CN103450334A - RGD peptide-modified carbolino-hexahydropyrazine-1,4-diketones and their preparation method, antithrombotic effect and use - Google Patents
RGD peptide-modified carbolino-hexahydropyrazine-1,4-diketones and their preparation method, antithrombotic effect and use Download PDFInfo
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Abstract
The invention discloses RGD peptide-modified carbolino-hexahydropyrazine-1,4-diketones, which are three novel conjugates of carbolino-hexahydropyrazine-1,4-diketone and RGD tetrapeptide and are shown in the general formula I. In the general formula I, R represents Arg-Gly-Asp-Val, Arg-Gly-Asp-Phe or Arg-Gly-Asp-Ser. The invention also discloses heterocyclic nucleuses of the novel conjugates, wherein R represents OH. The invention also discloses a preparation method and in-vitro anti-platelet aggregation effects of the novel conjugates, and also discloses an antithrombotic use of the novel conjugates in a rat thrombus formation model. A result shows that the three novel conjugates of carbolino-hexahydropyrazine-1,4-diketone and RGD tetrapeptide (wherein R represents Arg-Gly-Asp-Val, Arg-Gly-Asp-Phe or Arg-Gly-Asp-Ser) and their heterocyclic nucleuses (wherein R represents OH) have good antithrombotic activity and clear application prospects in antithrombotic agent preparation.
Description
Technical field
The present invention relates to general formula 1 representative (R represents Arg-Gly-Asp-Val, Arg-Gly-Asp-Phe and Arg-Gly-Asp-Ser) carboline hexahydropyrazine-1, three kinds of Novel conjugates of 4-diketone and RGD tetrapeptide, and their heteronucleus (R represents OH), the preparation method who relates to them, the In Vitro Anti platelet aggregation that also relates to them, further relate to their anti thrombotic actions on the rat suppository formation model.Result shows, general formula 1 of the present invention (R represents Arg-Gly-Asp-Val, Arg-Gly-Asp-Phe and Arg-Gly-Asp-Ser) carboline hexahydropyrazine-1, three kinds of Novel conjugates and their heteronucleus (R represents OH) of 4-diketone and RGD tetrapeptide have good antithrombotic acitivity, and clear and definite application prospect is arranged in the preparation of antithrombotic agent.The invention belongs to biomedicine field.
Background technology
In the world, the M & M of thrombotic diseases all ranks first.Thrombus in the thrombus patient body has two kinds, a kind of be by thrombocyte by Fibrinogen and the crosslinked thrombus formed of white cell, another kind is by Fibrinogen and the crosslinked thrombus formed of thrombocyte by thrombocyte.
Palatelet-selectin exists with lysotype palatelet-selectin and two kinds of forms of insoluble type palatelet-selectin.Under Platelet Activation, insoluble type palatelet-selectin moves quickly into the hematoblastic surface expression of activation and is cut into the lysotype palatelet-selectin from the thrombocyte theca interna and enters blood circulation.Lysotype palatelet-selectin mediation form a large amount of stable by thrombocyte by Fibrinogen and the crosslinked thrombus formed of white cell.Although suppress insoluble type palatelet-selectin express and be cut into the lysotype palatelet-selectin be considered to be the design antithrombotic reagent important target spot, almost do not have antithrombotic compound to be associated with this target spot.This situation makes the contriver express and be cut into the compound of lysotype palatelet-selectin as the important research direction using finding the insoluble type palatelet-selectin of inhibition.Under appropriate design and the support of the selection result widely, carboline the hexahydropyrazine-Isosorbide-5-Nitrae-diketone-3-acetic acid of formula II representative are confirmed as one of lead compound.Experimental study shows, 10
-8under M concentration, it can make the amount of the thrombocyte expression palatelet-selectin of rat activation be reduced to 110.12 ± 3.96ng/ml (p<0.001) from 210.55 ± 2.98ng/ml.
Glycoprotein iib/iiia alienation when thrombocyte is activated, be combined with Fibrinogen, makes thrombocyte by Fibrinogen and the crosslinked formation thrombus of thrombocyte.The combination of research glycoprotein iib/iiia and Fibrinogen α chain and Fibrinogen γ chain, determined RGDS, RGDV and RGDF are the pass key sequences that causes Fibrinogen to be identified by glycoprotein iib/iiia and be combined with Fibrinogen in during platelet aggregation.Adopting the correlated series of RGDF or RGDS or RGDV to occupy under Platelet Activation fibrinogenic binding site on glycoprotein iib/iiia is to suppress by thrombocyte the important means by Fibrinogen and the crosslinked thrombus formed of thrombocyte.
At the carboline that has obtained the formula II representative hexahydropyrazine-Isosorbide-5-Nitrae-diketone-3-acetic acid 10
-8after effectively suppressing the such breakthrough of thrombocyte expression palatelet-selectin of rat activation under M concentration, the RGD peptide is created to being innovated and gordian technique by the core of the novel antithrombotic agent of Fibrinogen and the crosslinked thrombus formed of thrombocyte by the thrombocyte of Fibrinogen and the crosslinked thrombus formed of white cell and the mediation of inhibition glycoprotein iib/iiia by thrombocyte of inhibition lysotype palatelet-selectin mediation in conjunction with just becoming the contriver with it.The progress of this core innovation and gordian technique must make the antithrombotic effective dose of compound of the present invention significantly descend.So the contriver has proposed the present invention.
