KR102398639B1 - Salts of amide derivatives and method for preparing the same - Google Patents

Abstract

지방족 또는 방향족의 다이설포네이트 또는 락탐 구조로 환형화된 아미노산(cyclised amino acid)염이 개시된다. 상기 아미드 유도체의 염은 수분을 흡습하지 않아 안정하면서도 물에 대한 용해도가 우수하다. In the present specification, as a salt of an amide derivative of Formula 1,
[Formula 1]

Disclosed are salts of cyclized amino acids with aliphatic or aromatic disulfonate or lactam structures. The salt of the amide derivative is stable because it does not absorb moisture and has excellent solubility in water.

Description

Salts of amide derivatives and a method for preparing the same

Disclosed herein are a salt of a novel amide derivative having excellent solubility and a method for preparing the same. More specifically, a salt of a novel amide derivative having excellent stability while not absorbing moisture while having excellent solubility, and a method for preparing the same are disclosed.

A specific amide derivative to which Mirabegron belongs was developed by Astellas Seiyaku. According to WO99/20607 and domestic patent 10-0506568, this compound has both an insulin secretion promoting action and an insulin sensitivity enhancing action, and also has an anti-obesity action and an anti-hyperlipidemic action based on a selective β3 receptor stimulator, and is useful for the treatment of diabetes. was reported to be a compound.

Mirabegron, a representative compound of the amide derivative, is (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl ]-acetanilide ((R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide), 2-amino-N -[4-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]phenyl]-4-thiazoleacetamide (2-amino-N-[4-[2-[ [(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]phenyl]-4-thiazoleacetamide), or 2-(2-amino-1,3-thiazol-4-yl)-N-[4- (2-{ [(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide (2-(2-amino-1,3-thiazol-4-yl)-N-[4 -(2-{ [(2R)- 2-hydroxy-2-phenylethyl] amino} ethyl )phenyl]acetamide).

In addition, the amide derivative can be used as a therapeutic agent for overactive bladder in WO 2004/041276. For example, it has been reported that it is useful as a therapeutic agent for overactive bladder accompanying a feeling of urgency, urinary incontinence, or frequent urination, in addition to overactive bladder accompanying enlarged prostate. Currently, it is sold under the trade name Betmiga as a treatment for dysuria.

As for the polymorphic form of Mirabegron, the anhydrous crystalline form α or β was disclosed in WO 2003/037881. Currently used as raw material is α-type. This α-form is a stable crystalline form, and hydrochloride reported in WO 2003/037881 is deliquescent due to moisture absorption in the presence of moisture, but it has been reported that α-form does not absorb moisture. And it has been reported as a crystalline form with excellent stability that does not undergo a phase change to another crystalline form.

However, according to the Mirabegron Guidelines (FDA/Draft Guidance on Mirabegron Active Ingredient), Mirabegron α was reported to be BCS class II with poor absorption due to its remarkably low solubility in water of 0.082 mg/ml. Accordingly, EP 2857389 discloses acetate salts as an effort for this, and WO 2016/049749 discloses bromate, tartrate, benzylate, oxalic acid salt, succinate, and the like. However, these patents do not disclose exact solubility or stability.

The criterion for selecting an excellent crystalline form is due to the most important physicochemical properties required for a drug. Select the thermodynamically most stable one, select one that is optimized for pharmaceutical raw materials and finished product manufacturing, improve drug solubility and dissolution rate, or The selection of the optimized crystalline form may vary depending on the purpose, such as to change the pharmacokinetic properties.

Therefore, there has been a demand for a novel salt of Mirabegron that does not absorb moisture and has a high solubility in water.

All of the above-mentioned prior publications are incorporated herein by reference in their entirety and are incorporated herein by reference.

WO 99/20607 KR 10-0506568 WO 2004/041276 WO 2003/037881 EP 2857389 WO 2016/049749

In one aspect, an object of the present invention is to provide a salt of a specific group of amide derivatives including mirabegron.

In one aspect, an object of the present invention is to provide a salt of an amide derivative having excellent solubility.

In one aspect, an object of the present invention is to provide a salt of an amide derivative having excellent water solubility.

In one aspect, an object of the present invention is to provide a salt of an amide derivative that is stable because it does not absorb moisture and has excellent solubility in water.

The present inventors have developed a crystalline salt and an amorphous salt as a result of research efforts.

