HK1139950A - N- hydroxy-4-{5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy} benzamidine 2 ethansulfonic acid salt, process for the preparation thereof and pharmaceutical composition comprising the same - Google Patents

Description

N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine 2 ethanesulfonate, method for preparing same and pharmaceutical composition comprising same

Technical Field

The present invention relates to N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine 2 ethanesulfonate, a preparation method thereof, a pharmaceutical composition for preventing and treating osteoporosis, bone fracture or allergic inflammatory disease comprising the same, and an oral preparation for preventing and treating osteoporosis, bone fracture or allergic inflammatory disease comprising the same.

Background

N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine has excellent efficacy in the treatment and prevention of osteoporosis (korean patent No. 10-454767), the treatment of bone fracture (korean patent No. 10-639041), and the treatment and prevention of allergic inflammatory diseases (korean patent No. 10-682199).

It is well known to those skilled in the art that active ingredients for pharmaceutical compositions must be readily soluble in water or in aqueous solutions over a wide range of pH values. However, since the solubility of N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine is low, it is required to develop a salt form having higher solubility in order to improve the bioavailability of the compound.

Accordingly, the inventors developed N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine 2 methanesulfonate having high solubility and stability (Korean patent publication No. 10-2006-.

Disclosure of Invention

Technical problem

Accordingly, the inventors conducted research to develop a salt form having better physicochemical properties such as stability, solubility and bioavailability than the previously invented N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine 2 methanesulfonate. Accordingly, the inventors synthesized N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine 2 ethanesulfonate, and they found that the 2 ethanesulfonate has not only excellent solubility, stability and bioavailability, but also a higher initial release rate than the 2 methanesulfonate, thereby accomplishing the present invention.

Technical scheme

The object of the present invention is to provide N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine 2 ethanesulfonate, a preparation method thereof, a pharmaceutical composition for preventing and treating osteoporosis, bone fracture or allergic inflammatory diseases comprising the same, and an oral formulation for preventing and treating osteoporosis, bone fracture or allergic inflammatory diseases comprising the same.

Detailed Description

In one aspect, the present invention relates to N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine 2 ethanesulfonate represented by the following formula 1.

< formula 1>

N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine is disclosed in the literature (Lee, Sun-Eun, Synthesis and Biological Activity of Natural products and Designed New Hybrid Compounds for the Treatment of LTB4Related diseases, Busan National University, a the science for a Ph.D. degree, August 1999).

The term "2 ethanesulfonate" as used herein refers to a compound wherein two molecules of ethanesulfonic acid are combined with one free base compound to form a salt, which for the purposes of the present invention, means the 2 ethanesulfonate salt of N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine.

The inventors found that 2 ethanesulfonate in which two molecules of ethanesulfonic acid are combined with N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine compound having low solubility has higher solubility, initial release rate and stability, and shows significantly higher in vivo bioavailability, compared to 2 methanesulfonate in which two molecules of methanesulfonic acid are combined with the benzamidine compound.

In detail, the 2 ethanesulfonic acid salt of N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine of the present invention is about 1.25 times as high as the solubility of its 2 methanesulfonic acid salt in distilled water, and the release rates after 5 minutes, 10 minutes and 15 minutes are about 2.8 times, about 1.4 times and about 1.2 times as high as that of its 2 methanesulfonic acid salt, respectively. Also, the content thereof is not changed in a stability test under a severe condition of 60 ℃ for two weeks, and it shows excellent chemical stability at high temperature. In addition, the 2 ethanesulfonate of the benzamidine compound exhibits a higher bioavailability when administered to a human body, a Cmax (maximum blood concentration) that is 1.3 times higher than the 2 methanesulfonate salt, a Tmax (time to reach maximum plasma concentration) that is 1.4 times faster than the 2 methanesulfonate salt, and an AUC (area under the blood concentration-time curve) that is about 1.2 times higher than the 2 methanesulfonate salt.

The 2 ethanesulfonic acid salt of N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine of the present invention may be in crystalline or amorphous form. A crystalline form of the 2 ethanesulfonic acid salt of N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine is preferred.

In another aspect, the present invention relates to a method for preparing 2 ethanesulfonic acid salt of N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine represented by formula 1.

In detail, the present invention provides a process for preparing 2 ethanesulfonic acid salt of N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine comprising the step of reacting N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine and ethanesulfonic acid in an inert solvent as shown in reaction scheme 1 below.

