WO2014032583A1

WO2014032583A1 - Selenazole formic acid type compound and preparation method and use thereof

Info

Publication number: WO2014032583A1
Application number: PCT/CN2013/082438
Authority: WO
Inventors: 宫平; 赵燕芳; 刘亚婧; 翟鑫
Original assignee: 沈阳药科大学
Priority date: 2012-08-28
Filing date: 2013-08-28
Publication date: 2014-03-06
Also published as: CN103130744A; CN103130744B

Abstract

Provided is a 2-(3-cyan-4-isobutoxyphenyl)-4-methyl-1, 3-selenazole-5- formic acid compound as represented by formula I, or pharmaceutically acceptable salt, hydrate, solvate and pro-drug thereof. Also provided are a preparation method and uses thereof. The compound as represented by formula I has the capability of reducing uric acid content in blood, and can be used to treat hyperuricemia and relevant diseases caused by hyperuricemia.

Description

Selenazolecarboxylic acid compound, preparation method and use thereof

Technical field

The invention relates to the technical field of medicine, in particular to a selenazolecarboxylic acid compound, a preparation method thereof and use thereof.

Background technique

Gout is a disease caused by a disorder of sputum metabolism in the body. The final product of sputum metabolism in human body is uric acid (UA), which is a weak acid with low solubility. Excessive or poor excretion can lead to hyperuricemia, about 5%~12% hyperuricemia. Patients develop gout, which can not only invade bones and joints, but also easily affect the kidneys and cardiovascular system. Primary gout and hyperuricemia are significantly positively associated with obesity, hyperlipidemia, hypertension, diabetes, and atherosclerosis. The occurrence of gout is closely related to people's diet and living habits. With the improvement of people's living standards and changes in diet structure, the incidence of gout is increasing year by year.

Febuxostat is an arylcyanothiazole acid compound, a new and highly effective non-steroidal xanthine oxidoreductase selective inhibitor developed by Teijin Corporation of Japan. It was first used in May 2008. The European Union is listed and listed in the United States in February 2009 and is approved by the FDA for the treatment of hyperuricemia. This is the first time that uric acid-lowering drugs approved in the United States have entered a new era since the introduction of allopurinol in 1964.

Fe buxostat

Febuxostat is a non-steroidal structural drug that is selective for the inhibition of xanthine oxidase and does not inhibit other enzymes in the synthesis and metabolism of purines and pyrimidines at therapeutic concentrations. Therefore, for patients with low or moderate liver and kidney function, it is still safe to take febuxostat and do not need to adjust the dose.

WO9209279 discloses a preparation method of 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid (febuxostat, febuxostat) and its application to gout and hyperuricemia Therapeutic effect.

The present inventors designed and synthesized a selenozolyl compound on the basis of the febuxostat structure, and provided a preparation method of the compound, which has the advantages of simple operation, high yield, easy purification and suitability of the product. The advantages of industrial production. Anti-uric acid activity studies have shown that the compounds have a better activity to lower blood uric acid content.

In addition, the anti-inflammatory activity test on the target compound showed that the compound also had a certain anti-inflammatory effect, and that the brouse had no anti-inflammatory action. For patients with acute gouty arthritis, due to the deposition of sodium urate microcrystals around the joint tissue, causing an inflammatory reaction, causing discomfort such as redness, heat and pain, and anti-inflammatory treatment is also symptomatic treatment for patients with clinical gout. The usual method. Therefore, the compound disclosed in the patent has both an effect of lowering the blood uric acid content and a certain anti-inflammatory effect, and is more favorable for the treatment of gout.

Summary of the invention:

It is an object of the present invention to provide a selenazolecarboxylic acid compound, a process for the preparation thereof and use thereof.

The selenazolecarboxylic acid compound is a compound of formula I _2- ( ₃ -cyano-4-isobutoxyphenyl)-4-methyl-1,3-selenazole-5-carboxylic acid, or a pharmaceutically acceptable compound thereof Salts, hydrates, solvates and prodrugs.

I

Wherein the pharmaceutically acceptable salt is:

2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-selenazole-5-formate;

2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-selenazole-5-formic acid potassium;

2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-selenazole-5-formate lithium;

Calcium 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-selenazole-5-carboxylate.

Wherein the pharmaceutically acceptable prodrug is a (C1-C4) fatty alcohol ester of a compound of formula I.

