CN103509011B - 1-(4-hydroxyl-3-formamido group acidic group-phenyl)-β-carboline, preparation, anti-inflammatory and anti-tumor activity and application - Google Patents

1-(4-hydroxyl-3-formamido group acidic group-phenyl)-β-carboline, preparation, anti-inflammatory and anti-tumor activity and application Download PDF

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CN103509011B
CN103509011B CN201210199828.5A CN201210199828A CN103509011B CN 103509011 B CN103509011 B CN 103509011B CN 201210199828 A CN201210199828 A CN 201210199828A CN 103509011 B CN103509011 B CN 103509011B
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hydroxyl
phenyl
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carbobenzoxy
benzyl ester
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CN103509011A (en
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赵明
彭师奇
王玉记
吴建辉
何浩亮
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Capital Medical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

[in formula, R is H or CH to the invention discloses 17 kinds of compounds of general formula I 2c 6h 5when R is H, AA is selected from L-Ala, L-Ile, L-Phe, L-Asp (OBzl), L-Leu, L-Val, L-Tyr, L-Glu (OBzl), L-Arg (NO 2), L-Trp, L-Met, L-Thr, L-Lys (Z), L-Ser (Me), L-Gly residue; When R is CH 2c 6h 5time AA-OBzl be OBzl jointly], disclose their preparation method, also disclose their anti-inflammatory activity and anti-tumor activity.Thus 17 kinds of compounds of general formula I have anti-inflammatory and antitumor dual function, can be used as tumor prevention and therapeutical agent use.

Description

1-(4-hydroxyl-3-formamido group acidic group-phenyl)-β-carboline, preparation, anti-inflammatory and anti-tumor activity and application
Technical field
(in formula, R is H or CH to the present invention relates to 17 kinds of compounds of general formula I 2c 6h 5, when R is H, AA is selected from L-Ala, L-Ile, L-Phe, L-Asp (OBzl), L-Leu, L-Val, L-Tyr, L-Glu (OBzl), L-Arg (NO 2), L-Trp, L-Met, L-Thr, L-Lys (Z), L-Ser (Me), L-Gly residue; When R is CH 2c 6h 5time AA-OBzl be OBzl jointly), relate to their preparation method, also relate to their anti-inflammatory activity and anti-tumor activity.Thus 17 kinds of compounds of general formula I have anti-inflammatory and antitumor dual function, can be used as tumor prevention and therapeutical agent use.The invention belongs to biomedicine field.
Background technology
The health of the malignant tumour serious threat mankind.According to the data that WHO announces, the year two thousand twenty whole world cancer morbidity will increase by 50%, and the annual newly-increased cancer patients's number in the whole world will reach 1,500 ten thousand people.In the research of cancer therapy drug, from organism, find natural antitumor activity component becomes the important channel finding new lead compound.In 175 kinds of cancer therapy drugs of whole world application, 57% is had directly or indirectly to derive from natural product.
Beta-carboline alkaloid derivative is a class natural product, and in recent years, its anti-tumor activity causes the concern of people.Contriver finds in long-term research, and the anti-tumor activity of β-carboline is rolled into a ball relevant with its two dimensional structure and 1 bit substituent.Introduce suitable substituting group at 1 and can produce non-cytotoxicity anti-tumor compounds.
O-hydroxy formyl amino acid formyl amino acid is outstanding anti-inflammatory group.Contriver recognizes according to the experience of studying for a long period of time, o-hydroxy formyl amino acid formyl amino acid is connected to 1 of β-carboline, not only can produce the new antitumoral compounds that anti-tumor activity is strong and toxicity is low, and compound can be made to obtain anti-inflammatory action.Inflammation played an important role in the stage such as tumorigenesis and transfer.Clinical study also shows, the medicine of anti-inflammatory can reduce inflammation part generation canceration to a certain extent.According to this understanding, the present invention proposes the compound with anti-inflammatory and antitumor dual function.
Summary of the invention
One of content of the present invention is to provide 17 kinds of compounds of general formula I representative, and in formula, R is H or CH 2c 6h 5, when R is H, AA is selected from L-Ala, L-Ile, L-Phe, L-Asp (OBzl), L-Leu, L-Val, L-Tyr, L-Glu (OBzl), L-Arg (NO 2), L-Trp, L-Met, L-Thr, L-Lys (Z), L-Ser (Me), L-Gly residue; When R is CH 2c 6h 5time AA-OBzl be OBzl jointly
(1) by the nucleophilic substitution of haloalkane 5-formylsalicylic acid and bromobenzyl reacted and generate 5-formylsalicylic acid benzyl ester;
(2) by Pictet-Spengler condensation 5-formylsalicylic acid benzyl ester and tryptamines reacted and generate 1-(4-hydroxyl-3-carbobenzoxy-(Cbz)-phenyl)-1,2,3,4-tetrahydro-beta-carbolines;
(3) with potassium permanganate, 1-(4-hydroxyl-3-carbobenzoxy-(Cbz)-phenyl)-1,2,3,4-tetrahydro-beta-carbolines are oxidized to 1-(4-hydroxyl-3-carbobenzoxy-(Cbz)-phenyl)-3,4-dihydros-β-carboline;
(4) under dicyclohexylcarbodiimide (DCC) and I-hydroxybenzotriazole (HOBt) exist, 5-formylsalicylic acid and L-amino-acid benzyl ester generate 4-hydroxyl-3-formyl amino acid formyl amino acid benzyl ester benzaldehyde;
(5) 4-hydroxyl-3-formyl amino acid formyl amino acid benzyl ester benzaldehyde and tryptamines carry out Pictet-Spengler condensation and generate 1-(4-hydroxyl-3-formyl amino acid formyl amino acid benzyl ester base-phenyl)-1,2,3,4-tetrahydro-beta-carbolines;
(6) with potassium permanganate, 1-(4-hydroxyl-3-formyl amino acid formyl amino acid benzyl ester base-phenyl)-1,2,3,4-tetrahydro-beta-carbolines are oxidized to 1-(4-hydroxyl-3-formyl amino acid formyl amino acid benzyl ester base-phenyl)-3,4-dihydros-β-carboline.
3rd content of the present invention is the anti-tumor activity of the 17 kinds of compounds evaluating general formula I representative.
4th content of the present invention is the anti-inflammatory activity of the 17 kinds of compounds evaluating general formula I representative.
5th content of the present invention is that 17 kinds of compounds of illustrating general formula I representative are preparing the application in anti-inflammatory and antitumor double activity medicine.
Accompanying drawing explanation
Fig. 1. prepare the synthetic route .i of compound in general formula I) NaHCO 3, DMF; Ii) DCC, HOBt, NMM; Iii) HAc, 80 DEG C; Iv) KMnO 4.5a middle AA is L-Ala residue, in 5b, AA is L-Ile residue, in 5c, AA is L-Phe residue, in 5d, AA is L-Asp (OBzl) residue, in 5e, AA is L-Leu residue, and in 5f, AA is L-Val residue, and in 5g, AA is L-Tyr residue, in 5h, AA is L-Glu (OBzl) residue, and in 5i, AA is L-Arg (NO 2) residue, in 5j, AA is L-Trp residue, and in 5k, AA is L-Met residue, and in 5l, AA is L-Thr residue, and in 5m, AA is L-Lys (Z) residue, and in 5n, AA is L-Ser (Me) residue, and in 5o, AA is L-Gly residue, and in 5p, R is that in H, 5q, R is CH 2c 6h 5.
The shortenings occurred in the present invention
Embodiment
In order to set forth the present invention further, provide a series of embodiment below.These embodiments are illustrative completely, and they are only used for being specifically described the present invention, not should be understood to limitation of the present invention.
Embodiment 1 prepares 1-(4-hydroxyl-3-carbobenzoxy-(Cbz)-phenyl)-3,4-dihydros-β-carboline (5p)
By 1.66g (10mmol) 5-formylsalicylic acid aldehyde and 924mg (11mmol) NaHCO under ice bath 3solid is dissolved in 30mL dry DMF.In the solution obtained, be added dropwise to 1.2mL (11mmol) bromobenzyl and stir, solution becomes faint yellow.Stirring at room temperature 24h, TLC (CH 2cl 2: CH 3oH=15: 1) display reaction terminates.A large amount of frozen water is added in reaction solution, faint yellow solid is had to separate out in reaction solution, filter after stirring 1h, the solid with ethyl acetate filtered dissolves, solution anhydrous sodium sulfate drying, filtration, filtrate reduced in volume are extremely dry, residue ether dissolution, and room temperature is placed, separating out 788mg (30%) 5-formylsalicylic acid benzyl ester, is needle-like crystal.768mg (3mmol) gained 5-formylsalicylic acid benzyl ester and 528mg tryptamines (3.3mmol) 10mL Glacial acetic acid are dissolved, reacts 48h under 80 DEG C of oil baths, TLC (CH 2cl 2: CH 3oH=20: 1) display reaction terminates.Add 200ml distilled water after question response liquid cools, have brown solid to separate out.This solid CH 2cl 2(30mL × 3) extract, the solution anhydrous sodium sulfate drying obtained, filtration, filtrate reduced in volume, residue column chromatographic isolation and purification (CH 2cl 2: CH 3oH=50: 1) 586mg (50%) 1-(4-hydroxyl-3-carbobenzoxy-(Cbz))-1,2,3,4-tetrahydro-beta-carbolines, are obtained.520mg (1.3mmol) 1-(4-hydroxyl-3-carbobenzoxy-(Cbz))-1,2,3,4-tetrahydro-beta-carboline acetone solutions, add 288mg (1.8mmol) KMnO in batches 4, after reaction 48h, TLC plate display (CH 2cl 2: CH 3oH=20: 1) 1-(4-hydroxyl-3-carbobenzoxy-(Cbz)-phenyl)-1,2,3,4-tetrahydro-beta-carboline disappears, and adds methyl alcohol termination reaction, filters out the residue in reaction solution, and by washed with methanol, direct column chromatographic isolation and purification (CH after gained filtrate reduced in volume 2cl 2: CH 3oH=50: 1).Obtaining 308mg (60%) title compound, is faint yellow solid.Mp 126-127 DEG C. (c=0.5, methyl alcohol) .ESI-MS (m/e) 397 [M+H] +.IR (KBr) 3405,3286,2949,2832,1709,1677,1592,1542,1444,1410,1376,1313,1289,1208,1155,1068,739,697. 1hNMR (300MHz, DMSO-d6) 8.24 (d, J=0.7Hz, 1H), 7.94 (m, 1H), 7.62 (d, J=2.6Hz, 1H), 7.52 ~ 7.32 (m, 6H), 7.24 (t, J=2.4Hz, 1H), 7.15 ~ 7.04 (m, 2H), 5.41 (s, 2H), 3.84 (t, J=2.8Hz, 2H), 2.85 (t, J=2.7Hz, 2H).
