Application of compound MT-1207 in reducing uric acid

Abstract

The present invention relates to the field of biomedicine technology, and specifically discloses the application of compound MT-1207 in reducing uric acid. The structure of the compound MT-1207 is shown in formula (I). The present invention first finds that compound MT-1207 has the effect of reducing uric acid. In the 2K2C rat model, the uric acid level of the model group rats increased significantly. After losartan administration, the creatinine and urea levels were further increased, aggravating the renal function damage of the 2K2C model rats; and the creatinine and urea levels of the 2K2C model rats were not deteriorated after MT-1207 administration, and uric acid had a significant reducing effect. In the hyperuricemia animal model, the uric acid level of the model group rats increased significantly, and the uric acid level was significantly reduced after MT-1207 administration. Therefore, compound MT-1207 has a significant effect of reducing uric acid, and can be used to prepare a drug that reduces uric acid levels or prevents uric acid levels from increasing.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and specifically, to the application of compound MT-1207 in reducing uric acid. Background Art

[0002] The chemical name of MT-1207 is 3-(4-(4-(1H-benzotriazol-1-yl)butyl)piperazin-1-yl)benzisothiazole hydrochloride, which is a new type of antihypertensive drug that has entered clinical trials in China. The patent titled "New Uses of Multitarget Compounds X7" (2019109311600) discloses the use of MT-1207 in the treatment of hypertension and target organ damage caused by hypertension. The patents titled "Uses of Benzo-Five-Membered Aza-Heterocyclic Piperazine Derivatives" (2012104869676, 2016108284104) disclose the use of MT-1207 in the treatment of diseases or disorders related to persistent pathological vasoconstriction or vasospasm of blood vessels. The paper "Pharmacological Characterization of MT-1207, a Novel Multitarget Antihypertensive Agent" published in 2021 discloses the pharmacological properties of MT-1207, the effectiveness and related therapeutic targets of MT-1207, indicating that MT-1207 is a novel and promising single-molecule multitarget antihypertensive drug.

[0003] Uric acid is a product of human purine metabolism and is mainly excreted from the body in the form of urine. Under normal circumstances, the production and excretion of uric acid in the human body are balanced. However, when this balance is disrupted, that is, when production increases or excretion decreases, uric acid will accumulate in the body, leading to an increase in uric acid levels.

[0004] In the prior art, there is no relevant report on the application of compound MT-1207 in reducing uric acid. Summary of the Invention

[0005] The object of the present invention is to provide an application of compound MT-1207 in the preparation of a drug for reducing uric acid levels or preventing an increase in uric acid levels in an individual in view of the deficiencies in the prior art. The structure of the compound MT-1207 is shown in formula (I).

[0006]

[0007] In the above application, preferably, the compound MT-1207 is used as the sole active ingredient.

[0008] In the above application, preferably, the compound MT-1207 and other drugs for reducing uric acid are used as active ingredients together.

[0009] In the above application, preferably, the drug further comprises one or more pharmaceutically acceptable auxiliary components; the pharmaceutically acceptable auxiliary components are excipients, fillers or diluents.

[0010] In the above application, more preferably, the drug comprises MT-1207 in a weight ratio of 0.01-99.99%, and auxiliary components in a weight ratio of 0.01-99.99%.

[0011] In the above application, more preferably, the drug comprises MT-1207 in a weight ratio of 0.01-99.99%, and other drugs for reducing uric acid in a weight ratio of 0.01-99.99%.

[0012] In the above application, preferably, the drug is prepared into a clinically acceptable pharmaceutical preparation according to the conventional pharmaceutical preparation methods.

[0013] In the above application, preferably, the drug is various conventional dosage forms in the art, preferably in the form of solid, semi-solid or liquid, and can be aqueous solution, non-aqueous solution or suspension, more preferably powder, granule, tablet, capsule, pill, solution, suspension or injection, etc. The preferred administration route of the drug is injection or oral administration. The injection administration preferably includes intravenous injection, intramuscular injection, intraperitoneal injection, intradermal injection or subcutaneous injection, etc.

[0014] The present invention first discovers that the compound MT-1207 has the effect of reducing uric acid. In the 2K2C rat model, the uric acid level of the rats in the model group significantly increased. After administration of losartan, the levels of creatinine and urea further increased, exacerbating the renal function injury of the 2K2C model rats; while after administration of MT-1207, the levels of creatinine and urea in the 2K2C model rats did not deteriorate, and there was an obvious effect of reducing uric acid. In the hyperuricemic animal model, the uric acid level of the rats in the model group significantly increased, and after administration of MT-1207, the uric acid level significantly decreased. Therefore, the compound MT-1207 has an obvious effect of reducing uric acid and can be used to prepare drugs for reducing uric acid level or preventing the increase of uric acid level. Description of the Drawings

[0015] Figure 1 . Schematic diagram of the 2K2C operation in rats.

