CN1390837A - 具有抗炎和抗肿瘤作用r-双或糖苯丙异硒唑取代化合物 - Google Patents
具有抗炎和抗肿瘤作用r-双或糖苯丙异硒唑取代化合物 Download PDFInfo
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Abstract
一种具有抗炎和抗肿瘤作用R-双或糖苯丙异硒唑取代化合物,属于具有抗炎、抗肿瘤的化合物,命名为苯并异硒唑酮2取代衍生物.它的结构式为右式,R’=-烷基苯丙异硒唑、-苯基苯丙异硒唑、-糖基苯丙异硒唑和苯丙异硒唑衍生金属配合物。即R’1化合物(I)命名:1,2-二[(1,2-苯并异硒唑-3(2H)一酮)]-乙烷;R2’化合物(II)命名:4,4’-二[2(1,2-苯并异硒唑-3(2H)一酮)]-联苯;R3’化合物(III)命名:2{2-(1,3,4,6-四-O-乙酰基)-2-去氧-D-吡喃葡萄糖基}-1,2-苯并异硒唑-3(2H)-酮。R4’化合物(IV)命名:二{乙-(1,2-苯丙异硒唑-3(2H)-酮)-乙酸}环己二胺合金属(II)。
Description
本发明是一种具有抗炎和抗肿瘤作用R-双或糖苯丙异硒唑取代化合物,即属于在Ebselen基础上改造成抗炎活性更高,适用性更广;低毒的新型抗炎活性化合物。
同时本发明也利用Ebselen抗氧化母核结构,定位改造出具有抗肿瘤活性的新型有机硒化合物。
已有文献说明,微量元素硒在生命科学的重要性,使得含硒药物成为众人瞩目的焦点。通常无机硒不易被吸收,在血液中维持时间短,生物活性较低,毒性大;有机硒易被肌体吸收,在血液中维持时间较长,在体内易被转化为有活性的代谢中间产物,生物活性较长,毒性相对较小。
硒是重要的微量元素之一,人体中血硒含量长期低于0.1ppm有可能引起肝坏死,心肌损伤,癌症和关节炎等众多疾病。
本发明的目的是在Ebselen基础上改造出抗炎性更高;适应性更广;毒性较低的新型抗炎药物;同时也利用Ebselen抗氧化母核结构定位改造出具有“生物应答调节剂”特点的抗肿瘤活性的有机硒化合物。
本发明的取代化合物特征:
1.其化合物药物的结构通式为
R’=-烷基苯丙异硒唑(I);-苯基苯丙异硒唑(II);-糖基苯丙异硒唑(III),即R1’为:1,2-={(1,2-苯并异硒唑-3(2H)-酮)}-乙烷;R2’为::4,4’-二{2(1,2-苯并异硒唑-3(2H)-酮)-联苯;R3’为:2{2-(1,3,4,6-四-O-乙酰基-2-去氧-D-吡喃葡萄糖基)}-1,2苯并异硒唑-3(2H)-酮;R4’二(乙-(1,2-苯丙并硒唑-3(2H)-酮)-乙酸环己二胺合金属名(II)。
2.化合物(I),即,1,2-二{2(1,2-苯并异硒唑-3(2H)-酮)}-乙烷的制作工艺如下:冰浴,N2保护下,向包含0.14ml乙二胺,1.29ml三乙胺的四氢呋喃中滴加1g2-硒氯苯甲酰氯于在四氢呋喃中的溶液,出现白色沉淀,搅拌3小时后得淡黄色乳浊液;减压蒸去溶剂,水洗,抽滤,DMSO重结晶得0.1g淡黄色固体,产率11%m.p>320℃。
3.化合物(II),即4,4’-二{(1,2)-苯并异硒唑-3(2H)-酮}-联苯的制作工艺如下:冰浴中,N2保护下,向包含0.182g联苯胺和0.62ml三乙胺的四氢呋喃中滴加0.5g2-硒氯苯甲酰氯的四氢呋喃溶液,搅拌3小时,产生大量白色固体,抽滤,用四氢呋喃,乙醇洗涤,DMSO重结晶,得浅淙色固体0.1g,产率18.2%,m.p>320℃
4.化合物(III),即2{2-(1,3,4,6-四-O-乙酰基)-2-去氧-D-吡喃葡萄糖基}-1,2苯并异硒唑-3(2H)-酮的制作工艺如下:在N2保护下,冰浴中,730mg{1,3,4,6-四乙酰基-D-氨基葡萄糖溶于氯仿中,加入0.64ml三乙胺,电磁搅拌下,缓慢滴入0.551g2-硒氯苯甲酰氯的氯仿溶液,搅拌2小时,反应液以硅胶拌样,经硅胶柱层析,石油醚∶乙酸乙酯=3∶1分离得淡黄色固体200mg,产率18%,m.p73-75℃
本化合物的结构及具体合成路线如下:
化合物R3’(III)命名:2{2-(1,3,,6,-四-O-乙酰基-2-去氧-D-吡喃葡萄糖基)}-1,2苯并异硒唑-3(2H)-酮。
为表明该化合物药理作用,现将相关药效结果列于表1、表2中。
表1E003体外生物活性初筛,它说明:表1是化合物(I)(E003)体外抗肿瘤活性筛选。结果表明,化合物(I)对Bel-7402人肝癌、对KB人鼻咽癌和人宫颈癌(HeLa)有抗癌活性。
