CN113773361B - Compound for treating hyperuricemia, composition thereof, preparation method and medical application - Google Patents
Compound for treating hyperuricemia, composition thereof, preparation method and medical application Download PDFInfo
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- CN113773361B CN113773361B CN202111241742.XA CN202111241742A CN113773361B CN 113773361 B CN113773361 B CN 113773361B CN 202111241742 A CN202111241742 A CN 202111241742A CN 113773361 B CN113773361 B CN 113773361B
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- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
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- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
Abstract
The invention discloses a compound for treating hyperuricemia, a composition, a preparation method, medical application and a quality control method thereof, wherein the compound has a structure shown in a formula I, and the medical application is characterized in that the compound is used for treating various diseases caused by hyperuricemia.
Description
Technical Field
The invention particularly relates to a compound for treating hyperuricemia, a composition thereof, a preparation method, medical application and a quality control method, wherein the compound has a structure shown in formula I, and the medical application is characterized in that the compound is used for treating various diseases caused by hyperuricemia.
Background
Febuxostat, a Xanthine Oxidase (XO) inhibitor suitable for the long-term treatment of hyperuricemia with gout symptoms, is chemically named 2- [ (3-cyano-4-isobutoxy) phenyl ] -4-methyl-5-thiazolecarboxylic acid, and has the following structural formula:
ursodeoxycholic acid, a medicament which can increase bile acid secretion, can reduce cholesterol and cholesterol ester in bile, is favorable for gradually dissolving cholesterol in gallstone, is used for treating the gallstone which is not suitable for operation treatment, has certain curative effect on cholecystitis, cholangitis and dyspepsia, and has the following structural formula:
hyperuricemia refers to the condition that under the normal purine diet, the uric acid level of two times of fasting blood on non-same day is higher than 420 mu mol/L in men and higher than 360 mu mol/L in women, namely hyperuricemia, and the uric acid is usually synthesized by purine metabolism and excreted through the kidney and the intestinal tract, so the hyperuricemia is often caused by excretion disorder or excessive uric acid production. Hyperuricemia is caused by purine metabolic disorder, purine is a main composition of nucleic acid, is mainly generated by endogenous nucleic acid catabolism, a small part is decomposed by exogenous nucleic acid-rich food, and uric acid is a final product of human purine metabolism due to lack of urate oxidase in human; hyperuricemia is also associated with excessive production or insufficient excretion of uric acid in the body.
By establishing a hyperuricemia animal model and systematically screening a laboratory compound library, the febuxostat acyl ursodesoxycholic acid polyethylene glycol ester derivative is unexpectedly found to have the effect of remarkably improving hyperuricemia. Further through synthesis process research, composition and activity evaluation research, a chemical synthesis process of the febuxostat acyl ursodesoxycholic acid polyethylene glycol ester derivative is established, and the effect of the febuxostat acyl ursodesoxycholic acid polyethylene glycol ester derivative on improving the hyperuricemia is systematically evaluated.
Disclosure of Invention
The invention aims to solve the technical problems that the invention provides an effective component for treating hyperuricemia, establishes a synthesis process thereof, further evaluates the effects of the effective component on preventing and treating the hyperuricemia and establishes a quality control method thereof.
The method is characterized by establishing a hyperuricemia animal model, systematically screening a laboratory compound library, and unexpectedly finding that the febuxostat acyl ursodesoxycholic acid polyethylene glycol ester derivative has the effect of remarkably improving hyperuricemia. Further, through synthesis process research, composition and activity evaluation research, a chemical synthesis process of the febuxostat acyl ursodesoxycholic acid polyethylene glycol ester derivative is established, synthesis reaction parameters of the febuxostat acyl ursodesoxycholic acid polyethylene glycol ester derivative are systematically investigated, reaction conditions are optimized, and the effect of the febuxostat acyl ursodesoxycholic acid polyethylene glycol ester derivative on improving hyperuricemia is systematically evaluated.
