WO2018014834A1 - 3-hydrocarbyl-5,6-dioxy-substituted phthalide compound and preparation method and use thereof - Google Patents

Abstract

Disclosed are a 3-hydrocarbyl-5,6-dioxy-substituted phthalide compound and a preparation method and use thereof. The structure of the phthalide compound is as shown in formula (I): wherein the definitions of R₁, R₂ and R₃ are as described in the specification and claims. The phthalide compound is easy to synthesize, has a good stability and safety, and has a significant anti-inflammatory activity and neuroprotective effects, and can be used in the preparation of drugs for preventing and/or treating nervous system diseases.

Description

3-hydrocarbyl-5,6-dioxosubstituted benzoquinone compound, preparation method and use thereof Technical field

The invention relates to a kind of 3-hydrocarbyl-5,6-dioxy-substituted benzoquinone compound, a preparation method thereof and use thereof, and belongs to the technical field of medicine.

Background technique

Neuroinflammation is closely related to the pathological process of many neurological diseases. These diseases involve Alzheimer's disease, vascular dementia, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, diabetic neuropathy, and brain tissue caused by ischemic stroke, hemorrhagic stroke, and trauma. Damage, etc. In addition, long-term or excessive inflammatory reactions may also lead to mental illness such as depression and anxiety. Inflammation in the brain is induced by activated microglia and reactive astrocytes. These cells are intrinsic immune cells in the brain. Under physiological conditions, they act to remove foreign substances such as pathogenic microorganisms and autologous necrotic cells in the central nervous system to maintain the stability of the inner environment of the nervous tissues. Under pathological conditions, glial cells are Sustained by various pathogenic substances, a large number of inflammatory factors such as tumor necrosis factor-α, interleukin-1β and interferon-γ are secreted to form a pathological cascade, resulting in neuronal damage or even death, induced or Aggravate neurological lesions. Recent studies have found that the risk-related molecular patterns (DAMPs) of the release of neuronal cells after stroke - the peroxide reductase family (Prxs) loses antioxidant activity, but activates macrophage TLR2/TLR4 and mediates neuroinflammation. The core pathophysiological mechanism of brain tissue damage after stroke [Nature Medicine. 2011, 17: 796; Nature Medicine. 2012, 18: 858].

Another important factor affecting the function of the nervous system is the lack of supply or imbalance of the body's material and energy, especially the lack of supply of glucose and oxygen and the imbalance of energy metabolism of other substances caused by cerebrovascular disease. For example, there is a significant positive correlation between the occurrence and development of neurodegenerative diseases and abnormal glucose and lipid metabolism such as diabetes, obesity, and hypercholesterolemia. In the early stage of the disease, the brain's utilization of sugar and cerebral blood flow decreased significantly, which led to changes in the blood flow of the patient's brain microcirculation, which limited the compensation of cerebral blood flow, and caused insufficient oxygen and glucose to the brain. The disorder of energy metabolism in the nervous system causes neurological diseases.

Therefore, inhibiting the excessive release of inflammatory factors under pathological conditions and improving the energy metabolism of the brain are important intervention strategies for relieving nerve damage.

China's natural medicine resources are rich, and its application history is long. It is a valuable asset for modern drug research and development. Active screening and structural modification of natural products derived from traditional drugs is still an effective means of discovering innovative drugs. Butylphthalide (NBP) is a benzoquinone compound extracted from celery seeds. Chuanxiong, Angelica, Sakamoto, etc. also contain this ingredient. Butylphthalide of natural origin is an optically active left-handed body. Current person The synthetic racemate is used as a new chemical entity in China for the treatment of mild to moderate acute ischemic stroke. Studies have shown that butylphthalide has significant neuroprotective effects, can increase cerebral blood flow in the ischemic region and reconstruct microcirculation in the ischemic region, protect mitochondrial function, inhibit platelet aggregation and thrombosis, and improve energy after global cerebral ischemia. The degree of metabolism and reduction of neurological damage involves multiple aspects of cerebral ischemic pathology and has significant therapeutic effects on stroke. In addition, butylphthalide has certain effects on many neurological diseases such as Alzheimer's disease, vascular dementia, Parkinson's disease, diabetic neuropathy, memory disorder, stroke, traumatic brain injury, epilepsy, and depression. Improvement.