表2 E001-E004对二甲苯所致小鼠耳肿胀抑制(抗炎初筛),它说明:化合物(I)、(II)和(III)(E001-E003)有优于消炎痛和阿司匹林的抗炎活性。
表1。
化合物名称 | 测试目的和模型 | 观察指标 | 测试效应 | 剂量或浓度 |
E003 | 抗肿瘤SRB法(Bel-7402人肝癌) | 抑制率% | 2.05 | 1μM |
7.28 | 5μM | |||
58.72 | 10μM | |||
82.46 | 50μM | |||
89.57 | 100μM | |||
抗肿瘤SRB法(KB人鼻咽癌) | 抑制率% | 2.94 | 1μM | |
4.61 | 5μM | |||
25.71 | 10μM | |||
92.49 | 50μM | |||
97.46 | 100μM | |||
E003 | 抗肿瘤SRB法(HeLa人宫颈癌) | 抑制率% | 4.89 | 1μM |
12.16 | 5μM | |||
64.12 | 10μM | |||
86.18 | 50μM | |||
88.12 | 100μM |
表2。
化合物名称生理盐水消炎痛阿司匹林EbselenE001E002E003E004 | 抗炎模型 | 肿胀度%14.6619.8910.636.224.819.857.918.51 | 抑制率(%) | 剂量或浓度 |
耳肿胀耳肿胀耳肿胀耳肿胀耳肿胀耳肿胀耳肿胀耳肿胀 | 68.72(与消炎痛比)41.48(与阿司匹林比)75.81(与消炎痛比)54.75(与阿司匹林比)50.47(与消炎痛比)7.33(与阿司匹林比)60.20(与消炎痛比)25.58(与阿司匹林比)57.21(与消炎痛比)19.94(与阿司匹林比) | 22mg/kg200mg/kg50mg/kg50mg/kg50mg/kg50mg/kg50mg/kg |
化合物(I)、(II)、(III)、(IV)是在考虑充分保留活性母核,增强功能基团的药物设计思路下,定位设计的一系列化合物;由于结构的特点因而在生物体内具有多作用靶点,从而具有多种生物活性。由于此化合物是以生物应答器中的调节点为靶标定向设计的抗肿瘤药物,因而在作为抗肿瘤药物时具有“生物应答调节剂”的抗肿瘤特点。是一类新型的具有全面调节机体、多作用靶点的抗肿瘤活性化合物。
本发明化合物是在科学、完整的思路下设计合成的,是新型的具有药物活性的系列化合物。它优于阿斯匹林的抗炎活性,使其可能成为一类抗炎新药;它显示出的抗肿瘤活性使其有望成为新型抗肿瘤药物。
本发明的附图如下:
图1为2-二{2(1,2-苯并异硒唑-3(2H)-酮)}-乙烷的1HNMR谱图。
图2为2-二{2(1,2-苯并异硒唑-3(2H)-酮)}-乙烷的EI-MS谱图。
图3为4,4’-二{2(1,2-苯并异硒唑-3(2H)-酮)}-联苯的1HNMR谱图。
图4为4,4’-二{2(1,2-苯并异硒唑-3(2H)-酮)}-联苯的EI-MS谱图。
图5为2[2-(1,3,4,6-四-O-乙酰基)-2-去氧-D-吡喃葡萄糖基]-1,2苯并异硒唑-3(2H)-酮(9)的1HNMR谱图。
图6为2[2-(1,3,4,6-四-O-乙酰基)-2-去氧-D-吡喃葡萄糖基]-1,2苯并异硒唑-3(2H)-酮(9)的FAB-MS谱图。
图7为2[2-(1,3,4,6-四-O-乙酰基)-2-去氧-D-吡喃葡萄糖基]-1,2苯并异硒唑-3(2H)-酮(9)的13CNMR谱图。
图8为2[2-(1,3,4,6-四-O-乙酰基)-2-去氧-D-吡喃葡萄糖基]-1,2苯并异硒唑-3(2H)-酮(9)的IR谱图。
本发明的附图说明如下:
如图1、图2所示:EI-MS:(m/z)(m+)424;1HNMR(DMSO-d6),7.37-7.98(8H,m,ArH),4.02(4H,S,-CH2CH2-)。
如图3、图4所示:EI-MS:(m/z)(m+)550;1HNMR(DMSO-d6),7.48-8.12(m,16H,ArH)。
如图5、图6、图7、图8所示:IR1745(-CO);UV(CHCl3)320nm,260nm(示异硒唑环);FAB-MS(m/z)566.3(M+K);1HNMR:δH(ppm)7.24-8.12(4H,m,ArH),6.20(IH,d,糖端基H),3.97-5.64(m,6H,糖环H),1.82-2.16(12H,m,-COCH3);13CNMR:δ(ppm)166.77,168.66,169.29,169.61,170.44(-CO),124.22,126.28,128.81,132.37,138.30(芳环碳),91.43,(糖端基碳,C-I),60.15,61.35,68.35,71.91,72.35,(糖环碳,C-2,3,4,5,6),20.34,20.48,20.55,20.78,(-COCH3)。
