(S)-2-Amino-3-{4-[(5-amino-2-phenylbenzo[d]oxazol-7-yl)methoxy]-3,5-dichlorophenyl}propanoic acid monohydrochloride, its monohydrate, and its crystals and its preparation method

Abstract

The present invention provides (S)-2-amino-3-{4-[(5-amino-2-phenylbenzo[d]oxazol-7-yl)methoxy]-3,5-dichlorophenyl}propanoic acid monohydrochloride, its monohydrate, and its crystals, as well as a method for preparing the same. Furthermore, the present invention also provides a pharmaceutical composition containing the compound that is useful as an anticancer agent.

Description

[Technical field]

[0001] The present invention relates to (S)-2-amino-3-{4-[(5-amino-2-phenylbenzo[d]oxazol-7-yl)methoxy]-3,5-dichlorophenyl}propanoic acid monohydrochloride, which has selective inhibitory activity against LAT1 (L-type amino acid transporter 1), its monohydrate, and crystals thereof, as well as a process for producing the same and a pharmaceutical composition containing the same. [Background technology]

[0002] In tumor cells, the expression of transporters that take in nutrients such as sugars and amino acids from the outside is increased in order to maintain rapid cell proliferation and enhanced intracellular metabolism. In particular, LAT1 is a transporter that is specifically expressed in tumor cells, and transports essential amino acids including leucine, which is also a signal factor, and plays an important role in supplying essential nutrients to tumor cells. In contrast, LAT2 (L-type amino acid transporter 2) is known to be widely expressed in normal cells as well. For this reason, a compound that has selective inhibitory activity against LAT1 can be an antitumor drug with fewer side effects. As a compound having such properties, (S)-2-amino-3-{4-[(5-amino-2-phenylbenzo[d]oxazol-7-yl)methoxy]-3,5-dichlorophenyl}propanoic acid (hereinafter sometimes referred to as "compound A") is known (Patent Document 1). [ka]

[0003] Also, an injection containing compound A, a pH adjuster, and cyclodextrins is known (Patent Document 2). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2008 / 081537 [Patent Document 2] Patent Publication No. 2017-155023 Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide a hydrochloride of compound A which is highly pure, does not easily form agglomerates when dried, has excellent solubility, and is easy to handle as a drug substance. [Means for solving the problem]

[0006] As a result of extensive research, the present inventors have discovered a new compound form of Compound A, namely, monohydrochloride monohydrate crystals, which is highly pure, unlikely to form agglomerates when dried, and has excellent solubility in the preparation solution used to manufacture a lyophilized formulation. They have also discovered that Compound A monohydrochloride monohydrate exists as a pseudo-polymorphic anhydrous crystal. Furthermore, the present inventors have discovered manufacturing conditions that enable selective production of crystals of Compound A monohydrochloride monohydrate, thereby completing the present invention.

[0007] That is, the present invention provides the following.

[0008] [1] Compound A monohydrochloride. [2] Compound A monohydrochloride monohydrate. [3] Compound A monohydrochloride anhydrous. [4] Crystal of compound A monohydrochloride monohydrate. [5] Crystals of compound A monohydrochloride anhydrous. [6] A method for producing compound A monohydrochloride monohydrate by adding hydrochloric acid to compound A in an aqueous organic solvent and adjusting the pH. [7] A method for producing compound A monohydrochloride monohydrate by adding hydrochloric acid to a salt of compound A and a base in an aqueous organic solvent to adjust the pH. [8] The method according to [7], wherein the salt of compound A and a base is an alkali metal salt of compound A. [9] A method for producing compound A monohydrochloride monohydrate by adding hydrochloric acid or a base to a salt of compound A and an acid in an aqueous organic solvent to adjust the pH.

[10] The method according to [9], wherein the salt of compound A and an acid is a hydrochloride salt of compound A.

[11] The method according to

[10] , wherein the salt of compound A and an acid is compound A monohydrochloride anhydrate.

[12] The method according to any one of [9] to

[11] , wherein the base used to adjust the pH is an inorganic base.

[13] The method according to any one of [9] to

[12] , wherein the base used to adjust the pH is one or more bases selected from sodium hydroxide, sodium carbonate, and sodium bicarbonate.

[14] The method according to any one of [6] to

[13] , wherein the water activity of the aqueous organic solvent is adjusted to be 0.5 to 1.0, and the pH is adjusted to be in the range of 1 to 2.

[15] A method for producing compound A monohydrochloride anhydride by reacting compound A with hydrochloric acid in an organic solvent.

[16] The production method according to

[15] , wherein the water activity of the organic solvent is less than 0.5, and 0.8 to 1.2 molar equivalents of hydrochloric acid are reacted with respect to compound A.

[17] A method for producing compound A monohydrochloride anhydrous, comprising suspending and stirring compound A monohydrochloride monohydrate in an organic solvent and removing the water of hydration.

[0009] Furthermore, the present invention provides the following:

[18] The crystal according to [4], characterized in that in powder X-ray diffraction, the diffraction angles expressed as 2θ are 7.1, 9.5, 18.9, 21.6 and 24.2°.

[19] In the infrared spectrum, the peaks are at 1393, 1381, 1342, 1329 and 1267 cm -1 The crystal according to [4], characterized in that it has a peak at

[20] The crystal according to [5], characterized in that in powder X-ray diffraction, the crystal has diffraction angles, expressed as 2θ, of 10.5°, 14.5°, 17.1°, 22.5° and 23.0°.

[21] In the infrared spectrum, the peaks are 1601, 1556, 1547, 1404 and 1269 cm -1 The crystal according to [5], characterized in that it has a peak at

[22] A pharmaceutical composition comprising a compound according to [1] or [2], or a crystal of any of [4],

[18] or

[19] , and a pharma- ceutically acceptable carrier.

[23] The pharmaceutical composition according to

[22] , which is for the treatment of cancer.

