(19)國家知識產(chǎn)權(quán)局(71)申請人內(nèi)蒙古大學(xué)地址010010內(nèi)蒙古自治區(qū)呼和浩特市賽罕區(qū)大學(xué)西路235號(72)發(fā)明人劉國都郭妍妍(74)專利代理機(jī)構(gòu)西安銘澤知識產(chǎn)權(quán)代理事務(wù)所(普通合伙)61223專利代理師吳瑩A61K38/12(2006.01)A61P35/02(2006.01)一種海洋環(huán)肽及其合成方法、用途本發(fā)明屬于藥物研究技術(shù)領(lǐng)域，具體涉及一種海洋環(huán)肽及其合成方法、用途。該海洋環(huán)肽的結(jié)構(gòu)式如式I所示。與天然的Galaxamide相比，本發(fā)明提供的含有D-亮氨酸的Galaxamide類似物對人類癌細(xì)胞表現(xiàn)出更大的抑制作用，且引入的D-亮氨酸數(shù)量越多，抗癌活性越強(qiáng)。同時利用其他氨基酸取代Galaxamide其中一個L-亮氨酸，合成的Galaxamide衍生物比天然Galaxamide更增殖的潛力；2AOAONNOO絲氨酸、0-甲基-D-酪氨酸、甲酯-D-天冬氨酸、3-氟-D-苯丙氨酸、2-甲基-D-苯丙氨酸、4-酸、3-甲基-D-苯丙氨酸和4-甲基-D-苯丙氨酸；R2~R5各自選自D-亮氨酸或L-亮氨酸。2.根據(jù)權(quán)利要求1所述的海洋環(huán)肽，其特征在于，所述海洋環(huán)肽的結(jié)構(gòu)式如下任一所3K08OOOONNOONHOONHON1O3.一種權(quán)利要求1所述海洋環(huán)肽的合成方法，其特征在于，包括以下步驟：以N-(叔丁氧羰基)-L-亮氨酸為原料進(jìn)行氮甲基化反應(yīng)，得到Boc-N-甲基-L-亮氨酸，或以N-(叔丁氧羰基)-D-亮氨酸為原料進(jìn)行氮甲基化反應(yīng)，得到Boc-N-甲基-D-亮氨酸；以所述Boc-N-甲基-L-亮氨酸及L-亮氨酸芐酯對甲苯磺酸鹽為原料進(jìn)行縮合反應(yīng)，得到二肽；或以所述Boc-N-甲基-D-亮氨酸及D-亮氨酸芐酯對甲苯磺酸鹽為原料進(jìn)行縮合反4對所述二肽進(jìn)行氫化還原以去除其C端芐基，得到產(chǎn)物D;對所述二肽進(jìn)行酸水解以去除其N端叔丁氧羰基，得到產(chǎn)物E;將所述產(chǎn)物D與所述產(chǎn)物G混合進(jìn)行縮合反應(yīng)，得到線性五肽；依次去除所述線性五肽C對所述產(chǎn)物J進(jìn)行大環(huán)內(nèi)酰胺化反應(yīng)，得到所述海洋環(huán)肽。4.根據(jù)權(quán)利要求3所述的合成方法，其特征在于，所述Boc-N-甲基-L-亮氨酸與-亮氨酸芐酯對甲苯磺酸鹽，或所述Boc-N-甲基-D-亮氨酸與D-亮氨酸芐酯對甲苯磺酸鹽的摩爾比均為1:1~2;所述產(chǎn)物E與氨基酸的混合摩爾比為1:1~2;所述產(chǎn)物D與所述產(chǎn)物G的摩爾比為1:1~2。5.根據(jù)權(quán)利要求4所述的合成方法，其特征在于，所述氮甲基化反應(yīng)是在-20~-10℃下攪拌30min~60min,然后在室溫下再攪拌12h~18h;所述Boc-N-甲基-L-亮氨酸及L-亮氨酸芐酯對甲苯磺酸鹽的縮合反應(yīng)，或Boc-N-甲基-D-亮氨酸及D-亮氨酸芐酯對甲苯磺酸鹽的縮合反應(yīng)均是在0℃~10℃下反應(yīng)6h~12h;所述二肽C端的氫化還原反應(yīng)是催化劑鈀的作用下于10℃~20℃反應(yīng)6h~12h;所述二肽N端的酸水解反應(yīng)是在-20℃~-10℃下反應(yīng)6h~12h;所述產(chǎn)物E與氨基酸的縮合反應(yīng)是在0℃~10℃下反應(yīng)6h~12h;所述產(chǎn)物D與所述產(chǎn)物G的縮合反應(yīng)是在0℃~10℃下反應(yīng)6h~12h;所述大環(huán)內(nèi)酰胺化反應(yīng)是在偶聯(lián)劑的作用下于0℃~10℃反應(yīng)12h~24h。6.根據(jù)權(quán)利要求5所述的合成方法，其特征在于，所述偶聯(lián)劑選自2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲六氟磷酸鹽、丙膦酸酐、二苯基磷酰疊氮化物、五氟苯基二苯基次膦酸酯或(苯并三唑-1-基氧基)三吡咯烷膦六氟磷酸鹽。7.一種權(quán)利要求1所述海洋環(huán)肽在制備抗癌藥物中的用途。8.根據(jù)權(quán)利要求7所述的用途，其特征在于，所述抗癌是對非小細(xì)胞肺癌、慢性粒細(xì)胞9.一種抗癌藥物，其特征在于，其以權(quán)利要求1所述海洋環(huán)肽作為唯一活性成分。10.根據(jù)權(quán)利要求9所述的抗癌藥物，其特征在于，所述藥物是由所述海洋環(huán)肽與藥學(xué)上可接受的輔料復(fù)配而成。5技術(shù)領(lǐng)域[0001]本發(fā)明屬于藥物研究技術(shù)領(lǐng)域，具體涉及一種海洋環(huán)肽及其合成背景技術(shù)[0002]化療是治療癌癥的重要方法之一，但絕大部分抗腫瘤藥物都具有耐藥性。在抗腫瘤治療過程中，腫瘤細(xì)胞對抗腫瘤藥物不敏感的現(xiàn)象稱為耐藥性?？鼓[瘤藥物耐藥的出現(xiàn)是癌癥化療失敗的主要原因之一，也是癌癥治療面臨的關(guān)鍵問題之一。從腫瘤細(xì)胞的角度出發(fā)，耐藥的發(fā)生機(jī)制可能是腫瘤細(xì)胞的異質(zhì)性、藥物轉(zhuǎn)運和代謝改變、藥物靶點的表達(dá)水藥性的發(fā)生與腫瘤微環(huán)境中浸潤的免疫和炎性細(xì)胞、癌癥相關(guān)成纖維細(xì)胞、血管內(nèi)皮細(xì)胞等其他細(xì)胞和組分也息息相關(guān)。[0003]腫瘤耐藥現(xiàn)象在小分子靶向抗癌藥物中較為常見，并且針對其耐藥機(jī)制設(shè)計出新的小分子藥物頗具挑戰(zhàn)。在眾多應(yīng)對抗腫瘤藥物耐藥的策略中，不斷篩選發(fā)現(xiàn)新型藥物、干擾腫瘤生長的特定信號通路、抑制腫瘤細(xì)胞增殖、提高治療效果是最具價值的策略之一。腫瘤發(fā)生耐藥后有新藥可更換、有新藥可聯(lián)合治療或交替治療，甚至利用新藥逆轉(zhuǎn)耐藥，是抗腫瘤和抗腫瘤耐藥的重要途徑。因此，亟待發(fā)現(xiàn)新的抗腫瘤藥物。