CN101591348B - 四氢咔啉酰氨基酸苄酯及其制备方法和应用 - Google Patents
四氢咔啉酰氨基酸苄酯及其制备方法和应用 Download PDFInfo
- Publication number
- CN101591348B CN101591348B CN2008101138579A CN200810113857A CN101591348B CN 101591348 B CN101591348 B CN 101591348B CN 2008101138579 A CN2008101138579 A CN 2008101138579A CN 200810113857 A CN200810113857 A CN 200810113857A CN 101591348 B CN101591348 B CN 101591348B
- Authority
- CN
- China
- Prior art keywords
- tetrahydrocarboline
- formyl radical
- residue
- obzl
- dmso
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 0 *C([C@](Cc1c(C2)[n]c3ccccc13)N2C([C@](C1)[*+]CC2=C1c1ccccc1*2)=O)=O Chemical compound *C([C@](Cc1c(C2)[n]c3ccccc13)N2C([C@](C1)[*+]CC2=C1c1ccccc1*2)=O)=O 0.000 description 1
Images
Abstract
本发明公开了具有抗肿瘤活性的通式I化合物及其制备方法和应用,属于生物医药领域。本发明采用S180小鼠模型评价了本发明化合物8a-s的抗肿瘤活性,实验结果表明,本发明化合物具有优秀的抗肿瘤活性,临床上可作为抗肿瘤剂应用。
Description
技术领域
本发明涉及具有抗肿瘤活性的化合物,尤其涉及具有抗肿瘤活性的N-(1.2.3.4-四氢咔啉酰)-1.2.3.4-四氢咔啉酰氨基酸苄酯类化合物及其制备方法,本发明还进一步涉及它们在制备抗肿瘤药物中的应用,属于生物医药领域。
背景技术
恶性肿瘤是一种严重威胁人类健康的常见病和多发病,人类因恶性肿瘤而引起的死亡率是所有疾病死亡率的第二位,仅次于心脑血管疾病。肿瘤的治疗方法有手术治疗,放射治疗和药物治疗(化学治疗)。目前,化学治疗仍然是临床治疗肿瘤的主要手段。寻找抗肿瘤药物是新药研究的热点之一。发明人认识到,在β-咔啉2位氮端再引入一个咔啉羧酸与3位羧基引入氨基酸苄基可能产生抗肿瘤作用。按照这种构想,发明人提出本发明。
发明内容
本发明目的之一是提供一类新的具有抗肿瘤活性的化合物。
本发明目的之二是提供一种制备上述具有抗肿瘤活性化合物的方法。
本发明上述目的是通过以下技术方案来实现的:
具有抗肿瘤活性的通式I化合物:
通式I
其中AA选自异亮氨酸残基(Ile)、甘氨酸残基(Gly)、缬氨酸残基(Val)、丙氨酸残基(Ala)、苯丙氨酸残基(Phe)、Asp(OBzl)、Glu(OBzl)、亮氨酸残基(Leu)、赖氨酸Lys(Z)、酪氨酸残基(Tyr)、甲硫氨酸残基(Met)、Ser(Bzl)、色氨酸残基(Trp)、脯氨酸残基(Pro)、Thr(BZl)、Arg(NO2)、谷氨酰胺残基(Gln)、天冬酰胺残基(Asn)或组氨酸残基(His);其中,所述的Arg是精氨酸残基,Thr是苏氨酸残基,Ser是丝氨酸残基,Asp是天冬氨酸残基,Glu是谷氨酸残基。
一种制备上述通式I化合物的方法,该方法包括:
(1)(在浓H2SO4和自来水存在下)将L-色氨酸转变为1,2,3,4-四氢咔啉羧酸;
(2)(在多聚磷酸存在下)将1,2,3,4-四氢咔啉羧酸转变为咔啉羧酸苄酯;
(3)(在(Boc)2O和三乙胺存在下)将1,2,3,4-四氢咔啉羧酸转变成N-叔丁氧羰基-1,2,3,4-四氢咔啉羧酸;
(4)(在DCC、HOBt存在下)将N-叔丁氧羰基-1,2,3,4-四氢咔啉羧酸和1,2,3,4-四氢咔啉羧酸苄酯缩合,生成N-叔丁氧羰基-1,2,3,4-四氢咔啉酰-1.2.3.4-四氢咔啉羧酸苄酯;
(5)(在Pd/C和无水乙醇存在下)将N-叔丁氧羰基-1,2,3,4-四氢咔啉酰-1.2.3.4-四氢咔啉羧酸苄酯氢解,生成N-叔丁氧羰基-1,2,3,4-四氢咔啉酰-1.2.3.4-四氢咔啉羧酸;
(6)(在DCC、HOBt、无水THF存在下)将N-叔丁氧羰基-1,2,3,4-四氢咔啉酰-1.2.3.4-四氢咔啉羧酸和氨基酸苄酯缩合,生成N-叔丁氧羰基-1,2,3,4-四氢咔啉酰-1.2.3.4-四氢咔啉酰氨基酸苄酯;
(7)(在HCl-EtOAc存在下)将N-叔丁氧羰基-1,2,3,4-四氢咔啉酰-1.2.3.4-四氢咔啉酰氨基酸苄酯脱Boc,生成N-(1,2,3,4-四氢咔啉酰)-1.2.3.4-四氢咔啉酰氨基酸苄酯。
其中,步骤(6)中所述的氨基酸苄酯选自Ile-OBzl、Gly-OBzl、Val-OBzl、Ala-OBzl、Phe-OBzl、Asp(OBzl)-OBzl、Glu(OBzl)-OBzl、Leu-OBzl、Lys(Z)-OBzl、Tyr-OBzl、Met-OBzl、Ser(Bzl)-OBzl、Trp-OBzl、Pro-OBzl、Thr(BZl)-OBzl、Arg(NO2)-OBzl、Gln-OBzl、Asn-Obzl或His-Obzl。
本发明的又一目的是提供一种具有抗肿瘤活性的药用组合物,该药用组合物由治疗上有效剂量的本发明通式I化合物与药学上可接受的载体组成,即将有效量的本发明通式I化合物与药学上可接受的载体或稀释剂配合后,按本领域常规的制剂方法将其制备成任意一种适宜的药物组合物。通常该组合物适合于口服给药和注射给药,也适合其他的给药方法。该组合物可以是片剂、胶囊剂、粉剂、颗粒剂、锭剂、栓剂,或口服液等液体制剂形式。根据不同 的给药方法,本发明药物组合物可以含有0.1%-99%重量,优选10-60%重量的本发明化合物。
本发明在肿瘤细胞模型和小鼠S180肉瘤模型上评价本发明通式I化合物(8a-s)的抗肿瘤活性,结果表明本发明的化合物它们具有优秀的抗肿瘤作用,临床上可作为抗肿瘤剂应用。
附图说明
图1本发明通式I化合物的结构图。
图2通式I化合物的合成路线图;i)甲醛和浓硫酸,室温搅拌;ii)(Boc)2O,三乙胺,DMF;iii)苄醇,多聚磷酸,油浴90℃;iv)DCC,HoBt,NMM;v)Pd/C,H2,乙醇;vi)L-AA-OBzl,DCC,HoBt,NMM,THF;vii)4N氯化氢-乙酸乙酯溶液。7a-s中AA选自Ile、Gly、Val、Ala、Phe、Asp(OBzl)、Glu(OBzl)、Leu、Lys(Z)、Tyr、Met、Ser(Bzl)、Trp、Pro、Thr(BZl)、Arg(NO2)、Gln、Asn或His;8a-s中AA选自Ile、Gly、Val、Ala、Phe、Asp(OBzl)、Glu(OBzl)、Leu、Lys(Z)、Tyr、Met、Ser(Bzl)、Trp、Pro、Thr(BZl)、Arg(NO2)、Gln、Asn或His。
具体实施方式
为了进一步阐述本发明,下面给出一系列实例。这些实例完全是例证性的,它们仅用来对本发明进行具体描述,不应当理解为对本发明的限制。
实施例1 1,2,3,4-四氢咔啉-3-羧酸(2)
将400ml水置于500ml的圆底烧瓶中,缓慢加入0.2ml浓硫酸摇匀.往得到的稀硫酸溶液中加入5.0g(24.5mmol)L-色氨酸,用超声振荡至L-色氨酸完全溶解。往得到的溶液中加入10ml浓度为35%的甲醛,搅拌,TLC板检测L-色氨酸原料点消失终止反应。往反应液中缓慢滴加氨水调pH6。静置半个小时,减压滤出生成的沉淀并用水洗。得到5.01g(95%)标题化合物,为无色固体干。Mp229-231℃。ESI-MS(m/z)217[M+H]+。
实施例2 N-Boc-1,2,3,4-四氢咔啉-3-羧酸(3)
冰浴下将1g 1,2,3,4-四氢咔啉-3-S-羧酸(4.63mmol)悬浮于含1.2g(5.50mmol)(Boc)2O的10ml DMF溶液中,然后加三乙胺调pH8-9,随着反应的进行混悬的溶液逐渐变澄清,溶液颜色为黄色,TLC板检测反应(氯仿∶甲醇=10∶1)原料点消失。停止反应,反应液蒸发至。残留物用乙酸乙酯溶解,得到的溶液用5%KHSO4水溶液洗涤3次,饱和的NaCl水溶液洗涤3次,无水Na2SO4干燥。过滤,滤液减压浓缩至干,残留物用氯仿洗涤,得到958mg(65.5%)目标化合物,为无色固体。Mp241-243℃;[α]D 25=64.4(C=1.0,甲醇);ESI-MS(m/z):317[M+H]+; 1HNMR(500MHz,DMSO-d6):δ/ppm=12.794(s,1H),10.887(d,J=23.5Hz,1H),7.293-7.440(m,J=8Hz,J=7.5Hz,2H),6.969-7.077(m,J=7Hz,J=7.5Hz,2H),5.1245(dd,J=5.5Hz,1H),4.742(t,J=17Hz,J=19Hz,H),4.4195(dd,J=20Hz,1H),3.323(m,J=7.5Hz,1H),2.985(m,J=6.5Hz,1H),1.460(s,9H).13CNMR(DMSO-d6)δ/ppm=173.28,155.56,136.66,130.81,126.76,121.41,119.01,118.03,111.47,104.99,80.27,60.20,53.86,28.49,23.34.
