CN101597289A - 2-tryptophyl-beta-tetrahydro carboline-3-formyol amino-acid benzyl ester and its production and application - Google Patents

2-tryptophyl-beta-tetrahydro carboline-3-formyol amino-acid benzyl ester and its production and application Download PDF

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CN101597289A
CN101597289A CNA2008101144033A CN200810114403A CN101597289A CN 101597289 A CN101597289 A CN 101597289A CN A2008101144033 A CNA2008101144033 A CN A2008101144033A CN 200810114403 A CN200810114403 A CN 200810114403A CN 101597289 A CN101597289 A CN 101597289A
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benzyl ester
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beta
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tryptophyl
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彭师奇
赵明
张丽娜
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Capital Medical University
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Abstract

The invention discloses 2-tryptophyl-beta-tetrahydro carboline-3-formyol amino-acid benzyl ester and its production and application, belong to biomedicine field.The structural formula of 2-tryptophyl of the present invention-beta-tetrahydro carboline-3-formyol amino-acid benzyl ester is shown in the general formula I, and AA is selected from Xie Ansuan residue, aspartic acid-γ-benzyl ester, glutamine, N in the formula ω-carbobenzoxy-(Cbz) Methionin, leucine residue, alanine residue, tryptophan residue, O-benzyl serine residue, phenylalanine residue, Isoleucine residue, glycine residue, histidine residues, methionine residue, L-glutamic acid-δ-benzyl ester, asparagine residue, proline residue, to methoxy-benzyl halfcystine, nitro arginine residues, threonine residues or tyrosine residues.The present invention is at tumor models and mouse S 180Estimated the anti-tumor activity of compound of Formula I on the sarcoma model, experimental result shows that general formula 1 compound of the present invention has outstanding anti-tumor activity, can be used as antineoplastic agent and uses.

Description

2-tryptophyl-beta-tetrahydro carboline-3-formyol amino-acid benzyl ester and its production and application
Technical field
The present invention relates to amino acid derivative, relate in particular to 2-tryptophyl-beta-tetrahydro carboline-3-formyol amino-acid benzyl ester with anti-tumor activity and preparation method thereof, the present invention also further relates to them as antineoplastic application, belongs to biomedicine field.
Background technology
Malignant tumour is a kind of common disease and frequently-occurring disease of serious threat human health, and the mortality ratio that the mankind cause because of malignant tumour is second of all disease death rates, is only second to cardiovascular and cerebrovascular diseases.The tumor treatment method has operative treatment, radiotherapy and pharmacological agent (chemotherapy).At present, chemotherapy remains the main means of clinical treatment tumour.Seeking antitumor drug is one of focus of new drug research.The contriver recognizes, with after beta-tetrahydro carboline carboxylate and the coupling of L-tryptophane again carboxyl terminal introduce amino acid and may produce antitumor action.According to this conception, the contriver proposes the present invention.
Summary of the invention
One of the object of the invention provides the compound that a class has anti-tumor activity;
Two of the object of the invention provides a kind of above-mentioned method with active compound for anti tumor for preparing.
Above-mentioned purpose of the present invention is achieved through the following technical solutions:
Compound of Formula I with anti-tumor activity:
Figure A20081011440300031
General formula I
AA is selected from Xie Ansuan residue, aspartic acid-γ-benzyl ester, glutamine residue, N in the formula ω-carbobenzoxy-(Cbz) lysine residue, leucine residue, alanine residue, tryptophan residue, O-benzyl serine residue, phenylalanine residue, Isoleucine residue, glycine residue, histidine residues, methionine residue, L-glutamic acid-δ-benzyl ester, asparagine residue, proline residue, to methoxy-benzyl halfcystine, nitro arginine, threonine residues or tyrosine residues.
A kind of method for preparing above-mentioned compound of Formula I, this method comprises:
(1) (at NaOH, (Boc) 2O and dioxane exist down) tryptophan transfer is become the Boc-tryptophane;
(2) (at rare H 2SO 4Under the existence of formaldehyde) tryptophan transfer is become beta-tetrahydro carboline-3-carboxylic acid;
(3) (in the presence of polyphosphoric acid and benzylalcohol heating) changes beta-tetrahydro carboline-3-carboxylic acid into beta-tetrahydro carboline-3-benzyl carboxylate;
(4) (in the presence of tosic acid, benzylalcohol and hexanaphthene) changes amino acid into amino-acid benzyl ester;
(5) (in the presence of DCC and HoBt) is with Boc-tryptophane and beta-tetrahydro carboline-3-benzyl carboxylate condensation prepared 2-(Boc-tryptophyl)-beta-tetrahydro carboline-3-benzyl carboxylate;
(6) (use Pd/C catalysis) 2-(Boc-tryptophyl)-beta-tetrahydro carboline-3-benzyl carboxylate hydrogenolysis is prepared 2-(Boc-tryptophyl)-beta-tetrahydro carboline-3-carboxylic acid;
(7) (in the presence of DCC, HoBt) is with 2-(Boc-tryptophyl)-beta-tetrahydro carboline-3-carboxylic acid and amino-acid benzyl ester condensation prepared 2-(Boc-tryptophyl)-beta-tetrahydro carboline-3-formyl amino acid formyl amino acid benzyl ester;
(8) (in the presence of HOAc, hydrogenchloride and ethyl acetate) sloughs Boc with 2-(Boc-tryptophyl)-beta-tetrahydro carboline-3-formyl amino acid formyl amino acid benzyl ester, promptly.
Wherein, the amino-acid benzyl ester described in the step (4) be selected from the two benzyl esters of Xie Ansuan benzyl ester, aspartic acid, glutamine benzyl ester, (N ω-carbobenzoxy-(Cbz)) Methionin benzyl ester, leucine benzyl ester, alanine benzyl ester, tryptophan benzyl ester, O-benzyl Serine benzyl ester, Isoleucine benzyl ester, phenylalanine benzyl ester, glycine benzyl ester, histamine acid benzyl ester, methionine(Met) benzyl ester, the two benzyl esters of L-glutamic acid, l-asparagine benzyl ester, proline(Pro) benzyl ester, to methoxy-benzyl halfcystine benzyl ester, nitro arginine benzyl ester, tyrosine benzyl ester or threonine benzyl ester.
Another purpose of the present invention provides a kind of medicinal compositions for the treatment of tumour, this medicinal compositions is gone up effective dose by treatment compound of Formula I of the present invention is with pharmaceutically acceptable excipient or assist and add agent and form, the compound of Formula I of the present invention that is about to significant quantity is with after pharmaceutically acceptable carrier or thinner cooperate, and by the formulation method of this area routine it is prepared into any one appropriate drug composition.Usually said composition is suitable for oral administration and drug administration by injection, also is fit to other medication.Said composition can be liquid preparation forms such as tablet, capsule, pulvis, granule, lozenge, suppository, or oral liquid.According to different medications, pharmaceutical composition of the present invention can contain 0.1%-99% weight, the The compounds of this invention of preferred 10-60% weight.
The present invention is at tumor models and mouse S 180Estimated the anti-tumor activity of compound of Formula I (2a-t) on the sarcoma model, experimental result shows that general formula 1 compound of the present invention has outstanding anti-tumor activity, can be used as antineoplastic agent and uses.
Description of drawings
The structural formula of Fig. 1 compound of Formula I of the present invention.
The synthetic route chart of Fig. 2 compound of Formula I of the present invention; The middle AA of 2a-t is selected from Xie Ansuan, aspartic acid-γ-benzyl ester, glutamine, N ω-carbobenzoxy-(Cbz) Methionin, leucine, L-Ala, tryptophane, O-benzyl Serine, phenylalanine, Isoleucine, glycine, Histidine, methionine(Met), L-glutamic acid-δ-benzyl ester, l-asparagine, proline(Pro), to methoxy-benzyl halfcystine, nitro arginine, Threonine or tyrosine residues.
Embodiment
In order further to set forth the present invention, provide a series of embodiment below.These embodiment are illustrative fully, and they only are used for the present invention is specifically described, and not should be understood to limitation of the present invention.
