KR20200117091A - Prodrug compound of mirabegron and its medical use for treating or alleviating overactive bladder diseases - Google Patents

Abstract

The present invention provides a novel prodrug of a mirabegron compound or pharmaceutically acceptable salts thereof, a pharmaceutical composition containing the same as an active component, and a pharmaceutical use thereof for treating or alleviating overactive bladder diseases.

Description

Prodrug compound of mirabegron and its medical use for treating or alleviating overactive bladder diseases {Prodrug compound of mirabegron and its medical use for treating or alleviating overactive bladder diseases}

The present invention relates to a novel precursor drug (prodrug) of a mirabegron compound or a pharmaceutically acceptable salt thereof, which is known to be useful for the treatment or amelioration of overactive bladder disease. The present invention also relates to a pharmaceutical composition comprising such a novel precursor drug or a pharmaceutically acceptable salt thereof as an active ingredient. The present invention also relates to a pharmaceutical use using such a precursor drug or a pharmaceutically acceptable salt thereof.

Irritable bladder disease is basically a disease that shows abnormal urination symptoms such as urgency, urinary incontinence, nocturia, and frequency. Overactive bladder disease is caused by abnormalities of smooth muscles constituting the bladder, damage to the inhibitory nerve pathways of the cerebral or spinal cord, overactivity of the detrusor muscles, and abnormalities of neurotransmitters.

Until now, new drugs with various mechanisms have been developed and used clinically. Among them, mirabegron of formula 1 is a beta3 sympathetic receptor agonist and Astellas Pharma Inc. .) and is commercially available under a brand name called Betamiga. Beta3 sympathetic receptors are mainly present in the human bladder, and its agonists have been reported to secrete inhibitory substances from the urinary epithelium and inhibit detrusor contraction. Beta Miga products are commercially available as sustained-release film-coated tablets of 25mg and 50mg doses as a prescription drug, and are prescribed by taking one 50mg tablet once a day.

[Formula 1]

Mirabegron is a substance first disclosed in Korean Patent No. 10-0506568 (Example 4), and this substance patent describes the effect as a diabetes treatment by promoting insulin secretion and enhancing insulin sensitivity as a β3-receptor agonist. . In addition, in the above patent, Mirabegron was presented in the form of dihydrochloride, but in the process of development afterwards, it was found that dihydrochloride has difficult properties to be developed as a pharmaceutical due to its strong hygroscopicity. Accordingly, Astellas Pharmaceutical, the patentee, has applied for a crystalline form patent (Korean Patent No. 10-0908796) that provides a stable crystalline form as a Mirabegron free base, that is, an α form and a β form, and a patent for use as a treatment for irritable bladder disease ( Korean Patent No. 10-0967070) was subsequently applied.

Mirabegron is a substance classified as Class 3 according to the Biopharmaceutics Classification System (BCS), and while exhibiting high solubility characteristics, it has low oral absorption. The absolute bioavailability (the degree of exposure to the blood of the drug) by oral administration is 29% when taking 25mg and 35% when taking 50mg, so it is dose dependent. In addition, it appears that the bioavailability of women is higher than that of men, and it is reported to be about 20 to 30% higher in the case of weight correction and 40 to 50% in the absence of weight correction. (Reference: Clinical Pharmacology And Biopharmaceutics Review, Application Number 202611Orig1s000, US FDA)

Mirabegron free base has been developed as a matrix-type sustained-release formulation containing polyethylene oxide, ferric oxide, etc. and is currently on the market. (European Patent Registration No. 1,205,190) However, this sustained-release formulation did not overcome the low oral absorption of Mirabegron, and furthermore, according to the clinical trial results, the change in the absorption of drugs according to the diet is very large, that is, the effect of food ( food effect). In other words, the pharmacokinetics of Mirabegron varies greatly by fasting, high-fat, or low-fat diet. Specifically, the maximum plasma concentration (C _max ) and the area under the curve; AUC) decreased by 45% and 17%, respectively, compared to the fasting state. In addition, C _max and AUC after a low-fat diet decreased by 75% and 51%, respectively, compared to the fasting state. These results mean that the drug concentration in the blood, that is, the therapeutic effect of the drug, changes significantly depending on the contents of the usual meal, the intake time, and the amount of meal from the perspective of a patient who takes drugs every day.

In order to improve the food effect and low oral absorption of Mirabegron described above, a method of manufacturing a sustained-release tablet using a hydrogel-forming polymer as a main excipient (European Patent Application No. 2,345,410), or a multilayer structure A method for preparing a sustained-release tablet through formulation (European Patent Application No. 2,554,168) has been known.

From another point of view, as a method for improving the problem of food effect and low oral absorption of Mirabegron, according to European Patent Registration No. 3,360,866, a new prodrug substance having a carbamate derivative of Mirabegron as a core structure Was presented. Specifically, a non-polar substituent was introduced into a polar secondary amine group to increase oral absorption, and an alkyl linker was inserted to increase the rate of exposure to the blood of Mirabegron through metabolic processes. A complex structure prodrug was presented. Particularly, the mirabegron derivative of Example 1 mentioned as a representative substance in the above patent has a faster time to reach the highest blood concentration (T _max ) compared to the administration of Mirabegron when administered orally to SD rats, and the highest concentration of drugs in the blood (C _max ) Is stated to be higher than that of Mirabegron administration. However, specific values for these pharmacokinetics were not presented, and T _max and C _max were related to the immediate-release effect of the drug, and oral absorption was not sufficiently demonstrated.