[24] A pharmaceutical comprising the pharmaceutical composition according to

[22] or

[23] in combination with at least one anticancer agent selected from the group consisting of anticancer agents selected from the group consisting of anticancer alkylating agents, anticancer antimetabolites, anticancer antibiotics, plant-derived anticancer agents, anticancer platinum coordination compounds, anticancer camptothecin derivatives, anticancer tyrosine kinase inhibitors, monoclonal antibodies, and interferons. Effect of the Invention

[0010] The present invention provides compound A monohydrochloride monohydrate and a method for producing the same. Compound A monohydrochloride monohydrate is highly pure, does not easily form aggregates when dried, and has excellent solubility in preparation solutions used in producing lyophilized preparations, making it useful as a pharmaceutical active ingredient.

[0011] The present invention further provides compound A monohydrochloride anhydride and a method for producing the same. Compound A monohydrochloride anhydride is useful as a raw material for producing compound A monohydrochloride monohydrate. [Brief description of the drawings]

[0012] [Figure 1] FIG. 1 shows an optical microscope image of compound A dihydrochloride. [Diagram 2] This shows the acid dissociation equilibrium of compound A hydrochloride. [Diagram 3] FIG. 1 shows the state of dissociation equilibrium of compound A at each pH. [Figure 4] FIG. 2 is a diagram showing an optical microscope image of compound A monohydrochloride monohydrate. [Diagram 5]FIG. 1 shows an optical microscope image of compound A·monohydrochloride·anhydrous. [Figure 6] FIG. 1 shows an example of an infrared absorption spectrum (ATR method) of compound A dihydrochloride. [Figure 7] FIG. 1 shows an example of a powder X-ray diffraction pattern of Compound A dihydrochloride. [Figure 8] FIG. 2 is an example of an infrared absorption spectrum (ATR method) of compound A monohydrochloride monohydrate. [Figure 9] FIG. 2 is a diagram showing an example of a powder X-ray diffraction pattern of Compound A monohydrochloride monohydrate. [Figure 10] FIG. 2 is an example of an infrared absorption spectrum (ATR method) of compound A·monohydrochloride·anhydrous. [Figure 11] FIG. 2 is a diagram showing an example of a powder X-ray diffraction pattern of Compound A monohydrochloride anhydrate. [Figure 12] This shows the appearance of blocky compound A dihydrochloride. [Figure 13] This is a diagram showing the appearance of compound A dihydrochloride in fine powder form. [Figure 14] FIG. 1 shows the appearance of powdered compound A monohydrochloride monohydrate. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The present invention will be described in detail below.

[0014] In this specification, unless otherwise specified, each term has the following meaning.

[0015] In the present invention, the term "drug substance" means an active ingredient of a medicine.

[0016] Compound A is (S)-2-amino-3-{4-[(5-amino-2-phenylbenzo[d]oxazol-7-yl)methoxy]-3,5-dichlorophenyl}propanoic acid.

[0017] Intermediate 1 is (S)-2-amino-3-{4-[(5-amino-2-phenylbenzo[d]oxazol-7-yl)methoxy]-3,5-dichlorophenyl}-2-[(tert-butoxycarbonyl)amino]propanoic acid.

[0018] Aliphatic hydrocarbons include, for example, pentane, hexane, cyclohexane, or heptane.

[0019] Aromatic hydrocarbons include, for example, benzene, toluene or xylene.

[0020] Examples of halogenated hydrocarbons include dichloromethane, chloroform, and dichloroethane.

[0021] Examples of alcohols include methanol, ethanol, 1-propanol, 2-propanol, butanol, and 2-methyl-2-propanol.

[0022] Examples of the ethers include diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and diethylene glycol diethyl ether.

[0023] The ketones include, for example, acetone, 2-butanone, or 4-methyl-2-pentanone.

[0024] Esters include, for example, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate or butyl acetate.

[0025] Examples of amides include N,N-dimethylformamide, N,N-dimethylacetamide, and 1-methyl-2-pyrrolidone.

[0026] The nitriles include, for example, acetonitrile or propionitrile.

[0027] The sulfoxides include, for example, dimethyl sulfoxide.

[0028] In general, the wave number (cm) in the infrared absorption spectrum (ATR method) -1 ) values ​​are ±2cm -1 Therefore, in the present invention, unless otherwise specified, when referring to "wave number Y", it means "wave number ((Y-2) to (Y+2)) cm -1 " Therefore, not only crystals with perfectly matching wave numbers of absorption peaks in infrared absorption spectrum (ATR method) but also crystals with wave numbers of absorption peaks within ±2 cm -1 Crystals that match within the error range are also included in the present invention.

[0029] Generally, the diffraction angle (2θ) in powder X-ray diffraction may have an error within the range of ±0.2°. Therefore, in the present invention, "diffraction angle (2θ) X°" means "diffraction angle (2θ) ((X-0.2) to (X+0.2))°" unless otherwise specified. Therefore, not only crystals in which the diffraction angle (2θ) in powder X-ray diffraction is completely the same, but also crystals in which the diffraction angle (2θ) is the same within the error range of ±0.2° are included in the present invention.

[0030] [Compound A] Compound A can be produced by the method described in Patent Document 1. Compound A is poorly soluble in various organic solvents, and is difficult to isolate by procedures such as extraction. Therefore, compound A is isolated by a method such as neutralization crystallization in a water-containing solvent.

[0031] [Compound A dihydrochloride] According to Patent Document 1, the hydrochloride of compound A can be produced by converting compound A into the hydrochloride according to a conventional method.

[0032] The present inventors, referring to the method described in Patent Document 1, deprotected (S)-2-amino-3-{4-[(5-amino-2-phenylbenzo[d]oxazol-7-yl)methoxy]-3,5-dichlorophenyl}-2-[(tert-butoxycarbonyl)amino]propanoic acid (hereinafter sometimes referred to as Intermediate 1) in a standard manner to obtain Compound A dihydrochloride as a fine crystalline solid (Figure 1).

[0033] Compound A dihydrochloride is characterized by powder X-ray diffraction with diffraction angles 2θ of 8.0, 8.8, 19.6, 22.2, 23.8, and 26.1°. Figure 7 shows the powder X-ray diffraction chart of Compound A dihydrochloride.