However, butyl benzoquinone also has some shortcomings. For example, the compound is a high-boiling oil, and its purification and purification have high requirements on production equipment; it is unstable in the body, and the metabolism is quickly cleared; it is an oil at room temperature, and it is not convenient to prepare an oral solid preparation, and currently only soft capsules are used for oral use. Has a special smell and may cause discomfort.

Studies have found that 2-(α-hydroxypentyl)benzoic acid and its salts rapidly undergo ring-closing reactions in plasma to form butylphthalide. The reaction of butylphthalide with a base to convert to a prodrug, 2-(α-hydroxypentyl)benzoic acid and a salt thereof, can improve the defect of poorly water-soluble butylphthalide. However, 2-(α-hydroxypentyl)benzoic acid and its salts, including inorganic salts such as potassium, sodium, calcium, magnesium, and zinc, and organic amine salts such as benzylamine, morpholine, and diethylamine, often have poor crystallinity. It has the disadvantages of strong hygroscopicity, easy decomposition, and instability in acidic or neutral environment. Further, an aqueous solution of a potassium salt or a sodium salt of 2-(α-hydroxypentyl)benzoic acid is alkaline (usually pH>9), and has a certain physiological irritancy.

The present inventors designed and synthesized a series of benzoquinone compounds against the deficiencies of the prior art, and selected benzoquinone compounds which are more active, safer and have better drug-forming properties.

Summary of the invention

The Applicant has proposed the present invention in order to overcome the drawbacks and deficiencies of butyl benzoquinone and to obtain better benzoquinones.

In a first aspect of the invention, there is provided a benzoquinone compound, or a pharmaceutically acceptable solvate, prodrug thereof, which is selected from the group consisting of Formula I:

Wherein: R _{1 is} selected from a C ₃ -C 6 hydrocarbon group; and R ₂ and R _{3 are} independently selected from hydrogen, C 1 -C ₃ alkyl, acetyl.

The "hydrocarbyl group" as used in the present invention means a linear or branched aliphatic hydrocarbon group including an alkyl group, an alkenyl group, and an alkynyl group.

The "solvate" as used in the present invention means an aggregate in which a compound represented by the formula I is associated with one or more solvent molecules during crystallization. The solvent molecule can be water or other organic solvent (e.g., ethanol, isopropanol, diethyl ether, ethyl acetate, acetone, etc.).

The "prodrug" as used in the present invention means a carboxylic acid and a salt thereof which are produced by reacting a phenylhydrazine compound represented by the formula I with a base and undergoing a ring opening reaction of the lactone. The above base includes inorganic bases (such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, etc.), organic bases (such as benzylamine, morpholine, ethylenediamine, ethanolamine, piperazine, choline, methylamine). , dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, etc.). The above carboxylic acid and its salt can be converted into a parent drug (benzoquinone compound represented by the formula I) under physiological conditions in vivo.

Based on the structure of the formula I, the benzoquinone compound of the invention is characterized in that R _{1 is} selected from the group consisting of n-propyl, n-butyl, n-pentyl, 2-allyl, 2-enbutyl, 3 -enylbutyl, 1-methyl-3-enylbutyl, 1-methyl-2-allyl, 2-methyl-2-allyl, 1,1-dimethyl-2- ene 1,1,2-dimethyl-2-allyl, 3-methyl-2-enylbutyl, 2,2-dimethyl-3-enylbutyl, 3-methyl-3-ene Base, 4-methyl-3-enpentyl, 1-methyl-1-vinyl, 1-ethyl-1-vinyl, 1-propyl-1-vinyl, 2-propargyl, 3 - alkynyl butyl; R ₂ and R _{3 are} independently selected from the group consisting of hydrogen, methyl, acetyl.

