CN108164419A - The preparation and application of the propofol prodrugs of monodisperse poly glycol monomethyl ether modification - Google Patents
The preparation and application of the propofol prodrugs of monodisperse poly glycol monomethyl ether modification Download PDFInfo
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- C07C69/96—Esters of carbonic or haloformic acids
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- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
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Abstract
The invention discloses the preparation and application of propofol prodrugs that a kind of monodisperse poly glycol monomethyl ether of structure novel is modified, and belong to organic chemistry and field of medicine and chemical technology.Monodisperse poly glycol monomethyl ether and Propofol by can the chemical bond of degradation in vivo be connected a series of prepare carbonates and acetic acid ester type respectively propofol prodrugs.This method by adjusting monodisperse poly glycol monomethyl ether chain length, corresponding water-soluble propofol prodrugs can be synthesized, monodisperse poly glycol monomethyl ether chain is longer, it is water-soluble better, water-soluble raising can be prepared into the preparation of aqueous solution, the defects of evading Fat Emulsion in propofol fat emulsion.The method of the present invention reaction is simple, mild condition, cost are relatively low, convenient for industrialized production.
Description
Technical field
The invention belongs to organic chemical synthesis and field of medicine and chemical technology, and in particular to a kind of poly- second of the monodisperse of structure novel
The preparation and application of the propofol prodrugs of glycol monomethyl ether modification.
Background technology
Propofol (2,6-Bis(1-methylethyl)phenol) is a kind of induced by alkyl hydroxybenzene intravenous injection GENERAL ANESTHETICS, has been widely accepted
As short-acting intravenous anesthetics, propofol intravenous anesthesia has that rapid-action, action time is short, and patient is without side effects such as cough, hiccups
The advantages of, in addition to as advantages a variety of possessed by anesthetic, Propofol also has other a series of valuable applications, it was reported that
It also has antiemetic, antianxiety, neuroprotection, antipruritic, analgesic, inhibits platelet aggregation, the generation for inhibiting induction type NO and other effects,
But it is practically insoluble in water, Propofol is clinically prepared into oil-in-water fatty oil emu, but should with the fat-soluble of height
The shortcomings that preparation is that the shelf-life is shorter, and sensitive to bacterium and fungal contamination, can cause injection pain, and lipid components can add
Low blood pressure and instantaneous apnea caused by weight Propofol, long-time service may lead to hyperlipidemia etc., these features very great Cheng
Its clinical practice is limited on degree.
Invention content
In view of the foregoing, the purpose of the present invention is to provide a kind of novel water-soluble propofol prodrugs, it is reduced
Side effect in clinical practice.
Technical scheme of the present invention can be realized by following technical measures：
A kind of propofol prodrugs of monodisperse poly glycol monomethyl ether modification, structure is as shown in general structure I：
Wherein Y is-OCO-or-OCCH2—。
In the general formula I, Y is-OCO-when the synthetic methods of propofol prodrugs include the following steps：
(1) make monodisperse poly glycol monomethyl ether and N, N'- carbonyl dimidazoles that monodisperse polyethyleneglycol first be obtained by the reaction
Ether carbonylic imidazole derivative；
(2) Propofol, alkali, solvent are added in into obtained monodisperse poly glycol monomethyl ether carbonylic imidazole derivative,
The propofol prodrugs of the carbonate shown in Formula II are obtained by the reaction under the conditions of 60 DEG C：
Preferably, the alkali includes 4-dimethylaminopyridine, pyridine, triethylamine, n,N-diisopropylethylamine, carbonic acid
Sodium, potassium carbonate.
Preferably, the solvent includes n,N-Dimethylformamide, dimethyl sulfoxide (DMSO), n,N-Dimethylaniline, dichloro
Methane, tetrahydrofuran.
In the general formula I, Y is-OCCH2- when the synthetic methods of propofol prodrugs include the following steps：
(1) monodisperse poly glycol monomethyl ether acetic acid is obtained by the reaction with bromo-acetic acid tert-butyl in monodisperse poly glycol monomethyl ether
Tert-butyl ester derivative；
(2) the monodisperse poly glycol monomethyl ether tert-butyl acetate derivative of gained with trifluoroacetic acid is reacted, sloughs uncle
Butyl obtains corresponding acid；
(3) acid obtained reacts to obtain the acetic acid esters shown in formula III under the action of alkali and condensing agent with Propofol
The propofol prodrugs of type：
Preferably, the alkali for 4-dimethylaminopyridine, pyridine, triethylamine, n,N-diisopropylethylamine, sodium carbonate,
Potassium carbonate.