Embodiment 2 prepares 4-hydroxyl-3-carbamino alanine carbobenzoxy-phenyl aldehyde (3a)
By the anhydrous CH of 2.49g (15mmol) 5-formylsalicylic acid aldehyde under ice bath 2cl 2dissolve.2.13g (15.75mmol) HOBt is first added in the solution obtained, then 4.33g (21mmol) DCC is added, after stirring half hour, add the tosilate of 5.79g (16.5mmol) ALANINE benzyl ester again, regulate pH to 9 with NMM, after reaction 8h, TLC (CH 2cl 2: CH 3oH=20: 1) tosilate showing ALANINE benzyl ester disappears, filter out the DCU generated in reaction, filtrate is washed (30mL × 3) with saturated sodium bicarbonate aqueous solution successively, saturated sodium-chloride water solution is washed (30mL × 3), aqueous potassium hydrogen sulfate is washed (5%, 30mL × 3), saturated sodium-chloride water solution is washed (30mL × 3), saturated sodium bicarbonate aqueous solution is washed (30mL × 3), saturated sodium-chloride water solution is washed (30mL × 3), anhydrous sodium sulfate drying.Filtration, filtrate reduced in volume are to dry.Residue column chromatography purification (CH 2cl 2: CH 3oH=40: 1) 4.32g (88%) 4-hydroxyl-3-carbamino alanine carbobenzoxy-phenyl aldehyde (3a) .Mp 93-94 DEG C, is obtained. (c=0.5, methyl alcohol) .ESI-MS (m/e) 326 [M-H] -.IR (KBr): 3321,3069,3038,2930,2853,1742,1676,1641,1582,1541,1493,1452,1387,1327,1302,1292,1163,1072,959,889,837,733,692,615,536. 1hNMR (300MHz, DMSO-d6) δ/ppm=9.85 (s, 1H), 8.52 (d, J=0.7Hz, 1H), 7.93 (d, J=2.1Hz, 1H), 7.44 ~ 7.30 (m, 5H), 7.08 (d, J=2.8Hz, 1H), 5.18 (s, 2H), 4.65 ~ 4.59 (m, 1H), 1.47 (d, J=2.4Hz, 3H).
Embodiment 3 prepares 1-(4-hydroxyl-3-carbamino alanine carbobenzoxy-phenyl)-1,2,3,4-tetrahydro-beta-carbolines (4a)
3.27g (10mmol) 4-hydroxyl-3-carbamino alanine carbobenzoxy-phenyl aldehyde (3a) is dissolved with 1.76g (11mmol) tryptamines 30mL Glacial acetic acid, after 80 DEG C of reaction 48h, TLC (CH 2cl 2/ CH 3oH=15/1) show 3a to disappear, reaction solution adds a large amount of distilled water after being chilled to room temperature, has yellow-brown solid to separate out, uses CH 2cl 2(30mL × 3) extract, CH 2cl 2layer anhydrous sodium sulfate drying, filtration, filtrate reduced in volume, residue column chromatographic isolation and purification (CH 2cl 2: CH 3oH=50: 1), obtain 1.5g (32%) 1-(4-hydroxyl-3-carbamino alanine carbobenzoxy-phenyl)-1,2,3,4-tetrahydro-beta-carboline (4a), for relative proportion is diastereomer (1R, the 3S)-body of 1: 1 and the mixture of (1S, 3S)-body.Isomer is not separated and is directly used in next step oxidizing reaction.(1R, 3S)-body: 1hNMR (300MHz, DMSO-d6) δ/ppm=10.53 (s, 1H), 7.99 (s, 1H), 7.46 (s, 1H), 7.37 ~ 7.33 (m, 5H), 7.31 ~ 7.25 (m, 2H), 7.07 ~ 6.91 (m, 3H), 5.28 (s, 1H), 5.17 (s, 1H), 4.61 ~ 4.57 (m, 1H), 3.27 ~ 3.18 (m, 1H), 3.13 ~ 3.05 (m, 1H), 2.95 ~ 2.74 (m, 2H), 1.91 (s, 1H), 1.45 (d, J=2.4Hz, 3H). (1S, 3S)-body: 1hNMR (300MHz, DMSO-d6) δ/ppm=10.51 (s, 1H), 7.99 (s, 1H), 7.49 (s, 1H), 7.37 ~ 7.33 (m, 5H), 7.31 ~ 7.25 (m, 2H), 7.07 ~ 6.91 (m, 3H), 5.28 (s, 1H), 5.17 (s, 1H), 4.61 ~ 4.57 (m, 1H), 3.27 ~ 3.18 (m, 1H), 3.13 ~ 3.05 (m, 1H), 2.95 ~ 2.74 (m, 2H), 1.91 (s, 1H), 1.45 (d, J=2.4Hz, 3H).
Embodiment 4 prepares 1-(4-hydroxyl-3-carbamino alanine carbobenzoxy-phenyl)-3,4-dihydros-β-carboline (5a)
By 1.41g (3mmol) 1-(4-hydroxyl-3-carbamino alanine carbobenzoxy-phenyl)-1,2,3,4-tetrahydro-beta-carboline (4a) acetone solution, adds 929mg (4.2mmol) KMnO in the solution obtained in batches 4, after reaction 48h, TLC (CH 2cl 2: CH 3oH=20: 1) show 4a to disappear, add methyl alcohol termination reaction.Residue in filtering reaction solution, the residue washed with methanol of filtering, the filtrate reduced in volume of merging, residue uses column chromatography purifying (CH 2cl 2/ CH 3oH=50: 1), obtaining 450mg (41%) 5a, is faint yellow solid.Mp 181-183 DEG C. (c=0.5, methyl alcohol) .ESI-MS (m/e) 588 [M+H] +.IR (KBr): 3406,2936,1741,1638,1572,1534,1480,1451,1433,1373,1332,1254,1227,1189,1154,1044,837,745,697. 1hNMR (300MHz, DMSO-d6) δ/ppm=8.46 (s, 1H), 7.75. (d, J=3.0Hz, 1H), 7.66 (d, J=3.0Hz, 1H), 7.54 (d, J=3.0Hz, 1H), 7.38 ~ 7.34 (m, 6H), 7.17 (t, J=2.5Hz 1H), 6.58 (s, 1H), 5.16 (s, 2H), 4.59 (m, 1H), 3.78 (t, J=2.4Hz, 2H), 3.12 (s, 2H), 1.42 (d, J=2.4Hz, 3H).
Embodiment 5 prepares 4-hydroxyl-3-formyl Isoleucine carbobenzoxy-phenyl aldehyde (3b)
Prepare the method for compound 3a by embodiment 2, obtain 4.65g (84%) 3b from 6.48g (16.5mmol) tosic acid ILE benzyl ester.Mp 86 DEG C. (c=0.5, methyl alcohol) .ESI-MS (m/e) 368 [M-H] -.IR (KBr): 3360,2965,2934,1736,1695,1641,1585,1541,1491,1456,1387,1302,1198,1148,1088,964,833,745,696,619. 1hNMR (300MHz, DMSO-d6) δ/ppm=9.87 (s, 1H), 8.55 (d, J=0.7Hz, 1H), 7.94 (d, J=2.7Hz, 1H), 7.40 ~ 7.30 (m, 5H), 7.12 (d, J=2.8Hz, 1H), 5.19 (d, J=1.8Hz, 2H), 4.57 ~ 4.52 (m, 1H), 2.03 ~ 1.98 (m, 1H), 1.28 ~ 1.18 (m, 2H), 0.92 ~ 0.84 (m, 6H).
Embodiment 6 prepares 1-(4-hydroxyl-3-formyl Isoleucine carbobenzoxy-phenyl)-1,2,3,4-tetrahydro-beta-carbolines (4b)
Prepare the method for compound 4a by embodiment 3, obtain 1.58g (31%) 4b from the different bright carbobenzoxy-phenyl aldehyde (3b) of 3.69g (10mmol) 4-hydroxyl-3-formyl.For relative proportion is diastereomer (1R, the 3S)-body of 1: 1 and the mixture of (1S, 3S)-body.Isomer is not separated and is directly used in next step oxidizing reaction.(1R, 3S)-body: 1hNMR (300MHz, DMSO-d6) δ/ppm=10.53 (s, 1H), 7.89 (s, 2H), 7.46 (s, 1H), 7.36 ~ 7.32 (m, 5H), 7.18 (d, J=2.8Hz, 1H), 7.07 ~ 6.89 (m, 3H), 5.30 (s, 1H), 5.16 (s, 1H), 4.54 (s, 1H), 3.21 ~ 3.18 (m, 1H), 3.11 ~ 3.05 (m, 1H), 2.91 ~ 2.74 (m, 2H), 1.90 (s, 1H), 1.46 ~ 1.42 (m, 1H), 1.27 ~ 1.17 (m, 1H), 0.91 (d, J=2.2Hz, 3H), 0.86 ~ 0.81 (m, 3H). (1S, 3S)-body: 1hNMR (300MHz, DMSO-d6) δ/ppm=10.53 (s, 1H), 7.89 (s, 2H), 7.44 (s, 1H), 7.36 ~ 7.32 (m, 5H), 7.24 (d, J=2.8Hz, 1H), 7.07 ~ 6.89 (m, 3H), 5.30 (s, 1H), 5.15 (s, 1H), 4.54 (s, 1H), 3.21 ~ 3.18 (m, 1H), 3.11 ~ 3.05 (m, 1H), 2.91 ~ 2.74 (m, 2H), 1.90 (s, 1H), 1.46 ~ 1.42 (m, 1H), 1.27 ~ 1.17 (m, 1H), 0.91 (d, J=2.2Hz, 3H), 0.86 ~ 0.81 (m, 3H).
Embodiment 7 prepares 1-(4-hydroxyl-3-formyl Isoleucine carbobenzoxy-phenyl)-3,4-dihydros-β-carboline (5b)
Prepare the method for compound 5a by embodiment 4, obtain 321mg (21%) 5b from 1-(4-hydroxyl-3-formyl Isoleucine carbobenzoxy-phenyl)-1,2,3,4-tetrahydro-beta-carbolines (4b).Mp 167-168 DEG C. (c=0.5, methyl alcohol) .ESI-MS (m/e) 510 [M+H] +.IR (KBr): 3413,2962,1738,1634,1572,1528,1480,1432,1377,1334,1225,1190,1153,745. 1hNMR (300MHz, DMSO-d6) δ/ppm=11.92 (s, 1H), 11.53 (s, 1H), 8.48 (d, J=1.0Hz, 1H), 7.76. (d, J=2.6Hz, 1H), 7.70 (m, 1H), 7.51 (d, J=2.8Hz, 1H), 7.41 ~ 7.28 (m, 6H), 7.18 (t, J=2.5Hz 1H), 6.60 (d, J=2.6Hz, 1H), 5.18 (s, 2H), 4.55 (m, 1H), 3.77 (t, J=2.5Hz, 2H), 3.15 (t, J=2.5Hz, 2H), 1.92 (s, 1H), 1.43 (m, 1H), 1.26 (m, 1H), 0.88 ~ 0.83 (m, 6H).
Embodiment 8 prepares 4-hydroxyl-3-formyl phenylalanine carbobenzoxy-phenyl aldehyde (3c)
Prepare the method for compound 3a by embodiment 2, obtain 5.44g (90%) 3c from 7.05g (16.5mmol) tosic acid L-Phe benzyl ester.Mp 105-106 DEG C. (c=0.5, methyl alcohol) .ESI-MS (m/e) 402 [M-H] -.IR (KBr): 3335,3254,3061,3034,2934,2851,2727,1742,1680,1641,1578,1541,1493,1456,1369,1310,1277,1198,1153,1088,959,843,741,696,625,529. 1hNMR (500MHz, DMSO-d6) δ/ppm=9.86 (s, 1H), 8.48 (s, 1H), 7.93 (d, J=2.2Hz, 1H), 7.39 ~ 7.20 (m, 10H), 7.09 (d, J=2.9Hz, 1H), 5.16 (s, 2H), 4.90 ~ 4.83 (m, 1H), 3.23 ~ 3.10 (m, 2H).
