KR20180138058A - Salts of amide derivatives and method for preparing the same - Google Patents

Abstract

In the present invention, a cyclised amino acid is disclosed as an aliphatic or aromatic disulfonate or lactam structure, which is a salt of an amide derivative represented by chemical formula 1. The salt of the amide derivative does not absorb moisture, and is stable and has excellent solubility in water. In chemical formula 1, the B ring is a substituted or unsubstituted heteroaryl group, X is a bond, hydroxy, lower alkylene, lower alkenylene, carbonyl or -NH-, and A is lower alkylene or -lower alkylene-O-.

Description

Salts of amide derivatives and methods for preparing same [0002]

Disclosed herein are salts of novel amide derivatives having excellent solubility and processes for their preparation. More specifically, there is disclosed a salt of a novel amide derivative which has excellent solubility but does not absorb moisture and has excellent stability, and a process for producing the salt.

The specific amide derivative to which Mirabegron belongs was developed by Astellas Seiyaku. According to WO99 / 20607 and Korean Patent No. 10-0506568, the compound has an insulin secretion promoting action and an insulin sensitization enhancing action, and also has an anti-obesity action and an anti-hyperlipemic action based on a selective? 3 receptor stimulant and is useful for the treatment of diabetes Compound. ≪ / RTI >

Mirabegron, a representative compound of the above amide derivatives, is a compound of the formula (I) which is a compound of the formula (I) -Acetanilide ((R) -2- (2-aminothiazol-4-yl) -4 '- [2- (2-amino-N- [4- [2 - [(2R) -2-hydroxy-2-phenylethyl] amino] ethyl] phenyl] -4- thiazoleacetamide. 2-phenylethyl] amino] ethyl] phenyl] -4-thiazoleacetamide) or 2- (2-amino- (2 - {[(2R) -2-hydroxy-2-phenylethyl] amino} ethyl) phenyl] acetamide - (2 - {[(2R) -2-hydroxy-2-phenylethyl] amino} ethyl) phenyl] acetamide.

In addition, the amide derivative can be used as a therapeutic agent for an overactive bladder in WO 2004/041276. For example, in addition to an overactive bladder due to enlargement of the prostate gland, it has been reported that it is useful as a therapeutic agent for an irritable bladder accompanied by urgency of urination, incontinence or urinary frequency. Betmiga is currently being marketed as a treatment for urinary incontinence.

Crystalline polymorphs of Mirabegron have been disclosed in WO 2003/037881 as anhydrous crystalline alpha or beta forms. At present, it is α-type which is used as a raw material medicinal substance. This? -Type is a stable crystalline form, and the hydrochloride reported in WO 2003/037881 is disrupted by moisture absorption in the presence of water, but it has been reported that the? -Type does not absorb moisture. And it was reported that it is a stable crystalline type which does not phase change into another crystal form.

However, according to the FDA / Draft Guidance on Mirabegron Active Ingredient, the Mira Begron Form A is reported to be poorly absorbed in BCS class II due to its low solubility in water of 0.082 mg / ml. Thus, EP 2857389 discloses nitrates, and WO 2016/049749 discloses bromates, tartarates, benzoates, oxalates, succinates, and the like. However, these patents do not disclose accurate solubility or stability.

The criteria for selecting the best crystalline form are due to the most important physico-chemical properties required by the drug, including choosing the most thermodynamically stable one, choosing one that is optimized for the production of the drug substance and the finished product, improving the solubility and dissolution rate of the drug The choice of crystal form that is optimized for its purpose can be changed.

Therefore, there has been a demand for a novel salt of mirabegron having high solubility in water, without moisture absorption.

All of the above mentioned prior art documents are incorporated herein by reference in their entirety as if fully incorporated herein by reference.

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

In one aspect, the present invention is directed to providing a salt of a particular group of amide derivatives comprising mirabegron.

In one aspect, the present invention provides a salt of an amide derivative having excellent solubility.

In one aspect, the present invention provides a salt of an amide derivative excellent in solubility in water.

