KR20200120177A - Novel Salt of 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine, method of preparing the same and pharmaceutical composition comprising the same - Google Patents

Abstract

The present invention relates to a 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine orotic acid salt, a manufacturing method thereof, and a pharmaceutical composition containing the same. A vonoprazan orotic acid salt of the present invention has remarkably excellent stability, hygroscopicity, and solubility, so as to be formulated stably, and has an advantage of long-term storage, thereby being able to be usefully used as an active component of the pharmaceutical composition for treating or inhibiting recurrence of gastric ulcers associated with inhibition of gastric acid secretion, duodenal ulcers, reflux esophagitis, and for sterilization aid of Helicobacter pylori.

Description

New salt of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine, preparation method thereof, and drugs containing same Chemical composition {Novel Salt of 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine, method of preparing the same and pharmaceutical composition comprising the same}

The present invention is an orotate salt of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1 H -pyrrol-3-yl] -N -methylmethanamine, and a method for preparing the same And it relates to a pharmaceutical composition comprising the same.

Potassium Competitive Acid Blockers (P-CAB) series anti-ulcer drugs are competitively bound to the K ⁺ binding site of the proton pump located in the final stage of acid secretion in gastric parietal cells, thereby exchanging protons (H ⁺ ). Inhibit gastric acid secretion

Potassium competitive gastric secretion inhibitor (P-CAB) is a next-generation drug that compensates for the shortcomings of Proton Pump Inhibitor (PPI) drugs, such as omeprazole, esomeprazole, and ilaprazole, which are widely prescribed in the gastric acid secretion inhibitor market. to be. PPI-type drugs act only on the active pump, so the expression of the drug is slow, it is not easy to suppress the secretion of gastric acid at night, there is a time limit when taking it due to the effect of food intake, and the gene of CYP2C19, which is mainly metabolized by PPI-type drugs. Due to polymorphism, large differences in drug efficacy among individuals and limitations due to drug interactions related to CYP2C19 enzyme exist as disadvantages. On the other hand, the potassium-competitive gastric secretion inhibitor (P-CAB)-based drug to which Bonofrazan belongs works not only on the active pump but also on the inactive pump, resulting in an immediate response, and has a long half-life, so it has the effect of continuously suppressing gastric acid secretion even at night. There is. Moreover, there is no restriction on the drug intake due to pharmacokinetics, and there is no specific restriction on the time taken. Unlike PPI drugs, because they are metabolized in CYP3A4, there is relatively little difference in drug efficacy between individuals, and concerns about drug interactions related to CYP2C19 enzymes are relatively high. It has the advantage of being less.

Such potassium competitive gastric secretion inhibitors include soraprazan (BY359), revaprazan (YH1885), AZD0865, YH4808, SCH 28080, CS-526 and vonoprazan (TAK-438). This includes.

Among them, the compound name of bonoprazane is 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1 H -pyrrol-3-yl] -N -methylmethanamine, It is a compound having a structure represented by Formula 1a.

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Bonoprazan represented by Formula 1a or a pharmaceutically acceptable salt thereof was first disclosed in International Publication No. WO 2007/026916, and is known to exhibit acid secretion inhibitory activity. However, the free base of bonofrazan is an oil compound at room temperature, which is not suitable for development as a drug, and has a disadvantage that it is not easy to handle industrially, so the present bonofrazan fumarate is a brand name of Takecab. Is being marketed in Japan.

In addition, various salts of bonofrazan have been reported in Chinese Patent No. CN 103951652, Chinese Patent Application No. CN 105693693, CN 107759568, and CN 108689991.

International Publication Patent Publication WO 2007/026916 Chinese Patent Publication No. CN 103951652 Chinese Patent Application Publication No. CN 105693693 Chinese Patent Publication No. CN 107759568 Chinese Patent Publication No. CN 108689991

Accordingly, the present inventors studied pharmaceutically acceptable salts of bonoprazan, which are excellent in solubility, stability, non-hygroscopicity, and processability into formulations, and as a result, bonoprazane orotate was equivalent to the physicochemical properties of bonofrazan fumarate. While having the above advantages, it was confirmed that the generation of related substances can be minimized and the solubility can be maximized during long-term storage, thereby completing the present invention.