Embodiment 1 preparation Boc-L-tryptophane
Under the ice bath 4.1g (2mol) L-tryptophane is dissolved in the 10mlNaOH aqueous solution (2N), in this solution, adds 4.9g (2.2mmol) (Boc) 2O and 5ml 1, the solution of 4-dioxane, compound of reaction stir and constantly reduce pressure and take out the CO that generates in the dereaction process 2Need after 48 hours TLC to detect reaction approximately and finish, decompression removes 1, the 4-dioxane, and residual nothing is used earlier saturated KHSO 4The aqueous solution is transferred pH 2, uses ethyl acetate extraction then three times, and the ethyl acetate layer of merging is given a baby a bath on the third day after its birth with the saturated NaCl aqueous solution and time then used anhydrous Na SO 4Dried overnight is filtered, and filters colorless solid that also concentrating under reduced pressure obtains with ethyl acetate-sherwood oil recrystallization.Yield: 85%.
Embodiment 2 preparation L-amino-acid benzyl fat
20mmolL-amino acid and 30ml phenylcarbinol stirred in the 100ml round-bottomed flask make dissolving.Add 3.78g (22mol) tosic acid then, 90 ℃ of stirrings.Take the water that generates in the reaction process out of with the hexanaphthene azeotropic.TLC detects the basic disappearance of raw material point after 24 hours, stops heating, cooling, and ice bath stirs a large amount of ether of adding down, separates out the amino-acid benzyl ester tosilate.Productive rate is between 86%-96%.Logical according to this method has been synthesized Xie Ansuan benzyl ester tosilate, the two benzyl ester tosilate of aspartic acid, N ω-carbobenzoxy-(Cbz) Methionin benzyl ester tosilate, leucine benzyl ester tosilate, the alanine benzyl ester tosilate, the tryptophan benzyl ester tosilate, O-benzyl Serine benzyl ester tosilate, phenylalanine benzyl ester tosilate, Isoleucine benzyl ester tosilate, the glycine benzyl ester tosilate, Histidine benzyl ester tosilate, methionine(Met) benzyl ester tosilate, the two benzyl ester tosilate of L-glutamic acid, proline(Pro) benzyl ester tosilate, the tosilate of the amino acid whose benzyl esters of L-such as threonine benzyl ester tosilate and tyrosine benzyl ester tosilate.
Embodiment 3 preparation beta-tetrahydro carboline-3-carboxylic acids
Slowly add the 0.2ml vitriol oil in the 500ml round-bottomed flask that contains 400ml water and shake up.Dilution heat of sulfuric acid that obtains and 5.0g (24.5mmol) L-tryptophane is stirred to the L-tryptophane and dissolves fully.Add 10ml formaldehyde (35%) in the solution that obtains, separate out a large amount of solids behind the stirring 10min, the TLC plate detects the L-tryptophane and disappears, and stops to stir.In reaction solution, slowly splash into 8ml ammoniacal liquor, transfer pH7.Reaction mixture sat 6h, decompression leaches the precipitation of generation, water flushing 5 times, dry 4.9g (95%) target compound that gets of filter Pie is light yellow solid.ESI(m/z)217[M+H] +.
Embodiment 4 preparation beta-tetrahydro carboline-3-benzyl carboxylates
Get 2g polyphosphoric acid heated and stirred and make it to be dissolved in 20ml benzylalcohol (Heating temperature is not higher than 50 ℃), treat to dissolve fully the back and add 1g beta-tetrahydro carboline-3-carboxylic acid, be warming up to 80 ℃ of stirrings, reaction solution turns brown gradually by yellow-green colour, and TLC detects the disappearance of raw material point after 12 hours.Reaction mixture cooling back adds the 50ml ether and powerful stirring of 70ml water spent the night, and has a large amount of yellow solids to separate out.Filter, the yellow blocks of solid that obtains is washed repeatedly with ether and water and is obtained Powdered light yellow carboline carboxylate benzyl ester phosphoric acid salt 1.3g.This phosphoric acid salt is suspended in the mixed solution of ethyl acetate and water, it is transparent that ice bath drips down triethylamine solution no insoluble particle and reaction solution to the reaction solution.After continuing to stir 12h, tell ethyl acetate layer also with 5% sodium bicarbonate aqueous solution washing 6 times, saturated sodium-chloride water solution washing 3 times, the ethyl acetate layer of telling concentrates with anhydrous sodium sulphate solid drying, filtration, filtrate decompression, the residue recrystallization gets 0.9g (67%) title compound, is the ivory buff powder.ESI(m/e)307[M+H] +。
Embodiment 5 preparation Boc-tryptophyl-beta-tetrahydro carboline-3-benzyl carboxylates (1A)
3.6g (11.8mmol) Boc-L-tryptophane is dissolved in 35ml anhydrous tetrahydro furan (THF), adds the solution of 1.4g (14.2mmol) N-hydroxybenzotriazole (HOBt) and 2.1g (14.2mmol) dicyclohexyl carbonyl diimine (DCC) and 15ml anhydrous tetrahydro furan (THF) under the ice bath inward.The reaction mixture ice bath stirred 20 minutes, got corresponding active ester solution.Add 2.3g (9.5mmol) beta-tetrahydro carboline-3-benzyl carboxylate and 6ml anhydrous tetrahydro furan (THF) in this solution and transfer the solution of pH=9 with N-methylmorpholine.The mixing solutions room temperature reaction that obtains 24 hours.TLC (developping agent CHCl 3: MeOH=10: 1) show that beta-tetrahydro carboline-3-benzyl carboxylate disappears.Stopped reaction, filtering dicyclohexylurea (DCU) (DCU), filtrate decompression is concentrated into dried.Residue acetic acid ethyl dissolution, ethyl acetate solution are used saturated NaHCO respectively 3The aqueous solution, 5%KHSO 4The aqueous solution, the saturated NaCl aqueous solution is washed 5 times.The ethyl acetate solution anhydrous Na of telling 2SO 4Dried overnight.Filtering Na 2SO 4, filtrate decompression concentrates, and obtains 4.98g (86%) title compound, is colorless solid.Mp 115-117 ℃; ESI (m/e) 550[M+H] +[α] D 20=24.30 (c 1.0, methyl alcohol); 1H-NMR (DMSO-d 6, 500MHz) δ=10.97 (s, 1H), 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). 13C-NMR (DMSO-d 6, 75MHz) δ=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.
Embodiment 6 preparation Boc-tryptophyl-beta-tetrahydro carboline-3-carboxylic acids (1B)
Earlier 1.5g (2.52mmol) Boc-tryptophyl-beta-tetrahydro carboline-3-benzyl carboxylate is dissolved in 20ml ethanol, add 300mgPd/C (20%) again, stir the air in the discharge reaction flask that reduces pressure down, feed hydrogen exchange, after replacing 3 times repeatedly, logical hydrogen stirring at room 24 hours, TLC (developping agent CHCl 3: MeOH=10: 1+1 drips Glacial acetic acid) show that Boc-tryptophyl-beta-tetrahydro carboline-3-benzyl carboxylate disappears.Stopped reaction, filtering Pd/C, filter residue washes three times with dehydrated alcohol, and filtrate decompression concentrates, and gets 1.1g (80%) title compound.IR?3396.64，2976.16，2850.79，1705.07，1643.35，1642.06，1510.26，1429.90，1454.33，1392.61，1367.33，1247.94，1234.44，1166.93，742.59。
Method is led in the preparation of embodiment 7 Boc-tryptophyl-beta-tetrahydro carboline-3-formyl amino acid formyl amino acid benzyl ester
1.2g (2.4mmol) Boc-tryptophyl-beta-tetrahydro carboline-3-carboxylic acid is dissolved in 15ml anhydrous tetrahydro furan (THF), adds the solution of 600mg (2.5mmol) N-hydroxybenzotriazole (HOBt), 800mg (2.5mmol) dicyclohexyl carbonyl diimine (DCC) and 10ml anhydrous tetrahydro furan (THF) under the ice bath inward.The reaction mixture ice bath stirred 20 minutes, got corresponding active ester solution.Add the N-methylmorpholine elder generation of 2.4mmol amino-acid benzyl ester and 2ml and 6ml anhydrous tetrahydro furan (THF) in this solution and with the solution of NMM accent pH9.The miscible fluid room temperature reaction that obtains spends the night.TLC (developping agent CHCl 3: MeOH=10: 1) show amino acid benzyl ester disappears.Stopped reaction, filtering dicyclohexylurea (DCU) (DCU), filtrate decompression is concentrated into dried.Residue acetic acid ethyl dissolution, ethyl acetate solution are used saturated NaHCO respectively 3The aqueous solution, 5%KHSO 4The aqueous solution, the saturated NaCl aqueous solution is washed 5 times.The ethyl acetate solution anhydrous Na of telling 2SO 4Dried overnight.Filtering Na 2SO 4, filtrate decompression concentrates, and residue is through purification by silica gel column chromatography.