Summary of the invention
One of content of the present invention is to provide four kinds of compounds of general formula I representative, and in formula, R is OH, Arg-Gly-Asp-Val, Arg-Gly-Asp-Phe or Arg-Gly-Asp-Ser.
Two of content of the present invention is to provide the method for the compound of synthetic general formula I representative, and the method comprises:
(1) prepare 3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid;
(2) prepare 3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylate methyl ester;
(3), by 3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylate methyl ester and Boc-Asp (OBzl) coupling, make 3S-N-[Boc-Asp (OBzl)]-1,2,3,4-tetrahydro-beta-carboline-3-carboxylate methyl ester;
(4) from 3S-N-[Boc-Asp (OBzl)]-1,2,3, the 3S-N-[Asp (OBzl) that the de-Boc of 4-tetrahydro-beta-carboline-3-carboxylate methyl ester makes]-1,2,3,4-tetrahydro-beta-carboline-3-carboxylate methyl ester hydrochloride preparation (3S, 12aS)-3-carbobenzoxy-(Cbz)-2,3,6,7,12, the 12a-hexahydropyrazine is [1 ', 2 ': 1,6] pyrido [3 also, 4-b] indoles-Isosorbide-5-Nitrae-diketone;
(5) (3S, 12aS)-3-carbobenzoxy-(Cbz)-2,3,6,7,12,12a-hexahydropyrazine also [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone in tetrahydrofuran (THF) and methyl alcohol under the catalysis of palladium charcoal hydrogenolysis be (3S, 12aS)-3-carboxymethyl-2,3,6,7,12,12a-hexahydropyrazine also [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone;
(6), by (3S, 12aS)-3-carboxymethyl-2,3,6,7,12, the 12a-hexahydropyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone and HClArg (NO also
2)-Gly-Asp (OBzl)-Val-OBzl, HClArg (NO
2)-Gly-Asp (OBzl)-Phe-OBzl or HClArg (NO
2)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl coupling preparation (3S, 12aS)-2,3,6,7,12, the 12a-hexahydropyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone-3-acetyl-Arg (NO also
2)-Gly-Asp (OBzl)-Val-OBzl, (3S, 12aS)-2,3,6,7,12, the 12a-hexahydropyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone-3-acetyl-Arg (NO also
2)-Gly-Asp (OBzl)-Phe-OBzl and (3S, 12aS)-2,3,6,7,12, the 12a-hexahydropyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone-3-acetyl-Arg (NO also
2)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl;
(7), by (3S, 12aS)-2,3,6,7,12, the 12a-hexahydropyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone-3-acetyl-Arg (NO also
2)-Gly-Asp (OBzl)-Val-OBzl, (3S, 12aS)-2,3,6,7,12, the 12a-hexahydropyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone-3-acetyl-Arg (NO also
2)-Gly-Asp (OBzl)-Phe-OBzl and (3S, 12aS)-2,3,6,7,12, the 12a-hexahydropyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone-3-acetyl-Arg (NO also
2)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl deprotection obtains (3S, 12aS)-2, 3, 6, 7, 12, 12a-hexahydropyrazine also [1 ', 2 ': 1, 6] pyrido [3, 4-b] indoles-1, 4-diketone-3-acetyl-Arg-Gly-Asp-Val, (3S, 12aS)-2, 3, 6, 7, 12, 12a-hexahydropyrazine also [1 ', 2 ': 1, 6] pyrido [3, 4-b] indoles-1, 4-diketone-3-acetyl-Arg-Gly-Asp-Phe and (3S, 12aS)-2, 3, 6, 7, 12, 12a-hexahydropyrazine also [1 ', 2 ': 1, 6] pyrido [3, 4-b] indoles-1, 4-diketone-3-acetyl-Arg-Gly-Asp-Ser.
Three of content of the present invention is to estimate four kinds of compounds of general formula 1 representative, and in formula, R is OH, Arg-Gly-Asp-Val, Arg-Gly-Asp-Phe or Arg-Gly-Asp-Ser, platelet aggregation inhibitory activity.
Four of content of the present invention is to estimate four kinds of compounds of general formula I representative, and in formula, R is OH, Arg-Gly-Asp-Val, Arg-Gly-Asp-Phe or Arg-Gly-Asp-Ser, antithrombotic acitivity.
Five of content of the present invention is four kinds of compounds of setting forth the general formula I representative, and in formula, R is OH, Arg-Gly-Asp-Val, Arg-Gly-Asp-Phe or Arg-Gly-Asp-Ser, the purposes in preparing antithrombotic reagent.
Six of content of the present invention is to investigate three kinds of compounds of general formula I representative, and in formula, R is Arg-Gly-Asp-Val, Arg-Gly-Asp-Phe or Arg-Gly-Asp-Ser, the nanometer particle size in the aqueous solution.