[0034] Compound A dihydrochloride also exhibits the following peaks in the infrared spectrum: 1736, 1483, 1474 and 1240 cm -1 It is characterized by having characteristic peaks at 1000 MHz and 1000 MHz. Figure 6 shows the infrared absorption spectrum of compound A dihydrochloride.

[0035] [ka]

[0036] [Acid dissociation equilibrium of compound A] Compound A has two or more basic sites that can form a salt with hydrochloric acid, and the equilibrium shown in Figure 2 is established. The acid dissociation constant (pK a ) was experimentally determined by neutralization titration, and the first acid dissociation constant (pK a1 ) is 1.0, the second acid dissociation constant (pK a2 ) was 2.2.

[0037] Here, the molar fractions of each component of compound A are expressed as [Compound A dihydrochloride], [Compound A monohydrochloride], and [Compound A], respectively, and the hydrogen ion concentration is [H + ], then equations 1 to 3 hold true.

[0038] (Formula 1)K a1 = [Compound A monohydrochloride] × [H+ ] / [Compound A dihydrochloride] (Formula 2)K a2 =[Compound A]×[H + ] / [Compound A monohydrochloride] Equation 3: [Compound A dihydrochloride] + [Compound A monohydrochloride] + [Compound A] = 1

[0039] Furthermore, for Formulas 1 to 3, [H + The equilibrium state graph shown in Figure 3 was created by substituting the values ​​of

[0043] and

[0044] . Figure 3 shows the dissociation equilibrium state of compound A at each pH.

[0040] As can be seen from Figure 3, when pH is 1.0 (=pK a1 ), compound A dihydrochloride is dominant and at pH 2.2 (=pK a2 ), compound A is dominant. Furthermore, when the pH is greater than 1.0 (= pK a1 )~2.2(=pK a2 ), compound A monohydrochloride is dominant and at pH 1.6 (=(pK a1 +pK a2 It is clear that the mole fraction is maximized when

[0041] In this way, when forming the hydrochloride of compound A, by controlling the pH range, it is possible to obtain a hydrochloride of any valence.

[0042] [Correlation between water activity and hydration of Compound A monohydrochloride] In the field of medicine, hydrates are extremely important substances for improving physicochemical properties such as solubility. Hydrates are characterized by the inclusion of water molecules in the crystal structure, and are generally difficult to obtain from solutions that do not contain free water.

[0043] For example, in the report by Simon et al. (Org. Process Res. Dev., 2009, 13(1), pp78-83) and in International Publication No. 2015 / 073476, the water activity of the system (hereinafter, a wThis indicates that the reaction can produce anhydrous or hydrates of different valence states.

[0044] Here, the water activity a w is an index that represents the proportion of free water contained in any substance, and as shown in Equation 4, the activity coefficient of water, γ w and the mole fraction of water x w It can be expressed as a product of

[0045] (Formula 4)a w =γ w x w

[0046] In addition, the activity coefficient of water in Eq. w can be estimated, for example, using the UNIQUAC formula (Abrams, DS et al.: AIChE J., 1975, 21, pp116-128).

[0047] The inventors of the present invention suspended and stirred compound A monohydrochloride monohydrate in various alcoholic waters with different water activities and found that compound A monohydrochloride became compound A monohydrochloride monohydrate and compound A monohydrochloride anhydrate depending on the water activity of the system. The results are shown in Table 1.

[0048] [Table 1]

[0049] That is, as shown in Table 1, when the water activity of the system is in the range of 0.45 or less, compound A monohydrochloride anhydride is obtained, and when the water activity of the system is in the range of 0.65 or more, compound A monohydrochloride monohydrate is obtained.

[0050] In this way, by controlling the water activity range, it is possible to selectively obtain compound A monohydrochloride anhydrate and compound A monohydrochloride monohydrate, respectively.

[0051] [Compound A monohydrochloride monohydrate] Compound A monohydrochloride monohydrate is a compound discovered by the present inventors.

[0052] [ka]

[0053] Compound A monohydrochloride monohydrate is a needle-to-column crystalline solid with a large aspect ratio (Figure 4), and is characterized by powder X-ray diffraction angles of 7.1, 9.5, 18.9, 21.6, and 24.2° (2θ). Figure 9 shows the powder X-ray diffraction chart of compound A monohydrochloride monohydrate.

[0054] Compound A monohydrochloride monohydrate also exhibits the following peaks in the infrared absorption spectrum: 1393, 1381, 1342, 1329 and 1267 cm -1 It is characterized by having characteristic peaks at 1000 MHz and 1000 MHz. Figure 8 shows the infrared absorption spectrum chart of compound A monohydrochloride monohydrate.

[0055] Compound A monohydrochloride monohydrate contains 1 molar equivalent of hydrogen chloride relative to compound A, and may contain 0.8 to 1.2 molar equivalents.

[0056] Furthermore, compound A monohydrochloride monohydrate contains 3.4 wt % water, and the content of water may be in the range of 2.8 to 4.1 wt %.

[0057] [Production method of compound A monohydrochloride monohydrate] Compound A monohydrochloride monohydrate can be prepared by adding hydrochloric acid to compound A in a water-containing organic solvent and adjusting the pH.

[0058] The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include alcohols, ethers, ketones, esters, amides, nitriles, and sulfoxides, which may be used in combination. Preferred solvents include alcohols, ethers, ketones, and nitriles, with alcohols being more preferred, and methanol, ethanol, 1-propanol, and 2-propanol being even more preferred.

[0059] The water activity of the solvent in the water-containing organic solvent may be 0.5 or more, and is preferably 0.65 or more.

[0060] The amount of the solvent used may be 1 to 50 times (v / w) the amount of compound A, and preferably 5 to 20 times (v / w).

[0061] The pH range for preparing Compound A monohydrochloride monohydrate may be from 1 to 2, preferably from 1.0 to 2.2, and more preferably from 1.2 to 2.0.

[0062] The reaction temperature may be from 0 to 60°C, preferably from 0 to 30°C.

[0063] The reaction time may be from 1 minute to 50 hours, and is preferably from 30 minutes to 12 hours.

[0064] The reaction atmosphere is not particularly limited, but it is preferable to carry out the reaction in an inert gas atmosphere, such as an argon gas atmosphere or a nitrogen gas atmosphere.