实施例3 1,2,3,4-四氢咔啉-3-羧酸苄酯(4)
70℃下先使20ml苄醇溶于2g多聚磷酸中,再加入咔啉羧酸1g并升温至90℃反应液逐渐溶解变澄清,TLC板检测反应,24小时原料点消失进行后处理.冷却,加入50ml乙醚和70ml水充分搅拌出现结晶,过滤,乙醚水反复洗得到黄白色的咔啉羧酸苄酯磷酸盐.将得到的咔啉羧酸苄酯磷酸盐混旋在乙酸乙酯中,滴加三乙氨至澄清,用5%碳酸氢钠洗涤6次,饱和氯化钠洗涤3次,无水硫酸钠干燥,过滤,旋干,得到黄白色的咔啉羧酸苄酯.M.p122-124℃;[α]D 25=53.4(C=1.0,甲醇);ESI-MS(m/z):307[M+H]+;1HNMR(500MHz,DMSO-d6):δ/ppm=7.275-7.401(m,7H),6.951(t,J=7.5Hz,1H),7.025(t,J=10Hz,1H),5.191(s,2H),3.9885(q,J=15.5Hz,2H),3.824(q,J=4.5Hz,J=8.5Hz,1H),2.9765(dd,J=4.5Hz,J=15Hz,1H),2.815(q,J=8.5Hz,J=15Hz,). 13CNMR(DMSO-d6):δ/ppm=173.21,136.57,136.23,133.46,128.90,128.71,128.46,128.21,127.30,120.97,118.79,117.73,111.33,105.83,66.15,55.63,41.7,25.26.
实施例4 Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-咔啉-3-酸苄酯(5)
冰浴下用无水THF将1.896g(6.0mmol)Boc-1,2,3,4-四氢咔啉-3-咔啉羧酸溶解,加入0.688g(5.10mmol)N-羟基苯并三氮唑(HOBt),完全溶解后加入1.373g(6.67mmol)二环己基羰二亚胺(DCC)。10分钟后加入含1.53g(5.0mmol)1,2,3,4-四氢咔啉-3-羧酸苄酯的无水THF溶液并用N-甲基吗啉调pH值8。反应化合物室温搅拌,TLC板检测(石油醚/丙酮,3∶1,Rf=0.2)原料点消失后滤除二环己基脲(DCU)。滤液减压浓缩,残留物用40ml乙酸乙酯溶解。得到的溶液依次用饱和NaHCO3水溶液、NaCl,5%KHSO4水溶液、饱和NaCl水溶液洗三次,无水Na2SO4 干燥。过滤,滤液减压浓缩得到2.244g(74%)标题化合物,为无色固体。Mp230-232℃;[α]D 25=41.9(C=1.0,甲醇);ESI-MS(m/z)606[M+H]+;1HNMR(300MHz,DMSO-d6)δ/ppm=10.823-10.977(m,J=27.5Hz,J=49.5Hz,2H),6.929-7.523(m,13H),5.766(m,1H),5.6145(m,1H),5.081-5.310(m,2H),4.495-5.080(m,4H),3.411-3.573(m,2H),2.946-3.176(m,2H),1.456(s,H). 13CNMR(DMSO-d6):δ/ppm=172.56,170.89,155.57,155.02,136.92,130.92,129.65,128.67,127.63,126.91,121.74,119.24,118.90,117.95,111.40,80.58,66.75,65.41,55.25,52.17,41.71,28.48,24.58,22.03.
实施例5 Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉羧酸(6)
在250ml圆底烧瓶中用150ml无水乙醇将0.4g(0.66mmol)Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-咔啉羧酸苄酯溶解,加入0.150g Pd/C,通入H2搅拌反应,TLC检测原料点消失后终止反应。反应化合物过滤滤液减压浓缩,得0.330g(97%)标题化合物,为无色固体;Mp245-248℃;[α]D 25=19.9(C=1.0,甲醇);ESI-MS(m/z):513[M-H]-.
实施例6 2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Ile-OBzl(7a)
冰浴下用无水THF将0.50g(0.973mmol)Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-咔啉羧酸溶解。往得到的溶液中加入0.135g(1.0mmol)N-羟基苯并三氮唑(HOBt),完全溶解后加入0.275g(1.33mmol)二环己基羰二亚胺(DCC)。10分钟后,加入0.497g(1.26mmol)Ile-OBzl的无水THF溶液并加N-甲基吗啉调pH值8。反应化合物室稳搅拌,TLC板检测(石油醚/丙酮,3∶1,Rf=0.3)原料点消失后滤出二环己基脲(DCU),滤液减压浓缩。残留物用40ml乙酸乙酯溶解后依次用饱和NaHCO3水溶液、饱和NaCl水溶液,5%KHSO4水溶液,饱和NaCl水溶液洗三次至。乙酸乙酯层用无水硫酸钠干燥。过滤,滤液减压浓缩,得到0.408g(59%)标题化合物,为无色固体。Mp133.7-135℃;[α]D 25=-23.0(C=1.0,甲醇);ESI-MS(m/z)718[M+H]+.IR(KBr)3365,2966,2928,1737,1676,1517,1452,1353,1160,1003,743,696.1HNMR(300MHz,DMSO-d6)δ/ppm=10.817-10.908(m,2H),8.294(m,1H),7.181-7.434(m,9H),7.896-7.803(m,4H),5.681(m,1H),5.415(m,1H),4.982-5.213(m,2H),4.510-4.980(m,4H),4.249(m,1H),2.931-3.184(m,5H),1.474(s,9H),1.189-1.310(m,2H),0.814-0.866(m,3H),0.634-0.669(m,3H). 13CNMR(DMSO-d6):δ/ppm=172.51,171.44,170.68,155.87,155.38,136.79,130.71,128.77,128.52,128.42,126.92,121.32,121.21,118.86,117.94,111.38,80.46,68.98,66.35,66.15,53.71,36.86,36.58,33.82,28.46,25.81,24.48,23.95,15.82.
实施例7 2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Gly-OBzl(7b)按照制备7a的操作,从0.785g(1.53mmol)2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉羧酸得0.400g(39.56%)标题化合物(无色固体)。TLC(石油醚/丙酮,3∶1,Rf=0.4);Mp145-148℃;[α]D 25=12.6(C=1.0,甲醇);ESI-MS(m/z):663[M+H]+.IR(KBr):3403,3328,2933,2844,1750,1674,1625,1525,1456,1372,1234,1196,1007,743,699.1HNMR(300MHz,DMSO-d6):δ/ppm=10.835-10.905(m,2H),8.565(m,1H),7.185-7.427(m,9H),6.930-7.094(m,4H),5.184-5.694(m,2H),4.610-5.180(m,5H),4.450(m,1H),3.650-4.110(m,2H),2.810-3.510(m,4H),1.466(s,9H).13CNMR(DMSO-d6):δ/ppm=171.95,170.97,169.84,157.20,155.22,136.84,131.13,129.37,128.82,127.05,126.98,121.40,118.98,118.03,111.59,105.49,80.63,66.30,56.32, 51.24,41.36,38.87,33.96,28.35,22.99,20.08.