The accompanying drawing explanation
The synthetic route chart of Fig. 1 7a-c.I) formaldehyde and concentrated hydrochloric acid; Ii) methyl alcohol and thionyl chloride; Iii) dicyclohexyl carbonyl diimine (DCC), N-hydroxy benzo triazole (HOBt), N-methylmorpholine (NMM) and tetrahydrofuran (THF); Iv) the hydrogenchloride ethyl acetate solution of 4N; Methyl alcohol and NMM solution; V) mixing solutions of methyl alcohol and tetrahydrofuran (THF), palladium charcoal, hydrogen; Vi) DCC, HOBt, NMM, tetrahydrofuran (THF); Vii) mixing solutions of methyl alcohol-tetrahydrofuran (THF) (1: 1), palladium charcoal, hydrogen; Viii) hydrochloride of DCC, HOBt, NMM, tetrahydrofuran (THF) and full guard RGD tetrapeptide; Wherein, AA=Val in 6a; AA=Phe in 6b; AA=Ser in 6c (Bzl); Ix) trifluoracetic acid, trifluoromethanesulfonic acid, AA=Val in 7a; AA=Phe in 7b; AA=Ser. in 7c
Particle diameter (nm) temporal evolution of 25 ℃ of lower 7a-c of Fig. 2
Particle diameter (nm) temporal evolution of 50 ℃ of lower 7a-c of Fig. 3
Embodiment
In order further to set forth the present invention, below provide a series of embodiment.These embodiment are illustrative fully, and they only are used for the present invention is specifically described, and not should be understood to limitation of the present invention.
400ml water is placed in to 500ml eggplant bottle, slowly adds the 0.2ml vitriol oil.Add 5.0g (24.5mmol) L-Trp in the dilute sulfuric acid aqueous solution obtained, sonic oscillation to L-Trp dissolves fully.Add the formaldehyde solution that 7.5ml concentration is 40% in solution, reaction mixture stirring at room 6 hours, thin-layer chromatography monitors L-Trp and disappears, termination reaction.Slowly drip strong aqua in reaction soln, adjust reaction mixture pH to 6, standing 0.5 hour.Decompress filter, the precipitation obtained washes with water, and the colorless solid leached is laid in culture dish, obtains 5.14g (97%) title compound after dry air.ESI-MS(m/e)：217[M+H]
+。
Add 50ml methyl alcohol in 100ml eggplant bottle, be as cold as below 0 ℃ with ice-salt bath, stir the lower 6ml (87mmol) of dropping SOCl
2, adding 5.0g (23.1mmol) (3S)-1,2,3 after dripping 10 minutes, 4-tetrahydro-beta-carboline-3-carboxylic acid, remove ice bath, stirred overnight at room temperature.The TLC monitoring raw material rear stopped reaction that substantially disappears, methyl alcohol and excessive SOCl are extracted in the water pump decompression out
2, residue is used dissolve with methanol again, and vacuum pump using circulatory water is drained, triplicate (10ml * 3), residue adds diethyl ether, and vacuum pump using circulatory water is drained, triplicate (10ml * 3).Residue adds 20ml water and 20ml ethyl acetate, and adds saturated NaHCO
3solution is adjusted pH 7-8, and ethyl acetate layer is collected in layering, and water layer is extracted with ethyl acetate (20ml * 3) again, combined ethyl acetate layer, saturated sodium-chloride washing three times, anhydrous Na
2sO
4drying, filter, and filtrate decompression is concentrated into dry, and residue column chromatography purification (sherwood oil-acetone system, 1: 1), obtain 3.6g (68%) title compound, is colourless powder.ESI-MS(m/e)：231[M+H]
+。
1.61g (5mmol) Boc-Asp (OBzl) is dissolved in to the 50ml anhydrous methylene chloride, add 742mg (6mmol) HOBt and 1.42g (6mmol) DCC under ice bath, stirring reaction solution after 5-10 minute becomes turbid, add 1.15g (5mmol) (3S)-1,2,3,4-tetrahydro-beta-carboline-3-carboxylate methyl ester, within 30 minutes, the recession deicing is bathed.Room temperature reaction 12 hours, TLC shows that raw material point disappears, stopped reaction, filtering DCU, filtrate is evaporated to dry at 30 ℃, the residue acetic acid ethyl dissolution.Then use successively saturated sodium bicarbonate aqueous solution, saturated sodium-chloride water solution, 5% aqueous potassium hydrogen sulfate, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution are respectively washed three times, the organic layer anhydrous sodium sulfate drying separated, filter, and filtrate is evaporated to dry at 30 ℃, obtaining 1.60g (60%) title compound, is colourless powder.ESI-MS(m/e)：558[M+Na]
+。
Embodiment 4 preparation (3S, 12aS)-3-carbobenzoxy-(Cbz)s-2,3,6,7,12, the 12a-hexahydropyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone (4) also