Korean Patent Registration No. 10-0506568 Korean Patent Registration No. 10-0908796 Korean Patent Registration No. 10-0967070 European Patent Registration No. 1,205,190 European Patent Application No. 2,345,410 European Patent Application No. 2,554,168 European patent registration number 3,360,866

Therefore, the problem to be solved by the present invention is to provide a precursor drug of Mirabegron having improved absorption rate, bioavailability, etc., a pharmaceutical composition comprising such a drug, and a pharmaceutical use of the drug to treat or improve overactive bladder disease.

In order to solve the above problems, the present invention provides a compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof.

[Formula 2]

The present inventors prepared and evaluated various prodrug compounds formed in an ester structure in the Mirabegron alcohol group, and not only aspects of physicochemical properties, stability, etc., but also absorption rate, bioavailability, and food variation according to minute differences in substituents attached to the ester structure. There was also a big difference in terms of the like, and the compound of Formula 2 exhibited a remarkably superior effect than other prodrug compounds having similar structures in not only the physicochemical properties for use as a pharmaceutical raw material, but also in various aspects mentioned above.

In the present invention, "pharmaceutically acceptable salts" include salts of a compound of the present invention and an active compound prepared with a relatively non-toxic acid. Acidic addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, pure or suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts are acetic acid, propionic acid, isobutyl acid, oxalic acid, maleic, malonic, benzoic, succinic acid, suberic, fumaric ( fumaric), mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric acid, tartaric acid, methanesulfonic, and their analogs. As well as salts derived from non-toxic organic acids, hydrogen chloride, hydrogen bromide, nitric acid, carbonic acid, monohydrogencarbonic, phosphoric, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrosulfuric acid, hydrogen iodide or phosphorous acid ( phosphorous acid) and analogues thereof. It also includes salts of amino acids such as alginate and analogs thereof, and analogs of organic acids such as glucuronic or galactunoric acids and analogs thereof.

The term "compound of the present invention" as used herein is meant to include not only the compound of Formula 2, but also clathrates, hydrates, solvates, or (crystalline) polymorphs thereof. In addition, the term "compound of the present invention" is meant to include a pharmaceutically acceptable salt of the compound of the present invention, unless a pharmaceutically acceptable salt thereof is mentioned. In one embodiment, the compound of the present invention is a stereoisomerically pure compound (e.g., substantially free of other stereoisomers (e.g., 85% ee or more, 90% ee or more, 95% ee or more, 97% ee Or more, or 99% ee or more)). That is, when the compound of Formula 2 or a salt thereof according to the present invention is tautomeric isomers and/or stereoisomers (e.g., geometrical isomers and conformational isomers), their separated isomers And mixtures each are also included in the scope of the compounds of the present invention. When the compound of the present invention or a salt thereof has an asymmetric carbon in the structure, their optically active compounds and racemic mixtures are also included in the scope of the compound of the present invention.

As used herein, the term "polymorph" refers to a solid crystalline form of the compound of the present invention or a complex thereof. Different polymorphs of the same compound exhibit different physical, chemical and/or spectral properties. Differences in terms of physical properties include, but are limited to, stability (e.g., thermal or light stability), compressibility and density (important for formulation and product manufacturing), and dissolution rate (which may affect bioavailability). It doesn't work. Differences in stability can be attributed to changes in chemical reactivity (e.g., differential oxidation, which discolors more quickly when composed of one polymorph than when composed of another polymorph) or mechanical characteristics (e.g., kinetic As the preferred polymorph, the stored tablet fragments thermodynamically convert to a more stable polymorph) or both (a tablet of one polymorph is more susceptible to degradation at high humidity). Other physical properties of polymorphs can influence their processing. For example, one polymorph may be more likely to form a solvate than another polymorph, for example due to its shape or size distribution of the particles, or may be more difficult to filter or wash.

The term "solvent compound" as used herein refers to a compound of the present invention or a pharmaceutically acceptable salt thereof comprising a stoichiometric or non-stoichiometric amount of a solvent bound by force between non-covalent molecules. Preferred solvents are volatile, non-toxic and can be administered in very small amounts to humans.

The term "hydrate" as used herein refers to a compound of the present invention or a pharmaceutically acceptable salt thereof containing a stoichiometric or non-stoichiometric amount of water bound by force between non-covalent molecules. .

The term "clathrate" as used herein refers to a compound of the present invention in the form of a crystal lattice including a space (eg, a channel) confining guest molecules (eg, solvent or water). Or its salt.

The compound represented by Chemical Formula 2 and other comparative compounds of the present invention may be synthesized, for example, in the following manner.

That is, the compound of Formula 2 can be synthesized by esterification with an acyl activator under acidic conditions using Mirabegron as a starting material. In addition, the X substituent of the acyl activator refers to a free functional group for activation, and may be selected from, for example, succinimidyl, O-acylisourea, chlorine atom, or bromine atom.