In one aspect, the present invention provides a salt of an amide derivative which is stable without moisture absorption, and which is excellent in solubility in water.

As a result of research efforts, the present inventors have developed a crystalline salt and an amorphous salt.

In one aspect, the present invention provides a salt of an amide derivative represented by the following general formula (1)

[Chemical Formula 1]

(Wherein,

B ring is a substituted or unsubstituted heteroaryl group, said substitution being a heteroaryl group substituted with a substituent selected from the group consisting of the following groups, or condensed with a benzene ring,

X is a bond, a hydroxy, a lower alkylene, a lower alkenylene, a carbonyl, a group represented by -NH-, wherein said lower alkylene or lower alkenylene is a substituted or unsubstituted group, And when X is a lower alkylene group, the hydrogen atom bonded to the carbon atom constituting the B ring and the lower alkyl group may be integrated 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 or different and are a hydrogen atom or lower alkyl,

R2 is a hydrogen atom or a halogen atom,

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

Wherein said substituent group is selected from the group consisting of halogen atom, lower alkyl, lower alkenyl, lower alkynyl, hydroxy, sulfanyl, halogeno lower alkyl, lower alkyl-O-, lower alkyl-S-, lower alkyl- Lower alkyl-SO-, lower alkyl-SO2-, lower alkyl-CO-, lower alkyl-CO-O-, carbamoyl, lower alkyl-NH-CO-, di- N-CO-, nitro, cyano, amino, guanidino, lower alkyl-CO-NH-, lower alkyl-SO2-NH-, lower alkyl-NH-, di- Alkylene-O-, and the substituent thereof is an aryl group, a heteroaryl group, a 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- -, di-lower alkyl-N-CO-, nitro, cyano, amino, guanidino, Alkyl-CO-NH-, lower alkyl-SO2-NH-, lower alkyl-NH-, di-lower alkyl-N- and substituents of these aryl and heteroaryl groups may also be substituted with halogen atoms , ≪ / RTI >

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 can be a C _1-6 alkane disulfonate.

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

According to the specification, a stable salt of an amide derivative showing various pharmacological activities such as a therapeutic agent for diabetes or a therapeutic agent for an overactive bladder can be provided. Specifically, it is possible to provide an amide derivative which is stable without moisture absorption, and which is excellent in solubility in water. Particularly, it is possible to provide Mirabegron which is stable to humidity and has a good water solubility. It is stable in long-term storage and has good solubility because it has little moisture absorption, so that it can be used as an oral preparation.

Figure 1 shows a powder X-ray diffraction pattern of a crystalline solid of Mirabegron heminafadisilate salt prepared according to one embodiment of the present invention.
Figure 2 shows the melting point peak results by differential scanning calorimetry (DSC) of a crystalline solid of Mirabegron heminafadisilate salt prepared according to one embodiment of the present invention in a closed pan.
Figure 3 shows a hydrogen nuclear magnetic resonance (H-NMR) analysis of the mirabegron heminafadisilate salt and napadysilicic acid, mirabegron free base prepared according to one embodiment of the present invention.
Figure 4 shows a powder X-ray diffraction pattern of a crystalline solid of the mirabegron hemlydicylate salt prepared according to one embodiment of the present invention.
FIG. 5 is a graph showing a melting point peak result of a crystalline solid of Mirabegron hemlydicylate salt prepared according to an embodiment of the present invention by a differential scanning calorimetry (DSC) in a closed pan.
FIG. 6 shows a hydrogen nuclear magnetic resonance (H-NMR) analysis of the mirabegron hemlydicylate salt and edicylic acid, mirabegron free base prepared according to one embodiment of the present invention.
Figure 7 shows a powder X-ray diffraction pattern of a mirabegron pyridolate amorphous salt prepared according to one embodiment of the present invention.
FIG. 8 shows the glass transition temperature results of the amorphous salt of mirabegron pyridolate prepared according to an embodiment of the present invention by differential scanning calorimetry (DSC) in a sealed fan.
FIG. 9 shows a hydrogen nuclear magnetic resonance (H-NMR) analysis of mirabegron pyridyl amorphous salt and L-pyroglutamic acid, mirabegron free base, prepared according to an embodiment of the present invention.
Figure 10 shows the solubility results of the novel mirabegron salt prepared according to one embodiment of the present invention.

