CN106349332B - imidazopyridinyl-KRGDV, its synthesis, antithrombotic activity and use - Google Patents
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Abstract
The present invention discloses the following formula 4,5,6, 7-tetrahydro-3H-imidazo [4, 5-c ] pyridine-6-formyl-Lys-Arg-Gly-Asp-Val, discloses its preparation method, discloses its antithrombotic activity, and therefore discloses its application in antithrombotic medicine
Description
Technical Field
The present invention relates to 4,5,6, 7-tetrahydro-3H-imidazo [4, 5-c ] pyridine-6-formyl-Lys-Arg-Gly-Asp-Val, to a process for its preparation, to their antithrombotic activity and thus to its use as antithrombotic agent. The invention belongs to the field of biological medicine.
Background
Coronary heart disease, cerebral apoplexy, angiitis and other very common cardiovascular and cerebrovascular diseases. With the continuous improvement of living standard of people, the number of the attack of cardiovascular and cerebrovascular diseases increases year by year. The prevalence of risk factors of cardiovascular and cerebrovascular diseases, and the prevalence rate of cardiovascular and cerebrovascular diseases in China is continuously increasing. According to statistics, 1 cardiovascular disease patient exists in every 5 adults. Thrombosis is an important cause of cardiovascular and cerebrovascular diseases. Prevention of thrombosis remains dependent on drug therapy. The thrombus medicines commonly used in clinic include aspirin, clopidogrel, warfarin and the like. They all have side effects such as bleeding and gastrointestinal irritation. Therefore, it is very meaningful to find antithrombotic drugs with good curative effect and little side effect.
In recent years, it has been found that compounds containing an imidazotetrahydropyridine heterocycle have an excellent structure for antithrombotic activity. The inventors have discovered that 4,5,6, 7-tetrahydro-3H-imidazo [4, 5-c ] pyridine-6-formyl-AA (AA being an amino acid residue) of the formula has a definite antithrombotic activity at an oral dose of 10 nmol/kgd.
However, the inventors have not satisfied the antithrombotic activity of the series of compounds. In order to further improve the activity, the inventors have conducted a series of experimental studies and finally found that the antithrombotic activity can be improved by substituting the thrombus-targeting peptide for AA in the already disclosed structure. According to these studies, the inventors have proposed the present invention.
Disclosure of Invention
the first aspect of the present invention provides 4,5,6, 7-tetrahydro-3H-imidazo [4, 5-c ] pyridine-6-formyl-Lys-Arg-Gly-Asp-Val.
In a second aspect, the present invention provides a process for the synthesis of 4,5,6, 7-tetrahydro-3H-imidazo [4, 5-c ] pyridine-6-formyl-Lys-Arg-Gly-Asp-Val, the process comprising:
(1) Carrying out Pictet-Spengler condensation on L-histidine and formaldehyde under the catalysis of dilute sulfuric acid to generate 4,5,6, 7-tetrahydro-3H-imidazo [4, 5-c ] pyridine-6-carboxylic acid;
(2) Conversion of 4,5,6, 7-tetrahydro-3H-imidazo [4, 5-c ] pyridine-6-carboxylic acid to 3, 5-di-Boc-4, 5,6, 7-tetrahydro-3H-imidazo [4, 5-c ] pyridine-6-carboxylic acid;
(3) Coupling 3, 5-di-Boc-4, 5,6, 7-tetrahydro-3H-imidazo [4, 5-c ] pyridine-6-carboxylic acid with lys (Boc) -OBzl to give 3, 5-di-Boc-4, 5,6, 7-tetrahydro-3H-imidazo [4, 5-c ] pyridine-6-formyl-lys (Boc) -OBzl;