The present invention has excellent physicochemical stability and non-hygroscopicity, which facilitates product handling and storage, enables mass production, and has excellent solubility to provide a pharmaceutical product with improved bioavailability. It is a specific challenge to provide a manufacturing method and a pharmaceutical composition comprising the same.

In order to solve the above problems, the present invention discloses the following means.

In one aspect, the present invention discloses a bonoprazan orotate salt represented by the following formula (1).

The orotate has 2θ values of 11.83±0.2°, 14.34±0.2°, 16.17±0.2°, 19.47±0.2°, 22.68±0.2°, 24.54±0.2°, and 26.54±0.2° of X-rays including peaks. It has an X-ray powder diffraction pattern.

In another embodiment, (a) the bonoprazan free base represented by the following [Chemical Formula 1a] is mixed with an organic solvent or a mixed solvent of an organic solvent and water, and orotic acid represented by the following [Chemical Formula 1b] is added to the reaction solution Manufacturing a;

(b) heating the reaction solution of step (a) and stirring under reflux;

(c) cooling and stirring the reaction solution of step (b); And

(d) It discloses a method for producing the bonoprazan orotate, which includes filtering and drying the product of step (c).

The organic solvent of step (a) may be one or a combination of two or more selected from the group consisting of methyl alcohol, ethyl alcohol, isopropyl alcohol, and acetone.

The orotic acid of step (a) may be added in a molar ratio of 1.0 to 1.1 equivalents based on 1 equivalent of bonoprazane free base.

In another embodiment, disclosed is a pharmaceutical composition for the treatment of gastric ulcer, duodenal ulcer, reflux esophagitis or recurrence inhibition and sterilization aid of Helicobacter pylori comprising the bonofrazan orotic acid.

The bonoprazan orotate according to the present invention can minimize the generation of related substances according to changes over time, and thus the amount of impurities generated during storage of a pharmaceutical product including the same can be greatly reduced, thereby increasing the stability of the formulation. In addition, the bonoprazan orotate salt of the present invention has excellent physicochemical properties by greatly improving stability, hygroscopicity and solubility according to pH, so that gastric ulcers, duodenal ulcers, reflux esophagitis are treated or recurrence suppressed It can be usefully used as an active ingredient in a new pharmaceutical composition for aiding sterilization.

1 shows a powder X-ray diffraction spectroscopy (Powder X-ray Diffraction pattern) of the bonoprazan orotate prepared in Example 1 of the present invention.
FIG. 2 shows a differential scanning calorimeter of bonoprazan orotate prepared in Example 1 of the present invention.
3 shows the color change of the bonofrazan orotate salt prepared in Example 1 and the bonofrazan salts obtained in Comparative Examples 1 to 5 after exposure to a light source.
Figure 4 is a schematic view showing the difference in solubility of the bonoprazan orotate prepared in Example 1 of the present invention and the bonoprazan fumarate obtained in Comparative Example 1.
5 is an X-ray powder diffraction spectroscopy (Powder X-ray Diffraction pattern) analysis result according to an accelerated test (40° C., 75% relative humidity) of the bonoprazan orotate prepared in Example 1 of the present invention. Is shown.
6 is a diagram illustrating a process of producing bonofrazan fumarate or a pathway for the generation of related substances that may occur under severe conditions.

The present invention provides a bonoprazan orotate, a method for preparing the same, and a pharmaceutical composition comprising the same.

In the following, we look at this in more detail.

Bonofrazan Orotate

The present invention is represented by the following formula (1) 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1 H -pyrrol-3-yl] -N -methylmethanamine (bono Prazan) orotate.

In the present invention, it is preferable that the bonoprazan orotate is in a crystalline form.

In X-ray powder diffraction pattern analysis, the 2θ diffraction angles were 11.83±0.2°, 14.34±0.2°, 19.47±0.2°, 22.68±0.2°, and 24.54 for the crystalline form of the bonofrazan orotate. It has a diffraction pattern of ±0.2°, preferably 11.83±0.2°, 14.34±0.2°, 16.17±0.2°, 19.47±0.2°, 22.68±0.2°, 24.54±0.2° and 26.54±0.2°, more preferably Has diffraction patterns of 11.24±0.2°, 11.83±0.2°, 14.34±0.2°, 16.17±0.2°, 19.47±0.2°, 20.96±0.2°, 22.68±0.2°, 24.54±0.2° and 26.54±0.2° .

