CN109761826B - O-desmethylvenlafaxine phenyl ether compound and preparation method and application thereof - Google Patents

Abstract

The invention relates to an O-desmethylvenlafaxine derivative, in particular to an O-desmethylvenlafaxine phenylate compound (a compound shown in a formula I), and also discloses a preparation process of the compound, application of the compound in treating pain, and a pharmaceutical composition containing the compound.

Description

O-desmethylvenlafaxine phenyl ether compound and preparation method and application thereof

Technical Field

The invention relates to an O-desmethylvenlafaxine derivative, in particular to an O-desmethylvenlafaxine phenylate compound, a preparation method thereof and application thereof in preparing a pain medicament.

Background

O-desmethylvenlafaxine is an antidepressant, an active metabolite of venlafaxine, is a second generation antidepressant and has much lower affinity or no affinity to neuroreceptors than the first generation, thereby reducing side effects and toxicity. Currently, Hewlett-packard in the United states has completed relevant clinical trials and obtained a production batch by the FDA at 3 months 2007. The action mechanism of O-desmethylvenlafaxine is the same as that of venlafaxine, and the O-desmethylvenlafaxine also belongs to a 5-hydroxytryptamine-norepinephrine reuptake inhibitor (SNRIs), plays a pharmacological role by inhibiting the double actions of 5-hydroxytryptamine (5-HT) and Norepinephrine (NE), is widely used for treating diseases such as depression and the like, and has good curative effects on various depression including unipolar depression, depression accompanied by anxiety, bipolar depression and refractory depression.

The long-term taking of O-desmethylvenlafaxine can cause a series of adverse reactions, particularly the adverse reactions of sedation and lethargy, which become important factors for limiting the use of the medicine and bring pain and trouble to patients.

In addition, O-desmethylvenlafaxine is now being studied with a greater focus on depression and less on the use of pain.

Disclosure of Invention

The inventor provides an O-desmethylvenlafaxine phenylate compound which has good analgesic effect and does not have the side effect of O-desmethylvenlafaxine of sedation and lethargy through research and experiments.

The invention provides a compound shown in formula I, an isomer thereof or a pharmaceutically acceptable salt thereof,

the invention also provides a preparation method of the compound shown in the formula I, wherein O-desmethylvenlafaxine reacts with iodobenzene under the action of a catalyst to prepare the compound shown in the formula I.

The preparation method is specifically as follows:

step 1:

adding O-desmethylvenlafaxine and 30% potassium methylate solution, adding excessive methanol, carrying out water bath at 85 ℃, carrying out reflux reaction for 60min, then removing the solvent under reduced pressure, and carrying out toluene with water for three times to obtain white-like solid powder;

step 2:

adding iodobenzene, cuprous iodide and excessive DMF into the white solid powder obtained in the step 1, heating in an oil bath under the protection of nitrogen at the external temperature of 152 ℃ for reaction for 72 hours, distilling under reduced pressure to remove most of DMF solvent, extracting with dichloromethane DCM, washing with 2% hydrochloric acid, drying organic phase anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain a dark brown viscous oily substance;

wherein the mass ratio of the O-desmethylvenlafaxine, the 30% potassium methoxide solution, the iodobenzene and the cuprous iodide added in the steps 1 and 2 is (3-4): (5-10): (2-4): 1;

and step 3:

purifying by column chromatography, eluting with ethyl acetate-dichloromethane-n-heptane at a mass ratio of 1: 1: 1 as eluent, and eluting with small polar impurities; then replacing tetrahydrofuran as eluent, eluting the compound shown in the formula (I), performing vacuum filtration, and removing tetrahydrofuran to obtain an oily substance; stirring with 10% potassium hydroxide water solution overnight to remove impurities in the oily substance, separating out brown solid, filtering to obtain filter cake, dissolving with tetrahydrofuran, filtering to remove insoluble substances, and removing tetrahydrofuran from the filtrate under reduced pressure to obtain yellow solid wet weight; and hot-dissolving and washing with ethyl acetate for 30min, cooling to room temperature, keeping the temperature in an ice-water bath for crystallization for 2h, performing suction filtration, and drying to obtain the final product.