实施例8 2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Val-OBzl(7c)
按照制备7a的操作,从0.330g(0.642mmol)2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉羧酸得0.253g(56.1%)标题化合物(无色固体)。TLC(石油醚/丙酮,3∶1,Rf=0.2);Mp125-127℃;[α]D 25=-18.0(C=1.0,甲醇);ESI-MS(m/z)704[M+H]+;IR(KBr):3349,2962,2843,1741,1678,1510,1454,1393,1368,1160,1003,741,696.1HNMR(300MHz,DMSO-d6)δ/ppm=10.814-10.879(m,2H),8.222(m,1H),7.180-7.435(m,9H),6.935-7.085(m,4H),5.655(m,1H),5.364(m,1H),4.310-5.290(m,6H),4.150(m,1H),2.810-3.495(m,5H),1.472(s,9H),0.827-0.915(m,6H).13CNMR(DMSO-d6)δ/ppm=172.64,172.07,170.93,156.05,155.25,136.82,130.59,129.26,128.79,127.19,126.97,121.21,118.87,117.96,111.57,105.25,80.61,66.58,54.60,52.49,52.26,41.73,35.51,28.44,23.71,22.99,14.40.
实施例9 2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Ala-OBzl(7d)按照制备7a的操作,从0.366g(0.712mmol)2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉羧酸得0.265g(42.65%)标题化合物(无色固体)。TLC(石油醚/丙酮,3∶1,Rf=0.3);Mp146-148℃;[α]D 25=-29.4(C=1.0,甲醇);ESI-MS(m/z):678[M+H]+.IR(KBr)3396,3328,2988,2842,1742,1674,1520,1457,1367,1165,740,697.1HNMR(300MHz,DMSO-d6):δ/ppm=10.810-10.884(m,J=13Hz,2H),8.4245(m,1H),7.180-7.430(m,9H),6.890-7.090(m,4H),5.635(m,1H),5345(m,1H),5.077(m,1H),4.810-4.990(m,3H),4.450-4.790(m,3H),4.258(m,1H),3.120-3.450(m,3H),2.890-3.097(m,1H),1.472(s,9H),1.291-1.368(m,3H).13CNMR(DMSO-d6)δ/ppm=172.55,171.96,170.96,170.16,155.32,136.77,131.56,128.74,128.40,128.09,126.91,121.23,118.88,117.98,111.40,105.02,80.54,66.19,54.24,50.67,48.46,48.04,41.49,28.47,24.94,24.01,17.40.
实施例10 2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Phe-OBzl(7e)按照制备7a的操作,从1.0g(1.95mmol)2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉羧酸得0.280g(19.3%)标题化合物(无色固体)。TLC(石油醚/丙酮,3∶1,Rf=0.3);Mp133-135℃;[α]D 25=-23.0(C=1.0,甲醇);ESI-MS(m/z):752[M+H]+;IR(KBr):3395,2958,2856,1741,1670,1496,1452,1167,1001,743,701.1HNMR(300MHz,DMSO-d6):δ/ppm=10.759-10.901(m,2H),8.350(m,1H),7.1815-7.423(m,14H),6.895-7.110(m,4H),5.633(m,1H),5.350(m,1H),4.680-5.190(m,5H),4.210-4.650(m,2H),2.850-3.490(m,6H),1.408(m,9H).13CNMR(DMSO-d6):δ/ppm=171.45,171.29,170.85,155.27,137.59,136.51,136.09,131.01,129.97,129.46,128.72,128.28,126.89,121.21,118.87,117.97,111.39,104.30,80.53,66.32,54.42,51.01,37.03,36.58, 28.49,23.58,22.99.
实施例11 2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Asp(OBzl)-OBzl(7f)
按照制备7a的操作,从0.929g(1.81mmol)2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉羧酸得0.622g(42.5%)标题化合物(无色固体)。TLC(石油醚/丙酮,3∶1,Rf=0.3);Mp114-117℃;[α]D 25=-10.9(C=1.0,甲醇);ESI-MS(m/z):810[M+H]+.IR(KBr):3367,2934,2869,1742,1681,1458,1380,1164,1020,748,702.1HNMR(300MHz,DMSO-d6):δ/ppm=10.837-10.883(m,J=4Hz,2H),8.541(m,J=8Hz,1H),7.185-7.429(m,14H),6.895-7.15(m,4H),5.635(m,1H),5.335(m,1H),4.645-5.215(m,8H),4.415(m,J=6Hz,1H),2.515-3.450(m,6H),1.417(s,9H). 13CNMR(DMSO-d6):δ/ppm=172.21,171.62,170.68,165.24,155.90,155.28,136.83,130.05,129.31,128.82,128.16,126.94,121.35,118.88,117.95,111.58,105.24,80.64,69.12,66.85,66.38,56.33,51.07,48.81,41.44,36.31,28.96,23.32,22.37.
实施例12 2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Glu(OBzl)-OBzl(7g)
按照制备7a的操作,从0.616g(1.2mmol)2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉羧酸得0.468g(47.4%)标题化合物(无色固体)。TLC(石油醚/丙酮,3∶1,Rf=0.25);Mp114-116℃;[α]D 25=-15.2(C=1.0,甲醇);ESI-MS(m/z):824[M+H]+;IR(KBr):3343,2978,2929,1737,1668,1500,1453,1365,1163,1005,740,699.1HNMR(300MHz,DMSO-d6):δ/ppm=10.811-10.875(m,2H),8.388(m,J=7.5Hz,1H),7.180-7.433(m,14H),6.890-7.110(m,4H),5.67(m,1H),5.25(m,1H),4.950-5.751(m,4H),4.66-4.910(m,3H),4.110-4.625(m,2H),2.896-3.510(m,4H),2.095-2.450(m,2H),1.810-2.090(m,2H),1.418(s,9H).13CNMR(DMSO-d6):δ/ppm=177.43,173.21,172.96,171.57,155.95,155.28,136.78,136.24,128.94,128.76,128.42,126.92,121.21,118.87,117.95,111.55,105.16,80.56,66.62,65.93,55.27,50.93,41.86,30.31,28.43,26.59,24.98,23.83,22.24.
实施例13 2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Leu-OBzl(7h)
按照制备7a的操作,从0.678g(1.32mmol)2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉羧酸得0.567g(60%)标题化合物(无色固体)。TLC(石油醚/丙酮,3∶1,Rf=0.3);Mp138.6-140.1℃;[α]D 25=-26.1(C=1.0,甲醇);ESI-MS(m/z):718[M+H]+;IR(KBr):3401,2963,2856,1740,1667,1500,1458,1373,1164,1007,743,699.1HNMR(300MHz,DMSO-d6):δ/ppm=10.818-10.885(m,2H),8.319(m,1H),7.150-7.440(m,9H),6.926-7.095(m,4H),5.643(m,1H),5.350(m,1H),4.390-5.150(m,6H),4.210(m,1H),2.850-3.490(m,4H),1.510-1.790(m,3H),1.485(s,9H),0.628-0.88(m,6H).13CNMR(DMSO-d6):δ/ppm=173.00,172.42,171.51,156.00,155.33,136.76,130.52,128.77,128.47,128.25,126.91,121.21,118.86,117.97,111.54,105.18,80.54,66.36,65.40, 54.06,50.93,41.91,41.39,28.45,25.36,24.54,23.70,22.21.
实施例14 2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Lys(Z)-OBzl(7i)
按照制备7a的操作,从0.726g(1.41mmol)2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉羧酸得0.90g(73.5%)标题化合物(淡黄色固体)。TLC(石油醚/丙酮,3∶1,Rf=0.3);Mp:116-118℃;[α]D 25=-20.4(C=1.0,甲醇);ESI-MS(m/z):867[M+H]+;IR(KBr):3323,3065,2934,2856,1684,1525,1453,1246,1163,1003,740,694.1HNMR(300MHz,DMSO-d6):δ/ppm=10.82-10.89(m,J=10Hz,2H),8.25-8.45(m,2H),7.186-7.43(m,14H),6.895-7.14(m,4H),5.640(m,1H),5.345(m,1H),4.511-5.185(m,8H),4.286(m,1H),2.895-3.550(m,6H),1.565-2.110(m,4H),1.46(s,9H),1.09-1.11(m,2H).13CNMR(DMSO-d6):δ/ppm=172.84,172.03,171.23,169.90,156.52,155.97,141.64,13.79,130.12,128.98,128.78,128.16,126.92,121.21,118.88,117.94,111.39,105.11,80.54,67.61,66.31,65.58,57.81,54.06,53.51,52.98,50.77,32.17,31.06,30.76,28.48,25.43,23.77,21.95.
实施例15 2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Tyr-OBzl(7j)
按照制备7a的操作,从0.725g(1.41mmol)2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉羧酸得0.850g(78.5%)标题化合物(淡黄色固体)。TLC(氯仿/甲醇,10∶1,Rf=0.4);Mp157-159℃;[α]D 25=-17.2(C=1.0,甲醇);ESI-MS(m/z):768[M+H]+;IR(KBr):3343,2939,2851,1735,1669,1518,1450,1367,1236,1166,1005,743,696.1HNMR(300MHz,DMSO-d6):δ/ppm=10.801-10.91(m,2H),9.335(s,1H),8.55(m,1H),7.185-7.42(m,9H),6.450-7.095(m,8H),5.636(m,1H),5.385(m,1H),4.661-5.155(m,6H),4.465(m,1H),3.550-3.986(m,2H),2.895-3.455(m,4H),1.46(s,9H).13CNMR(DMSO-d6):δ/ppm=171.56,171.44,170.93,156.50,155.29,136.78,136.53,131.18,130.43,130.02,129.62,129.35,128.69,128.39,127.33,122.33,121.22,120.66,118.89,117.95,111.58,104.33,80.53,66.34,66.20,54.94,50.71,42.02,38.86,36.42,28.54,23.65,22.55.
