CN103159758B - (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline amic acid, its synthesis, anti-thrombus activity and the application as antithrombotic agent - Google Patents

(1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline amic acid, its synthesis, anti-thrombus activity and the application as antithrombotic agent Download PDF

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CN103159758B
CN103159758B CN201110415209.0A CN201110415209A CN103159758B CN 103159758 B CN103159758 B CN 103159758B CN 201110415209 A CN201110415209 A CN 201110415209A CN 103159758 B CN103159758 B CN 103159758B
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tetrahydro
nitrophenyl
beta
carboline
benzyl ester
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CN103159758A (en
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赵明
彭师奇
王玉记
吴建辉
李伟
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Capital Medical University
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Abstract

The invention discloses (the 1S of general formula I, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline amic acid, disclose they synthesis, disclose they In Vitro Anti platelet aggregation activity, further disclose antithrombotic acitivity in their bodies on rat suppository model.Thus the invention discloses the potential applicability in clinical practice of (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline amic acid as antithrombotic agent.

Description

(1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline amic acid, its synthesis, anti-thrombus activity and the application as antithrombotic agent
Invention field
The present invention relates to (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline amic acid, relate to their synthesis, relate to their In Vitro Anti platelet aggregation activity, relate to their antithrombotic acitivities on rat suppository formation model further.Thus the present invention relates to the potential applicability in clinical practice of (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline amic acid as antithrombotic agent.The invention belongs to biomedicine field.
Background technology
Thrombotic diseases is a kind of common cardiovascular and cerebrovascular disease, often shows as myocardial infarction, Ischemic Cerebral Infarction, venous thromboembolism etc.There is 1 ~ 3 people that multi-form thrombotic diseases occurs in every thousand people every year, have a strong impact on human health.Anti-bolt conventional clinically at present and thrombolytic drug all also exist such or such shortcoming, as the toxic side effect such as hemorrhage, liver injury, mucosal lesion, find the important directions that the medicine for treating thrombus thing more safe and effective, toxic side effect is little is drug research research.
It is generally acknowledged that platelet aggregation that the formation of thrombus and many factors cause, adhesion are relevant with release.Antiplatelet drug becomes the focus of people's research.It is extensively cognitive by people that tetrahydro-beta-carboline-3-carboxylic acid has anti-platelet activity, but the bioavailability that water-soluble and fat-soluble all official posts obtain it is very low, and certain structure of modification is imperative.In the research of carboline class antithrombotic reagent, contriver disclosed and can improve water-soluble with amino acid modified Tetrahydrocarboline and improve bioavailability.Contriver finds can obtain active better carboline parent nucleus toward 1 introducing p-nitrophenyl of carboline in exploration for many years.Find according to these, inventors herein propose (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline amic acid, their synthesis, the invention of their In Vitro Anti platelet aggregation activity and their antithrombotic acitivities on rat suppository model.
Summary of the invention
First content of the present invention is preparation (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline amic acid, and this content comprises:
1) L-Trp methyl esters is prepared;
2) L-Trp methyl esters and paranitrobenzaldehyde generate (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylate methyl ester through Pictet-Spengler condensation;
3) (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylate methyl ester saponification, generates (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid;
4) (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid and amino-acid benzyl ester coupling are prepared (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline acyl aminoacid benzyl ester;
5) (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline acyl aminoacid benzyl ester saponification preparation (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline amic acid.
Step 1) the preparation of tryptophan methyl ester be included in methanol solution and drip thionyl chloride, then add tryptophane.
Step 2) (1S, 3S)-1-p-nitrophenyl-1, the preparation of 2,3,4-tetrahydro-beta-carboline-3-carboxylate methyl ester is included in tryptophan methyl ester and paranitrobenzaldehyde in the methanol solution of hydrochloric acid and carries out being separated by column chromatography after Pictet-Spengler condensation.
Step 3) (1S, 3S)-1-p-nitrophenyl-1,2, the preparation of 3,4-tetrahydro-beta-carboline-3-carboxylic acid comprises under cryosel bath to (1S, 3S)-1-p-nitrophenyl-1,2, it is 12 that 3,4-tetrahydro-beta-carboline-3-carboxylate methyl ester tetrahydrofuran solution first drips 2N sodium hydroxide solution to pH, and the HCl solution dripping 2N after having reacted again is 2 to pH.
Step 4) (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid and amino-acid benzyl ester linked reaction are carried out under DCC, HOBt and NMM exist, and wherein amino-acid benzyl ester is selected from L-Leu benzyl ester, TYR benzyl ester, L-Phe benzyl ester, ALANINE benzyl ester, Valine benzyl ester, L-Trp benzyl ester, L-Aspartic acid two benzyl ester, L-N ε-Boc-Methionin benzyl ester, L-Methionine benzyl ester, Serine benzyl ester, L-PROLINE benzyl ester, glycine benzyl ester or L-glutaminate benzyl ester.During with the ester coupling of L-PROLINE benzyl, first (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid is prepared as N-tertbutyloxycarbonyl-(1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid, then with the coupling of L-PROLINE benzyl ester, then in the ethyl acetate solution of hydrogenchloride, slough tertbutyloxycarbonyl.