(4) saponification of 3, 5-di-Boc-4, 5,6, 7-tetrahydro-3H-imidazo [4, 5-c ] pyridine-6-formyl-lys (Boc) -OBzl in 2N NaOH solution to 3, 5-di-Boc-4, 5,6, 7-tetrahydro-3H-imidazo [4, 5-c ] pyridine-6-formyl-lys (Boc);
(5)Boc-Arg(NO2) Coupling with glycine benzyl ester to obtain Boc-Arg (NO)2)-Gly-OBzl；
(6)Boc-Arg(NO2) Saponification of-Gly-OBzl in 2N NaOH solution to Boc-Arg (NO)2)-Gly；
(7) Boc-Asp (OBzl) is coupled with benzyl valine to obtain Boc-Asp (OBzl) -Val-OBzl;
(8) Boc-Asp (OBzl) -Val-OBzl is put into an ethyl acetate solution of 4N hydrogen chloride to obtain L-Asp (OBzl) -Val-OBzl;
(9)Boc-Arg(NO2) Coupling of-Gly with L-Asp (OBzl) -Val-OBzl to obtain Boc-Arg (NO)2)-Gly-Asp(OBzl)-Val-
OBzl；
(10)Boc-Arg(NO2) Obtaining L-Arg (NO) from-Gly-Asp (OBzl) -Val-OBzl in ethyl acetate solution of 4N hydrogen chloride2)-Gly-Asp(OBzl)-Val-OBzl；
(11)3, 5-di-Boc-4, 5,6, 7-tetrahydro-3H-imidazo [4, 5-c]pyridine-6-formyl-Lys (Boc) and L-Arg (NO)2) -Gly-Asp (OBzl) -Val-OBzl coupling to obtain 3, 5-di-Boc-4, 5,6, 7-tetrahydro-3H-imidazo [4, 5-c]pyridine-6-formyl-Lys (Boc) -Arg (NO)2)-Gly-Asp(OBzl)-Val-OBzl；
(12)3, 5-di-Boc-4, 5,6, 7-tetrahydro-3H-imidazo [4, 5-c]pyridine-6-formyl-Lys (Boc) -Arg (NO)2) -Gly-Asp (OBzl) -Val-OBzl in TFA/TFMSA to obtain 4,5,6, 7-tetrahydro-3H-imidazo [4, 5-c]pyridine-6-formyl-Lys-Arg-Gly-Asp-Val.
The third aspect of the present invention is to evaluate the antithrombotic effect of 4,5,6, 7-tetrahydro-3H-imidazo [4, 5-c ] pyridine-6-formyl-Lys-Arg-Gly-Asp-Val on SD rats.
Drawings
FIG. 1 is a synthetic route for 4,5,6, 7-tetrahydro-3H-imidazo [4, 5-c ] pyridine-6-formyl-Lys-Arg-Gly-Asp-Val.
i)HCHO，H2SO4，65℃；ii)(Boc)2O，4N NaOH；iii)HOBt，DCC，THF；iv)2N NaOH，CH3OH；v)HCl/EA；vi)TFA/TFMSA。
Detailed Description
To further illustrate the invention, a series of examples are given below. These examples are purely illustrative and are intended to be a detailed description of the invention only and should not be taken as limiting the invention.
EXAMPLE 1 preparation of 4,5,6, 7-tetrahydro-3H-imidazo [4, 5-c ] pyridine-6-carboxylic acid (1)
To a solution of 5g (32.3mmol) L-His in 18mL water was slowly added 0.8mL H dropwise with stirring in an ice bath2SO4And completely dissolving. To this solution was added 6mL of 40% aqueous formaldehyde solution. The ice bath was removed and the reaction was run at 60 ℃ for 8h and TLC (ethyl acetate: water: glacial acetic acid 4: 1) monitored for the disappearance of the starting material spots. The reaction solution was cooled to room temperature, and the pH was adjusted to 6 with concentrated ammonia water in an ice bath, whereupon a large amount of colorless solid precipitated. And (5) filtering. The filter residue was washed with water and acetone to give 4.52g (84%) of the title compound. ESI-MS (m/e): 168[ M + H ]]+。
EXAMPLE 2 preparation of 3, 5-di-Boc-4, 5,6, 7-tetrahydro-3H-imidazo [4, 5-c ] pyridine-6-carboxylic acid (2)