[0004]Galaxamide是一種具有抗腫瘤活性的新型海洋環(huán)肽，具有成為新型抗癌藥物的潛力。其獨特的化學(xué)結(jié)構(gòu)和藥理特性，為癌癥治療提供了新的研究思路和潛在的藥物選擇。但Galaxamide仍然存在抗腫瘤活性較低、不具備廣譜抗腫瘤活性的缺陷。發(fā)明內(nèi)容[0005]鑒于以上技術(shù)問題，本發(fā)明提供一種海洋環(huán)肽本發(fā)明提供的具體技術(shù)方案如下：本發(fā)明提供一種海洋環(huán)肽，其結(jié)構(gòu)式如式I所示：基-D-絲氨酸、0-甲基-D-酪氨酸、甲酯-D-天冬氨酸、3-氟-D-苯丙氨酸、2-甲基-D-苯丙氨甲硫氨酸、3-甲基-D-苯丙氨酸和4-甲基-D-苯丙氨酸；R2~R5各自選自D-亮氨酸或L-亮氨[0006]作為本發(fā)明的一個優(yōu)選實施例，所述海洋環(huán)肽的結(jié)構(gòu)式如下任一所示：67K11K12K16K17K16K17O|OONH。C**oNNH本發(fā)明還提供一種所述海洋環(huán)肽的合成方法，包括以下步驟：以N-(叔丁氧羰基)-L-亮氨酸為原料進(jìn)行氮甲基化反應(yīng)，得到Boc-N-甲基-L-亮氨酸，或以N-(叔丁氧羰基)-D-亮氨酸為原料進(jìn)行氮甲基化反應(yīng)，得到Boc-N-甲基-D-亮氨酸；以所述Boc-N-甲基-L-亮氨酸及L-亮氨酸芐酯對甲苯磺酸鹽為原料進(jìn)行縮合反應(yīng)，得到二肽；或以Boc-N-甲基-D-亮氨酸及D-亮氨酸芐酯對甲苯磺酸鹽為原料進(jìn)行縮合反對所述二肽進(jìn)行氫化還原以去除其C端芐基，得到產(chǎn)物D;對所述二肽進(jìn)行酸水解以去除其N端叔丁氧羰基，得到產(chǎn)物E;將所述產(chǎn)物E與氨基酸混合進(jìn)行縮合反應(yīng)，得到三肽，脫去N末端Boc基團(tuán)，得到產(chǎn)物G;將所述產(chǎn)物D與所述產(chǎn)物G混合進(jìn)行縮合反應(yīng)，得到線性五肽；依次去除所述線性五肽C端芐基及N末端Boc基團(tuán)，得到產(chǎn)物J;對所述產(chǎn)物J進(jìn)行大環(huán)內(nèi)酰胺化反應(yīng)，得到所述海洋環(huán)肽。[0012]作為本發(fā)明的一個優(yōu)選實施例，所述Boc-N-甲基-L-亮氨酸與-亮氨酸芐酯對甲苯8磺酸鹽，或所述Boc-N-甲基-D-亮氨酸與D-亮氨酸芐酯對甲苯磺酸鹽的摩爾比均為1:1~2;所述產(chǎn)物E與氨基酸的混合摩爾比為1:1~2;所述產(chǎn)物D與所述產(chǎn)物G的摩爾比為1:1~2。[0013]作為本發(fā)明的一個優(yōu)選實施例，所述氮甲基化反應(yīng)是在-20~-10℃下攪拌30min~60min,然后在室溫下再攪拌12h~18h;所述Boc-N-甲基-L-亮氨酸及L-亮氨酸芐酯對甲苯磺酸鹽的縮合反應(yīng)，或Boc-N-甲基-D-亮氨酸及D-亮氨酸芐酯對甲苯磺酸鹽的縮合反應(yīng)均是在0℃~10℃下反應(yīng)6h~12h;所述二肽C端的氫化還原反應(yīng)是催化劑鈀作用下于10℃~20℃反應(yīng)6h~12h;所述二肽N端的酸水解反應(yīng)是在-20℃~-10℃下反應(yīng)6h~12h;所述產(chǎn)物E與氨基酸的縮合反應(yīng)是在0℃~10℃下反應(yīng)6h~12h;所述產(chǎn)物D與所述產(chǎn)物G的縮合反應(yīng)是在0℃~10℃下反應(yīng)6h~12h;所述大環(huán)內(nèi)酰胺化反應(yīng)是在偶聯(lián)劑的作用下于0℃~10℃反應(yīng)12h~24h。[0014]作為本發(fā)明的一個優(yōu)選實施例，所述偶聯(lián)劑選自2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲六氟磷酸鹽、丙膦酸酐、二苯基磷酰疊氮化物、五氟苯基二苯基次膦酸酯或(苯并三唑-1-基氧基)三吡咯烷膦六氟磷酸鹽。[0015]進(jìn)一步優(yōu)選地，所述偶聯(lián)劑選自(苯并三唑-1-基氧基)三吡咯烷膦六氟磷酸鹽。[0016]本發(fā)明還提供一種所述海洋環(huán)肽在制備抗癌藥物中的用途。[0017]作為本發(fā)明的一個優(yōu)選實施例，所述抗癌是對非小細(xì)胞肺癌、慢性粒細(xì)胞白血病、[0018]本發(fā)明還提供一種抗癌藥物，其以所述海洋環(huán)肽作為唯一活性成分。[0019]作為本發(fā)明的一個優(yōu)選實施例，所述藥物是由所述海洋環(huán)肽與藥學(xué)上可接受的輔料組成。[0020]作為本發(fā)明的一個優(yōu)選實施例，所述藥物為口服制劑或注射制劑。[0021]對比現(xiàn)有技術(shù)，本發(fā)明的有益效果為：本發(fā)明設(shè)計和合成了兩個系列Galaxamide衍生物，其中第一系列主要涉及將L-亮氨酸改為D-亮氨酸并改變D-亮氨酸位置和數(shù)量，第二系列包括將一個L-亮氨酸被其他氨基氨酸和4-甲基-D-苯丙氨酸。一方面，與天然的Galaxamide相比，含有D-亮氨酸的Galaxamide類似物對人類癌細(xì)胞表現(xiàn)出更大的抑制作用。Galaxamide中引入的D-亮氨酸數(shù)量越多，抗癌活性越強(qiáng)。含有四個D-亮氨酸的類似物對多種人類癌細(xì)胞系如HepG2、MCF-7、SW480和U87顯示出最強(qiáng)的細(xì)胞凋亡作用。另一方面，通過將其他氨基酸取代Galaxamide其中一個L-亮氨酸，合成的Galaxamide衍生物比天然Galaxamide更有效，具有抑制人類癌細(xì)[0022]本發(fā)明制備Galaxamide衍生物的關(guān)鍵步驟是大環(huán)內(nèi)酰胺化。本發(fā)明對中間產(chǎn)物J大環(huán)內(nèi)酰胺化生產(chǎn)Galaxamide衍生物的肽偶聯(lián)劑進(jìn)行了初步分析：2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲六氟磷酸鹽和丙膦酸酐的反應(yīng)轉(zhuǎn)化率較差，而使用二苯基磷酰疊氮化物和五氟苯基二苯基次膦酸酯產(chǎn)生中等產(chǎn)率的大內(nèi)酰胺化反應(yīng)物，(苯并三唑-1-基氧基)三吡咯烷膦六氟磷酸鹽主要產(chǎn)生了預(yù)期的產(chǎn)物海洋環(huán)肽。