RU2822483C1 - Celecoxib prodrug, method for its preparation and use - Google Patents

Abstract

FIELD: chemistry; pharmaceutics.

SUBSTANCE: invention relates to a prodrug of celecoxib of formula I or a pharmaceutically acceptable salt thereof, a method for production thereof, medicinal agent or a pharmaceutical composition based thereon and use thereof for preparing a medicinal agent for preventing and/or treating inflammation of eye tissue. Also disclosed are eye drops for preventing and/or treating inflammation of eye tissue, containing the following components per 100 ml of eye drops: 0.1 g of a compound of formula I according to cl. 1 or 2, 0.05 g of Tween-80, 0.45 g of polyoxyethylene hydrogenated castor oil 40, 0.9 g of sodium chloride, 0.01 g of benzalkonium chloride, the rest is distilled water; wherein the pH value of the eye drops is 5.5–6.5.

EFFECT: use of the group of inventions makes it possible to effectively treat inflammations of eye tissue.

10 cl, 2 dwg, 4 tbl, 4 ex

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

The present invention relates to the field of medicine, in particular to the prodrug celecoxib, a method for its preparation and use.

BACKGROUND OF THE ART

Celecoxib is an anti-inflammatory and analgesic drug that selectively inhibits cyclooxygenase-2, which allows it to inhibit the production of prostaglandins and reduce swelling and pain during inflammation. In clinical practice, it is used primarily to treat joint pain and limited mobility caused by osteoarthritis of the knee. It also has a good therapeutic effect on rheumatism and rheumatoid arthritis. In addition, it can effectively relieve acute pain, such as after injury or surgery, and chronic pain, such as low back muscle strain, cervical spondylosis, internal and external shoulder epicondylitis. Eye drops made directly from celecoxib have lower concentrations in the eye tissue.

DISCLOSURE OF THE INVENTION

The subject of the present invention is a prodrug of celecoxib and a pharmaceutically acceptable salt thereof.

The structure of the prodrug celecoxib is presented as Formula I:

A pharmaceutically acceptable salt of a compound of formula I refers to a salt that, within the bounds of reasonable medical judgment, is suitable for use in contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., and also has a reasonable effect/risk ratio.

Pharmaceutically acceptable salts of the compound of Formula I include, but are not limited to, citrate, salicylate, L-tartrate, fumarate, sodium salt, potassium salt, calcium salt, hydrochloride, acetate, nitrate, sulfate, bisulfate, phosphate, hydrogen phosphate, oxalate, lactate, lysinate, aspartate and the like.

The present invention also provides a process for preparing the above compound of formula I.

The method for preparing a compound of formula I in accordance with the present invention includes the following steps:

1) a compound of formula II (celecoxib) and a compound of formula III (Boc-β-alanine) are reacted in the presence of EDCI/DMAP/triethylamine to obtain a compound of formula IV (SZY1907-05); And

2) the compound of formula IV is reacted with a solution of hydrogen chloride in ethyl acetate to obtain the compound of formula I.

In step 1) of the above-described method, the molar ratio of the compound of formula II to the compound of formula III is 1:1.4.

In step 1) of the above method, the molar ratio of the compound of formula II to EDCI, DMAP and triethylamine is 1:2.3:0.31:3, respectively.

In step 1) of the above-described method, the reaction is carried out in a solvent, where the solvent is in particular DCM (dichloromethane).

In step 1) of the above method, the reaction is carried out under stirring at room temperature and monitored by TLC until the raw material is exhausted.

In step 1) of the above method, after completion of the reaction, the following post-processing steps are additionally carried out: washing once with 3% dilute hydrochloric acid, washing once with saturated ammonium chloride, washing with saturated sodium chloride until neutral, drying the organic phase with sodium sulfate, rotary drying to obtain white solid; dissolving the white solid in ethanol, adding an equivalent amount of water, raising the temperature to reflux until the white solid is completely dissolved, slowly cooling to precipitate the product, vacuum filtration and drying to obtain SZY1907-05.

In step 2) of the above method, the molar ratio of the compound of formula IV and hydrogen chloride is 0.05:1.71.

In step 2) of the above method, the reaction condition is stirring at room temperature; During the reaction process, a solid gradually precipitates, and the reaction is monitored by TLC until the raw material runs out.

