CN100351248C - 染料木素衍生物及其制法和用途 - Google Patents
染料木素衍生物及其制法和用途 Download PDFInfo
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Abstract
一类染料木素衍生物,它有如下通式,式中:R1,R2,R3=-H或-(CH2)nX,其中:n=1~6,X=-H、卤素、烷硫基或三级氨基,R4=-H或-SO3H。它能应用于制备治疗骨质疏松症的药物。本发明公开了其制法。
Description
技术领域
本发明涉及异黄酮类化合物染料木素衍生物及其制法,以及它们在制备预防或治疗骨质疏松症药物中的应用。
背景技术
染料木素(Genistein)是一种异黄酮类化合物,它存在于豆科植物中。现有的研究表明,中国和日本乳腺癌和前列腺癌发病率相对较低,可能与食用黄豆有关,日本人血浆总异黄酮水平比西方人高7~100倍,而黄豆是染料木素唯一的膳食来源。
骨质疏松症(Osteoporosis)是以骨组织显微结构退化,骨矿成分和骨基质等比例地逐渐减少,骨质变薄,骨小梁数量减少,骨脆性增加和骨折发生危险度升高的一种全身骨代谢障碍性疾病。骨质疏松症是危及老年人健康的最常见疾病,特别是绝经期和绝经期后的妇女。美国约有1400~2500万人患有骨质疏松症,医药开支每年在200亿美元以上(参见:Ray,N.F.;Chan,J.K.Medicalexpenditures for the treatment of osteoporosis fracture in the United States in 1995report from the National Osteoporosis Foundation.J.Bone Miner Res.1998,12:24-35.)。在中国,绝经后女性骨质疏松发病率可高达25%-50%,并随着年龄增大发病率增高(参见:Nguyen,T.V.;Center,J.R.;EismanJ.A.Association betweenbreaster cancer and bone mineral density.The Dubbo osteoporosis epidemiologystudy.Muturitas,2000,36(1):27-34.)。由于绝经后的女性容易患骨质疏松症,所以绝经后妇女骨质疏松症已成为原发性骨质疏松症的同义语,被称为是“一种使1/4妇女倒下的严重疾病”。因此,寻找治疗及预防骨质疏松的药物已成为当前医药的热门课题。
异黄酮类化合物是一类植物性激素,广泛存在于豆科植物中。作为植物雌激素,异黄酮与17β雌二醇具有相似的结构。现已证明异黄酮类化合物是一种雌激素样化合物,能与内源性雌激素受体结合发挥雌激素样作用。在内源性雌激素水平较低时,表现为雌激素促效剂(Estrogenic agonist)(参见:Rickard,D.J.;Monroe,D.G;Ruesink,T.J.;Khosla,S.;Riggs,B.L.;Spelsberg,T.C.Phytoestrogengenistein acts as an estrogen agonist on human osteoblastic cells through estrogenreceptors alpha and beta.Cell.Biochem.2003,89,633-646.,)而在内源性雌激素水平较高时,又可表现为雌激素拮抗剂(Estrogenic antagonist)(参见:Wang,D.H.;Gutkowska,J.;Marcinkiewicz,M.Genistein supplementation stimulates theoxytocin system in the aorta of ovariectomized rats.Cardiovascular Research 2003,57(1):186-194.)。这种双向生物调节作用被称为雌激素受体调节剂(参见:Lonard,D.M.;Smith,C.L.Molecular perspectives on selective estrogen receptor modulators(SERMs):progress in understanding their tissue-specific agonist and antagonistactions,Steroids,2002,67(1):15-24.,)可用于治疗妇女更年期综合症和骨质疏松症,但不会诱导乳腺癌、子宫癌的发生(参见:Ishimi,Y.;Arai,N.;Wang,X.X.;Wu,J.;Umegaki,K.;Miyaura,C.;Takeda,A.;Ikegami,S.Diffference in effective dosageof genistein on bone and uterus in ovarietomized mice.Biochem.Biophys.Res.Commun.2000,274,69-701.)