用較低濃度的乙腈作為溶劑時，加入(苯并三唑-1-基氧基)三吡咯烷膦六氟磷酸鹽和4-二甲氨基吡啶，反應(yīng)液的稀釋減少了二聚體產(chǎn)物的生成，產(chǎn)率達(dá)到50%。此外，通過在4h內(nèi)緩慢加入中間產(chǎn)物J來模擬高度稀9Cyclo(Me-L-Leu-L-Leu-D-Leu-ML-Leu-OH,其產(chǎn)率為94%,結(jié)構(gòu)式如下：由10.0g,40.8mmoB2和17.6g,44.9mmolL-亮氨酸芐酯對甲苯磺酸鹽、6.0g,固體的C2,即N-Boc-Me-L-Leu-L-Leu-0Bn,其產(chǎn)率為82%產(chǎn)率，結(jié)構(gòu)式如下：10.0g、28.7mmol,產(chǎn)率為86%,其結(jié)構(gòu)式如下：將混合物過濾并真空濃縮以得到D2,即N-Boc-Me-L-Leu-L-Leu-0H,其產(chǎn)量為10.0g、27.9mmol,產(chǎn)率為84%,結(jié)構(gòu)式如下：由10.0g,28.7mmolE2和7.2g,31.5mmolN-Boc-D-Leu-OH、4.2g,31.5mmol為13.2g、28.7mmol,產(chǎn)率為86%,結(jié)構(gòu)式如下：[0030](7)N-Boc-Me-L-Leu-L-Leu-D-Leu-Me-L由10.0g,27.9mmolD2和14.1g,30.7mmolG2、4.1g,30.7mmolHOBT、5.9g,脫溶劑，并通過硅膠色譜法純化粗產(chǎn)物，得到呈白色固體狀的H2,即N-Boc-Me-L-Leu-L-Leu-D-Leu-Me-L-Leu-L-Leu-OBn,其產(chǎn)量為20.0g、25.0mmol,產(chǎn)率除去過量的TFA和DCM,得到無色油狀的I2,即N-Me-L-Leu-L-Leu-D-Leu-Me-L-Leu-L-Leu-混合物過濾并真空濃縮以得到J2,即N-Me-L-Leu-L-Leu-D-Leu-Me-L-Leu-L-Leu-OH,其產(chǎn)量為17.0g、27.9mmol,產(chǎn)率為84%,1H),7.20(d,J=8.8Hz,1H),5.11(dd,J=9.5,65.6Hz,1H),4.71(q,J=7.6Hz,1H),4.49(dd,J=10.4,5.2Hz,1H),4.15(ddd,J=10.4,8.1,5.2Hz,1H),2.98(s,3H),2.73(s,3H),1.75-1.32(m,15H),1.02-0.61(m,30H).13c171.36,170.83,170.56,57.93,53.65,51.38,48.34,47.70,41.40,438.70,37.23,35.17,31.34,29.88,25.26,24.93,24.87,2423.40,23.15,23.03,22.98,22.07,21.98,21.92,21.70.HRMS(ESIforC??H??9N?0?[M+Na]':616.4414;found:616.4實施例2Cyclo(Me-L-Leu-L-Leu-D-Pro-Me與實施例1的不同僅在于將N-Boc-D-Leu-OH替換成N-Boc-D-Pro-OH,制備得到呈白色固體的化合物K3,即Cyclo(Me-L-Leu-L-Leu-D-Pro-Me-L-Leu-L-Leu),產(chǎn)量為66mg、0.112mmol,51%產(chǎn)率，其結(jié)構(gòu)式如下：[0035]HNMR(600MHz,DMSO-d?)δ7.37(d,J=7.3Hz,1H),6.89(d,J=7.5Hz,1H),4.91(t,J=7.8Hz,1H),4.7510.5,5.8Hz,1H),4.33(ddd,J=11.6,7.5,4.2Hz,1H),3.51(t,J=8.51H),3.45(q,J=5.3,3.8Hz,1H),3.02(d,J=11.7H1H),2.04-1.91(m,1H),1.88(dd,J=12.5,6.61.74-1.66(m,1H),1.65-1.29(m,11H),0.99MHz,DMSO-d?)δ173.85,172.95,171.28,170.24,169.51,57.55,56.01,550.16,47.93,46.42,42.25,36.75,36.33,31.00,30.79,28.4625.08,24.87,24.69,23.69,23.43,23.25,23.20,22.73,22.37,21.95,HRMS(ESI)calcd.forC3??H?N?0?[M+Na]:600.4101;found:600.4223.實施例3Cyclo(Me-L-Leu-L-Leu-D-Phe-Me與Galaxamide的不同僅在于將N-Boc-D-Leu-OH替換成N-Boc-D-Phe-OH,制備得到呈白色固體的化合物K4,即Cyclo(Me-L-Leu-L-Leu-D-Phe-Me-L-Leu-L-Leu),產(chǎn)量為70mg、MHz,DMSO-d?)δ7.60(d,J=7.8Hz,1H),7.57(d,J-7.04(m,5H),5.06(dd,J=9.8,6.0Hz,1H),4.76(q,J=7.5Hz,1H),4.58(dd,J=10.1,5.6Hz,1H),3.05(dd,J=13.1,8.4Hz,1H),2.97Hz,1H),2.63(s,3H),1.86-1.45(m,7H),1.40(q,J=8.2,7.3Hz,4H),1.24-1.07(m,1H),0.97-0.59(m,24H).13CN(151MHz,DMSO-d?)δ174.22,171.82,171.28,170.86,170.38,138.17,129.65,128.43,126.63,57.70,53.65,51.56,51.1737.20,35.23,31.20,29.84,25.24,24.84,24.75,24.65,23.47,23.3822.16,22.00,21.88.HRMS(ESI)calcd.forC?5H5?N?0?