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

Examples of a "lower alkyl group" are methyl, ethyl and straight or branched chain propyl, butyl, pentyl, or hexyl, preferably an alkyl group of 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 " are monocyclic heteroaryl groups such as furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, Thiazolyl, thiadiazolyl, triazolyl, and tetrazolyl), and bicyclic heteroaryl groups (e.g., naphthyridinyl and pyridopyrimidinyl).

Examples of the "halogen atom" are a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and examples of the "haloaryl lower alkyl group" include the above-mentioned aryl lower alkyl group in which the hydrogen atom (s) ).

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

Since the compound of formula (1), which is an amide derivative of the present invention, has one or more asymmetric carbon atoms, there are optical isomers such as (R) -compound and (S) -conjugate, racemate, diastereomer and the like. The compounds of formula (1) herein include both isolated isomers and mixtures thereof.

The starting materials for preparing the compounds of formula (1) according to the present disclosure can be readily prepared by methods known in the art or commercially available.

In one embodiment, the amide derivative compound according to the present specification may have R of formula (1) as an amino group.

In one embodiment, the amide derivative compound according to the present disclosure may be a thiazolyl of formula (I).

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

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

In one embodiment, an amide derivative compound according to the present disclosure may be represented by R1a and R1b in the formula (1) may be hydrogen.

In one embodiment, an amide derivative compound according to the present disclosure may be a hydrogen of formula (1).

In one embodiment, the amide derivative compound according to the present disclosure may have z in formula (1) = CH-.

In one embodiment, the amide derivative compound according to the present disclosure can be a hydrogen of formula (1).

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

[Formula 1-1]

The method for producing the amide derivative of the present invention is described below by way of example of the compound of the formula (1-1).

[Reaction Scheme 1]

A) reacting an aromatic amine derivative of Formula 2 (e.g., Formula 2-1) wherein the alkylamine is substituted with a carboxyl protecting group with a phthalimide of Formula 3 (e.g., Formula 3-1) Reacting a thiazole derivative to prepare a compound of formula 5 (e. G., Formula 5-1); And b) the intermediate obtained in step a) is subjected to a decarboxylation protecting group reaction to obtain a compound of formula 6 (e.g., formula 6-1) and then reacting it with a compound of formula 4 (e. G. -1), and then the compound of formula 1 (for example, formula 1-1), which is the final compound, can be prepared through a dephthalimide protecting group reaction. Such a new synthesis method can produce mirabegron as an economical and reasonable manufacturing method as compared with the conventional manufacturing method including a hydrogen reaction.

(2)

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

(2-1).

 (3)

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

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

 [Formula 3-1]

[Chemical Formula 4]

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

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

 [Formula 4-1]

[Chemical Formula 5]

(Wherein C and D are protecting groups, and R, B, X, A, R 1a and R 1b are as defined in the above formula (1)).

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

[Formula 5-1]

[Chemical Formula 6]

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

[Formula 6-1]

(7)

Wherein D is a protecting group and R, B, X, A, R 1a, R 1b, z, and R 2 are as defined in Formula 1.

[Formula 7-1]

In one embodiment, the salt of the amide derivative may be crystalline or amorphous.

In one embodiment, the aliphatic or aromatic disulfonate may be crystalline. In one embodiment, the aliphatic disulfonate can be a C _1-6 alkane disulfonate. For example, the aliphatic disulfonate can be ethane disulfonate, i.e., 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. Any amino acid can be used as long as the amino acid can be cyclized into a lactam structure. For example, it may be L-pyroglutamic acid. For example, the cyclized amino acid salt of the lactam structure may be a pidolate. For example, the salt of the amide derivative may be mirabegron pyridolate.