In addition, as shown in FIG. 2, the bonoprazane orotate of the present invention exhibits an endothermic peak at 234.8°C when the temperature rise rate is 10°C/min in the differential scanning calorimetry (DSC) analysis using DSC Q20 of TA.

Bonofrazan Orotate Manufacturing method

The present invention provides a method for producing bonoprazan orotate. Specifically, it provides a method for producing a bonoprazan orotate, comprising crystallizing by reacting a bonoprazan free base represented by the following [Chemical Formula 1a] with an orotic acid represented by the following [Chemical Formula 1b] in a reaction solvent do. The bonofrazan orotate salt of the present invention is present as a salt material formed by ion bonding of the free base of bonofrazan of the following [Chemical Formula 1a] and the orotic acid of the following [Chemical Formula 1b] at 1:1.

In one embodiment, the manufacturing method of the present invention

(a) preparing a reaction solution by mixing the bonoprazan free base represented by [Chemical Formula 1a] with an organic solvent or a mixed solvent of an organic solvent and water, and adding orotic acid represented by [Chemical Formula 1b] thereto ;

(b) heating the reaction solution of step (a) and stirring under reflux;

(c) cooling and stirring the reaction solution of step (b); And

(d) filtering and drying the product of step (c).

In the production method of the present invention, the used bonoprazan free base may be directly prepared or purchased by a known method.

In the manufacturing method of the present invention, the reaction solvent in step (a) may be an organic solvent or a mixed solvent of an organic solvent and water. As an organic solvent, methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, t-butyl alcohol, ethyl acetate, acetonitrile, acetone, methyl tert-butyl ether, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, It may be one or a combination of two or more selected from the group consisting of dimethyl sulfoxide, dimethylformamide, and dimethylacetamide. Preferably, the organic solvent may be one or a combination of two or more from an organic solvent composed of methyl alcohol, ethyl alcohol, isopropyl alcohol and acetone.

The amount of the solvent used in the reaction for producing the bonoprazan orotate is 1 to 30 times by volume, and preferably 4 to 20 times by volume, based on 1 weight of the bonofrazan free base.

In the production method of the present invention, orotic acid may be used in an amount of 1.0 to 1.5 equivalents, and preferably 1.0 to 1.1 equivalents, based on 1 equivalent of bonofrazan free base.

In the manufacturing method of the present invention, the temperature heated in step (b) may be performed at 40° C. to the reflux temperature of the reaction solvent. It is preferably carried out at a temperature of 65 ℃ to 75 ℃.

Hereinafter, the present invention will be described in detail by examples. However, the following examples are only illustrative of the present invention, and the contents of the present invention are not limited to the following examples.

Example

Example 1: 1 -[5-(2- Fluorophenyl )-1-(pyridin-3- Ilsulfonyl )-One H -Pyrrol-3-yl]- N -Methylmethanamine ( Bonofrazan )of Orotate Produce

2.5 g of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1 H -pyrrol-3-yl] -N -methylmethanamine (bonoprazan) 20.0 mL After adding methyl alcohol, 1.1 g of orotic acid was added. After stirring at reflux for 30 minutes, the mixture was cooled to room temperature and stirred for 12 hours. The obtained solid was filtered, washed with methyl alcohol, and dried to obtain 3.23 g of bonoprazane orotate. (Yield 89.7%, purity 99.96%)

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.88~8.90(dd, 1H), 8.56~8.57(d, 1H), 7.86~7.89(m, 1H), 7.81~7.82(m, 1H), 7.60~7.64(m, 1H), 7.50~7.56(m, 1H), 7.20~7.25(m, 2H), 7.06~7.10(m, 1H), 6.52~6.52(d, 1H), 5.75(s, 1H) ), 4.02(s, 2H), 2.55(s, 3H)

Example 2: 1 -[5-(2- Fluorophenyl )-1-(pyridin-3- Ilsulfonyl )-One H -Pyrrol-3-yl]- N -Methylmethanamine ( Bonofrazan )of Orotate Produce

2.5 g of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1 H -pyrrol-3-yl] -N -methylmethanamine (bonoprazan) in 12.5 mL Of acetone was added, followed by addition of 1.1 g of orotic acid. After stirring at reflux for 30 minutes, the mixture was cooled to room temperature and stirred for 12 hours. The obtained solid was filtered, washed with acetone, and then dried to obtain 3.53 g of bonofrazan orotate. (Yield 98.0%, purity 99.85%)

