CN101906097B - 1,3-dioxane compounds as well as synthesizing method and medical application thereof - Google Patents

1,3-dioxane compounds as well as synthesizing method and medical application thereof Download PDF

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CN101906097B
CN101906097B CN2009100851559A CN200910085155A CN101906097B CN 101906097 B CN101906097 B CN 101906097B CN 2009100851559 A CN2009100851559 A CN 2009100851559A CN 200910085155 A CN200910085155 A CN 200910085155A CN 101906097 B CN101906097 B CN 101906097B
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tetrahydroisoquinoline
serine
formyl radical
boc
preparation
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CN101906097A (en
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赵明
彭师奇
杨贞春
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Capital Medical University
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Capital Medical University
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Abstract

The invention discloses 1,3-dioxane compounds as well as a synthesizing method and medical application thereof. The synthesizing method comprises the following steps of: compounding tetrahydroisoquinoline and 1,3-dioxane, and then modifying the N end of the tetrahydroisoquinoline by using 20 kinds of endogenous amino acid to obtain the 1,3-dioxane compounds with excellent antithrombotic activities, which are evaluated by adopting a rat thrombus model. The experimental results indicate that the compounds all have excellent antithrombotic activities and can be clinically used as antithrombotic agents.

Description

1,3-dioxanes compounds and compound method thereof and in medical science, use
Technical field
The present invention relates to six lopps compounds, relate in particular to and have 1 of antithrombotic acitivity, the 3-dioxanes compounds, the invention still further relates to this 1, the compound method of 3-dioxanes compounds and they belong to biomedicine field as the application of pharmaceutical preparations having antithrombotic activity.
Background technology
The M & M of cardiovascular and cerebrovascular diseases day by day rises at present.The major cause that causes cardiovascular and cerebrovascular diseases is to form thrombus in the blood vessel.Thrombocyte plays a part very crucial in the thrombotic process.Anticoagulant, and then suppress the important step that thrombosis has become the various cardiovascular disordeies of prevention.So the research to medicament for resisting platelet aggregation also receives publicity day by day.
Thromboxane (TXA 2) be arachidonic meta-bolites, be a kind of strong platelet aggregating agent, many cardiovascular disordeies and TXA 2Excessive generation relevant, so thromboxane synthetase inhibitor and thromboxane receptor antagonist be the focus of research at present, especially based on 1, the research of 3-dioxane parent nucleus.And it is reported that tetrahydroisoquinoline has good platelet aggregation inhibitory activity; The contriver recognizes that with tetrahydroisoquinoline and 1 the 3-dioxane combines, and is terminal modified to tetrahydroisoquinoline N with 20 kinds of endogenous amino acid; The antithrombotic reagent that can obtain, so the contriver proposes the present invention.
Summary of the invention
One of the object of the invention is with tetrahydroisoquinoline and 1, and the 3-dioxane combines, and with 20 kinds of endogenous amino acid tetrahydroisoquinoline N end is modified, and obtains one type and has 1 of outstanding antithrombotic acitivity, the 3-dioxanes compounds;
Two of the object of the invention provides a kind of synthetic above-mentioned 1, the method for 3-dioxanes compounds;
Three of the object of the invention provides above-mentioned, a kind of purposes of 3-dioxanes compounds in medical science.
Above-mentioned purpose of the present invention realizes through following technical scheme:
Have 1 of antithrombotic acitivity, 3-dioxanes compounds, its structural formula are shown in the general formula I:
Figure G2009100851559D00021
General formula I
Wherein, AA is selected from hydrogen, Val, Leu, Ile, Gly, Ala, Trp, Thr, Met, Asp, Pro, Phe, Lys or Tyr.
Another object of the present invention provides a kind of above-mentioned 1 of antithrombotic acitivity that has for preparing, the method for 3-dioxanes compounds, and this method may further comprise the steps:
(1) preparation N-[(3S)-N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-Serine glycol; (2) preparation 1,2,3,4-tetrahydroisoquinoline acyl Serine glycol; (3) with 1,2,3, the two pure and mild paranitrobenzaldehyde condensations of 4-tetrahydroisoquinoline acyl Serine generate 5-[1,2,3,4 ,-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1, the 3-dioxane; (4) with 5-[1,2,3,4 ,-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane and Fmoc-AA condensation prepared generate 5-[Fmoc-AA-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane; (5) 5-(Fmoc-AA-1,2,3,4-tetrahydroisoquinoline-3-formyl radical)-2-p-nitrophenyl-1,3-dioxane alkaline hydrolysis promptly gets; Wherein, AA is selected from hydrogen, Val, Leu, Ile, Gly, Ala, Trp, Thr, Met, Asp, Pro, Phe, Lys or Tyr.
