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2-羥基-3-脫氧五環(huán)三萜類化合物及其衍生物、其制備方法及用途的制作方法

文檔序號(hào):3536477閱讀:419來源:國知局

專利名稱::2-羥基-3-脫氧五環(huán)三萜類化合物及其衍生物、其制備方法及用途的制作方法
技術(shù)領(lǐng)域
:本發(fā)明涉及藥物領(lǐng)域,具體涉及一系列2—羥基一3—脫氧五環(huán)三萜類化合物及其衍生物,本發(fā)明還公開了上述化合物的制備方法及其醫(yī)藥用途,尤其是在制備抗糖尿病藥物、抗腦缺血藥物、抗心血管疾病藥物、降血脂藥物、降膽固醇藥物、減肥藥物、抗動(dòng)脈粥樣硬化藥物、抗腫瘤藥物、抗HIV藥物和抗肝炎藥物等方面的應(yīng)用。
背景技術(shù)
:五環(huán)三萜類化合物在植物界中的分布非常廣泛,是許多常用中草藥(如甘草、山茱萸和女貞子等)的主要有效成分,具有保肝、抗炎、抗病毒、抗氧化、抗腫瘤和降血糖等廣泛的生物活性(Nat.Prod.R印.,2006,23,394-411;BotanicalStudies,2006,47,339-368)。在降血糖方面,柳占彪等報(bào)道了齊墩果酸對(duì)四氧嘧啶誘導(dǎo)的高血糖大鼠有顯著的降血糖效果(中國藥學(xué)雜志,1994,29,725-726),苗德田等的研究進(jìn)一步肯定了齊墩果酸的降血糖作用(武警醫(yī)學(xué)院學(xué)報(bào)1998,7,148-150)。韓國學(xué)者最近報(bào)道了熊果酸、科羅索酸代表一類新型PTP1B抑制劑(PlantaMed.2006,72,26卜263),而PTP1B被認(rèn)為是一個(gè)具有很大潛力的治療2型糖尿病的靶點(diǎn)。發(fā)明人先期的中國專利申請(qǐng)CN1682740A公開了五環(huán)二萜類化合物具有抑制糖原磷酸化酶的作用,因而可用于降血糖、抗缺血性心腦血管疾病、抗腫瘤和降血脂等。在抗心腦血管疾病方面,F(xiàn)ujimoto等報(bào)道了一些天然五環(huán)三萜化合物能高度特異性地拮抗人內(nèi)皮素A型受體,經(jīng)結(jié)構(gòu)修飾得到的化合物S-0139具有更好的活性和生物利用度。S-0139現(xiàn)已進(jìn)入II期臨床研究用于治療心腦血管疾病(CurrentOpinioninInvestigationalDrugs,2002,3,1051-1055)。Somova等報(bào)道了齊墩果酸的抗高血壓作用(o/Be&'ci/7&2003,10,115-121),并進(jìn)一步實(shí)驗(yàn)驗(yàn)證了齊墩果酸、熊果酸、山楂酸甲酯和熊果醇等具有強(qiáng)心及抗心率失?;钚?Phytomedicine,2004,11,121-129)。阿江欖仁酸是從阿江欖樹分離到的一種五環(huán)三萜酸,研究表明,阿江欖仁酸對(duì)異丙腎上腺素誘導(dǎo)的心肌異常具有顯著的心臟保護(hù)效果(Bio.Pharm.Bull.2003,26,41-46)。Sudharsan等報(bào)道了羽扇豆醇能抗環(huán)磷酰胺引起的心肌損傷,提示羽扇豆醇具有心臟保護(hù)作用(H咖anExp.Tox.,2005,24,313-318)。關(guān)騰等報(bào)道了山楂酸具有顯著的抗缺血性腦損傷作用,提示山楂酸可用作抗腦缺血藥物(中國臨床藥理學(xué)與治療學(xué),2007,12,381-384)。在調(diào)節(jié)脂代謝方面,Lee等報(bào)道了天然五環(huán)三萜化合物是新型的ACAT抑制劑(Biol.Pharm.Bull.2006,29,382—384),而ACAT是降膽固醇和抗動(dòng)脈粥樣硬化的有效藥物靶點(diǎn),提示此類化合物可作降血脂和抗動(dòng)脈粥樣硬化藥物。PCT專利申請(qǐng)W003011267報(bào)道了山楂酸和熊果酸等五環(huán)三砲化合物可用作減肥藥。在保肝/抗肝炎方面,齊墩果酸和甘草酸制劑作為抗肝炎藥物已經(jīng)在臨床上得到了廣泛應(yīng)用。在抗腫瘤方面,白樺脂酸作為抗黑色素瘤藥物已經(jīng)在美國進(jìn)入I期臨床。齊墩果酸的一個(gè)衍生物-CDD0作為抗腫瘤藥已進(jìn)入I期臨床。中國專利申請(qǐng)CN1650869報(bào)道了貝萼皂苷元的抗癌效果。美國專利申請(qǐng)6174876報(bào)道了乳香酸在治療腦癌方面的應(yīng)用。在抗病毒方面,白樺脂酸的一個(gè)衍生物-PA-457作為抗HIV藥物已在美國進(jìn)入II期臨床。西班牙的Carcia-Granados等也證實(shí)了山楂酸作為艾滋病病毒蛋白酶抑制劑在抗艾滋病方面的潛在應(yīng)用價(jià)值(SpainPatent:ES2140329,2000-2-16)。Cinatl等報(bào)道甘草酸及其衍生物的抗SARS病毒活性(Lancet,2003,361,2045-2046;J.Med.Chem.,2005,48,1256-1258)。Baltina等報(bào)道了白樺酸及其衍生物具有抗流感病毒和皰疹病毒活性(Bioorganic&MedicinalChemistryLetters2003,13,3549-3552).在抗炎方面,Banno等報(bào)道了科羅索酸對(duì)TPA(12-0-四癸?;鸩ù?13-醋酸酯)誘導(dǎo)的炎癥反應(yīng)具有顯著的抑制作用,其抗炎作用強(qiáng)于抗炎藥吲哚美辛(BiosciBiotech.Biochem,2004,68,85-90)。Aggarwal等報(bào)道了熊果酸的抗炎作用可能是通過抑制核因子ka卯a(chǎn)-B而實(shí)現(xiàn)的(CancerRes.2003,63,4375)。
發(fā)明內(nèi)容此前文獻(xiàn)報(bào)道的五環(huán)三萜類化合物多是3-羥基或2,3-二羥基五環(huán)三砲類化合物及其衍生物,本發(fā)明首次公開了3-羥基五環(huán)三砲類化合物的區(qū)域異構(gòu)體2-羥基-3-脫氧五環(huán)三砲類化合物及其衍生物、其制備方法及醫(yī)藥用途,尤其是用于治療糖尿病(特別是2型糖尿病)及其并發(fā)癥、缺血性心血管疾病(特別是心肌梗死、心絞痛、心律失常、冠心病等)、腦缺血疾病(特別是中風(fēng)、腦梗塞和缺血性神經(jīng)退行性疾病等)、代謝綜合征、高血脂、動(dòng)脈粥樣硬化、炎癥、肥胖、高血壓、肝炎、HIV感染、流感、SARS病毒感染和腫瘤等。本發(fā)明公開的新化合物包括通式I和通式II所示的五環(huán)三砲類化合物或其藥學(xué)上可接受的鹽或酯其中R!獨(dú)立代表氫、OR9、NHR9、N(R10)2、S02NH2、NHOR9、NH2NHR9;112獨(dú)立代表氫、OR9、NHR9、N(R1())2、S02NH2、NHOR9、NH2NHR9;或者與112—起代表O或NOR9;R3代表氫或甲基,R4代表氫或甲基,并且,當(dāng)R3代表氫時(shí),R4僅代表甲基;當(dāng)&代表甲基時(shí),R4僅代表氫;R5代表CH3、CH2OR9、COORk)、CONHR9、CON(R,。)2、NHR9;R6獨(dú)立代表氫、OR9、NHR9、N(R10)2、S02NH2、NHOR9、NH2NHR9;R7獨(dú)立代表氫、OR9、NHR9、N(R10)2、S02NH2、NHOR9、NH2NHR9;或者Re與R7—起代表O或NOR9;Rs代表CH3、CH2OR9、COOR10、CONHR9、CON(R1())2、NHR9;R9代表氫或Rw、R。CO,R10SO2;R,o代表1~10個(gè)碳的非取代的或X取代的直鏈或支鏈烷烴、烯烴、炔烴、苯基、節(jié)基、萘基;X代表H、F、Cl、Br、I、CN、N02、NH2、CF3、SH、OH、OCH3、OC2H5、COOH、COOCH3、COOC2H5、l-10個(gè)碳的直鏈或支鏈烷烴、烯烴、炔烴、苯基、芐基、萘基。上述化合物中優(yōu)選的化合物為其中R,獨(dú)立代表氫、OR9;R2獨(dú)立代表氫、OR9;或者R4與R2—起代表0或NOR9;R3代表氫或甲基,R4代表氫或甲基,并且,當(dāng)R3代表氫時(shí),R4僅代表甲基;當(dāng)R3代表甲基時(shí),R"又代表氫;Rs代表CH3、CH2OR9、COOR10;Rs獨(dú)立代表氫、OR9;R7獨(dú)立代表氫、OR9;或者R6與R7—起代表O或NOR9;Rs代表CH3、CH2OR9、COOR10;R9代表氫或Rl0、RioCO;Rh)代表110個(gè)碳的非取代的或X取代的直鏈或支鏈烷烴、烯烴、炔烴、苯基、節(jié)基、萘基;X代表H、F、Cl、Br、I、CN、N02、NH2、CF3、SH、OH、OCH3、OC2H5、COOH、COOCH3、COOC2H5、110個(gè)碳的直鏈或支鏈烷烴、烯烴、炔烴、苯基、芐基、萘基。更為優(yōu)選的化合物是2-羰基-3-脫氧齊墩果酸-28—芐酯2-羰基-3-脫氧熊果酸-28-芐酯2-羰基-3-脫氧齊墩果酸2-羰基-3-脫氧熊果酸2-后基-3-脫氧齊墩果酸-28-節(jié)酯2-肟基-3-脫氧熊果酸-28-芐酯2-肟基-3-脫氧齊墩果酸2-肟基-3-脫氧熊果酸2-(e)-羥基-3-脫氧齊敦果酸-28-芐酯2-(e)-羥基-3-脫氧熊果酸-28-芐酯2-(a)-羥基-3-脫氧齊敦果酸-28-芐酯2-(a)-羥基-3-脫氧熊果酸-28-芐酯2-(0)-羥基-3-脫氧齊墩果酸2-(P)-羥基-3-脫氧熊果酸2-(a)-羥基-3-脫氧齊敦果酸2-(a)-羥基-3-脫氧熊果酸2-(P)-羥基-3-脫氧齊敦果酸-28-甲酯2--羥基-3-脫氧齊敦果酸-28-乙酯2--羥基-3-脫氧齊敦果酸-28-丙酯2--羥基-3-脫氧齊敦果酸-28-丁酯2--羥基-3-脫氧齊敦果酸-28-烯丙酯2--羥基-3-脫氧齊敦果酸-28-(2-溴乙酯)2--羥基-3-脫氧齊敦果酸-28-(3-溴丙酯)2-(e)-羥基-3-脫氧齊敦果酸-28-(4-溴丁酯)2-(e)-羥基-3-脫氧齊敦果酸-28-乙酸乙酯2--乙酰氧基-3-脫氧-齊敦果酸-28-芐酯2-(e)-丙酰氧基-3-脫氧-齊敦果酸-28-芐酯2-(e)-丁酰氧基-3-脫氧-齊敦果酸-28-芐酯2-(e)-苯甲酰氧基-3-脫氧-齊敦果酸-28-節(jié)酯2-(e)-對(duì)叔丁基苯甲酰氧基-3-脫氧-齊敦果酸-28-節(jié)酯2-(p)-0-琥珀?;?3-脫氧齊敦果酸-28-芐酯2-(e)-乙酰氧基_3-脫氧-齊敦果酸2--丙酰氧基-3-脫氧-齊敦果酸2--丁酰氧基-3-脫氧-齊敦果酸2--苯甲酰氧基-3-脫氧-齊敦果酸2--對(duì)叔丁基苯甲酰氧基-3-脫氧-齊敦果酸2--0-琥珀?;?3-脫氧齊敦果酸2--0-(3',3'-二甲基琥珀酰基)-3-脫氧齊敦果酸2--0-(2',2'-二甲基琥珀?;?