Example 3: 1 -[5-(2- Fluorophenyl )-1-(pyridin-3- Ilsulfonyl )-One H -Pyrrol-3-yl]- N -Methylmethanamine ( Bonofrazan )of Orotate Produce

2.5 g of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1 H -pyrrol-3-yl] -N -methylmethanamine (bonoprazan) in 12.5 mL A mixture of methyl alcohol and 50.0 mL of water was added, and then 1.1 g of orotic acid was added. After stirring at reflux for 30 minutes, the mixture was cooled to room temperature and stirred for 12 hours. The obtained solid was filtered, washed with a mixture of methyl alcohol and water, and dried to obtain 3.13 g of bonoprazan orotate. (Yield 87.0%, purity 99.96%)

Example 4: 1 -[5-(2- Fluorophenyl )-1-(pyridin-3- Ilsulfonyl )-One H -Pyrrol-3-yl]- N -Methylmethanamine ( Bonofrazan )of Orotate Produce

2.5 g of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1 H -pyrrol-3-yl] -N -methylmethanamine (bonoprazan) in 10.0 mL A mixture of ethyl alcohol and 50.0 mL of water was added, followed by addition of 1.1 g of orotic acid. After stirring at reflux for 30 minutes, the mixture was cooled to room temperature and stirred for 12 hours. The obtained solid was filtered, washed with a mixture of ethyl alcohol and water, and then dried to obtain 3.00 g of bonoprazan orotate. (Yield 83.2%, purity 99.84%)

Example 5: 1 -[5-(2- Fluorophenyl )-1-(pyridin-3- Ilsulfonyl )-One H -Pyrrol-3-yl]- N -Methylmethanamine ( Bonofrazan )of Orotate Produce

2.5 g of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1 H -pyrrol-3-yl] -N -methylmethanamine (bonoprazan) in 10.0 mL After adding a mixture of acetone and 50.0 mL of water, 1.1 g of orotic acid was added. After stirring at reflux for 30 minutes, the mixture was cooled to room temperature and stirred for 12 hours. The obtained solid was filtered, washed with a mixture of acetone and water, and dried to obtain 2.76 g of bonoprazan orotate. (Yield 76.8%, purity 99.85%)

Comparative example

Comparative example 1: 1 -[5-(2- Fluorophenyl )-1-(pyridin-3- Ilsulfonyl )-One H -Pyrrol-3-yl]- N -Methylmethanamine ( Bonofrazan )of Fumarate Produce

1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1 H -pyrrol-3-yl] -N -methylmethanamine (bonoprazane) fumarate of Comparative Example 1 Was prepared according to the method described in Example 8 of Korean Patent Registration No. 1115857.

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.87~8.88(dd, 1H), 8.55~8.56(d, 1H), 7.86~7.89(m, 1H), 7.74~7.74(d, 1H), 7.59~7.63(m, 1H), 7.49~7.55(m, 1H), 7.20~7.25(m, 2H), 7.08~7.12(m, 1H), 6.48~6.49(d, 1H), 6.47(s, 2H) ), 3.86(s, 2H), 2.42(s, 3H)

Comparative example 2: 1 -[5-(2- Fluorophenyl )-1-(pyridin-3- Ilsulfonyl )-One H -Pyrrol-3-yl]- N -Methylmethanamine ( Bonofrazan ) Of trans- Cinnamate Produce

2.0 g of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1 H -pyrrol-3-yl] -N -methylmethanamine (bonoprazan) was added in 20 mL of It was dissolved by adding ethyl acetate, and then 0.90 g of trans-cinnamic acid and 20 mL of methyl tert-butyl ether were added. After stirring at reflux for 30 minutes, the mixture was cooled to room temperature and stirred for 12 hours. The obtained solid was filtered, washed with a mixture of ethyl acetate and methyl tert-butyl ether, and dried to obtain 2.49 g of bonofrazan trans-cinnamate. (Yield 87.0%, purity 99.96%)

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.86~8.87(dd, 1H), 8.56~8.57(d, 1H), 7.87~7.90(m, 1H), 7.59~7.62(m, 4H), 7.48~7.53(m, 1H), 7.41~7.45(d, 2H), 7.33~7.40(m, 3H), 7.19~7.25(m, 2H), 7.09~7.3(m, 1H), 6.49~6.53(d , 1H), 6.44~6.44(d, 1H), 3.67(s, 2H), 2.32(s, 3H)