Wherein, described N-[(3S)-N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-Serine glycol can prepare with reference to following method:
(1) at SOCl 2Existence changes the L-Serine into the L-serine methylester down with methyl alcohol; (2) in the presence of dense HCl and water, change the L-phenylalanine(Phe) into 1,2,3,4-Tetrahydroisoquinoli-dicarboxylic acid moiety; (3) at (Boc) 2With 1,2,3,4-Tetrahydroisoquinoli-dicarboxylic acid moiety changed N-tertbutyloxycarbonyl tetrahydroisoquinoline under O and NaOH existed; (4) L-serine methylester and the condensation of N-tertbutyloxycarbonyl tetrahydroisoquinoline generate N-[(3S)-N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-serine methylester in the presence of DCC, HOBt.
Described 1,2,3,4-tetrahydroisoquinoline acyl Serine glycol can prepare with reference to following method:
(1) at NaBH 4Following with the THF existence with N-t-butoxycarbonyl amino acyl-1,2,3, the reduction of 4-tetrahydroisoquinoline acyl serine methylester, generation N-[(3S)-and N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-Serine glycol; (2) in the presence of hydrogenchloride-THF with N-t-butoxycarbonyl amino acyl-1,2,3, the acidolysis of 4-tetrahydroisoquinoline acyl silk glycol generates 1,2,3,4-tetrahydroisoquinoline acyl Serine glycol.
Estimate the antithrombotic acitivity of compound of the present invention on the rat anti thrombus model, test-results shows that chemical combination of the present invention has outstanding antithrombotic acitivity, can be used as pharmaceutical preparations having antithrombotic activity and uses.
Another purpose of the present invention provides the medicinal compsns of the above-mentioned general formula compound of a kind of the present invention of containing, and this medicinal compsns is gone up effective dose by treatment The compounds of this invention is with pharmaceutically acceptable excipient or assist and add agent and form; That is: with the The compounds of this invention of significant quantity with after pharmaceutically acceptable carrier or thinner cooperate, the formulation method conventional by this area is prepared into any one appropriate drug compsn with it.Usually said composition is suitable for oral administration and drug administration by injection, also is fit to other medication.Said composition can be liquid preparation forms such as tablet, capsule, pulvis, granule, lozenge, suppository, or oral liquid.According to different medications, pharmaceutical composition of the present invention can contain 0.1%-99% weight, the The compounds of this invention of preferred 10-60% weight.
Description of drawings
The synthetic route chart of Fig. 1 The compounds of this invention; I) formaldehyde and concentrated hydrochloric acid, 80 ℃ of oil bath condensing refluxes; Ii) (Boc) 2O, the NaOH ice bath; Iii) SOCl 2, CH 3The OH cryosel is bathed iv) Ser-OMe, DCC, HoBt, NMM ice bath; V) NaBH 4, THF; Vi) vii) paranitrobenzaldehyde of 4N HCl/THF, BF 3Et 2O, CH 3The CN ice bath; Viii) Fmoc-AA, DCC, HoBt, NMM ice bath; Wherein AA represents H, Val, Leu, Ile, Gly, Ala, Trp, Thr, Met, Asp, Pro, Phe, Lys, Tyr; Ix) NaOH/CH 3OH, CH 2Cl 2, ice bath; AA represents H, Val, Leu, Ile, Gly, Ala, Trp, Thr, Met, Asp, Pro, Phe, Lys, Tyr.
Embodiment
In order further to set forth the present invention, provide a series of instances below.These instances are illustrative fully, and they only are used for the present invention is specifically described, and are not to be understood that to be limitation of the present invention.
