CN102827307A - Beta-cyclodextrin-modified tetrahydro-beta-carboline carboxylic acid derivatives, and preparation method and application thereof - Google Patents
Beta-cyclodextrin-modified tetrahydro-beta-carboline carboxylic acid derivatives, and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides four beta-cyclodextrin-modified tetrahydro-beta-carboline carboxylic acid derivatives represented by 10a-d, and a preparation method thereof. The invention further provides the functions of the compounds in resisting platelet aggregation and further in resisting thrombosis, through the evaluations of the anti-thrombotic effects of the compounds on rats carotid arterial and venous bypass circulation thrombosis models and in-vitro anti-platelet-aggregation effects of the compounds. The method provided by the invention is simple. The raw materials are easy to obtain, and are safe and cheap. Obtained products have anti-platelet-aggregation and anti-thrombotic activities, such that the products are beneficial for the developments of anti-platelet medicines. Therefore, the four beta-cyclodextrin-modified tetrahydro-beta-carboline carboxylic acid derivatives provided by the invention have clinical application potentials as anti-thrombotic agents.
Description
Technical field
The present invention relates to the tetrahydrochysene-β-Ka Lin carboxylic acid derivative of 4 kinds of beta-cyclodextrins modifications of general formula 10a-d representative; Be specifically related to 6-[(1,2,3; 4-tetrahydrochysene-β-Ka Lin-3)-formyl radical-amino acid]-6-deoxidation-beta-cyclodextrin compounds; The preparation method who also relates to them further relates to their anti thrombotic action and application on rat arteriovenous shut circulation thrombus model, the invention belongs to biomedicine field.
Background technology
Thrombotic diseases is one of major disease of serious harm human health.Cause thrombotic factor a lot, the unusual and abnormal hemodynamics of blood vessel endothelium injury, inside and outside blood coagulation system etc., hematoblastic gathering plays important effect to thrombosis.Therefore, the antiplatelet drug of seeking high-efficiency low-toxicity is the focus that people study always.
Tetrahydrochysene-β-Ka Lin carboxylic acid is from the Longstamen Onion Bulb of Allium macrostemon or integration of drinking and medicinal herbs, to separate a kind of vegeto-alkali that obtains; Have clear and definite platelet aggregation inhibitory activity, bibliographical information its platelet aggregation inhibitory activity of experiment in vitro proof of carboline carboxylate be six times of Frosst).Achievement in research before the laboratory shows, endogenic amino acid is introduced 3 carboxyls of tetrahydrochysene-β-Ka Lin carboxylic acid, can improve water-soluble, carry high transmittance film property, enhancing platelet aggregation-against and antithrombotic acitivity.
Beta-cyclodextrin be outside hydrophilic in not hydrophobic frustum-like shape molecule, can form host-guest complex with the hydrophobicity guest molecule, and itself have good biocompatibility, so beta-cyclodextrin has very big application potential improving on the drug molecule physico-chemical property.Usually beta-cyclodextrin inclusion guest molecule can play water-soluble, the enhanced stability that improves guest molecule, the effect of raising bioavailability.But; After getting in the body, might before arriving focus, dissociate the host-guest complex of physics inclusion; Forefathers' work shows with chemical bond cyclodextrin molecular is connected on the drug molecule; Can reduce host-guest complex and arrive preceding the dissociating of focus, let Schardinger dextrins more effectively improve the effect of guest molecule physico-chemical property with bringing into play.
Based on these reasons; The present invention is a parent nucleus with tetrahydrochysene-β-Ka Lin carboxylic acid; Connect beta-cyclodextrin and parent nucleus with the endogenous neutral amino acids as flexible chain, obtain tetrahydrochysene-β-Ka Lin carboxylic acid derivative that novel beta-cyclodextrin is modified, and it is carried out inside and outside antithrombotic evaluation; Expectation can improve bioavailability of medicament, obtains better antithrombotic acitivity
Summary of the invention
First content of the present invention provides the tetrahydrochysene-β-Ka Lin carboxylic acid derivative of 4 kinds of beta-cyclodextrins modifications of general formula 10a-d representative, and is as follows:
Wherein, R is selected from H, CH
3, CH (CH
3)
2Or CH (CH
3) CH
2CH
3
Second content of the present invention provides the tetrahydrochysene-β-Ka Lin carboxylic acid derivative of 4 kinds of beta-cyclodextrins modifications of general formula 10a-d representative; Both 6-[(1; 2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical-amino acid]-preparation method of 6-deoxidation-beta-cyclodextrin (amino acid is glycocoll, L-L-Ala, L-Xie Ansuan or L-Isoleucine); As shown in Figure 1, this method comprises the steps:
1) in the presence of zero(ppm) water and sulfuric acid, L-tryptophane and formaldehyde at room temperature react becomes tetrahydrochysene-β-Ka Lin carboxylic acid;
2) at N, dinethylformamide (DMF) exists down with triethylamine, and step 1 products therefrom and tert-Butyl dicarbonate (DIBOC) at room temperature react, and become N-Boc-1, and 2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid;
3) in the presence of thionyl chloride and methyl alcohol, amino acid whose hydroxyl is replaced by methyl esters, and said amino acid is glycocoll, L-L-Ala, L-Xie Ansuan or L-Isoleucine;
4) in the presence of I-hydroxybenzotriazole (HoBt) and NSC 57182 (DCC); Step 2 products therefrom and HClAA-OMe (AA is glycyl, L-alanyl, L-is valyl or the L-isoleucyl) condensation in anhydrous tetrahydro furan becomes N-[(2-N-Boc-1; 2; 3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical]-amino acid methyl ester;
5) in methyl alcohol, be N-[(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical]-amino acid with N-[(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical]-amino acid methyl ester saponification;
6) in the presence of methylene dichloride, Tosyl chloride and tosic acid at room temperature dewater and form tosic acid acid anhydride (Ts
2O);
7) in zero(ppm) water, use Ts
2O becomes 6-O-(p-tosyl group)-beta-cyclodextrin with the single 6-OH tosylation of beta-cyclodextrin;
8) in the presence of zero(ppm) water, 6-O-(p-tosyl group)-beta-cyclodextrin is become 6-nitrine-6-deoxidation-beta-cyclodextrin by the sodium azide azide.Afterwards, in the presence of DMF and strong aqua, 6-nitrine-6-deoxidation-beta-cyclodextrin generation transamination becomes 6-amino-6-deoxidation-beta-cyclodextrin;
9) dry DMF is existed down N-[(2-N-Boc-1,2; 3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical]-amino acid and 6-amino-6-deoxidation-beta-cyclodextrin condensation become 6-[(2-N-Boc-1,2; 3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical-amino acid]-6-deoxidation-beta-cyclodextrin;
10) 6-[(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical-amino acid]-6-deoxidation-beta-cyclodextrin removes Boc and becomes 6-[(1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical-amino acid]-6-deoxidation-beta-cyclodextrin in trifluoracetic acid (TFA).