Preferably:

2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-selenazole-5-carboxylic acid methyl ester;

Ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-selenazole-5-carboxylate.

The present invention also encompasses a pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof as an active ingredient, in admixture with a pharmaceutically acceptable carrier or excipient. The composition is prepared and prepared into a clinically acceptable dosage form, and the above pharmaceutically acceptable excipient refers to any diluent, adjuvant and/or carrier which can be used in the pharmaceutical field. The derivatives of the present invention can be used in combination with other active ingredients as long as they do not cause other adverse effects such as allergic reactions.

The pharmaceutical compositions of the present invention can be formulated in a number of dosage forms containing some of the commonly used excipients in the pharmaceutical arts. A plurality of dosage forms as described above may be injectables, tablets, capsules, aerosols, suppositories, films, pills, topical tinctures, ointments, and the like.

Carriers for use in the pharmaceutical compositions of the present invention are common types available in the pharmaceutical arts, including: binders, lubricants, disintegrants, solubilizers, diluents, stabilizers, suspending agents, non-pigmenting, flavoring agents , preservatives, solubilizers and matrices. The pharmaceutical preparations can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally or topically), and if certain drugs are unstable under gastric conditions, they can be formulated into enteric coated tablets.

The compounds of the present invention include hydrates and solvates thereof. They have all the properties described herein.

The preparation method of the compound of the present invention is as shown in FIG. 1 and includes the following steps:

(1) 4-hydroxyphenyl selenoamide (B) is dissolved in an organic solvent, and 2-chloroacetoacetic acid fatty alcohol ester is added thereto, and reacted at 40 to 120 ° C for 4 to 16 hours to obtain an intermediate hydrazine.

(2) The intermediate C is dissolved in an organic solvent, and urotropine is added thereto, and the reaction is carried out at 40 to 120 ° C for 10 to 30 hours to obtain an intermediate 1).

(3) Intermediate D and isobromobutane are added to an organic solvent, and the reaction is carried out at 40-120 ° C for 5-15 hours under a base catalysis to obtain intermediate E.

(4) Intermediate E is reacted with hydroxylamine hydrochloride in an organic solvent at a reaction temperature of 70 to 170 ° C for a reaction time of 5 to 15 hours to obtain a fatty alcohol ester (F) of the compound of the formula I.

(5) adding intermediate F to the polar protic solvent, the reaction temperature is 50-120 ° C under the action of a base, the reaction time is 0.5-6 hours, and the reaction liquid is adjusted to pH 1-7 after completion of the reaction. A compound of formula I is obtained.

The method for preparing the compound of the present invention, wherein the 2-chloroacetoacetic acid fatty alcohol ester used in the step (1) is preferably methyl 2-chloroacetoacetate, ethyl 2-chloroacetoacetate or propyl 2-chloroacetoacetate, 2 - butyl chloroacetoacetate.

Particularly preferred is methyl 2-chloroacetoacetate and ethyl 2-chloroacetoacetate.

The preparation method of the compound of the present invention, wherein the preferred reaction temperature in the step (1) is 60-100 ° C, and the reaction time is 6-10 hours.

The preparation method of the compound of the present invention, wherein the preferred reaction temperature in the step (2) is 60-100 ° C, and the reaction time is 15-25 hours.

The preparation method of the compound of the present invention, wherein the base used in the step (3) may be an inorganic base or an organic base: the inorganic base is preferably potassium hydrogencarbonate, sodium hydrogencarbonate, anhydrous potassium carbonate, anhydrous sodium carbonate, potassium hydroxide or Sodium hydroxide; the organic base is preferably triethylamine, pyridine, 4-dimethylaminopyridine or sodium acetate.

The preparation method of the compound of the present invention, wherein potassium iodide is preferably added to the step (3).

The preparation method of the compound of the present invention, wherein the preferred reaction temperature in the step (3) is 60-100 ° C, and the reaction time is 6-10 hours.

The preparation method of the compound of the present invention, wherein sodium formate is preferably added in the step (4).