In step 2) of the above process, after completion of the reaction, the following post-processing steps are carried out: rotary drying, drip washing of the solid with ethyl acetate, collection of filter cake and rotary drying to constant weight to obtain the compound of formula I.

Another object of the present invention is the use of a compound of formula I.

The present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention and/or treatment of inflammation of ocular tissue.

A medicinal product prepared using a compound of formula I as an active ingredient for the prevention and/or treatment of inflammation of ocular tissue also falls within the scope of protection of the present invention.

The drug may be administered, for example, into muscular, intradermal, subcutaneous, venous or mucosal tissue of the body by injection, spray, nasal drops, eye drops, penetration, absorption, physical or chemical means; or it is mixed or encapsulated with other substances and then introduced into the body.

If necessary, one or more pharmaceutically acceptable carriers can also be added to said drug. Pharmaceutically acceptable carriers include a conventional diluent, excipient, filler, adhesive, humectant, disintegrant, sorbent, surfactant, adsorption vehicle, lubricant and the like.

The present invention also provides a medicament or pharmaceutical composition for the prevention and/or treatment of inflammation of ocular tissue, the active ingredient of which includes a compound of formula I or a pharmaceutically acceptable salt thereof.

Such a drug or pharmaceutical composition may be prepared in liquid form, such as eye drops, injections or other forms, in accordance with conventional methods known to those skilled in the art.

The present invention also provides eye drops for the prevention and/or treatment of inflammation of the ocular tissue.

The eye drops of the present invention contain the following components per 100 ml of eye drops: 0.1 g of a compound of formula I, 0.05 g of Tween-80, 0.45 g of polyoxyethylene 40 hydrogenated castor oil, 0.9 g of sodium chloride , 0.01 g benzalkonium chloride, the rest is distilled water; in this case, the pH value of eye drops is 5.5-6.5.

The compound of formula I according to the present invention has good solubility and is relatively stable during storage. Pharmacokinetic experiments show that celecoxib can be found in ocular tissues, distributed in the cornea, conjunctiva and aqueous humor, and the concentration of celecoxib reaches relatively high levels, and thus the compound of formula I is an excellent prodrug of celecoxib. Moreover, the distribution of the control compound SZY1907-P4 is practically negligible, and the concentration of celecoxib-derived eye drops in the cornea, conjunctiva and aqueous humor is also relatively low. The compound of formula I has a notable absorption advantage, the concentration of the drug in ocular tissue is significantly higher than that of the celecoxib group and the control group SZY1907-P4, and thus the compound can be obtained in the form of liquid preparations such as eye drops and injections for treatment inflammatory processes.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the H-NMR spectrum of SZY1907-P3.

Figures 2A and 2B show the LC and -MS spectra of SZY1907-P3, respectively.

IMPLEMENTATION OF THE INVENTION

The present invention is further characterized in conjunction with the specific examples below, but is not limited to the examples below. The methods described are conventional unless otherwise indicated. Raw materials are commercially available unless otherwise noted.

Example 1. Preparation of compound SZY19G7-P3 of formula I

Receiving SZY1907-05:

Nelecoxib (20.00 g, 0.0525 mol) and DCM (400 ml) were added to a three-neck flask, then Boc-β-alanine (0.0735 mol), EDCI (0.121 mol), triethylamine (0.158 mol), DMAP (0.0164 mol). The reaction was carried out under stirring at room temperature and monitored by TLC until the raw material was exhausted.

Post-treatment: wash once with 3% dilute hydrochloric acid, wash once with saturated ammonium chloride, wash with saturated sodium chloride until neutral, dry the organic phase with sodium sulfate, rotary dry to obtain a white solid; dissolving the white solid in ethanol, adding an equivalent amount of water, raising the temperature to reflux until the white solid is completely dissolved, slowly cooling to precipitate the product, vacuum filtration and drying to obtain SZY1907-05, with a yield of about 95%, and purity more than 98%.

Condition: White solid.

Getting SZY1907-P3:

SZY1907-05 (28.00 g, 0.05 mol) was added to a three-neck flask, followed by a solution of hydrogen chloride in ethyl acetate (3.8 mol/L, 450 ml), the solid gradually precipitated during the reaction, which was monitored by TLC until the raw material runs out.

