CN114712365B

CN114712365B - Application of TRK inhibitor in preparation of medicament for treating tardive dyskinesia

Info

Publication number: CN114712365B
Application number: CN202210632032.8A
Authority: CN
Inventors: 左爱侠; 孙丽芳; 张敏; 戴欣汝; 柳澜昱; 董晓东
Original assignee: Shandong Luye Pharmaceutical Co Ltd
Current assignee: Shandong Luye Pharmaceutical Co Ltd
Priority date: 2022-06-07
Filing date: 2022-06-07
Publication date: 2022-08-23
Anticipated expiration: 2042-06-07
Also published as: CN114712365A

Abstract

The invention relates to the technical field of medicines, in particular to application of a TRK inhibitor shown as a formula (I) in preparing a medicine for treating tardive dyskinesiaThe application is as follows. The TRK inhibitor can be combined with a pharmaceutically acceptable carrier to form a pharmaceutical composition, and is administered by oral administration, parenteral administration, transmucosal administration or transdermal administration. The TRK inhibitor can obviously reduce the autonomous movement distance of a rat, obviously induces the eyelid ptosis of the rat, and has the effect of treating tardive dyskinesia.

Description

Application of TRK inhibitor in preparation of medicament for treating tardive dyskinesia

Technical Field

The invention relates to the technical field of medicines, in particular to application of a TRK inhibitor in preparing a medicine for treating tardive dyskinesia.

Background

Tardive Dyskinesia (TD) is a disease characterized by abnormal involuntary repetitive movements of the face, trunk or other parts of the body. Mainly induced by antipsychotics, the incidence rate of oral general antipsychotics is about 20-40%, and oral long-acting antipsychotics is about 50%. The specific pathogenesis of TD is not clear, but the current accepted pathogenesis is receptor sensitization, namely, postsynaptic receptors are blocked by drugs for a long time to cause the sensitivity of the postsynaptic receptors to be up-regulated, and the direct pathway and the indirect pathway of nigrostriatal dopamine are unbalanced, so that involuntary repetitive movement is shown.

In 4 months of 2017, the FDA approved the p-toluenesulfonate salt of valiphenazine (VBZ. TsOH) for the treatment of adult tardive dyskinesia, which is esterified from DHTBZ, a metabolite of tetrabenazine, and has clear therapeutic effect, good safety and tolerability. However, because the number of patients with tardive dyskinesia is large and the number of drugs on the market is small, more drugs for treating the tardive dyskinesia still need to be provided to meet the wide clinical requirement.

A class of pyrazolopyrimidine derivatives as selective TRK inhibitors is disclosed in WO2020063965a1, including compound WX001B (LPM 4870108), which is useful as a TRK kinase inhibitor for the treatment of TRK kinase-associated diseases such as tumors or various cancers. Meanwhile, the literature (John et al, Promyosin kinase Small molecule inhibitor research progress [ J ]. university of science and technology, 2021 (6): 73-79.) also discloses that the compound LPM4870108 shown in formula (I) is effective on both wild type and acquired drug-resistant mutation, and is intended for treating "solid tumor patients positive for NTRK gene fusion and drug-resistant mutation thereof". However, no report is available on the treatment of tardive dyskinesia by the compound LPM4870108 shown in the formula (I).

Disclosure of Invention

Through a large number of researches, the inventors find that the TRK inhibitor (i.e. the compound LPM4870108) shown in the formula (I) has the effect of treating tardive dyskinesia and can be used for preparing a medicament for treating tardive dyskinesia.

The technical scheme is as follows:

the invention provides application of a TRK inhibitor (namely a compound LPM4870108) shown in a formula (I) in preparation of a medicament for treating tardive dyskinesia.

In one embodiment of the present invention, the TRK inhibitor of formula (I) is combined with a pharmaceutically acceptable carrier to form a pharmaceutical composition.

In one embodiment of the present invention, the pharmaceutically acceptable carrier is selected from one or more of fillers, binders, diluents, disintegrants, lubricants, emulsifiers, humectants, colorants, flavoring agents, antioxidants and wetting agents.