实施例16 2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Met-OBzl(7k)
按照制备7a的操作,从0.520g(1.012mmol)2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉羧酸得0.210g(28.3%)标题化合物(无色固体)。TLC(氯仿/甲醇,10∶1,Rf=0.6);Mp:131-133.2℃;[α]D 25=16.5(C=1.0,甲醇);ESI-MS(m/z):736[M+H]+;IR(KBr):3406,3328,2978,2924,2846,1740,1666,1521,1452,1367,1239,1161,1112,1003,743,694.1HNMR(300MHz,DMSO-d6):δ/ppm=10.799-10.883(m,J=24.5Hz,2H),8.23(m,J=8Hz,1H),7.157-7.468(m,9H),6.896-7.084(m,4H),5.231-5.830(m,J=6.5Hz,1H),4.910-5.131(m,J=12Hz,J=12.5Hz,3H),4.635-4.9(m,2H), 4.272-4.625(m,2H),2.896-3.610(m,4H),1.984-2.490(m,4H),1.610-1.944(m,3H),1.419(s,9H). 13CNMR(DMSO-d6):δ/ppm=172.69,171.87,170.82,156.44,155.94,136.81,130.14,129.36,128.85,128.48,126.93,121.36,118.88,117.97,111.58,105.32,80.86,66.49,56.33,55.01,54.10,51.68,41.89,30.97,29.96,28.50,23.84,22.94,14.94。
实施例17 2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Ser(Bzl)-OBzl(71)
按照制备7a的操作,从0.771g(1.50mmol)2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉羧酸0.608g(52%)标题化合物(无色固体)。石油醚/丙酮,3∶1,Rf=0.3);Mp:120-122℃;[α]D 25=-15.4(C=1.0,甲醇);ESI-MS(m/z):782[M+H]+;IR(KBr):3411,3323,2988,2934,2856,1749,1674,1511,1455,1367,1234,1157,1005,742,697.1HNMR(300MHz,DMSO-d6):δ/ppm=10.820-10.909(m,J=16Hz,2H),8.515(m,J=8Hz,1H),7.154-7.428(m,14H),6.979-7.088(m,4H),5.679(m,J=6.5Hz,1H),5.3745(m,J=4.5Hz,1H),4.256-5.091(m,9H),3.510-3.896(m,J=4.5Hz,2H),2.955-3.450(m,J=6.5Hz,J=15.5Hz,4H),14.457(s,9H).13CNMR(DMSO-d6):δ/ppm=173.02,172.38,171.16,170.74,155.75,138.22,136.79,130.78,129.17,128.72,128.64,128.17,128.09,127.96,126.93,121.35,118.90,117.94,111.59,105.01,80.46,72.84,69.79,69.47,66.56,66.42,53.74,41.92,41.49,28.49,24.56,22.31.
实施例18 2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Trp-OBzl(7m)
按照制备7a的操作,从0.60g(1.167mmol)2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉羧酸得0.560g(60.74%)标题化合物(无色固体)。石油醚/丙酮,3∶1,Rf=0.3);Mp:155-156℃;[α]D 25=-17.8(C=1.0,甲醇);ESI-MS(m/z):791[M+H]+.IR(KBr)3406,3323,2973,2856,2355,1742,1671,1508,1457,1363,1239,1161,1005,745,697.1HNMR(300MHz,DMSO-d6):δ/ppm=10.775-10.903(m,J=24.5Hz,3H),8.565(m,1H),7.188-7.522(m,9H),6.899-7.093(m,9H),5.635(m,1H),5.355(m,1H),4.511-5.198(m,6H),4.315(m,1H),2.896-3.450(m,6H),1.413(s,9H). 13CNMR(DMSO-d6):δ/ppm=171.86,171.06,170.01,155.27,136.53,136.07,130.40,128.66,128.27,128.06,127.51,126.90,124.17,121.50,118.91,118.42,111.59,105.20,80.53,66.32,60.21,56.33,54.16,50.93,42.01,38.86,28.57,23.73,22.44.
实施例19 2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Pro-OBzl(7n)
按照制备7a的操作,从0.833g(1.623mmol)2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉羧酸得0.230g(20.25%)标题化合物(无色固体)。石油醚/丙酮,3∶1,Rf=0.3);Mp:150-152℃;[α]D 25=-2.7(C=1.0,甲醇);ESI-MS(m/z):702[M+H]+;IR(KBr):3391,3328,2939,2846,1743,1645,1577,1453,1236,1166,1090,1005,740,697.1HNMR(300MHz,DMSO-d6): δ/ppm=10.725-10.919(m,J=27.5Hz,2H),7.4825(m,J=8Hz,3H),7.408(m,J=7.5Hz,1H),7.193-7.375(m,7H),6.982-7.095(m,4H),5.639(m,1H),5.325(m,1H),5.115(t,J=17Hz,1H),4.866-4.897(m,2H),4.738-4.813(m,2H),4.665(m,1H),4.184(dd,J=7Hz,1H),2.960-3.350(m,4H),2.740-2.890(m,2H),1.450-2.186(m,4H),1.445(s,9H).13CNMR(DMSO-d6):δ/ppm=172.11,171.89,168.97,157.13,155.61,136.66,131.51,129.69,128.78,128.06,126.99,121.27,118.92,117.81,111.58,105.90,80.41,66.06,59.34,52.04,50.90,49.83,48.01,46.65,41.96,33.82,28.52,24.93,23.00,21.65.
实施例20 2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Thr(Bzl)-OBzl(7o)
按照制备7a的操作,从1.004g(1.953mmol)2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉羧酸得0.785g(50.55%)标题化合物(无色固体)。TLC(石油醚/丙酮,3∶1,Rf=0.3);Mp123-125℃;[α]D 25=-19.1(C=1.0,甲醇);ESI-MS(m/z):796[M+H]+;IR(KBr):3348,2978,2856,1744,1681,1506,1455,1367,1236,1156,1093,1003,743,697.1HNMR(300MHz,DMSO-d6):δ/ppm=10.821-10.912(m,2H),8.3(m,J=9Hz,1H),7.187-7.410(m,14H),6.896-7.172(m,4H),5.678(m,1H),5.466(m,1H),4.495-5.210(m,7H),3.965-4.496(m,3H),2.895-3.410(m,4H),1.465(s,9H),0.829-1.283(m,3H).13CNMR(DMSO-d6):δ/ppm=173.22,172.59,171.98,170.46,155.59,138.57,136.52,131.06,130.06,128.73,128.59,128.45,128.05,126.93,121.21,118.87,117.86,111.38,105.07,80.50,74.45,70.68,66.52,56.79,53.15,50.51,42.00,41.54,28.48,25.16,22.27,16.13.
实施例21 2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Arg(NO2)-OBzl(7p)
按照制备7a的操作,从0.860g(1.673mmol)2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉羧酸得0.80g(67.85%)标题化合物(淡黄色固体)。TLC(氯仿/甲醇,10∶1,Rf=0.4);Mp 170-172℃;[α]D 25=-22.1(C=1.0,甲醇);ESI-MS(m/z):806[M+H]+;IR(KBr):3314,2934,2848,1737,1664,1537,1457,1261,1156,998,740,694.1HNMR(300MHz,DMSO-d6):δ/ppm=10.84-10.89(m,2H),8.561(m,1H),7.100-7.44(m,9H),6.895-7.095(m,4H),5.634(m,1H),5.375(m,1H),4.689-5.198(m,6H),4.485(m,1H),2.896-3.510(m,6H),1.510-1.896(m,4H),1.465(s,9H).13CNMR(DMSO-d6):δ/ppm=171.85,171.27,159.80,155.53,136.78,136.50,130.13,129.43,128.77,126.91,122.30,121.23,118.89,117.94,112.93,105.05,80.56,67.40,66.40,5475,52.48,50.74,31.78,31.14,29.45,28.47,25.34,23.83,22.24.
实施例22 2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Gln-OBzl(7q)
按照制备7a的操作,从0.843g(1.64mmol)2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉羧酸得0.720g(60%)标题化合物(无色固体)。TLC(氯仿/甲醇,10∶1,Rf=0.5);Mp157.9-159℃; [α]D 25=-12.1(C=1.0,甲醇);ESI-MS(m/z):733[M+H]+.IR(KBr)3372,2973,2856,1737,1674,1510,1453,1394,1368,1163,1010,738,693.1HNMR(300MHz,DMSO-d6):δ/ppm=10.827-10.905(m,2H),8.435(m,J=7.5Hz,1H),7.185-7.463(m,9H),6.896-7.096(m,4H),5.650(m,J=7Hz,1H),5.310(m,1H),4.610-5.115(m,5H),4.415(m,1H),4.235(m,1H),3.110-3.510(m,3H),2.995(m,1H),1.996-2.210(m,2H),1.780-1.950(m,2H),1.471(s,9H). 13CNMR(DMSO-d6):δ/ppm=173.90,172.77,171.88,171.17,170.61,155.95,136.75,130.65,128.95,128.85,128.34,128.12,126.90,121.26,118.90,117.96,111.57,105.17,80.70,66.43,53.94,52.53,52.22,50.67,41.75,31.63,28.55,27.23,26.59,23.88.