The preparation method of the compound of the present invention, wherein the preferred reaction temperature in the step (4) is 90-140 ° C, and the reaction time is 8-12 hours. The preparation method of the compound of the present invention, wherein the base used in the step (5) may be an inorganic base or an organic base: the inorganic base is preferably potassium hydrogencarbonate, sodium hydrogencarbonate, anhydrous potassium carbonate, anhydrous sodium carbonate, potassium hydroxide. Or sodium hydroxide; the organic base is preferably triethylamine, pyridine or sodium acetate.

The preparation method of the compound of the present invention, wherein in the step (5), ra is preferably 2-5.

The preparation method of the compound of the present invention, wherein the preferred reaction temperature in the step (5) is 60-100 ° C, and the reaction time is 1-5 hours.

The compound of the present invention has an activity of inhibiting uric acid production, and thus it can be used for the prevention and/or treatment of hyperuricemia in a mammal.

The compound of the present invention has an activity of inhibiting uric acid production and lowering hyperuricemia uric acid, and thus it can be used for preventing and/or treating gout, arthritis or heart failure diseases caused by hyperuricemia.

The clinical dose of the selenazolecarboxylic acid compound of the above formula I for use in a patient can be based on: the therapeutic efficacy and bioavailability of the active ingredients in the body, their metabolism and excretion rate, and the age, sex, and disease period of the patient. Adjustment, however, the daily dose for adults should generally be 40 to 80 mg, preferably 40 mg. If you can't achieve the goal of blood uric acid <6. Omg / dL after two weeks of taking, you can increase the dose to 80mg, but it is not recommended to use more than 80mg. Mild to moderate liver and kidney dysfunction does not affect the administration of this drug, no need to adjust the dose.

A mammal is a human or an animal.

The amount of active ingredient, i.e., the compound according to the invention, in the pharmaceutical compositions and their unit dosage forms can vary, depending on the particular application and the desired concentration. In general, the active ingredient will be present in an amount between 0.5% and 90% by weight based on the total weight of the composition.

In combination therapy, the compounds of the invention and other compounds may be administered simultaneously or at intervals, and when administered simultaneously, the compounds of the invention and other compounds may be combined in a single pharmaceutical composition or in separate compositions. The present invention also provides a process for the preparation of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a fatty alcohol ester. It is to be understood that the scope of the following examples and preparations are not intended to limit the scope of the invention in any way.

The following synthetic schemes describe the preparation of the compounds of formula I of the present invention, all of which are prepared by the methods described in these schematics, by methods well known to those of ordinary skill in the art of organic chemistry, or are commercially available. All of the variable factors in the schematic are as defined below or as defined in the claims.

The preparation method comprises the following steps:

Route 1. Synthetic route of the compound of formula I

1) using 4-hydroxy-benzonitrile as raw material, and reacting excess sodium selenide in a polar solvent to obtain compound B;

2) Compound B is reacted with 2-chloroacetoacetate in a polar solvent to prepare compound C; wherein 2-chloroacetoacetate is methyl 2-chloroacetoacetate or 2-chloroacetoacetic acid Ethyl ester

3) Compound C is reacted with urotropine in a hot polyphosphoric acid/ethanol system to produce compound D;

4) Compound D is reacted with an excess of isobromobutane in the presence of an inorganic base and potassium iodide in a polar solvent to produce Compound E;

5) Compound E in the presence of an organic base, and hydroxylamine hydrochloride in a polar solvent to produce a compound F;

6) Compound F is reacted with an excess of an inorganic strong base in a polar solvent to prepare Compound I. The in vivo anti-uric acid production activity and anti-inflammatory activity of the compound of the present invention were studied as follows:

1) Effect on serum uric acid content in normal rats

352 male Wistar rats were selected and weighed between 200-220 g. The effects of the compound of Example 3 and the positive control drug febuxostat on serum uric acid content in normal rats were tested and determined by uric acid test kit (phosphoric acid method).

