CN113801180B

CN113801180B - Compound for treating cataract, composition thereof, preparation method and medical application

Info

Publication number: CN113801180B
Application number: CN202111227468.0A
Authority: CN
Inventors: 王金辉; 黄健; 李春莉; 杨璐; 张珂; 姚红; 孙义凡; 甘春丽; 孙仁宽; 王雁丽; 卢立娜
Original assignee: Shenzhen Honghui Biomedicine Co ltd
Current assignee: Shenzhen Honghui Biomedicine Co ltd
Priority date: 2021-10-21
Filing date: 2021-10-21
Publication date: 2023-04-14
Anticipated expiration: 2041-10-21
Also published as: CN113801180A

Abstract

The invention discloses a compound for treating cataract, a composition, a preparation method and medical application thereof, wherein the compound has a structure shown in a formula I (n is 1-50). The compound can be used for treating lens turbidness diseases such as cataract and the like.

Description

Compound for treating cataract, composition thereof, preparation method and medical application

Technical Field

The invention particularly relates to and discloses a series of baicalin derivatives, and a preparation method, application and a quality control method thereof.

Background

Baicalin is a flavonoid compound extracted and separated from radix Scutellariae, and is light yellow powder with bitter taste at room temperature. Is insoluble in methanol, ethanol, acetone, chloroform and nitrobenzene, is almost insoluble in water, and is soluble in hot acetic acid. When the ferric trichloride is in contact with the ferric trichloride, the ferric trichloride shows green, and when the ferric trichloride is in contact with the lead acetate, orange precipitate is generated. The yellow color of the solution dissolved in alkali and ammonia water is changed into black brown color after a while. Has remarkable biological activity, has the functions of bacteriostasis, diuresis, anti-inflammation, cholesterol reduction, thrombosis resistance, asthma relief, fire purging, detoxification, hemostasis, miscarriage prevention, allergy resistance and spasmolysis, is a specific inhibitor of liver sialidase of mammals, has the function of regulating certain diseases, and also has stronger physiological efficiency of anticancer reaction. Is mainly used for treating damp-warm syndrome, summer-warm syndrome, chest distress, emesis, damp-heat distention and fullness, dysentery, jaundice, cough due to lung-heat, hyperpyrexia, polydipsia, blood heat, emesis, carbuncle, swelling, sore and restlessness. In addition, baicalin can absorb ultraviolet rays, remove oxygen free radicals and inhibit the generation of melanin, and is a good raw material of functional cosmetic.

The chemical structure of baicalin is as follows:

in the process of modifying the structure of the extract, the inventor discovers that the baicalin polyethylene glycol ester compound has a remarkable effect of treating cataract by screening different activities, establishes a synthesis process of the baicalin polyethylene glycol ester by further researching synthesis process, composition and activity evaluation, and establishes a content determination method for the compound in the baicalin polyethylene glycol ester compound so as to improve the optimization of process parameters of the extract and calibrate the quality of the extract.

Disclosure of Invention

The invention aims to solve the technical problems that the effective components for treating cataract are invented, the synthesis process is established, the effect of preventing and treating cataract is further evaluated, and the quality control method is established.

We have synthesized a large number of baicalin derivatives, and screened different pharmacological activities, and found that the baicalin polyethylene glycol ester derivatives can effectively prevent and treat cataract in rat cataract models caused by D-galactose.

To this end, the present invention provides a compound having the structure shown in formula I:

wherein n is 1 to 50.

Preferably, n is 1 to 10.

More preferably, n is 1 to 5.

Most preferably, where n is 1 to 2.

The most preferred specific compounds are: baicalin ethoxy ethyl ester.

The invention further provides application of the compound shown in the general formula I in preparing a medicament for treating cataract, wherein the cataract is lenticular turbidimetric disease.

The invention further provides a preparation method of the compound shown in the general formula I, which comprises the following steps:

1) Preparation of baicalin sodium salt

Suspending baicalin in water, stirring to obtain suspension, adding organic sodium salt such as sodium carbonate or inorganic acid sodium salt or sodium hydroxide under stirring, and reacting; after reaction, organic solvent such as absolute ethyl alcohol is dripped, precipitation, suction filtration, washing of the precipitation with crystallization solvent, recrystallization with organic solvent and drying are carried out continuously to obtain baicalin sodium salt.

Wherein, the polymerization degree n of the 2-bromoethyl ether compound is =1-50; the organic sodium salt comprises sodium methoxide, sodium ethoxide, sodium tartrate, sodium phthalate, sodium citrate, etc., and the inorganic sodium salt comprises sodium carbonate, sodium bicarbonate, sodium sulfate, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, etc.; the reaction temperature is room temperature reaction or heating reaction, the optimized temperature is room temperature-80 ℃, and the optimal condition is room temperature; the reaction time is 10min to 2 days, the optimization is 0.1 to 8 hours, and the optimal time is 0.1 to 0.7 hour; the organic solvent for reaction precipitation is absolute ethyl alcohol, hydrous ethyl alcohol, methanol, propanol, acetone and the like, and is optimized to be absolute ethyl alcohol and hydrous ethyl alcohol; the organic solvent for recrystallization is absolute ethyl alcohol, hydrous ethyl alcohol, methanol, propanol, acetone, a mixed solvent of the absolute ethyl alcohol and the hydrous ethyl alcohol, and the like, and is optimized to be the absolute ethyl alcohol and the hydrous ethyl alcohol; the recrystallization temperature is 0-80 ℃, the optimized temperature is 0-room temperature, and the optimal condition is 0 ℃ (ice-water bath).