[0065] In addition, a salt of compound A and a base may be used as compound A used in this reaction. The type of salt of compound A and a base is not particularly limited as long as it does not affect the reaction, and examples thereof include salts with inorganic bases and organic bases. Preferred salts include salts with inorganic bases, and more preferred salts are salts with alkali metals.

[0066] Furthermore, as compound A used in this reaction, a salt of compound A and an acid may be used, and the pH may be adjusted by adding hydrochloric acid or a base.

[0067] The type of salt formed from compound A and an acid is not particularly limited as long as it does not affect the reaction, and examples thereof include salts with mineral acids and carboxylic acids. Preferred salts include salts with mineral acids, and hydrochlorides are more preferred. That is, the hydrochloride of compound A used in this reaction may be compound A monohydrochloride anhydride.

[0068] The type of base used for adjusting the pH may be an inorganic base, preferably an alkali metal base, more preferably sodium hydroxide, sodium carbonate, or sodium hydrogen carbonate. These may be used alone or in combination of two or more.

[0069] [Compound A monohydrochloride anhydrous] Compound A monohydrochloride anhydrate is a compound discovered by the present inventors.

[0070] [ka]

[0071] Compound A monohydrochloride anhydrate is a fine crystalline solid, characterized by powder X-ray diffraction with diffraction angles 2θ of 10.5, 14.5, 17.1, 22.5, and 23.0°. Figure 11 shows the powder X-ray diffraction chart of Compound A monohydrochloride monohydrate.

[0072] Compound A·1 hydrochloride anhydride exhibits the following peaks in the infrared absorption spectrum: 1601, 1556, 1547, 1404 and 1269 cm -1 It is characterized by having characteristic peaks at 1000 MHz and 1000 MHz. Figure 10 shows the infrared absorption spectrum chart of compound A·monohydrochloride·anhydrous.

[0073] Compound A monohydrochloride anhydride contains 1 molar equivalent of hydrogen chloride relative to compound A, and may contain 0.8 to 1.2 molar equivalents.

[0074] [Production method of compound A monohydrochloride anhydride] Compound A monohydrochloride anhydrous can be prepared by reacting compound A with 1 molar equivalent of hydrogen chloride in an organic solvent.

[0075] The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include alcohols, ethers, ketones, esters, and nitriles, which may be used in combination. Preferred solvents include alcohols, ethers, and esters, and more preferred are methanol, ethanol, ethyl acetate, tetrahydrofuran, and dioxane.

[0076] The water activity of the solvent may be less than 0.5, and is preferably 0.3 or less.

[0077] The amount of the solvent used may be 1 to 50 times (v / w) the amount of compound A, and preferably 5 to 20 times (v / w).

[0078] The amount of hydrogen chloride to be reacted may be 1 molar equivalent, more preferably 0.8 to 1.2 molar equivalents, and further preferably 0.9 to 1.1 molar equivalents.

[0079] The reaction temperature may be from 0 to 60°C, preferably from 0 to 30°C.

[0080] The reaction time may be from 1 minute to 50 hours, and is preferably from 30 minutes to 12 hours.

[0081] The reaction atmosphere is not particularly limited, but it is preferable to carry out the reaction in an inert gas atmosphere, such as an argon gas atmosphere or a nitrogen gas atmosphere.

[0082] Compound A monohydrochloride anhydrate can also be prepared by suspending and stirring compound A monohydrochloride monohydrate in an organic solvent and removing the water of hydration.

[0083] The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include alcohols, ethers, ketones, esters, and nitriles, which may be used in combination. Preferred solvents include alcohols, ketones, and esters, and more preferred are methanol, ethanol, 1-propanol, 2-propanol, acetone, and ethyl acetate.

[0084] The water activity of the solvent may be less than 0.5, and is preferably 0.3 or less.

[0085] The amount of the solvent used may be 1 to 50 times (v / w) the amount of compound A, and preferably 5 to 20 times (v / w).

[0086] The reaction temperature may be from 0 to 60°C, preferably from 0 to 30°C.

[0087] The reaction time may be from 1 minute to 50 hours, and is preferably from 30 minutes to 12 hours.

[0088] The reaction atmosphere is not particularly limited, but it is preferable to carry out the reaction in an inert gas atmosphere, such as an argon gas atmosphere or a nitrogen gas atmosphere.

[0089] That is, the above method makes it possible to selectively obtain compound A monohydrochloride anhydride and compound A monohydrochloride monohydrate, respectively. Furthermore, compound A monohydrochloride monohydrate can be prepared from compound A monohydrochloride anhydride. Furthermore, the use of compound A monohydrochloride monohydrate is advantageous for the preparation of the pharmaceutical compositions described below.

[0090] Target of administration In the present invention, the subject (patient) is a warm-blooded animal, and may be a human or non-human mammal. In one embodiment, the subject is a human.

[0091] Pharmaceutical Compositions Compound A·1 hydrochloride of the present invention is administered to a patient as a pharmaceutical composition together with a pharma- ceutically acceptable diluent, excipient or carrier (collectively referred to herein as "carrier"). The pharma- ceutically acceptable diluent, excipient or carrier is in a unit dosage form, such as a tablet, pill, capsule, powder, granule, sterile solution or suspension, aerosol or liquid spray, drops, injection or suppository. The pharmaceutical composition is for oral, parenteral, intranasal, sublingual or rectal administration, or administration by inhalation. The pharmaceutical composition of the present invention can be prepared by a method known in the art. Here, "pharma- ceutically acceptable" means non-toxic to the subject (patient).

[0092] Furthermore, Compound A·1 hydrochloride of the present invention can be administered in intranasal form by topical use of suitable intranasal vehicles, or via transdermal routes using those forms of transdermal skin patches well known to those of ordinary skill in the art.

[0093] Additionally, Compound A·1 hydrochloride of the present invention can be administered in intranasal form by topical use of suitable intranasal vehicles, or via transdermal routes using transdermal skin patch forms well known to those skilled in the art. Dosage regimens for administration in the form of a transdermal delivery system will be continuous throughout the dosage regimen.

