KR20220091233A - Prodrug of Dapagliflozin, Process of Preparing the Same and Pharmaceutical Composition Comprising the Same - Google Patents

Abstract

The present invention provides a dapagliflozin prodrug, a method for preparing the same, and a pharmaceutical composition comprising the same. Since the dapagliflozin prodrug according to the present invention has excellent stability against heat and moisture, it can be usefully used in the manufacture of pharmaceutical preparations.

Description

Dapagliflozin prodrug, method for preparing same and pharmaceutical composition comprising same {Prodrug of Dapagliflozin, Process of Preparing the Same and Pharmaceutical Composition Comprising the Same}

The present invention relates to a dapagliflozin prodrug, a method for preparing the same, and a pharmaceutical composition comprising the same. More particularly, the present invention relates to a dapagliflozin prodrug having excellent stability against heat and moisture, a method for preparing the same, and a pharmaceutical composition comprising the same.

Diabetes mellitus is a disease that causes complications such as renal dysfunction, cardiovascular disease, cerebrovascular disease, etc. because the blood sugar in the body is not normally controlled and exists at a high concentration higher than the standard value. Diabetes mellitus is divided into type 1 diabetes and type 2 diabetes. Type 2 diabetes is a case in which insulin is secreted but insufficient or the insulin secreted is not used properly. 90% to 95% of all diabetes mellitus occupies

SGLT-2 (sodium glucose cotransporter 2) is a transporter responsible for excessive glucose reabsorption in the kidneys together with SGLT-1 (sodium glucose cotransporter 1), and SGLT-2 plays most roles. Therefore, when an SGLT-2 inhibitor inhibits the SGLT-2 transporter, blood sugar is excreted in the urine, which lowers blood sugar, which in turn causes the excretion of calories, resulting in weight loss.

One of the drugs developed based on this effect is dapagliflozin, which is currently sold worldwide as forxiga or farxiga.

Dapagliflozin of the following formula (2) was first disclosed in International Patent Publication WO 2001/027128.

[Formula 2]

However, dapagliflozin has problems in that it is amorphous, has a low melting point, and cannot maintain a constant quality due to its moisture content.

Accordingly, Korean Patent Laid-Open No. 10-2018-0098173 discloses a novel glucose derivative that has a relatively higher melting point than dapagliflozin, lower hygroscopicity, and excellent storage stability. However, the patent does not disclose a crystalline form of a glucose derivative, and it still lacks stability to heat and moisture, and purification using column chromatography is required during the manufacturing process, so the purification process takes a lot of time and money. there was

International Patent Publication WO 2001/027128 Korean Patent Publication No. 10-2018-0098173

It is an object of the present invention to provide a dapagliflozin prodrug having excellent stability against heat and moisture.

Another object of the present invention is to provide a method for preparing the dapagliflozin prodrug in a simple, one-step reaction without a purification process by column chromatography in high purity and high yield.

Another object of the present invention is to provide a pharmaceutical composition comprising the dapagliflozin prodrug as an active ingredient.

One embodiment of the present invention relates to a compound represented by the following formula (1).

[Formula 1]

In one embodiment of the present invention, the compound represented by Formula 1 may be in a crystalline form.

The crystal form is characterized by a characteristic 2theta (2theta, 2θ) diffraction angle peak in an X-ray powder diffraction spectrum irradiated with a Cu-Kα light source, a relative peak intensity according to each diffraction angle, and a distance between crystal planes.

Specifically, in the compound represented by Formula 1 of the present invention, I/I ₀ (I: intensity of the peak at each diffraction angle, I ₀ : intensity of the largest peak) in X-ray powder diffraction analysis is 10% or more diffraction The angle (2θ) was 3.66±0.2, 9.65±0.2, 10.60±0.2, 11.14±0.2, 13.48±0.2, 14.64±0.2, 18.51±0.2, 18.81±0.2, 19.36±0.2, 19.59±0.2, 20.56±0.2 , 21.32±0.2, 22.20±0.2, 23.22±0.2, 23.90±0.2, 25.58±0.2 and 28.58±0.2 (hereinafter referred to as 'Crystalline Form I').