Preferably, the solvent is dichloromethane, tetrahydrofuran, dichloroethanes, n,N-Dimethylformamide, dimethyl
Sulfoxide, N, accelerine.
Preferably, the condensing agent includes dicyclohexylcarbodiimide, diisopropylcarbodiimide, (1- (3- diformazan ammonia
Base propyl) -3- ethyl carbodiimides, N, N, N ', N '-tetramethyl chloromethane amidine hexafluorophosphate.
Preferably, the monodisperse poly glycol monomethyl ether discloses the technical side of implementation according to CN201310710498.6
Case carries out.
Above-mentioned propofol prodrugs are generating tranquilizing soporific and/or anesthesia as through approach outside vein or vein to animal or people
Application in the CNS inhibition drug of effect.
Description of the drawings
Using attached drawing, the invention will be further described, but the embodiment in attached drawing does not form any limit to the present invention
System.
Fig. 1 is that Propofol influences the cell survival rate of A549 cells with compound 1a-1f and 2a-2f obtained by embodiment
Measurement result；
Fig. 2 is that Propofol influences the cell survival rate of L929 cells with compound 1a-1f and 2a-2f obtained by embodiment
Measurement result.
Specific embodiment
To make the present invention easier to understand, specific embodiments of the present invention are further illustrated below.
The synthesis of 1 Formula II carbonate propofol prodrugs of embodiment
(1) synthesis (n=2) of compound 1a
Two poly glycol monomethyl ether carbonylic imidazole derivatives (1.17g, 5.46mmol) are dissolved in N,N-dimethylformamide
In (50mL) solution, addition Propofol (1.95g, 10.92mmol) and 4-dimethylaminopyridine (0.14g, 1.10mmol), 60 DEG C
After reaction, n,N-Dimethylformamide solution is evaporated off in lower reaction 48h, column chromatography purify to obtain compound 1a (1.42g,
80%).1H NMR(400MHz,CDCl3)δ7.25-7.12(m,3H),4.51-4.35(m,2H),3.85-3.75(m,2H),
3.70-3.68 (m, 2H), 3.59-3.57 (m, 2H), 3.41 (s, 3H), 3.09-2.98 (m, 2H), 1.21 (d, J=6.9Hz,
12H).13C NMR(100MHz,CDCl3)δ153.9,145.7,140.5,126.8,124.1,71.9,70.6,69.0,67.7,
59.1,27.3,23.3.HRMS(ESI)calcd for C18H28NaO5 +([M+Na]+),347.1829；found,347.1833.
(2) synthesis (n=3) of compound 1b
Three poly glycol monomethyl ether carbonylic imidazole derivatives (1.15g, 5.45mmol) are dissolved in N,N-dimethylformamide
In (50mL) solution, addition Propofol (3.17g, 17.81mmol) and 4-dimethylaminopyridine (0.27g, 2.23mmol), 60 DEG C
After reaction, n,N-Dimethylformamide solution is evaporated off in lower reaction 48h, column chromatography purify to obtain compound 1b (1.36g,
83%).1H NMR(400MHz,CDCl3)δ7.25-7.13(m,3H),4.48-4.32(m,2H),3.83-3.78(m,2H),
3.73-3.64 (m, 6H), 3.59-3.54 (m, 2H), 3.39 (s, 3H), 3.09-2.98 (m, 2H), 1.21 (d, J=6.9Hz,
12H).13C NMR(100MHz,CDCl3)δ153.9,145.7,140.5,126.8,124.1,71.9,70.8-70.5(m),
68.9,67.7,59.0,27.2,23.3.HRMS(ESI)calcd for C20H32NaO6+([M+Na]+),391.2091；
found,391.2084.HRMS(ESI)calcd for C20H32NaO6+([M+Na]+),391.2091；found,391.2084.
