CN103450371A - Tetrahydro-beta-carbolinyl-3-formacyl-diethylenetriamino-beta-cyclodextrins, and preparation, antithrombotic activity and application thereof - Google Patents

Tetrahydro-beta-carbolinyl-3-formacyl-diethylenetriamino-beta-cyclodextrins, and preparation, antithrombotic activity and application thereof Download PDF

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CN103450371A
CN103450371A CN2012101809832A CN201210180983A CN103450371A CN 103450371 A CN103450371 A CN 103450371A CN 2012101809832 A CN2012101809832 A CN 2012101809832A CN 201210180983 A CN201210180983 A CN 201210180983A CN 103450371 A CN103450371 A CN 103450371A
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beta
cyclodextrin
tetrahydro
diethylenetriamine
carboline
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李莉
赵明
王玉记
安然
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Capital Medical University
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Abstract

The invention discloses 6-[(1,2,3,4-tetrahydro-beta-carbolinyl-3)-formacyl-diethylenetriamino]-6-desoxy-beta-cyclodextrins prepared by connecting tetrahydro-beta-carbolinylcarboxylic acid to cyclodextrins by using diethylenetriamine as a connecting arm and a preparation method thereof. The invention further discloses favorable in-vivo antithrombotic activity of the compounds. The invention provides excellent candidate compounds for developing medicines with high bioavailability and strong antithrombotic activity.