Comparative example 3: 1 -[5-(2- Fluorophenyl )-1-(pyridin-3- Ilsulfonyl )-One H -Pyrrol-3-yl]- N -Methylmethanamine ( Bonofrazan )of Of camsylate Produce

2.0 g of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1 H -pyrrol-3-yl] -N -methylmethanamine (bonoprazan) in 6.0 mL Methyl alcohol and 50.0 mL of ethyl acetate were added, followed by addition of 1.35 g of camsylic acid. After stirring at reflux for 30 minutes, the mixture was cooled to room temperature and stirred for 12 hours. The obtained solid was filtered, washed with ethyl acetate, and dried to obtain 2.80 g of bonofrazan camsylate. (Yield 85.8%, purity 99.96%)

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.89~8.91(dd, 1H), 8.67(s, 1H), 8.57~8.58(d, 1H), 7.87~7.90(m, 1H), 7.82~ 7.82(d, 1H), 7.62~7.65(m, 1H), 7.52~7.57(m, 1H), 7.22~7.26(m, 2H), 7.08~7.12(m, 1H), 6.51~6.51(d, 1H) ), 4.02(s, 2H), 2.86~2.89(d, 1H), 2.63~2.71(m, 1H), 2.56(s, 3H), 2.36~2.40(d, 1H), 2.20~2.26(dt, 1H) ), 1.92~1.94(t, 1H), 1.77~1.87(m, 2H), 1.23~1.32(m, 2H), 1.03(s, 3H), 0.73(s, 3H)

Comparative example 4: 1 -[5-(2- Fluorophenyl )-1-(pyridin-3- Ilsulfonyl )-One H -Pyrrol-3-yl]- N -Methylmethanamine ( Bonofrazan )of Music acid salt Produce

2.0 g of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1 H -pyrrol-3-yl] -N -methylmethanamine (bonoprazan) in 16.0 mL After adding methyl alcohol, 1.19 g of music acid was added. After stirring at reflux for 30 minutes, the mixture was cooled to room temperature and stirred for 12 hours. The obtained solid was filtered, washed with methyl alcohol, and dried to obtain 2.92 g of bonofrazan music acid salt. (Yield 91.7%, purity 99.96%)

¹ H NMR(400MHz, DMSO-d ₆ ): δ8.87~8.89(dd, 1H), 8.55~8.56(d, 1H), 7.90~7.93(m, 1H), 7.77(s, 1H), 7.62~ 7.65(dd, 1H), 7.50~7.55(m, 1H), 7.20~7.25(m, 2H), 7.09~7.13(m, 1H), 6.50~6.51(d, 1H), 4.03(s, 2H), 3.89(s, 2H), 3.68(s, 2H), 2.44(s, 3H)

Comparative example 5: 1 -[5-(2- Fluorophenyl )-1-(pyridin-3- Ilsulfonyl )-One H -Pyrrol-3-yl]- N -Methylmethanamine ( Bonofrazan )of Adipic Produce

2.0 g of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1 H -pyrrol-3-yl] -N -methylmethanamine (bonoprazan) was added to 6 mL. After completely dissolving in methyl alcohol, 0.89 g of adipic acid and 12 ml of methyl tert-butyl ether were added to precipitate crystals. After stirring at room temperature for 12 hours, the obtained solid was filtered, washed with a mixture of methyl alcohol and methyl tert-butyl ether, and then dried to obtain 2.55 g of bonoprazane adipate. (Yield 89.9%, purity 99.78%)

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.86~8.87(dd, 1H), 8.56~8.56(d, 1H), 7.86~7.89(m, 1H), 7.59~7.63(m, 2H), 7.48~7.54(m, 1H), 7.20~7.25(m, 2H), 7.10~7.14(m, 1H), 6.41~6.42(d, 1H), 3.62(s, 2H), 2.28(s, 3H), 2.12~2.16(t, 4H), 1.45~1.49(m, 4H)

Measurement method and condition

The purity of the compound was measured by high performance liquid chromatography (HPLC). In addition, purity was analyzed by referring to the paper published in the Journal of Pharmaceutical and Biomedical Analysis (2018; Vol.