(3) synthesis (n=4) of compound 1c
Four poly glycol monomethyl ether carbonylic imidazole derivatives (0.42g, 1.38mmol) are dissolved in N,N-dimethylformamide
In (50mL) solution, addition Propofol (0.99g, 5.54mmol) and 4-dimethylaminopyridine (0.08g, 0.69mmol), 60 DEG C
After reaction, n,N-Dimethylformamide solution is evaporated off in lower reaction 48h, column chromatography purify to obtain compound 1c (0.40g,
70%).1H NMR(400MHz,CDCl3)δ7.25-7.12(m,3H),4.44-4.39(m,2H),3.83-3.75(m,2H),
3.72-3.64 (m, 10H), 3.59-3.52 (m, 2H), 3.38 (s, 3H), 3.09-2.98 (m, 2H), 1.21 (d, J=6.9Hz,
12H).13C NMR(100MHz,CDCl3)δ153.9,145.7,140.5,126.8,124.1,71.9,70.8-70.3(m),
68.9,67.7,59.0,27.3,23.3.HRMS(ESI)calcd for C22H36NaO7 +([M+Na]+),435.2353；
found,435.2347。
(4) synthesis (n=6) of compound 1d
Six poly glycol monomethyl ether carbonylic imidazole derivatives (1.70g, 4.35mmol) are dissolved in N,N-dimethylformamide
In (50mL) solution, addition Propofol (1.55g, 8.70mmol) and 4-dimethylaminopyridine (0.11g, 0.87mmol), 60 DEG C
After reaction, n,N-Dimethylformamide solution is evaporated off in lower reaction 48h, column chromatography purify to obtain compound 1d (1.47g,
68%).1H NMR(400MHz,CDCl3)δ7.25-7.10(m,3H),4.47-4.38(m,2H),3.82-3.78(m,2H),
3.72-3.62 (m, 18H), 3.57-3.53 (m, 2H), 3.38 (s, 3H), 3.09-2.98 (m, 2H), 1.21 (d, J=6.9Hz,
12H).13C NMR(100MHz,CDCl3)δ153.9,145.7,140.4,126.8,124.1,71.9,70.8-70.4(m),
68.9,67.7,59.0,27.2,23.3.HRMS(ESI)calcd for C26H44NaO9 +([M+Na]+),523.2878；
found,523.2885。
(5) synthesis (n=7) of compound 1e
Seven poly glycol monomethyl ether carbonylic imidazole derivatives (2.05g, 4.72mmol) are dissolved in N,N-dimethylformamide
In (50mL) solution, addition Propofol (3.36g, 18.88mmol) and 4-dimethylaminopyridine (0.28g, 2.36mmol), 60 DEG C
After reaction, n,N-Dimethylformamide solution is evaporated off in lower reaction 48h, column chromatography purify to obtain compound 1e (1.89g,
74%).1H NMR(400MHz,CDCl3)δ7.26-7.12(m,3H),4.47-4.35(m,2H),3.83-3.78(m,2H),
3.73-3.63 (m, 22H), 3.58-3.51 (m, 2H), 3.38 (s, 3H), 3.09-2.98 (m, 2H), 1.22 (d, J=6.9Hz
12H).13C NMR(100MHz,CDCl3)δ153.9,145.7,140.4,126.8,124.1,71.9,70.8-70.3(m),
68.9,67.7,59.0,27.2,23.3.HRMS(ESI)calcd for C28H52NO10 +([M+NH4]+),562.3586；
found,562.3582。
(6) synthesis (n=10) of compound 1f
Ten poly glycol monomethyl ether carbonylic imidazole derivatives (2.22g, 3.91mmol) are dissolved in N,N-dimethylformamide
In (50mL) solution, addition Propofol (1.39g, 7.82mmol) and 4-dimethylaminopyridine (0.14g, 1.10mmol), 60 DEG C
After reaction, n,N-Dimethylformamide solution is evaporated off in lower reaction 48h, column chromatography purify to obtain compound 1f (2.01g,
74%).1H NMR(400MHz,CDCl3)δ7.26-7.12(m,3H),4.49-4.35(m,2H),3.83-3.77(m,2H),
3.72-3.63 (m, 34H), 3.58-3.52 (m, 2H), 3.38 (s, 3H), 3.09-2.98 (m, 2H), 1.21 (d, J=6.9Hz,
12H).13C NMR(100MHz,CDCl3)δ153.8,145.7,140.4,126.8,124.0,71.9,70.8-70.2(m),
68.9,67.7,59.0,27.2,23.3.HRMS(ESI)calcd for C34H64NO13 +([M+NH4]+),694.4372；
found,694.4368。
The synthesis of 2 formula III acetic acid ester type propofol prodrugs of embodiment
(1) synthesis (n=2) of compound 2a
Two poly glycol monomethyl ether tert-butyl acetate derivatives (1.80g, 7.68mmol) are dissolved in dichloromethane (30mL),
Trifluoroacetic acid (14.2mL, 192.00mmol) and methyl phenyl ethers anisole (0.96ml, 8.83mmol) are added in, drains, obtains after 5h is stirred at room temperature
To corresponding acid.Under nitrogen protection, the acid and the dichloro of 4-dimethylaminopyridine (0.47g, 3.84mmol) that obtain one step up
Dicyclohexylcarbodiimide (1.90g, 9.22mmol) is added in methane (50mL) solution, is stirred after ten minutes, Propofol
(2.05g, 11.52mmol), which is dissolved in dichloromethane (10mL), to be slowly added dropwise in reaction solution, restores to be stirred at room temperature after dripping
16h.After reaction, it filters, filtrate is washed twice with dilute hydrochloric acid, is spin-dried for organic phase, column chromatography purifies to obtain compound 2a
(1.47g, 57%).1H NMR(400MHz,CDCl3)δ7.25-7.15(m,3H),4.50(s,2H),3.88-3.83(m,2H),
3.78-3.73(m,2H),3.71-3.66(m,2H),3.60-3.55(m,2H),3.39(s,3H),2.94-2.82(m,2H),
1.19 (d, J=6.9Hz, 12H)13C NMR(100MHz,CDCl3)δ169.2,145.0,140.3,126.7,124.0,71.9,
71.1,70.7,70.6 68.4,59.1,27.6,23.3.HRMS(ESI)calcd for C19H30NaO5 +([M+Na]+),
361.1985；found,361.1981.