5g (29.9mmol) of 4,5,6, 7-tetrahydro-3H-imidazo [4, 5-c) are stirred in an ice bath]To a solution of pyridine-6-carboxylic acid in 40mL of water was added 40mL of 14.3g (65.7mmol) dissolved in 1, 4-dioxane (Boc)2O, pH adjusted to 8-9 with 4N NaOH solution, reacted at room temperature for 24h, TLC (dichloromethane: methanol 15: 1) monitored disappearance of starting material spot. Saturated KHSO is used for reaction liquid4Adjusting pH of the solution to 7, evaporating 1, 4-dioxane under reduced pressure, and adding saturated KHSO4The solution was adjusted to pH 2. Extraction was carried out three times with ethyl acetate and the ester layer was washed three times with saturated NaCl. Drying with anhydrous sodium sulfate for 30min, and filtering. The filtrate was evaporated to dryness under reduced pressure. A small amount of ethyl acetate was added to dissolve it just, and it was left to stand. Solid is precipitated and filtered. 1.2g (11%) of the title compound are obtained as a colorless solid. ESI-MS (m/e): 368[ M + H]+。
EXAMPLE 3 preparation of 3, 5-di-Boc-4, 5,6, 7-tetrahydro-3H-imidazo [4, 5-c ] pyridine-6-formyl-Lys (Boc) -OBzl (3)
367mg (1mmol) of 3, 5-di-Boc-4, 5,6, 7-di-tert-hydro-3H-imidazo [4, 5-c ] is added with 20mL of dry Tetrahydrofuran (THF) under ice bath]Pyridine-6-carboxylic acid is dissolved. 142mg (1.05mmol) of HOBt and 258mg (1.25mmol) of DCC were added, and the mixture was stirred and activated for 30 min. 558mg (1.1 mmo) of dry THF are introduced into a 10mL portion of flaskl) Tos · lys (boc) -OBzl, adjusting the pH to 8 with NMM, adding the solution dropwise to the reaction solution, and finally adjusting the pH of the reaction solution to 8 with NMM. The reaction was carried out at room temperature for 5h and TLC (petroleum ether: acetone; 3: 1) showed disappearance of starting material. Filtering to remove Dicyclohexylurea (DCU), evaporating the reaction solution under reduced pressure, dissolving the residue with ethyl acetate, and sequentially dissolving with saturated NaHCO3Solution, saturated NaCl solution, 5% KHSO4Solution, saturated NaCl solution, saturated NaHCO3The solution and the saturated NaCl solution were washed three times each. Anhydrous Na for ethyl acetate layer2SO4Drying for 30min, filtering, and evaporating the filtrate under reduced pressure. The resulting yellow oil was purified by silica gel column chromatography (petroleum ether/acetone as eluent) to give 248mg (36%) of the title compound as a colorless solid. ESI-MS (m/e): 686[ M + H]+。
EXAMPLE 4 preparation of 3, 5-di-Boc-4, 5,6, 7-tetrahydro-3H-imidazo [4, 5-c ] pyridine-6-formyl-Lys (Boc) (4)
685mg (1mmol) of 3, 5-di-Boc-4, 5,6, 7-tetrahydro-3H-imidazo [4, 5-c ] is reacted with 20mL of methanol in an ice bath]pyridine-6-formyl-Lys (Boc) -OBzl was dissolved, pH was adjusted to 12 with 2N NaOH solution, ice-bath was performed for 5h, TLC (petroleum ether: acetone ═ 3: 1) showed disappearance of the starting spot. With saturated KHSO4The solution was adjusted to pH 7. Methanol is distilled off under reduced pressure and saturated KHSO is used4Adjusting pH of the solution to 2, extracting with ethyl acetate for 3 times, washing ethyl acetate layer with saturated NaCl solution for three times, and adding anhydrous Na2SO4Drying for 30min, filtering, and spin-drying the filtrate. 584mg (98%) of the title compound are obtained as a colorless solid. ESI-MS (m/e): 596[ M + H]+。
EXAMPLE 5 preparation of Boc-Arg (NO)2)-Gly-OBzl