In one embodiment, the salt of the amide derivative may be a salt formed by ion-binding 2: 1 of mirabegron free base and nappadic acid. In one embodiment, the salt of the amide derivative may be mirabegron heminafadisylate of formula (8). That is, it may be (R) -2- (2-aminothiazol-4-yl) -4 '- [2 - [(2-hydroxy-2- phenylethyl) amino] ethyl] acetic ananilide or palydic acid :

[Chemical Formula 8]

In one embodiment, the salt of the amide derivative may be a salt formed by ionic bonding of Mirabegron free base and edicylic acid 2: 1. In one embodiment, the salt of the amide derivative may be mirabegron hemlydicylate of formula (9). That is, it may be (R) -2- (2-aminothiazol-4-yl) -4 '- [2- (2-hydroxy-2-phenylethyl) amino] ethyl] acetic ananilide eddylic acid.

[Chemical Formula 9]

In one embodiment, the salt of the amide derivative may be an amorphous salt formed by ion-binding 1: 1 of Mirabegron free base and L-pyroglutamic acid. In one embodiment, the salt of the derivative may be mirabegron pyridolate of formula (10). That is, it may be (R) -2- (2-aminothiazol-4-yl) -4 '- [2 - [(2-hydroxy-2-phenylethyl) amino] ethyl] acetic ananilide pyroglutamic acid.

[Chemical formula 10]

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

(i) a powder X-ray diffraction pattern (PXRD) analysis of the powder X-ray diffraction pattern (PXRD) having peaks characteristic 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 ; And

(ii) Endothermic peak at endothermic start 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 the powder X-ray diffraction of the crystal form of Mirabegron hemipadysylate salt according to one embodiment can be as shown in Table 1 below.

In one embodiment, the mirabegon hemidiadylate can be a salt of an amide derivative that is a crystal having one or more of the following characteristics:

(i) a powder X-ray diffraction pattern (PXRD) analysis of the powder X-ray diffraction pattern (PXRD) having peaks characteristic 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 ; And

(ii) an endothermic peak at an endothermic start temperature of 255.77 ° C ± 3 ° C and an endothermic temperature of 261.50 ° C ± 3 ° C in a differential scanning calorimetry (DSC) analysis.

The intensity and peak position of the powder X-ray diffraction of one embodiment of the crystalline form of mirabegron hemisidylate salt according to one embodiment can be as shown in Table 2 below.

Mirabegron heminafadisilate salt according to one embodiment of the present invention can also be identified by the characteristic powder X-ray diffraction (PXRD) analysis results as shown in FIG.

Mirabegron heminafadisilate salt according to one embodiment of the present invention can also be identified by its characteristic differential scanning calorimetry (DSC) results using a sealed fan as shown in FIG.

Mirabegron heminafadisilate salt according to one embodiment of the present invention can also be identified by the characteristic hydrogen nuclear magnetic resonance spectroscopic (1H-NMR) analysis as shown in FIG.

The mirabegon hemidiadylate salt according to one embodiment of the present invention can also be identified by the characteristic powder X-ray diffraction (PXRD) analysis results as shown in FIG.

The mirabeglone hemlydicylate salt of the present invention can also be identified by its characteristic differential scanning calorimetry (DSC) results using an enclosure as shown in Fig.

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

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

In one embodiment, the mirabeglon pyridylate has an amorphous powder X-ray diffraction pattern that does not exhibit a 2? Diffraction angle in a powder X-ray diffraction (PXRD) analysis and is characterized by a differential scanning calorimetry (DSC) , 93.74 DEG C +/- 3 DEG C and 96.47 DEG C +/- 3 DEG C, respectively.

The mirabegron pyridolate amorphous salt of the present invention can also be identified by its characteristic differential scanning calorimetry (DSC) results using a sealed fan as shown in Fig.

The amorphous salt of mirabegon pyridolate of the present invention can also be identified by the characteristic hydrogen nuclear magnetic resonance spectroscopic (1H-NMR) analysis as shown in Fig.