On the other hand, when the acyl activator is derived from an amino acid, the amine group included at this time is an appropriate protecting group, for example, t-butoxycarbonyl (Boc), fluorenylmethyloxycarbonyl (Fmoc), or It is protected with a functional group selected from carboxybenzyl (Cbz), which can be subjected to a deprotection process in a separate step to produce a final compound.

On the other hand, in the present reaction, the reaction does not proceed under basic or neutral conditions commonly used in esterification reactions, or there are many by-products. Therefore, even if the reaction partially proceeds, a lot of effort is required to purify the compound of Formula 2 with high purity, and the yield is very low, so industrial productivity is greatly reduced. Therefore, the reaction conditions must be made under acid conditions. The acid used in the reaction is specifically an inorganic acid selected from sulfuric acid, hydrochloric acid, phosphoric acid, boric acid, bromic acid, or fluoric acid, or an organic acid selected from acetic acid, formic acid, oxalic acid, trifluoroacetic acid, trifluorosulfonic acid, or perchloric acid. Includes. In addition, after the reaction is complete, the liquidity in a series of synthesis processes such as neutralization, extraction, crystallization, etc., should be excluded from strong basicity, specifically, it should be carried out under conditions selected from acidic, neutral, or weak base of pH 8 or less, and preferably It is good to maintain acidic conditions.

Meanwhile, since the starting material Mirabegron and the reaction product, the compound of Formula 2, have a chemical structure including a basic functional group, they exist as a salt type material under acidic conditions. Therefore, it is very important to select an appropriate solvent for dissolving a substance in each step of a series of synthesis processes such as reaction, extraction, and crystallization.

The esterification reaction is carried out in an inert polar solvent such as dichloromethane, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethylformamide, or an acid in a reaction solvent selected from N-methyl-2-pyrrolidone. It can be made by adding. Alternatively, an organic acid, for example, a liquid organic acid selected from acetic acid, formic acid, oxalic acid, trifluoroacetic acid, trifluorosulfonic acid, or perchloric acid may be used without using a separate reaction solvent.

The present inventors have created and manufactured a novel compound with a new structure capable of dramatically increasing the oral absorption rate upon oral administration by modifying the chemical structure of the Mirabegron compound. The concentration of the mirabegron substance exposed in the blood after oral administration of the novel compound thus prepared in vivo is ultimately directly proportional to the efficacy of the drug for the treatment or improvement of overactive bladder disease. This is based on the concentration of the mirabegron substance exposed in the blood after oral administration of mirabegron, and the novel compound according to the present invention, that is, after oral administration of the precursor drug, the metabolic process of the mirabegron substance exposed in the blood. By comparing the concentration, it means that the dose can be proportionally applied when the mirabegron precursor drug is administered orally.

The present inventors prepared and evaluated compounds having various chemical structures in order to derive a novel compound with improved oral absorption of Mirabegron. In addition, in terms of the physicochemical aspect of the compound, the absorption of the drug was evaluated by considering the degree of fat solubility, considering that the absorption of the drug is basically performed by passive diffusion. In order to prevent a decrease in absorption due to an excessively low water solubility, It was also evaluated whether it could show solubility.

Particularly, it is believed that some of the compounds according to the present invention can act as a substrate for amino acid transporters such as PepT1 and LAT1 among transmembrane transporters present in the intestinal mucosa. Therefore, it is thought that some of the compounds according to the present invention have increased bioavailability due to active transport by amino acid transporters. However, the present invention is not limited to this theoretical mechanism.

Specifically, as a result of the pharmacokinetic evaluation of the compound of Formula 2 according to the present invention, the relative bioavailability compared to the orally administered Mirabegron was 137.28%, indicating a remarkable increase. In addition, the time to reach the highest blood concentration (T _max ) when administered orally with Mirabegron is 3 hours and the highest concentration (C _max ) of the drug in the blood is 239 ng/ml, whereas in the case of the compound of the present invention, the time to reach the highest blood concentration ( T _max ) was 0.38 hours, and the highest concentration (C _max ) of the drug in the blood was 302 ng/ml, demonstrating that the absorption of the drug was remarkably improved.

In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of Formula 2 or a pharmaceutically acceptable salt thereof according to the present invention, and a pharmaceutically acceptable carrier.

As used herein, an “effective amount or effective amount” slows or minimizes overactive bladder disease; Or an amount of a compound of the present invention sufficient to provide a therapeutic benefit in the treatment or management of overactive bladder disease.

As the pharmaceutically acceptable carrier, for example, a carrier for oral administration or a carrier for parenteral administration may be used. Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. In addition, the carrier for parenteral administration may include water, suitable oils, saline, aqueous glucose and glycol, and the like, and may further include stabilizers and preservatives. Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid. Suitable preservatives are benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. Other pharmaceutically acceptable carriers may be referred to as those described in the following documents. (Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995)

The pharmaceutical composition of the present invention can be administered to mammals including humans by any route of administration, and can be administered orally or parenterally. However, the oral route of administration is more preferred in view of the excellent oral absorption of the compound of the present invention.

Parenteral administration methods include, for example, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual or rectal administration. However, it is not limited thereto. For example, the pharmaceutical composition of the present invention may be prepared in an injectable formulation and administered by a method of lightly pricking the skin with a 30 gauge thin injection needle, or by applying it directly to the skin.