Compound crystalline Form I represented by Formula 1 of the present invention has weak strength other than the X-ray powder diffraction peak, 7.31±0.2, 15.44±0.2, 19.81±0.2, 22.67±0.2, 24.49±0.2, 25.16±0.2, 25.93± 0.2, 26.68±0.2, 27.00±0.2, 27.54±0.2, 29.26±0.2, 29.48±0.2, 30.70±0.2, 31.20±0.2, 32.11±0.2, 32.91±0.2, 33.70±0.2, 34.00±0.2, 34.63±0.2, 35.17±0.2, 35.56±0.2, 36.94±0.2, 37.96±0.2, 38.49±0.2, 40.55±0.2, 41.54±0.2, 41.91±0.2, 42.80±0.2, 43.87±0.2, 45.15±0.2, 47.19±0.2 and 48.18± It may additionally have an X-ray powder diffraction peak at a diffraction angle (2θ) of 0.2. In this case, "weak intensity" refers to a peak having an I/I ₀ (relative intensity) of less than 10%.

The compound crystalline Form I represented by Formula 1 of the present invention has a high melting point of 105±3° C. and excellent thermal stability.

In addition, the compound crystalline Form I represented by Formula 1 of the present invention may have a purity of 99% or more.

In addition, the compound crystalline Form I represented by Formula 1 of the present invention exhibits an endothermic point of 105.9° C. in differential scanning calorimetry.

Since the compound represented by Formula 1 of the present invention, particularly the compound crystalline Form I of Formula 1, hardly absorbs water and has excellent stability against moisture, generation of related substances due to moisture in preparations containing the same By suppressing the drug, the stability of the formulation can be greatly improved, and the storage of raw materials and the manufacturing process are convenient and safe.

One embodiment of the present invention relates to a method for preparing a compound of Formula 1 below, the method of the present invention comprises:

(i) reacting the compound of Formula 2 with the compound of Formula 3 in the presence of a base.

[Formula 1]

[Formula 2]

[Formula 3]

The preparation method of the present invention may further include purifying the compound of Formula 1 obtained in step (i) by recrystallization.

Hereinafter, the manufacturing method of the present invention will be described in more detail with reference to Scheme 1 below. The method described in Scheme 1 below is merely an example of a method typically used, and the reaction reagents, reaction conditions, etc. may be changed according to the case.

[Scheme 1]

The compound of Formula 1 can be prepared by reacting a compound of Formula 2 with a compound of Formula 3 in the presence of a base.

As the base, sodium carbonate, sodium hydrogen carbonate, triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, or the like may be used, but is not limited thereto. As the lutidine, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, etc. may be used. have. Examples of the collidine include 2,3,4-collidine, 2,3,5-collidine, 2,3,6-collidine, 2,4,5-collidine, 2,4,6-collidine, 3,4,5-collidine and the like can be used.

The base may be used in an amount of 1 to 10 equivalents based on 1 equivalent of the compound of Formula 2.

Examples of the reaction solvent include methyl acetate, ethyl acetate, tert-butylethyl ether, diethyl ether, dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, 1,4-dioxane, dimethylformamide, and dimethylform. Acetamide, dimethyl sulfoxide, etc. may be used, but is not limited thereto.

The reaction may be carried out at a temperature of -40 to 10 ℃ for 0.5 to 24 hours.

The compound of Formula 1 obtained from the above reaction may be purified by recrystallization.

The recrystallization is performed in a polar solvent such as toluene, methyl acetate, ethyl acetate, isopropyl ether, diethyl ether, tert-butyl ethyl ether, dichloromethane and 1,2-dichloroethane and non-polar such as n-heptane, n-hexane and cyclohexane. It may be carried out using a mixed solvent of a solvent, but is not limited thereto.

The recrystallization may be performed at a temperature of 0 to 82 °C.

According to the preparation method of the present invention, it is possible to mass-produce the compound of Formula 1 with high purity and high yield through a simple recrystallization process without a separate column chromatography purification process.

In one embodiment of the present invention, the compound represented by Formula 1 can be hydrolyzed to dapagliflozin in vivo and can be used as a dapagliflozin prodrug.

Accordingly, one embodiment of the present invention relates to a pharmaceutical composition for treating diabetes, particularly type 2 diabetes, comprising the compound represented by Formula 1 together with a pharmaceutically acceptable carrier.

The pharmaceutical composition of the present invention may include another physiologically active material in addition to the compound represented by Formula 1 above.