[0094] In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of Compound A·monohydrochloride·monohydrate of the present invention in admixture with a pharma- ceutically acceptable carrier.

[0095] In one embodiment, the Compound A monohydrochloride monohydrate in the pharmaceutical composition is in a crystalline form. In one embodiment, the crystalline form is present in about 5% to about 100% by weight of the drug substance. In another embodiment, the crystalline form is present in about 10% to about 100% by weight of the drug substance. In another embodiment, the crystalline form is present in about 25% to about 100% by weight of the drug substance. In another embodiment, the crystalline form is present in about 50% to about 100% by weight of the drug substance. In yet another embodiment, substantially all of the drug substance is in the crystalline form.

[0096] The dosage of the active ingredient of the present invention to obtain the intended effect of the present invention will be in the range of about 0.01 mg per kg of body weight per day (mg / kg / day) to about 100 mg / kg / day, preferably 0.01 to 10 mg / kg / day, and most preferably 0.1 to 5.0 mg / kg / day. For oral administration, the pharmaceutical composition is preferably provided in the form of a tablet containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of active ingredient for adjusting the dosage to the patient to be treated. The pharmaceutical composition typically contains about 0.01 mg to about 500 mg of active ingredient, preferably about 1 mg to about 200 mg of active ingredient. For intravenous administration, the dosage will be in the range of about 0.1 to about 10 mg / kg. The crystals of the present invention may be administered in a single daily dose, or the total daily dose may be divided into two, three or four doses administered daily.

[0097] Alternatively, the pharmaceutical compositions of the present invention comprise a therapeutically effective amount of an active ingredient of the present invention in admixture with a pharma- ceutically acceptable carrier, wherein the active ingredient comprises about 1% to about 100% by weight, about 5% to about 100% by weight, about 10% to about 100% by weight, about 50% to about 100% by weight, about 70% to about 100% by weight, or about 80% to about 100% by weight of compound A monohydrochloride monohydrate.

[0098] For example, for oral administration in the form of a tablet or capsule, the active drug components can be combined with an oral non-toxic, pharmacologically acceptable inert carrier, such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc.; for oral administration in liquid form, the oral drug components can be combined with any oral non-toxic, pharmacologically acceptable inert carrier, such as ethanol, glycerol, water, etc. Furthermore, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the composition, if necessary. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, gum tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, etc. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. The disintegrants include, without being restricted thereto, starch, methylcellulose, agar, bentonite, xanthan gum and the like.

[0099] In particular, since the compound A monohydrochloride monohydrate of the present invention can be used as an anticancer agent, it can be preferably formulated as an injection, which contains the compound A monohydrochloride monohydrate of the present invention, a pH adjuster, and cyclodextrins.

[0100] Injections include, for example, intravenous, subcutaneous, and intramuscular injections, and intravenous drip infusions.

[0101] Examples of pH adjusters that can be incorporated into the injectable preparation of the present invention include alkali metal hydroxides such as sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide, alkali metal hydrides such as sodium hydride and potassium hydride, and carbonates of alkali metals or alkaline earth metals. In particular, sodium hydroxide and sodium carbonate are preferred, and sodium hydroxide is more preferred.

[0102] The injectable preparation according to the present invention can be appropriately adjusted to an appropriate pH using a pH adjuster. The pH of the injectable preparation according to this embodiment is preferably 3 to 6, more preferably 3 to 5, even more preferably 3 to 4.5, and particularly preferably 3.5 to 4.5.

[0103] Examples of cyclodextrins that can be incorporated into the injectable preparation according to the present invention include unmodified cyclodextrin and modified cyclodextrin. Examples of unmodified cyclodextrin include α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, etc. Examples of modified cyclodextrin include dimethyl-α-cyclodextrin, dimethyl-β-cyclodextrin, dimethyl-γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, sulfobutylether-α-cyclodextrin, sulfobutylether-β-cyclodextrin, sulfobutylether-γ-cyclodextrin, maltosyl-α-cyclodextrin, etc., which can be used alone or in combination.

[0104] The cyclodextrins contained in the injectable preparation according to the present invention are preferably hydroxypropyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin, and more preferably sulfobutylether-β-cyclodextrin.

[0105] If necessary, a buffering agent, a suspending agent, a solubilizing agent, a stabilizer, an isotonicity agent, a preservative, and the like may be added to the injection according to the present invention.

[0106] Examples of the buffer include borate buffer, phosphate buffer, citrate buffer, acetate buffer, and Tris buffer.

[0107] Examples of suspending agents include methylcellulose, polysorbate 80, hydroxyethylcellulose, gum arabic, powdered tragacanth, sodium carboxymethylcellulose, and polyoxyethylene sorbitan monolaurate.

[0108] Examples of solubilizing agents include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, macrogol, and glycerin fatty acid esters.

[0109] Stabilizers include sodium sulfite, sodium metasulfite, etc., isotonicity agents include glycerin, sodium chloride, etc., and preservatives include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, sorbic acid, etc.

[0110] The injection according to the present invention may be a freeze-dried preparation. Such a freeze-dried preparation can be dissolved in one or more of the following solvents before use: distilled water for injection, infusion solution, and electrolyte solution, and used as an injection to be dissolved when used.

[0111] The pH of the lyophilized preparation when dissolved in water is preferably 3 to 6, more preferably 3 to 5, even more preferably 3 to 4.5, and particularly preferably 3.5 to 4.5.

[0112] The freeze-dried preparation can be produced by a conventionally known method for producing freeze-dried preparations, for example, a method in which the preparation is frozen at a temperature of -25°C or lower, and then dried while increasing the temperature to room temperature while maintaining a degree of vacuum of about 20 Pa or lower.

[0113] The dosage regimen in which the pharmaceutical composition of the present invention is administered is selected according to a variety of factors, including the type, race, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; and the patient's hepatic and renal function. A physician, veterinarian, or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.

[0114] Compound A·1 hydrochloride of the present invention, particularly compound A·1 hydrochloride·monohydrate, acts as a selective LAT1 inhibitor, suppresses tumor growth, and can be an effective anticancer agent.