Description

Tetrahydro-beta-carboline-3-formyl radical-diethylenetriamine-beta-cyclodextrin, its preparation, antithrombotic acitivity and application
Technical field
The present invention relates to a kind of tetrahydro-beta-carboline with antithrombotic acitivity of synthetic-3-formyl radical-diethylenetriamine--beta-cyclodextrin; particularly relate to this strategy that beta-cyclodextrin is modified, the invention still further relates to the preparation method of this compound and preparing as the application in the antithrombotic agent medicine.
Background technology
In recent years, China's population aging degree is increasingly sharpened, and the thrombotic diseases incidence constantly rises.Although antithrombotic reagent comprises anti-platelet drug, anticoagulation medicine and thrombolytic three major types medicine and all obtaining remarkable progress aspect Application and Development and clinical treatment, the novel antithrombotic drug candidate that develops the independent brand of safer and more effective, high bioavailability is still one of focus of current new drug development.Beta-carboline alkaloid is a very important class in indoles alkaloid.This Alkaloid is of a great variety, shows biological activity widely, as anti-tumor activity, platelet aggregation-against, insecticidal activity, bacteriostatic activity, anti-oxidant activity, antiviral activity, antidepressant activity etc.3S-1 wherein, 2,3,4-Tetrahydrocarboline carboxylic acid In Vitro Anti platelet aggregation ability is 6 times of acetylsalicylic acid.Yet extremely low water-soluble of carboline carboxylate limited its application as antithrombotic agent.
Cyclodextrin be D-type Glucopyranose with the end to end ring molecule of Isosorbide-5-Nitrae-glycosidic bond, there is hydrophobic inner chamber and hydrophilic outer wall.The hydroxyl of its hydrophilic outer wall can be selected sex modification.Method by covalent linkage is coupled to drug molecule on the limit arm of cyclodextrin, can delay medicine release in vivo.The interarea of natural cyclodextrin and side hydroxyl can be selected to modify the systematic function cyclodextrin derivative by various groups.The present invention takes the method for chemosynthesis that carboline carboxylate is coupled on the arm of cyclodextrin interarea limit and forms monosubstituted cyclodextrin by flexible chain diethylenetriamine covalent linkage, this compound can improve the water-soluble of carboline carboxylate significantly, improve bioavailability, thereby effectively bring into play the antithrombotic acitivity in the carboline carboxylate body.
Summary of the invention
First content of the present invention is that it is 6-[(1 that a kind of chemical name is provided, 2,3,4-tetrahydro-beta-carboline-3)-formyl radical-diethylenetriamine]-compound of 6-deoxidation-beta-cyclodextrin, its structural formula is as follows:
Figure BSA00000728731500011
Second content of the present invention is to provide 6-[(1,2,3,4-tetrahydro-beta-carboline-3)-formyl radical-diethylenetriamine]-preparation method of 6-deoxidation-beta-cyclodextrin (7), the method comprises:
1) under distilled water and sulfuric acid existence, L-Trp at room temperature reacts and becomes the tetrahydro-beta-carboline carboxylic acid with formaldehyde;
2) under DMF (DMF) and triethylamine exist, step 1 products therefrom at room temperature reacts with tert-Butyl dicarbonate (DIBOC), becomes N-Boc-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid;
3), under methylene dichloride exists, Tosyl chloride and tosic acid at room temperature dewater and form tosic acid acid anhydride (Ts 2o);
4), in distilled water, use Ts 2o becomes 6-O-(p-tosyl group)-beta-cyclodextrin by the single 6-OH tosylation of beta-cyclodextrin;
5), in diethylenetriamine, 6-O-(p-tosyl group)-beta-cyclodextrin reaction generates 6-diethylenetriamine-6-deoxidation-beta-cyclodextrin;
6) under dry DMF is existed, N-Boc-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid and 6-diethylenetriamine-6-deoxidation-beta-cyclodextrin condensation becomes 6-[(N-Boc-1,2,3,4-tetrahydro-beta-carboline-3)-formyl radical-diethylenetriamine]-6-deoxidation-beta-cyclodextrin;
7) 6-[(N-Boc-1 in trifluoracetic acid (TFA), 2,3,4-tetrahydro-beta-carboline-3)-formyl radical-diethylenetriamine]-6-deoxidation-beta-cyclodextrin removes Boc and obtains 6-[(1,2,3,4-tetrahydro-beta-carboline-3)-formyl radical-diethylenetriamine]-6-deoxidation-beta-cyclodextrin;
This preparation method can summarize by the synthetic route of Fig. 1.
The 3rd content of the present invention is that the antithrombotic acitivity of compound 7 and the application in preparing antithrombotic agent are provided.
The present invention selects beta-cyclodextrin that carboline carboxylate modifies as antithrombotic agent, the compound 7 that the introducing by the wetting ability cyclodextrin significantly improves water-soluble, and in the body of carboline carboxylate, antithrombotic acitivity is improved.
The accompanying drawing explanation
Fig. 1 is 6-[(1 of the present invention, 2,3,4-tetrahydro-beta-carboline-3)-formyl radical-diethylenetriamine]-synthetic route of 6-deoxidation-beta-cyclodextrin (7).
I. formaldehyde, sulfuric acid, water (room temperature); Ii. (Boc) 2o, triethylamine, DMF (room temperature); Iii. methylene dichloride, Tosyl chloride (room temperature); Iv. water (room temperature); V. diethylenetriamine (80 ℃, nitrogen protection); Vi.N-hydroxy benzo triazole (HOBt) and dicyclohexylcarbodiimide (DCC), ice bath; Vii.TFA (room temperature).
Embodiment
Below in conjunction with accompanying drawing, embodiment and testing data, above-mentionedly to the present invention with other technical characterictic and advantage, be described in more detail.
Embodiment 1 preparation 1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (1)
Drip the 0.1mL vitriol oil in 200.0mL water, add 5.000g tryptophane (24.5mmol), after tryptophane dissolves fully, drip formaldehyde 5.0mL.Termination reaction after reaction 6h, strong aqua is adjusted system pH to 6, produces a large amount of white precipitates.Reaction mixture freezes a few hours 4 ℃ of refrigerator and cooled, filters and obtains title compound 3.985g, productive rate 75%.ESI/MS(m/e)：217[M+H] +.
Embodiment 2 preparation N-Boc-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (2)
1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (5.000g, 23.1mmol) is suspended in 50.0mL DMF, adds Boc2O (6.545g, 30.1mmol) under ice bath, drips triethylamine and adjusts reaction system pH to 10.After reacting completely, dry up DMF, the acetic acid ethyl dissolution mixture, 5% sal enixum is washed three times, and saturated NaCl solution is washed twice to ester layer pH neutrality, anhydrous Na 2sO 4dry ester layer.After the elimination siccative, be spin-dried for ethyl acetate, with a small amount of chloroform, faint yellow solid washed colourlessly, obtain clean title compound 4.308g, productive rate 59%.ESI/MS(m/e)：317[M+H] +.