The biological evaluation test shows that: in vitro experiments indicate that the compound shown in the formula I can be combined with 5-hydroxytryptamine transporter (SERT), norepinephrine transporter (NET) or dopamine transporter (DAT) to inhibit the reuptake of 5-HT, NE and DA. In vivo tests show that the compound shown as the formula I, the isomer or the pharmaceutically acceptable salt thereof has the treatment effect of pain and can reduce or eliminate adverse reactions such as sedation, lethargy and the like. Wherein, in phase II (15-40min), the accumulative time of the mouse for foot contraction, foot shaking and foot licking is obviously shortened (p is less than 0.01, p is less than 0.001), and the compound of the formula I, namely the low/medium/high dose group (16mg/kg, 32mg/kg and 64mg/kg), generates obvious pain inhibition effect in formalin-induced nociception, which indicates that the compound of the formula I has central analgesic effect; meanwhile, the experiment of the neuropathic pain of the Spinal Nerve Ligation (SNL) of the rat shows that the SNL model rat generates obvious mechanical allodynia and thermal hyperalgesia phenomenon (p <0.001) and the compound of the formula I generates obvious inhibition effect on both contact induced pain and hyperalgesia after 60 minutes of administration, and the compound of the formula I has obvious inhibition effect on spontaneous discharge and induced discharge generated by external stimulation. Meanwhile, in a side effect detection test, a rat SNL rotating rod test shows that the compound of the formula I has no influence on the movement coordination capacity of an SNL rat, a normal rat autonomic activity test shows that the compound of the formula I has no influence on the autonomic activity capacity of a normal rat and has no sedative effect, and a pentobarbital sodium induced normal mouse subthreshold dose hypnosis test shows that the number of mice with the applied compound of the formula I which have the disappearance of righting reflex is consistent with a solvent control group, so that the compound of the formula I has no hypnotic side effect, and when the compound of the formula I shows analgesic effect on triple reuptake inhibition of 5-HT, NE and DA, the drug effect is similar to that of pregabalin, but the compound of the formula I has no sedative and lethargy side effect obviously.

Accordingly, the present invention provides the use of a compound of formula i for the manufacture of a medicament for the treatment of pain; the invention also provides the technical effects that when the compound of the formula I is used for preparing the medicine for treating pain, the compound of the formula I does not generate the side effects of lethargy and sedation in the process of treating pain.

The invention also provides a pharmaceutical composition which comprises a therapeutically effective amount of the compound of formula I and a pharmaceutical excipient.

The pharmaceutical composition provided by the invention is prepared into oral preparations, such as tablets, capsules or oral emulsions; injections, such as intravenous emulsions, liposomes or lipid nanoparticles.

Drawings

FIG. 1: mouse formalin pain model;

FIG. 2: compound touch-induced pain data for formula I;

FIG. 3: hyperalgesia data for compounds of formula I;

FIG. 4: the compound of formula I has the effects of spontaneous discharge (A), brush-induced discharge (B), von Frey filament-induced discharge (D) and pinch-induced discharge;

FIG. 5: data on the motor coordination ability of the compound of formula I in SNL rats;

FIG. 6: data on the effect of compounds of formula I on the ability to voluntarily move in normal rats;

FIG. 7: hypnotic data for compounds of formula I.

Detailed Description

The present invention is described in detail below by way of examples, but is not meant to be limited to any of the disadvantages of the present invention. Having described the invention in detail and illustrated the specific embodiments thereof, it will be apparent to those skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.

Example 1:

step 1:

115g O-desmethylvenlafaxine, 200g of 30% potassium methoxide solution and 100ml of methanol are added into a 2L single-mouth bottle, water bath is carried out for 85 ℃, the solvent is removed under reduced pressure after reflux reaction for 60min, and white solid powder is obtained.

Step 2:

82g of iodobenzene, 30g of cuprous iodide and 1200ml of DMF are added into the white solid powder obtained in the step 1, the mixture is heated in an oil bath under the protection of nitrogen at the external temperature of 152 ℃ for reaction for 72 hours, most of DMF solvent is removed by distillation under reduced pressure, the mixture is extracted by dichloromethane DCM, washed by 2% hydrochloric acid, dried by organic phase anhydrous sodium sulfate and then the solvent is removed under reduced pressure, and 190g of dark brown viscous oily matter is obtained.

