CN111803499B

CN111803499B - Medicine composition II for treating gout and hyperuricemia

Info

Publication number: CN111803499B
Application number: CN202010838794.4A
Authority: CN
Inventors: 左之利; 彭佳乐; 刘兴勇; 张利; 张树群; 孙威; 周业珩
Original assignee: Sichuan University of Science and Engineering
Current assignee: Sichuan University of Science and Engineering
Priority date: 2018-06-13
Filing date: 2018-06-13
Publication date: 2021-09-14
Anticipated expiration: 2038-06-13
Also published as: CN108853112A; CN111920811A; CN108853112B; CN111803499A; CN111920811B

Abstract

The invention discloses a pharmaceutical composition II for treating gout and hyperuricemia, which has a general structure shown in formula II. The application of a series of compounds with xanthine oxidase inhibitory activity in the preparation of anti-gout and anti-hyperuricemia drugs provided by the invention is proved by in vitro enzyme activity experiments to have obvious Xanthine Oxidase (XO) inhibitory effect.

Description

Medicine composition II for treating gout and hyperuricemia

Technical Field

The invention relates to application of a compound in inhibiting xanthine oxidase activity and a pharmaceutical composition for treating gout and hyperuricemia based on the division with the application number of 201810609568.1, wherein the application date is 2018, 6 and 13, and the invention is named as the application of the compound in inhibiting xanthine oxidase activity and the pharmaceutical composition for treating gout and hyperuricemia, belongs to the technical field of medicines, and particularly relates to the application of the compound in inhibiting xanthine oxidase activity and the pharmaceutical composition for treating gout and hyperuricemia.

Background

Gout (Gout) is a group of clinical syndromes formed by deposition of urate on joints and soft tissues due to hyperuricemia caused by in vivo purine metabolic disorders or decreased excretion of Uric Acid (UA), etc. The end product of human purine metabolism is uric acid, a weak acid with very low solubility, which can cause hyperuricemia with either excessive production or poor excretion. Statistically, about 6% to 12% of patients with hyperuricemia develop gout, which has become the second major metabolic disease after diabetes.

During purine metabolism, xanthine oxidase catalyzes the oxidation of xanthine and/or hypoxanthine to form uric acid. Therefore, inhibition of xanthine oxidase activity can reduce uric acid production, and thus, can play a role in treating hyperuricemia and gout.

The currently marketed drugs mainly include Allopurinol (Allopurinol), febuxostat (Febxostat) and Topiroxostat (Topiroxostat), although all of the three have the effect of obviously reducing uric acid, the types of the Allopurinol are very limited, the Allopurinol has certain toxic and side effects, the febuxostat has selectivity on xanthine oxidase inhibition, and other enzymes in purine and pyrimidine synthesis and metabolic processes cannot be inhibited at the treatment concentration.

Disclosure of Invention

In view of the above-mentioned disadvantages of the prior art, the present invention aims to provide the use of the compound in inhibiting xanthine oxidase activity and a pharmaceutical composition for treating anti-gout and anti-hyperuricemia.

In order to achieve the purpose, the technical scheme adopted by the invention is as follows:

the application of the compound with the general formula I in inhibiting the activity of xanthine oxidase,

the general formula I is shown as formula I:

the general formula I is a pyridylthiophene derivative;

wherein the R1 radical is

The R2 radical being

The R3 radical being

The R4 radical being

Or R3R4 is:

further, the compounds represented by the above general formula I are

Use of a compound having the general formula ii:

the general formula II is thiazole acrylonitrile derivatives;

wherein the R1 group is:

the R2 group is:

further, the compound represented by the above general formula II is

Use of a compound having the general formula iii, wherein the general formula iii is represented by the formula iii:

the general formula III is quinoline amide derivatives;

wherein the R1 radical is

The R2 radical being

Further, the compound represented by the above general formula III is

Further, the invention provides a pharmaceutical composition, which comprises the compounds shown in the general formulas I, II and III, or pharmaceutically acceptable salts, hydrates or solvates of the compounds.