Embodiment 3 preparation 4-toluenesulphonic acids acid anhydrides (3)
TsCl (8.000g, 42.0mmol) and TsOHH 2o (2.000g, 11mmol) is dissolved in the 50.0mL methylene dichloride, under room temperature, stirs and spends the night.Obtain title compound 4.970g after reacting liquid filtering after recrystallization, productive rate 62%.ESI/MS(m/e)：327[M+H] +.
Embodiment 4 preparation 6-O-(p-tosyl group)-beta-cyclodextrins (4)
Beta-cyclodextrin (10.000g, 88.1mmol) is dissolved in 220.0mL water, adds Ts 2o (4.261g, 13.1mmol) reacts 2h.Drip the 10%NaOH aqueous solution in reaction solution, filter after stirring 20min.Adjust filtrate pH value to neutrality, separate out a large amount of colorless solids, filter and obtain colorless solid 2.969g, productive rate 26%.ESI/MS(m/e)：1290[M+H] +.
Embodiment 5 preparation 6-diethylenetriamines-6-deoxidation-beta-cyclodextrin (5)
CD-OTs (1.000g) and 3mL diethylenetriamine stirring heating under 90 ℃ of conditions.After reaction 8h, be spin-dried for solvent, productive rate 95%.ESI/MS(m/e)：1243[M+Na] +.
Embodiment 6 preparation 6-[(2-N-Boc-1,2,3,4-tetrahydro-beta-carboline-3)-formyl radical-diethylenetriamine]-6-deoxidation-beta-cyclodextrin (6)
By the N-Boc-1 of 0.379g, 2,3,4-tetrahydro-beta-carboline-3-carboxylic acid is dissolved in the 10mL dry DMF, and ice-water bath is stirred to whole dissolvings, adds HoBt (0.243g, 2.8mmol), adds DCC (0.371g, 1.8mmol) under ice bath.After 30min, the 6-of 0.610g diethylenetriamine-6-deoxidation-beta-cyclodextrin is dropped in reaction.After 12h, stop reaction, the reaction solution decompress filter, obtain the thick product of colourless micro-bloom end 0.769g.Obtain pure title compound 0.048g, productive rate 6.36% through column chromatography for separation.ESI/MS(m/e)：1519[M+H] +. 1HNMR(D 2O，500MHZ，TMS，ppm)：δ＝1.46(s，9H)，δ＝2.65-3.05(m，2H)，δ＝3.10-4.45(br，67H)，δ＝4.6-5.25(m，7H)，δ＝7.15(t，1H，J＝7.5Hz)，δ＝7.2(t，1H，J＝7.5Hz)，δ＝7.45(d，1H，J＝7.5Hz)，δ＝7.45(d，1H，J＝7.5Hz).
Embodiment 7 preparation 6-[(1,2,3,4-tetrahydro-beta-carboline-3)-formyl radical-diethylenetriamine]-6-deoxidation-beta-cyclodextrin (7)
By 6-[(2-N-Boc-1,2,3,4-tetrahydro-beta-carboline-3)-formyl radical-diethylenetriamine]-6-deoxidation-beta-cyclodextrin (0.200g, 0.13mmol) is dissolved in 3mL trifluoroacetic acid (TFA), stirring at room 6-8h.After stopping reaction, revolve except a large amount of TFA, drip strong aqua 5mL under ice-water bath, then remove solvent, obtain faint yellow solid 0.182g.Product, after sephadex G-25 purifying, obtains faint yellow sterling 0.106g, productive rate 57%.Mp：270-271℃.ESI/MS(m/e)：1419[M+H] +. 1HNMR(D 2O，500MHZ，TMS，ppm)：δ＝2.45(s，3H)，δ＝2.90-4.15(br，60H)，δ＝4.9(m，3H)，δ＝7.10(t，1H，J＝7.5Hz)，δ＝7.35(t，1H，J＝7.5Hz)，δ＝7.85(d，1H，J＝7.5Hz)，δ＝8.00(d，1H，J＝7.5Hz).
The oral antithrombotic acitivity of compound 7 on test example 1 rat suppository model
Compound 7 is made into to 10 μ mol/mL normal saline solutions, is 1 μ mol/kg for the dosage in body.Parent nucleus 1 is made into 50 μ mol/L normal saline solutions, for the dosage in body, is 5 μ mol/kg.The positive drug acetylsalicylic acid is made into the 10g/L normal saline solution, and the solution of 55.5mmol/mL, be 180 μ mol/kg for the dosage in body.Blank is physiological saline, and antithrombotics is heparin sodium 2.4mg/mL normal saline solution.
The polyethylene jacket that is used to form bypass circuit in the experiment long silk thread through precise weighing of 6cm of packing in advance.Polyethylene tube (except silk thread), through 1% silicone oil diethyl ether solution silanization, is avoided occurring that haemolysis causes the damage of animal in operation.
By laboratory animal SD male rat random packet, n=12, the volume of rat oral gavage administration is 3mL/kg, after gavage 30min, with urethane (20g/100mL, 7mL/kg) anesthesia, separates right common carotid artery and the total vein of left neck.The total vein distal end of ligation neck, cut an osculum, and a polyethylene tube that is full of the heparin sodium normal saline solution is inserted to the total vein of neck fixing, by the dosage of 1mL/kg, injects the heparin sodium normal saline solution.Ligation arteria carotis communis distal end, clamp the arteria carotis communis proximal part with bulldog clamp, cuts an osculum, and the polyethylene tube the other end is inserted to arteria carotis communis fixing.Unclamp bulldog clamp, blood flow flows into neck total vein in left side from right carotid through polyethylene tube, forms bypass circuit.Take out silk thread after 15min, record wet weight of thrombus.Data are in Table 1, and with the ANOVA check, to the data analysis that takes statistics, p<0.05 thinks that there were significant differences.
The impact of table 1 compound on thrombus weight
Figure BSA00000728731500051
Figure BSA00000728731500052
Annotate: n=12, wet weight of thrombus is expressed as average
Figure BSA00000728731500053
a) with physiological saline and acetylsalicylic acid group than p<0.01; B) with the physiological saline group than p<0.01_, with the acetylsalicylic acid group than p>0.05.
The impact of the different oral dosage compounds of table 2 on wet weight of thrombus
Figure BSA00000728731500054
Figure BSA00000728731500055
Annotate: n=12, a) and physiological saline, 7 groups of 100nmol/kg 7 and 10nmol/kg are than p<0.01; B) with physiological saline and 10nmol/kg7 group p<0.01; C) with the physiological saline group than p<0.01.
Result shows, compound 7 demonstrates the antithrombotic acitivity more outstanding than the parent nucleus of 5 μ m/kg under 1 μ mol/kg dosage, and its active acetylsalicylic acid with 180 μ mol/kg is suitable.In addition, compound shows the antithrombotic acitivity progressively reduced under 1 μ mol/kg, 100nmol/kg, 10nmol/kg dosage.Visible, the anti thrombotic action of compound 7 presents dose-dependence.In body, the antithrombotic acitivity experiment shows that the mode by covalent linkage is connected on the limit arm of cyclodextrin by carboline carboxylate, has not only improved the water-soluble of carboline carboxylate, has improved the interior antithrombotic acitivity of body of click woods carboxylic acid simultaneously.
Above-described embodiment is described the preferred embodiment of the present invention; not scope of the present invention is limited; design under the prerequisite of spirit not breaking away from the present invention; various distortion and improvement that those of ordinary skills make technical scheme of the present invention, all should fall in the definite protection domain of the claims in the present invention book.

