專利名稱：：2-色氨酰-β-四氫咔啉-3-甲酰基氨基酸芐酯及其制備方法和應(yīng)用的制作方法
技術(shù)領(lǐng)域：
：本發(fā)明涉及氨基酸衍生物，尤其涉及具有抗腫瘤活性的2-色氨酰-P-四氫咔啉-3-甲?；被崞S酯及其制備方法，本發(fā)明還進(jìn)一步涉及它們作為抗腫瘤的應(yīng)用，屬于生物醫(yī)藥領(lǐng)域。
背景技術(shù)：
：惡性腫瘤是一種嚴(yán)重威脅人類健康的常見(jiàn)病和多發(fā)病，人類因惡性腫瘤而引起的死亡率是所有疾病死亡率的第二位，僅次于心腦血管疾病。腫瘤的治療方法有手術(shù)治療，放射治療和藥物治療(化學(xué)治療)。目前，化學(xué)治療仍然是臨床治療腫瘤的主要手段。尋找抗腫瘤藥物是新藥研究的熱點(diǎn)之一。發(fā)明人認(rèn)識(shí)到，將P-四氫咔啉羧酸和L-色氨酸偶聯(lián)后再羧基端引入氨基酸可能產(chǎn)生抗腫瘤作用。按照這種構(gòu)想，發(fā)明人提出本發(fā)明。
發(fā)明內(nèi)容本發(fā)明目的之一是提供一類具有抗腫瘤活性的化合物；本發(fā)明目的之二是提供一種制備上述具有抗腫瘤活性化合物的方法。本發(fā)明上述目的是通過(guò)以下技術(shù)方案來(lái)實(shí)現(xiàn)的具有抗腫瘤活性的通式I化合物通式I式中AA選自纈氨酸殘基、天冬氨酸-Y-芐酯、谷氨酰胺殘基、NW-芐氧羰基賴氨酸殘基、亮氨酸殘基、丙氨酸殘基、色氨酸殘基、O-芐基絲氨酸殘基、苯丙氨酸殘基、異亮氨酸殘基、甘氨酸殘基、組氨酸殘基、蛋氨酸殘基、谷氨酸-S-芐酯、天冬酰胺殘基、脯氨酸殘基、對(duì)甲氧基節(jié)基半胱氨酸、硝基精氨酸、蘇氨酸殘基或酪氨酸殘基。一種制備上述通式I化合物的方法，該方法包括(1)(在NaOH、(Boc)20和二氧六環(huán)存在下)將色氨酸轉(zhuǎn)變?yōu)锽oc-色氨酸；(2)(在稀H2S04和甲醛的存在下)將色氨酸轉(zhuǎn)變?yōu)?5-四氫咔啉-3-羧酸；(3)(在多聚磷酸和芐醇存在下加熱)將(3-四氫咔啉-3-羧酸轉(zhuǎn)變?yōu)閜-四氫咔啉-3-羧酸節(jié)酯；(4)(在對(duì)甲苯磺酸、節(jié)醇和環(huán)己垸存在下)將氨基酸轉(zhuǎn)變?yōu)榘被崞S酯；(5)(在DCC和HoBt存在下)將Boc-色氨酸與(3-四氫咔啉-3-羧酸芐酯縮合制備2-(Boc-色氨酰)-卩-四氫咔啉-3-羧酸芐酯；(6)(用？(1/(:催化)將2-(800色氨酰)-卩-四氫咔啉-3-羧酸芐酯氫解制備2-(80(>色氨酰)-卩-四氫咔啉-3-羧酸；(7)(在DCC、HoBt存在下)將2-(Boc-色氨酰)-p-四氫咔啉-3-羧酸和氨基酸芐酯縮合制備2-(800-色氨酰)+四氫咔啉-3-甲酰氨基酸芐酯；(8)(在HOAc、氯化氫和乙酸乙酯存在下)將2-(Boc-色氨酰)-卩-四氫咔啉-3-甲酰氨基酸芐酯脫去Boc,即得。其中，步驟(4)中所述的氨基酸芐酯選自纈氨酸芐酯、天冬氨酸雙芐酯、谷氨酰胺芐酯、(N"-芐氧羰基)賴氨酸芐酯、亮氨酸芐酯、丙氨酸芐酯、色氨酸芐酯、0-芐基絲氨酸芐酯、異亮氨酸芐酯、苯丙氨酸節(jié)酯、甘氨酸芐酯、組胺酸芐酯、蛋氨酸芐酯、谷氦酸雙芐酯、天冬酰胺芐酯、脯氨酸芐酯、對(duì)甲氧基芐基半胱氨酸芐酯、硝基精氨酸芐酯、酪氨酸芐酯或蘇氨酸芐酯。本發(fā)明的又一目的是提供一種治療腫瘤的藥用組合物，該藥用組合物由治療上有效劑量的本發(fā)明通式I化合物與藥學(xué)上可接受的賦型劑或者輔加劑組成，即將有效量的本發(fā)明通式I化合物與藥學(xué)上可接受的載體或稀釋劑配合后，按本領(lǐng)域常規(guī)的制劑方法將其制備成任意一種適宜的藥物組合物。通常該組合物適合于口服給藥和注射給藥，也適合其他的給藥方法。該組合物可以是片劑、膠囊劑、粉劑、顆粒劑、錠劑、栓劑，或口服液等液體制劑形式。根據(jù)不同的給藥方法，本發(fā)明藥物組合物可以含有O.1%-99%重量，優(yōu)選10-60%重量的本發(fā)明化合物。本發(fā)明在腫瘤細(xì)胞模型和小鼠S咖肉瘤模型上評(píng)價(jià)了通式I化合物(2a-t)的抗腫瘤活性，實(shí)驗(yàn)結(jié)果表明，本發(fā)明通式l化合物具有優(yōu)秀的抗腫瘤活性，可作為抗腫瘤劑應(yīng)用。圖l本發(fā)明通式I化合物的結(jié)構(gòu)式。圖2本發(fā)明通式I化合物的合成路線圖；2a-t的中AA選自纈氨酸、天冬氨酸-Y-芐酯、谷氨酰胺、N"-芐氧羰基賴氨酸、亮氨酸、丙氨酸、色氨酸、0-芐基絲氨酸、苯丙氨酸、異亮氨酸、甘氨酸、組氨酸、蛋氨酸、谷氨酸-s-芐酯、天冬酰胺、脯氨酸、對(duì)甲氧基芐基半胱氨酸、硝基精氨酸、蘇氨酸或酪氨酸殘基.具體實(shí)施例方式為了進(jìn)一步闡述本發(fā)明，下面給出一系列實(shí)施例。這些實(shí)施例完全是例證性的，它們僅用來(lái)對(duì)本發(fā)明進(jìn)行具體描述，不應(yīng)當(dāng)理解為對(duì)本發(fā)明的限制。實(shí)施例l制備Boc-L-色氨酸冰浴下將4.1g(2mo1)L-色氨酸溶于10mlNaOH水溶液(2N)，往該溶液中加4.9g(2.2mmo1)(Boc)20與5m11，4-二氧六環(huán)的溶液，反應(yīng)化合物攪拌并不斷減壓抽去反應(yīng)過(guò)程中生成的C02。約需48小時(shí)后TLC檢測(cè)到反應(yīng)完成，減壓除去l，4-二氧六環(huán)，殘留無(wú)先用飽和KHS04水溶液調(diào)pH2，然后用乙酸乙酯萃取三次，合并的乙酸乙酯層用飽和NaCl水溶液洗三次后用無(wú)水NaS04干燥過(guò)夜，過(guò)濾，濾也減壓濃縮得到的無(wú)色固體用乙酸乙酯-石油醚重結(jié)晶。收率85%。實(shí)施例2制備L-氨基酸芐脂將20mmolL-氨基酸和30ml苯甲醇在100ml圓底燒瓶中攪拌使溶解。然后加3.78g(22md)對(duì)甲苯磺酸，9(TC攪拌。用環(huán)己烷共沸帶出反應(yīng)過(guò)程中生成的水。24小時(shí)后TLC檢測(cè)原料點(diǎn)基本消失，停止加熱，冷卻，冰浴攪拌下加入大量乙醚，析出氨基酸芐酯對(duì)甲苯磺酸鹽。產(chǎn)率在86%-96%之間。依此通法合成了纈氨酸芐酯對(duì)甲苯磺酸鹽、天冬氨酸雙芐酯對(duì)甲苯磺酸鹽、N"-芐氧羰基賴氨酸芐酯對(duì)甲苯磺酸鹽、亮氨酸芐酯對(duì)甲苯磺酸鹽、丙氨酸芐酯對(duì)甲苯磺酸鹽、色氨酸芐酯對(duì)甲苯磺酸鹽、O-芐基絲氮酸節(jié)酯對(duì)甲苯磺酸鹽、苯丙氨酸芐酯對(duì)甲苯磺酸鹽、異亮氨酸芐酯對(duì)甲苯磺酸鹽、甘氨酸芐酯對(duì)甲苯磺酸鹽、組氨酸芐酯對(duì)甲苯磺酸鹽、蛋氨酸節(jié)酯對(duì)甲苯磺酸鹽、谷氨酸雙芐酯對(duì)甲苯磺酸鹽、脯氨酸芐酯對(duì)甲苯磺酸鹽、蘇氨酸芐酯對(duì)甲苯磺酸鹽和酪氨酸芐酯對(duì)甲苯磺酸鹽等L-氨基酸的節(jié)酯的對(duì)甲苯磺酸鹽。實(shí)施例3制備p-四氫昨啉-3-羧酸往含400ml水的500ml圓底燒瓶中緩慢加入0.2ml濃硫酸并搖勻。得到的稀硫酸溶液與5.0g(24.5mmol)L-色氨酸攪拌至L-色氨酸完全溶解。往得到的溶液中加入10ml甲醛(35%),攪拌10min后析出大量固體，TLC板檢測(cè)L-色氨酸消失，停止攪拌。往反應(yīng)液中緩慢滴入8ml氨水，調(diào)pH7。反應(yīng)混合物靜置6h,減壓濾出生成的沉淀,用水沖洗5次，濾餅干燥得4.9g(95%)目標(biāo)化合物，為淺黃色固體。ESI(m/z)217[M+H]+.實(shí)施例4制備P-四氫咔啉-3-羧酸芐酯取2g多聚磷酸加熱攪拌使之溶于20ml芐醇(加熱溫度不高于5(TC)，待完全溶解后加入lgp-四氫昨啉-3-羧酸，升溫至8(TC攪拌，反應(yīng)液由黃綠色逐漸變棕色，12小時(shí)后TLC檢測(cè)原料點(diǎn)消失。反應(yīng)混合物冷卻后加入50ml乙醚和70ml水強(qiáng)力攪拌過(guò)夜，有大量黃色固體析出。過(guò)濾,得到的黃色塊狀固體用乙醚和水反復(fù)洗得到粉末狀淺黃色咔啉羧酸芐酯磷酸鹽1.3g。將該磷酸鹽混懸于乙酸乙酯和水的混合液中，冰浴下滴加三乙胺溶液至反應(yīng)液中無(wú)不溶顆粒且反應(yīng)液透明。繼續(xù)攪拌12h后，分出乙酸乙酯層并用5%碳酸氫鈉水溶液洗滌6次、飽和氯化鈉水溶液洗滌3次,分出的乙酸乙酯層用無(wú)水硫酸鈉固體干燥、過(guò)濾、濾液減壓濃縮，殘留物重結(jié)晶得0.9g(67%)標(biāo)題化合物，為淺黃白色粉末。ESI(m/e)307[M+H]+。實(shí)施例5制備Boc-色氨酰-p-四氫咔啉-3-羧酸芐酯(1A)將3.6g(11.8mmol)Boc-L-色氨酸溶于35ml無(wú)水四氫呋喃(THF)，冰浴下往里加1.4g(14.2mmo1)N-羥基苯并三唑(HOBt)和2.1g(14.2mmo1)二環(huán)己基羰二亞胺(DCC)和15ml無(wú)水四氫呋喃(THF)的溶液。反應(yīng)混合物冰浴攪拌20分鐘，得對(duì)應(yīng)的活潑酯溶液。往該溶液中加入2.3g(9.5mmol)p-四氫咔啉-3-羧酸芐酯與6ml無(wú)水四氫呋喃(THF)并用N-甲基嗎啉調(diào)pH-9的溶液。得到的混合溶液室溫反應(yīng)24小時(shí)。TLC(展開(kāi)劑CHCl3:MeOH=10:1)顯示(3-四氫咔啉-3-羧酸芐酯消失。停止反應(yīng)，濾除二環(huán)己基脲(DCU)，濾液減壓濃縮至干。殘留物用乙酸乙酯溶解，乙酸乙酯溶液分別用飽和NaHC03水溶液，5XKHS04水溶液，飽和NaCl水溶液洗5次。分出的乙酸乙酯溶液用無(wú)水Na2S04干燥過(guò)夜。濾除Na2S04，濾液減壓濃縮，得到4.98g(86%)標(biāo)題化合物，為無(wú)色固體。