-3-脫氧齊敦果酸1-烯-2-羥基-3-羰基-28-三苯甲基醚白樺脂醇2--羥基-28-三苯甲基醚白樺脂醇2-羰基-3-脫氧-28-三苯甲基醚白樺脂醇2-羰基-3-脫氧-28—乙酸酯白樺脂醇2-羰基-3-脫氧白樺脂醇2--羥基-3-脫氧-28-三苯甲基醚白樺脂醇2-(a)--羥基-3-脫氧-28-三苯甲基醚白樺脂醇2-(P〉-羥基-3-脫氧白樺脂醇2-(a)--羥基-3-脫氧白樺脂醇2--乙酰氧基-3-脫氧-28-三苯甲基醚白樺脂醇2--丁酰氧基-3-脫氧-28-三苯甲基醚白樺脂醇2-(P)-0-(3',3,-二甲基琥珀?;?-3-脫氧-28-三苯甲基醚白樺脂醇2-(P)-0-(2',2,-二甲基琥珀?;?-3-脫氧-28-三苯甲基醚白樺脂醇2-(P)-乙酰氧基-3-脫氧白樺脂醇2-(e)-丙酰氧基-3-脫氧白樺脂醇2-(e)-丁酰氧基-3-脫氧白樺脂醇2-(P)-苯甲酰氧基-3-脫氧白樺脂醇2-(e)-0-(3',3'-二甲基琥珀酰基)-3-脫氧白樺脂醇2-。)-0-(2',2'-二甲基琥珀酰基)-3-脫氧白樺脂醇2-羰基-3-脫氧白樺酸2-(P)-羥基-3-脫氧白樺酸通式I和通式II所示的五環(huán)三萜類化合物均是新化合物,這些新化合物可以用如下所示的方法制備,如2-羰基-3-脫氧五環(huán)三萜化合物的制備TsCITsCI上式中,R3、R4、Rs和Rs的定義如前所述。上式中的(2p,3p)-2,3-二羥基五環(huán)三萜化合物的制備可參照文獻(xiàn)方法(CollectionofCzechoslovakChemicalCommunications,1989,54,1036-42)進(jìn)行。在堿催化下,(2|3,3&)-2,3-二羥基五環(huán)三萜化合物與對(duì)甲苯磺酰氯或苯磺酰氯反應(yīng),得到2-羰基-3-脫氧五環(huán)三萜化合物。所采用的堿包括吡啶、三乙胺、碳酸鉀、碳酸鈉、碳酸氫鈉、碳酸氫鉀、氫氧化鈉和氫氧化鉀,優(yōu)先采用吡使。所采用的溶劑包括吡啶、二氯甲烷、1,2-二氯乙垸、氯仿、甲苯、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、乙腈、四氫呋喃和二氧六環(huán),或者用這些溶劑任選組成的混合溶劑,優(yōu)先采用吡啶、1,2-二氯乙垸、甲苯、N,N-二甲基甲酰胺或四氫呋喃。反應(yīng)溫度可控制在0度至150度,優(yōu)先采用室溫至80度作為反應(yīng)溫度。2-肟基-3-脫氧五環(huán)三萜化合物的制備<formula>formulaseeoriginaldocumentpage13</formula><formula>formulaseeoriginaldocumentpage13</formula>上式中,R3、R4、R5和Rs的定義如前所述。上式中的2-羰基-3-脫氧五環(huán)三路化合物與鹽酸羥氨在堿催化下反應(yīng),生成2-肟基-3-脫氧五環(huán)三萜化合物。所采用的堿包括吡啶、三乙胺、碳酸鉀、碳酸鈉、碳酸氫鈉、碳酸氫鉀、氫氧化鈉和氫氧化鉀,優(yōu)先采用吡淀。所采用的溶劑包括吡啶、二氯甲垸、1,2-二氯乙垸、氯仿、甲苯、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、乙腈、四氫呋喃和二氧六環(huán),或者用這些溶劑任選組成的混合溶劑,優(yōu)先采用吡啶、1,2-二氯乙垸、甲苯、N,N-二甲基甲酰胺或四氫呋喃。反應(yīng)溫度可控制在O度至150度,優(yōu)先采用室溫至80度作為反應(yīng)溫度。2-羥基-3-脫氧五環(huán)三萜化合物的制備<formula>formulaseeoriginaldocumentpage13</formula><formula>formulaseeoriginaldocumentpage13</formula>上式中,R3、R4、R5和Rs的定義如前所述。上式中的2-羰基-3-脫氧五環(huán)三萜化合物在還原劑的作用下生成2-羥基-3-脫氧五環(huán)三萜化合物。所采用的還原劑選自硼氫化鈉、硼氫化鉀、異丙醇/異丙醇鋁、硼垸/四氫呋喃和硼垸/二甲硫醚,優(yōu)先采用硼氫化鈉(鉀)。所采用的溶劑選自四氫呋喃、乙醇、甲醇、乙醚、叔丁基甲醚、乙酸乙酯、甲酸乙酯、乙酸甲酯L二氧六環(huán)或上述溶劑的混合物,優(yōu)先采用四氫呋喃/乙醇作為反應(yīng)溶劑。反應(yīng)溫度可控制在零度至60度,優(yōu)先采用零度至室溫作為反應(yīng)溫度。2-0-?;?3-脫氧五環(huán)三萜化合物的制備:上式中,R3、R4、R5、Rg和Rui的定義如前所述。按照常規(guī)的羥基酯化方法,上式中的2-羥基-3-脫氧五環(huán)三萜化合物與各種酰氯、酸酐或羧酸反應(yīng),得到2-0-?;?3-脫氧五環(huán)三砲化合物。3-脫氧五環(huán)三萜-28-酯化合物的制備<formula>formulaseeoriginaldocumentpage14</formula>上式中,RhR2、R3、R4、Re、R7和Rn)的定義如前所述。按照常規(guī)的羧基烷基化酯化方法,上式中的3-脫氧五環(huán)三萜-28-酸與各種鹵代烷烴反應(yīng),得到3-脫氧五環(huán)三萜-28-酯化合物。下面是部分藥理學(xué)試驗(yàn)及結(jié)果一、2—羥基—3—脫氧五環(huán)三萜類化合物及其衍生物對(duì)糖原磷酸化酶抑制活性的實(shí)驗(yàn)試劑的配制1)顯色液的配制稱量鉬酸銨5g,溶解于500ml1MHC1中,用攪拌器攪拌,至全部溶解后在加入孔雀綠190mg,繼續(xù)攪拌至全部溶解,并用錫箔紙避光;2)緩沖液<formula>formulaseeoriginaldocumentpage14</formula>的配制①精密稱量Hepes0.5958g,溶于5mlH20中,用10MNaOH調(diào)PH至7.2,配制成終濃度為0.5M的H印es;②精密稱量KC10.3728g,溶于5mlH20中,配制成終濃度為1M的KC1;③精密稱量MgCI20.0255g,溶于lmlH20中,配制成終濃度為125mM的MgCl2;④精密稱量EGTA0.0476g,溶于5mlH20中,用10MNaOH調(diào)PH至7.0,配制成終濃度為25mM的EGTA;⑤精密稱量G-l-P0.0152g,溶于10mlH20中,配制成終濃度為5mM的G-l-P;⑥精密稱量glycogen10mg,溶于lmlH20中,配制成終濃度為10mg/ml的glycogen;3)陽性藥caffeine溶液的配制將caffeine溶于10mlH20配制0.5、5、50和500PM的溶液;4)配制GPa溶液取1"1的GPa加入到100w1反應(yīng)體系中,終濃度為250ng/100u1;5)待測試化合物溶液的配制將待測試化合物溶于DMSO配制成濃度為10mM溶液,取適量化合物溶液加入到反應(yīng)體系中至不同終濃度。測定rabbit肌糖原磷酸化酶活性的量效曲線通過讀取不同濃度的GPa加入顯色液后的在655nm下的OD值,來測定其量效曲線。由量效曲線可選擇GPa的量為250ng.實(shí)驗(yàn)步驟1)設(shè)計(jì)PC(陽性對(duì)照)、Blank(空白對(duì)照)、陽性藥(咖啡因);2)加反應(yīng)buffer52iU;3)加測試化合物至終濃度;4)加酶lyl,終濃度為250ng/100n1;5)加顯色液150ul;6)2025攝氏度條件下反應(yīng)20分鐘;7)在波長655nm條件下比色;8)數(shù)據(jù)的讀取及抑制率的計(jì)算抑制率=[陽性對(duì)照-待測樣品]/[陽性對(duì)照-空白對(duì)照]。測試結(jié)果表l列出了部分五環(huán)三萜化合物對(duì)rabbit肌糖原磷酸化酶的抑制活性數(shù)據(jù),結(jié)果顯示,多數(shù)五環(huán)三萜化合物對(duì)糖原磷酸化酶具有顯著的抑制活性。表1、2—羥基一3—脫氧五環(huán)三萜類化合物及其衍生物對(duì)rabbit肌糖原磷酸化酶的抑制活性<table>tableseeoriginaldocumentpage15</column></row><table><table>tableseeoriginaldocumentpage16</column></row><table><table>tableseeoriginaldocumentpage17</column></row><table><table>tableseeoriginaldocumentpage18</column></row><table><table>tableseeoriginaldocumentpage19</column></row><table><table>tableseeoriginaldocumentpage20</column></row><table>*在濃度為20nM時(shí)的抑制率;**在濃度為20fxM時(shí)無活性;***在濃度為200(HiM時(shí)無活性。由以上試驗(yàn)可見,本發(fā)明所提供的2—羥基一3—脫氧五環(huán)三萜類化合物及其衍生物具有抑制糖原磷酸化酶的活性,因此可以用于治療與糖原代謝異常相關(guān)的疾病,如糖尿病、缺血性心腦血管疾病和腫瘤等。此外,鑒于五環(huán)三萜類化合物具有多靶點(diǎn)和生物活性廣泛的特點(diǎn),本發(fā)明所提供的2—羥基一3—脫氧五環(huán)三萜類化合物及其衍生物還可用于抗動(dòng)脈粥樣硬化、抗炎、減肥、降血脂、代謝綜合征、降血壓、保肝/抗肝炎、抗HIV感染、抗流感和抗SARS病毒感染等。