CN1370778A - Beta-tetrahydro carboline carboxylic acid, its RGD conjugate, their synthesis and medical application - Google Patents
Beta-tetrahydro carboline carboxylic acid, its RGD conjugate, their synthesis and medical application Download PDFInfo
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- CN1370778A CN1370778A CN01144616A CN01144616A CN1370778A CN 1370778 A CN1370778 A CN 1370778A CN 01144616 A CN01144616 A CN 01144616A CN 01144616 A CN01144616 A CN 01144616A CN 1370778 A CN1370778 A CN 1370778A
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Abstract
The present invention relates to the synthesis of beta-tetrahydro carboline carboxylic acid and its nanoparticle preparation; liquid phase process of gradually grafting peptide to obtain protected tetrapeptide intermediate, which, after eliminating its Boc, is condensated with N-Boc-beta-tetrahydro carboline carboxylic acid and further HF treated to eliminate its protection to obtain the said compound; the nanoparticle of tetrahydro carboline carboxylic acid and the in-vitro and in-vivo activity of said compound in-vitro and in-vivo experiments show that the compound of the present invention has excellent activity of resisting blood platelet aggregation, effect of resisting cell adhesion and effect of resisting thrombus.
Description
Invention field
The present invention relates to beta-tetrahydro carboline carboxylate and RGD conjugate thereof, they synthetic and in medically application.
Technical background
Platelet aggregation plays an important role in thrombosis.Normal thrombocyte is activated under the inducing of thrombogen, adenosine diphosphate (ADP) or collagen, discharges arachidonic acid (AA).AA generates endoperoxide (PGH2) through cyclooxygenase catalysis.PGH2 generates thromboxane A2 (TXA2) under the effect of isomerase, cause platelet aggregation and adhesion.Behind the platelet activation, glycoprotein iib/iiia (GP IIb/IIIa) acceptor on surface exposes, and occurred conformation changes, and combines with Fibrinogen, causes thrombosis.
In the process of research GP IIb/IIIa acceptor and scleroproein α chain and γ chain combination, find that the RGD sequence that exists among the scleroproein is mediation it self and GP IIb/IIIa bonded pass key sequence (SamanenJ., et al., J.Med.Chem., 1991,34,3114).
The contriver adopts liquid phase method to synthesize RGDS, RGDV and RGDF, and confirm that they can suppress thrombosis (what contain the RGD tetrapeptide synthesizes and function Acta Pharmaceutica Sinica, 1997,32,271 for Zhao Ming, Peng Shiqi).The contriver notices that the beta-tetrahydro carboline carboxylate is a kind of composition in the Chinese medicine Longstamen Onion Bulb, has platelet aggregation inhibitory activity (Yao new life etc., Chinese pharmaceutical chemistry magazine, 1995,5,134).The contriver has synthesized the Tetrahydrocarboline carboxylic acid by the Pictet-Spengler reaction, finds the water-soluble extreme difference of this compound of ordinary method gained, and various biological activity determinations are carried out in inconvenience.
The contriver once reported, contained the tetrapeptide of RGD, for example RGDS, can be thrombolytic agent, for example urokinase is transported to the thrombosis position, has clear and definite target (Ling Shichang, Zhao Ming, Peng Shiqi, the liposome that RGDS modifies is as the research of pharmaceutical carrier targeting thrombolysis, journal of Beijing Medical University, 1994,26,174).
Description of drawings
Fig. 1 is the preparation route map of carboline carboxylate nano particle and N-BOC carboline carboxylate.
Fig. 2 is the synthetic route chart that contains the intermediate of RGD tetrapeptide and correspondence.
Fig. 3 is the synthetic route chart of carboline carboxylate-RGDAA conjugate.
Summary of the invention
According to above-mentioned cognition, the present invention has carried out two aspects to the beta-tetrahydro carboline carboxylate and has modified.On the one hand, synthesized N-Boc-beta-tetrahydro carboline carboxylate by route shown in Figure 1, comprise that tryptophane prepares the beta-tetrahydro carboline carboxylate with formaldehyde reaction in the presence of vitriolic, this compound in DMF in the presence of triethylamine with Boc-N3 or BOC anhydride reaction, make N-Boc-beta-tetrahydro carboline carboxylate; And the nano particle that has prepared the beta-tetrahydro carboline carboxylate, be included in toluene (or similar non-polar solvent), the vitriol oil (or other acid, example hydrochloric acid) and under the existence of TWEEN 80 (or similarly tensio-active agent), makes L-tryptophane and formaldehyde reaction, separate then and freeze-drying.
The present invention has synthesized the protection tetrapeptide of general formula (1) according to route shown in Figure 2, and AA is L-Ser in general formula (1), L-Val or L-Phe residue.The compound of general formula (1) obtains corresponding polypeptide RGDS, RGDV and RGDF through the HF deprotection.The compound of general formula (1) obtains the intermediate that general formula is HCL.Arg (Tos)-Gly-Asp (OcHex)-AAoBzl through the HCL deprotection, and wherein the definition of AA and general formula (1) are together.
The present invention is compound and the coupling of N-Boc-beta-tetrahydro carboline carboxylate of HCL.Arg (Tos)-Gly-Asp (OcHex)-AAoBzl with general formula according to route shown in Figure 3; through the HF deprotection; obtain the compound of general formula (2), wherein the definition of AA and general formula (1) are together.
The present invention has adopted external and the intravital model evaluation nano particle of beta-tetrahydro carboline carboxylate, the platelet aggregation inhibitory activity of the compound of RGDS, RGDV, RGDF and general formula (2), anti-cell adhesive attraction, and anti thrombotic action.The result shows, the compound of the nano particle of beta-tetrahydro carboline carboxylate provided by the invention and general formula (2), and beta-tetrahydro carboline carboxylate-RGDAA conjugate all shows outstanding platelet aggregation inhibitory activity, anti-cell adhesive attraction, and anti thrombotic action.