The benzoquinone compound of the present invention is further preferably selected from the following compounds:

In a second aspect of the invention, the benzoquinone compound can be prepared by the following method:

Compound 1 was reacted with HCl and a 37% formaldehyde solution at 10 to 80 ° C for 4 to 12 hours to obtain Compound 2. The compound 2 is reacted with N-bromosuccinimide (NBS) at 20 to 100 ° C for 2 to 8 hours using CCl ₄ or benzene as a solvent and benzoyl peroxide as a catalyst to obtain a compound 3. Compound 3 is reacted with water at 20 to 100 ° C for 1 to 4 hours to form Compound 4. Compound 4 is reacted with a halogenated alkaloid Grignard reagent (e.g., R ₁ MgBr, R ₁ MgCl, etc.) to give the target compound 5.

In a third aspect of the invention, there is provided a pharmaceutical composition comprising a safe and effective amount of one or more benzoquinone compounds, and pharmaceutically acceptable solvates, prodrugs thereof.

The "composition" as used in the present invention means a product obtained by mixing one or more substances or components. The composition of the present invention comprises 1% by weight to 95% by weight, preferably 10% by weight to 80% by weight, of the benzoquinone compound of the first aspect, and a pharmaceutically acceptable solvate thereof, a prodrug thereof, The total weight of the pharmaceutical composition.

The "safe and effective amount" as used in the present invention means that the benzoquinone compound of the present invention is administered in a dose sufficient to significantly improve the condition without causing serious side effects. A safe and effective amount of a compound of the invention may depend on the route of administration, The patient's age, weight, type of disease, and severity thereof vary. For a person weighing 60 kg, the daily dose is usually from 10 mg to 1500 mg, preferably from 30 mg to 600 mg. It can be administered once or in multiple doses.

As one of the preferred embodiments, the pharmaceutical composition may be further added with one or more pharmaceutically acceptable carriers to prepare a pharmaceutically acceptable pharmaceutical preparation.

As used herein, "pharmaceutically acceptable carrier" means one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. . By "compatibility" it is meant herein that the components of the composition are capable of blending with the benzoquinone compounds of the invention and with each other without significantly reducing the efficacy of the benzoquinone compound. Pharmaceutically acceptable carriers include sugars (such as sucrose, lactose, glucose, etc.), starches (such as potato starch, corn starch, etc.), cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, Cellulose acetate, etc., dextrin and its derivatives, micronized silica gel, gelatin, talc, calcium sulfate, solid lubricants (such as magnesium stearate, stearic acid, etc.), vegetable oils (such as soybean oil, sesame oil, Peanut oil, olive oil, castor oil, cottonseed oil, corn germ oil, palm oil, etc.), alcohol solvents (such as ethanol, propylene glycol, glycerin, mannitol, sorbitol, polyethylene glycol, etc.), surfactants, emulsifiers , wetting agents, colorants, flavors, stabilizers, antioxidants, preservatives, no heat source water.

The "pharmaceutical preparation" according to the present invention includes tablets, capsules, pills, granules, pills, powders, troches, injections, freeze-dried powders, syrups, oral liquids, patches, inhalation powders, Sprays are administered orally, intravenously, intramuscularly, subcutaneously, sublingually, transdermally, orally sprayed, or nasally.

A fourth aspect of the invention provides the use of the phenylhydrazine compound of the first aspect, and a pharmaceutically acceptable solvate thereof, a prodrug thereof, or a pharmaceutical composition according to the third aspect, for use in the preparation of prophylaxis and/or A drug that treats nervous system diseases.

The "neurological diseases" according to the present invention include Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, diabetic neuropathy, ischemic stroke, hemorrhagic stroke, and brain trauma. Caused by nerve damage, depression, vascular dementia, neuropathic pain.

In another preferred embodiment, the prevention and/or treatment of a nervous system disease is achieved by inhibiting excessive release of inflammatory factors under pathological conditions.

In another preferred embodiment, the prevention and/or treatment of a nervous system disorder is achieved by improving brain blood vessels and blood flow states, and regulating energy metabolism in the brain.