Embodiment 9 prepares 1-(4-hydroxyl-3-formyl phenylalanine carbobenzoxy-phenyl)-1,2,3,4-tetrahydro-beta-carbolines (4c)
Prepare the method for compound 4a by embodiment 3, obtain 1.8g (33%) 4c from 4.03g (10mmol) 4-hydroxyl-3-formyl phenylalanine carbobenzoxy-phenyl aldehyde (3c).For relative proportion is diastereomer (1R, the 3S)-body of 1: 1 and the mixture of (1S, 3S)-body.(1R, 3S)-body: 1hNMR (300MHz, DMSO-d6) δ/ppm=10.59 (s, 1H), 7.93 (d, J=0.7Hz, 1H), 7.76 (s, 1H), 7.35 ~ 7.15 (m, 12H), 7.09 ~ 6.97 (m, 3H), 6.89 (s, 1H), 5.41 (s, 1H), 5.13 (s, 2H), 4.84 ~ 4.79 (m, 1H), 3.16 ~ 3.08 (m, 2H), 1.91 ~ 1.82 (m, 1H). (1S, 3S)-body: 1hNMR (300MHz, DMSO-d6) δ/ppm=10.59 (s, 1H), 7.91 (d, J=0.7Hz, 1H), 7.48 (s, 1H), 7.35 ~ 7.15 (m, 12H), 7.09 ~ 6.97 (m, 3H), 6.91 (s, 1H), 5.41 (s, 1H), 5.13 (s, 2H), 4.84 ~ 4.79 (m, 1H), 3.16 ~ 3.08 (m, 2H), 1.91 ~ 1.82 (m, 1H).
Embodiment 10 prepares 1-(4-hydroxyl-3-formyl phenylalanine carbobenzoxy-phenyl)-3,4-dihydros-β-carboline (5c)
Prepare the method for compound 5a by embodiment 4, obtain 374mg (21%) 5c from 1.63g (3mmol) 1-(4-hydroxyl-3-formyl phenylalanine carbobenzoxy-phenyl)-1,2,3,4-tetrahydro-beta-carbolines (4c).Mp 176-176 DEG C. (c=0.5, methyl alcohol) .ESI-MS (m/e) 544 [M+H] +.IR (KBr): 3421,2929,1741,1638,1572,1544,1517,1482,1432,1378,1332,1227,1187,744,698. 1h-NMR (300MHz, DMSO-d6) δ/ppm=8.44. (d, J=0.8Hz, 1H), 7.75 (d, J=1.3Hz, 1H), 7.66 (m, 1H), 7.54 (d, J=3.8Hz, 1H), 7.39 ~ 7.15 (m, 12H), 6.59 (s, 1H), 5.11 (d, J=0.6Hz, 2H), 4.81 (m, 2H), 3.76 (t, J=2.6Hz, 2H), 3.17 ~ 3.03 (m, 4H).
Embodiment 11 prepares the two carbobenzoxy-phenyl aldehyde (3d) of 4-hydroxyl-3-carbamyl aspartic acid
Prepare the method for compound 3a by embodiment 2, obtain 5.88g (85%) 3d from the two benzyl ester of 8g (16.5mmol) tosic acid L-Aspartic acid.Mp 94-96 DEG C. (c=0.5, methyl alcohol) .ESI-MS (m/e) 460 [M-H] -.IR (KBr): 3381,3065,3038,2953,2903,2839,2810,2741,1748,1717,1695,1639,1589,1549,1485,1458,1379,1356,1300,1217,1194,1126,1069,957,907,860,831,754,704,619,583,511. 1hNMR (500MHz, DMSO-d6) δ/ppm=12.82 (s, 1H), 9.87 (s, 1H), 8.47 (d, J=0.7Hz, 1H), 7.96 (d, J=2.3Hz, 1H), 7.35 ~ 7.27 (m, 10H), 7.13 (d, J=2.8Hz, 1H), 5.16 (s, 2H), 5.10 (s, 2H), 5,05 ~ 5,03 (m, 1H), 3.10 (t, J=1.9Hz, 2H).
Embodiment 12 prepares 1-(the two carbobenzoxy-phenyl of 4-hydroxyl-3-carbamyl aspartic acid)-1,2,3,4-tetrahydro-beta-carbolines (4d)
Prepare the method for compound 4a by embodiment 3, obtain 2.23g (37%) 4d from the two carbobenzoxy-phenyl aldehyde (3d) of 4.61g (10mmol) 4-hydroxyl-3-carbamyl aspartic acid.For relative proportion is diastereomer (1R, the 3S)-body of 1: 1 and the mixture of (1S, 3S)-body.(1R, 3S)-body: 1hNMR (300MHz, DMSO-d6) δ/ppm=10.45 (s, 1H), 7.91 ~ 7.88 (m, 1H), 7.51 (s, 1H), 7.45 (s, 1H), 7.38 ~ 7.26 (m, 10H), 7.25 (s, 1H), 7.05 ~ 6.90 (m, 3H), 5.18 (s, 1H), 5.14 (s, 2H), 5.08 (s, 2H), 5.05 ~ 5.01 (m, 1H), 3.21 ~ 3.14 (m, 1H), 3.05 ~ 3.01 (m, 3H), 2.89 ~ 2.70 (m, 2H), 1.91 (s, 1H). (1S, 3S)-body: 1hNMR (300MHz, DMSO-d6) δ/ppm=10.45 (s, 1H), 7.91 ~ 7.88 (m, 1H), 7.51 (s, 1H), 7.42 (s, 1H), 7.38 ~ 7.26 (m, 10H), 7.22 (s, 1H), 7.05 ~ 6.90 (m, 3H), 5.18 (s, 1H), 5.14 (s, 2H), 5.08 (s, 2H), 5.05 ~ 5.01 (m, 1H), 3.21 ~ 3.14 (m, 1H), 3.05 ~ 3.01 (m, 3H), 2.89 ~ 2.70 (m, 2H), 1.91 (s, 1H).
Embodiment 13 prepares 1-(the two carbobenzoxy-phenyl of 4-hydroxyl-3-carbamyl aspartic acid)-3,4-dihydros-β-carboline (5d)
The method of compound 5a is prepared by embodiment 4, from 1.81g (3mmol) 1-(the two carbobenzoxy-phenyl of 4-hydroxyl-3-carbamyl aspartic acid)-1,2,3,4-tetrahydro-beta-carboline (4d) obtains 414mg (23%) 5d.Mp 168-169 DEG C. (c=0.5, methyl alcohol) .ESI-MS (m/e) 602.3 [M+H] +.IR (KBr): 3424,2924,1738,1639,1580,1545,1512,1483,1433,1377,1332,1226,1186,744,698. 1hNMR (300MHz, DMSO-d6) δ/ppm=8.47. (d, J=0.8Hz, 1H), 7.75. (d, J=1.4Hz, 1H), 7.67 (m, 1H), 7.55 (d, J=3.8Hz, 1H), 7.39 ~ 7.33 (m, 11H), 7.17 (t, J=2.5Hz 1H), 6.62 (s, 1H), 5.13 (s, 2H), 5.09 (s, 2H), 5.03 (t, J=2.0Hz, 1H), 3.77 (t, J=2.5Hz, 2H), 3.13 (s 2H), 3.0 (d, J=1.0Hz, 2H).
Embodiment 14 prepares 4-hydroxyl-3-formyl leucine carbobenzoxy-phenyl aldehyde (3e)
Prepare the method for compound 3a by embodiment 2, obtain 4.82g (87%) 3e from 6.48g (16.5mmol) tosic acid L-Leu benzyl ester.Mp 87-88 DEG C. (c=0.5, methyl alcohol) .ESI-MS (m/e) 368 [M-H] -.IR (KBr): 2928,2851,1746,1697,1638,1566,1491,1389,1206,1078,949,835,741,669. 1hNMR (300MHz, DMSO-d6) δ/ppm=9.87 (s, 1H), 8.54 (d, J=0.5Hz, 1H), 7.95 (d, J=2.3Hz, 1H), 7.35 ~ 7.30 (m, 5H), 7.11 (d, J=1.9Hz, 1H), 5.18 (d, J=0.7Hz, 2H), 4.67 ~ 4.61 (m, 1H), 1.93 ~ 1.91 (m, 2H), 1.50 ~ 1.48 (m, 1H), 0.92 (d, J=2.0Hz, 6H).
Embodiment 15 prepares 1-(4-hydroxyl-3-formyl leucine carbobenzoxy-phenyl)-1,2,3,4-tetrahydro-beta-carbolines (4e)
Prepare the method for compound 4a by embodiment 3, obtain 1.73g (31%) 4e from 3.69g (10mmol) 4-hydroxyl-3-formyl leucine carbobenzoxy-phenyl aldehyde (3e).For relative proportion is diastereomer (1R, the 3S)-body of 1: 1 and the mixture of (1S, 3S)-body.(1R, 3S)-body: 1hNMR (300MHz, DMSO-d6) δ/ppm=10.47 (s, 1H), 7.94 ~ 7.91 (m, 1H), 7.42 (s, 1H), 7.36 ~ 7.28 (m, 5H), 7.24 ~ 7.16 (m, 2H), 7.03 ~ 6.96 (m, 2H), 6.89 (s, 1H), 5.19 (s, 1H), 5.15 (s, 2H), 4.61 ~ 4.57 (m, 1H), 3.23 ~ 3.18 (m, 1H), 3.07 ~ 2.95 (m, 1H), 2.98 ~ 2.70 (m, 2H), 1.90 (s, 1H), 1.76 ~ 1.59 (m, 3H), 0.92 ~ 0.89 (m, 6H). (1S, 3S)-body: 1hNMR (300MHz, DMSO-d6) δ/ppm=10.45 (s, 1H), 7.94 ~ 7.91 (m, 1H), 7.45 (s, 1H), 7.36 ~ 7.28 (m, 5H), 7.24 ~ 7.16 (m, 2H), 7.03 ~ 6.96 (m, 2H), 6.86 (s, 1H), 5.19 (s, 1H), 5.15 (s, 2H), 4.61 ~ 4.57 (m, 1H), 3.23 ~ 3.18 (m, 1H), 3.07 ~ 2.95 (m, 1H), 2.98 ~ 2.70 (m, 2H), 1.90 (s, 1H), 1.76 ~ 1.59 (m, 3H), 0.92 ~ 0.89 (m, 6H).
Embodiment 16 prepares 1-(4-hydroxyl-3-formyl leucine carbobenzoxy-phenyl)-3,4-dihydros-β-carboline (5e)
With preparing the identical method of embodiment 4 compound 5a, with 1.45g (3mmol) 1-(4-hydroxyl-3-formyl leucine carbobenzoxy-phenyl)-1,2,3,4-tetrahydro-beta-carboline (4e) obtains 306mg (20%) 5e.Mp 163-164 DEG C. (c=0.5, methyl alcohol) .ESI-MS (m/e) 510.3 [M+H] +.IR (KBr): 3420,3060,2953,1741,1634,1572,1527,1503,1480,1433,1376,1333,1227,1189,1153,745,698. 1h-NMR (300MHz, DMSO-d6) δ/ppm=8.48. (d, J=0.9Hz, 1H), 7.75. (d, J=1.7Hz, 1H), 7.67 (m, 1H), 7.55 (d, J=2.7Hz, 1H), 7.40 ~ 7.29 (m, 6H), 7.15 (t, J=2.3Hz, 1H), 6.62 (d, J=3.0Hz, 1H), 5.15 (s, 2H), 4.61 (m, 1H), 3.78 (t, J=2.6Hz, 2H), 3.13 (t, J=2.6Hz, 2H), 1.72 ~ 1.57 (m, 3H), 0.93 ~ 0.87 (m, 6H).