The invention provides a compound with a structure shown in a formula I or a pharmaceutically acceptable salt thereof,
wherein n is 1-50
Preferably, where n is 1-10
Preferably, where n is 1-5
Preferably, where n is 1-2
A preferred specific compound of the present invention is a compound of n ═ 1, designated as: febuxostat acylursodeoxycholic acid ethoxy ethyl ester
The pharmaceutically acceptable salts of the present invention include salts with acids, or salts with bases, such as salts with organic or inorganic acids, or salts with alkali metals or alkaline earth metals.
The present invention further provides a pharmaceutical composition comprising a compound of the structure of formula I or a pharmaceutically acceptable salt thereof, preferably in any pharmaceutical formulation form that can be taken, said pharmaceutical formulation form being selected from the group consisting of: tablet, capsule, pill, suppository, aerosol, oral liquid, granule, powder, injection, syrup, medicated liquor, tincture, distillate, and pellicle.
The invention further provides a preparation method of the compound with the structure shown in the formula I or the pharmaceutically acceptable salt thereof, wherein the preparation method comprises the steps of esterifying ursodeoxycholic acid polyethylene glycol and reacting with febuxostat.
Or, firstly, the ursodeoxycholic acid is acidified and the febuxostat is reacted, and then the polyethylene glycol esterification is carried out on the reaction product.
Preferably, the preparation method comprises the following steps:
1) preparation of ursodeoxycholic acid polyethylene glycol ester
Dissolving ursodeoxycholic acid in polyethylene glycol ether, adding inorganic acid or organic acid at room temperature, and stirring. Removing most of the solvent under reduced pressure after the reaction is finished, adding an organic solvent, washing with purified water, washing with saturated saline solution, drying with anhydrous sodium sulfate, removing the solvent to obtain oily matter, and purifying by silica gel column chromatography to obtain ursodeoxycholic acid polyethylene glycol ester.
Wherein the inorganic acid sodium for catalysis comprises carbonic acid, sodium bicarbonate, sulfuric acid, phosphoric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, etc., and is optimized to be sulfuric acid; the organic acid for catalysis comprises tartaric acid, phthalic acid, citric acid, formic acid, acetic acid, 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 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 8 to 18 hours, and the optimal time is 14 to 16 hours; the organic solvent added after the reaction is finished comprises dichloromethane, chloroform, ethyl acetate, n-butanol, acetone and the like, and is optimized into dichloromethane and chloroform; the mobile phase of the purification chromatography organic solvent is petroleum ether-ethyl acetate, petroleum ether-acetone, petroleum ether-dichloromethane, dichloromethane-ethyl acetate, dichloromethane-methanol, petroleum ether-ethyl acetate-acetone, petroleum ether-ethyl acetate-methanol, dichloromethane-ethyl acetate, petroleum ether-ethyl acetate-acetone, petroleum ether-ethyl acetate-methanol, and is preferably dichloromethane-methanol, petroleum ether-ethyl acetate, petroleum ether-dichloromethane, petroleum ether-ethyl acetate-acetone, and most preferably dichloromethane-methanol, and dichloromethane-ethyl acetate-methanol.
2) Acylation reaction of febuxostat
Dissolving febuxostat in an organic solvent, sequentially adding ursodeoxycholic acid polyethylene glycol ester and DIEA, stirring for a certain time, then adding HBTU, stirring, adding the organic solvent after the reaction is finished, washing with purified water, washing with saturated saline solution, drying with anhydrous sodium sulfate, removing the solvent to obtain an oily substance, and purifying by silica gel column chromatography to obtain the febuxostat acyl ursodeoxycholic acid polyethylene glycol ester.
