CN116196303A

CN116196303A - Application of anthraquinone derivative in preparation of anti-platelet and anti-ischemic cerebral apoplexy medicines

Info

Publication number: CN116196303A
Application number: CN202310470346.7A
Authority: CN
Inventors: 辛光
Original assignee: West China Hospital of Sichuan University
Current assignee: West China Hospital of Sichuan University
Priority date: 2023-04-27
Filing date: 2023-04-27
Publication date: 2023-06-02
Anticipated expiration: 2043-04-27
Also published as: CN116196303B

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to application of anthraquinone derivatives in preparation of anti-platelet and anti-ischemic cerebral apoplexy medicines. In order to prevent abnormal activation of platelets and prevent or treat ischemic cerebral apoplexy, the invention provides anthraquinone derivative 1-chloro-2-iodo-3, 4-dihydroxy-9, 10-anthraquinone, animal experiments show that the anthraquinone derivative has excellent anti-platelet and anti-ischemic cerebral apoplexy activity, can obviously increase the anti-platelet and anti-cerebral apoplexy activity compared with parent alizarin, chloro-iodo derivatives, and has better safety. Can provide a new medicine source for treating thrombosis and ischemic cerebral apoplexy, and has potential significant economic and social benefits.

Description

Application of anthraquinone derivative in preparation of anti-platelet and anti-ischemic cerebral apoplexy medicines

Technical Field

The invention belongs to the technical field of biological medicines, and particularly relates to application of anthraquinone derivatives in preparation of anti-platelet and anti-ischemic cerebral apoplexy medicines.

Background

Ischemic stroke is a sudden infarction or restriction of cerebral vessels, resulting in a deficiency of oxygen and other nutrients. Also known as "transient ischemic attacks," can cause "tissue infarction" of the central nervous system. Ischemic stroke is very common in China. Therefore, there is no choice but to study the prevention and treatment of this disease.

At present, the anti-platelet treatment of the ischemic cerebral apoplexy is of great interest because the occurrence of the ischemic cerebral apoplexy is caused by blood vessel blockage, namely thrombosis, and the main cause of the thrombosis is abnormal activation of platelets. However, currently clinically used antiplatelet drugs are often associated with toxic side effects, e.g., aspirin can cause thrombocytopenia in patients; furthermore, more severely, 55-60% of current clinical stroke patients are resistant to commonly used antithrombotics. Therefore, development of novel antiplatelet medicines for preventing and treating ischemic cerebral apoplexy is urgent.

Alizarin (Alizarin) is a natural anthraquinone derivative which has various pharmacological activities including anti-inflammatory, antibacterial and antiviral activities, and previous researches of the applicant find that the Alizarin (Alizarin) has antiplatelet and cerebral apoplexy activity, but the Alizarin (Alizarin) has poor effectiveness, and severely limits the application of the Alizarin in preventing and treating ischemic cerebral apoplexy.

Disclosure of Invention

In order to better resist the activity of platelets and cerebral apoplexy, the invention provides the application of anthraquinone derivative 1-chloro-2-iodo-3, 4-dihydroxyl-9, 10-anthraquinone (a compound shown as a formula I and defined as a compound 1) in preparing the anti-platelet and/or anti-ischemic cerebral apoplexy drugs, wherein the anthraquinone derivative can obviously improve the anti-platelet and cerebral apoplexy activity of alizarin.

The invention provides application of a compound shown in a formula I or salt thereof in preparing an anti-platelet and/or anti-ischemic cerebral apoplexy medicament:

formula I.

Further, the medicament reduces ischemic stroke platelet activation, reduces platelet aggregation, integrin activation and/or P-selectin expression.

Further, the medicament reduces ischemic stroke mortality and nerve damage score.

Further, the medicament reduces secretion of inflammatory factors in serum and brain tissue.

Further, the medicament reduces at least one of cerebral tissue edema or necrosis or inflammatory infiltration of ischemic stroke brain tissue injury.

Further, the medicine is a preparation prepared by taking a compound shown in a formula I or salt thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.

Further, the preparation is a slow release agent or a controlled release agent.

Further, the auxiliary material is at least one of glyceryl behenate, hypromellose and magnesium stearate.

Further, the preparation is an oral preparation, a nasal mucosa administration preparation, an oral mucosa administration preparation or an injection preparation.

Further, the preparation is tablets, granules, capsules, oral liquid, nasal spray or injection.