。从大量的研究文献看出,这种新型的雌激素受体调节剂—异黄酮类化合物及其衍生物,将会成为市场上最具有潜力的治疗骨质疏松症药物之一。
发明内容
本发明的目的在于提供一类新的异黄酮类化合物,即染料木素衍生物以及它们的制法和用途。
本发明的技术方案如下:
一类染料木素衍生物,它有如下通式:
式中:R1,R2,R3=-H或-(CH2)nX,其中:n=1~6,X=-H、卤素、烷硫基或三级氨基,R4=-H或-SO3H。
上述的染料木素衍生物,所述的卤素是溴,所述的烷硫基是2-羟基乙硫基,所述的三级氨基是N-吡啶基。
一种染料木素衍生物的制法,它是将染料木素与α-卤代烷或α,ω-二卤代烷在40~80℃反应8~48小时,制得X为H或卤素的染料木素衍生物,将X为H或卤素的染料木素衍生物再与硫醇在48℃反应12小时或与三级胺在160℃反应2小时制得X为烷硫基或三级氨基的染料木素衍生物。
将上述制得的染料木素衍生物与浓硫酸在0℃反应8~10小时,制得R4为磺酸基的染料木素衍生物。
上述的染料木素衍生物的制法,可以用超声波辅助反应,以加快反应,缩短反应时间。
本发明的染料木素衍生物对卵巢切除的大鼠骨质疏松有明显的缓解作用,而且其子宫的增重不明显,本发明的染料木素衍生物几乎没有毒性,因此可以应用于制备治疗骨质疏松症的药物。
附图说明
图1为大鼠股骨的X-射线透视图,其中:Sham为假手术组,灌服试剂空白;Ovx为卵巢切除组,灌服试剂空白。10为卵巢切除组,每天灌服化合物10(25μmol/kg),E2为卵巢切除组每天灌服雌二醇(17β-Estradiol,E2)(0.5μmol/kg)作为阳性对照,G为卵巢切除组每天灌服母体化合物染料木素(genistein,25μmol/kg)作为阳性对照。
具体实施方式
本发明制备了表1所列的化合物。
实施例一:4′,5-二羟基-7-(2-溴乙氧基)-异黄酮(1)的制备染料木素(0.27g,1mmol),1,2-二溴乙烷(4.7g,25mmol),K2CO3(0.07g,0.5mmol)溶解在60ml的DMF中,40℃在40Hz超声波作用下,反应1.5小时(或在40℃下加热搅拌反应8小时)。反应完成后,反应混合物冷却到室温,滤除不溶物后,滤液减压蒸馏得到淡黄色固体,丙酮中重结晶得到浅黄色针状晶体,产率86%。Mp 175-178℃;IR(KBr)cm-1:3421(OH),2922(CH2),1665(C=O);1H NMR(DMSO-d6):δ3.81(t,2H,CH2Br),4.43(t,2H,OCH2),6.41(m,1H,H-8),6.67(m,1H,H-6),6.82(d,2H,H-3′,H-5′),7.38(d,2H,H-2′,H-6′),8.39(s,1H,H-2),9.64(s,1H,4′-OH),12.95(s,1H,5-OH)。
表1.本发明的染料木素衍生物通式I中各R基团所代表的取代基
实施例二:5-羟基-4′,7-二-(2-溴乙氧基)-异黄酮(2)的制备
染料木素(0.27g,1mmol),1,2-二溴乙烷(9.4g,50mmol),K2CO3(0.14g,1mmol)溶解在60ml的DMF中,60℃在40Hz超声波作用下,反应3小时(或在60℃下加热搅拌反应16小时)。反应完成后,反应混合物冷却到室温,滤除不溶物后,滤液减压蒸馏得到淡黄色固体,丙酮中重结晶得到浅黄色针状晶体,产率82%。Mp 140-142℃;IR(KBr)cm-1:3447(OH),2929(CH2),1663(C=O);1HNMR(DMSO-d6):δ3.80(m,4H,2(CH2Br)),4.34(t,2H,OCH2),4.44(t,2H,OCH2),6.44(t,1H,H-8),6.70(t,1H,H-6),7.03(d,2H,H-3′,H-5′),7.50(d,2H,H-2′,H-6′),8.42(s,1H,H-2),12.93(s,1H,5-OH)。
实施例三:4′,5-二羟基-7-(3-溴丙氧基)-异黄酮(3)的制备