Embodiment 17 prepares 4-hydroxyl-3-formyl α-amino-isovaleric acid carbobenzoxy-phenyl aldehyde (3f)
Prepare the method for compound 3a by embodiment 2, obtain 4.79g (90%) 3f from 6.25g (16.5mmol) tosic acid Valine benzyl ester.Mp 115-116 DEG C. (c=0.5, methyl alcohol) .ESI-MS (m/e) 354 [M-H] -.IR (KBr): 3350,2965,2934,2853,1736,1692,1641,1585,1535,1491,1379,1302,1200,1146,829,754,696,623,538. 1hNMR (300MHz, DMSO-d6) δ/ppm=9.88 (s, 1H), 8.54 (d, J=0.7Hz, 1H), 7.94 (d, J=2.1Hz, 1H), 7.44 ~ 7.35 (m, 5H), 7.12 (d, J=2.8Hz, 1H), 5.19 (d, J=1.4Hz, 2H), 4.52 ~ 4.47 (m, 1H), 2.27 ~ 2.18 (m, 1H), 0.95 (d, J=2.3Hz, 6H).
Embodiment 18 prepares 1-(4-hydroxyl-3-formyl α-amino-isovaleric acid carbobenzoxy-phenyl)-1,2,3,4-tetrahydro-beta-carbolines (4f)
Prepare the method for compound 4a by embodiment 3, obtain 1.75g (34%) 4f from 3.55g (10mmol) 4-hydroxyl-3-formyl α-amino-isovaleric acid carbobenzoxy-phenyl aldehyde (3f).For relative proportion is diastereomer (1R, the 3S)-body of 1: 1 and the mixture of (1S, 3S)-body.(1R, 3S)-body: 1hNMR (300MHz, DMSO-d6) δ/ppm=10.49 (s, 1H), 9.70 (s, 1H), 7.90 ~ 7.98 (m, 1H), 7.46 (s, 1H), 7.39 ~ 7.28 (m, 4H), 7.22 ~ 7.18 (m, 2H), 7.06 ~ 6.88 (m, 3H), 5.27 (s, 1H), 5.15 (s, 2H), 4.48 (s, 1H), 4.30 ~ 4.18 (m, 1H), 3.22 ~ 3.03 (m, 2H), 2.91 ~ 2.73 (m, 2H), 2.23 ~ 2.14 (m, 1H), 0.92 (d, J=2.3Hz, 6H). (1S, 3S)-body: 1hNMR (300MHz, DMSO-d6) δ/ppm=10.49 (s, 1H), 9.70 (s, 1H), 7.90 ~ 7.98 (m, 1H), 7.43 (s, 1H), 7.39 ~ 7.28 (m, 4H), 7.22 ~ 7.18 (m, 2H), 7.06 ~ 6.88 (m, 3H), 5.27 (s, 1H), 5.16 (s, 2H), 4.48 (s, 1H), 4.30 ~ 4.18 (m, 1H), 3.22 ~ 3.03 (m, 2H), 2.91 ~ 2.73 (m, 2H), 2.23 ~ 2.14 (m, 1H), 0.92 (d, J=2.3Hz, 6H).
Embodiment 19 prepares 1-(4-hydroxyl-3-formyl α-amino-isovaleric acid carbobenzoxy-phenyl)-3,4-dihydros-β-carboline (5f)
Prepare the method for compound 5a by embodiment 4, obtain 371mg (25%) 5f from 1.49g (3mmol) 1-(4-hydroxyl-3-formyl α-amino-isovaleric acid carbobenzoxy-phenyl)-1,2,3,4-tetrahydro-beta-carbolines (4f).Mp 162-163 DEG C. (c=0.5, methyl alcohol) .ESI-MS (m/e) 496 [M+H] +.IR (KBr): 3422,2961,1738,1632,1572,1535,1502,1481,1433,1376,1334,1228,1190,1152,746,695. 1h-NMR (300MHz, DMSO-d6) δ/ppm=8.47. (d, J=0.9Hz, 1H), 7.77. (d, J=2.7Hz, 1H), 7.65 (m, 1H), 7.55 (d, J=2.8Hz, 1H), 7.39 ~ 7.26 (m, 6H), 7.18 (t, J=2.5Hz, 1H), 6.56 (d, J=2.5Hz, 1H), 5.16 (s, 2H), 4.48 (d, J=1.8Hz, 1H), 3.77 (t, J=2.5Hz, 2H), 3.15 (s, 2H), 2.22 ~ 2.09 (m, 1H), 0.93 (d, J=1.8Hz, 6H).
Embodiment 20 prepares 4-hydroxyl-3-formyltyrosine carbobenzoxy-phenyl aldehyde (3g)
Prepare the method for compound 3a by embodiment 2, obtain 5.22g (83%) 3g from 7.31g (16.5mmol) tosic acid TYR benzyl ester.Mp 83-84 DEG C. (c=0.5, methyl alcohol) .ESI-MS (m/e) 418 [M-H] -.IR (KBr): 3323,2930,2853,1744,1692,1639,1582,1516,1452,1383,1302,1271,1196,957,818,754,696,536. 1hNMR (500MHz, DMSO-d6) δ/ppm=9.87 (s, 1H), 8.52 (s, 1H), 8.05 (d, J=1.3Hz, 1H), 7.38 ~ 7.31 (m, 7H), 7.21 (t, J=1.4Hz, 1H), 7.11 (d, J=1.7Hz, 1H), 7.03 (d, J=1.7Hz, 2H), 6.67 (d, J=1.9Hz, 2H), 5.16 (s, 2H), 4.82 ~ 4.78 (m, 1H), 3.14 ~ 3.05 (m, 2H).
Embodiment 21 prepares 1-(4-hydroxyl-3-formyltyrosine carbobenzoxy-phenyl)-1,2,3,4-tetrahydro-beta-carbolines (4g)
Prepare the method for compound 4a by embodiment 3, obtain 1.68g (30%) 4g with 4.19g (10mmol) 4-hydroxyl-3-formyltyrosine carbobenzoxy-phenyl aldehyde (3g).For relative proportion is diastereomer (1R, the 3S)-body of 1: 1 and the mixture of (1S, 3S)-body.(1R, 3S)-body: 1hNMR (300MHz, DMSO-d6) δ/ppm=10.42 (s, 1H), 7.94 (s, 1H), 7.48 (s, 1H), 7.40 (s, 1H), 7.32 ~ 7.24 (m, 4H), 7.23 ~ 7.16 (m, 2H), 7.12 ~ 6.94 (m, 4H), 6.86 (d, J=0.8Hz, 1H), 6.64 (s, 1H), 5.13 (s, 2H), 5.07 (s, 1H), 4.84 ~ 4.68 (m, 1H), 3.18 ~ 3.11 (m, 2H), 3.00 ~ 2.92 (m, 2H), 2.75 ~ 2.64 (m, 2H), 1.89 (s, 1H). (1S, 3S)-body: 1hNMR (300MHz, DMSO-d6) δ/ppm=10.34 (s, 1H), 7.83 (s, 1H), 7.46 (s, 1H), 7.36 (s, 1H), 7.32 ~ 7.24 (m, 4H), 7.23 ~ 7.16 (m, 2H), 7.12 ~ 6.94 (m, 4H), 6.83 (d, J=0.8Hz, 1H), 6.61 (s, 1H), 5.13 (s, 2H), 5.07 (s, 1H), 4.84 ~ 4.68 (m, 1H), 3.18 ~ 3.11 (m, 2H), 3.00 ~ 2.92 (m, 2H), 2.75 ~ 2.64 (m, 2H), 1.89 (s, 1H).
Embodiment 22 prepares 1-(4-hydroxyl-3-formyltyrosine carbobenzoxy-phenyl)-3,4-dihydros-β-carboline (5g)
Prepare the method for compound 5a by embodiment 4, obtain 352mg (21%) 5g from 1.68g (3mmol) 1-(4-hydroxyl-3-formyltyrosine carbobenzoxy-phenyl)-1,2,3,4-tetrahydro-beta-carbolines (4g).Mp 186-188 DEG C. (c=0.5, methyl alcohol) .ESI-MS (m/e) 560 [M+H] +.IR (KBr): 3414,2928,1738,1640,1574,1547,1514,1482,1438,1374,1328,1228,1190,749,692. 1h-NMR (300MHz, DMSO-d6) δ/ppm=8.43 (s, 1H), 7.76. (d, J=2.6Hz, 1H), 7.65 (d, J=2.8Hz, 1H), 7.54 (d, J=1.8Hz, 1H), 7.36 ~ 7.28 (m, 6H), 7.17 (t, J=2.5Hz, 1H), 7.01 (d, J=2.8Hz, 2H), 6.64 (d, J=2.7Hz, 2H), 5.10 (s, 2H), 4.71 (t, J=2.1Hz 1H), 3.75 (t, J=2.1Hz, 2H), 3.38 (s, 1H), 3.14 (s, 2H), 3.04 ~ 2.95 (m, 2H).
Embodiment 23 prepares the two carbobenzoxy-phenyl aldehyde (3h) of 4-hydroxyl-3-carbamylglutamic
Prepare the method for compound 3a by embodiment 2, obtain 5.56g (78%) 3h from the two benzyl ester of 8.23g (16.5mmol) tosic acid Pidolidone.Mp 98-99 DEG C. (c=0.5, methyl alcohol) .ESI-MS (m/e) 474 [M-H] -.IR (KBr): 3360,3067,3034,2938,1732,1694,1643,1585,1535,1491,1456,1387,1362,1302,1277,1215,1198,1171,1078,964,827,741,696,619. 1hNMR (500MHz, DMSO-d6) δ/ppm=12.95 (s, 1H), 9.87 (s, 1H), 8.52 (d, J=0.4Hz, 1H), 7.97 (d, J=1.3Hz, 1H), 7.39 ~ 7.28 (m, 10H), 7.12 (d, J=1.7Hz, 1H), 6.61 (d, J=3.9Hz, 1H), 5.19 (s, 2H), 5.08 (s, 2H), 4.69 ~ 4.64 (m, 1H), 2.55 (t, J=1.4Hz, 2H), 2.27 ~ 2.21 (m, 1H), 2.16 ~ 2.08 (m, 1H).