A fifth aspect of the invention provides the use of the phenylhydrazine compound of the first aspect, and a pharmaceutically acceptable solvate thereof, a prodrug or a pharmaceutical composition according to the third aspect, for:

(a) preparing a medicament for preventing and/or treating damage caused by inflammation-induced nerve cells;

(b) for the preparation of a medicament for preventing and/or treating nerve cell damage induced by cerebral vascular occlusion.

Beneficial effect

The benzoquinone compound disclosed in the invention can alleviate peroxidase 4 (Prx4)-induced cell inflammatory damage, has significant neuroprotective effect, and has better effect than butylphthalide; the benzoquinone compound disclosed in the present invention is crystalline Sexual solid, not easy to absorb moisture, no obvious odor, stable physicochemical properties, can be more conveniently prepared than the butyl benzoquinone which is oily at normal temperature; the benzoquinone compound disclosed in the present invention is at pH 1 ～ It is stable in the range of 9 and is superior to butylphthalide in plasma. The benzoquinone compound disclosed in the present invention has low toxicity and good safety.

DRAWINGS

Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings, in which:

Figure 1 shows the concentration of NO in the blank group, model group, and RAW264.7 macrophages treated with different concentrations of the compounds of the present invention (C-1 to C-6) and butylphthalide (NBP). Compared with the model group: *P<0.05, **P<0.01.

Figure 2 is a graph showing the effects of the compounds (C-1 to C-3) and butylphthalide (NBP) of the present invention on neuropathological changes of cerebral ischemia in mice.

Detailed ways

The following examples are intended to further illustrate the invention, but are not intended to limit the scope of the invention. The invention is further illustrated in detail below with reference to the examples, but those skilled in the art will understand that the invention is not limited to the examples and the methods of preparation used. Furthermore, equivalent substitutions, combinations, improvements or modifications of the invention may be made by those skilled in the art in light of the description of the invention.

Example 1 Preparation of 5,6-dimethoxybenzoquinone

280 ml of a 37% aqueous formaldehyde solution was slowly introduced into HCl gas for 2 hours, 36.4 g of 3,4-dimethoxybenzoic acid was added, and the reaction was carried out at 60 ° C for 10 hours with continuous passage of HCl. After the reaction mixture was concentrated under reduced pressure, water (240 ml) was added, and the mixture was stirred, and then aqueous ammonia was adjusted to pH 7, and the precipitate was allowed to stand. The precipitate was filtered, washed with water several times and then crystallised from MeOH toield.

Example 2 Preparation of 3-hydroxy-5,6-dimethoxyphenylhydrazine

6.76 g of 5,6-dimethoxyphenylhydrazine, 116 mg of benzoyl peroxide, and 7.0 g of N-bromosuccinimide were dissolved in 88 ml of CCl ₄ and heated under reflux for 4 hours. The reaction solution was allowed to stand at 4 ° C for 12 hours. Filter to remove the precipitate. The filtrate was concentrated, 30 ml of water was added, and the mixture was heated to reflux for 1.5 hours. The reaction solution was allowed to stand at 4 ° C for 12 hours. After filtration, the cake was washed with ice water, and dried under reduced pressure at 50 ° C to afford white crystals.

Example 3 Preparation of 3-(3'-methyl-2'-ene)butyl-5,6-dimethoxyphenylhydrazine

1.0 g of Mg powder, protected with N ₂ , 10 ml of anhydrous THF was added, and 5 ml of a solution of 3-methyl-2-enylbutyl-1-bromide in THF (3-methyl-2-enylbutyl) was added dropwise at 5 °C. -1-bromo 5.6 g was dissolved in THF (15 ml). After the reaction was initiated, the remaining solution was added dropwise and reacted at 5 ° C for 2 hours to obtain a Grignard reagent. 3.0 g of 3-hydroxy-5,6-dimethoxyphenylhydrazine was dissolved in 27 ml of anhydrous THF, and the mixture was added dropwise to a fresh Grignard reagent solution at 0 ° C, and reacted at 30 ° C for 12 hours. 10 ml of a saturated NH ₄ Cl solution was added, and after the reaction was stabilized, 13 ml of 10% hydrochloric acid was added, and the mixture was reacted at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate. The organic phase was concentrated and applied to a silica gel column eluting with petroleum ether-ethyl acetate (5:1) to yield white solids: 2.1 g, 3-(3'-methyl-2'-ene)butyl-5,6 -Dimethoxybenzoquinone: HR-TOF-MS (m/z): 261.1122 ([MH] ^- , calculated: 261.1127, [C ₁₅ H ₁₇ O ₄ ] ^- ); ¹ H-NMR (400 MHz, CDCl ₃ ): δ7.25(1H, s), δ7.23(1H, s), δ5.49(1H, t), δ5.02(1H, t), δ3.88(3H, s), δ3. 84 (3H, s), δ 2.77 (1H, m), δ 2.46 (1H, m), δ 1.64 (3H, s), δ 1.58 (3H, s).