The 3rd content of the present invention is anti thrombotic action and the external antiplatelet aggregative activity on rat neck arteriovenous shut circulation thrombus model through the tetrahydrochysene-β-Ka Lin carboxylic acid derivative of 4 kinds of beta-cyclodextrins modifications estimating general formula 10a-d representative, and the application of this compounds in the preparation pharmaceutical preparations having antithrombotic activity is provided.
Description of drawings
Fig. 1 is the synthetic route of the tetrahydrochysene-β-Ka Lin carboxylic acid derivative of beta-cyclodextrin modification provided by the invention, wherein i. formaldehyde, sulfuric acid, water (room temperature); Ii (Boc)
2O, triethylamine, DMF (room temperature); Iii. sulfur oxychloride, methyl alcohol (cryosel bath); Iv.HoBt, DCC and amino acid methyl ester (ice bath); V. sodium hydroxide, methyl alcohol (ice bath); Vi. methylene dichloride, Tosyl chloride (room temperature); Vii. water (room temperature); Viii. sodium azide, triphen phosphorus, water, DMF (80 ℃, room temperature); Ix.HoBt, DCC and N-[(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical] amino acid (ice bath); X. trifluoracetic acid (room temperature).
Embodiment
In order further to set forth the present invention, provide a series of embodiment below.These embodiment are illustrative fully, and they only are used for the present invention is specifically described, and are not to be understood that to be limitation of the present invention.
Embodiment 1 preparation 1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid (1)
Drip the 0.1ml vitriol oil in 200ml water, add 5.0000g tryptophane (24.5mmol), treat that tryptophane dissolves fully after, drip formaldehyde 5ml.Termination reaction behind the reaction 6h, strong aqua is transferred system pH value to 6, produces a large amount of white precipitates.Reaction mixture froze several hours 4 ℃ of refrigerator and cooled, filtered to obtain title compound 4.0129g, productive rate 75.8%.ESI/MS(m/e)：217[M+H]
+
Embodiment 2 preparation N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid (2)
4.000g (18.5mmol) 1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid is suspended among the 45mlDMF, ice bath adds Boc down
2O 5.2360g (24.1mmol) drips triethylamine and transfers reaction system PH to 10.After reacting completely, dry up DMF, ETHYLE ACETATE redissolution product mixture, 5% sal enixum is given a baby a bath on the third day after its birth inferior, and saturated NaCl solution is washed twice to ester layer PH neutrality, anhydrous Na
2SO
4Dry ester layer.Behind the elimination siccative, revolve dry ethyl acetate, faint yellow solid is washed white, obtain clean title compound 3.3400g, productive rate 57% with minimum of chloroform.ESI/MS(m/e)：317[M+H]
+
Embodiment 3HClGly-OMe (3a)
Cryosel is bathed down, and the 2.6ml sulfur oxychloride slowly is added drop-wise in the 20ml methyl alcohol, behind the activation 20min, adds glycocoll 0.7500g (10mmol).TLC (chloroform: methyl alcohol=10: 1) detection reaction fully after, drain methyl alcohol with water pump.Small amount of methanol redissolution product is drained methyl alcohol, 3-5 time repeatedly again.Add about 35ml ether, stirred for several ten minutes, inclining ether, repeats the white solid that obtains doing 3-5 time.Obtain the colourless needle 0.6400g of pure title compound, productive rate 85% through methyl alcohol ether recrystallization.R
f＝0.42。ESI/MS(m/e)：148[M+Na]
+
Embodiment 4 preparation HClAla-OMe (3b)
Cryosel is bathed down, and the 2.6ml sulfur oxychloride slowly is added drop-wise in the 20ml methyl alcohol, behind the activation 20min, adds L-Ala 0.8900g (10mmol).TLC (chloroform: methyl alcohol=10: 1) detection reaction fully after, drain methyl alcohol with water pump.Small amount of methanol redissolution product is drained methyl alcohol, 3-5 time repeatedly again.Add about 35ml ether, stirred for several ten minutes, inclining ether, repeats the white solid that obtains doing 3-5 time.Obtain the colourless bulk crystals 1.2500g of pure title compound, productive rate 90% through methyl alcohol ether recrystallization.R
f＝0.41。ESI/MS(m/e)：140[M+H]
+
Embodiment 5 preparation HClVal-OMe (3c)
Cryosel is bathed down, and the 2.6ml sulfur oxychloride slowly is added drop-wise in the 20ml methyl alcohol, behind the activation 20min, adds Xie Ansuan 1.1700g (10mmol).TLC (chloroform: methyl alcohol=10: 1) detection reaction fully after, drain methyl alcohol with water pump.Small amount of methanol redissolution product is drained methyl alcohol, 3-5 time repeatedly again.Add about 35ml ether, stirred for several ten minutes, inclining ether, repeats the white solid that obtains doing 3-5 time.Obtain the colourless bulk crystals 1.4360g of pure title compound, productive rate 86% through methyl alcohol ether recrystallization.R