(2) synthesis (n=3) of compound 2b
Three poly glycol monomethyl ether tert-butyl acetate derivatives (1.30g, 4.67mmol) are dissolved in dichloromethane (30mL),
Trifluoroacetic acid (7.0mL, 93.40mmol) and methyl phenyl ethers anisole (0.6ml, 5.60mmol) are added in, is drained after 5h is stirred at room temperature, obtains phase
The acid answered.Under nitrogen protection, the acid and the dichloromethane of 4-dimethylaminopyridine (0.29g, 2.34mmol) that obtain one step up
Dicyclohexylcarbodiimide (1.90g, 9.22mmol) is added in (50mL) solution, is stirred after ten minutes, Propofol (1.15g,
It 5.60mmol) is dissolved in dichloromethane (10mL) and being slowly added dropwise in reaction solution, restore that 16h is stirred at room temperature after dripping.Reaction
After, it filters, filtrate is washed twice with dilute hydrochloric acid, is spin-dried for organic phase, column chromatography purifies to obtain compound 2b (1.10g, 62%)
。1H NMR(400MHz,CDCl3)δ7.25-7.15(m,3H),4.49(s,2H),3.87-3.82(m,2H),3.78-3.73(m,
2H), 3.73-3.64 (m, 6H), 3.58-3.54 (m, 2H), 3.38 (s, 3H), 2.94-2.83 (m, 2H), 1.19 (d, J=
6.9Hz,12H).13C NMR(100MHz,CDCl3)δ169.2,145.0,140.3,126.8,124.1,71.9,71.1,70.7-
70.4(m),68.4,59.1,27.6,23.3.HRMS(ESI)calcd for C21H34NaO6 +([M+Na]+),405.2248；
found,405.2243。
(3) synthesis (n=4) of compound 2c
Four poly glycol monomethyl ether tert-butyl acetate derivatives (1.50g, 4.65mmol) are dissolved in dichloromethane (30mL),
Trifluoroacetic acid (8.6mL, 116.32mmol) and methyl phenyl ethers anisole (0.6ml, 5.58mmol) are added in, drains, obtains after 5h is stirred at room temperature
Corresponding acid.Under nitrogen protection, the acid and the dichloromethane of 4-dimethylaminopyridine (0.28g, 2.33mmol) that obtain one step up
Dicyclohexylcarbodiimide (1.15g, 5.58mmol) is added in alkane (50mL) solution, is stirred after ten minutes, Propofol (1.24g,
It 6.98mmol) is dissolved in dichloromethane (10mL) and being slowly added dropwise in reaction solution, restore that 16h is stirred at room temperature after dripping.Reaction
After, it filters, filtrate is washed twice with dilute hydrochloric acid, is spin-dried for organic phase, column chromatography purifies to obtain compound 2c (0.87g, 44%)
。1H NMR(400MHz,CDCl3)δ7.26-7.13(m,3H),4.49(s,2H),3.86-3.81(m,2H),3.78-3.73(m,
2H), 3.70-3.63 (m, 10H), 3.57-3.52 (m, 2H), 3.38 (s, 3H), 2.98-2.74 (m, 2H), 1.19 (d, J=
6.9Hz,12H).13C NMR(100MHz,CDCl3)δ169.2,145.0,140.3,126.8,124.0,71.9,71.1,70.8-
70.4(m),68.4,59.1,27.6,23.5.HRMS(ESI)calcd for C23H38NaO7 +([M+Na]+),449.2510；
found,449.2500。
(4) synthesis (n=6) of compound 2d
Six poly glycol monomethyl ether tert-butyl acetate derivatives (1.04g, 2.44mmol) are dissolved in dichloromethane (30mL),
Trifluoroacetic acid (4.5mL, 112.50mmol) and methyl phenyl ethers anisole (0.3ml, 5.40mmol) are added in, drains, obtains after 5h is stirred at room temperature
Corresponding acid.Under nitrogen protection, the acid and the dichloromethane of 4-dimethylaminopyridine (0.15g, 1.22mmol) that obtain one step up
Dicyclohexylcarbodiimide (0.60g, 2.92mmol) is added in alkane (50mL) solution, is stirred after ten minutes, Propofol (0.65g,
It 3.65mmol) is dissolved in dichloromethane (10mL) and being slowly added dropwise in reaction solution, restore that 16h is stirred at room temperature after dripping.Reaction