Further, the preparation is effervescent tablets or sublingual tablets.

Preferably, the preparation is a sustained release agent, and the oral administration dosage is 0.4-4.1mg/kg (weight of human body)/time, 1 time every two days.

More preferably, the preparation is a sustained release agent, and the oral administration dose is 0.8mg/kg (weight of human body)/time, 1 time every two days.

In a preferred embodiment of the present invention, the effective dose of the compound of formula I or a salt thereof may vary depending on the mode of administration, age and weight of the patient, severity of the illness and other relevant factors, and the recommended dose for oral administration is 100-1000 mg/time, 1-3 times daily; the recommended dosage of the injection administration agent is 15-45 mg/time, 1 time a day; the spray is administered by inhalation at a recommended dose of 500-1000 mg per time, 1-3 times daily.

In the preferred embodiment of the invention, the 1 dose of the compound administered to mice by stomach irrigation in the examples is 50-100 mg/kg (weight of mice), and the dosage converted into the administration of human is 4.1-8.1mg/kg (weight of human body) per time, 1-2 times daily. Among them, the effect is preferably that the effective dose of Compound 1 to mice is 50 mg/kg (weight of mice), and the dose converted into human administration is 4.1mg/kg (weight of human body)/time, 2 times daily.

In the preferred technical scheme of the invention, the slow release agent for the mice is 5-50 mg/kg (weight of the mice), and the dosage for the adults is 0.4-4.1mg/kg (weight of the human body) in terms of conversion, and is 1 time per two days. The effect is preferably that the sustained release agent is administered to the mice at a dose of 10. 10 mg/kg (weight of the mice), and the dose is converted into an adult dose of 0.8mg/kg (weight of the human body) 1 time every two days.

In a preferred embodiment of the invention, the medicament contains one or more inert, non-toxic, pharmacologically suitable excipients.

Preferably, the excipient is selected from at least one of a carrier (e.g. microcrystalline cellulose, lactose, mannitol, starch), a solvent (e.g. liquid polyethylene glycol), an emulsifier, a dispersant, a humectant (e.g. sodium lauryl sulfate, polyoxysorbitan oleate, propylene glycol), a binder (e.g. polyvinylpyrrolidone), a stabilizer (e.g. an antioxidant such as ascorbic acid), a colorant (e.g. an inorganic pigment such as iron oxide), a perfume.

The beneficial effects are that: the invention provides application of anthraquinone derivative 1-chloro-2-iodo-3, 4-dihydroxy-9, 10-anthraquinone in preparing medicines for resisting blood platelet and ischemic cerebral apoplexy. Animal experiments show that the anthraquinone derivative has excellent antiplatelet and anti-ischemic cerebral apoplexy activity, can obviously increase the antiplatelet and anti-cerebral apoplexy activity compared with the parent alizarin and chloro-iodo-derivative, and has better safety. The application of the anthraquinone derivative can provide a new medicine source for treating thrombosis and ischemic cerebral apoplexy, and has potential significant economic and social benefits. The preparation prepared from the anthraquinone derivative 1-chloro-2-iodo-3, 4-dihydroxyl-9, 10-anthraquinone has application prospect as an anti-platelet and ischemic cerebral apoplexy medicament, is expected to become an innovative medicament for treating ischemic cerebral apoplexy with high efficiency and low toxicity, and has wide industrialization prospect.

Drawings

FIG. 1 shows the maximum platelet-tolerant dose (A) and the lethal dose (B) of the compound of test example 2 according to the present invention.

Detailed Description

The new direction and the new strategy are provided for developing new medicines for preventing and treating ischemic cerebral apoplexy, the occurrence of the ischemic cerebral apoplexy is caused by vascular blockage as thrombosis, and the main factor of the thrombosis is abnormal activation of platelets, so that the anti-platelet treatment of the ischemic cerebral apoplexy is of great concern, however, the clinical cerebral apoplexy patients have tolerance to common anti-platelet medicines at present, and development of novel anti-platelet and ischemic cerebral apoplexy medicines is urgently needed.