1.595g (5mmol) of Boc-Arg (NO) was added with stirring in an ice bath2)30 mL of dry THF was added. 708mg (5.25mmol) of HOBt and 1.291g (6.25mmol) of DCC were added successively, and activation was carried out for 30 min. 2.022g (6mmol) of tos.Gly-OBzl was dissolved in dry THF, and then the pH was adjusted to 8 with NMM, and the solution was added dropwise to the reaction solution, and finally the pH was adjusted to 8 with NMM. After 12 hours at room temperature, TLC (dichloromethane: methanol 20: 1) showed the reaction was complete, the reaction mixture was evaporated to dryness under reduced pressure, the remaining oil was dissolved in ethyl acetate and filteredFiltering to remove DCU, and sequentially using saturated NaHCO for filtrate3Solution, saturated NaCl solution, saturated KHSO4Solution, saturated NaCl solution, saturated NaHCO3The solution and the saturated NaCl solution are washed for three times respectively, and the ethyl acetate layer is washed by anhydrous Na2SO4Drying for 30min, and filtering. The filtrate was concentrated to dryness under reduced pressure, and the resulting yellow oil was dissolved in methylene chloride and then allowed to stand to precipitate as a solid. And (5) filtering. 1.866g (80%) of the title compound are obtained as a colorless solid. ESI-MS (m/e): 467[ M + H ]]+。
EXAMPLE 6 preparation of Boc-Arg (NO)2)-Gly
Under ice-bath, 1.680g (5mmol) of Boc-Arg (NO) was washed with 40mL of methanol2) -Gly-OBzl was dissolved, pH adjusted to 12 with 2n naoh solution, reacted in ice bath for 5h, TLC (dichloromethane: methanol ═ 20: 1) showed disappearance of the starting point. With saturated KHSO4The solution was adjusted to pH 7. Methanol is distilled off under reduced pressure and saturated KHSO is used4Adjusting pH of the solution to 2, extracting with ethyl acetate three times, washing ethyl acetate layer with saturated NaCl solution three times, and adding anhydrous Na2SO4Drying for 30min, and filtering. The filtrate was concentrated to dryness under reduced pressure. 1.737g (92%) of the title compound are obtained as a colorless solid. ESI-MS (m/e): 375[ M + H ]]-。
EXAMPLE 7 preparation of Boc-Asp (OBzl) -Val-OBzl
2.081g (81%) of the title compound were obtained as a colorless solid according to the method of example 5 from 1.615g (5mmol) of Boc-Asp (OBzl) and 2.369g (6mmol) of tos.Val-OBzl. ESI-MS (m/e): 513[ M + H]+。
EXAMPLE 8 preparation of HCl Asp (OBzl) -Val-OBzl
In an ice bath and with stirring, 1.024g (2mmol) of Boc-Asp (OBzl) -Val-OBzl were dissolved with a small amount of dry ethyl acetate. To the solution was added 20ml of a 4N ethyl acetate solution of hydrogen chloride, and the reaction was carried out for 6 hours in an ice bath, and after completion of the reaction by TLC (petroleum ether: acetone: 3: 1), the reaction mixture was concentrated to dryness under reduced pressure. To the residue was added dry ethyl acetate, concentrated to dryness under reduced pressure, and repeated twice. To the residue was added anhydrous ether, and the mixture was concentrated to dryness under reduced pressure and repeated three times. 0.751g (91%) of the title compound is obtained as a pale yellow solid. ESI-MS (m/e): 413[ M + H]+。
EXAMPLE 9 preparation of Boc-Arg (NO)2)-Gly-Asp(OBzl)-Val-OBzl
From 1.880g (5mmol) Boc-Arg (NO) according to example 52) -Gly and 2.700g (6mmol) HCl. Asp (OBzl) -Val-OBzl gave 2.903g (75%) of the title compound as a colorless solid. ESI-MS (m/e): 771[ M + H]+。
EXAMPLE 10 preparation of HCl.Arg (NO)2)-Gly-Asp(OBzl)-Val-OBzl
from 1.540g (2mmol) Boc-Arg (NO) according to example 82) -Gly-Asp (OBzl) -Val-OBzl gave 1.187g (89%) of the title compound as a light yellow solid. ESI-MS (m/e): 671[ M + H]+。
EXAMPLE 11 preparation of 3, 5-di-Boc-4, 5,6, 7-tetrahydro-3H-imidazo [4, 5-c]pyridine-6-formyl-Lys (Boc) -Arg (NO)2)-Gly-Asp(OBzl)-Val-OBzl (5)