[0115] The type of cancer to be treated by the pharmaceutical composition of the present invention is not particularly limited, and examples thereof include fibroma, lipoma, myxoma, chondroma, osteoma, hemangioendothelioma, lymphoma, myeloma, myelosarcoma, reticuloma, reticulum cell sarcoma, melanoma, myoma, neuroma, glioma, neurilemmoma, sarcoma, osteosarcoma, myoma, fibrosarcoma, papilloma, adenoma, cyst, brain tumor, cervical cancer, tongue cancer, pharyngeal cancer, laryngeal cancer, thyroid cancer, esophageal cancer, lung cancer, breast cancer, pancreatic cancer, gastric cancer, small intestinal cancer such as duodenum, jejunum, and ileum, large intestinal cancer such as colon, cecum, and rectum, bladder cancer, kidney cancer, liver cancer, gallbladder cancer, prostate cancer, uterine body cancer, cervical cancer, ovarian cancer, and other carcinomas, as well as mixed tumors and metastatic tumors thereof. In particular, from the viewpoint that LAT1 is highly expressed on cancer cells, it is preferable that the pharmaceutical composition of the present invention is a preventive or therapeutic agent for pancreatic cancer, bladder cancer, breast cancer, and gastric cancer.

[0116] Combination treatment In carrying out the present invention, the pharmaceutical composition of the present invention may be administered simultaneously with other anticancer drugs. In addition, the pharmaceutical composition of the present invention may be administered first and then the other anticancer drugs, or the other anticancer drugs may be administered first and then the pharmaceutical composition of the present invention. Furthermore, the pharmaceutical composition of the present invention may be administered first and then the other anticancer drugs may be administered separately at a certain time, or the other anticancer drugs may be administered first and then the pharmaceutical composition of the present invention may be administered separately at a certain time. Such an administration order and administration interval can be appropriately selected by a person skilled in the art depending on the formulation containing the pharmaceutical composition of the present invention used, the formulation containing the anticancer drug used in combination with it, the type of cancer cells to be treated, the condition of the patient, and the like.

[0117] As used herein, "simultaneously" refers to use at approximately the same time for treatment, and "separately" refers to use at different times for treatment, such as using one drug on the first day and another drug on the second day for treatment. "Sequentially" refers to use in order, such as using one drug first and then using another drug after a set time.

[0118] As used herein, the term "anticancer alkylating agent" refers to an alkylating agent having anticancer activity, and examples thereof include nitrogen mustard N-oxide, cyclophosphamide, melphalan, busulfan, mitobronitol, carboquone, thioteba, and temozolomide.

[0119] As used herein, "anticancer antimetabolite" refers to an antimetabolite having anticancer activity, and examples thereof include methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil, tegafur, doxifluridine, cytarabine, cytarabine ocfosfate, enocitabine, gemcitabine, and fludarabine.

[0120] As used herein, the term "anticancer antibiotic" refers to an antibiotic having anticancer activity, and examples thereof include actinomycin D, doxorubicin, daunorubicin, neocarzinostatin, bleomycin, mitomycin C, aclarubicin, idarubicin, and sirolimus.

[0121] As used herein, the term "plant-derived anticancer agent" includes compounds having anticancer activity found in plants or chemically modified versions of such compounds. Examples of plant-derived anticancer agents include vincristine, vinblastine, vindesine, etoposide, sobuzoxane, docetaxel, and paclitaxel.

[0122] As used herein, "anticancer camptothecin derivatives" refers to cancer cell growth inhibitory compounds that are structurally related to camptothecin, including camptothecin itself, such as camptothecin, topotecan, and irinotecan.

[0123] As used herein, "anticancer platinum coordination compound" refers to a platinum coordination compound having anticancer activity, and examples thereof include cisplatin; cis-diamminediaquoplatinum(II)-ion; chloro(diethylenetriamine)-platinum(II) chloride; dichloro(ethylenediamine)-platinum(II); diammine(1,1-cyclobutanedicarboxylato)platinum(II) (carboplatin); spiroplatin; iproplatin; (1,2-diaminocyclohexane)oxalatoplatinum(II); ormaplatin; carboplatin; oxaliplatin, and the like.

[0124] As used herein, the term "anticancer tyrosine kinase inhibitor" refers to a tyrosine kinase inhibitor having anticancer activity, and examples thereof include gefitinib, imatinib, sorafenib, sunitinib, dazatinib, and erlotinib.

[0125] As used herein, the term "monoclonal antibody" refers to an antibody produced by a single clone of antibody-producing cells, and examples thereof include cetuximab, bevacizumab, rituximab, alemtuzumab, trastuzumab, ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, and durvalumab.

[0126] As used herein, "interferon" refers to interferon having anticancer activity, such as interferon α, interferon α-2a, interferon α-2b, interferon β, interferon γ-1a, and interferon γ-n1.

[0127] Thus, the present invention provides a medicine comprising the pharmaceutical composition of the present invention in combination with at least one anticancer agent selected from the group consisting of anticancer alkylating agents, anticancer antimetabolites, anticancer antibiotics, plant-derived anticancer agents, anticancer platinum coordination compounds, anticancer camptothecin derivatives, anticancer tyrosine kinase inhibitors, monoclonal antibodies, and interferons, administered in the same package or in separate packages.

[0128] In addition, in the combination preparation consisting of two separate preparations according to the present invention, preferably, either or both of the two separate preparations are parenteral preparations, and more preferably, either or both of the two separate preparations are injections or infusions.

[0129] Working Example The present invention will now be described with reference to Test Examples, Reference Examples and Examples, but the present invention is not limited to these.

[0130] Powder X-ray diffraction was measured using a powder X-ray diffractometer RINT2100 manufactured by Rigaku Corporation.

[0131] [Conditions for powder X-ray diffraction measurement] Anticathode: Cu Tube voltage: 40kV Tube current: 30mA Scan axis: 2θ

[0132] Infrared absorption spectra were measured using an infrared spectrophotometer IR Prestige-21 manufactured by Shimadzu Corporation.