Subsequent processing: rotary drying, drip washing of the solid with 200 ml ethyl acetate, collection of filter cake and rotary drying to constant weight to obtain a product with a yield of about 85%, and a purity of more than 99%.

Condition: White solid.

¹ H-NMR H ₂ O δ: 7.55-7.53 (d, J=7.6 Hz, 2H), 6.83-6.81 (d, J=6.8 Hz, 2H), 6 .54-6.46 (m, 4H), 6.15 (s, 1H), 3.05-3.04 (m, 2H). 2.64 (m, 2H), 1.76 (m, 3H). LC-MS: m/z=453.5(M+1).

The results of the structural confirmation are presented in Figure 1 and Figures 2A and 2B.

Example 2: Preparation of various forms of SZY1907-P3 salt

1. Preparation of SZY1907-P3 citrate:

SZY1907-P3 was dissolved in water, 1 mol/L sodium hydroxide was added dropwise until a solid precipitated, then vacuum filtered, dried, weighed and dissolved 100 mg of the solid in methanol, to which 42 mg of citric acid was added and stirred for 30 min until clarification, the methanol was dried using a rotary dryer to obtain 140 mg of citrate.

2. Preparation of trans-butenedioic acid salt SZY1907-P3:

SZY1907-P3 was dissolved in water, 1 mol/L sodium hydroxide was added dropwise until a solid precipitated, then vacuum filtered, dried, weighed and dissolved 100 mg of the solid in methanol, to which 26 mg of fumaric acid was added and stirred for 30 min. before clarification, the methanol was dried by rotary drying to obtain 110 mg of fumaric acid salt.

3. Preparation of salicylate SZY1907-P3:

SZY1907-P3 was dissolved in water, 1 mol/L sodium hydroxide was added dropwise until a solid precipitated, then vacuum filtered, dried, weighed and dissolved 100 mg of the solid in methanol, to which 31 mg of salicylic acid was added and stirred for 30 min. before clarification, the methanol was dried by rotary drying to obtain 120 mg of salicylate.

4. Preparation of L-tartrate SZY1907-P3;

SZY1907-P3 was dissolved in water, 1 mol/L sodium hydroxide was added dropwise until a solid precipitated, then vacuum filtered, dried, weighed and dissolved 100 mg of the solid in methanol, to which 33 mg of L-tartaric acid was added and stirred for 30 minutes before clarification, the methanol was dried using a rotary dryer to obtain 125 mg of L-tartrate.

Example 3: Preliminary Solubility and Stability Study of ZY1907-P3

In the initial solubility study of SZY1907-P3, it was found that the solubility of its hydrochloride is pH-related and has a certain dependence on pH, and therefore the solubility curves of its prototype and its salt form were determined at different pH values.

Currently, the prototype, citrate, acetate, tartrate, etc. are defined, the characteristic data is shown in Table 1 below.

It can be noted that the solubility of prototype P3 and its various salt forms has a strong pH dependence. At pH≥4, the solubility is less than 1 mg/ml.

At the same time, data on the stability of the prototype were measured at various pH values, the results are shown in Table 2 below.

From Table 2 it can be seen that there is no significant change in purity during storage for 5 days.

Comparative Example 1: Preparation of SZY1907-P4 Compound

Receiving SZY1907-06:

Celecoxib (1.34 g, 3.5 mmol) and DCM (26 ml) were added to a three-neck flask, then N-methyl-Boc-β-alanine (4.9 mmol), EDCI (8.05 mmol), triethylamine (10.5 mmol), DMAP (1 mmol), stirred at room temperature and monitored by TLC until raw material was exhausted.

Post-treatment: wash once with 3% dilute hydrochloric acid, wash once with saturated ammonium chloride, wash with saturated sodium chloride until neutral, dry the organic phase with sodium sulfate, rotary dry to obtain a white solid; stirring the white solid and passing through a column, washing with dichloromethane/methanol and eluting the product at 30:1 (v/v); selection and rotary drying to obtain 1.3 g of a white solid.

Condition: White solid.

Getting SZY1907-P4:

SZY1907-04 (1.00 g, 1.77 mmol) was added to a three-neck flask, then a solution of hydrogen chloride in ethyl acetate (3.8 mol/L, 30 ml) was added, stirred and monitored with TLC until raw materials will stop.

