A (N,N-dimethylamino)carbamic acid-4,5-dimethoxy-2-[(1E)-3-methoxy-propenyl]phenyl ester compound, and a preparation method and application thereof

Abstract

The application belongs to the technical field of pharmaceutical chemistry and provides a kind of (( N , N -Dimethylamino) methylate-4,5-dimethoxy-2-[(1 E )-3-methoxy-acryl] phenyl ester compound and its preparation method and application.The structure formula of the (( N , N -Dimethylamino) methylate-4,5-dimethoxy-2-[(1 E )-3-methoxy-acryl] phenyl ester compound provided by the application is.The (( N , N -Dimethylamino) methylate-4,5-dimethoxy-2-[(1 E )-3-methoxy-acryl] phenyl ester compound provided by the application not only can significantly reduce the incidence of general tonic seizures, but also can significantly prolong the latent period of seizures and reduce the Racine score of seizures, has significant antiepileptic activity, and is safe, and has potential for preparing antiepileptic drugs.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemistry, and more particularly to a ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E [3-Methoxy-propenyl]phenyl ester compounds, their preparation methods and applications. Background Technology

[0002] Epilepsy is a chronic neurological disorder characterized by spontaneous, recurrent seizures accompanied by abnormal electrical activity in the brain. It is one of the most common neurological disorders, and its pathogenesis includes: 1) abnormal ion channel function; 2) neurotransmitter imbalance; 3) irregular glial system; 4) neuroinflammation and oxidative stress; and 5) abnormal neural circuits. Based on clinical seizure type, epileptic seizures can be classified into generalized tonic-clonic seizures (grand mal seizures), absence seizures (petit mal seizures), partial seizures, special seizures, and status epilepticus. Treatment methods for epilepsy include surgery, dietary adjustments, and medication, with medication being the preferred treatment method.

[0003] Most currently marketed and investigational antiepileptic drugs primarily target ion channels, exerting their pharmacological effects by reducing the excitability of the nervous system. Their mechanisms of action include: 1) Inhibition of voltage-gated sodium ion channels: Voltage-gated sodium ion channels are the main ion channels constituting the rapid depolarization of neuronal action potentials. Inhibiting voltage-gated sodium ion channel currents can inhibit the generation and transmission of action potentials; representative drugs are carbamazepine and phenytoin sodium. 2) Enhancement of GABAA receptor (γ-aminobutyric acid type A receptor) activity: GABAA receptors are activated by the endogenous neurotransmitter GABA (γ-aminobutyric acid), producing inhibitory Cl... -1) Current enhances the activity of GABAA receptors, which can reduce cell membrane potential and decrease neuronal excitability, making it a target of benzodiazepine antiepileptic drugs. 2) Activation of voltage-gated potassium channels: After potassium channels open, potassium ions flow out in large quantities, reducing cell membrane potential; retigabine, developed by GlaxoSmithKline, is the first potassium channel opener for the treatment of epilepsy. 3) Inhibition of ionotropic glutamate receptors: Glutamate is an important neurotransmitter in the central nervous system. Ionotropic glutamate receptors are coupled to cation channels and are divided into three types: NMDA receptors, KA receptors, and AMPA receptors. Glutamate-mediated neuronal overexcitation plays a key role in inducing epileptic seizures; therefore, inhibiting ionotropic glutamate receptors can treat epilepsy. Representative drugs include the NMDA receptor antagonist ketamine and the AMPA receptor antagonist perampanel. 5) Inhibition of voltage-gated calcium channels: Voltage-gated calcium channels can be classified into L-type, T-type, N-type, R-type, and P / Q-type calcium channels according to their activation voltage and current characteristics. Antiepileptic drugs gabapentin and pregabalin are N-type calcium channel inhibitors, while ethosuximide is a T-type calcium channel inhibitor. In addition, the mechanisms of action of antiepileptic drugs also include regulating neurotransmitter release through presynaptic action (representative drugs are levetiracetam and brivaracetam) and mechanism-targeting drugs (carbonic anhydrase (CA) inhibitors and rapamycin (mTOR) inhibitors).

[0004] Although several antiepileptic drugs have been approved for clinical use, 30% of patients still cannot achieve effective relief due to headaches, depression, cognitive impairment, sedation, memory decline, and other factors. Therefore, developing new, safe, and effective antiepileptic drugs has significant clinical value and social implications. Summary of the Invention

[0005] The purpose of this invention is to address the shortcomings of existing technologies and provide a ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E [3-Methoxy-propenyl]phenyl ester compounds, their preparation methods and applications.

[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0007] This invention provides a ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E [3-Methoxy-propenyl]phenyl ester compound, wherein... N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E The structural formula of the 3-methoxy-propenyl]phenyl ester compound is: .

[0008] The present invention also provides the aforementioned ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E The preparation method of the [-3-methoxy-propenyl]phenyl ester compound includes the following steps:

[0009] 1) A solution of 2,4,5-trimethoxybenzaldehyde and a solution of boron tribromide were mixed and reacted to obtain compound b;

[0010] 2) Compound b, ethoxyformylmethylenetriphenylphosphine, and toluene were mixed and reacted to obtain compound c;

[0011] 3) React a mixed solution of imidazole and tert-butyldimethylchlorosilane with a solution of compound c to obtain compound d;

[0012] 4) Compound d and diisobutylaluminum hydride were mixed in toluene and reacted to obtain compound e;

[0013] 5) Compound e and tetrabutylammonium fluoride were reacted in tetrahydrofuran to remove the protecting group, yielding compound f;

[0014] 6) React the compound f solution and sodium hydride solution once, then add... N , N -Dimethylcarbamoyl chloride undergoes a secondary reaction to give compound g;

[0015] 7) A solution of compound g is reacted with a sodium hydride solution in one reaction, followed by the addition of iodomethane in a second reaction, to obtain ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E [3-Methoxy-propenyl]phenyl ester compounds.