After, it filters, filtrate is washed twice with dilute hydrochloric acid, is spin-dried for organic phase, column chromatography purifies to obtain compound 2d (0.56g, 45%)
。1H NMR(400MHz,CDCl3)δ7.25-7.14(m,3H),4.49(s,2H),3.87-3.82(m,2H),3.77-3.73(m,
2H), 3.71-3.63 (m, 18H), 3.57-3.53 (m, 2H), 3.38 (s, 3H), 2.94-2.83 (m, 2H), 1.19 (d, J=
6.9Hz,12H).13C NMR(100MHz,CDCl3)δ169.2,145.0,140.3,126.8,124.0,71.9,71.1,70.8-
70.4(m),68.4,59.1,27.6,23.2.HRMS(ESI)calcd for C27H50NO9 +([M+NH4]+),532.3480；
found,532.3474。
(5) synthesis (n=7) of compound 2e
Seven poly glycol monomethyl ether tert-butyl acetate derivatives (1.64g, 3.61mmol) are dissolved in dichloromethane (30mL),
Trifluoroacetic acid (6.9mL, 90.00mmol) and methyl phenyl ethers anisole (0.5ml, 4.33mmol) are added in, is drained after 5h is stirred at room temperature, obtains phase
The acid answered.Under nitrogen protection, the acid and the dichloromethane of 4-dimethylaminopyridine (0.22g, 1.80mmol) that obtain one step up
Dicyclohexylcarbodiimide (0.90g, 4.33mmol) is added in (50mL) solution, is stirred after ten minutes, Propofol (0.97g,
It 5.41mmol) is dissolved in dichloromethane (10mL) and being slowly added dropwise in reaction solution, restore that 16h is stirred at room temperature after dripping.Reaction
After, it filters, filtrate is washed twice with dilute hydrochloric acid, is spin-dried for organic phase, column chromatography purifies to obtain compound 2e (1.20g, 60%)
。1H NMR(400MHz,CDCl3)δ7.25-7.15(m,3H),4.49(s,2H),3.86-3.82(m,2H),3.77-3.73(m,
2H), 3.72-3.61 (m, 22H), 3.57-3.53 (m, 2H), 3.38 (s, 3H), 2.93-2.83 (m, 2H), 1.19 (d, J=
6.9Hz,12H).13C NMR(100MHz,CDCl3)δ169.2,145.0,140.3,126.7,124.0,71.9,71.1,70.8-
70.3(m),68.4,59.0,27.6,23.3.HRMS(ESI)calcd for C29H54NO10 +([M+NH4]+),576.3742；
found,576.3737。
(6) synthesis (n=10) of compound 2f
Ten poly glycol monomethyl ether tert-butyl acetate derivatives (2.09g, 3.56mmol) are dissolved in dichloromethane (30mL),
Trifluoroacetic acid (7.3mL, 89.00mmol) and methyl phenyl ethers anisole (0.5ml, 4.27mmol) are added in, is drained after 5h is stirred at room temperature, obtains phase
The acid answered.Under nitrogen protection, the acid and the dichloromethane of 4-dimethylaminopyridine (0.22g, 1.78mmol) that obtain one step up
Dicyclohexylcarbodiimide (0.88g, 4.27mmol) is added in (50mL) solution, is stirred after ten minutes, Propofol (1.27g,
It 7.12mmol) is dissolved in dichloromethane (10mL) and being slowly added dropwise in reaction solution, restore that 16h is stirred at room temperature after dripping.Reaction
After, it filters, filtrate is washed twice with dilute hydrochloric acid, is spin-dried for organic phase, column chromatography purifies to obtain compound 2f (1.29g, 44%)
。1H NMR(400MHz,CDCl3)δ7.25-7.12(m,3H),4.49(s,2H),3.86-3.82(m,2H),3.76-3.72(m,
2H), 3.70-3.61 (m, 34H), 3.57-3.52 (m, 2H), 3.37 (s, 3H), 2.95-2.78 (m, 2H), 1.19 (d, J=
6.9Hz,12H).13C NMR(100MHz,CDCl3)δ169.2,145.0,140.3,126.7,124.0,71.9,71.1,70.8-
70.3(m),68.4,59.0,27.6,23.3.HRMS(ESI)calcd for C35H66NO13 +([M+NH4]+),708.4529；
found,708.4525。
3 solubility test of embodiment is tested
Using dissolvings of the determined by ultraviolet spectrophotometry compound 1a-1f and 2a-2f in PBS buffer solution (pH=7.4)