The compound of Example 3 and febuxostat were suspended in 0.4% CMC-Na. After 550 rats were adaptively fed for 5 days in the animal room, they were randomly divided into 22 groups (blank group 1 group, Example 3 compound, Example 1 compound, Example 2 compound, Example 4 compound, Example 5 compound, and implementation). The compound of Example 6 and the control drug, febuxostat (3 groups), each group of 352, were weighed separately and all were fasted overnight. The compound of Example 3, the compound of Example 1, the compound of Example 2, the compound of Example 4, the compound of Example 5, the compound of Example 6, and the comparative drug febuxostat group were respectively 0.3 mg/kg, 1 mg/kg and 4%CMC-Na溶液。 The 3mg / kg dose was administered by gavage, the blank control group was 0.4% CMC-Na solution. Blood samples were taken from the eyelids before and 2, 4, and 6 hours after administration, respectively. 0.5 ml, centrifuged at 5000 rpm for 3 min, carefully absorbed 200 uL of plasma (heparin anticoagulation), frozen at -20 ° C until the plasma melted, according to uric acid The assay kit (phosphoric acid method) instructions are used for the operation. The drug action was expressed as the inhibition rate of plasma uric acid before administration at each time point after administration, and the ED50 value at each time point was calculated. The results are shown in Tables 1 and 2.

Table 1 Inhibition rate of uric acid in plasma of normal rats

Group 1J

Dose inhibition rate (%)

(mg/kg) 2 hours 4:00 pm

0.3 36.36 35.59 38.55 Example 1 1 43.23 40.66 45.58

3 56.65 60.12 61.10

0.3 38.56 30.32 35.21 Example 2 1 45.65 46.61 41.25

3 48.25 49.12 55.90

0.3 56.18 61.45 45.05 Example 3 1 69.51 71.09 52.63

3 77.86 79.81 56.26

0.3 52.12 49.12 46.26 Example 4 1 60.32 68.15 56.25

3 65.78 66.23 57.28

0.3 49.86 47.75 44.37 Example 5 1 60.59 57.88 51.12

3 66.37 60.22 56.66

0.3 36.69 31.10 30.18 Example 6 1 44.23 42.11 40.22

3 49.52 48.85 47.99

0.3 27.33 28.56 14.72 Example 7 1 30.57 31.44 18.47

3 35.32 36.15 26.38

0.3 54.25 36.17 36.06 febuxostat 1 65.22 49.70 48.02

3 72.06 62.84 60.75 Table 2 ED _5Q (mg/kg) of uric acid in plasma of normal rats

2) Effect on serum uric acid content in rats with hyperuricemia

368 male Wistar rats were selected and weighed between 200-220 g. The effects of the compound of Example 3 and the positive control drug febuxostat on the serum uric acid content of hyperuricemia induced by potassium oxonate were tested in uric acid test. Box (phosphoric acid method) determination.

The compound of Example 3 and febuxostat were suspended in 0.4% CMC-Na. After 368 rats were adaptively fed for 5 days in the animal room, they were randomly divided into 23 groups (blank group 1 group, potassium oxonate group 1 group, compound of Example 3, compound of Example 1, compound of Example 2, Example 4). The compound, the compound of Example 5, the compound of Example 6, and the control drug, febuxostat (3 groups), each group of 16 were weighed separately and all were fasted overnight. In addition to the blank group, each group was intraperitoneally injected with potassium oxonate 250 mg/kg. After 1 hour, the compound group of Example 3 and the non-butbutan group of the control group were dosed at 0.3 mg/kg, 1 mg/kg and 3 mg/kg, respectively. The solution was administered by gavage, and the blank control group was 0.4% CMC-Na solution. 2 hours before administration and 2 hours after administration (Examples 1, 2 and 4 hours after administration), blood was taken from the eyelids at 0.5 ml, centrifuged at 5000 rpm for 3 min, and 200 uL of plasma (heparin anticoagulation) was carefully aspirated at -20 °C. Freeze for testing.

After the plasma has melted, proceed as described in the uric acid assay kit (phosphoric acid method). There was a significant difference in uric acid value between the oxonate group and the blank group. The model was established and the results are shown in Table 3. The drug action was expressed as the inhibition rate of plasma uric acid in the potassium oxonate group. The results are shown in Table 4.

Table 3 uric acid value of each group of animals

Group dose (mg/kg) Mean value of uric acid value (μιηοΙ/L) Blank group 0 227.55±137.96 Potassium oxonate 250 388.91±77.93 Example 1 0.3 289.66±99.03

£8S and OZ OAV 0.3 28.59 Example 3 1 3.3 33.47

3 56.12

0.3 24.43 Example 4 1 4.0 30.32

3 49.98

0.3 21.10 Example 5 1 4.6 31.15

3 46.44

0.3 25.11 Example 6 1 6.9 26.98

3 46.46

0.3 1.73 Example 7 1 >10 6.04

3 22.46

0.3 26.90 febuxostat 1 4.4 32.77

3 48.32 Conclusion: The compounds of Examples 1-7 all have a better effect of lowering the uric acid content in plasma, wherein the compounds of Examples 3, 4 and 5 have a lowering effect on the plasma uric acid content than the positive drug febuxostat. .