The pharmaceutical composition of the present invention may be formulated as a formulation for oral administration or parenteral administration according to the route of administration as described above.

In the case of a formulation for oral administration, the composition of the present invention may be formulated using a method known in the art as a powder, granule, tablet, pill, dragee, capsule, liquid, gel, syrup, slurry, suspension, etc. I can. For example, oral preparations can obtain tablets by blending the active ingredient with a solid excipient, pulverizing it, adding a suitable adjuvant, and processing it into a granule mixture. Examples of suitable excipients include sugars including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol and maltitol, and starches including corn starch, wheat starch, rice starch and potato starch, cellulose, Fillers such as celluloses including methyl cellulose, sodium carboxymethylcellulose and hydroxypropylmethyl-cellulose, gelatin, and polyvinylpyrrolidone may be included. In addition, in some cases, cross-linked polyvinylpyrrolidone, agar, alginic acid or sodium alginate may be added as a disintegrant. Furthermore, the pharmaceutical composition of the present invention may further include an anti-aggregating agent, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent and a preservative.

In the case of a formulation for parenteral administration, it can be formulated in the form of injections, creams, lotions, ointments for external use, oils, moisturizers, gels, aerosols, and nasal inhalants by methods known in the art. These formulations are described in Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour, a formula generally known for all pharmaceutical chemistry.

The total dose of the compound of the present invention may be administered to a patient as a single dose, and may be administered by a fractionated treatment protocol that is administered in multiple doses for a long time. The pharmaceutical composition of the present invention may vary the content of the active ingredient according to the symptoms of the disease. Preferably, the preferred total dose of the compound of the present invention may be about 0.01 μg to 1,000 mg, most preferably 0.1 μg to 100 mg per 1 kg of patient body weight per day. However, the dosage of the compound of the present invention is not only the route of administration and the number of treatments, but also the patient's age, weight, health condition, sex, disease severity, diet, excretion rate, and other factors. It will be possible to determine an appropriate effective dosage. The pharmaceutical composition according to the present invention is not particularly limited in its formulation, route of administration, and method of administration as long as it exhibits the effects of the present invention.

In addition, the compound of the present invention may be administered as an individual therapeutic agent or administered in combination with other therapeutic agents. When administered in combination with other therapeutic agents, the compound of the present invention and other therapeutic agents may be administered simultaneously, separately or sequentially. At this time, the other therapeutic agent may be a substance already known to have an effect of treating or improving overactive bladder disease. When the compound of the present invention is administered in combination with another therapeutic agent, the compound of the present invention and the other therapeutic agent may be separately formulated into separate containers, or may be formulated in combination in the same formulation.

In order to administer the compounds presented in the present invention to the human body, a representative pharmaceutical method is described in detail by using a tablet as shown in Table 1 below.

(Unit: mg per tablet) Composition 1 Composition 2 Drug substance (compound of formula 2 or salt thereof) 50 25 Lactose 30 20 Sodium lauryl sulfate (SLS) 10 5 Polyvinyl pyrrolidone (PVP) 5 2 Sodium croscarmellose 5 5 Microcrystalline cellulose 5 5 Magnesium stearate 5 3 Total amount 110 65

The present invention also provides a pharmaceutical composition for the treatment or improvement of overactive bladder disease, comprising the compound of Formula 2 or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient. That is, the present invention provides a pharmaceutical use of the compound of Formula 2 or a pharmaceutically acceptable salt thereof according to the present invention for the treatment or improvement of overactive bladder disease.

In yet another aspect, the present invention provides a method of treating or ameliorating an overactive bladder disease comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula 2 or a pharmaceutically acceptable salt thereof. In another aspect, the subject is a human. In one aspect, the treatment is a preventative treatment. In another embodiment, the treatment is a palliative treatment. In another embodiment, the treatment is a restorative treatment.

The present invention provides a compound effective in the treatment or amelioration of an overactive bladder disease, a pharmaceutical composition comprising them as an active ingredient, their pharmaceutical use, and a treatment method comprising administering them to an individual in need of treatment or prevention. The compound according to the present invention or a pharmaceutically acceptable salt thereof, as an active ingredient of a pharmaceutical product, has various advantages in various aspects such as solubility, and particularly has excellent bioavailability after oral administration.

FIG. 1 is a graph of the time-dependent blood concentration of Mirabegron detected in blood after oral administration of a comparative substance, Mirabegron, and a single oral administration of a compound of Example 2 (compound of Formula 2), which is an embodiment of the present invention, to a male SD rat. In FIG. 1, ▲ is the result of the oral administration group of Mirabegron, and △ is the result of the oral administration group of the compound of Example 2.
FIG. 2 is a graph of the hourly blood concentration of Mirabegron detected in the blood after a single oral administration of a male beagle dog in a fasting and feeding state of the compound of Example 2 according to the present invention. In FIG. 2, ▲ is the result of oral administration of the compound of Example 2 in a fasting state, and △ is the result of oral administration of the compound of Example 2 in the feeding state.

The present invention will be described in more detail based on the following examples, but this is not intended to limit the scope of the present invention. In addition, those of ordinary skill in the art will be able to make various modifications and modifications to the present invention within the scope not detrimental to the spirit of the present invention.