Claims (4)
1.一种具有抗炎和抗肿瘤作用R-双或糖苯丙异硒唑取代化合物,其特征在于:其化合物药物的结构式为:R’=烷基苯丙异硒唑;苯基苯丙异硒唑;糖基苯丙异硒唑,即R’1化合物(I)命名:1,2-二[(1,2-苯并异硒唑-3(2H)一酮)]-乙烷;R2’化合物(II)命名:4,4’-二[2(1,2-苯并异硒唑-3(2H)-酮)]-联苯;R3’化合物(III)命名:2{2-(1,3,4,6-四-O-乙酰基)-2-去氧-D-吡喃葡萄糖基}-1,2苯并异硒唑-3(2H)-酮。
2.据权利要求1所述的一种具有抗炎和抗肿瘤作用R-双或糖苯丙异硒唑取代化合物,其特征在于:1,2-二{2(1,2-苯并异硒唑-3(2H)-酮)}-乙烷的制作工艺如下:冰浴,N2保护下,向包含0.14ml乙二胺,1.29ml三乙胺的四氢呋喃中滴加1g2-硒氯苯甲酰氯于四氢呋喃中的溶液,出现白色沉淀,搅拌3小时后得淡黄色乳液;减压蒸去溶剂,水洗抽滤,DMSO重结晶得0.1g淡黄色固体,产率11%,m.p>320℃
3.根据权利要求1所述的具有抗炎和抗肿瘤作用R-双或糖苯丙异硒唑取代化合物,其特征在于:4,4`-二{2(1,2)-苯并异硒唑-3(2H)-酮}-联苯的制作工艺如下:冰浴中,N2保护下向包含0.1842g联苯胺和0.62ml三乙胺的四氢呋喃中滴加0.5g2-硒氯苯甲酰氯的四氢呋喃溶液,搅拌3小时,产生大量白色固体,抽滤,用四氢呋喃,乙醇洗涤,DMSO重结晶,得浅淙色固体0.1g产率,18.2%,m.p>320℃。
4.权利要求1所述的具有抗炎和抗肿瘤作用R-双或糖苯丙异硒唑取代化合物,其特征在于:2{2-(1,3,4,6-四-O-乙酰基)-2-去氧-D-吡喃葡萄糖基}-1,2苯并异硒唑-3(2H)一酮的制作工艺如下:在N2保护下,冰浴中,730mg{1,3,4,6-四乙酰基-D-氨基葡萄糖溶于氯仿中,加入0.64ml三乙胺,电磁搅拌下,缓慢滴入0.551g 2-硒氯苯甲酰氯的氯仿溶液,搅拌2小时,反应液以硅胶拌样,经硅胶柱层析,石油醚∶乙酸乙酯=3∶1分离得淡黄色固体200mg,产率18%,m.p73-75℃。
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CNB011186666A CN1166651C (zh) | 2001-06-08 | 2001-06-08 | 具有抗炎和抗肿瘤作用r-双或糖苯丙异硒唑取代化合物 |
EP02742662A EP1422225B1 (en) | 2001-06-08 | 2002-06-10 | Benzoisoselenazole derivatives with anti-inflammation, antineoplastic and anti-thrombosis activity and their use |
RU2003134946/04A RU2324688C2 (ru) | 2001-06-08 | 2002-06-10 | Производные бисбензизоселеназолонила с противоопухолевым, противовоспалительным и антитромботическим действием и их применение |
JP2004503452A JP4500672B2 (ja) | 2001-06-08 | 2002-06-10 | 抗炎症、抗ウイルスおよび抗血栓症活性を有するベンゾイソセレンアゾール誘導体ならびにそれらの使用 |
AT02742662T ATE540030T1 (de) | 2001-06-08 | 2002-06-10 | Benzoisoselenazolderivate mit entzündungshemmender, antineoplastischer und antithrombotischer wirkung und deren verwendungen |