Step 5) (1S, 3S)-1-p-nitrophenyl-1,2, it is 12 that the tetrahydrofuran solution of 3,4-tetrahydro-beta-carboline acyl aminoacid benzyl ester first drips 2N sodium hydroxide solution to pH, and the HCl solution dripping 2N after having reacted again is 2 obtain (1S to pH, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline amic acid.First content of the present invention can describe by the synthetic route of Fig. 1.
Accompanying drawing explanation
Fig. 1. the synthetic route .i of (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline amic acid) methyl alcohol and thionyl chloride; Ii) paranitrobenzaldehyde and concentrated hydrochloric acid; Iii) tetrahydrofuran (THF) and 2N sodium hydroxide solution; Iv) DCC, HOBt, tetrahydrofuran (THF) and NMM; V) tetrahydrofuran (THF), 2N sodium hydroxide solution and 2N HCl solution.In 4a and 5a, AA is that in L-Leu residue, 4b and 5b, AA is that in TYR residue, 4c and 5c, AA is that in L-Phe residue, 4d and 5d, A A is that in ALANINE residue, 4e and 5e, A A is Valine residue; In 4f and 5f AA be in L-Trp residue, 4g AA be the protection of side chain benzyl ester L-Aspartic acid residue, AA is that in L-Aspartic acid residue, 4h and 5h, AA is that in L-lysyl, 4i and 5i, AA is that in L-Methionine residue, 4j and 5j, AA is that in Serine residue, 4k and 5k, AA is that in L-PROLINE residue, 4l and 5l, AA is glycine residue in 5g; In 4m and 5m, AA is L-glutaminate residue.
Second content of the present invention evaluates the platelet aggregation inhibitory activity of (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline amic acid (5a-m).
3rd content of the present invention evaluates the antithrombotic acitivity of (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline amic acid (5a-m).
In order to set forth the present invention further, provide a series of embodiment below.These embodiments are illustrative completely, and they are only used for being specifically described the present invention, not should be understood to limitation of the present invention.
Embodiment
Embodiment 1 prepares L-Trp methyl esters
Under ice-salt bath, in 150ml methyl alcohol, drip 15ml thionyl chloride while stirring, after half an hour, add L-Trp 10.2g (50mmol), remove cryosel bath, stirring at room temperature two days.Stopped reaction after TLC plate display raw material disappears substantially.Methyl alcohol is removed in decompression.Residue dissolve with methanol also decompression removes methyl alcohol.This operation in triplicate.Residue ether dissolution also decompression removes ether.This operation in triplicate.Finally use methanol/ether recrystallization, obtain white solid 12.6g (99.0%) altogether through twice recrystallization.Mp：218-220℃； ＝17.9(c＝5.0，CH 3OH)；ESI +-MS(m/e)：219[M+H] +.
Embodiment 2 prepares (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylate methyl ester
5ml concentrated hydrochloric acid is slowly added in 30ml methyl alcohol, 2.55g (10mmol) L-Trp methyl ester hydrochloride and 1.66g (11mmol) paranitrobenzaldehyde is added in dilute hydrochloric acid solution, microwave heating 75 DEG C reaction two hours, TLC plate display primitive reaction is complete.With strong aqua adjust pH to 6, filter and obtain yellow solid.Carry out column chromatography by petrol ether/ethyl acetate, obtain 1.28g (36.1%) (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylate methyl ester.ESI-MS(m/e)：352[M+H] +；1H-NMR(300MHz，DMSO-d6)：δ/ppm＝10.400(s，1H)，8.242(d，J＝9.0Hz，2H)，7.662(d，J＝8.7Hz，2H)，7.472(d，J＝7.2Hz，1H)，7.209(d，J＝7.5Hz，1H)，7.056～6.950(m，2H)，5.397(s，1H)，3.918(dd，J＝3.9Hz，J＝11.1Hz，1H)，3.726(s，3H)，3.110～3.052(m，1H)，2.929～2.835(m，1H).
Embodiment 3 prepares (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid
Cryosel bath dissolves 3.51g (10mmol) (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylate methyl ester with tetrahydrofuran (THF) under stirring, and drips 2N sodium hydroxide solution adjust ph to 12, by TLC plate detection reaction.After raw material point disappears substantially, by 2N hydrochloric acid solution adjust ph to 2, filter, filter residue distillation washing, drying obtains yellow solid 3.0g (90%).ESI-MS(m/e)：338[M+H] +； 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝10.400(s，1H)，8.242(d，J＝8.4Hz，2H)，7.672(d，J＝8.7Hz，2H)，7.465(d，J＝7.2Hz，1H)，7.196(d，J＝7.2Hz，1H)，7.044-6.917(m，2H)，5.424(s，1H)，3.764(dd，J＝3.9Hz，J＝11.1Hz，1H)，3.084(dd，J＝2.7Hz，J＝15.0Hz，，1H)，2.875-2.781(m，1H).