Mp115-117°C;ESI(m/e)550[M+H]+;[tt]D20=24.30(cl.0，甲醇)；！H-NMR(DMSO-d6,500MHz)S=l0.97(s,lH),10.86(d,J=15Hz,1H),7.57(t，J=10Hz，1H),7.48(d,J=10Hz,1H),7.39(m,4H),7.20(m,4H)，6.65(d,J=5Hz,1H),5.05(s,2H),4.31(s,2H),3.47(s,2H),2.98(d,J=5Hz,2H),1.34(s,3H)."C-NMR(DMSO-d6,75MHz)5=206.91,170.82，155.86,136.55,136.16，129.68,128.69,127.79,127.55,126.65,119.19,111.49,110.19,78.66,66.64,55.20,33.82，31.13,28.58;IR:3356.14，3307.92,2974.23,1735.93，1708.93,1678.71,1527.62,1452.40,1420.54,1363.67,1309.67，1244.09,1168.86,734.88。實(shí)施例6制備Boc-色氨酰-p-四氫咔啉-3-羧酸(IB)先將1.5g(2.52mmoDBoc-色氨酰-(3-四氫咔啉-3-羧酸芐酯溶于20ml乙醇，再加入300mgPd/C(20%),攪拌下減壓排出反應(yīng)瓶中的空氣，通入氫氣置換，反復(fù)置換3次后，通氫氣室溫?cái)嚢?4小時(shí)，TLC(展開(kāi)劑CHC13:MeOH二10:1+1滴冰醋酸)顯示Boc-色氨酰-l3-四氫咔啉-3-羧酸芐酯消失。停止反應(yīng)，濾除Pd/C，濾渣用無(wú)水乙醇沖洗三次，濾液減壓濃縮，得l.lg(80%)標(biāo)題化合物。IR3396.64,2976.16,2850.79,1705.07,1643.35,1642.06,1510.26,1429.90,1454.33，1392.61,1367.33,1247.94,1234.44,1166.93,742.59。實(shí)施例7Boc-色氨酰-p-四氫咔啉-3-甲酰氨基酸芐酯的制備通法將1.2g(2.4mmo1)Boc-色氨酰-(3-四氫咔啉-3-羧酸溶于15ml無(wú)水四氫呋喃(THF)，冰浴下往里加600mg(2.5mmo1)N-羥基苯并三唑(HOBt)、800mg(2.5mmo1)二環(huán)己基羰二亞胺(DCC)和10ml無(wú)水四氫呋喃(THF)的溶液。反應(yīng)混合物冰浴攪拌20分鐘，得對(duì)應(yīng)的活潑酯溶液。往該溶液中加入2.4mmo1氨基酸芐酯與2ml的N-甲基嗎啉先及6ml無(wú)水四氫呋喃(THF)并用NMM調(diào)pH9的溶液。得到的混溶液室溫反應(yīng)過(guò)夜。TLC(展開(kāi)劑CHCl3:MeOH二10:1)顯示氨基酸芐酯消失。停止反應(yīng)，濾除二環(huán)己基脲(DCU),濾液減壓濃縮至干。殘留物用乙酸乙酯溶解，乙酸乙酯溶液分別用飽和NaHC03水溶液，5XKHS04水溶液，飽和NaCl水溶液洗5次。分出的乙酸乙酯溶液用無(wú)水Na2S04干燥過(guò)夜。濾除Na2S04，濾液減壓濃縮，殘留物經(jīng)硅膠柱層析純化。實(shí)施例8Boc-色氨酰-p-四氫咔啉-3-甲酰基-纈氨酸芐酯(la)的數(shù)據(jù)1.17g(62.42%)。Mp114-115。C;ESI(m/e)364[M+H]+;[otD20=-114.20(cl.O,甲醇);iH-NMR(DMSO-d6,500MHz)S=10.87(d,J=10Hz,lH),8.33(t,J=5Hz,lH),7.635(d,J=5Hz,1H),7.51(d，J=10Hz，1H),7.41(m,4H),7.21(m,4H),4.95(s,1H),4.33(m,4H)，4.18(m,2H),4.03(t,IH)，3.305(d，J=5Hz,1H),3.14(m,2H)，1.38(s,3H),0.83(s,3H).13C-NMR(DMSO-d6,75MHz)5=171.60,170.17,155.80,136.57,129.86,128.89,127.86,127.62,121.11，118.83，111.51,110.20，78.52,66.00,56.31,55.35,30.90,30.50,28.59,18.23;IR3402.43,3307.92,2966.52,1735.93,1680.00，1643.35,1498.69,1454.33,1390.68,1367.53,1366.67,1307.74,1234.44,1163.08,740.67。實(shí)施例9Boc-色氨酰-P-四氫咔啉-3-甲?；?天冬氨酸雙芐酯(lb)的數(shù)據(jù)1.06g(63.8%).Mp102-104°C;ESI(m/e)364[M+H]+;[<t]D20=7.36(c1.0，甲醇)；！H-NMR(DMSO-d6,500MHz)S=10.90(s,IH),10.87(s，IH),8.65(d,J=5Hz，IH),8.485(d,J=5Hz，IH),7.65(d,J=10Hz,IH),7.515(d,J=10Hz,IH),7.37(m,5H),7.18(m,4H)，5.74(d,J=10Hz,2H),4.98(m，2H),4.12(s,IH),3.36(s,IH),3.14(m,2H),1.36(s，4H).13C-NMR(DMSO-d6，75MHz)S=173.11,171.10,170.08，156.32,136.72,136.62，136.09,130.10,129.18,128.05，127.63,126.83,121.11，119.04,111.36，110.72，109.30，79.28,66.70,55.29,52.31,49.50,36.04,28.57,23.40;IR3388.93,3307.92，2954.95,2922.16,1746.65,1683.86,1641.42,1489.05,1456.26,1373.32,1338.60,1282.66,1247.94,1234.44,1163.08,740.67。實(shí)施例10Boc-色氨酰-p-四氫咔啉-3-甲?；?谷氨酰胺芐酯(lc)的數(shù)據(jù)0.87g(73.8%)。Mp154.5-157.0oC;ESI(m/e)721[M+H]+;[a]D20=39.23(cl.O,甲醇)；iH-NMR(DMSO-d6,500MHz)S=10.84(dd,J=15Hz,J=10Hz,IH),8.33(s,lH),7.63(m,5H),7.31(m,4H),5.62(q,J=5Hz,JN5Hz，2H),5.10(q,J=15Hz，J=15Hz,1H),4.25(d,J=15Hz,2H),3.15(m，2H),2.26(q,J=5Hz,J=5Hz,2H),2.10(s,2H)，1.33(t,J=10Hz,IH);13C-NMR(DMSO-d6,75MHz)S=174.48，173.33,172.42,171.63,155.63,136.58,130.34,130.24,128.33,127.81,126.85,124.23,121.15，120.68,111.80,110.77,78.59,65.37，55.33,53.25,51.48，39.42,31.13,27.36;IR3388.93,3329.14，2974.23,1687.71,1641.42,1622.13,1489.05,1456.26,1388.75,1367.33,1336.67,1263.37，1163.08,740.67。實(shí)施例11Boc-色氨酰-p-四氫咔啉-3-甲?；?(N(o-芐氧羰基)賴氨酸芐酯(ld)的數(shù)據(jù)1.05g(81.2%)。Mp101-103°C;ESI(m/e)833[M+H]+;[a]D20=33.56(c4.0,甲醇)；！H-NMR(DMSO-d6,500MHz)S=10.88(d,J=15Hz,IH),8.45(d,J=5Hz,lH),8.36(d，J=10Hz,IH),7.64(d,J=10Hz，IH)，7.40(m,4H),7.19(m,4H),7.06(m,3H),5.735(d,J=5Hz，2H)，4.96(m,2H),4.215(d，J=5Hz,2H),3.085(d,J=5Hz,IH),2.94(m,3H),1.38(s,3H),1.28(s,2H),0.91(m,2H);13C-NMR(DMSO-d6,75MHz)5=172.90,172.00,170.01,156.50,136.47,136.31,130.19,129.71,128.05,127.59,119.08,111.37,109.25,79.27,66.24,65.59,55.24，53.15,52.58,50.28,38.91,30.92,30.43,28.58,21.93;IR3390.86,3288.63,3057.17,2972.31,2953.02,1739.79,1678.07,14894.83,1452.40，1336.67,1305.81，1365.60,1236.37,1165.00,740.67。實(shí)施例12Boc-色氨酰-p-四氫咔啉-3-甲?；?亮氨酸芐酯(le)的數(shù)據(jù)1.37g;(79.5%);Mp:113-115。C;ESI(m/e)707[M+H]+;[ct]D20=38.27(c-1.0,甲醇)；！H-NMR(DMSO-^，500MHz)5=10.89(d,J=15Hz，1H),8.45(d,J=10Hz,1H),7.61(dd,J=10Hz,J=5Hz,IH),7.34(m,5H),7.20(m,4H),7.08(m,IH),5.70(s,2H),5.14(dd,J=10Hz,J=7.5Hz,IH),4.98(m，2H),2.9(m,2H)，1.52(m，2H)，1.40(s,3H),0.880(d,J=5Hz,3H);13C-NMR(DMSO75MHz)S=169.