Previous studies by the applicant have found that halogenated modifications may increase the affinity of alizarin parent drug to target protein, increasing pharmacological effects, and thus the following compounds 1-3 were designed, and the applicant found that a significant increase in activity did occur, albeit with only minor structural modifications. Meanwhile, the novel antiplatelet drug 1-chloro-2-iodo-3, 4-dihydroxyl-9, 10-anthraquinone (compound 1) can be found to obviously improve the antiplatelet activity of alizarin and cerebral apoplexy. Compared with the parent alizarin and chloro-iodo derivatives, the anti-platelet and cerebral apoplexy preventing and treating activities of the parent alizarin and chloro-iodo derivatives can be obviously increased, and the safety is better.

The scheme of the present invention will be explained below with reference to examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.

EXAMPLE 1 Synthesis of

Compounds

1,2, 3

1) Synthesis of 1-chloro-2-iodo-3, 4-dihydroxy-9, 10-anthraquinone (Compound 1)

Alizarin 0.48 g and N-iodosuccinimide 0.22. 0.22 g are taken, tetrahydrofuran is taken as a solvent, reacted for 3 hours at normal temperature, and water is added for catalysis and concentration to obtain a crude product. Taking 0.46 g crude product, 35 mL acetic acid and 5 mL concentrated hydrochloric acid, placing into a heat-stabilized 100 ℃ oil bath, gradually adding 0.54 g MnO ₂ The reaction was carried out for 1 hour. Separating with chromatographic column to obtain compound 1.

¹ H NMR (400 MHz, Chloroform-d) δ 7.79 (dd, J = 6.2, 3.2 Hz, 2H), 7.90 – 7.81 (m, 1H), 7.74 (dd, J = 5.8, 3.3 Hz, 1H), 6.36 (s, 1H). HRMS (ESI−) Calc. for C ₁₄ H ₇ ClIO ₄ : 400.9078 [M+H] ⁺ ; Found 400.9038 [M+H] ⁺ 。

2) Synthesis of 1, 2-dichloro-3, 4-dihydroxy-9, 10-anthraquinone (Compound 2)

Taking alizarin 0.48 g and N-chlorosuccinimide 0.52 and g, reacting for 3 hours at normal temperature by taking tetrahydrofuran as a solvent, adding water for catalysis, concentrating to obtain a crude product, and separating by a chromatographic column to obtain the compound 2.

¹ H NMR (500 MHz, Chloroform-d) δ 7.93 (dd, J = 6.2, 3.6 Hz, 2H), 7.95 – 7.83 (m, 1H), 7.76 (dd, J = 6.2, 3.7 Hz, 1H), 6.30 (s, 1H). HRMS (ESI+) Calc. for C ₁₄ H ₇ Cl ₂ O ₄ : 308.9721 [M+H] ⁺ ; Found 308.9631[M+H] ⁺ 。

3) Synthesis of 1, 2-diiodo-3, 4-dihydroxy-9, 10-anthraquinone (Compound 3)

Taking alizarin 0.48 g and N-iodosuccinimide 0.92 and g, reacting for 3 hours at normal temperature by taking tetrahydrofuran as a solvent, adding water for catalysis, concentrating to obtain a crude product, and separating by a chromatographic column to obtain the compound 3.

¹ H NMR (400 MHz, Chloroform-d) δ 7.95 (dd, J = 5.8, 3.0 Hz, 2H), 7.90 – 7.80 (m, 1H), 7.77 (dd, J = 5.8, 3.3 Hz, 1H), 6.36 (s, 1H). HRMS (ESI+) Calc. for C ₁₄ H ₇ I ₂ O ₄ : 492.8434 [M+H] ⁺ ; Found 492.8451[M+H] ⁺ 。

Test example 1 anti-platelet Activity assay of the Compounds prepared in example 1

Aggregation degree detection: after incubation of

compounds

1,2, 3, alizarin with extracted SD rat Platelet Rich Plasma (PRP) for 30 min, platelet aggregation was detected using an AG400 platelet semiautomatic aggregation detector.

Platelet integrin activation assay: after wild-type mouse platelets were extracted, platelets were resuspended with a desktop fluid. Platelets were then pre-incubated with drug (50, 100. Mu.M) for 3 min h, followed by 15 min incubation with the fluorescent reagent JON/A-fluorescein isothiocyanate JON/A (FITC), and 0.05U/mL thrombin was added 5 min prior to sample detection to induce platelet activation, flow cytometry detection was performed using FACScan, and data were quantified using FlowJo treatment.

