HK1238636B - Sodium salt of uric acid transporter inhibitor and crystalline form thereof - Google Patents

Description

A sodium salt of a uric acid transporter inhibitor and its crystalline form

Technical Field

The present invention relates to sodium 1-((6-bromoquinolin-4-yl)thio)cyclobutylcarboxylate, its type I crystal, and its preparation method and use. The compound of formula (I) prepared according to the method of the present invention can be used to treat gout.

Background Art

In recent years, with improvements in economic living standards, the prevalence of gout has steadily increased, with the age of onset trending younger. It is more common in men and postmenopausal women, with a peak incidence in the 40s and 50s. Clinical manifestations include hyperuricemia, recurrent attacks of acute gouty arthritis, tophi deposits, characteristic chronic arthritis, and joint deformities. It often involves the kidneys, leading to chronic interstitial nephritis and renal urate stones. Hyperuricemia is a prerequisite for the development of gout—defined as a serum uric acid saturation concentration of approximately 420 μmol/L (70 mg/L) at 37°C. Hyperuricemia is defined as a concentration above this level. However, only a subset of individuals with hyperuricemia develop clinical gout, and the underlying mechanism is unclear. Only when hyperuricemia develops urate crystal deposition, arthritis, and/or nephropathy, or kidney stones, can it be considered gout. Therefore, hyperuricemia is a key biochemical hallmark of gout and is closely associated with its development. Hyperuricemia is closely related to the occurrence of hypertension, hyperlipidemia, atherosclerosis, obesity, and insulin resistance, and has become a serious metabolic disease that threatens human health.

Uric acid is the end product of purine metabolism in humans. Due to mutations in the uricase gene during human evolution, this enzyme is deficient and cannot be metabolized into soluble allantoin for excretion. Therefore, the serum uric acid concentration in hyperuricemia is too high. The onset of hyperuricemia is due to: (1) increased production of uric acid, which accounts for 15% to 20% of gout. Excessive intake of a high-purine diet, or increased uric acid synthesis from amino acids and nucleotides in the body and nucleic acid catabolism produce excessive uric acid; (2) reduced excretion and increased reabsorption of uric acid are the main mechanisms of hyperuricemia and gout, accounting for approximately 80% to 85%. Approximately 95% of uric acid reabsorption is completed by uric acid transporter 1 (URAT1) located in the epithelial cells of the proximal tubules of the kidney. URAT1 is an integral membrane protein located in the kidney and belongs to the solute carrier protein 22 (SLC22) family. It performs urate-anion exchange and is responsible for regulating urate levels in the blood. Therefore, URAT1 inhibitors can promote uric acid excretion by inhibiting this reabsorption.

There are few anti-gout drugs on the Chinese pharmaceutical market, and no new or better anti-gout drugs have been developed. Allopurinol and benzbromarone remain the mainstays. Febuxostat, approved by the FDA in 2009, is a xanthine oxidase (XO) inhibitor that treats gout by reducing uric acid production. RDEA-594 (Lesinurad), developed by Ardea Biosciences, promotes uric acid excretion by inhibiting the uric acid transporter 1 (URAT1), thereby lowering serum uric acid concentrations. Its efficacy is unaffected by renal function and allopurinol dosage. Within the clinical dosage range, it does not affect the transport of OAT1/OAT3 (Organic Anion Transporter 1/3). It also exhibits higher target specificity and fewer drug interactions than other uricosurics.

However, RDEA-594 was discovered during a clinical trial for the treatment of HIV infection. Its activity against the uric acid transporter URAT1 is relatively low, with an IC50 of approximately 7 μM. Furthermore, high doses are used in clinical practice. Therefore, there is still much room for further exploration of the URAT1 target.

WO2014183555 discloses a class of compounds with higher inhibitory activity against the uric acid transporter URAT1, which can effectively inhibit the reabsorption of uric acid and excrete uric acid from the body, thereby permanently reducing blood uric acid levels and achieving the purpose of treating gout. The compounds include the following:

In order to further improve its solubility in water, we developed the sodium salt of the compound (Formula I), and the solubility in water was increased from almost insoluble to about 0.14 mg/mL. On the other hand, the crystal structure of the active ingredient of the medicine often affects the chemical stability of the drug. Different crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, and sometimes are accompanied by the production of other morphologies of crystals. In general, amorphous drug products do not have a regular crystal structure and often have other defects, such as poor product stability, fine crystallization, difficult filtration, easy agglomeration, poor fluidity, etc. Therefore, it is very necessary to improve the various properties of the above-mentioned products. On the basis of discovering its new development form, we also need to conduct in-depth research to find a new crystal form with high crystal purity and good chemical stability.