In one aspect, the present invention provides a salt of an amide derivative of Formula 1,

[Formula 1]

(In the above formula,

Ring B is a substituted or unsubstituted heteroaryl group, wherein the substitution is a heteroaryl group substituted with a substituent selected from the following substituent groups or condensed with a benzene ring,

X is a group represented by a bond, hydroxy, lower alkylene, lower alkenylene, carbonyl, -NH-, wherein the lower alkylene or lower alkenylene is a substituted or unsubstituted group, and the substitution is a lower alkyl group substitution, and when X is a lower alkylene group, a hydrogen atom bonded to a carbon atom constituting the B ring and the lower alkyl group are united to form a lower alkylene group to form a ring,

A is a group represented by lower alkylene or -lower alkylene-O-,

R1a and R1b are each independently the same as or different from each other, and are a hydrogen atom or lower alkyl;

R2 is a hydrogen atom or a halogen atom,

Z is a nitrogen atom or a group represented by =CH-,

The substituent group is a halogen atom, lower alkyl, lower alkenyl, lower alkynyl, hydroxy, sulfanyl, halogeno lower alkyl, lower alkyl-O-, lower alkyl-S-, lower alkyl-O-CO-, carboxy , sulfonyl, sulfinyl, lower alkyl-SO-, lower alkyl-SO2-, lower alkyl-CO-, lower alkyl-CO-O-, carbamoyl, lower alkyl-NH-CO-, di-lower alkyl- N-CO-, nitro, cyano, amino, guanidino, lower alkyl-CO-NH-, lower alkyl-SO2-NH-, lower alkyl-NH-, di-lower alkyl-N- and -O-lower A substituent selected from alkylene-O-, and these substituents are aryl group, heteroaryl group, halogen atom, hydroxy, sulfanyl, halogeno lower alkyl, lower alkyl-O-, lower alkyl-S-, lower alkyl -O-CO-, carboxy, sulfonyl, sulfinyl, lower alkyl-SO-, lower alkyl-SO2-, lower alkyl-CO-, lower alkyl-CO-O-, carbamoyl, lower alkyl-NH-CO -, di-lower alkyl-N-CO-, nitro, cyano, amino, guanidino, lower alkyl-CO-NH-, lower alkyl-SO2-NH-, lower alkyl-NH-, di-lower alkyl- may also be substituted with a substituent of N- and the substituents of their aryl group, heteroaryl group may also be substituted with a halogen atom,

wherein R is a hydrogen atom, a halogen atom, a lower alkyl group, an amino group, an aryl lower alkyl group or a haloaryl lower alkyl group);

The salt is an aliphatic or aromatic disulfonate, or a cyclized amino acid salt with a lactam structure.

In one embodiment, the aliphatic disulfonate may be a C _1-6 alkane disulfonate.

In one embodiment, the aromatic disulfonate may be a C _6-22 aromatic disulfonate.

According to the present specification, it is possible to provide a stable salt of an amide derivative exhibiting various pharmacological activities, such as a therapeutic agent for diabetes or a therapeutic agent for overactive bladder. Specifically, it is possible to provide an amide derivative having excellent solubility in water while being stable because it does not absorb moisture. In particular, it is possible to provide a mirabegron that is stable to humidity and has excellent water solubility. It is stable in long-term storage due to low moisture absorption and has excellent solubility, so it can be used as an oral drug.

1 shows a powder X-ray diffraction pattern of a crystalline solid of mirabegron heminafadisylate salt prepared according to an embodiment of the present invention.
Figure 2 shows the melting point peak result by the temperature differential scanning calorimetry (DSC) in a closed pan of the crystalline solid of Mirabegron heminafadisylate salt prepared according to an embodiment of the present invention.
3 is a view showing a hydrogen nuclear magnetic resonance (H-NMR) analysis diagram of mirabegron heminafadisylate salt, nafadisylic acid, and mirabegron free base prepared according to an embodiment of the present invention.
4 shows a powder X-ray diffraction pattern of a crystalline solid of mirabegron hemiedisylate salt prepared according to an embodiment of the present invention.
5 shows the melting point peak result by the temperature differential scanning calorimetry (DSC) in a closed pan of the crystalline solid of Mirabegron hemiedisylate salt prepared according to an embodiment of the present invention.
6 shows a hydrogen nuclear magnetic resonance (H-NMR) analysis diagram of mirabegron hemiedisylate salt, edisylic acid, and mirabegron free base prepared according to an embodiment of the present invention.
7 shows a powder X-ray diffraction pattern of mirabegron pidolate amorphous salt prepared according to an embodiment of the present invention.
8 shows the glass transition temperature results by the temperature differential scanning calorimetry (DSC) in a closed pan of mirabegron pidolate amorphous salt prepared according to an embodiment of the present invention.
9 shows a hydrogen nuclear magnetic resonance (H-NMR) analysis diagram of mirabegron pidolate amorphous salt, L-pyroglutamic acid, and mirabegron free base prepared according to an embodiment of the present invention.
10 shows the solubility results of mirabegron novel salt prepared according to an embodiment of the present invention.

In the definitions used in the formulas herein, the term "lower" means a straight or branched chain hydrocarbon having 1 to 6 carbon atoms, unless otherwise specified.

Examples of "lower alkyl groups" are methyl, ethyl and straight or branched propyl, butyl, pentyl, or hexyl, preferably alkyl groups having 1 to 4 carbon atoms, particularly preferably methyl, ethyl, propyl or isopropyl.

Examples of the "lower alkylene group" include a divalent group obtained by removing one hydrogen atom from the "lower alkyl group", preferably an alkylene group having 1 to 4 carbon atoms, particularly preferably methylene, ethylene, propylene or butylene.