2) Preparation of baicalin derivatives

Weighing baicalin sodium salt, adding organic solvents such as DMF (dimethyl formamide) and the like for dissolving, adding 2-bromoethyl ether compounds into reaction liquid, pouring water into the reaction liquid after reaction, adding a proper amount of organic solvents such as ethyl acetate and the like, standing for 9h in an ice water bath, standing for 6h at 4 ℃, separating out crystals, performing suction filtration on the crystals, washing the crystals with the crystallization solvents, continuously recrystallizing with the organic solvents, and drying to obtain the baicalin derivative.

Wherein the organic solvent for reaction comprises dichloromethane, chloroform, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (TMF), ethyl acetate, acetone, etc., and is preferably Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (TMF); the reaction temperature is room temperature reaction or heating reaction, the optimized temperature is room temperature-160 ℃, and the optimal condition is 60-120 ℃; the reaction time is 10min-2 days, optimized to be 2-12 hours, and optimally 6-10 hours; the water adding amount of the reaction solution is 2-50 times of that of the reaction solution, the optimization is 8-20 times, and the optimal addition amount is 10-15 times; the organic solvent for crystallization of the reaction solution is ethyl acetate, dichloromethane, chloroform, n-butanol and the like, and is optimized to be ethyl acetate; the addition amount of the organic solvent for reaction liquid crystallization is 0.1-20 times of the reaction liquid, is optimized to be 0.2-5 times, and is optimally 0.5-2 times; the organic solvent for recrystallization is absolute ethyl alcohol, hydrous ethyl alcohol, methanol, propanol, acetone and a mixed solvent thereof, and is optimized to be absolute ethyl alcohol, hydrous ethyl alcohol, ethyl acetate and a mixed solvent thereof; the recrystallization temperature is 0-80 ℃, the optimized temperature is 0-room temperature, and the optimal condition is 0 ℃ (ice water bath).

The present invention further provides a second method of preparation, said method comprising the steps of: weighing baicalin, adding organic solvent such as DMF (dimethyl formamide) and the like for dissolving, adding 2-bromoethyl ether compound into reaction liquid, pouring water into the reaction liquid after reaction, adding a proper amount of organic solvent such as ethyl acetate and the like, standing, precipitating crystals, carrying out suction filtration on the crystals, washing the crystals with a crystallization solvent, continuously recrystallizing with the organic solvent, and drying to obtain the baicalin derivative.

Wherein, the polymerization degree n of the 2-bromoethyl ether compound is =1-50; the organic solvent for reaction comprises dichloromethane, chloroform, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (TMF), ethyl acetate, acetone, etc., and is preferably Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (TMF); the reaction temperature is room temperature reaction or heating reaction, the optimized temperature is room temperature-160 ℃, and the optimal condition is 60-120 ℃; the reaction time is 10min-2 days, the optimization is 2-12 hours, and the optimal time is 6-10 hours; the water adding amount of the reaction solution is 2-50 times of that of the reaction solution, the optimization is 8-20 times, and the optimal addition is 10-15 times; the organic solvent for crystallizing the reaction liquid is ethyl acetate, dichloromethane, chloroform, n-butanol and the like, and is optimized to be ethyl acetate; the adding amount of the organic solvent for crystallization of the reaction solution is 0.1-20 times of the reaction solution, is optimized to be 0.2-5 times, and is optimally 0.5-2 times; the organic solvent for recrystallization is absolute ethyl alcohol, hydrous ethyl alcohol, methanol, propanol, acetone and a mixed solvent thereof, and is optimized to be absolute ethyl alcohol, hydrous ethyl alcohol, ethyl acetate and a mixed solvent thereof; the recrystallization temperature is 0-80 ℃, the optimized temperature is 0-room temperature, and the optimal condition is 0 ℃ (ice water bath).

The invention further provides a method for measuring the content of the compound shown in the general formula I by an HPLC method, which comprises the following steps:

1) Test solution: precisely weighing 5-50mg of the compound shown in the general formula I, dissolving the compound in methanol, and fixing the volume to about 100 mu g/ml to obtain the compound.

2) Chromatographic conditions are as follows: ODS column (4.6X 150 mm), detection wavelength: 278nm; column temperature: 30 ℃; flow rate: 1mL/min; sample introduction amount: 10 mu L of the solution; methanol was used as mobile phase a, and 0.3% phosphoric acid water was used as mobile phase B, and gradient elution was performed as specified in table 1 below.

TABLE 1 determination of baicalin derivative content chromatographic flow term gradient conditions

Wherein, the compound is shown in the general formula I, wherein n is 1-50.

Preferably, n is 1 to 10.

More preferably, n is 1 to 5.

Most preferably, where n is 1 to 2.