Embodiment 24 prepares 1-(the two carbobenzoxy-phenyl of 4-hydroxyl-3-carbamylglutamic)-1,2,3,4-tetrahydro-beta-carbolines (4h)
Prepare the method for compound 4a by embodiment 3, obtain 1.73g (28%) 4h from the two carbobenzoxy-phenyl aldehyde (3h) of 4.75g (10mmol) 4-hydroxyl-3-carbamylglutamic.For relative proportion is diastereomer (1R, the 3S)-body of 1: 1 and the mixture of (1S, 3S)-body.(1R, 3S)-body: 1hNMR (300MHz, DMSO-d6) δ/ppm=10.39 (s, 1H), 7.94 ~ 7.91 (m, 1H), 7.51 (s, 1H), 7.40 (s, 1H), 7.35 ~ 7.27 (m, 9H), 7.22 ~ 7.16 (m, 2H), , 7.03 ~ 6.98 (m, 2H), 6.87 (s, 1H), 5.16 (s, 2H), 5.07 (s, 3H), 4.64 ~ 4.61 (m, 1H), 3.18 ~ 3.13 (m, 1H), 3.01 ~ 2.93 (m, 1H), 2.79 ~ 2.65 (m, 2H), 2.26 ~ 2.08 (m, 4H), 1.91 (s, 1H). (1S, 3S)-body: 1hNMR (300MHz, DMSO-d6) δ/ppm=10.37 (s, 1H), 7.94 ~ 7.91 (m, 1H), 7.51 (s, 1H), 7.43 (s, 1H), 7.35 ~ 7.27 (m, 9H), 7.22 ~ 7.16 (m, 2H), , 7.03 ~ 6.98 (m, 2H), 6.84 (s, 1H), 5.16 (s, 2H), 5.07 (s, 3H), 4.64 ~ 4.61 (m, 1H), 3.18 ~ 3.13 (m, 1H), 3.01 ~ 2.93 (m, 1H), 2.79 ~ 2.65 (m, 2H), 2.26 ~ 2.08 (m, 4H), 1.91 (s, 1H).
Embodiment 25 prepares 1-(the two carbobenzoxy-phenyl of 4-hydroxyl-3-carbamylglutamic)-3,4-dihydros-β-carboline (5h)
The method of compound 5a is prepared by embodiment 4, with 1.54g (2.5mmol) 1-(the two carbobenzoxy-phenyl of 4-hydroxyl-3-carbamylglutamic)-1,2,3,4-tetrahydro-beta-carboline (4h) obtains 307mg (20%) 5h.Mp 139-140 DEG C. (c=0.5, methyl alcohol) .ESI-MS (m/e) 616.4 [M+H] +.IR (KBr): 3428,3031,2939,1737,1638,1573,1517,1483,1433,1376,1332,1227,1186,836,745,697. 1h-NMR (300MHz, DMSO-d6) δ/ppm=11.84 (s, 1H), 8.47 (d, J=0.8Hz, 1H), 7.75. (d, J=2.7Hz, 1H), 7.67 (m, 1H), 7.54 (d, J=2.8Hz, 1H), 7.36 ~ 7.28 (m, 10H), 7.17 (t, J=2.5Hz, 1H), 6.61 (s, 2H), 5.17 (s, 2H), 5.07 (s, 2H), 4.67 (m, 1H), 3.78 (t, J=2.5Hz, 2H), 3.12 (s, 2H), 2.20 (m, 1H), 2.02 (m, 1H).
Embodiment 26 prepares 4-hydroxyl-3-formyl Nitro-Arginine carbobenzoxy-phenyl aldehyde (3i)
Prepare the method for compound 3a by embodiment 2, obtain 5.21g (76%) 3i from 5.67g (16.5mmol) hydrochloric acid L-NG-nitroarginine benzyl ester.Mp 99-100 DEG C. (c=0.5, methyl alcohol) .ESI-MS (m/e) 472 [M+H] +.IR (KBr): 3312,2941,1744,1692,1636,1597,1533,1491,1383,1381,1186,1078,833,785,696,619. 1hNMR (300MHz, DMSO-d6) δ/ppm=9.89 (s, 1H), 8.53 (d, J=0.6Hz, 1H), 7.74 (d, J=0.6Hz, 1H), 7.44 ~ 7.28 (m, 6H), 7.13 (d, J=2.8Hz, 1H), 5.19 (s, 2H), 4.65 ~ 4.58 (m, 1H), 3.24 ~ 3.08 (m, 2H), 1.99 ~ 1.71 (m, 2H), 1.64 ~ 1.56 (m, 3H).
Embodiment 27 prepares 1-(4-hydroxyl-3-formyl Nitro-Arginine carbobenzoxy-phenyl)-1,2,3,4-tetrahydro-beta-carbolines (4i)
Prepare the method for compound 4a by embodiment 3, obtain 1.86g (31%) 4i with 4.75g (10mmol) 4-hydroxyl-3-formyl Nitro-Arginine carbobenzoxy-phenyl aldehyde (3i).For relative proportion is diastereomer (1R, the 3S)-body of 1: 1 and the mixture of (1S, 3S)-body.(1R, 3S)-body: 1hNMR (300MHz, DMSO-d6) δ/ppm=10.47 (s, 1H), 7.81 (s, 1H), 7.75 (d, J=0.7Hz, 2H), 7.45 ~ 7.34 (m, 5H), 7.22 (s, 2H), 7.05 ~ 6.94 (m, 4H), 6.89 (s, 1H), 5.38 (s, 1H), 5.21 (s, 2H), 4.67 ~ 4.58 (m, 1H), 3.18 (s, 1H), 3.02 ~ 2.96 (m, 2H), 2.75 ~ 2.65 (m, 2H), 2.24 ~ 2.16 (m, 3H), 1.91 (s, 1H), 1.82 ~ 1.77 (m, 2H), 1.70 ~ 1.61 (m, 2H). (1S, 3S)-body: 1hNMR (300MHz, DMSO-d6) δ/ppm=10.47 (s, 1H), 7.80 (s, 1H), 7.72 (d, J=0.8Hz, 2H), 7.45 ~ 7.34 (m, 5H), 7.24 (s, 2H), 7.05 ~ 6.94 (m, 4H), 6.89 (s, 1H), 5.38 (s, 1H), 5.21 (s, 2H), 4.67 ~ 4.58 (m, 1H), 3.18 (s, 1H), 3.02 ~ 2.96 (m, 2H), 2.75 ~ 2.65 (m, 2H), 2.24 ~ 2.16 (m, 3H), 1.91 (s, 1H), 1.82 ~ 1.77 (m, 2H), 1.70 ~ 1.61 (m, 2H).
Embodiment 28 prepares 1-(4-hydroxyl-3-formyl Nitro-Arginine carbobenzoxy-phenyl)-3,4-dihydros-β-carboline (5i)
Prepare the method for compound 5a by embodiment 4, obtain 394mg (22%) 5i from 1.8g (3mmol) 1-(4-hydroxyl-3-formyl Nitro-Arginine carbobenzoxy-phenyl)-1,2,3,4-tetrahydro-beta-carbolines (4i).Mp 153-154 DEG C. (c=0.5, methyl alcohol) .ESI-MS (m/e) 598 [M+H] +.IR (KBr): 3411,3230,2931,1736,1630,1545,1480,1432,1377,1332,1258,1228,1189,1153,836,746,698. 1h-NMR (300MHz, DMSO-d6) δ/ppm=8.47 (d, J=0.9Hz, 1H), 7.77. (d, J=2.7Hz, 1H), 7.72 (d, J=2.5Hz, 1H), 7.54 (d, J=2.7Hz, 1H), 7.38 ~ 7.31 (m, 6H), 7.19 (t, J=2.5Hz, 1H), 6.75 (d, J=2.6Hz, 1H), 5.16 (s, 2H), 4.61 (m, 1H), 3.83 (t, J=2.7Hz, 2H), 3.17 (s, 4H), 1.90 ~ 1.76 (m, 2H), 1.60 ~ 1.55 (m, 2H).
Embodiment 29 prepares 4-hydroxyl-3-formyl tryptophan benzyl ester group-phenyl aldehyde (3j)
Prepare the method for compound 3a by embodiment 2, obtain 5.17g (78%) 3j from 5.43g (16.5mmol) hydrochloric acid L-Trp benzyl ester.Mp 81-81 DEG C. (c=0.5, methyl alcohol) .ESI-MS (m/e) 441 [M-H] -.IR (KBr): 3381,3042,2938,1736,1686,1639,1585,1541,1491,1456,1383,1277,1200,833,745,696,619. 1hNMR (500MHz, DMSO-d6) δ/ppm=12.83 (s, 1H), 9.88 (s, 1H), 8.55 (d, J=0.4Hz, 1H), 7.94 (d, J=1.7Hz, 1H), 7.38 ~ 7.25 (m, 5H), 7.19 (d, J=0.4Hz, 1H), 7.11 ~ 7.07 (m, 2H), 6.99 (t, J=1.4Hz, 1H), 5.18 ~ 5.11 (m, 2H), 4.94 ~ 4.89 (m, 1H), 3.42 ~ 3.33 (m, 2H).
Embodiment 30 prepares 1-(4-hydroxyl-3-formyl tryptophan benzyl ester group-phenyl)-1,2,3,4-tetrahydro-beta-carbolines (4j)
Prepare the method for compound 4a by embodiment 3, obtain 1.86g (31%) 4j from 4.42g (10mmol) 4-hydroxyl-3-formyl tryptophan benzyl ester group-phenyl aldehyde (3j).For relative proportion is diastereomer (1R, the 3S)-body of 1: 1 and the mixture of (1S, 3S)-body.(1R, 3S)-body: 1hNMR (300MHz, DMSO-d6) δ/ppm=10.89 (s, 1H), 10.40 (s, 1H), 7.91 ~ 7.88 (m, 1H), 7.54 (s, 1H), 7.44 (s, 1H), 7.36 ~ 7.29 (m, 3H), 7.23 ~ 7.14 (m, 4H), 7.07 ~ 6.93 (m, 3H), 6.84 (s, 1H), 5.13 (s, 1H), 5.09 (s, 2H), 4.85 (m, 1H), 3.31 ~ 3.23 (m, 2H), 3.18 ~ 3.13 (m, 1H), 3.03 ~ 2.95 (m, 1H), 2.85 ~ 2.67 (m, 2H), 1.91 (s, 1H). (1S, 3S)-body: 1hNMR (300MHz, DMSO-d6) δ/ppm=10.86 (s, 1H), 10.40 (s, 1H), 7.91 ~ 7.88 (m, 1H), 7.51 (s, 1H), 7.42 (s, 1H), 7.36 ~ 7.29 (m, 3H), 7.23 ~ 7.14 (m, 4H), 7.07 ~ 6.93 (m, 3H), 6.87 (s, 1H), 5.13 (s, 1H), 5.09 (s, 2H), 4.85 (m, 1H), 3.31 ~ 3.23 (m, 2H), 3.18 ~ 3.13 (m, 1H), 3.03 ~ 2.95 (m, 1H), 2.85 ~ 2.67 (m, 2H), 1.91 (s, 1H).
Embodiment 31 prepares 1-(4-hydroxyl-3-formyl tryptophan benzyl ester group-phenyl)-3,4-dihydros-β-carboline (5j)
Prepare the method for compound 5a by embodiment 4, obtain 393mg (27%) 5j from 1.46g (2.5mmol) 1-(4-hydroxyl-3-formyl tryptophan benzyl ester group-phenyl)-1,2,3,4-tetrahydro-beta-carbolines (4j).Mp 177-178 DEG C. (c=0.5, methyl alcohol) .ESI-MS (m/e) 583 [M+H] +.IR (KBr): 3407,3056,2923,1737,1633,1572,1520,1480,1432,1376,1333,1225,1189,742,697. 1h-NMR (300MHz, DMSO-d6) δ/ppm=8.47 (d, J=0.9Hz, 1H), 7.75. (d, J=2.7Hz, 1H), 7.65 (m, 1H), 7.54 (d, J=2.7Hz, 1H), 7.39 ~ 7.29 (m, 5H), 7.22 ~ 7.14 (m, 4H), 7.08 (t, J=2.6Hz, 1H), 6.98 (d, J=2.4Hz, 1H), 6.58 (d, J=2.3Hz, 1H), 5.10 (m, 2H), 4.87 (t, J=2.1Hz 1H), 3.76 (t, J=2.5Hz, 2H), 3.26 (d, J=2.0Hz, 2H), 3.12 (s, 2H).