[0016] Preferably, the solvent of the 2,4,5-trimethoxybenzaldehyde solution in step 1) is dichloromethane, and the molar volume ratio of 2,4,5-trimethoxybenzaldehyde to dichloromethane is 40~60 mmol: 140~160 mL.

[0017] Step 1) The solvent for the boron tribromide solution is dichloromethane, and the molar volume ratio of boron tribromide to dichloromethane is 40~60 mmol: 40~60 mL;

[0018] The molar ratio of 2,4,5-trimethoxybenzaldehyde to boron tribromide is 40~60:40~60;

[0019] The reaction temperature in step 1) is 20~40℃.

[0020] Preferably, in step 2), the molar ratio of compound b to ethoxyformylmethylenetriphenylphosphine is 15-25:17-28, and the molar volume ratio of compound b to toluene is 15-25 mmol:30-50 mL.

[0021] The reaction temperature in step 2) is 20~40℃.

[0022] Preferably, the solvent of the compound c solution in step 3) is N , N -Dimethylformamide, compound C and N , N The molar volume ratio of dimethylformamide is 10~20 mmol: 20~40 mL;

[0023] Step 3) The solvent for the mixed solution of imidazole and tert-butyldimethylchlorosilane is N , N -Dimethylformamide, imidazole, tert-butyldimethylchlorosilane and N , N The molar volume ratio of dimethylformamide is 25~40 mmol: 12~25 mmol: 2~10 mL;

[0024] The molar ratio of compound c, tert-butyldimethylchlorosilane, and imidazole is 10~20:12~25:25~40;

[0025] The reaction temperature in step 3) is 20~40℃.

[0026] Preferably, in step 4), the molar ratio of compound d to diisobutylaluminum hydride is 5~10:15~30, and the molar volume ratio of compound d to toluene is 5~10 mmol:20~50 mL.

[0027] The reaction temperature in step 4) is 20~40℃.

[0028] Preferably, in step 5), the molar ratio of compound e to tetrabutylammonium fluoride is 3~10:5~10, and the molar volume ratio of tetrabutylammonium fluoride to tetrahydrofuran is 5~10 mmol:5~10 mL.

[0029] Step 5) The temperature for the deprotection reaction is 20~40℃.

[0030] Preferably, the solvent for the compound f solution in step 6) is tetrahydrofuran, and the molar volume ratio of compound f to tetrahydrofuran is 2~8 mmol: 5~15 mL;

[0031] Step 6) The solvent for the sodium hydride solution is tetrahydrofuran and N , N -Dimethylformamide, sodium hydride, tetrahydrofuran and N , N The molar volume ratio of dimethylformamide is 2~10 mmol: 10~30 mL: 5~15 mL;

[0032] Compound f, sodium hydride and N , N The molar ratio of -dimethylcarbamoyl chloride is 2~8:2~10:2~10;

[0033] Step 6) The temperature of the first reaction is -15~-5℃, and the reaction time is 5~15min;

[0034] The temperature of the secondary reaction in step 6) is 20~40℃.

[0035] Preferably, the solvent of the compound g solution in step 7) is tetrahydrofuran, and the molar volume ratio of compound g to tetrahydrofuran is 2~8 mmol: 5~15 mL;

[0036] Step 7) The solvent for the sodium hydride solution is tetrahydrofuran and N , N -Dimethylformamide, sodium hydride, tetrahydrofuran and N , N The molar volume ratio of dimethylformamide is 2~10 mmol: 10~30 mL: 1~5 mL;

[0037] The molar ratio of compound g, sodium hydride, and iodomethane is 2~8:2~10:5~10;

[0038] Step 7) The temperature of the first reaction is -15~-5℃, and the reaction time is 5~15min;

[0039] The temperature of the secondary reaction in step 7) is 20~40℃.

[0040] The present invention also provides the aforementioned ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E Application of 3-methoxy-propenyl]phenyl ester compounds in the preparation of antiepileptic drugs.

[0041] The beneficial effects of this invention are:

[0042] The present invention ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E[3-Methoxy-propenyl]phenyl ester compounds can not only significantly reduce the incidence of generalized tonic-clonic seizures, but also significantly prolong the latency of seizures and reduce the Racine score of seizures. They have significant antiepileptic activity, high safety, and potential for the preparation of antiepileptic drugs. Detailed Implementation

[0043] This invention provides a ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E [3-Methoxy-propenyl]phenyl ester compound, wherein... N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E The structural formula of the 3-methoxy-propenyl]phenyl ester compound is: .

[0044] The present invention also provides the aforementioned ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E The preparation method of the [-3-methoxy-propenyl]phenyl ester compound includes the following steps:

[0045] 1) A solution of 2,4,5-trimethoxybenzaldehyde and a solution of boron tribromide were mixed and reacted to obtain compound b;

[0046] 2) Compound b, ethoxyformylmethylenetriphenylphosphine, and toluene were mixed and reacted to obtain compound c;

[0047] 3) React a mixed solution of imidazole and tert-butyldimethylchlorosilane with a solution of compound c to obtain compound d;

[0048] 4) Compound d and diisobutylaluminum hydride were mixed in toluene and reacted to obtain compound e;

[0049] 5) Compound e and tetrabutylammonium fluoride were reacted in tetrahydrofuran to remove the protecting group, yielding compound f;

[0050] 6) React the compound f solution and sodium hydride solution once, then add... N , N -Dimethylcarbamoyl chloride undergoes a secondary reaction to give compound g;

[0051] 7) A solution of compound g is reacted with a sodium hydride solution in one reaction, followed by the addition of iodomethane in a second reaction, to obtain ( N , N-Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E [3-Methoxy-propenyl]phenyl ester compounds.