Embodiment 4 prepares (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-formyl amino acid formyl amino acid benzyl ester (4a-m)
337mg (1.0mmol) (1S is added in 50ml eggplant bottle, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid, adds 3ml anhydrous tetrahydro furan and dissolves, stir under ice bath, add 162mg (1.2mmol) HOBt, 247mg (1.2mmol) DCC and form A liquid.In 25ml eggplant bottle, add the tetrahydrofuran solution of 1.05mmolL-amino-acid benzyl ester, add NMM and adjust pH to form B liquid.In A liquid, add B liquid after half an hour, add NMM and regulate pH to 9.TLC plate detection reaction progress.React rear mistake and filter dicyclohexylurea (DCU) (DCU), concentrating under reduced pressure is except desolventizing, residue adds acetic acid ethyl dissolution, use 5% sodium hydrogen carbonate solution respectively, saturated nacl aqueous solution, 5% potassium hydrogen sulfate solution, saturated nacl aqueous solution, saturated sodium bicarbonate solution, saturated nacl aqueous solution respectively washes 3 times.Ethyl acetate layer anhydrous sodium sulfate drying 1 hour, filters, and concentrating under reduced pressure, except desolventizing, obtains crude product.Carry out separation by column chromatography again and obtain sterling.Eluent.Sherwood oil: ethyl acetate 5: 1-3: 1 gradient elution.
(1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-formyl-L-Leu benzyl ester (4a)
Output: 227 (42%).ESI-MS(m/e)：541[M+H] +； 1H-NMR(300MHz，CDCl 3)：δ/ppm＝10.404(s，1H)，8.273-8.223(m，3H)，7.667(d，J＝8.7Hz，，2H)，7.437-7.321(m，6H)，7.231-7.204(m，1H)，7.063-6.697(m，2H)，5.378(d，J＝7.2Hz，，1H)，5.160(s，2H)，4.484-4.410(m，1H)，3.744-3.674(m，1H)，3.324(s，1H)，3.030(dd，J＝5.7Hz，，J＝15.0Hz，，1H)，2.793-2.706(m，2H)，1.688-1.517(m，3H)，0.903(d，J＝6.3Hz，，3H)，0.868(d，J＝6.0Hz，，3H).
(1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-formyl-TYR benzyl ester (4b)
Output: 141mg (24%).ESI-MS(m/e)：591[M+H] +； 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝10.428(s，1H)，9.272(s，1H)，8.282-195(m，3H)，7.648(d，J＝8.7Hz，2H)，7.433-7.196(m，9H)，7.056-6.910(m，2H)，6.661-6.609(m，2H)，5.354(d，J＝6.3Hz，1H)，5.113(s，2H)，5.068-4.996(m，1H)，4.561(dd，J＝7.2Hz，J＝14，4Hz，1H)，3.644-3.622(m，1H)，3.575-3.536(m，1H)，3.009-2.856(m，2H)，2.770-2.692(m，1H).
(1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-formyl-L-Phe benzyl ester (4c)
Output: 278mg (48%).E SI-MS(m/e)：575[M+H] +； 1H-NMR(300MHz，CDCl 3)：δ/ppm＝8.229(d，J＝8.7Hz，2H)，7.583～7.541(m，2H)，7.501(d，J＝8.7Hz，2H)，7.390～7.356(m，3H)，7.336～7.303(m，2H)，7.282(s，1H)，7.255～7.224(m，1H)，7.206～7.137(m，5H)，7.014(dd，J＝1.8Hz，J＝7.2Hz，2H)，5.311(s，1H)，5.179(dd，J＝12.0Hz，J＝21.0Hz，2H)，4.984(dd，J＝6.3Hz，J＝14.4Hz，1H)，3.796～3.721(m，1H)，3.316～3.244(m，1H)，3.223～3.177(m，1H)，3.117(dd，J＝6.3Hz，J＝13.8Hz，1H)，2.829～2.732(m，1H)，2.1(s，1H).
(1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-formyl-ALANINE benzyl ester (4d)
Output: 284mg (57%).ESI-MS(m/e)：499[M+H]+；1H-NMR(300MHz，DMSO-d6)：δ/ppm＝10.845(s，1H)，8.312(d，J＝7.2Hz，1H)，8.204(d，J＝8.7Hz，2H)，7.513(d，J＝8.7Hz，2H)，7.434～7.286(m，7H)，7.104～6.984(m，2H)，5.369(s，1H)，5.126(dd，J＝12.6Hz，J＝15.6Hz，2H)，4.323(dq，J＝7.2Hz，J＝28.8Hz，1H)，3.525～3.452(m，1H)，2.954～2.891(m，1H)，2.735～2.643(m，1H)，1.322(d，J＝7.2Hz，3H).