染料木素(0.27g,1mmol),1,3-二溴丙烷(5.1g,25mmol),K2CO3(0.07g,0.5mmol)溶解在60ml的DMF中,40℃在40Hz超声波作用下,反应1.5小时(或在40℃下加热搅拌反应8小时)。反应完成后,反应混合物冷却到室温,滤除不溶物后,滤液减压蒸馏得到淡黄色固体,丙酮中重结晶得到浅黄色针状晶体,产率85%。Mp 124-126℃;IR(KBr)cm-1:3423(OH),2934(CH2),1663(C=O);1H NMR(DMSO-d6):δ2.24(m,2H,CH2),3.65(t,2H,CH2Br),4.18(t,2H,OCH2),6.41(d,1H,H-8),6.67(s,1H,H-6),6.82(d,2H,H-3′,H-5′),7.38(d,2H,H-2′,H-6′),8.40(s,1H,H-2),9.63(s,1H,4′-OH),12.95(s,1H,5-OH)。
实施例四:5-羟基-4′,7-二-(3-溴丙氧基)-异黄酮(4)的制备
染料木素(0.27g,1mmol),1,3-二溴丙烷(10.2g,50mmol),K2CO3(0.14g,1mmol)溶解在60ml的DMF中,60℃在40Hz超声波作用下,反应3小时(或在60℃下加热搅拌反应16小时)。反应完成后,反应混合物冷却到室温,滤除不溶物后,滤液减压蒸馏得到淡黄色固体,丙酮中重结晶得到浅黄色针状晶体,产率80%。Mp 128-130℃;IR(KBr)cm-1:3447(OH),2927,2875(CH2),1661(C=O);1H NMR(DMSO-d6):δ2.24(m,4H,2(CH2)),3.65(m,4H,2(CH2Br)),4.08(m,4H,2(OCH2)),6.41(s,1H,H-8),6.66(s,1H,H-6),6.97(d,2H,H-3′,H-5′),7.50(d,2H,H-2′,H-6′),8.43(s,1H,H-2),12.91(s,1H,5-OH)。
实施例五:4′,5,7-三-(3-溴丙氧基)-异黄酮(5)的制备
染料木素(0.27g,1mmol),1,3-二溴丙烷(15.3g,75mmol),K2CO3(0.49g,3.5mmol)溶解在60ml的DMF中,80℃在40Hz超声波作用下,反应4小时(或在80℃下加热搅拌反应48小时)。反应完成后,反应混合物冷却到室温,滤除不溶物后,滤液减压蒸馏得到淡黄色固体,丙酮中重结晶得到无色针状晶体,产率90%。Mp 110-112℃;IR(KBr)cm-1:3447(OH),2930,2874(CH2),1644(C=O);1H NMR(DMSO-d6):δ2.22(m,6H,3(CH2)),3.66(m,4H,2(CH2Br)),3.82(t,2H,CH2Br),4.08(m,4H,2(OCH2)),4.23(t,2H,OCH2),6.53(t,1H,H-8),6.69(d,1H,H-6),6.97(d,2H,H-3′,H-5′),7.41(d,2H,H-2′,H-6′),8.20(s,1H,H-2)。
实施例六:4′,5-二羟基-7-[2-(2-羟基乙硫基)-乙氧基]-异黄酮(6)的制备
将4′,5-二羟基-7-(2-溴乙氧基)-异黄酮(0.37g,1mmol),巯基乙醇(0.15g,2mmol),三乙胺(0.11g,1mmol)溶解在50ml的乙醇中,48℃在40Hz超声波作用下,反应2小时(或在48℃下加热搅拌反应12小时)。反应完成后,反应混合物减压蒸馏得到淡黄色固体,用水洗涤后,丙酮中重结晶得到白色针状晶体,产率85%。Mp 132-135℃;IR(KBr)cm-1:3420(OH),2926(CH2),1664(C=O)1047(C-OH);1H NMR(DMSO-d6):δ2.66(t,2H,CH2-S),2.91(t,2H,S-CH2),3.55(q,2H,CH2-O),4.24(t,2H,OCH2),6.40(d,1H,H-8),6.66(t,1H,H-6),6.82(d,2H,H-3′,H-5′),7.38(d,2H,H-2′,H-6′),8.40(s,1H,H-2),9.62(s,1H,4′-OH),12.95(s,1H,5-OH);MS(ESI)calcd for C19H18O6S 374.0818,found,374.1095,[M+H]+375.1173,[2M+Na]+771.2198。
实施例七:5-羟基-4′,7-二-[2-(2-羟基乙硫基)-乙氧基]-异黄酮(7)的制备