The most preferred specific compounds are: baicalin ethoxy ethyl ester.

The invention further comprises a pharmaceutical composition containing the compound shown in the general formula I, which comprises any one of the pharmaceutical preparation forms for administration, such as oral medicines, non-oral medicines and the like, and specifically comprises tablets, capsules and granules, injections, pills, patches and the like.

The invention further discovers that Vc and weak acidic conditions can protect the stability of the compound shown in the general formula I in the preparation.

The invention carries out drug effect test on the compound shown in the general formula I, and finds that the compound has the efficacy of preventing and treating cataract.

Therefore, the invention provides the application of the compound shown in the general formula I in the preparation of the medicine for preventing and treating cataract caused by various reasons, such as: cataract caused by galactosemia, senile cataract, cataract caused by trauma and diabetic complication cataract, cataract caused by hypothyroidism, and lens opacity caused by heavy metal poisoning or other reasons.

The compound shown in the general formula I and having the effect of preventing and treating cataract disclosed by the invention provides hope for the majority of cataract patients lacking medical treatment at present, and has far-reaching social significance and application value.

Drawings

FIG. 1 shows the chemical structure of baicalin derivatives

FIG. 2 HPLC chromatogram of baicalin ethoxyethyl ester (compound obtained in example 1, n =1 in chemical formula)

FIG. 3 is a photograph of an eyeball of a rat cataract slit lamp before, during and after the treatment of baicalin ethoxyethyl

FIG. 4 shows a preparation of baicalin ethoxyethyl ester (compound obtained in example 1, n =1 in chemical formula) ¹ HNMR NMR

FIG. 5 shows a preparation of baicalin ethoxyethyl ester (compound obtained in example 1, n =1 in chemical formula) ¹³ CNMR nuclear magnetic map

FIG. 6 DEPT NMR spectra of baicalin ethoxyethyl ester (compound obtained in example 1, n =1 in chemical formula)

FIG. 7 shows a schematic diagram of a compound of baicalin ethoxyethyl ester (the compound obtained in example 1, n =1 in the chemical formula) ¹ H- ¹ H COSY nuclear magnetic spectrum

FIG. 8 NOESY NMR spectra of baicalin ethoxyethyl ester (compound obtained in example 1, n =1 in chemical formula)

FIG. 9 HMQC NMR spectra of baicalin ethoxyethyl ester (compound obtained in example 1, n =1 in chemical formula)

FIG. 10 HMBC NMR spectra of baicalin ethoxyethyl ester (compound obtained in example 1, n =1 in chemical general formula)

Detailed Description

The following examples illustrate the utility of the invention, which is not limited thereby.

Example 1: preparation of baicalin ethoxy ethyl ester

1) Preparation of baicalin sodium salt

Weighing 500mg of baicalin in a test tube. Adding 3.88ml water, stirring to form suspension, adding 1.12ml 0.5mol/L sodium carbonate (and baicalin molar ratio of 0.5/1) while stirring, and reacting at room temperature for 30min. Then 20ml of absolute ethyl alcohol is respectively dripped into the mixture and crystallized for 6 hours under the condition of ice-water bath. Then carrying out suction filtration, washing, recrystallizing the precipitate with absolute ethyl alcohol, and drying to obtain baicalin sodium salt, wherein the yield is as follows: 90.62 percent.

2) Preparation of baicalin ethoxy ethyl ester

Weighing 8.17g (5 times) of 2-bromoethyl ether, adding the 2-bromoethyl ether into 300ml of DMF, slowly adding 5.00g of baicalin sodium salt and a proper amount of sodium iodide catalyst in batches while stirring, continuously stirring, reacting for 12 hours at 90 ℃, taking reaction liquid, adding 1500ml (5 times) of water into the reaction liquid after the reaction is finished, adding 300ml of ethyl acetate, violently shaking, standing overnight in ice water bath, carrying out suction filtration next day, recrystallizing crystals by absolute ethyl alcohol, and drying to obtain 3.59g of a product, wherein the yield is 81.2%.

And (3) nuclear magnetic spectrum identification: ¹ H-NMR(400MHz,CDCl ₃ ) Delta (ppm)) 12.60 (1H, s, 5-OH), 8.71 (1H, br.s, 6-OH), 8.07-8.09 (2H, m, mono-substituted benzene ring), 7.58-7.60 (3H, m, mono-substituted benzene ring), 7.07 (1H, s, H-8), 7.02 (1H, s, H-3), 5.55-5.56 (2H, br.d), 5.32-5.35 (2H, br.d), 4.24 (1H, d, glc-1'), 4.16-4.25 (2H, m), 3.38-3.57 (6H, m, containing 3 OH), 1.00 (3H, t, CH, t, H, 1, 3H, m, 3H, 6-3, H, m, 1H, 1, 3, H, t, C, H-1, C, 1, and C ₃ )； ¹³ C-NMR(100MHz,CDCl ₃ ) Delta (ppm): 182.99, 169.18, 163.98, 151.67, 149.63, 147.24, 132.52, 131.30, 131.06, 129.59 (2C), 126.82 (2C), 106.59, 105.24, 100.34, 94.21, 75.65, 75.50, 73.23, 71.77, 67.89, 66.02, 64.68, 15.39. And passed through DEPT, ¹ H- ¹ H COSY, NOESY, HMQC and HMBC confirm the chemical structures (shown in the attached drawing).