Examples of "heteroaryl groups" include monocyclic heteroaryl groups such as furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidyl, pyri dazinyl, pyrazinyl, thiadiazolyl, triazolyl and tetrazolyl) and bicyclic heteroaryl groups such as naphthylidinyl and pyridopyrimidinyl.

Examples of a "halogen atom" are a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and an example of a "haloaryl lower alkyl group" is that in the above-mentioned aryl lower alkyl group, the hydrogen atom(s) of aryl is a halogen atom(s) ) replaced by wait.

When X is a bond, it means that the carbon atom of the group -CO- is directly bonded to the ring B.

Since the compound of Formula 1, which is an amide derivative of the present specification, has one or more asymmetric carbon atoms, optical isomers, for example, (R)-compound and (S)-compound, racemates, diastereomers, and the like exist. The compound of Formula 1 herein includes both and each of the isolated isomers and mixtures thereof.

Starting materials for preparing the compound of Formula 1 according to the present specification can be easily prepared by methods known in the art or purchased from the market.

In one embodiment, in the amide derivative compound according to the present specification, R in Formula 1 may be an amino group.

In one embodiment, in the amide derivative compound according to the present specification, B of Formula 1 may be thiazolyl.

In one embodiment, the amide derivative compound according to the present specification may be methylene, in which X of Formula 1 is a divalent group obtained by removing one hydrogen atom from a methyl group.

In one embodiment, the amide derivative compound according to the present specification may be methylene, in which A of Formula 1 is a divalent group obtained by removing one hydrogen atom from a methyl group.

In one embodiment, in the amide derivative compound according to the present specification, R1a and R1b of Formula 1 may be hydrogen.

In one embodiment, in the amide derivative compound according to the present specification, R2 of Formula 1 may be hydrogen.

In one embodiment, in the amide derivative compound according to the present specification, z of Formula 1 may be =CH-.

In one embodiment, in the amide derivative compound according to the present specification, R 2 of Formula 1 may be hydrogen.

In one embodiment, the amide derivative compound of Formula 1 may be a compound of Formula 1-1 below:

[Formula 1-1]

Taking the compound of Formula 1-1 as an example, the method for preparing the amide derivative of the present specification is described in Scheme 1 below.

[Scheme 1]

As shown in Scheme 1, a) an aromatic amine derivative in which an alkyl amine of Formula 2 (eg, Formula 2-1) is substituted with a carboxyl protecting group and a phthalimide of Formula 3 (eg, Formula 3-1) is substituted preparing a compound of Formula 5 (eg, Formula 5-1) by reacting a thiazole derivative; and b) the intermediate obtained in step a) is decarboxylated to obtain a compound of Formula 6 (eg, Formula 6-1), which is reacted with a compound of Formula 4 (eg, Formula 4) to react with a compound of Formula 7 (eg, Formula 7) After preparing the compound of -1), a final compound of Formula 1 (eg, Formula 1-1) may be prepared through a dephthalimide protecting group reaction. This novel synthesis method can manufacture Mirabegron in an economical and reasonable manufacturing method compared to the existing manufacturing method including hydrogen reaction.

[Formula 2]

(Wherein, C is a protecting group, and R1a, R1b, and A are defined as in Formula 1 above.)

[Formula 2-1].

[Formula 3]

(Wherein, D is a protecting group, and R, B, and X are defined as in Formula 1 above.)

In one embodiment, the compound of Formula 3 may be 2-(1,3-dioxo-2H-isoindol-2-yl)-4-thiazoleacetic acid of Formula 3-1 below:

[Formula 3-1]

[Formula 4]

(Wherein, R2 and Z are defined as in Formula 1 above.)

In one embodiment, the compound of Formula 4 may be (R)-2-chloro-1-phenylethanol of Formula 4-1:

[Formula 4-1]

[Formula 5]

(Wherein, C and D are protecting groups, and R, B, X, A, R1a, and R1b are defined as in Formula 1 above.)

The C protecting group and the D protecting group may be different from each other.

[Formula 5-1]

[Formula 6]

(Wherein, D is a protecting group, and R, B, X, A, R1a, and R1b are defined as in Formula 1 above.)

[Formula 6-1]

[Formula 7]

In the above formula, D is a protecting group, and R, B, X, A, R1a, R1b, z, and R2 are defined as in Formula 1 above.)

[Formula 7-1]

In one embodiment, the salt of the amide derivative may be in a crystalline form or an amorphous form.

In one embodiment, the aliphatic or aromatic disulfonate may be in a crystalline form. In one embodiment, the aliphatic disulfonate may be a C _1-6 alkane disulfonate. For example, the aliphatic disulfonate may be ethane disulfonate, that is, edisylate. In one embodiment, the aromatic disulfonate may be a C _6-22 aromatic disulfonate. For example, the aromatic disulfonate may be napadisilate.