Platelet P-selectin expression assay: after wild-type mouse platelets were extracted, platelets were resuspended with a desktop fluid. Platelets were then pre-incubated with drug (50, 100. Mu.M) for 3 min h, then incubated with fluorescent reagent CD 62P-R-phycoerythrin CD62P (PE) for 15 min, and thrombin at 0.05U/mL was added 5 min prior to sample detection to induce platelet activation, flow cytometry detection was performed using FACScan, and data were quantified using FlowJo treatment. Table 1 shows the results of the above procedure after pre-incubation of platelets with 50. Mu.M drug.

Wherein, the solvent group refers to a platelet and physiological saline group: model group refers to the platelet plus thrombin group: the pharmaceutical group (compounds 1-3, alizarin) is platelet plus thrombin plus drug.

Abnormal activation of platelets mediates thrombosis, which is the cause of ischemic stroke. Thus, in order to evaluate the anti-ischemic stroke activity of compound 1, applicants tested compound 1 for antithrombin-induced abnormal platelet activation activity, including platelet aggregation level, integrin activation and P-selectin expression. As can be seen from the results in Table 1, compound 1 has significant antiplatelet activity, which can significantly reduce the thrombin-induced platelet aggregation level [ ]P< 0.05), integrin (GPIIb/IIIa) activationP< 0.05) and P-Selectin (P-Selectin) expressionP< 0.001); and the antiplatelet activity is obviously higher than that of the parent alizarin, the chlorine substituted alizarin compound 2 and the iodine substituted alizarin compound 3.

Test example 2 toxicity of Compound 1 prepared in example 1 against platelets and mice

C57BL/6 mouse platelets were taken, and

different compounds

1,2, 3 and alizarin were added respectively for incubation for 50 min. The maximum tolerated dose of drug to platelets was measured by measuring extracellular Lactate Dehydrogenase (LDH) release. The results are shown in FIG. 1A. The results of monitoring the Lethal Dose (LD) of

compounds

1,2, 3 and alizarin in C57BL/6 mice with a single gastric lavage by observing the death of mice in 24 h are shown in FIG. 1B.

Experimental results show that the maximum tolerance dose of the compound 1 to the platelets is far greater than that of the analogues of the compound 1, namely the chlorinated compound 2, the iodinated compound 3 and the parent nucleus alizarin, and the experimental results show that the compound 1 has better cell safety compared with other iodinated analogues and the parent nucleus thereofP<0.05). Similarly, the lethal dose results of the compound show that the lethal dose of the compound 1 is far greater than that of the analogues of the compound 2, the iodo compound 3 and the parent alizarinP<0.001 Experimental results show that compound 1 has better in vivo safety compared with other iodo-analogues and their parent nuclei.

Test example 3 detection of anti-ischemic Stroke Activity of Compound 1 prepared in example 1

1) Grouping and administration: each group of 10C 57BL/6 mice was divided into a sham operation group, a model group, a dosing group and an alizarin control group. Compound 1 and alizarin were administered for 7 days (2 doses per day) in the administration group and alizarin control group, respectively, by gastric lavage at 25, 50, 150 mg/kg/d, and the model group was administered the same volume of vehicle (physiological saline) for 7 days.

2) Molding and collecting samples: each group of mice was anesthetized and fixed by intraperitoneal injection of pentobarbital sodium, and incisions were made by ophthalmic scissors along the right side of the median line of the mice' necks, and the common carotid artery vessel on the right side of the mice was blunt-isolated from the external carotid artery with forceps. The common carotid artery of the mice is ligated by using silk thread and the external carotid artery of the mice is hooked, the carotid artery of the mice is rapidly inserted into a nylon thread plug special for the mice, and the thread plug is slowly withdrawn after being placed in the carotid artery of the mice for 60 min. 24 hours after molding was completed, bederson injury scores (0 for no nerve injury; 1 for inability to fully extend contralateral forepaw in tail-suspension experiments; 2 for reduced ability of forelimb to resist thrust from contralateral; 3 for sustained contralateral rotation; higher scores indicate more severe mouse injury) and mNSS injury scores (lowest 3, highest 18, higher scores give better neurological function); (2) pentobarbital sodium anesthetics, rapidly stripping mouse brain, staining with 2,3, 5-triphenyltetrazolium chloride (TTC), quantifying cerebral infarction area using Image J software, and taking blood sample for detection factor.