Degree.First, the solution of measure compound various concentration is ultraviolet absorptivity at 257nm in wavelength, draws standard curve, is returned
Return curvilinear equation, then prepare the saturated solution of compound, supernatant is taken to be diluted to a certain concentration after saturated solution is centrifuged, so
After measure it and locate absorbance value for 257nm in wavelength, bringing the value into calibration curve equation, to obtain compound saturation molten through converting
Concentration after liquid dilution, compound solubility in PBS buffer solution (pH=7.4) can be obtained multiplied by with extension rate.Dissolving
Spend measurement result it is as shown in table 1, the chain of monodisperse poly glycol monomethyl ether is longer, and the solubility of propofol prodrugs is better, when n >=
When 7, the rising of solubility drastically, compound 1f, 2e and 2f solubility does not measure the upper limit very well.
Solubility (unit mg/mL) of the 1 compound 1a-1f and 2a-2f of table in PBS buffer solution (pH=7.4)
4 cell survival rate of embodiment is tested
(1) preparation of solution
The preparation of DMEM high sugar culture solutions：Buy DMEM high glucose mediums, every bottle of 500mL, add in 10% fetal calf serum
With 1% Pen .- Strep solution, i.e. every bottle of culture medium add in 50mL fetal calf serum and 5mL Pen .- Strep it is molten
Liquid, the preparation of culture medium carry out in superclean bench, and the sugared culture solutions of DMEM high of preparation place 4 DEG C of preservations of refrigerator.
The preparation of PBS buffer solution：In 1000mL conical flasks, sodium chloride 8g, potassium chloride 0.2g, 12 hypophosphite monohydrates are weighed
Disodium hydrogen 2.9g, potassium dihydrogen phosphate 0.2g are added in after 800mL pure water is sufficiently stirred dissolving and are settled to 1000mL, high pressure sterilization
4 DEG C of preservations of refrigerator are placed afterwards.
The preparation of MTT solution：MTT dry powder 0.5g are weighed, are dissolved in 100mL PBS buffer solution, with 0.22 μM of membrane filtration
After degerming, -12 DEG C of preservations of refrigerator are placed.
(2) cell survival rate measures
Cell survival rate, which measures, selects Non-small cell lung carcinoma (A549) and l cell (L929)
A：Cell survival rate is measured using Non-small cell lung carcinoma (A549)
DMEM high sugared culture solution of the culture solution that A549 cells use for above-mentioned preparation, condition of culture is 37 DEG C, containing 5%
CO2Constant incubator.Specific steps：
1) it takes the logarithm the cell in growth period, is diluted 10 times with the sugared culture solutions of DMEM high.
2) the 200 diluted cell suspensions of μ L are added in each hole of 96 orifice plates, 37 DEG C of incubator incubates for 24 hours.
3) compound of being tested is diluted to 0.05mM, 100 μ L/ holes of dosing, incubator 37 with the sugared culture solutions of DMEM high
DEG C incubate for 24 hours.
4) MTT of 20 a concentration of 5mg/mL of μ L, 37 DEG C of incubation 4h of incubator are added in.
5) 200 μ L DMSO are added in by cell dissolution, microplate reader measures the OD values under 490nm.
6) data are handled, obtain cell survival rate.