Example 4 Preparation of 3-propargyl-5,6-dimethoxybenzoquinone

Mg powder 3.0g, N ₂ protection, add anhydrous THF 30ml, add 15ml of 2-propargyl-1-bromide-containing THF solution (2-propargyl-1-bromide 4.5g in THF 40ml) at 5 °C After the reaction is initiated, the remaining solution is added dropwise and reacted at 10 ° C for 1 hour to obtain a Grignard reagent. 9.0 g of 3-hydroxy-5,6-dimethoxyphenylhydrazine was dissolved in 80 ml of anhydrous THF, and the mixture was added dropwise to a fresh Grignard reagent solution at 0 ° C, and reacted at 45 ° C for 8 hours. 40 ml of a saturated NH ₄ Cl solution was added, and after the reaction was stabilized, 40 ml of 10% hydrochloric acid was added, and the mixture was reacted at room temperature for 4 hours. The reaction solution was extracted with ethyl acetate. The organic phase was concentrated and applied to a silica gel column eluting with petroleum ether-ethyl acetate (3:1) to afford 6.8 g of white solid, 3-propypropyl-5,6-dimethoxybenzoquinone: white solid; HR-TOF-MS (m/z): 231.0651 ([MH] ^- , calculated: 231.0657, [C ₁₃ H ₁₁ O ₄ ] ^- ); ¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.29 (1H) , s), δ 7.11 (1H, s), δ 5.45 (1H, q), δ 3.99 (3H, s), δ 3.95 (3H, s), δ 2.95 (1H, m), δ2 .68 (1H, m), δ 2.09 (1H, t).

Example 5 Plasma Stability of Benzoquinone Compounds

Add 195 μl of 1:1 diluted male SD rat plasma to the centrifuge tube with phosphate buffer (pH 7.4), then add 5 μl of the test compound DMSO solution at a concentration of 40 μmol/L, conceal, vortex and mix, 37 Incubate for 3 hours at °C. The reaction was quenched with 600 μl of cold acetonitrile, immediately mixed and centrifuged for HPLC measurement. The remaining percentage was calculated by incubating the compound concentration at zero time for 100%. The results are as follows:

Numbering	Compound name	Percentage remaining
C-1	3-(3'-methyl-2'-ene)butyl-5,6-dimethoxybenzoquinone	94.1%
C-2	3-(1',1'-dimethyl-2'-ene)propyl-5,6-dimethoxybenzoquinone	89.4%
C-3	3-(1'-methyl-2'-ene)propyl-5,6-dimethoxybenzoquinone	91.6%
C-4	3-propargyl-5,6-dimethoxybenzoquinone	88.9%
C-5	3-(2'-methyl-2'-ene)propyl-5,6-dimethoxybenzoquinone	93.7%
C-6	3-n-butyl-5,6-dimethoxybenzoquinone	87.0%
C-7	3-(2'-ethyl)butyl-5,6-dimethoxybenzoquinone	85.7%
C-8	3-(1',2'-dimethyl-2'-ene)propyl-5,6-dimethoxybenzoquinone	89.3%
C-9	3-(3'-ethyl)butyl-5,6-dimethoxybenzoquinone	83.5%
NBP	3-n-butylphenylhydrazine	71.8%

