WO2020096041A1 - (s)-2-amino-3-{4-[(5-amino-2-phenylbenzo[d]oxazol-7-yl)methoxy]-3,5-dichlorophenyl}propanoic acid·monochloride, monohydrate thereof, crystal thereof, and method for producing same - Google Patents

(s)-2-amino-3-{4-[(5-amino-2-phenylbenzo[d]oxazol-7-yl)methoxy]-3,5-dichlorophenyl}propanoic acid·monochloride, monohydrate thereof, crystal thereof, and method for producing same Download PDF

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WO2020096041A1
WO2020096041A1 PCT/JP2019/043856 JP2019043856W WO2020096041A1 WO 2020096041 A1 WO2020096041 A1 WO 2020096041A1 JP 2019043856 W JP2019043856 W JP 2019043856W WO 2020096041 A1 WO2020096041 A1 WO 2020096041A1
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amino
phenylbenzo
dichlorophenyl
oxazol
methoxy
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PCT/JP2019/043856
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French (fr)
Japanese (ja)
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仁 遠藤
勇太 小林
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ジェイファーマ株式会社
十全化学株式会社
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Priority to JP2020555623A priority Critical patent/JPWO2020096041A1/en
Publication of WO2020096041A1 publication Critical patent/WO2020096041A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D263/57—Aryl or substituted aryl radicals

Definitions

  • the present invention provides (S) -2-amino-3- ⁇ 4-[(5-amino-2-phenylbenzo [d] oxazole) having a selective inhibitory activity against LAT1 (L-type amino acid transporter 1).
  • the present invention relates to -7-yl) methoxy] -3,5-dichlorophenyl ⁇ propanoic acid monohydrochloride, its monohydrate, its crystals, a process for producing the same, and a pharmaceutical composition containing the same.
  • LAT1 is a transporter that is specifically expressed in tumor cells, transports essential amino acids including leucine that is also a signal factor, and plays an important role in supplying essential nutrition to tumor cells.
  • LAT2 L-type amino acid transporter 2
  • LAT1 can be an antitumor drug with few side effects.
  • Patent Document 2 injections containing compound A, a pH adjusting agent, and cyclodextrins are known.
  • An object of the present invention is to provide a hydrochloride salt of Compound A which has high purity, is hard to agglomerate during drying, has excellent solubility, and is easy to handle as a drug substance.
  • the present invention provides the following.
  • the present invention provides the following.
  • [18] The powder X-ray diffraction according to [4], which has diffraction angles of 7.1, 9.5, 18.9, 21.6 and 24.2 ° represented by 2 ⁇ . Crystals.
  • the crystal according to [4] which has peaks at 1393, 1381, 1342, 1329 and 1267 cm ⁇ 1 in the infrared absorption spectrum.
  • the powder X-ray diffraction according to [5] which has diffraction angles of 10.5, 14.5, 17.1, 22.5 and 23.0 ° represented by 2 ⁇ . Crystals.
  • the crystal according to [5] which has peaks at 1601, 1556, 1547, 1404 and 1269 cm ⁇ 1 in the infrared absorption spectrum.
  • a pharmaceutical composition comprising the compound according to [1] or [2], or the crystal of any of [4], [18] or [19], and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition according to [22] which is used for treating cancer.
  • the present invention provides compound A.1 hydrochloride monohydrate and a method for producing the same.
  • Compound A / 1-hydrochloride / monohydrate is of high purity, hardly clumps during drying, and has excellent solubility in a prepared solution when producing a freeze-dried preparation, and thus is useful as a drug substance for a drug.
  • the present invention provides compound A / 1 hydrochloride / anhydride and a method for producing the same.
  • Compound A ⁇ 1 hydrochloride ⁇ anhydride is useful as a raw material for producing compound A ⁇ 1 hydrochloride ⁇ monohydrate.
  • the “drug substance” means an active ingredient of a medicine.
  • Compound A is (S) -2-amino-3- ⁇ 4-[(5-amino-2-phenylbenzo [d] oxazol-7-yl) methoxy] -3,5-dichlorophenyl ⁇ propanoic acid ..
  • Examples of the aliphatic hydrocarbons include pentane, hexane, cyclohexane or heptane.