B：Cell survival rate is measured using l cell (L929)
DMEM high sugared culture solution of the culture solution that L929 cells use for above-mentioned preparation, condition of culture is 37 DEG C, containing 5%
CO2Constant incubator.Specific steps：
1) it takes the logarithm the cell in growth period, is diluted 10 times with the sugared culture solutions of DMEM high.
2) the 200 diluted cell suspensions of μ L are added in each hole of 96 orifice plates, 37 DEG C of incubator incubates for 24 hours.
3) compound of being tested is diluted to 0.05mM, 100 μ L/ holes of dosing, incubator 37 with the sugared culture solutions of DMEM high
DEG C incubate for 24 hours.
4) MTT of 20 a concentration of 5mg/mL of μ L, 37 DEG C of incubation 4h of incubator are added in.
5) 200 μ L DMSO are added in by cell dissolution, microplate reader measures the OD values under 490nm.
6) data are handled, obtain cell survival rate.
(3) cell survival rate measurement result
The result of measure is the cell survival rate when compound concentration is 0.05mM.Fig. 1 is Propofol, compound
1a-1f and 2a-2f is to the cell survival rate of A549 cells, and Fig. 2 is Propofol, and compound 1a-1f and 2a-2f is to L929 cells
Cell survival rate；It can be seen that when Drug level is 0.05mM from Fig. 1 and Fig. 2, cell survival rate is both greater than 90%, this
Concentration illustrates in therapeutic dose, these propofol prodrugs are all safe close to the therapeutic dose of Propofol.
5 Animal Anesthesia of embodiment is tested
Here the propofol prodrugs of good water solubility that solubility test result is shown only are investigated.It is big to choose 12 healthy SDs
Mouse, weight are randomly divided into five groups in 180-200g, every group 3, before the test with raised in the observation period by normal condition.It will
The compound 1f, 2e and 2f of good water solubility are dissolved in respectively in injection physiological saline.Using commercially available propofol emulsion as pair
According to product, dosage is measured by the effective dose 13mg/kg (0.073mmol/kg) of Propofol.Using tail vein injection, see
Rat anesthesia phenomenon is examined, records the duration of anesthesia, experimental result is shown in Table 2.
The different compounds of table 2 are to the anaesthetic effect of rat
| Compound | Phenomenon after injection | Duration of anaesthesia |
| Reference substance | There is anesthesia reaction | 10.25 minutes |
| 1f | There is anesthesia reaction | 5.56 minute |
| 2e | There is anesthesia reaction | 10.50 minutes |
| 2f | There is anesthesia reaction | 8.5 minute |
Claims (10)
1. a kind of propofol prodrugs of monodisperse poly glycol monomethyl ether modification, which is characterized in that its structure is shown in formula I：
Wherein Y is-OCO-or-OCCH2—。
2. propofol prodrugs according to claim 1, which is characterized in that n 2,3,4,6,7 or 10.
3. the preparation method of propofol prodrugs according to claim 1 or 2, which is characterized in that in the general formula I, Y for-
OCO-when the synthetic methods of propofol prodrugs include the following steps：
(1) make monodisperse poly glycol monomethyl ether and N, N'- carbonyl dimidazoles that monodisperse poly glycol monomethyl ether carbonyl be obtained by the reaction
Base imdazole derivatives；
(2) Propofol, alkali, solvent are added in into obtained monodisperse poly glycol monomethyl ether carbonylic imidazole derivative, 60
The propofol prodrugs of the carbonate shown in Formula II are obtained by the reaction under the conditions of DEG C：
4. according to the method described in claim 3, it is characterized in that, the alkali includes 4-dimethylaminopyridine, pyridine, three second
Amine, N, N- diisopropylethylamine, sodium carbonate, potassium carbonate.
5. according to the method described in claim 3, it is characterized in that, the solvent includes n,N-Dimethylformamide, diformazan
Base sulfoxide, N, accelerine, dichloromethane, tetrahydrofuran.
6. the preparation method of propofol prodrugs according to claim 1, which is characterized in that in the general formula I, Y for-
OCCH2- when the synthetic methods of propofol prodrugs include the following steps：
(1) the tertiary fourth of monodisperse poly glycol monomethyl ether acetic acid is obtained by the reaction with bromo-acetic acid tert-butyl in monodisperse poly glycol monomethyl ether
Ester derivant；
(2) the monodisperse poly glycol monomethyl ether tert-butyl acetate derivative of gained with trifluoroacetic acid is reacted, sloughs tertiary butyl
Obtain corresponding acid；
(3) acid obtained reacts to obtain the acetic acid ester type shown in formula III under the action of alkali and condensing agent with Propofol
Propofol prodrugs：
7. according to the method described in claim 6, it is characterized in that, the alkali is 4-dimethylaminopyridine, pyridine, three second
Amine, N, N- diisopropylethylamine, sodium carbonate, potassium carbonate.