Take 300mg (0.5mmol) (3S)-N-[Boc-Asp (OBzl)]-1,2,3,4-tetrahydro-beta-carboline-3-carboxylate methyl ester (3) is in the 50ml round-bottomed flask, the hydrogenchloride ethyl acetate solution that adds 3ml 4N under ice bath, on connect drying tube, after 30 minutes, TLC shows raw material point disappearance, stopped reaction.Water pump pressure reducing and steaming ethyl acetate, residue adds ethyl acetate again, and vacuum pump using circulatory water is drained, triplicate (5ml * 3).Residue adds diethyl ether, and vacuum pump using circulatory water is drained, triplicate (5ml * 3), and the 245mg colourless powder obtained, with after the 3ml dissolve with methanol, drips NMM conditioned reaction liquid pH 8-9, TLC monitoring after 6 hours, raw material point disappears.Be evaporated to dry except desolventizing, residue 150ml acetic acid ethyl dissolution, be placed in the 250ml separating funnel, wash (30ml * 3), saturated sodium-chloride water solution with saturated sodium bicarbonate aqueous solution successively and wash (30ml * 3), 5% aqueous potassium hydrogen sulfate and wash that (30ml * 3), saturated sodium-chloride water solution are washed (30ml * 3), saturated sodium bicarbonate aqueous solution washes (30ml * 3) and saturated sodium-chloride water solution is washed (30ml * 3).The ethyl acetate layer anhydrous sodium sulfate drying merged, filter, and filtrate decompression is concentrated into dry, obtains 193mg (84%) title compound, is colourless powder.ESI-MS(m/e)：404[M+H]
+。
Take 500mg (1.24mmol) (3S, 12aS)-3-carbobenzoxy-(Cbz)-2,3,6,7,12,12a-hexahydropyrazine also [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone (4) sample is in 250ml eggplant bottle, with after 50ml THF and 50ml dissolve with methanol, add 50mg palladium carbon, discharge the interior air of bottle and pass into hydrogen, reacting 2 hours, TLC monitoring reaction raw material point disappears, filter, methyl alcohol is flush cake repeatedly, and filtrate decompression concentrates to obtain 370mg (95%) title compound, is colourless powder.ESI-MS(m/e)：314[M+H]
+。
Embodiment 6 preparation Boc-Asp (OBzl)-Val-OBzl
Under ice bath and stirring, 2.2g (6.81mmol) Boc-Asp (OBzl) is dissolved in the THF of 150ml drying, adds 1.01g (7.49mmol) HOBt, stirring and dissolving.Add 1.68g (8.17mmol) DCC, ice bath stirring reaction 30 minutes after a moment in mixed solution.2.71g (7.15mmol) TosVal-OBzl is dissolved with anhydrous THF, under ice bath, add NMM to adjust pH to 7 to add in above-mentioned reaction solution afterwards.Drip the pH to 8-9 of NMM conditioned reaction liquid.Remove ice bath, stirring at room reaction 12h, TLC shows that in raw material, Boc-Asp (OBzl) disappears.Filter, be spin-dried for THF, add the 180ml ethyl acetate that resistates is dissolved, use successively saturated NaHC0
3extraction is washed three times, and saturated NaCl extraction is washed three times, 5%KHS0
4extraction is washed three times, and saturated NaCl extraction is washed three times, saturated NaHC0
3extraction is washed three times, and saturated NaCl extraction is washed three times.By the ethyl acetate layer anhydrous Na
2s0
4dried overnight.Remove by filter Na
2s0
4, concentrating under reduced pressure, except desolventizing, obtains 3.30g (95%) title compound, is colorless solid.ESI-MS(m/e)：513[M+H]
+.
Embodiment 7 preparation Boc-Arg (N0
2)-Gly-OBzl
Method by embodiment 6 makes 8.0g (91%) title compound, ESI-MS (m/e): 467[M+H]
+.
Embodiment 8 preparation Boc-Asp (OBzl)-Phe-OBzl
Method by embodiment 6 makes 3.70g (97%) title compound, ESI-MS (m/e): 561[M+H]
+.
Embodiment 9 preparation Boc-Asp (OBzl)-Ser (Bzl)-OBzl
Method by embodiment 6 makes 3.86g (91.90%), ESI-MS (m/e): 591[M+H]
+.
Embodiment 10 preparation HClAsp (OBzl)-Val-OBzl
(1.33g, 2.6mmol) Boc-Asp (0Bzl)-Val-OBzl is placed in to 100ml eggplant bottle, adds few dry ethyl acetate of trying one's best to make its dissolving, become micro-yellow transparent solution.Under ice bath, to the ethyl acetate solution (4N) that adds 10ml hydrogenchloride in reaction flask, put immediately cotton and CaCl are housed
2drying tube.After stirring 3h under ice bath, reaction solution becomes white opacity, and some plate monitoring raw material point disappears.Under warm water bath, the reaction mixture concentrating under reduced pressure is removed to ethyl acetate, obtain colourless powder.Add again a small amount of ethyl acetate, drain, repeat twice.Adding ether 3 times again, all drain ether at every turn, obtain 1.13g (97%) title compound, is colourless powder.ESI-MS(m/e)：413[M+H]
+.
Embodiment 11 preparation HClAsp (OBzl)-Phe-OBzl
Method by embodiment 10 makes 1.90g (99%) title compound, ESI-MS (m/e): 461[M+H]
+.
Embodiment 12 preparation HClAsp (OBzl)-Ser (Bzl)-OBzl
Method by embodiment 10 makes 3.3g (99%) title compound, ESI-MS (m/e): 491[M+H]
+.