< reaction scheme 1>

The ethanesulfonic acid used in the preparation method of the present invention is a salt approved by the US FDA for use in pharmaceuticals, which is a colorless stable liquid having no hygroscopicity and corrosiveness. Also, since ethanesulfonic acid is non-toxic, it provides a safe environment during the preparation process, and since it is easy to handle, it is easy to mass-produce.

The inert solvent used in the preparation method of the present invention includes ethyl acetate, methanol, ethanol, isopropanol, acetone, acetonitrile, hexane and isopropyl ether. Among them, ethanol is preferred.

1 equivalent of N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine is reacted with 2 to 4 equivalents, preferably 2.1 to 2.5 equivalents, of ethanesulfonic acid in an inert solvent at-20 ℃ to 40 ℃, preferably 0 ℃ to 20 ℃, for 10 minutes to 5 hours, preferably 30 minutes to 2 hours.

By this preparation method, the 2 ethanesulfonic acid salt of N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine can be prepared in a high yield of 86% or more.

In another aspect, the present invention relates to a pharmaceutical composition for preventing and treating osteoporosis, bone fracture or allergic inflammatory diseases, which comprises the 2 ethanesulfonic acid salt of N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine.

The term "osteoporosis" as used herein, also known as "osteopenia", means a condition characterized by excessive loss of organic and inorganic bone matrix without structural abnormalities in the remaining bone, which results in the bone filling pores like a sponge and thus becoming compressible and brittle. The excellent clinical efficacy of the N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine compound in the prevention and treatment of osteoporosis is described in detail in Korean patent No. 10-454767 and International patent No. WO/03007947.

The term "fracture" as used herein means a state in which the continuity of bone tissue is completely or incompletely broken, and includes various physical injuries of the bone, which are classified according to anatomical regions (epiphyseal, metaphyseal, diaphyseal and intra-articular, or proximal, middle and distal, etc.), severity of fracture (complete, incomplete, etc.), direction of fracture (transverse, oblique, spiral, longitudinal, etc.), presence or absence of open injury (open, closed), number of fracture fragments (simple or linear, comminuted, segmental, etc.), stability of fracture (stable, unstable), and degree of displacement of fracture fragments. The N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine compound significantly reduced the volume of callus, significantly increased the bone mineral content and mechanical strength of callus, significantly reduced the amount of connective tissue and soft tissue in callus, and significantly increased the bone tissue density in rats, compared to the control group not treated with the benzamidine compound (korean patent No. 10-639041).

The term "allergic inflammatory disease" as used herein refers to nonspecific inflammatory diseases caused by various allergens, including allergic rhinitis, asthma, allergic conjunctivitis, allergic dermatitis, atopic dermatitis, contact dermatitis, urticaria, anaphylaxis, insect allergy, food allergy, and drug allergy.

The prevention and treatment efficacy of the N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine compound on allergic inflammatory diseases was determined in a mouse model of asthma induced by chronic ovalbumin exposure. The benzamidine compound was administered for 18 days starting on the day of immunization with ovalbumin. At 15 days post immunization, experimental animals were stimulated with ovalbumin and sacrificed three days later to study changes in lung weight, cellular characteristics of peripheral blood samples and bronchoalveolar lavage fluid, and histopathological changes in lung tissue. Oral administration of the benzamidine compound inhibited the increase in lung weight compared to the control group administered with sterile distilled water alone. The total number of leukocytes and the number of eosinophils were significantly increased in asthmatic mice compared to normal mice, whereas they were significantly decreased in asthmatic mice administered with the benzamidine compound in a dose-dependent manner compared to the control group. Also, the number of eosinophils in bronchoalveolar lavage fluid was significantly increased in asthmatic mice compared to normal mice, whereas they were significantly decreased in asthmatic mice administered with the benzamidine compound in a dose-dependent manner compared to the control group. The asthmatic mice administered with the benzamidine compound had a significantly increased alveolar area as compared to the control group (korean patent No. 10-682199).

In addition to the above ingredients, the composition of the present invention may further comprise one or more pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers may include common excipients, disintegrants, wetting agents, fillers, thickeners, binders, lubricants, glidants, antioxidants, buffering agents, surfactants, dispersing agents, and combinations of two or more thereof.