实施例23 2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Asn-OBzl(7r)
按照制备7a的操作,从1.013g(1.971mmol)2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉羧酸得0.572g(40.42%)标题化合物(无色固体)。TLC(石油醚/丙酮,1∶1,Rf=0.3);Mp162-164℃;[α]D 25=-2.5(C=1.0,甲醇);ESI-MS(m/z):719[M+H]+;IR(KBr):3353,2983,2919,2856,1739,1679,1508,1450,1402,1370,1161,1005,743,696.1HNMR(300MHz,DMSO-d6):δ/ppm=10.817-10.897(m,J=14Hz,2H),8.3205(m,1H),7.183-7.497(m,9H),6.890-7.095(m,4H),5.650(m,1H),5.436(m,1H),4.410-5.225(m,7H),2.896-3.495(m,6H),1.472(s,9H).13CNMR(DMSO-d6):δ/ppm=206.95,172.34,171.60,171.28,170.47,155.33,136.75,131.15,129.94,128.70,127.96,126.92,121.21,118.87,117.94,111.37,105.32,80.55,66.27,56.51,53.75,49.37,41.54,39.15,36.75,28.33,23.70,23.01.
实施例24 2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-His-OBzl(7s)
按照制备7a的操作,从0.850g(1.654mmol)2-Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉羧酸得0.20g(16.32%)标题化合物(无色固体)。TLC(氯仿/甲醇,10∶1,Rf=0.3);Mp180-182℃;[α]D 25=-8.0(C=1.0,甲醇);ESI-MS(m/z):742[M+H]+.IR(KBr):3349,2983,2942,2857,1744,1664,1456,1370,1164,1003,745,699.1HNMR(300MHz,DMSO-d6):δ/ppm=10.844-10.824(m,J=5Hz,2H),8.578(m,J=7Hz,1H),7.963(s,1H),7.186-7.425(m,9H),6.895-7.115(m,5H),5.656(m,J=1.5Hz,1H),5.345(m,J=16.5Hz,1H),4.685-5.126(m,5H),4.315-4.525(m,2H),2.895-3.489(m,6H),1.476(s,9H).13CNMR(DMSO-d6):δ/ppm=172.24,171.06,170.60,163.42,155.26,136.77,135.01,132.52,131.16,129.91,128.73,128.32,126.91,125.99,121.21,118.87,117.95,116.88,114.41,105.37,80.59,66.33,65.36,54.53,52.91,51.24,41.43,32.78,28.47,23.68,22.86.
实施例25 1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Ile-OBzl(8a)
将50mg(0.07mmol)Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Ile-OBzl溶于 2ml乙酸乙酯中,再往得到的溶液中加1ml的氯化氢-乙酸乙酯溶液。TLC(石油醚/丙酮,3∶1,Rf=0.3)检测原料点消失,停止反应。反应混合物减压浓缩至干,残留物用10ml乙醚处理后再减压浓缩至干。操作重复3次。最后往残留物中加入10ml乙醚研磨,滤得40mg(88%)标题化合物,为黄色固体。Mp166-168℃;[α]D 25=-129.0(C=1.0,甲醇);ESI-MS(m/z):618[M+H]+.1HNMR(300MHz,DMSO-d6)δ/ppm=11.37(m,1H),10.35(m,1H),9.85(m,1H),8.65(m,1H),7.18-7.56(m,9H),6.98-7.15(m,4H),5.05-5.45(m,J=7.05HZ,3H),4.75-4.95(m,J=12.3HZ,J=10.5HZ,2H),4.35-4.65(m,3H),4.21(m,J=6.45HZ,1H),3.28-3.48(m,J=4.15HZ,J=4.75HZ,3H),2.89-3.15(m,2H),1.31-1.55(m,2H),0.79-0.89(m,6H).13CNMR(DMSO-d6)172.34,171.27,169.68,136.82,136.20,129.53,128.93,128.77,127.17,126.24,122.19,119.60,118.27,111.96,105.14,67.50,66.32,57.06,53.93,50.88,42.30,36.87,25.84,24.98,21.52,15.89,11.57。
实施例26 1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Gly-OBzl(8b)
按照制备8a的操作,从0.12g(1(0.182mmol)Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Gly-OBzl得0.100g(98%)标题化合物(无色固体)。Mp180-183℃;[α]D 25=-74.4(C=1.0,甲醇);ESI-MS(m/z):562[M+H]+.1HNMR(300MHz,DMSO-d6)δ/ppm=11.29(m,1H),10.25(m,1H),9.85(m,1H),8.75(m,1H),7.25-7.56(m,9H),6.89-7.18(m,4H),5.35(m,J=5.9HZ,2H),5.10-5.25(m,2H),4.98-5.04(m,2H),4.35-4.55(m,2H),3.75-4.05(m,J=5.6HZ,3H),3.31-3.50(m,J=14.7HZ,J=4.3HZ,2H),2.89-3.18(m,J=6.3HZ,2H).13CNMR(DMSO-d6)172.35,170.02,169.63,136.81,136.22,129.84,128.94,128.36,127.09,126.30,122.18,119.63,118.03,111.85,105.21,67.29,66.39,55.10,48.00,33.80,23.26,21.51。
实施例27 1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Val-OBzl(8c)
按照制备8a的操作,从0.30g(0.43mmol)Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Val-OBzl得0.265g(97.1%)标题化合物(无色固体)。Mp68-170℃;[α]D 25=-98.9(C=1.0,甲醇);ESI-MS(m/z):604[M+H]+.1HNMR(300MHZ,DMSO-d6):δ/ppm=11.37(m,1H),10.25(m,1H),9.89(m,1H),8.56(m,1H),7.18-7.59(m,9H),6.98-7.15(m,4H),5.10-5.35(m,J=10HZ,3H),4.75-4.96(m,J=10HZ,3H),4.35-4.65(m,J=15HZ,3H),3.35-3.51(m,3H),2.89-3.15(m,J=15HZ,2H),0.81-0.89(m,6H).13CNMR(DMSO-d6)172.35,171.46,169.69,136.81,136.22,129.55,128.95,128.79,128.48,127.17,122.19,121.47,119.59,111.95,104.94,67.52,66.35,58.47,57.78,50.86,33.80,30.08,24.32,21.53,17.98。
实施例28 1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Ala-OBzl(8d)
按照制备8a的操作,从0.09g(0.13mmol)Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3- 甲酰基-Ala-OBzl得0.072g(96.32%)标题化合物(无色固体)。Mp176-178℃;[α]D 25=-77.6(C=1.0,甲醇);ESI-MS(m/z):576[M+H]+.HNMR(300MHZ,DMSO-d6)δ/ppm=11.34(m,1H),10.35(m,1H),9.88(m,1H),8.68(m,1H),7.15-7.56(m,9H),6.98-7.10(m,4H),5.25-5.49(m,J=7.5HZ,2H),5.05-5.20(m,2H),4.81-4.92(m,2H),4.25-4.52(m,J=8.5HZ,3H),3.25-3.49(m,J=3.5HZ,2H),2.89-3.10(m,J=15.5HZ,J=7.5HZ,2H),1.46-1.48(m,3H);13CNMR(DMSO-d6)172.41,170.71,169.60,136.78,136.31,130.05,128.97,128.50,128.07,126.22,122.19,121.37,119.60,111.96,105.18,67.43,66.26,54.52,48.59,33.81,24.91,21.55,17.43。
实施例29 1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Phe-OBzl(8e)
按照制备8a的操作,从0.180g(0.24mmol)Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Phe-OBzl得0.152g(92.3%)标题化合物(无色固体)。Mp54-156℃;[α]D 25=-88.3(C=1.0,甲醇);ESI-MS(m/z):652[M+H]+.HNMR(300MHZ,DMSO-d6):δ/ppm=11.35(m,1H),10.89(m,1H),9.98(m,1H),8.85(m,1H),7.15-7.57(m,14H),6.98-7.12(m,4H),5.12-5.45(m,2H),4.90-5.10(m,3H),4.75(m,1H),4.25-4.65(m,3H),3.30-3.51(m,2H),2.89-3.29(m,4H).13CNMR(DMSO-d6)172.36,170.55,169.30,137.77,136.84,136.18,129.89,129.67,129.44,129.04,128.81,128.67,128.32,128.11,127.68,122.22,119.41,118.01,111.55,105.05。
实施例30 1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Asp(OBzl)-OBzl(8f)