(1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-formyl-Valine benzyl ester (4e)
Output: 282mg (53%).ESI-MS(m/e)：527[M+H] +。 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝10.862(s，1H)，8.218(d，J＝8.7Hz，1H)，8.099(d，J＝8.1Hz，2H)，7.531(d，J＝8.4Hz，2H)，7.439～7.282(m，7H)，7.103～6.980(m，2H)，5.371(s，1H)，5.147(dd，J＝12.6Hz，J＝20.1Hz，2H)，4.236(dd，J＝6.0Hz，J＝7.8Hz，2H)，3.566～3.521(m，1H)，3.442～3.391(m，1H)，2.965(dd，J＝4.5Hz，J＝15.0Hz，2H)，2.142～2.031(m，1H)，0.884(dd，J＝1.8Hz，J＝6.6Hz，2H).
(1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-formyl-L-Trp benzyl ester (4f)
Output: 202mg (33%).ESI-MS(m/e)：614[M+H] +； 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝10.954(s，1H)，10.878(s，1H)，8.253(d，J＝7.5Hz，1H)，8.148(d，J＝8.1Hz，1H)，7.939(s，1H)，7.510(d，J＝7.8Hz，1H)，7.446-7.373(m，3H)，7.312-7.281(m，4H)，7.205-6.944(m，7H)，5.259(s，1H)，4.638-4.574(m，1H)，3.209-3.168(m，1H)，2.957-2.890(m，2H)，2.734-2.650(m，2H).
The two benzyl ester (4g) of (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-formyl-L-Aspartic acid
Output: 233mg (37%).ESI-MS(m/e)：633[M+H] +； 1H-NMR(300MHz，CDCl 3)：δ/ppm＝8.213(d，J＝8.4Hz，2H)，7.616(d，J＝8.4Hz，2H)，7.557～7.546(m，3H)，7.518(s，1H)，7.362～7.229(m，10H)，7.211～7.147(m，2H)，5.346(s，1H)，5.164(s，2H)，5.057(s，2H)，5.030～4.913(m，1H)，3.818(dd，J＝4.2Hz，J＝11.1Hz，1H)，3.369～3.260(m，1H)，3.126(dd，J＝4.8Hz，J＝17.1Hz，1H)，2.964(dd，J＝4.8Hz，J＝17.1Hz，1H)，2.857(dd，J＝2.4Hz，J＝15.3Hz，1H)，2.065(s，1H).
(1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline acyl Methionin benzyl ester (4h)
Output: 118mg (21%).ESI-MS(m/e)：556[M+H] +； 1H-NMR(300MHz，DMSO- d6)：δ/ppm＝11.188(s，1H)，8.275(d，J＝8.4Hz，2H)，8.105(s，1H)，7.631(d，J＝8.7Hz，1H)，7.478-7.322(m，7H)，7.191-7.069(m，2H)，6.166(s，1H)，5.159(s，1H)，4.328-4.239(m，1H)，3.734(m，1H)，3.184(d，J＝7.5Hz，1H)，2.967(dd，J＝10.5Hz，J＝15.6Hz，1H)，2.713(d，J＝5.7Hz，2H)，1.734(m，2H)，1.559(m，2H)，1.436-1.343(m，2H).
(1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-formyl-L-methionine benzyl ester (4i)
Output: 209mg (36%).ESI-MS(m/e)：559[M+H] +； 1H-NMR(300MHz，DMSO- d6)：δ/ppm＝10.835(s，1H)，8.308(d，J＝7.5Hz，1H)，8.198(d，J＝8.7Hz，2H)，7.524(d，J＝9.0Hz，2H)，7.437-7.280(m，7H)，7.101-6.981(m，2H)，5.369(s，1H)，5.136(dd，J＝12.3Hz，J＝16.2Hz，2H)，4.502-4.431(m，1H)，3.507-3.462(m，1H)，2.948(dd，J＝4.5Hz，J＝15.3，1H)，2.715(dd，J＝9.0Hz，J＝15.0Hz，1H)，2.013-1.975(m，6H).
(1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-formyl-Serine benzyl ester (4j)
Output: 162mg (31%).ESI-MS(m/e)：515[M+H] +； 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝10.403(s，1H)，8.264(d，J＝8.7Hz，2H)，8.149(d，J＝7.8Hz，1H)，7.670(d，J＝8.7Hz，1H)，7.457-7.337(m，6H)，7.213(d，J＝7.8Hz，1H)，7.009(dt，J＝6.9Hz，J＝7.8Hz，2H)，5.393(d，J＝6.3Hz，1H)，5.172(s，2H)，4.496(dd，J＝3.9Hz，J＝7.5Hz，1H)，3.855-3.782(m，1H)，3.739-3.669(m，2H)，3.071-3.020(m，1H)，2.892(s，1H)，2.836-2.793(m，1H)，2.735(s，1H).