-Analyzer: Waters e2695 alliance / Waters 2489 UV/Vis detector

-Column: Phenomenex Gemini C18 (250 mm × 4.6 mm, 5 μm)

-Mobile phase: A-0.03 M sodium phosphate buffer (pH 6.5) / MeOH / Acetonitrile = 72/25/3

B-0.03 M sodium phosphate buffer (pH 6.5) / Acetonitrile = 30/70

-Sample solvent: 10% Acetonitrile

-Sample concentration: 1 mg/ml

-Sample injection volume: 10 µl

-Flow rate: 1.0 ml/min

-Column temperature: 25 ℃

-Detector: UV detector (detection wavelength: 230 nm)

-Analysis method and time

Time (minutes) Mobile phase A Mobile phase B 0 100 0 10 74 26 24 0 100 26 0 100 35 100 0 40 100 0

The differential scanning calorimeter (DSC) was measured using TA's DSC Q20, and the powder X-ray diffraction spectrum (Powder X-ray DiffractionSpectrum) was measured using Bruker's D8 ADVANCE. ¹ H nuclear magnetic resonance spectrum (NMR) was measured using Bruker's AVANCE II 400 (400MHz). Experimental example

Experimental example One: Light stability exam

Bonofrazan prepared in Example 1 Orotate and the bonofrazan obtained in Comparative Examples 1 to 5 Each sample of the other salts was placed in a transparent glass container and stored for 3 days while being exposed to a light source in a light stability chamber. Three days after exposure to the light source, each sample was analyzed for purity using HPLC, and the results are shown in Table 2 below.

At this time, the light stability meter used CARON Photostability Chamber Model 6545, and the amount of light exposure was under the conditions of 2.4 million lux-hr/m ^{2 of} overall illumination and 400 W·hr/m ² of near UV. Proceeded.

Results of photostability tests on bonofrazan orotate and other salts Test compound Early
(Purity, %) 3 days later
(Purity, %) Related substances increase
(%) Example 1 Orotate 99.96 98.79 1.17 Comparative Example 1 Fumarate 99.96 98.75 1.21 Comparative Example 2 Trans-cinnamate 99.96 95.91 4.05 Comparative Example 3 Camsylate 99.96 96.67 3.29 Comparative Example 4 Music acid salt 99.96 94.76 5.20 Comparative Example 5 Adipate 99.78 97.90 1.88

As can be seen in Table 2, the bonoprazan orotate of Example 1 has superior photostability equal to or higher than the bonoprazan fumarate of Comparative Example 1, and compared with the other salts of Comparative Examples 2 to 5 As a result, it was confirmed that it has 1.6 to 4.4 times excellent photostability. In addition, as a result of comparing the color change after exposure to a light source, as shown in FIG. 3, the bonofrazan fumarate of Comparative Example 1 and the salts of Comparative Examples 2 to 5 were browned, but the bonofrazan o It was confirmed that the rotate salt remained white without color change. Such excellent photostability means that when using the bonofrazan orotic acid of the present invention, it can act very advantageously for handling or storage when commercialized.

Experimental example 2 : Stability test under acid, base and oxidizing conditions

According to the Journal of Pharmaceutical and Biomedical Analysis (2018; Vol. 149: 133-142), the process of preparing bonofrazan fumarate of Comparative Example 1 or the generation route of related substances that may occur under severe conditions is shown in FIG. 6. In addition, it is described in the above paper that bonofrazan fumarate decomposes in base and oxidizing conditions.

Stability of the bonoprazan orotate prepared in Example 1 and the bonoprazan fumarate obtained in Comparative Example 1 under acid, base, and oxidation conditions were evaluated by using HPLC as an increase in the amount of impurities related substances. It is shown in Table 3 below.

At this time, in the experiment under acidic conditions, samples were taken at intervals of 6 hours and 24 hours after stirring at 100° C. at 300 rpm in 1N HCl solution, diluted in an analysis solvent, and analyzed by HPLC.

In addition, in the experiment under basic conditions, 0.1N NaOH solution was added, stirred at 25° C. at 300 rpm, and samples were taken at intervals of 6 and 24 hours, diluted in an analysis solvent, and analyzed by HPLC.

In addition, in the experiment of oxidizing conditions, a 3% hydrogen peroxide solution was added, stirred at 100° C. at 300 rpm, and samples were taken at intervals of 6 and 24 hours, diluted in an analysis solvent, and analyzed by HPLC.