The data of embodiment 8 Boc-tryptophyl-beta-tetrahydro carboline-3-formyl radical-Xie Ansuan benzyl ester (1a)
1.17g(62.42％)。Mp 114-115 ℃; ESI (m/e) 364[M+H] +[α] D 20=-114.20 (c 1.0, methyl alcohol); 1H-NMR (DMSO-d 6, 500MHz) δ=10.87 (d, J=10Hz, 1H), 8.33 (t, J=5Hz, 1H), 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, 1H), 3.305 (d, J=5Hz, 1H), 3.14 (m, 2H), 1.38 (s, 3H), 0.83 (s, 3H). 13C-NMR (DMSO-d 6, 75MHz) δ=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; IR 3402.43,3307.92, and 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.
The data of the two benzyl esters (1b) of embodiment 9 Boc-tryptophyl-beta-tetrahydro carboline-3-formyl radical-aspartic acid
1.06g (63.8%) .Mp 102-104 ℃; ESI (m/e) 364[M+H] +[α] D 20=7.36 (c 1.0, methyl alcohol); 1H-NMR (DMSO-d 6, 500MHz) δ=10.90 (s, 1H), 10.87 (s, 1H), 8.65 (d, J=5Hz, 1H), 8.485 (d, J=5Hz, 1H), 7.65 (d, J=10Hz, 1H), 7.515 (d, J=10Hz, 1H), 7.37 (m, 5H), 7.18 (m, 4H), 5.74 (d, J=10Hz, 2H), 4.98 (m, 2H), 4.12 (s, 1H), 3.36 (s, 1H), 3.14 (m, 2H), 1.36 (s, 4H). 13C-NMR (DMSO-d 6, 75MHz) δ=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; IR 3388.93,3307.92, and 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.
The data of embodiment 10 Boc-tryptophyl-beta-tetrahydro carboline-3-formyl radical-glutamine benzyl ester (1c)
0.87g(73.8％)。Mp 154.5-157.0 ℃; ESI (m/e) 721[M+H] +[α] D 20=39.23 (c 1.0, methyl alcohol); 1H-NMR (DMSO-d 6, 500MHz) δ=10.84 (dd, J=15Hz, J=10Hz, 1H), 8.33 (s, 1H), 7.63 (m, 5H), 7.31 (m, 4H), 5.62 (q, J=5Hz, J=5Hz, 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, 1H); 13C-NMR (DMSO-d 6, 75MHz) δ=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; IR 3388.93,3329.14, and 2974.23,1687.71,1641.42,1622.13,1489.05,1456.26,1388.75,1367.33,1336.67,1263.37,1163.08,740.67.
The data of embodiment 11 Boc-tryptophyl-beta-tetrahydro carboline-3-formyl radical-(N ω-carbobenzoxy-(Cbz)) Methionin benzyl ester (1d)
1.05g(81.2％)。Mp 101-103 ℃; ESI (m/e) 833[M+H] +[α] D 20=33.56 (c=1.0, methyl alcohol); 1H-NMR (DMSO-d 6, 500MHz) δ=10.88 (d, J=15Hz, 1H), 8.45 (d, J=5Hz, 1H), 8.36 (d, J=10Hz, 1H), 7.64 (d, J=10Hz, 1H), 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, 1H), 2.94 (m, 3H), 1.38 (s, 3H), 1.28 (s, 2H), 0.91 (m, 2H); 13C-NMR (DMSO-d 6, 75MHz) δ=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; IR 3390.86,3288.63, and 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.
The data of embodiment 12 Boc-tryptophyl-beta-tetrahydro carboline-3-formyl radical-leucine benzyl ester (1e)
1.37g; (79.5%); Mp:113-115 ℃; ESI (m/e) 707[M+H] +[α] D 20=38.27 (c=1.0, methyl alcohol); 1H-NMR (DMSO-d 6, 500MHz) δ=10.89 (d, J=15Hz, 1H), 8.45 (d, J=10Hz, 1H), 7.61 (dd, J=10Hz, J=5Hz, 1H), 7.34 (m, 5H), 7.20 (m, 4H), 7.08 (m, 1H), 5.70 (s, 2H), 5.14 (dd, J=10Hz, J=7.5Hz, 1H), 4.98 (m, 2H), 2.9 (m, 2H), 1.52 (m, 2H), 1.40 (s, 3H), 0.880 (d, J=5Hz, 3H); 13C-NMR (DMSO-d 6, 75MHz) δ=169.96,156.42,136.63,136.48,136.13,130.15,129.63,127.84,127.56,121.53,121.12,119.09,111.48,111.34,110.68,109.19,79.27,66.25,52.36,50.92,41.88,38.94,28.56,23.77,23.17,21.13; IR 3390.86,3311.78, and 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.
The data of embodiment 13 Boc-tryptophyl-beta-tetrahydro carboline-3-formyl radical-alanine benzyl ester (1f)
1.00g (82.3%); Mp 115-117 ℃; ESI (m/e) 664[M+H] +[α] D 20=20.17 (c=1.0, methyl alcohol); 1H-NMR (DMSO-d 6, 500MHz) δ=10.90 (d, J=15Hz, 1H), 8.195 (d, J=5Hz, 1H), 7.54 (t, J=7.5Hz, 1H), 7.41 (m, 4H), 7.16 (m, 4H), 6.84 (dd, J=10Hz, J=5Hz, 1H), 5.665 (d, J=5Hz, 1H), 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-d 6, 75MHz) δ=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; IR 3388.93,3296.35, and 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.
The data of embodiment 14 Boc-tryptophyl-beta-tetrahydro carboline-3-formyl radical-tryptophan benzyl ester (1g)
1.22g (78.7%); Mp 129-130 ℃; ESI (m/e) 801[M+H] +[α] D 20=0.80 ° (c=1.0, methyl alcohol); 1H-NMR (DMSO-d 6, 500MHz) δ=10.87 (d, J=10Hz, 1H), 8.78 (d, J=10Hz, 1H), 8.495 (d, J=5Hz, 1H), 8.015 (d, J=5Hz, 1H), 7.51 (m, 4H), 7.25 (m, 4H), 7.03 (m, 4H), 6.37 (s, 1H), 5.765 (d, J=5Hz, 2H), 5.595 (d, J=5Hz, 2H), 4.50 (t, J=10Hz, 1H), 4.375 (q, J=5Hz, J=5Hz, 1H), 3.00 (q, J=5Hz, J=5Hz, 2H), 1.40 (s, 3H); 13C-NMR (DMSO-d 6, 75MHz) δ=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; IR 3365.78,3305.99, and 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.
The data of embodiment 15 Boc-tryptophyl-beta-tetrahydro carboline-3-formyl radical-O-benzyl Serine benzyl ester (1h)
1.08g (82.0%); Mp:111-117 ℃; ESI (m/e) 758[M+H] +[α] D 20=39.10 (c=1.0, methyl alcohol); 1H-NMR (DMSO-d 6, 500MHz) δ=10.69 (s, 1H), 10.65 (s, 1H), 8.90 (q, J=5Hz, J=5Hz, 1H), 7.73 (d, J=10Hz, 1H), 7.61 (t, J=5Hz, 1H), 7.25 (m, 5H), 7.09 (m, 4H), 6.84 (d, J=5Hz, 1H), 5.34 (s, 1H), 5.29 (t, 1H), 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-d 6, 75MHz) δ=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; IR 3410.15,3292.49, and 2974.23,2927.94,1743.65,1678.07,1469.76,1442.75,1390.68,1365.60,1336.67,1236.37,1163.08,740.67.