f＝0.45。ESI/MS(m/e)：168[M+H]
+
Embodiment 6 preparation HClIle-OMe (3d)
Cryosel is bathed down, and the 2.6ml sulfur oxychloride slowly is added drop-wise in the 20ml methyl alcohol, behind the activation 20min, adds Isoleucine 1.3100g (10mmol).TLC (chloroform: methyl alcohol=10: 1) detection reaction fully after, drain methyl alcohol with water pump.Small amount of methanol redissolution product is drained methyl alcohol, 3-5 time repeatedly again.Add about 35ml ether, stirred for several ten minutes, inclining ether, repeats the white solid that obtains doing 3-5 time.Obtain the colourless bulk crystals 1.5740g of pure title compound, productive rate 87% through methyl alcohol ether recrystallization.R
f＝0.46。ESI/MS(m/e)：182[M+H]
+
Embodiment 7 preparation preparation [(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical]-glycine methyl esters (4a)
1.2640g 2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin carboxylic acid (4.0mmol) is dissolved in the 30ml anhydrous tetrahydro furan, adds HoBt o.6480g (4.8mmol), and ice bath adds 0.9840g DCC (4.8mmol) (a) down.5ml anhydrous tetrahydro furan suspendible HClGly-OMe 0.5000g (4.0mmol), 0.5mlNMM transfers PH to 9 (b).After 30 minutes b is added among a, and transfer PH to 9 with NMM.TLC (chloroform: methyl alcohol=125: 1) monitoring reaction fully after, stop reaction, filter DCU, revolve dry tetrahydrofuran.Redissolve product with amount of ethyl acetate, the DCU that elimination is separated out uses saturated NaHCO successively
3, the saturated NaCl aqueous solution, 5%KHSO
4, the saturated NaCl aqueous solution, saturated NaHCO
3Give a baby a bath on the third day after its birth time with each collection of saturated NaCl, the ester layer that obtains is through anhydrous Na
2SO
4Drying is revolved dried after several hours, obtain the xanchromatic product.The heavy 1.4697g of product, productive rate 94.7%.R
f＝0.30。ESI/MS(m/e)：388[M+H]
+
Embodiment 8 preparation [(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical]-alanine methyl esters (4b)
1.2640g 2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin carboxylic acid (4.0mmol) is dissolved in the 30ml anhydrous tetrahydro furan, adds HoBt 0.5600g (4.8mmol), and ice bath adds 0.9840g DCC (4.8mmol) (a) down.5ml anhydrous tetrahydro furan suspendible HClAla-OMe 0.7240g (4.0mmol), 0.5mlNMM transfers PH to 9 (b).After 30 minutes b is added among a, and transfer PH to 9 with NMM.TLC (chloroform: stop reaction methyl alcohol=125: 1), filter DCU, revolve dry tetrahydrofuran.Redissolve product with amount of ethyl acetate, the DCU that elimination is separated out uses saturated NaHCO successively
3, the saturated NaCl aqueous solution, 5%KHSO
4, the saturated NaCl aqueous solution, saturated NaHCO
3Give a baby a bath on the third day after its birth time with each collection of saturated NaCl, the ester layer that obtains is through anhydrous Na
2SO
4Drying is revolved dried after several hours, obtain the xanchromatic product.The heavy 1.5484g of product, productive rate 96.5%.R
f＝0.32。ESI/MS(m/e)：402[M+H]
+
Embodiment 9 preparation [(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical]-valine methyl esters (4c)
1.2640g 2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin carboxylic acid (4.0mmol) is dissolved in the 30ml anhydrous tetrahydro furan, adds HoBt 0.6480g (4.8mmol), and ice bath adds 0.9840g DCC (4.8mmol) (a) down.5ml anhydrous tetrahydro furan suspendible HClVal-OMe 0.6680g (4.0mmol), 0.5mlNMM transfers PH to 9 (b).After 30 minutes b is added among a, and transfer PH to 9 with NMM.TLC (chloroform: stop reaction methyl alcohol=125: 1), filter DCU, revolve dry tetrahydrofuran.Redissolve product with amount of ethyl acetate, the DCU that elimination is separated out uses saturated NaHCO successively
3, the saturated NaCl aqueous solution, 5%KHSO
4, the saturated NaCl aqueous solution, saturated NaHCO
3Give a baby a bath on the third day after its birth time with each collection of saturated NaCl, the ester layer that obtains is through anhydrous Na
2SO
4Drying is revolved dried after several hours, obtain the xanchromatic product.The heavy 1.5857g (containing solvent) of product, productive rate 94.8%.R
f＝0.35。ESI/MS(m/e)：430[M+H]
+
Embodiment 10 preparation [(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical]-Isoleucine methyl esters (4d)
1.2640g 2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin carboxylic acid (4.0mmol) is dissolved in the 30ml anhydrous tetrahydro furan, adds HoBt 0.6480g (4.8mmol), and ice bath adds 0.9840g DCC (4.8mmol) (a) down.5ml anhydrous tetrahydro furan suspendible HClIle-OMe 0.7240g (4.0mmol), 0.5mlNMM transfers PH to 9 (b).After 30 minutes b is added among a, and transfer PH to 9 with NMM.TLC (chloroform: stop reaction methyl alcohol=125: 1), filter DCU, revolve dry tetrahydrofuran.Redissolve product with amount of ethyl acetate, the DCU that elimination is separated out uses saturated NaHCO successively