3) Effect on ear swelling in mice

Materials and Methods

Animals 40 MK mice, all male, weighing 18-21 g, were provided by Liaoning Changsheng.

Reagent xylene analytical pure

Test Example 1~5 compound, febuxostat, positive control is aspirin

Methods Forty mice were randomly divided into 4 groups: Example 1 group (50 mg/kg), febuxostat group (50 mg/kg), aspirin group (200 mg/kg) and blank control group. Two hours after the test, 40 μl of xylene was evenly applied to the front and back of the right ear of the mouse. The mice were sacrificed by cervical dislocation 1 hour later. The ears were cut along the baseline of the auricle, and the round ears were placed at the same position on both ears with a 6 mm diameter puncher, weighed, and the swelling degree and inhibition rate were calculated. Ear swelling = right ear weight - left ear weight; inhibition rate = (average ear swelling in the blank control group - average ear swelling in the administration group) / average ear swelling in the blank control group χ 100%.

test results After the inflammation, the mice in each group showed high redness in the right ear. Aspirin had a very significant inhibitory effect on xylene-induced ear swelling in mice, and the inhibition rate was 53.1% (p<0.01). The compound of Example 3 also had a good inhibitory effect on ear swelling, inhibition rate. The expression of 16.64% (p<0.05) was not significantly affected by p-xylene-induced mouse ear swelling (P>0.05). The results are shown in Table 5.

Table 5 Ear swelling of each group of mice (mean sd)

(Ρ<0. 05*, Ρ<0. 01**)

The results showed that the compounds of Examples 1 to 5 all had a certain anti-inflammatory action, and the compound of Example 3 had the strongest anti-inflammatory activity. Therefore, the compounds of Examples 1 to 5 are all beneficial for the relief of joint swelling and pain symptoms during the onset of gout; the non-busotan has no obvious anti-inflammatory effect. detailed description:

The following examples are intended to illustrate and not to limit the scope of the invention. The nuclear magnetic resonance spectrum of the compound was determined by Bruker ARX-300, and the mass spectrum was determined by Agi lent 1100 LC/MSD, and the reagents used were either analytically pure or chemically pure.

Example 1 : Preparation of ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-selenazole-5-carboxylate

[1] Preparation of intermediate 4-hydroxyphenyl selenoamide

NaBH 451. 5 g (0. 276 mol) was added portionwise to a suspension of 100 g (1. 265 mol) of Se in 1000 ml of ethanol at 0-5 °C under nitrogen. After stirring at room temperature for 30 min, 135 ml (1.68 mol) of pyridine and 50 g (0.42 mol) of 4-hydroxybenzonitrile were separately added and heated to 80 ° C for 30 min. 2%, yield 67. 2%, a yield of 67.2 g, a yield of 67. 2%, a yield of 67.2 g, a yield of 67.2%. .

[2] Preparation of intermediate 2-(4-hydroxyphenyl)-4-methyl-1,3-selenazole-5-carboxylate

4-Hydroxyphenylselenoic acid 50 g (0.327 mol) was added to 400 mL of absolute ethanol, and ethyl 2-chloroacetoacetate 50 ml (0.343 mol) was added dropwise at room temperature. After the dropwise addition, the reaction was carried out at 81 ° C for 8 h. The mixture was cooled and allowed to stand overnight.

MS: [M+H] 312. 01; 1H-匪R (DMS0-d6): 7. 80 (d, 2 H), 6. 89 (d, 2 H), 5. 08 (s, 1 H) , 4. 25 (m _; 2 H), 2. 64 (s, 3 H), 1. 29 (t, 3H) . [3] Preparation of intermediate 2-(3-formyl-4-hydroxyphenyl)-4-methyl-1,3-selenazole-5-carboxylic acid ethyl ester 500 ml polyphosphoric acid, (4-hydroxybenzene) Ethyl 4-methyl-1,3-selenazole-5-carboxylic acid ethyl ester 100 g (0.38 mol), urotropine 55 g (0.39 mol) was added to absolute ethanol, and reacted at 81-85 ° C for 20 h. After cooling, 1500 ml of water was added, and the mixture was thoroughly stirred, and a large amount of solid was precipitated. The yield was 69. 6 g, yield 69%.