And step 3:

purification was performed by column chromatography eluting with ethyl acetate-dichloromethane-n-heptane (1: 1: 1) and the less polar impurities first. Then tetrahydrofuran was used as an eluent to elute the compound of formula (I), followed by suction filtration under reduced pressure to remove tetrahydrofuran and obtain 30g of an oily substance. In order to remove impurities contained in the oily matter, 150ml of 10% potassium hydroxide aqueous solution is stirred overnight for treatment, a brown solid is separated out, a filter cake is dissolved by tetrahydrofuran, insoluble substances are removed by filtration, and the tetrahydrofuran is removed from filtrate under reduced pressure to obtain a yellow solid wet weight of 20 g; and then 100ml of ethyl neo-acetate is used for hot-melt washing for 30min, the mixture is cooled to room temperature, then the ice-water bath is used for heat preservation and crystallization for 2h, and the white solid (13 g) is obtained after suction filtration and drying, wherein the yield is about 10%. 1H NMR (400MHz, CDCl3) delta 0.80-0.90(m,1H),0.90-1.00(m,1H),2..28-2.32(m,8H), 2.96-3.00(m,1H),3.29(t,1H),6.90-6.92(m,2H),7.00-7.02(m,2H),7.07-7.12(m,3H),7.31-7.35(m, 2H).

Biological evaluation

Example 2: in vitro experiments

Test 1: radioligand binding assays

1.1 test cells: CHO cell

1.2 Experimental drugs: a compound of formula I, nisoxetine, BTCP, imipramine, desipramine

1.3 Experimental design:

to determine the binding of LPM580098 to 5-hydroxytryptamine transporter (SERT), norepinephrine transporter (NET) or dopamine transporter (DAT), respectively, radioligand binding experiments were performed.

1.4 Experimental procedures:

homogenizing CHO cell membranes in the presence or absence of a compound of formula I, respectively^[3H]Nisoxetine or^[3H]Incubation of BTCP at 4 deg.C for 120min, or with^[3H]Imipramine was incubated at 22 ℃ for 60 min. Only 10. mu.M LPM580098 was tested in this experiment, and compound non-specific binding was determined in the presence of 1. mu.M desipramine, 10. mu.M BTCP and 10. mu.M imipramine, respectively. The reaction was carried out by rapid filtration in vacuo using a glass fiber filter pre-soaked with 0.3% polyethyleneimine and then washing the 96-well cell culture plates several times with ice-cold 50mM Tris-HCl. A scintillation counter counts its radioactivity. Specific binding was estimated as the difference between total specific binding and non-specific binding, and the results were expressed as percent inhibition of control radioligand specific binding.

1.5 results:

LPM580098 binds to SERT, NET and DAT respectively and shows certain binding affinity, and the inhibition efficiency is 90.3%, 45.0% and 77.5% respectively.

And (3) testing 2: neurotransmitter reuptake assay

2.1 Experimental materials: brain tissue synaptosome

2.2 Experimental medication: a compound of formula I

2.3 Experimental design: evaluation of the inhibitory Effect of LPM580098 on 5-HT, NE or DA reuptake

2.4 Experimental procedure: the prepared synaptosomes are contacted with 0.2. mu. Ci in the presence or absence of a compound of formula I, respectively^[3H]5-HT，0.2μCi^[3H]NE or 0.2. mu. Ci^[3H]DA was incubated at 37 ℃ for 15min, the reaction was performed by rapid filtration in vacuo using a glass fiber filter, and the 96-well cell culture plates were washed several times with ice-cold 50mM Tris-HCl. The scintillation counter counts its radioactivity and calculates the IC₅₀The value is obtained.

2.5 results:

LPM580098 effectively blocks in a dose-dependent manner^[3H]5-HT，^[3H]NE or^[3H]DA uptake into rat synaptosomes, IC inhibition of 5-HT, NE and DA reuptake₅₀The values were 0.89. + -. 0.13. mu.M, 3.94. + -. 0.31. mu.M and 1.63. + -. 0.39. mu.M, respectively.

