CN102344408B

CN102344408B - Double-effect anesthetic

Info

Publication number: CN102344408B
Application number: CN 201110212210
Authority: CN
Inventors: 熊利泽; 文爱东; 孙晓莉; 奚苗苗; 陈雷; 朱艳荣
Original assignee: Fourth Military Medical University FMMU
Current assignee: Fourth Military Medical University FMMU
Priority date: 2011-07-27
Filing date: 2011-07-27
Publication date: 2013-06-05
Anticipated expiration: 2031-07-27
Also published as: CN102344408A

Abstract

The invention discloses a double-effect anesthetic represented by a structural formula (I). With the anesthetic, frequencies of administration can be reduced, an anesthesia induction process is more convenient, and adverse reactions caused by single-agents can be reduced. The anesthetic provided by the invention is advantaged in fast effect, short duration, high anesthesia efficacy, high controllability during operation, and fast recovery after operation.

Description

Double-effect anesthetic

Technical field

The present invention relates to a kind of Novel narcotics that has analgesia, calm double effects concurrently, belong to medical technical field.

Background technology

Anesthesia induction in operation at present needs to use simultaneously analgesia and sedation anesthesia medicine, often unites clinically to give narcotic analgesics fentanyl class and anesthetic and sedative drugs Disoprofol.Remifentanil is a kind of opioid drug of ultrashort effect, and that rapid-action, effect is disappeared is fast, analgesic activity is strong, but sedative effect extremely a little less than.Untoward reaction comprises cardiovascular inhibition, opium sample central nervous system effects, respiration inhibition effect etc.Disoprofol is a kind of fugitive phenolic group alkanes medicine, and is rapid-action, the time length is short, revive rapidly steadily, but analgesic activity weak, be insoluble in water, use clinically formulation to be emulsion, less stable.Untoward reaction comprises propofol infusion syndrome, circulation restraining effect, respiration inhibition effect etc.There are some researches show that the remifentanil target level increases, can reduce the target level of Disoprofol under the identical anesthesia depth conditions, significantly reduce the consumption of peri-operation period Disoprofol.

Clinically, remifentanil and Disoprofol must be distinguished administration, use inconvenience in art.If can design synthetic a kind of medicine that has analgesia and sedative effect concurrently, just can make the patient be in rapidly " dormancy " state, for the recovery of organ dysfunction gains time, create conditions, doctor's administration number of times is anaesthetized in minimizing, makes during anesthesia induction more convenient.

Summary of the invention

The purpose of this invention is to provide the Novel narcotics that has analgesia, sedative effect concurrently, narcotic analgesics and anesthetic and sedative drugs are united two into one, reduced anesthesia doctor's administration number of times, make during anesthesia induction more convenient, reduced simultaneously the untoward reaction of single medicine and solved the problems such as medicine self stability.

Implementation procedure of the present invention is as follows:

Compound shown in general structure (I),

。

Double-effect anesthetic synthetic method of the present invention: remifentanil (as using sodium hydroxide) all or part of ester that carries out under alkaline condition is hydrolyzed, and then obtains compound shown in general structure (I) with Disoprofol esterification reaction.

Specifically, synthetic method 1: remifentanil is hydrolyzed under room temperature, alkaline condition and obtains compound 1,Compound 1With Disoprofol reaction preparation compound 2

Concrete synthetic route is as follows,

Synthetic method 2: remifentanil hydrolysis under backflow (approximately 100 ℃), alkaline condition obtains compound 3,Compound 3With Disoprofol reaction preparation compound 4.

Concrete synthetic route is as follows:

The medicine that Pharmacodynamic evidence, the present invention are synthesized has analgesia, calm double pharmacological action concurrently.

The present invention uses with the form of conventional medicinal preparations.Described conventional medicine with preparation contain as activeconstituents in preparation with pharmaceutically acceptable carrier, this medicinal preparations can be solid form such as tablet, capsule, powder, pill, granule, can be also liquid form such as injection, emulsion etc.

Can contain auxiliary substance, stablizer, wetting agent and other additive commonly used in above-mentioned preparation, as lactose, citric acid, tartrate, Magnesium Stearate, terra alba, sucrose, W-Gum, talcum powder, gelatin, agar, pectin, peanut oil, sweet oil, theobroma oil, ethylene glycol, xitix, N.F,USP MANNITOL etc.

Above-mentioned preparation can be made according to the preparation technology of various preparation routines.

The present invention contains the newtype drug molecule of remifentanil and Disoprofol skeleton structure, the drug effect result shows that it not only has analgesia, calm double effects, reduced anesthesia doctor's administration number of times, can also reduce the untoward reaction of single medicine and solve the problem such as medicine self stability.

Embodiment

Synthesizing of embodiment 1 compound 2

With 4.12g(10mmol) remifentanil joins in 20 mL water, under stirring at room, drips 50mL 10% NaOH, stirs 1h.Reaction solution gets white solid with toluene band water, is compound 1, need not purifying and directly throws next step.With Disoprofol 1.8g(10mmol) be dissolved in 50 mL methylene dichloride EDC hydrochloride 1.92g(10mmol), DMAP 0.25g(2mmol), compound 1 is added in reaction solution, room temperature reaction 3h.Pour in reaction solution in 50mL water, separatory, the organic phase anhydrous magnesium sulfate drying, removal of solvent under reduced pressure, column chromatography for separation get target product 2.4g, overall yield 48%.