The results in table 2 show the effect of the dosing group (compound 1 low, medium, high dose group) on the area of cerebral infarction. As can be seen from Table 2, compound 1 of the present embodiment can reduce the infarct size (A) and the activation was greater than that of the control groupP<0.05 The optimal effect dose is 50 mg/kg/d.

Table 3 shows the effect of the dosing group (low, medium, high dose group of Compound 1) on serum IL-1β levels. From Table 3, the drug group can reduce the serum inflammatory factor level of cerebral apoplexy due to ischemia and the activity is obviously better than that of the alizarin administration group of the control groupP<0.05 The optimal effect dose is 50 mg/kg/d. Values are expressed as mean ± SEM.

Table 4 shows the effect of the dosing group (compound 1 low, medium, high dose group) on neurological scores for ischemic stroke patterns. From Table 4, it is clear that compound 1 can reduce ischemic stroke model, and the effect is significantly better than that of parent alizarin (P < 0.05), and the optimal effect dose is 50 mg/kg. Values are expressed as mean ± SEM.

Table 5 shows the effect of the dosing group (compound 1 low, medium, high dose group) on the mortality of ischemic stroke patterns. From Table 5, it is clear that Compound 1 can reduce the death rate of ischemic cerebral apoplexy model, and the effect is significantly better than that of parent alizarinP<0.05 The optimal effect dose is 50 mg/kg/d.

Test example 4 preparation of Compound 1 sustained release preparation

The ischemic cerebral apoplexy patients and dangerous persons need to be administrated throughout the year, if the sustained-release preparation can be prepared, the administration frequency can be reduced, the fluctuation of the blood concentration of the organism can be reduced, the compliance of the patients can be increased, the effect of the medicine can be improved, and the toxic and side effects can be reduced. The alizarin derivative has a short half-life, so that the preparation of the compound 1 sustained-release preparation is necessary, and the compound 1 sustained-release tablet is prepared according to the implementation of the following method. Wherein HPMC K100M is pharmaceutical grade hydroxypropyl methylcellulose K100M; ATO is glyceryl behenate Compritol 888.

1) Prescription information

Note that: N/A indicates that the stock does not need equipment, is not applicable or does not relate to equipment; the manual tablet pressing method is that a tablet pressing machine is used for manually pressing tablets and then crushing the tablets for granulating.

2) Analysis results

3) Summary

The compound 1 sustained release tablet is successfully prepared, and the sustained release effect reaches more than 72 h.

Test example 5 detection of the anti-ischemic Stroke Activity of Compound 1 sustained-release preparation

1) Grouping and administration: each group of 10C 57BL/6 mice was divided into a sham operation group, a model group, a dosing group and a control group. The drug group directly taking the compound 1 as the raw material drug (API) is administrated with 50 mg/kg/d of compound 1 by intragastric administration (twice daily), the compound 1 sustained release preparation group is administrated with 5, 10, 50 mg/kg/2d of sustained release preparation by intragastric administration every other day (1, 3,5, 7 days), the administration is carried out for 7 days, and the model group is administrated with the same volume of solvent physiological saline of the drug group for 7 days.

As can be seen from Table 10, the sustained release preparation of Compound 1 reduced the infarct size and the activity was superior to that of Compound 1, which was the control group with the optimum dose of APIP<0.05 And the optimal effect dose of the slow release preparation is 10 mg/kg/2d.

From Table 11, the sustained release preparation group can reduce the serum inflammatory factor level of cerebral arterial thrombosis and has obviously better activity than the control group of the optimal dosage of the compound 1 as the APIP<0.05 And the optimal effect dose of the slow release preparation is 10 mg/kg/2d. Values are expressed as mean ± SEM.

As can be seen from table 12, compound 1 can reduce the nerve damage activity in ischemic stroke better than compound 1 as the API optimal dose control group, and the optimal effect dose of the sustained release preparation is 10 mg/kg/2d. Values are expressed as mean ± SEM.

From Table 13, it is clear that the bulk drug and the sustained release preparation of Compound 1 do not affect the platelet count of the mice with cerebral ischemia. Values are expressed as mean ± SEM.