The compositions of the present invention may be administered orally or parenterally. For oral administration, the composition may be prepared in solid form, such as tablets, capsules, pills or powders; or in liquid form, such as suspension, syrup or solution. For parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, intranasal, etc.), the composition may be formulated as an injection, ointment, patch, etc. These dosage forms can be manufactured according to the type of disease or ingredient as appropriate by an appropriate method known in the art or a method described in Remington's Pharmaceutical Science (latest edition), Mack Publishing Company, Easton PA.

Preferably, the oral formulation may be prepared with one or more carbonates selected from alkali metal carbonate, alkali metal bicarbonate and alkaline earth metal carbonate and/or one or more disintegrants selected from sodium carboxymethyl starch, calcium carboxymethyl cellulose and croscarmellose sodium. The formulation significantly improves the release rate and bioavailability by inhibiting the gelation of the 2 ethanesulfonate upon contact with water during the initial period of release. During the release of the 2 ethanesulfonate, the above carbonate and/or disintegrant regionally forms a neutral pH or weakly alkaline environment at the diffusion layer in contact with water, or rapidly disperses the composition, thereby effectively suppressing gelation caused by hydration at the initial stage of release.

The carbonate used in the oral formulation is selected from alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; and alkaline earth metal carbonates such as calcium carbonate and magnesium carbonate. Sodium bicarbonate or calcium carbonate is preferred. The carbonate may be contained in an amount of about 0.4 to 6 parts by weight, preferably 0.5 to 2 parts by weight, based on 1 part by weight of the 2 ethanesulfonate. In the case where the carbonate is used in an amount of less than 0.4 parts by weight, the release rate of the compound cannot be increased. More than 6 parts by weight of carbonate may generate gas in the gastrointestinal tract and thus cause abdominal distension.

The disintegrant used in the oral preparation is selected from one or more of sodium carboxymethyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose and croscarmellose sodium. Sodium carboxymethyl starch or croscarmellose sodium is preferred. The disintegrant rapidly absorbs water at the initial stage of release and largely swells to disperse the particles of 2 ethanesulfonate represented by formula 1, thereby effectively inhibiting gelation starting at the surface of the formulation, resulting in an increase in the release rate of the compound. The content of the disintegrant is 0.5 to 5 parts by weight based on 1 part by weight of the 2 ethanesulfonate represented by the above formula. In the case where the disintegrant is used in an amount of less than 0.5 parts by weight, the drug cannot be uniformly dispersed, so that the inhibition of gelation by the carrier is reduced at the initial stage of release, and finally, the release rate of the drug is not improved. More than 5 parts by weight of the disintegrant does not have any further enhancing effect on the drug release rate and increases the volume of the formulation, thus causing inconvenience in taking the drug and reducing patient compliance.

The oral formulation may be prepared by mixing the 2 ethanesulfonate and both the disintegrant and carbonate. The combined use of a disintegrant and a carbonate improves the release properties of the drug relative to the use alone. In the case of using a disintegrant and a carbonate in combination, the oral formulation of the present invention preferably comprises 0.5 to 5 parts by weight of the disintegrant and 0.1 to 6 parts by weight of the carbonate, based on 1 part by weight of the 2 ethanesulfonate. In the case where the disintegrant and the carbonate are used in amounts of less than 0.5 parts by weight and 0.1 parts by weight, respectively, they cannot exhibit a proper inhibition effect on gelation. In the case where the amount of the disintegrant and the carbonate exceeds 5 parts by weight and 6 parts by weight, respectively, satisfactory patient compliance cannot be achieved.

In addition, the oral formulation may further comprise an excipient. In order to increase the drug release rate by effectively inhibiting gelation and thus rapidly dispersing the drug, the excipient is preferably an inorganic excipient such as monocalcium phosphate, calcium phosphate, heavy magnesium oxide, precipitated calcium carbonate and magnesium carbonate. More preferably, calcium dihydrogen phosphate, calcium phosphate or heavy magnesium oxide. In contrast, organic excipients such as microcrystalline cellulose (avicel), mannitol, corn starch and lactose had no enhancing effect on the release rate of the drug.

In addition, the oral formulation may further comprise conventional additives that are pharmaceutically acceptable. Examples of additives include binders, glidants, surfactants, colorants and taste/odor masking agents. Pharmaceutically acceptable conventional binders and glidants are available. Examples of binders are maltose, gum arabic and hydroxypropyl cellulose. Examples of glidants are carnauba wax, light anhydrous silicic acid, synthetic aluminum silicate, stearic acid, magnesium stearate and talc.