Embodiment 1 preparation (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (1)
In 4.0g (24.2mmol) L-phenylalanine(Phe), dropwise add 21.6ml formaldehyde earlier, dropwise add 36ml 35% concentrated hydrochloric acid again.The suspension oil bath that obtains is heated to 2 two hours phenylalanine(Phe)s of 80-90 ℃ of stirring and dissolves fully, reacts after 2.5 hours, begins to have colourless deposition to generate, and reacts TLC (CHCl 7 hours 3/ CH 3OH=5/1) show that the L-phenylalanine(Phe) disappears, suction filtration gets the 4.2g colorless solid, and the gained colorless solid is joined in the 86ml ethanol (80%) 80 ℃ of oil baths heating 9 hours; Dissolve to colorless solid; Be cooled to room temperature, slowly drip 1ml (1.376g Pottasium Hydroxide is dissolved in 1ml zero(ppm) water) potassium hydroxide solution, have colourless deposition to separate out; Cross and filter 4.02g (94%) title compound, be colorless solid.MP:302.1-302.5 ℃, [α] D 25=-68 (c 1 methyl alcohol); ESI-MS (m/z) 176 [M-1] -
Embodiment 2 preparation (3S)-N-Boc-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (2)
The following 2.49g of ice bath (62.15mmol) sodium hydroxide dissolves in 62.2ml water, adds 10g (56.49mmol) then (3S)-1,2,3, and 4-tetrahydroisoquinoline-3-carboxylic acid is processed suspension.With 40ml THF dissolving 14.8g (67.8mmol) (Boc) 2O adds in the suspension.Reaction mixture stirred 48 hours, the solution becomes clarification, and TLC (ethyl acetate/petroleum ether: 1: 3) shows (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid disappears, and stops reaction.The reaction mixture concentrating under reduced pressure is removed THF, and the oily matter that obtains is used acetic acid ethyl dissolution.The solution that obtains is used 5%KHSO successively 4Wash with the saturated NaCl aqueous solution.Organic layer is concentrated into dried with anhydrous sodium sulfate drying, filtration, filtrate decompression, the oily matter that obtains stirred 24 hours with ethyl acetate/petroleum ether (1: 10), and the colorless solid that obtains filters, and obtains 12.5g (79.9%) title compound.ESI-MS (m/z) 278.2 [M+1] +, [α] D 25=-6.78 (c1 methyl alcohol);
Embodiment 3 preparation L-serine methyl ester hydrochlorides
The 50ml anhydrous methanol is dripping thionyl chloride 3.75ml (0.050mol) under ice bath, adds L-Serine 5g (0.042mol) behind the 30min, and stirring at room 24h, TLC monitor to raw material disappearance termination reaction.Water pump is taken the intact sulfur oxychloride SOCl of unreacted away 2And HCl, with sherwood oil grind repeatedly white solid 7.34g (productive rate 99%), Mp:161 ℃-162 ℃
Embodiment 4 preparation N-[(3S)-and N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-serine methylester (3)
Ice bath down with anhydrous THF with 5.54g (20mmol) (3S)-N-Boc-1,2,3; 4-tetrahydroisoquinoline-3-carboxylic acid dissolving; Add 2.8g (21mmol) N-hydroxy benzo triazole (HOBt), the dissolving back adds 4.9g (24mmol) dicyclohexyl carbonyl diimine (DCC), obtains reaction solution (I).Be suspended in 2.6g (16.7mmol) HClSer-OMe among the anhydrous THF, add N-methylmorpholine (NMM) and transfer pH value 8~9, get reaction solution (II).Add (I) in (II), stirring at room 12h, TLC (petrol ether/ethyl acetate, 3: 1) show that HClSer-OMe disappears.Leach NSC 30023 (DCU), filtrate decompression is concentrated into dried, and residue is used the 80ml acetic acid ethyl dissolution.The solution that obtains is used saturated NaHCO successively 3The aqueous solution, the saturated NaCl aqueous solution, 5%KHSO 4The aqueous solution, the saturated NaCl aqueous solution, saturated NaHCO 3The aqueous solution, the saturated NaCl aqueous solution are respectively given a baby a bath on the third day after its birth inferior.Ethyl acetate layer is used anhydrous Na 2SO 4Drying, filtration, filtrate decompression concentrate 5.68g (90%) title compound, be colorless solid