Therefore, compound of the present invention can be used for treating thrombotic diseases, and for example thrombocyte rising, cerebral thrombosis, coronary heart disease, myocardial infarction, venous thrombosis, embolism class diseases are as cerebral embolism, pulmonary infarction etc.
In order further to set forth the present invention, provide some embodiment below.It is worthy of note that these embodiment are interpreted as explanation of the invention, to the present invention without any the restriction on the meaning.The preparation of embodiment 1. beta-tetrahydro carboline carboxylates
The H2SO4 of 25ml1N adds 5g (24.5mmol) tryptophane in the stirring, add 75ml water again, the formaldehyde solution of 4ml (45.6mmol) 38%, reaction solution becomes clarification, separates out a large amount of solids about 5Min, react after 4 hours, be added dropwise to the 8ml strong aqua, transfer PH near neutral, standing over night, the a small amount of cold wash of suction filtration, filter cake is drained, dry again solid (1) 5.1g (buff powder, yield 96%) the MP:280-282 C that gets; EI-MS:217 (M+1); H-NMR (DMSO): δ 10.99 (1H, s), 7.44 (1H, d, 7.5), (7.33 1H, t, 8.0), 7.08 (1H, t, 8.0), 6.99 (1H, t, 7.5), 4.22 (1H, d, 4.8), 3.69 (1H, dd, 10.5,5.0), 3.14 (1H, dd, 10.5,2.4), the preparation of (2.83 1H, ddd, 10.5,5.0,2.4) embodiment 2:N-Boc-beta-tetrahydro carboline carboxylates (2)
1.1g (5mmol) compound 87 is suspended among the 15ml DMF, add the 1.4ml triethylamine, ice bath stir down in solution the suspended particle size evenly after, drip 1.1g (7.7mmol) Boc-N3 in the 30min, rise to 40 ℃ behind the 24hr, add 20% aqueous citric acid solution 5ml after 3 days, use ethyl acetate extraction, organic layer MgSO4 drying, filter, filtrate decompression is distilled to dried, and residue CHCl3 recrystallization gets title compound 0.9g (56%) mp165-170 TOF-MS:317[M+1]
+, 339[M+Na]
+, 355[M+K]
1H-NMR (DMSO-d
6) .1.46 (s, 9H ,-Boc), 3.25 ~ 3.34 (m, 2H, 4-H), 4.29 ~ 4.75 (m, 2H, 1-H), 5.02 ~ 5.14 (m, 1H, 3-H), 6.92 ~ 7.41 (Ar-H (5,6 for m, 4H, 7,8)), 10.87 (s, 1H, 9-H), 12.77 (s, 1H ,-COOH) embodiment 3: the preparation of beta-tetrahydro carboline carboxylate nano particle (1)
Add the dense H2SO4 of 0.05ML in the 10ML deionized water, add L-tryptophane 1G in the stirring, add 20ML toluene again, 0.02ML TWEEN80, vigorous stirring adds 38% formaldehyde solution 0.8ML, react after 4 hours, add the 0.4ML strong aqua, leave standstill 1HR, divide and remove toluene layer and supernatant liquid (water layer), add the 10ML deionized water again, leave standstill 1HR after stirring 2MIN, divide and go supernatant liquor, lower floor's freeze-drying to get the loose dry powder of off-white color.Preparation Boc-Ser (Bzl) OBzl of (TLC is pure point, and RF is identical with the contrast of beta-tetrahydro carboline carboxylate) embodiment 4:RGDS (6)
33mg (0.10mmol) Cs
2CO
3Be dissolved in distilled water, join in the ethanol solution of 59mg (0.20mmol) Boc-Ser (Bzl)-OH, removal of solvent under reduced pressure behind the 40min, residue is put moisture eliminator and is spent the night, and the white solid that obtains is dissolved in dry DMF, drips 34mg (0.2mmol) bromobenzyl, after 50 ℃ of constant temperature stir 16hr, filtering CsBr precipitation, filtrate decompression is distilled to dried, the residue acetic acid ethyl dissolution, use saturated sodium bicarbonate aqueous solution successively, saturated sodium-chloride water solution, the washing of 5% aqueous potassium hydrogen sulfate, the organic layer anhydrous sodium sulfate drying of telling, filter, filtrate is at 37 ℃ of following concentrating under reduced pressure, and residue grinds with sherwood oil, gets title compound 76mg (99%).HCl·Ser(Bzl)OBzl
77mg (0.2mmol) Boc-Ser (Bzl) OBzl is dissolved in 6ml 4mol/L anhydrous hydrogen chloride-ethyl acetate solution, stirring at room, and TLC shows that raw material point disappears behind the 1hr.Reaction mixture is concentrating under reduced pressure at room temperature, and residue also at room temperature concentrates with acetic acid ethyl dissolution, and for several times, up to Ex-all free hydrogenchloride, residue grinds with anhydrous diethyl ether so repeatedly, gets title compound, is directly used in next step reaction.Boc-Asp(OcHex)-Ser(Bzl)OBzl
63mg (0.2mmol) Boc-Asp (OcHex)-OH is dissolved among the anhydrous THF of 3ml, and ice bath adds 30mg (0.22mmol) N-hydroxy benzo triazole and 48mg (0.22mmol) DCC down, and is stand-by behind the mixing 30min.64mg (0.2mmol) HClSer (Bzl) OBzl is dissolved in the anhydrous THF of 5ml, drips N-methylmorpholine and make pH value of solution 8 ~ 9, the mixture that adding obtains above, behind 0 ℃ of reaction 2hr, room temperature reaction 12hr, TLC show that raw material point disappears, stopped reaction, filtering DCU, filtrate is evaporated to dried at 37 ℃, the residue acetic acid ethyl dissolution, use saturated sodium bicarbonate aqueous solution successively, saturated sodium-chloride water solution, the washing of 5% aqueous potassium hydrogen sulfate, the organic layer anhydrous sodium sulfate drying of telling.Filter, filtrate is evaporated to dried at 37 ℃, obtain 101-103 ℃ of mp of title compound 114mg (98%) [α]