具體實(shí)施例方式實(shí)施例12-羰基-3-脫氧齊燉果酸-28—芐酯的制備2-(P)-羥基齊墩果酸-28-芐酯(2g)溶解于15mL吡啶中,加入對(duì)甲苯磺酰氯(2.03g)50。C左右攪拌24小時(shí),停止加熱,冷卻后向反應(yīng)液中緩慢滴加1N鹽酸調(diào)節(jié)ra^3,用乙酸乙酯30mLX4提取,加入飽和碳酸氫鈉溶液洗滌,最后加飽和食鹽水洗滌,得乙酸乙酯層,無水Na2S04干燥,蒸干,快速柱層析(石油醚乙酸乙酯=50:1),得2-羰基-3-脫氧齊墩果酸-28-節(jié)酯1.3g,收率62。5%。'HNMR(300腿z'CDC13)Sppm:0.59(s,3H),0.88(s,6H),0.90(s,3H),0.92(s,3H)'1.05(s'3H),1.16(s,3H)'2.92(dd,J=4.0Hz,14.lHz,1H),5.02-5.12(m,2H),5.23(t,J=3.2Hz,1H),7.26-7.36(m,5H);13CNMR(300MHz,CDC13)S卯m:16.4'16.6,19.1,23.1,23.3,23.6,25.8,27.6,30.7,32.3,32.4,33.1,33.5,33.9'39.2,39.8,41.4,41.9,42.8,45.9,46.8,47.3,55.6,55.7,56.4,66.0,122.1,127.9'128.0,128.4,136.4'143.8,177.3,211.8;ESI-MSm/z:583.2[M+K]+.實(shí)施例22_羰基-3-脫氧熊果酸-28-芐酯的制備以2-(|3)-羥基熊果酸-28-芐酯為原料,參照實(shí)施例1的方法制得2-羰基-3-脫氧熊果酸-28-節(jié)酯。泊NMR(300隨z,CDC]3)Sppm:0.61(s,3H),0.86(s,3H),0.88(s,3H),0.89(s,3H)'0.97(s,3H),1.06(s,3H),1.11(s,3H),2.34(d,1Hz,1H),4.97(d,,12.4Hz,1H),5.10(d,.戶12.4Hz,1H),5.23(brs,1H),7.28-7.35(m,5H);"C剛R(300MHz,CDC13)SPpm:16.5,16.7,17.0,19.0,21.1,23.2,23.3,23.5,24.2,28.0,30,6,32.7,33.5,36.6,38.8,39.1,39.1,40.0,42.2,42.8,47.1,48.1,52.9,55.5,55.8,56.3,66.0,125.2,128.0,128.2,128.4,136.3,138.2,177.1,211.8;ESI-MSm/z:545.4[M+H]+.實(shí)施例32-羰基-3-脫氧齊墩果酸的制備向2-羰基-3-脫氧齊墩果酸-28-芐酯(1.0g)中加入30mL四氫呋喃,力n10%Pd/C(0.lg),室溫常壓氫化過夜,原料反應(yīng)完全后,以四氫呋喃稀釋反應(yīng)物,過濾除去Pd/C,濾液蒸去溶劑后得粉狀固體,加入適量正已烷將少量附著的顏色除去,過濾后得白色粉末狀3-異構(gòu)齊墩果酸0.8g,收率95.9%。'H固R(300MHz,C5D5N)5ppm:0.82(s,3H),0.86(s,3H),0.96(s,3H),l.Ol.(s,3H),1.25(brs,6H),1.29(s,3H),3,30(d,,12.6Hz,1H),5.46(brs,1H);':iCNMR(300MHz,CDC13)Sppm:14.3,16.5,17.0,19.3,22.8,22.9,23.4,23.7,23.8,26.1,28.3,29.6,29.9,30.0,31.0,32.1,32.8,33.1,33.2,33.3,34.3,39.1,39.6,40.1,42.0,42.3,43.0,46.5,46.7,47.5,55.4,55.6,56.5,122.1,144.9,180.1,210.3;ESI-MSm/z:453.3[M-H]—.實(shí)施例42-羰基-3-脫氧熊果酸的制備以2-羰基-3-脫氧熊果酸-28-芐酯為原料,參照實(shí)施例3的方法制得2-羰基-3-脫氧熊果酸。'HNMR(300MHz,C5D5N)Sppm:0.81(s,3H),0.84(s,3H),0.96(brs,9H),1.22(brs,6H),2.62(d,,10.68Hz,1H),5.44(brs,1H);'3C簡R(300MHz,C5D5N)Sppm:16.7,17.1,17.5,19.3,21.4,23.4,23.6,23.9,24.9,28.7,31.1,33.1,33.3,37.4,39.0,39.4,39.6,40.4,42.7,42.9,47.4,48.1,53.6,55,5,55.9,56.5,125.2,139.4,179.8,210.4;ESI-MSm/z:453.5[M-H]—實(shí)施例52-肟基-3-脫氧齊墩果酸-28-芐酯的制備2—羰基一3_脫氧齊敦果酸-28-芐酯(O.lg)溶解于0.6mL吡啶中,加入鹽酸羥氨(0.025g)室溫?cái)嚢?小時(shí)。向反應(yīng)液中緩慢滴加1N鹽酸調(diào)節(jié)PH"3,用乙酸乙酯10mLX4提取,加入飽和碳酸氫鈉溶液洗滌,最后加飽和食鹽水洗滌,得乙酸乙酯層,無水Na2S(X干燥,蒸干,快速柱層析(石油醚乙酸乙酯=6:1),得2-肟基-3-脫氧齊墩果酸-28-芐酯0.095g,收率93.1%。'H麗R(300MHz,CDCl])Sppm:0.59(s,6H),0.83(s,3H),0.84(s'6H),0.86(s,3H),0.90(s,6H),0.92(s,6H),1.00(s,3H),1.03(s,3H),1.15(s,6H),2.92(dd,,4.lHz,13.4Hz,2H),3.14(d,,13.6Hz,1H),3.29(d,,12.7Hz,1H),5.01—5.13(m'4H),5.30(brs,1H)'5.31(brs,1H),7.28—7.35(m,10H);13CNMR(300MHz,CDC1》S卯m:15.5,15.9,16.6'16.7,22.3,22.8,23.1,23.4,23.5,23.6,25.8,27.6,30.7,32.3,32.4,32.5,32.8,33.1,33.9,36.8,38.7,39.4,39.6,39.7,40.7,40.8,41.4,41.8,45.9,46.2'46.8,47.0,47.2,56.3,56.4'65.9,66.0,122.3,127.9,128.0,128.4,136.4,143.6,143.7'159.4,159.5,177.3,177.4;ESI-MSm/z:560.4[M+H]+.實(shí)施例62-肟基-3-脫氧熊果酸-28-芐酯的制備以2—羰基一3—脫氧熊果酸-28-芐酯為原料,參照實(shí)施例5的方法制得2-肟基-3_脫氧熊果酸-28-芐酯。'HNMR(300MHz,CDC13)Sppm:0.63(s,6H),0.81(s,3H),0.83(s,3H),0.85(s,6H),0.86(s,6H),0.95(s,6H),1.01(s,3H),1.04(s,3H),1.10(s,6H),3.15(dd,,1.9Hz,13.5Hz,1H),3.32(d,,13.0Hz,1H),4.95—5.14(m,4H),5.25(m,2H),7.25—7.36(m,10H);'3CNMR(300MHz'CDC13)Sppm:15.6,16.1,16.7,16.8,16.9,18.7,18.8,21.1,22.3,22.9,23.3,23.4,23.5,24.3,28.0,30.7,32.7,32.8,32.8,32.9,36.6,36.9,37.0,38.8,39.0,39.1,39.5,39.9,40.0,40.8,41.0,42.1,42.2,46.1,46.6,47.0,47.1,48.1,52.9,56.2,56.3,66.0,125.4,127.9,128.2,128.4,136.3,138.1,138.2,160.3,177.1;ESI-MSm/z:560.4[M+H]+.實(shí)施例72-月虧基-3-脫氧齊墩果酸的制備以2-肟基-3-脫氧齊墩果酸-28-芐酯為原料,參照實(shí)施例3的方法制得2-肟基-3-脫氧齊敦果酸。'HNMR(300MHz,DMSO-d6)Sppm:0.71(s,3H),0.72(s,3H),0.76(s,6H),0.81(s,3H),0.88(brs,12H),0.95(s,3H),0.97(s,3H),1.13(s,6H),1.24(s,3H),2.75(d,,10.4Hz,2H),2.99(d,,13.0Hz,1H),3.15(d,,12.3Hz,1H),5.20(brs,2H),10.15(s,1H),10.17(s,1H),12.05(brs'2H);13CNMR(300MHz,CDC13)Sppm:15.0,15.5,16.4,16.5,18.1,18.2,21.9,22.6,22.7,22.9,23.2,25.4,27.1,28.8,30.2,32.0,32.3,32.4'32.7,33.2,35.9,36.0,37.8,38.7,38.8,38.9,39.0,40.3,40.7,41.3,45.4,45.5,45.6'46.0,46.3,46.5,55.3,55.4,121.2,121.3,143.6,143.7,155.3,178.3;ESI-MSm/z:468.3[M-H]—.實(shí)施例82_肟基-3-脫氧熊果酸的制備以2-肟基-3-脫氧熊果酸-28-芐酯為原料,參照實(shí)施例3的方法制得2-肟基-3-脫氧熊果酸。NMR(300MHz,DMS0-d6)5ppm:0.75(s,12H),0.82(s,12H),0.92(s,6H),0.95(s,3H),0.96(s,3H),1.08(s'6H),2.99(d,,12.0Hz,1H),3.17(d,,12.3Hz,1H),5.15(brs,2H),10.13(brs,2H),11.93(brs,2H);'3C麗R(300MHz,CDC13)Sppm:15.4,15.8,16.6,16.7,17.1,18.3,18.4,21.1,22.2,22.8'22.9,23.0,23.3,23,9,27.6,30.3,32.4,32.5,32.6,36.1,36.4'38.1,38.6,38.9,39.0,39.1,39.5,40.1,40.3,40.5,41.8,45.8,46.1,46.4,46.6,46.9,52.5,55.5,55.6,124.5,138.2,138.3,155.5,178.2;ESI—MSm/z:470.4[M+H]+.