Embodiment 5 preparation N-[(3S)-and N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-Serine glycol (4)
With 5 dissolvings of 0.378g (1mmol) compound, ice bath adds 0.152g (4mmol) NaBH following minute three times with THF 4, behind the reaction 12h, TLC (CHCl 3/ CH 3OH, 10: 1) show that raw material disappears.With the HCl aqueous solution adjust pH 5-6 of 2N, concentrating under reduced pressure is removed THF under the ice bath vigorous stirring, and residue is used EtOAc/H 2O dissolving, separatory, water layer are used the EtOAc extracted twice, and the ester layer is with 5% KHSO 4The aqueous solution, the saturated NaCl aqueous solution are respectively given a baby a bath on the third day after its birth inferior, and the ester layer is used anhydrous Na 2SO 4Drying, filtration, filtrate decompression concentrate 0.210g (60%) title compound, be colorless solid [α] D 25=-8.67 (c 0.65CH 2Cl 2/ CH 31: 1 V/V of OH); ESI-MS (m/z): 351 [M+H] +
Embodiment 6 preparation N-[(3S)-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-Serine glycol (5)
With a small amount of anhydrous THF dissolving of 0.210g (0.6mmol) compound 4 usefulness, ice bath drips 2ml 4N HCl/THF solution down, stirring reaction, and behind about 2h, TLC (CHCl 3/ CH 3OH, 10: 1) show that raw material disappears, in reaction solution, pour a large amount of ether into, there is colorless solid to separate out, leave standstill, inclining supernatant, and solid adds diethyl ether and takes out three times, gets oily matter, directly is used for step reaction down.ESI-MS(m/z):251[M+H] +
Embodiment 7 preparation 5-[(3S)-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyls-1,3-dioxane (6)
In 0.287g (1mmol) compound 5, add the 2ml acetonitrile and suspend, add 0.302g (2mmol) paranitrobenzaldehyde, ice bath stirs down, slowly drips 0.25ml BF 3Et 2O, reaction solution becomes clarification, and along with reaction, reaction solution becomes the jelly shape.TLC (CHCl 3/ CH 3OH, 10: 1) monitoring, initial point does not have colour developing, filters, and filter cake is washed till white with EtOAc, and filter cake is transferred in the 100ml eggplant bottle, adds saturated NaHCO 3The aqueous solution, adjust pH to 8 stirs half a hour, filters, and gets title compound, colorless solid 0.214g (56%); Mp:217-217.4 ℃; [α] D 25=-53.23; (c 0.65 CH 2Cl 2/ CH 31: 1 V/V of OH); ESI-MS (m/z): 384.2 [M+H] +
Embodiment 8 preparation 5-[(3S)-and N-Fmoc-Val-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (7a)
Ice bath dissolves 0.289g (0.85mmol) Fmoc-Val with anhydrous THF down; Add 0.1g (0.74mmol) N-hydroxy benzo triazole (HOBt); The dissolving back adds 0.175g (0.85mmol) dicyclohexyl carbonyl diimine (DCC) and obtains reaction solution (I); Be suspended in 0.272g (0.71mmol) compound 6 in the dry DMF, add N-methylmorpholine (NMM) and transfer pH value 8~9, get reaction solution (II).Add in (II) stirring at room 24h, TLC (CH to (I) 2Cl 2/ CH 3OH, 20: 1) show that compound 8 disappears.Leach NSC 30023 (DCU), filtrating dries up, and residue is used the 10ml acetic acid ethyl