[實施例4Cyclo(Me-L-Leu-L-Leu-L-Val-M與實施例1的不同僅在于將N-Boc-D-Leu-OH替換成N-Boc-L-Val-OH,制備得到呈白色固體的化合物K5,即Cyclo(Me-L-Leu-L-Leu-L-Val-Me-L-Leu-L-Leu),產(chǎn)量為67mg、7.53-6.64(m,1H),5.31-4.84(m,1H),4.81-4(m,1H),4.20-3.93(m,1H),3.93-3.52(m,1H),3.36(s,1H),3.17(s,1H),2.90(s,1H),2.78(s,1H),2.58(d,J=16.2Hz,1H),2.42(s,1H-1.24(m,12H),0.87(dtdd,J=37.4,24.0,13.2,6.4Hz,30H).13cNMR(151MHz,DMSO-d?)δ174.07,171.13,170.83,169.38,167.86,60.20,57.76,53.52,50.98,47.69,42.98,41.48,38.17,37.00,29.07,28.95,25.2924.88,24.75,24.60,24.55,24.41,23.25,23.22,23.18,23.13,2322.97,22.81,22.37,22.35,22.16.HRMS(ESI)calcd.forC?1602.4257;found:602.4375.實施例5Cyclo(Me-L-Leu-L-Leu-Gly-M與實施例1的不同僅在于將N-Boc-D-Leu-OH替換成N-Boc-Gly-OH,制備得到呈白色固體的化合物K6,即Cyclo(Me-L-Leu-L-Leu-G1y-Me-L-Leu-L-Leu),產(chǎn)量為62mg、[0038]HNMR(600MHz,DMSO-d?)δ7.92(dd,J=65.6,8.3Hz,1H),7.76-7.38(m,1H),7.22(d,J=4.3Hz,1H),5.04(t,J=7.7Hz,1H),4.83(td,J=9.0,4.6Hz,1H),4.60(dd,J=13.8,9.1Hz,1H),4.45(dd,J=9.7,5.3Hz,1H),4.09(ddd,J=10.8,8.1,4.8Hz,1H),3.25(d,J=13.7Hz,1H),3.01(s,3H),2.64(s,3H),1.78-1.30(m,12H),1.03-0.62(m,24H).13cNMR(δ174.67,171.72,171.31,170.27,170.141.45,38.29,37.36,35.06,31.62,31.45,30.35,25.28,24.84,24.81,223.62,23.49,23.35,23.05,22.26,22.13,22.00,21.38.HRMS(EforC?8H51N?O?[M+Na]:560.3788;found:560.3422.Cyclo(Me-L-Leu-L-Leu-D-Ala-M與實施例1的不同僅在于將N-Boc-D-Leu-OH替換成N-Boc-D-Ala-OH,制備得到呈白色固體的化合物K7,即Cyclo(Me-L-Leu-L-Leu-D-Ala-Me-L-Leu-L-Leu),產(chǎn)量為59mg、[0039]HNMR(600MHz,DMSO-d?)δ7.78(d,J=8.3Hz,1H),7.21(d,J=8.4Hz,1H),4.74(dd,J=8.7,6.1Hz,1H),4.40(dd,J=10.1,5.1Hz,1H),4.12(ddd,J=12.1,8.2,4.3Hz,1H),3.01(s,3H),2.63(s,3H),1.80-1.65(m,2H),1.65-1.29(m,10H),1.12(d,J=6.3Hz,3H),1.04-0.60(m,24H).13cNMR(151MHz,DMSO-d?)δ174.88,172.24,171.62,170.87,17051.46,48.43,45.25,41.50,38.45,37.38,35.00,31.48,29.5724.81,23.68,23.55,23.31,23.06,22.28,22.07,21.92,21.31,17Cyclo(Me-L-Leu-L-Leu-0-Me-D-Ser-M得到呈白色固體的化合物K8,即Cyclo(Me-L-Leu-L-Leu-0-Me-D-Ser[0040]HNMR(600MHz,DMSO-d?)δ7.80(d,J=8.2Hz,1H),7.31(1H),7.09(d,J=9.0Hz,1H),5.10(t,J=7.7Hz,1H)2H),4.45(dd,J=10.1,4.9Hz,1H),4.13(ddd,J=10.8,8.2,4.6Hz,(t,J=8.6Hz,1H),3.28(dd,J=9.4,5.7Hz,1H)2.67(s,3H),1.78-1.6571.70,58.77,58.04,53.60,51.35,48.59,48.36,41.40,38.44,3731.39,29.72,25.27,24.95,24.80,23.63,23.51,23.27,23.12,221.98,21.48.HRMS(ESI)calcd.forC?0H55N?0?[M+Na]':604.4050;found:實施例8Cyclo(Me-L-Leu-L-Leu-0-Tyr-M呈白色固體的化合物K9,即Cyclo(Me-L-Leu-L-Leu-0-Tyr-Me-L-Leu-L-Leu)4.78(dtd,J=39.0,8.5,6.1Hz,2H),4.57(dd,J=10.2,5.6Hz,1H),4.11(ddd,J=9.6,7.9,5.6Hz,1H),3.70(s,3H),2.96(s,3H),2.94(s,1H),2.69(dd,J=13.1,6.4Hz,1H),2.62(s,3H),1.78174.14,171.96,171.27,170.89,170.357.69,55.39,53.61,51.53,51.33,48.19,41.37,38.77,37.1531.18,29.87,25.23,24.85,24.75,24.63,23.47,23.41,23.38,222.01,21.92.HRMS(ESI)calcd.forC?6H59N?0?