D 20+ 15 (C2, CHCl
3) HClAsp (OcHex)-Ser (Bzl) OBzl
116mg (0.2mmol) Boc-Asp (OcHex)-Ser (Bzl) OBzl is dissolved in 6ml 4mol/L anhydrous hydrogen chloride-ethyl acetate solution, stirring at room, and TLC shows that raw material point disappears behind the 1hr.Reaction mixture is concentrating under reduced pressure at room temperature, and residue also at room temperature concentrates with acetic acid ethyl dissolution, and for several times, up to Ex-all free hydrogenchloride, residue grinds with anhydrous diethyl ether so repeatedly, gets title compound, is directly used in next step reaction.Boc-Gly-Asp(OcHex)-Ser(Bzl)OBzl
35mg (0.2mmol) Boc-Gly-OH is dissolved among the anhydrous THF of 3ml, and ice bath adds 30mg (0.22mmol) N-hydroxy benzo triazole and 48mg (0.22mmol) DCC down, and is stand-by behind the mixing 30min.104mg (0.2mmol) HClAsp (OcHex)-Ser (Bzl) OBzl is dissolved in the anhydrous THF of 5ml, drip N-methylmorpholine and make pH value of solution 8 ~ 9, the mixture that adding obtains above, behind 0 ℃ of reaction 2hr, room temperature reaction 12hr, TLC shows that raw material point disappears, stopped reaction, filtering DCU, filtrate is evaporated to dried at 37 ℃, the residue acetic acid ethyl dissolution, use saturated sodium bicarbonate aqueous solution successively, saturated sodium-chloride water solution, the washing of 5% aqueous potassium hydrogen sulfate, the organic layer anhydrous sodium sulfate drying of telling.Filter, filtrate is evaporated to dried at 37 ℃, obtain 160-163 ℃ of mp of title compound 120mg (94%) [α]
D 20-3 (C2, CHCl
3) HClGly-Asp (OcHex)-Ser (Bzl) OBzl
128mg (0.2mmol) Boc-Gly-Asp (OcHex)-Ser (Bzl) OBzl is dissolved in 6ml 4mol/L anhydrous hydrogen chloride-ethyl acetate solution, stirring at room, and TLC shows that raw material point disappears behind the 1hr.Reaction mixture is concentrating under reduced pressure at room temperature, and residue also at room temperature concentrates with acetic acid ethyl dissolution, and for several times, up to Ex-all free hydrogenchloride, residue grinds with anhydrous diethyl ether so repeatedly, gets title compound, is directly used in next step reaction.Boc-Arg(Tos)-Gly-Asp(OcHex)-Ser(Bzl)OBzl (6)
86mg (0.2mmol) Boc-Arg (Tos)-OH is dissolved among the anhydrous THF of 4ml, and ice bath adds 30mg (0.22mmol) N-hydroxy benzo triazole and 48mg (0.22mmol) DCC down, and is stand-by behind the mixing 30min.115mg (0.2mmol) HClGly-Asp (OcHex)-Ser (Bzl) OBzl is dissolved in the anhydrous THF of 5ml, drip N-methylmorpholine and make pH value of solution 8 ~ 9, the mixture that adding obtains above, behind 0 ℃ of reaction 1hr, room temperature reaction 12hr, TLC shows that raw material point disappears, stopped reaction, filtering DCU, filtrate is evaporated to dried at 37 ℃, the residue acetic acid ethyl dissolution, use saturated sodium bicarbonate aqueous solution successively, saturated sodium-chloride water solution, the washing of 5% aqueous potassium hydrogen sulfate, the organic layer anhydrous sodium sulfate drying of telling.Filter, filtrate is evaporated to dried at 37 ℃, gets crude product, through silica gel H 60 column chromatographic isolation and purifications, gets 73-75 ℃ of mp of title compound 133mg (70%) [α]
D 20-3 (C2, CHCl
3) the preparation Boc-ValOBzl of embodiment 5:RGDV (7)
33mg (0.10mmol) Cs
2CO
3Be dissolved in distilled water, join in the ethanol solution of 43mg (0.20mmol) Boc-Val-OH, removal of solvent under reduced pressure behind the 40min, residue is put moisture eliminator and is spent the night, and the white solid that obtains is dissolved in dry DMF, drips 34mg (0.2mmol) bromobenzyl, after 50 ℃ of constant temperature stir 16hr, filtering CsBr precipitation, filtrate decompression is distilled to dried, the residue acetic acid ethyl dissolution, use saturated sodium bicarbonate aqueous solution successively, saturated sodium-chloride water solution, the washing of 5% aqueous potassium hydrogen sulfate, the organic layer anhydrous sodium sulfate drying of telling, filter, filtrate is at 37 ℃ of following concentrating under reduced pressure, and residue grinds with sherwood oil, gets title compound 61mg (99%).HCl·ValOBzl