From the above data, applicants confirmed that anthraquinone derivative 1-chloro-2-iodo-3, 4-dihydroxy-9, 10-anthraquinone (compound 1) (1) significantly reduced platelet activation, reduced platelet aggregation, integrin activation and P-selectin expression; (2) reducing mortality, infarct size, inflammatory factors and neurological scores of a mouse ischemic stroke model, and having remarkable anti-ischemic stroke activity; (3) the effect is obviously better than that of parent nucleoalizarin, monochloroalizarin and monoiodoalizarin; (4) the safety of compound 1 is significantly increased compared to its parent nucleus and analogues; (5) the compound 1 is found to be taken as a raw material drug and is orally infused into the stomach of a mouse, and the optimal in-vivo effect dose is 50 mg/kg/d; (6) the API of the drug or the slow release formulation does not change the platelet count.

Because alizarin compounds have short half-life and long-term administration is needed for administration of antiplatelet and ischemic cerebral apoplexy, a slow release preparation of the compound 1 is designed and prepared, and the slow release effect of the slow release tablet prepared by the (1) can reach more than 72 hours through an oral administration and drug infusion experiment of mice, so that the slow release tablet has excellent slow release effect; (2) the anti-ischemic stroke effect of the administration every two days is obviously better than that of the administration of the API (bulk drug) twice a day, and (3) the optimal anti-ischemic stroke effect dosage of the compound 1 sustained release preparation is proved to be 10 mg/kg/2d.

The applicant can know according to the equivalent dose conversion formula of mice and human bodies, which is given by the industry guide 'Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers' 7 and page table 1 given by the FDA, that the recommended dose of the prepared sustained release preparation of the compound 1 to the human body is as follows: the raw material medicine for the mice is 50-100 mg/kg (weight of the mice), and the dosage for the adults is 4.1-8.1mg/kg (weight of the human body) per time, 1-2 times per day. The effect is preferably 50 mg/kg (weight of mice) of the drug substance administered to mice, and the dose converted into an adult dose is 4.1mg/kg (weight of human body) per time, 2 times a day.

The slow release agent is 5-50 mg/kg (weight of mice) and is converted into 0.4-4.1mg/kg (weight of human body) for human, and the slow release agent is 1 time every two days. The effect is preferably that the sustained release agent is administered to the mice at a dose of 10 mg/kg (weight of the mice), and the converted human dose is 0.8mg/kg (weight of the human body) 1 time per two days.

It is to be noted that the particular features, structures, materials, or characteristics described in this specification may be combined in any suitable manner in any one or more embodiments. Furthermore, the various embodiments described in this specification, as well as the features of the various embodiments, can be combined and combined by one skilled in the art without contradiction.

Claims

1. The application of a compound shown in a formula I or a salt thereof in preparing an anti-platelet and/or anti-ischemic cerebral apoplexy medicament:

formula I.

2. Use according to claim 1, characterized in that: the medicament satisfies at least one of the following:

reducing ischemic stroke platelet activation, reducing platelet aggregation, integrin activation and/or P-selectin expression;

reducing ischemic stroke mortality and nerve damage score;

reducing secretion of inflammatory factors in serum and brain tissue;

reducing at least one of cerebral tissue edema or necrosis and inflammatory infiltration of cerebral arterial thrombosis.

3. Use according to claim 1, characterized in that: the medicine is a preparation prepared by taking a compound shown in a formula I or salt thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.

4. Use according to claim 3, characterized in that: the preparation is a slow release agent or a controlled release agent.

5. Use according to claim 3, characterized in that: the auxiliary material is at least one of glyceryl behenate, hypromellose or magnesium stearate.

6. Use according to claim 3, characterized in that: the preparation is an oral preparation, a nasal mucosa administration preparation, an oral mucosa administration preparation or an injection preparation.

7. Use according to claim 3, characterized in that: the preparation is a sustained release agent, and the oral administration dosage is 0.4-4.1mg/kg (weight of human body)/time, 1 time every two days.

8. Use according to claim 7, characterized in that: the preparation is a sustained release agent, and the oral administration dosage is 0.8mg/kg (weight of human body)/time, 1 time every two days.

9. Use according to claim 1, characterized in that: the effective dose of the compound shown in the formula I or the salt thereof in the medicament is as follows: recommended doses for oral administration are 100-1000 mg/time, 1-3 times daily; the recommended dosage for injection administration is 15-45 mg/time, 1 time a day; the spray is administered by inhalation at a recommended dose of 500-1000 mg per time, 1-3 times daily.

10. Use according to claim 1, characterized in that: the effective dose of the compound shown in the formula I or the salt thereof in the medicament is as follows: orally administered for 1-2 times daily at a dosage of 4.1-8.1mg/kg (weight of human body).