Example 2: preparation of baicalin ethoxy ethyl ester

Weighing 9.6g (6 times) of 2-bromoethyl ether, adding the 2-bromoethyl ether into 300ml of DMF, slowly adding 5.00g of baicalin and a proper amount of sodium iodide catalyst in batches while stirring, continuously stirring, reacting for 8 hours at 80 ℃, after the reaction is finished, adding 2100ml (7 times) of water into the reaction solution, adding 450ml of ethyl acetate (1.5 times) into the reaction solution, violently shaking, standing in an ice water bath overnight, carrying out suction filtration for the next day, recrystallizing crystals by using absolute ethyl alcohol, and drying to obtain 2.63g of a product, wherein the yield is 59.4%.

Example 3: preparation of baicalin dimer glycol ester (general formula n = 2)

Weighing 8.3g (4 times) of 2-bromoethoxyethyl ether, adding the 2-bromoethoxyethyl ether into 300ml of DMF, slowly adding 5.00g of baicalin and a proper amount of sodium iodide catalyst in batches under stirring, continuously stirring, reacting for 8 hours at 80 ℃, taking 2100ml (7 times) of water into reaction liquid after the reaction is finished, adding 450ml of ethyl acetate (1.5 times), violently shaking, standing in an ice-water bath overnight, carrying out suction filtration next day, recrystallizing crystals by using absolute ethyl alcohol, and drying to obtain 2.99g of a product, wherein the yield is 62.3%.

Example 4: preparation of baicalin polyglycol ester-5 (general formula n = 5)

Weighing 19.6g (5 times) of 2-bromopolyethoxyethylether (n = 5), adding the 2-bromopolyethoxyethylether into 500ml of DMF, slowly adding 5.00g of baicalin and a proper amount of sodium iodide catalyst in batches under stirring, continuously stirring, reacting for 8h at 80 ℃, after the reaction is finished, adding 2000ml (4 times) of water into the reaction solution, adding 500ml of ethyl acetate (1 time), violently shaking, standing in an ice water bath overnight, carrying out suction filtration the next day, recrystallizing crystals by using absolute ethyl alcohol, and drying to obtain 3.07g of a product, wherein the yield is 51.9%.

Example 5: preparation of baicalin polyglycol ester-50 (general formula n = 50)

Weighing 36.3g (5 times) of 2-bromopolyethoxyethyl ether (n = 50), adding the 2-bromopolyethoxyethyl ether into 800ml of DMF, slowly adding 5.00g of baicalin and a proper amount of sodium iodide catalyst in batches under stirring, continuously stirring, reacting for 8h at 80 ℃, after the reaction is finished, adding 4000ml (5 times) of water into a reaction solution, adding 400ml of ethyl acetate (0.5 time) into the reaction solution, violently shaking, standing in an ice-water bath overnight, performing suction filtration next day, recrystallizing crystals with absolute ethyl alcohol, and drying to obtain 9.52g of a product, wherein the yield is 41.7%.

Example 6: preparation of composition-baicalin ethoxy ethyl ester tablet

Taking the baicalin ethoxy ethyl ester powder obtained in the example 1 and auxiliary materials such as starch, microcrystalline cellulose and the like, respectively sieving with a 100-mesh sieve, weighing and uniformly mixing according to the proportion of each formula, adding a proper amount of 80% ethanol to prepare a soft material, granulating with a 16-mesh sieve, and drying with hot air at 50 ℃ for 90min. And (4) after finishing the granules by using a 14-mesh sieve, adding a proper amount of talcum powder and magnesium stearate, and tabletting to obtain the tablet.

The prescription composition is as follows: each tablet is 500mg, and contains baicalin ethoxy ethyl ester 100mg.

The prescription is as follows:

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example 7: preparation of composition-baicalin polyethylene glycol ester-5 capsule

Taking the baicalin polyethylene glycol ester-5 powder obtained in the example 4 and auxiliary materials such as starch, microcrystalline cellulose and the like, respectively sieving with a 100-mesh sieve, weighing and uniformly mixing according to the proportion of each formula, adding a proper amount of 80% ethanol to prepare a soft material, granulating with a 16-mesh sieve, and drying with hot air at 50 ℃ for 90min. And after the 14-mesh sieve is sized, adding a proper amount of talcum powder and magnesium stearate, and filling capsules to obtain the capsule.

The prescription composition is as follows: each capsule is 250mg, and the content of baicalin polyethylene glycol ester-5 is 150mg.

The prescription is as follows:

example 8: preparation of composition-baicalin dimer glycol ester (general formula n = 2) granule

Taking the baicalin dipolyethylene glycol ester (general formula n = 2) powder obtained in the example 3 and auxiliary materials such as starch, microcrystalline cellulose and the like, respectively sieving through a 100-mesh sieve, weighing and uniformly mixing according to the proportion of each formula, adding a proper amount of 80% ethanol to prepare a soft material, granulating through a 16-mesh sieve, and drying for 90min through hot air at 50 ℃. And (4) after finishing the granules by using a 14-mesh sieve, adding a proper amount of talcum powder and magnesium stearate, and bagging to obtain the finished product.

