本文選題：SGLT2抑制劑 + Dapagliflozin�。� 參考：《天津醫(yī)科大學(xué)》2014年博士論文

【摘要】：目的:Ⅱ型糖尿病是一種以胰島素相對不足和血糖過高為主要特征的慢性代謝疾病,能夠誘發(fā)一系列并發(fā)癥。由于發(fā)病機(jī)制復(fù)雜,病程長,目前的治療藥物難以有效控制血糖水平,因此臨床上迫切需要具有全新作用機(jī)制的新型降糖藥。原尿中99%的葡糖糖流經(jīng)腎小管時被重吸收,其重吸收主要依賴于兩種鈉-葡萄糖協(xié)同轉(zhuǎn)運(yùn)蛋(sodium-dependent glucose cotrans-porters,SGLTs)介導(dǎo):SGLT2 起主要作用,轉(zhuǎn)運(yùn)重吸收葡萄糖的90%;SGLT1轉(zhuǎn)運(yùn)重吸收葡萄糖的10%。選擇性地抑制SGLT2的活性,能夠減少葡萄糖的重吸收,增加尿糖,降低血糖水平,已成為治療Ⅱ型糖尿病的的新型靶標(biāo)。目前報(bào)道的SGLT2抑制劑主要是O-芳基糖苷抑制劑、C-芳基糖苷抑制劑,O-芳基糖苷抑制劑選擇性較低、代謝不穩(wěn)定,而C-芳基糖苷抑制劑克服了以上不足之處,取得了巨大的成績,其中Dapagliflozin和Canagflozin兩種SGLT2抑制劑已分別在歐洲和美國上市。我們以Dapagliflozin為先導(dǎo)化合物,設(shè)計(jì)、合成新型SGLT2抑制劑并進(jìn)行活性篩選,期望能夠獲得新的有效的的SGLT2抑制劑。方法:我們深刻分析Dapagliflozin、Empagliflozin和Canagliflozin等C-芳基抑制劑的分子結(jié)構(gòu),發(fā)現(xiàn)這些化合物的結(jié)構(gòu)具有很大的相似性,即分子左端為一個葡萄糖片斷,該葡萄糖片斷通過C-糖苷鍵與一個苯環(huán)相連,該苯環(huán)的間位通過—個亞甲基與另外一個芳基相連。針對上述SGLT2抑制劑尤其是Dapagliflozin的分子結(jié)構(gòu)特點(diǎn),我們設(shè)計(jì)了三類化合物:單甲基C-碳糖苷類、偕二甲基C-碳糖苷類和環(huán)丙基C-碳糖苷類,三類化合物均以Dapagliflozin作為陽性對照藥,進(jìn)行了體內(nèi)抗血糖活性評價(jià),部分化合物還進(jìn)行了體外活性測試。對實(shí)驗(yàn)室合成的SGLT2抑制劑D6進(jìn)行逆合成分析:發(fā)現(xiàn)化合物D6有兩個結(jié)構(gòu)特點(diǎn):一是糖環(huán)部分的6位-去氧,二是碳糖苷,所以6-脫氧和碳糖苷是合成D6的關(guān)鍵步驟�？紤]到生產(chǎn)需要和專利避開,我們以先構(gòu)建碳糖苷,后構(gòu)建6-去氧為策略,采用匯聚式的合成方法,經(jīng)過多次試驗(yàn)最終確定了 D6的新的合成路線。結(jié)果:通過匯聚式的合成路線合成目標(biāo)化合物。在第1-3章節(jié)中,以取代的苯甲酸和葡萄糖酸內(nèi)酯為起始物,經(jīng)過酰氯化或酯化、傅克反應(yīng)、Simmons-Smith反應(yīng)、溴-鋰交換、三乙基硅烷還原、乙酰化和脫乙�；炔襟E合成了單甲基類化合物3個、偕二甲基類化合物3個、環(huán)丙基類化合物7個,化合物通過IH-NMR、13C-NMR和HR-MS、IR表征了它們的結(jié)構(gòu),體內(nèi)活性測試發(fā)現(xiàn)它們均有較好的抗高血糖活性,部分藥物具有一定的成藥性。我們以碘化物為起始原料,經(jīng)過催化氫化、酸性催化水解、Swern氧化、溴-鋰交換、芐基脫保護(hù)反應(yīng)成功地合成D6,并對催化氫化、酸性催化水解和芐基脫保護(hù)等步驟進(jìn)行反復(fù)試驗(yàn)和多次優(yōu)化,找到了一條產(chǎn)率高、易操作、重復(fù)性強(qiáng)的合成D6的工藝路線,并且發(fā)現(xiàn)SrCl_2對甲基糖苷的酸性水解具有極為有效的催化作用,為D6的藥理、毒理等實(shí)驗(yàn)提供了有力的原料保障。結(jié)論:論文結(jié)合設(shè)計(jì)合成的三類C-芳基糖苷類SGLT2抑制劑的化學(xué)結(jié)構(gòu)和藥理活性,發(fā)現(xiàn)它們的活性強(qiáng)弱為:單甲基類活性強(qiáng)于環(huán)丙基類,再強(qiáng)于偕二甲基類,即在SGLT2抑制劑的兩芳基之間亞甲基處添加基團(tuán)活性保留,且基團(tuán)越大活性越弱,苯環(huán)上的取代基以氯最優(yōu)。這是學(xué)術(shù)上首次系統(tǒng)和科學(xué)地闡明了SGLT2抑制劑結(jié)構(gòu)中的兩苯環(huán)之間亞甲基上的構(gòu)效關(guān)系,是對SGLT2抑制劑構(gòu)效關(guān)系研究的重要補(bǔ)充,在此研究基礎(chǔ)上我們有可能發(fā)現(xiàn)更好的成藥分子。開發(fā)的D6的新路線開辟了合成各類脫氧C-糖苷的一種通用方法;該新合成工藝,具有穩(wěn)定性好和易操作的優(yōu)點(diǎn),并具有自主知識產(chǎn)權(quán),目前已被實(shí)驗(yàn)室中試采用,已在公斤級中試平臺上運(yùn)行四批,穩(wěn)定可靠,為D6的臨床前研究提供了有力的物質(zhì)保障。在學(xué)術(shù)界首次發(fā)現(xiàn)甲基糖苷水解共催化劑SrCl_2,高效、綠色、可控,現(xiàn)已在實(shí)驗(yàn)室的小規(guī)模實(shí)驗(yàn)中廣泛使用,并在公斤級平臺上得到了驗(yàn)證。
[Abstract]:Objective: diabetes is a relative lack of insulin and hyperglycemia is the main characteristic of chronic metabolic diseases, can cause a series of complications. Because the pathogenesis is complex, long course of disease, the treatment is difficult to effectively control the blood glucose level, therefore clinically urgent need for new antidiabetic drugs with new mechanisms of action. 99% of the glucose in urine flow tubular reabsorption is, its reabsorption mainly depends on two kinds of sodium glucose co transporter (sodium-dependent glucose, cotrans-porters, SGLTs) - mediated: SGLT2 plays a major role, transport of glucose reabsorption 90%; SGLT1 transport of glucose reabsorption of 10%. selectively inhibits the activity of SGLT2, to reduce glucose reabsorption and increase urine glucose, reduce blood sugar levels, has become a new target for the treatment of type II diabetes. The reported SGLT2 inhibitor is O- aryl Glucosidase inhibitors, C- aryl glucoside inhibitors, O- aryl glucoside inhibitors lower selectivity, metabolic instability, and C- aryl glucoside inhibitors to overcome the above shortcomings, has made great achievements, including Dapagliflozin and Canagflozin two kinds of SGLT2 inhibitors have been respectively in European and American market. We design with Dapagliflozin as the leading compound,, synthesis of novel SGLT2 inhibitors and activity screening, is expected to be a new effective inhibitor of SGLT2. Methods: We deeply analyze Dapagliflozin, Empagliflozin and