将5-羟基-4′,7-二-(2-溴乙氧基)-异黄酮(0.48g,1mmol),巯基乙醇(0.30g.4mmol),三乙胺(0.22g.2mmol)溶解在50ml的乙醇中,48℃在40Hz超声波作用下,反应2小时(或在48℃下加热搅拌反应12小时)。反应完成后,反应混合物减压蒸馏得到淡黄色固体,用水洗涤后,丙酮中重结晶得到白色针状晶体,产率80%。Mp 66-68℃;IR(KBr)cm-1:3431(OH),2924,2854(CH)2,1663(C=O),1048(C-OH);1H NMR(DMSO-d6):δ2.66(t,4H,2(CH2-S)),2.90(q,4H,2(S-CH2)),3.55(q,4H,2(CH2-O)),4.15(t,2H,OCH2),4.25(t,2H,OCH2),6.42(d,1H,H-8),6.69(d,1H,H-6),7.00(t,2H,H-3′,H-5′),7.50(d,2H,H-2′,H-6′),8.46(s,1H,H-2),12.92(s,1H,5-OH);MS(ESI)calcd for C23H26O7S2478.1111,found,478.1499,[M+H]+479.1577,[M+Na]+501.1599,[2M+Na]+979.2706,[2M+K]+995.2557。
实施例八:4′,5-二羟基-7-[3-(2-羟基乙硫基)-丙氧基]-异黄酮(7)的制备
将4′,5-二羟基-7-(3-溴丙氧基)-异黄酮(0.39g,1mmol),巯基乙醇(0.15g,2mmol),三乙胺(0.11g,1mmol)溶解在30ml的乙醇中,48℃在40Hz超声波作用下,反应2小时(或在40℃下加热搅拌反应12小时)。反应完成后,反应混合物减压蒸馏得到淡黄色固体,用水洗涤后,丙酮中重结晶得到白色针状晶体,产率85%。Mp 152-154℃;IR(KBr)cm-1:3434(OH),2942,2920,2876(CH2),1664(C=O),1042(C-OH);1H NMR(DMSO-d6):δ1.95(m,2H,CH2),2.56(t,2H,CH2-S),2.64(t,2H,S-CH2),3.50(q,2H,CH2-O),4.14(t,2H,OCH2),6.39(q,1H,H-8),6.65(q,1H,H-6),6.80(m,2H,H-3′,H-5′),7.37(d,2H,H-2′,H-6′),8.40(s,1H,H-2),9.62(s,1H,4′-OH),12.95(s,1H,5-OH);MS(ESI)calcd for C20H20O6S388.0974,found,388.143,[M+H]+389.1221,[2M+Na]+799.1726。
实施例九:5-羟基-4′,7-二-[3-(2-羟基乙硫基)-丙氧基]-异黄酮(9)的制备
将5-羟基-4′,7-二-(3-溴丙氧基)-异黄酮(0.51g,1mmol),巯基乙醇(0.30g.4mmol),三乙胺(0.22g,2mmol)溶解在30ml的乙醇中,48℃在40Hz超声波作用下,反应2小时(或在48℃下加热搅拌反应12小时)。反应完成后,反应混合物减压蒸馏得到淡黄色固体,用水洗涤后,丙酮中重结晶得到无色针状晶体,产率80%。Mp 102-105℃;IR(KBr)cm-1:3421(OH),2923,2877(CH2),1671(C=O),1049(C-OH);1H NMR (DMSO-d6):δ1.93(m,4H,2(CH2)),2.56(t,4H,2(CH2-S)),2.64(m,4H,2(S-CH2)),3.51(t,4H,2(CH2-O)),4.14(t,4H,2(OCH2)),6.39(t,1H,H-8),6.64(t,1H,H-6),6.80(d,2H,H-3′,H-5′),7.36(d,2H,H-2′,H-6′),8.39(s,1H,H-2);MS(ESI)calcd for C25H30O7S2506.1423,found,506.1587,[M+H]+507.1665,[M+Na]+529.1236,[2M+Na]+1035.6531。
实施例十:4′,5,7-三-[3-(2-羟基乙硫基)-丙氧基]-异黄酮(10)的制备