實(shí)施例92-羥基-3-脫氧齊敦果酸-28-芐酯的制備2—羰基一3—脫氧齊敦果酸-28-芐酯(0.12g)溶解于5mL四氫呋喃中,加入lml乙醇,冰浴冷卻至0r,加入硼氫化鈉(0.012g),室溫?cái)嚢?小時(shí)。向反應(yīng)液中緩慢滴加1N鹽酸調(diào)節(jié)PH"3,用乙酸乙酯15mLX4提取,加入飽和碳酸氫鈉溶液洗滌,最后加飽和食鹽水洗滌,得乙酸乙酯層,無水Na2S04干燥,蒸干,快速柱層析(石油醚乙酸乙酯=25:1),得2-(P)-羥基-3-脫氧齊墩果酸-28-芐酯0.106g,收率88%。'HNMR(300MHz,CDC13)Sppm:0.63(s,3H),0.86(s,3H),0.93(s,6H),1.01(s,3H),1.13(s,3H),1.16(s,3H),2.92(d,,10.9Hz,1H),4.08(brs,1H),5.06-5.12(m,2H),5.32(brs,1H),7.26-7.34(m,5H);13CNMR(300MHz,CDC13)Sppm:16.8,18.5,19.0,23.1,23.4,23.6,24.6,25.9,27.5,29.7,30.7,32.4,32.5,32.6,33.1,33.9,37.8,39.6,41.5,41.9,45.9,46.6,46.8,47.2,48.0,53.5,65.9,67.6,122.8,127.9,128.0,128.4,136.5,143.7,177.4;ESI-MSm/z:569.2[M+Na]+.同時(shí)得到2-(a)-羥基-3-脫氧齊墩果酸-28-芐酯0.006g,收率5%。&NMR(300MHz,CDCl3)Sppm:0.61(s,3H),0.85(s,3H),0.90(s,6H),0.92(s,3H),0.93(s,3H),1.13(s,3H),2.92(dd,,4.1Hz,13.7Hz,1H),3.84-3.92(m,1H),5.02-5.12(m,2H),5.32(t,,3.2Hz'1H)'7.26-7.35(m,5H);13CNMR(300MHz,CDC13)Sppm:16.4,17.0,18.4,22.6,23.1,23.5'23.7,25.9,27.6,29.7,30.7,32,4,32.7'33.1,33.5,33.9,34.9,39.0,39.5,41.4,41.8,45.9,46.8,49.5,51.2,55.7,65.1,65.9,122.5,127.9'128.0,128.4'136.5,143.7,177.4;ESI隱MSw/z:569.2[M+Na]+.實(shí)施例102-羥基-3-脫氧熊果酸-28-節(jié)酯的制備以2—羰基—3—脫氧熊果酸-28-節(jié)酯為原料,參照實(shí)施例9的方法制得2-(e)-羥基-3-脫氧熊果酸-28-芐酯。'H簡R(300MHz,CDCh)5ppm0.65(s,3H),0.85(s,3H),0,93(s,3H),0.94(s,3H),1.01(s,3H),1.07(s,3H),2.27(d,,戶11.3Hz,1H),4.06-4.10(m,1H),4.97(d,,12.5Hz,1H),5.10(d,,戶12.5Hz,1H),5.26(t,,3.6Hz,1H),7.28—7.36(m,5H);13CNMR(300MHz,CDC13)Sppm16.9,17.0,18.7'19.0,23.4,23.6,24.3,24.7,27.9,29.6,29.7,30.7,32.7,32.9,33.1,36.7,37.8'38.9,39.1,39.9,42.3,46.6,47.6'48.1,48.2,53.1,53.5'66.0,67,6,126.0,127.9,128.2,128.4,136.4,138.1,177.2;ESI-MSw/z:569.4[M+Na]+,同時(shí)得到2-(a)-羥基-3-脫氧熊果酸-28-芐酯。'H醒R(300MHz,CDC13)S卯m0.65(s,3H),0.86(s,3H),0.87(s,3H),0.94(brs'6H),0.95(s,3H),1.08(s,3H),2.27(d,戶11.6Hz,1H),3.89(m,1H),4.98(d,,12.5Hz,1H),5.10(d,戶12.5Hz,1H),5.25(t,,3.6Hz,1H),7.26-7.36(m,5H);13C麗R(300MHz,CDC13)S卯m16.6,17.0,17.1,18.4,21.1,22.7,23.4,23.6,24.3,28.0,30.7,33.0,33.6,34.9,36.7,38.9,39.0,39.2,39.8,42,2,47.7,48.2,49.8,51.3,53.0,55.7,65.2,66.0,125.8,128.0,128.2,128.4,136.5,138.3,177.2;ESI-MSw/z:569.4[M+Na]+.實(shí)施例112-(e)-羥基_3-脫氧齊墩果酸的制備以2-(0)-羥基-3-脫氧齊墩果酸-28-芐酯為原料,參照實(shí)施例3的方法制得2-(0)-羥基-3-脫氧齊墩果酸。'H麗R(300MHz,C5D5N)Sppm:0.82(s,3H),0.86(s,3H),0.96(s,3H),L01(s,3H),1.25(brs,6H),1.29(s,3H),3.29(dd,戶4.2Hz,13.8Hz,1H)'4.33-4.36(m,1H),5.50(t,/=3,3Hz,1H);l3C函R(300MHz,C5D5N)Sppm:23.8,23.9,24.7,26.2,28.3,31.0,33.0,33.2,33.3,33.8,34.3,38.1'40.1,42.1,42.4,46.5,46.7,47.4,47.6,48.5,54.8,66.9,122.8,144.8,180.1;ESI-MS歷/z:479.3[M+Na]'.實(shí)施例122-(P)-羥基_3-脫氧熊果酸的制備以2-(P)-羥基-3-脫氧熊果酸-28-芐酯為原料,參照實(shí)施例3的方法制得2-(P)-羥基-3-脫氧熊果酸。'H麗R(300MHz,CDC13)S,:0.79(s,3H),0.85(s,3H),0.87(s,3H),0.92(s,3H),0.93(s,3H),0.99(s,3H),1.25(S,3H),4.08(brs,1H),5.28(brs,1H);13CNMR(300MHz,C5D5N)Sppm:17.6,18.4,19.3,21.4,23.9,24.0,24.8,25.1,28.7,31.2,33.0,33.5,33.8,37.5,38.0,39.5,39.6,40.4,42.9,47.7,47.8,48.2,48.6,53.8,54.8,66.9,126.0,139.3;ESI-MS歷/z:455.3[M—H]—.實(shí)施例132-(e)-0-(3',3'-二甲基琥珀?;?-3-脫氧齊敦果酸和2-(e)-0-(2',2'_二甲基琥珀?;?-3-脫氧齊敦果酸的制備2-(e)-羥基-3-脫氧齊墩果酸-28-芐酯(0.15g)溶解于吡啶(2ml)中,加入2,2—二甲基琥珀酸酐(O.llg)和DMAP(0.07g),85。C攪拌,15小時(shí)后加入2N鹽酸(15ml)中和,用乙酸乙酯萃取三次,有機(jī)層用飽和碳酸氫鈉水溶液和飽和食鹽水洗滌至中性,無水硫酸鈉干燥,過濾,濃縮,快速柱層析(石油醚/乙酸乙酯=3/1),得2-朋-(3-羧基-3-甲基-1-丁酰氧基)-3-脫氧齊敦果酸-28-芐酯和2-((3)-(3-羧基-2,2-二甲基-l-丙酰氧基)-3-脫氧齊敦果酸-28-芐酯混合物無色固體140mg,收率77.0%。將所得混合物(0.13g),溶解于DMF(1.5ml)中,加入碳酸鉀(0.04g,0.28mmo1,1.5eq),滴加氯化節(jié)(0.026ml,0.23mmo1,1.2eq),室溫?cái)嚢瑁?小時(shí)后加入水(10ml),用乙酸乙酯萃取三次,有機(jī)層用飽和食鹽水洗滌至中性,無水硫酸鈉干燥,過濾,濃縮,快速柱層析(石油醚/乙酸乙酯=60/1),得2-((3)-(4-節(jié)酯-3,3-二甲基丁二酸酯)-3-脫氧齊敦果酸-28-芐酯,無色固體70mg,收率48.2%。同時(shí)得到2-((3)-(4-芐酯-2,2-二甲基丁二酸酯)-3-脫氧齊敦果酸-28-芐酯,無色油狀物20mg,收率13.8%。以2-((3)-(4-節(jié)酯-3,3-二甲基丁二酸酯)-3-脫氧齊敦果酸-28-芐酯為原料,參照實(shí)施例3的方法制得2-(e)-0-(3,,3'-二甲基琥珀?;?-3-脫氧齊敦果酸。麗R(300MHz,C5D5N)Sppm:0.87(s,3H),0.96(s,3H),0.99(s,3H),1.00(s,3H),1.02(s,3H),1.17(s,3H),1.24(s,3H),1.53(s,6H),2.86(d,,1.2Hz,2H),3.29(dd,,3.3Hz,13.8Hz,1H),5.27(m,1H),5.47(brs,1H);l:,C醒R(300MHz,C5D5N)SPpm:17.3,17.4,18.9,23.6,23.7,24.0'25.9,26.0,26.1,28.2,29.9,30,9,32.5,32.9,33.2,33.3,34.2,37.5,39.9,40.8,42.0,42.4,43.4,43.5,45.1'46.4,46.7,48.4,54.4,70.6,122.5,144.9,171.2,179.3,180.2;ESI-MS:583.4[M_H]—.以2-(P)-(4-節(jié)酯-2,2-二甲基丁二酸酯)-3-脫氧齊敦果酸-28-卡酯為原料,參照實(shí)施例3的方法制得2-(P)-0-(2',2,-二甲基琥珀?;?_3-脫氧齊敦果酸。'H麵R(300MHz,C5D5N)S卯m:0.86(s,3H),0.93(s,3H),0.98(s,3H),1.00(s,3H),1.07(s,3H),1.19(s,3H),1.24(s,3H),1.44(s,3H),1.45(s,3H),2.90(s,2H),3.29(dd,戶3.9Hz,13.7Hz,1H),5.46(brs,2H);13C賺(300MHz,C5D5N)Sppm:17.2,17.5,18.9,23.8,24.0,25.7,25.8,26.3,28.3'31.0,32.5,33.1,33.3,33.7,34.4,37.4,40.1,40.7,42.1,42.5,43.5,43.9,45.0,46.5,46.8,48.5,55.0,70.7,122.6,124.2,144.9,173.8,176.4,180.1;ESI-MSm/z:607.4[M+Na]+.