The data of embodiment 16 Boc-tryptophyl-beta-tetrahydro carboline-3-formyl radical-Isoleucine benzyl ester (1i)
1.26g (71.2%); Mp 120-122 ℃; ESI (m/e) 706[M+H] +[α] D 20=24.8 (c=1.0, methyl alcohol); 1H-NMR (DMSO-d 6, 500MHz) δ=10.92 (s, 1H), 10.85 (d, J=5Hz, 1H), 8.29 (s, 1H), 7.62 (d, J=10Hz, 1H), 7.40 (t, J=10Hz, 1H), 7.37 (t, J=5Hz, 1H), 7.32 (m, 4H), 7.22 (m, 4H), 7.135 (d, J=5Hz, 1H), 6.99 (s, 1H), 5.765 (d, J=5Hz, 2H), 5.59 (d, J=10Hz, 2H), 4.87 (t, J=5Hz, 2H), 4.21 (t, J=5Hz, 1H), 3.26 (d, J=10Hz, 1H), 2.99 (m, 1H), 1.37 (s, 3H), 1.28 (m, 2H), 1.155 (d, J=5Hz, 2H), 0.74 (t, J=5Hz, 3H); 13C-NMR (DMSO-d 6, 75MHz) δ=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; IR 3309.85,2962.66, and 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.
The data of embodiment 17 Boc-tryptophyl-beta-tetrahydro carboline-3-formyl radical-phenylalanine benzyl ester (1j)
0.99g (70.3%); Mp:124-126 ℃; ESI (m/e) 740[M+H] +[α] D 20=14.6 (c=1.0, methyl alcohol); 1H-NMR (DMSO-d 6, 500MHz) δ=10.87 (s, 1H), 10.86 (d, J=5Hz, 1H), 8.56 (d, J=5Hz, 1H), 8.40 (d, J=10Hz, 1H), 7.64 (t, J=5Hz, 1H), 7.30 (m, 5H), 7.21 (m, 4H), 6.90 (m, 4H), 5.07 (s, 2H), 5.03 (d, J=5Hz, 2H), 4.98 (q, J=5Hz, 1H), 4.41 (t, J=5Hz, 1H), 4.35 (d, J=5Hz, 1H), 3.12 (d, J=5Hz, 2H), 2.10 (s, 2H), 1.41 (s, 3H); 13C-NMR (DMSO-d 6, 75MHz) δ=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; IR 3402.43,3304.06, and 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.
The data of embodiment 18 Boc-tryptophyl-beta-tetrahydro carboline-3-formyl radical-glycine benzyl ester (1k)
1.09g (76.5%); Mp 139-143 ℃; ESI (m/e) 650[M+H] +[α] D 20=19.9 (c=1.0, methyl alcohol); 1H-NMR (DMSO-d 6, 500MHz) δ=10.89 (d, J=5Hz, 1H), 10.87 (s, 1H), 8.48 (dd, J=10Hz, J=5Hz, 1H), 8.41 (s, 1H), 7.465 (d, J=5Hz, 1H), 7.40 (d, J=10Hz, 1H), 7.28 (m, 5H), 7.12 (m, 4H), 7.025 (d, J=15Hz, 1H), 5.735 (d, J=5Hz, 2H), 4.945 (d, J=5Hz, 1H), 4.835 (d, J=5Hz, 2H), 4.31 (s, 1H), 4.28 (s, 1H), 3.04 (dd, J=10Hz, J=5Hz, 2H), 1.40 (s, 3H); 13C-NMR (DMSO-d 6, 75MHz) δ=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; IR 3394.72,3296.35, and 2974.94,2927.94,1743.65,1639.49,1498.69,1452.40,1367.53,1336.67,1278.81,1234.44,1165.00,738.74.
The data of embodiment 19 Boc-tryptophyl-beta-tetrahydro carboline-3-formyl radical-histamine acid benzyl ester (11)
0.56g (53.2%); Mp 138-140 ℃; ESI (m/e) 730[M+H] +[α] D 20=19.9 (c=1.0, methyl alcohol); 1HNMR (CDCl 3) δ/ppm=13.4 (s, 1H), 10.23 (s, 1H), 10.01 (s, 1H), 8.02 (s, 1H), 7.45 (s, 1H), 7.27 (d, J=5Hz, 1H), 7.19 (m, 5H), 7.18 (m, 4H), 6.88 (s, 1H), 6.86 (d, J=7.5Hz, 1H), 6.65 (d, J=5Hz, 1H), 5.87 (s, 2H), 5.59 (d, J=7.5Hz, 2H), 4.61 (s, 2H), 4.81 (t, J=5Hz, 1H), 3.06 (d, J=5Hz, 2H), 3.00 (d, J=10Hz, 2H), 2.51 (m, 1H), 1.99 (s, 2H), 1.39 (s, 9H); 13CNMR (CDCl 3) δ/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.
The data of embodiment 20 Boc-tryptophyl-beta-tetrahydro carboline-3-formyl radical-methionine(Met) benzyl ester (1m)
1.06g (55.4%); Mp 97-99 ℃; ESI-MS (m/e) 746[M+H] +[α] D 20=33.5 (c=1.0, methyl alcohol); 1H-NMR (DMSO-d 6, 500MHz) δ=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-d 6, 75MHz) δ=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; IR 3400.50,3304.06, and 3055.24,2970.38,2918.30,1747.51,1685.96,1498.69,1456.26,1367.53,1338.60,1234.44,1163.38,740.67.
The data of the two benzyl esters (1n) of embodiment 21 Boc-tryptophyl-beta-tetrahydro carboline-3-formyl radical-L-glutamic acid
0.96g (63.2%); Mp 99-101 ℃; ESI-MS (m/e) 834[M+H] +[α] D 20=8.2 (c=1.0, methyl alcohol); 1H-NMR (DMSO-d 6, 500MHz) δ=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, 1H), 7.40 (m, 4H), 7.18 (m, 4H), 5.725 (d, J=5Hz, 2H), 5.13 (m, 1H), 5.06 (s, 2H), 3.31 (m, 2H), 1.31 (s, 3H); 13C-NMR (DMSO-d 6, 75MHz) δ=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; IR 3311.78,3273.20, and 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.
The data of embodiment 22 Boc-tryptophyl-beta-tetrahydro carboline-3-formyl radical-l-asparagine benzyl ester (1o)
1.17g (56.2%); Mp 141-143 ℃; ESI (m/e) 726[M+H] +[α] D 20=7.2 (c=1.0, methyl alcohol) 1H-NMR (DMSO-d 6, 500MHz) δ=10.88 (s, 1H), 10.84 (s, 1H), 8.44 (d, J=5Hz, 1H), 7.66 (d, J=5Hz, 1H), 7.43 (d, J=5Hz, 1H), 7.23 (m, 4H), 7.04 (m, 4H), 5.74 (d, J=10Hz, 2H), 4.72 (t, J=5Hz, 1H), 4.68 (t, J=7.5Hz, 1H), 4.61 (s, 2H), 4.59 (t, J=5Hz, 1H), 3.35 (d, J=10Hz, 2H), 3.12 (m, 2H), 2.59 (d, J=5Hz, 2H), 1.39 (s, 3H); 13C-NMR (DMSO-d 6, 75MHz) δ=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; IR 3348.42,3331.07, and 2974.23,2927.94,1739.79,1678.07,1496.76,1456.26,1390.68,1367.53,1336.67,1309.67,1161.15,740.67.