[0016] Figure 2 . Effects of MT-1207 on the 2K2C rat model. A-E. Body weight (A), serum creatinine (B), urea (C), uric acid (D) and K + level (E) of rats in each group after intragastric administration for 3 days; F-J. Body weight (F), serum creatinine (G), urea (H), uric acid (I) and K +Horizontal (J). For the 3-day administration experiment, n = 8 - 12; for the 9-week administration experiment, n = 10 - 16; * P < 0.05, ** P < 0.01, *** P < 0.001 vs model group (Model); # P < 0.05, ## P < 0.01, ### P < 0.001 vs sham operation control group (Sham).

[0017] Figure 3 . Effects of MT-1207 on hyperuricemic rat models. A - D. Body weight (A), serum creatinine (B), urea (C), and uric acid (D) levels of rats at 1 week after intragastric administration; E - H. Body weight (E), serum creatinine (F), urea (G), and uric acid (H) levels of rats at 2 weeks after intragastric administration. n = 10 - 11, * P < 0.05, ** P < 0.01, *** P < 0.001 vs model group (Model); # P < 0.05, ## P < 0.01 vs normal control group (Vehicle). Detailed implementation manners

[0018] The present invention will be further described below in conjunction with specific implementation manners. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. In addition, it should be understood that after reading the content recorded in the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

[0019] In the present invention, the compound MT-1207 can be obtained by commercial purchase or prepared by the disclosed preparation methods. The structure of the compound MT-1207 is shown in formula (I),

[0020]

[0021] In the 2K2C rat model, the uric acid level of the model group rats increased significantly. After administration of losartan, the creatinine and urea levels were further increased, exacerbating the renal function damage of the 2K2C model rats; while after administration of MT-1207, the creatinine and urea levels of the 2K2C model rats were not deteriorated, and there was an obvious effect of reducing uric acid. In the hyperuricemic animal model, the uric acid level of the model group rats increased significantly, and after administration of MT-1207, the uric acid level decreased significantly. Therefore, the compound MT-1207 has an obvious effect of reducing uric acid and can be used to prepare drugs for reducing uric acid levels or preventing the increase of uric acid levels.

[0022] The compound MT-1207 of the present invention can be prepared into a suitable pharmaceutical composition for oral administration, parenteral administration, administration by inhalation spray, rectal administration, intranasal administration, sublingual administration, buccal administration, transdermal administration or implantation administration. The parenteral administration includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The compound MT-1207 of the present invention is preferably administered orally, sublingually, intravenously, intramuscularly or subcutaneously. The pharmaceutical composition may contain one or more conventional pharmaceutically acceptable carriers, adjuvants or media, such as: diluents, excipients such as water; binders such as cellulose derivatives, gelatin, polyvinylpyrrolidone, etc.; fillers such as starch; disintegrants such as calcium carbonate, sodium bicarbonate; lubricants such as calcium stearate or magnesium stearate; and other adjuvants such as flavoring agents and sweetening agents.

[0023] The pharmaceutical composition containing the compound MT-1207 of the present invention may be in the form of a sterile injection, such as a sterile aqueous or oily suspension. The suspension can be formulated using suitable dispersing or wetting agents and suspending agents according to techniques known in the art. The sterile injection may also be a sterile injection solution or suspension in a non-toxic diluent or solvent suitable for parenteral administration, such as a solution in 1,3-butanediol. The available media and solvents that can be used are mannitol, water and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. Any mild fixed oil can be used, including synthetic glycerol monoesters or diesters. Fatty acids, such as oleic acid and its glyceride derivatives, can be used in injectable preparations, and natural pharmaceutically acceptable oils can also be used therein, such as olive oil or castor oil, especially in their polyoxethylated forms. The oil solution or suspension may also contain long-chain alcohol diluents or dispersing agents or similar alcohols.

[0024] The pharmaceutical composition containing the compound MT-1207 of the present invention can be administered orally in any orally administrable dosage form, including but not limited to capsules, tablets, powders, granules and aqueous suspensions and solutions. The dosage form is prepared according to techniques well-known in the field of pharmaceutical formulations. For tablets for oral use, the commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also usually added. For oral administration in capsule form, available diluents include lactose and dried corn starch. When an aqueous suspension is administered orally, the active ingredient can be combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents can be added.