[0052] In this invention, the structural formula of 2,4,5-trimethoxybenzaldehyde (compound a) is as follows: The structural formula of compound b is The structural formula of compound c is The structural formula of compound d is The structural formula of compound e is The structural formula of compound f is The structural formula of compound g is .

[0053] In this invention, the ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E The synthetic route for the [3-methoxy-propenyl]phenyl ester compound is as follows:

[0054] .

[0055] In this invention, the solvent of the 2,4,5-trimethoxybenzaldehyde solution in step 1) is preferably dichloromethane, and the molar volume ratio of 2,4,5-trimethoxybenzaldehyde to dichloromethane is preferably 40~60 mmol: 140~160 mL, more preferably 45~55 mmol: 142~150 mL, and even more preferably 48~52 mmol: 145~147 mL;

[0056] Step 1) The solvent of the boron tribromide solution is preferably dichloromethane, and the molar volume ratio of boron tribromide to dichloromethane is preferably 40~60 mmol: 40~60 mL, more preferably 45~55 mmol: 45~55 mL, and even more preferably 48~52 mmol: 48~52 mL.

[0057] The molar ratio of 2,4,5-trimethoxybenzaldehyde to boron tribromide is preferably 40~60:40~60, more preferably 45~55:45~55, and even more preferably 48~52:48~52;

[0058] The reaction temperature in step 1) is preferably 20~40℃, more preferably 22~35℃, and even more preferably 25~30℃.

[0059] In this invention, the reaction in step 1) is preferably monitored by TLC until the reactants have reacted completely.

[0060] In this invention, it is preferable to first cool the 2,4,5-trimethoxybenzaldehyde solution described in step 1), and then mix it with the boron tribromide solution;

[0061] The cooling temperature is preferably -20 to -10°C, and more preferably -15°C.

[0062] In this invention, step 1) is preferably carried out in a nitrogen atmosphere, and after the reaction in step 1) is completed, extraction is preferably performed to obtain compound b;

[0063] The reagents used for extraction are preferably dichloromethane and / or ethyl acetate, and the number of extractions is preferably 1 to 5 times, more preferably 2 to 4 times, and even more preferably 3 times.

[0064] In this invention, the molar ratio of compound b to ethoxyformylmethylenetriphenylphosphine in step 2) is preferably 15-25:17-28, more preferably 18-22:18-25, and even more preferably 19-20:20-23; the molar volume ratio of compound b to toluene is preferably 15-25 mmol:30-50 mL, more preferably 18-22 mmol:35-45 mL, and even more preferably 19-20 mol:40 mL.

[0065] The reaction temperature in step 2) is preferably 20~40℃, more preferably 22~35℃, and even more preferably 25~30℃.

[0066] In this invention, the reaction in step 2) is preferably monitored by TLC until the reactants have completely reacted.

[0067] In this invention, step 2) is preferably carried out in a nitrogen atmosphere.

[0068] In this invention, the solvent of the compound c solution in step 3) is preferably... N , N -Dimethylformamide, compound C and N , N The preferred molar volume ratio of dimethylformamide is 10-20 mmol: 20-40 mL, more preferably 12-18 mmol: 25-35 mL, and even more preferably 13-15 mmol: 27-30 mL;

[0069] Step 3) The solvent for the mixed solution of imidazole and tert-butyldimethylchlorosilane is preferably... N , N -Dimethylformamide, imidazole, tert-butyldimethylchlorosilane and N , NThe preferred molar-volume ratio of dimethylformamide is 25-40 mmol: 12-25 mmol: 2-10 mL, more preferably 30-35 mmol: 15-22 mmol: 3-9 mL, and even more preferably 32-34 mmol: 17-20 mmol: 4-8 mL;

[0070] The molar ratio of compound c, tert-butyldimethylchlorosilane and imidazole is preferably 10~20:12~25:25~40, more preferably 12~18:15~22:30~35, and even more preferably 13~15:17~20:32~34;

[0071] The reaction temperature in step 3) is preferably 20~40℃, more preferably 22~35℃, and even more preferably 25~30℃.

[0072] In this invention, the reaction described in step 3) is preferably monitored by TLC until the reactants have completely reacted.

[0073] In this invention, step 3) is preferably carried out in a nitrogen atmosphere, and after the reaction in step 3) is completed, extraction is preferably performed to obtain compound d;

[0074] The reagents used for extraction are preferably dichloromethane and / or ethyl acetate, and the number of extractions is preferably 1 to 5 times, more preferably 2 to 4 times, and even more preferably 3 times.

[0075] In this invention, the molar ratio of compound d to diisobutylaluminum hydride in step 4) is preferably 5~10:15~30, more preferably 6~9:17~28, and even more preferably 6.5~8.5:20~25; the molar volume ratio of compound d to toluene is preferably 5~10mmol:20~50mL, more preferably 6~9mmol:25~45mL, and even more preferably 6.5~8.5mmol:30~40mL.