%,156.42,136.63，136.48,136.13，130.15,129.63,127.84，127.56,121.53,121.12,119.09，111.48,111.34,110.68,109.19,79.27,66.25,52.36,50.92，41.88,38.94,28.56,23.77,23.17,21.13;IR3390.86,3311.78,2958.80,1741.72,1685.79,1378.07,1529.55,1498.69，1454.33,1336.67,1305.81，1246.02,1234.44,1165.00,740.67。實(shí)施例13Boc-色氨酰-p-四氫咔啉-3-甲酰基-丙氨酸芐酯(lf)的數(shù)據(jù)l.OOg(82.3%);Mp115-117。C;ESI(m/e)664[M+H]+;[a]D20=20.17(c-1.0,甲醇)；^-NMR(DMSO-c/6,500MHz)5=10.90(d,J=15Hz,IH),8.195(d,J=5Hz,IH),7.54(t,J=7.5Hz,IH),7.41(m,4H),7.16(m,4H),6.84(dd,J=10Hz，J=5Hz,IH)，5.665(d，J=5Hz,IH),5.43(s,2H),5.08(m，2H),4.23(t，J=7.5Hz,2H),3.96(m,2H),1.41(s,3H),1.38(s,3H);13C-NMR(DMSO-4,75MHz)5=172.64，170.61,136.56,136.10,130.24,129.66,128.61,127.52,126.61，121.65,119.15,118.49,111.60,110.10,109.56,78.66,66.66，66.54,55.33,51.42，28.67,23.18,18.71,18.61;IR3388.93,3296.35,3057.17,2976.16,2931.80,1739.79,1678.07,1527.62,1496.76,1456.26,1390.68,1365.60,1338.60,1305.81,1236.37,1197.79,1161.15,740.67。實(shí)施例14Boc-色氨酰-p-四氫咔啉-3-甲?；?色氨酸芐酯(lg)的數(shù)據(jù)1.22g(78.7%);Mp129-130°C;ESI(m/e)801[M+H]+;[a]D20=0.80°(c4.0,甲醇)；^-NMR(DMSO-4,500MHz)5=10.87(d,J=10Hz,IH),8.78(d，J=10Hz，IH),8.495(d,J=5Hz,1H),8.015(d,J=5Hz,IH),7.51(m,4H),7.25(m,4H),7.03(m，4H),6.37(s，IH),5.765(d，J=5Hz,2H)，5.595(d,J=5Hz,2H),4.50(t,J=10Hz,IH),4.375(q,J=5Hz,J=5Hz,IH),3.00(q,J=5Hz,J=5Hz,2H),1.40(s,3H);13C-NMR(DMSO-A,75MHz)5=173.09,171.93，169.89,156.49,136.59,136.24,129.56，128.11，127.36,126.77,121.32,118.96,111.45,110.72，109.85,79.33,66.29,54.56，53.90,33.83,28.26,28.58,21.16;IR3365.78,3305.99,3032.10,2974.23,2927.94,1735.93,1678.07,1642.06,1498.69,1438.90,1365.60,1338.60,1232.51,1161.15,740.67。實(shí)施例15Boc-色氨酰-p-四氫咔啉-3-甲?；?0-芐基絲氨酸芐酯(lh)的數(shù)據(jù)1.08g(82.0%);Mp:111-117°C;ESI(m/e)758[M+H]+;[a]D20=39.10(c-1.0,甲醇)；^-NMR(DMSO-4500MHz)5=10.69(s,IH),10.65(s,IH),8.90(q,J=5Hz,J=5Hz,IH)，7.73(d,J=10Hz,IH),7.61(t,J-5Hz,lH),7.25(m,5H),7.09(m,4H),6.84(d,J=5Hz,IH),5.34(s,IH)，5.29(t,IH),5.10(d,J=5Hz,2H),4.73(q,J=5Hz,2H)，3.54(t,J=7.5Hz,2H),1.38(s，3H);13C-NMR(DMSO-475MHz)S=173.24,171.78,170.11,156.08,136.57,136.58,130.07，128.79,127.81,127.68,126.87,121.12,118.96,111.37,110.66,109.42,79.11,72.71,69.31，54.91,53.02,39.09,28.59,23.98;IR3410.15,3292.49,2974.23，2927.94,1743.65,1678.07，1469.76,1442.75,1390.68,1365.60，1336.67,1236.37,1163.08,740.67。實(shí)施例16Boc-色氨酰-p-四氫昨啉-3-甲?；?異亮氨酸芐酯(li)的數(shù)據(jù)1.26g(71.2%);Mp120-122。C;ESI(m/e)706[M+H]+;[汰]020=24.8(c4.0,甲醇)；^-NMR(DMSO-c/6,500MHz)S=10.92(s,IH),10.85(d,J=5Hz,IH),8.29(s,lH),7.62(d,J=10Hz，IH)，7.40(t，J=10Hz,lH),7.37(t,J=5Hz,IH),7.32(m,4H),7.22(m,4H),7.135(d,J=5Hz,IH),6.99(s，IH),5.765(d,J=5Hz,2H),5.59(d,J=10Hz,2H),4.87(t,J=5Hz,2H),4.21(t，J=5Hz,IH)，3.26(d,J=10Hz,IH)，2.99(m,IH),1.37(s,3H),1.28(m,2H),1.155(d,J=5Hz,2H),0.74(t,J=5Hz,3H);13C-NMR(DMSO-c/6,75MHz)5=172.98,171.60,170.17,156.14,136.56,136.56，136.20,129.98,128.80,127.80,121.11,119.01，118.88,111.35,109.34,79.06,78.58，66.24,54.95,36.84,28.58,28.52，25.31，22.66,15.80,11.16;IR3309.85,2962.66,2927.94,1737.86,1698.64,1639.49,1523.76,1498.69,1454.33,1365.60,1336.67,1307.74,1244.09,1234.44,1165.00,740.67。實(shí)施例17Boc-色氨酰-p-四氫咔啉-3-甲?；?苯丙氨酸芐酯(lj)的數(shù)據(jù)0.99g(70.3%);Mp:124-126°C;ESI(m/e)740[M+H]+;[a]D20=14.6(c-1.0,甲醇)；^-NMR(DMSO-4,500MHz)5=10.87(s,IH),10.86(d，J=5Hz，IH)，8.56(d,J=5Hz,IH),8.40(d,J=10Hz,IH)，7.64(t,J=5Hz,IH),7.30(m,5H),7.21(m,4H),6.卯(m,4H),5.07(s,2H),5.03(d,J=5Hz,2H),4.98(q，J=5Hz,IH),4.41(t,J=5Hz,1H),4.35(d,J=5Hz,IH)，3.12(d,J=5Hz,2H),2.10(s,2H),1.41(s,3H);13C-NMR(DMSO-4,75MHz)5=171.56,169.78,156.55,137.59,136.40,136.23,129.53,129.38,128.34,127.83，127.53,124.15,121.08,119.11,111.33,110.76，109.08，66.47,54.44,52.35,38.36,36.39,28.67，28.56,21.25;IR3402.43,3304.06,2974.23,2931.80,17393.39，1678.07，1649.14,1496.76,1444.68,1365.60,1336.67,1305,81,1234.44，1166.93,742.59。實(shí)施例18Boc-色氨酰-p-四氫咔啉-3-甲酰基-甘氨酸芐酯(lk)的數(shù)據(jù)1.09g(76.5%);Mp139-143。C;ESI(m/e)650[M+H]+;[o_]D20=19.9(c=1.0,甲醇)；^-NMR(DMSO-4,500MHz)5=10.89(d,J=5Hz,IH),10.87(s,IH),8.48(dd,J=10Hz,J=5Hz,IH),8.41(s,IH)，7.465(d,JN5Hz,IH),7.40(d,J=10Hz，IH),7.28(m,5H),7.12(m，4H),7.025(d,J=15Hz，IH),5.735(d,J=5Hz,2H),4.945(d,J=5Hz,IH)，4.835(d,J=5Hz，2H),4.31(s,IH),4.28(s,IH),3.04(dd,J=10Hz,J=5Hz,2H),1.40(s,3H);13C-NMR(DMSO-^4,75MHz)5=171.33,169.88,155.80,136.69,136.24,130.07,128.84，129.34,127.82,126.85,124.19,121.37,118.90,118.00,111.80，111.50,109.65,66.31,52.31,28.61，22.28;IR3394.72，3296.35,2974.94,2927.94,1743.65，1639.49,1498.69,1452.40,1367.53,1336.67,1278.81,1234.44，1165.00,738.74。