  • aromatic hydrocarbons examples include benzene, toluene or xylene.
  • halogenated hydrocarbons examples include dichloromethane, chloroform or dichloroethane.
  • alcohols examples include methanol, ethanol, 1-propanol, 2-propanol, butanol or 2-methyl-2-propanol.
  • ethers include diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether or diethylene glycol diethyl ether.
  • ketones examples include acetone, 2-butanone and 4-methyl-2-pentanone.
  • esters examples include methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate or butyl acetate.
  • amides examples include N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone.
  • nitriles examples include acetonitrile and propionitrile.
  • sulfoxides include dimethyl sulfoxide.
  • the wave number (cm ⁇ 1 ) value in the infrared absorption spectrum (ATR method) may have an error within a range of ⁇ 2 cm ⁇ 1 . Therefore, in the present invention, “wave number Y” means “wave number ((Y-2) to (Y + 2)) cm ⁇ 1 ”, unless otherwise specified. Therefore, the present invention includes not only crystals in which the wave numbers of absorption peaks in the infrared absorption spectrum (ATR method) completely match, but also crystals in which the wave numbers of absorption peaks match within an error range of ⁇ 2 cm ⁇ 1 .
  • the diffraction angle (2 ⁇ ) in powder X-ray diffraction may have an error within a range of ⁇ 0.2 °. Therefore, the term “diffraction angle (2 ⁇ ) X °” in the present invention means “diffraction angle (2 ⁇ ) ((X ⁇ 0.2) to (X + 0.2)) °”, unless otherwise specified. To do. Therefore, the present invention includes not only a crystal whose diffraction angle (2 ⁇ ) in powder X-ray diffraction completely matches, but also a crystal whose diffraction angle (2 ⁇ ) matches within an error range of ⁇ 0.2 °.
  • 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 operations such as extraction. Therefore, the compound A is isolated by a method such as neutralization crystallization in a water-containing solvent.
  • the hydrochloride salt of Compound A can be produced by converting Compound A into a hydrochloride salt according to a conventional method.
  • Compound A ⁇ 2 hydrochloride has a diffraction angle represented by 2 ⁇ of 8.0, 8.8, 19.6, 22.2, 23.8 and 26.1 ° in powder X-ray diffraction. Characterize.
  • FIG. 7 shows a powder X-ray diffraction chart of compound A ⁇ 2 hydrochloride.
  • Compound A ⁇ 2 hydrochloride is characterized by having characteristic peaks at 1736, 1483, 1474 and 1240 cm ⁇ 1 in the infrared absorption spectrum.
  • FIG. 6 shows an infrared absorption spectrum chart of Compound A ⁇ 2 hydrochloride.
  • Compound A has two or more basic sites capable of forming a salt with hydrochloric acid, and the equilibrium shown in FIG. 2 is established.
  • the acid dissociation constant (pK a ) of Compound A was experimentally determined by neutralization titration, the first acid dissociation constant (pK a1 ) was 1.0 and the second acid dissociation constant (pK a2 ) was 2.2. Met.
  • Equation 1 the molar fraction of each component of the compound A is expressed as [compound A ⁇ dihydrochloride], [compound A ⁇ monohydrochloride], [compound A], and the hydrogen ion concentration is [H + ]. If expressed, Equations 1 to 3 hold.
  • FIG. 3 is a diagram showing a state of dissociation equilibrium of compound A at each pH.
  • the water activity a w is an index representing the ratio of free water contained in an arbitrary substance, and is represented by the product of the water activity coefficient ⁇ w and the water mole fraction x w as shown in Equation 4. be able to.
  • Equation 4 water activity coefficient ⁇ w in Equation 4 can be estimated using, for example, the UNIQUAC equation (Abrams, DS, et al .: AIChE J., 1975, 21, pp116-128).
  • Compound A ⁇ 1 hydrochloride is compound A ⁇ 1 hydrochloride depending on the water activity of the system. It has been found that it is a monohydrochloride monohydrate and a compound A monohydrochloride anhydrate. The results are shown in Table 1.