[0076] The reaction temperature in step 4) is preferably 20~40℃, more preferably 22~35℃, and even more preferably 25~30℃.

[0077] In this invention, the reaction in step 4) is preferably monitored by TLC until the reactants have completely reacted.

[0078] In this invention, the mixing in step 4) is preferably performed by first dissolving compound d in toluene, cooling it, and then adding diisobutylaluminum hydride for mixing.

[0079] The cooling temperature is preferably -80 to -75°C, and more preferably -78°C.

[0080] In this invention, step 4) is preferably carried out under a nitrogen atmosphere, and after the reaction in step 4) is completed, extraction is preferably performed to obtain compound e;

[0081] The reagents used for extraction are preferably dichloromethane and / or ethyl acetate, and the number of extractions is preferably 1 to 5 times, more preferably 2 to 4 times, and even more preferably 3 times.

[0082] In this invention, the molar ratio of compound e and tetrabutylammonium fluoride in step 5) is preferably 3~10:5~10, more preferably 4~9:6~9, and even more preferably 5~8:6.5~8.5; the molar volume ratio of tetrabutylammonium fluoride and tetrahydrofuran is preferably 5~10mmol:5~10mL, more preferably 6~9mmol:6~9mL, and even more preferably 6.5~8.5mmol:6.5~8.5mL.

[0083] The temperature of the deprotection reaction in step 5) is preferably 20~40℃, more preferably 22~35℃, and even more preferably 25~30℃.

[0084] In this invention, the deprotection reaction in step 5) is preferably monitored by TLC until the reactants have completely reacted.

[0085] In this invention, the solvent of the compound f solution in step 6) is preferably tetrahydrofuran, and the molar volume ratio of compound f to tetrahydrofuran is preferably 2~8 mmol: 5~15 mL, more preferably 3~7 mmol: 8~12 mL, and even more preferably 4~6 mmol: 10 mL;

[0086] Step 6) The solvent for the sodium hydride solution is preferably tetrahydrofuran and... N , N -Dimethylformamide, sodium hydride, tetrahydrofuran and N , N The preferred molar volume ratio of dimethylformamide is 2~10 mmol: 10~30 mL: 5~15 mL, more preferably 4~8 mmol: 15~25 mL: 8~12 mL, and even more preferably 5~7 mmol: 20 mL: 10 mL;

[0087] Compound f, sodium hydride and N , N The molar ratio of -dimethylcarbamoyl chloride is preferably 2~8:2~10:2~10, more preferably 3~7:4~8:4~8, and even more preferably 4~6:5~7:5~7;

[0088] Step 6) The temperature of the first reaction is preferably -15~-5℃, more preferably -12~-8℃, and even more preferably -10℃; the reaction time is preferably 5~15min, more preferably 8~12min, and even more preferably 10min.

[0089] The preferred temperature for the secondary reaction in step 6) is 20~40℃, more preferably 22~35℃, and even more preferably 25~30℃.

[0090] In this invention, the secondary reaction in step 6) is preferably monitored by TLC until the reactants have completely reacted.

[0091] In this invention, step 6) is preferably carried out under a nitrogen atmosphere, and after the secondary reaction in step 6) is completed, extraction is preferably performed to obtain compound g;

[0092] The reagents used for extraction are preferably dichloromethane and / or ethyl acetate, and the number of extractions is preferably 1 to 5 times, more preferably 2 to 4 times, and even more preferably 3 times.

[0093] In this invention, the solvent of the compound g solution in step 7) is preferably tetrahydrofuran, and the molar volume ratio of compound g to tetrahydrofuran is preferably 2~8 mmol: 5~15 mL, more preferably 3~7 mmol: 6~14 mL, and even more preferably 4~6 mmol: 8~10 mL.

[0094] Step 7) The solvent for the sodium hydride solution is preferably tetrahydrofuran and... N , N -Dimethylformamide, sodium hydride, tetrahydrofuran and N , N The preferred molar volume ratio of dimethylformamide is 2~10 mmol: 10~30 mL: 1~5 mL, more preferably 4~8 mmol: 12~28 mL: 1.5~4.5 mL, and even more preferably 5~7 mmol: 15~25 mL: 2 mL;

[0095] The molar ratio of compound g, sodium hydride and iodomethane is preferably 2~8:2~10:5~10, more preferably 3~7:4~8:6.5~9.5, and even more preferably 4~6:5~7:7~9;

[0096] Step 7) The temperature of the first reaction is preferably -15~-5℃, more preferably -12~-8℃, and even more preferably -10℃; the reaction time is preferably 5~15min, more preferably 8~12min, and even more preferably 10min.

[0097] The preferred temperature for the secondary reaction in step 7) is 20~40℃, more preferably 22~35℃, and even more preferably 25~30℃.

[0098] In this invention, the secondary reaction in step 7) is preferably monitored by TLC until the reactants have completely reacted.

[0099] In this invention, step 7) is preferably carried out under a nitrogen atmosphere, and after the secondary reaction in step 7) is completed, extraction is preferably performed to obtain ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E [3-Methoxy-propenyl]phenyl ester compounds;

[0100] The reagents used for extraction are preferably dichloromethane and / or ethyl acetate, and the number of extractions is preferably 1 to 5 times, more preferably 2 to 4 times, and even more preferably 3 times.

[0101] The present invention also provides the aforementioned ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E Application of 3-methoxy-propenyl]phenyl ester compounds in the preparation of antiepileptic drugs.