[4] The intermediate 2- (3-formyl-4-isobutoxyphenyl) -4-methyl-1, 3-selenazole-5-carboxylic acid ethyl ester. (0. 687 mol), polyethylene glycol-600 6 g (0. Olmol), added to 650 ml of DMF, and stirred for 5 minutes. Ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methyl-1,3-selenazole-5-carboxylate 50 g (0.172 mol) was added, and stirring was continued for 5 minutes. Next, potassium iodide, 11.4 g (0.069 mol), isobromobutane 94. 2 g (0. 687 mol), and 75-80 ° C were added for 10 hours. Concentrated under reduced pressure, cooled, poured into a large amount of water, allowed to stand, and suction filtered to give an orange solid 50 g, yield 75%.

[5] Preparation of ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-selenazole-5-carboxylate

Add 2-(3-formyl-4-isobutoxyphenyl)-4-methyl-1,3-selenazole-5-carboxylic acid ethyl ester 50g (0. 144mol) to

After stirring in 600 ml of formic acid, 25 g (0.173 mol) of sodium formate and 12.5 g (0.23 mol) of hydroxylammonium hydrochloride were added, and the reaction was carried out at 110 ° C for 10 hours. The reaction was stopped, and the solid was crystallized, suction filtered, washed with water, and dried to give a white solid (33 g, yield: 67%).

MS: [M+H] 393. 06; 1H-匪R (DMS0-d6): 8. 30 (d, 1 H), 8. 22 (dd, 1 H), 7. 36 (dd, 1 H) ,

4. 26 (dd, 2 H), 4. 01 (d, 2 H) , 2. 66 (s, 3 H), 2. 05 (m, 1 H), 1. 30 (t, 1 H), 1. 02 (d,

6 H) .

Example 2: Preparation of methyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-selenazole-5-carboxylate According to the preparation method of Example 1, intermediate The yield of the compound [2] was obtained by using 2,2 ml (0. 343 mol) of 2-chloroacetoacetic acid methyl ester.

Example 3: Preparation of 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-selenazole-5-carboxylic acid

5克。 Sodium 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-selenazole-5-carboxylate crude product 45g (0. 13mol), sodium hydroxide 5. 8g (0. 145 mol) was added to 450 ml of water and reacted at 80 ° C for 2 h. The reaction was adjusted to pH 3, and a milky white solid precipitated and stood still. 6%。 By weight filtration, the compound of Example 3 40. 5g, yield 85.6%.

MS: [M+H] 365. 03; 1H-匪R (DMS0-d6): 13. 23 (s, 1 H), 8. 28 (s, 1 H), 8. 19 (dd, 1 H) ,

7. 32 (d, 1 H), 3. 99 (d, 2 H) , 2. 62 (s, 3 H), 2. 08 (m, 1H), 1. 01 (s, 6 H) .

Example 4: Preparation of 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-selenazole-5-formate

2-(3-Cyano-4-isobutoxyphenyl)-4-methyl-1,3-selenazole-5-carboxylic acid 36.4 g (0.1 mol) dissolved in 100 ml of ethanol, ice bath A solution of 6. 8 g (0.1 mol) of ethanol sodium in 50 ml of ethanol was added dropwise and stirred until fully dissolved. 5%。 The solvent was evaporated under reduced pressure.

Example 5: Preparation of 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-selenazole-5-carboxylic acid potassium Take 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-selenazole-5-carboxylic acid 36. 4g (0. lmol) dissolved in 100ml of ethanol, ice bath A solution of 8. 4 g (0.1 mol) in 60 ml of ethanol was added dropwise and stirred until fully dissolved. The 5%. The yield of the compound of Example 5 was 35. 2g, the yield was 87.6%.

Example 6: Preparation of 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-selenazole-5-formic acid lithium

Take 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-selenazole-5-carboxylic acid 36. 4g (0. lmol) dissolved in 100ml of ethanol, ice bath Add 3 g of potassium alkoxide to a solution of 8 g (0.1 mol) in 40 ml of ethanol, and stir until fully dissolved. 6%。 The solvent was evaporated under reduced pressure.