In one embodiment of the present invention, the pharmaceutical composition can be prepared into various pharmaceutically acceptable dosage forms, such as tablets, capsules, oral liquids, suspensions, granules, powders, fine granules, pills, mini-tablets, instant films, nasal sprays, transdermal patches, injections or various sustained and controlled release preparations, and the like. The pharmaceutical composition may be administered to a patient orally, parenterally, transmucosally, or transdermally, and the parenteral administration includes subcutaneous, intradermal, intramuscular, or intravenous. The dose to be administered may be appropriately adjusted depending on the age and sex of the patient.

In one embodiment of the invention, the pharmaceutical composition may be in the form of, for example, a tablet, a capsule, a liquid capsule, a suspension, or a liquid. The pharmaceutical compositions are preferably prepared in dosage unit form containing a specific amount of the active ingredient. For example, the pharmaceutical composition comprises 0.1mg to 1000mg of the compound of formula (I) LPM4870108, preferably 0.25mg to 250mg, more preferably 0.5mg to 100 mg. The daily dosage may vary widely depending on the condition of the patient and other factors, but can be determined using conventional methods.

Detailed Description

While the present invention will be described more fully hereinafter with reference to the specific embodiments, it is to be understood by those skilled in the art that the following examples are included as part of the present invention and are intended to illustrate and not limit the scope of the invention.

In the present invention, those who do not specify the specific conditions are performed according to the conventional conditions or the conditions recommended by the manufacturer, and the reagents or instruments used are not specified by the manufacturer, and the conventional products can be obtained by commercially purchasing them.

In the present invention, the test data are expressed as MEAN. + -. standard error (MEAN. + -. SEM), and the difference between groups is analyzed by one-way Analysis of Variance (ANOVA) using SPSS statistics 18.0 software. All tests were two-sided, with P <0.05 indicating that the differences were statistically significant.

EXAMPLE 1 drug formulation method

A certain amount of the compound LPM4870108 (prepared according to the method disclosed in WO2020063965A 1) of formula (I) is weighed, and a proper amount of CMC-Na solution is added to be stirred and dissolved on a magnetic stirrer to prepare the required concentration (7.5 mg/ml, 15 mg/ml and 30 mg/ml). In the following experiments, the doses of LPM 48701081.5 mg/kg, 3.0 mg/kg and 6.0mg/kg were administered to rats, respectively.

Valbenazine (VBZ) p-toluenesulfonate (VBZ. TsOH) solution: weighing appropriate amount of the drug, dissolving with normal saline, diluting to required drug concentration (10 mg/ml), and administering to rat at dosage of 2 mg/kg.

Sodium carboxymethyl cellulose (0.5% CMC-Na) solution: and (3) slowly and uniformly pouring 5 g of CMC-Na powder into 1L of physiological saline, and placing the mixture on a magnetic stirrer to be heated, stirred and dissolved until the solution is clear and transparent.

Example 2 Effect of LPM4870108 Compound of formula (I) on rat autonomic Activity

1. Test method

Reference is made to the test method of the FDA declaration data PHARMACOLOGY REVIEW (S) section of Valbenazine p-toluenesulfonate (APPLICATION NUMBER:209241Orig1S 000) pages 19-21 (https:// www.accessdata.fda. gov/drug of da _ docs/nda/2017/209241Orig1S000PharmR. pdf).

The day before the experiment was randomly divided into 5 groups based on male rat body weight (200 ± 20 g): control group (saline), VBZ. TsOH 2mg/kg group, compound of formula (I) LPM 48701081.5, 3.0, 6.0mg/kg group, 12 animals per group. Tsoh and the compound of formula (I) LPM4870108 are both administered by gavage, the groups are shown in table 1.

TABLE 1 movement grouping and administration

Note: VBZ · TsOH and compound of formula (I) LPM4870108 as free base.

1 day before the experiment, rats were pre-acclimated in a test chamber for 10 min and fasted at 17. On the day of the experiment, animals were acclimated in the testing laboratory for at least 1 h. After the corresponding drugs are given to each group of rats by single intragastric administration, the rats are placed into a detection box, and the total movement distance of the rats 0.5-1.5 h after administration is recorded and analyzed by using a TopScan monitoring system. The total movement distance of the rats within 0.5-1.5 h after the administration was recorded and analyzed by using a TopScan monitoring system, and the Reduction Rate (RR) of the total movement distance was calculated, wherein RR = (control movement distance-administration movement distance)/control movement distance = 100%.