Embodiment 32 prepares 4-hydroxyl-3-formylmethionine carbobenzoxy-phenyl aldehyde (3k)
Prepare the method for compound 3a by embodiment 2, obtain 4.64g (80%) 3k from 4.52g (16.5mmol) hydrochloric acid METHIONINE benzyl ester.Mp 90-91 DEG C. (c=0.5, methyl alcohol) .ESI-MS (m/e) 386 [M-H] -.IR (KBr): 3345,2934,2851,1740,1694,1643,1585,1547,1493,1437,1375,1300,1198,1082,914,829,746,696,619. 1hNMR (300MHz, DMSO-d6) δ/ppm=9.87 (s, 1H), 8.53 (d, J=0.7Hz, 1H), 7.96 (d, J=2.2Hz, 1H), 7.39 ~ 7.29 (m, 5H), 7.12 (d, J=2.8Hz, 1H), 5.19 (d, J=0.7Hz, 2H), 4.78 ~ 4.71 (m, 1H), 2.62 ~ 2.54 (m, 2H), 2.18 ~ 2.10 (m, 2H), 2.04 (s, 1H).
Embodiment 33 prepares 1-(4-hydroxyl-3-formylmethionine carbobenzoxy-phenyl)-1,2,3,4-tetrahydro-beta-carbolines (4k)
Prepare the method for compound 4a by embodiment 3, obtain 1.38g (26%) 4k from 3.57g (10mmol) 4-hydroxyl-3-formylmethionine carbobenzoxy-phenyl aldehyde (3k).For relative proportion is diastereomer (1R, the 3S)-body of 1: 1 and the mixture of (1S, 3S)-body.(1R, 3S)-body: 1hNMR (300MHz, DMSO-d6) δ/ppm=10.56 (s, 1H), 8.00 ~ 7.97 (m, 1H), 7.37 (s, 2H), 7.37 ~ 7.28 (m, 5H), 7.26 ~ 7.25 (m, 2H), 6.93 (s, 2H), 5.32 (s, 1H), 5.17 (s, 2H), 4.72 (m, 1H), 3.26 ~ 3.21 (m, 1H), 3.13 ~ 3.07 (m, 1H), 2.95 ~ 2.75 (m, 2H), 2.15 ~ 2.07 (m, 2H), 2.01 (s, 1H), 2.01 (s, 3H), 1.92 (s, 1H). (1S, 3S)-body: 1hNMR (300MHz, DMSO-d6) δ/ppm=10.54 (s, 1H), 8.00 ~ 7.97 (m, 1H), 7.36 (s, 2H), 7.37 ~ 7.28 (m, 5H), 7.24 ~ 7.22 (m, 2H), 6.90 (s, 2H), 5.32 (s, 1H), 5.17 (s, 2H), 4.72 (m, 1H), 3.26 ~ 3.21 (m, 1H), 3.13 ~ 3.07 (m, 1H), 2.95 ~ 2.75 (m, 2H), 2.15 ~ 2.07 (m, 2H), 2.01 (s, 1H), 2.00 (s, 3H), 1.92 (s, 1H).
Embodiment 34 prepares 1-(4-hydroxyl-3-formylmethionine carbobenzoxy-phenyl)-3,4-dihydros-β-carboline (5j)
The method of compound 5a is prepared by embodiment 4, from 1.32g (2.5mmol) 1-(4-hydroxyl-3-formylmethionine carbobenzoxy-phenyl)-1,2,3,4-tetrahydro-beta-carboline (4k) obtains 355mg (27%) 5k.Mp 158-159 DEG C. (c=0.5, methyl alcohol) .ESI-MS (m/e) 528 [M+H] +.IR (KBr): 3420,2921,1740,1631,1573,1536,1433,1375,1335,1152,1068,743. 1h-NMR (300MHz, DMSO-d6) δ/ppm=8.46 (d, J=0.8Hz, 1H), 7.74 (d, J=2.3Hz, 1H), 7.67 (m, 1H), 7.54 (d, J=2.7Hz, 1H), 7.38 ~ 7.26 (m, 6H), 7.17 (t, J=2.5Hz, 1H), 6.61 (s, 1H), 5.17 (s, 2H), 4.71 (m, 1H), 3.78 (t, J=2.5Hz, 2H), 3.12 (s, 2H), 2.55 (s, 1H), 2.52 (s, 1H), 2.15 ~ 1.92 (m, 5H).
Embodiment 35 prepares 4-hydroxyl-3-formyl threonine benzyl ester base-phenyl aldehyde (31)
Prepare the method for compound 3a by embodiment 2, obtain 4.07g (76%) 3l from 4.02g (16.5mmol) hydrochloric acid L-threonine benzyl ester.Mp 77-78 DEG C. (c=0.5, methyl alcohol) .ESI-MS (m/e) 356 [M-H] -.IR (KBr): 3319,2930,2853,1736,1692,1641,1582,1541,1491,1449,1383,1279,1213,1088,829,750,698,629. 1hNMR (300MHz, DMSO-d6) δ/ppm=9.89 (s, 1H), 8.55 (d, J=0.7Hz, 1H), 7.95 (d, J=2.1Hz, 1H), 7.48 ~ 7.36 (m, 5H), 7.15 (d, J=2.8Hz, 1H), 5.75 (s, 1H), 5.18 (s, 2H), 4.62 ~ 4.49 (m, 1H), 4.31 ~ 4.29 (m, 1H), 3.87 (d, J=2.1Hz, 3H).
Embodiment 36 prepares 1-(4-hydroxyl-3-formyl threonine benzyl ester base-phenyl)-1,2,3,4-tetrahydro-beta-carbolines (4l)
Prepare the method for compound 4a by embodiment 3, obtain 1.35g (27%) 4l from 3.87g (10mmol) 4-hydroxyl-3-formyl threonine benzyl ester base-phenyl aldehyde (3l).For relative proportion is diastereomer (1R, the 3S)-body of 1: 1 and the mixture of (1S, 3S)-body.(1R, 3S)-body: 1hNMR (300MHz, DMSO-d6) δ/ppm=10.48 (s, 1H), 9.33 (s, 1H), 7.93 (s, 1H), 7.45 ~ 7.42 (m, 1H), 7.37 ~ 7.29 (m, 6H), 7.25 ~ 7.22 (m, 1H), 7.05 ~ 6.95 (m, 3H), 5.36 (s, 1H), 5.16 (s, 2H), 4.57 ~ 4.40 (m, 1H), 4.30 ~ 4.18 (m, 1H), 3.18 ~ 3.05 (m, 2H), 2.87 ~ 2.71 (m, 2H), 1.91 (s, 1H), 1.13 (d, J=2.1Hz, 3H). (1S, 3S)-body: 1hNMR (300MHz, DMSO-d6) δ/ppm=10.48 (s, 1H), 9.33 (s, 1H), 7.92 (s, 1H), 7.45 ~ 7.42 (m, 1H), 7.37 ~ 7.29 (m, 6H), 7.25 ~ 7.22 (m, 1H), 7.05 ~ 6.95 (m, 3H), 5.36 (s, 1H), 5.16 (s, 2H), 4.57 ~ 4.40 (m, 1H), 4.30 ~ 4.18 (m, 1H), 3.18 ~ 3.05 (m, 2H), 2.87 ~ 2.71 (m, 2H), 1.91 (s, 1H), 1.15 (d, J=2.1Hz, 3H).
Embodiment 37 prepares 1-(4-hydroxyl-3-formyl threonine benzyl ester base-phenyl)-3,4-dihydros-β-carboline (5l)
Prepare the method for compound 5a by embodiment 4, obtain 311mg (25%) 5l from 1.28g (2.5mmol) 1-(4-hydroxyl-3-formyl threonine benzyl ester base-phenyl)-1,2,3,4-tetrahydro-beta-carbolines (4l).Mp 165-166 DEG C. (c=0.5, methyl alcohol) .ESI-MS (m/e) 496 [M-H] -.IR (KBr): 3287,2976,2933,1739,1630,1573,1541,1433,1379,1332,1298,1255,1192,1155,840,742. 1h-NMR (300MHz, DMSO-d6) δ/ppm=8.48 (d, J=0.7Hz, 1H), 7.75 (d, J=2.7Hz, 1H), 7.67 (d, J=2.4Hz, 1H), 7.54 (d, J=2.8Hz, 1H), 7.41 ~ 7.31 (m, 5H), 7.17 (t, J=2.5Hz, 1H), 6.61 (s, 1H), 5.18 (s, 2H), 4.61 ~ 4.57 (m, 1H), 4.24 (t, J=2.5Hz, 1H), 3.77 (t, J=2.5Hz, 2H), 3.12 (s, 2H), 1.12 (d, J=2.1Hz, 3H).
Embodiment 38 prepares 4-hydroxyl-3-formyl-N 6-carbobenzoxy-(Cbz) Methionin carbobenzoxy-phenyl aldehyde (3m)
The method of compound 3a is prepared, from 6.68g (16.5mmol) N by embodiment 2 6-carbobenzoxy-(Cbz)-1B benzyl ester hydrochloride obtains 6.29g (81%) 3m.Mp 101-102 DEG C. (c=0.5, methyl alcohol) .ESI-MS (m/e) 517 [M-H] -.IR (KBr): 3319,3034,2916,2853,1701,1638,1589,1541,1456,1375,1215,1136,961,739,698,669,619. 1hNMR (500MHz, DMSO-d6) δ/ppm=9.87 (s, 1H), 8.55 (d, J=0.7Hz, 1H), 7.96 (d, J=2.8Hz, 1H), 7.37 ~ 7.22 (m, 10H), 7.12 (d, J=1.8Hz, 1H), 5.18 (s, 2H), 4.99 (s, 2H), 4.60 ~ 4.53 (m, 1H), 3.02 ~ 2.95 (m, 2H), 1.88 ~ 1.36 (m, 6H).