The reported values in relation to the DSC temperature charts may show a deviation of +/- 3 ° C because the temperature observed through the DSC has a deviation in the range of ± 3 ° C depending on the rate of temperature rise, It is because.

The most reasonable method for identifying and determining the mirabegron heminafadisilate salt, mirabegron hemidicylate salt, mirabegron pyridolate amorphous salt of the present invention is characterized by the characteristic (X-ray) of powder X-ray diffraction (PXRD) The diffraction angle is based on the 2 &thetas; diffraction angle, and is specified based on the result of the DSC measurement of the temperature differential scanning calorimeter (DSC).

In another aspect, the present invention is a process for preparing a salt of an amide derivative as described above.

In one embodiment, the production method may be a reaction crystallization method. For example, the process may comprise mixing a free base solution of the amide derivative and a solution of an aliphatic or aromatic di-sulfonate solution, stirring and vacuum drying. The process may be for the preparation of an aliphatic or aromatic disulfonate salt.

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

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

In one aspect, the present invention is a pharmaceutical composition comprising the amide derivative salt as an active ingredient. In one embodiment, the pharmaceutical composition may be a pharmaceutical composition for improving, treating or preventing diabetes or an overactive bladder. Since these medicinal uses are already well known in the art and are also commercially available, data proving their pharmacological effects are omitted here. For example, the salt of the amide derivative is used as a therapeutic agent for an irritable bladder accompanied by urgency, incontinence or urinary frequency in addition to an overactive bladder according to enlargement of the prostate gland.

The pharmaceutical composition containing the salt of an amide derivative described in the present specification as an active ingredient may be in any form of oral administration by means of tablets, pills, capsules, granules, powders or the like or parenteral administration by inhalants or the like. As the solid composition for oral administration, tablets, powders, granules and the like are used. In such a solid composition one or more active substances may be mixed with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium metasilicate aluminate And the like. The composition may contain additives inert according to conventional methods, for example, a lubricant such as magnesium stearate, disintegrants such as sodium carboxymethyl starch, and a solubilizing agent. Tablets or pills may be coated with a sugar or a gastric or enteric coating if desired.

The dose is appropriately determined according to the individual case in consideration of the symptom, the age and sex of the subject to be administered, and in the case of ordinary oral administration, 0.01 mg / kg to 100 mg / kg per adult is used, It can be administered in two to four divided doses.

Hereinafter, the present invention will be described in more detail with reference to examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Example

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

(CAS No. 954268-27-0) (20.0 g, 0.069 mole) and a mixture of hydro- carbons (hydroxymethyl) Roxybenzotriazole hydrate (11.9 g, 0.077 mole) was dissolved in dichloromethane (160 ml) and then 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 to 5 ° C for 30 minutes. To the suspended reaction solution, 16.4 g (0.069 mole) of [2- (4-aminophenyl) ethyl] carbamic acid butyl ester (CAS No. 94838-59-2) g, 0.069 mole), and the mixture was stirred at room temperature (20 to 25 ° C) for 24 hours. After completion of the reaction, the reaction solution is cooled to 0 to 5 ° C, stirred for 12 hours, and filtered. After filtration, the filtrate was washed with dichloromethane (20 ml), and the filtrate was extracted with a brine solution (200 ml). The extraction was carried out three times. An organic layer was obtained and concentrated under reduced pressure at 35 to 40 ° C. The obtained solid was vacuum-dried at 35 to 40 ° C for 15 hours to obtain the compound of 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.