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); after DIEA is added, the reaction time is 10min-2 days, the optimal time is 0.1-8 hours, and the optimal time is 0.1-0.5 hour; the HBTU is added, and then the reaction time is 10min-2 days, the optimal time is 18-32 hours, and the optimal time is 18-24 hours; after the reaction is finished, adding organic solvents including dichloromethane, chloroform, ethyl acetate, n-butyl alcohol, acetone and the like, and optimizing the organic solvents into dichloromethane and chloroform; the mobile phase of the purification chromatography organic solvent is petroleum ether-ethyl acetate, petroleum ether-acetone, petroleum ether-dichloromethane, dichloromethane-ethyl acetate, dichloromethane-methanol, petroleum ether-ethyl acetate-acetone, petroleum ether-ethyl acetate-methanol, dichloromethane-ethyl acetate, petroleum ether-ethyl acetate-acetone, petroleum ether-ethyl acetate-methanol, and is preferably dichloromethane-methanol, petroleum ether-ethyl acetate, petroleum ether-dichloromethane, petroleum ether-ethyl acetate-acetone, and most preferably dichloromethane-methanol, and dichloromethane-ethyl acetate-methanol.
The present inventors have investigated the formulation and process of tablets, capsules and granules of a compound of formula I or a pharmaceutically acceptable salt thereof and have unexpectedly found that Vc and mildly acidic conditions can protect the stability of a compound of formula I or a pharmaceutically acceptable salt thereof in a formulation.
The invention carries out systematic pharmacological evaluation on the compound with the structure shown in the formula I or pharmaceutically acceptable salt thereof, finds that the compound can prevent and treat hyperuricemia, further finds that the compound is superior to a parent compound in curative effect, and has the unexpected effects of reducing side effects, improving bioavailability and the like.
The discovery of the invention provides hope for patients with hyperuricemia who lack medical treatment at present, and has profound social significance and application value.
Drawings
FIG. 1 is a chemical structural diagram of a compound with a structure of formula I
FIG. 2, scheme of the Synthesis Process
FIG. 3 shows the results of biochemical index detection and HE staining of serum of mouse with high uric acid content
A: uric acid (Uric acid), B: creatinine (Cr), C: urea Nitrogen (BUN), D: HE staining (verification 200X, scale bar 20 μm)
P <0.05 and control (Ctrl), # p <0.05 and model (PO)
FIG. 4 is a 1HNMR nuclear magnetic spectrum of febuxostat acylursodeoxycholic acid ethoxy ethyl ester (the compound obtained in example 1, wherein n is 1 in the chemical formula)
FIG. 5 is a 13CNMR nuclear magnetic spectrum of febuxostat acylursodeoxycholic acid ethoxy ethyl ester (the compound obtained in example 1, wherein n is 1 in the chemical formula)
Detailed Description
The following examples illustrate the utility of the invention, which is not limited thereby.
Example 1: preparation of febuxostat acylursodeoxycholic acid ethoxy ethyl ester
1.0g (2.54mmol) of ursodeoxycholic acid was dissolved in 8ml of ethylene glycol ethyl ether, and 1 drop of concentrated sulfuric acid was added thereto at room temperature, followed by stirring for 15 hours. After the reaction, most of the solvent was removed under reduced pressure, 50ml of dichloromethane was added, washed with purified water 3 times, washed with saturated brine 2 times, dried over anhydrous sodium sulfate, and the solvent was removed to obtain an oil, and subjected to silica gel column chromatography with dichloromethane: purifying with methanol (100: 5) to obtain ursodeoxycholic acid monoethylene glycol ethyl ester 958mg with yield 81%.
Then, 652mg (2.06mmol) of febuxostat is dissolved in 10ml of DMF, 958mg (2.06mmol) of ethylene glycol ursodeoxycholate and 681 μ L (4.12mmol) of DIEA are added, after stirring for 10min at room temperature, 782mg (2.06mmol) of HBTU are added, after 20 hours of reaction at room temperature, 50ml of dichloromethane is added, washing is carried out for 4 times with purified water, washing is carried out for 2 times with saturated saline solution, drying is carried out with anhydrous sodium sulfate, the solvent is removed to obtain oily matter, and dichloromethane is subjected to silica gel column chromatography: the ethanol ethyl ester of febuxostat ursodeoxycholic acid is obtained by purifying methanol 100:8, 1.02g is obtained, and the yield is 65%.