Example 3: in vivo experiments

Test 1: mouse formalin pain model

1.1 Experimental animals: KM mouse, 18-22g

1.2 Experimental drugs and reagents: the compound of formula I, pregabalin, CMC-Na solution and formaldehyde solution

1.3 Experimental design: the experiments were divided into 6 groups:

1. a normal group; 2. a model group; 3. pregabalin group (60 mg/kg); 4. a compound of formula I (16 mg/kg); 5. a compound of formula I (32 mg/kg); 6. a compound of formula I (64 mg/kg).

1.4 Experimental procedures:

1.4.1 mice were gavaged for 1h in advance;

1.4.2 the mouse to be tested is put into a transparent mouse cage, the model is made after 5min adaptation, namely, a 25ul micro-injector is inserted into the middle toe part of the right rear sole of the mouse, 20 mu L of 2.5% formalin solution is injected when the needle head reaches the center part of the sole of the foot (20 mu L of physiological saline is injected by the same method in a normal group), the needle is sealed, and the leakage of the liquid is effectively avoided. The bulging and whitening of the sole center can be seen after the molding;

1.4.3 immediately observing after molding, and respectively recording the time for lifting, shaking and licking feet of the mice for 0-5min (phase I) and 15-40min (phase II).

1.5 results:

the results are shown in figure 1, at phase I (0-5min), none of the compounds of formula I-low/medium/high dose groups (16mg/kg, 32mg/kg, 64mg/kg) exhibited analgesia (p >0.05) compared to the model group; in phase II (15-40min), the compound of formula I-low/medium/high dose group (16mg/kg, 32mg/kg, and 64mg/kg) produced significant pain suppression in formalin-induced nociception and was partially dose-dependent, as indicated by mouse paw withdrawal, paw shaking, and significantly shorter cumulative time to lick the paw compared to the model group (p <0.01, p <0.001, p < 0.001). In summary, the results of phase II indicate that the compounds of formula I have central analgesic effects, and the specific data indicate central analgesic effects.

And (3) testing 2: rat Spinal Nerve Ligation (SNL) neuropathic pain model

2.1 Experimental animals: SD rat, 180-220g.

2.2 Experimental drugs and reagents: a compound of formula I, pregabalin, physiological saline, CMC-Na solution, chloral hydrate, benzalkonium bromide, iodophor, and penicillin powder

2.3 Experimental design: the experiments were divided into 4 groups: normal group, model group, pregabalin group (30mg/kg), compound of formula I group (16 mg/kg).

2.3.1 behavioral testing analgesic action of Compounds of formula I Using mechanical pain, thermal pain test

2.3.2 in vivo WDR Single neuron electrophysiological experiments for exploring the effects of the compounds of formula I on the spontaneous and evoked discharges of Single neurons directly after spinal nerve ligation;

2.4 Experimental procedure:

2.4.1 spinal nerve ligation model preparation:

after the rats are anesthetized by 10% chloral hydrate, hairs about 2cm above and below two iliac parts at the leg root of the rats are removed by a depilator, a longitudinal opening (the opening is as small as possible on the premise that nerves can be found) is formed at about 0.5cm of the right side of a spinal column, an L6 transverse process is exposed under a cold light lamp, a large forceps is used for directly breaking off the hairs, a small cotton ball prepared in advance is used for wiping to further expose an L5 nerve, bone residues are removed as much as possible under light, a No. 6-0 line is tied, muscles and skin are sutured layer by using a No. 2-0 line, iodophor disinfection is carried out, penicillin is injected into left leg muscles (8 ten thousand units/bottle, 2ml of physiological saline is injected for dissolution, 0.4 ml/mouse is injected), and the left leg muscle is continuously injected for 3 days after the operation.