[0025] The pharmaceutical composition containing the compound MT-1207 of the present invention can be administered by nasal aerosol or inhalation. Such compositions can be prepared according to techniques well known in the pharmaceutical formulation art and can be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0026] The pharmaceutical composition containing the compound MT-1207 of the present invention can also be administered in the form of suppositories for rectal administration. The composition can be prepared by mixing the compound of the present invention with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and thus will melt in the rectum to release the active ingredient. Such substances include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0027] The pharmaceutical composition containing the compound MT-1207 of the present invention can be prepared by conventional methods in the medical field, wherein the weight ratio of the active ingredient is 0.01 - 99.99%, depending on the condition to be treated or prevented and the characteristics of the subject to whom the compound is administered. The dosage regimen for the given compound MT-1207 can be readily determined by those skilled in the art using the content disclosed herein.

[0028] The compound MT-1207 of the present invention can be used in combination with one or more other active pharmaceutical ingredients. The combination drug can be in the form of a single composition containing the compound MT-1207 of the present invention and one or more other active pharmaceutical ingredients, or in the form of a combination of two or more separate compositions.

[0029] Examples

[0030] 1. Experimental materials

[0031] 1.1. Drugs

[0032] MT-1207 (abbreviation: MT): white or off-white crystalline powder, production batch number: 20181201, stored sealed in a 4°C refrigerator.

[0033] Losartan Potassium (abbreviation: Los): Ningbo Menovo Pharmaceutical Co., Ltd., batch number: LOSB-4-06210326, stored protected from light and sealed in a 4°C refrigerator.

[0034] 1.2. Experimental reagents

[0035] Potassium oxonate: produced by Shanghai Aladdin Biochemical Technology Co., Ltd., specification: 100 g, batch number: H2017152.

[0036] Fructose: Produced by Adamas Reagent Co., Ltd., Specification: 2.5 kg, Batch Number: P2417308.

[0037] Pentobarbital Sodium: Produced by Merck KGaA, Germany, imported and repackaged.

[0038] Sodium Carboxymethyl Cellulose: CMC-Na, Produced by Sinopharm Chemical Reagent Co., Ltd., Specification: 500 g, Batch Number: F20050302.

[0039] 1.3. Experimental Animals

[0040] SD rats, SPF grade, male, Supplier: Shanghai Bikai Keyi Biotechnology Co., Ltd., Production License Number: SCXK(Shanghai)2018-0006.

[0041] 1.4. Experimental Instruments

[0042] U-shaped silver clip: Produced by Shanghai Olcott Biotechnology Co., Ltd.

[0043] Automatic biochemical analyzer: Produced by Hitachi High-Technologies Corporation, Japan, Model: HITACHI 7180.

[0044] 2. Experimental Methods

[0045] 2.1. Dose Setting, Grouping and Drug Administration

[0046] In this experiment, drug administration studies were conducted on the two-kidney two-clip (2K2C) model and hyperuricemia model of rats.

[0047] (1) In the 2K2C model, the experiment was divided into:

[0048] Sham operation control group (Sham);

[0049] 2K2C model group (Model);

[0050] 2K2C model losartan potassium treatment group (Los): Losartan potassium dose 20 mg / kg;

[0051] 2K2C model MT-1207 treatment group (MT): MT-1207 dose 10 mg / kg, 20 mg / kg.

[0052] In the experiment, gavage administration and drug diet feeding were used. In the 3-day acute drug administration experiment, gavage administration was used, and the administration volume was 5 mL / kg; in the 9-week long-term drug administration treatment, drug diet feeding was given, and the rats freely ingested the drug-containing feed.

[0053] (2) In the hyperuricemia model, the experiment was divided into:

[0054] Normal control group (Vehicle): Given normal drinking water and intragastrically administered with 0.5% CMC-Na;

[0055] Model group (Model): Given 10% fructose drinking water and intragastrically administered with potassium oxonate at 0.1 g / kg;

[0056] Losartan potassium treatment group (Los): Given 10% fructose drinking water and intragastrically administered with potassium oxonate at 0.1 g / kg and losartan potassium at 20 mg / kg;

[0057] MT-1207 treatment group (MT): Given 10% fructose drinking water and intragastrically administered with potassium oxonate at 0.1 g / kg and MT-1207 at 10 mg / kg.

[0058] Potassium oxonate, losartan potassium and MT-1207 were prepared with 0.5% CMC-Na, and the total intragastric administration volume for rats was 5 mL / kg.