In one embodiment, the cyclized amino acid salt of the lactam structure may be amorphous. As the amino acid, any amino acid may be used as long as it can be cycled into a lactam structure. For example, it may be L-pyroglutamic acid. For example, the cyclized amino acid salt may be pidolate. For example, the salt of the amide derivative may be mirabegron pidolate.

In one embodiment, the salt of the amide derivative may be a salt produced by ionic bonding of mirabegron free base and naphadisylic acid in a 2:1 ratio. In one embodiment, the salt of the amide derivative may be mirabegron heminafadisylate of Formula 8 below. That is, (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]anilidenapadisylic acid acetate. :

[Formula 8]

In one embodiment, the salt of the amide derivative may be a salt produced by ionic bonding of mirabegron free base and edisylic acid in a 2:1 ratio. In one embodiment, the salt of the amide derivative may be mirabegron hemiedisylate of Formula 9 below. That is, it may be (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetic acid anilideedisylic acid.

[Formula 9]

In one embodiment, the salt of the amide derivative may be an amorphous salt produced by ionic bonding between mirabegron free base and L-pyroglutamic acid in a 1:1 ratio. In one embodiment, the salt of the derivative may be mirabegron pidolate represented by the following formula (10). That is, it may be (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]anilidepyroglutamic acid acetate.

[Formula 10]

In one embodiment, the mirabegron heminafadisylate may be a salt of a crystalline amide derivative having one or more of the following characteristics:

(i) Powder X-ray diffraction pattern with characteristic peaks at 2θ diffraction angles of 6.14±0.2, 11.457±0.2, 16.45±0.2, 17.764±0.2, 26.018±0.2 and 27.132±0.2 in powder X-ray diffraction (PXRD) analysis ; and

(ii) Endothermic peaks of endothermic onset temperature 201.34°C±3°C and endothermic temperature 204.33°C±3°C in differential scanning calorimetry (DSC) analysis.

The intensity and peak position of powder X-ray diffraction of the crystalline form of Mirabegron heminafadisylate according to an embodiment may be as shown in [Table 1] below.

In one embodiment, the mirabegron hemiedisylate may be a salt of an amide derivative that is a crystal having one or more of the following characteristics:

(i) Powder X-ray diffraction pattern with characteristic peaks at 2θ diffraction angles of 10.332±0.2, 10.572±0.2, 16.742±0.2, 20.791±0.2, 21.294±0.2 and 23.112±0.2 in powder X-ray diffraction (PXRD) analysis ; and

(ii) Endothermic peaks of endothermic onset temperature of 255.77°C±3°C and endothermic temperature 261.50°C±3°C in differential scanning calorimetry (DSC) analysis.

Intensity and peak positions of powder X-ray diffraction of an embodiment of the crystalline form of Mirabegron hemiedisylate salt according to an embodiment may be as shown in [Table 2] below.

Mirabegron heminafadisylate salt according to an embodiment of the present invention can also be identified by its characteristic powder X-ray diffraction (PXRD) analysis result as shown in FIG. 1 .

Mirabegron heminafadisylate salt according to an embodiment of the present invention can also be identified by its characteristic temperature differential scanning calorimetry (DSC) results using a closed pan as shown in FIG. 2 .

Mirabegron heminafadisylate salt according to an embodiment of the present invention can also be identified by its characteristic hydrogen nuclear magnetic resonance spectroscopy (1H-NMR) analysis result, as shown in FIG. 3 .

Mirabegron hemiedisylate salt according to an embodiment of the present invention can also be identified by its characteristic powder X-ray diffraction (PXRD) analysis result, as shown in FIG. 4 .

The mirabegron hemiedisylate salt of the present invention can also be identified by its characteristic temperature differential scanning calorimetry (DSC) results using a closed pan as shown in FIG. 5 .

The mirabegron hemiedisylate salt of the present invention can also be identified by its characteristic hydrogen nuclear magnetic resonance spectroscopy (1H-NMR) analysis result, as shown in FIG. 6 .

Mirabegron pidolate amorphous salt of the present invention can also be identified by its characteristic powder X-ray diffraction (PXRD) analysis results, as shown in FIG. 7 .

In one embodiment, the mirabegron pidolate has an amorphous powder X-ray diffraction pattern in which a 2θ diffraction angle does not appear in powder X-ray diffraction (PXRD) analysis, and 93.37°C ± 3°C in differential scanning calorimetry (DSC) analysis , may be a salt of an amide derivative having a glass transition temperature of 93.74°C±3°C and 96.47°C±3°C.

Mirabegron pidolate amorphous salt of the present invention can also be identified by its characteristic temperature differential scanning calorimetry (DSC) results using a closed pan as shown in FIG. 8 .

Mirabegron pidolate amorphous salt of the present invention can also be identified by its characteristic hydrogen nuclear magnetic resonance spectroscopy (1H-NMR) analysis result, as shown in FIG. 9 .