61mg (0.2mmol) Boc-ValOBzl is dissolved in 6ml 4mol/L anhydrous hydrogen chloride-ethyl acetate solution, stirring at room, and TLC shows that raw material point disappears behind the 1hr.Reaction mixture is concentrating under reduced pressure at room temperature, and residue also at room temperature concentrates with acetic acid ethyl dissolution, and for several times, up to Ex-all free hydrogenchloride, residue grinds with anhydrous diethyl ether so repeatedly, gets title compound, is directly used in next step reaction.Boc-Asp(OcHex)-ValOBzl
63mg (0.2mmol) Boc-Asp (OcHex)-OH is dissolved among the anhydrous THF of 3ml, and ice bath adds 30mg (0.22mmol) N-hydroxy benzo triazole and 48mg (0.22mmol) DCC down, and is stand-by behind the mixing 30min.49mg (0.2mmol) HClValOBzl is dissolved in the anhydrous THF of 5ml, drips N-methylmorpholine and make pH value of solution 8 ~ 9, the mixture that adding obtains above, behind 0 ℃ of reaction 2hr, room temperature reaction 12hr, TLC show that raw material point disappears, stopped reaction, filtering DCU, filtrate is evaporated to dried at 37 ℃, the residue acetic acid ethyl dissolution, use saturated sodium bicarbonate aqueous solution successively, saturated sodium-chloride water solution, the washing of 5% aqueous potassium hydrogen sulfate, the organic layer anhydrous sodium sulfate drying of telling.Filter, filtrate is evaporated to dried at 37 ℃, obtain 95-98 ℃ of mp of title compound 99mg (98%) [α]
D 20+ 13 (C2, CHCl
3) HClAsp (OcHex)-ValOBzl
101mg (0.2mmol) Boc-Asp (OcHex)-ValOBzl is dissolved in 6ml 4mol/L anhydrous hydrogen chloride-ethyl acetate solution, stirring at room, and TLC shows that raw material point disappears behind the 1hr.Reaction mixture is concentrating under reduced pressure at room temperature, and residue also at room temperature concentrates with acetic acid ethyl dissolution, and for several times, up to Ex-all free hydrogenchloride, residue grinds with anhydrous diethyl ether so repeatedly, gets title compound, is directly used in next step reaction.Boc-Gly-Asp(OcHex)-ValOBzl
35mg (0.2mmol) Boc-Gly-OH is dissolved among the anhydrous THF of 3ml, and ice bath adds 30mg (0.22mmol) N-hydroxy benzo triazole and 48mg (0.22mmol) DCC down, and is stand-by behind the mixing 30min.88mg (0.2mmol) HClAsp (OcHex)-ValOBzl is dissolved in the anhydrous THF of 5ml, drips N-methylmorpholine and make pH value of solution 8 ~ 9, the mixture that adding obtains above, behind 0 ℃ of reaction 2hr, room temperature reaction 12hr, TLC show that raw material point disappears, stopped reaction, filtering DCU, filtrate is evaporated to dried at 37 ℃, the residue acetic acid ethyl dissolution, use saturated sodium bicarbonate aqueous solution successively, saturated sodium-chloride water solution, the washing of 5% aqueous potassium hydrogen sulfate, the organic layer anhydrous sodium sulfate drying of telling.Filter, filtrate is evaporated to dried at 37 ℃, obtain 163-165 ℃ of mp of title compound 107mg (95%) [α]
D 20+ 7 (C2, CHCl
3) HClGly-Asp (OcHex)-ValOBzl
112mg (0.2mmol) Boc-Gly-Asp (OcHex)-ValOBzl is dissolved in 6ml 4mol/L anhydrous hydrogen chloride-ethyl acetate solution, stirring at room, and TLC shows that raw material point disappears behind the 1hr.Reaction mixture is concentrating under reduced pressure at room temperature, and residue also at room temperature concentrates with acetic acid ethyl dissolution, and for several times, up to Ex-all free hydrogenchloride, residue grinds with anhydrous diethyl ether so repeatedly, gets title compound, is directly used in next step reaction.Boc-Arg(Tos)-Gly-Asp(OcHex)-ValOBzl (7)
86mg (0.2mmol) Boc-Arg (Tos)-OH is dissolved among the anhydrous THF of 4ml, and ice bath adds 30mg (0.22mmol) N-hydroxy benzo triazole and 48mg (0.22mmol) DCC down, and is stand-by behind the mixing 30min.99mg (0.2mmol) HClGly-Asp (OcHex)-ValOBzl is dissolved in the anhydrous THF of 5ml, drip N-methylmorpholine and make pH value of solution 8 ~ 9, the mixture that adding obtains above, behind 0 ℃ of reaction 2hr, room temperature reaction 12hr, TLC shows that raw material point disappears, stopped reaction, filtering DCU, filtrate is evaporated to dried at 37 ℃, the residue acetic acid ethyl dissolution, use saturated sodium bicarbonate aqueous solution successively, saturated sodium-chloride water solution, the washing of 5% aqueous potassium hydrogen sulfate, the organic layer anhydrous sodium sulfate drying of telling.Filter, filtrate is evaporated to dried at 37 ℃, gets crude product, through silica gel H 60 column chromatographic isolation and purifications, gets 79-81 ℃ of mp of title compound 132mg (76%) [α]
D 20-6 (C2, CHCl
3) the preparation Boc-PheOBzlN of embodiment 6:RGDF (8)
α-(tert-butyloxycarbonyl)-Phenylalanine-Benzyl Ester
33mg (0.10mmol) Cs
2CO