Stability test results in acid, base and oxygen conditions Test compound Increased amount of related substances (%) Acid (1N HCl) Base (0.1 N NaOH) Oxidation (3% H ₂ O ₂ ) 6 hours 24 hours 6 hours 24 hours 6 hours 24 hours Example 1
(Orotate) 0.00 0.02 13.65 45.83 0.98 10.24 Comparative Example 1
(Fumarate) 0.12 0.35 46.32 98.61 14.70 53.66 Compared to Comparative Example 1
Example 1
Amount of related substances 12 times
Great 17.5 times
Great 3.4 times
Great 2.2 times
Great 15.0 times
Great 5.2 times
Great

As can be seen in Table 3, the amount of related substances generated in the bonoprazan orotate of Example 1 was significantly lower than that of the bonoprazan fumarate of Comparative Example 1. Specifically, 12 to 17.5 times in acid conditions, 2.2 to 3.4 times in basic conditions, and 5.2 to 15.0 times in oxidizing conditions are excellent, which means that the bonoprazane orotate of the present invention exhibits excellent stability under severe conditions. .

Experimental example 3 : Solubility test

The solubility of the bonoprazan orotate prepared in Example 1 and the bonoprazan fumarate obtained in Comparative Example 1 were measured. Specifically, bonoprazan orotate and bonoprazan fumarate were added to purified water, pH 1.2 buffer, pH 4.1 buffer, and pH 6.8 buffer, respectively, and stirred at 37±1° C. 300 rpm for 24 hours. After stirring for 24 hours, the solid remaining in each buffer solution was filtered through a filter (0.45 µm, Whatman, USA), diluted in an HPLC sample analysis solution, and analyzed by HPLC. The results are shown in Table 4 below.

Solubility test result of bonoprazan orotate and fumarate (solubility, mg/ml) Test compound pH 1.2 pH 4.1 pH 6.8 Purified water Example 1 (orotate) 67.57 17.33 30.44 16.49 Comparative Example 1 (fumarate) 37.19 9.75 12.12 8.04

As can be seen in Table 4 and FIG. 4, the solubility of the bonoprazan orotate of Example 1 was approximately twice as good as that of the bonoprazan fumarate of Comparative Example 1 under each pH condition. This means that when the bonoprazan orotate of the present invention is developed as a drug, absorption, dissolution and bioavailability can be improved compared to a commercially available product that is a bonoprazan fumarate.

Experimental example 4: hygroscopicity test

The bonoprazan orotate prepared in Example 1 and the bonoprazan fumarate obtained in Comparative Example 1 were each stored for 7 days in a chamber with a relative humidity of 60% and 92% at 25°C for 7 days at 25° C. The mass change of the sample was measured, and the results are shown in Table 5.

Hygroscopic test result of bonoprazane orotate and fumarate (weight increase rate, %) Test compound 60% relative humidity 92% relative humidity Example 1 (orotate) + 0.14 + 0.23 Comparative Example 1 (fumarate) + 0.25 + 0.29

As can be seen in Table 5, the bonoprazan orotate of Example 1 exhibited superior non-hygroscopicity compared to the bonoprazan fumarate of Comparative Example 1. In particular, it can be seen that bonoprazane orotate has a very low hygroscopicity of 0.23% even at a relative humidity of 92%, so that even if the raw material is exposed to moisture in the air, it can be stably stored. This means that the storage stability of the bonoprazan orotate of the present invention is excellent, so that long-term storage is possible, and it can be more easily commercialized.

Experimental example 5 : Accelerated stability test in solid state

Bonofrazan prepared in Example 1 Accelerated test (acceleration condition: 40±2° C., 75±5% relative humidity) was carried out with the orotate salt and the bonofrazan other salts obtained in Comparative Examples 1 to 5. After 1, 4, 8 and 12 weeks, samples were taken and analyzed for purity using HPLC, and the results are shown in Table 6 below.