First, examples according to the present invention are described below. Representative examples corresponding thereto along with specific preparation steps are described below, and compounds having different substituents may be prepared through similar steps. Those of ordinary skill in the art will be able to easily prepare compounds having different substituents with reference to the following representative examples.

Preparation Example 1:

Mirabegron was added to 4 times the volume of trifluoroacetic acid and stirred to completely dissolve. After cooling this mixture in an ice container, 1.2 equivalents of an acyl activator was slowly added thereto, followed by stirring overnight. After the reaction was completed, a 10-fold volume of methyl t-butyl ether was temporarily added and then stirred vigorously to obtain a homogeneous suspension. This was filtered and washed with methyl t-butyl ether to obtain the target compound as a crude crystal. The obtained crude crystal was again suspended in 5 times the volume of isopropanol, heated to 40° C. to completely dissolve, and then 1.2 equivalent of concentrated hydrochloric acid was added and stirred for 10 minutes. Five times the volume of tetrahydrofuran was added thereto, followed by stirring overnight to obtain a homogeneous suspension. After filtering this, it was washed with a 1:1 mixture of isopropanol and tetrahydrofuran, and then washed again with methyl t-butyl ether. Vacuum-dried at 50° C. to obtain the target compound as a hydrochloric acid solid.

Preparation Example 2:

Mirabegron was added to 4 times the volume of trifluoroacetic acid and stirred to completely dissolve. After cooling this mixture in an ice container, 1.2 equivalents of an acyl activator was slowly added thereto, followed by stirring for about 1 to 24 hours. After confirming that the reaction was complete, a 10-fold volume of methyl t-butyl ether was temporarily added and then stirred vigorously to obtain a homogeneous suspension. This was filtered and washed with methyl t-butyl ether to obtain the target compound as a crude crystal. The obtained crude crystal was again dissolved in 10 times the volume of methanol, and a 5% palladium catalyst (Pd/C) adsorbed on activated carbon was added at a 10% weight ratio. The mixture was stirred at room temperature under hydrogen gas (H ₂ gas) at normal pressure for about 1 hour to 24 hours, and then it was confirmed that the reaction was complete. The reaction solution was filtered using a celite adjuvant, and then a filtrate was obtained and concentrated in vacuo. After 5 times the volume of isopropanol was added to the concentrated residue and completely dissolved, 1.2 equivalents of concentrated hydrochloric acid was added and stirred for 10 minutes. Five times the volume of tetrahydrofuran was added thereto, followed by stirring overnight to obtain a homogeneous suspension. After filtering this, it was washed with a 1:1 mixture of isopropanol and tetrahydrofuran, and then washed again with methyl t-butyl ether. Vacuum-dried at 50° C. to obtain the target compound as a hydrochloride solid.

Example 1: (R)-2-((4-(2-(2-aminothiazol-4-yl)acetamido)phenethyl)amino)-1-phenylethyl acetate dihydrochloride

Using 10 g (0.025 mol) of Mirabegron and 1.2 equivalents of acetyl chloride, 11.6 g (90.0%) of the title compound as a pale yellow solid was obtained according to the method of Preparation Example 1. The results of nuclear magnetic resonance analysis and mass spectrometry are shown in Table 2 below.

Example 2: (R)-2-((4-(2-(2-aminothiazol-4-yl)acetamido)phenethyl)amino)-1-phenylethyl isobutyrate dihydrochloride

Using 10 g (0.025 mol) of Mirabegron and 1.2 equivalents of isobutyryl chloride, 10.4 g (76.4%) of the title compound as a pale yellow solid was obtained according to the method of Preparation Example 1. The results of nuclear magnetic resonance analysis and mass spectrometry are shown in Table 2 below.

Example 3: (R)-4-(2-((4-(2-(2-aminothiazol-4-yl)acetamido)phenethyl) amino)-1-phenylethoxy)-4- Oxobutanoic acid hydrochloride

According to the method of Preparation Example 2 using 10 g (0.025 mol) of Mirabegron and 1.2 equivalents of 2-oxo-2-phenylethyl 4-chloro-4-oxobutanoate, 11.6 g of the title compound as a yellow solid (90.0% ) Was obtained. The results of nuclear magnetic resonance analysis and mass spectrometry are shown in Table 2 below.

Example 4: (R)-2-((4-(2-(2-aminothiazol-4-yl)acetamido)phenylethyl)amino)-1-phenylethyl 2,5-dihydroxybenzo Eight dihydrochloride

Using 10 g (0.025 mol) of Mirabegron and 1.2 equivalents of 2,5-bis(benzyloxy)benzoyl chloride, 12.4 g (81.2%) of the title compound as a pale yellow solid was obtained according to the method of Preparation Example 2. The results of nuclear magnetic resonance analysis and mass spectrometry are shown in Table 2 below.

Example 5: (R)-2-((4-(2-(2-aminothiazol-4-yl)acetamido)phenethyl) amino)-1-phenylethyl 2-hydroxy-2-phenyl Acetate dihydrochloride

Using 10 g (0.025 mol) of Mirabegron and 1.2 equivalents of 2-(benzyloxy)-2-phenylacetyl chloride, 10.2 g (67.0%) of the title compound as a pale yellow solid was obtained according to the method of Preparation Example 2. The results of nuclear magnetic resonance analysis and mass spectrometry are shown in Table 2 below.