The prescription composition is as follows: each bag contains 1g of baicalin-dipolyethylene glycol ester (general formula n = 2) 150mg.

The prescription is as follows:

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example 9: preparation of composition-baicalin polyethylene glycol ester-50 (general formula n = 50) granule

Taking the baicalin polyethylene glycol ester-50 (general formula n = 50) powder obtained in the example 5 and auxiliary materials such as starch, microcrystalline cellulose and the like, respectively sieving with a 100-mesh sieve, weighing and uniformly mixing according to the proportion of each formula, adding a proper amount of 80% ethanol to prepare a soft material, sieving with a 16-mesh sieve to prepare granules, and drying with hot air at 50 ℃ for 90min. After 14 meshes of sieve is finished, adding a proper amount of talcum powder and magnesium stearate, and bagging to obtain the finished product.

The prescription composition is as follows: each bag contains 2g of baicalin polyethylene glycol ester-50 (general formula n = 50) 500mg.

The prescription is as follows:

example 10: baicalin polyglycol ester for treating cataract caused by galactosemia

180 healthy rats with the weight of 180-220g are selected for male and female. 20 animals were selected as a blank group, and the remaining animals were intraperitoneally injected with a 50% aqueous solution of D-galactose at a dose of 10g/kg once a day for 15 consecutive days while being fed with 5% D-galactose solution for free drinking for 12 days, and the blank group animals were intraperitoneally injected with an equal volume of 0.9% sodium chloride injection and fed with tap water for drinking. When the D-galactose injection is finished, the crystal turbidity degree is checked under a slit lamp microscope, rats with all turbid crystals and no obvious change are removed, 100 rats with similar turbidity degrees are selected and randomly divided into 5 groups according to sex and the crystal turbidity degree, and each group comprises 20 rats. Both male and female. The 5 groups were a model group, a positive drug control group (zhangyanming tablets group), and an administration group: baicalin ethoxyethyl ester (formula n = 1) 80mg/kg dose group, baicalin polyethylene glycol ester (formula n = 5) 100mg/kg dose group, and baicalin polyethylene glycol ester (formula n = 50) 400mg/kg dose group.

Administration: distilled water was given to the normal control group and the model group, 2 tablets/kg dose of ophthalmic blepharming tablet was given to the positive drug control group after molding, 80mg/kg dose group of baicalin ethoxyethyl ester (formula n = 1), 100mg/kg dose group of baicalin polyethylene glycol ester (formula n = 5), and 400mg/kg dose group of baicalin polyethylene glycol ester (formula n = 50) were given to the drug group after molding. The administration route is intragastric administration. The dose volumes were 10ml/kg body weight. The administration is carried out once every 9-11 days for 30 consecutive days. The crystal turbidity was checked for 5 days, 10 days, 15 days, 20 days, 30 days of administration, and the scores were scored according to the crystal turbidity score criteria. The rat crystal opacity score criteria are shown in table 2.

TABLE 2 rat Crystal opacity Scale

Phases	Turbidity of crystals	Score value
			1	Clarification of crystals	0
2	Fine cavitation bubbles appear around the crystal	0.1
				The vacuole accounts for 1/3 of the area of the precordial cortex of the crystal	0.7
	The vacuole accounts for 2/3 of the area of the precordial cortex of the crystal	1.0
			3	Vacuole liquefaction or opalescence or punctate and strip-shaped white turbidity	2.0
4	The crystals are dispersed in a flaky white precipitate	3.0
			5	Onset of cloudiness of the crystalline nuclei	4.0
6	The crystals are all turbid	5.0

The results show (see table 3): the normal control group animals had clear crystals and no lesions. After the injection of D-galactose is stopped, the crystal turbidity can still slowly rise, so that the crystal turbidity is maintained at a higher level. After molding, the baicalin ethoxyethyl (general formula n = 1) 80mg/kg dose group, the baicalin polyethylene glycol ester-5 (general formula n = 5) 100mg/kg dose group and the baicalin polyethylene glycol ester-50 (general formula n = 50) 400mg/kg dose group have obvious treatment effects; comprehensive analysis proves that the baicalin derivative has obvious therapeutic action on the D-galactose cataract of the rat, and the action intensity is stronger than that of the cataract of an equivalent amount.

TABLE 3 Effect on Crystal haze

Note: * P <0.05 compared to model group; * P <0.01 in comparison with model groups

Example 11: activity test for treating diabetic cataract

180 spontaneous diabetic rats with the weight of 180-200g are selected and used as both male and female. 20 animals were selected as a blank group, and the remaining animals were intraperitoneally injected with 50% of D-galactose at a dose of 8g/kg once a day for 15 consecutive days while being fed with 5% of D-galactose solution for free drinking for 12 days, and animals of the blank group were intraperitoneally injected with sodium chloride injection solution of 0.9% in volume, etc., and fed with tap water for drinking. When the D-galactose injection is finished, the crystal turbidity degree is checked under a slit lamp microscope, rats with all turbid crystals and no obvious change are removed, 100 rats with similar turbidity degrees are selected and randomly divided into 5 groups according to sex and the crystal turbidity degree, and each group comprises 20 rats. They are used in combination as male and female. The 5 groups were a model group, a positive drug control group (zhangyanming tablets group), and an administration group: baicalin ethoxyethyl ester (formula n = 1) 80mg/kg dose group, baicalin polyethylene glycol ester-5 (formula n = 5) 100mg/kg dose group, and baicalin polyethylene glycol ester-50 (formula n = 50) 400mg/kg dose group.