8. according to the method described in claim 6, it is characterized in that, the solvent is dichloromethane, tetrahydrofuran, two chloroethenes
Alkane, N,N-dimethylformamide, dimethyl sulfoxide (DMSO), N, accelerine.
9. according to the method described in claim 6, it is characterized in that, the condensing agent includes dicyclohexylcarbodiimide, two
Diisopropylcarbodiimide, (1- (3- dimethylamino-propyls) -3- ethyl carbodiimides, N, N, N ', N '-tetramethyl chloromethane amidine hexafluoro
Phosphate.
10. propofol prodrugs described in claim 1 are generating tranquilizing soporific as through approach outside vein or vein to animal or people
And/or the application in the CNS inhibition drug of anesthetic effect.
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060100160A1 (en) * | 2004-07-12 | 2006-05-11 | Xenoport, Inc. | Amino acid derived prodrugs of propofol, compositions and uses thereof |
| CN101420963A (en) * | 2006-02-09 | 2009-04-29 | 安佐制药股份有限公司 | Multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin for treatment of breast, colorectal, pancreatic, ovarian and lung cancers |
| CN102321239A (en) * | 2011-05-30 | 2012-01-18 | 河北科技大学 | Preparation method of water-soluble toluylene compound prodrugs |
| CN102381972A (en) * | 2011-09-08 | 2012-03-21 | 四川大学华西医院 | Propofol hydroxy acid ester compound with ester constitutional terminal, preparation method for same and application thereof |
| CN103360590A (en) * | 2012-04-12 | 2013-10-23 | 南京康海磷脂生物技术有限公司 | Preparation method of methoxy polyethylene glycol-bi-fatty acryl phosphatidyl ethanolamine |
| CN103642023A (en) * | 2013-12-20 | 2014-03-19 | 武汉大学 | Synthesis method for single molecular weight polyethylene glycol and derivative thereof |
| CN104507899A (en) * | 2013-05-09 | 2015-04-08 | 四川海思科制药有限公司 | Phenol derivative and preparation method and use in medicine thereof |
| CN107303393A (en) * | 2016-04-19 | 2017-10-31 | 石家庄蒎格医药科技有限公司 | The preparation and application of prodrug are conjugated in Propofol polyethylene glycol |
-
2017
- 2017-12-25 CN CN201711422744.2A patent/CN108164419B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060100160A1 (en) * | 2004-07-12 | 2006-05-11 | Xenoport, Inc. | Amino acid derived prodrugs of propofol, compositions and uses thereof |
| CN101420963A (en) * | 2006-02-09 | 2009-04-29 | 安佐制药股份有限公司 | Multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin for treatment of breast, colorectal, pancreatic, ovarian and lung cancers |
| CN102321239A (en) * | 2011-05-30 | 2012-01-18 | 河北科技大学 | Preparation method of water-soluble toluylene compound prodrugs |
| CN102381972A (en) * | 2011-09-08 | 2012-03-21 | 四川大学华西医院 | Propofol hydroxy acid ester compound with ester constitutional terminal, preparation method for same and application thereof |
| CN103360590A (en) * | 2012-04-12 | 2013-10-23 | 南京康海磷脂生物技术有限公司 | Preparation method of methoxy polyethylene glycol-bi-fatty acryl phosphatidyl ethanolamine |
| CN104507899A (en) * | 2013-05-09 | 2015-04-08 | 四川海思科制药有限公司 | Phenol derivative and preparation method and use in medicine thereof |
| CN103642023A (en) * | 2013-12-20 | 2014-03-19 | 武汉大学 | Synthesis method for single molecular weight polyethylene glycol and derivative thereof |
| CN107303393A (en) * | 2016-04-19 | 2017-10-31 | 石家庄蒎格医药科技有限公司 | The preparation and application of prodrug are conjugated in Propofol polyethylene glycol |
Non-Patent Citations (2)
| Title |
|---|
| ZEQIONG YU ET AL.: "Application of Monodisperse PEGs in Pharmaceutics: Monodisperse Polidocanols", 《MOLECULAR PHARMACEUTICS》 * |
| 李正化: "《药物化学 第三版》", 31 January 2000, 人民卫生出版社 * |
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