Embodiment 13 preparation Boc-Arg (N0
2)-Gly
By 6.0g (12.85mmol) Boc-Arg (NO
2)-Gly-OBzl is dissolved in 20ml methyl alcohol, and ice bath adds the about 5ml of 2N NaOH under stirring, and the pH of reaction solution is adjusted to 12, ice bath stirring reaction 1 hour, and the TLC monitoring shows raw material Boc-Arg (NO
2)-Gly-OBzl disappears.Use saturated KHSO
4reaction solution pH is adjusted to 7, and concentrating under reduced pressure is removed methyl alcohol.Add 10ml distilled water in resistates, use saturated KHSO
4its pH is adjusted to 2, is extracted with ethyl acetate, each 150ml, extract three times.Ethyl acetate layer is merged, wash three times with saturated NaCl, by the ethyl acetate layer anhydrous Na
2sO
4dried overnight.Remove by filter anhydrous Na
2sO
4, filtrate decompression is concentrated, obtains 4.75g (98%) title compound, is colourless powder.ESI-MS(m/e)：377[M+H]
+.
Embodiment 14 preparation Boc-Arg (N0
2)-Gly-Asp (OBzl)-Val-OBzl
Method by embodiment 6 makes 3.8g (76%) title compound, ESI-MS (m/e): 771[M+H]
+.
Embodiment 15 preparation HClArg (N0
2)-Gly-Asp (OBzl)-Val-OBzl
Method by embodiment 10 makes 3.0g (99%) title compound, ESI-MS (m/e): 671[M+H]
+.
Embodiment 16 preparation Boc-Arg (NO
2)-Gly-Asp (OBzl)-Phe-OBzl
Method by embodiment 6 makes 3.9g (84%) title compound, ESI-MS (m/e): 819[M+H]
+.
Embodiment 17 preparation HClArg (N0
2)-Gly-Asp (OBzl)-Phe-OBzl
Method by embodiment 10 makes 3.3g (99%) title compound, ESI-MS (m/e): 719[M+H]
+.
Embodiment 18 preparation Boc-Arg (NO
2)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl
Method by embodiment 6 makes 4.6g (80%) title compound, ESI-MS (m/e): 849[M+H]
+.
Embodiment 19 preparation HClArg (N0
2)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl
Method by embodiment 10 makes 3.3g (99%) title compound, ESI-MS (m/e): 749[M+H]
+.
Embodiment 20 preparation (3S, 12aS)-2,3,6,7,12, the 12a-hexahydropyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone-3-acetyl-Arg (NO also
2)-Gly-Asp (OBzl)-Val-OBzl (6a)
Take 313mg (1mmol) (3S, 12aS)-2,3,6,7,12,12a-hexahydropyrazine also [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-1,4-diketone-3-acetic acid (5) is in 50ml eggplant bottle, add dry DMF and dissolve, add 162mg (1.2mmol) HOBt and 247mg (1.2mmol) DCC under ice bath, 5-10 minute Precipitation.Anhydrous THF dissolves 706.5mg (1mmol) HClArg (NO
2)-Gly-Asp (OBzl)-Val-OBzl also adds in above-mentioned reaction solution, NMM regulates pH 8-9, within 30 minutes, the recession deicing is bathed, TLC monitoring reaction after 12 hours, raw material disappears, and filters, filtrate is poured in culture dish and is dried up, residue is molten by ethyl acetate is muddy shape, with glue head dropper, sucks in separating funnel, uses successively saturated NaHCO
3extraction is washed three times, and saturated NaCl extraction is washed three times, 5%KHSO
4extraction is washed three times, and saturated NaCl extraction is washed three times, saturated NaHCO
3extraction is washed three times and saturated NaCl extraction is washed three times.By the ethyl acetate layer anhydrous Na
2sO
4dried overnight.Filter, filtrate decompression is concentrated, and residue obtains 720mg (75%) title compound with purification by silica gel column chromatography.ESI-MS(m/e)：966[M+H]
+.
1H?NMR(300MHz，DMSO-d6)：δ/ppm＝10.94(s，1H)，8.18(m，7H)，7.45(d，J＝7.5Hz，1H)，7.35(m，11H)，7.07(t，J＝7.2Hz，1H)，6.99(t，J＝7.2Hz，1H)，5.40(d，J＝16.5Hz，1H)，5.10(m，4H)，4.77(m，1H)，4.25(m，5H)，3.72(m，2H)，3.20(m，1H)，3.00(m，5H)，2.67(m，3H)，2.07(m，1H)，1.65(s，1H)，1.46(s，3H)，0.85(m，7H).
Embodiment 21 preparation (3S, 12aS)-3-2,3,6,7,12,12a-hexahydropyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone-3-acetyl-Arg (NO also
2)-Gly-Asp (OBzl)-Phe-OBzl (6b)
According to the method for embodiment 20, from 5 and HClArg (NO
2)-Gly-Asp (OBzl)-Phe-OBzl obtains 748mg (74%) title compound.ESI-MS(m/e)：1014[M+H]
+.
1H?NMR(500MHz，DMSO-d6)：δ/ppm＝10.93(s，1H)，8.42(m，1H)，8.36(d，J＝10Hz，1H)，8.25(m，3H)，8.17(d，J＝10Hz，1H)，7.45(d，J＝5Hz，1H)，7.35(m，9H)，7.25(m，4H)，7.20(m，3H)，7.07(t，J＝10Hz，1H)，7.00(t，J＝10Hz，1H)，5.40(d，J＝20Hz，1H)，5.05(m，4H)，4.73(m，1H)，4.50(dd，J1＝5Hz，J2＝15Hz，1H)，4.30(m，1H)，4.27(d，J＝5Hz，1H)，4.24(m，1H)，4.21(s，1H)，4.17(s，1H)，3.73(d，J＝5Hz，1H)，3.71(d，J＝5Hz，1H)，3.20(m，1H)，3.00(m，5H)，2.67(m，3H)，1.66(s，1H)，1.46(s，3H)，0.85(m，1H).