按照制备8a的操作,从0.238g(0.294mmol)Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Asp(OBzl)-OBzl得0.210g(96.1%)标题化合物(无色固体)。Mp140-142℃;[α]D 25=-103.7(C=1.0,甲醇);ESI-MS(m/z):710[M+H]+.HNMR(300MHZ,DMSO-d6):δ/ppm=11.33(m,1H),10.25(m,1H),9.89(m,1H),8.85(m,1H),7.22-7.56(m,14H),6.96-7.20(m,4H),5.35(m,1H),5.20(m,1H),5.15(m,1H),4.65-5.05(m,5H),4.35-4.49(m,3H),3.35-3.50(m,2H),2.80-3.25(m,4H).13CNMR(DMSO-d6)172.36,170.52,170.29,169.46,136.83,136.06,128.90,128.79,128.52,128.38,126.92,122.21,119.43,117.96,111.57,105.25,67.82,66.88,54.79,49.44,41.09,40.88,39.36,36.16,23.49,21.52。
实施例31 1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Glu(OBzl)-OBzl(8g)按照制备8a的操作,从0.35g(0.425mmol)Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Glu(OBzl)-OBzl得0.319g(98.7%)标题化合物(无色固体)。Mp135-137℃;[α]D 25=-96.4(C=1.0,甲醇);ESI-MS(m/z):724[M+H]+.HNMR(300MHZ,DMSO-d6)δ/ppm=11.27(m,1H),10.25(m,1H),9.89(m,1H),8.69(m,1H),7.19-7.56(m,14H),6.98-7.18(m,4H),5.30(m,J=6.5HZ,1H),5.21(m,J=3.5HZ,1H),4.95-5.15(m,4H),4.85-4.95(m,2H),4.21-4.55(m, 3H),3.15-3.45(m,J=6.5HZ,2H),2.89-3.12(m,J=12HZ,2H),2.35-2.49(m,2H),1.95-2.18(m,2H). 13CNMR(DMSO-d6)173.21,172.59,171.38,169.80,136.77,136.23,129.94,129.45,128.78,128.31,128.17,127.08,122.22,121.39,119.03,111.87,105.21,67.66,66.44,65.97,52.28,50.98,30.49,26.46,24.10,21.53。
实施例32 1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Leu-OBzl(8h)
按照制备8a的操作,从0.264g(0.368mmol)Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Leu-OBzl得0.225g(93.5%)标题化合物(无色固体)。Mp156-158℃;[α]D 25=-57.3(C=1.0,甲醇);ESI-MS(m/z):618[M+H]+.HNMR(300MHZ,DMSO-d6)δ/ppm=11.36(m,1H),10.30(m,1H),9.85(m,1H),8.65(m,1H),7.21-7.57(m,9H),6.98-7.20(m,J=5HZ,J=10HZ,4H),5.35(m,J=10HZ,1H),5.05-5.28(m,2H),4.78-4.95(m,3H),4.25-4.55(m,3H),3.30-3.49(m,2H),2.89-3.25(m,2H),1.55-1.79(m,2H),1.50(m,1H),0.77-0.95(m,6H).13CNMR(DMSO-d6)172.42,172.39,169.63,136.78,136.30,129.49,128.97,128.69,128.13,127.16,122.19,119.60,117.92,111.97,104.97,67.52,66.29,54.60,50.98,42.22,40.88,33.79,24.90,23.19,22.44,21.56。
实施例33 1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Lys(Z)-OBzl(8i)
按照制备8a的操作,从0.363g(0.419mmol)Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Lys(Z)-OBzl得0.330g(98.09%)标题化合物(无色固体)。Mp134-136℃;[α]D 25=-54.0(C=1.0,甲醇);ESI-MS(m/z):767[M+H]+.HNMR(300MHZ,DMSO-d6)δ/ppm=11.28(m,1H),10.95(m,1H),10.20(m,1H),9.85(m,1H),8.57(m,1H),7.21-7.56(m,14H),6.98-7.20(m,4H),5.15-5.35(m,J=10.5HZ,2H),4.95-5.10(m,J=6.5HZ,4H),4.75-4.90(m,J=14HZ,2H),4.05-4.55(m,J=9.5HZ,J=12HZ,3H),3.15-3.51(m,3H),2.89-3.12(m,J=10.5HZ,J=15.5HZ,3H),1.65-1.78(m,2H),1.21-1.49(m,4H).13CNMR(DMSO-d6)172.35,171.84,169.82,156.55,136.81,136.29,130.01,129.49,128.77,128.16,127.09,122.22,119.61,118.04,111.62,105.33,67.53,66.26,65.58,54.60,53.03,52.35,50.93,42.23,30.88,29.42,23.05,21.51。
实施例34 1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Tyr-OBzl(8j)
按照制备8a的操作,从0.350g(0.456mmol)Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Tyr-OBzl得0.315g(97.9%)标题化合物(无色固体)。Mp175-178℃;[α]D 25=-77.6(C=1.0,甲醇);ESI-MS(m/z):668[M+H]+.HNMR(300MHZ,DMSO-d6)δ/ppm=11.25(m,1H),10.90(m,1H),10.25(m,1H),9.95(m,1H),8.65(m,1H),7.21-7.56(m,9H),6.89-7.20(m,6H),6.58-6.75(m,J=5HZ,2H),5.12-5.35(m,2H),5.05(m,J=15HZ,1H),4.65-4.98(m,3H),4.25-4.48(m,3H),3.25-3.45(m,2H),2.89-3.20(m,4H).13CNMR(DMSO-d6)172.43,170.63,169.49,156.54,136.79, 136.14,130.88,130.45,129.38,128.78,128.24,128.18,127.60,122.27,121.54,119.07,115.64,111.66,105.23,67.51,66.42,55.12,54.78,42.01,36.05,35.68,23.60,21.51。
实施例35 1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Met-OBzl(8k)
按照制备8a的操作,从0.15g(0.204mmol)Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Met-OBzl得0.134g(97.78%)标题化合物(无色固体)。Mp165-168℃;[α]D 25=-82.5(C=1.0,甲醇);ESI-MS(m/z):635[M+H]+.1H NMR(300MHZ,DMSO-d6):δ/ppm=11.27(m,1H),10.30(m,1H),9.85(m,1H),8.65(m,1H),7.21-7.56(m,9H),6.88-7.20(m,4H),4.95-5.45(m,6H),4.35-4.52(m,3H),3.25-3.45(m,2H),2.89-3.15(m,2H),2.35-2.45(m,2H),2.05-2.15(m,2H),1.85-1.95(m,3H). 13CNMR(DMSO-d6)172.35,170.72,169.54,136.81,136.27,129.92,129.57,128.87,128.20,127.10,126.23,122.22,121.39,118.63,111.63,105.24,66.52,56.49,54.57,52.07,42.28,31.05,30.13,28.82,23.51,21.51,14.89。
实施例36 1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Ser(Bzl)-OBzl(8l)
按照制备8a的操作,从0.322g(0.412mmol)Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Ser(Bzl)-OBzl得0.286g(96.68%)标题化合物(无色固体)。Mp148-150℃;[α]D 25=-78.8(C=1.0,甲醇);ESI-MS(m/z):682[M+H]+ HNMR(300MHZ,DMSO-d6)δ/ppm=11.304(m,1H),10.20(m,1H),9.85(m,1H),8.78(m,1H),7.15-7.56(m,14H),6.98-7.12(m,4H),5.01-5.35(m,J=11HZ,J=9.5HZ,2H),4.75-5.00(m,J=11.5HZ,2H),4.25-4.65(m,6H),3.15-3.58(m,4H),2.89-3.10(m,2H).13CNMR(DMSO-d6)172.41,170.15,169.60,137.78,136.77,136.15,129.47,128.90,128.13,127.98,127.13,126.76,126.21,122.22,121.48,119.02,111.62,105.21,72.96,69.61,67.82,66.55,54.54,51.31,42.22,24.71,21.53。
实施例37 1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Trp-OBzl(8m)