The data of embodiment 23 Boc-tryptophyl-beta-tetrahydro carboline-3-formyl radical-proline(Pro) benzyl ester (1p)
0.99g (80.3%); Mp 133-135 ℃; ESI (m/e) 690[M+H] +[α] D 20=-118.8 (c=1.0, methyl alcohol); 1H-NMR (DMSO-d 6, 500MHz) δ=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-d 6, 75MHz) δ=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; IR 3390.86,3315.63, and 3057.17,2974.23,1743.65,1639.49,1496.67,1454.82,1365.60,1336.67,1271.09,1238.30,1166.93,740.67.
Embodiment 24 Boc-tryptophyl-beta-tetrahydro carboline-3-formyl radical-to the data of methoxy-benzyl halfcystine benzyl ester (1q)
1.32g (78.6%); Mp 101-103 ℃; ESI (m/e) 816[M+H] +[α] D 20=-14.3 (c=1.0, methyl alcohol); 1H-NMR (DMSO-d 6, 500MHz) δ=10.89 (d, J=15Hz, 1H), 8.495 (d, J=5Hz, 1H), 7.650 (d, J=5Hz, 1H), 7.500 (m, 5H), 7.25 (m, 5H), 7.150 (m, 4H), 5.805 (d, J=5Hz, 2H), 4.83 (s, 1H), 3.70 (s, 2H), 3.63 (s, 3H), 3.375 (d, J=5Hz, 2H), 1.340 (s, 3H); 13C-NMR (DMSO-d 6, 75MHz) δ=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; IR 3402.43,3307.92, and 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.
The data of embodiment 25 Boc-tryptophyl-beta-tetrahydro carboline-3-formyl radical-nitro arginine benzyl ester (1r)
1.01g (79.0%); Mp 103-105 ℃; ESI (m/e) 795[M+H] +[α] D 20=18.6 (c=1.0, methyl alcohol); 1H-NMR (DMSO-d 6, 500MHz) δ=10.89 (s, 1H), 10.86 (s, 1H), 8.49 (d, J=10Hz, 1H), 8.33 (s, 1H), 7.64 (d, J=10Hz, 1H), 7.60 (d, J=10Hz, 1H), 7.485 (d, J=5Hz, 1H), 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, 1H), 1.67 (m, 1H), 1.38 (s, 3H); 13C-NMR (DMSO-d 6, 75MHz) δ=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; IR 3311.78,3273.20, and 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.
The data of embodiment 26 Boc-tryptophyl-beta-tetrahydro carboline-3-formyl radical-threonine benzyl ester (1s)
1.38g (71.0%); Mp 125-127 ℃; ESI (m/e) 694[M+H] +[α] D 20=9.7 (c=1.0, methyl alcohol); 1H-NMR (DMSO-d 6, 500MHz) δ=10.87 (t, J=7.5Hz, 1H), 10.77 (s, 1H), 8.18 (d, J=10Hz, 1H), 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-d 6, 75MHz) δ=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.IR 3373.50,3313.71,2958.80,2924.09,2852.72,1743.65,1685.79,1624.06,1498.69,1442.75,1390.68,1367.53,1334.74,1307.74,1234.44,1165.00,740.67.
The data of embodiment 27 Boc-tryptophyl-beta-tetrahydro carboline-3-formyl radical-tyrosine benzyl ester (1t)
1.20g (43.2%); Mp 145-146 ℃; ESI (m/e) 778[M+H] +[α] D 20=29.9 (c=1.0, methyl alcohol); 1H-NMR (DMSO-d 6, 500MHz) δ=10.86 (d, J=10Hz, 1H), 8.525 (d, J=5Hz, 1H), 7.78 (d, J=10Hz, 1H), 7.50 (m, 5H), 7.25 (m, 5H), 5.605 (d, J=5Hz, 1H), 4.94 (m, 2H), 3.38 (m, 2H), 3.09 (d, J=10Hz, 2H), 1.43 (s, 3H); 13C-NMR (DMSO-d 6, 75MHz) δ=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; IR 3392.79,3311.78, and 2974.23,2927.94,1739.79,1643.35,1502.55,1440.83,1367.53,1338.60,1242.16,1234.44,1166.93,738.74.
Method is led in the preparation of embodiment 28 2-tryptophyl-beta-tetrahydro carboline-3-formyl radical-amino-acid benzyl ester hydrochloride
3.18mmol Boc-tryptophyl-beta-tetrahydro carboline-3-formyl radical-amino-acid benzyl ester is placed the 50mL eggplant-shape bottle and uses the 2mL acetic acid ethyl dissolution.Ice bath slowly splashes into 2mL 4N hydrogenchloride/EtOAc down in the solution that obtains.0 ℃ of stirring of reaction mixture is evaporated to dried after 3 hours, residue extracts (10ml * 4) repeatedly with ether earlier, uses methyl alcohol-ether recrystallization then, obtains title compound.
The data of embodiment 29 2-tryptophyl-beta-tetrahydro carboline-3-formyl radical-Xie Ansuan benzyl ester hydrochloride (2a)
0.092g(80％)；ESI(m/e)590[M-H] -. 1HNMR(CDCl 3)：δ/ppm＝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，J＝10Hz，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)； 13CNMR(CDCl 3)δ/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。
The data of the two benzyl ester hydrochlorides (2b) of embodiment 30 2-tryptophyl-beta-tetrahydro carboline-3-formyl radical-aspartic acid
0.107g(83％)；ESI(m/e)696[M-H] -. 1HNMR(CDCl 3)δ/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，1H)，5.78(d，J＝7.5Hz，1H)，5.21(s，2H)，5.18(s，2H)，5.02(d，J＝3Hz，1H)，4.96(t，J＝5Hz，1H)，4.34(s，2H)，3.40(t，J＝7.5Hz，1H)，3.04(d，J＝10Hz，1H)，2.94(d，J＝7.5Hz，2H)，2.87(d，J＝7.5Hz，1H)，1.99(s，2H)； 13CNMR(CDCl 3)δ/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。
The data of embodiment 31 2-tryptophyl-beta-tetrahydro carboline-3-formyl radical-glutamine benzyl ester hydrochloride (2c)
0.083g(81％)；ESI(m/e)602[M-H] -. 1HNMR(CDCl 3)：δ/ppm＝10.06(s，1H)，8.15(s，1H)，7.23(m，5H)，7.19(m，4H)，7.00(m，1H)，6.95(d，J＝7.5Hz，1H)，6.82(s，1H)，6.32(s，2H)，5.28(d，J＝5Hz，2H)，4.93(t，J＝7.5Hz，1H)，4.88(s，1H)，4.50(s，2H)，4.33(t，J＝7.5Hz，1H)，3.94(m，1H)，3.06(d，2H)，2.12(m，2H)，1.92(s，2H)； 13CNMR(CDCl 3)δ/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。
The data of embodiment 32 2-tryptophyl-beta-tetrahydro carboline-3-formyl radical-(N ω-carbobenzoxy-(Cbz)) Methionin benzyl ester hydrochloride (2d)
0.078g(82.0％)；ESI-MS(m/e)709[M-H] -.1HNMR(CDCl3)δ/ppm＝10.91(s，1H)，10.87(s，1H)，8.24(s，1H)，8.09(s，1H)，7.29(m，10H)，7.27(m，1H)，7.19(m，4H)，7.17(d，J＝7.5Hz，1H)，6.75(t，J＝5Hz，1H)，5.79(d，J＝7.5Hz，2H)，5.24(s，2H)，4.92(t，J＝5Hz，1H)，4.42(s，2H)，4.39(t，J＝7.5Hz，1H)，4.03(m，1H)，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(CDCl3)δ/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。
The data of embodiment 332-tryptophyl-beta-tetrahydro carboline-3-formyl radical-leucine benzyl ester hydrochloride (2e)
0.103g(90％)；ESI-MS(m/e)604[M-H] -. 1HNMR(CDCl 3)δ/ppm＝11.02(s，1H)，10.87(s，1H)，8.23(s，1H)，7.72(d，J＝7.5Hz，1H)，7.31(m，1H)，7.27(m，5H)，7.20(m，4H)，7.02(d，J＝5Hz，1H)，6.97(t，J＝10Hz，1H)，5.68(d，J＝5Hz，1H)，5.24(s，2H)，4.98(t，J＝7.5Hz，1H)，4.58(d，J＝5Hz，2H)，4.40(s，2H)，4.18(m，1H)，3.40(m，1H)，2.51(s，2H)，1.10(t，J＝5Hz，1H)，7.32(d，J＝6Hz，6H)； 13CNMR(CDCl 3)δ/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。