  • Compound A ⁇ 1 hydrochloride ⁇ monohydrate is a needle-to-columnar crystalline solid having a large aspect ratio (FIG. 4), and is represented by 2 ⁇ in powder X-ray diffraction of 7.1, 9.5, It is characterized by having diffraction angles of 18.9, 21.6 and 24.2 °.
  • FIG. 9 shows a powder X-ray diffraction chart of compound A / 1 hydrochloride / monohydrate.
  • Compound A ⁇ 1 hydrochloride ⁇ monohydrate is characterized by having characteristic peaks at 1393, 1381, 1342, 1329 and 1267 cm ⁇ 1 in the infrared absorption spectrum.
  • FIG. 8 shows an infrared absorption spectrum chart of compound A / 1 hydrochloride / monohydrate.
  • the compound A monohydrochloride monohydrate contains 1 molar equivalent of hydrogen chloride with respect to the compound A, and may be contained in the range of 0.8 to 1.2 molar equivalents.
  • the compound A / 1 hydrochloride / monohydrate contains 3.4 wt% of water, and may be contained in the range of 2.8 to 4.1 wt%.
  • Compound A ⁇ hydrochloride monohydrate can be produced by adding hydrochloric acid to compound A in a water-containing organic solvent to adjust the pH.
  • 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. These may be mixed and used.
  • Preferable solvents include alcohols, ethers, ketones and nitriles, alcohols are more preferable, and methanol, ethanol, 1-propanol and 2-propanol are further preferable.
  • the water activity of the solvent in the water-containing organic solvent may be 0.5 or more, preferably 0.65 or more.
  • the amount of the solvent used may be 1 to 50 times (v / w) the amount of Compound A, preferably 5 to 20 times (v / w).
  • the pH range for preparing the compound A / 1-hydrochloride / monohydrate may be in the range of 1-2, preferably 1.0-2.2, and 1.2-2.0. Is more preferable.
  • the reaction temperature may be 0 to 60 ° C, preferably 0 to 30 ° C.
  • the reaction time may be 1 minute to 50 hours, preferably 30 minutes to 12 hours.
  • the reaction atmosphere is not particularly limited, but it is preferable to carry out under an inert gas atmosphere.
  • the inert gas atmosphere include an argon gas atmosphere and a nitrogen gas atmosphere.
  • a salt composed of the compound A and a base may be used as the compound A used in this reaction.
  • the type of salt composed of the compound A and the base is not particularly limited as long as it does not affect the reaction, and examples thereof include salts with an inorganic base and an organic base.
  • Preferred salts include salts with inorganic bases, and salts with alkali metals are more preferred.
  • a salt of the compound A and an acid may be used, and the pH may be adjusted by adding hydrochloric acid or a base.
  • the type of salt composed of 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, with the hydrochloride salt being more preferred. That is, the hydrochloride salt of Compound A used in this reaction may be Compound A ⁇ 1 hydrochloride ⁇ anhydride.
  • Examples of the type of base used for pH adjustment include inorganic bases, alkali metal bases are preferable, and sodium hydroxide, sodium carbonate, and sodium hydrogen carbonate are more preferable. These may be used alone or in combination of two or more.
  • Compound A / 1 hydrochloride / anhydrous is a fine crystalline solid, and is 10.5, 14.5, 17.1, 22.5 and 23.0 ° represented by 2 ⁇ in powder X-ray diffraction. It has a diffraction angle of.
  • FIG. 11 shows a powder X-ray diffraction chart of compound A / 1 hydrochloride / monohydrate.
  • Compound A / 1-hydrochloride / anhydride is characterized by having characteristic peaks at 1601, 1556, 1547, 1404 and 1269 cm ⁇ 1 in the infrared absorption spectrum.
  • FIG. 10 shows an infrared absorption spectrum chart of compound A / 1-hydrochloride / anhydrous.
  • the compound A / 1-hydrochloride / anhydride contains 1 molar equivalent of hydrogen chloride with respect to the compound A, and may be contained in the range of 0.8 to 1.2 molar equivalents.
  • Compound A / 1 hydrochloride / anhydrous can be produced by reacting compound A with 1 molar equivalent of hydrogen chloride in an organic solvent.
  • 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 are mixed. May be used.
  • Preferable solvents include alcohols, ethers and esters, with methanol, ethanol, ethyl acetate, tetrahydrofuran and dioxane being more preferable.