(1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-formyl-L-PROLINE benzyl ester (4k)
Under ice bath, 337mg (1.0mmol) (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline carboxylic acid is suspended in containing 280mg (1.3mmol) (Boc) 2in the tetrahydrofuran solution of O, then add triethylamine and regulate pH9, TLC plate detection reaction, after raw material point disappears, decompression removing tetrahydrofuran (THF), uses acetic acid ethyl dissolution residue, then washs 3 times with 5% potassium hydrogen sulfate solution, saturated nacl aqueous solution washs 3 times, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains N-Boc-(1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline carboxylic acid.Then in 50ml eggplant bottle, 437mg (1.0mmol) N-Boc-(1S is added, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid, adds 3ml anhydrous tetrahydro furan and dissolves, stir under ice bath, add 162mg (1.2mmol) HOBt, 247mg (1.2mmol) DCC and form A liquid.In 25ml eggplant bottle, add the tetrahydrofuran solution of 1.05mmol amino-acid benzyl ester, add NMM and adjust pH to form B liquid.In A liquid, add B liquid after half an hour, add NMM and regulate pH to 9.TLC plate detection reaction progress.React rear mistake and filter DCU, concentrating under reduced pressure is except desolventizing, after residue adds acetic acid ethyl dissolution, respectively wash 3 times with 5% sodium hydrogen carbonate solution, saturated nacl aqueous solution, 5% potassium hydrogen sulfate solution, saturated nacl aqueous solution, saturated sodium bicarbonate solution and saturated nacl aqueous solution respectively.Ethyl acetate layer anhydrous sodium sulfate drying 1 hour, filters, and concentrating under reduced pressure, except desolventizing, obtains crude product.Carry out separation by column chromatography again and obtain sterling.Eluent: sherwood oil: ethyl acetate 5: 1-3: 1 gradient elution.Under cryosel bath is stirred, add the ethyl acetate solution of 4N hydrogenchloride to N-Boc-(1R, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline acyl proline(Pro) benzyl ester, reaction terminates rear decompression and removes ethyl acetate.Residue with Ethyl acetate dissolves and reduces pressure removes ethyl acetate.This operation in triplicate.Residue ether dissolution also decompression removes ether.This operation in triplicate.Obtaining 164mg (30%) target compound, is blister solid.ESI-MS(m/e)：547[M+Na] +； 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝10.876(s，1H)，8.255～8.181(m，3H)，7.498(d，J＝8.7Hz，2H)，7.423(d，J＝8.7Hz，1H)，7.315～7.264(m，2H)，7.106～6.931(m，3H)，5.354(s，2H)，5.116(dd，J＝12.6Hz，J＝18.6Hz，1H)，4.367(dd，J＝3.9Hz，J＝8.7Hz，1H)，4.03(dd，J＝7.2Hz，J＝14.4Hz，1H)，3.631～3.603(m，1H)，3.362(s，1H)，2.885(s，1H)，2.752-2.667(m，1H)，2.193-2.083(m，1H)，1.992(s，1H)，1.885-1.712(m，1H).
(1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline acyl glycine benzyl ester (4l)
Output: 111mg (23%).ESI +-MS(m/e)：485[M+H] +； 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝10.845(s，1H)，8.379(d，J＝6.0Hz，1H)，8.211(d，J＝8.7Hz，2H)，7.522(d，J＝8.7Hz，2H)，7.462(d，J＝7.5Hz，1H)，7.373-7.282(m，6H)，7.104-6.979(m，1H)，5.396(d，J＝4.5Hz，1H)，3.951(d，J＝6.0Hz，2H)，3.497-3.451(m，1H)2.979(dd，J＝4.5Hz，J＝15.0Hz，1H)，2.814-2.763(m，1H).
(1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-formyl-L-glutaminate benzyl ester (4m)
Output: 105mg (19%).ESI +-MS(m/e)：556[M+H] +； 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝10.443(s，1H)，8.329(d，J＝8.7Hz，1H)，8.261(d，J＝8.7Hz，2H)，7.678(d，J＝8.4Hz，2H)，7.436-7.322(m，7H)，7.055-6.962(m，2H)，5.371(s，1H)，5.115s，2H)，4.422-4.351(m，1H)，3.764-3.688(m，1H)，3.356(s，1H)，3.044-2.994(m，1H)，2.798-2.717(m，2H)，2.088-1.909(m，2H).
Embodiment 5 prepares (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-formyl amino acid formyl amino acid (5a-m)
Cryosel bath takes 0.1mmol (1S under stirring in 50ml eggplant bottle, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline acyl aminoacid benzyl ester, add the anhydrous THF of 2ml and dissolve, drip 2N sodium hydroxide solution adjust ph to 12, by TLC plate detection reaction.After raw material point disappears substantially, obtain yellow solid with 2N hydrochloric acid solution adjust ph to 2, filtration, filter residue distillation washing, drying.
(1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-formyl-L-Leu (5a)
Output: 39mg (88%).ESI-MS(m/e)：449[M-H] -。 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝12.360(s，1H)，8.872(s，2H)，8.411-8.363(m，5H)，7.310(d，J＝7.8Hz，1H)，7.597(d，J＝6.，9Hz，1H)，7.323(d，J＝6.9Hz，1H)，4.274(s，1H)，1.738-1.582(m，3H)，0.944-0.886(m，6H).