The oral preparation may contain pharmaceutically acceptable conventional excipients or adjuvants in addition to the above ingredients, and may be formulated into solid preparations for oral administration such as tablets, capsules, granules and fine granules by conventional pharmaceutical methods. That is, according to the present invention, the composition may be formulated into granules, or glidants and other pharmaceutically acceptable additives may be added, and then filled directly into hard capsules in the form of powder or granules. In addition, pharmaceutical additives for tableting may be added to the composition and tabletted according to a known method.

The dosage of the composition of the present invention may vary depending on the body weight, age, sex, health state and diet of the patient, administration period, administration route, excretion rate, severity of disease, etc. The 2 ethanesulfonic acid salt of N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine represented by formula 1 may be administered, for example, in a daily dose of 1 to 1,000mg/kg, preferably 10 to 500 mg/kg. The daily dose may be divided into one or more doses.

The composition can be used alone or in combination with surgery, hormone therapy, drug therapy and biological response modifiers for the prevention and treatment of osteoporosis, bone fractures or allergic inflammatory diseases.

The present invention will be better understood from the following examples, which should not be construed as limiting the invention.

Examples

Example 1: n-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy]Preparation of pentoxy benzamidine 2 ethanesulfonate

3g (6.614mmol) of N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine were dissolved in 30ml of ethanol and mixed with 1.14ml (2.2 equivalents) of ethanesulfonic acid while stirring at room temperature for one hour. The resulting solution was then mixed with 30ml of acetone and 60ml of hexane while stirring for one hour. The resulting solid was recovered by filtration, washed with acetone, and dried in vacuo. As a result, 4.17g (yield: 86%) of N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine 2 ethanesulfonate was obtained as a white solid.

The ethanesulfonic acid content and melting point of the obtained N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine 2 ethanesulfonic acid salt were analyzed, and the results were as follows.

The ethanesulfonic acid content (theoretical value: 32.7%, measured value: 33.0%),

melting point: 141 deg.C

Comparative example 1: n-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy]Preparation of pentoxy benzamidine

N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine was prepared according to the method described in the document Lee, Sun-Eun, Synthesis and Biological Activity of Natural products and Designed New Hybrid Compounds for the treatment of LTB4Related diseases, the docusal thesis, the Graduate School, bus national university, 1999 August.

Comparative example 2: n-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy]Preparation of pentoxy benzamidine 2 mesylate salt

N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine 2 methanesulfonate was prepared according to the method described in Korean patent publication No. 10-2006-57511.

Experimental example 1: evaluation of solubility

The N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine 2 ethanesulfonate prepared in example 1, the N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine prepared in comparative example 1, were measured at room temperature, and solubility (. mu.g/ml) of N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine 2 methanesulfonate prepared in comparative example 2 in various solvents.

The results are shown in Table 1 below.

[ TABLE 1 ]

As shown in Table 1, the solubility of the 2 ethanesulfonic acid salt of N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine was 1.25 times higher than that of its 2 methanesulfonate salt.

Experimental example 2: evaluation of Release RatePrice of

The N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine 2 ethanesulfonic acid salt prepared in example 1, the N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine prepared in comparative example 1, were measured at a paddle rotation speed of 50rpm, and the release rate (%) of N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine 2 methanesulfonate prepared in comparative example 2 in a buffer solution (pH 1.2).

The results are shown in Table 2 below.

[ TABLE 2 ]

As shown in Table 2, the 2 ethanesulfonate salt of N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine exhibited about 2.8 times, about 1.4 times, and about 1.2 times higher release rates after 5 minutes, 10 minutes, and 15 minutes, respectively, than its 2 methanesulfonate salt.

Experimental example 3: evaluation of stability

The N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine 2 ethanesulfonate prepared in example 1 was placed in a clear glass bottle and stored in an open state under accelerated conditions (60 ℃ C. + -2/75% RH. + -. 5) for 2 weeks. The samples were then analyzed by HPLC (Waters Module 1). The analysis was performed using a column packed with octadecylsilylated silica gel (Shiseido CAPCELL PAKC18, UG 120, particle size 5 μm) under the following conditions: ultraviolet detection: 256nm, sample size: 10 μ L, mobile phase flow rate: 1.5 mL/min. The amount of the compound is calculated as an area percentage.

The results are given in Table 3 below.