Example 7: Preparation of 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-selenazole-5-carboxylate

_ , _

The compound of Example 4 was added. 7 g (0.1 mol);:, into 500 ml of water, and stirred under reflux for 30 minutes, then 66 g (0.6 mol) of an aqueous solution of anhydrous calcium chloride was added, and refluxing was continued for 1 hour, and solids were precipitated. 2%。 The yield of 85.2%.

The compounds of Examples 1-7 are shown in Table 6.

Table 6 Example compound structure and chemical name

Real

Structure type chemical name

example

2-0 cyano-4-isobutoxyphenyl; )-4-

1

Methyl-1,3-selenazole-5-formic acid ethyl ester

Eight 1

2-(3-cyano-4-isobutoxybenzene

2

,- Ύ ^Q -methyl-1,3-selenosole-5-carboxylic acid methyl ester

N 0 - -

\

2-(3-cyano-4-isobutoxybenzene

3

Base;) -4-methyl-1,3-selenazole-5-carboxylic acid

The compound of the formula I of the present invention, and a pharmaceutically acceptable salt, fatty alcohol ester, hydrate, solvate or prodrug thereof, may be administered alone, but usually administered in a mixture with a pharmaceutically acceptable carrier. According to the desired route of administration and standard pharmaceutical practice, various pharmaceutical dosage forms of such compounds, such as injections, tablets, capsules, aerosols, suppositories, films, pills, topical tinctures and ointments, are separately used below. The preparation method illustrates its new application in the pharmaceutical field.

Example 8: Tablet

Using a compound containing the compound of claim 1 (exemplified by the compound of Example 1), 25 g, which was mixed according to a general pharmaceutical tableting method and an auxiliary material, was compressed into 100 tablets.

Example 9: Injection

Using a compound containing the compound of claim 1 (taking the compound of Example 1 as an example) 25 g, the activated carbon is adsorbed according to a conventional method of pharmacy, filtered through a 0.65 μπι microporous membrane filter, and filled in a nitrogen tank. Water needle preparation, a total of 100 bottles.

Example 10: Capsule

Using 25 g of the compound containing the compound of claim 1 (exemplified by the compound of Example 1), the excipients were mixed according to the requirements of the pharmacy capsule, and then filled into 100 hollow capsules.

Example 11: Aerosol 10 g of the compound containing the compound of claim 1 (exemplified by the compound of Example 1) was dissolved in an appropriate amount of propylene glycol, and then distilled water and other pellets were added to prepare a 500 mL clear solution.

Example 12: Suppository

Using 10 g of the compound containing the compound of claim 1 (exemplified by the compound of Example 1), it is added to the appropriate amount of glycerin, ground and added to the melted glycerin gelatin, uniformly ground, and poured into a model of the lubricant. , prepared 50 suppositories.

Example 13: Membrane

Using a compound containing the compound of claim 1 (exemplified by the compound of Example 1) 10 g, polyvinyl alcohol, medicinal glycerin, water, etc. are stirred and expanded, heated and dissolved, filtered through an 80 mesh screen, and the compound of Example 1 is added. The mixture was stirred and dissolved in the filtrate, and 100 film-coated membranes were applied.

Example 14: Pills

10 g of the compound containing the compound of claim 1 (exemplified by the compound of Example 1) was heated and melted with a substrate such as gelatin, and then dropped into a low-temperature liquid paraffin to prepare a pellet of 1000 pills.

Example 15: Topical tincture

Using 10 g of the compound containing the compound of claim 1 (exemplified by the compound of Example 1), it is prepared by mixing and grinding with an auxiliary agent such as an emulsifier according to a conventional pharmaceutical method, and adding distilled water to 200 mL.

Example 16: Ointment

Using a compound containing the compound of Claim 1 (taking the compound of Example 1 as an example) 10 g, it was finely ground and then mixed with 500 g of an oily base such as petrolatum.

Although the present invention has been described in terms of specific embodiments, modifications and equivalents are obvious to those skilled in the art and are included in the scope of the invention.