Summary of the Invention

The object of the present invention is to provide a compound as shown in formula (I), namely, sodium 1-((6-bromoquinolin-4-yl)thio)cyclobutylcarboxylate, which improves to a certain extent the properties required of the compound disclosed in WO2014183555 when used as a pharmaceutical active ingredient.

The compound represented by formula (I) can be obtained by reacting 1-((6-bromoquinolin-4-yl)thio)cyclobutanecarboxylic acid with sodium hydroxide.

We investigated a series of crystalline products obtained from the compound of formula (I) under different crystallization conditions, performed X-ray diffraction and DSC tests on the obtained crystalline products, and found that under certain specific crystallization conditions, a crystalline form with good stability can be obtained, which we call Type I crystal. The DSC spectrum of type I crystal in the present application shows that there is no absorption within 300°C, indicating that its melting point is greater than 300°C. The X-ray powder diffraction pattern is shown in Figure 1, which uses Cu-Ka radiation and is expressed in 2θ angles and interplanar spacing (d value). There are characteristic peaks near 9.08 (9.73), 11.73 (7.54), 12.19 (7.26), 15.59 (5.68), 16.28 (5.44), 17.73 (5.00), 18.16 (4.88), 18.80 (4.72), 19.48 (4.55), 20.80 (4.27), 23.16 (3.84), 27.54 (3.24) and 30.37 (2.94).

The present invention also provides a method for preparing type I crystals of the compound of formula (I). Specifically, the method comprises the following steps:

(1) dissolving any crystalline or amorphous sodium 1-((6-bromoquinolin-4-yl)thio)cyclobutanecarboxylate solid in an appropriate amount of solvent by heating, and cooling for crystallization;

(2) Filter, wash and dry.

In step (1), the solvent is selected from a mixed solvent of any one of alcohols or ketones having less than or equal to 3 carbon atoms and water; more preferably, water/isopropanol, water/acetone, acetone/water/acetone, or acetone/water/isopropanol.

In one embodiment of the present invention, the preferred mixed solvent is a mixture of acetone/water/acetone. The ratio is not particularly limited. In a preferred embodiment of the present invention, the volume ratio of the three is 1:1:5. When the mixed solvent is acetone/water/acetone, it means that sodium 1-((6-bromoquinolin-4-yl)thio)cyclobutanecarboxylate is first dissolved in the acetone/water mixture, and then a portion of acetone is added for crystallization. Acetone/water/isopropanol also has a similar meaning.

The method of recrystallization is not particularly limited and can be carried out using conventional recrystallization procedures. For example, the raw material compound of formula (I) can be dissolved by heating in an organic solvent, then slowly cooled and stirred to crystallize. After crystallization is complete, the desired crystals can be obtained by filtration and drying. It should be noted that the filtered crystals are usually vacuum dried under reduced pressure at approximately 30 to 100°C, preferably 40 to 60°C, to remove the recrystallization solvent.

The crystal form of the obtained crystals was studied by differential scanning calorimetry (DSC) and X-ray diffraction pattern determination, and the solvent residue in the obtained crystals was detected.

The crystals of the compound of formula (I) prepared according to the method of the present invention contain no or only a low content of residual solvents, which meets the limit requirements for residual solvents in pharmaceutical products stipulated in the National Pharmacopoeia. Therefore, the crystals of the present invention can be preferably used as pharmaceutical active ingredients.

Studies have shown that the type I crystals of the compound of formula (I) prepared by the present invention have good stability under conditions of light, high temperature, and high humidity, and have good crystal stability under conditions of grinding, pressure, and heat, and can meet the pharmaceutical requirements of production, transportation, and storage. The production process is stable, repeatable, and controllable, and can be adapted to industrial production.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is an X-ray powder diffraction pattern of type I crystal of the compound of formula (I).

Figure 2 shows the DSC spectrum of type I crystals of the compound of formula (I).

DETAILED DESCRIPTION

The present invention will be explained in more detail below with reference to the embodiments. The embodiments of the present invention are only used to illustrate the technical solutions of the present invention and are not intended to limit the essence and scope of the present invention.