2.4.2 mechanical pain determination:

the rats are administered with the gastric lavage 1h in advance, and are adapted in a metabolism cage for 20min, so that the rats are explored and adapted to a new environment. Then, the rats were perpendicularly pricked with von Frey fiber to the right hind arch of the foot. The measurement was started from 2.0g by the up-down method. That is, if 2.0g had a reaction (raising, shaking, licking), 1.4g was measured; if 2.0g of the reaction solution was not reacted, 4.0g of the reaction solution was used, and the reaction was repeated. If 2.0g of the first reaction occurs, the reaction is marked as X, and 6 times are counted from 2.0 g; if 2.0g of the first unreacted, the reaction was marked as O, and 5 times from the first reaction. Statistical analysis of the data was performed according to the classical literature of Quantitative assessment of functional allodynia in the rat paw. Only measuring mechanical pain 1 day before administration, then screening qualified rats according to the PWT <4g principle, randomly grouping the rats by adopting a random interval grouping method according to a threshold value, and measuring the mechanical pain on the 1 st, 7 th and 14 th days after continuous administration.

2.4.3 hot pain assay:

the normal rat is used for debugging the thermal pain radiometer in advance, so that the thermal pain incubation period of the normal rat is 10-12 s. Performing intragastric administration 1h in advance, testing a rat after the rat adapts for 10min on a glass plate of a thermal pain tester, irradiating the right hind arch of the rat with a radiant heat source, stopping irradiation when the rat raises and shakes feet and licks the feet, and recording the latency time; when the rats did not respond within 20s of irradiation, irradiation was stopped (tissue damage was prevented), and the parallel measurement was performed for 5 times between groups.

2.4.4 in vivo WDR neuron electrophysiology:

after modeling of spinal nerve ligation, rats with PWT <4g were screened with von Frey filaments for electrophysiological experiments. On the day of electrophysiological recording, animals in each experimental group were gavaged 1h before recording. Animals were anesthetized with urethane via the abdominal cavity (1.0-1.5 g/kg). During the whole experiment process, the animals need to be under deep anesthesia, and the anesthesia depth of the animals is monitored by observing the carotid blood pressure, the respiratory rhythm and the muscle tension. After the corneal reflection and the plantar reflection of the animal disappear, a jugular vein cannula is used for maintaining anesthesia, a carotid artery cannula is used for monitoring the blood pressure of the animal, and an air tube cannula is connected with a breathing machine to enable the animal to breathe stably; the rectal temperature of the animals was monitored using a temperature control system, and the body temperature of the animals was maintained at 37. + -. 0.5 ℃. Animals are fixed in an ST-7 stereotaxic system, the back skin is cut open, parallel incisions are made along muscles on two sides of a spinal column, and the expanded part of the spinal cord and the lumbar is positioned. The spine was fixed to spinal clamps and a discectomy was performed, exposing L4-L6 horizontal spinal cords. Fixing the back skins at two sides of the body on a metal bracket respectively, manufacturing an oil groove, pouring warm paraffin oil, and removing the hard ridge membrane under a dissecting microscope. The carbon fiber electrode is moved to the surface of the spinal cord by an electronic micromanipulation system and slowly enters the spinal cord. Search for pain neurons with receptor fields on the hairless skin of the hind paw in the dorsal horn of the spinal cord and exclude joint and muscle firing. After a single WDR neuron was isolated and identified, the following indices were recorded in sequence:

a. recording 5-10min of stable spontaneous discharge;

b. brush stimulation-induced discharge: gently stimulating the receptive field with a brush for 10 times, each time for 1 second and at an interval of 1 second;

c. mechanical stimulation induced discharge: mechanical stimulus (von Frey filaments: 1g,4g,8g,15 g; 1s on,1s off; 10 times/intensity; stimulus interval 10 s; mechanical stimulus-induced discharges were recorded;

d. pinch stimulus-induced discharge: the vascular clamp receptive field was recorded for 10 seconds for the nociceptive evoked discharges.

2.5 results:

fig. 2 is a graph of the pain-induced results of the touch and fig. 3 is a graph of the hyperalgesia results. As can be seen from fig. 2 and fig. 3, SNL model rats developed significant mechanical allodynia and thermal hyperalgesia (p <0.001) compared to the sham group, and the compound of formula I produced significant inhibition of both allodynia and hyperalgesia 60 minutes after administration.