Administration: distilled water was administered to the normal control group and the model group, and 2 tablets/kg dose of diaverine, 80mg/kg dose of baicalin ethoxyethyl ester (formula n = 1), 100mg/kg dose of baicalin polyethylene glycol ester-5 (formula n = 5), and 400mg/kg dose of baicalin polyethylene glycol ester-50 (formula n = 50) were administered to the positive drug control group. The administration route is intragastric administration. The dose volumes were 10ml/kg body weight. The medicine is administered once every 9-11 days for 30 days. The opacity of the crystals was checked at 5 days, 10 days, 15 days, 20 days and 30 days of administration and scored according to the opacity score. The opacity scores of the rat crystals are shown in Table 2.

The results showed (see table 4) that the normal control animals had clear crystals and no lesions. After the injection of D-galactose is stopped, the crystal turbidity can still slowly rise, so that the crystal turbidity is maintained at a higher level. The baicalin ethoxyethyl (general formula n = 1) 80mg/kg dose group, the baicalin polyethylene glycol ester-5 (general formula n = 5) 100mg/kg dose group and the baicalin polyethylene glycol ester-50 (general formula n = 50) 400mg/kg dose group have obvious treatment effect on the D-galactosyl cataract of the diabetic rat, and the action intensity is stronger than that of the equivalent dose of the cataract eye mask tablet.

TABLE 4 Effect on crystal haze

Example 12: activity test for treating senile cataract

180 rats of 1 year old are selected, and the rats are used for male and female purposes and have the weight of 450-550g. 20 animals were selected as a blank group, and the remaining animals were intraperitoneally injected with 50% of D-galactose at a dose of 10g/kg once a day for 15 consecutive days while being fed with 5% of D-galactose solution for free drinking for 12 days, and animals of the blank group were intraperitoneally injected with sodium chloride injection solution of 0.9% in volume, etc., and fed with tap water for drinking. When the injection of the D-galactose is finished, the turbidity degree of the crystals is checked under a slit lamp microscope, rats with all turbid crystals and no obvious change are removed, 100 rats with similar turbidity degrees are selected and randomly divided into 5 groups according to sex and the turbidity degree of the crystals, and each group comprises 20 rats. Both male and female. The 5 groups were a model group, a positive drug control group (zhangyanming tablets group), and an administration group: baicalin ethoxyethyl ester (formula n = 1) 80mg/kg dose group, baicalin diglycol ester (formula n = 2) 100mg/kg dose group, and baicalin polyglycol ester-50 (formula n = 50) 400mg/kg dose group.

Administration: distilled water was administered to the normal control group and the model group, and 2 tablets/kg dose of diafenthimine, 80mg/kg dose of baicalin ethoxyethyl ester (formula n = 1), 100mg/kg dose of baicalin dipolyglycol ester (formula n = 2), and 400mg/kg dose of baicalin polyethylene glycol ester-50 (formula n = 50) were administered to the positive drug control group. The administration route is intragastric administration. The administration volumes were all 10ml/kg body weight. The administration is carried out once every 9-11 days for 30 consecutive days. The opacity of the crystals was checked at 5 days, 10 days, 15 days, 20 days and 30 days of administration and scored according to the opacity score. The rat crystal opacity score criteria are shown in table 2.

The results show that the normal control group animals have clear crystals and no lesion. After the injection of D-galactose is stopped, the crystal turbidity can still slowly rise, so that the crystal turbidity is maintained at a higher level. The baicalin ethoxyethyl (general formula n = 1) 80mg/kg dose group, the baicalin diglycol ester (general formula n = 2) 100mg/kg dose group and the baicalin polyglycol ester-50 (general formula n = 50) 400mg/kg dose group have obvious treatment effect on the senile cataract, and the action intensity is stronger than that of an equivalent amount of the cataract development tablet. See table 5.

TABLE 5 Effect on crystal haze

Example 13: treating cataract caused by trauma

180 rats with the weight of 180-220g are selected for male and female application. 20 animals were removed from the test specimen as a blank control group, and the remaining animals were subjected to 20-cm-height beating of the eyeball 100 times weekly using a 20-g iron ball. After the first beating, the turbidity degree of the crystals is checked under a slit lamp microscope, rats with all turbid crystals and no obvious change are removed, 100 rats with similar turbidity degrees are selected and randomly divided into 5 groups according to gender and the turbidity degree of the crystals, and each group comprises 20 rats. Both male and female. The 5 groups were a model group, a positive drug control group (zhangyanming tablets group), and an administration group: baicalin ethoxyethyl ester (formula n = 1) 80mg/kg dose group, baicalin diglycol ester (formula n = 2) 100mg/kg dose group, and baicalin polyglycol ester-50 (formula n = 50) 400mg/kg dose group.