Further, the pharmaceutical composition comprises 12-20 parts by weight of the compounds shown in the general formulas I, II and III or pharmaceutically acceptable salts, hydrates or solvates of the compounds, and the balance of excipients, based on 100 parts by weight.

Further, the excipient comprises one or more of a filler, a binder, a disintegrant, a lubricant, or a glidant; the filler comprises starch, sugar powder, microcrystalline cellulose, mannitol, compressible starch or lactose; the adhesive comprises starch slurry, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, polyvinylpyrrolidone or sodium carboxymethyl cellulose; the disintegrant comprises sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, or hydroxypropyl starch; the lubricant is 0.1-5% of magnesium stearate; the glidant is 0.1-3% of talcum powder.

Furthermore, the adhesive of the invention is 0.1 to 15 percent of hydroxypropyl cellulose, the filling agent is 5 to 70 percent of microcrystalline cellulose, and the disintegrating agent is 10 to 60 percent of crospovidone.

Further, the dosage form of the pharmaceutical composition comprises tablets, capsules, pills or suspensions.

Compared with the prior art, the invention has the following beneficial effects:

the invention provides application of compounds shown as formulas I, II and III in inhibiting xanthine oxidase activity and a pharmaceutical composition for treating gout resistance and hyperuricemia resistance, and in vitro enzyme activity experiments prove that the compounds have obvious Xanthine Oxidase (XO) inhibition effect.

Detailed Description

The present invention will be described in further detail with reference to specific examples.

First, source of target compound

All compounds of the invention were purchased from specs, Netherlands (website: http:// www.specs.com, compounds from the specs library, corresponding numbers as follows:

table 1: numbering and Structure of Compounds of the invention

In vitro pharmacological testing of the Compounds of the invention

2.1 principle of the experiment

Xanthine oxidase catalyzes xanthine to form uric acid. If the compound has an inhibitory effect on xanthine oxidase, the amount of xanthine catalyzed by xanthine oxidase decreases, uric acid produced accordingly decreases, and absorbance accordingly decreases.

2.2 materials of the experiment

13 test compounds, KH₂PO₄，K₂HPO₄NaOH, xanthine oxidase, allopurinol, dimethyl sulfoxide (DMSO), and distilled water.

2.3 in vitro Activity test method

1) Preparing a buffer solution: 0.9560g KH are precisely weighed₂PO₄，5.3020g K₂HPO₄Adding distilled water for dissolving, and diluting to 500mL to obtain Phosphate Buffer Solution (PBS) containing 75mM phosphate ions and having pH of 7.4.

2) Preparation of a substrate: 3.65mg of xanthine is precisely weighed, a small amount of 0.5M NaOH solution is added for dissolving, and PBS is used for fixing the volume to 50mL to obtain 0.48mM substrate solution which needs to be prepared for use.

3) Preparing an enzyme solution: the liquid transfer gun takes 100 mu L of xanthine oxidase, adds PBS, and fixes the volume to 25ml to obtain a xanthine oxidase solution of 0.04U.mL < -1 >, and the enzyme solution needs to be prepared for use.

4) Preparation of a test sample: an appropriate amount of sample was weighed precisely, and the sample was dissolved with a small amount of DMSO (content: less than 5%) and then diluted with PBS buffer so that the concentration of the sample at the time of reaction was 15. mu.M, 25. mu.M, 35. mu.M, 50. mu.M, and 100. mu.M.

5) Using allopurinol (IC)₅₀2.68 μ M) was added to the test tube, 200 μ L of each of the test sample solution, the positive control solution, and a blank solution (blank is PBS), and 500 μ L, PBS2800 μ L of the enzyme solution and 2800 μ L of the enzyme solution were added to the test tube, incubated at 37 ℃ for 15min, then 500 μ L of the substrate was added to initiate the reaction, and the reaction was read 1 time at 295nm every 30 seconds, and the absorbance a was recorded for a total of 5 min.