實(shí)施例19Boc-色氨酰-p-四氫昨啉-3-甲酰基-組胺酸芐酯(11)的數(shù)據(jù)0.56g(53.2%);Mp138-140°C;ESI(m/e)730[M+H]+;[a]D20=19.9(c=1.0,甲醇);工HNMR(CDCl3)S/ppm=13.4(s,IH),10.23(s,IH),10.01(s,IH)，8.02(s,IH),7.45(s,IH),7.27(d,J=5Hz,IH),7.19(m,5H),7.18(m,4H),6.88(s,IH),6.86(d，J=7.5Hz,IH),6.65(d,J=5Hz,IH),5.87(s,2H),5.59(d,J=7.5Hz,2H),4.61(s,2H),4.81(t,J=5Hz,IH),3.06(d,J=5Hz,2H)，3.00(d,J=10Hz,2H),2.51(m,IH),1.99(s,2H),1.39(s,9H);13CNMR(CDC13)S/ppm=172.30,169.88,157.21,136.64,131.24,130.22,128.78,127.74,121.64,121.15,118.91,118.70,111.36，110.51，104.89,78.72,66.55,55.17，52.43,34.94，31.10,29.73,28.57,27.40，24.89,22.80;IR3331.07,3070.68,2926.01,2848.86，2115.91,1627.92,1507.06,1448.54,1435.04,1363.67,1346.30,1309.67,1271.09,1230.58,1186.22,1157.29,891.11,738.74。實(shí)施例20Boc-色氨酰-p-四氫咔啉-3-甲?；?蛋氨酸芐酯(lm)的數(shù)據(jù)1.06g(55.4%);Mp97-99°C;ESI-MS(m/e)746[M+H]+;[ct]D20=33.5(c=L0,甲醇)；丄H-NMR(DMSO-4,500MHz)5=10.895(d,J=15Hz,1H)，7.57(d，J=10Hz,1H),7.30(m,5H),7.12(m,5H),6.705(d,J=5Hz,1H),5.595(d,J=5Hz,2H)，4.66(t,J=7.5Hz,2H),3.605(d,J=5Hz，2H)，2.955(q,J=10Hz,2H),2.38(s,3H),1.50(s,3H);13C-NMR(DMSO-c/6，75MHz)5=170.87,155.46,136.48,128.87,128.24,127.86,121.36,118.82,110.20,66.24,50.83,39.44,33.82,28.56，24.39;IR3400.50,3304.06,3055.24,2970.38,2918.30,1747.51，1685.96,1498.69,1456.26,1367.53,1338.60,1234.44,1163.38,740.67。實(shí)施例21Boc-色氨酰-p-四氫咔啉-3-甲?；?谷氨酸雙芐酯(ln)的數(shù)據(jù)0.96g(63.2%);Mp99-101。C;ESI-MS(m/e)834[M+H]+;[汰]020=8.2(c=1.0,甲醇)；工H-NMR(DMSO-t/6,500MHz)5=10.87(d,J=10Hz,1H),8.505(d,J=5Hz,1H),8.445(d,J=5Hz，1H),7.635(d,J=5Hz,1H),7.54(t,J=5Hz,IH),7.40(m,4H),7.18(m,4H),5.725(d,J=5Hz,2H),5.13(m,IH),5.06(s,2H)，3.31(m,2H),1.31(s,3H);13C-NMR(DMSO-^,75MHz)5=172.89，171.53,170.16，156.40,136.56,129.73,128.84,127.58,121.31,118.85,117.89,111.34,79.34,66.40,52.41,30.51，28.55,26.46,21.93;IR3311.78,3273.20,2951090,2924.09,1735.93,1678.07,1624.06,1498.69,1454.33，1390.68,0367.53,1338.60,1350.81,1236.37,1163.08,740.67。實(shí)施例22Boc-色氨酰-p-四氫咔啉-3-甲酰基-天冬酰胺芐酯(10)的數(shù)據(jù)1.17g(56.2%);Mp141-143。C;ESI(m/e)726[M+H]+;[<i]D20=7.2(c=1.0,甲醇^H-NMR(DMSO-4,500MHz)5=10.88(s,IH),10.84(s，IH),8.44(d,J=5Hz,IH),7.66(d,J=5Hz,IH),7.43(d,J=5Hz,IH),7.23(m,4H),7.04(m,4H),5.74(d,J=10Hz,2H),4.72(t，J=5Hz,IH),4.68(t,J=7.5Hz，IH),4.61(s，2H),4.59(t,J=5Hz,IH),3.35(d,J=10Hz,2H),3.12(m,2H),2.59(d,J=5Hz,2H)，1.39(s,3H);13C-NMR(DMSO-^4,75MHz)5=173.07,171.64,170.89,156.05,136.34,130.07,127.97,127.27,121.44,121.10,118.93,110.74,109.45,79.65,66.37,55.08,52.54,49.72,38.85,36.97,31.12,28.58;IR3348.42,3331.07,2974.23，2927.94,1739.79,1678.07,1496.76，1456.26,1390.68,1367.53，1336.67，1309.67,1161.15,740.67。實(shí)施例23Boc-色氨酰-P-四氫咔啉-3-甲酰基-脯氨酸芐酯(lp)的數(shù)據(jù)0.99g(80.3%);Mp133-135°C;ESI(m/e)690[M+H]+;[a]D20=-118.8(c二1.0，甲醇)；iH-NMR(DMSO-^,500MHz)^10.88,(d,J=10Hz,1H),7.645(d,J=5Hz，1H),7.64(m,1H)，7.28(m,5H),7.22(m,4H),5.78(d,J=10Hz,2H),4.84(m，2H)，4.38(t,J=10Hz,2H),3.48(m,2H),3.07(m,2H)，1.38(s,3H);13C-NMR(DMSO-d6，75MHz)5=172.28，171.97,155.71，136.58,136.45,130.10，128.97,127.73,127.63,126.92,121.06,118.86,111.32，110.43,104.71,78.70，66.28,59.17，52.76,47.04，31.12,28.80,28.59,22.89,22.02;IR3390.86,3315.63,3057.17，2974.23,1743.65,1639.49,1496.67,1454.82,1365.60,1336.67,1271.09,1238.30,1166.93,740.67。實(shí)施例24Boc-色氨酰-p-四氫咔啉-3-甲?；?對(duì)甲氧基芐基半胱氨酸芐酯(lq)的數(shù)據(jù)1.32g(78.6%);Mp101-103°C;ESI(m/e)816[M+H]+;[ct]D20=-14.3(。=1.0,甲醇)；丄H-NMR(DMSO-4,500MHz)5=10.89(d,J=15Hz,IH),8.495(d,J=5Hz,IH),7.650(d,J=5Hz,IH),7.500(m,5H),7.25(m,5H),7.150(m,4H),5.805(d,J=5Hz,2H),4.83(s，IH)，3.70(s,2H),3.63(s,3H),3.375(d,J=5Hz,2H)，1.340(s,3H);13C-NMR(DMSO-t/6,75MHz)5=172.79,170.54,156.45,138.22,136.45,136.16,129.79,129.24,128.82,127.58，127.29,121.14,119.11,111.37,110.77,109.19，79,34，78.58,66.69,55.37,52.44，35.59,32.18,28.16,21.58;IR3402.43,3307.92,2966.52,2931.80,1741.72,1680.00,1643.35,1498.69,1454.33,1390.68,1367.53,1336.67,1307.74,1234.44,1163.08,740.67。實(shí)施例25Boc-色氨酰-p-四氫咔啉-3-甲酰基-硝基精氨酸芐酯(lr)的數(shù)據(jù)l.Olg(79.0%);Mp103-105°C;ESI(m/e)795[M+H]+;[n]D20=18.6(c=1.0,甲醇)；!H-NMR(DMSO-4,500MHz)5=10.89(s,IH),10.86(s,IH),8.49(d,J=10Hz,IH),8.33(s,IH),7.64(d:J=10Hz,IH),7.60(d，J=10Hz,IH),7.485(d，JN5Hz，IH),7.33(m,4H),7.17(m,4H),5.73(d,J=10Hz,2H),5.15(t,J=7.5Hz,2H),4.91(m,2H),4.18(t,J=7.5Hz,2H),3.58(t,J=5Hz,2H),2.10(s,IH)，1.67(m，IH),1.38(s,3H);13C-NMR(DMSO-475MHz)5=171.98,170.10,159.81,156.34,136.61,136.32，130.20,136.24,130.20,129.78,128.89,127.84,127.60,121.14，119.06,111.37,110.68,109.27,79.65,78.60,66.58,52.86,31.15,28.26，22.05;IR3311.78，3273.20,2974.23,2931.80，1793.79,1685.79,1624.06,1529.55,1454.33,1440.83,1390.68,1365.60,1338.60,1255.66，1163.08,740.67。