From 906mg (1.52mmol) of 3, 5-di-Boc-4, 5,6, 7-tetrahydro-3H-imidazo [4, 5-c ] according to the method of example 5]pyridine-6-formyl-Lys (Boc) and 1.06g HCl. Arg (NO)2) -Gly-Asp (OBzl) -Val-OBzl gave 1.39g (73%) of the title compound as a colourless solid. ESI-MS (m/e): 1248[ M + H]+。
EXAMPLE 12 preparation of 3, 5-di-Boc-4, 5,6, 7-tetrahydro-3H-imidazo [4, 5-c ] pyridine-6-formyl-Lys-Arg-Gly-Asp-Val (6)
60mg (0.05mmol) of 3, 5-di-Boc-4, 5,6, 7-tetrahydro-3H-imidazo [4, 5-c ] is stirred in ice bath]pyridine-6-formyl-Lys (Boc) -Arg (NO)2) To (E) -Gly-Asp (OBzl) -Val-OBzl was added dropwise 1.8mL of trifluoroacetic acid to completely dissolve the compound. 0.6mL of trifluoromethanesulfonic acid was added dropwise and the solution turned into a greenish black color. Adding a drying tube, carrying out ice-bath reaction for 25min, adding a large amount of diethyl ether, and separating out colorless solid. After centrifugation, the supernatant was discarded, and the solid was further added with diethyl ether and washed repeatedly three times. The resulting solid was dissolved with a small amount of water, the pH was adjusted to 8 with diluted ammonia and then to 7 with diluted glacial acetic acid. Desalting via Sephadex G10 column, and freeze-drying gave 20.8mg (60%) of the title compound as a colorless solid. And Mp: 193.2-194.0 ℃ ESI-MS (m/e): 723[ M + H]+.1H-NMR(500Hz，DMSO-d6)：δ/ppm＝10.269(s，1H)，8.976(d，J＝8.0Hz，1H)，8.549(s，1H)，8.252(d，J＝7.0Hz，1H)，8.107(d，J＝8.0Hz，1H)，7.449(s，1H)，6.997(d，J＝8.5Hz，2H)，4.370(dd，J＝12.0Hz，6.0Hz，1H)，4.275(m，1H)，4.228(m，1H)，3.855(m，2H)，3.710(dd，J＝26.0Hz，15.5Hz，1H)，3.618(dd，J＝16.5Hz，5.5Hz，1H)，3.472(dd，J＝9.0Hz，4.5Hz，1H)，3.177(m，1H)，2.740(m，3H)，2.564(m，2H)，2.253(dd，J＝16.0Hz，5.0Hz，1H)，2.006(m，1H)，1.961(m，2H)，1.871(m，5H)，1.669(m，2H)，1.530(m，4H)，1.285(m，2H)，0.776(d，J＝6.5Hz，6H)。
Experimental example 1 evaluation of antithrombotic Activity of Compound 6
Male SD rats (200. + -.20 g) were randomly divided into groups of 12 animals, kept for 1 day and stopped overnight. After 30min of gavage administration of a physiological saline solution of Compound 6 (dose of 10nmol/kg) or aspirin (dose of 167. mu. mol/kg) or a physiological saline (dose of 10mL/kg), rats were anesthetized with a physiological saline solution of 20% Ulipraz, followed by surgery. The right carotid artery and the left jugular vein of the rat were isolated, accurately weighed silk was placed in the bypass cannula, one end of the tube was inserted into the left vein and the other end was inserted into the right artery and injected with 0.2mL heparin sodium anticoagulation. Allowing blood flow to flow from the right artery through the bypass cannula into the left vein, taking out the thread with thrombus after 15min, weighing, calculating the weight of the thread before and after blood circulation, and performing t-test to obtain the weight of the thrombus represented by the mean value + -SDmg and representing the antithrombotic activity. The data are shown in Table 1. The results show that oral administration of 10nmol/kg of compound 6 is as effective in inhibiting thrombosis as oral administration of 167 μmol/kg of aspirin. The compound 6 has 16700 times stronger activity than aspirin and obtains unexpected technical effect.
TABLE 1.10nmol/kg antithrombotic Activity of Compound 6
n is 12; a) the ratio p to normal saline is less than 0.01, and the ratio p to aspirin is more than 0.05.