Administration: the next day after the first tap. Distilled water was administered to the normal control group and the model group, and 2 tablets/kg dose of diafenthimine, 80mg/kg dose of baicalin ethoxyethyl ester (formula n = 1), 100mg/kg dose of baicalin dipolyglycol ester (formula n = 2), and 400mg/kg dose of baicalin polyethylene glycol ester-50 (formula n = 50) were administered to the positive drug control group. The administration route is intragastric administration. The dose volumes were 10ml/kg body weight. The administration is carried out once every 9-11 days for 30 consecutive days. The opacity of the crystals was checked at 5 days, 10 days, 15 days, 20 days and 30 days of administration and scored according to the opacity score. The rat crystal opacity score criteria are shown in table 2.

The results showed (see table 6) that the crystals of the normal control animals were clear and no lesions were present. The crystal turbidity of the model group can still be maintained at a higher level. The baicalin ethoxyethyl ester (general formula n = 1) 80mg/kg dosage group, the baicalin diglycol ester (general formula n = 2) 100mg/kg dosage group and the baicalin polyglycol ester-50 (general formula n = 50) 400mg/kg dosage group have obvious treatment effect on the cataract caused by trauma, and the action strength is stronger than that of an equivalent amount of the cataract eye mask. .

TABLE 6 Effect on crystal haze

Note: * P <0.05 compared to model group; * Comparison with model group, P <0.01

Example 14: activity test for treating hypothyroidism complicated with cataract

180 spontaneous hypothyroidism rats are selected, and the rats are used for male and female purposes and have the weight of 180-200g. 20 animals were selected as a blank group, and the remaining animals were intraperitoneally injected with 50% of D-galactose at a dose of 10g/kg once a day for 15 consecutive days while being fed with 5% of D-galactose solution for free drinking for 12 days, and animals of the blank group were intraperitoneally injected with sodium chloride injection solution of 0.9% in volume, etc., and fed with tap water for drinking. When the D-galactose injection is finished, the crystal turbidity degree is checked under a slit lamp microscope, rats with all turbid crystals and no obvious change are removed, 100 rats with similar turbidity degrees are selected and randomly divided into 5 groups according to sex and the crystal turbidity degree, and each group comprises 20 rats. Both male and female. The 5 groups were a model group, a positive drug control group (zhangyanming tablets group), and an administration group: baicalin ethoxyethyl ester (formula n = 1) 80mg/kg dose group, baicalin dipolyglycol ester (formula n = 2) 100mg/kg dose group, and baicalin polyethylene glycol ester-50 (formula n = 50) 400mg/kg dose group.

Administration: distilled water was administered to the normal control group and the model group, and 2 tablets/kg dose of diaverine, 80mg/kg dose of baicalin ethoxyethyl ester (formula n = 1), 100mg/kg dose of baicalin diglycol ester (formula n = 2), and 400mg/kg dose of baicalin polyglycol ester-50 (formula n = 50) were administered to the positive drug control group. The administration route is intragastric administration. The administration volumes were all 10ml/kg body weight. The administration is carried out once every 9-11 days for 30 consecutive days. The crystal turbidity was checked for 5 days, 10 days, 15 days, 20 days, 30 days of administration, and the scores were scored according to the crystal turbidity score criteria. The rat crystal opacity score criteria are shown in table 2.

The results show (see table 7): the normal control group animals had clear crystals and no lesions. After the injection of D-galactose is stopped, the crystal turbidity can still slowly rise, so that the crystal turbidity is maintained at a higher level. The baicalin ethoxyethyl (general formula n = 1) 80mg/kg dose group, the baicalin diglycol ester (general formula n = 2) 100mg/kg dose group and the baicalin polyglycol ester-50 (general formula n = 50) 400mg/kg dose group have obvious treatment effect on hypothyroidism complicated by cataract, and the action intensity is stronger than that of an equivalent amount of the cataract eye mask tablet.

TABLE 7 Effect on crystal haze

Note: * P <0.05 compared to model set; * P <0.01 in comparison with model groups

Example 15: activity test for treating heavy metal poisoning induced cataract

Selecting 25 litters of rats, wherein the weight of the newborn rat is 20-30g, and selecting 6-8 young rats in each litter, and keeping the young rats as female and male as possible. Taking 3 litters of the young mice for male and female use as a blank control group, injecting 0.0173% sodium selenite subcutaneously at the cervical spine part of the rest of the young mice with the dose of 3.46mg/kg and the volume of 2ml/100g on the 1 st, 3 th and 5 th days, examining crystals under a slit lamp microscope on the 7 th day, removing the young mice with all turbid crystals and no obvious change, randomly dividing the selected young mice into 5 groups according to the sex and the turbid degree of the crystals, and using 20 mice in each group for male and female use. 5 groups are respectively a model group and a positive medicine group (zhangyanming tablets), and the administration group comprises: baicalin ethoxyethyl ester (formula n = 1) 80mg/kg dose group, baicalin dipolyglycol ester (formula n = 2) 100mg/kg dose group, and baicalin polyethylene glycol ester-50 (formula n = 50) 400mg/kg dose group.