dissolution.Filter, the solution that obtains is used 5%NaHCO successively 3The aqueous solution, the saturated NaCl aqueous solution, it is inferior respectively to give a baby a bath on the third day after its birth.Ethyl acetate layer is used anhydrous Na 2SO 4Drying, filtration, filtrate decompression concentrate, through silica gel column chromatography obtain 0.3g (60%) title compound (CH 2Cl 2: CH 3OH=20: 1, Rf=0.26), be colorless solid; Mp:108.2-109.6 ℃; [α] D 25=-67.33 (C 0.65; CH 2Cl 2/ CH 31: 1 V/V of OH); ESI-MS (m/z): 727.3 [M+Na] +
Embodiment 9 preparation 5-[(3S)-and N-Fmoc-Leu-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (7b)
According to the operation of preparation 7a, get 0.312g (43%) title compound, (CH from 0.414g (1.23mmol) Fmoc-Leu and 0.392g (1.02mmol) compound 6 2Cl 2: CH 3OH=20: 1, Rf=0.25), colorless solid.Mp:118.2-120.0℃[α] D 25=-63.88(C?0.55?CH 2Cl 2/CH 3OH?1∶1?V/V);ESI-MS(m/z):719.2[M+H] +
Embodiment 10 preparation 5-[(3S)-and N-Fmoc-Ile-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (7c)
According to the operation of preparation 7a, 0.221g (0.63mmol) Fmoc-Ile and 0.2g (0.52mmol) compound 6 get 0.242g (65%) title compound, (CH 2Cl 2: CH 3OH=20: 1, Rf=0.25), colorless solid.Mp:101.9-102.5°C;[α] D 25=-56.10(C?0.7?CH 2Cl 2/CH 3O?1∶1?V/V);ESI-MS(m/z)719.2[M+H] +
Embodiment 11 preparation 5-[(3S)-and N-Fmoc-Gly-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl 1,3-dioxane (7d)
According to the operation of preparation 7a, 0.279g (0.94mmol) Fmoc-Gly and 0.3g (0.78mmol) compound 6 get 0.3g (58%) title compound, (CH 2Cl 2: CH 3OH=20: 1, Rf=0.20), colorless solid.Mp:128.3-128.9℃[α] D 25=-64.67(C?0.2?CH 2Cl 2/CH 3OH?1∶1?V/V);ESI-MS(m/z):663.2[M+H] +,685.2[M+Na] +
Embodiment 12 preparation 5-[(3S)-and N-Fmoc-Ala-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (7e)
According to the operation of preparation 7a, 0.298g (0.95mmol) Fmoc-Ala-OH and 0.306g (0.80mmol) compound 6 get 0.3g (55%) title compound, (CH 2Cl 2: CH 3OH=20: 1, Rf=0.26), colorless solid; Mp169.9-171.8 ℃ [α] D 25=-52.53 (C 0.5 CH 2Cl 2/ CH 31: 1 V/V of OH); ESI-MS (m/z): 699 [M+Na] +
Embodiment 13 preparation 5-[(3S)-and N-Fmoc-Trp-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl 1,3-dioxane (7f)
According to the operation of preparation 7a, 0.511g (1.20mol) Fmoc-Trp and 0.383g (1mmol) compound 6 get 0.352g (45%) title compound, (CH 2Cl 2: CH 3OH=20: 1, Rf=0.22), yellow solid.Mp:129.4-130.5℃[α] D 25=-16.29(C?0.8?CH 2Cl 2/CH 3OH?1∶1?V/V);ESI-MS(m/z):792[M+H] +;814.5[M+Na] +
Embodiment 14 preparation 5-[(3S)-and N-Fmoc-Thr-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (7g)
According to the operation of preparation 7a, 0.260g (0.76mmol) Fmoc-Thr and 0.244g (0.63mmol) compound 6 get 0.204g (46%) title compound, (CH 2Cl 2: CH 3OH=20: 1, Rf=0.18), colorless solid.Mp:98.5-100.1℃;[α] D 25=-40.85(C?0.9CH 2Cl 2/CH 3OH?1∶1?V/V);ESI-MS(m/z):729.5[M+Na] +
Embodiment 15 preparation 5-[(3S)-and N-Fmoc-Met-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (7h)
According to the operation of preparation 7a, 0.387g (1.04mmol) Fmoc-Met and 0.333g (0.87mmol) compound 6 get 0.278g (43%) title compound, (CH 2Cl 2: CH 3OH=20: 1, Rf=0.23), colorless solid.Mp:195.2-196.2℃;[α] D 25=-59.95(C?0.7?CH 2Cl 2/CH 3OH?1∶1?V/V);ESI-MS(m/z):759.6[M+Na] +
Embodiment 16 preparation 5-[(3S)-and N-Fmoc-Asp (OBzl)-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (7i)