The pharmaceutical composition according to the present invention may be administered orally, and may be formulated in various forms such as tablets, capsules, granules, powders, emulsions, suspensions, syrups, and the like. The various types of pharmaceutical compositions include excipients, fillers, extenders, binders, disintegrators, lubricants, lubricants, preservatives, antioxidants, isotonic agents, buffers, coating agents, sweeteners, solubilizers, bases ), dispersing agents, wetting agents, suspending agents, stabilizing agents, coloring agents, fragrances, and the like, can be prepared by known techniques using pharmaceutically acceptable carriers commonly used in each formulation.

In the preparation of the drug, the content of the compound represented by Formula 1 of the present invention varies depending on the form of the drug, but is preferably a concentration of 10 to 90% by weight, more preferably a concentration of 30 to 80% by weight.

The dosage of the pharmaceutical composition of the present invention is variously changed in a wide range depending on the type of mammal including the person to be treated, the route of administration, body weight, sex, age, the degree of disease, the judgment of a doctor, and the like. In general, in the case of oral administration, the dosage of the active ingredient may be about 1-240 mg, preferably 5-180 mg, more preferably 10-120 mg per day based on a general adult weighing about 60 kg. The above-mentioned daily dose may be used at one time or in divided doses depending on the severity of the disease, the judgment of the doctor, and the like.

The dapagliflozin prodrug according to the present invention not only has a higher melting point and lower hygroscopicity than dapagliflozin, but also has excellent stability against heat and moisture due to its crystallinity, so that the raw material storage and manufacturing process are convenient. and it's safe

In addition, according to the preparation method of the present invention, the compound of Formula 1 can be mass-produced with high purity and high yield through a simple recrystallization process without a separate column chromatography purification process.

1 is an X-ray powder diffraction diagram of the compound crystalline Form I represented by Formula 1;
2 is a differential scanning calorimetry diagram of the compound crystalline Form I represented by Formula 1;

Hereinafter, the present invention will be described in more detail by way of Examples. These examples are only for illustrating the present invention, and it will be apparent to those skilled in the art that the scope of the present invention is not limited to these examples.

Example 1: Preparation of the compound of formula 1

After filling the reaction part with nitrogen gas, 150 g of dapagliflozin and 1.5 kg of dichloromethane were added, followed by stirring. After cooling the reaction part to -20 °C, 79 g of pyridine was added and acetyl chloride was added. After stirring for 30 minutes, 1.5 kg of purified water was added for extraction. 1 It was washed with 1 kg of aqueous hydrochloric acid solution and then washed with 1 kg of aqueous sodium hydrogen carbonate solution. 45 g of magnesium sulfate was added to remove moisture, followed by filtration. After concentration under reduced pressure, it was dissolved in 450 g of tert-butylethyl ether and then added to 4.5 kg of n-heptane to obtain the compound of Formula 1 (yield 81%). The purity of the obtained compound of Formula 1 was measured by high performance liquid chromatography (HPLC), and the water content was measured with a Karl-Fisher moisture meter. In addition, the melting point of the obtained compound of Formula 1 was measured. The results are shown below.

HPLC purity: 99.46%

Moisture (Karl Fisher Method): 0.4%

Melting Point: 105±3℃

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.31 (d, 1H), 7.15 (s, 1H), 7.14 (d, 1H), 7.04 (d, 2H), 6.76 (d, 2H), 4.33-4.24 ( m, 2H), 4.03 (d, 1H), 4.00 (s, 1H), 3.95 (d, 1H), 3.92 (d, 1H), 3.91 (d, 1H), 3.91 (d, 1H), 3.8 (br -s, 3H), 3.52 (t, 1H), 3.46-3.42 (m, 1H), 3.36 (q. 2H), 2.01 (s, 3H), 1.34 (t. 3H)

¹³ C NMR (100 MHz, CDCl ₃ ): δ 172.08, 157.38, 139.11, 136.89, 134.18, 131.09, 130.22, 129.79, 129.66, 126.29, 114.43, 81.01, 77.80, 77.60, 74.76, 63.33, 63.76, 70.33, 63.76 , 20.88, 14.83

Example 2: Preparation of the compound of formula 1

After filling the reaction part with nitrogen gas, 150 g of dapagliflozin and 1.5 kg of ethyl acetate were added, followed by stirring. After cooling the reaction part to -15 °C, 85 g of triethylamine was added, and acetyl chloride was added. After stirring for 2 hours, 1.5 kg of purified water was added for extraction. 1 It was washed with 1 kg of aqueous hydrochloric acid solution and then washed with 1 kg of aqueous sodium hydrogen carbonate solution. 45 g of magnesium sulfate was added to remove moisture, followed by filtration. After concentration under reduced pressure, it was dissolved in 450 g of diethyl ether and then added to 4.5 kg of n-hexane to obtain the compound of Formula 1 (yield 79%). The purity of the obtained compound of Formula 1 was measured by high performance liquid chromatography (HPLC), and the water content was measured with a Karl-Fisher moisture meter. In addition, the melting point of the obtained compound of Formula 1 was measured. The results are shown below.