(1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-formyl-TYR (5b)
Output: 36mg (73%).ESI-MS(m/e)：498[M-H] -。 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝12.236(s，1H)，8.544-8.444(m，3H)，8.356(d，J＝8.1Hz，2H)，7.781-7.708(m，1H)，7.638(d，J＝8.4Hz，1H)，7.349-7.294(m，2H)，7.136-7.045(m，2H)，6.729-6.702(m，2H)，4.755(d，J＝7.5Hz，1H)，4.489(s，1H)，4.0326(m，1H)，3.801-3.733(m，1H)，3.189(m，3H)，3.030(d，J＝5.4Hz，1H).
(1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-formyl-L-Phe (5c)
Output: 39mg (82%).ESI-MS(m/e)：483[M-H] -。 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝10.460(s，1H)，8.438-8.297(m，1H)，8.224(d，J＝7.8Hz，2H)，7.728-7.613(m，3H)，7.454(d，J＝7.2Hz，1H)，7.325(d，J＝7.2Hz，1H)，7.226-7.189(m，5H)，7.027(t，J＝7.2Hz，2H)，5.340(s，1H)，4.218(d，J＝3.9Hz，1H)，3.171-3.142(m，1H)，3.046-3.001(m，2H)，2.663(t，J＝6.6Hz，1H).
(1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-formyl-ALANINE (5d)
Output: 35mg (86%).ESI-MS(m/e)：407[M-H] -。 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝12.203(s，1H)，9.005-8.947(m，1H)，8.486-8.455(m，4H)，7.818(d，J＝8.4Hz，1H)，7.748(d，J＝8.1Hz，1H)，7.644(d，J＝7.5Hz，1H)，7.357(d，J＝7.5Hz，1H)，7.290(d，J＝8.4Hz，1H)，4.735-4.611(m，1H)，2.997-2.919(m，2H)，2.801-2.757(m，2H)，2.588(d，J＝2.7Hz，1H)，2.559(m，3H).
(1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-formyl-Valine (5e)
Output: 34mg (78%).ESI-MS(m/e)：435[M-H] -。 1H-NMR(300MHz，DMS0-d 6)：δ/ppm＝12.272(s，1H)，8.949(s，1H)，8.601(d，J＝9.0Hz，1H)， 8.511-8，450(m，3H)，8.391(d，J＝8.4Hz，2H)，7.756(d，J＝8.1Hz，1H)，7.663-7.613(m，1H)，7.375-7.304(m，2H)，5.213(d，J＝5.1Hz，1H)，4.568-4.497(m，2H)，2.296(d，J＝6.0Hz，1H)，1.000-0.983(m，8H).
(1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-formyl-L-Trp (5f)
Output: 37mg (72%).ESI-MS(m/e)：522[M-H] -。 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝10.860(s，1H)，10.431(s，1H)，8.423(d，J＝8.4Hz，1H)，8.226(d，J＝7.8Hz，1H)，7.826-7.727(m，1H)，7.563(d，J＝8.4Hz，，2H)，7.461(d，J＝7.2Hz，1H)，7.359-7.288(m，4H)，7.220(d，J＝6.9Hz，1H)，7.146(s，1H)，7.059-6，966(m，2H)，6.916-6.814(m，1H)，5.315(s，1H)，4.516-4.465(m，2H)，3.616(d，J＝8.4Hz，1H)，3.328-3.291(m，1H)，3.053(d，J＝14.1Hz，1H)，2.730-2.642(m，1H).
(1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-formyl-L-Aspartic acid (5g)
Output: 38mg (85%).ESI-MS(m/e)：451[M-H] -。 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝12.243(s，1H)，10.872(s，1H)，8.487-8.452(m，2H)，8.339(d，J＝8.4Hz，1H)，7.8020(d，J＝8.4Hz，2H)，7.553(d，J＝7.2Hz，1H)，7.385-7.274(m，2H)，7.134(d，J＝7.2Hz，1H)，7.093-7.044(m，1H)，4.710-4.643(m，1H)，2.934(d，J＝5.4Hz，1H)，2.816-2.769(m，2H)，1.916(s，2H).
(1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-formyl-1B (5h)
Output: 34mg (73%).ESI-MS(m/e)：464[M-H] -。 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝12.403(s，1H)，9.301(d，J＝7.2Hz，1H)，8.488-8.456(m，1H)，8.359-8.281(m，4H)，7.849(d，J＝8.4Hz，2H)，7.537(d，J＝7.5Hz，1H)，7.360-7.276(m，1H)，7.151-7.035(m，1H)，4.303(s，1H)，3.590-3.465(m，1H)，3.174(t，J＝10.5Hz，1)，2.758(s，2H)，1.798-1.519(m，7H).