3, the saturated NaCl aqueous solution, 5%KHSO
4, the saturated NaCl aqueous solution, saturated NaHCO
3Give a baby a bath on the third day after its birth time with each collection of saturated NaCl, the ester layer that obtains is through anhydrous Na
2SO
4Drying is revolved dried after several hours, obtain the xanchromatic product.The heavy 1.6302g (containing solvent) of product, productive rate 92.0%.This solid is prone to the moisture absorption should seal preservation.R
f＝0.36。ESI/MS(m/e)：466[M+Na]
+
Embodiment 11 preparation [(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical]-glycocoll (5a)
0.7740g [(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical]-glycine methyl ester (2mmol) is dissolved in the 20ml methyl alcohol, ice bath is the cooling several minutes down, slowly drips 2N NaOH 4.5ml reaction is carried out.The omnidistance ice bath that keeps of reaction.TLC (chloroform: methyl alcohol=100: 1) monitoring reaction fully after, stopped reaction is used saturated KHSO
4Transfer reaction solution PH to neutral, revolve dried methyl alcohol,, obtain yellow suspension liquid with 20ml water redissolution resistates.Use saturated KHSO
4Transfer resistates pH value to 1, separate out white-yellowish solid, ethyl acetate extraction three times is collected the ester layer, and saturated NaCl aqueous solution collection is washed the ester layer to neutral, anhydrous Na
2SO
4Revolve dry ethyl acetate after dry several hours and obtain yellow solid 0.7430g, productive rate 96.0%.R
f(chloroform: methyl alcohol=5: 1)=0.38.8ESI/MS(m/e)：374[M+H]
+
Embodiment 12 preparation [(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical]-L-Ala (5b)
0.8020g [(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical]-alanine methyl ester (2mmol) is dissolved in the 20ml methyl alcohol, ice bath is the cooling several minutes down, slowly drips 2N NaOH 4.5ml reaction is carried out.The omnidistance ice bath that keeps of reaction.TLC (chloroform: methyl alcohol=100: 1) monitoring reaction fully after, stopped reaction is used saturated KHSO
4Transfer reaction solution PH to neutral, revolve dried methyl alcohol,, obtain yellow suspension liquid with 20ml water redissolution resistates.Use saturated KHSO
4Transfer resistates pH value to 1, separate out white-yellowish solid, ethyl acetate extraction three times is collected the ester layer, and saturated NaCl aqueous solution collection is washed the ester layer to neutral, anhydrous Na
2SO
4Revolve dry ethyl acetate after dry several hours and obtain yellow solid 0.7610g, productive rate 98.3%.R
f(chloroform: methyl alcohol=5: 1)=0.38.ESI/MS(m/e)：388[M+H]
+
Embodiment 13 preparation [(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical]-Xie Ansuans (5c)
0.8580g [(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical]-valine methyl ester (2mmol) is dissolved in the 20ml methyl alcohol, ice bath is the cooling several minutes down, slowly drips 2N NaOH 4.5ml reaction is carried out.The omnidistance ice bath that keeps of reaction.TLC (chloroform: methyl alcohol=100: 1) monitoring reaction fully after, stopped reaction is used saturated KHSO
4Transfer reaction solution PH to neutral, revolve dried methyl alcohol,, obtain yellow suspension liquid with 20ml water redissolution resistates.Use saturated KHSO
4Transfer resistates pH value to 1, separate out white-yellowish solid, ethyl acetate extraction three times is collected the ester layer, and saturated NaCl aqueous solution collection is washed the ester layer to neutral, anhydrous Na
2SO
4Revolve dry ethyl acetate after dry several hours and obtain yellow solid 0.7727g, productive rate 93.1%.R
f(chloroform: methyl alcohol=5: 1)=0.41.ESI/MS(m/e)：416[M+H]
+
Embodiment 14 preparation [(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical]-Isoleucines (5d)
0.8860g [(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical]-Isoleucine methyl esters (2mmol) is dissolved in the 20ml methyl alcohol, ice bath is the cooling several minutes down, slowly drips 2N NaOH 4.5ml reaction is carried out.The omnidistance ice bath that keeps of reaction.TLC (chloroform: methyl alcohol=100: 1) monitoring reaction fully after, stopped reaction is used saturated KHSO
4Transfer reaction solution PH to neutral, revolve dried methyl alcohol,, obtain yellow suspension liquid with 20ml water redissolution resistates.Use saturated KHSO
4Transfer resistates pH value to 1, separate out white-yellowish solid, ethyl acetate extraction three times is collected the ester layer, and saturated NaCl aqueous solution collection is washed the ester layer to neutral, anhydrous Na