Administration: the normal control group is administered with distilled water by intragastric administration; 2 tablets/kg of the eye-obstructing tablet is given to the positive medicine group by gastric lavage; baicalin ethoxyethyl ester (formula n = 1) 80mg/kg dose group, baicalin dipolyglycol ester (formula n = 2) 100mg/kg dose group, and baicalin polyethylene glycol ester-50 (formula n = 50) 400mg/kg dose group; the model group was gavaged with distilled water. The gastric lavage solution amount is 1ml/100g body weight, and the administration is carried out once every 8-11 days for 60 days. The crystal opacity was checked at 5 days, 10 days, 20 days, 30 days, 40 days, 50 days and 60 days of administration, and the scores were scored according to the opacity scale of the rat crystals in Table 2.

The results show (see table 8): the normal control rats had clear crystals and no lesions. After the injection of sodium selenite is stopped, the crystal turbidity can still slowly rise, and the crystal turbidity can still be maintained at a higher level. Baicalin ethoxyethyl ester (general formula n = 1) 80mg/kg dose group, baicalin diglycol ester (general formula n = 2) 100mg/kg dose group and baicalin polyglycol ester-50 (general formula n = 50) 400mg/kg dose group have significant therapeutic effects on selenium cataract in rats. The therapeutic effect is strong and the cataract-treating tablets are strong.

TABLE 8 Effect on Crystal opacity in rats with selenium cataract

Note: * P <0.05 compared to model group; * P <0.01 compared to model group.

Example 16: prevention of cataract by galactosemia test

Selecting 120 wistar rats with the weight of 100-120g. The weight was randomly divided into 6 groups of 20 animals each, each male and female half. The six groups are blank control group, model group, positive drug group, baicalin ethoxy ethyl ester group, baicalin dipolyglycol ester group and baicalin polyethylene glycol ester-50 group.

Administration: in the blank control group, distilled water is given for intragastric administration; the model group is filled with distilled water; the positive medicine is given to the zhangyanming tablets (2 tablets/kg); administration group: baicalin ethoxyethyl ester (formula n = 1) 80mg/kg dose group, baicalin dipolyglycol ester (formula n = 2) 100mg/kg dose group, and baicalin polyethylene glycol ester-50 (formula n = 50) 400mg/kg dose group. The gavage volume is 1ml/100g body weight, and the administration is carried out once every 9-11 days for 18 consecutive days.

Cataract modeling: on the fourth day of administration, molding was started, and the five groups of animals, except for the blank control group, were each intraperitoneally injected with 50% d-galactose (formulated with water for injection) at a dose of 10g/kg once a day for 15 days continuously while being given a 5-th-percentile d-galactose solution (formulated with tap water) for 12 days of free drinking.

The opacity of the rat crystals was examined by slit lamp microscopy for 13 days (10 days for molding), 15 days (12 days for molding) and 18 days (15 days for molding) of the drug, respectively, and the scores were obtained according to the opacity scale of the crystals as shown in Table 2.

The results show (see table 9): the normal control rats had clear crystals and no lesions. Model group rats had a marked rise in crystal turbidity during the molding. The baicalin ethoxyethyl ester (general formula n = 1) 80mg/kg dosage group, the baicalin diglycol ester (general formula n = 2) 100mg/kg dosage group and the baicalin polyglycol ester-50 (general formula n = 50) 400mg/kg dosage group have certain prevention effect on cataract caused by D-galactose of rats, and the action intensity is stronger than that of equivalent dose of the cataract-treating eye mask.

TABLE 9 Effect on opacity of D-galactose cataract rat crystals

Note: * P <0.05 compared to model group; * P <0.01 compared to model group.

Example 17: determination of content

1) Test solution: precisely weighing 50mg of baicalin ethoxy ethyl ester in the claim 1, dissolving in methanol, and fixing the volume to about 100 μ g/ml.

2) Chromatographic conditions are as follows: ODS column (4.6X 150 mm), detection wavelength: 278nm; column temperature: 30 ℃; flow rate: 1mL/min; sample injection amount: 10 mu L of the solution; methanol was used as mobile phase a, and 0.3% phosphoric acid water was used as mobile phase B, and gradient elution was performed as specified in the following table.

Gradient elution conditions:

flow rate mL/min	Time min	Methanol	0.3% phosphoric acid water
				1	0	10	90
1	15	60	40
				1	30	98	2
1	40	98	2

Claims

1. A compound having a structure shown in formula I or a pharmaceutically acceptable salt thereof

Wherein n is 1 to 50.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 1 to 10.

3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein n is 1 to 5.

4. A compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein n is 1 to 2.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein the compound is: baicalin ethoxy ethyl ester.

6. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof.

7. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention and treatment of cataract.

8. Use according to claim 7, wherein the cataract is: cataract caused by galactosemia, senile cataract, cataract caused by trauma and diabetes complicated cataract, cataract caused by hypothyroidism, and lenticular opacity caused by heavy metal poisoning or other reasons.