Canagliflozin, the molecular structure of C- aryl inhibitors, found that the structures of these compounds are very similar, which is a molecular fragment of glucose, the glucose fragment connected with a benzene ring by C- glycosidic bond between the benzene ring, through a methylene linked with another aryl. Based on the above SGLT2 Inhibitor especially the molecular structure characteristics of Dapagliflozin, we designed three compounds: single methyl glucoside C- carbon, with two methyl carbon C- glycosides and cyclopropyl C- carbon glycosides, three compounds with Dapagliflozin as positive control medicine, the in vivo activity of glucose evaluation, some compounds were tested in vitro activity test. The SGLT2 inhibitor D6 synthesis laboratory for inverse synthetic analysis: we found that compound D6 has two structural characteristics: one is the sugar moiety 6 - deoxy, two carbon glycoside, so 6- deoxidation and carbon glycoside is a key step in the synthesis of D6. Considering the production needs and avoid the first US patent. After the construction of the carbon glycoside, construct 6- DNA as the strategy, the synthesis method is convergent, after many tests finally identified a new synthetic route of D6. Results: the compounds synthesized by convergent goal in section 1-3. In the chapter, using benzoic acid and gluconic acid lactone substituted as the starting material, after esterification or acylation, Friedel Crafts reaction, Simmons-Smith reaction, bromine lithium exchange, three ethyl silane reduction, acetylation and deacetylation and other steps of the synthesis of methyl compounds 3, 3 with two methyl compounds. Cyclopropyl compounds 7 were characterized by IH-NMR, 13C-NMR, IR and HR-MS, their structures were characterized, in vivo activity test found that they have good anti hyperglycemic activity, drug resistance has become a part of us. With iodide as the starting material, through catalytic hydrogenation, acid catalyzed hydrolysis, oxidation of Swern, lithium bromide exchange, benzyl deprotected was successfully synthesized D6 and catalytic hydrogenation, the acid catalyzed hydrolysis and benzyl based protection steps were repeated testing and optimization, and found a high yield, easy operation, strong repeatability of the synthesis of D6. Route, and found that the SrCl_2 of methyl glucoside acid hydrolysis is extremely effective in catalysis, D6 pharmacology, provides a strong material guarantee for toxicological experiments. Conclusion: the combination of chemical structure and drug design and synthesis of three kinds of C- aryl glucoside SGLT2 inhibitor activity, that activity of their for single class activity stronger than methyl cyclopropane base, strong in two with methyl, which is between two aryl methylene groups add SGLT2 inhibitor activity retention, and the activity of the weak group, the substituent on the benzene ring with chlorine. This is the first optimal academic system and scientifically expound the structure-activity relationship between the methylene SGLT2 inhibitor in the structure of two benzene rings, is an important complement to the structure-activity relationship of SGLT2 inhibitors, on the basis of this study, we may find a better route. New molecular medicine development D6 development A general method for synthesis of deoxy C- glucoside; the new synthetic technology, has the advantages of good stability and easy operation, and has independent intellectual property rights, has been used in the laboratory test, test platform has operated four batches in kilograms in stable and reliable for clinical D6 study provides strong material. In the academic circles for the first time found methyl glycoside hydrolysis catalyst is SrCl_2, green, efficient, controllable, is now widely used in small scale experiments in the laboratory, and has been verified in the kilo platform.

【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2014
【分類號】：R914;R96

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