Example 6: (R)-2-((4-(2-(2-aminothiazol-4-yl)acetamido)phenethyl) amino)-1-phenylethyl 2-hydroxypropanoate 2 Hydrochloride

Using 10 g (0.025 mol) of Mirabegron and 1.2 equivalents of 2-(benzyloxy) propanoyl chloride, 10.0 g (73.2%) of the title compound as a pale yellow solid was obtained according to the method of Preparation Example 2. The results of nuclear magnetic resonance analysis and mass spectrometry are shown in Table 2 below.

Example 7: (R)-2-((4-(2-(2-aminothiazol-4-yl)acetamido)phenethyl) amino)-1-phenylethyl pivalate dihydrochloride

Using 10 g (0.025 mol) of Mirabegron and 1.2 equivalents of pivaloyl chloride, 10.8 g (77.4%) of the title compound as an off-white solid was obtained according to the method of Preparation Example 1. The results of nuclear magnetic resonance analysis and mass spectrometry are shown in Table 2 below.

Example 8: (R)-2-((4-(2-(2-aminothiazol-4-yl)acetamido)phenethyl) amino)-1-phenylethyl L-leucinate trihydrochloride

Using 10 g (0.025 mol) of Mirabegron and 1.2 equivalents of benzyl (S)-(1-chloro-4-methyl-1-oxopentan-2-yl) carbamate, according to the method of Preparation Example 2 7.8 g (50.0%) of the title compound was obtained. The results of nuclear magnetic resonance analysis and mass spectrometry are shown in Table 2 below.

Example 9: (R)-2-((4-(2-(4-aminothiazol-2-yl)acetamido)phenethyl)amino)-1-phenylethyl hexanoate dihydrochloride

According to the method of Preparation Example 1 using 10 g (0.025 mol) of Mirabegron and 1.2 equivalents of hexanoyl chloride, 8.4 g (58.7%) of the title compound as a pale brown solid was obtained. The results of nuclear magnetic resonance analysis and mass spectrometry are shown in Table 2 below.

Example 10: (R)-2-((4-(2-(4-aminothiazol-2-yl)acetamido)phenethyl)amino)-1-phenylethyl 2-ethylhexanoate dihydrochloride

Using 10 g (0.025 mol) of Mirabegron and 1.2 equivalents of 2-ethylhexanoyl chloride, 8.1 g (53.9%) of the title compound as a pale yellow solid was obtained according to the method of Preparation Example 1. The results of nuclear magnetic resonance analysis and mass spectrometry are shown in Table 2 below.

The results of nuclear magnetic resonance analysis and mass spectrometry of the Example compounds are shown in Table 2 below.