Subsequent processing: rotary drying to obtain a white solid; dissolution in methanol, adding 2 ml triethylamine, stirring the sample and passing through a column, washing with dichloromethane/methanol and eluting the product at 15:1 (v/v), collecting the organic phase, adding 5 ml hydrochloride in ethyl acetate, rotary drying to obtain 0. 6 g white solid.

Condition: White solid.

¹ H-NMR H ₂ O δ: 7.56-7.54 (d, J=8.0 Hz, 2H), 6.87-6.84 (d, J=7.6 Hz, 2H), 6 .59-6.50 (m, 4H), 6.20 (s, 1H), 3.06-3.03 (m, 2H), 2.63-2.54 (m, 5H), 1.78 (m, 3H). LC-MS: m/z=467.5(M+1).

Example 4. Study of ophthalmic pharmacokinetics of compound SZY1907-P3 and compound SZY1907-P4

Purpose of the study: To compare the content of the active compound celecoxib in the tissues of each eye to identify the lead compound with excellent pharmacokinetic characteristics after ophthalmic administration of SZY1907-P3, SZY1907-P4 and celecoxib to New Zealand rabbits.

Experimental materials:

Product under study:

SZY1907-P3: white powder, molecular formula: C ₂₀ H ₂₀ ClF ₃ N ₄ O ₃ S, molecular weight: 488.91, lot number: 20201106, purity: 99.85%, storage conditions: 2-8°C , expiration date until May 05. 2021.

SZY1907-P4: white solid, molecular formula: C ₂₁ H ₂₂ ClF ₃ N ₄ O ₃ S, molecular weight: 502.9, lot number: 20200801, purity: 98.99%, storage conditions: 2-8° C, expiration date: July 31, 2021.

Celecoxib: white powdery solid, molecular formula: C ₁₇ H ₁₄ F ₃ N ₃ O ₂ S, molecular weight: 381.37, lot number: 20190701, repeat purity: 99.87%, storage conditions: 2- 8°C, protected from light, expiration date until June 27, 2021.

Solvent: The composition of SZY1907-P3/P4 eye drops is shown in Table 3.

Table 3 shows the components of the solvent and their purpose.

Celecoxib solvent: 2% polyethylene glycol 400+98% aqueous solution of 7.5% methylated β-cyclodextrin.

Auxiliary products and main reagents:

Methanol (chromatographically pure): Merck, Germany. Formic acid (chromatographically pure): Aladdin. Methylated-β-cyclodextrin: MedChem Express. Polyethylene glycol 400: Solarbio Life Sciences.

Distilled water: Guangzhou Watsons Food & Beverage Co., Ltd. Twin-80: VETEC.

Polyoxyethylene hydrogenated castor oil 40: Croda.

Benzalkonium chloride solution (concentration 80%): Sinopharm Chemical Reagent Co., Ltd.

Sodium Chloride: VETEC INC.

Diazepam methanol solution: Provided by New Drug Evaluation Center of Hebei Yiling Pharmaceutical Research Institute Co. Experimental system: Animal genus: New Zealand rabbit. Animal level: Normal level.

Sex and number of animals: 12 males were purchased, 9 of them were selected for this experiment, and the remaining 3 were used for taking blank tissue samples. Age of animals at the time of purchase: 3-5 months. Weight of animals at the time of purchase: 1.5-2.0 kg.

Adaptation period: Newly received animals were in adaptation conditions for 3-5 days. During this time, we observed how the animals drink water, eat food, what is their health status, and whether there are any symptoms of disease or mortality.

Identification: Numbered with ear marker.

Basis for Experimental Design

Accepted Standard: Technical Guide for Non-Clinical Pharmacokinetic Studies of Drugs published by the State Food and Drug Administration.

Dosage and distribution by group

Group allocation: 9 male New Zealand rabbits were randomly divided into 3 groups of 3 animals each.

Dosage: According to the composition of Guangzhou Zhongshan Ophthalmic Center, the concentration of SZY1907-P3/P4 in eye drops is 0.1%. Thus, the SZY1907-P3/P4 dose was set to 0.100 mg per New Zealand rabbit and the celecoxib dose to 0.075 mg per New Zealand rabbit (close to the equimolar dose of SZY1907-P3/P4). Specific groups and dosages are given in Table 4.