Acceleration (40±2 ℃, relative humidity 75±5 %) Stability test result (purity %) Test compound Early 1 week 4 weeks 8 weeks 12 weeks Example 1 Orotate 99.96 99.96 99.93 99.95 99.96 Comparative Example 1 Fumarate 99.96 99.96 99.94 99.95 99.96 Comparative Example 2 trans-cinnamate 99.96 99.97 99.96 99.95 99.96 Comparative Example 3 Camsylate 99.96 99.96 99.95 99.92 99.93 Comparative Example 4 Music acid salt 99.96 99.96 99.95 99.95 99.95 Comparative Example 5 Adipate 99.78 99.80 99.77 99.79 99.79

As can be seen in Table 6, it can be seen that the bonofrazan orotate is a very stable material. In addition, XRD was measured to determine whether the crystalline form of the bonoprazan orotate of Example 1 stored for 12 weeks under accelerated conditions (40±2° C., 75±5% relative humidity) showed no change in crystalline form. It was confirmed and shown in FIG. 5. From the results of the accelerated stability and the analysis of the crystal form, it can be seen that the bonofrazan orotate salt of the present invention is a stable solid phase that does not change over time in thermodynamics.

Experimental example 6: Severe stability test in solid state

Bonofrazan prepared in Example 1 Orotate and Bonoprazan obtained in Comparative Examples 1 to 5 Samples of other salts were stored at 60°C and 80°C, respectively. After 1 week, 4 weeks and 8 weeks, samples were taken and analyzed using HPLC, and the results are shown in Tables 7 and 8 below.

Bonoprazan orotate, fumarate and other salts
Severe stability test result at 60 ℃ (purity, %) Test compound Early 1 week 4 weeks 8 weeks Example 1 Orotate 99.96 99.96 99.96 99.96 Comparative Example 1 Fumarate 99.96 99.95 99.95 99.95 Comparative Example 2 trans-cinnamate 99.96 99.96 99.93 99.93 Comparative Example 3 Camsylate 99.96 99.93 99.94 99.94 Comparative Example 4 Music acid salt 99.96 99.96 99.95 99.95 Comparative Example 5 Adipate 99.78 99.78 99.77 99.77

Bonoprazan orotate, fumarate and other salts
Severe stability test result at 80 ℃ (purity, %) Test compound Early 1 week 4 weeks 8 weeks Example 1 Orotate 99.96 99.96 99.96 99.96 Comparative Example 1 Fumarate 99.96 99.92 99.94 99.94 Comparative Example 2 trans-cinnamate 99.96 99.95 99.92 99.89 Comparative Example 3 Camsylate 99.96 99.94 99.94 99.94 Comparative Example 4 Music acid salt 99.96 99.92 99.94 99.91 Comparative Example 5 Adipate 99.78 99.73 99.68 99.64

As can be seen in Tables 7 and 8, it was confirmed that the bonofrazan orotate of the present invention is a very stable material that does not generate related substances and does not change in purity for 8 weeks even when stored under severe conditions of 60 ℃ and 80 ℃. I did. This means that the bonoprazan orotate salt of the present invention is stable in the manufacturing process, easy to handle, and useful for mass production because it has superior thermal stability compared to the bonoprazan salts obtained in Comparative Examples 1 to 5. do.

The bonofrazan orotate according to the present invention can treat gastric ulcer, duodenal ulcer, reflux esophagitis or suppress recurrence and aid in sterilization of Helicobacter pylori, so it can be used as a pharmaceutical in the pharmaceutical industry and medical fields.

Claims (5)

Bonoprazan orotate represented by the following formula (1)
Formula 1

The peak of claim 1, wherein the orotate has a 2θ value of 11.83±0.2°, 14.34±0.2°, 16.17±0.2°, 19.47±0.2°, 22.68±0.2°, 24.54±0.2°, and 26.54±0.2°. Bonoprazane orotate, characterized by an X-ray powder diffraction (XRPD) pattern containing (a) preparing a reaction solution by mixing the bonoprazan free base represented by the following [Formula 1a] with an organic solvent or a mixed solvent of an organic solvent and water, and adding orotic acid represented by the following [Formula 1b] ;

(b) heating the reaction solution of step (a) and stirring under reflux;
(c) cooling and stirring the reaction solution of step (b); And
(d) a method for producing the bonoprazan orotate salt of claim 1, comprising filtering and drying the product of step (c). The method of claim 3, wherein the organic solvent in step (a) is one or a combination of two or more selected from the group consisting of methyl alcohol, ethyl alcohol, isopropyl alcohol, and acetone. Manufacturing method. A pharmaceutical composition for the treatment of gastric ulcer, duodenal ulcer, reflux esophagitis or recurrence inhibition and sterilization aid of Helicobacter pylori containing the bonofrazan orotic acid of claim 1

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