Claims (3)

1. a brand-new compound, the 6-[(1 that the Tetrahydrocarboline carboxylic acid is connected with cyclodextrin by diethylenetriamine, 2,3,4-tetrahydro-beta-carboline-3)-formyl radical-diethylenetriamine]-6-deoxidation-beta-cyclodextrin, its structural formula is:
Figure FSA00000728731400011
。
2. a method for preparing the described compound of claim 1 is characterized in that comprising the following steps:
1) under distilled water and sulfuric acid existence, L-Trp at room temperature reacts and becomes the tetrahydro-beta-carboline carboxylic acid with formaldehyde;
2) under DMF (DMF) and triethylamine exist, step 1 products therefrom at room temperature reacts with tert-Butyl dicarbonate (DIBOC), becomes N-Boc-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid;
3), under methylene dichloride exists, Tosyl chloride and tosic acid at room temperature dewater and form tosic acid acid anhydride (Ts 2o);
4), in distilled water, use Ts 2o becomes 6-O-(p-tosyl group)-beta-cyclodextrin by the single 6-OH tosylation of beta-cyclodextrin;
5), in diethylenetriamine, 6-O-(p-tosyl group)-beta-cyclodextrin reaction is become to 6-diethylenetriamine-6-deoxidation-beta-cyclodextrin;
6) under dry DMF is existed, N-Boc-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid and 6-diethylenetriamine-6-deoxidation-beta-cyclodextrin condensation becomes 6-[(N-Boc-1,2,3,4-tetrahydro-beta-carboline-3)-formyl radical-diethylenetriamine]-6-deoxidation-beta-cyclodextrin;
7) 6-[(N-Boc-1 in trifluoracetic acid (TFA); 2; 3; 4-tetrahydro-beta-carboline-3)-formyl radical-diethylenetriamine]-6-deoxidation-beta-cyclodextrin removes Boc becomes 6-[(1; 2; 3,4-tetrahydro-beta-carboline-3)-formyl radical-diethylenetriamine]-6-deoxidation-beta-cyclodextrin.
3. anti thrombotic action and as the application of antithrombotic compound in the body of the described compound of claim 1.
CN2012101809832A 2012-06-01 2012-06-01 Tetrahydro-beta-carbolinyl-3-formacyl-diethylenetriamino-beta-cyclodextrins, and preparation, antithrombotic activity and application thereof Pending CN103450371A (en)

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