将4′,5,7-三-(3-溴丙氧基)-异黄酮(0.63g,1mmol),巯基乙醇(0.30g,4mmol),三乙胺(0.33g,3mmol)溶解在30ml的乙醇中,48℃在40Hz超声波作用下,反应2小时(或在48℃下加热搅拌反应12小时)。反应完成后,反应混合物减压蒸馏得到淡黄色固体,用水洗涤后,丙酮中重结晶得到无色针状晶体,产率80%。Mp 78-80℃;IR(KBr)cm-1:3430(OH),2922,2872(CH)2,1639(C=O),1051(C-OH);1H NMR(DMSO-d6):δ1.96(m,6H,3(CH2)),2.56(m,6H,3(CH2-S)),2.66(m,4H,2(S-CH2)),2.78(t,2H,S-CH2),3.51(m,6H,3(CH2-O)),4.06(m,4H,2(OCH2)),4.16(t,2H,OCH2),6.50(s,1H,H-8),6.64(d,1H,H-6),6.95(d,2H,H-3′,H-5′),7.40(d,2H,H-2′,H-6′),8.16(s,1H,H-2);MS(ESI)calcd for C30H40O8S3624.1872,found,624.2096,[M+H]+625.2174,[M+Na]+647.1933,[2M+Na]+1272.3999。
实施例十一:三溴化-4′,5,7-三-[3-(N-吡啶基)-丙氧基]-异黄酮(11)的制备
将4′,5,7-三-(3-溴丙氧基)-异黄酮(0.63g,1mmol),无水吡啶10ml,160℃下反应2小时。反应完成后,反应混合物减压蒸馏得到淡黄色固体,用乙醇洗涤后,水中重结晶得到无色针状晶体,产率80%。Mp 260℃(dec.);1H NMR(D2O):δ2.45-2.51(m,6H,3(CH2)),4.06-4.13(m,6H,3(OCH2),4.70-4.80(m,6H,3(CH2-N+),6.24(d,1H,H-8),6.51(d,1H,H-6),6.85(d,2H,H-3′,H-5′),7.27(d,2H,H-2′,H-6′),8.32(s,1H,H-2);(吡啶环上)7.82(t,2H,2(H-4)),7.93(s,H,H-4),7.95(t,4H,2(H-3),2(H-5)),8.44(t,2H,H-3,H-5),8.73(d,2H,H-2,H-6),8.80(t,4H,2(H-2),2(H-6))。
实施例十二:4′,5-二羟基-7-甲氧基异黄酮-3′-磺酸(12)的制备
将98%的浓硫酸0.5ml,4′,5-二羟基-7-甲氧基异黄酮(0.28g,1mmol)放置在三角烧瓶中,在0℃,25Hz超声波作用下,反应0.5小时(或在0℃下加热搅拌反应8小时),反应完成后,反应混合物加水稀释得到白色固体,固体用水重结晶得到白色针状晶体,产率80%。Mp 365℃(dec.);IR(KBr)cm-1:3419(OH),2956(CH3),1655(C=O),1179(S=O);1H NMR(DMSO-d6):δ3.86(s,3H,7-OCH3),6.41(s,1H,H-8),6.66(s,1H,H-6),6.84(d,1H,H-5′),7.39(t,1H,H-6′),7.70(d,1H,H-2′),8.43(s,1H,H-2);MS(ESI)calcd for C16H12O8S 364.0248,found,364.0343,[M-H]-363.0256(negative ion mode)。化合物12用NaOH中和得到其相应的钠盐。
实施例十三:5-羟基-4′,7-二甲氧基异黄酮-3′-磺酸(13)的制备
将98%的浓硫酸0.5ml,4′,7-二甲氧基-5-羟基-异黄酮(0.30g,1mmol)放置在三角烧瓶中,在0℃,25Hz超声波作用下,反应0.5小时(或在0℃下加热搅拌反应8小时),反应完成后,反应混合物加水稀释得到白色固体,固体用水重结晶得到白色针状晶体,产率85%。mp 360℃(dec.);IR(KBr)cm-1:3421(OH),2957(CH3),1654(C=O),1199(S=O);1H NMR(DMSO-d6):δ3.78(s,3H,7-OCH3),3.86(s,3H,4′-OCH3),6.41(s,1H,H-8),6.67(s,1H,H-6),7.01(d,1H,H-5′),7.45(q,1H,H-6′),7.89(d,1H,H-2′),8.42(s,1H,H-2),12.92(s,1H,5-OH);MS(ESI)calcd for C17H14O8S 378.0404,found,378.0410,[M-H]-377.0332(negativeion mode)。化合物13用NaOH中和得到其相应的钠盐。
实施例十四:4′,5,7-三甲氧基异黄酮-3′-磺酸(14)的制备