Claims (3)
1. 4,5,6, 7-tetrahydro-3H-imidazopyridine-6-formyl-Lys-Arg-Gly-Asp-Val of the formula,
2. A process for the preparation of 4,5,6, 7-tetrahydro-3H-imidazopyridine-6-formyl-Lys-Arg-Gly-Asp-Val of claim 1 which comprises:
(1) Carrying out Pictet-Spengler condensation on L-histidine and formaldehyde under the catalysis of dilute sulfuric acid to generate 4,5,6, 7-tetrahydro-3H-imidazopyridine-6-carboxylic acid;
(2) Conversion of 4,5,6, 7-tetrahydro-3H-imidazopyridine-6-carboxylic acid to 3, 5-di-Boc-4, 5,6, 7-tetrahydro-3H-imidazopyridine-6-carboxylic acid;
(3)3, 5-di-Boc-4, 5,6, 7-tetrahydro-3H-imidazopyridine-6-carboxylic acid with NωCoupling of-Boc-Lys-OBzl to give 3, 5-di-Boc-4, 5,6, 7-tetrahydro-3H-imidazopyridine-6-formyl-Nω-Boc-Lys-OBzl；
(4)3, 5-di-Boc-4, 5,6, 7-tetrahydro-3H-imidazopyridine-6-formyl-NωSaponification of-Boc-Lys-OBzl in 2N NaOH solution to 3, 5-di-Boc-4, 5,6, 7-tetrahydro-3H-imidazopyridine-6-formyl-Nω-Boc-Lys；
(5)Boc-NG-NO2coupling-Arg and glycine benzyl ester to obtain Boc-NG-NO2-Arg-Gly-OBzl；
(6)Boc-NG-NO2saponifying-Arg-Gly-OBzl in 2N NaOH solution to obtain Boc-NG-NO2-Arg-Gly；
(7) Coupling Boc-beta-carboxylic acid-OBzl-Asp and valine benzyl ester to obtain Boc-beta-carboxylic acid-OBzl-Asp-Val-OBzl;
(8) The Boc-beta-carboxylic acid-OBzl-Asp-Val-OBzl is put into an ethyl acetate solution of 4N hydrogen chloride to obtain L-beta-carboxylic acid-OBzl-Asp-Val-OBzl;
(9)Boc-NG-NO2coupling the-Arg-Gly with L-beta-carboxylic acid-OBzl-Asp-Val-OBzl to obtain Boc-NG-NO2-Arg-Gly- β -carboxylic acid-OBzl-Asp-Val-OBzl;
(10)Boc-NG-NO2The L-N is obtained by the-Arg-Gly-beta-carboxylic acid-OBzl-Asp-Val-OBzl in the ethyl acetate solution of 4N hydrogen chlorideG-NO2-Arg-Gly- β -carboxylic acid-OBzl-Asp-Val-OBzl;
(11)3, 5-di-Boc-4, 5,6, 7-tetrahydro-3H-imidazopyridine-6-formyl-NωBoc-Lys with L-NG-NO2coupling-Arg-Gly-beta-carboxylic acid-OBzl-Asp-Val-OBzl to obtain 3, 5-di-Boc-4, 5,6, 7-tetrahydro-3H-imidazopyridine-6-formyl-Nω-Boc-Lys-NG-NO2-Arg-Gly- β -carboxylic acid-OBzl-Asp-Val-OBzl;
(12)3, 5-di-Boc-4, 5,6, 7-tetrahydro-3H-imidazopyridine-6-formyl-Nω-Boc-Lys-NG-NO2-Arg-Gly- β -carboxylic acid-OBzl-Asp-Val-OBzl in TFA/TFMSA to give 4,5,6, 7-tetrahydro-3H-imidazopyridine-6-formyl-Lys-Arg-Gly-Asp-Val.
3. use of 4,5,6, 7-tetrahydro-3H-imidazopyridine-6-formyl-Lys-Arg-Gly-Asp-Val according to claim 1 for the preparation of an antithrombotic medicament.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102796167A (en) * | 2011-05-26 | 2012-11-28 | 首都医科大学 | (S)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-formyl-L-prolyl-L-alanyl-L-amino acid, and preparation method and application thereof |
| CN103450198A (en) * | 2012-05-29 | 2013-12-18 | 首都医科大学 | Imidazo pyrido imidazole-3-substituted benzyl acetates, and synthesis, antineoplastic activities and application thereof |
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| CN102796167A (en) * | 2011-05-26 | 2012-11-28 | 首都医科大学 | (S)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-formyl-L-prolyl-L-alanyl-L-amino acid, and preparation method and application thereof |
| CN103450198A (en) * | 2012-05-29 | 2013-12-18 | 首都医科大学 | Imidazo pyrido imidazole-3-substituted benzyl acetates, and synthesis, antineoplastic activities and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 寡肽药物先导结构的发现与优化;赵明等;《北京大学学报（医学版）》;20021231;第34卷(第5期);第507页第1.2节，第508-509页第1.4节 * |
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