按照制备8a的操作,从0.31g(0.392mmol)Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Trp-OBzl得0.262g(92%)标题化合物(无色固体)。Mp184-186℃;[α]D 25=-67.4(C=1.0,甲醇);ESI-MS(m/z):691[M+H]+.HNMR(300MHZ,DMSO-d6)δ/ppm=11.36(m,1H),10.97(m,1H),10.25(m,1H),9.89(m,1H),8.75(m,1H),7.15-7.57(m,13H),6.98-7.13(m,5H),4.98-5.35(m,2H),4.87(m,1H),4.71(m,1H),4.25-4.55(m,4H),4.10(m,1H),3.31-3.49(m,2H),3.15-3.29(m,2H),2.89-3.14(m,2H).13CNMR(DMSO-d6)172.43,171.87,169.78,136.78,136.62,136.14,129.97,129.52,128.74,128.07,127.11,124.26,122.20,121.66,119.59,111.95,109.83,105.07,67.51,66.30,54.60,53.25,48.01,41.01,33.80,24.91,21.55。
实施例38 1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Pro-OBzl(8n) 按照制备8a的操作,从0.2g(0.28mmol)Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Pro-OBzl得0.179g(98.2%)标题化合物(无色固体)。Mp169-171℃。[α]D 25=-62.4(C=1.0,甲醇);ESI-MS(m/z):602[M+H]+.HNMR(300MHZ,DMSO-d6):δ/ppm=11.32(m,1H),10.25(m,1H),9.85(m,1H),7.15-7.57(m,9H),6.98-7.13(m,4H),5.11-5.35(m,2H),4.55-5.09(m,2H),4.25-4.55(m,5H),3.61(m,1H),3.15-3.49(m,4H),3.01(m,1H),1.72(m,1H),1.63(m,1H),1.15-1.25(m,2H). 13CNMR(DMSO-d6)172.41,171.50,169.10,136.73,136.29,130.05,128.96,128.40,128.15,126.88,122.17,119.51,118.36,111.85,104.55,67.73,66.45,59.05,58.95,47.97,45.68,33.79,28.20,24.89,22.41,21.54。
实施例39 1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Thr(Bzl)-OBzl(8o)
按照制备8a的操作,从0.35g(0.440mmol l)Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Thr(Bzl)-OBzl得0.316g(98.12%)标题化合物(无色固体)。Mp154-156℃;[α]D 25=-64.7(C=1.0,甲醇);ESI-MS(m/z):696[M+H]+.HNMR(300MHZ,DMSO-d6)δ/ppm=11.37(m,1H),10.25(m,1H),9.89(m,1H),8.45(m,1H),7.19-7.56(m,14H),6.89-7.15(m,4H),5.05-5.48(m,3H),4.98(m,J=3HZ,2H),4.89(m,1H),4.51-4.75(m,2H),4.25-4.45(m,5H),3.25-3.45(m,J=4HZ,J=2HZ,2H),2.89-3.10(m,J=12HZ,2H),1.14-1.19(m,3H).13CNMR(DMSO-d6)172.42,170.41,169.75,138.48,136.78,136.00,129.42,128.91,128.63,128.59,128.49,128.03,127.87,126.72,122.20,121.49,119.04,111.95,105.18,74.73,72.86,67.67,66.78,57.05,54.58,50.78,41.02,39.86,22.23,21.55,16.51。
实施例40 1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Arg(NO2)-OBzl(8p)
按照制备8a的操作,从0.146g(0.207mmol l)Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Arg(NO2)-OBzl得0.126g(94.84%)标题化合物(无色固体)。Mp174-175℃;[α]D 25=-26.7(C=1.0,甲醇);ESI-MS(m/z):706[M+H]+.HNMR(300MHZ,DMSO-d6)δ/ppm=11.269(m,1H),10.96(m,1H),10.15(m,1H),9.89(m,1H),8.65(m,1H),7.89-8.15(m,2H),7.13-7.56(m,9H),6.98-7.10(m,4H),4.78-5.45(m,9H),4.15-4.55(m,2H),2.89-3.45(m,4H),1.65-1.85(m,2H),1.45-1.55(m,2H).13CNMR(DMSO-d6)172.38,171.70,169.61,159.80,136.80,136.22,130.00,128.78,128.18,127.06,126.23,122.22,121.58,119.04,111.62,105.06,66.36,54.61,52.73,50.99,42.24,28.41,25.50,24.07,23.62,21.51。
实施例41 1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Gln-OBzl(8q)
按照制备8a的操作,从0.35g(0.478mmol)Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Gln-OBzl得0.318g(99.5%)标题化合物(无色固体)。Mp179-181℃;[α]D 25=-80.3(C=1.0, 甲醇);ESI-MS(m/z):633[M+H]+.HNMR(300MHZ,DMSO-d6)δ/ppm=11.30(m,1H),10.95(m,1H),10.56(m,1H),10.25(m,1H),9.85(m,1H),8.75(m,1H),7.21-7.56(m,9H),6.98-7.20(m,4H),5.05-5.35(m,4H),4.75-4.95(m,2H),4.15-4.55(m,3H),3.15-3.52(m,2H),2.89-3.12(m,2H),2.15-2.25(m,4H).13CNMR(DMSO-d6)174.13,172.44,171.70,169.62,136.76,136.27,130.06,129.47,128.53,128.17,127.10,122.19,119.51,118.04,111.55,105.06,66.32,56.99,54.55,51.01,32.14,31.89,31.68,28.72,25.11,21.55。
实施例42 1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Asn-OBzl(8r)
按照制备8a的操作,从0.35g(0.487mmol)Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-Asn-OBzl得0.259g(81.79%)标题化合物(无色固体)。Mp194-196℃;[α]D 25=-137.0(C=1.0,甲醇);ESI-MS(m/z):619[M+H]+.HNMR(300MHZ,DMSO-d6)δ/ppm=11.28(m,1H),10.95(m,1H),10.15(m,1H),10.25(m,1H),9.85(m,1H),8.55(m,J=13.5HZ,1H),8.45(m,1H),7.15-7.57(m,9H),6.98-7.14(m,4H),5.05-5.45(m,J=6.5HZ,2H),4.89-5.03(m,J=3HZ,J=12HZ,2H),4.81(m,1H),4.35-4.69(m,J=10HZ,4H),2.89-3.51(m,4H),2.55-2.65(m,2H).13CNMR(DMSO-d6)172.38,171.38,170.10,169.46,136.79,136.32,130.02,129.23,128.75,127.04,126.25,122.20,121.37,119.03,111.87,105.13,66.42,54.62,51.18,49.68,41.97,37.05,36.76,23.24,21.52。
实施例43 1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-His-OBzl(8s)
按照制备8a的操作,从0.15g(0.202mmol)Boc-1,2,3,4-四氢咔啉-3-甲酰基-1,2,3,4-四氢咔啉-3-甲酰基-His-OBzl得0.135g(99%)标题化合物(无色固体)。Mp1183-185℃;[α]D 25=-72.5(C=1.0,甲醇);ESI-MS(m/z):642[M+H]+.HNMR(300MHZ,DMSO-d6):δ/ppm=11.25(m,1H),10.98(m,1H),10.05(m,1H),9.25(m,1H),8.98(m,1H),7.55(dd,J=5HZ,1H),7.20-7.49(m,9H),6.98-7.18(m,4H),5.25-5.45(m,J=5HZ,2H),5.01-5.23(m,2H),4.98(m,J=15HZ,3H),4.89(m,J=15HZ,2H),4.35-4.68(m,3H),3.28-3.48(m,2H),2.89-3.25(m,4H).13CNMR(DMSO-d6)171.40,170.18,169.42,136.82,136.06,135.43,135.22,130.67,129.41,128.82,128.18,126.82,122.19,121.39,120.04,119.53,111.96,105.17,66.74,65.88,54.94,51.27,4.11,38.98,25.97,23.57,22.37。
实验例1本发明化合物的抗肿瘤活性实验
1)实验材料
受试化合物:本发明实施例25-43所制备的化合物8a-8s;
阳性对照品:阿糖胞苷
实验动物:ICR小鼠,雄性,体重20±2g(±s);由北京大学医学部动物实验中心提供。每10只小鼠一组,空白及阳性对照各一组。
瘤源:小鼠S180肉瘤,由北京大学医学部动物实验中心提供,自行传代维持。
溶剂:0.5%CMC-Na溶液。
2)实验方法
a剂量设置
受试化合物8a-8s及阳性对照设为8.9μmol/kg,均采用腹腔单次给药。
b药物配制
受试化合物8a-8s在水中难溶,实验时加入少量的吐温80润湿助溶,逐渐加入0.5%CMC-Na溶液至所需要浓度即可。阳性对照品阿糖胞苷为水溶性,采用0.5%CMC-Na溶解即可。
3)给药剂量及给药方案
受试化合物均以腹腔单次给药。按相应的给药剂量每天一次,0.2ml/鼠,连续给药7天,共给药7次。
阴性对照以等体积的相应溶液,均以腹腔给药。按相应的给药剂量每天一次,0.2ml/鼠,连续给药7天,共给药7次。
阳性对照品阿糖胞苷按8.9μmol/kg的剂量,腹腔给药。每天一次,0.2ml/鼠,连续给药7天,共给药7次。
4)动物模型的建立
采用体内抗肿瘤腋皮下接种模型:在无菌条件下抽取接种7d后取生长旺盛S180腹水瘤瘤液,用生理盐水稀释成(1∶2)的液体充分混合,将肿瘤细胞悬液用新鲜配制的培养基稀释计数按如下公式计算细胞浓度和细胞存活率。