Embodiment 22 preparation (3S, 12aS)-2,3,6,7,12, the 12a-hexahydropyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone-3-acetyl-Arg (NO also
2)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl (6c)
According to the method for embodiment 20, from 5 and HCl.Arg (NO
2)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl obtains 790mg (76%) title compound.ESI-MS(m/e)：613[M+H]
+.
1H?NMR(DMSO-d
6，300MHz)：δ＝10.96(s，1H)，10.76(s，1H)，8.48(s，1H)，7.79(m，1H)，7.56(d，J＝7.8Hz，1H)，7.44(d，J＝7.8Hz，1H)，7.32(t，J＝7.8Hz，2H)，7.04(m，4H)，6.88(s，1H)，6.59(d，J＝7.2Hz，1H)，5.36(d，J＝16.5Hz，1H)，4.29(dd，J1＝3.9Hz，J2＝11.7Hz，1H)，4.24(d，J＝16.5Hz，1H)，4.10(m，1H)，3.97(s，1H)，3.27(dd，J1＝3.6Hz，J2＝15.3Hz，1H)，3.02(m，3H)，2.82(m，2H)，1.69(m，2H)，1.30-1.36(m，13H).
Embodiment 23 preparation (3S, 12aS)-2,3,6,7,12, the 12a-hexahydropyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone-3-acetyl-Arg-Gly-Asp-Val (7a) also
By 200mg (0.2mmol) (3S, 12aS)-2,3,6,7,12, the 12a-hexahydropyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone-3-acetyl-Arg (NO also
2)-Gly-Asp (OBzl)-Val-OBzl (6a) is placed in 250ml eggplant bottle, and ice bath slowly adds 8ml trifluoracetic acid and 2ml trifluoromethanesulfonic acid under stirring, and bottleneck adds a drying tube, starts reaction.After 2h, TLC monitoring raw material point disappears.Add a large amount of ether (about 200ml) stir about in ice bath downhill reaction liquid 20 minutes, product is separated out, turn off agitator, after standing 10 minutes, the supernatant that inclines, triplicate.With water pump, ether is drained for the last time, added the ammoniacal liquor of about 1ml 10%, tune pH is 7-8, the SephedaxG10 desalination, and the aqueous solution lyophilize obtained obtains 125mg (82%) title compound .Mp:214-214 ℃.
(c=0.32, CH
3oH) .ESI-MS (m/e): 739[M-H]
-.
1h NMR (300MHz, D
2o-d6): δ/ppm=8.42 (s, 1H), 7.54 (d, J=7.5Hz, 1H), 7.42 (d, J=7.8Hz, 1H), 7.19 (t, J=6.9Hz, 1H), 7.13 (t, J=7.5Hz, 1H), 5.42 (d, J=16.8Hz, 1H), 4.58 (d, J=7.5Hz, 1H), 4.54 (d, J=8.4Hz, 1H), 4.32 (m, 1H), 4.21 (d, J=17.1Hz, 1H), 4.00 (m, 5H), 3.30 (d, J=11.7Hz, 1H), 2.88 (m, 3H), 2.60 (m, 6H), 2.05 (m, 1H), 1.51 (m, 2H), 1.23 (m, 1H), 0.82 (t, J=8.7Hz, 6H).
Embodiment 24 preparation (3S, 12aS)-2,3,6,7,12, the 12a-hexahydropyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone-3-acetyl-Arg-Gly-Asp-Phe (7b) also
According to the method for embodiment 23, from (3S, 12aS)-3-2,3,6,7,12,12a-hexahydropyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone-3-acetyl-Arg (NO also
2)-Gly-Asp (OBzl)-Phe-OBzl (6b) obtains 138mg (85%) title compound .Mp:222-223 ℃.
(c=0.65, CH
3oH) .ESI-MS (m/e): 789[M+H]
+.
1h NMR (300MHz, D
2o-d6): δ/ppm=7.50 (d, J=6Hz, 1H), 7.45 (d, J=15.0Hz, 1H), 7.22 (m, 8H), 5.46 (d, J=12.0Hz, 1H), 4.35 (m, 1H), 4.20 (d, J=15.0Hz, 1H), 3.85 (m, 3H), 3.11 (m, 3H), (2.90 m, 3H), 2.60 (m, 4H), 2.40 (m, 2H), 1.90 (m, 13H), 1.12 (m, 4H).
Embodiment 25 preparation (3S, 12aS)-2,3,6,7,12, the 12a-hexahydropyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone-3-acetyl-Arg-Gly-Asp-Ser (7c) also
According to the method for embodiment 23, from (3S, 12aS)-2,3,6,7,12, the 12a-hexahydropyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone-3-acetyl-Arg (NO also
2)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl (6c) obtains 142mg (83%) title compound .Mp:201-202 ℃.
(c=0.65, CH
3oH) .ESI-MS (m/e): 727[M-H]
-.