實(shí)施例142-(6)-羥基-3-脫氧齊敦果酸-28_甲酯的制備將2-(e)-羥基-3-脫氧齊墩果酸(0.05g),溶解于DMF(lml)中,加入碳酸鉀(0.03g),滴加碘甲烷(0.008ml),室溫?cái)嚢瑁?小時(shí)后加入水(10ml),用乙酸乙酯萃取三次,有機(jī)層用飽和食鹽水洗滌至中性,無水硫酸鈉干燥,過濾,濃縮,快速柱層析(石油醚/乙酸乙酯=7/1),得2-(e)-羥基-3-脫氧齊敦果酸-28-甲酯,白色固體49mg,收率94.9%。'HNMR(300MHz,CDC13)Sppm:0.73(s,3H),0.89(s,3H),0.92(s,6H),1.00(s,3H),1.12(s,3H),1.18(s,3H),2.85(dd,,3.4Hz,14Hz,1H),4.08(d,,4.8Hz,1H),5.30(brs,1H);'3C陋R(300MHz,CDC13)Sppm:16.8'18.5,19.0,23.1,23.4,23.6,24.6,25.9,27.6,30.0,30.7,32.4,32.5,32.7,33.0,33.1,33.9,37.8,39.6,41.4,41.9,45.8,46.6,46.8,47.2,48.0,51.5,53.5,67.7,122.6,143.7,178.3;ESI-MSotA:493.4[M+Na]+.實(shí)施例152-(e)-羥基-3-脫氧齊敦果酸-28-乙酯的制備以2-(e)-羥基-3-脫氧齊墩果酸及溴乙烷為原料,參照實(shí)施例14的方法制得2-(e)-羥基_3-脫氧齊敦果酸-28-乙酯。'HNMR(300MHz,CDC13)Sppm0.75(s,3H),0.89(s,3H),0.92(s,6H),1.00(s,3H),1.13(s,3H),1.18(s,3H),1.25(s,3H),2.86(dd,戶3.7Hz,13.8Hz,1H),4.03-4.13(m,3H),5.31(brs,1H);13CNMR(300MHz,CDC13)Sppm:14.3,16.9,18.5,19.0,23.0,23.5,23.6,24.7,25.9,27.6,30.0,30.7,32.4,32.6,32.7,33.0,33.1,34.0'37.8'39.7,41.4,41.9,45.9,46.6,47.3,48.0,53.5,60.1,67.7,122.6,143.8'177.7;ESI-MS:507.5[M+Na]+.實(shí)施例162-(P)-羥基-3-脫氧齊敦果酸-28-(2-溴乙酯)的制備以2-(e)-羥基_3-脫氧齊墩果酸及1,2-二溴乙烷為原料,參照實(shí)施例14的方法制得2-(e)-羥基-3-脫氧齊敦果酸-28_(2-溴乙酯)。'謁R(300MHz,CDC13)Sppm:0.75(s,3H),090(s,3H),0.93(s,3H),1.00(s,3H),1.14(s,3H),1.18(s,3H),1.25(s,3H),2.88(dd,戶3.5Hz,13.6Hz,1H),3.50(t,,戶6.OHz,2H),4.06-4.10(m,1H),4.29-4.37(m,2H),5.33(t,,3.1Hz,1H);13CNMR(300MHz,CDC13)Sppm:17.0,18.5,19.0,23.0'23.5,23.6,24.6,25.9,27.6,29.0,29.7,30.7,32.5,32.6,32.7,33.1,33.9,37.8,39.7,41.4,41.9'45.8,46.6,46.9,47.3,48.0,53.5,63.6,67.7,122.9,143.4,177.3;ESI-MS歷/z:601.3[M+K]+.實(shí)施例172-(e)-羥基-3-脫氧齊敦果酸-28-乙酸乙酯的制備以2-(e)-羥基-3-脫氧齊墩果酸及溴乙酸乙酯為原料,參照實(shí)施例14的方法制得2-(e)-羥基-3-脫氧齊敦果酸-28-乙酸乙酯。'H濯R(300MHz,CDC13)Sppm0.74(s,3H),090(s,3H),0.93(s,6H),1.00(s,3H),1.13(s,3H),1.18(s,3H),1.27(t,,7.1Hz,3H),2.88(dd,,4.OHz,13.6Hz,1H),4.08(brs,1H),4.20(q,戶7.1Hz,2H),4.55(q,,15.7Hz,2H),5.32(t,,戶3.4Hz,1H);13C麗R(300MHz,CDC1》Sppm14.1,16.8'18.5,19.0,23.2,23.5,23.6,24.6,25.8,27.6,29.7,30.7,32.2,32.5'32.7,33.0,33.1,33.9,37.8,39.7,41.4,41.9'45.9,46.6,46.8,47.3,48.1,53.5,60.5,61.2,67.7,122.8,143.5,168.1,177.0;ESI-MS歷/z:565.3[M+Na]+.實(shí)施例182-(P)-乙酰氧基-3-脫氧-齊敦果酸-28-節(jié)酯的制備將2-(P)-羥基-3-脫氧-齊敦果酸芐酯(90mg),溶解于吡啶(4ml)中,加入乙酐(lml),室溫?cái)嚢瑁?小時(shí)后加入稀鹽酸調(diào)pH二3,用乙酸乙酯萃取三次,有機(jī)層用飽和碳酸氫鈉溶液洗滌,飽和食鹽水洗滌至中性,無水硫酸鈉干燥,過濾,濃縮,快速柱層析(石油醚/乙酸乙酯=30/1),得白色固體76mg,收率78.4%。'H隨R(300MHz,CDC13)Sppm0.65(s,3H),092(s,3H)'0.94(s'6H),1.01(s,3H)'1.13(s,3H),1.15(s,3H),2.04(s,3H),2.93(dd,,4.1Hz,13.7Hz'1H),5.04—5.15(m,3H),5.31(t,,3.5Hz,1H),7.28-7.38(tn,5H);1:!CNMR(300MHz,CDC1S)S卯m17.0,17.1,18.7,21.5'23.2,23.5,23.7,23.8,26.0,27.7,30.8,32.5,32.7,33.1,33.4,34.1'37.4,39.7,41.6,42.0,43.5,46.0,46.9,48.2,54.6,66.0,70.7,122.7,127.9,128.1'128.4,136.6,143.8,170.4,177.4;ESI-MS/zz/z:611.5[M+Na]+.實(shí)施例192-(e)-乙酰氧基-3-脫氧-齊敦果酸的制備以2-(e)-乙酰氧基-3-脫氧-齊敦果酸-28-芐酯為原料,參照實(shí)施例3的方法制得2-(e)-乙酰氧基-3-脫氧-齊敦果酸。'H醒R(300MHz,CDC1:,)Sppm0.77(s,3H),091(s,3H),0.92(s,3H)0.93(s,3H),0.98(s,3H),1.13(s,3H),1.14(s,3H),2.00(s,3H),2.93(dd,/=4.4Hz,13.6Hz,1H),5.05-5.10(m,1H),5.29(t,,3.4Hz,1H);l3C畫R(300MHz,CDC13)Sppm17.1,18.7,21.5,23.1,23.5,23.6,23.7,26.0,27.7,30.7,32.5,32.6,33.1,33.4,33.9,37.4,39.7,41.3,41.9,43.5,45.9,46.6,48.2,54.6,70.7,122.9,143.6,170.4,182.2,208.8;ESI-MS歷/z:521.4[M+Na]+.實(shí)施例202-(e)-苯甲酰氧基-3-脫氧-齊敦果酸-28-芐酯的制備以2-(e)-羥基-3-脫氧-齊敦果酸芐酯和苯甲酰氯為原料,參照實(shí)施例18的方法制得2-(P)-苯甲酰氧基-3-脫氧-齊敦果酸-28-芐酯。'H腿(300MHz,CDC1JSppm0.64(s,3H),090(s,3H),0.92(s,3H),0.96(s,3H),1.08(s,3H),1.15(s,3H),1.26(s,3H),2.93(m,1H)'5.01—5.13(m,2H),5.29—5.39(m,2H),7.25—7.34(m,5H),7.41-7.47(m,2H),7.52-7.55(m,1H),8.00-8.03(m,2H);'3CNMR(300MHz,CDC13)Sppm17.0,17.1,18.7,23.2,23.5,23.7,23.8,26.0,27.6,30.7,32.5,32.7,33.1,33.6,34.0,37.2,39.7,41.5,42.0,43.5,43.8,46.0,46.9,48.2,54.9,66.0,71.5,122.7,127.9,128.0,128.4,129.5,131.1,132.7,136.6,143.8,160.7,166.2,177.4.實(shí)施例212-(e)-苯甲酰氧基-3-脫氧-齊敦果酸的制備以2-(0)-苯甲酰氧基-3-脫氧-齊敦果酸-28-芐酯為原料,參照實(shí)施例3的方法制得2-(p)-苯甲酰氧基-3-脫氧-齊敦果酸。'H隨R(300MHz,CDCUSppm0.78(s,3H),091(s,3H),0.93(s,3H),0.97(s'3H),1.08(s,3H),1.15(s,3H),1,24(s,3H),2.84(m,1H),5.29(brs,2H),5.38(t,J=3.87Hz,1H),7.40—7.46(m,2H),7.51-7.57(m,1H),7.99-8.03(m,2H);'3CNMR(300MHz,CDC1:,)S卯m17.1,17.2,18.7,23.1,23.5,23.6,23.8,26,0,27.7,29.7,30.7,32.5,32.6,32.7,33.0,33.6,33.9,37.3,39.7,41.3,42.0,43.5,43.8,46.0,46.6,48.2,54.9,71.5,122.9,128.4,129.5,131.1,132.6,143.6,166.2,182.0.實(shí)施例221-烯-2-羥基-3-羰基-28-三苯甲基醚白樺脂醇的制備將3-羰基-28-三苯甲基醚白樺脂醇(L14g)溶于叔丁醇(80ml)中,加入叔丁醇鉀(0.821g),3(TC下攪拌,10h后反應(yīng)結(jié)束。