MS:523.50(ES ⁺),? ₁H-NMR(400MHz,?CDCl ₃):?7.42-7.12(m,8H),?3.81(s,3H),?2.94(m,2H),?2.79-2.72(m,6H),?2.48(t,2H),?2.33(t,2H),?1.89(t,2H),?1.62(t,2H),?1.58(m,12H),?0.96(t,3H)。

Synthesizing of embodiment 2 compounds 4

With 4.12g(10mmol) remifentanil joins in 20 mL water, under stirring at room, drips 50mL 10% NaOH, 100 ℃ of reaction 4h.Reaction solution gets white solid with toluene band water, is compound 3, need not purifying and directly throws next step.With Disoprofol 3.6g(20mmol) be dissolved in 50 mL methylene dichloride EDC hydrochloride 3.84g(20mmol), DMAP 0.50g(4mmol), compound 3 is added in reaction solution, room temperature reaction 3h.Pour in reaction solution in 50mL water, separatory, the organic phase anhydrous magnesium sulfate drying, removal of solvent under reduced pressure, column chromatography for separation get target product 2.3g, overall yield 35%.

MS:669.53(ES ⁺),? ¹H-NMR(400MHz,CDCl ₃):?7.40-7.11(m,11H),?2.98(m,4H),?2.79-2.70(m,6H),?2.45(t,2H),?2.38(t,2H),?1.79(t,2H),?1.67(t,2H),?1.63(m,24H)?,?0.95(t,3H)。

Embodiment 3: pharmacodynamic study

1, test materials

Kunming mouse, body weight 18 ~ 22g is provided by The Fourth Military Medical University's Experimental Animal Center; Disoprofol (P), remifentanil (R) provide for Yichang people's good fortune medicine company limited liability company, and P-R is self-control; Mb-4a digital display thermostatic electrothermal plate, big Yongxing Instr Ltd. of Beijing section.

2, testing program and result

(1) analgesic effect:

Analgesic effect adopts the hot plate method evaluation.The mean value that secondary reacts bitterly before the medication is got the mouse of Basic Pain Threshold in 10-30s and is tested as Basic Pain Threshold.60 of the female mices that the threshold of pain is qualified are divided into following 6 groups (n=10) at random: 1. negative control group: give physiological saline (10ml/kg, i.v.); 2. P organizes: before induced pain, 1min gives P(15mg/kg, i.v.); 3. R organizes: before induced pain, 1min gives R(0.7mg/kg, i.v.); 4. P+R group: respectively before induced pain 4,1min gives P(15mg/kg, i.v.) and R(0.7mg/kg, i.v.); 5. P-R organizes: before induced pain, 1min gives P-R (28mg/kg, i.v.).Each group is respectively at measuring its threshold of pain after administration 1,5,15,30, during 50 min.

Obtained experimental data all calculates through SPSS 11.0 statistical data process softwares, and experimental result all is expressed as

, use ANOVA to carry out the statistical test of difference between many group means, relatively adopt in twos the LSD method.P＜0.05 thinks that difference has statistical significance.

Experimental result shows, the Basic Pain Threshold there was no significant difference of experimental animal (P〉0.05).P group is not observed analgesic effect, difference that each time point threshold of pain compares with negative control group that there are no significant (P〉0.05); R group has stronger analgesic effect, and time remaining is 15min approximately, after administration 1,5, the 15min threshold of pain is compared with negative control group and P group significant difference all (P＜0.05); Obvious analgesic effect appears in P+R group 1min, but the time length be about 5min, after administration, the 1min threshold of pain is compared with negative control group and P group all has significant difference (P＜0.05), compares with the R group to there is no significant difference (P〉0.05); P-R group after administration 1,5, the analgesic effect of 15min and negative control group, R group, P+R group compare and all significantly strengthen (P＜0.05), the 5min threshold of pain extends 0.74min, 0.47min, 0.83min than negative control group, R group, P+R group, and 15min organizes than negative control group, R group, P+R the threshold of pain and extends 0.57min, 0.48min, 0.60min.The experimental result prompting, P-R has analgesic effect preferably.

(2) hypnotic effect:

60 of mouse, male and female half and half are divided into following 6 groups (n=10) at random: 1. negative control group: give physiological saline (10ml/kg, i.v.); 2. P organizes: give P(15mg/kg, i.v.); 3. R organizes: give R(0.7mg/kg, i.v.); 4. P+R group: give respectively P(15mg/kg, i.v.), R(0.7mg/kg, i.v.); 5. P-R organizes: before induced pain, 1min gives P-R (28mg/kg, i.v.).Observe righting reflex loss rate (take righting reflex loss〉30 s as) after administration and calculate the rate of falling asleep; With injection to time of righting reflex loss as Sleep latency; With righting reflex loss to righting reflex time of recovery as the sleep extended period.

, use ANOVA to carry out the statistical test of difference between many group means, relatively adopt in twos LSD method, X ²Relatively each organizes the difference of the rate of falling asleep in check. P＜0.05 thinks that difference has statistical significance.

Experimental result shows, negative control group, R group are not all observed hypnotic effect; The rate of falling asleep of P group, P+R group, P-R group is 100%, has compared significant difference (P＜0.05) with negative control group, R group; The Sleep latency of P-R group and sleep extended period significantly are longer than the P group, P+R organizes (P＜0.05).The experimental result prompting, P-R has hypnotic effect preferably.

As seen, Disoprofol and remifentanil have synergy, both share have rapid-action, the time length is short, strong, the art of controllability finishes the advantage such as fast of reviving in high, the art of anesthesia usefulness, is desirable combination drug method.

Claims

1. the compound shown in general structure (I),

。

2. the synthetic method of the described compound of claim 1 is characterized in that: remifentanil is all or part of under alkaline condition carries out the ester hydrolysis, then obtains compound shown in general structure (I) with Disoprofol esterification reaction.

3. the pharmaceutical composition that contains the described compound of claim 1.

4. the application of the described compound of claim 1 in the preparation anaesthetic.

5. use according to claim 4, it is characterized in that: this medicine is injection, emulsion, tablet, capsule, powder, pill or granule.