[0102] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0103] Example 1

[0104] Under a nitrogen atmosphere, 51 mmol of 2,4,5-trimethoxybenzaldehyde was dissolved in 146 mL of dichloromethane to obtain a 2,4,5-trimethoxybenzaldehyde solution. 51 mmol of boron tribromide was dissolved in 51 mL of dichloromethane to obtain a boron tribromide solution. The 2,4,5-trimethoxybenzaldehyde solution was cooled to -15 °C, and the boron tribromide solution was added dropwise. After the addition was complete, the reaction was carried out at 30 °C, and the reaction was monitored by TLC until the reactants were completely reacted. The reaction was quenched at 0 °C by adding 50 mL of water, followed by extraction with dichloromethane (3 extractions, each using 50 mL of dichloromethane). The organic phases were collected and combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (initial solvent: petroleum ether and ethyl acetate in a 6:1 volume ratio; final solvent: dichloromethane), and then slurried with petroleum ether to obtain compound b. The mass of compound b was 8.4 g, with a yield of 90.4%.

[0105] The characterization of compound b yielded the following results: 1HNMR (400MHz, CDCl3) δ11.40 (s, 1H), 9.71 (s, 1H), 6.91 (s, 1H), 6.48 (s, 1H), 3.94 (s, 3H), 3.88 (s, 3H).

[0106] Under nitrogen protection, 19.2 mmol of compound b was dissolved in 40 mL of toluene. 21.2 mmol of ethoxyformylmethylenetriphenylphosphine was added at 30 °C, and the reaction was carried out at 30 °C. The reaction was monitored by TLC until the reactants were completely reacted. Insoluble solids were filtered off, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (initial solvent: dichloromethane and ethyl acetate, v / v ratio 15:1; final solvent: dichloromethane and ethyl acetate, v / v ratio 10:1). The product was then slurried with dichloromethane to obtain compound c. The mass of compound c was 3.3 g, with a yield of 68.1%.

[0107] The characterization of compound c yielded the following results: 1 H NMR (400 MHz, DMSO- d 6) δ 9.86 (s, 1H), 7.84 (d, J = 16.0 Hz, 1H), 7.15 (s, 1H), 6.50 (s, 1H), 6.46 (d, J = 16.0 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.74 (s, 3H), 3.72 (s, 3H), 1.24 (t, J = 7.2Hz, 3H).

[0108] Under nitrogen protection, 13.1 mmol of compound c was dissolved in 27 mL of solution. N , N Solution of compound c was obtained by reacting 17.0 mmol of tert-butyldimethylchlorosilane and 33.7 mmol of imidazole in 5 mL of dimethylformamide. N , NA mixed solution of imidazole and tert-butyldimethoxychlorosilane was obtained from dimethylformamide. Solution c of compound c was added to the mixed solution of imidazole and tert-butyldimethoxychlorosilane at 30°C, and the reaction was carried out at 30°C, monitored by TLC until the reactants reacted completely. The reaction was quenched by adding 10 mL of saturated sodium bicarbonate solution, followed by extraction with ethyl acetate (3 times, 30 mL ethyl acetate each time). The organic phases were collected and combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (using petroleum ether and ethyl acetate in a 4:1 volume ratio) to obtain compound d. The mass of compound d was 4.7 g, with a yield of 97.9%.

[0109] Under nitrogen protection, 8.2 mmol of compound d was dissolved in 30 mL of toluene, cooled to -78 °C, and 20.5 mmol of diisobutylaluminum hydride was added at -78 °C. The reaction was initiated at 30 °C, and TLC was monitored until the reactants were fully reacted. 20 mL of methanol was added, followed by 20 mL of 1 mol / L hydrochloric acid to quench the reaction. The mixture was then extracted with dichloromethane (3 times, 30 mL of dichloromethane each time), and the organic phases were collected and combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (using petroleum ether and ethyl acetate in a 3:1 v / v ratio) to give compound e. The mass of compound e was 2.5 g, with a yield of 94.0%.

[0110] The compound e was characterized, and the results are as follows: 1 H NMR (400 MHz, CDCl3) δ 6.96 (s, 1H), 6.86(dd, J = 16.0, 1.6 Hz, 1H), 6.36 (s, 1H), 6.18 (dt, J = 16.0, 6.4 Hz, 1H), 4.30 (dd, J = 6.4, 1.6 Hz, 2H), 3.86 (s, 3H), 3.83 (s, 3H), 1.57 (s, 1H), 1.03 (s, 9H), 0.19 (s, 6H).

[0111] 8.5 mmol of tetrabutylammonium fluoride was dissolved in 8.5 mL of tetrahydrofuran, and then 6.3 mmol of compound e was added. The deprotecting reaction was carried out at 30 °C, and the reaction was monitored by TLC until the reactants were completely reacted. The reaction system was concentrated to obtain a crude product, which was purified by column chromatography (using dichloromethane and methanol in a 20:1 volume ratio). The crude product was then slurried with dichloromethane to obtain compound f. The mass of compound f was 1.24 g, with a yield of 93.6%.

[0112] The compound f was characterized, and the results are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ 9.13 (s, 1H), 6.94 (s, 1H), 6.69 (d, J = 16.0 Hz, 1H), 6.45 (s, 1H), 6.18 (dt, J = 16.0, 5.6 Hz, 1H), 4.71 (t, J = 5.6 Hz, 1H), 4.06 (t, J = 5.6 Hz, 2H), 3.69 (s, 6H).

