Ⅱ-a1溶于10ml的2-丁酮(无水),缓慢滴加氯乙酰氯,85℃回流1小时,冷却至室温,加入K2CO3,回流3小时,反应结束后减压浓缩去除溶剂,加入乙酸乙酯溶解,饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩去除溶剂,所述脱氢枞酰苯肼Ⅱ-a1、氯乙酰氯与K2CO3的摩尔比为0.26:0.26:3;所述2-丁酮(无水)与氯乙酰氯的体积比为10ml:21μL;产物用硅胶柱层析纯化,所述石油醚/丙酮的体积比为200:1,得到化合物I-a1的淡黄色固体。
4.根据权利要求3所述的通式(I)所示结构的脱氢枞酸噁二嗪类杂环衍生物I-a1至I-a9,I-b1至I-b2的制备方法,其特征在于:
所述含有不同取代基的苯肼盐酸盐为对甲基苯肼盐酸盐时,则步骤(2)中,相同条件下,制得化合物I-a2;
所述含有不同取代基的苯肼盐酸盐为对乙基苯肼盐酸盐3时,则步骤(2)中,相同条件下,制得化合物I-a3;
所述含有不同取代基的苯肼盐酸盐的苯肼盐酸盐为对氟苯肼盐酸盐4时,则步骤(2)中,相同条件下,制得化合物I-a4;
所述含有不同取代基的苯肼盐酸盐的苯肼盐酸盐为对氯苯肼盐酸盐5时,则步骤(2)中,相同条件下,制得化合物I-a5;
所述含有不同取代基的苯肼盐酸盐的苯肼盐酸盐为对溴苯肼盐酸盐时,则步骤(2)中,相同条件下,制得化合物I-a6;
所述含有不同取代基的苯肼盐酸盐的苯肼盐酸盐为对硝基苯肼盐酸盐7时,则步骤(2)中,相同条件下,制得化合物I-a7;
所述含有不同取代基的苯肼盐酸盐的苯肼盐酸盐为对氰基苯肼盐酸盐8时,则步骤(2)中,相同条件下,制得化合物I-a8;
所述含有不同取代基的苯肼盐酸盐的苯肼盐酸盐为对三氟甲基苯肼盐酸9时,则步骤(2)中,相同条件下,制得化合物I-a9;
所述含有不同取代基的苯肼盐酸盐的苯肼盐酸盐为邻甲基苯肼盐酸盐b1时,则步骤(2)中,相同条件下,制得化合物I-b1;
所述含有不同取代基的苯肼盐酸盐的苯肼盐酸盐为邻氯苯肼盐酸盐b2时,则步骤(2)中,相同条件下,制得化合物I-b2。
5.根据权利要求4所述的通式(I)所示结构的脱氢枞酸噁二嗪类杂环衍生物I-a1至I-a9,I-b1至I-b2的制备方法,其特征在于:
所述不同取代基苯肼盐酸盐是由对应的取代基苯胺经过亚硝酸钠重氮盐后再用氯化亚锡还原制得。
6.根据权利要求1所述的通式(I)所示结构的脱氢枞酸噁二嗪类杂环衍生物I-a10的制备方法,其特征在于包括如下步骤:
(1)脱氢枞酸经过氯化亚砜酰氯化反应得到脱氢枞酰氯,其结构如下:
(2)脱氢枞酰氯与含有对硝基的苯肼盐酸盐反应得到相对应取代基的脱氢枞酰苯肼衍生物,结构式如式Ⅱ-a7所示:
(3)脱氢枞酰对硝基苯肼与氯乙酰氯反应环化,得到相对应取代基的脱氢枞酸噁二嗪类杂环衍生物,结构式如式Ⅰ-a7所示:
(4)2-脱氢枞基-4-对硝苯基-1,3,4-噁二嗪-5-酮被铁粉还原,得到2-脱氢枞基-4-对胺苯基-1,3,4-噁二嗪-5-酮,结构式如式Ⅰ-a10所示:
7.权利要求1所述的一种具有通式(I)所示结构的脱氢枞酸噁二嗪类杂环衍生物及其药学上可接受的盐在制备抗菌药物中应用。
8.根据权利要求7所述的应用,其特征在于:所述菌类为细菌。
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