2SO
4Revolve dry ethyl acetate after dry several hours and obtain yellow solid 0.7430g, productive rate 95.5%.R
f(chloroform: methyl alcohol=5: 1)=0.41.ESI/MS(m/e)：430[M+H]
+
Embodiment 15 preparation 4-toluenesulphonic acids acid anhydrides (6)
8.0000g TsCl (42mmol) and 2.0000g TsOHH2O (11mmol) are dissolved in the 50ml methylene dichloride stirred overnight under the room temperature.Revolve dry dichloromethane behind the reacting liquid filtering, behind methylene dichloride and normal hexane recrystallization, obtain the colourless bar-shaped crystallization 4.5778g of title compound, productive rate 57.2%.ESI/MS(m/e)：327[M+H]
+
Embodiment 16 preparation 6-O-(p-tosyl group)-beta-cyclodextrins (7)
10g beta-cyclodextrin (88mmol) is dissolved in the 220ml water, adds fine ground Ts
2O 4.261g (13mmol) crystallization is stirring reaction 2h at low temperatures.In reaction solution, drip the 10%NaOH aqueous solution, stir the 20min after-filtration.Use NH
4Cl transfers the filtrating pH value to neutral, separates out a large amount of white solids, and refrigerator and cooled is hidden and spent the night, and filters and obtains white solid 2.9693g, productive rate 26.1%.ESI/MS(m/e)：1290[M+H]
+
Embodiment 17 preparation 6-amino-6-deoxidation-beta-cyclodextrins (8)
1.2890g CD-OTs (1mmol) is suspended in the 35ml water, adds 0.7170g NaN after being heated to 80 ℃
3(11mmol), the solution clarification that becomes rapidly.Continue heating 5.5 hours, reaction solution is splashed in the 300ml acetone, produce deposition, obtain white solid after the drying.Solid is dissolved among the 24ml DMF, adds PPh
30.3660g (14mmol), drip the 2.5ml strong aqua again, separate out a small amount of white solid in the solution.React after 5 hours, reaction solution splashes into acetone, obtains deposition, obtains product 1.0819g, productive rate 95.0% after the deposition drying.ESI/MS(m/e)：1157[M+Na]
+。
Embodiment 18 preparation 6-[(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical-glycocoll]-6-deoxidation-beta-cyclodextrins (9a)
With 0.3946mg [(2-N-Boc-1; 2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical]-glycocoll (1.1mmol) is dissolved in the 5ml dry DMF; Add HoBt 0.1428g (1.1mmol); Ice bath adds DCC 0.2169g (1.1mmol) down, reacts a hour recession deicing and bathes, and continues one hour (a) of reaction under the room temperature.With 1.2000g β CD-NH
2Suspend with DMF, transfer pH value to 9 (b) with NMM.B is splashed among a.Reaction is carried out stopping after 2 days, and elimination by product DCU removes solvent, the thick product of faint yellow solid 1.3206g that obtains doing.Obtain pure title compound 0.5300g, productive rate 34.1% through column chromatography for separation.ESI/MS(m/e)：1490[M+H]
+.
1HNMR(D
2O，500MHZ，TMS，ppm)：δ＝1.45(s，9H)，δ＝2.85-3.15(m，2H)，δ＝3.30-4.15(br，60H)，δ＝5.0(m，7H)，δ＝7.05(t，1H，J＝7.5Hz)，δ＝7.15(t，1H，J＝7.5Hz)，δ＝7.40(d，1H，J＝7.5Hz)，δ＝7.50(d，1H，J＝7.5Hz)
Embodiment 19 preparation 6-[(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical-L-Ala]-6-deoxidation-beta-cyclodextrins (9b)
With 0.3870g [(2-N-Boc-1; 2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical]-L-Ala (1mmol) is dissolved in the 5ml dry DMF; Add HoBt 0.1620g (1.2mmol); Ice bath adds DCC 0.2560g (1.2mmol) down, reacts a hour recession deicing and bathes, and continues one hour (a) of reaction under the room temperature.With 1.1340g β CD-NH
2(1mmol) suspend, transfer pH value to 9 (b) with NMM with DMF.B is splashed among a.After reaction was carried out 2 days, elimination by product DCU removed the thick product of white solid 1.2139g that solvent obtains doing.Obtain pure title compound 0.5506g, productive rate 38.6% through column chromatography for separation.ESI/MS(m/e)：1504[M+H]
+.
1HNMR(D
2O，500MHZ，TMS，ppm)：δ＝0.85(d，3H，J＝6.5Hz)，δ＝1.40-1.55(s，10H)，δ＝2.85(m，1H)，δ＝3.05(m，2H)，δ＝3.20-4.10(br，49H)，δ＝4.80-5.05(m，7H)，δ＝7.05(t，1H，J＝7.5Hz)，δ＝7.15(t，1H，J＝7.5Hz)，δ＝7.40(d，1H，J＝7.5Hz)，δ＝7.50(d，1H，J＝7.5Hz).
Embodiment 20 preparation 6-[(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical-Xie Ansuan }-6-deoxidation-beta-cyclodextrin (9c)
With 0.4150g [(2-N-Boc-1; 2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical]-Xie Ansuan (1mmol) is dissolved in the 5ml dry DMF; Add HoBt 0.1620g (1.2mmol); Ice bath adds DCC 0.2560g (1.2mmol) down, reacts a hour recession deicing and bathes, and continues one hour (a) of reaction under the room temperature.With 1.1340g β-CD-NH
2(1mmol) suspend, transfer pH value to 9 (b) with NMM with DMF.B is splashed among a.After reaction was carried out 2 days, elimination by product DCU removed the thick product of white solid 1.4050g that solvent obtains doing.Obtain pure title compound 0.1920g, productive rate 17.0% through column chromatography for separation.ESI/MS(m/e)：1532[M+H]
+.