蒸千叔丁醇,冰浴下,1NHC1中和反應(yīng)液至PH^5。乙酸乙酯萃取(20mlX2,15mlX2),飽和碳酸氫鈉溶液及飽和食鹽水洗滌有機(jī)層至中性,無水NaS04干燥,過濾,濃縮,快速柱層析(石油醚/乙酸乙酯=80:1),得1_烯-2-羥基-3-羰基-28-三苯甲基醚白樺脂醇,白色粉末960mg,收率82.76%。'H麗R(300MHz,CDC13)S卯m:0.56(s,3H),0.88(s,3H)'1.05(s,3H),1.08(s,3H),1.12(s,3H),1.63(s,3H),2.17-2.26(m,3H),2.93,3.11(d,J=8.8Hz,each1H)'4.54,4.59(d,J=2.2Hz,each1H),5.85(s'1H'disappearafterD20exchange),6.37(s,1H),7.47-7.50(m,6H),7.26-7.33(ra,6H),7.22-7.25(tn,3H);l3CNMR(300MHz,CDC13)Sppm-14.1,14.6,16.3,18.7,19.1,20.1,21.0,22.7,25.0,26.8,27.1,29.3,29.6,29.7,29.9,30.0,31.9,33.8,35.2,37.4'38.5,41.4,42.8,43.9,45.5'47.5,47.8,48.8,53.9,59.6,85.9,109.5,126.8,127.7,128.8,143.8,144.5,150.5,201.2;ESI—MSm/z:719.5[M+Na]+.實(shí)施例232-(P)-羥基-28-三苯甲基醚白樺脂醇的制備將1-烯-2-羥基-3-羰基-28-三苯甲基醚白樺脂醇(900nig)溶于THF(25ml)中,加入乙醇(5ml),冰浴冷卻至O'C,緩慢加入硼氫化鈉(136mg),自然升溫至室溫,lh后反應(yīng)結(jié)束,減壓蒸千大部分有機(jī)溶劑,1NHC1中和反應(yīng)液至ra&5。乙酸乙酯萃取(20mlX2,15mlX2),飽和碳酸氫鈉溶液及飽和食鹽水洗滌有機(jī)層至中性,無水NaS04干燥,過濾,濃縮,快速柱層析(石油醚/乙酸乙酯=8:1)得2-(e)-羥基-28-三苯甲基醚白樺脂醇,白色粉末650mg,產(chǎn)率為65%。4NMR(300MHz,CDC13)Sppm:0.53(s,3H),0.88(s,3H),0.96(s,6H),1.07(s,3H),1.63(s,3H),2.04-2.23(m,6H),2.90,3.13(d,J=8.8Hz,each1H),3.15(d,J=3.4Hz,1H),4.02-4.03(m,1H),4.51,4.58(d,J=2.0Hz,eachlH),7.46-7.50(m,6H),7.26-7.32(m,6H),7.21-7.24(m,3H);'3C剛R(300MHz,CDC13)Sppm:14.7,15.9,17.0,17.1,18.1,19.1'20.9,25.2'26.8'29.4,29.6,29.7,29.9'30.2,34.1,35.2,36.8,37.2,38.1,40.7,42.6,44.4,47.6,47.7,48.9,50.8,55.2,59.6,71.2,85.9,109.3,126.8,127.7,128.8,144.5,150.8;ESI—MSm/z:723.5[M+Na]+.實(shí)施例242_羰基-3-脫氧-28-三苯甲基醚白樺脂醇的制備將2-(e)-羥基-28-三苯甲基醚白樺脂醇(500mg)溶于吡啶(3ml)中,加入對(duì)甲苯磺酰氯(546.3呢),6(TC溫度下攪拌反應(yīng)。12h后反應(yīng)結(jié)束,冷卻至室溫,INHC1中和反應(yīng)液至PH"5,乙酸乙酯萃取(20mlX2,15mlX2),飽和碳酸氫鈉溶液及飽和食鹽水洗滌有機(jī)層至中性,無水NaS04干燥,過濾,濃縮,快速柱層析(石油醚/乙酸乙酯=80:1)得2-羰基-3-脫氧-28-三苯甲基醚白樺脂醇,白色粉末321mg,產(chǎn)率為72.9%。'HNMR(300MHz,CDC1:,)Sppm:0.50(s,3H),0.76(s,3H),0.85(s,3H),0.93(s,3H),1.03(s,3H),1.63(s,3H),1.82-1.87(m,1H),2.09-2.32(m,6H),2.90,3.11(d,J=8.8Hz,each1H),4.52,4.58(d,J=2.0Hz,each1H),7.46-7.49(m,6H),7.25-7.32(m,6H),7.19-7.24(m,3H);13CNMR(300MHz,CDC13)Sppm:14.7,15.517.1,19.0,19.1,20.9,23.1,25.0,26.9,29.6,29.7,29.9,30.1,33.3,33.7,35.2,37.2,39.0,40.0,42.6,42.9,47.6,47.7,48.8,50.0,55.6,56.0,56.5,59.6,85.9,109.5,126.8,127.7,128.8:144.5,150.6,212.2;ESI-MSm/z:721.3[M+K]+.實(shí)施例252-羥基-3-脫氧-28-三苯甲基醚白樺脂醇的制備將2-羰基-3-脫氧-28-三苯甲基醚白樺脂醇(lg)溶于THF(15ml)中,加入3ml乙醇,冰浴下緩慢加入硼氫化鈉(0.15g),自然升溫至室溫,lh后反應(yīng)結(jié)束。減壓蒸干大部分有機(jī)溶劑,INHC1中和反應(yīng)液至PH^5。乙酸乙酯萃取(50mlX2,25mlXl,15mlXl),飽和碳酸氫鈉溶液及飽和食鹽水洗滌有機(jī)層至中性,無水NaS04干燥,過濾,濃縮,快速柱層析(石油醚/乙酸乙酯二25:l)得2-(e)-羥基-3-脫氧-28-三苯甲基醚白樺脂醇,白色粉末750mg,產(chǎn)率為75%。'H腿(300MHz,CDC1JS卯m:0.52(s,3H),0.89(s,3H),0.90(s,3H),0.98(s'3H),1.01(s'3H),1.64(s,3H)'1.82-1.87(m'1H),2.17-2.20(m,3H),2.90,3.14(d,J=8.8Hz,each1H),3.99—4.02(m,1H),4.52,4.58(d,J=2.1Hz,each1H),7.47-7.49(m,6H),7.25-7.32(m,6H),7.22-7.24(m,3H);'3C麵R(300MHz,CDC13)5ppm:14.7'15.7'19.1,19.7,21.2,24.8,25.3,26.8,29.9,30.1,32.5,32.8,33.6,35.2'37.4,38.2,40.8,42.5,46.3,47.6,47.7,48.2,48.9,50.8,52.7,59.6,67.5,85.8'109.3,126.8,127.7,128.8,144.5,150.8;ESI-MSm/z:723.4[M+K]+.同時(shí)得到2-(a)-羥基-3-脫氧-28-三苯甲基醚白樺脂醇,白色粉末100mg,分離產(chǎn)率為10%。'H層R(300MHz,CDC1》5ppm:0.50(s,3H),0.79(s,3H),0.82(s,3H),0.89(s,3H),0.90(s,3H),1.63(s,3H),1.95-1.98(m,1H),2.12-2.23(m,3H),2.90,3.12(d,J=8.8Hz,each1H),3.79-3.87(m,1H),4.52,4.57(d,J=2.1Hz,each1H),7.46-7.49(m,6H),7.25-7.32(m,6H),7.19-7.24(m,3H);13CNMR(300MHz,CDC1》Sppm:14.7,15.7,17.1,18.4,19.1,20.7,22.4'25.1,26.9,29.9,30.1,33.4,34.0,34.9,35.2,37.2'39.2'40.8,42.5,47.6,47.8,48.9,49.7,50.3,51.2,55.8,59.6,65.3,85.8,109.4,126.8,127.7,128.8,144.5,150.7;ESI-MSm/z:723.4[M+K]+.實(shí)施例262-(0)-羥基-3-脫氧白樺脂醇的制備將2-(e)-羥基-3-脫氧-28-三苯甲基醚白樺脂醇(50mg)溶于無水乙醇(5ml)中,加入PPTS(91.25mg,),7CTC下攪拌,20h后原料消失。減壓蒸除乙醇,加冰水20ml,乙酸乙酯萃取(25mlX2,15mlX2),飽和食鹽水洗滌有機(jī)層,無水NaS(X干燥過濾,濃縮,快速柱層析(石油醚/乙酸乙酯=10:1),得2-羥基-3-脫氧白樺脂醇,白色粉末32mg,產(chǎn)率為99%。'HNMR(300MHz,CDC1:,)Sppm:0.93(s,3H),0.98(s,6H),1.03(s'3H),1.06(s,3H),1.71(s'3H),1.92-1.98(m,3H),2.35-2.44(m,1H)'3.34,3.80(d,J=10.8Hz,each1H),4.00—4.11(m,1H),4.60,4.70(d,J=l.8Hz,each1H);13CNMR(300MHz,CDC13)Sppm:14.1,14.8,15.9,19.2,19.8,21.4,22.7,24.8,25.5,27.1,29.3,29.4,29.7,29.7,29.9,31.9,32.6,32.9,33.8,34.0,37.6,38.3,41.2,42.9'46.5,47.8,47.9,48.4,48.9,51.0,52.9,60.6'67.5,109.3,150.5;ESI-MSm/z:465.4[M+Na]+..實(shí)施例272-(0)-0-(3',3,-二甲基琥珀?;?_3-脫氧-28-三苯甲基醚白樺脂醇的制備將2-(P)-羥基-3-脫氧-28-三苯甲基醚白樺脂醇(150mg)溶于吡啶(2ml)中,加入DMAP(53.44mg,),2,2—二甲基琥珀酸酐(112.3mg),95。C下攪拌20h后原料消失。INHC1中和反應(yīng)液至^"5。乙酸乙酯萃取(50mlX2,25mlXl,15mlXl),飽和碳酸氫鈉溶液及飽和食鹽水洗滌有機(jī)層至中性,無水NaS04干燥,濃縮,快速柱層析(石油醚/乙酸乙酯二50:l),得2-(e)-0-(3',3,-二甲基琥珀酰基)-3-脫氧-28-三苯甲基醚白樺脂醇,白色粉末100mg,產(chǎn)率為56.2%。'