[M+Na]':680.4363;found:實施例9Cyclo(Me-L-Leu-L-Leu-Methylester-D-Asp-M與實施例1的不同僅在于將N-Boc-D-Leu-OH替換成N-Boc-甲酯-D-天冬氨酸，得到呈白色固體的化合物K10,即Cyclo(Me-L-Leu-L-Leu-Methylester-D-Asp-Me-L-Leu-L-6.4Hz,2H),5.09(dd,J=9.6,6.0Hz,1H),4.99(td,J=9.6,4.3(td,J=8.9,4.8Hz,1H),4.47(dd,J=9.9,5.0Hz,1H),4.05(ddd,J=118.0,4.4Hz,1H),3.55(s,3H),3.00(s,3H),2.78(dd,J=16.1,10.12.67(s,3H),2.47(dd,J=16.1,4.3Hz,1H),1.78-1.28(m,13H),0.88(dddd,J=47.8,27.7,10.8,6.1Hz,24H).13CNMR(151MHz,DMSO-d171.57,171.15,171.05,170.84,170.33,5746.57,41.30,38.24,37.35,36.25,34.91,31.40,29.62,25.25,24.80,23.64,23.49,23.43,23.11,22.07,22.01,21.94,21.45.HRMS(EforC??H?5N?O?[M+Na]:632.3999;found:632.3621.實施例10Cyclo(Me-L-Leu-L-Leu-3-Flu-D-Phe-M與實施例1的不同僅在于將N-Boc-D-Leu-0H替換成N-Boc-3-氟-D-苯丙氨酸，得到呈白色固體的化合物K11,即Cyclo(Me-L-Leu-L-Leu-3-Flu-D-Phe-Me-L-Leu-L-Leu),其產(chǎn)[0043]HNMR(600MHz,DMSO-d?)δ7.59(t,J=9.1Hz,2H),7.41H),7.27(q,J=7.4Hz,1H),7.10-6.83(m,3H),5.07(dd,J=10.0,5.91H),4.89(q,J=7.8Hz,1H),4.75(q,J=7.8Hz,1H),4.09(td,J=8.7,5.6Hz,1H),3.05(dd,J=13.2,7.8(s,3H),2.79(dd,J=13.2,6.8Hz,1H),2.66(s,3H),1.711.00-0.58(m,24H).13CNMR(151MHz,DM170.84,170.42,163.27,141.20,141116.35,60.18,57.71,53.72,51.57,50.91,35.25,31.21,29.88,25.23,24.85,24.76,24.69,23.46,23.40,222.16,22.00,21.88,21.80.HRMS(ESI)calcd.forC?5H?found:668.4134.Cyclo(Me-L-Leu-L-Leu-2-Me-D-Phe-M到呈白色固體的化合物K12,即Cyclo(Me-L-Leu-L-Leu-2-Me-D-Phe-Me-L-Leu-[0044]HNMR(600MHz,DMSO-d?)δ7.66(d,J=8.0Hz,1H),7.50(d,1H),7.45(d,J=8.3Hz,1H),7.18-6.85(m,4H),5.04(dd,J=9.9,6.11H),4.90(td,J=8.8,5.6Hz,1H),4.76(q,J=7.6Hz,1H)5.4Hz,1H),4.12(td,J=8.8,5.3Hz,1H),3.08(dd,J=13.5,9.0Hz,12.96(s,3H),2.75(dd,J=13.5,5.6Hz,1H),2.59(s,3H),2.32(s,3H),1.77-1.29(m,11H),1.18-1.04(m,1H),1.00-0.53(m,24H).13cDMSO-d?)δ174.18,171.72,171.26,171.04,170.25,136.70,136.12,130.08,126.74,125.88,57.71,53.61,37.15,35.14,34.92,31.18,29.80,25.24,24.81,24.75,24.61,223.19,22.14,22.00,21.88,21.80,19.54.HRMS(ESI)calcd.forC?6H??N?O?[M+H]:664.4414;found:664.4438.實施例12Cyclo(Me-L-Leu-L-Leu-4-Ch1-D-Phe-M呈白色固體的化合物K13,即Cyclo(Me-L-Leu-L-Leu-4-Ch1-D-Phe-Me-L-Leu-L-Leu),產(chǎn)量[0045]HNMR(600MHz,DMSO-d?)δ7.58(dd,J=27.1,8.2Hz,2H),7.42(dd,J=20.0,8.1Hz,1H),7.30-7.16(m,4H),5.04(dt,J=10.5,5.24.80(m,1H),4.80-4.68(m,1H),4.57(dt,J=11.6,5.8Hz,1H),4.18-3.81(m,1H),3.03(ddd,J=20.0,12.9,8.0Hz,113.3,6.4Hz,1H),2.64(d,J=12.2138.18,131.65,129.66,128.45,128.35,48.23,41.36,38.72,37.18,35.22,31.21,29.86,25.23,24.84,24.76,223.47,23.39,23.35,23.18,22.17,22.01,21.90,21.87.HRMS(EforC?5H??ClN?O[M+H]:684.3868;found:684.3854.Cyclo(Me-L-Leu-L-Leu-4-Bro-D-Phe-M呈白色固體的化合物K14,即Cyclo(Me-L-Leu-L-Leu-4-Bro-D-Phe-Me-L-Leu-8.1Hz,1H),7.20(ddt,J=22.1,14.2,7.5Hz,5H),5.05(t,J=7.94.87(q,J=8.0Hz,1H),4.75(q,J=7.6Hz,1H),4.57(dd,J=10.3,5.61H),4.11(q,J=7.8Hz,1H),3.04(dd,J=13.12.76(dd,J=13.3,6.2Hz,1H),2.63(s,3H),1.92-1.08170.40,138.17,129.66,128.45,126.638.73,37.81,37.19,35.23,31.21,29.86,25.23,24.84,24.76,23.38,23.19,22.18,22.00,21.90,21.87.HRMS(ESI)calcd.forC??H??BrN?O?[M+H]?:728.3363;found:728.2113.與實施例1的不同僅在于將N-Boc-D-Leu-0H替換成N-Boc-D-環(huán)己基-甘氨酸，得到呈白色固體的化合物K15,即Cyclo(Me-L-Leu-L-Leu-D-cyclohexyl-Gly-Me-L-Leu-L-Leu),產(chǎn)量為70mg、0.110mmol,51%產(chǎn)率，其結(jié)構(gòu)式如下：1H),7.39(d,J=7.8Hz,1H),5.10(dd,J=10.2,6.0HHz,1H),4.69-4.54(m,1H),4.43(t,J=9.5Hz,1H),4.24,2.8NMR(151MHz,DMSO-d?)