The data of embodiment 34 2-tryptophyl-beta-tetrahydro carboline-3-formyl radical-alanine benzyl ester hydrochloride (2f)
0.089g(91.0％)；ESI(m/e)562[M-H] -. 1HNMR(CDCl 3)δ/ppm＝11.02(s，1H)，10.87(s，1H)，8.23(s，1H)，7.72(d，J＝7.5Hz，1H)，7.31(m，1H)，7.27(m，5H)，7.20(m，4H)，7.02(d，J＝5Hz，1H)，6.97(t，J＝5Hz，1H)，5.68(d，J＝5Hz，1H)，5.24(s，2H)，4.98(t，J＝7.5z，1H)，4.58(d，J＝5Hz，2H)，4.40(s，2H)，4.18(m，1H)，3.40(m，1H)，2.51(s，2H)，1.10(t，J＝5Hz，1H)，7.32(d，J＝6Hz，6H)； 13CNMR(CDCl 3)δ/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。
The data of embodiment 35 2-tryptophyl-beta-tetrahydro carboline-3-formyl radical-tryptophan benzyl ester hydrochloride (2g)
0.107g(80％)；ESI(m/e)677[M-H] -. 1HNMR(CDCl 3)δ/ppm＝10.50(s，1H)，8.14(s，1H)，10.06(s，1H)，7.26(d，J＝2.5Hz，1H)，7.21(m，5H)，7.18(m，8H)，6.97(m，1H)，6.92(t，J＝7.5Hz，1H)，6.75(t，J＝5Hz，1H)，5.40(s，2H)，4.92(d，J＝3.0Hz，1H)，4.80(d，J＝10.25Hz，1H)，4.45(s，2H)，4.37(m，1H)，3.18(d，J＝7.5Hz，1H)，3.07(d，J＝8.3Hz，4H)，2.00(s，1H)； 13CNMR(CDCl 3)δ/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。
The data of embodiment 36 2-tryptophyl-beta-tetrahydro carboline-3-formyl radical-O-benzyl Serine benzyl ester hydrochloride (2h)
0.088g(86.0％)；ESI(m/e)654[M-H] -. 1HNMR(CDCl 3)δ/ppm＝10.55(s，1H)，8.20(s，1H)，7.26(t，J＝7.5Hz，1H)，7.20(m，10H)，7.10(m，4H)，6.96(d，J＝7.5Hz，1H)，6.71(d，J＝7.5Hz，1H)，5.53(d，J＝7.5Hz，2H)，4.98(t，J＝5Hz，1H)，4.86(t，J＝5Hz，1H)，4.67(s，2H)，3.90(m，1H)，3.88(d，J＝10Hz，2H)，3.21(d，J＝7.5Hz，4H)，1.99(s，2H)； 13CNMR(CDCl 3)δ/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。
The data of embodiment 37 2-tryptophyl-beta-tetrahydro carboline-3-formyl radical-Isoleucine benzyl ester hydrochloride (2i)
0.111g(93％)；ESI(m/e)604[M-H] -.1HNMR(CDCl3)δ/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(CDCl3)δ/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。
The data of embodiment 38 2-tryptophyl-beta-tetrahydro carboline-3-formyl radical-phenylalanine benzyl ester hydrochloride (2j)
0.120g(91％)；ESI(m/e)638[M-H] -.1HNMR(CDCl 3)δ/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，1H)，4.80(t，J＝7.5Hz，1H)，4.45(s，2H)，3.80(t，J＝？？Hz，1H)，3.29(d，J＝7.5Hz，2H)，3.07(d，J＝7.8Hz，1H)，2.91(d，J＝7.3Hz，2H)，2.50(s，2H)； 13CNMR(CDCl 3)δ/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。
The data of embodiment 39 2-tryptophyl-beta-tetrahydro carboline-3-formyl radical-glycine benzyl hydrochloride (3k)
0.078g(96％)；ESI(m/e)547[M-H] -.1HNMR(CDCl3)δ/ppm＝9.08(s，1H)，8.93(s，1H)，8.19(s，1H)，7.53(m，1H)，7.44(m，1H)，7.32(m，5H)，7.22(m，4H)，6.98(d，J＝5Hz，1H)，6.97(d，J＝5Hz，1H)，5.89(d，J＝5Hz，2H)，5.47(s，2H)，5.03(t，J＝5Hz，1H)，5.00(s，2H)，4.27(m，1H)，3.09(m，1H)，3.01(d，J＝7.5Hz，2H)，1.99(s，2H)； 13CNMR(CDCl 3)δ/ppm＝169.97，166.32，165.89，136.61，128.67，127.58，127.07，124.49，121.47，118.95，118.05，111.97，109.51，66.72，65.36，49.50，42.28，41.77，28.79，15.62。
The data of embodiment 40 2-tryptophyl-beta-tetrahydro carboline-3-formyl radical-Histidine benzyl ester hydrochloride (2l)
0.087g(81％)；ESI(m/e)628[M-H] -.1HNMR(CDCl 3)δ/ppm＝10.52(s，1H)，9.55(s，1H)，8.06(s，1H)，7.44(d，J＝10Hz，1H)，7.25(s，5H)，7.17(m，4H)，7.07(m，1H)，6.18(t，J＝5Hz，1H)，5.85(d，J＝5Hz，2H)，5.77(d，J＝7.5Hz，1H)，4.87(t，J＝7.5Hz，1H)，4.83(t，J＝5Hz，1H)，4.55(s，2H)，4.00(t，J＝7.5Hz，1H)，3.12(d，J＝10Hz，2H)，3.06(m，2H)，1.21(s，2H)； 13CNMR(CDCl 3)δ/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。
The data of embodiment 41 2-tryptophyl-beta-tetrahydro carboline-3-formyl radical-methionine(Met) benzyl ester hydrochloride (2m)
0.096g(85％)；ESI(m/e)618[M-H] -. 1HNMR(CDCl 3)δ/ppm＝10.99(s，1H)，10.88(s，1H)，8.26(s，1H)，7.27(m，1H)，7.22(m，5H)，7.17(m，4H)，6.84(s，1H)，6.82(d，J＝7.5Hz，1H)，5.54(s，2H)，4.55(d，J＝5Hz，1H)，4.53(s，2H)，3.69(m，1H)，3.42(t，J＝7.5Hz，2H)，3.12(d，J＝5Hz，2H)，2.79(d，J＝5Hz，2H)，2.43(t，J＝10Hz，2H)，2.41(m，2H)，2.09(s，3H)，2.01(s，2H)； 13CNMR(CDCl 3)δ/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。
The data of the two benzyl ester hydrochlorides (2n) of embodiment 42 2-tryptophyl-beta-tetrahydro carboline-3-formyl radical-L-glutamic acid
0.078g(86％)；ESI(m/e)710[M-H] -. 1HNMR(CDCl 3)δ/ppm＝11.01(s，1H)，10.85(s，1H)，8.23(s，1H)，7.36(m，10H)，7.26(m，1H)，7.18(m，4H)，6.97(d，J＝7.5Hz，1H)，5.78(d，J＝7.5Hz，1H)，5.40(s，2H)，4.99(t，J＝10Hz，1H)，4.82(t，J＝5Hz，1H)，4.39(s，2H)，4.34(m，1H)，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(CDCl 3)δ/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。
The data of embodiment 43 2-tryptophyl-beta-tetrahydro carboline-3-formyl radical-l-asparagine benzyl ester hydrochloride (2o)
0.089g(87％)；ESI(m/e)605[M-H] -. 1HNMR(CDCl 3)δ/ppm＝10.48(s，1H)，10.46(s，1H)，8.15(s，1H)，7.27(m，1H)，7.23(m，5H)，7.19(m，4H)，6.86(d，J＝10Hz，1H)，6.73(d，J＝7.5Hz，1H)，5.79(d，J＝7.5Hz，2H)，4.92(t，J＝7.5Hz，1H)，10.64(t，J＝5Hz，1H)，4.50(s，2H)，4.40(t，J＝7.5Hz，1H)，3.04(d，J＝10Hz，2H)，2.65(d，J＝7.5Hz，2H)，1.99(s，2H)； 13CNMR(CDCl 3)δ/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。
The data of embodiment 44 2-tryptophyl-beta-tetrahydro carboline-3-formyl radical-proline benzyl ester hydrochloride (2p)
0.122g(89％)；ESI(m/e)588[M-H] -. 1HNMR(CDCl 3)δ/ppm＝10.34(s，1H)，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，1H)，4.45(s，1H)，4.31(t，J＝7.5Hz，2H)，4.01(m，1H)，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(CDCl 3)δ/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。
Embodiment 45 2-tryptophyl-beta-tetrahydro carboline-3-formyl radical-to the data 0.121g (83%) of methoxy-benzyl halfcystine benzyl ester hydrochloride (2q); ESI (m/e) 668[M-H] -. 1HNMR (CDCl 3) δ/ppm=10.88 (s, 1H), 8.24 (s, 1H), 7.22 (m, 5H), 7.19 (m, 4H), 7.04 (m, 1H), 7.00 (d, J=7.5Hz, 1H), 5.30 (s, 2H), 4.93 (m, 2H), 4.41 (s, 2H), 3.77 (m, 1H), 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 (CDCl 3) δ/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.