Test instruments used in the experiment

1.DSC spectrum

Instrument model: Mettler Toledo DSC 1 Stare ^e System

Purge gas: nitrogen

Heating rate: 10.0℃/min

Temperature range: 40-300℃

2. X-ray diffraction spectrum

Instrument model: Bruker D8 Focus X-ray powder diffractometer

Radiation: Monochromatic Cu-Kα radiation (λ=1.5406)

Scanning mode: θ/2θ, scanning range: 2-40°

Voltage: 40KV, Current: 40mA

Example 1

At 25°C, 1.0 g, 2.96 mmol of 1-((6-bromoquinolin-4-yl)thio)cyclobutanecarboxylic acid (prepared according to the method disclosed in WO 2014/183555) was added to a 50 mL three-necked reaction flask, along with 4.0 g of anhydrous ethanol. A solution of sodium hydroxide in water (0.5 mL) (118 mg, 2.96 mmol) was added dropwise with stirring, and the reaction was stirred. The mixture was filtered, the filter cake washed with anhydrous ethanol, and then dried under vacuum at 40°C to yield 850 mg of a white to pale yellow powder (84.0% yield). The X-ray diffraction spectrum of this crystalline sample is shown in Figure 1. The crystals have characteristic peaks at approximately 9.08 (9.73), 11.73 (7.54), 12.19 (7.26), 15.59 (5.68), 16.28 (5.44), 17.73 (5.00), 18.16 (4.88), 18.80 (4.72), 19.48 (4.55), 20.80 (4.27), 23.16 (3.84), 27.54 (3.24), and 30.37 (2.94). The DSC spectrum is shown in Figure 2. No absorption is observed within 300°C, indicating that the melting point is greater than 300°C. This crystal form is defined as Form I.

Example 2

1.0 g, 2.78 mmol) of the compound of formula (I) (prepared according to Example 1) was placed in a 250 ml single-necked flask, 30 ml of water was added, and the solution was heated under reflux to dissolve. The solution was then concentrated under reduced pressure to approximately 3 ml. 150 ml of isopropanol was slowly added, and the solution was stirred to crystallize. The next day, the solution was filtered and dried to obtain 689 mg of a white solid, with a yield of 68.9%. Comparison of the X-ray diffraction pattern and DSC spectrum of the crystalline sample confirmed that the product was Form I.

Example 3

1.0 g, 2.78 mmol) of the compound of formula (I) (prepared according to Example 1) was placed in a 150 ml single-necked flask, 30 ml of water was added, and the mixture was heated under reflux to dissolve the clear solution. The solution was then concentrated under reduced pressure to dryness. 30 ml of isopropanol was added directly, and the mixture was stirred to crystallize. The next day, the mixture was filtered and dried to obtain 812 mg of a white solid, with a yield of 81.2%. Comparison of the X-ray diffraction pattern and DSC spectrum of the crystalline sample confirmed that the product was Form I.

Example 4

1.0 g, 2.78 mmol) of the compound of formula (I) (prepared according to Example 1) was placed in a 150 ml single-necked flask, 30 ml of water was added, and the solution was heated under reflux to dissolve. The solution was then concentrated under reduced pressure to approximately 3 ml. 30 ml of acetone was slowly added, and the mixture was stirred to crystallize. The next day, the solution was filtered and dried to obtain 918 mg of a white solid, with a yield of 91.8%. Comparison of the X-ray diffraction pattern and DSC spectrum of the crystalline sample confirmed that the product was Form I.

Example 5

1.0 g, 2.78 mmol) of the compound of formula (I) (prepared according to Example 1) was placed in a 150 ml single-necked bottle, 24 ml of acetone/water (v/v = 1:1) was added, and the mixture was heated under reflux to dissolve. 60 ml of acetone was then slowly added, and the mixture was refluxed for 10 min. Heating was stopped, and the mixture was stirred to crystallize. The next day, the mixture was filtered and dried to obtain 688 mg of a white solid, with a yield of 68.8%. Comparison of the X-ray diffraction pattern and DSC spectrum of the crystalline sample confirmed that the product was Form I.

Example 6

1.0 g, 2.78 mmol) of the compound of formula (I) (prepared according to Example 1) was placed in a 150 ml single-necked bottle. 24 ml of acetone/water (v/v = 1:1) was added and heated under reflux to dissolve the solution. 60 ml of isopropanol was then slowly added and the solution was refluxed for 10 min. Heating was stopped and the solution was stirred to crystallize. The next day, the solution was filtered and dried to obtain 752 mg of a white solid, with a yield of 75.2%. Comparison of the X-ray diffraction pattern and DSC pattern of the crystalline sample confirmed that the product was Form I.

Example 7

1.0 g, 2.78 mmol) of the compound of formula (I) (prepared according to Example 1) was placed in a 500 ml single-necked flask, 30 ml of water was added, and the mixture was heated under reflux to dissolve. 300 ml of acetone was slowly added, and the mixture was stirred to crystallize. The next day, the mixture was filtered and dried to obtain 728 mg of a white solid, with a yield of 72.8%. Comparison of the X-ray diffraction pattern and DSC spectrum of the crystalline sample confirmed that the product was Form I.