HPLC purity: 99.55%

Moisture (Karl Fisher Method): 0.3%

Melting Point: 105±3℃

Example 3: Preparation of compound of formula 1

After filling the reaction part with nitrogen gas, 150 g of dapagliflozin and 1.5 kg of tetrahydrofuran were added, followed by stirring. After the reaction part was cooled to -10°C, 90 g of diisopropylethylamine was added and acetyl chloride was added. After stirring for 1 hour, 1.5 kg of purified water was added for extraction. 1 It was washed with 1 kg of aqueous hydrochloric acid solution and then washed with 1 kg of aqueous sodium hydrogen carbonate solution. 45 g of magnesium sulfate was added to remove moisture, followed by filtration. After concentration under reduced pressure, it was dissolved in 450 g of toluene and then added to 4.5 kg of cyclohexane to obtain a compound of Formula 1 (yield 75%). The purity of the obtained compound of Formula 1 was measured by high performance liquid chromatography (HPLC), and the water content was measured with a Karl-Fisher moisture meter. In addition, the melting point of the obtained compound of Formula 1 was measured. The results are shown below.

HPLC purity: 99.36%

Moisture (Karl Fisher Method): 0.4%

Melting Point: 105±3℃

Example 4: Preparation of the compound of formula 1

After filling the reaction part with nitrogen gas, 150 g of dapagliflozin and 1.5 kg of dimethylformamide were added, followed by stirring. After cooling the reaction part to 0 °C, 85 g of sodium carbonate was added, and acetyl chloride was added thereto. After stirring for 1 hour, 1.5 kg of purified water was added for extraction. 1 It was washed with 1 kg of aqueous hydrochloric acid solution and then washed with 1 kg of aqueous sodium hydrogen carbonate solution. 45 g of magnesium sulfate was added to remove moisture, followed by filtration. After concentration under reduced pressure, it was dissolved in 450 g of dichloromethane and then added to 4.5 kg of cyclohexane to obtain a compound of Formula 1 (yield 78%). The purity of the obtained compound of Formula 1 was measured by high performance liquid chromatography (HPLC), and the water content was measured with a Karl-Fisher moisture meter. In addition, the melting point of the obtained compound of Formula 1 was measured. The results are shown below.

HPLC purity: 99.52%

Moisture (Karl Fisher Method): 0.5%

Melting Point: 105±3℃

Experimental Example 1: XRD analysis

X-ray powder diffraction analysis (XRD) of the compound of Formula 1 prepared in Example 1 was performed, and the results are shown in FIG. 1 .

X-ray powder diffraction analysis (XRD) obtained a diffraction pattern in the range of 3 to 40 °2θ using a powder X-ray diffractometer. X-ray powder diffraction analysis conditions were as follows.

- Instrument: Malvern Panalytical AERIES 600

- Time per step: 39.58 s

- Scanning method: Continuously scanning

- Detector: PIXcel1D

From FIG. 1, it was confirmed that the compound of Formula 1 prepared in Example 1 had a crystalline form. Characteristic peaks shown in the XRD of FIG. 1 are shown in Table 1 below, where '2θ' denotes a diffraction angle, and 'I/I ₀ ' denotes the relative intensity of the peak.

2θ I/I ₀ (%) 2θ I/I ₀ (%) 3.66 70.54 27.54 2.39 7.31 8.71 28.58 20.19 9.65 16.67 29.26 8.65 10.60 100.00 29.48 8.56 11.14 40.94 30.70 5.08 13.48 32.33 31.20 4.53 14.64 74.62 32.11 9.04 15.44 3.16 32.91 2.82 18.51 83.42 33.70 3.57 18.81 35.04 34.00 1.46 19.36 16.86 34.63 1.46 19.59 26.66 35.17 1.17 19.81 7.14 35.56 1.16 20.56 33.67 36.94 2.79 21.32 11.42 37.96 3.26 22.20 20.11 38.49 6.96 22.67 4.36 40.55 2.66 23.22 32.88 41.54 3.95 23.90 12.73 41.91 2.70 24.49 6.46 42.80 6.24 25.16 4.10 43.87 4.42 25.58 25.37 45.15 2.56 25.93 7.58 47.19 1.97 26.68 5.00 48.18 1.39 27.00 2.26

Experimental Example 2: Differential Scanning Calorimetry (DSC)

Differential scanning calorimetry (DSC) was performed on the compound of Formula 1 prepared in Example 1.