细胞浓度=4大方格内活细胞数/4×104×稀释倍数=细胞数/ml
细胞存活率=活细胞数/(活细胞数+死细胞数)×100%
将存活率大于90%的瘤液用匀浆法制备成1×107个/ml的细胞悬液,于相应宿主腋皮下接种0.2ml/鼠,制成实体瘤动物模型。
5)检测指标及方法
a.体内神经毒性观察
每日观察给药各组动物的反应小鼠的自主活动、精神状态、毛发、呼吸、饮食,粪便性状。
b.实体瘤抑瘤率和体重增长的测定
各组连续给药7d后,于第8d脱颈椎处死小鼠,称取体重(处死体重),然后用镊子固定小鼠右腋肿瘤生长部位,剪开皮肤,暴露肿瘤,钝性剥离,称重,按如下公式计算抑瘤率。
抑瘤率%=[(阴性对照组平均瘤重-给药组平均瘤重)/阴性对照组平均瘤重]×100%
体重增长(g)=处死体重-原始体重-瘤重
c.统计方法
本实验数据统计均采用t检验和方差分析,以(x±SD)表示。
d实验结果
表1本发明化合物(8a-s)对S180荷瘤小鼠的抑瘤率及体重的影响
组别 | 抑瘤率% | 瘤重(g) | 体重增加(g) |
NS | —— | 0.91±0.11 | 3.95±1.67 |
Arc | 37.17±6.00d | 0.61±0.13d | 4.04±0.74 |
8a | 24.27±4.96c | 0.69±0.04c | 4.11±1.06 |
8b | 50.72±6.02c | 0.47±0.26c | 5.02±1.04 |
8c | 63.73±7.01e | 0.32±0.13e | 6.02±1.16 |
8d | 9.44±6.93 | 0.86±0.17 | 4.99±1.02 |
8e | 23.35±12.88b | 0.73±0.18b | 3.28±1.81 |
8f | 72.34±9.30f | 0.25±0.10f | 4.93±0.84 |
8g | 78.77±15.14f | 0.20±0.16f | 4.31±1.93 |
8h | 36.96±3.12c | 0.57±0.07c | 5.43±1.64 |
8i | 72.16±8.61f | 0.25±0.09f | 5.33±1.96 |
8j | 65.17±5.98d | 0.33±0.05d | 5.41±1.84 |
8k | 31.25±6.39b | 0.63±0.12b | 5.17±2.05 |
8l | 39.02±7.90d | 0.55±0.12d | 4.50±1.65 |
8m | 27.40±2.14c | 0.65±0.09c | 3.99±2.28 |
8n | 57.54±5.20e | 0.38±0.07e | 4.48±2.02 |
8o | 37.91±7.70c | 0.56±0.13c | 4.94±1.69 |
8p | 35.28±6.97c | 0.59±0.10c | 4.88±2.59 |
8q | 61.60±15.46e | 0.34±0.17e | 4.17±2.17 |
8r | 57.54±5.20e | 0.38±0.07e | 5.40±1.79 |
8s | 46.23±13.42c | 0.48±0.16c | 2.02±1.24 |
a)Arc(阿糖胞苷)和8a-s给药剂量为8.9μmol/kg,NS=生理盐水,n=10,瘤重和体重增加表示为 x±SDg;抑制率表示为x±SD%;给药后各组动物没有观察到出现文献报道的震颤、跳跃、抽搐、强直、仰卧、呼吸加快的症状;b)与NS比较p<0.05;c)与NS比较p<0.01;d)与NS比较p<0.001;e)与NS比较p<0.001,与阿糖胞苷比较p<0.01;f)与NS和阿糖胞苷比较p<0.001。
实验结果表明,本发明化合物(8a-8s)具有确切的抗肿瘤活性。
Claims (4)
2.一种制备权利要求1所述通式I化合物的方法,该方法包括:
(1)将L-色氨酸转变为1,2,3,4-四氢咔啉羧酸;
(2)将1,2,3,4-四氢咔啉羧酸转变为咔啉羧酸苄酯;
(3)将1,2,3,4-四氢咔啉羧酸转变成N-叔丁氧羰基-1,2,3,4-四氢咔啉羧酸;
(4)将N-叔丁氧羰基-1,2,3,4-四氢咔啉羧酸和1,2,3,4-四氢咔啉羧酸苄酯缩合,生成N-叔丁氧羰基-1,2,3,4-四氢咔啉酰-1.2.3.4-四氢咔啉羧酸苄酯;
(5)将N-叔丁氧羰基-1,2,3,4-四氢咔啉酰-1.2.3.4-四氢咔啉羧酸苄酯氢解,生成N-叔丁氧羰基-1,2,3,4-四氢咔啉酰-1.2.3.4-四氢咔啉羧酸;
(6)将N-叔丁氧羰基-1,2,3,4-四氢咔啉酰-1.2.3.4-四氢咔啉羧酸和氨基酸苄酯缩合,生成N-叔丁氧羰基-1,2,3,4-四氢咔啉酰-1.2.3.4-四氢咔啉酰氨基酸苄酯;
(7)将N-叔丁氧羰基-1,2,3,4-四氢咔啉酰-1.2.3.4-四氢咔啉酰氨基酸苄酯脱去叔丁氧羰基,即得。
3.一种治疗肿瘤的药物组合物,由治疗上有效量的权利要求1所述的通式I化合物和 药学上可接受的辅料组成。
4.权利要求1所述的通式I化合物在制备抗肿瘤药物中的用途。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2008101138579A CN101591348B (zh) | 2008-05-30 | 2008-05-30 | 四氢咔啉酰氨基酸苄酯及其制备方法和应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2008101138579A CN101591348B (zh) | 2008-05-30 | 2008-05-30 | 四氢咔啉酰氨基酸苄酯及其制备方法和应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN101591348A CN101591348A (zh) | 2009-12-02 |
CN101591348B true CN101591348B (zh) | 2011-07-27 |
Family
ID=41406245
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2008101138579A Expired - Fee Related CN101591348B (zh) | 2008-05-30 | 2008-05-30 | 四氢咔啉酰氨基酸苄酯及其制备方法和应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN101591348B (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102241693B (zh) * | 2010-05-10 | 2013-08-28 | 首都医科大学 | N,N"-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰氨基酸苄酯及其合成方法和应用 |
CN109912587B (zh) * | 2017-12-12 | 2020-07-28 | 首都医科大学 | 侧链保护氨基酰氨基正己酰咔啉羧酸苄酯,其制备,活性和应用 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1910183A (zh) * | 2004-01-23 | 2007-02-07 | 希龙公司 | 四氢咔啉化合物作为抗癌药 |
-
2008
- 2008-05-30 CN CN2008101138579A patent/CN101591348B/zh not_active Expired - Fee Related
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1910183A (zh) * | 2004-01-23 | 2007-02-07 | 希龙公司 | 四氢咔啉化合物作为抗癌药 |
Also Published As
Publication number | Publication date |
---|---|
CN101591348A (zh) | 2009-12-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105288648B (zh) | 一种亲水性药物的磷脂化合物、其药物组合物及应用 | |
AU2010208071B2 (en) | Cyclosporin analogues for preventing or treating hepatitis C infection | |
US8163707B2 (en) | 4′-allene-substituted nucleoside derivatives | |
US8575119B2 (en) | 2′-chloroacetylenyl substituted nucleoside derivatives | |
CN101591335B (zh) | N-(l-氨基酰)-1,2,3,4-四氢咔啉酰氨基酸苄酯及其合成方法及应用 | |
CN102241604B (zh) | 氨基酸修饰的姜黄素及其合成方法和应用 | |
CN103083680B (zh) | 聚乙二醇-氨基酸寡肽-依诺替康药物结合物及其药物组合物 | |
CN104936970A (zh) | 用于hcv感染的2′-氯核苷类似物 | |
CN101497584B (zh) | 异喹啉-3-甲酰氨基酸苄酯及其制备和应用 | |
CN105813640A (zh) | 作为免疫调节剂的环肽类化合物 | |
US20110206637A1 (en) | Antiviral agents | |
WO2012125900A1 (en) | 2'-allene-substituted nucleoside derivatives | |
US20230270889A1 (en) | Fluorescently-Traceable Amino Acid Derivative And Preparation Methods And Use Thereof | |
CN104159911A (zh) | 作为免疫调节剂的模拟肽化合物 | |
CN101142225A (zh) | 具有抗炎活性的大环内酯 | |
CN106232616B (zh) | 两亲性合成抗菌肽、其药物组合物及其用途 | |
TWI633889B (zh) | 具有溶栓、抗栓和自由基清除三重活性的化合物,以及藥物組合物及其用途 | |
CN101591348B (zh) | 四氢咔啉酰氨基酸苄酯及其制备方法和应用 | |
CN103044521A (zh) | 天冬氨酸酶靶向激活的阿霉素衍生物、其制备方法和用途 | |
CN101597288B (zh) | 2-氨基酰-β-咔啉-3-甲酰色氨酸苄酯及其制备方法和应用 | |
CN103965458A (zh) | 聚乙二醇-氨基酸寡肽-达沙替尼结合物及其药物组合物 | |
CN101597289B (zh) | 2-色氨酰-β-四氢咔啉-3-甲酰基氨基酸苄酯及其制备方法和应用 | |
CN105960399B (zh) | 酶抑制剂环氧酮化合物 | |
CN110418653B (zh) | 一种果胶-阿霉素轭合物及其制备方法和用途 | |
CN107686508A (zh) | 阿霉素‑rgds,其合成,活性和应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20110727 Termination date: 20140530 |