Example 6 Effect of Phenylhydrazine Compound on NO Secretion by Cells

RAW264.7 macrophages in the logarithmic growth phase were adjusted to a cell density of 5 × 10 ⁵ /ml, seeded in a 96-well plate, 100 μl / well, and cultured in a 37 ° C, 5% CO ₂ incubator. After the cells were attached for 20 hours, the medium in the well was discarded, and 80 μl/well of basal medium was added, and 10 μl/well of the test compound at different concentrations was added, and after 1 hour, Prx4 was added to a final concentration of 20 nmol/ml. The cell supernatant was collected after 20 hours. The color content was measured by NaNO ₂ using a colorimetric method, and the NO content was detected at a wavelength of 550 nm. The results are shown in Fig. 1.

The results showed that Prx4 can stimulate the inflammatory response of RAW264.7 macrophages, resulting in a significant increase in NO content, while the benzoquinone compound of the present invention can inhibit the increase of NO secretion caused by Prx4 and reduce the degree of inflammatory damage of cells, and the effect is better. NBP.

Example 7 Neuroprotective effect on cerebral ischemia in mice

SPF male C57 mice were randomly divided into groups of 8 and the literature was used to prepare a model of cerebral ischemia in which the bilateral common carotid arteries were transiently ligated (Free Radical Biology and Medicine. 2011, 50: 1780-1786; Neuropharmacology. 2014) , 77: 453-464). At the time of ischemia reperfusion, 24 hours and 48 hours, 30 mg/kg of different benzoquinone compounds (C-1 group, C-2 group, C-3 group, NBP group) or blank vehicle (Sham group) were administered by intraperitoneal injection. And Model group). After 72 hours of reperfusion, neurobehavioral evaluation was performed. The animals were sacrificed and the brain Nissl staining was used to detect the number of surviving neurons in the hippocampal CA1 region and the striatum CPu brain region. The results are shown in Fig. 2.

Compared with the sham operation group (Sham group), the bilateral common carotid arteries in the mice were temporarily ligated to cause cerebral ischemia, causing neurobehavioral disorders, neuronal loss and astrocyte overactivation in the model group (Model group); After cerebral ischemia and reperfusion, different phenylhydrazine compounds were given. C-1, C-2 and C-3 all showed strong neuroprotective effects, which could not only improve the mice 24 hours after 48 hours of hypoperfusion. Hour and 72 hours of neurobehavioral function, also It can increase the number of neurons in the hippocampus and striatum brain regions, and the effect is better than NBP.

Example 8 Acute toxicity to mice

SPF grade ICR mice, 18-20 g, male and female, 3 days after adaptive feeding, fasted for 12 hours and weighed randomly into groups: vehicle group and drug group (C-1, C-2, C-3). Each test compound was prepared by suspending 0.5% carboxymethylcellulose sodium solution before use, and the dosage was 1.0 g/20 ml/kg; the vehicle group was intragastrically administered with 20 ml/kg of blank solvent. After the administration, the animals were kept in a single cage within 48 hours, and the animals were continuously observed 2 hours after the drug, and the animals were weighed 7 days and 14 days after the drug.

Under the experimental conditions, C-1, C-2, C-3 gavage dose of 1.0g/kg showed no adverse reactions in ICR mice; during the 14-day observation period, each drug-administered group and the vehicle group were small. There was no difference in body weight gain and no animal death. The results showed that the safe doses of C-1, C-2 and C-3 administered to mice were more than 1.0g/kg.

Example 9 Preparation of tablets

1. Prescription (1000 tablets):

3-(3'-ethyl)butyl-5,6-dimethoxybenzoquinone (C-9)	100g
starch	50g
Microcrystalline cellulose	20g
Magnesium stearate	2g
Sodium carboxymethyl cellulose	5g
50% ethanol	Moderate amount

2. Process: pulverize and mix 3-(3'-ethyl)butyl-5,6-dimethoxyphenylhydrazine, starch, microcrystalline cellulose, sodium carboxymethylcellulose to 50% ethanol Appropriate amount as a wetting agent to make soft materials, sieve through 20 mesh sieve, dry at 60-80 ° C, whole grain, add magnesium stearate to mix, compress, and film coat.