[0059] 2.2. Experimental method

[0060] (1) Effect of MT-1207 on 2K2C animal model

[0061] Rats were fasted for 12 h before the 2K2C surgical model establishment, and water was not restricted. The next day, the model was made. The rats weighed 130 - 150 g and were anesthetized by intraperitoneal injection of 2% sodium pentobarbital (40 mg / kg) at a dosing volume of 2 mL / kg. Then the rats were fixed in the supine position on the rat table, the chest and abdomen area was shaved, and the skin surface was disinfected with iodophor disinfectant and 75% ethanol. An incision was made 1.5 cm below the xiphoid process of the rat, and the skin was incised about 1.5 cm along the midline of the abdomen distally. The muscle layer was cut along the linea alba, and the incision was opened with a retractor to expose the field of view. The retractor was gently lifted upward, and the organs and tissues above and around the right kidney of the rat were pushed aside with a moistened sterile cotton swab. Then the tissues were pushed aside with a cotton ball piece above and below the kidney to fully expose the field of view around the renal blood vessels. The kidney was turned over with a cotton swab, and the surrounding adipose tissue was gently separated with forceps to expose the renal artery. The renal artery was carefully separated and then a U-shaped silver clip with an inner diameter of 0.2 mm ( Figure 1 ) was put on, and each tissue was reset. The contralateral renal artery was separated in the same way and a silver clip was put on. After each tissue was reset, 40,000 - 80,000 units of sodium penicillin were dropped, and then the muscle and skin were sutured layer by layer. The animal was kept warm on an electric blanket until it woke up and then put back into the cage for feeding. The operation of the sham operation group rats was similar to that of the 2K2C model establishment, but only the bilateral renal arteries were dissected and no U-shaped silver clip was put on.

[0062] Two weeks after the operation, the rats were grouped, namely the Sham group, the Model group, the 20 mg / kg losartan potassium group and the MT-1207 treatment groups (10 mg / kg, 20 mg / kg).

[0063] Observe the effects of acute administration of MT-1207 on rats. Rats in each group were given the corresponding drugs by gavage, with a dosing volume of 5 mL / kg. The Sham group and the Model group were given 0.5% CMC-Na solvent. The drugs were administered continuously for 3 days. 1 hour after the last administration, the rats were anesthetized with isoflurane gas, and 1 mL of blood was collected from the orbital cavity. After standing at room temperature for 2 hours, the serum was separated by centrifugation. The centrifuge was set at 3000g × 20 min. The upper clear serum was carefully aspirated and stored at -80 °C in the refrigerator for later use. Detection was performed using an automatic biochemical analyzer to measure the serum creatinine, urea, uric acid, and K + levels.

[0064] Observe the effects of long-term administration and treatment of MT-1207 on rats. A new batch of 2K2C models with a 0.2 mm stenosis degree of the renal artery was prepared and grouped as described above. Two weeks after the operation, the rats in each group were fed the corresponding drug feed. MT-1207 was set at two doses of 10 mg / kg and 20 mg / kg, and the Sham group and the Model group were given ordinary rat feed. After 9 weeks of administration, 1 mL of blood was collected from the orbital cavity of each rat, and the serum was obtained by centrifugation for detection.

[0065] (2) Effects of MT-1207 on hyperuricemia animal models

[0066] After the rats were purchased, they were acclimated for 3 days. After 3 days, the rats were randomly divided into 4 groups to start the experiment. The normal control group was given ordinary drinking water and gavage with 0.5% CMC-Na solvent; the model group was given 10% fructose drinking water and gavage with 0.1 g / kg potassium oxonate; the losartan potassium and MT-1207 groups were given 10% fructose drinking water and gavage with 0.1 g / kg potassium oxonate and the corresponding drugs.

[0067] At 1 week and 2 weeks after administration, 1 hour after gavage administration, the rats in each group were anesthetized with isoflurane gas, 1 mL of blood was collected from the orbital cavity, and after standing at room temperature for 2 hours, the serum was separated by centrifugation. The centrifuge was set at 3000g × 20 min. The upper clear serum was carefully aspirated and stored at -80 °C in the refrigerator for later use. Detection was performed using an automatic biochemical analyzer to measure the serum creatinine, urea, and uric acid levels.

[0068] 3. Experimental results

[0069] (1) Hypouricemic effect of MT-1207 on 2K2C animal models

[0070] Figure 2 As shown, before the acute administration experiment for 3 consecutive days, the body weights of the rats in each group were at the same level. The detection results after 3 days of gavage administration showed that the creatinine and uric acid levels of the rats in the model group were significantly increased, and the K + level was significantly decreased. Among them, for K +The reducing effect is due to the increased aldosterone level caused by the secretion of renin due to renal artery stenosis, which plays a role in sodium retention and potassium excretion. Consistent with the principle in the hypertension treatment guidelines that prohibits the use of sartan drugs in patients with bilateral renal artery stenosis, after administration of losartan, the renal function injury of 2K2C model rats was aggravated. Compared with the model group, the levels of creatinine and urea were further increased, and due to the reduced glomerular filtration, the serum K + concentration increased. After administration of MT-1207, the levels of creatinine and urea in 2K2C model rats did not deteriorate. It had a reducing effect on creatinine and uric acid and could maintain the balance of blood potassium.