According to the operation of preparation 7a, 0.62g (1.39mmol) Fmoc-Asp (OBzl) and 0.445g (1.16mmol) compound 6 get 0.48g (51%) title compound, (CH 2Cl 2: CH 3OH=20: 1, Rf=0.25), colorless solid.Mp:102.4-103.8℃;[α] D 25=-20.88(C?0.9?CH 2Cl 2/CH 3OH?1∶1?V/V);ESI-MS(m/z):833.8[M+Na] +
Embodiment 17 preparation 5-[(3S)-and N-Fmoc-Pro-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (7j)
According to the operation of preparation 7a, 0.351g (1.04mmol) Fmoc-Pro and 0.333g (0.87mmol) compound 6 get 0.353g (58%) title compound, (CH 2Cl 2: CH 3OH=20: 1, Rf=0.21), colorless solid.Mp:116.7-118.4℃;[α] D 25=-55.70(C?1?CH 2Cl 2/CH 3OH?1∶1?V/V);ESI-MS(m/z):725.5[M+H] +
Embodiment 18 preparation 5-[(3S)-and N-Fmoc-Phe-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl 1,3-dioxane (7k)
According to the operation of preparation 7a, 0.403g (1.04mmol) Fmoc-Phe and 0.333g (0.87mmol) compound 6 get 0.340g (52%) title compound, (CH 2Cl 2: CH 3OH=20: 1, Rf=0.24), colorless solid.Mp:186-186.8℃;[α] D 25=-51.68(C?1.05?CH 2Cl 2/CH 3OH?1∶1?V/V);ESI-MS(m/z):775.4[M+23] +
Embodiment 19 preparation 5-[(3S)-N-(Fmoc) 2-Lys-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (7l)
According to the operation of preparation 7a, 0.708g (1.20mmol) (Fmoc) 2-Lys and 0.383g (1.00mmol) compound 6 gets 0.45g (47%) title compound, (CH 2Cl 2: CH 3OH=20: 1, Rf=0.26), colorless solid.Mp:107.8-108.9℃;[α] D 25=-33.76(C?0.7?CH 2Cl 2/CH 3OH?1∶1?V/V);ESI-MS(m/z):978.4[M+23] +
Embodiment 20 preparation 5-[(3S)-and N-Fmoc-Tyr-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (7m)
According to the operation of preparation 7b, 0.241g (0.6mmol) Fmoc-Tyr and 0.191g (0.5mmol) compound 6 get 0.17g (44%) title compound, (CH 2Cl 2: CH 3OH=20: 1, Rf=0.26), colorless solid.Mp:128.3-130.2℃;[α] D 25=-43.71(C?0.35?CH2Cl2/CH3OH?1∶1?V/V);ESI-MS(m/z):791.5[M+Na] +
Embodiment 21 preparation 5-[(3S)-and N-Val-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8a)
0.25g 7a is used a small amount of CH 2Cl 2Dissolving.Drip the NaOH/CH of 0.25N 3OH solution, pH value about 11, ice bath is reaction 6h down, and the TLC detection reaction is complete, (CH 2Cl 2: CH 3OH=20: 1), be evaporated to driedly, solid is worn away three times with ether, again with a small amount of washing, title compound 0.12g (71%); Mp:89.2-91.0 ℃; [α] D 25=-21.24 (C 0.75 CH 2Cl 2/ CH 31: 1 V/V of OH); ESI-MS (m/z): 483 [M+H] +
Embodiment 22 preparation 5-[(3S)-and N-Leu-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl 1,3-dioxane (8b)
Operation according to preparation 8a gets 0.172g (83%) title compound (colorless solid) from 0.300g (0.41mmol) 7b.Mp:100.8-101.6℃;[α] D 25=-47.00(C?0.8CH 2Cl 2/CH 3OH?1∶1?V/V);ESI-MS(m/z)497.5[M+H] +
Embodiment 23 preparation 5-[(3S)-and N-Ile-1,2,3,4 ,-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8c)
Operation according to preparation 8a gets 0.120g (87%) title compound (colorless solid) from 0.200g (0.27mmol) 7c.Mp:101.1-103.1℃;[α] D 25=-43.92(C?0.65CH 2Cl 2/CH 3OH?1∶1?V/V);ESI-MS(m/z):497.3[M+H] +
Embodiment 24 preparation 5-[(3S)-and N-Gly-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8d)
Operation according to preparation 8a gets 0.151g (91%) title compound (colorless solid) from 0.250g (0.38mmol) 7d.Mp:126.9-129.0℃[α] D 25=-18.2(C?0.5CH 2Cl 2/CH 3OH?1∶1?V/V);ESI-MS(m/z):441.3[M+H] +;463.3[M+Na] +
Embodiment 25 preparation 5-[(3S)-and N-Ala-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8e)
Operation according to preparation 8a gets 0.156g (90%) title compound (colorless solid) from 0.260g (0.38mmol) 7e.Mp:87.5-89.2℃;[α] D 25=-45.94(C?0.55?CH 2Cl 2/CH 3OH?1∶1?V/V);ESI-MS(m/z):455.4[M+H] +