3Be dissolved in distilled water, join in the ethanol solution of 53mg (0.20mmol) Boc-Phe-OH, removal of solvent under reduced pressure behind the 40min, residue is put moisture eliminator and is spent the night, and the white solid that obtains is dissolved in dry DMF, drips 34mg (0.2mmol) bromobenzyl, after 50 ℃ of constant temperature stir 16hr, filtering CsBr precipitation, filtrate decompression is distilled to dried, the residue acetic acid ethyl dissolution, use saturated sodium bicarbonate aqueous solution successively, saturated sodium-chloride water solution, the washing of 5% aqueous potassium hydrogen sulfate, the organic layer anhydrous sodium sulfate drying of telling, filter, filtrate is at 37 ℃ of following concentrating under reduced pressure, and residue grinds with sherwood oil, gets title compound 70mg (99%).HCl·PheOBzl
71mg (0.2mmol) Boc-PheOBzl is dissolved in 6ml 4mol/L anhydrous hydrogen chloride-ethyl acetate solution, stirring at room, and TLC shows that raw material point disappears behind the 1hr.Reaction mixture is concentrating under reduced pressure at room temperature, and residue also at room temperature concentrates with acetic acid ethyl dissolution, so repeatedly for several times, up to Ex-all free hydrogenchloride, residue grinds with anhydrous diethyl ether, gets title compound, is directly used in next step reaction Boc-Asp (OcHex)-PheOBzl
63mg (0.2mmol) Boc-Asp (OcHex)-OH is dissolved among the anhydrous THF of 3ml, and ice bath adds 30mg (0.22mmol) N-hydroxy benzo triazole and 48mg (0.22mmol) DCC down, and is stand-by behind the mixing 30min.58mg (0.2mmol) HClPheOBzl is dissolved in the anhydrous THF of 5ml, drips N-methylmorpholine and make pH value of solution 8 ~ 9, the mixture that adding obtains above, behind 0 ℃ of reaction 2hr, room temperature reaction 12hr, TLC show that raw material point disappears, stopped reaction, filtering DCU, filtrate is evaporated to dried at 37 ℃, the residue acetic acid ethyl dissolution, use saturated sodium bicarbonate aqueous solution successively, saturated sodium-chloride water solution, the washing of 5% aqueous potassium hydrogen sulfate, the organic layer anhydrous sodium sulfate drying of telling.Filter, filtrate is evaporated to dried at 37 ℃, obtain 96-98 ℃ of mp of title compound 109mg (99%) [α]
D 20+ 12 (C2, CHCl
3) HClAsp (OcHex)-PheOBzl
110mg (0.2mmol) Boc-Asp (OcHex)-PheOBzl is dissolved in 6ml 4mol/L anhydrous hydrogen chloride-ethyl acetate solution, stirring at room, and TLC shows that raw material point disappears behind the 1hr.Reaction mixture is concentrating under reduced pressure at room temperature, and residue also at room temperature concentrates with acetic acid ethyl dissolution, so repeatedly for several times, up to Ex-all free hydrogenchloride, residue grinds with anhydrous diethyl ether, gets title compound, is directly used in next step reaction Boc-Gly-Asp (OcHex)-PheOBzl
35mg (0.2mmol) Boc-Gly-OH is dissolved among the anhydrous THF of 3ml, and ice bath adds 30mg (0.22mmol) N-hydroxy benzo triazole and 48mg (0.22mmol) DCC down, and is stand-by behind the mixing 30min.98mg (0.2mmol) HClAsp (OcHex)-PheOBzl is dissolved in the anhydrous THF of 5ml, drips N-methylmorpholine and make pH value of solution 8 ~ 9, the mixture that adding obtains above, behind 0 ℃ of reaction 2hr, room temperature reaction 12hr, TLC show that raw material point disappears, stopped reaction, filtering DCU, filtrate is evaporated to dried at 37 ℃, the residue acetic acid ethyl dissolution, use saturated sodium bicarbonate aqueous solution successively, saturated sodium-chloride water solution, the washing of 5% aqueous potassium hydrogen sulfate, the organic layer anhydrous sodium sulfate drying of telling.Filter, filtrate is evaporated to dried at 37 ℃, obtain 165-170 ℃ of mp of title compound 121mg (97%) [α]
D 20-2 (C2, CHCl
3) HClGly-Asp (OcHex)-PheOBzl
122mg (0.2mmol) Boc-Gly-Asp (OcHex)-PheOBzl is dissolved in 6ml 4mol/L anhydrous hydrogen chloride-ethyl acetate solution, stirring at room, and TLC shows that raw material point disappears behind the 1hr.Reaction mixture is concentrating under reduced pressure at room temperature, residue also at room temperature concentrates with acetic acid ethyl dissolution, so repeatedly for several times, up to Ex-all free hydrogenchloride, residue grinds with anhydrous diethyl ether, get title compound, be directly used in next step reaction Boc-Arg (Tos)-Gly-Asp (OcHex)-PheOBzl (8)
86mg (0.2mmol) Boc-Arg (Tos)-OH is dissolved among the anhydrous THF of 4ml, and ice bath adds 30mg (0.22mmol) N-hydroxy benzo triazole and 48mg (0.22mmol) DCC down, and is stand-by behind the mixing 30min.109mg (0.2mmol) HClGly-Asp (OcHex)-PheOBzl is dissolved in the anhydrous THF of 5ml, drip N-methylmorpholine and make pH value of solution 8 ~ 9, the mixture that adding obtains above, behind 0 ℃ of reaction 2hr, room temperature reaction 12hr, TLC shows that raw material point disappears, stopped reaction, filtering DCU, filtrate is evaporated to dried at 37 ℃, the residue acetic acid ethyl dissolution, use saturated sodium bicarbonate aqueous solution successively, saturated sodium-chloride water solution, the washing of 5% aqueous potassium hydrogen sulfate, the organic layer anhydrous sodium sulfate drying of telling.Filter, filtrate is evaporated to dried at 37 ℃, gets crude product, through silica gel H 60 column chromatographic isolation and purifications, gets 79-81 ℃ of mp of title compound 110mg (60%) [α]