δ173.99,172.50,171.08,154.13,53.69,51.32,48.22,41.24,37.04,35.61,31.12,30.226.45,25.91,25.20,24.96,24.72,23.46,23.24,22.24,22.14,21.90,21.74.HRMS(ESI)calcd.forC??H?1N?O?[M+Na]:642.4570;found:642.5435.實施例15Cyclo(Me-L-Leu-L-Leu-D-phenyl-Gly-Me與實施例1的不同僅在于將N-Boc-D-Leu-0H替換成N-Boc-D-苯基-甘氨酸，得到呈白色固體的化合物K16,即Cyclo(Me-L-Leu-L-Leu-D-phenyl-Gly-Me-L-Leu-L-Leu),產(chǎn)量為72mg、0.112mmol,52%產(chǎn)率，其結(jié)構(gòu)式如下：[0048]HNMR(600MHz,DMSO-d?)δ7.89(d,J=8.21H),7.31(dt,J=29.4,7.8Hz,5Hz,1H),4.86(td,J=9.4,4.0Hz,1H),4.47(dd,J=9.9,5.4Hz,1H),4.20(td,J=9.4,8.8,4.7Hz,1H),3.03(s,3H),2.80(s,3H),1.84-1.13(m,13H),0.89(tdd,J=59.3,14.5,6.6Hz,24H).13cNMR(151MHz,DMSO-d?)δ174.79,171.80,171.29,170.19,138.81,153.44,51.38,48.46,41.42,38.36,37.45,35.01,31.47,30.124.81,24.78,24.57,23.64,23.56,23.31,23.04,22.25,22.18,21.90HRMS(ESI)calcd.forC3?H?5N?0?[M+Na]:636.4101;found:636.4421.實施例16Cyclo(Me-L-Leu-L-Leu-D-Val-Me0.110mmol,51%產(chǎn)率，其結(jié)構(gòu)式如下：[0049]HNMR(600MHz,DMSO-d?)δ7.62(d,J=7.8Hz,1H),7.57(d,J=9.1Hz,1H),7.37(d,J=7.7Hz,1H),5.12(dd,J=10.3,5.7Hz,1H),4.63(dd,J=10.4,5.7Hz,1H),4.38(t,J=9.4Hz,1H),4.24(d,J=7.4Hz,1H),2.95(s,3H),2.83(s,3H),2.04(dt,J=9.7,6.7Hz,1H),1.76-172.68,171.07,170.99,170.71,57.439.12,37.01,35.66,31.08,30.30,29.94,25.20,24.99,24.95,23.46,23.25,23.14,22.27,22.24,21.89,21.69,19.62,18.86.HRcalcd.forC?1H??N?O?[M+H]?:602.4257;found:602.4375.實施例17Cyclo(Me-L-Leu-L-Leu-D-Met-Me固體的化合物K18,即Cyclo(Me-L-Leu-L-Leu-D-Met-Me-L-Leu-L-Leu),產(chǎn)量為70mg、0.110mmol,52%產(chǎn)率，其結(jié)構(gòu)式如下：[0050]HNMR(600MHz,DMSO-d?)δ7.71(d,J=8.1Hz,1H),7.33(d,J=8.2Hz,1H),7.26(d,J=8.9Hz,1H),5.12(dd,J=9.5,6.3Hz,1H),4.81(dq,J=22.7.3Hz,2H),4.47(dd,J=10.1,5.0Hz,1H),4.16(ddd,J=10.7,8.0,5.01H),2.99(s,3H),2.70(s,3H),2.44(dtd,J=19.1,9.6,9.1,5.4Hz,3H),1.66-1.447.0Hz,3H),0.88(dddd,J=48.4,35.5,14.9,6.5Hz,24H).13CNMR(151MHz,DMSO-d?)δ174.59,171.62,171.47,48.49,48.36,41.37,38.55,37.27,35.06,31.48,31.37,29.96,29.78,24.86,24.83,24.78,23.56,23.52,23.41,23.12,22.03,22.0014.91.HRMS(ESI)calcd.forC??H??N?O?S[M+Na]:6實施例18Cyclo(Me-D-Leu-L-Leu-L-Leu-Me取9.0g,38.9mmolN-Boc-D-亮氨酸、25g,177.3mmolCH?I、5.5g,137.5mmol分散在礦物油中的NaH。混合后在-20℃下攪拌60min,然后在室溫下再攪拌12h。用100ml水溶液淬滅，使用乙酸乙酯洗滌混合物。此后，用1NHCl溶液將水溶液酸化至pH=5并用乙酸乙酯萃取，所得乙酸乙酯萃取物經(jīng)Na?SO?干燥，過濾并蒸發(fā)，得到無色油狀的B3,即N-Boc-Me-D-Leu-OH,產(chǎn)量為8.8g、35.8mol,92%產(chǎn)率。由10.0g,40.8mmolB3和31.5g,44.9mmolL-亮氨酸芐酯對甲苯磺酸鹽、6.0g,44.9mmolHOBt、8.5g,44.9mmolEDCI在10℃下反應(yīng)6h,合成C3。以正己烷、乙酸乙酯積比90:10混合作為洗脫溶劑，并通過硅膠色譜法純化粗產(chǎn)物，得到呈白色固體的C3,即N-Boc-Me-D-Leu-L-Leu-OBn,產(chǎn)量為14.6g、32.6mol,80%產(chǎn)率。由15.0g,33.4mmolC3、10mlTFA、40mlDCM混合后在-10℃下反應(yīng)6h,合成E3。之后，真空除去過量的TFA和DCM以產(chǎn)生呈無色油狀的E3,即N-Me-D-Leu-L-Leu-0Bn,產(chǎn)量為混合物過濾并真空濃縮以得到D3,即N-Boc-Me-D-Leu-L-Leu-OH,產(chǎn)量為9.6g、26.7mmol,80%產(chǎn)率。