實(shí)施例26Boc-色氨酰-p-四氫咔啉-3-甲酰基-蘇氨酸芐酯(ls)的數(shù)據(jù)1.38g(71.0%);Mp125-127。C;ESI(m/e)694[M+H]+;[a〗D20=9.7(c=1.0，甲醇)；！H-NMR(DMSO-^，500MHz)5=10.87(t,J=7.5Hz,lH),10.77(s，1H),8.18(d,J=10Hz,lH),7.98(d,J=10Hz,1H)，7.31(m，5H),7.08(m,5H),5.88(d,J=15Hz,2H),5.05(m，2H),3.11(m,2H),3.01(m，2H)，2.10(s，1H),1.37(s,3H),1.31(s,3H);13C-NMR(DMSO-^4,75MHz)S=171.87,136.74,136.54,129.53,128.10,127.79,126.94,126.85,124.26,121.08,118.88,118.47,111.49,111.33，110.59,109.60,66.81,66.65,58.62,58.30,54.55,31.75,31.13,20.61.IR3373.50,3313.71,2958.80，2924.09,2852.72,1743.65,1685.79,1624.06,1498.69,1442.75，13卯.68,1367.53,1334.74，1307.74,1234.44,1165.00，740.67。實(shí)施例27Boc-色氨酰-p-四氫咔啉-3-甲?；?酪氨酸節(jié)酯(lt)的數(shù)據(jù)1.20g(43.2%);Mp145-146°C;ESI(m/e)778[M+H]+;[a]D20=29.9(c4.0，甲醇)；^-NMR(DMSO-4500MHz)5=10.86(d,J=10Hz,IH),8.525(d,J=5Hz,1H),7.78(d,J=10Hz,IH),7.50(m，5H),7.25(m,5H),5.605(d，J=5Hz,IH),4.94(m,2H),3.38(m，2H),3.09(d,J=10Hz,2H),1.43(s,3H);13C-NMR(DMSO-a6,75MHz)S=171.47,169.92,156.60,136.59,136.07,130.35，129.68,128.36,128.03,127.83,127.58,126.75,121.34,119.52,119.52,118.75,115.60,111.85,110.18，79.37,66.35,54.85,35.76,31.14,28.59,24.93;IR3392.79,3311.78,2974.23，2927.94,1739.79,1643.35,1502.55,1440.83,1367.53,1338.60,1242.16,1234.44,1166.93,738.74。實(shí)施例282-色氨酰-p-四氫咔啉-3-甲?；?氨基酸芐酯鹽酸鹽的制備通法將3.18mmolBoc-色氨酰-p-四氫咔啉-3-甲酰基-氨基酸芐酯置于50mL茄形瓶中并用2mL乙酸乙酯溶解。冰浴下往得到的溶液中緩慢滴入2mL4N氯化氫/EtOAc。反應(yīng)混合物0。C攪拌3小時(shí)后減壓濃縮至干,殘留物先用乙醚反復(fù)抽取(10mlx4)，然后用甲醇-乙醚重結(jié)晶，得到標(biāo)題化合物。實(shí)施例292-色氨酰-p-四氫咔啉-3-甲?；?纈氨酸芐酯鹽酸鹽(2a)的數(shù)據(jù)0.092g(80%);ESI(m/e)590[M-H]..iHNMR(CDCl3):S/ppn^10.99(s,1H),10.92(s,1H)，8.11(s，1H),7.40(m,1H),7.30(m,5H),7.21(m,4H),7.01(d,JN10Hz，1H),6.97(s,1H),5.25(d，J=10Hz,1H),4.93(t,J=7.5Hz，1H)，4.85(d，J-10Hz,1H),4.54(s,2H),3.93(m,1H),3.06(d,J=10Hz,2H),2.80(d,J=10Hz,2H),2.08(s,2H)，1.05(d，J=7.5Hz,6H);"CNMR(CDC13)S/ppm=167.99,136.55,136.20，129.00,128.82,127.63,125.32,121.74,119.16,118.94,112.08,107.26,66.34,65.37,57.71,52.74,33.80,24.90,18.58,17.92,15.63。實(shí)施例302-色氨酰-p-四氫咔啉-3-甲?；?天冬氨酸雙節(jié)酯鹽酸鹽(2b)的數(shù)據(jù)0.107g(83%);ESI(m/e)696[M-町.toMR(CDC13)S/ppm=10.42(s,1H)，8.23(s,1H)，7.27(d,J=2Hz,1H),7.21(m,10H),7.14(m，4H),6.76(t，J=10Hz,IH),5.78(d,J=7.5Hz,IH)，5.21(s，2H),5.18(s,2H),5.02(d,J=3Hz,IH),4.96(t,J=5Hz，IH),4.34(s,2H),3.40(t,J=7.5Hz，IH),3.04(d，J=10Hz,IH),2.94(d,J=7.5Hz，2H),2.87(d,J=7,5Hz，IH),1.99(s,2H);13CNMR(CDC13)S/ppm=170.51,169.50,136.51,136.20,129.77,128.77,127.53，126.74,121.62,119.04,106.85,104.21,66.71,66.28,54.97,51.016,49.31,36.11,17.63,22.81。實(shí)施例312-色氨酰-p-四氫咔啉-3-甲酰基-谷氨酰胺芐酯鹽酸鹽(2c)的數(shù)據(jù)0.083g(81%);ESI(m/e)602[M-H]..iHNMR(CDCl3):S/ppm:10.06(s,IH),8.15(s,IH),7.23(m,5H)，7.19(m,4H),7.00(m,IH),6.95(d，J=7.5Hz,IH),6.82(s,IH),6.32(s,2H),5.28(d,J=5Hz,2H)，4.93(t,J=7.5Hz,IH),4.88(s,IH),4.50(s,2H),4.33(t,J=7.5Hz,IH),3.94(m,IH),3.06(d,2H),2.12(m,2H),1.92(s,2H);13CNMR(CDC13)S/ppm=172.36,171.55,170.50,136.45,129.77,127.60,127.35,123.01,121.55,121.20,120.00,119.06,111.80,111.45,106.78,56.48,52.27,41.62,27.23,23.86,21.51。實(shí)施例322-色氨酰-P-四氫咔啉-3-甲?；?(Nco-芐氧羰基)賴氨酸芐酯鹽酸(2d)的數(shù)據(jù)0.078g(82.0%);ESI陽(yáng)MS(m/e)709[M-H]..IHNMR(CDC13)S/ppm=10.91(s,IH),10.87(s,IH),8.24(s,IH),8.09(s,IH),7.29(m,10H),7.27(m，IH),7.19(m,4H),7.17(d,J=7.5Hz,IH),6.75(t,J=5Hz,IH),5.79(d,J=7.5Hz,2H),5.24(s,2H),4.92(t,J=5Hz,IH),4.42(s,2H),4.39(t,J=7.5Hz,IH),4.03(m，IH),3.05(q,J=7.5Hz,J=7.5Hz,2H)，2.09(s,2H),1.92(m,2H),1.64(m,2H),1.33(m,2H);13CNMR(CDC13)5/ppm=171.99，170.03,169.76,156.55,137.74,136.75，130.01,129.76,128.20,127.57,121.56,119.20,111.58,106.78,66.27,65.36，52.56,50.87,42.26,30.94,29.44,23.16,15.62。實(shí)施例332-色氨酰-p-四氫咔啉-3-甲?；?亮氨酸芐酯鹽酸鹽(2e)的數(shù)據(jù)0.103g(90%);ESI-MS(m/e)60爭(zhēng)-町.(CDC13)S/ppm=11.02(s,IH),10.87(s，lH),8.23(s,IH),7.72(d,J=7.5Hz,IH),7.31(m,IH),7.27(m，5H),7.20(m,4H),7.02(d,J=5Hz，IH),6.97(t，J=10Hz,IH),5.68(d,J=5Hz,IH),5.24(s,2H),4.98(t,J=7.5Hz,IH),4.58(d,J=5Hz,2H),4.40(s，2H)，4.18(m，IH),3.40(m,IH),2.51(s,2H),1.10(t,J=5Hz，IH)，7.32(d，J=6Hz，6H);13CNMR(CDC13)5/ppm=172.22,171.07，170.02,169.77,129.93,129.70,128.19,127.53,121.63,119.18,111.57,106.76,106.39,66.27,65.36,54.38,50.99,42.24,24.21,23.14,21.74。實(shí)施例342-色氨酰-p-四氫咔啉-3-甲酰基-丙氨酸芐酯鹽酸鹽(2Q的數(shù)據(jù)0.089g(91.0%);ESI(m/e)562[M-H]-.