HNMR(300MHz,C5D5N)Sppm:0.70(s'3H),0.87(s,3H),0.91(s,3H),1.02(s,3H),1.09(s,3H),1.52(s,3H),1.53(s,3H),1.71(s,3H),2.34-2.39(m,3H),2.87(s,2H),3.15,3.49(d,,8.8Hz,each1H),4.71,4.75(d,/=2.0Hz,each1H),5.29(m,1H),7.69-7.72(m,6H),7.38—7.46(m,6H),7.28-7.33(m,3H);13CNMR(300MHz,C5D5N)Sppm:14.0,14.6,15.9,18.7,18.9,19.0,21.0,22.7,24.1,25.4,25.8,27.1,29.3,29.3,29.7,30.0,31.9,32.5,32.6,33.8,35.3,37.3,37.6,40.6,40.9,42.7,42.9,44.1,44.9,47.8,49.0,50.7,53.4,59.7,70.4,86.2,109.7'127.1,128.0,129.0,134.4,134.6,144.9,150.7,171.0'179.0;ESI—MS歷/z:835.5[M+Na]+.實(shí)施例282-(e)-0-(3',3'-二甲基琥珀?;?-3-脫氧白樺脂醇的制備將2-(e)-(3-羧基-3-甲基-l-丁酰氧基)-3-脫氧_28-三苯甲基醚白樺脂醇(80mg)溶于無水乙醇(5ml)中,加入PPTS(84.3mg),70。C下攪拌20h后原料消失。減壓蒸除乙醇,加冰水20ml,乙酸乙酯萃取(25mlX2,15mlX2),飽和食鹽水洗滌有機(jī)層,無水NaS04干燥,濃縮,快速柱層析(石油醚/乙酸乙酯=4:1),得2-(P)-0-(3,,3'-二甲基琥珀?;?_3-脫氧白樺脂醇,白色粉末42mg,產(chǎn)率為75°/。。'H剛R(300MHz,C5D5N)Sppm:0.88(s,3H),0.97(s,3H),0.991(s,3H),1.00(s,3H),1.09(s,3H),1.54(s,3H),1.55(s,3H),1.78(s,3H),2.1—2.18(m,1H),2.37—2.45(m,2H),2.57-2.65(m,1H),2.88(s'2H)3.64'4.07(d,./=8.8Hz,each1H),4.77,4.90(d,,2.0Hz,each1H),5.30(m,1H);13CNMR(300MHz,C5D5N)S卯m:14.9,16.1,18.9,19.1,19.3'21.5,24.4,25.8,26.0,26.1,27.6,30.0,30.1,30.5,32.8,32.9,34.1,34.9,37.8,38.0,40.9,41,4,43.2,43.2,44.5,45.2,48.4,48.6,49.2,51.2,53.8,59.6,70.1,109.9,151.4,171.3,179.3;ESI-MS歷/z:593.5[M+Na]+.實(shí)施例292-(e)-乙酰氧基-3-脫氧-28-三苯甲基醚白樺脂醇的制備以2-(e)-羥基-3-脫氧-28-三苯甲基醚白樺脂醇和乙酸酐為原料,參照實(shí)施例27的方法制得2-(e)-乙酰氧基-3-脫氧-28-三苯甲基醚白樺脂醇。'H麗R(300MHz,CDCL)S卯m:0.54(s,3H),0.89(s,3H),0.91(s,3H),0.95(s'3H),0.98(s,3H),1.66(s,3H),1.98(s,3H),2.90,3.14(d,J=8.7Hz,each1H),4.51,4.57(brs,each1H),5.05(m,1H),7.19-7.33(m,9H),7.47-7.50(m,6H);l3CNMR(300MHz,CDC13)Sppm:14.8,15.9,18.5,18.9,19.1,21.2,21.5,24.0,25.4,27.0,30.0,30.3,32.7,32.8,33.8,35.3,37.5,37.8,41.0,42.8,43.1,44.3,47.7,47.8,49.0,50.9,53.7,59.8,70.7,86.0,109.4,126.8,127.7,128.9,144.6,150.8,170.4.實(shí)施例302-(e)-乙酰氧基-3-脫氧白樺脂醇的制備以2-(P)-乙酰氧基-3-脫氧-28-三苯甲基醚白樺脂醇為原料,參照實(shí)施例28的方法制得2-(0)-乙酰氧基-3-脫氧白樺脂醇。'H畫R(300MHz,CDC13)Sppm:0.92(s,3H),0.95(s'3H),0.97(s,3H),1.03(s,3H),1.04(s,3H),1.67(s,3H),2.00(s,3H),2.33-2.43(m,1H),3.33,3.79(d,/=10.8Hz,each1H),4.58,4.67(brs,each1H),5.05(m,1H);l3C醒R(300MHz,CDC13)Sppm:14.8,16.0,18.4,18.6,18.9,19.1,21.3,21.5,24.0,25.5,27.1,29.3,29.9,32.7,32.9,33.9,34.1,37.5,37.8,41.2,43.0,43.1,44.3,47.9,48.9,51.0,53.8,58.5,60.7,70.7,109.7,150.4,170.4.實(shí)施例312-羰基-3-脫氧-28—乙酸酯白樺脂醇的制備將2-羰基-3-脫氧-28—三苯甲基醚白樺脂醇(600mg)溶于冰醋酸(4ml)中,加熱至60。C,12h后反應(yīng)結(jié)束。減壓蒸除溶劑,快速柱層析(石油醚/乙酸乙酯二15:l),得2-羰基-3-脫氧-28—乙酸酯白樺脂醇,白色粉末300mg,產(chǎn)率為70.8%。'HNMR(500MHz,CDC13)S卯m:0.84(s,3H)'0.87(s,3H),1.01(s,3H),1.04(s,3H),1.05(s,3H),1.68(s,3H),2.06(s,3H),2.13-2.16(m,1H),2.24-2.27(m,1H),2.42-2.45(m,1H),3.85,4.26(d,,8.8Hz,each1H),4.60,4.69(d,,2.0Hz,each1H);13CNMR(500MHz,CDC13)S卯m:14.8,15.7,17.2,19.0,19.2,20.9,21.0,23.1,25.1,27.1,29.6,29.8,37.5,39.0,41.3,42.8,42.9,46.3,47.7,48.8,50.1,55.7,56.1,56.5,62.7,109.9,149.9,171.5'212.2;ESI-MS//z:483.5[M+H]+.實(shí)施例322-羰基-3-脫氧白樺脂醇的制備將2-羰基-3-脫氧-28—乙酸酯白樺脂醇(300mg)溶于THF(6ml)中,加入甲醇4ml,滴加4NNaOH溶液,室溫反應(yīng)2h。蒸干有機(jī)溶劑,冰浴下,INHC1中和反應(yīng)液至PH"5。乙酸乙酯萃取(50mlX2,25mlXl,15mlXl),飽和碳酸氫鈉溶液及飽和食鹽水洗滌有機(jī)層至中性,無水NaS(X干燥,濃縮,快速柱層析(石油醚/乙酸乙酯=8:1),得2-羰基_3-脫氧白樺脂醇,白色粉末260mg,產(chǎn)率為96.7%。'HNMR(300MHz,CDC13)Sppm:0.80(s,3H),0.83(s'3H),1.02(s,3H),1.03(s,3H),1.05(s,3H),1.68(s,3H)'2.06(s,3H),1.88—1.93(m,4H),2.16-2.17(m,1H),2.24—2.34(m,1H),2.34—2.39(m,2H),3.34,3.79(d',戶8.8Hz,each1H),4.59,4.68(d,,戶2.0Hz,each1H);':'CNMR(300MHz,CDC1:,)Sppm:14.8,15.7,17.2,19.1,19.2,21.1,23.1,25.2,27.2,29.2,29,8,33.4,33.8,34.0,37.3,39.0,41.4,42.9,43.0,47.8,47.9,48.8,50.2,55.8,56.2,56.5,60.6,109,8'150.3,212.0;ESI-MS歷/z:441.3[M+H]+.實(shí)施例332-(e)-羥基-3-脫氧白樺酸的制備將2-(P)羥基-3-脫氧白樺脂醇(100mg)溶于二氯甲垸(5ml)中,將催化量的KBr,Bu4N+Br-,TEMPO(10.6mg)溶于水(0.8ml)中加入二氯甲垸溶液,再5%碳酸氫鈉溶液(0.7ml)加入反應(yīng)液中。冰浴下緩慢滴加次氯酸鈉溶液lml。自然升溫至室溫,20h后反應(yīng)完全。分出有機(jī)層,飽和食鹽水洗滌2次后,直接滴加亞氯酸鈉溶液(25%)1.5ml。半小時(shí)后反應(yīng)完全,加入飽和亞硫酸氫鈉溶液5ml猝滅反應(yīng)。減壓蒸除大部分有機(jī)溶劑后乙酸乙酯萃取,飽和食鹽水洗滌有機(jī)層2次。無水硫酸鈉干燥,過濾,濃縮,快速柱層析(石油醚/乙酸乙酯=4:1),得2-(e)羥基-3-脫氧白樺酸,白色固體50mg,產(chǎn)率48.5%。'HNMR(300MHz,C5D5N)Sppm:0.89(s,3H),0.99(s,3H),1.01(s,3H),1.06(s,3H),1.19(s,3H),1.75(s,3H),2.15-2.21(m'2H),2.44-2.71(m,2H),3.41-3.49(m,1H),4.28(m,lH),4.86,4.69(d,J=2.0Hz,each1H);13CNMR(300MHz,CDC13)S卯m:15.00,16.4,19.5,19.6,21.8,24.9,26.4,30.3,31.4,33.0,33.1,33.2,34.6,37.6,38.5,38.9,41.4,42.6,43.1,47.5,47.8,48.7,50.0,51.6,54.1,56.8,66.7,109.8,151.4;ESI-MSm/z:455.4[M-H]—.權(quán)利要求1.