Differential scanning calorimetry was performed using a differential scanning calorimeter manufactured by Mettler Toledo at a heating rate of about 10°C/min in the range of -10°C to 200°C with a sample weight of about 3 mg. The oven was constantly purged with nitrogen gas at a flow rate of 50 mL/min. The results of differential scanning calorimetry are shown in FIG. 2 .

The differential scanning calorimetry analysis result of FIG. 2 showed a characteristic having one endothermic peak at 105.9°C.

Experimental Example 3: Hygroscopicity test

While leaving the compound of Formula 1 prepared in Examples 1 to 4 at a temperature of 25±2° C. and a relative humidity of 60±5%, the moisture content was measured over time with a Karl-Fisher moisture meter. . The results are shown in Table 2 below.

division Moisture content (%) before neglect 1 hours 3 hours 5 hours 10 hours Dapagliflozin 2.12 2.78 3.64 4.12 4.56 Example 1 0.42 0.43 0.46 0.48 0.48 Example 2 0.51 0.52 0.56 0.56 0.57 Example 3 0.54 0.54 0.54 0.56 0.58 Example 4 0.44 0.45 0.46 0.47 0.47

From Table 2, it can be seen that the compound of Formula 1 prepared in Examples 1 to 4 maintains the moisture content within 1% at a temperature of 25±2° C. and a relative humidity of 60±5% and hardly absorbs moisture. have. From this, since the compound of Formula 1 according to the present invention has excellent stability against moisture, it is possible to greatly improve the stability of the preparation by suppressing the generation of related substances due to moisture in the preparation containing it, as well as the raw material It can be seen that the storage and manufacturing process are convenient and safe.

Claims (12)

A compound represented by the following formula (1):
[Formula 1]

A compound according to claim 1 in crystalline form. The value of the diffraction angle (2θ) of claim 2, wherein I/I ₀ (I: intensity of the peak at each diffraction angle, I ₀ : intensity of the largest peak) in X-ray powder diffraction analysis is 10% or more 3.66±0.2, 9.65±0.2, 10.60±0.2, 11.14±0.2, 13.48±0.2, 14.64±0.2, 18.51±0.2, 18.81±0.2, 19.36±0.2, 19.59±0.2, 20.56±0.2, 21.32±0.2, 22.20± 0.2, 23.22±0.2, 23.90±0.2, 25.58±0.2 and 28.58±0.2. The compound according to claim 2, wherein, in differential scanning calorimetry, the endothermic point exhibits a value of 105.9°C. The compound according to claim 1, wherein the melting point is 105±3°C. The compound according to claim 1 having a purity of at least 99%. (i) A method for preparing a compound of Formula 1, comprising reacting a compound of Formula 2 with a compound of Formula 3 in the presence of a base:
[Formula 2]

[Formula 3]

[Formula 1]

The method according to claim 7, wherein the base in step (i) is one selected from the group consisting of sodium carbonate, sodium hydrogen carbonate, triethylamine, diisopropylethylamine, pyridine, lutidine and collidine. The above manufacturing method. 8. The method of claim 7, wherein the reaction solvent in step (i) is methyl acetate, ethyl acetate, tert-butylethyl ether, diethyl ether, dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, 1,4 - A method for producing at least one selected from the group consisting of dioxane, dimethylformamide, dimethylformacetamide and dimethylsulfoxide. The method according to claim 7, further comprising purifying the compound of Formula 1 obtained in step (i) by recrystallization. 11. The method of claim 10, wherein the recrystallization is toluene, methyl acetate, ethyl acetate, isopropyl ether, diethyl ether, tert-butyl ethyl ether, dichloromethane and one or more polar solvents selected from the group consisting of 1,2-dichloroethane and A manufacturing method performed using a mixed solvent of one or more non-polar solvents selected from the group consisting of n-heptane, n-hexane and cyclohexane. A pharmaceutical composition for the treatment of diabetes comprising a compound according to any one of claims 1 to 6 together with a pharmaceutically acceptable carrier.

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