輸MR(CDC13)S/ppm=11.02(s，IH),10.87(s，IH),8.23(s,IH),7.72(d,J=7.5Hz,IH),7.31(m,IH),7.27(m,5H),7.20(m,4H),7.02(d,J=5Hz,IH)，6.97(t，J=5Hz，IH),5.68(d,J=5Hz,IH),5.24(s,2H),4.98(t,J=7.5z,IH),4.58(d,J=5Hz,2H),4.40(s,2H),4.18(m,IH),3.40(m,IH),2.51(s,2H),1.10(t,J=5Hz，IH),7.32(d,J=6Hz,6H);13CNMR(CDC13)S/ppm=172.22，171.07,170.02,169.77,129.93,129.70,128.19，127.53，121.63,119.18,111.57,106.76,106.39，66.27,65.36，54.38,50.99,42.24,24.21,23.14,21.74。實(shí)施例352-色氨酰-p-四氫咔啉-3-甲?；?色氨酸芐酯鹽酸鹽(2g)的數(shù)據(jù)0.107g(80%);ESI(m/e)677[M-H]-.iHNMR(CDCl3)S/ppm=10.50(s,IH),8.14(s,IH)，10.06(s,IH),7.26(d，J=2.5Hz,IH),7.21(m,5H),7.18(m,8H),6.97(m,IH),6.92(t,JM7.5Hz,IH),6.75(t,J=5Hz,IH),5.40(s,2H),4.92(d,J=3.0Hz,IH)，4.80(d,J=10.25Hz,IH),4.45(s,2H),4.37(m,IH)，3.18(d,J=7.5Hz,IH),3.07(d,J=8.3Hz,4H),2.00(s,IH);13CNMR(CDC13)S/ppm=172.03,170.06,136.62,128.73,128.30,126.72,125.18，124.27,119.03,117.99,111.93，66.34,65.37,53.99,51.61,47.98,33.80，27.93,25.81,24.91,15.63。實(shí)施例362-色氨酰-p-四氫昨啉-3-甲?；?0-節(jié)基絲氨酸芐酯鹽酸鹽(2h)的數(shù)據(jù)0.088g(86.0%);ESI(ra/e)654[M-H]-.i麗MR(CDC13)S/ppm=10.55(s,IH),8.20(s,IH),7.26(t,J=7.5Hz,IH),7.20(m,10H),7.10(m,4H),6.96(d,J=7.5Hz,IH),6.71(d,J=7.5Hz,IH):5.53(d,J=7.5Hz,2H),4.98(t,J=5Hz，IH),4.86(t,J=5Hz，IH)，4.67(s,2H),3.90(m,IH)，3.88(d,J=10Hz，2H),3.21(d,J=7.5Hz,4H),1.99(s,2H);"CNMR(CDC13)S/ppm=171.28,170.18,169.71,138.26,137.77，136.58,130.09,129.74,128.71,128.13,127.97,121.54,119.01,117.90，111.96,106.79,72.77,69.54,66.53,54.27,52.99，26.40，23.75。實(shí)施例372-色氨酰-P-四氫咔啉-3-甲?；?異亮氨酸芐酯鹽酸鹽(2i)的數(shù)據(jù)O.lllg(93%);ESI(m/e)604[M-町.1HNMR(CDC13)S/ppm=10.92(s,1H),8.24(s，1H),7.27(m，1H),7.22(m,5H),7.20(m,1H),7.14(m,4H),6.93(s,2H),5.83(d,J=10Hz,1H),5.24(s,2H),4.91(t，J=10Hz,3H),4.88(t,J=5Hz,1H),4.54(s,2H)，4.15(t,J=7.5Hz,1H),3.14(m,1H)，3.06(d,J=10Hz,2H),1.99(s,2H),1.06(d,J=5Hz,3H),0.88(t,J=5Hz，3H);13CNMR(CDC13)S/ppm=171.46,169.96,167.98，136.75,130.28，129.81,128.77,127.61,126.79,121.50，119.15,111.59,106.68,104.28,66.31,57.12，53.88，36.91,33.80,27.43,25.41,24.89，15.89,11.62。實(shí)施例382-色氨酰-p-四氫咔啉-3-甲?；?苯丙氨酸芐酯鹽酸鹽(2j)的數(shù)據(jù)0.120g(91%);ESI(m/e)638[M-H]-.1HNMR(CDC13)S/ppm=10.82(s,1H),10.76(s,1H),8.17(s,1H),7.25(m，5H),7.22(m，1H)，7.18(m,4H),7.15(m,1H),6.98(m,1H),6.93(d,J=5Hz,1H),6.76(t,J=7.5Hz,1H),5.75(d,J=7.5Hz,1H),4.94(t,J=5Hz,IH),4.80(t,J=7.5Hz，IH),4.45(s,2H),3.80(t,J=Hz,IH),3.29(d,J=7.5Hz,2H),3.07(d,J=7.8Hz，IH)，2.91(d,J=7.3Hz，2H)，2.50(s,2H);13CNMR(CDC13)S/ppm=171.42,170.86,169.88,137.71,136.12,129.89,129.05,128.78,127.53,126.93,126.72,121.67,119.20,119.05,111.61,111.43,106.87,66.46,63.65,54.14,51.44,36.73,36.53,23.15。實(shí)施例392-色氨酰-p-四氫咔啉-3-甲?；?甘氨酸芐酯鹽酸鹽(3k)的數(shù)據(jù)0.078g(96%);ESI(m/e)547[M-H]—.1HNMR(CDCD)S/ppm=9.08(s,IH),8.93(s,IH),8.19(s,IH)，7.53(m,IH),7.44(m,IH)，7.32(m，5H)，7.22(m,4H),6.98(d,J=5Hz,IH),6.97(d，J=5Hz,IH),5.89(d,J=5Hz，2H)，5.47(s，2H),5.03(t，J=5Hz,IH)，5.00(s,2H),4.27(m,IH),3.09(m,IH),3.01(d,J=7.5Hz,2H),1.99(s,2H);13CNMR(CDC13)5/ppm=169.97,166.32165.89,136.61，128.67,127.58，127.07,124.49,121.47,118.95,118.05,111.97,109.51,66.72,65.36，49.50,42.28，41.77,28.79,15.62。實(shí)施例402-色氨酰-P-四氫咔啉-3-甲?；?組氨酸芐酯鹽酸鹽(21)的數(shù)據(jù)0.087g(81%);ESI(m/e)628[M-H]-.l麗MR(CDC13)S/ppm=10.52(s,IH),9.55(s,IH),8.06(s,IH),7.44(d，J=10Hz,IH),7.25(s,5H),7.17(m,4H),7.07(m,IH),6.18(t,J=5Hz,IH),5.85(d,J=5Hz，2H),5.77(d,J=7.5Hz，IH),4.87(t,J=7.5Hz，IH),4.83(t,J=5Hz,IH)，4.55(s,2H),4.00(t,J=7.5Hz,IH),3.12(d,J=10Hz,2H),3.06(m,2H),1.21(s,2H);13CNMR(CDC13)S/ppm=170.31,169.97,157.20,136.64,129.69,128.23,127.57，121.53,11904,118.31,111.57,106.52,63.63,53.20,48.00,33.77，25.80,22.95。實(shí)施例412-色氮酰-p-四氫咔啉-3-甲酰基-蛋氨酸芐酯鹽酸鹽(2m)的數(shù)據(jù)0.096g(85%);ESI(m/e)618[M-H]—.iflNMR(CDC13)S/ppm=10.99(s,IH),10.88(s，IH),8.26(s,IH),7.27(m,IH),7.22(m,5H),7.17(m,4H),6.84(s,IH),6.82(d,J=7.5Hz,IH),5.54(s,2H),4.55(d，J=5Hz,IH),4.53(s,2H),3.69(m,IH),3.42(t,J=7.5Hz,2H),3.12(d,J=5Hz，2H),2.79(d,J=5Hz，2H),2.43(t,J-lOHz,2H),2.41(m,2H),2.09(s,3H),2.01(s,2H);13CNMR(CDC13)5/ppm=167.97，136.53,128.87,128.22,127.62,125.68,121.71,119.13,118.48，112.07,107.26,65.83,65.47,49.65，45.93,42.35,27.64。實(shí)施例422-色氨酰-p-四氫味啉-3-甲?；?谷氨酸雙芐酯鹽酸鹽(211)的數(shù)據(jù)0.078g(86%);ESI(m/e)710[M-H]-.1HNMR(CDC13)S/ppm=11.01(s,IH),10.85(s,IH),8.23(s,IH)，7.36(m,10H),7.26(m,IH),7.18(m,4H),6.97(d,J:7.5Hz,IH),5.78(d,JK7.5Hz,IH),5.40(s,2H)，4.99(t,J=10Hz,IH),4.82(t,J=5Hz,IH),4.39(s,2H),4.34(m,IH),3.18(d,J=5Hz,2H),2.35(q,J=5Hz,J=5Hz,2H),2.24(t,J=7.5Hz,2H),1.99(s,2H);13CNMR(CDC13)S/ppm=172.55,172.40,171.39,136.84,136.59,136.20,129.96,128.87，128.21，127.58,121.65,119.20，111.59,111.42,106.85,66.45,65.98,52.29,33.80,27.61,26.37,24.13,23.25。