1h NMR (300MHz, D
2o-d6): δ/ppm=7.39 (d, J=6.3Hz, 1H), 7.31 (d, J=6.9Hz, 1H), 7.10 (m, 1H), (7.02 m, 1H), 5.28 (d, J=16.5Hz, 1H), 4.40 (m, 1H), 4.20 (m, 2H), 4.02 (m, 2H), 3.89 (m, 4H), 3.77 (m, 3H), 3.11 (m, 2H), 2.90 (m, 2H), 2.65 (m, 7H), 1.96 (s, 1H), (1.49 m, 2H), 1.20 (m, 2H), 1.09 (m, 2H).
The In Vitro Anti platelet aggregation activity of test example 1 compound 5 and 7a-c
Pig carotid artery is got 3.8% Sodium Citrate for blood (Sodium Citrate/pig blood, 1/9) anti-freezing.Centrifugal 10 minutes of 1000r/min platelet rich plasma, then with 3000r/min centrifugal 10 minutes, obtain platelet poor plasma.Add platelet poor plasma in platelet rich plasma, the platelet count in platelet rich plasma is adjusted to 2 * 10
9/ ml.With adenosine diphosphate (ADP), (ADP, final concentration is 10
-5m, sigma), (PAF, final concentration is 10 to platelet activation factor
-7m, sigma) and arachidonic acid (AA, final concentration is 0.15 mg/ml, sigma) and zymoplasm (TH, final concentration 2 * 10
-5m) for the inductor induced platelet, assemble.Measure the platelet aggregation rate that these inductors cause on platelet aggregation instrument.Compound 5 and 7a-c physiological saline solution, final concentration is 10,1,0.1,0.01,0.001 and 0.0001 μ M.Add various concentration compounds 5 and the 7a-c platelet aggregation rate that these inductors cause afterwards upper mensuration of platelet aggregation instrument (CHRONO-LOG, USA, 490-2D).Each sample replication 6 times.The difference of nothing and the platelet aggregation rate that these inductors cause when compound 5 and 7a-c are arranged is exactly the inhibiting rate of compound 5 and 7a-c platelet aggregation that these inductors are caused.By compound 5 and 7a-c 10,1,0.1,0.01,0.001 and inhibiting rate during 0.0001 μ M obtain IC
50value.Measurement result is as shown in table 1, and compound 5 has certain In Vitro Anti platelet aggregation activity, and two 7a-c have outstanding In Vitro Anti platelet aggregation activity.
The antiplatelet aggregative activity of table 1 7a-c (n=6)
The oral antithrombotic acitivity of test example 2 compounds 5 and 7a-c
Before experiment, 7a-c being made into to 0.33nmol/l normal saline solution (adding a small amount of tween 80 to soak hydrotropy), is 0.1nmol/kg for the dosage in body.5 are made into 0.33nmol/l normal saline solution (adding a small amount of tween 80 to soak hydrotropy), for the dosage in body, are 10nmol/kg.Positive drug Asprin is made into the 10g/l normal saline solution, and the concentration of 55.5mmol/l, be 167mmol/kg for the dosage in body.Blank is physiological saline, and antithrombotics is heparin sodium 2.4mg/ml normal saline solution.By the male SD rat random packet, n=12, give rat oral gavage with (3ml/kg), after 30 minutes, with urethane (20g/100ml, 7ml/kg), after anesthesia, separates right carotid and left jugular vein.A 6cm, the silk thread of long prior precise weighing is placed in polyethylene tube, and after intubate being full of to the normal saline solution (50IU/ml) of heparin sodium, an end inserts the left side vein, from an end, adds quantitative heparin sodium anti-freezing, then inserts the right side artery.Blood flow flows into the left side vein from the right side artery polyethylene tube of flowing through.Take out the silk thread with thrombus after 15min, dip in gently drop of blood on filter paper, put into weighted centrifuge tube in advance, accurately weigh and record.Weight reduction calculates the weight in wet base of thrombus.And record weight in wet base.Each compound repeats 12 administrations.The wet weight of thrombus of each group of statistics
and be t and check.Result shows that 7a-c has good antithrombotic acitivity (table 2).
Table 2 7a-c is on the thrombotic impact of SD male rat
N=12; A) with the physiological saline group than p<0.01; B) with physiological saline group and 5 than p<0.01.
The particle diameter of test example 3 7a-c
7a-c is made into to 10 with distilled water
-5the solution of mM.The particle size data of eight days compounds of METHOD FOR CONTINUOUS DETERMINATION, in the time of 25 ℃, result as shown in Figure 2.Result shows that 25 ℃ of concentration are 10
-5during mM, 7a-c can be assembled into the nanometer ball that particle diameter is 200-400nm.When temperature rises to 50 ℃, it is large that the particle diameter of 7a becomes, the particle diameter of 7b and 7c diminish (Fig. 3).Totally see that 7a-c can form stable nanometer ball in the aqueous solution.
Claims (6)
1. four kinds of compounds that general formula I represents, in formula, R is OH, Arg-Gly-Asp-Val, Arg-Gly-Asp-Phe or Arg-Gly-Asp-Ser.