The data 0.086g (85%) of embodiment 46 2-tryptophyl-beta-tetrahydro carboline-3-formyl radical-nitro arginine benzyl ester hydrochloride (2r); ESI (m/e) 692[M-H] -. 1HNMR (CDCl 3) δ/ppm=10.01 (s, 1H), 9.10 (s, 1H), 8.08 (s, 1H), 8.03 (s, 1H), 7.31 (m, 1H), 7.29 (m, 5H), 7.22 (m, 4H), 7.16 (m, 1H), 7.00 (d, J=2.5Hz, 1H), 6.97 (d, J=7.5Hz, 1H), 6.95 (d, J=7.5Hz, 1H), 5.24 (s, 2H), 4.95 (t, J=7.5Hz, 1H), 4.50 (s, 2H), 4.03 (m, 1H), 3.07 (d, J=10Hz, 1H), 3.03 (t, J=10Hz, 2H), 2.50 (t, J=5Hz, 2H), 2.09 (s, 2H), 1.99 (s, 1H), 1.92 (s, 1H), 1.73 (m, 2H), 1.57 (m, 2H); 13CNMR (CDCl 3) δ/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.
The data of embodiment 47 2-tryptophyl-beta-tetrahydro carboline-3-formyl radical-threonine benzyl ester hydrochloride (2s)
0.101g(87％)；ESI(m/e)592[M-H] -. 1HNMR(CDCl 3)δ/ppm＝10.78(s，1H)，10.55(s，1H)，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(CDCl 3)δ/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。
The data of embodiment 48 2-tryptophyl-beta-tetrahydro carboline-3-formyl radical-tyrosine benzyl ester hydrochloride (2t)
0.098g(83％)；ESI-MS(m/e)654[M-H] -. 1HNMR(CDCl 3)δ/ppm＝10.76(s，1H)，8.14(s，1H)，7.27(d，J＝5Hz，1H)，7.20(m，5H)，7.10(m，4H)，6.97(d，J＝7.5Hz，1H)，6.87(d，J＝7.5Hz，1H)，6.79(s，1H)，6.76(d，J＝7.5Hz，2H)，6.55(s，2H)，5.07(s，1H)，4.94(t，J＝7.5Hz，1H)，4.82(t，J＝5Hz，1H)，4.03(t，1H)，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(CDCl 3)δ/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。
The evaluation of experimental example 1 The compounds of this invention (2a-t) anti-tumour cell proliferative activity
1) given the test agent
The compound compound (2a-t) that embodiment of the invention 29-48 is prepared; Be mixed with desired concn with the PBS that contains 1%DMSO.
2) human cancer cell strain
S180 cell (ascitogenous sarcoma cell), H22 cell (Murine Ascitic Hepatoma Cells strain)
3) key instrument
Microplate reader: 450, Biorad company
High-pressure sterilizing pot: 400Ep-Z, Bruckmanning company
Cell incubator: INC153, memmer company
Refrigerated centrifuge: SPD111V, Thermo company
96 porocyte culture plates: Costar company
Quartzy automatic dual pure water distiller: 1810-B, Jiangsu high honour instrument Manufacturing Co., Ltd
4) main agents
MTT: four tetrazolium bromides (3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyl-tetrazolium bromide) (Flka), is dissolved among the PBS, and concentration is 5mg/ml, filtration sterilization, and 4 ℃ keep in Dark Place.
PBS: contain NaCl 8.2g in every liter of solution, KCl 0.20g, Na 2HPO 4.H 2O1.56g, KH 2PO 40.2g pH 7.4
RPMI-1640 substratum: Gibco company
DMEM substratum: Gibco company
Mccy ' the s 5A medium+L-Glutamine substratum of improvement: Gibco company
Foetal calf serum: Hyclone company
Penicillin: Zhongnuo Pharmaceutical (Shijiazhuang) Co., Ltd., Shiyao Group
Streptomycin sulphate: Zhongnuo Pharmaceutical (Shijiazhuang) Co., Ltd., Shiyao Group
DMSO:Hyclone company.
All the other agents useful for same are commercially available analytical pure.
5) experimental technique of The compounds of this invention 2a-t anti-tumour cell proliferative evaluation
Respectively that growth conditions is good, be in the HL-60 cell of logarithmic phase with 5 * 10 4The density of individual/mL is inoculated in 96 orifice plates, every hole 100 μ l, by default concentration gradient add to be measured, through the sample of sterilising treatment, control group adds the solvent of isopyknic sample dissolution.Continue to cultivate after 48 hours, it is the MTT solution of 5mg/ml that every hole adds 25 μ l concentration, continue to place 37 ℃ to hatch four hours, the careful sucking-off supernatant liquor of centrifugal 5min (2500rpm), every hole adds the DMSO dissolve purple residue (first a ceremonial jade-ladle, used in libation) of 100 μ l, all dissolvings of about 15min precipitation of vibrating are measured O.D. (absorption value), wavelength 570nm on the 570nm microplate reader.
Calculate sample under each sample concentration to the inhibiting rate of tumour cell according to formula " relative survival rate=(D pastille-D blank)/(D contrast-D blank) * 100% ".
Experiment repeats 3 times, with inhibiting rate drug level is mapped, and obtains IC by graphing method 50(half effective inhibition concentration) value.
6) experimental result
Experimental result sees Table 1.
Table 1 2a-t anti-tumour cell proliferative activity (IC 50± SD μ M)
Compound S180 H22
2a 7.50±3.68 ＞10
2b 5.85±2.16 5.64±1.23
2c ＞10 ＞10
2d ＞10 ＞10
2e 6.46±2.36 6.37±1.63
2f ＞10 ＞10
2g 5.93±1.66 4.92±2.01
2h 6.81±2.68 9.87±3.66
2i 6.67±2.31 6.32±1.68
2j 5.37±2.64 5.40±2.31
2k 9.98±5.32 9.95±1.98
2l 7.75±3.65 ＞10
2m ＞10 ＞10
2n 5.68±1.32 5.72±2.31
2o ＞10 ＞10
2p ＞10 ＞10
2q 7.65±2.31 ＞10
2r ＞10 ＞10
2s ＞10 9.86±3.55
2t ＞10 ＞10
Arc 5.46±3.98 8.66±2.44
1A 7.96±3.96 7.06±4.33
The anti-tumor activity experiment of experimental example 2 The compounds of this invention 2a-t
1) experiment material
The compound compound (2a-t) that test-compound: embodiment of the invention 29-48 is prepared;
Positive reference substance is a cytosine arabinoside
Laboratory animal: SCI mouse (KM cleans level), male, body weight 20 ± 2g (x ± s); Provide available from experimentation on animals center, Department Of Medicine, Peking University.One group of per 12 mouse, each one group of blank and positive control.