(1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-formyl-L-Methionine (5i)
Output: 36mg (76%).ESI-MS(m/e)：467[M-H] -。 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝12.177(s，1H)，9.136(d，J＝8.7Hz，1H)，8.954(s，1H)，8.490-8.405(m，4H)，7.735(d，J＝8.1Hz，1H)，7.644(d，J＝7.2Hz，1H)，7.381-7.244(m，2H)，5.191-5.102(m，1H)，4.939-4.894(m，1H)，4.214-4.102(m，7H)，3.657(d，J＝12Hz，1H)，2.935(d，J＝4.5Hz，2H).
(1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-formyl-Serine (5j)
Output: 31mg (74%).ESI-MS(m/e)：423[M-H] -。 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝12.354(s，1H)，8.960(s，1H)，8.809(d，J＝8.1Hz，1H)，8.500-8.431(m，5H)，7.783(d，J＝8.1Hz，7H)，7.663-7.613(m，1H)，7.376-7.308(m，1H)，4.615(d，J＝3.9Hz，1H)，3.975-3.939(m，2H)，3.850-3.826(m，2H).
(1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-formyl-L-PROLINE (5k)
Output: 30mg (69%).ESI-MS(m/e)：434[M-H] -。 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝12.062(d，J＝213Hz，1H)，8.789(d，J＝174Hz，1H)，8.488-8.415(m，3H)，8.347-8.287(m，2H)，7.874-7.561(m，2H)，7.359-7.311(m，2H)，5.408(d，J＝8.7Hz，1H)，4.408(d，J＝105Hz，1H)，4.090-4.069(m，1H)，3.734-3.688(m，2H)，2.348-2.306(m，1H)，1.947-1.799(m，6H).
(1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-formyl-L-glycine (51)
Output: 35mg (89%).ESI-MS(m/e)：393[M-H] -。 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝12.093(s，1H)，8.945(s，1H)，8.476(s，4H)，7.734-7.621(m，2H)，7.422-7.377(m，4H)，5.199(s，2H)，4.239(d，J＝6.0Hz，2H)，4.095(d，J＝5.7Hz， 1H).
(1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-formyl-L-glutaminate (5m)
Output: 38mg (82%).ESI-MS(m/e)：464[M-H] -。 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝12.160(s，1H)，8.512-8.412(m，3H)，8.273(d，J＝8.4Hz，1H)，7.751-7.618(m，2H)，7.402-7.279(m，3H)，7.228(d，J＝5.1Hz，1H)，4.572(s，1H)，4.498(s，1H)，4.206(d，J＝6.9Hz，1H)，3.176-3.097(m，1H)，2.877-2.685(m，1H)，2.453-2.399(m，1H)，2.249-2.089(m，5H).
Embodiment 6 In Vitro Anti platelet aggregation activity is evaluated
Pig carotid artery gets blood, with 3.8% Sodium Citrate (V sodium Citrate: V individual blood=1: 9) anti-freezing.Centrifugal 10 minutes of 1000g/min platelet rich plasma (PRP), then with 3000g/min centrifugal 10 minutes, obtain platelet poor plasma (PPP).With collagen (ADP), platelet activation factor (PAF), zymoplasm (TH) and arachidonic acid (AA) for inductor induced platelet aggregation.Parent nucleus 3 and (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-formyl amino acid formyl amino acid (5a-m) all use physiological saline solution.The parallel survey of each data 6 times.Table 1 data declaration parent nucleus and 13 amino acid modified target compounds do not have restraining effect all to the platelet aggregation of ADP induction, table 2 data declaration does not have restraining effect to the platelet aggregation that PAF induces, the platelet aggregation that table 3 data declaration is induced TH is inhibited, and the platelet aggregation that table 4 data declaration is induced AA is inhibited.Can also see that the present invention's some target compounds after amino acid modified suppress the platelet aggregation of TH and AA induction to strengthen than parent nucleus restraining effect by data.
Show 15a-m impact on the platelet aggregation of ADP induction under 100 μMs of concentration
Show 25a-m impact on the platelet aggregation of PAF induction under 100 μMs of concentration
Show 35a-m impact on the platelet aggregation of TH induction under 100 μMs of concentration
Show 45a-m impact on the platelet aggregation of AA induction under 100 μMs of concentration
The antithrombotic acitivity evaluation of embodiment 75a-m
Before experiment, compound (parent nucleus 3 and 5a-m) being made into 0.33nmol/1 normal saline solution (add a small amount of tween 80 and soak hydrotropy), is 1.0nmol/kg for the dosage in body.Positive drug Asprin is made into 10g/l normal saline solution, i.e. the concentration of 55.5mmol/l, is 167 μm of ol/kg for the dosage in body.Blank is physiological saline, and antithrombotics is heparin sodium 2.4mg/ml normal saline solution.By male SD rat random packet, often organize 12 rats.Compound (5a-m), parent nucleus 3, blank and positive drug are divided into 15 groups, with (3ml/kg) to rat oral gavage, after 30 minutes, with urethane (20g/100ml, 7ml/kg), after anesthesia, are separated right carotid and left jugular vein.The silk thread of prior precise weighing long for a 6cm is placed in polyethylene tube, and after intubate being full of the normal saline solution (50IU/ml) of heparin sodium, left side vein is inserted in one end, adds quantitative heparin sodium anti-freezing, then insert right artrial from one end.Blood flow flows through polyethylene tube from right artrial and flows into left side vein, takes out silk thread and record wet weight of thrombus after 15 minutes.Data list table 3 in.