[0113] Under nitrogen protection, 5.0 mmol of sodium hydride was dissolved in 20 mL of anhydrous tetrahydrofuran and 10 mL of... N , N A sodium hydride solution was obtained by reacting compound f with dimethylformamide. 4.8 mmol of compound f was dissolved in 10 mL of tetrahydrofuran to obtain a solution of compound f. The solution of compound f was added to the sodium hydride solution at -10 °C, and the reaction was carried out once at -10 °C for 10 min. After the first reaction was completed, 5.3 mmol of compound f was added to the reaction system. N , N -Dimethylcarbamoyl chloride was reacted twice at 30°C, and the reaction was monitored by TLC until the reactants were completely reacted. The reaction was quenched by adding 10 mL of saturated ammonium chloride solution, followed by extraction with ethyl acetate (3 times, 20 mL ethyl acetate each time). The organic phases were collected and combined. The organic phase was washed three times with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (initial solvent: petroleum ether and ethyl acetate in a 3:2 volume ratio; final solvent: ethyl acetate) to give compound g. The mass of compound g was 1.2 g, with a yield of 88.9%.

[0114] The compound g was characterized, and the results are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ 7.09 (s, 1H), 6.67 (s, 1H), 6. 47 (dt, J = 16.0, 1.6 Hz, 1H), 6.30 (dt, J = 16.0, 5.2 Hz, 1H), 4.84 (t, J = 5.2 Hz, 1H), 4.10 (td, J= 5.2, 1.6 Hz, 2H), 3.78 (s, 3H), 3.72 (s, 3H), 3.07 (s, 3H), 2.91 (s, 3H).

[0115] Under nitrogen protection, 5.2 mmol of sodium hydride was dissolved in 15 mL of anhydrous tetrahydrofuran and 2 mL of... N , N In dimethylformamide, a sodium hydride solution was obtained. 4.3 mmol of compound g was dissolved in 8 mL of tetrahydrofuran to obtain a solution of compound g. The compound g solution was added to the sodium hydride solution at -10 °C, and the reaction was carried out once at -10 °C for 10 min. After the first reaction, 8.6 mmol of iodomethane was added to the reaction system, and a second reaction was carried out at 30 °C, monitored by TLC until the reactants were completely reacted. The reaction was quenched by adding 10 mL of saturated ammonium chloride solution, followed by extraction with ethyl acetate (3 times, 20 mL ethyl acetate each time). The organic phases were collected and combined, washed three times with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (using petroleum ether and ethyl acetate in a 3:1 volume ratio) to obtain ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E [3-Methoxy-propenyl]phenyl ester compounds. N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E The mass of the 3-methoxy-propenyl]phenyl ester compound was 640 mg, and the yield was 50.4%.

[0116] right( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E The compound was characterized as follows: [3-methoxy-propenyl]phenyl ester. 1 H NMR (400 MHz, DMSO- d 6) δ 7.12 (s, 1H), 6.69 (s, 1H), 6.48 (dt, J = 16.0, 1.6 Hz, 1H), 6.27 (dt, J = 16.0, 5.6 Hz, 1H), 4.02 (dd, J= 5.6, 1.2 Hz, 2H), 3.79 (s, 3H), 3.72 (s, 3H), 3.27 (s, 3H), 3.07 (s, 3H), 2.91 (s, 3H);

[0117] 13 C NMR (100 MHz, DMSO- d 6) δ 154.1, 148.8, 146.5, 142.2, 126.1, 124.5,120.9, 108.3, 107.2, 72.4, 57.2, 55.8, 55.7, 36.4, 36.1.

[0118] Experimental Example 1

[0119] The (prepared using Example 1) N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E The protective effect of 3-methoxy-propenyl]phenyl ester compound against a PTZ-induced mouse model of epilepsy was tested using the following method:

[0120] 100mg ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E [3-Methoxy-propenyl]phenyl ester compound and 1.0 g of polyethylene glycol-15-hydroxystearate (HS-15) were placed in a beaker, and 8 mL of physiological saline was added. The mixture was stirred with a magnetic stirrer at 65 °C until completely dissolved. After cooling to room temperature, the volume was adjusted to 10 mL with physiological saline, and then filtered through a 0.22 μm microporous membrane to obtain a clear and homogeneous micelle solution. 300 mg of PTZ was dissolved in 30 mL of physiological saline to obtain a PTZ solution with a concentration of 10 mg / mL. Twenty SPF-grade adult male KM mice, each weighing 25–35 g, were selected. The mice were randomly divided into two groups of 10 each: a model group and an experimental group. Each mouse was injected with PTZ solution at a dose of 70 mg / kg to induce generalized tonic-clonic seizures (Racine score ≥4), with seizures lasting at least 5 seconds. Three minutes later, both groups of mice were administered the drug via intraperitoneal injection; the model group received physiological saline, and the experimental group received the micelle solution. After the injection, mice were observed for 30 minutes, and their Racine scores and seizure latency were recorded. The generalized tonic seizure rate (TSR) was also calculated. Racine scores of 1-3 were classified as clonic seizures, and Racine scores of 4-5 were classified as generalized tonic seizures. If no seizures occurred within 30 minutes, the latency was recorded as 1800 seconds.

[0121] The Racine scoring criteria are: Grade 0 (normal non-epileptic activity), Grade 1 (wet dog-like shaking or scratching), Grade 2 (head nodding or tail wagging), Grade 3 (unilateral forelimb extension or unilateral limb clonus), Grade 4 (multiple limb clonus or tonic), and Grade 5 (fall and generalized tonic-clonic seizures).

[0122] The test results are shown in Table 1.