compound Nuclear magnetic resonance analysis Mass spectrometry Example 1 ¹ H NMR (400MHz, DMSO-d ₆ ) δ 2.10 (3H, s), 2.88-3.10 (4H, m), 3.30-3.35 (1H, m), 3.55-3.78 (7H, m), 6.10 (1H, d), 6.72 (1H, s), 7.25-7.45 (8H, m), 7.61 (2H, d), 9.10 (1H, br s), 9.34 (1H, br s), 9.40 (1H, br s), 10.50 (1H, s) [M+1] ⁺ , 439.1 Example 2 ¹ H NMR (400MHz, DMSO-d ₆ ) δ 1.07 (6H, d), 2.68-2.70 (1H, m), 2.88-2.99 (2H, m), 3.08-3.18 (2H, m), 3.21-3.30 ( 1H, m), 3.35-3.75 (6H, m), 5.95 (1H, d), 6.65 (1H, s), 7.15 (2H, d), 7.30-7.42 (6H, m), 7.55 (2H, d) , 8.95-9.25 (2H, br s), 9.38 (1H, br s), 10.55 (1H, s) [M+1] ⁺ , 467.2 Example 3 ¹ H NMR (400MHz, DMSO-d ₆ ) δ 2.52 (2H, t), 2.70 (2H, t), 2.90-2.98 (2H, m), 3.10-3.28 (3H, m), 3.35-3.71 (6H, m), 5.95 (1H, d), 6.65 (1H, s), 7.20 (2H, d), 7.35-7.41 (6H, m), 7.55 (2H, d), 9.58 (2H, br s), 10.55 ( 1H, s) [M+1] ⁺ , 497.1 Example 4 ¹ H NMR (400MHz, DMSO-d ₆ ) δ 2.95-3.08 (2H, m), 3.11-3.33 (2H, m), 3.35-3.40 (1H, m), 3.66-3.70 (1H, m), 3.73 ( 2H, s), 6.30 (1H, s), 6.72 (1H, s), 7.20 (2H, d), 7.35-7.60 (6H, m), 7.68 (2H, d), 7.80 (2H, d), 7.87 -7.91 (1H, m), 8.70 (1H, d), 8.85 (1H, d), 9.30-9.52 (3H, br s), 10.48 (1H, s) [M+1] ⁺ , 533.1 Example 5 ¹ H NMR (400MHz, DMSO-d ₆ ) δ 2.45-2.68 (2H, m), 3.05-3.23 (2H, m), 3.38-3.45 (2H, m), 3.80 (2H, s), 5.76 (1H, s) 6.18 (1H, s), 6.70 (1H, s), 7.15 (2H, d), 7.45-7.68 (6H, m), 7.80 (2H, d), 7.86 (2H, d), 7.87-7.90 ( 1H, m), 8.70-8.85 (2H, m), 9.30-9.42 (3H, br s), 10.58 (1H, s) [M+1] ⁺ , 531.2 Example 6 ¹ H NMR (400MHz, DMSO-d ₆ ) δ 1.44 (3H, s), 2.78-2.95 (2H, m), 3.10-3.22 (2H, m), 3.30-3.37 (1H, m), 3.40-3.88 ( 7H, m), 4.55 (1H, q), 6.05 (1H, d), 6.85 (1H, s), 7.20 (2H, d), 7.31-7.45 (6H, m), 7.55 (2H, d), 9.15 -9.25 (2H, br s), 9.53 (1H, br s), 10.68 (1H, s) [M+1] ⁺ , 469.1 Example 7 ¹ H NMR (400MHz, DMSO-d ₆ ) δ 1.14 (9H, s), 2.90-2.92 (2H, m), 3.10-3.18 (2H, m), 3.25-3.28 (1H, m), 3.30-3.68 ( 5H, m), 3.70 (2H, s), 5.90 (1H, d), 6.75 (1H, s), 7.15 (2H, d), 7.30-7.40 (6H, m), 7.55 (2H, m), 9.00 -9.15 (2H, br s), 9.32 (1H, br s), 10.40 (1H, s) [M+1] ⁺ , 481.2 Example 8 ¹ H NMR (400MHz, DMSO-d ₆ ) δ 0.95 (6H, d), 1.44-1.48 (1H, m), 1.88-1.96 (2H, m), 3.20-3.68 (6H, m), 3.90 (1H, d), 4.33 (1H, d), 6.10 (1H, d), 6.59 (1H, s), 7.22 (2H, d), 7.30-7.44 (5H, m), 7.50 (2H, d), 8.60-8.95 (3H, br s), 9.12 (2H, br s), 9.53 (2H, br s), 11.40 (1H, s) [M+1] ⁺ , 510.2 Example 9 ¹ H NMR (400MHz, DMSO-d ₆ ) δ0.83 (3H, t), 1.16-1.30 (4H, m), 1.53 (2H, qnt), 2.40-2.48 (2H, m), 2.90-3.07 (2H , m), 3.10-3.25 (2H, m), 3.26-3.37 (1H, m), 3.38-3.53 (1H, m), 3.75 (2H, s), 6.02 (1H, d), 6.70 (1H, s ), 7.20 (2H, d), 7.31-7.47 (5H, m), 7.59 (2H, d), 9.40-9.49 (3H, br s), 9.72 (1H, br s), 10.70 (1H, s) [M+1] ⁺ , 495.2 Example 10 ¹ H NMR (400MHz, DMSO-d ₆ ) δ0.66-0.79 (3H, m), 0.79-0.87 (3H, m), 0.90-1.31 (5H, m), 1.33-1.63 (3H, m), 2.35 -2.46 (1H, m), 2.90-3.05 (2H, m), 3.07-3.23 (2H, m), 3.25-3.37 (1H, m), 3.44-3.56 (1H, m), 3.73 (2H, s) , 5.98-6.05 (1H, m), 6.71 (1H, s), 7.19 (2H, d), 7.33-7.45 (5H, m), 7.59 (2H, d), 9.42-9.51 (3H, br s), 9.70 (1H, broad s), 10.70 (1H, s) [M+1] ⁺ , 523.3

Experimental Example 1: Rat single oral administration pharmacokinetic evaluation

The pharmacokinetic test for the example compound, that is, the mirabegron precursor drug, was performed as follows. Specifically, following oral administration of the example compounds to male SD (Sprague-Dawley) rats once, and tracking the kinetics of the Mirabegron drug released into the blood by metabolic processes, oral administration of a standard substance (mirabegron) The efficacy of the compounds of the present invention was demonstrated by comparison with poetry. (Male SD Rats, 5 mice per each group) Test substances (standard substances or example compounds) were prepared in the same manner and administered to rats at a dose of 0.1 mmol/kg, and plasma was separated after blood collection at a predetermined time. Analysis of the drug was performed using HPLC (XBridge column C ₁₈ , Waters, mobile phase 0.1% formic acid:acetonitrile (30:70, %/%)) and MS/MS (ESI positive, MRM), and rat donor plasma And each of the commercial standard solutions were mixed in a ratio of 9:1 to prepare and weigh at concentrations of 5, 50, 100, 500, 100 and 5,000 ng/ml. In addition, the preparation of the QC sample was prepared by mixing rat donor plasma and a standard solution for QC at a ratio of 9:1, and at concentrations of 100, 750 and 2,500 ng/ml. In the pretreatment method, 100 μl of a plasma sample was transferred to a tube for centrifugation, 10 μl of an internal standard solution and 300 μl of methanol were added, followed by mixing for about 30 seconds. The tube was centrifuged at 3,000 xg (4°C) for about 5 minutes, and the supernatant was taken and transferred to an LC vial, and then injected into the instrument. In addition, the concentration of the active ingredient, that is, Mirabegron, in rat plasma was quantified by applying a previously verified analysis method. As the pharmacokinetic parameter, WinNonlin 5.2 (Pharsight, USA) program was used, and AUC _0-t , AUC _0-∞ , C _max , T _max , and t _1/2 were calculated by Noncompartment modeling (best fit). The pharmacokinetic parameter results were expressed as mean (Mean) and standard deviation (SD), and statistically processed using the SPSS program (Statistical Package for the Social Sciences, 10.0K, USA).