Values reported with respect to the DSC thermogram may show a difference of ± 3 °C, which means that the temperature observed through DSC may vary in the range of ± 3 °C depending on the rate of temperature increase, the sample preparation method, and the type of instrument used. because it can

The most rational method for identifying and determining the mirabegron heminafadisylate salt, mirabegron hemiedisylate salt, and mirabegron pidolate amorphous salt of the present invention is the characteristic characteristic of the powder X-ray diffraction (PXRD) analysis. The 2θ diffraction angle is the basis, and it is specified by the temperature differential scanning calorimeter (DSC) measurement result.

In another aspect, the present invention is a method for preparing a salt of the above-described amide derivative.

In one embodiment, the preparation method may be a reaction crystallization method. For example, the method may include mixing and stirring the free base solution of the amide derivative and the aliphatic or aromatic disulfonate solution, followed by vacuum drying. The method may be for the preparation of an aliphatic or aromatic disulfonate salt.

In one embodiment, the manufacturing method may be a slurry method. For example, the method may include adding a mixture of a free base of an amide derivative and an aliphatic or aromatic disulfonic acid to a solvent, stirring the mixture, and then vacuum drying. The method may be for the preparation of an aliphatic or aromatic disulfonate salt.

In one embodiment, the manufacturing method may be a vacuum evaporation crystallization method. For example, the method comprises the steps of mixing a free base solution of an amide derivative and an amino acid solution, stirring, and evaporating under reduced pressure to precipitate a solid; and adding a solvent to the precipitated solid, stirring, filtration under reduced pressure, and vacuum drying. The method may be for the preparation of a cyclized amino acid salt with a lactam structure.

In one aspect, the present invention is a pharmaceutical composition comprising a salt of the amide derivative as an active ingredient. In one embodiment, the pharmaceutical composition may be a pharmaceutical composition for improvement, treatment or prevention of diabetes or overactive bladder. Since these medicinal uses are already widely known in the art, and some are even being marketed, data proving the pharmacological effect thereof will be omitted in the present specification. For example, the salt of the amide derivative is used as a therapeutic agent for overactive bladder accompanying a feeling of urgency, urinary incontinence, or frequent urination, in addition to overactive bladder accompanying enlarged prostate.

The pharmaceutical composition containing the salt of the amide derivative disclosed herein as an active ingredient may be in any form of oral administration by tablets, pills, capsules, granules, powders, etc. or parenteral administration by inhalants, etc. As a solid composition for oral administration, tablets, powders, granules, and the like are used. In such solid compositions, one or more active substances may contain at least one inert excipient, for example, lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium metasilicate aluminate. mixed with etc. The composition may contain an inactive additive according to a conventional method, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, and a solubilizing agent. Tablets or pills may be coated with a sugar coating or a gastric or enteric coating agent, if necessary.

The dosage is appropriately determined in each case in consideration of symptoms, age, sex, etc. of the subject, but in the case of conventional oral administration, it is about 0.01 mg/kg to 100 mg/kg per day for adults, and it is administered once or It can be administered in 2 to 4 divided doses.

The present invention will be described in more detail with reference to the following examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .

Example

Preparation Example 1; Preparation of [4-{2-(2-(1,3-dioxoindol-2-yl)thiazol-4-yl)acetamido}phenylethyl]carbamic acid tertbutyl ester (Formula 5-1)

2-(1,3-dioxo-2H-isoindol-2-yl)-4-thiazoleacetic acid (Formula 3-1) (CAS No. 954268-27-0) (20.0 g, 0.069 mole) and the hydride After hydroxybenzotriazole hydrate (11.9 g, 0.077 mole) was dissolved in dichloromethane (160 ml), it was cooled to 0-5°C. N,N-dicyclohexylcarbodiimide (14.3 g, 0.069 mole) was dissolved in dichloromethane (40 ml) and slowly added dropwise to the cooled mixture, followed by stirring at 0-5° C. for 30 minutes. [2-(4-aminophenyl)ethyl]carbamic acid tertbutyl ester (Formula 2-1) (CAS No. 94838-59-2) (16.4 g, 0.069 mole) and triethylamine (7.02) in the suspended reaction solution g, 0.069 mole) and stirred at room temperature (20-25° C.) for 24 hours. After completion of the reaction, the reaction solution is cooled to 0-5° C., stirred for 12 hours, and filtered. After filtration, it is washed with dichloromethane (20 ml), a filtrate is obtained, and brine solution (200 ml) is added and extracted. The extraction was carried out three times to obtain an organic layer, and the solid obtained by concentration under reduced pressure at 35 to 40 ° C. was vacuum dried at 35 to 40 ° C. for 15 hours to obtain Chemical Formula 5-1 (30.5 g, yield 87%).

¹ H NMR (400 MHZ, CDCl ₃ ) δ 1.42 (s, 9H), 2.62 (t, 2H), 3.03 (t, 2H), 3.88 (s, 2H), 7.00 (s, 1H), 7.17 (d, 2H), 7.45 (d, 2H), 7.92 (d, 2H), 7.93 (d, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 28.4, 35.0, 36.2, 39.9, 79.5, 104.3, 121.5, 123.7, 127.9, 132.0, 132.2, 135.0, 135.7, 150.8, 155.9, 167.1, 169.9, 171.9.