[0123] Table 1. Example 1 ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E Protective effect of 3-methoxy-propenyl]phenyl ester compound on a mouse model of epilepsy

[0124]

[0125] Compared with the model group, P≤0.01, the latency period was determined by independent samples t-test, the Racine score was determined by Mann-Whitney U test, and the incidence of tetany was determined by Fisher exact test.

[0126] As can be seen from Table 1, ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E [3-Methoxy-propenyl]phenyl ester compounds can significantly reduce the incidence of generalized tonic-clonic seizures, significantly prolong the latency of seizures, and also significantly reduce the Racine score of seizures. These results indicate that... N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E [3-Methoxy-propenyl]phenyl esters have significant antiepileptic activity and can be used to prepare candidate drugs for the clinical prevention and treatment of epilepsy.

[0127] Experimental Example 2

[0128] The (prepared using Example 1) N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E The protective effect of 3-methoxy-propenyl]phenyl ester compound against mouse maximal electric shock (MES) model was tested using the following method:

[0129] 100mg ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1E [3-Methoxy-propenyl]phenyl ester compound and 1.0 g of polyethylene glycol-15-hydroxystearate (HS-15) were placed in a beaker, and 8 mL of physiological saline was added. The mixture was stirred with a magnetic stirrer at 65 °C until completely dissolved. After cooling to room temperature, the volume was adjusted to 10 mL with physiological saline, and then filtered through a 0.22 μm microporous membrane to obtain a clear and homogeneous micelle solution. Twelve SPF-grade adult male KM mice, each weighing 25–35 g, were selected. The mice were randomly divided into two groups of six each: a model group and an experimental group. The model group was administered physiological saline via intraperitoneal injection, while the experimental group was administered the micelle solution. Five minutes after drug administration, the two alligator clips on the electrode output lines of the physiological pharmacology electronic stimulator were moistened with physiological saline and then clamped onto both ears of the mice. The pulse width of the physiological pharmacology electronic stimulator was set to 20 ms, the interval to 10 ms, the wave number to 100, the voltage to 200V, the current limit to 4mA, and the waveform to be "positive pulse + interval + negative pulse". The "start" button was pressed, and the mice were observed to see if they exhibited tonic-clonic seizures with forelimb flexion and hindlimb extension. The test results are shown in Table 2.

[0130] Table 2. Examples of Example 1 ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E Protective effect of 3-methoxy-propenyl]phenyl ester compounds on maximal electroshock model

[0131]

[0132] Compared with the model group, P≤0.001, protection rate was determined using Fisher's exact test.

[0133] As can be seen from Table 2, ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E [3-Methoxy-propenyl]phenyl ester compounds can significantly inhibit tonic-clonic seizures. This result further illustrates that ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E [3-Methoxy-propenyl]phenyl ester compounds have strong anti-epileptic activity.

[0134] Experimental Example 3

[0135] The (prepared using Example 1) N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 EThe acute toxicity test results of the [3-methoxy-propenyl]phenyl ester compound in mice were tested using the following method:

[0136] 100mg ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E [3-Methoxy-propenyl]phenyl ester compound and 1.0 g of polyethylene glycol-15-hydroxystearate (HS-15) were placed in a beaker, and 8 mL of physiological saline was added. The mixture was stirred with a magnetic stirrer at 65 °C until completely dissolved. After cooling to room temperature, the volume was adjusted to 10 mL with physiological saline, and then filtered through a 0.22 μm microporous membrane to obtain a clear and homogeneous micelle solution. Eighty healthy adult KM mice, weighing 18–22 g, half male and half female, were used. The mice were randomly divided into 8 groups, with 5 male mice and 5 female mice in each group. One group was a blank control group, which received physiological saline. The other 7 groups were drug treatment groups, which were administered intraperitoneally at doses of 400 mg / kg, 480 mg / kg, 570 mg / kg, 690 mg / kg, 830 mg / kg, 1000 mg / kg, and 1200 mg / kg, respectively. N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E Mice were treated with a 3-methoxy-propenyl]phenyl ester compound micelle solution and observed for 14 days. Mice mortality was assessed using the PROBIT model. 50 And a 95% confidence limit.

[0137] Acute toxicity test results

[0138] ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E Intraperitoneal injection of micelized [3-methoxy-propenyl]phenyl ester compound at doses exceeding 0.4 g / kg resulted in toxic symptoms in mice including decreased spontaneous activity, unsteady gait, tremors, and tonic convulsions. The severity and duration of toxic symptoms were dose-dependent. Table 3 shows the mortality rates of mice in each group two weeks later. The median lethal dose (LD50) was calculated using the PROBIT model. 50 = 747 mg / kg, 95% confidence limit is 663~843 mg / kg.

[0139] Table 3. Example 1 ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E Acute toxicity of 3-methoxy-propenyl]phenyl ester compounds

[0140]

[0141] As can be seen from Table 3, ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E [3-Methoxy-propenyl]phenyl ester compounds have high safety.

[0142] This invention provides a ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E [3-methoxy-propenyl]phenyl ester compounds, their preparation methods and applications, and the present invention ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E The 3-methoxy-propenyl]phenyl ester compound not only significantly reduced the incidence of generalized tonic seizures and the Racine score of seizures in a pentylenetetrazol-induced epileptic mouse model, but also significantly prolonged the latency of seizures, demonstrating significant antiepileptic activity and safety.