1H NMR(400MHz,CDCl3)δ8.17(1H,d,J＝2.0Hz),8.09(1H,dd,J＝8.8,2.0Hz),7.01(1H,d,J＝8.8Hz),4.88(1H,m),4.22(2H,t,J＝46Hz),3.90(2H,d,J＝6.4Hz),3.63(2H,t,J＝4.8Hz),3.60(1H,m),3.54(2H,q,J＝7.0Hz),2.76(3H,s),2.39(1H,m),2.28-2.19(2H,m),2.03(1H,d,J＝12.0Hz),1.90–1.76(8H,m),1.73–1.61(4H,m),1.52–1.42(7H,m),1.36–1.31(4H,m),1.22(6H,t,J＝6.5Hz),1.09(8H,d,J＝6.8Hz),0.99(3H,s),0.94(3H,d,J＝6.4Hz),0.69(3H,s)。13C NMR(100MHz,CDCl3)174.2,167.0,162.4,161.5,161.0,132.4,132.0,126.1,122.2,115.3,112.6,103.0,75.7,75.2,71.2,68.3,66.6,63.5,55.7,55.0,43.7,43.7,42.4,40.1,39.2,36.6,35.2,34.6,34.1,33.3,31.1,30.9,28.6,28.1,26.8,26.7,23.3,21.2,19.0,19.0,18.4,17.5,15.1,12.1。
Example 2: preparation of febuxostat acylursodeoxycholic acid dimer glycol ester (general formula n ═ 2)
1.0g (2.54mmol) of ursodeoxycholic acid is dissolved in 16ml of 2-bromoethoxyethyl ether, 1 drop of concentrated sulfuric acid is added at room temperature, and stirring is carried out for 20 hours. After the reaction, most of the solvent was removed under reduced pressure, 100ml of dichloromethane was added, washed with purified water 3 times, washed with saturated brine 3 times, dried over anhydrous sodium sulfate, and the solvent was removed to obtain an oil, and subjected to silica gel column chromatography with dichloromethane: the mixture was purified with methanol 100:6 to obtain 1.09g of dideoxy-cholic acid dimer glycol ester with a yield of 84.5%.
Then, 680mg (2.15mmol) of febuxostat is dissolved in 20ml of DMF, 1.09g (2.15mmol) of ursodeoxycholic acid dimer ethylene glycol ester and 711 μ L (4.30mmol) of DIEA are added, stirring is carried out at room temperature for 10min, then 816mg (2.15mmol) of HBTU is added, reaction is carried out at room temperature for 24 h, 200ml of dichloromethane is added, washing is carried out for 4 times by purified water, washing is carried out for 2 times by saturated saline, drying is carried out by anhydrous sodium sulfate, the solvent is removed, and then oil is obtained, and dichloromethane is subjected to silica gel column chromatography: the febuxostat ursodeoxycholic acid dipolyethylene glycol ester is obtained by purifying methanol 100:9, the weight of the febuxostat ursodeoxycholic acid dipolyethylene glycol ester is 1.18g, and the yield is 71.2%.
Example 3: preparation of febuxostat acyl ursodesoxycholic acid polyethylene glycol ester-5 (general formula n ═ 5)
1.0g (2.54mmol) of ursodeoxycholic acid was dissolved in 30ml of 2-bromopolyethoxyethylether (n ═ 5), and 1 drop of concentrated sulfuric acid was added thereto at room temperature, followed by stirring for 20 hours. After the reaction, most of the solvent was removed under reduced pressure, 100ml of dichloromethane was added, washed with purified water 3 times, washed with saturated brine 3 times, dried over anhydrous sodium sulfate, and the solvent was removed to obtain an oil, and subjected to silica gel column chromatography with dichloromethane: the methanol is 100:6, and the ursodeoxycholic acid polyethylene glycol ester-5 is obtained by purification, the weight is 1.43g, and the yield is 80.4%.