2. Test results

Tsoh significantly reduced rat motility at 2mg/kg dose (P <0.01, vs control). The compound LPM4870108 shown in the formula (I) can obviously reduce the moving distance of rats (P <0.01, vs control group) within the dose range of 1.5-3.0 mg/kg, and can inhibit the autonomous movement of rats in a dose-dependent manner (Table 2).

TABLE 2 autonomous movement distance of each group of rats 0.5-1.5 h after single gavage administration of SD rats

Note: results are expressed as mean ± SEM, n = 12. ^** P<0.01 administration group vs. control group.

EXAMPLE 3 pharmacodynamic study of LPM4870108 Compound of formula (I) to induce rat blepharoptosis

1. Test method

Reference is made to the FDA declaration data PHARMACOLOGY REVIEW (S) section of valphenazine p-toluenesulfonate (APPLICATION NUMBER:209241 origin 1S 000) at pages 19-21 (https:// www.accessdata.fda.gov/drug of da _ docs/nda/2017/209241 origin 1S000PharmR. pdf).

The day before the test, the rats were randomly divided into 5 groups according to their body weights (200 ± 20 g): control group (saline), VBZ. TsOH 2mg/kg group, compound of formula (I) LPM 48701081.5, 3.0 and 6.0mg/kg group, 12 animals per group. Animal grouping and dosing information is detailed in table 3. The administration routes of VBZ tosylate and the compound of formula (I) LPM4870108 are both intragastric administration.

TABLE 3 movement grouping and administration

Note: VBZ. TsOH and compound of formula (I) LPM4870108 as free base.

Fasting began 1 day prior to the trial at 17. On the day of the experiment, animals were acclimated in the testing laboratory for at least 1 h. And (3) carrying out single intragastric administration on the corresponding drugs of each group of rats, putting the animals into the cages after administration, respectively putting the animals on the platform after 1h, 2h, 4h and 8h after administration, observing the upper eyelid ptosis condition of the rats after 1min stabilization, and grading according to the ptosis degree of the upper eyelid. Rat upper eyelid ptosis was divided into five grades and the degree of ptosis was evaluated according to the following rating scale: 0= open eyes; 0.5= upper eyelid ptosis 1/4; 1= upper eyelid ptosis 1/2; 1.5= upper eyelid ptosis 3/4; 2= eyes fully closed. The upper eyelid droop 1/2 is an effective model above.

2. Test results

Tsoh at 2mg/kg dose, at 1h, 2h, 4h and 8h administration, the blepharoptosis score was significantly higher than the control group (P <0.01, vs control group at each time point). Compound LPM4870108 of formula (I) induced significant eyelid ptosis in rats at doses of 1.5 mg/kg, 3mg/kg and 6mg/kg after administration for 1h, 2h, 4h and 8h (P <0.01 at each time point, vs control group for each group) and was dose-dependent (Table 4).

TABLE 4 evaluation of blepharoptosis in SD rats at various time points after a single gavage administration

Note: results are expressed as mean ± SEM, n = 12. ^* P<0.01 administration group vs. control group.

Claims

1. The application of the TRK inhibitor shown in the formula (I) in preparing a medicament for treating tardive dyskinesia,

。

2. use according to claim 1, characterized in that: the TRK inhibitor shown in the formula (I) is combined with a pharmaceutically acceptable carrier to form a pharmaceutical composition.

3. Use according to claim 2, characterized in that: the pharmaceutically acceptable carrier is selected from one or more of fillers, binders, disintegrants, lubricants, emulsifiers, colorants, flavoring agents, antioxidants and wetting agents.

4. Use according to any one of claims 2 to 3, wherein: the pharmaceutical composition is administered to a patient orally, parenterally or transmucosally.

5. Use according to claim 4, characterized in that the parenteral administration comprises subcutaneous, intradermal, intramuscular or intravenous.