[0071] In the long-term administration experiment, after the rats in each group were fed with the corresponding drug-containing feed for 9 weeks, their body weights were maintained at the same level. The serum test results showed that compared with the sham operation group, the levels of urea, uric acid and K + in the model group animals changed significantly. The levels of creatinine, urea, uric acid and K + in the losartan potassium treatment group were all higher than those in the sham operation group. Among them, the levels of creatinine, uric acid and K + were significantly increased compared with the model group, and urea also had an increasing trend. These results suggest that losartan potassium aggravated the renal function injury of 2K2C model rats. Compared with the model group, the MT-1207 10mg / kg and 20mg / kg groups had no effect on creatinine and urea, but had a significant effect on reducing the uric acid level and could maintain the balance of blood potassium.

[0072] (2) Hypouricemic effect of MT-1207 on hyperuricemic animal models

[0073] The structure of potassium oxonate is similar to the purine ring of uric acid and can competitively bind to uricase, inhibiting the activity of uricase and reducing the catabolism of uric acid, thus causing a short-term increase in uric acid in the rats. Fructose is rapidly phosphorylated by fructokinase in hepatocytes, leading to the depletion of intracellular ATP and the production of a large amount of AMP. The depletion of ATP can activate purine metabolic enzymes, causing further metabolism of AMP to generate hypoxanthine, which is oxidized to xanthine by xanthine oxidase and finally generates uric acid, increasing the synthesis of uric acid. Potassium oxonate is excreted relatively quickly when administered alone and cannot be used for long-term modeling. The combined administration method is often used. The long-term application of low-dose potassium oxonate is relatively safe. Therefore, low-dose potassium oxonate is often combined with fructose to make up for the defect of unstable increase in blood uric acid when using fructose alone for modeling.

[0074] As Figure 3 shown, after the rats were modeled by intragastric administration of potassium oxonate and drinking 10% fructose water for 1 week, their body weights were significantly lower than those of the normal control group. After 2 weeks, they gradually recovered and approached the normal control level. The renal function levels of the rats in the normal control group given 0.5% CMC-Na solvent were relatively close at 1 week and 2 weeks and remained basically stable during the administration process.

[0075] Compared with the normal control group, the serum uric acid in the model group increased very significantly at 1 week and 2 weeks after modeling, the serum urea decreased significantly, while the serum creatinine increased at 1 week after modeling but showed no obvious change at 2 weeks after modeling. It was also observed that the urine excretion volume of the animals in each modeling group increased sharply. This phenomenon may be related to the sharp decrease in serum urea level within 2 weeks, possibly due to the osmotic diuresis caused by high-concentration fructose, resulting in the excretion of urea together with urine.

[0076] In this hyperuricemia model experiment, losartan had a significant effect on reducing uric acid level at 1 week and 2 weeks after administration. MT-1207 also had an obvious effect on reducing uric acid level.

[0077] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the method of the present invention, several improvements and supplements can be made, and these improvements and supplements should also be regarded as the protection scope of the present invention.

Claims

1. Use of compound MT-1207 in the preparation of a drug for reducing uric acid levels in an individual or preventing elevated uric acid levels, wherein the structure of compound MT-1207 is shown in formula (I), Formula (I).

2. The use according to claim 1, characterized in that: The compound MT-1207 serves as the sole active ingredient.

3. The use according to claim 1, characterized in that: The compound MT-1207 is used as an active ingredient together with other drugs for lowering uric acid.

4. The use according to claim 1, characterized in that: The drug further comprises one or more pharmaceutically acceptable auxiliary ingredients; the pharmaceutically acceptable auxiliary ingredient is an excipient.

5. The use according to claim 1, characterized in that: The drug further comprises one or more pharmaceutically acceptable auxiliary ingredients; the pharmaceutically acceptable auxiliary ingredient is a filler.

6. The use according to claim 1, characterized in that: The drug is prepared into a clinically acceptable drug preparation according to a conventional drug preparation method.

7. The use according to claim 6, characterized in that: The pharmaceutical preparation is a granule, capsule, tablet, suspension, emulsion, solution or injection, and the drug can be applied to an individual in need of treatment by oral administration, intravenous injection, intravenous drip, intramuscular injection or subcutaneous injection in different dosage forms.

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