  • the water activity of the solvent should be less than 0.5, preferably 0.3 or less.
  • the amount of the solvent used may be 1 to 50 times (v / w) the amount of Compound A, preferably 5 to 20 times (v / w).
  • 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.
  • the reaction temperature may be 0 to 60 ° C, preferably 0 to 30 ° C.
  • the reaction time may be 1 minute to 50 hours, preferably 30 minutes to 12 hours.
  • the reaction atmosphere is not particularly limited, but it is preferable to carry out under an inert gas atmosphere.
  • the inert gas atmosphere include an argon gas atmosphere and a nitrogen gas atmosphere.
  • the compound A / 1-hydrochloride / anhydrous can also be produced by suspending and stirring Compound A / 1-hydrochloride / monohydrate in an organic solvent and removing water of hydration.
  • 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 are mixed. May be used.
  • Preferable solvents include alcohols, ketones and esters, with methanol, ethanol, 1-propanol, 2-propanol, acetone and ethyl acetate being more preferable.
  • the water activity of the solvent should be less than 0.5, preferably 0.3 or less.
  • the amount of the solvent used may be 1 to 50 times (v / w) the amount of Compound A, preferably 5 to 20 times (v / w).
  • the reaction temperature may be 0 to 60 ° C, preferably 0 to 30 ° C.
  • the reaction time may be 1 minute to 50 hours, preferably 30 minutes to 12 hours.
  • the reaction atmosphere is not particularly limited, but it is preferable to carry out under an inert gas atmosphere.
  • the inert gas atmosphere include an argon gas atmosphere and a nitrogen gas atmosphere.
  • the subject of administration is a warm-blooded animal, which is a human or non-human mammal. In one embodiment, the administration subject is a human.
  • compositions The compound A ⁇ 1 hydrochloride of the present invention is used as a pharmaceutical composition together with a pharmaceutically acceptable diluent, excipient or carrier (these are collectively referred to as “carrier” in the present specification). Administered to patients.
  • Said pharmaceutically acceptable diluent, excipient or carrier can be in the form of a prescribed dosage form, for example tablets, pills, capsules, powders, granules, sterile solutions or suspensions, aerosols or liquid sprays, drops, A unit dosage form such as an injection or a suppository.
  • Said 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.
  • the term "pharmaceutically acceptable” means non-toxic to administration subjects (patients).
  • the Compound A • 1 hydrochloride salt of the invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patch forms well known to those of ordinary skill in that art. It can be administered by the dermal route.
  • the Compound A • 1 hydrochloride salt of the invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patch forms well known to those of ordinary skill in that art. It can be administered by the dermal route. Dose administration for administration in the form of transdermal delivery systems will be continuous throughout the dosing schedule.
  • the pharmaceutical composition comprises a therapeutically effective amount of compound A.1 hydrochloride monohydrate of the invention in admixture with a pharmaceutically acceptable carrier.
  • Compound A.1 hydrochloride monohydrate in the pharmaceutical composition is in crystalline form.
  • the crystalline form is present at about 5% to about 100% by weight of the drug substance.
  • the crystalline form is present at about 10% to about 100% by weight of the drug substance.
  • the crystalline form is present at about 25% to about 100% by weight of the drug substance.
  • the crystalline form is present at about 50% to about 100% by weight of the drug substance.
  • substantially all of the drug substance is in said crystalline form.
  • the dose of the drug substance, which is the active ingredient of the present invention, for obtaining the intended effect of the present invention is about 0.01 mg / kg body weight per day (mg / kg / day) to about 100 mg / kg / day, preferably Will range from 0.01 to 10 mg / kg / day, and most preferably 0.1 to 5.0 mg / kg / day.
  • a pharmaceutical composition in the form of a tablet containing 0, 15.0, 25.0, 50.0, 100 and 500 milligrams of active ingredient.
  • Pharmaceutical compositions typically contain from about 0.01 mg to about 500 mg of active ingredient, preferably from about 1 mg to about 200 mg.
  • the dose for intravenous administration will be in the range of about 0.1 to about 10 mg / kg.
  • the crystals of the invention may be given in a single daily dose, or the total daily dose may be administered in divided doses of 2, 3 or 4 times daily.