将98%的浓硫酸0.5ml,4′,5,7-三甲氧基异黄酮(0.31g,1mmol)放置在三角烧瓶中,在0℃,25Hz超声波作用下,反应0.5小时(或在0℃下加热搅拌反应8小时),反应完成后,反应混合物加水稀释得到白色固体,固体用水重结晶得到白色针状晶体,产率85%。Mp 360℃(dec.);IR(KBr)cm-1:3431(OH),2955(CH3),1653(C=O)1180(S=O);1H NMR(DMSO-d6):δ3.66(s,3H,5-OCH3),3.72(s,3H,7-OCH3),3.81(s,3H,4′-OCH3),6.26(d,1H,H-8),6.36(d,1H,H-6),7.00(d,1H,H-5′),7.32(q,1H,H-6′),7.72(d,1H,H-2′),7.94(s,1H,H-2);MS(ESI)calcd for C18H16O8S 392.0560,found,392.0515,[M+H]+393.0593。化合物14用NaOH中和得到其相应的钠盐。
实施例十五:4′,5-二羟基-7-(2-溴乙氧基)-异黄酮-3′-磺酸(15)的制备
将98%的浓硫酸0.5ml,4′,5-二羟基-7-(2-溴乙氧基)-异黄酮(0.37g,1mmol)放置在三角烧瓶中,在0℃,25Hz超声波作用下,反应0.5小时(或在0℃下加热搅拌反应8小时),反应完成后,反应混合物加水稀释得到白色固体,固体用水重结晶得到白色针状晶体,产率78%。Mp 347℃(dec.);1H NMR(DMSO-d6+D2O):δ3.57(t,2H,CH2Br),4.17(t,2H,OCH2),6.12(s,1H,H-8),6.32(s,1H,H-6),6.88(d,1H,H-5′),7.29(d,1H,H-6′),7.65(s,1H,H-2′),7.98(s,1H,H-2)。化合物15用NaOH中和得到其相应的钠盐。
实施例十六:4′,5-二羟基-7-(3-溴丙氧基)-异黄酮-3′-磺酸(16)的制备
将98%的浓硫酸0.5ml,4′,5-二羟基-7-(3-溴丙氧基)-异黄酮(0.39g,1mmol)放置在三角烧瓶中,在0℃,40Hz超声波作用下,反应0.5小时(或在0℃下加热搅拌反应10小时),反应完成后,反应混合物加水稀释得到白色固体,固体用水重结晶得到白色针状晶体,产率76%。Mp 344℃(dec.);1H NMR(DMSO-d6):δ2.27(m,2H,CH2),3.64(t,2H,CH2Br),4.22(t,2H,OCH2),6.43(d,1H,H-8),6.70(d,1H,H-6),6.83(d,1H,H-5′),7.38(q,1H,H-6′),7.69(d,1H,H-2′),8.44(s,1H,H-2),10.65(s,1H,4-OH),12.90(s,1H,5OH)。化合物16用NaOH中和得到其相应的钠盐。
实施例十七:5-羟基-4′,7-二-(3-溴丙氧基)-异黄酮-3′-磺酸(17)的制备
将98%的浓硫酸0.5ml,5-羟基-4′,7-二(3-溴丙氧基)-异黄酮(0.51g,1mmol)放置在三角烧瓶中,在0℃,40Hz超声波作用下,反应0.5小时(或在0℃下加热搅拌反应8小时),反应完成后,反应混合物加水稀释得到白色固体,固体用水重结晶得到白色针状晶体,产率73%。Mp 312℃(dec.);1H NMR(D2O):δ2.33(m,4H,2CH2),3.65(t,2H,CH2Br),3.82(t,2H,CH2Br),4.22(t,2H,OCH2),4.30(t,2H,OCH2),6.40(d,1H,H-8),6.58(d,1H,H-6),7.18(d,1H,H-5′),7.69(q,1H,H-6′),8.10(d,1H,H-2′),8.20(d,1H,H-2。化合物17用NaOH中和得到其相应的钠盐。
实施例十八:本发明的染料木素衍生物对骨质疏松症的预防和治疗效果
为了评价通式(I)化合物对骨的作用效果,利用卵巢切除大鼠作为模型进行了体内活性评价,同时对活性好的化合物进行了急性毒性实验,实验结果如图1,表2和表3所示:
表2.染料木素及其衍生物对骨的作用效果
组别 | 化合物 | 右侧股骨的骨密度(g/cm2) | 右侧股骨的骨矿物含量(g) | 子宫重量(g) |