Preparation Example 2; Preparation of N-(4-2-aminoethyl)phenyl)-2-(2-(1,3-dioxoindolin-2-yl)thiazol-4-yl)acetamide (Formula 6-1)

Formula 5-1 (30.0 g, 0.059 mole) obtained through Example 1 was dissolved in dichloromethane (150 ml) and cooled to 0-5°C. TFA (67.7 ml, 0.88 mole) was added to the cooled reaction solution and stirred at room temperature (20-25° C.) for 4 hours. After completion of the reaction, the reaction solution was cooled to 5-10° C., and 9% aqueous sodium hydrogen carbonate solution (250 ml) was added, stirred for 30 minutes, and extracted. The extraction was performed three times. Purified water (200 ml) was added to the organic layer obtained by extraction, followed by stirring and extraction for 15 minutes. Sodium sulfate (10 g) was added to the organic layer obtained by extraction, stirred for 20 minutes, and filtered. The filtrate obtained by filtration was concentrated under reduced pressure at 35-40°C and vacuum dried at 30-35°C for 15 hours to obtain Chemical Formula 6-1 (21.6 g, yield 90%).

¹ H NMR (400 MHZ, CDCl ₃ ) δ 2.71 (t, 2H), 2.98 (t, 2H), 3.88 (s, 2H), 7.00 (s, 1H), 7.17 (d, 2H), 7.45 (d, 2H), 7.92 (d, 2H), 7.93 (d, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 36.2, 39.0, 41.9, 104.3, 121.5, 123.7, 127.9, 132.0, 132.2, 135.0, 135.7, 150.8, 167.1, 169.9, 171.9.

Preparation Example 3; (R)-2-(2-(1,3-dioxoindolin-2-yl)thiazol-4-yl)-N-(4-(2-((2-hydroxy-2-phenylethyl) Preparation of ) amino) ethyl) phenyl) acetamide (Formula 7-1)

Formula 6-1 (20.0 g, 0.049 mole) was dissolved in ethanol (200 ml) and triethylamine (10.4 g, 0.1 mole) was added thereto, followed by stirring at room temperature (20-25° C.) for 20 minutes. (R)-2-chloro-1-phenylethanol (CAS No. 56751-12-3) (7.8 g, 0.05 mole) of Chemical Formula 4-1 was added to the reaction solution and refluxed for 18 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure at 45-50° C., purified water (100 ml) and dichloromethane (200 ml) were added, and the mixture was extracted by stirring for 15 minutes. Dichloromethane (100 ml) was added to the water layer, stirred and extracted for 15 minutes to obtain an organic layer, combined with the organic layer obtained from the first extraction, and concentrated under reduced pressure at 35-40° C., and a 1:1 mixed solution of ethyl acetate and heptane (5 ml ), and put silica in short packing (diameter 10cm X height 2.5cm), and a 1:2 mixed solution (400 ml) of ethyl acetate and heptane was flowed. The filtrate obtained by filtration was concentrated under reduced pressure at 40-45°C, and then vacuum dried at 40-45°C for 12 hours to obtain Chemical Formula 7-1 (20.2 g, yield 78%).

¹ H NMR (400 MHZ, CDCl ₃ ) δ 2.59 (t, 2H), 2.88 (t, 2H), 2.90 (t, 1H) 3.15 (t, 1H), 3.88 (s, 2H), 4.87 (t, 1H) ), 7.00 (s, 1H), 7.17 (d, 2H), 7.25 (t, 1H), 7.34 (t, 2H), 7.43 (d, 2H) 7.45 (d, 2H), 7.92 (d, 2H), 7.93 (d, 2H), ; ¹³ C NMR (100 MHz, CDCl ₃ ) δ 35.6, 36.2, 48.8, 53.7, 69.4, 104.3, 121.5, 123.7, 127.1, 127.6, 127.9, 128.9, 132.0, 132.2, 135.0, 135.7, 137.7, 150.8, 167.1, 169.9 , 171.9.

Preparation Example 4; 2-(2-amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]a Preparation of cetamide

Formula 7-1 (20.0 g, 0.037 mole) was dissolved in ethanol (500 ml), and hydrazine monohydrate (2.9 g, 0.045 mole) was slowly added dropwise. When the dropwise addition was complete, it was refluxed for 3 hours. After completion of the reaction, the reaction solution was cooled to room temperature (20-25°C), concentrated under reduced pressure at 40-45°C, dichloromethane (200ml) was added, and the precipitate was filtered off. Purified water (200 ml) is added to the filtrate obtained by filtration for extraction. The extraction was performed twice. Sodium sulfate (10 g) was added to the organic layer obtained by washing with water, stirred and filtered, and then concentrated under reduced pressure at 40-45°C. The concentrated solid was vacuum-dried at 45-50° C. for 12 hours to obtain Chemical Formula 1-1 (12.6 g, yield 84%).