D 20-8 (C2, CHCl
3) embodiment 7:HClArg (Tos)-Gly-Asp (OcHex)-Ser (Bzl) OBzl (9)
189mg (0.2mmol) Boc-Arg (Tos)-Gly-Asp (OcHex)-Ser (Bzl) OBzl is dissolved in 6ml4mol/L anhydrous hydrogen chloride-ethyl acetate solution, stirring at room, and TLC shows that raw material point disappears behind the 1hr.Reaction mixture is concentrating under reduced pressure at room temperature, and residue also at room temperature concentrates with acetic acid ethyl dissolution, and for several times, up to Ex-all free hydrogenchloride, residue grinds with anhydrous diethyl ether so repeatedly, gets title compound.The preparation of embodiment 8:HClArg (Tos)-Gly-Asp (OcHex)-ValOBzl (10)
174mg (0.2mmol) Boc-Arg (Tos)-Gly-Asp (OcHex)-ValOBzl is dissolved in 6ml 4mol/L anhydrous hydrogen chloride-ethyl acetate solution, stirring at room, and TLC shows that raw material point disappears behind the 1hr.Reaction mixture is concentrating under reduced pressure at room temperature, and residue also at room temperature concentrates with acetic acid ethyl dissolution, and for several times, up to Ex-all free hydrogenchloride, residue grinds with anhydrous diethyl ether so repeatedly, gets title compound.The preparation of embodiment 9:HClArg (Tos)-Gly-Asp (OcHex)-PheOBzl (11)
184mg (0.2mmol) Boc-Arg (Tos)-Gly-Asp (OcHex)-PheOBzl is dissolved in 6ml 4mol/L anhydrous hydrogen chloride-ethyl acetate solution, stirring at room, and TLC shows that raw material point disappears behind the 1hr.Reaction mixture is concentrating under reduced pressure at room temperature, and residue also at room temperature concentrates with acetic acid ethyl dissolution, and for several times, up to Ex-all free hydrogenchloride, residue grinds with anhydrous diethyl ether so repeatedly, gets title compound.Embodiment 10: the preparation of carboline acyl-RGDS (5)
64mg (0.2mmol) compound 99 is dissolved among the anhydrous THF of 4ml, and ice bath adds 30mg (0.22mmol) N-hydroxy benzo triazole and 48mg (0.22mmol) DCC down, gets mixture behind the 1hr.177mg (0.2mmol) HClArg (Tos)-Gly-Asp (OcHex)-Ser (BzL) OBzl is dissolved in the anhydrous THF of 5ml, drip N-methylmorpholine and make pH value of solution 8 ~ 9, the mixture that adding obtains above, behind 0 ℃ of reaction 2hr, room temperature reaction 12hr, TLC shows that raw material point disappears, stopped reaction, filtering DCU, filtrate is evaporated to dried at 37 ℃, residue is with acetic acid ethyl dissolution and use saturated sodium bicarbonate aqueous solution successively, saturated sodium-chloride water solution and the washing of 5% aqueous potassium hydrogen sulfate, the organic layer anhydrous sodium sulfate drying of telling.Filter, filtrate is evaporated to dried at 37 ℃, gets crude product, through silica gel H 60 column chromatographic isolation and purifications, gets 94-98 ℃ of mp of title compound (12) 174mg (76%) [α]
D 20+ 23 (C1, CHCl
3) TOF-MS (m/e) 1148[M+1]
+1160[M+Na]
+, 1186[M+K]
+N-[(2,3,4,9-tetrahydro-β Carboline-3-yl)-formyl]-Arginyl-Glycyl-Aspartyl-Serine (15)
115mg (0.1mmol) compound 101 is with after 1ml methyl-phenoxide and 2ml anhydrous HF are mixed, 0 ℃ of reaction 1hr, HF is removed in decompression, feeds anhydrous HF 6ml once more, 0 ℃ of reaction 1hr, HF is removed in decompression, and residue solidifies with anhydrous diethyl ether, solids Sephadex G10 desalination, distilled water is moving phase, triketohydrindene hydrate detects collects the aqueous solution, after the lyophilize, gets 258-260 ℃ of mp of title compound 40mg (63%) [α]
D 20-11 (C0.5, H2O) TOF-MS (m/e) 632[M+1]
+654[M+Na]
+, 670[M+K]
+Embodiment 11: the preparation N-[(2-N-tert-butyloxycarbonyl-3 of carboline acyl-RGDV (16), 4,9-trihydro-β Carboline-3-yl)-formyl]-Arginyl-(N
ωToluenesulonyl)-and Glycyl-Aspartyl-(β-Cyclohexylester)-Valine Benzyl Ester (13)
64mg (0.2mmol) compound 99 is dissolved among the anhydrous THF of 4ml, and ice bath adds 30mg (0.22mmol) N-hydroxy benzo triazole and 48mg (0.22mmol) DCC down, gets mixture behind the 1hr.161mg (0.2mmol) HClArg (Tos)-Gly-Asp (OcHex)-ValOBzl is dissolved in the anhydrous THF of 5ml, drip N-methylmorpholine and make pH value of solution 8 ~ 9, the mixture that adding obtains above, behind 0 ℃ of reaction 2hr, room temperature reaction 12hr, TLC shows that raw material point disappears, stopped reaction, filtering DCU, filtrate is evaporated to dried at 37 ℃, residue is with acetic acid ethyl dissolution and use saturated sodium bicarbonate aqueous solution successively, saturated sodium-chloride water solution and the washing of 5% aqueous potassium hydrogen sulfate, the organic layer anhydrous sodium sulfate drying of telling.Filter, filtrate is evaporated to dried at 37 ℃, gets crude product, through silica gel H 60 column chromatographic isolation and purifications, gets 118-120 ℃ of mp of title compound 154mg (72%) [α]