The method of administration of the drug corresponded to the clinical method and was an ophthalmic administration, and the drug was simultaneously injected into the rabbit's left and right eyes.

Receipt and storage of the study product (the volume of the drug in subsequent operations can be adjusted depending on real needs).

0.1% SZY1907-P3 Eye Drops: Weigh 0.01000 g of SZY1907-P3, add 0.00500 g of Tween-80 and 0.04500 g of polyoxyethylene hydrogenated castor oil 40 and mix with a glass rod until an emulsified solution is obtained. While stirring, 5 ml of distilled water was slowly added and then dissolved for further use. Weighed 0.09000 g of sodium chloride and 0.001.25 g of 80% benzalkonium chloride, added 2 ml of distilled water and stirred until dissolved. Both solutions were combined and the volume was adjusted to 10 ml. The pH was adjusted between 5.5 and 6.5 using 1 mol/L NaOH solution.

0.1% SZY1907-P4 Eye Drops: Weigh out 0.01000 g of SZY1907-P4, add 0.00500 g of Tween-80 and 0.04500 g of polyoxyethylene hydrogenated castor oil 40 and mix with a glass rod until an emulsified solution is obtained. While stirring, 5 ml of distilled water was slowly added and then dissolved for further use. Weighed 0.09000 g of sodium chloride and 0.00125 g of 80% benzalkonium chloride, added 2 ml of distilled water and stirred until dissolved. Both solutions were combined and the volume was adjusted to 10 ml. The pH was adjusted between 5.5 and 6.5 using 1 mol/L NaOH solution.

0.075% celecoxib eye drops: 0.00750 g celecoxib was placed in a 1.5 ml centrifuge tube, then 200 µl polyethylene glycol 400 was added, centrifuged at 12000 rpm for 60 s, transferred to a 10 ml volumetric flask, added 7 A .5% aqueous solution of methylated-β-cyclodextrin for volume control was shaken until the solution became clear and clear to obtain eye drops.

Administration of the study product: simultaneous injection of a rabbit into the left and right eyes in a dose of 50 μl per eye. Precise administration using a pipette: While gently pulling the rabbit's eyelid down into a cup shape, using a pipette, accurately draw up 50 µl of eye drops and drop them into the eyelid, then passively close the rabbit's eyes for 10 seconds.

Indicators, time and composition of observations: sampling: intraocular fluid, cornea and conjunctiva are collected 1 hour after drug administration. Collection of aqueous humor: From animals sacrificed during the experiment, approximately 200 μl of aqueous humor is collected using a 1 ml syringe at the junction of the pupil and iris (note that when collecting aqueous humor, the tangent plane of the syringe needle was directed downward to prevent splashing of intraocular fluid). Harvesting the cornea: Fix the eyeball with forceps, dissect the cornea and iris using curved scissors and cut the cornea where they are connected. The extracted cornea is washed with ultrapure water, the surface liquid is removed using filter paper, and precise weighing and cryopreservation are carried out. Collection of the conjunctiva: The conjunctiva of the upper and lower eyelids is clamped with forceps and cut with scissors. The removed conjunctiva is cleaned with ultrapure water, the surface liquid is removed using filter paper, and precise weighing and cryopreservation are carried out.

Processing of tissue samples: obtaining a cornea/conjunctiva homogenate: first, the cornea/conjunctiva of the left and right eyes is cut into small pieces with small scissors, then a 50% aqueous solution of methanol is added (weight-to-volume ratio 1:10), crushed using a grinder (the procedure is Cycle 4 times at 6500 rpm per cycle for 30 s and wait for 20 s), centrifuge at 4000 rpm in a low-speed centrifuge for 10 min, supernatant aspirate and cryopreserve for measurements.

Pre-treatment before sample detection: intraocular fluid sample: remove 50 μl of intraocular fluid, add 200 μl of internal standard working solution (100 ng/ml diazepam in methanol solution), vortex for 5 min, centrifuge at 12,000 rpm in a high-speed centrifuge for 10 minutes; the supernatant is aspirated and loaded into an automatic sampler vial for measurements.

Corneal and conjunctival samples: take 50 μl of the homogenate supernatant, add 200 μl of the working solution according to the internal standard (100 ng/ml diazepam in methanol solution), mix by vortex method for 5 min, centrifuge at 12,000 rpm in a high-speed centrifuge for 10 min; the supernatant is aspirated and loaded into an automatic sampler vial for measurements.