Claims

Claims, compound 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-selenazole-5-carboxylic acid of formula I, or a pharmaceutically acceptable salt thereof , hydrates, solvates and prodrugs. . The compound of formula I according to claim 1, wherein the pharmaceutically acceptable salt is 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-selenazole -Sodium 5-formate; 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-selenazole-5-carboxylic acid potassium; 2-(3-cyano-4- Lithium isobutoxyphenyl)-4-methyl-1,3-selenazole-5-carboxylate; 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1, Calcium 3-selenazole-5-formate. , The compound according to claim 1, wherein the pharmaceutically acceptable prodrug is the (C1-C4) fatty alcohol ester of the compound of formula I. , the compound according to claim 3, wherein the pharmaceutically acceptable prodrug is 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-selenium Azole-5-carboxylic acid methyl ester; 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-selenazole-5-carboxylic acid ethyl ester. , a pharmaceutical composition containing any one of the compounds described in claims 1-4. , a compound of formula I according to claim 1, 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-selenazole-5-carboxylic acid, or its pharmaceutically acceptable The preparation method of accepted salts, hydrates, solvates and prodrugs is characterized by comprising the following steps:

(1) Dissolve 4-hydroxyphenylselenamide (B) in an organic solvent, add 2-chloroacetoacetate fatty alcohol ester, and react at 40-120°C for 4-16 hours to obtain intermediate 0.

(2) Dissolve intermediate C in an organic solvent, add methenamine, and react at 40-120°C for 10-30 hours to obtain intermediate 1).

(3) Add intermediate D and isobromobutane to the organic solvent, and react under alkali catalysis at 40-120°C for 5-15 hours to obtain intermediate £. (4) Intermediate E is reacted with hydroxylamine hydrochloride in an organic solvent, the reaction temperature is 70-170°C, and the reaction time is 5-15 hours, to obtain the fatty alcohol ester (F) of the compound of formula I.

(5) Add intermediate F to the polar protic solvent, under the action of alkali, the reaction temperature is 50-120°C, the reaction time is 0.5-6 hours, after the reaction is completed, adjust the pH of the reaction solution to 1-7, Compounds of formula I are obtained.

, The preparation method according to claim 6, characterized in that the 2-chloroacetoacetate fatty alcohol ester used in step (1) is:

2-Chloroacetoacetate methyl ester, 2-chloroacetoacetoacetate ethyl ester, 2-chloroacetoacetoacetate propyl ester, 2-chloroacetoacetoacetate butyl ester.

The preparation method according to claim 6, characterized in that the preferred reaction temperature in step (1) is 60-100°C, and the reaction time is 6-10 hours.

The preparation method according to claim 6, characterized in that the preferred reaction temperature in step (2) is 60-100°C, and the reaction time is 15-25 hours.

0. The preparation method according to claim 6, characterized in that the alkali used in step (3) is an inorganic alkali or an organic alkali: the inorganic alkali is potassium bicarbonate, sodium bicarbonate, anhydrous potassium carbonate, anhydrous sodium carbonate , potassium hydroxide or sodium hydroxide; organic bases are triethylamine, pyridine, 4-dimethylaminopyridine, and sodium acetate.

1. The preparation method according to claim 6, characterized in that potassium iodide is added in step (3).

The preparation method according to claim 6, characterized in that the preferred reaction temperature in step (3) is 60-100°C, and the reaction time is 6-10 hours.

3. The preparation method according to claim 6, characterized in that sodium formate is added in step (4).

, The preparation method according to claim 6, characterized in that the steps

The reaction temperature in (4) is 90-140°C, and the reaction time is 8-12 hours.

5. The preparation method according to claim 6, characterized in that the alkali used in step (5) is an inorganic alkali or an organic alkali: the inorganic alkali is potassium bicarbonate, sodium bicarbonate, anhydrous potassium carbonate, anhydrous sodium carbonate , potassium hydroxide or sodium hydroxide; organic bases are triethylamine, pyridine, and sodium acetate.

6. The preparation method according to claim 6, characterized in that the preferred pH in step (5) is 2-5.

7. The preparation method according to claim 6, characterized in that the preferred reaction temperature in step (5) is 60-100°C. 8. Use of a compound according to any one of claims 1 to 4 in the preparation of a medicament for the treatment and/or prevention of hyperuricemia. 9. Use of a compound according to any one of claims 1 to 4 in the preparation of a medicament for the treatment and/or prevention of gout, arthritis or heart failure caused by hyperuricemia.