  • the active drug component can be an oral, non-toxic, pharmaceutically 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, any oral non-toxic pharmacologically acceptable inert carrier for oral drug component , For example, it can be used in combination with ethanol, glycerol, water and the like. Moreover, when desired, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the composition.
  • suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the composition.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or ⁇ -lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. .. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • the compound A / 1 monohydrochloride / monohydrate of the present invention can be used as an anticancer agent, it can be preferably formulated as an injection.
  • Such an injection includes the compound A ⁇ monohydrochloride ⁇ monohydrate of the present invention, a pH adjuster and cyclodextrins.
  • Examples of the injection include intravenous, subcutaneous, intramuscular injection, and intravenous drip infusion.
  • Examples of the pH adjuster that can be added to the injection according to the present invention include alkali metal hydroxides such as sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide, sodium hydride and potassium hydride.
  • alkali metal hydroxides such as sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide, sodium hydride and potassium hydride.
  • Examples thereof include alkali metal hydrides, carbonates of alkali metals or alkaline earth metals, and the like. Particularly, sodium hydroxide and sodium carbonate are preferable, and sodium hydroxide is more preferable.
  • the injection according to the present invention can be appropriately adjusted to a suitable pH using a pH adjuster.
  • the pH of the injection according to the present embodiment is preferably 3 to 6, more preferably 3 to 5, further preferably 3 to 4.5, and 3.5 to 4.5. It is particularly preferable that
  • cyclodextrins that can be added to the injection according to the present invention include unmodified cyclodextrin and modified cyclodextrin.
  • unmodified cyclodextrin examples include ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin and the like.
  • modified cyclodextrin examples include dimethyl- ⁇ -cyclodextrin, dimethyl- ⁇ -cyclodextrin, dimethyl- ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, hydroxypropyl- ⁇ - Examples thereof include cyclodextrin, sulfobutyl ether- ⁇ -cyclodextrin, sulfobutyl ether- ⁇ -cyclodextrin, sulfobutyl ether- ⁇ -cyclodextrin, and maltosyl- ⁇ -cyclodextrin, which can be used alone or in combination. ..
  • the cyclodextrins to be added to the injection according to the present invention are preferably hydroxypropyl- ⁇ -cyclodextrin and sulfobutylether- ⁇ -cyclodextrin, more preferably sulfobutylether- ⁇ -cyclodextrin.
  • a buffer 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.
  • buffer examples include borate buffer, phosphate buffer, citrate buffer, acetate buffer, Tris buffer and the like.
  • suspending agent examples include methyl cellulose, polysorbate 80, hydroxyethyl cellulose, gum arabic, tragacanth powder, sodium carboxymethyl cellulose, polyoxyethylene sorbitan monolaurate and the like.
  • solubilizing agent examples include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinic acid amide, polyoxyethylene sorbitan monolaurate, macrogol, and glycerin fatty acid ester.
  • Stabilizers include sodium sulfite, sodium metasulfite, etc.
  • isotonic agents include glycerin, sodium chloride, etc.
  • preservatives include methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbin. Acid etc. are mentioned.
  • the injection according to the present invention may be a freeze-dried preparation.
  • a lyophilized preparation can be used as a ready-to-use injection for injection by dissolving it in one or more solvents of distilled water for injection, infusion solution, and electrolytic solution at the time of use.
  • the pH of the freeze-dried preparation when dissolved in water is preferably 3 to 6, more preferably 3 to 5, further preferably 3 to 4.5, and 3.5 to 4. 5 is particularly preferable.
  • the freeze-dried preparation can be produced by a conventionally known method for producing a freeze-dried preparation.
  • the freeze-dried preparation is frozen at a temperature of ⁇ 25 ° C. or lower, and then heated to room temperature while maintaining the vacuum degree at about 20 Pa or less. Examples include a method of drying while heating.
  • the dosing regimen to which the pharmaceutical composition of the present invention is applied depends on 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 liver and renal function of the patient. It is selected according to various factors including the above. A doctor, 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.
  • the compound A.1 hydrochloride of the present invention of the present invention acts as a selective LAT1 inhibitor, suppresses tumor growth, and is an effective anticancer agent. Can be.