Dissolving 645mg (2.04mmol) of febuxostat in 30ml of DMF, adding 1.43g (2.04mmol) of ursodeoxycholic acid polyethylene glycol ester-5 and DIEA 675 mu L (4.08mmol), stirring at room temperature for 20min, adding 775mg (2.15mmol), reacting at room temperature for 28 h, adding 300ml of dichloromethane, washing with purified water for 4 times, washing with saturated saline solution for 2 times, drying with anhydrous sodium sulfate, removing the solvent to obtain an oily substance, performing silica gel column chromatography on dichloromethane: the methanol is 100:10, and the febuxostat ursodeoxycholic acid polyethylene glycol ester-5 is obtained by purification, the weight is 1.21g, and the yield is 62.9%.
Example 4: preparation of febuxostat acyl ursodesoxycholic acid polyethylene glycol ester-50 (general formula n ═ 50)
1.0g (2.54mmol) of ursodeoxycholic acid was dissolved in 200ml of 2-bromopolyethoxyethylethyl ether (n ═ 50), and 1 drop of concentrated sulfuric acid was added thereto at room temperature, followed by stirring for 24 hours. After the reaction, most of the solvent was removed under reduced pressure, 500ml of dichloromethane was added, washed with purified water 3 times, washed with saturated brine 3 times, dried over anhydrous sodium sulfate, and the solvent was removed to obtain an oil, and subjected to silica gel column chromatography with dichloromethane: the methanol is 100:7, and the ursodeoxycholic dimer glycol ester-50 is obtained after purification, the weight is 3.58g, and the yield is 81.6%.
Dissolving febuxostat 655mg (2.07mmol) in 50ml DMF, adding 3.58g (2.07mmol) ursodeoxycholic acid polyethylene glycol ester-50 and DIEA 684 μ L (4.14mmol), stirring at room temperature for 10min, adding HBTU 785mg (2.07mmol), reacting at room temperature for 24 hr, adding dichloromethane 500ml, washing with purified water for 4 times, washing with saturated saline solution for 2 times, drying with anhydrous sodium sulfate, removing solvent to obtain oil, performing silica gel column chromatography on dichloromethane: the methanol is 100:10, and the febuxostat ursodeoxycholic acid polyethylene glycol ester-50 is obtained through purification, the weight is 3.35g, and the yield is 55.8%.
Example 5: preparation of febuxostat acyl ursodesoxycholic acid ethoxy ethyl ester tablet
The febuxostat acyl ursodesoxycholic acid ethoxy ethyl ester powder obtained in the embodiment 1 and auxiliary materials such as starch, microcrystalline cellulose and the like are respectively sieved by a 100-mesh sieve, weighed and uniformly mixed according to the proportion of each prescription, added with a proper amount of 80% ethanol to prepare soft materials, granulated by a 16-mesh sieve, and dried by hot air at 50 ℃ for 90 min. 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 contains 300mg of febuxostat acyl ursodesoxycholic acid ethoxy ethyl ester and 30 mg.
The prescription is as follows:
example 6: preparation of febuxostat acyl ursodesoxycholic acid polyethylene glycol ester-5 capsule
The febuxostat acyl ursodesoxycholic acid polyethylene glycol ester-5 powder obtained in the embodiment 3 and auxiliary materials such as starch, microcrystalline cellulose and the like are respectively sieved by a 100-mesh sieve, weighed and mixed uniformly according to the proportion of each formula, added with a proper amount of 80% ethanol to prepare soft materials, sieved by a 16-mesh sieve for granulation, and dried by hot air at 50 ℃ for 90 min. And (4) after finishing the granules by using a 14-mesh sieve, adding a proper amount of talcum powder and magnesium stearate, and filling the mixture into capsules to obtain the capsule.