1HNMR(D
2O，500MHZ，TMS，ppm)：δ＝0.98(q，6H，J＝12.9Hz，7.1Hz)，δ＝1.45(s，9H)，δ＝2.20(m，1H)，δ＝2.85(m，1H)，δ＝2.98-4.30(br，53H)，δ＝4.78-5.20(m，7H)，δ＝6.98(t，1H，J＝7.5Hz)，δ＝7.08(t，1H，J＝7.5Hz)，δ＝7.30(d，2H，J＝10Hz).
Embodiment 21 preparation preparation 6-[(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical-Isoleucine]-6-deoxidation-β-rings are stuck with paste (9d)
With 0.4290g [(2-N-Boc-1; 2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical]-Isoleucine (1mmol) is dissolved in the 5ml dry DMF; Add HoBt 0.1620g (1.2mmol); Ice bath adds DCC 0.2560g (1.2mmol) down, reacts a hour recession deicing and bathes, and continues one hour (a) of reaction under the room temperature.With 1.1340g β CD-NH
2(1mmol) suspend, transfer pH value to 9 (b) with NMM with DMF.B is splashed among a.After reaction was carried out 2 days, elimination by product DCU removed the thick product of faint yellow solid 1.3206g that solvent obtains doing.Obtain pure title compound 0.6797g, productive rate 44.0% through column chromatography for separation.ESI/MS(m/e)：1546[M+H]
+.
1HNMR(D
2O，500MHZ，TMS，ppm)：δ＝0.80(m，6H)，δ＝1.12(m，2H)，δ＝1.45(s，9H)，δ＝2.79-4.30(br，57H)，δ＝4.62-5.18(m，9H)，δ＝7.05(t，1H，J＝7.5Hz)，δ＝7.15(t，1H，J＝7.5Hz)，δ＝7.40(d，1H，J＝7.5Hz)，δ＝7.50(d，1H，J＝7.5Hz).
Embodiment 22 preparation 6-[(1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical-glycocoll]-6-deoxidation-beta-cyclodextrins (10a)
0.2000g6-[(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical-glycocoll]-6-deoxidation-beta-cyclodextrin (0.13mmol) is dissolved in 3mlTFA, stirring at room 6-8 hour.Stop revolving a large amount of TFA after the reaction, ice bath drips strong aqua 5ml down, removes solvent then, obtains faint yellow solid 0.1706g.Product obtains yellowish colour purity article 0.0900g, productive rate 48% behind sephadex G-25 purifying.Mp：238-240℃.[a]
D 25＝+95.0(c＝1.0，H
2O).ESI/MS(m/e)：1390[M+H]
+.IR(KBr)：3329，2802，1155，1081，1030，939，755，567cm
-1.
1HNMR(D
2O，500MHZ，TMS，ppm)：δ＝2.85-3.15(m，2H)，δ＝3.30-4.15(br，60H)，δ＝5.0(m，7H)，δ＝7.05(t，1H，J＝7.5Hz)，δ＝7.15(t，1H，J＝7.5Hz)，δ＝7.40(d，1H，J＝7.5Hz)，δ＝7.50(d，1H，J＝7.5Hz).
13C-NMR(75MHz，DMSO-d
6，ppm)：δ＝173.43，169.34，136.25，134.18，127.59，120.88，118.75，117.68，111.31，106.96，102.67，102.43，102.33，83.98，82.35，82.21，82.04，81.89，73.49，72.90，72.58，70.26，60.41，56.78，42.41，42.17，24.89.Anal.Calcd?for?C
56H
84N
4O
36·8H
2O：C：43.86；H：6.57；N：3.65.Found：C：44.38；H：6.25；N：4.08.
Embodiment 23 preparation 6-[(1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical-L-Ala]-6-deoxidation-beta-cyclodextrins (10b)
0.2000g6-[(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical-L-Ala]-6-deoxidation-beta-cyclodextrin (0.13mmol) is dissolved in 3mlTFA, stirring at room 6-8 hour.Stop revolving a large amount of TFA after the reaction, ice bath drips strong aqua 5ml down, removes solvent then, obtains faint yellow solid 0.1689g.Product obtains yellowish colour purity article 0.1050g, productive rate 74% behind sephadex G-25 purifying.Mp：246-248℃.[a]
D 25＝+29.3(c＝1.0，H
2O).ESI/MS(m/e)：1404[M+H]
+.IR(KBr)：3307，2361，1514，1334，1155，1081，1031，875，561cm
-1.
1HNMR(D
2O，500MHZ，TMS，ppm)：δ＝1.30(d，3H，J＝6.3Hz)，δ＝2.85-3.15(m，2H)，δ＝3.30-4.15(br，50H)，δ＝5.0(m，7H)，δ＝4.30(q，1H，J＝5Hz)，δ＝7.05(t，1H，J＝7.5Hz)，δ＝7.15(t，1H，J＝7.5Hz)，δ＝7.40(d，1H，J＝7.5Hz)，δ＝7.50(d，1H，J＝7.5Hz).
13C-NMR(75MHz，DMSO-d
6，ppm)：δ＝173.00，172.66，136.20，134.16，127.56，120.87，118.75，117.71，111.31，106.98，102.40，82.06，81.89，73.46，72.89，72.47，63.52，60.38，56.74，48.49，24.88，24.88，19.36.