Embodiment 39 prepares 1-(4-hydroxyl-3-formyl-N 6-carbobenzoxy-(Cbz) Methionin carbobenzoxy-phenyl)-1,2,3,4-tetrahydro-beta-carbolines (4m)
The method of compound 4a is prepared, from 5.18g (10mmol) 4-hydroxyl-3-formyl-N by embodiment 3 6-carbobenzoxy-(Cbz) Methionin carbobenzoxy-phenyl aldehyde (3m) obtains 2.11g (32%) 4m.For relative proportion is diastereomer (1R, the 3S)-body of 1: 1 and the mixture of (1S, 3S)-body.(1R, 3S)-body: 1hNMR (300MHz, DMSO-d6) δ/ppm=10.49 (s, 1H), 7.98 (s, 1H), 7.51 (s, 1H), 7.43 (s, 1H), 7.35 ~ 7.29 (m, 9H), 7.27 ~ 7.22 (m, 3H), 7.05 ~ 6.95 (m, 2H), 6.92 (s, 1H), 5.23 (s, 1H), 5.16 (s, 2H), 5.00 (s, 2H), 4.53 (s, 1H), 3.22 ~ 3.18 (m, 1H), 3.09 ~ 2.97 (m, 3H), 2.90 ~ 2.73 (m, 2H), 1.91 (s, 1H), 1.84 ~ 1.82 (m, 2H), 1.42 ~ 1.33 (m, 4H). (1S, 3S)-body: 1hNMR (300MHz, DMSO-d6) δ/ppm=10.47 (s, 1H), 7.98 (s, 1H), 7.51 (s, 1H), 7.45 (s, 1H), 7.35 ~ 7.29 (m, 9H), 7.27 ~ 7.22 (m, 3H), 7.05 ~ 6.95 (m, 2H), 6.89 (s, 1H), 5.23 (s, 1H), 5.16 (s, 2H), 5.00 (s, 2H), 4.53 (s, 1H), 3.22 ~ 3.18 (m, 1H), 3.09 ~ 2.97 (m, 3H), 2.90 ~ 2.73 (m, 2H), 1.91 (s, 1H), 1.84 ~ 1.82 (m, 2H), 1.42 ~ 1.33 (m, 4H).
Embodiment 40 prepares 1-(4-hydroxyl-3-formyl-N 6-carbobenzoxy-(Cbz) Methionin carbobenzoxy-phenyl)-3,4-dihydros-β-carboline (5m)
The method of compound 5a is prepared, from 1.98g (3mmol) 1-(4-hydroxyl-3-formyl-N by embodiment 4 6-carbobenzoxy-(Cbz) Methionin carbobenzoxy-phenyl)-1,2,3,4-tetrahydro-beta-carbolines (4m) obtain 454mg (23%) 5m.Mp 169-170 DEG C. (c=0.5, methyl alcohol) .ESI-MS (m/e) 659 [M+H] -.IR (KBr): 3421,2937,1714,1637,1573,1521,1481,1375,1332,1255,835,738,698. 1h-NMR (500MHz, DMSO-d6) δ/ppm=8.47 (s, 1H), 7.77 (d, J=2.0Hz, 1H), 7.69 (d, J=2.0Hz, 1H), 7.54 (d, J=1.0Hz, 1H), 7.39 ~ 7.26 (m, 11H), 7.18 (t, J=2.0Hz, 1H), 6.64 (s, 1H), 5.16 (s, 2H), 5.01 (s, 2H), 4.58 ~ 4.54 (m, 1H), 3.80 (t, J=2.0Hz, 2H), 3.35 (s, 2H), 2.99 ~ 2.96 (m, 2H), 1.85 ~ 1.74 (m, 2H) 1.45 ~ 1.33 (m, 4H).
Embodiment 41 prepares 4-hydroxyl-3-formyl Serine carbobenzoxy-phenyl aldehyde (3n)
Prepare the method for compound 3a by embodiment 2, obtain 3.65g (71%) 3n from 3.8g (16.5mmol) hydrochloric acid Serine benzyl ester.Mp 79-82 DEG C. (c=0.5, methyl alcohol) .ESI-MS (m/e) 342 [M-H] -.IR (KBr): 3323,3038,2934,2851,1746,1695,1636,1584,1533,1493,1456,1279,1202,1076,837,745,627,527. 1hNMR (300MHz, DMSO-d6) δ/ppm=9.88 (s, 1H), 8.55 (d, J=0.7Hz, 1H), 7.97 (d, J=2.0Hz, 1H), 7.40 ~ 7.31 (m, 5H), 7.13 (d, J=2.8Hz, 1H), 5.32 (s, 1H), 5.19 (s, 2H), 4.76 ~ 4.67 (m, 1H), 3.94 ~ 3.82 (m, 1H).
Embodiment 42 prepare 1-[4-hydroxyl-3-formyl-Serine (S-formyl radical)-carbobenzoxy-phenyl)-1,2,3,4-tetrahydro-beta-carbolines (4n)
Prepare the method for compound 4a by embodiment 3, obtain 1.62g 4n from 3.87g (10mmol) 4-hydroxyl-3-formyl Serine carbobenzoxy-phenyl aldehyde (3n).For relative proportion is diastereomer (1R, the 3S)-body of 1: 1 and the mixture of (1S, 3S)-body.(1R, 3S)-body: 1hNMR (300MHz, DMSO-d6) δ/ppm=10.41 (s, 1H), 9.59 (s, 1H), 7.91 (s, 1H), 7.43 ~ 7.28 (m, 6H), 7.20 (s, 2H), 7.03 ~ 6.89 (m, 3H), 5.16 (s, 2H), 5.08 (s, 1H), 4.64 (s, 2H), 3.92 ~ 3.86 (m, 1H), 3.80 ~ 3.75 (m, 1H), 3.18 ~ 3.11 (m, 1H), 3.01 ~ 2.93 (m, 1H), 2.83 ~ 2.65 (m, 2H), 1.89 (s, 3H). (1S, 3S)-body: 1hNMR (300MHz, DMSO-d6) δ/ppm=10.39 (s, 1H), 9.59 (s, 1H), 7.90 (s, 1H), 7.43 ~ 7.28 (m, 6H), 7.23 (s, 2H), 7.03 ~ 6.89 (m, 3H), 5.16 (s, 2H), 5.08 (s, 1H), 4.64 (s, 2H), 3.92 ~ 3.86 (m, 1H), 3.80 ~ 3.75 (m, 1H), 3.18 ~ 3.11 (m, 1H), 3.01 ~ 2.93 (m, 1H), 2.83 ~ 2.65 (m, 2H), 1.89 (s, 3H).
Embodiment 43 prepare 1-[4-hydroxyl-3-formyl-Serine (S-formyl radical)-carbobenzoxy-phenyl)-3,4-dihydros-β-carboline (5n)
The method of compound 5a is prepared by embodiment 4; from 1.58g (3mmol) 1-(4-hydroxyl-3-formyl-formyl radical-Serine carbobenzoxy-phenyl)-1; 2,3,4-tetrahydro-beta-carboline (4n) obtains 330mg (21%) 5n.Mp 177-178 DEG C. (c=0.5, methyl alcohol) .ESI-MS (m/e) 548 [M+Na] +.IR (KBr): 3061,2939,1743,1633,1574,1516,1433,1375,1332,1228,1188,1076,1045,742. 1h-NMR (300MHz, DMSO-d6) δ/ppm=11.86 (s, 1H), 8.47 (s, 1H), 7.76 (d, J=2.7Hz, 1H), 7.67 (d, J=3.0Hz, 1H), 7.54 (d, J=2.8Hz, 1H), 7.38 ~ 7.33 (m, 6H), 7.18 (t, J=2.5Hz, 1H), 6.61 (d, J=3.9Hz, 1H), 5.2 (s, 2H), 4.98 ~ 4.94 (m, 1H), 4.46 ~ 4.35 (m, 2H), 3.87 (t, J=2.6Hz, 2H), 3.15 (t, J=2.4Hz, 2H), 1.97 (s, 3H).
Embodiment 44 prepares 4-hydroxyl-3-formylglycine carbobenzoxy-phenyl aldehyde (3o)
Prepare the method for compound 3a by embodiment 2, obtain 4.22g (90%) 3o from 5.56g (16.5mmol) glycine benzyl ester p-toluene sulfonic acid salt.Mp 125-127 DEG C. (c=0.5, methyl alcohol) .ESI-MS (m/e) 312 [M-H] -.IR (KBr): 3347,3067,2930,2853,1744,1680,1641,1584,1545,1489,1456,1387,1356,1310,1285,1198,937,837,727,692,625,540. 1hNMR (300MHz, DMSO-d6) δ/ppm=9.86 (s, 1H), 8.47 (d, J=0.7Hz, 1H), 7.96 (d, J=2.2Hz, 1H), 7.44 ~ 7.30 (m, 5H), 7.13 (d, J=1.8Hz, 1H), 5.18 (s, 2H), 4.17 (s, 2H).
Embodiment 45 prepares 1-(4-hydroxyl-3-formylglycine carbobenzoxy-phenyl)-1,2,3,4-tetrahydro-beta-carbolines (4o)
Prepare the method for compound 4a by embodiment 3, obtain 1.68g (37%) 4o from 3.13g (10mmol) 4-hydroxyl-3-formyl Serine carbobenzoxy-phenyl aldehyde (3o). 1HNMR(300MHz，DMSO-d6)δ/ppm＝10.49(s，1H)，7.83(d，J＝0.6Hz，1H)，7.81(s，1H)，7.75(d，J＝0.7Hz，1H)，7.50～7.34(m，5H)，7.23(s，1H)，7.05～6.96(m，3H)，5.23(s，1H)，5.20(s，2H)，4.75～4.58(m，2H)，3.03～2.96(m，2H)，2.74～2.70(m，2H)，1.84～1.76(m，1H)。
Embodiment 46 prepares 1-(4-hydroxyl-3-formylglycine carbobenzoxy-phenyl)-3,4-dihydros-β-carboline (5o)
Prepare the method for compound 5a by embodiment 4, obtain 353mg (26%) 5o from 1.37g (3mmol) 1-(4-hydroxyl-3-formylglycine carbobenzoxy-phenyl)-1,2,3,4-tetrahydro-beta-carbolines (4o).Mp 149-150 DEG C. (c=0.5, methyl alcohol) .ESI-MS (m/e) 454 [M+H] +.IR (KBr): 3424,2932,1742,1638,1572,1545,1524,1483,1439,1382,1332,1260,1192,1176,739,692. 1h-NMR (300MHz, DMSO-d6) δ/ppm=11.81 (s, 1H), 11.61 (s, 1H), 10.54 (s, 1H), 8.46 (s, 1H), 7.75 (d, J=2.5Hz, 1H), 7.66 (d, J=2.4Hz, 1H), 7.53 (d, J=2.7Hz, 1H), 7.40 ~ 7.30 (m, 6H), 7.17 (t, J=2.5Hz, 1H), 6.57 (s, 1H), 5.16 (s, 2H), 4.18 (d, J=1.9Hz, 2H), 3.76 (d, J=2.5Hz, 2H), 3.12 (s, 2H).
The anti-tumour cell proliferative activity evaluation of experimental example 1 compound 5a-q
Compound 5a-q of the present invention is all mixed with desired concn with 1640 substratum containing 0.25%DMSO.K562, HL60 and HT-29 tri-strain tumour cell equal purchased from American standard type culture collection institute (ATCC).RPMI-1640 culture medium dry powder is purchased from Gibco company.Often liter of PBS damping fluid contains 8.2g NaCl, 0.2g KCl, 1.56g Na 2hPO 4h 2o and 0.2g KH 2pO 4, pH value 7.4.Foetal calf serum is purchased from Hyclone company, and 0.25% trypsin solution is purchased from Hyclone company, and penicillin and Streptomycin sulphate are purchased from solarbio company.Four tetrazolium bromides (MTT), purchased from solarbio company, are dissolved in PBS solution, make the solution of 5mg/mL, use after filtration sterilization, keep in Dark Place.Zorubicin (ADR) is purchased from Beijing Hua Feng United Technologies Corp., and DMSO (DMSO) is purchased from Hyclone company.