Embodiment 26 preparation 5-[(3S)-and N-Trp-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8f)
Operation according to preparation 8a gets 0.152g (79%) title compound (colorless solid) from 0.300g (0.38mmol) 7f.Mp:128.5-130.2℃;[α] D 25=8.48(C?0.9?CH 2Cl 2/CH 3OH?1∶1?V/V);ESI-MS(m/z):570.4[M+H] +
Embodiment 27 preparation 5-[(3S)-and N-Thr-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8g)
Operation according to preparation 8a gets 0.08g (78%) title compound (colorless solid) from 0.150g (0.21mmol) 7g.Mp:142-144℃;[α] D 25=-42.57(C?0.8?CH 2Cl 2/CH 3OH?1∶1?V/V);ESI-MS(m/z):485.2[M+H] +
Embodiment 28 preparation 5-[(3S)-and N-Met-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8h)
Operation according to preparation 8a gets 0.124g (81%) title compound (colorless solid) from 0.220g (0.30mmol) 7h.Mp:111.8-113.2℃;[α] D 25=-42.00(C?0.5?CH 2Cl 2/CH 3OH?1∶1?V/V);ESI-MS?m/z):515.3[M+H] +
Embodiment 29 preparation 5-[(3S)-and N-Asp-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8i)
According to the NaOH/CH of the operation for preparing 8a with 0.5N 3OH suspension solution adjust pH 12, after reacting completely, under the vigorous stirring, the KHSO with 5% 4The slow adjust pH 5-6 of solution revolves CH 2Cl 2/ CH 3OH, residue adds less water, CH 2Cl 2Extract anhydrous Na three times 2SO 4Drying is filtered, and revolves driedly, and ether is given a baby a bath on the third day after its birth time, gets 0.170g (70%) title compound (faint yellow solid) from 0.400g (0.49mmol) 7i.Mp:90.0-91.6℃[α] D 25=-80.87(C0.5?CH 2Cl 2/CH 3OH?1∶1?V/V);ESI-MS(m/z):513.4[M+15] +
Embodiment 30 preparation 5-[(3S)-and N-Pro-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8j)
Operation according to preparation 8a gets 0.177g (90%) title compound (colorless solid) from 0.290g (0.41mmol) 7j.Mp:188.1-189.0℃;[α] D 25=-73.33(C?0.6?CH 2Cl 2/CH 3OH?1∶1?V/V);ESI-MS(m/z):481.4[M+H] +
Embodiment 31 preparation 5-[(3S)-and N-Phe-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8k)
Operation according to preparation 8a gets 0.162g (92%) title compound (colorless solid) from 0.250g (0.33mmol) 7k.Mp:154.0-155.8℃;[α] D 25=-16.12(C?0.55?CH 2Cl 2/CH 3OH?1∶1?V/V)ESI-MS(m/z):531.6[M+H] +;553.6[M+Na] +
Embodiment 32 preparation 5-[(3S) N-Lys-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyls-1,3-dioxane (8l)
Operation according to preparation 8a gets 0.190g (90%) title compound (colorless solid) from 0.400g (0.42mmol) 7l; Mp:129.3-131.1 ℃; [α] D 25=-45.47 (C 0.65 CH 2Cl 2/ CH 31: 1 V/V of OH); ESI-MS (m/z): 512.3 [M+H] +
Embodiment 33 preparation 5-[(3S)-and N-Tyr-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8m)
Operation according to preparation 8a gets 0.079g (74%) title compound (colorless solid) from 0.150g (0.20mmol) 7m.Mp:110.9-112.3℃;[α] D 25=-39.65(C?0.7?CH 2Cl 2/CH 3OH?1∶1?V/V);ESI-MS(m/z):547.3[M+H] +
Antithrombotic acitivity test in the body of Test Example 1 The compounds of this invention
1) test materials
Test-compound: the compound that the embodiment of the invention is prepared is numbered 6 respectively, 8a-m;
Positive reference substance is a Frosst)
Laboratory animal: the Wistar rat, male, body weight 180-220; Provide by animal portion of the Capital University of Medical Sciences.
Solvent: saline water
Polyethylene tube (two kinds of external diameter 1.6mm and 1.3mm), heparin (50IU/ml), Ethylurethanm, silk thread.
2) TP
1. dosage setting
Test-compound 6,8a-m are 10nmol/kg, all adopt the vein single administration.Frosst) is 20mg/Kg.