FIG. 4 shows the effect of compounds of formula I on (A) spontaneous discharge, (B) brush-induced discharge, (C) von Frey filament-induced discharge (D) pinch-induced discharge. Wherein (A) the frequency of spontaneous firing of extracellular single WDR neurons in the model group is significantly increased in the absence of external stimuli, whereas the frequency of firing is significantly decreased following administration of the compound of formula I. The electrical signal for the model group was significantly enhanced for mechanical stimuli such as brush, von Frey filament and pinch reactions, while the electrical signal was significantly reduced after administration of the compound of formula I. In conclusion, the compound of the formula I has obvious inhibition effect on spontaneous discharge and induced discharge generated by external stimulation.

2.6 conclusion:

electrophysiological experiments of mechanical pain, thermal pain and in vivo WDR show that the compound of the formula I has an obvious analgesic effect on neuropathic pain induced by spinal nerve ligation, and the drug effect is similar to that of pregabalin.

And (3) testing: side effect detection

3.1 rat SNL rotating rod experiment

3.1.1 Experimental animals: SD rat, 180-220 g;

3.1.2 Experimental drugs and reagents: LPM580098, pregabalin, physiological saline, CMC-Na solution, chloral hydrate, benzalkonium bromide, iodophor and penicillin powder;

3.1.3 Experimental design: the experiments were divided into 4 groups: normal group, model group, pregabalin group (30mg/kg), compound of formula I group (16 mg/kg);

a. the behavioral test adopts the mechanical pain and thermal pain experiments to explore the analgesic effect of LPM580098

b. In-vivo WDR single neuron electrophysiological experiments are used for exploring the influence of LPM580098 on the spontaneous and induced discharge of single neurons after spinal nerve ligation;

3.1.4 Experimental procedures:

spinal nerve ligation model preparation: after the rats are anesthetized by 10% chloral hydrate, hairs about 2cm above and below two iliac parts at the leg root of the rats are removed by a depilator, a longitudinal opening (the opening is as small as possible on the premise that nerves can be found) is formed at about 0.5cm of the right side of a spinal column, an L6 transverse process is exposed under a cold light lamp, a large forceps is used for directly breaking off the hairs, a small cotton ball prepared in advance is used for wiping to further expose an L5 nerve, bone residues are removed as much as possible under light, a No. 6-0 line is tied, muscles and skin are sutured layer by using a No. 2-0 line, iodophor disinfection is carried out, penicillin is injected into left leg muscles (8 ten thousand units/bottle, 2ml of physiological saline is injected for dissolution, 0.4 ml/mouse is injected), and the left leg muscle is continuously injected for 3 days after the operation.

Rats were first trained on an automatic acceleration rotarod apparatus at a constant speed of 4rpm/s for 2 times, 5min each time. The other 5 experimental revolutions were automatically accelerated after 5min from 4rpm/s to 40rpm/s, and the time(s) in the rod was recorded for each group of rats.

3.1.5 results:

FIG. 5 shows the results of experiments with similar rod durations in rats as the model group (p >0.05) after administration of the compound of formula I, indicating that the compound of formula I has no effect on the motor coordination capacity of SNL rats.

3.2 Normal rat Activity test

3.2.1 Experimental animals: SD rat, 180-220g.

3.2.2 Experimental drugs and reagents: the compound of formula I, pregabalin, duloxetine, physiological saline and CMC-Na solution.

3.2.3 Experimental design: the experiments were divided into 4 groups: normal group, pregabalin group (30mg/kg), duloxetine group (12mg/kg) compound of formula I group (16 mg/kg).

3.2.4 Experimental procedures: the rats are subjected to intragastric administration 1h in advance, and the rats are placed into a test box 10min before testing to be explored to adapt to a new environment. Then recording the autonomous activity of the rat within 10-20min, analyzing the movement distance of the rat within 10min by software as a detection index, and carrying out parallel measurement among groups.

3.2.5 results:

FIG. 6 shows the results of the experiment, in which the distance traveled by the rats after the compound of formula I was administered was not significantly increased or decreased, and was not significantly different (p >0.05) compared to the vehicle control group, indicating that the compound of formula I had no effect on the ability of normal rats to voluntarily move and had no sedative effect.