實(shí)施例432-色氨酰-p-四氫昨啉-3-甲?；?天冬酰胺芐酯鹽酸鹽(20)的數(shù)據(jù)0.089g(87%);ESI(m/e)605[M-H]-.^MR(CDC13)S/ppm=10.48(s,IH),10.46(s,IH),8.15(s,IH),7.27(m,IH),7.23(m,5H)，7.19(m，4H),6.86(d,J=10Hz,IH),6.73(d,J=7.5Hz，IH),5.79(d,J=7.5Hz,2H),4.92(t，J=7.5Hz,IH),10.64(t,J=5Hz,IH),4.50(s,2H),4.40(t,JK7.5Hz:IH),3.04(d,J=10Hz,2H),2.65(d,J=7.5Hz，2H),1.99(s,2H);13CNMR(CDC13)S/ppm=171.24:169.72，136.59,128.76,128.01,127.57,126.88,121.57,119.01,117.93,111.88,106.41,89.25,66.39,54.65，49.61,36.85,29.36,26.45,21.80。實(shí)施例442-色氨酰-p-四氫咔啉-3-甲?；?脯氨酸芐酯鹽酸鹽(2p)的數(shù)據(jù)0.122g(89%);ESI(m/e)588[M-町.i冊(cè)MR(CDC13)S/ppm=10.34(s,IH),8.16(s,1H),7.27(m，1H),7.24(m,5H)，7.17(m,4H),7.06(m,1H)，6.92(d,J=7.5Hz，1H),6.82(t,J=10Hz,1H),5.72(d,J=7.5Hz,2H)，4.89(t,J=10Hz，IH),4.45(s，IH),4.31(t,J=7.5Hz,2H),4.01(m,IH),3.80(t,J=7.5Hz,2H),3.09(d,J=7.5Hz,2H),3.06(d,J=5Hz,2H),2.30(m,2H),2.00(s，2H);13CNMR(CDC13)S/ppm=173.40,169.07,136.86，136.50，128.97,128.00,127.58,125.61,121.68,121.37,119.21,119.06,111.57,111.38，106.74,67.76,59.15,51.39,49.30,47.21，28.92,23.46,22.30。實(shí)施例452-色氨酰-p-四氫咔啉-3-甲?；?對(duì)甲氧基芐基半胱氨酸芐酯鹽酸(2q)的數(shù)據(jù)0.121g(83%);ESI(m/e)668[M-H]-.輸MR(CDC13)5/ppm=10.88(s,IH),8.24(s,IH),7.22(m,5H),7.19(m,4H),7.04(m,IH),7.00(d,J=7.5Hz,IH),5.30(s,2H),4.93(m，2H),4.41(s,2H),3.77(m,IH),3.72(s,2H),3.37(s,3H),3.32(t,J=10Hz,2H),2.82(t,J=7.5Hz，4H),1.92(s,2H);13CNMR(CDC13)S/ppm=170.59,170.09,169.75,136.70,136.16,129.44,129.22,128.15，127.54,127.24,121.69,121.64,119.05,112.05,111.60,111.45,66.71,65.35,52.32,35.77，35.53,32.10,23.99。實(shí)施例462-色氨酰-p-四氫咔啉-3-甲?；?硝基精氨酸芐酯鹽酸鹽(2r)的數(shù)據(jù)0.086g(85%);ESI(m/e)692[M-H]..1HNMR(CDC13)S/ppm=10.01(s,IH),9.10(s,IH),8.08(s,IH)，8.03(s,IH),7.31(m,IH),7.29(m,5H),7.22(m,4H),7.16(m,IH),7.00(d,J=2.5Hz,IH)，6.97(d,J=7.5Hz,IH),6.95(d,J=7.5Hz,IH),5.24(s,2H),4.95(t,J=7.5Hz,IH),4.50(s，2H)，4.03(m,IH),3.07(d,J-10Hz,IH),3.03(t,J=10Hz,2H),2.50(t,J=5Hz,2H),2.09(s,2H),1.99(s,IH),1.92(s,IH),1.73(m,2H),1.57(m,2H);13CNMR(CDC13)S/ppm=172.36,171.95,159.82，136.79,136.27,128.88,128.24,127.60,126.87,124.90,121.55,119.05,113.42,111.88,66.47,65.33，63.65,52.48,50.97,28.41,25.46,21.51。實(shí)施例472-色氨酰-P-四氫咔啉-3-甲?；?蘇氨酸芐酯鹽酸鹽(2s)的數(shù)據(jù)O.lOlg(87%);ESI(m/e)592[M-H]-.t麗MR(CDC13)5/ppm=10.78(s,IH),10.55(s,IH),8.32(s,1H),7.27(m，1H)，7.23(m,5H),7.12(m，4H),6.97(m,1H),6.82(d,J=5Hz,1H),6.78(s,1H),6.71(d，J=10Hz,1H),5.53(s,2H),4.93(m,1H),4.69(t,J=5Hz,1H),4.52(t,J=5Hz，1H)，4.46(s,2H)，2.51(d,J=5Hz,1H),1.91(s，2H),1.23(d,J=5Hz,3H);13CNMR(CDC13)5/ppm=171.58,170.23,169.44,136.32,130.17,129.59,128.80,127.68,127.58,126.52,121.50，119.21，111,55，68.13，67.37,65.34,58.90，51.56,42.24,27.41,20.76，20.09,16.63。實(shí)施例482-色氨酰-p-四氫咔啉-3-甲?；?酪氨酸芐酯鹽酸鹽(2t)的數(shù)據(jù)0.098g(83%);ESI-MS(m/e)654[M-町.toMR(CDC13)5/ppm=10.76(s,IH),8.14(s,IH),7.27(d，J=5Hz，IH)，7.20(m,5H),7.10(m,4H),6.97(d,J=7.5Hz,IH)，6.87(d，J=7.5Hz,IH),6.79(s，IH),6.76(d,J=7.5Hz，2H)，6.55(s,2H),5.07(s,IH),4.94(t,J=7.5Hz,IH),4.82(t,J=5Hz,IH),4.03(t,IH),3.31(d,J=7.5Hz,2H),3.25(d,J=Hz,2H)，2.96(t,J=7.5Hz,2H),1.99(s,2H);13CNMR(CDC13)S/ppm=169.49,136.46,136.16,130.49，130.43,128.74,127.69，127.55,121.66,121.25，119.55,111.44,110.18,106.59,66.39,63.69,54.13,52.80,35.83,33.80,23.14,15.62。實(shí)驗(yàn)例1本發(fā)明化合物(2a-t)抗腫瘤細(xì)胞增殖活性評(píng)價(jià)l)受試樣品本發(fā)明實(shí)施例29-48所制備的化合物化合物(2a-t);用含lXDMSO的PBS配制成所需濃度。2)人癌細(xì)胞株S180細(xì)胞(腹水型肉瘤細(xì)胞)，H22細(xì)胞(小鼠腹水型肝癌細(xì)胞株)3)主要儀器酶標(biāo)儀450，Biorad公司高壓滅菌鍋400Ep-Z，Bruckmanning公司細(xì)胞孵育箱INC153,memmer公司低溫離心機(jī)SPD111V，Thermo公司96孔細(xì)胞培養(yǎng)板Costar公司石英自動(dòng)雙重純水蒸餾器1810—B，江蘇榮華儀器制造有限公司4)主要試劑MTT:四噻唑藍(lán)(3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl-tetrazoliumbromide)(Flka)，溶于PBS中，濃度為5mg/ml，過(guò)濾除菌，4'C避光保存。PBS:每升溶液中含有NaCl8.2g，KC10.20g，Na2HP04.H201.56g,KH2PO40.2g，pH7.4RPMI-1640培養(yǎng)基Gibco公司DMEM培養(yǎng)基Gibco公司改良的Mccy's5Amedium十L-Glutamine培養(yǎng)基Gibco公司胎牛血清Hyclone公司青霉素石藥集團(tuán)中諾藥業(yè)(石家莊)有限公司鏈霉素石藥集團(tuán)中諾藥業(yè)(石家莊)有限公司DMSO:Hyclone公司。其余所用試劑均為市售分析純.5)本發(fā)明化合物2a-t抗腫瘤細(xì)胞增殖評(píng)價(jià)的實(shí)驗(yàn)方法分別將生長(zhǎng)狀態(tài)良好、處于對(duì)數(shù)生長(zhǎng)期的HL-60細(xì)胞以5xl(^個(gè)/mL的密度接種于96孔板，每孔100pl,按預(yù)設(shè)的濃度梯度加入待測(cè)、經(jīng)滅菌處理的樣品，對(duì)照組加入等體積的溶解樣品的溶媒。繼續(xù)培養(yǎng)48小時(shí)后，每孔加25pl濃度為5mg/ml的MTT溶液，繼續(xù)置于37'C孵育四個(gè)小時(shí)，離心5min(2500rpm)小心吸出上清液，每孔加入100pl的DMSO溶解紫色殘留物(甲瓚)，振蕩約15min沉淀全部溶解，于570nm酶標(biāo)儀上測(cè)定aD.(吸收值)，波長(zhǎng)570跳按照公式"相對(duì)生存率=^!含藥-D空白)/CD對(duì)照-"空白)x100%"計(jì)算每一個(gè)樣品濃度下的樣品對(duì)腫瘤細(xì)胞的抑制率。