PCT/CN2002/000412 WO2003095436A1 (fr) | 2001-06-08 | 2002-06-10 | Derives de benzoisoselenazole ayant une activite anti-inflammatoire, antivirale et antithrombose et leur utilisation |
AU2002346271A AU2002346271A1 (en) | 2001-06-08 | 2002-06-10 | Benzoisoselenazole derivatives with anti-inflammation, antivirus and anti-thrombosis activity and their use |
ES02742662T ES2378983T3 (es) | 2001-06-08 | 2002-06-10 | Derivados de benzoisoselenazolonilo que tienen actividades antineoplásica, antiinflamatoria y antitrombótica y su uso |
US10/479,883 US7495019B2 (en) | 2001-06-08 | 2002-06-10 | Benzoisoselenazole derivatives with anti-inflammation, antivirus and antithrombosis activity and their use |
CA2450087A CA2450087C (en) | 2001-06-08 | 2002-06-10 | Benzisoselenazolonyl derivatives having antineoplastic, anti-inflammatory and antithrombotic activities as well as their use |
US12/349,829 US8609702B2 (en) | 2001-06-08 | 2009-01-07 | Benzoisoselenazole derivatives with anti-inflammation, antivirus and antithrombosis activity and their use |
US12/351,100 US7820829B2 (en) | 2001-06-08 | 2009-01-09 | Bisbenzisoselenazolonyl derivatives having antineoplastic, anti-inflammatory and antithrombotic activities as well as their use |
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2001
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2002
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RU2003134946A (ru) | 2005-06-10 |
AU2002346271A1 (en) | 2003-11-11 |
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CA2450087A1 (en) | 2003-11-20 |
ATE540030T1 (de) | 2012-01-15 |
CN1166651C (zh) | 2004-09-15 |
US20090117204A1 (en) | 2009-05-07 |
WO2003095436A1 (fr) | 2003-11-20 |
EP1422225B1 (en) | 2012-01-04 |
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US8609702B2 (en) | 2013-12-17 |
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US20050014801A1 (en) | 2005-01-20 |
RU2324688C2 (ru) | 2008-05-20 |
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