abcdefghijOvxSham | 678910121314染料木素E2-- | 0.284±0.0150.281±0.0060.287±0.0080.279±0.0160.290±0.0100.278±0.0070.286±0.0110.283±0.0140.268±0.0110.295±0.0070.233±0.0120.319±0.010 | 0.2589±0.0020.2614±0.0030.2577±0.0020.2592±0.0040.2674±0.0020.2516±0.0020.2602±0.0010.2641±0.0020.2411±0.0040.2620±0.0030.2045±0.0030.3010±0.003 | 0.0661±0.0080.0704±0.0060.0714±0.0070.0650±0.0040.0599±0.0060.0741±0.0080.0589±0.0080.0629±0.0090.0701±0.0050.2647±0.0300.0633±0.0080.3549±0.015 |
在表2中,卵巢切除组a到h组中的大鼠每天分别灌服相应的测试化合物(25μmol/kg),卵巢切除组i每天灌服母体化合物染料木素(25μmol/kg)作为阳性对照,卵巢切除j组每天灌服雌二醇(17β-Estradiol,E2)(0.5μmol/kg)作为阳性对照。Ovx组为卵巢切除组,灌服试剂空白。Sham组为假手术组,不切除卵巢,灌服试剂空白。实验进行两个月后大鼠被断颈处死,进行各项指标测定。骨密度使用Lunar DPX-IQ Dual-energy X-ray Densitometer进行测量,表中的数据结果表示为mean±SEM(n=6)。结果显示,Ovx组的大鼠相比于假手术组骨密度下降了27%,骨矿物含量下降了32%(p<0.01);e组(灌服测试化合物10)相比于Ovx组的大鼠骨密度增加了24%,骨矿物含量增加了31%(p<0.01);e组(灌服测试化合物10)的大鼠相比于i组(灌服母体化合物染料木素)骨密度增加了8%,骨矿物含量增加了11%(p<0.01)。结果同时显示,测试化合物对大鼠的子宫未产生显著的影响,但雌二醇显著地增加了大鼠的子宫重量。
表3.染料木素及其主要活性衍生物的急性毒性实验结果
组别 | 每组小鼠数目 | 受试化合物 | 给药量(mg/kg) |
123456 | 101010101010 | 染料木素6781013 | 72901009812906104761684810800 |
在表3中,测试化合物在限量实验中,给予表中相应的量,均无死亡例。表明这些化合物不但能够明显地增加骨密度和骨的矿物含量,而且是无毒的,很有希望成为预防和治疗骨质疏松的药物。
Claims (6)
2.一种权利要求1所述的染料木素衍生物的制法,其特征是:将染料木素与α-溴代烷或α,ω-二溴代烷在40~80℃反应8~48小时,制得X为H或溴的染料木素衍生物。
3.一种权利要求1所述的染料木素衍生物的制法,其特征是:将X为H或溴的染料木素衍生物与2-羟基乙硫醇在48℃反应12小时或与吡啶在160℃反应2小时制得X为2-羟基乙硫基或N-吡啶基的染料木素衍生物。
4.一种权利要求1所述的染料木素衍生物的制法,其特征是:将权利要求2或3制得的染料木素衍生物与浓硫酸在0℃反应8~10小时,制得R4为磺酸基的染料木素衍生物。
5.根据权利要求2、3或4所述的染料木素衍生物的制法,其特征是用超声波辅助反应,以缩短反应时间。
6.权利要求1所述的染料木素衍生物在制备治疗骨质疏松症药物中的应用。
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CN100462361C (zh) * | 2007-01-31 | 2009-02-18 | 陕西师范大学 | 芒柄花素-3′-磺酸钠、樱黄素-3′-磺酸钠及其制备方法和药物用途 |
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CN104262313B (zh) * | 2014-09-25 | 2018-01-09 | 山东理工大学 | 含苯基哌嗪的染料木素衍生物制法及其抗菌活性 |
CN104193717B (zh) * | 2014-09-25 | 2018-02-02 | 山东理工大学 | 含苯基哌嗪的染料木素衍生物的制备方法及其应用 |
CN106065389A (zh) * | 2016-08-08 | 2016-11-02 | 山东理工大学 | 一种促进木瓜蛋白酶活性的方法及其在啤酒澄清中的应用 |
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