Table 35a-m is on the thrombotic impact of SD male rat
N=10, wet weight of thrombus is used represent; A) with physiological saline than p < 0.01.

Claims (8)

1. the compound of general formula I, in formula, AA is L-Leu residue, TYR residue, L-Phe residue, ALANINE residue, Valine residue, L-Trp residue, the L-Aspartic acid residue of side chain benzyl ester protection, 1B residue, L-Methionine residue, Serine residue, L-PROLINE residue, glycine residue or L-glutaminate residue
2. prepare the method for the compound of claim 1, the method comprises:
1) L-Trp methyl esters is prepared;
2) L-Trp methyl esters and paranitrobenzaldehyde generate (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylate methyl ester through Pictet-Spengler condensation;
3) (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylate methyl ester saponification, generates (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid;
4) (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid and amino-acid benzyl ester coupling are prepared (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline acyl aminoacid benzyl ester;
5) (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline acyl aminoacid benzyl ester saponification preparation (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline amic acid.
3. in accordance with the method for claim 2, it is characterized in that step 1) described in the preparation method of tryptophan methyl ester be included in methanol solution and drip thionyl chloride, then add tryptophane.
4. in accordance with the method for claim 2, it is characterized in that step 2) (1S, 3S)-1-p-nitrophenyl-1,2,3, the preparation method of 4-tetrahydro-beta-carboline-3-carboxylate methyl ester is included in tryptophan methyl ester and paranitrobenzaldehyde in the methanol solution of hydrochloric acid and carries out being separated by column chromatography after Pictet-Spengler condensation, obtain (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylate methyl ester.
5. in accordance with the method for claim 2, it is characterized in that step 3) (1S, 3S)-1-p-nitrophenyl-1,2,3, the preparation method of 4-tetrahydro-beta-carboline-3-carboxylic acid comprises under cryosel bath to (1S, 3S)-1-p-nitrophenyl-1,2,3, it is 12 that 4-tetrahydro-beta-carboline-3-carboxylate methyl ester tetrahydrofuran solution first drips 2N sodium hydroxide solution to pH, the HCl solution dripping 2N after having reacted again is 2 obtain (1S, 3S)-1-p-nitrophenyl-1,2 to pH, 3,4-tetrahydro-beta-carboline-3-carboxylic acid.
6. in accordance with the method for claim 2, it is characterized in that step 4) (1S, 3S)-1-p-nitrophenyl-1, 2, 3, (1S is prepared in 4-tetrahydro-beta-carboline-3-carboxylic acid and amino-acid benzyl ester coupling, 3S)-1-p-nitrophenyl-1, 2, 3, 4-tetrahydro-beta-carboline acyl aminoacid benzyl ester, reaction is at dicyclohexyl carbonyl diimine (DCC), carry out under N-hydroxy benzo triazole (HOBt) and N-methylmorpholine (NMM) exist, wherein amino-acid benzyl ester is selected from L-Leu benzyl ester, TYR benzyl ester, L-Phe benzyl ester, ALANINE benzyl ester, Valine benzyl ester, L-Trp benzyl ester, the two benzyl ester of L-Aspartic acid, L-N ε-Boc-Methionin benzyl ester, L-Methionine benzyl ester, Serine benzyl ester, L-PROLINE benzyl ester, glycine benzyl ester or L-glutaminate benzyl ester, during with the ester coupling of L-PROLINE benzyl, first (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid is prepared as N-tertbutyloxycarbonyl-(1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid, again with the coupling of L-PROLINE benzyl ester, then in the ethyl acetate solution of hydrogenchloride, slough tertbutyloxycarbonyl.
7. in accordance with the method for claim 2, it is characterized in that step 5) (1S, 3S)-1-p-nitrophenyl-1,2,3, it is 12 that the tetrahydrofuran solution of 4-tetrahydro-beta-carboline acyl aminoacid benzyl ester first drips 2N sodium hydroxide solution to pH, the HCl solution dripping 2N after having reacted again is 2 obtain (1S, 3S)-1-p-nitrophenyl-1,2 to pH, 3,4-tetrahydro-beta-carboline amic acid.
8. the compound of claim 1 is preparing the application in antithrombotic reagent.
CN201110415209.0A 2011-12-13 2011-12-13 (1S, 3S)-1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline amic acid, its synthesis, anti-thrombus activity and the application as antithrombotic agent Expired - Fee Related CN103159758B (en)

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