¹ H NMR (400 MHZ, DMSO-d6) δ 2.88-2.93 (m, 2H), 3.13-3.32 (m, 3H), 3.45 (s, 2H) 4.87 (m, 1H), 6.15 (brs, 1H), 6.29 (s, 1H), 6.88 (brs, 2H), 7.17 (d, 2H), 7.30-7.34 (m, 1H), 7.38-7.41 (m, 4H), 7.56 (d, 2H) 8.61 (brs, 1H) ), 10.05 (brs, 1H); ¹³ C NMR (100 MHz, DMSO-D6) δ 31.2, 40.5, 48.4, 53.8, 68.6, 104.1, 119.6, 126.3, 128.2, 128.8, 129.3, 132.4, 138.2, 142.2, 167.5, 169.3.

[Example 1] Mirabegron heminafadisylate production through reaction crystallization using amorphous free base of Mirabegron

5 g of the amorphous mirabegron free base prepared in the above preparation example was dissolved in 50 ml of methanol at room temperature. And 2.3 g of napadisylic acid was dissolved in 23 ml of acetone. The two solvents were mixed and stirred at room temperature for 1 hour. Then, it was filtered under reduced pressure and vacuum dried at 45°C for 16 hours to obtain 5.8 g of Mirabegron heminafadisylate.

[Example 2] Preparation of Mirabegron Heminafadisylate by Slurry Method Using Mirabegron Free Base Amorphous

After mixing 5 g of amorphous mirabegron free base and 2.3 g of napadisylic acid prepared in the above preparation example, 60 ml of isopropyl alcohol was added. After that, the mixture was stirred at room temperature for 2 hours, filtered under reduced pressure, and vacuum dried at 45°C for 16 hours to obtain 5.2 g of Mirabegron heminafadisylate.

[Example 3] Mirabegron hemiedisylate production through reaction crystallization using amorphous free base of Mirabegron

5 g of the amorphous mirabegron free base prepared in the above preparation example was dissolved in 50 ml of methanol at room temperature. And 1.5 g of edicylic acid was dissolved in 15 ml of ethyl acetate. The two solvents were mixed and stirred at room temperature for 1 hour. Then, it was filtered under reduced pressure and vacuum dried at 45°C for 16 hours to obtain 3.8 g of Mirabegron hemi-edisylate.

[Example 4] Preparation of Mirabegron Hemiedisylate by Slurry Method Using Mirabegron Free Base Amorphous

After mixing 5 g of the amorphous mirabegron free base prepared in the above preparation example and 1.5 g of edisylic acid, 50 ml of methanol was added. After that, the mixture was stirred at room temperature for 1 hour, filtered under reduced pressure, and vacuum dried at 45°C for 16 hours to obtain 4.5 g of Mirabegron hemiedisylate.

[Example 5] Mirabegron pidolate amorphous salt preparation through vacuum evaporation crystallization using amorphous mirabegron free base

5 g of the amorphous mirabegron free base prepared in the above preparation example was dissolved in 50 ml of methanol at room temperature. Then, 1.7 g of L-pyroglutamic acid was dissolved in 17 ml of acetone. The two solvents were mixed and stirred at room temperature for 1 hour. Then, the solvent was evaporated under reduced pressure using a concentrator to precipitate a solid. After 30 ml of ethyl acetate was added to the precipitated solid, the mixture was stirred at room temperature for 30 minutes. Then, it was filtered under reduced pressure and vacuum dried at 45 degrees for 16 hours to obtain 4.2 g of mirabegron pidolate.

[Experimental Example 1] Powder X-ray diffraction (PXRD)

PXRD analysis was performed on an X-ray powder diffractometer using Cu Kα radiation (D8 Advance). The instrument was equipped with tube power, and the amperage was set at 45 kV and 40 mA. The divergence and scattering slits were set at 1°, and the light receiving slits were set at 0.2 mm. Continuous θ-2θ scans from 5 to 35° 2θ at 3°/min (0.4 sec/0.02° interval) were used. The results are shown in Fig. 1 (Example 1), Fig. 4 (Example 3), and Fig. 7 (Example 5).

[Experimental Example 2] Temperature differential scanning calorimetry (DSC)

Using DSC Q20 obtained from TA, DSC measurements (see FIGS. 2, 5 and 8) were performed in a closed pan at a scan rate of 10° C./min from 20° C. to 300° C. under nitrogen purge. The results are shown in Fig. 2 (Example 1), Fig. 5 (Example 3), and Fig. 8 (Example 5).

[Experimental Example 3] Solubility evaluation of mirabegron novel salt

Mirabegron α type is an extremely poorly soluble solid with low solubility in water or pH 6.8. The aqueous solubility and solubility at pH 6.8 of the mirabegron heminafadisylate salt, hemiedisylate salt, and pidolate amorphous salt prepared in Examples 1, 3 and 5 were measured and compared with Mirabegron α-form and the results are summarized in [Table 4] below, and the dissolution visual results are shown in FIG. 10 . And the analysis conditions are as shown in [Table 3] below.