Embodiment 24 preparation 6-[(1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical-Xie Ansuan]-6-deoxidation-beta-cyclodextrins (10c)
With 0.2000g6-[(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical-Xie Ansuan }-6-deoxidation-beta-cyclodextrin (0.13mmol) is dissolved in 3mlTFA, stirring at room 6-8 hour.Stop revolving a large amount of TFA after the reaction, ice bath drips strong aqua 5ml down, removes solvent then, obtains faint yellow solid 0.1620g at last.Product obtains yellowish colour purity article 0.0700g, productive rate 37% behind sephadex G-25 purifying.Mp：255-256℃.[a]
D 25＝+65.0(c＝1.0，H
2O).ESI/MS(m/e)：1432[M+H]
+.IR(KBr)：3303，2895，2358，1651，1558，1522，1454，1333，1154，1081，1031，941，753，706，581cm
-1.
1HNMR(D
2O，500MHZ，TMS，ppm)：δ＝0.83(dd，6H，J＝12.9Hz，7.1Hz)，δ＝1.92(m，1H)，δ＝2.85-3.15(m，2H)，δ＝3.28-4.20(br，59H)，δ＝4.89-5.02(m，6H)，δ＝6.98(t，1H，J＝7.5Hz)，δ＝7.08(t，1H，J＝7.5Hz)，δ＝7.30(d，2H，J＝10Hz).
13C-NMR(75MHz，DMSO-d
6，ppm)：δ＝172.80，171.94，136.21，134.16，127.55，120.88，118.75，117.72，111.31，107.02，102.44，102.25，84.54，83.50，82.60，82.09，81.81，73.48，72.92，72.47，70.33，69.84，60.42，56.92，32.40，31.68，29.73，25.32，24.95，19.67，18.23.
Embodiment 25 preparation 6-[(1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical-Isoleucine]-6-deoxidation-beta-cyclodextrins (10d)
0.2000g6-[(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical-Isoleucine]-6-deoxidation-β-ring is stuck with paste (0.13mmol) be dissolved in 3mlTFA, stirring at room 6-8 hour.Stop revolving a large amount of TFA after the reaction, ice bath drips strong aqua 5ml down, removes solvent then, obtains faint yellow solid 0.1666g.Product obtains yellowish colour purity article 0.0535g, productive rate 29% behind sephadex G-25 purifying.Mp：249-251℃.[a]
D 25＝+72.3(c＝1.0，H
2O).ESI/MS(m/e)：1446[M+H]
+.IR(KBr)：3310，2359，1772，1652，1558，1506，1334，1154，1080，1031，942，580cm
-1.
1HNMR(D
2O，500MHZ，TMS，ppm)：δ＝0.80(m，6H)，δ＝1.12(m，2H)，δ＝2.99-4.30(br，72H)，δ＝4.62-5.08(m，14H)，δ＝7.05(t，1H，J＝7.5Hz)，δ＝7.15(t，1H，J＝7.5Hz)，δ＝7.40(d，1H，J＝7.5Hz)，δ＝7.50(d，1H，J＝7.5Hz).
13C-NMR(75MHz，DMSO-d
6，ppm)：δ＝172.75，172.06，136.25，134.15，127.60，120.86，118.74，117.73，111.30，106.99，102.63，102.44，83.48，82.09，81.85，73.47，72.93，72.49，69.86，63.57，60.88，60.40，56.81，32.33，30.35，30.04，26.20，24.96，24.55，15.78，14.89，12.07，11.66.
The external platelet aggregation inhibitory activity test of experimental example 1 compound 10a-d
The physiological salt soln of configuration platelet aggregation inductor (all deriving from SIGMA company): ADP concentration 500 μ mol/ml, PAF concentration 50 μ mol/ml, AA concentration 7.4mg/ml, TH concentration 1U/ml-5U/ml.Parent nucleus 1 and target compound 10a-d use DMSO to be made into the solution of concentration as 50mmol/ml.Negative control group is the DMSO 99.8MIN. group, and positive controls is the Frosst) group.
The serum bottle collection fresh pig blood that adds 3.8% liquor sodii citratis in advance in 10% ratio that use is handled through silylanization; Preserved down the fresh pig whole blood rapidly with the rotating speed of 1000r/min centrifugal 10 minutes, and collected supernatant and be platelet rich plasma (PRP) for 37 ℃.Centrifugal 10 minutes of remaining whole blood 3000r/min collects supernatant and is platelet poor plasma (PPP).PRP and PPP all are kept under 37 ℃.With ADP, PAF, TH, AA are that inductor (deriving from SIGMA company) induced platelet is assembled.Each data horizontal survey 6 times.
Table 1 be parent nucleus 1 and compound 10a-d to PAF, ADP, TH, the influence (n=6) of AA inductive platelet aggregation effect.
Table 1
Table 1 data declaration The compounds of this invention 10a-d is to PAF, ADP, and TH, the effect of AA inductive platelet aggregation all has certain restraining effect, and restraining effect is better than parent nucleus 1, and stronger to the restraining effect of PAF, TH inductive platelet aggregation.
Rat arteriovenous shut circulation model 10a-d antithrombotic acitivity experiment in the experimental example 2 oral administration bodies
Compound 10a-d is made into 10 μ mol/ml physiological salt solns, and being used for intravital dosage is 1 μ mol/kg.Parent nucleus 1 is made into 50 μ M physiological salt solns, and being used for intravital dosage is 5 μ mol/kg.The positive drug Frosst) is made into the 10g/l physiological salt soln, i.e. the solution of 55.5mmol/ml, and being used for intravital dosage is 180 μ mol/kg.Blank is a saline water, and antithrombotics is a heparin sodium 2.4mg/ml physiological salt soln.