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

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

Production Example 3; (R) -2- (2- (1,3-dioxoindolin-2-yl) thiazol- ) Amino) ethyl) phenyl) acetamide (Formula 7-1)

(20.0 g, 0.049 mole) was dissolved in ethanol (200 ml), triethylamine (10.4 g, 0.1 mole) was added thereto, and the mixture was stirred at room temperature (20 to 25 ° C) for 20 minutes. (R) -2-chloro-1-phenylethanol (CAS No. 56751-12-3) (7.8 g, 0.05 mole) of the formula 4-1 was added to the reaction solution and refluxed for 18 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure at 45 to 50 ° C, purified water (100 ml) and dichloromethane (200 ml) were added thereto, and the mixture was stirred for 15 minutes. Dichloromethane (100 ml) was added to the water layer, and the mixture was stirred and extracted for 15 minutes to obtain an organic layer. The organic layer was extracted with the first extraction and concentrated under reduced pressure at 35 to 40 ° C. A 5: 1 mixture of ethyl acetate and heptane ), The silica was shortly packed (diameter 10 cm x height 2.5 cm), and the mixture was mixed with a mixture of ethyl acetate and heptane 1: 2 (400 ml). The filtrate obtained by filtration was concentrated under reduced pressure at 40 to 45 ° C and then vacuum dried at 40 to 45 ° C for 12 hours to obtain a compound of 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 2H), 7.42 (d, 2H), 7.92 (d, 2H), 7.00 (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.

Production Example 4; 2-phenylethyl] amino} ethyl) phenyl] acetic acid; < RTI ID = 0.0 & Manufacture of cetamide

The compound of 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 addition was complete, reflux was carried out for 3 hours. After completion of the reaction, the reaction solution was cooled to room temperature (20 to 25 ° C), concentrated under reduced pressure at 40 to 45 ° C, and dichloromethane (200 ml) was added thereto to remove the precipitate by filtration. To the filtrate obtained by filtration, purified water (200 ml) is added to extract. The extraction was carried out twice. Sodium sulfate (10 g) was added to the organic layer washed with water, stirred and filtered, and then concentrated under reduced pressure at 40 to 45 ° C. The solid obtained by concentration was vacuum-dried at 45 to 50 ° C for 12 hours to obtain the compound of 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), 2H), 7.17 (d, 2H), 7.30-7.34 (m, 1H), 7.38-7. 41 (m, 4H), 7.56 ), 10.05 (br s, 1H); ¹³ C NMR (100 MHz, DMSO-D6)? 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] Production of Mirabegron hemipandylate by reaction crystallization method using Amira Begron free base amorphous

5 g of the amorphous form of Mirabegron free base prepared in the Preparation Example was dissolved in 50 ml of methanol at room temperature. Then, 2.3 g of napadic acid was dissolved in 23 ml of acetone. The two solvents were mixed and stirred at room temperature for 1 hour. The mixture was filtered under reduced pressure, and vacuum dried at 45 ° C. for 16 hours to obtain 5.8 g of Mirabegron hemipadcylate.

[Example 2] Production of Mirabegron hemipandilate by slurry method using Amira Begron free base amorphous

5 g of the amorphous form of Mirabegron free base and 2.3 g of napadic acid prepared in the Preparation Example were mixed and 60 ml of isopropyl alcohol was added thereto. Thereafter, 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 heminafadicylate.

[Example 3] Production of Mirabegron hemimidylate through reaction crystallization using Amira Begron free base amorphous

5 g of the amorphous form of Mirabegron free base prepared in the Preparation Example was dissolved in 50 ml of methanol at room temperature. And 1.5 g of eddysilicic acid were dissolved in 15 ml of ethyl acetate. The two solvents were mixed and stirred at room temperature for 1 hour. The precipitate was filtered under reduced pressure, and vacuum dried at 45 ° C for 16 hours to obtain 3.8 g of mirabegron hemidylsilate.

[Example 4] Preparation of Mirabegron hemimidylate by slurry method using Amira Begron free base amorphous

5 g of Amira Begron free base amorphous prepared in the above Preparation Example and 1.5 g of edicylic acid were mixed and then 50 ml of methanol was added. Thereafter, 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 hemicylate.