Knurl source: mouse S 180Sarcoma is provided by experimentation on animals center, Department Of Medicine, Peking University, goes down to posterity voluntarily and keeps.
Solvent: physiological saline, 0.5%CMC-Na solution.
2) dosage setting
Test-compound 2a-t and cytosine arabinoside are made as 8.9 μ mol/kg, all adopt the abdominal cavity single-dose.
3) medicine preparation
Test-compound 2a-t indissoluble in water adds the wetting hydrotropy of a spot of tween 80 during experiment, add 0.5%CMC-Na solution to required concentration gradually and get final product.Cytosine arabinoside is water-soluble, adopts physiological saline solution.
4) dosage and dosage regimen
Test-compound 2a-t is all with the abdominal cavity single-dose.By corresponding dosage once a day, the 0.2ml/ mouse, successive administration 7 days, administration is 7 times altogether.
Negative control is with isopyknic corresponding solution, all with intraperitoneal administration.By corresponding dosage once a day, the 0.2ml/ mouse, successive administration 7 days, administration is 7 times altogether.
Cytosine arabinoside is by the dosage of 8.9 μ mol/kg, intraperitoneal administration.Once a day, the 0.2ml/ mouse, successive administration 7 days, administration is 7 times altogether.
5) animal model
Adopt anti-tumor in vivo armpit subcutaneous vaccination model: under aseptic condition, extract inoculation and get the vigorous S of growth after 7 days 180Ascitic tumor knurl liquid, be diluted to the liquid thorough mixing of (1: 2) with physiological saline, the tumour cell suspension is dyeed with freshly prepared 0.2% trypan blue, count by the white blood cell count(WBC) method behind the mixing, dye blue person and be dead cell, tinter is not a viable cell, is calculated as follows cell concn and cell survival rate.
Viable count/4 * 10 in the big grid in cell concn=4 4* extension rate=cell count/ml
Cell survival rate=viable count/(viable count+dead cell number) * 100%
Survival rate is prepared into 1 * 10 greater than 90% knurl liquid with the homogenate method 7The cell suspension of individual/ml in corresponding host's armpit subcutaneous vaccination 0.2ml/ mouse, is made the solid tumor animal model.
6) detect index and method
7) neurotoxicity is observed in the body
Observe autonomic activities, the mental status, hair, breathing, the diet of the reaction mouse of each treated animal of administration every day, the ight soil proterties.
8) mensuration of solid tumor tumour inhibiting rate and body weight gain
Each is organized successive administration and took off cervical vertebra after 7 days in the 8th day and put to death mouse, takes by weighing body weight (execution body weight), with the fixing right armpit tumor location of mouse of tweezers, cuts off skin then, the exposure tumour, and blunt separation is weighed, and is calculated as follows tumour inhibiting rate.
The average knurl of the average knurl weight-administration of tumour inhibiting rate %=[(negative control group group is heavy)/the average knurl of negative control group is heavy] * 100%
Body weight gain (g)=execution body weight-original body weight-knurl is heavy
9) mensuration of liver weight, spleen index and thymus index
Adopt the mouse after weighting method is promptly peeled off tumour, dissect again and take out brain, liver, kidney and spleen, take by weighing brain heavy (g), liver heavy (g), kidney heavy (g), spleen heavy (mg), and be calculated as follows spleen index.
Spleen index (mg/kg)=spleen weight/execution body weight
10) statistical method
This experimental data statistics all adopts t check and variance analysis, with (x ± SD) expression.
11) experimental result
Test-compound 2a-t is to lotus S 180The anti-tumor in vivo activity experiment result of sarcoma lists table 2 in.Dosage is 8.9 μ mol/kg, and after 7 days, average tumor weight is 1.69 ± 0.61g to 049 ± 0.12g through continuous intraperitoneal administration; The average tumor weight of negative control group is 1.76 ± 0.54g, there are 10 compounds to have remarkable antitumor effect, compound compound 2a wherein, e, i, l, m, anti-tumor activity and the cytosine arabinoside of r (the heavy scope of knurl is 0.49 ± 0.12g to 0.63 ± 0.20g, compares p＜0.05 with the physiological saline group) are suitable.
Table 2 test-compound 2a-t is to lotus S 180The influence of mouse tumor weight a
Figure A20081011440300241
A) Arc (cytosine arabinoside) and 2a-t dosage are 8.9 μ mol/kg, the NS=solvent, and n=12, average knurl heavily is expressed as x ± SD g; B) compare p＜0.01 with NS, compare p＞0.05 with cytosine arabinoside; C) compare p＜0.01 with NS, compare p＜0.05 with cytosine arabinoside;

Claims (5)

1, the compound of Formula I that has anti-tumor activity:
General formula I
AA is selected from Xie Ansuan residue, aspartic acid-γ-benzyl ester, glutamine residue, N in the formula ω-carbobenzoxy-(Cbz) lysine residue, leucine residue, alanine residue, tryptophan residue, O-benzyl serine residue, phenylalanine residue, Isoleucine residue, glycine residue, histidine residues, methionine residue, L-glutamic acid-δ-benzyl ester, asparagine residue, proline residue, to methoxy-benzyl halfcystine, nitro arginine residues, threonine residues or tyrosine residues.
2, a kind of method for preparing the described compound of Formula I of claim 1 comprises:
(1) tryptophan transfer is become the Boc-tryptophane;
(2) tryptophan transfer is become beta-tetrahydro carboline-3-carboxylic acid;
(3) change beta-tetrahydro carboline-3-carboxylic acid into beta-tetrahydro carboline-3-benzyl carboxylate;
(4) change amino acid into amino-acid benzyl ester;
(5) with Boc-tryptophane and beta-tetrahydro carboline-3-benzyl carboxylate condensation prepared 2-(Boc-tryptophyl)-beta-tetrahydro carboline-3-benzyl carboxylate;
(6) 2-(Boc-tryptophyl)-beta-tetrahydro carboline-3-benzyl carboxylate hydrogenolysis is prepared 2-(Boc-tryptophyl)-beta-tetrahydro carboline-3-carboxylic acid;
(7) with 2-(Boc-tryptophyl)-beta-tetrahydro carboline-3-carboxylic acid and prepared amino-acid benzyl ester condensation prepared 2-(Boc-the tryptophyl)-beta-tetrahydro carboline-3-formyl amino acid formyl amino acid benzyl ester of step (4);
(8) 2-(Boc-tryptophyl)-beta-tetrahydro carboline-3-formyl amino acid formyl amino acid benzyl ester is sloughed protecting group Boc, promptly.
3, in accordance with the method for claim 2, it is characterized in that: the amino-acid benzyl ester described in the step (4) is selected from Xie Ansuan benzyl ester, the two benzyl esters of aspartic acid, glutamine benzyl ester, (N ω-carbobenzoxy-(Cbz)) Methionin benzyl ester, leucine benzyl ester, alanine benzyl ester, tryptophan benzyl ester, O-benzyl Serine benzyl ester, Isoleucine benzyl ester, phenylalanine benzyl ester, glycine benzyl ester, the histamine acid benzyl ester, methionine(Met) benzyl ester, the two benzyl esters of L-glutamic acid, l-asparagine benzyl ester, proline(Pro) benzyl ester, to methoxy-benzyl halfcystine benzyl ester, nitro arginine benzyl ester, tyrosine benzyl ester or threonine benzyl ester.
4, a kind of pharmaceutical composition for the treatment of tumour is gone up the described compound of Formula I of claim 1 of significant quantity and pharmaceutically acceptable carrier or auxiliary material by treatment and is formed.
5, the purposes of the described compound of claim 1 in the preparation antitumor drug.
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