[0133] [Infrared absorption spectrum measurement conditions] ATR method

[0134] Nuclear magnetic resonance spectra (NMR spectra) were measured using a BRUKER AV400 nuclear magnetic resonance spectrometer. [Nuclear magnetic resonance spectrum measurement conditions] 400MHz

[0135] The moisture content was measured by a quantitative method using a Mitsubishi Chemical Analytical moisture analyzer CA-200 / KF-200.

[0136] Reference Example 1: Preparation of Compound A dihydrochloride Compound A hydrochloride was produced with reference to the method described in Patent Document 1. Under a nitrogen atmosphere, 4N hydrogen chloride / ethyl acetate solution (200mL, 20vol / wt) was added dropwise to tetrahydrofuran (200mL, 20vol / wt) of intermediate 1 (10.0g, 17.5mmol) at 15-22°C over 45 minutes, and the mixture was stirred at 22-24°C for 4.5 hours. The reaction solution was concentrated under reduced pressure until it was 200mL or less, ethyl acetate (200mL, 20vol / wt) was added, and the reaction solution was concentrated again under reduced pressure until it was 250mL or less. Ethanol (300mL, 30vol / wt) was added to the concentrated reaction solution at 45°C, and the mixture was stirred at 45-50°C for 1.5 hours, after which the reaction solution was cooled to 25°C and stirred at 20-25°C for 1 hour. The precipitated solid was filtered, and the filter residue was washed with ethanol (50mL, 5vol / wt) to obtain a pale yellow wet solid (17.8g).

[0137] The obtained wet solid (17.8 g) was suspended in ethanol (300 mL, 30 vol / wt) under a nitrogen atmosphere, heated to 60°C, and stirred at 60-65°C for 1 h. The suspension was cooled to 25°C and stirred at 20-25°C for 1 h. The solid was filtered, and the filter residue was washed with ethanol (50 mL, 5 vol / wt) to obtain a white wet solid (17.5 g). The obtained wet solid was vacuum dried at 50°C for 15 h to obtain compound A dihydrochloride (7.4 g, 13.6 mmol) as a white solid. Yield: 78% Moisture: 1.5% Chloride (neutralization titration): 1.82 molar equivalents

[0138] 1 H-NMR (DMSO-d6) σ value: 8.20~8.14 (2H, m), 7.79 (1H, d, J=1.6Hz), 7.70~7.62 (3H, m), 7.57 (1H, d, J=1.6Hz), 7.52 (2H, s), 5.40 (2H, s), 4.30~4.16 (1H, m), 3.21 (1H, dd, J=14.4, 6.0Hz), 3.12 (1H, dd, J=14.4, 6.9Hz). Infrared absorption spectrum: shown in FIG. Powder X-ray diffraction pattern: shown in FIG.

[0139] Example 1: Preparation of Compound A monohydrochloride monohydrate 1 To a suspension of compound A dihydrochloride (10.0 g, 18.3 mmol) in 2-propanol (25 mL, 2.5 vol / wt) / water (75 mL, 7.5 vol / wt), concentrated hydrochloric acid (0.46 g, 4.6 mmol) was added and dissolved by heating to 50°C. The pH of the reaction solution was 1.2. The reaction solution was gradually cooled to 23°C over 50 minutes, and the precipitation of a solid was confirmed. The suspension was cooled to 5°C and stirred at 2-5°C for 1 hour. The solid was filtered, and the filter residue was washed with 2-propanol (30 mL, 3.0 vol / wt) to obtain a white wet solid (11.6 g). The obtained wet solid was air-dried in a fume hood for 16 hours to obtain compound A monohydrochloride monohydrate (9.3 g). The moisture content of this solid was measured to be 19.4%.

[0140] A portion (1.00 g) of the obtained compound A monohydrochloride monohydrate was dried at 45°C and 2 kPa under vacuum for 1 hour to obtain compound A monohydrochloride monohydrate (0.84 g, 1.6 mmol). The moisture content of this solid was measured to be 4.0%. Yield: 81% Moisture: 4.0% Chloride (neutralization titration): 0.87 molar equivalents

[0141] 1 H-NMR (DMSO-d6) σ value: 8.17~8.07 (2H, m), 7.68~7.55 (3H, m), 7.50 (2H, s), 6.96 (1H, d, J=2.1Hz), 6.90 (1H, d, J=2.1Hz), 5.23(2H, s), 4.28~4.17(1H, m), 3.19(1H, dd, J=14.4, 5.9Hz), 3.10(1H, dd, J=14.4, 7.0Hz). Infrared absorption spectrum: shown in FIG. Powder X-ray diffraction pattern: shown in FIG.

[0142] Example 2: Preparation of Compound A monohydrochloride monohydrate 2 Under a nitrogen atmosphere, 4N hydrogen chloride / ethyl acetate solution (27mL, 3vol / wt) was added dropwise to intermediate 1 (9.0g, 15.7mmol) in ethyl acetate (81mL, 9vol / wt) at 22-25°C over 50 minutes, and the mixture was stirred at 22-28°C for 24 hours. Water (31.5mL, 3.5vol / wt) was added dropwise to this reaction solution at 25-29°C over 30 minutes, and then 1N aqueous sodium hydroxide solution (35mL, 3.5vol / wt) was added dropwise at 25°C over 1 hour. Ethyl acetate (72mL, 8vol / wt) was added to this reaction solution, and the organic layer was removed by liquid separation. Activated carbon (0.90 g, 0.10 wt / wt) was added to the resulting aqueous layer, followed by water (9 mL, 1.0 vol / wt), and the mixture was stirred at 25°C for 1 hour. The activated carbon was then removed by filtration, and the filter cake was washed with 0.1N hydrochloric acid (18 mL, 2 vol / wt). 2-propanol (18 mL, 2 vol / wt) was added to the resulting filtrate. At this time, the pH of the reaction solution was 0.7. 1N aqueous sodium hydroxide solution (26 mL, 2.9 vol / wt) was added dropwise to the reaction solution over 1 hour at 25°C, and the mixture was stirred at 25°C for 30 minutes, and solid precipitation was confirmed. At this time, the pH of the reaction solution was 1.1. To this reaction solution, 1N aqueous sodium hydroxide solution (7mL, 0.8vol / wt) was added, and the pH was adjusted to 1.3. The mixture was then stirred at 20-27℃ for 15 hours, cooled to 5℃, and stirred at 0-5℃ for 2.5 hours. The solid was filtered, and the filter residue was washed with 0.1N hydrochloric acid / 2-propanol mixture (9vol / 1vol, 50mL, 5.6vol / wt) and then with water / 2-propanol mixture (1vol / 9vol, 45mL, 4.5vol / wt) to obtain a milky white wet solid (15.3g). The obtained wet solid was air-dried in a fume hood for 3.5 hours, and then vacuum-dried at 45℃ and 2.5kPa for 17 hours to obtain compound A·monohydrochloride·monohydrate (7.3g, 13.9mmol) as a white solid. Yield: 89% Moisture: 4.7%