  • 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, hemangioma, hemangioendothelioma, lymphoma, and myeloma.
  • the pharmaceutical compositions of the present invention may be administered concurrently with other anticancer agents.
  • other anticancer agents may be continuously administered after administration of the pharmaceutical composition of the present invention, or the pharmaceutical composition of the present invention may be continuously administered after administration of the other anticancer agent. May be administered.
  • the pharmaceutical composition of the present invention may be administered, and the other anticancer agent may be administered separately at a certain time, or the other anticancer agent may be administered and the present invention may be separately provided at a certain time. May be administered.
  • Such administration sequence and administration interval depending on the formulation containing the pharmaceutical composition of the present invention to be used, and the formulation containing an anticancer agent used in combination therewith, the type of cancer cells to be treated, the condition of the patient, etc. A person skilled in the art can appropriately select.
  • “simultaneously” means to be used for treatment at almost the same time, and “separately” means to be used for treatment separately at different times, for example, one day.
  • “Sequentially” means to be used in order, for example, one drug is used first, and then another drug is used for treatment after a predetermined time.
  • anticancer alkylating agent means an alkylating agent having anticancer activity, and includes, for example, nitrogen mustard N-oxide, cyclophosphamide, melphalan, busulfan, mitbronitol, Carbocon, thioteva, temozolomide and the like can be mentioned.
  • anticancer antimetabolite refers to an antimetabolite having anticancer activity, and includes, for example, methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil, tegafur, doxyfluridine, Examples include cytarabine, cytarabine ocfosfate, enocitabine, gemcitabine or fludarabine.
  • anticancer antibiotic refers to an antibiotic having anticancer activity, and includes, for example, actinomycin D, doxorubicin, daunorubicin, neocarzinostatin, bleomycin, mitomycin C, aclarubicin, idarubicin or Examples include sirolimus.
  • the “plant-derived anticancer agent” includes a compound having an anticancer activity found from a plant or a chemically modified product of the compound.
  • examples of the “plant-derived anticancer agent” include vincristine, vinblastine, vindesine, etoposide, sobuzoxane, docetaxel, paclitaxel and the like.
  • Anticancer camptothecin derivative as used herein means a cancer cell growth inhibitory compound that includes camptothecin itself and is structurally related to camptothecin, and examples thereof include camptothecin, topotecan, and irinotecan.
  • anticancer platinum coordination compound refers to a platinum coordination compound having anticancer activity, for example, cisplatin; cis-diamminediacoplatinum (II) -ion; chloro (diethylenetriamine) -Platinum (II) chloride; dichloro (ethylenediamine) -platinum (II); diammine (1,1-cyclobutanedicarboxylato) platinum (II) (carboplatin); spiroplatin; iproplatin; (1,2-diaminocyclohexane) oxalato Platinum (II); ormaplatin; carboplatin; oxaliplatin and the like.
  • anticancer tyrosine kinase inhibitor refers to a tyrosine kinase inhibitor having anticancer activity, and examples thereof include gefitinib, imatinib, sorafenib, sunitinib, dazatinib, erlotinib and the like.
  • the term "monoclonal antibody” refers to an antibody produced by antibody-producing cells of a single clone, for example, cetuximab, bevacizumab, rituximab, alemtuzumab, trastuzumab, ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, etc. Is mentioned.
  • interferon refers to interferon having anticancer activity, and examples thereof include interferon ⁇ , interferon ⁇ -2a, interferon ⁇ -2b, interferon ⁇ , interferon ⁇ -1a, interferon ⁇ -n1 and the like. Can be mentioned.
  • the pharmaceutical composition of the present invention an anticancer alkylating agent, an anticancer antimetabolite, an anticancer antibiotic, a plant-derived anticancer agent, an anticancer platinum At least one anticancer agent selected from the group consisting of a coordination compound, an anticancer camptothecin derivative, an anticancer tyrosine kinase inhibitor, a monoclonal antibody, and an interferon;
  • a pharmaceutical product in which the above are combined is provided. They are administered in the same packaged formulation or as separate packaged formulations.
  • one or both of the two separate preparations is a parenteral preparation, and more preferably one of the two separate preparations.
  • One or both is an injection or drip.