Example 10 Preparation of Injection

1. Prescription (1000 bottles):

3-n-butyl-5,6-dimethoxybenzoquinone (C-6)	50g
PEG-400	2L
Injection with ethanol	5L

2. Process: Add 3-(3'-methyl-2'-ene)butyl-5,6-dimethoxyphenylhydrazine to PEG-400, stir to dissolve, add ethanol to a sufficient amount, stir well The solution is filtered and potted. Dilute with 0.9% sodium chloride injection or 5% glucose injection before use, intravenous drip.

Claims (10)

1. A benzoquinone compound characterized by a structural formula such as Formula I:

   

   Wherein: R _{1 is} selected from a C ₃ -C 6 hydrocarbon group; and R ₂ and R _{3 are} independently selected from hydrogen, C 1 -C ₃ alkyl, acetyl.
2. The benzoquinone compound according to claim 1, wherein R _{1 is} selected from the group consisting of n-propyl, n-butyl, n-pentyl, 2-allyl, 2-enbutyl, 3-enbutyl, and 1 -methyl-3-enylbutyl, 1-methyl-2-allyl, 2-methyl-2-allyl, 1,1-dimethyl-2-allyl, 1,2- Dimethyl-2-allyl, 3-methyl-2-enylbutyl, 2,2-dimethyl-3-enylbutyl, 3-methyl-3-enylbutyl, 4-methyl 3-enylpentyl, 1-methyl-1-vinyl, 1-ethyl-1-vinyl, 1-propyl-1-vinyl, 2-propargyl, 3-ynylbutyl; R ₂ and R _{3 are} independently selected from the group consisting of hydrogen, methyl, and acetyl.
3. The benzoquinone compound according to claim 1, which comprises the following compounds:

   

   
4. A pharmaceutically acceptable solvate or prodrug of a benzoquinone compound according to any one of claims 1 to 3, wherein:

   The solvate refers to an aggregate of a compound represented by Formula I, which is associated with one or more solvent molecules during crystallization;

   Preferably, the solvent molecule is water or an organic solvent such as ethanol, isopropanol, diethyl ether, ethyl acetate, acetone or the like;

   The prodrug is a carboxylic acid and a salt thereof formed by reacting a phenylhydrazine compound represented by the formula I with a base and undergoing ring opening reaction of a lactone;

   The base includes an inorganic base or an organic base;

   Further preferably, the inorganic base comprises sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide;

   Further preferably, the organic base includes, for example, benzylamine, morpholine, ethylenediamine, ethanolamine, piperazine, choline, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine and the like.
5. A pharmaceutical composition comprising: (a) a therapeutically effective amount of a benzoquinone compound selected according to any one of claims 1 to 3 and a benzoquinone compound according to claim 4. One or more of a pharmaceutically acceptable solvate, a prodrug; and (b) one or more pharmaceutically acceptable carriers.
6. The benzoquinone compound according to any one of claims 1 to 3, and the pharmaceutically acceptable solvate of the phenylhydrazine compound according to claim 4, the prodrug or the pharmaceutical composition according to claim 5 in the preparation of the prophylaxis And/or use in medicines for treating neurological diseases.
7. The use according to claim 6, wherein said nervous system diseases include Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, diabetic neuropathy change.
8. The use according to claim 6, wherein the neurological diseases include ischemic stroke, hemorrhagic stroke, nerve damage caused by brain trauma, depression, vascular dementia, and neuropathic pain.
9. The benzoquinone compound according to any one of claims 1 to 3, and the pharmaceutically acceptable solvate of the phenylhydrazine compound according to claim 4, the prodrug or the pharmaceutical composition according to claim 5 in the preparation of the prophylaxis And/or use in the treatment of a drug that induces damage to nerve cells by inflammation.
10. The benzoquinone compound according to any one of claims 1 to 3, and the pharmaceutically acceptable solvate of the phenylhydrazine compound according to claim 4, the prodrug or the pharmaceutical composition according to claim 5 in the preparation of the prophylaxis And/or use in the treatment of a medicament for inducing nerve cell damage by cerebral vascular occlusion.

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