Equipment: Liquid chromatography-mass spectrometry: Waters Xevo TQD/PDA ACQUITY UPLC liquid chromatography-mass spectrometer equipped with an electrospray ionization source (ESI source) (Waters).

Data management system: Masslynx V4.1 (Waters).

Data processing: Data are calculated by relating the peak area of the sample to the internal standard. To calculate the regression, the weighted (W=1/X2) least squares method is used, a linear regression equation is obtained, and after substituting the ratio coefficient into the equation, the drug concentration is calculated.

Experiment results:

From the above results, it can be seen that celecoxib can be found in ocular tissues, distributed in the cornea, conjunctiva and intraocular fluid, and the concentration of celecoxib reaches a relatively high level, and thus, the compound of formula I is an excellent prodrug of celecoxib. Moreover, the distribution of the control compound SZY1907-P4 is practically negligible, and the concentration of celecoxib-derived eye drops in the cornea, conjunctiva and aqueous humor is also relatively low. The compound of formula I SZY1907-P3 has a noticeable advantage in terms of absorption, the concentration of the drug in ocular tissue is significantly higher than that of the celecoxib group and the control group SZY1907-P4, and thus the compound can be obtained in the form of liquid preparations such as eye drops and injections for the treatment of inflammatory processes.

Claims (20)

1. Compound of formula I or a pharmaceutically acceptable salt thereof 2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt of the compound of formula I includes citrate, salicylate, L-tartrate, fumarate, sodium salt, potassium salt, calcium salt, hydrochloride, acetate, nitrate, sulfate, bisulfate, phosphate, hydrogen phosphate, oxalate, lactate, lysinate and aspartate. 3. A method for producing a compound of formula I according to claim 1, including the following steps: 1) a compound of formula II and a compound of formula III reacted in the presence of EDCI/DMAP/triethylamine to obtain the compound of formula IV 2) the compound of formula IV reacts with a solution of hydrogen chloride in ethyl acetate to obtain a compound of formula I. 4. The method according to claim 3, where in stage 1) the molar ratio of the compound of formula II to the compound of formula III is 1:1.4; in step 1) the molar ratio of the compound of formula II to EDCI, DMAP and triethylamine is 1:2.3:0.31:3, respectively; in step 1) the reaction is carried out in a solvent, where the solvent is DCM; And In step 1), the reaction is carried out under stirring at room temperature and monitored by TLC until the raw material is exhausted. 5. The method according to claim 3 or 4, where in step 1) the method additionally includes the following post-processing steps upon completion of the reaction: once washing with 3% dilute hydrochloric acid, once washing with saturated ammonium chloride, washing with saturated sodium chloride until neutral, drying the organic phase with sodium sulfate, rotary drying to obtain a white solid; dissolving the white solid in ethanol, adding an equivalent amount of water, heating and refluxing until the white solid is completely dissolved, slowly cooling to precipitate the product, vacuum filtration and drying to obtain the compound of formula IV. 6. Method according to any one of paragraphs. 3-5, where in stage 2) the molar ratio of the compound of formula IV and hydrogen chloride is 0.05:1.71; And at stage 2) the reaction condition is stirring at room temperature; During the reaction, a solid gradually precipitates and the reaction is monitored by TLC until the raw material runs out. 7. Method according to any one of paragraphs. 3-6, wherein in step 2) the method further includes the following post-processing steps after completion of the reaction: rotary drying, drip washing of the solid with ethyl acetate, collection of filter cake and rotary drying to constant weight to obtain a compound of formula I. 8. Use of a compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2 for the preparation of a medicinal product for the prevention and/or treatment of inflammation of ocular tissue. 9. A medicinal product or pharmaceutical composition for the prevention and/or treatment of inflammation of the ocular tissue, containing as an active ingredient a compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2. 10. Eye drops for the prevention and/or treatment of inflammation of the eye tissue, containing the following components per 100 ml of eye drops: 0.1 g of a compound of formula I according to claim 1 or 2, 0.05 g Tween-80, 0.45 g polyoxyethylene hydrogenated castor oil 40, 0.9 g sodium chloride, 0.01 g benzalkonium chloride, the rest is distilled water; in this case, the pH value of eye drops is 5.5-6.5.