The results of oral administration of each test substance and the relative bioavailability of the example compounds relative to the standard substance are summarized in Table 3 below.

Test substance Relative bioavailability (F, %) compared to standard material (Miravegron) Test substance Relative bioavailability (F, %) compared to standard material (Miravegron) Example 1 109.21 Example 6 108.41 Example 2 137.28 Example 7 108.69 Example 3 98.71 Example 8 108.11 Example 4 101.12 Example 9 102.10 Example 5 91.13 Example 10 105.66

When the standard mirabegron was administered orally, the average AUC _0-24 was 869 hr*ng/ml, the average AUC _inf 885 hr*ng/ml, the average C _max was 239 ng/ml, and the average T _max was 3.0. The time, the average t _1/2 was 4.26 hours. On the other hand, for the compound of Formula 2 according to the present invention, the average AUC _0-24 is 1,193 hr*ng/ml, the average AUC _inf is 1,204 hr*ng/ml, the average C _max is 302 ng/ml, and the average T _max is 0.38 hours, average t _1/2 was 3.87 hours, relative bioavailability was 137.28%. After oral administration of the compound of Formula 2 and the standard substance, the trend of the blood concentration of Mirabegron by time is as shown in FIG. 1.

As shown in the results of Table 3, the compound of Formula 2 (Example 2) according to the present invention was very superior to the compounds having similar oral administration bioavailability.

Experimental Example 2: Single-dose pharmacokinetic evaluation of beagle dogs in fasting and feeding states

The pharmacokinetic test for the example compound, that is, the mirabegron precursor drug, was performed as follows. Specifically, the compound of Example 2, which has excellent bioavailability in rats, and Mirabegron, a standard substance, were administered orally to 3 male beagle dogs each in a fasting and feeding state, respectively, and then Mirabegron released into the blood by metabolic processes. The efficacy of the compound of the present invention was demonstrated by tracking the kinetics of the drug and comparing it with the oral administration of a standard substance (mirabegron). Test substances (standard substances or example compounds) were prepared by the same method, and then administered to beagle dogs at a dose of 1.26 μmmol/kg, blood was collected at a predetermined time, and plasma was separated. The analysis of the drug was performed in the same manner as in Experimental Example 1, and the results of oral administration of each test substance in fasting and feeding states are summarized in Table 4 below.

Test substance Diet AUC _0-24 (hr*ng/ml) Cmax (ng/ml) Standard material (Miravegron) Fasting 127.5 ± 12.0 15.6 ± 0.6 Fed 77.5 ± 6.7 11.8 ± 0.5 Example 2 Fasting 203.5 ± 14.8 20.2 ± 4.1 Fed 208.6 ± 12.8 20.5 ± 0.4

As shown in the results of Table 4, Mirabegron, which is a standard material, shows a difference between AUC and Cmax in fasting and feeding states, and it is found that AUC decreases by 60% and Cmax by 75% in the fasting state in the feeding state. I can. On the other hand, it was confirmed that AUC and Cmax were similarly identified in the compound of this patent regardless of whether or not they were fed. According to the US FDA's "CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 202611Orig1s000", in clinical trials in humans, it has been reported that Mirabegron shows a large difference in oral blood levels depending on diet. It has been reported that the blood concentration of Mirabegron by oral administration on a high fat diet decreased by 45% and 17%, respectively, compared to the fasted state. Compared to that, it is known to decrease by 76% and 51%, respectively, so the blood concentration of mirabegron when administered orally varies depending on the presence or absence of diet and the content of fat during diet.

On the other hand, according to "Report on the Deliberation Results, June 3, 2011, Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau Ministry of Health, Labor and Welfare", mirabegrones in a pharmacokinetic test using dogs were used for fasting and oral intake. It has been reported that blood levels also show a large difference.

The precursor compounds of Mirabegron according to the present invention exhibit a constant oral blood concentration (AUC, Cmax) regardless of the presence or absence of a diet in a pharmacokinetic test using dogs, unlike the standard substance Mirabegron. By improving the food effect of this, it is thought that it will have great advantages in the proper administration, dosage setting and ease of administration for pharmacological activity.

Claims (7)

A compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof.
[Formula 2]

A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. A pharmaceutical composition for the treatment or improvement of overactive bladder disease, comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. In preparing the compound of claim 1 or a pharmaceutically acceptable salt thereof, a method comprising reacting mirabegron and an acyl activator under acidic conditions. The method of claim 4, wherein the acyl activator is isobutyryl chloride. The method of claim 4, wherein the acid is trifluoroacetic acid. The method according to claim 4, characterized in that after the reaction is completed, the subsequent steps of neutralization, extraction, and crystallization are performed in acidic, neutral, or weak base of pH 8 or less.

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