3.3 Pentobarbital sodium-induced normal mice subliminal dose hypnosis experiment

3.3.1 Experimental animals: KM mouse, 18-22g

3.2.2 Experimental drugs and reagents: a compound of formula I, diazepam, pregabalin, duloxetine, sodium pentobarbital, CMC-Na solution and normal saline;

3.2.3 Experimental design: the experiments were divided into 5 groups: normal group, diazepam group (3mg/kg), pregabalin group (60mg/kg), duloxetine group (24mg/kg) formula I group (16mg/kg)

3.2.4 Experimental procedures:

a preliminary experiment is carried out before a formal experiment, and the maximum subthreshold dose (28mg/kg) of the sodium pentobarbital which enables 90-100% of mice to have no disappearance of orthotropic reflex is determined. Animals in the diazepam group are subjected to intraperitoneal injection for 0.5h after the animals are administered, and animals in other administration groups are subjected to intraperitoneal injection for 50min, wherein the sleeping conditions of the animals within 30min are observed. Each group tested 2 mice per round.

Observation indexes are as follows: the disappearance of righting reflex is taken as a sleep judgment standard (the disappearance of righting reflex is taken when the animal is placed in a supine state from a prone position, the animal can not recover a normal body position, and the time is more than 1 min). The number of animals in each experimental group that appeared to sleep was recorded.

3.2.5 results:

figure 7 shows the results of the experiment, the number of mice showing disappearance of righting reflex after administration of the compound of formula I is consistent with the vehicle control group, indicating that the compound of formula I has no hypnotic side effects.

3.2.6 conclusion:

the compound of the formula I is a novel 5-HT, NE and DA triple reuptake inhibitor, has obvious analgesic effect and similar drug effect to pregabalin, but has no side effect of sedation and lethargy.

Claims (7)

1. An O-desmethylvenlafaxine phenyl ether compound of formula i:

2. a process for the preparation of a compound of formula i as claimed in claim 1, characterized in that it comprises the following steps:

step 1: adding O-desmethylvenlafaxine and 30% potassium methylate solution, adding excessive methanol, carrying out water bath at 85 ℃, carrying out reflux reaction for 60min, then removing the solvent under reduced pressure, and carrying out toluene with water for three times to obtain white-like solid powder;

step 2: adding iodobenzene, cuprous iodide and excessive DMF into the white solid powder obtained in the step 1, heating in an oil bath under the protection of nitrogen at the external temperature of 152 ℃ for reaction for 72 hours, distilling under reduced pressure to remove most of DMF solvent, extracting with dichloromethane DCM, washing with 2% hydrochloric acid, drying organic phase anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain a dark brown viscous oily substance;

wherein the mass ratio of the O-desmethylvenlafaxine, the 30% potassium methoxide solution, the iodobenzene and the cuprous iodide added in the steps 1 and 2 is (3-4): (5-10): (2-4): 1;

and step 3: purifying by column chromatography, and purifying by using ethyl acetate-dichloromethane-n-heptane in a mass ratio of 1: 1: 1, eluting the small polar impurities firstly; then replacing tetrahydrofuran as eluent, eluting the compound shown in the formula I, performing suction filtration under reduced pressure, and removing tetrahydrofuran to obtain an oily substance; stirring with 10% potassium hydroxide water solution overnight to obtain brown solid, dissolving filter cake with tetrahydrofuran, filtering to remove insoluble substances, and removing tetrahydrofuran from the filtrate under reduced pressure to obtain yellow solid wet weight; and hot-dissolving and washing with ethyl acetate for 30min, cooling to room temperature, keeping the temperature in an ice-water bath for crystallization for 2h, performing suction filtration, and drying to obtain the final product.

3. Use of a compound according to claim 1 for the manufacture of a medicament for the treatment of pain.

4. A pharmaceutical composition characterized by comprising a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable excipient.

5. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition is formulated as an oral preparation or an injection.

6. Pharmaceutical composition according to claim 5, characterized in that the oral formulation is a tablet, a capsule or an oral emulsion.

7. The pharmaceutical composition of claim 5, wherein the injectable formulation is an intravenous emulsion, a liposome, or a lipid nanoparticle.

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