通式I或II所示的五環(huán)三萜類化合物或其藥學(xué)上可接受的鹽或酯其中R1獨(dú)立代表氫、OR9、NHR9、N(R10)2、SO2NH2、NHOR9、NH2NHR9;R2獨(dú)立代表氫、OR9、NHR9、N(R10)2、SO2NH2、NHOR9、NH2NHR9;或者R1與R2一起代表O或NOR9;R3代表氫或甲基,R4代表氫或甲基,并且,當(dāng)R3代表氫時(shí),R4僅代表甲基;當(dāng)R3代表甲基時(shí),R4僅代表氫;R5代表CH3、CH2OR9、COOR10、CONHR9、CON(R10)2、NHR9;R6獨(dú)立代表氫、OR9、NHR9、N(R10)2、SO2NH2、NHOR9、NH2NHR9;R7獨(dú)立代表氫、OR9、NHR9、N(R10)2、SO2NH2、NHOR9、NH2NHR9;或者R6與R7一起代表O或NOR9;R8代表CH3、CH2OR9、COOR10、CONHR9、CON(R10)2、NHR9;R9代表氫或R10、R10CO,R10SO2;R10代表1~10個(gè)碳的非取代的或X取代的直鏈或支鏈烷烴、烯烴、炔烴、苯基、芐基、萘基;X代表H、F、Cl、Br、I、CN、NO2、NH2、CF3、SH、OH、OCH3、OC2H5、COOH、COOCH3、COOC2H5、1~10個(gè)碳的直鏈或支鏈烷烴、烯烴、炔烴、苯基、芐基、萘基。2、權(quán)利要求1的化合物,其特征在于R獨(dú)立代表氫、OR9;R2獨(dú)立代表氫、OR9;或者R,與R2—起代表0或NOR9;R3代表氫或甲基,R4代表氫或甲基,并且,當(dāng)R3代表氫時(shí),R4僅代表甲基;當(dāng)R3代表甲基時(shí),R4僅代表氫;Rs代表CH3、CH2OR9、COOR10;R6獨(dú)立代表氫、OR9;R獨(dú)立代表氫、OR9;或者R6與R7—起代表O或NOR9;Rs代表CH3、CH2OR9、COOR10;R9代表氫或R,0、R1QCO;Rhj代表1~10個(gè)碳的非取代的或X取代的直鏈或支鏈烷烴、烯烴、炔烴、苯基、芐基、萘基;X代表H、F、Cl、Br、I、CN、N02、NH2、CF3、SH、OH、OCH3、OC2H5、COOH、COOCH3、COOC2H5、110個(gè)碳的直鏈或支鏈烷烴、烯烴、炔烴、苯基、芐基、萘基。3、權(quán)利要求2的化合物,為下列任一結(jié)構(gòu)的化合物2-羰基-3-脫氧齊墩果酸-28—芐酯2-羰基-3-脫氧熊果酸-28-芐酯2-羰基-3-脫氧齊墩果酸2-羰基-3-脫氧熊果酸2-肟基-3-脫氧齊墩果酸-28-節(jié)酯2-肟基-3-脫氧熊果酸-28-芐酯2-肟基-3-脫氧齊墩果酸2_肟基-3-脫氧熊果酸2-(p)-羥基-3-脫氧齊敦果酸-28-芐酯2->-羥基-3-脫氧熊果酸-28-芐酯2-:a)-羥基-3-脫氧齊敦果酸-28-節(jié)酯2-(a>-羥基-3-脫氧熊果酸-28-節(jié)酯2-〔p>-羥基-3-脫氧齊墩果酸2-〔r>-羥基-3-脫氧熊果酸2-:a,>-羥基-3-脫氧齊敦果酸2-〔a:>-羥基-3-脫氧熊果酸2-〔p:>-羥基-3-脫氧齊敦果酸-28-甲酯2-_羥基-3-脫氧齊敦果酸-28-乙酯2->-羥基_3-脫氧齊敦果酸-28-丙酯2--羥基_3-脫氧齊敦果酸-28-丁酯2-:e)-羥基-3-脫氧齊敦果酸-28-烯丙酯2-:p)-羥基-3-脫氧齊敦果酸-28-(2-溴乙酯)2-(:e〕-羥基_3-脫氧齊敦果酸-28-(3-溴丙酯)2-(:e)-羥基-3-脫氧齊敦果酸-28-(4-溴丁酯)2-(-羥基_3-脫氧齊敦果酸-28-乙酸乙酯2-(-乙酰氧基-3-脫氧-齊敦果酸-28-芐酯2H-丙酰氧基-3_脫氧-齊敦果酸-28-芐酯2-(-丁酰氧基-3-脫氧-齊敦果酸-28-芐酯2-<-苯甲酰氧基-3-脫氧-齊敦果酸-28-芐酯2-<-對(duì)叔丁基苯甲酰氧基-3-脫氧-齊敦果酸-28-芐酯2-<-0-琥珀酰基-3-脫氧齊敦果酸-28-芐酯2--乙酰氧基-3-脫氧-齊敦果酸2-<-丙酰氧基-3-脫氧-齊敦果酸2--丁酰氧基-3-脫氧-齊敦果酸2--苯甲酰氧基-3_脫氧-齊敦果酸2-<:p:-對(duì)叔丁基苯甲酰氧基-3-脫氧-齊敦果酸2-<-0-琥珀?;?3-脫氧齊敦果酸2--0-(3',3'-二甲基琥珀?;?-3-脫氧齊敦果酸2—:0:-0-(2',2'-二甲基琥珀?;?-3-脫氧齊敦果酸1-烯-2-羥基-3-羰基-28-三苯甲基醚白樺脂醇2-(e)-羥基-28-三苯甲基醚白樺脂醇2-羰基-3-脫氧-28-三苯甲基醚白樺脂醇2-羰基-3-脫氧-28—乙酸酯白樺脂醇2-羰基-3-脫氧白樺脂醇2-(e)-羥基-3-脫氧-28-三苯甲基醚白樺脂醇2-(a)-羥基-3-脫氧-28-三苯甲基醚白樺脂醇2-(e)-羥基-3-脫氧白樺脂醇2-(oc)-羥基-3-脫氧白樺脂醇2-(3)-乙酰氧基-3-脫氧-28-三苯甲基醚白樺脂醇2-(P)-丁酰氧基-3-脫氧_28-三苯甲基醚白樺脂醇2-(e)-0-(3',3,-二甲基琥珀?;?-3-脫氧-28-三苯甲基醚白樺脂醇2-(P)-0-(2',2,-二甲基琥珀?;?-3-脫氧-28-三苯甲基醚白樺脂醇2-(e)-乙酰氧基-3-脫氧白樺脂醇2-(e)-丙酰氧基-3-脫氧白樺脂醇2-(e)-丁酰氧基-3-脫氧白樺脂醇2-(e)-苯甲酰氧基-3-脫氧白樺脂醇2-(P)-0-(3',3'-二甲基琥珀酰基)-3-脫氧白樺脂醇2-(P)-0-(2',2'-二甲基琥珀?;?-3-脫氧白樺脂醇2-羰基-3-脫氧白樺酸2-(e)-羥基-3-脫氧白樺酸4、權(quán)利要求l的化合物,其中藥學(xué)上可接受的鹽為通式I或II所示化合物的鈉鹽、鐘鹽、銨鹽、有機(jī)胺鹽或堿性氨基酸(如賴氨酸和精氨酸)鹽。其藥學(xué)上可接受的鹽還包括通式I或II所示化合物與下列酸形成的酸加成鹽鹽酸、氫溴酸、硫酸、碳酸、檸檬酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、馬來酸、甲磺酸、苯磺酸或?qū)妆交撬帷?、權(quán)利要求l的化合物的制備方法,包括以下步驟(1)2-羰基-3-脫氧五環(huán)三萜化合物的制備<formula>formulaseeoriginaldocumentpage4</formula>上式中,R3、R4、R5和Rs的定義如前所述。在堿催化下,(2p,3p)-2,3-二羥基五環(huán)三萜化合物與對(duì)甲苯磺酰氯或苯磺酰氯反應(yīng),得到2-羰基-3-脫氧五環(huán)三萜化合物。所采用的堿包括吡啶、三乙胺、碳酸鉀、碳酸鈉、碳酸氫鈉、碳酸氫鉀、氫氧化鈉或氫氧化鉀,優(yōu)先采用吡啶。所采用的溶劑包括吡啶、二氯甲烷、1,2-二氯乙垸、氯仿、甲苯、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、乙腈、四氫呋喃或二氧六環(huán),或者用這些溶劑任選組成的混合溶劑,優(yōu)先采用吡啶、1,2-二氯乙烷、甲苯、N,N-二甲基甲酰胺或四氫呋喃。反應(yīng)溫度可控制在0度至150度,優(yōu)先采用室溫至80度作為反應(yīng)溫度。(2)2-肟基-3-脫氧五環(huán)三萜化合物的制備上式中,R3、R4、R5和Rs的定義如前所述。上式屮的2-羰基-3-脫氧五環(huán)三萜化合物與鹽酸羥氨在堿催化下反應(yīng),生成2-肟基-3-脫氧五環(huán)三萜化合物。所采用的堿包括吡啶、三乙胺、碳酸鉀、碳酸鈉、碳酸氫鈉、碳酸氫鉀、氫氧化鈉或氫氧化鉀,優(yōu)先采用吡啶。所采用的溶劑包括吡啶、二氯甲垸、1,2-二氯乙垸、氯仿、甲苯、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、乙腈、四氫呋喃或二氧六環(huán),或者用這些溶劑任選組成的混合溶劑,優(yōu)先采用吡啶、1,2-二氯乙烷、甲苯、N,N-二甲基甲酰胺或四氫呋喃。反應(yīng)溫度可控制在0度至150度,優(yōu)先采用室溫至80度作為反應(yīng)溫度。(3)2-羥基-3-脫氧五環(huán)三萜化合物的制備<formula>formulaseeoriginaldocumentpage5</formula>上式中,R3、R4、Rs和Rs的定義如前所述。上式中的2-羰基-3-脫氧五環(huán)三萜化合物在還原劑的作用下生成2-羥基-3-脫氧五環(huán)三萜化合物。所采用的還原劑選自硼氫化鈉、硼氫化鉀、異丙醇/異丙醇鋁、硼烷/四氫呋喃或硼烷/二甲硫醚,優(yōu)先采用硼氫化鈉(鉀)。所采用的溶劑選自四氫呋喃、乙醇、甲醇、乙醚、叔丁基甲醚、乙酸乙酯、甲酸乙酯、乙酸甲酯^二氧六環(huán)或上述溶劑的混合物,優(yōu)先采用四氫呋喃/乙醇作為反應(yīng)溶劑。反應(yīng)溫度可控制在零度至60度,優(yōu)先采用零度至室溫作為反應(yīng)溫度。(4)2-0-?;?3-脫氧五環(huán)三萜化合物的制備上式中,R3、R4、R5、Rs和Rw的定義如前所述。按照常規(guī)的羥基酯化方法,上式中的2-羥基-3-脫氧五環(huán)三萜化合物與各種酰氯、酸酐或羧酸反應(yīng),得到2-0-?;?3-脫氧五環(huán)三萜化合物。(5)3-脫氧五環(huán)三萜-28-酯化合物的制備p>上式中,&、R2、R3、R4、R6、R7和Rw的定義如前所述。按照常規(guī)的羧基垸基化酯化方法,上式中的3-脫氧五環(huán)三萜-28-酸與各種鹵代垸烴反應(yīng),得到3-脫氧五環(huán)三萜-28-酯化合物。6、一種藥物組合物,其中含有治療有效量的通式I或II所示化合物和藥學(xué)上可接受的載體。7、權(quán)利要求1至4中任一項(xiàng)的化合物在制備用于預(yù)防和治療糖尿病、心血管疾病、腦血管疾病和腫瘤的藥物中的用途。8、權(quán)利要求7的用途,其中糖尿病是2型糖尿病。9、權(quán)利要求7的用途,其中心血管疾病是心肌梗死、心絞痛、心律失常、冠心病、動(dòng)脈粥樣硬化、心衰、高血壓或肺動(dòng)脈高血壓。10、權(quán)利要求7的用途,其中腦血管疾病是中風(fēng)、腦梗死、腦梗塞、腦缺血或缺血性神經(jīng)退行性疾病。全文摘要本發(fā)明涉及藥物領(lǐng)域,具體涉及一系列通式I或II的五環(huán)三萜化合物、其制備方法及其在制備用于預(yù)防和治療糖尿病、心血管疾病、腦血管疾病和腫瘤的藥物中的用途。R<sub>1-8</sub>的定義見說明書。文檔編號(hào)C07J63/00GK101367861SQ200710026109公開日2009年2月18日申請(qǐng)日期2007年8月15日優(yōu)先權(quán)日2007年8月15日發(fā)明者孫宏斌,璞張,張陸勇,軍柳,佳郝申請(qǐng)人:中國藥科大學(xué)
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