2. the method for compound of the general formula I of preparation claim 1, the method comprises:
(1) prepare 3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid;
(2) prepare 3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylate methyl ester;
(3), by 3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylate methyl ester and Boc-Asp (OBzl) coupling, make 3S-N-[Boc-Asp (OBzl)]-1,2,3,4-tetrahydro-beta-carboline-3-carboxylate methyl ester;
(4) from 3S-N-[Boc-Asp (OBzl)]-1,2,3, the 3S-N-[Asp (OBzl) that the de-Boc of 4-tetrahydro-beta-carboline-3-carboxylate methyl ester makes]-1,2,3,4-tetrahydro-beta-carboline-3-carboxylate methyl ester hydrochloride preparation (3S, 12aS)-3-carbobenzoxy-(Cbz)-2,3,6,7,12, the 12a-hexahydropyrazine is [1 ', 2 ': 1,6] pyrido [3 also, 4-b] indoles-Isosorbide-5-Nitrae-diketone;
(5) (3S, 12aS)-3-carbobenzoxy-(Cbz)-2,3,6,7,12,12a-hexahydropyrazine also [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone in tetrahydrofuran (THF) and methyl alcohol under the catalysis of palladium charcoal hydrogenolysis be (3S, 12aS)-2,3,6,7,12,12a-hexahydropyrazine also [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone-3-acetic acid;
(6), by (3S, 12aS)-2,3,6,7,12, the 12a-hexahydropyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone-3-acetic acid and HClArg (NO also
2)-Gly-Asp (OBzl)-Val-OBzl, HClArg (NO
2)-Gly-Asp (OBzl)-Phe-OBzl or HClArg (NO
2)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl coupling preparation (3S, 12aS)-2,3,6,7,12, the 12a-hexahydropyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone-3-acetyl-Arg (NO also
2)-Gly-Asp (OBzl)-Val-OBzl, (3S, 12aS)-2,3,6,7,12, the 12a-hexahydropyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone-3-acetyl-Arg (NO also
2)-Gly-Asp (OBzl)-Phe-OBzl and (3S, 12aS)-2,3,6,7,12, the 12a-hexahydropyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone-3-acetyl-Arg (NO also
2)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl;
(7), by (3S, 12aS)-2,3,6,7,12, the 12a-hexahydropyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone-3-acetyl-Arg (NO also
2)-Gly-Asp (OBzl)-Val-OBzl, (3S, 12aS)-2,3,6,7,12, the 12a-hexahydropyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone-3-acetyl-Arg (NO also
2)-Gly-Asp (OBzl)-Phe-OBzl and (3S, 12aS)-2,3,6,7,12, the 12a-hexahydropyrazine is [1 ', 2 ': 1,6] pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone-3-acetyl-Arg (NO also
2)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl deprotection obtains (3S, 12aS)-2, 3, 6, 7, 12, 12a-hexahydropyrazine also [1 ', 2 ': 1, 6] pyrido [3, 4-b] indoles-1, 4-diketone-3-acetyl-Arg-Gly-Asp-Val, (3S, 12aS)-2, 3, 6, 7, 12, 12a-hexahydropyrazine also [1 ', 2 ': 1, 6] pyrido [3, 4-b] indoles-1, 4-diketone-3-acetyl-Arg-Gly-Asp-Phe and (3S, 12aS)-2, 3, 6, 7, 12, 12a-hexahydropyrazine also [1 ', 2 ': 1, 6] pyrido [3, 4-b] indoles-1, 4-diketone-3-acetyl-Arg-Gly-Asp-Ser.
3. the compound that general formula I represents, in formula, R is Arg-Gly-Asp-Val, Arg-Gly-Asp-Phe or Arg-Gly-Asp-Ser, the nanometer particle size in the aqueous solution.
4. the compound of general formula I representative, in formula, R is OH, Arg-Gly-Asp-Val, Arg-Gly-Asp-Phe or Arg-Gly-Asp-Ser, platelet aggregation inhibitory activity.
5. the compound of general formula I representative, in formula, R is OH, Arg-Gly-Asp-Val, Arg-Gly-Asp-Phe or Arg-Gly-Asp-Ser, antithrombotic acitivity.
6. the compound of claim 1, in formula, R is OH, Arg-Gly-Asp-Val, Arg-Gly-Asp-Phe or Arg-Gly-Asp-Ser, the purposes in preparing antithrombotic reagent.
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| CN112010934A (en) * | 2019-05-28 | 2020-12-01 | 首都医科大学 | Acetyl RGD modified hexacyclic piperazinedione, preparation, transfer-resistant activity and application thereof |
| CN112010929A (en) * | 2019-05-28 | 2020-12-01 | 首都医科大学 | RGD sequence peptide modified hexacyclic piperazinedione, preparation, transfer-resistant activity and application thereof |
| CN112010934B (en) * | 2019-05-28 | 2022-08-02 | 首都医科大学 | Acetyl RGD modified hexacyclic piperazinedione, preparation, transfer-resistant activity and application thereof |
| CN112010929B (en) * | 2019-05-28 | 2022-08-05 | 首都医科大学 | RGD sequence peptide modified hexacyclic piperazinedione, preparation, transfer-resistant activity and application thereof |
| CN113754725A (en) * | 2020-06-04 | 2021-12-07 | 首都医科大学 | Synthesis, bioactivity and application of dimethyl dioxane-tetrahydro-beta-carboline-3-formyl-RGDV |
| CN113754725B (en) * | 2020-06-04 | 2024-04-23 | 首都医科大学 | Synthesis, biological activity and application of dimethyl dioxane-tetrahydro-beta-carboline-3-formyl-RGDV |
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