The polyethylene jacket that is used to form bypass circuit in the experiment is packed 6cm length in advance through accurate silk thread of weighing.Polyethylene tube (removing silk thread) through 1% silicone oil diethyl ether solution silylanization, the damage that haemolysis causes animal occurs in avoiding performing the operation.
With laboratory animal SD male rat random packet, n=12, the volume of rat oral gavage administration are 3ml/kg, and (20g/100ml, 7ml/kg) anesthesia separates RCCA and the total vein of left neck with urethane after 30 minutes to irritate stomach.The total vein distal end of ligation neck is cut an osculum, and a polyethylene tube that is full of the heparin sodium physiological salt soln is inserted the total vein of neck and fixing, injects the heparin sodium physiological salt soln by the dosage of 1ml/kg.Ligation carotid atery distal end is clamped the carotid atery proximal part with bulldog clamp, cuts an osculum, and the polyethylene tube the other end is inserted carotid atery and 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 15 minutes, the record wet weight of thrombus.
Table 2 is that parent nucleus 1 and compound 10a-d are to the thrombotic influence of oral absorption approach SD male rat.Table 3 is that the compound 10a-d of various dose is to the thrombotic influence of oral absorption approach SD male rat.
Table 2
N=12, target compound group 10a-p dosage is 1 μ mol/kg, and 1 dosage is 5 μ mol/kg, and control group 5a-d dosage is 5 μ mol/kg, and control group 11a-d dosage is 1 μ mol/kg, aspirin dose is 180umol/kg,
A=and saline water group ratio, p＜0.05; B=and saline water group, p＜0.01; C=and Frosst) group are than p＜0.05; D=and Frosst) are than p＜0.01.
Table 3
N=12, a=and saline water group ratio, p＜0.05; B=and saline water group, p＜0.01; C=and Frosst) group are than p＜0.05; D=and Frosst) are than p＜0.01.
4 target compounds of table 2 data declaration are compared with parent nucleus, and outstanding antithrombotic acitivity is all arranged, and when dosage was 1umol/kg, active comparing with the positive drug Frosst) do not have significant difference.The activity of 4 target compounds of table 3 data declaration all has dose-dependently.
Claims (3)
1. tetrahydrochysene-β-Ka Lin carboxylic acid derivative of modifying of 4 kinds of beta-cyclodextrins of general formula 10a-d representative, as follows:
Wherein, R is selected from H, CH
3, CH (CH
3)
2Or CH (CH
3) CH
2CH
3
2. prepare the method for the tetrahydrochysene-β-Ka Lin carboxylic acid derivative of the described beta-cyclodextrin modification of claim 1, this method comprises the steps:
1) in the presence of zero(ppm) water and sulfuric acid, L tryptophane and formaldehyde at room temperature react becomes tetrahydrochysene-β-Ka Lin carboxylic acid;
2) at N, dinethylformamide (DMF) exists down with triethylamine, and step 1 products therefrom and tert-Butyl dicarbonate (DIBOC) at room temperature react, and become N-Boc-1, and 2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid;
3) in the presence of thionyl chloride and methyl alcohol, amino acid whose hydroxyl is replaced by methyl esters, and said amino acid is glycocoll, L-L-Ala, L-Xie Ansuan or L-Isoleucine;
4) in the presence of I-hydroxybenzotriazole (HoBt) and NSC 57182 (DCC); Step 2 products therefrom and HClAA-OMe (AA is glycyl, L-alanyl, L-is valyl or the L-isoleucyl) condensation in anhydrous tetrahydro furan becomes N-[(2-N-Boc-1; 2; 3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical]-amino acid methyl ester;
5) in methyl alcohol, be N-[(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical]-amino acid with N-[(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical]-amino acid methyl ester saponification;
6) in the presence of methylene dichloride, Tosyl chloride and tosic acid at room temperature dewater and form tosic acid acid anhydride (Ts
2O);
7) in zero(ppm) water, use Ts
2O becomes 6-O-(p-tosyl group)-beta-cyclodextrin with the single 6-OH tosylation of beta-cyclodextrin;
8) in the presence of zero(ppm) water, 6-O-(p-tosyl group)-beta-cyclodextrin is become 6-nitrine-6-deoxidation-beta-cyclodextrin by the sodium azide azide.Afterwards, in the presence of DMF and strong aqua, 6-nitrine-6-deoxidation-beta-cyclodextrin generation transamination becomes 6-amino-6-deoxidation-beta-cyclodextrin;
9) dry DMF is existed down N-[(2-N-Boc-1,2; 3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical]-amino acid and 6-amino-6-deoxidation-beta-cyclodextrin condensation become 6-[(2-N-Boc-1,2; 3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical-amino acid]-6-deoxidation-beta-cyclodextrin;
10) 6-[(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical-amino acid]-6-deoxidation-beta-cyclodextrin removes Boc and becomes 6-[(1,2,3,4-tetrahydrochysene-β-Ka Lin-3)-formyl radical-amino acid]-6-deoxidation-beta-cyclodextrin in trifluoracetic acid (TFA).
3. the application of tetrahydrochysene-β-Ka Lin carboxylic acid derivative in the preparation pharmaceutical preparations having antithrombotic activity of the described beta-cyclodextrin modification of claim 1.
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