For HT-29 cell: growth conditions is good, be in the HT-29 cell of logarithmic phase by 5 × 10 4the density of individual/mL is inoculated in 96 orifice plates, every hole 100 μ L.At 37 DEG C, 96 orifice plates are placed in 5%CO 2cultivating in incubator treats adherent in 4 hours.Cell adds the solution of the desired concn be mixed with containing 1640 substratum of 0.25%DMSO of the compound 5a-q through sterilising treatment by the concentration gradient preset, every hole 25 μ L, control wells adds isopyknic RPMI-1640, parallel 6 holes.At 37 DEG C, 96 orifice plates are placed in 5%CO 2cultivate 48 hours in incubator.Every hole adds the MTT solution that 25 μ L concentration are 5mg/mL afterwards, continues cultivation 4 hours.Careful sucking-off supernatant liquor, every hole adds 100 μ L DMSO dissolve purple residue (first a ceremonial jade-ladle, used in libation), and Oscillating Flat makes precipitation all dissolve in 10 minutes, measures O.D. value (absorbancy), wavelength 570nm in 540nm microplate reader.
The inhibiting rate of the sample under each sample concentration to tumour cell is calculated according to formula " relative survival rate=(D pastille-D is blank)/(it is blank that D contrasts-D) × 100% ".
Test parallel repetition 3 times, with inhibiting rate, compound concentration is mapped, calculate the IC of the compounds of this invention 5a-q 50(half effective inhibition concentration) value.
For K562 and HL60 cell: respectively that growth conditions is good, be in K562 and the HL60 cell of logarithmic phase according to 4 × 10 4the density of individual/mL is inoculated in 96 orifice plates, every hole 100 μ L.Cell adds the solution of the desired concn be mixed with containing 1640 substratum of 0.25%DMSO of the compound 5a-q through sterilising treatment by the concentration gradient preset, every hole 25 μ L, control wells adds isopyknic RPMI-1640, parallel 6 holes.At 37 DEG C, 96 orifice plates are placed in 5%CO 2cultivate 48 hours in incubator.Afterwards, every hole adds the MTT solution that 25 μ L concentration are 5mg/mL, continues cultivation 4 hours.Centrifugal 3 minutes (3000rpm/min).Careful sucking-off supernatant liquor, every hole adds 100 μ L DMSO dissolve purple residue (first a ceremonial jade-ladle, used in libation), and Oscillating Flat makes precipitation all dissolve in 10 minutes, measures O.D. value (absorbancy) in 540nm microplate reader.
The inhibiting rate of the sample under each sample concentration to tumour cell is calculated according to formula " relative survival rate=(D pastille-D is blank)/(it is blank that D contrasts-D) × 100% ".
Test parallel repetition 3 times, with inhibiting rate, compound concentration is mapped, calculate the IC of the compounds of this invention 5a-q 50(half effective inhibition concentration) value.
Experimental result lists table 1 in.IC 50value show 5a-q in vitro inhibition tumor cell propagation IC 50be 20 to be greater than μM, therefore there is no obvious cytotoxicity.
Table 1 extracorporeal anti-tumor cell-proliferation activity (IC 50± SD, μM)
Experimental example 2 compound 5a-q anti-tumor in vivo activity rating
Inoculation eugonic S180 ascitic tumor knurl liquid after 7 days is extracted under aseptic condition, the liquid of (1: 3) is become fully to mix with normal saline dilution, by freshly prepared 0.2% Trypan Blue of tumor cell suspension, by white blood cell count(WBC) method counting after mixing, contaminate blue person for dead cell, tinter is not viable cell, and presses cell concn=(in 4 block plaid viable count/4) × 10 4extension rate=cell count/mL and cell survival rate=viable count/(viable count+dead cell number) × 100% calculate cell concn and cell survival rate.
ICR male mice (cleaning grade, body weight is 20 ± 2g, purchased from Beijing Vital River Experimental Animals Technology Co., Ltd.), every 12 mouse one group.Knurl liquid homogenate method S180 viable cell survival rate being greater than 90% is prepared into 1.5 × 10 7the cell suspension of individual/mL, in the subcutaneous vaccination of ICR male mice armpit (0.2mL/ only), causes lotus S 180 solid tumor mouse and accepts treatment.Physiological saline is added gradually to desired concn after compound 5a-q (dosage is 10 μm of ol/kg) adds a small amount of tween 80 hydrotropy.Positive control is that Zorubicin (dosage is 2 μm of ol/kg) adds physiological saline to desired concn.Blank is physiological saline (dosage is 3ml/kg).They every day abdominal injection 1 time.Successive administration 7 days.Treatment, to the 8th day, claims Mouse Weight, and de-cervical vertebra puts to death mouse, and takes the tumour of each group of mouse and each main organs is weighed, and finally adds up the tumour inhibiting rate of each group of medicine.The curative effect of solid tumor represents with the heavy inhibition percentage of knurl, is calculated as follows: tumor-like hyperplasia %=(1-administration group knurl heavy/blank group knurl weight) × 100%.Spleen index=spleen heavy (mg)/put to death body weight (g).This experimental data statistics all adopts t inspection and variance analysis.
Experimental result lists table 2 in.Under 10 μm of ol/kg dosage, all compounds and Zorubicin have significant restraining effect (comparing P < 0.01 with blank group) to S180 mouse tumor, wherein the restraining effect of compound 5a is the most obvious, and tumour inhibiting rate is 54.5%; Compound 5p also has reasonable anti-tumor activity, and significantly better than the activity of 5p has these four compounds of 5j, 5f, 5a and 5d, and tumour inhibiting rate all reaches more than 45%.
Table 25a-q on the impact of the tumor weight of S180 tumor-bearing mice ( ± SD)
Note: n=12a) compare P < 0.01. with physiological saline
Most antitumor drug, while killing tumor cell, also reduces immunologic function, causes spleen index significantly to reduce.What the present invention measured shows from spleen index, compares with blank, and under 2 μm of ol/kg dosage, Zorubicin causes spleen index to reduce by 50%, and compound 5a-q does not cause spleen index to reduce.Visible, compound 5a-q does not reduce the immunologic function for the treatment of mouse.
Experimental example 3 compound 5a anti-tumor in vivo dose-effect relationship
According to the method for test example 2, compound 5a chooses high, medium and low three dosage, i.e. the dosage effect dependence of 10 μm of ol/kg, 1 μm of ol/kg and 0.1 μm ol/kg, tri-dosage investigation compounds.Result lists table 3 in.The tumour for the treatment of mouse heavily shows, the antitumor action show dose effect dependence of 5a.
Table 3. various dose 5a is on the impact of mice bearing S180 tumor weight
Note: n=12, a) with physiological saline, 1 μm of ol/kg5a and 0.1 μm of ol/kg 5a group than P < 0.01; B) with physiological saline and 0.1 μm of ol/kg 5a group than P < 0.01.
Experimental example 4 compound 5a, p, q interior anti-inflammatory activity is evaluated
In order to confirm that 5a-q has anti-inflammatory action, select anti-tumor activity high, neutralize low representative compound 5a, p, q carry out anti-inflammatory screening.ICR male mice (cleaning grade, body weight is 20 ± 2g, purchased from Beijing Vital River Experimental Animals Technology Co., Ltd.), every 12 mouse one group.ICR male mice is divided into physiological saline group, acetylsalicylic acid group (dosage is 167 μm of ol/kg) and 5a, p, q group (dosage is 10 μm of ol/kg) at random.Tranquillization 1 day before mouse uses, operation room keeps room temp 22 DEG C, often organizes mouse 12.Difference gastric infusion when experiment starts, single administration was coated with dimethylbenzene (0.03mL) toward the auris dextra gabarit of small white mouse after 30 minutes, was put to death by small white mouse cervical dislocation after 2 hours.Respectively on a left side, circular auricle got by the punch tool of right two ear diameter 7mm, weighs, and obtains the weight difference of two circle auricles as swelling.Anti-inflammatory curative effect represents with swelling, is calculated as follows: swelling=auris dextra former weight-former of left ear weight.This experimental data statistics all adopts t inspection and variance analysis.
Experimental result lists table 4 in.5a, p, q dimethylbenzene incite inflammation auricle swelling degree result is as table.Under 10 μm of ol/kg dosage, 5a, p, q have remarkable restraining effect through gastric infusion to inflammation.Because 5a-q is analog, 5a, p, q represent again the compound that anti-tumor activity in series is high, neutralize low three aspects, so can think that anti-inflammatory action is one of essential property of 5a-q.
Table 4 mouse dimethylbenzene anti-inflammation models data statistics result
Note: n=12; A) with physiological saline group than P < 0.01; B) with physiological saline group than P < 0.05.

Claims (10)

1. the compound that represents of general formula (I), in formula, R is that H, AA are selected from L-Ala, L-Ile, L-Phe, L-Asp (OBzl), L-Leu, L-Val, L-Tyr, L-Glu (OBzl), L-Arg (NO 2), L-Trp, L-Met, L-Thr, L-Lys (Z), L-Ser (Me), L-Gly residue;
2. the compound that represents of general formula (I), is characterized in that: in formula, R is H, AA-OBzl is OBzl jointly;
3. prepare the method for claim 1 general formula (I) compound, the method comprises the following steps:
(1) under dicyclohexylcarbodiimide (DCC) and I-hydroxybenzotriazole (HOBt) exist, 5-formylsalicylic acid and L-amino-acid benzyl ester generate 4-hydroxyl-3-formyl amino acid formyl amino acid benzyl ester base-phenyl aldehyde;
(2) 4-hydroxyl-3-formyl amino acid formyl amino acid benzyl ester benzaldehyde and tryptamines carry out Pictet-Spengler condensation and generate 1-(4-hydroxyl-3-formyl amino acid formyl amino acid benzyl ester base-phenyl)-1,2,3,4-tetrahydro-beta-carbolines;
(3) with potassium permanganate, 1-(4-hydroxyl-3-formyl amino acid formyl amino acid benzyl ester base-phenyl)-1,2,3,4-tetrahydro-beta-carbolines are oxidized to 1-(4-hydroxyl-3-formyl amino acid formyl amino acid benzyl ester base-phenyl)-3,4-dihydros-β-carboline.
4. prepare the method for claim 2 general formula (I) compound, the method comprises the following steps:
(1) by the nucleophilic substitution of haloalkane 5-formylsalicylic acid and bromobenzyl reacted and generate 5-formylsalicylic acid benzyl ester;
(2) by Pictet-Spengler condensation 5-formylsalicylic acid benzyl ester and tryptamines reacted and generate 1-(4-hydroxyl-3-carbobenzoxy-(Cbz)-phenyl)-1,2,3,4-tetrahydro-beta-carbolines;
(3) with potassium permanganate, 1-(4-hydroxyl-3-carbobenzoxy-(Cbz)-phenyl)-1,2,3,4-tetrahydro-beta-carbolines are oxidized to 1-(4-hydroxyl-3-carbobenzoxy-(Cbz)-phenyl)-3,4-dihydros-β-carboline.
5. the compound that claim 1 general formula (I) represents is preparing the application in antitumor drug.
6. the compound that claim 1 general formula (I) represents is preparing the application in anti-inflammatory drug.
7. the compound that claim 1 general formula (I) represents is preparing the application in anti-inflammatory and antitumor drug.
8. the compound that claim 2 general formula (I) represents is preparing the application in antitumor drug.
9. the compound that claim 2 general formula (I) represents is preparing the application in anti-inflammatory drug.
10. the compound that claim 2 general formula (I) represents is preparing the application in anti-inflammatory and antitumor drug.
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