2.4 results of the experiment

The inhibition (%) was calculated from the change in A values in the sample group and blank group using the following formula, wherein the inhibition (%) was (1-A)_{Sample (I)}/A_{Blank space}) X 100%, inhibition results are shown in the table below.

Table 2: inhibition of Xanthine Oxidase (XO) by compounds

2) As shown in the inhibition tables, the compounds PJL-1, PJL-2 and PJL-3 exhibited high enzyme inhibition.

Thirdly, the compounds PJL-1, PJL-2 and PJL-3 of the present invention have Xanthine Oxidase (XO) inhibitory activity IC₅₀Measurement of (2)

Compounds having slightly higher inhibitory activity against Xanthine Oxidase (XO), i.e., compounds PJL-1, PJL-2 and PJL-3, have been screened through the above-mentioned experiments, and IC of inhibitory activity thereof was further measured₅₀The value is obtained.

The specific experimental procedures are as above, and the experimental results are shown in table 3:

(1) inhibition ratio (%) - (1-A)_{Sample (I)}/A_{Blank space}) X 100%, results are shown in the table below.

Table 3: inhibition rate of compounds PJL-1, PJL-2 and PJL-3 at different concentrations

(2)IC₅₀The value: converting the inhibition rate into corresponding enzyme activity, and calculating IC₅₀Values, results see table 4:

table 4: IC of Compounds PJL-1, PJL-2, PJL-3₅₀Value of

Pharmaceutical compositions of the compounds of the present invention and their pharmaceutically acceptable salts, hydrates or solvates

(1) The pharmaceutical composition is made into tablets according to the following formulation

The preparation method comprises the following steps: the method adopts dry granulation and tabletting. The compound is sequentially mixed with microcrystalline cellulose, hydroxypropyl methylcellulose and the added crospovidone, the mixture is sieved for three times by a 80-mesh sieve, and is granulated by a dry granulation machine, and the granules are dried at 80 ℃ after being granulated, wherein the moisture content is less than 3%. Adding crospovidone, magnesium stearate and pulvis Talci, mixing, tabletting, and coating film.

(2) The pharmaceutical composition is prepared into capsules according to the following formula

Name (R)	Mass/g	Percent/%)	Function of
				Compounds of the invention	12	12％	Main medicine
Microcrystalline cellulose	40	40％	Filler
				Lactose	30	30％	Filler
Low-substituted hydroxypropyl cellulose	7	7％	Adhesive agent
				Magnesium stearate	2	2％	Lubricant agent
Talcum powder	1	1％	Glidants

The preparation method comprises the following steps: mixing the compound of the invention and the auxiliary materials, sieving by a 60-mesh sieve, granulating, drying, finishing granules, and filling capsules to obtain the compound.

The above examples of the present invention are merely illustrative of the present invention and are not intended to limit the embodiments of the present invention. Variations and modifications in other variations will occur to those skilled in the art upon reading the foregoing description. Not all embodiments are exhaustive. All obvious changes and modifications of the present invention are within the scope of the present invention.

Claims

1. The application of a compound II or a pharmaceutically acceptable salt thereof in preparing a medicament for treating gout and hyperuricemia is characterized in that the structural formula of the compound II is as follows:

。

2. the use according to claim 1, comprising 12 to 20 parts by weight of the compound according to claim 1, or a pharmaceutically acceptable salt thereof, based on 100 parts by weight, with the balance being excipients.

3. The use according to claim 2, wherein the excipient comprises one or more of a filler, a binder, a disintegrant, a lubricant, or a glidant; the filler comprises starch, sugar powder, microcrystalline cellulose, mannitol, and lactose; the adhesive comprises starch slurry, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, polyvinylpyrrolidone or sodium carboxymethyl cellulose; the disintegrant comprises sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, or hydroxypropyl starch; the lubricant is magnesium stearate; the glidant is talcum powder.

4. The use according to claim 3, wherein the pharmaceutical composition is in a dosage form comprising a tablet, capsule, pill or suspension.