  • the powder X-ray diffraction was measured using a powder X-ray diffractometer RINT2100 manufactured by Rigaku Corporation.
  • the infrared absorption spectrum was measured using an infrared spectrophotometer IR Prestige-21 manufactured by Shimadzu Corporation.
  • the nuclear magnetic resonance spectrum (NMR spectrum) was measured using a nuclear magnetic resonance apparatus AV400 manufactured by BRUKER. [Nuclear magnetic resonance spectrum measurement conditions] 400 MHz
  • the water content was measured by a quantitative method using a water content measuring device CA-200 / KF-200 manufactured by Mitsubishi Chemical Analytic.
  • Reference Example 1 Production Example of Compound A ⁇ Dihydrochloride
  • a compound A ⁇ hydrochloride was produced with reference to the method described in Patent Document 1.
  • tetrahydrofuran 200 mL, 20 vol / wt
  • Intermediate 1 10.0 g, 17.5 mmol
  • 4N hydrogen chloride / ethyl acetate solution 200 mL, 20 vol / wt
  • the mixture was stirred at 22 to 24 ° C. for 4.5 hours.
  • the reaction solution was concentrated under reduced pressure to 200 mL or less, ethyl acetate (200 mL, 20 vol / wt) was added, and the reaction solution was concentrated again under reduced pressure to 250 mL or less.
  • Ethanol 300 mL, 30 vol / wt was added to the concentrated reaction solution at 45 ° C. and stirred at 45 to 50 ° C. for 1.5 hours, then the reaction solution was cooled to 25 ° C. and stirred at 20 to 25 ° C. for 1 hour. did.
  • the precipitated solid was filtered and the filtration residue was washed with ethanol (50 mL, 5 vol / wt) to obtain a pale yellow wet solid (17.8 g).
  • 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 suspended and stirred at 60 to 65 ° C. for 1 hour. The suspension was cooled to 25 ° C and stirred at 20-25 ° C for 1 hour. The solid was filtered and the filter residue was washed with ethanol (50 mL, 5 vol / wt) to give a white wet solid (17.5 g). The obtained wet solid was vacuum dried at 50 ° C. for 15 hours to obtain Compound A.2 hydrochloride (7.4 g, 13.6 mmol) as a white solid. Yield: 78% Water content: 1.5% Chloride (neutralization titration): 1.82 molar equivalents
  • Example 1 Preparation example 1 of compound A monohydrochloride monohydrate
  • a suspension of Compound A ⁇ 2 hydrochloride (10.0 g, 18.3 mmol) in 2-propanol (25 mL, 2.5 vol / wt) / water (75 mL, 7.5 vol / wt) was added with concentrated hydrochloric acid (0.46 g).
  • 4.6 mmol was added and heated to 50 ° C. to dissolve.
  • the pH of the reaction solution was 1.2.
  • the reaction solution was gradually cooled to 23 ° C. over 50 minutes, and solid precipitation was confirmed.
  • the suspension was cooled to 5 ° C and stirred at 2-5 ° C for 1 hour.
  • Example 2 Preparation example 2 of compound A ⁇ monohydrochloride ⁇ monohydrate Under a nitrogen atmosphere, a 4N hydrogen chloride / ethyl acetate solution (27 mL, 3 vol / wt) was added to Intermediate 1 (9.0 g, 15.7 mmol) in ethyl acetate (81 mL, 9 vol / wt) at 22 to 25 ° C. for 50 minutes. The mixture was added dropwise over 20 minutes and stirred at 22 to 28 ° C. for 24 hours. Water (31.5 mL, 3.5 vol / wt) was added dropwise to this reaction solution at 25 to 29 ° C.
  • Example 3 Preparation Example of Compound A ⁇ 1 Hydrochloride ⁇ Anhydrous Compound A ⁇ 1 Hydrochloride ⁇ monohydrate (1.00 g, 1.9 mmol) was suspended in acetone (20 mL, 20 vol / wt), The mixture was stirred at room temperature for 22 hours. The solid was filtered to give a wet solid (0.95g). The obtained wet solid was vacuum dried at 45 ° C. and 1.3 kPa for 2 hours to obtain Compound A ⁇ 1 hydrochloride ⁇ anhydride (0.65 g, 1.3 mmol) as a light brown solid. The 1 H-NMR chemical shift value of the obtained compound A ⁇ 1 hydrochloride ⁇ anhydride was consistent with that of compound A ⁇ 1 hydrochloride ⁇ monohydrate. Yield: 67% Water content: 0.7%
  • Test Example Evaluation of Solubility of Compound A / Hydrochloride in Cyclodextrin Solution
  • a preparation solution ie, cyclodextrin solution
  • the solubility was evaluated.