[0054]5)N-Boc-L-Leu-Me-D-由10.0g,28.7mmolE3和13.3g,57.5mmolN-Boc-L-Leu-OH、4.2g,31.5mmolHOBT、6.0g,31.5mmolEDCI在10℃下反應(yīng)6h,合成F3。以正己烷、乙酸乙酯按照體積比80:20混合作為洗脫溶劑，并通過硅膠色譜法純化粗產(chǎn)物，得到白色固體狀的F3,即N-Boc-L-Leu-Me-D-Leu-L-Leu-OBn,產(chǎn)量為13.2g、,23.5mmol,82%產(chǎn)率。[0055](6)N-L-Leu-Me-D-Le由15.0g,33.4mmolF3、10mlTFA、40mlDCM在-10℃下反應(yīng)6h,合成G3.之后，真空除去過量的TFA和DCM以產(chǎn)生呈無色油狀的G3,即N-L-Leu-Me-D-Leu-L-Leu-0Bn,產(chǎn)量為[0056](7)N-Boc-Me-D-Leu-L-Leu-L由10.0g,27.9mmolD3和25.7g,55.8mmolG3、4.1g,30.7mmolHOBT、5.9g,30.7mmolEDCI在0℃下反應(yīng)12h,合成H3。以正己烷、乙酸乙酯按照體積比70:30混合作為洗脫溶劑，并通過硅膠色譜法純化粗產(chǎn)物，得到呈白色固體狀的H3,即N-Boc-Me-D-Leu-L-Leu-L-Leu-Me-D-Leu-L-Leu-OBn,產(chǎn)量為20.0g、25.0mmol,88%產(chǎn)率。空除去過量的TFA和DCM,得到無色油狀的I3,即N-Me-D-Leu-L-Leu-L-Leu-Me-D-Leu-L-Leu-OBn,產(chǎn)量為20.1g、28.7mmol,85%產(chǎn)率。[0058](9)N-Me-D-Leu-L-Leu-L由23.4g,33.4mmolI3、5g,4.7mmol10%Pd/C、1atmH?于10℃反應(yīng)12h,合成J3。將混合物過濾并真空濃縮以得到J3,即N-Me-D-Leu-L-Leu-L-Leu-Me-D-Leu-L-Leu-OH,產(chǎn)量為17.0g、27.9mmol,85%收率。乙酯按照體積比60:40混合作為洗脫溶劑，并通過柱色譜法純化，得到呈白色固體的化合物K03,即Cyclo(Me-D-Leu-L-Leu-L-Leu-Me-D-Leu-L-Leu),產(chǎn)量為67mg、0.113mmol,51%產(chǎn)[0060]HNMR(600MHz,DMSO-d?)δ8.29(d,J1H),7.01(d,J=9.4Hz,1H),5.06(t,J=7.8Hz,1H),4.73-4.50(m,2H),4.16(td,J=9.5,5.1δ173.74,171.69,171.50,171.16,169.72,55.88,53.48,52.31,47.62,47.52,41.65,41.26,40.92,37.10,34.91,30.89,29.31,24.99,24.88,24.83,224.67,23.43,23.34,23.22,23.01,22.88,22.74,22.27,22.13,21.37(ESI)calcd.forC??H??N?0?[M+Na]:616.4414;found:616.4393.實施例19Cyclo(Me-D-Leu-L-Leu-D-Leu-Me與實施例18的不同僅在于步驟(2)及步驟(5)不同，具體為：由10.0g,40.8mmolN-Boc-Me-D-Leu-OH和17.6g,44.9mmolD-亮氨酸芐酯對甲苯酸乙酯按照體積比90:10混合作為洗脫溶劑，并通過硅膠色譜法純化粗產(chǎn)物，得到呈白色固體的C1,即N-Boc-Me-D-Leu-L-Leu-0Bn,產(chǎn)量為14.6g、32.6mol,80%產(chǎn)率。[0061]5)N-Boc-D-Leu-Me-D-31.5mmolN-Boc-D-Leu-OH、4.2g,31.5mmolHOBT、6.0g,31.5mmolEDCI在5℃下反應(yīng)8h,合成F1。以正己烷、乙酸乙酯按照體積比80:20混合作為洗脫溶劑，并通過硅膠色譜法純化粗[0062]利用F1按照與實施例18相同的步驟制備得到呈白色固體的化合物K01,即Cyclo(Me-D-Leu-L-Leu-D-Leu-Me-D-Leu-L-Leu),產(chǎn)量為71mg、0.120mmol,55%產(chǎn)率，其結(jié)構(gòu)式[0063]HNMR(600MHz,DMSO-d?)δ8.29(d,J=8.7Hz,1H),7.45(d,J=8.91H),7.01(d,J=9.4Hz,1H),5.06(t,J=7.8Hz,1H),4.80(q,J=3.64.69-4.52(m,2H),4.16(q,J=4.3Hz,1H),2.95(s,3H),2.54(s,3H),1.82171.69,171.50,171.16,169.72,55.41.26,40.92,37.10,34.91,30.89,29.31,24.99,24.88,24.83,24.76,223.43,23.34,23.22,23.01,22.88,22.74,22.27,22.13,21.37.HRcalcd.forC??H??N?0?[M+Na]:616.4414;found:616.43實施例20Cyclo(Me-L-Leu-D-Leu-L-Leu-Me與實施例18的不同僅在于步驟(1)及步驟(5)不同；具體為：取9.0g,38.9mmolL-亮氨酸、25g,177.3mmolCH?I、5.5g,137.5mmol分散在礦物油中的NaH?；旌虾笤?20℃下攪拌60min,然后在室溫下再攪拌1用乙酸乙酯洗滌混合物。此后，用1NHCl溶液將水溶液酸化至pH=5并用乙酸乙酯萃取，所得乙酸乙酯萃取物經(jīng)Na?SO?干燥，過濾并蒸發(fā)，得到無色油狀的B21,即N-量為9.0g、36.7mol,94%產(chǎn)率。[0064]5)N-Boc-L-Leu-Me-L-由前述步驟制備得到的10.0g,28.7mmolN-Me-L-Leu-D-Leu-0Bn和7.2g,31.5mmolN-Boc-L-Leu-OH、4.2g,31.5mmolHOBT、6.0g,31.5mmolEDCI在10℃下反應(yīng)6h,合成F21。