The prescription composition is as follows: 250mg of each capsule, and 40mg of febuxostat acyl ursodesoxycholic acid polyethylene glycol ester-5.
The prescription is as follows:
example 7: preparation of febuxostat acylursodeoxycholic acid dipolyethylene glycol ester (general formula n ═ 2) granules
The febuxostat acyl ursodesoxycholic acid dimer glycol ester (general formula n is 2) powder obtained in the example 2 and auxiliary materials such as starch, microcrystalline cellulose and the like are respectively sieved by a 100-mesh sieve, weighed and mixed uniformly according to the proportion of each formula, added with a proper amount of 80% ethanol to prepare soft materials, sieved by a 16-mesh sieve for granulation, and dried by hot air at 50 ℃ for 90 min. 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 febuxostat acyl ursodeoxycholic acid dipolyethylene glycol ester (general formula n is 2)30 mg.
The prescription is as follows:
example 8: preparation of febuxostat acyl ursodesoxycholic acid polyethylene glycol ester-50 (general formula n ═ 50) granules
The febuxostat acyl ursodesoxycholic acid polyethylene glycol ester-50 (general formula n is 50) powder obtained in the example 4 and auxiliary materials such as starch, microcrystalline cellulose and the like are respectively sieved by a 100-mesh sieve, weighed and mixed uniformly according to the proportion of each formula, added with a proper amount of 80% ethanol to prepare soft materials, granulated by a 16-mesh sieve, and dried by hot air at 50 ℃ for 90 min. 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 febuxostat acyl ursodeoxycholic acid polyethylene glycol ester-50 (general formula n is 50)120 mg.
The prescription is as follows:
example 9: febuxostat acylursodesoxycholic acid ethoxyethyl ester for treating hyperuricemia
The experimental steps are as follows:
60 ICR male mice were randomly divided into 6 groups, fasted for 1 hour before the experiment and freely drunk water, and mice in each group except the control group were gavaged with PO to increase serum uric acid level. Febuxostat and the test compound febuxostat acylursodeoxycholic acid ethoxy ethyl ester were administered in the stomach after 1 hour, and febuxostat acylursodeoxycholic acid ethoxy ethyl ester were dissolved in a 0.5% CMC-Na solution, wherein febuxostat was used as a positive control drug. The administration was continued for 7 days.
And taking materials after the seventh day of administration. And (3) fixing the left kidney of each group of mice with the number of 1-4 in 4% paraformaldehyde, and quickly freezing the right kidney in liquid nitrogen and then storing in a-80 refrigerator.
The results show that:
1) uric acid (Uric acid), creatinine (Cr) and urea nitrogen (BUN) detection results: as shown in the following figure, febuxostat can reduce the increase of Uric acid (Uric acid), creatinine (Cr) and urea nitrogen (BUN) induced by PO when the dosage is 5 mg/kg; febuxostat acylursodeoxycholic acid ethoxy ethyl ester is concentration-dependent on the reduction of Uric acid (Uric acid), creatinine (Cr) and urea nitrogen (BUN) in serum, and has the best effect of reducing Uric acid at high dose.
2) HE staining results (renal tissue): as shown in the following figure, the kidney of the control group showed normal glomerular and tubular structures, and the tubular cell boundary of the kidney of the model group was not obvious and swollen. The positive drug group kidney was normal in renal tubule histology treated with febuxostat. Kidneys of febuxostat acylursodeoxycholic acid ethoxyethyl ester treated group showed a recovery of renal tubule histology.
Claims (5)
1. A compound having the structure of formula I or a pharmaceutically acceptable salt thereof,
wherein n is 1.
2. A process for the preparation of a compound according to claim 1 or a pharmaceutically acceptable salt thereof comprising the reaction steps of
Wherein n is 1.
3. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof.
4. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of hyperuricemia.
5. The use according to claim 4, wherein the hyperuricemia is gout.
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