[ TABLE 3 ]

	Content (%)
		Initial stage	100.00
After 1 week	99.88
		After 2 weeks	99.86

As shown in Table 3, the accelerated test at 60 ℃ did not cause a change in the content of the N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine 2 ethanesulfonate in distilled water. Also, the N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine 2 ethanesulfonate was found to have high chemical stability at high temperatures.

Experimental example 4: pharmacokinetic evaluation (bioavailability)

N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine 2 ethanesulfonate prepared in example 1 and N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine 2 methanesulfonate prepared in comparative example 2 were administered to SD rats at a dose of 50mg/kg, respectively. At the given time points (0, 0.5, 1, 1.5, 2, 3, 5 and 8 hours), the rats were lightly anesthetized with ether, and blood samples were collected from the retroorbital venous plexus and stored at-20 ℃ until concentration analysis. Plasma samples were mixed with an equal volume of internal standard solution (prepared by dissolving betamethasone in acetonitrile to a final concentration of 30 μ g/ml) under stirring for 1min and centrifuged at 12,000rpm for 10 min. The plasma samples were analyzed for active components by HPLC (Model: Waters Module 1). Pharmacokinetic parameters [ maximum blood concentration (Cmax) and area under the blood concentration-time curve (AUC) ] were calculated from the data obtained by non-compartmental model analysis using WinNonlin program (Version 1.0, Scientific consensus inc., USA).

The results are shown in Table 4 below.

[ TABLE 4 ]

As shown in table 4, the N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine 2 ethanesulfonate exhibited high bioavailability in distilled water, Cmax (highest blood concentration) of 2 ethanesulfonate was 1.3 times higher than 2 methanesulfonate, Tmax (time to reach highest plasma concentration) of 2 ethanesulfonate was 1.4 times faster than 2 methanesulfonate, and AUC (area under blood concentration-time curve) of 2 ethanesulfonate was about 1.2 times higher than 2 methanesulfonate, compared to 2 methanesulfonate of the benzamidine compound.

Industrial applicability

The 2 ethanesulfonic acid salt of N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine of the present invention has superior solubility, stability and bioavailability, as well as a high initial release rate, compared to the 2 methanesulfonic acid salt. In particular, since the 2 ethanesulfonic acid salt of N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine exhibits a higher Cmax (maximum blood concentration) and AUC (area under the blood concentration-time curve), and a faster Tmax (time to reach maximum plasma concentration), blood concentration thereof rapidly reaches an effective level, thus resulting in a more rapid drug action. Accordingly, the 2 ethanesulfonic acid salt of N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine having improved bioavailability can be used for the prevention or treatment of osteoporosis, bone fractures, and allergic inflammatory diseases even at low concentrations.

Claims (10)

1. N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine 2 ethanesulfonate represented by the following formula 1,

< formula 1>

2. A process for the preparation of N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine 2 ethanesulfonate according to claim 1, comprising the step of reacting N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine and ethanesulfonic acid in an inert solvent.

3. The method of claim 2, wherein the inert solvent is one or more selected from the group consisting of ethyl acetate, methanol, ethanol, isopropanol, acetone, acetonitrile, hexane, and isopropyl ether.

4. A pharmaceutical composition for preventing and treating osteoporosis, comprising N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine 2 ethanesulfonate according to claim 1 and a pharmaceutically acceptable carrier.

5. A pharmaceutical composition for treating bone fracture comprising N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine 2 ethanesulfonate according to claim 1 and a pharmaceutically acceptable carrier.

6. A pharmaceutical composition for preventing and treating allergic inflammatory diseases, which comprises N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine 2 ethanesulfonate according to claim 1 and a pharmaceutically acceptable carrier.

7. An oral preparation for preventing and treating osteoporosis, bone fracture and allergic inflammatory diseases, which comprises N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine 2 ethanesulfonate according to claim 1 and (a) one or more carbonates selected from the group consisting of alkali metal carbonate, alkali metal bicarbonate and alkaline earth metal carbonate; (b) one or more disintegrants selected from sodium carboxymethyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose and croscarmellose sodium; or a combination of (a) and (b).

8. The oral formulation of claim 7, wherein the carbonate is sodium bicarbonate or calcium carbonate and the disintegrant is sodium carboxymethyl starch or croscarmellose sodium.

9. The oral formulation of claim 7 or 8, further comprising an inorganic excipient.

10. The oral formulation of claim 9, wherein the inorganic excipient is monocalcium phosphate, calcium phosphate, heavy magnesium oxide, precipitated calcium carbonate, magnesium carbonate, or a mixture thereof.