Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D293/00—Heterocyclic compounds containing rings having nitrogen and selenium or nitrogen and tellurium, with or without oxygen or sulfur atoms, as the ring hetero atoms
  • C07D293/02—Heterocyclic compounds containing rings having nitrogen and selenium or nitrogen and tellurium, with or without oxygen or sulfur atoms, as the ring hetero atoms not condensed with other rings
  • C07D293/04—Five-membered rings
  • C07D293/06—Selenazoles; Hydrogenated selenazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

• the invention relates to the technical field of medicine, in particular to a selenazolecarboxylic acid compound, a preparation method thereof and use thereof.
• 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.
• U uric acid
• 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.
• 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.
• Anti-uric acid activity studies have shown that the compounds have a better activity to lower blood uric acid content.
• 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.
• 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.
• 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.
• the pharmaceutically acceptable prodrug is a (C1-C4) fatty alcohol ester of a compound of formula I.
• the present invention also encompasses a pharmaceutical composition
• 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.
• 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:
• 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.
• methyl 2-chloroacetoacetate and ethyl 2-chloroacetoacetate are particularly preferred.
• 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 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 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 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.
• 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.
• 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 preparation method comprises the following steps:
• 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).
• Example 3 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 ⁇
• 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.
• Example 3 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.
• Example 3 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.
• Test Example 1 ⁇ 5 compound, febuxostat, positive control is aspirin
• Example 1 group 50 mg/kg
• febuxostat group 50 mg/kg
• aspirin group 200 mg/kg
• blank control group 40 ⁇ l 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 ⁇ 100%.
• 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.
• 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 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 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 4 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 activated carbon is adsorbed according to a conventional method of pharmacy, filtered through a 0.65 ⁇ microporous membrane filter, and filled in a nitrogen tank. Water needle preparation, a total of 100 bottles.
• 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.
• 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.

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Citations (4)

• 2012
  • 2012-08-28 CN CN201210308640.XA patent/CN103130744B/zh not_active Expired - Fee Related
• 2013
  • 2013-08-28 WO PCT/CN2013/082438 patent/WO2014032583A1/fr not_active Ceased

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