2. medicine preparation
Test-compound 6,8a-m and Frosst) are all used physiological saline solution
3. measuring method
Male SD rat (anaesthetize, and isolates RCCA and left external jugular vein, puts into the long silk thread of 6cm of weighing in advance in the stage casing of polyethylene tube by body weight 180~220g) abdominal injection Sodital sodium solutions; (50IU/kg) is full of polyethylene tube with heparin-saline, and an end is inserted left external jugular vein, with syringe with heparin (3ml/kg); Physiological salt soln (the 40mg/10ml of Frosst); 3ml/Kg), 6,8a-m (10nmol/kg; Physiological salt soln 3ml/kg) slowly injects polyethylene tube from the other end; Original heparin has been pushed in the left external jugular vein in managing this moment, and major part is a test compound solution in the pipe, then the injectable drug end is inserted RCCA.Blood flows to left external jugular vein from RCCA through polyethylene tube, and middle Herba Clinopodii behind the 15min takes out silk thread and weighs, and gross weight deducts silk thread weight and is wet weight of thrombus
4. statistical method
This experimental data statistics all adopts t check and variance analysis, with (x ± SD) expression.
5. test-results
The influence that table 18a-n forms rat suppository
Figure G2009100851559D00111
N=10 a) compares p<0.01 with saline water; B) compare p<0.05 with saline water
Can find out that from table 1 The compounds of this invention 6,8a-m are compared the difference with significance with saline water under 10nmol/kg dosage, be outstanding pharmaceutical preparations having antithrombotic activity.

Claims (6)

1. have 1 of antithrombotic acitivity, 3-dioxanes compounds, its structural formula are shown in the general formula I:
Figure FSB00000774390400011
general formula I
Wherein, R is selected from the group that forms behind the hydroxyl on the amino acid decarboxylize that hydrogen or R be selected from Val, Leu, Ile, Gly, Ala, Trp, Thr, Met, Asp, Pro, Phe, Lys or Tyr representative;
Described have 1 of an antithrombotic acitivity, and in the 3-dioxanes compounds, the carbon atom that * indicated is the S configuration.
2. a synthetic claim 1 is described 1, and the method for 3-dioxanes compounds may further comprise the steps:
(1) preparation N-[(3S)-N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-Serine glycol; (2) preparation N-[(3S)-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-Serine glycol; (3), generate 5-[(3S)-1,2,3,4-tetrahydroisoquinoline-3-formamido group]-2-p-nitrophenyl-1, the 3-dioxane with N-[(3S)-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-Serine two pure and mild paranitrobenzaldehyde condensations; (4) with 5-[(3S)-1,2,3,4-tetrahydroisoquinoline-3-formamido group]-2-p-nitrophenyl-1,3-dioxane and Fmoc-AA condensation prepared generate
5-[(3S)-and N-Fmoc-R-1,2,3,4-tetrahydroisoquinoline-3-formamido group]-2-p-nitrophenyl-1, the 3-dioxane; (5) 5-[(3S)-N-Fmoc-R-1,2,3,4-tetrahydroisoquinoline-3-formamido group]-2-p-nitrophenyl-1,3-dioxane alkaline hydrolysis promptly gets; Wherein, R such as claim 1 definition, AA is selected from hydrogen, or Fmoc-AA representative is with the amino acid AA of Fmoc protection, AA is selected from Val, Leu, Ile, Gly, Ala, Trp, Thr, Met, Asp, Pro, Phe, Lys or Tyr.
3. according to the described method of claim 2, it is characterized in that described N-[(3S)-N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-Serine glycol prepares according to following method:
(1) at SOCl 2Existence changes the L-Serine into the L-serine methylester down with methyl alcohol; (2) in the presence of dense HCl and water, change the L-phenylalanine(Phe) into (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; (3) at (Boc) 2With (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid changed (3S)-N-Boc-1 under O and NaOH existed, and 2,3,4-tetrahydroisoquinoline-3-carboxylic acid; (4) L-serine methylester and (3S)-N-Boc-1 in the presence of DCC, HOBt, 2,3,4-tetrahydroisoquinoline-3-carboxylic acid condensation generates N-[(3S)-N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-serine methylester; (5) at NaBH 4Exist down N-[(3S)-N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-serine methylester reduction with THF, generate N-[(3S)-N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-Serine glycol; (6) in the presence of hydrogenchloride-THF with N-[(3S)-N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-Serine glycol acidolysis, generate N-[(3S)-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-Serine glycol.
4. pharmaceutical composition is characterized in that: it is described 1 to go up the claim 1 of significant quantity by treatment or prevention, and 3-dioxanes compounds and pharmaceutically acceptable carrier are formed.
5. pharmaceutical composition is characterized in that: it is described 1 to go up the claim 1 of significant quantity by treatment or prevention, and 3-dioxanes compounds and acceptable accessories are formed.
6. claim 1 is described 1, the application of 3-dioxanes compounds in the preparation pharmaceutical preparations having antithrombotic activity.
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