Example 8

Samples of the Form I crystals obtained in Example 1 were laid out open and tested for stability under conditions of illumination (4500 Lux), high temperature (40°C, 60°C), and high humidity (RH 75%, RH 90%). The samples were sampled for 5 and 10 days. The purity determined by HPLC is shown in Table 1.

Table 1. Stability of Type I Crystal Sample of Compound (I)

The results of the stability study showed that the type I crystal sample had good stability under conditions of exposure to light, high temperature and high humidity when placed in the open air.

Example 9

The type I crystal of the compound of formula (I) obtained according to the method of Example 1 was ground, heated and tableted. The research results showed that the crystal form was stable. Detailed experimental data are shown in Table 2 below.

Table 2. Study on the special stability of type I crystals of compound of formula (I)

Example 10

The pharmacokinetic properties of the compound of Example 1 in rats were evaluated using SD rats. LC/MS/MS was used to determine plasma concentrations of the compound at different times following oral and intravenous administration. The pharmacokinetic behavior of the compound in rats was investigated and its pharmacokinetic characteristics were evaluated. The pharmacokinetic parameters of the compound of the present invention are shown in Table 3. The experimental results demonstrate that the compound of the present invention is well absorbed and exhibits significant oral absorption. Calculated based on the average AUC0-t, the absolute bioavailability of the compound in rats following a single oral administration of 3 mg/kg was 74.1%.

Table 3. Pharmacokinetic parameters of the compound after single oral gavage and intravenous injection in rats (n=6, half male and half female)

Example 11

Canine pharmacokinetic testing of the compound of Example 1 of the present invention was performed in Beagle dogs. LC/MS/MS was used to determine plasma concentrations of the compound of Example 1 at different times following oral and intravenous administration. The pharmacokinetic behavior of the compound of the present invention in dogs was investigated and its pharmacokinetic characteristics were evaluated. The pharmacokinetic parameters of the compound of the present invention are shown in Table 4. The results demonstrate that the compound of the present invention is well absorbed and exhibits significant oral absorption. The absolute bioavailability of the compound in dogs after a single oral administration of 3 mg/kg was 59.5%, calculated as the average AUC _0-t .

Table 4. Pharmacokinetic parameters of the compound after single oral gavage and intravenous injection in dogs (n=6, half male and half female)

Claims (7)

1. The type I crystal of sodium 1-((6-bromoquinoline-4-yl)thio)cyclobutylcarboxylate, as shown in formula (I), was subjected to Cu-Ka radiation, and X-ray powder diffraction patterns were obtained, expressed as 2θ angles and interplanar spacings. Characteristic peaks were observed at approximately 9.08, 11.73, 12.19, 15.59, 16.28, 17.73, 18.16, 18.80, 19.48, 20.80, 23.16, 27.54, and 30.37. 2. The type I crystal of sodium 1-((6-bromoquinoline-4-yl)thio)cyclobutylcarbamate as shown in formula (I) according to claim 1, characterized in that an X-ray powder diffraction pattern in terms of 2θ angle and interplanar spacing is obtained by using Cu-Ka radiation, wherein the crystal has the X-ray powder diffraction pattern shown in Figure 1. 3. A method for preparing type I crystals according to claim 1 or 2, the method comprising the following steps: 1) Dissolve sodium 1-((6-bromoquinoline-4-yl)thio)cyclobutylcarboxylate solid of any crystal form or amorphous form in an appropriate amount of solvent by heating, cool and crystallize, wherein the solvent is selected from any one of alcohols or ketones with 3 or fewer carbon atoms and water as a mixed solvent. 2) Filter the crystals, wash, and dry. 4. The method according to claim 3, wherein the solvent in step 1) is selected from water/isopropanol, water/acetone, acetone/water/acetone, acetone/water/isopropanol. 5. A pharmaceutical composition comprising type I crystals of sodium 1-((6-bromoquinoline-4-yl)thio)cyclobutylcarboxylate as shown in formula (I) according to claim 1 or 2, and a pharmaceutically acceptable carrier. 6. Use of the type I crystal of sodium 1-((6-bromoquinoline-4-yl)thio)cyclobutylcarboxylate as shown in formula (I) according to claim 1 or 2, or the pharmaceutical composition according to claim 5, in the preparation of a medicament for treating diseases related to uric acid transporter 1 (URAT1). 7. The use according to claim 6, wherein the disease is gout.