HPLC analysis conditions for determination of mirabegron solubility mobile phase A:B = 90:10 (v/v) A 10mmol/LK ₂ HPO ₄ solution B Methanol flow rate 1 ml/min UV 250 nm Run time 35 min diluent Methanol Injection volume 5 μl Column X-Bridge C18 25cmX4.6mmX5μm

Solubility of Mirabegron novel salt and α crystalline form H ₂ O pH6.8 Mirabegron α type 0.082 mg/ml 0.092 mg/ml Mirabegron Napadisylate 0.62 mg/ml 0.64 mg/ml Mirabegron Edisylate 2.21 mg/ml 2.35 mg/ml Mirabegron Fidolate 10.45 mg/ml 10.92 mg/ml

As shown in [Table 4], it was confirmed that the new salt of Mirabegron had significantly improved water solubility and solubility at pH 6.8 than that of Mirabegron α-type. And for further verification, the solubility results of mirabegron α type and mirabegron novel salt are shown in FIG. 10 .

[Experimental Example 4] Hygroscopicity evaluation of mirabegron novel salt

40 mg each of Mirabegron novel salt prepared in Examples 1, 3 and 5 was placed in a desiccator of 33%, 57%, 64%, 75%, and 93% of relative humidity for at least two days to absorb moisture, and then moisture Karl Fischer analysis was attempted. As a result, it was confirmed that all of them did not absorb moisture because the weight % of moisture did not appear.

As described above in detail a specific part of the present invention, for those of ordinary skill in the art, this specific description is only a preferred embodiment, and it is clear that the scope of the present invention is not limited thereto. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims (16)

As a salt of an amide derivative,
The amide derivative is mirabegron,
The salt is an aliphatic or aromatic disulfonate, or a cyclized amino acid salt with a lactam structure,
The aliphatic disulfonate is mirabegron hemiedisylate,
The aromatic disulfonate is mirabegron heminafadisylate,
The amino acid salt cyclized into the lactam structure is mirabegron pidolate,
salts of amide derivatives. According to claim 1,
The aliphatic or aromatic disulfonate is a salt of an amide derivative in a crystalline form. According to claim 1,
The amino acid salt cyclized into the lactam structure is an amorphous salt of an amide derivative. delete delete delete delete delete According to claim 1,
The mirabegron heminafadisylate is
A salt of an amide derivative which is a crystal having one or more of the following characteristics:
(i) Powder X-ray diffraction pattern with characteristic peaks at 2θ diffraction angles of 6.14±0.2, 11.457±0.2, 16.45±0.2, 17.764±0.2, 26.018±0.2 and 27.132±0.2 in powder X-ray diffraction (PXRD) analysis ; and
(ii) Endothermic peaks of endothermic onset temperature 201.34°C±3°C and endothermic temperature 204.33°C±3°C in differential scanning calorimetry (DSC) analysis. According to claim 1,
The mirabegron hemiedisylate is
A salt of an amide derivative which is a crystal having one or more of the following characteristics:
(i) Powder X-ray diffraction pattern with characteristic peaks at 2θ diffraction angles of 10.332±0.2, 10.572±0.2, 16.742±0.2, 20.791±0.2, 21.294±0.2 and 23.112±0.2 in powder X-ray diffraction (PXRD) analysis ; and
(ii) Endothermic peaks of endothermic onset temperature of 255.77°C±3°C and endothermic temperature 261.50°C±3°C in differential scanning calorimetry (DSC) analysis. According to claim 1,
The mirabegron fidolate is
It has an amorphous powder X-ray diffraction pattern that does not show 2θ diffraction angle in powder X-ray diffraction (PXRD) analysis. A salt of an amide derivative having a glass transition temperature. A pharmaceutical composition for improving, treating or preventing diabetes or overactive bladder comprising the salt of an amide derivative according to any one of claims 1 to 3 and 9 to 11 as an active ingredient. delete 11. A method for preparing a salt of an amide derivative according to any one of claims 1, 2, and 9 to 10, comprising:
The manufacturing method is
A method for preparing a salt of an amide derivative, comprising mixing and stirring a free base solution of an amide derivative and a solution of an aliphatic or aromatic disulfonate, followed by vacuum drying. 11. A method for preparing a salt of an amide derivative according to any one of claims 1, 2, and 9 to 10, comprising:
The manufacturing method is
A method for preparing a salt of an amide derivative, comprising adding a mixture of a free base of the amide derivative and an aliphatic or aromatic disulfonic acid to a solvent, stirring the mixture, and then vacuum drying. 12. A method for preparing an amide derivative according to any one of claims 1, 3, and 11, comprising:
The manufacturing method is
mixing and stirring the free base solution of the amide derivative and the amino acid solution, followed by evaporation under reduced pressure to precipitate a solid; and
A method for preparing a salt of an amide derivative comprising adding a solvent to the precipitated solid, stirring, filtration under reduced pressure, and vacuum drying.

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