[Example 5] Preparation of mirabegron pyramidate amorphous salt through vacuum evaporation crystallization method using amira beigron free base amorphous

5 g of the amorphous form of Mirabegron free base prepared in the 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. The solvent was then evaporated under reduced pressure using a concentrator to precipitate a solid. 30 ml of ethyl acetate was added to the precipitated solid, and the mixture was stirred at room temperature for 30 minutes. The mixture was filtered under reduced pressure, and vacuum-dried at 45 ° C for 16 hours to obtain 4.2 g of Mirabegron pidolate.

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

PXRD analysis was performed on a (D8 Advance) X-ray powder diffractometer using Cu K? Radiation. The instrument was equipped with a tube force, and the current was set at 45 kV and 40 mA. The divergence and scattering slits were set at 1 DEG, and the light receiving slits were set at 0.2 mm. 2-theta continuous scan of 3 ° / min (0.4 sec / 0.02 ° interval) from 5 to 35 ° 2θ was 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 from TA, DSC measurements (see FIGS. 2, 5, and 8) were performed in a sealed fan 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] Evaluation of solubility of a new salt of mirabegron

Mirabegron Form A is an extremely poorly soluble solid with low solubility in water or pH 6.8. The solubilities of the mirabegron heminafadisilate salt, hemidecylate salt and pyridolate amorphous salt prepared in Examples 1, 3 and 5 were measured at the water solubility and pH 6.8, and compared with the Mira Begron type The results are summarized in Table 4 below, and the soluble visual results are shown in FIG. The analysis conditions are shown in Table 3 below.

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

Solubility of Mirabegron new salt and α-crystal form H ₂ O pH 6.8 Mirabegron α type 0.082 mg / ml 0.092 mg / ml Mirabegron paddysylate 0.62 mg / ml 0.64 mg / ml Mirabegron edisilate 2.21 mg / ml 2.35 mg / ml Mirabegron Pyrdrate 10.45 mg / ml 10.92 mg / ml

As shown in the above Table 4, it was confirmed that the new salt of mirabegron was more improved in solubility at pH 6.8 than in the case of the mirabegron type. And the solubility results of the novel mirabeglone a and mirabegron salts for further proof are shown in Fig.

[Experimental Example 4] Evaluation of hygroscopicity of a new salt of mirabegron

40 mg of the new mirabegron salt prepared according to Examples 1, 3 and 5 was placed in a desiccator having a relative humidity of 33%, 57%, 64%, 75% and 93% for two days or more, The analysis was attempted. As a result, it was confirmed that all of the moisture was not absorbed by the water because no moisture content was observed.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (16)

As a salt of an amide derivative represented by the following formula (1)
[Chemical Formula 1]