D 20+ 22 (C1, CHCl
3) TOF-MS (m/e) 1070[M+1]
+1091[M+Na]
+, 1108[M+K]
+N-[(2,3,4,9-tetrahydro-β Carboline-3-yl)-formyl]-Arginyl-Glycyl-Aspartyl-Valine (16)
107mg (0.1mmol) compound 103 is with after 1ml methyl-phenoxide and 2ml anhydrous HF are mixed, 0 ℃ of reaction 1hr, HF is removed in decompression, feeds anhydrous HF 6ml once more, 0 ℃ of reaction 1hr, HF is removed in decompression, and residue solidifies with anhydrous diethyl ether, solids Sephadex G10 desalination, distilled water is moving phase, triketohydrindene hydrate detects collects the aqueous solution, after the lyophilize, gets title compound 44mg (68%) mp more than 300 [α]
D 20-24 (C0.5, H
2O) TOF-MS (m/e) 644[M+1] embodiment 12: the preparation N-[(2-N-tert-butyloxycarbonyl-3 of carboline acyl-RGDF (17), 4,9-trihydro-β Carboline-3-yl)-formyl]-Arginyl-(N
ωToluenesulonyl)-and Glycyl-Aspartyl-(β-Cyclohexylester)-Phenylalanine Benzyl Ester (14)
64mg (0.2mmol) compound 99 is dissolved among the anhydrous THF of 4ml, and ice bath adds 30mg (0.22mmol) N-hydroxy benzo triazole and 48mg (0.22mmol) DCC down, gets mixture behind the 1hr.171mg (0.2mmol) HClArg (Tos)-Gly-Asp (OcHex)-PheOBzl is dissolved in the anhydrous THF of 5ml, drip N-methylmorpholine and make pH value of solution 8 ~ 9, the mixture that adding obtains above, behind 0 ℃ of reaction 2hr, room temperature reaction 12hr, TLC shows that raw material point disappears, stopped reaction, filtering DCU, filtrate is evaporated to dried at 37 ℃, residue is with acetic acid ethyl dissolution and use saturated sodium bicarbonate aqueous solution successively, saturated sodium-chloride water solution and the washing of 5% aqueous potassium hydrogen sulfate, the organic layer anhydrous sodium sulfate drying of telling.Filter, filtrate is evaporated to dried at 37 ℃, gets crude product, through silica gel H 60 column chromatographic isolation and purifications, gets 108-110 ℃ of mp of title compound 163mg (73%) [α]
D 20+ 22 (C1, CHCl3) TOF-MS (m/e) 1118[M+1]
+1140[M+Na]
+, 1156[M+K]
+N-[(2,3,4; 9-tetrahydrochysene-β carboline-3-yl)-formyl radical]-arginyl-glycyl-aspartyl-phenylalanine N-[(2; 3,4,9-tetrahydro-β Carboline-3-yl)-formyl]-Arginyl-Glycyl-Aspartyl-Phenylalanine (17)
112mg (0.1mmol) compound 105 is with after 1ml methyl-phenoxide and 2ml anhydrous HF are mixed, 0 ℃ of reaction 1hr, HF is removed in decompression, feeds anhydrous HF 6ml once more, 0 ℃ of reaction 1hr, HF is removed in decompression, and residue solidifies with anhydrous diethyl ether, solids Sephadex G10 desalination, distilled water is moving phase, triketohydrindene hydrate detects collects the aqueous solution, after the lyophilize, gets 260-263 ℃ of mp of title compound 47mg (68%) [α]
D 20-10 (C0.5, H
2O) TOF-MS (m/e) 692[M+1]
+Embodiment 13: external platelet aggregation inhibitory activity is measured
Normal rabbit blood is with 3.8% Sodium Citrate anti-freezing, the centrifugal platelet rich plasma (PRP) that makes, regulating the thrombocyte numeration is 200,000/μ l, measure platelet aggregation rate with the standard nephelometry, inductor is platelet activating factor (PAF, final concentration 10-7mol/L) and the peak value of adenosine diphosphate (ADP) (ADP, final concentration 10-7mol/L) MA (AM%) expression curve of platelet aggregation.The platelet aggregation inhibitory activity of each compound is listed in the table, and to the data analysis that takes statistics, P＜0.05 is promptly thought significant difference with ANOVA check.Table?1.Effect?of?the?compounds?on?the?platelet?aggregation?inducedby?ADP(10
-5mol/L)
Am％( x±SD)，at?the?Dose?ofCompd
10
-7mol/L 10
-6mol/L 10
-5mol/LNS 56.72±5.151 53.66±2.41 45.16±4.78
a 24.60±1.99
a6 52.85±2.46 40.54±3.18
a 14.22±2.49
a7 51.16±4.25
b 29.40±2.95
a 9.80±1.98
a8 35.70±2.14
a 22.11±3.16
a 7.36±1.10
a15 50.16±3.44
b 43.05±3.90
a 16.11±2.05
a，c16 50.20±4.01
b 26.01±2.45
a，c 10.75±1.56
a，c17 36.05±3.00
a，c 21.05±3.06
a，c 9.01±2.15
a，cN＝8；NS＝vehicle；a)compare?to?NS，P＜0.001；b)compare?to?NS，P＜0.01；.c)compare?to?1，P＜0.001.Table?2.Effect?of?the?compounds?on?the?platelet?aggregation?inducedby?PAF(10
-7mol/L)
Am％( x±SD)，at?the?Dose?ofCompd
10
-7Mol/L 10
-6Mol/L 10
-5Mol/LNS 58.90 ± 4.651 55.15 ± 3.16 50.18 ± 3.49 35.66 ± 2.46
a6 57.20 ± 3.90 36.15 ± 3.45
a21.16 ± 2.55
a7 54.36 ± 4.11 34.17 ± 2.99
a19.56 ± 1.98
a8 39.18 ± 2.55
a23.80 ± 2.34
a7.81 ± 1.85
a15 56.10 ± 3.25 34.15 ± 3.18
A, c28.07 ± 2.58
A, c16 54.10 ± 3.90
b35.05 ± 3.12
A, c24.11 ± 2.35
A,, c17 36.05 ± 3.60
A, c25.54 ± 2.80
A, c20.05 ± 2.41