以正己烷、乙酸乙酯按照體積比80:20混合作為洗脫溶劑，并通過硅膠色譜法純化粗產(chǎn)物，得到白色固體狀的F21,即N-Boc-L-Leu-Me-L-Leu-D-Leu-0Bn,產(chǎn)量為13.7g、[0065]利用F21按照實施例18中的方法最終得到呈白色固體的化合物K21,即Cyclo(Me-[0066]HNMR(600MHz,DMSO-d?1H),7.01(d,J=9.4Hz,1H),5.06(t,J=7.71H),4.64(t,J=8.4Hz,2H),4.15(dt,J=9.5,δ173.73,171.69,171.50,171.15,169.72,5541.65,41.24,40.92,37.09,34.90,30.89,29.30,24.98,24.87,24.82,224.66,23.43,23.35,23.22,23.02,22.88,22.74,22.26,22.12,21.36(ESI)calcd.forC??H??N?05[M+Na]:616.4414;found:616.4393.實施例21Cyclo(Me-L-Leu-D-Leu-D-Leu-Me與實施例18的不同僅在于步驟(1)及步驟(5)不同，具體為：由9.0g,38.9mmolL-亮氨酸、25g,177.3mmolCH?I、5.5g,137.5mmol分散在礦物油中的NaH?；旌虾笤?20℃下攪拌60min,然后在室溫下再攪拌12h。用100ml水溶液淬滅，使用乙酸乙酯洗滌混合物。此后，用1NHCl溶液將水溶液酸化至pH=5并用乙酸乙酯萃取，所得乙酸乙酯萃取物物經(jīng)Na?SO?干燥，過濾并蒸發(fā)，得到無色油狀的B22,即N-Boc-Me-L-Leu-0H,產(chǎn)量為9.0g、36.7mol,94%產(chǎn)率。[0067]5)N-Boc-D-Leu-Me-L-由前述制備的10.0g,28.7mmolN-Me-L-Leu-D-Leu-OBn和7.2g,31.5mmolN-Boc-D-Leu-OH、4.2g,31.5mmolHOBT、6.0g,31.5mmolEDCI在10℃下反應(yīng)6h,合成F22.以正己烷、乙酸乙酯按照體積比80:20混合作為洗脫溶劑，并通過硅膠色譜法純化粗產(chǎn)物，得到白色固體狀的F22,即N-Boc-D-Leu-Me-L-Leu-D-Leu-OBn,產(chǎn)量為13.2g、23.5mmol,82%產(chǎn)率。[0068]利用F22按照實施例18中的方法最終得到呈白色固體的化合物K22,即Cyclo(Me-L-Leu-D-Leu-D-Leu-Me-L-Leu-D-Leu)[0069]HNMR(600MHz,DMSO-d?)δ8.30(d,J=8.7Hz,1H),7.46(d,J=8.8Hz,1H),7.01(d,J=9.4Hz,1H),5.06(t,J=7.71H),4.64(t,J=8.4Hz,2H),4.15(dt,J=9.5,4.7(s,3H),1.88-1.15(m,15H),1.15-0.41(m,30H).13CNδ173.73,171.69,171.50,171.15,169.72,5541.65,41.24,40.92,37.09,34.90,30.89,29.30,24.98,24.87,24.82,224.66,23.43,23.35,23.22,23.02,22.88,22.74,22.26,22.12,21.36實施例22Cyclo(Me-D-Leu-D-Leu-L-Leu-Me與實施例18的不同僅在于步驟(2)與步驟(5)不同，具體為：由10.0g,40.8mmolN-Boc-Me-D-Leu-OH和17.6g,44.9mmolD-亮氨酸芐酯對甲苯磺酸鹽、6.0g,44.9mmolHOBt、8.5g,44.9mmolEDCI在10℃下反應(yīng)6h,合成C23.以正己烷、乙酸乙酯按照體積比90:10混合作為洗脫溶劑，并通過硅膠色譜法純化粗產(chǎn)物，得到呈白色固體的C23,即N-Boc-Me-D-Leu-D-Leu-0Bn,產(chǎn)量為15.0g、33.4mol,81%產(chǎn)率。[0070](5)N-Boc-L-Leu-Me-D-L由前述步驟制備的10.0g,28.7mmolN-Me-D-Leu-D-Leu-0Bn和7.2g,31.5mmolN-己烷、乙酸乙酯按照體積比80:20混合作為洗脫溶劑，并通過硅膠色譜法純化粗產(chǎn)物，得到白色固體狀的F23,即N-Boc-L-Leu-Me-D-Leu-D-Leu-OBn,產(chǎn)量為13.7g、24.4mmol,85%產(chǎn)[0071]利用F23按照實施例18中的方法最終得到呈白色固體的化合物K23,即Cyclo(Me-1H),7.19(d,J=8.8Hz,1H),5.11(t,J=7.6Hz,1H),4.77(d,J=7.4Hz,1H),4.71(d,J=7.8Hz,1H),4.49(dd,J=10.1,5.2Hz,1H),4.27-3.96(m,1H2.99(s,3H),2.73(s,3H),1.73-1.26(m,15H),0.87(tdd,J=33.3,12.5,170.57,57.94,53.64,51.37,48.34,47.69,41.40,41.09,38.70,37.23,35.17,31.34,29.88,25.26,24.92,24.87,24.81,24.77,23.50,23.40,22.98,22.06,21.97,21.91,21.70.HRMS(ESI)calcd.forC?2H?N?0?[M+Na]+:616.4414;found:616.4393.實施例23Cyclo(Me-D-Leu-D-Leu-D-Leu-Me由10.0g,40.8mmolB3和17.6g,44.9mmolD-亮氨酸芐酯對甲苯磺酸鹽、6.0g,由前述制備的10.0g,28.7mmolN-Me-D-Leu-D-Leu-0Bn和7.2g,31.5mmolN-Boc-D-Leu-OH、4.2g,31.5mmolHOBT、6.0g,31.5mmolEDCI在10℃下反應(yīng)6h,合成F24.以正己[0074]利用F24按照實施例18中的方法最終得到呈白色固體的化合物K24,即Cyclo(Me-1H),7.19(d,J=8.8Hz,1H),5.11(t,J=7.64.71(d,J=7.8Hz,1H),4.49(dd,J=10.1,5.2Hz,1H),4.272.99(s,3H),2.73(s,3H),1.73-1.26(m,15H),0.87(tdd,J=33.3,12.5,170.57,57.94,53.64,51.37,48.34,47.69,31.34,29.88,25.26,24.92,24.87,24.81,24.77,23.50,23.40,222.98,22.06,21.97,21.91,21.