(Wherein,
B ring is a substituted or unsubstituted heteroaryl group, said substitution being a heteroaryl group substituted with a substituent selected from the group consisting of the following groups, or condensed with a benzene ring,
X is a bond, a hydroxy, a lower alkylene, a lower alkenylene, a carbonyl or a group represented by -NH-, wherein said lower alkylene or lower alkenylene is a substituted or unsubstituted group, And when X is a lower alkylene group, the hydrogen atom bonded to the carbon atom constituting the B ring and the lower alkyl group may be integrated 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 or different and are a hydrogen atom or lower alkyl,
R2 is a hydrogen atom or a halogen atom,
Z is a group represented by a nitrogen atom or = CH-,
Wherein said substituent group is selected from the group consisting of halogen atom, lower alkyl, lower alkenyl, lower alkynyl, hydroxy, sulfanyl, halogeno lower alkyl, lower alkyl-O-, lower alkyl-S-, lower alkyl- Lower alkyl-SO-, lower alkyl-SO2-, lower alkyl-CO-, lower alkyl-CO-O-, carbamoyl, lower alkyl-NH-CO-, di- N-CO-, nitro, cyano, amino, guanidino, lower alkyl-CO-NH-, lower alkyl-SO2-NH-, lower alkyl-NH-, di- Alkylene-O-, and the substituent thereof is an aryl group, a heteroaryl group, a 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- -, di-lower alkyl-N-CO-, nitro, cyano, amino, guanidino, Alkyl-CO-NH-, lower alkyl-SO2-NH-, lower alkyl-NH-, di-lower alkyl-N- and substituents of these aryl and heteroaryl groups may also be substituted with halogen atoms , ≪ / RTI >
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 may be an aliphatic or aromatic disulfonate or a cyclized amino acid salt with a lactam structure,
The aliphatic disulfonate is a C _1-6 alkane disulfonate,
_Wherein said aromatic disulfonate is a C _6-22 aromatic disulfonate. The method according to claim 1,
Wherein said aliphatic or aromatic disulfonate is a crystalline amide derivative. The method according to claim 1,
Wherein the amino acid salt cyclized with the lactam structure is an amorphous amide derivative salt. The method of claim 2,
Wherein the aromatic disulfonate is a napadisilate salt of an amide derivative. 3. The method of claim 2,
Wherein said aliphatic disulfonate is edisylate. 4. The salt of claim 3, wherein the amino acid is L-pyroglutamic acid. The salt of claim 6, wherein the amino acid salt cyclized with the lactam structure is a pidolate. The salt of claim 1, wherein the salt of the amide derivative is Mirabegron heminafadicilate, Mirabegron hemidicylate or Mirabegron pyridolate. 9. The method of claim 8,
The above-mentioned Mirabegron heminafadicylate is a compound represented by the following formula
A salt of an amide derivative which is a crystal having at least one of the following characteristics:
(i) a powder X-ray diffraction pattern (PXRD) analysis of the powder X-ray diffraction pattern (PXRD) having peaks characteristic 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 ; And
(ii) Endothermic peak at endothermic start temperature 201.34 ° C ± 3 ° C and endothermic temperature 204.33 ° C ± 3 ° C in differential scanning calorimetry (DSC) analysis. 9. The method of claim 8,
The mirabegron hemlydicylate may be, for example,
A salt of an amide derivative which is a crystal having at least one of the following characteristics:
(i) a powder X-ray diffraction pattern (PXRD) analysis of the powder X-ray diffraction pattern (PXRD) having peaks characteristic 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 ; And
(ii) an endothermic peak at an endothermic start temperature of 255.77 ° C ± 3 ° C and an endothermic temperature of 261.50 ° C ± 3 ° C in a differential scanning calorimetry (DSC) analysis. 9. The method of claim 8,
The mirabeglon pyridolate is a compound of formula
Ray diffraction (PXRD) analysis showed that the powder had an amorphous powder X-ray diffraction pattern in which no 2? Diffraction angle appeared, and in differential scanning calorimetry (DSC) analysis, 93.37 캜 3 캜, 93.74 캜 3 캜, and 96.47 캜 3 A salt of an amide derivative having a glass transition temperature. 11. A pharmaceutical composition comprising an amide derivative salt according to any one of claims 1 to 11 as an active ingredient. 13. The pharmaceutical composition according to claim 12, wherein said pharmaceutical composition is for improving, treating or preventing diabetes or an overactive bladder. A process for preparing a salt of an amide derivative according to any one of claims 1, 2, 4, 5 and 8 to 10,
In the above manufacturing method,
A method for preparing a salt of an amide derivative, which comprises mixing a free base solution of an amide derivative and an aliphatic or aromatic disulfonate solution, stirring and vacuum drying. A process for preparing a salt of an amide derivative according to any one of claims 1, 2, 4, 5 and 8 to 10,
In the above manufacturing method,
A free base of an amide derivative, and a mixture of an aliphatic or aromatic di-sulfonic acid in a solvent, stirring the mixture, and then vacuum drying the salt. 13. A process for producing an amide derivative according to any one of claims 1, 3, 6 to 8, and 11,
In the above manufacturing method,
Mixing a free base solution of an amide derivative with an amino acid solution, stirring the mixture, and evaporating the mixture under reduced pressure to precipitate a solid; And
Adding a solvent to the precipitated solid, stirring the solution, filtering under reduced pressure, and vacuum drying the salt.

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