A, cN=8; NS=vehicle; A) .compare to NS, P＜0.001; B) .compare to NS, P＜0.01; P＜0.01; .P＜0.01; .c) .compare to 1, P＜0.001. embodiment 14: external anti-adhesion activity is measured
Adopt the SACC-LM cell and the thrombocyte of the high lung SACC clone that shifts, measuring method is according to document (Br.J.Cancer 1995,71 for Chiang H., et al, 265), and data see Table
Table?3.Effect?of?the?compounds?on?the?adhesion?of?SACC-LM?and
platelet
Compd ％， x±SD
NS 78.3±4.0
1 45.6±2.4
a
6 35.8±2.1
a
7 32.1±1.9
a
8 29.7±1.9
a
15 36.1±1.4
a，b
16 30.2±2.4
a，b
17 28.1±1.6
a，b
N＝8；NS＝vehicle；a).compare?to?NS，P＜0.001；b).compare?to
1, P＜0.001. embodiment 15.: antithrombotic acitivity is measured in the body
Laboratory animal is 250-300g male Wistar rat (Peking University's animal center provides), and test compound is with before being dissolved in physiological saline and being stored in the frozen water.Rat separates right carotid and left jugular vein after anaesthetizing with vetanarcol (80.0mg/Kg).A long silk thread of accurately weighing in advance of 6cm is put into the centre of polyethylene intubate, after intubate being full of the normal saline solution (50IU/ml) of heparin sodium, an end inserts the left side vein, adds quantitative heparin sodium aqua anti-freezing from the other end, and the adding testing compound, insert the right side artery again.Blood flow flows into the left side vein from the right side artery polyethylene tube of flowing through, take out silk thread after 15 minutes and write down weight in wet base, silk thread in moisture eliminator, preserves two week the back write down dry weights.Data see Table, and to the data analysis that takes statistics, P＜0.05 is promptly thought significant difference with ANOVA check.Table?4.Effect?of?the?compounds?on?the?thrombus?weight( x±SD)Compd Wet?thrombus(mg) Dry?thrombus(mg)NS 45.92±6.23 8.95±1.971 42.99±3.80 7.17±0.70
a6 43.61±5.78 7.68±2.407 34.62±3.20
b 6.03±1.06
b8 26.61±3.44
a 4.14±0.95
a15 28.09±4.42
a，c 4.98±1.21
b，d16 29.49±4.30
b，e 4.87±1.04
b，e17 22.30±2.43
a，f 2.76±0.45
a，g
N＝8；dosage，5μmol/kg；NS＝vehicle；a)compare?to?NS(3ml/kg)，P＜0.001；b)compare?to?NS(3ml/kg)，P＜0.01；c)compare?to?6，P＜0.01；d)compare?to?6，P＜0.05；e)compare?to?7，P＜0.05；f)compare?to?8，P＜0.001；g)compare?to?8，P＜0.01.
Claims (9)
1, the beta-tetrahydro carboline carboxylate compound of the protection of following structural formula:
2, the preparation method of the compound of claim 1, comprise that tryptophane prepares the beta-tetrahydro carboline carboxylate with formaldehyde reaction in the presence of vitriolic, this compound in DMF in the presence of triethylamine with Boc-N3 or BOC anhydride reaction, make N-Boc-beta-tetrahydro carboline carboxylate.
3, the Tetrahydrocarboline carboxylic acid nanometer formulation of following structural formula, its preparation method are included under the existence of non-polar solvent, acid and TWEEN 80 or similar tensio-active agent, make L-tryptophane and formaldehyde reaction, separate then and freeze-drying:
4, the compound of following general formula (II):
Wherein AA is L-Ser, L-Val or L-Phe residue.
5, the preparation method of the compound of general formula (II); comprise that general formula is compound and the coupling of N-Boc Tetrahydrocarboline carboxylic acid of HCL.Arg (Tos)-Gly-Asp (OcHex)-AAoBzl, through the HF deprotection, obtains the compound of general formula (2); wherein AA is L-Ser, L-Val or L-Phe residue.
6, the application of the Nano compound of claim 3 in medical science.
7, the Nano compound of claim 3 is in preparation treatment thrombotic diseases, for example application in the medicine of cerebral thrombosis, coronary heart disease, myocardial infarction, cerebral embolism, lower limb vein thrombus.
8, the application of the compound of claim 4 in medical science.
9, the compound of claim 4 is in preparation treatment thrombotic diseases, for example application in the medicine of cerebral thrombosis, coronary heart disease, myocardial infarction, cerebral embolism, lower limb vein thrombus.
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| CN108948145B (en) * | 2017-05-18 | 2021-09-24 | 首都医科大学 | 1R-methyl-beta-tetrahydrocarboline acyl-K (PAK) -RGDV, and synthesis, activity and application thereof |
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| CN110615828A (en) * | 2018-06-04 | 2019-12-27 | 首都医科大学 | 1S-methyl-beta-tetrahydrocarboline acyl-K and synthesis, activity and application thereof |
| CN110615828B (en) * | 2018-06-04 | 2022-09-02 | 首都医科大学 | 1S-methyl-beta-tetrahydrocarboline acyl-K and synthesis, activity and application thereof |
| CN111434768A (en) * | 2019-01-14 | 2020-07-21 | 大江生医股份有限公司 | Probiotic bacterial strain for improving respiratory tract health and composition and application thereof |
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