[0143] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A kind of ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E [3-methoxy-propenyl]phenyl ester compound, characterized in that, The ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E The structural formula of the 3-methoxy-propenyl]phenyl ester compound is: 。 2. The claim 1 as described in ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E A method for preparing 3-methoxy-propenyl]phenyl ester compounds, characterized in that, It includes the following steps: 1) A solution of 2,4,5-trimethoxybenzaldehyde and a solution of boron tribromide were mixed and reacted to obtain compound b; 2) Compound b, ethoxyformylmethylenetriphenylphosphine, and toluene were mixed and reacted to obtain compound c; 3) React a mixed solution of imidazole and tert-butyldimethylchlorosilane with a solution of compound c to obtain compound d; 4) Compound d and diisobutylaluminum hydride were mixed in toluene and reacted to obtain compound e; 5) Compound e and tetrabutylammonium fluoride were reacted in tetrahydrofuran to remove the protecting group, yielding compound f; 6) React the compound f solution and sodium hydride solution once, then add... N , N -Dimethylcarbamoyl chloride undergoes a secondary reaction to yield compound g; 7) A solution of compound g is reacted with a sodium hydride solution in one reaction, followed by the addition of iodomethane in a second reaction, to obtain ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E [3-Methoxy-propenyl]phenyl ester compounds.

3. As described in claim 2 ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E A method for preparing 3-methoxy-propenyl]phenyl ester compounds, characterized in that, Step 1) The solvent for the 2,4,5-trimethoxybenzaldehyde solution is dichloromethane, and the ratio of 2,4,5-trimethoxybenzaldehyde to dichloromethane is 40~60 mmol: 140~160 mL. Step 1) The solvent for the boron tribromide solution is dichloromethane, and the ratio of boron tribromide to dichloromethane is 40~60 mmol: 40~60 mL; The molar ratio of 2,4,5-trimethoxybenzaldehyde to boron tribromide is 40~60:40~60; The reaction temperature in step 1) is 20~40℃.

4. As described in claim 2 ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E A method for preparing 3-methoxy-propenyl]phenyl ester compounds, characterized in that, Step 2) The molar ratio of compound b to ethoxyformylmethylenetriphenylphosphine is 15~25:17~28, and the molar ratio of compound b to toluene is 15~25 mmol:30~50 mL; The reaction temperature in step 2) is 20~40℃.

5. As described in claim 2 ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E A method for preparing 3-methoxy-propenyl]phenyl ester compounds, characterized in that, Step 3) The solvent of the compound c solution is N , N -Dimethylformamide, compound C and N , N The dosage ratio of dimethylformamide is 10~20mmol: 20~40mL; Step 3) The solvent for the mixed solution of imidazole and tert-butyldimethylchlorosilane is N , N -Dimethylformamide, imidazole, tert-butyldimethylchlorosilane and N , N The dosage ratio of dimethylformamide is 25~40 mmol: 12~25 mmol: 2~10 mL; The molar ratio of compound c, tert-butyldimethylchlorosilane, and imidazole is 10~20:12~25:25~40; The reaction temperature in step 3) is 20~40℃.

6. As described in claim 2 ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E A method for preparing 3-methoxy-propenyl]phenyl ester compounds, characterized in that, Step 4) The molar ratio of compound d to diisobutylaluminum hydride is 5~10:15~30, and the molar ratio of compound d to toluene is 5~10 mmol:20~50 mL; The reaction temperature in step 4) is 20~40℃.

7. The method according to claim 2 ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E A method for preparing 3-methoxy-propenyl]phenyl ester compounds, characterized in that, Step 5) The molar ratio of compound e to tetrabutylammonium fluoride is 3~10:5~10, and the molar ratio of tetrabutylammonium fluoride to tetrahydrofuran is 5~10 mmol:5~10 mL; Step 5) The temperature for the deprotection reaction is 20~40℃.

8. As described in claim 2 ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E A method for preparing 3-methoxy-propenyl]phenyl ester compounds, characterized in that, Step 6) The solvent for the compound f solution is tetrahydrofuran, and the ratio of compound f to tetrahydrofuran is 2~8 mmol: 5~15 mL; Step 6) The solvent for the sodium hydride solution is tetrahydrofuran and N , N -Dimethylformamide, sodium hydride, tetrahydrofuran and N , N The dosage ratio of dimethylformamide is 2~10 mmol: 10~30 mL: 5~15 mL; Compound f, sodium hydride and N , N The molar ratio of -dimethylcarbamoyl chloride is 2~8:2~10:2~10; Step 6) The temperature of the first reaction is -15~-5℃, and the reaction time is 5~15min; The temperature of the secondary reaction in step 6) is 20~40℃.

9. As described in claim 2 ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E A method for preparing 3-methoxy-propenyl]phenyl ester compounds, characterized in that, Step 7) The solvent for the compound g solution is tetrahydrofuran, and the ratio of compound g to tetrahydrofuran is 2~8 mmol: 5~15 mL; Step 7) The solvent for the sodium hydride solution is tetrahydrofuran and N , N -Dimethylformamide, sodium hydride, tetrahydrofuran and N , N The dosage ratio of dimethylformamide is 2~10 mmol: 10~30 mL: 1~5 mL; The molar ratio of compound g, sodium hydride, and iodomethane is 2~8:2~10:5~10; Step 7) The temperature of the first reaction is -15~-5℃, and the reaction time is 5~15min; The temperature of the secondary reaction in step 7) is 20~40℃.

10. The claim 1 as described in ( N , N -Dimethylamino)formic acid-4,5-dimethoxy-2-[(1 E Application of 3-methoxy-propenyl]phenyl ester compounds in the preparation of antiepileptic drugs.

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