[0143] 1H-NMR (DMSO-d6) σ value: 8.14~8.08 (2H, m), 7.75~7.57 (3H, m), 7.50 (2H, s), 6.94 (1H, d, J=2.1Hz), 6.88 (1H, d, J=2.1Hz), 5.23(2H, s), 4.25~4.19(1H, m), 3.20(1H, dd, J=14.4, 5.9Hz), 3.10(1H, dd, J=14.4, 6.9Hz). Infrared absorption spectrum: coincident with that shown in FIG. Powder X-ray diffraction pattern: coincident with that shown in FIG.

[0144] Example 3: Preparation of Compound A monohydrochloride anhydride Compound A monohydrochloride monohydrate (1.00 g, 1.9 mmol) was suspended in acetone (20 mL, 20 vol / wt) and stirred at room temperature for 22 hours. The solid was filtered to obtain a wet solid (0.95 g). The wet solid was dried at 45°C and 1.3 kPa under vacuum for 2 hours to obtain compound A monohydrochloride anhydride (0.65 g, 1.3 mmol) as a light brown solid. 1 The H-NMR chemical shift values ​​were consistent with compound A monohydrochloride monohydrate. Yield: 67% Moisture: 0.7%

[0145] 1 H-NMR (DMSO-d6) σ value: 8.14~8.08 (2H, m), 7.75~7.57 (3H, m), 7.49 (2H, s), 6.94 (1H, d, J=2.1Hz), 6.88 (1H, d, J=2.1Hz), 5.23(2H, s), 4.27~4.20(1H, m), 3.19(1H, dd, J=14.4, 5.9Hz), 3.09(1H, dd, J=14.4, 7.0Hz). Infrared absorption spectrum: shown in FIG. Powder X-ray diffraction pattern: shown in FIG.

[0146] Test example: Evaluation of the solubility of Compound A hydrochloride in cyclodextrin solution Each hydrochloride salt of compound A prepared according to the Reference Examples and Examples was subjected to an evaluation of its solubility in the preparation solution (i.e., cyclodextrin solution) used in producing a lyophilized formulation. The test conditions were in accordance with Formulation 19 (compound A concentration: 6.25 mg / mL, cyclodextrin concentration: 20%, final adjusted pH: 3.5) described in Patent Document 2. The results are shown below.

[0147] [Table 2]

[0148] Compound A dihydrochloride is a fine crystal that tends to form lumps, and it took more than 11 hours for the lump-like Compound A dihydrochloride (Figure 12) to dissolve. The time required for powdered Compound A dihydrochloride (Figure 13) was somewhat improved, dissolving in 3 hours. On the other hand, Compound A monohydrochloride monohydrate is a powder that tends not to form lumps (Figure 14), and it took only 0.5 hours to dissolve.

[0149] Thus, compound A monohydrochloride monohydrate had superior solubility in the preparation solution used to produce the lyophilized formulation compared to compound A dihydrochloride. [Industrial Applicability]

[0150] The (S)-2-amino-3-{4-[(5-amino-2-phenylbenzo[d]oxazol-7-yl)methoxy]-3,5-dichlorophenyl}propanoic acid monohydrochloride monohydrate of the present invention is highly pure, does not easily form agglomerates when dried, and has excellent solubility in preparation solutions used in producing lyophilized preparations, and is therefore useful as a pharmaceutical active ingredient.

Claims

1. A compound comprising cyclodextrins (S )-2-amino-3-{4-[(5-amino-2-phenylbenzo[d]oxazole- 7-yl)methoxy]-3,5-dichlorophenyl}propanoic acid, monohydrochloride, monohydrate A crystal, In powder X-ray diffraction, the 2θ values ​​are 7.1, 9.5, 18.9, 21.6 and 2 4. Having a diffraction angle of 2°; and / or In the infrared absorption spectrum, 1393, 1381, 1342, 1329 and 126 having a peak at 7 cm-1; A crystal characterized by:

2. (S)-2-amino-3-{4-[(5-amino-2-phenylbenzo[d]oxazo (7-yl)methoxy]-3,5-dichlorophenyl}propanoic acid, monohydrochloride, monohydrate A crystal of a solvate, In powder X-ray diffraction, the 2θ values ​​are 7.1, 9.5, 18.9, 21.6 and 2 4. Having a diffraction angle of 2°; and / or In the infrared absorption spectrum, 1393, 1381, 1342, 1329 and 126 having a peak at 7 cm-1; The method for producing an injection, comprising the step of dissolving the crystal in a cyclodextrin solution, method.

3. The manufacturing method described in claim 2, wherein the injectable is for treating cancer.

4. (S)-2-amino-3-{4-[(5-amino-2-phenylbenzo[d]oxazo (7-yl)methoxy]-3,5-dichlorophenyl}propanoic acid, monohydrochloride, monohydrate The solvate is suspended and stirred in an organic solvent to remove the water of hydration, (5-amino-2-phenylbenzo[d]oxazol-7-yl)methoxy]-3,5 -dichlorophenyl}propanoic acid monohydrochloride anhydride - Patent application

5. A compound comprising (S)-2-(cyclodextrin) and (S)-2-(cyclodextrin) for use as a drug substance in a freeze-dried preparation containing cyclodextrins. Amino-3-{4-[(5-amino-2-phenylbenzo[d]oxazol-7-yl ) methoxy]-3,5-dichlorophenyl}propanoic acid monohydrochloride monohydrate.

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