實(shí)驗(yàn)重復(fù)3次,以抑制率對(duì)藥物濃度作圖，按作圖法求出IC50(半數(shù)有效抑制濃度)值。6)實(shí)驗(yàn)結(jié)果實(shí)驗(yàn)結(jié)果見(jiàn)表l。表l2a-t抗腫瘤細(xì)胞增殖活性(IC5Q±SD^M)<table>tableseeoriginaldocumentpage21</column></row><table><table>tableseeoriginaldocumentpage22</column></row><table>實(shí)驗(yàn)例2本發(fā)明化合物2a-t的抗腫瘤活性實(shí)驗(yàn)1)實(shí)驗(yàn)材料受試化合物本發(fā)明實(shí)施例29-48所制備的化合物化合物(2a-1);陽(yáng)性對(duì)照品為阿糖胞苷實(shí)驗(yàn)動(dòng)物SCI小鼠(KM清潔級(jí))，雄性，體重20士2g(J土s);購(gòu)自北京大學(xué)醫(yī)學(xué)部動(dòng)物實(shí)驗(yàn)中心提供。每12只小鼠一組，空白及陽(yáng)性對(duì)照各一組。瘤源小鼠Si80肉瘤，由北京大學(xué)醫(yī)學(xué)部動(dòng)物實(shí)驗(yàn)中心提供，自行傳代維持。溶劑生理鹽水，0.5XCMC-Na溶液。2)劑量設(shè)置受試化合物2a-t及阿糖胞苷設(shè)為8.9pmol/kg，均采用腹腔單次給藥。3)藥物配制受試化合物2a-t在水中難溶，實(shí)驗(yàn)時(shí)加入少量的吐溫80潤(rùn)濕助溶，逐漸加入0.5%CMC-Na溶液至所需要濃度即可。阿糖胞苷為水溶性，采用生理鹽水溶解。4)給藥劑量及給藥方案受試化合物2a-t均以腹腔單次給藥。按相應(yīng)的給藥劑量每天一次，0.2ml/鼠，連續(xù)給藥7天，共給藥7次。陰性對(duì)照以等體積的相應(yīng)溶液，均以腹腔給藥。按相應(yīng)的給藥劑量每天一次，0.2m1/鼠，連續(xù)給藥7天，共給藥7次。阿糖胞苷按8.9pmol/kg的劑量，腹腔給藥。每天一次，0.2ml/鼠，連續(xù)給藥7天，共給藥7次。5)動(dòng)物模型采用體內(nèi)抗腫瘤腋皮下接種模型在無(wú)菌條件下抽取接種7天后取生長(zhǎng)旺盛S咖腹水瘤瘤液，用生理鹽水稀釋成(1:2)的液體充分混合，將腫瘤細(xì)胞懸液用新鮮配制的0.2%臺(tái)盼藍(lán)染色,混勻后按白細(xì)胞計(jì)數(shù)方法計(jì)數(shù)，染藍(lán)色者為死細(xì)胞，不染色者為活細(xì)胞，按如下公式計(jì)算細(xì)胞濃度和細(xì)胞存活率。細(xì)胞濃度z4大方格內(nèi)活細(xì)胞數(shù)/4xl0、稀釋倍數(shù)^細(xì)胞數(shù)/ml細(xì)胞存活率=活細(xì)胞數(shù)/(活細(xì)胞數(shù)+死細(xì)胞數(shù))x100%將存活率大于90Q/。的瘤液用勻漿法制備成lxl0MVml的細(xì)胞懸液，于相應(yīng)宿主腋皮下接種0.21111/鼠，制成實(shí)體瘤動(dòng)物模型。6)檢測(cè)指標(biāo)及方法7)體內(nèi)神經(jīng)毒性觀察每日觀察給藥各組動(dòng)物的反應(yīng)小鼠的自主活動(dòng)、精神狀態(tài)、毛發(fā)、呼吸、飲食，糞便性狀。8)實(shí)體瘤抑瘤率和體重增長(zhǎng)的測(cè)定各組連續(xù)給藥7天后于第8天脫頸椎處死小鼠,稱取體重(處死體重)，然后用鑷子固定小鼠右腋腫瘤生長(zhǎng)部位，剪開(kāi)皮膚，暴露腫瘤，鈍性剝離，稱重，按如下公式計(jì)算抑瘤率。抑瘤率％=[(陰性對(duì)照組平均瘤重-給藥組平均瘤重)/陰性對(duì)照組平均瘤重]x100%體重增長(zhǎng)(g)=處死體重-原始體重-瘤重9)肝重、脾指數(shù)和胸腺指數(shù)的測(cè)定采用稱重法即剝離腫瘤后的小鼠,再解剖取出腦、肝、腎、和脾,稱取腦重(g)、肝重(g)、腎重(g)、脾重(mg)，并按如下公式計(jì)算脾指數(shù)。脾指數(shù)(mg/kg)-脾重/處死體重10)統(tǒng)計(jì)方法本實(shí)驗(yàn)數(shù)據(jù)統(tǒng)計(jì)均采用f檢驗(yàn)和方差分析，以(7±&0)表示。11)實(shí)驗(yàn)結(jié)果受試化合物2a-t對(duì)荷S削肉瘤的體內(nèi)抗腫瘤活性實(shí)驗(yàn)結(jié)果列入表2。給藥劑量為8.9pmol/kg，經(jīng)連續(xù)腹腔給藥7天以后，平均腫瘤重量為1.69士0.61g至049士0.12g;陰性對(duì)照組的平均腫瘤重量為1.76i0.54g，有10個(gè)化合物具有顯著的抗腫瘤作用，其中化合物化合物2a，e，i，l，m，r(瘤重范圍為0.49士0.12g至0.63士0.20g，與生理鹽水組比較p0.05)的抗腫瘤活性與阿糖胞苷相當(dāng)。表2受試化合物2a-1對(duì)荷S18Q小鼠腫瘤重量的影響a化合物抑瘤率％瘤重NS0.76±0.16Arc30.02±0.44a0.56±0.1340.52±1.05a0.57±0.202b2.16±3.260.74±0.262c9.58±3.590.91±0.332d17.23±2.36b0.72±0.192e29.04±1.01a0.63±0.202f-1.39±3.900.78±0.092g21.19±3.42b0.57±0.252h10.67±2.470.78±0.242i35.45±7.390.75±0.442j18.22±5.670.74±0.152k24.61±2.14b0.57±0.222145.44±0.22a0.50±0.232m44.03土0.00r0.49±0.142n-7.24土2.630.92士0.272o13.14±3.580.80±0.412p15.35±3.220.90±0.402q8.69±1.270.71±0.242r35.55±1.21b0.47±0.262s-6.55±2.750.97±0.292t17.46±1.690.86±0.33a)Arc(阿糖胞苷)和2a-t給藥劑量為8.9"mol/kg,昭=溶媒，n=12,平均瘤重表示為3f±SDg;b)與NS比較p〈0.01,與阿糖胞苷比較p〉0.05;c)與NS比較p〈0.01，與阿糖胞苷比較p<0.05;權(quán)利要求1、具有抗腫瘤活性的通式I化合物id="icf0001"file="A2008101144030002C1.tif"wi="55"he="27"top="36"left="64"img-content="drawing"img-format="tif"orientation="portrait"inline="yes"/>通式I式中AA選自纈氨酸殘基、天冬氨酸-γ-芐酯、谷氨酰胺殘基、Nω-芐氧羰基賴氨酸殘基、亮氨酸殘基、丙氨酸殘基、色氨酸殘基、O-芐基絲氨酸殘基、苯丙氨酸殘基、異亮氨酸殘基、甘氨酸殘基、組氨酸殘基、蛋氨酸殘基、谷氨酸-δ-芐酯、天冬酰胺殘基、脯氨酸殘基、對(duì)甲氧基芐基半胱氨酸、硝基精氨酸殘基、蘇氨酸殘基或酪氨酸殘基。2、一種制備權(quán)利要求1所述通式I化合物的方法，包括-(1)將色氨酸轉(zhuǎn)變?yōu)锽oc-色氨酸；(2)將色氨酸轉(zhuǎn)變?yōu)閜-四氫咔啉-3-羧酸；(3)將p-四氫咔啉-3-羧酸轉(zhuǎn)變?yōu)閜-四氫咔啉-3-羧酸芐酯；(4)將氨基酸轉(zhuǎn)變?yōu)榘被崞S酯；(5)將Boc-色氨酸與p-四氫咔啉-3-羧酸芐酯縮合制備2-(800色氨酰)-|3-四氫咔啉-3-羧酸芐酯；(6)將2-(Boc-色氨酰)-卩-四氫咔啉-3-羧酸芐酯氫解制備2-(Boc-色氨酰)-卩-四氫咔啉-3-羧酸；(7)將2-(Boc-色氨酰)-p-四氫咔啉-3-羧酸和步驟(4)所制備的氨基酸芐酯縮合制備2-(Boc-色氨酰)-p-四氫咔啉-3-甲酰氨基酸芐酯；(8)將2-(Boc-色氨酰)-p-四氫咔啉-3-甲酰氨基酸芐酯脫去保護(hù)基Boc，即得。3、按照權(quán)利要求2所述的方法，其特征在于步驟(4)中所述的氨基酸芐酯選自纈氨酸芐酯、天冬氨酸雙芐酯、谷氨酰胺芐酯、(N"-芐氧羰基)賴氨酸芐酯、亮氨酸芐酯、丙氨酸芐酯、色氨酸芐酯、0-芐基絲氨酸芐酯、異亮氨酸芐酯、苯丙氨酸芐酯、甘氨酸節(jié)酯、組胺酸芐酯、蛋氨酸芐酯、谷氨酸雙芐酯、天冬酰胺芐酯、脯氨酸芐酯、對(duì)甲氧基芐基半胱氨酸芐酯、硝基精氨酸芐酯、酪氨酸芐酯或蘇氨酸芐酯。4、一種治療腫瘤的藥物組合物，由治療上有效量的權(quán)利要求1所述的通式I化合物和藥學(xué)上可接受的載體或輔料組成。5、權(quán)利要求l所述的化合物在制備抗腫瘤藥物中的用途。全文摘要本發(fā)明公開(kāi)了2-色氨酰-β-四氫咔啉-3-甲?；被崞S酯及其制備方法和應(yīng)用，屬于生物醫(yī)藥領(lǐng)域。本發(fā)明2-色氨酰-β-四氫咔啉-3-甲酰基氨基酸芐酯的結(jié)構(gòu)式為通式I所示，式中AA選自纈氨酸殘基、天冬氨酸-γ-芐酯、谷氨酰胺、N^ω-芐氧羰基賴氨酸、亮氨酸殘基、丙氨酸殘基、色氨酸殘基、O-芐基絲氨酸殘基、苯丙氨酸殘基、異亮氨酸殘基、甘氨酸殘基、組氨酸殘基、蛋氨酸殘基、谷氨酸-δ-芐酯、天冬酰胺殘基、脯氨酸殘基、對(duì)甲氧基芐基半胱氨酸、硝基精氨酸殘基、蘇氨酸殘基或酪氨酸殘基。本發(fā)明在腫瘤細(xì)胞模型和小鼠S₁₈₀肉瘤模型上評(píng)價(jià)了通式I化合物的抗腫瘤活性，實(shí)驗(yàn)結(jié)果表明，本發(fā)明通式1化合物具有優(yōu)秀的抗腫瘤活性，可作為抗腫瘤劑應(yīng)用。文檔編號(hào)C07K5/08GK101597289SQ20081011440公開(kāi)日2009年12月9日申請(qǐng)日期2008年6月2日優(yōu)先權(quán)日2008年6月2日發(fā)明者張麗娜,彭師奇,明趙申請(qǐng)人:首都醫(yī)科大學(xué)