  • the test conditions were according to the 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.
  • Compound A.2-hydrochloride has a property of being fine crystals and easily lumped, and it took 11 hours or more until the lumpy compound A.2-hydrochloride (FIG. 12) was dissolved.
  • the time required for dissolution was somewhat improved, and it was dissolved in 3 hours.
  • the compound A / 1 hydrochloride / monohydrate had a property of being powdery and was unlikely to clump (FIG. 14), and the time required for dissolution was 0.5 hours.

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Abstract

Provided are (S)-2-amino-3-{4-[(5-amino-2-phenylbenzo[d]oxazol-7-yl)methoxy]-3,5-dichlorophenyl}propanoic acid·monochloride, a monohydrate thereof, a crystal thereof, and method for producing same. Further provided is a pharmaceutical composition that contains said compound and is useful as an anticancer agent.

Description

（Ｓ）－２－アミノ－３－｛４－［（５－アミノ－２－フェニルベンゾ［ｄ］オキサゾール－７－イル）メトキシ］－３，５－ジクロロフェニル｝プロパン酸・１塩酸塩、その１水和物、およびその結晶とその製造方法(S) -2-Amino-3- {4-[(5-amino-2-phenylbenzo [d] oxazol-7-yl) methoxy] -3,5-dichlorophenyl} propanoic acid monohydrochloride, part 1 Hydrate, its crystal and method for producing the same
　本発明は、ＬＡＴ１（Ｌ型アミノ酸トランスポーター１）に対し選択的な阻害活性を有する、（Ｓ）－２－アミノ－３－｛４－［（５－アミノ－２－フェニルベンゾ［ｄ］オキサゾール－７－イル）メトキシ］－３，５－ジクロロフェニル｝プロパン酸・１塩酸塩、その１水和物、および、その結晶と、その製造法、及びそれを含有する医薬組成物に関する。 The present invention provides (S) -2-amino-3- {4-[(5-amino-2-phenylbenzo [d] oxazole) having a selective inhibitory activity against LAT1 (L-type amino acid transporter 1). The present invention relates to -7-yl) methoxy] -3,5-dichlorophenyl} propanoic acid monohydrochloride, its monohydrate, its crystals, a process for producing the same, and a pharmaceutical composition containing the same.
　腫瘍細胞では、急速な細胞増殖や亢進した細胞内代謝を維持するため、糖やアミノ酸等の栄養を外部から取り入れるトランスポーターの発現が高まっている。とりわけＬＡＴ１は、腫瘍細胞に特異的に発現しているトランスポーターで、シグナル因子でもあるロイシンを含む必須アミノ酸を輸送しており、腫瘍細胞に必須な栄養を供給するという重要な役割を担っている。これに対し、ＬＡＴ２（Ｌ型アミノ酸トランスポーター２）は、正常細胞にも広く発現していることが知られている。このため、ＬＡＴ１に対し選択的な阻害活性を有する化合物は、副作用の少ない抗腫瘍薬となりうる。このような性質を有する化合物として、（Ｓ）－２－アミノ－３－｛４－［（５－アミノ－２－フェニルベンゾ［ｄ］オキサゾール－７－イル）メトキシ］－３，５－ジクロロフェニル｝プロパン酸（以下、「化合物Ａ」と称することもある）が知られている（特許文献１）。
Figure JPOXMLDOC01-appb-C000001
 In tumor cells, in order to maintain rapid cell growth and increased intracellular metabolism, the expression of transporters that take in nutrients such as sugars and amino acids from the outside is increasing. In particular, LAT1 is a transporter that is specifically expressed in tumor cells, transports essential amino acids including leucine that is also a signal factor, and plays an important role in supplying essential nutrition to tumor cells. .. On the other hand, LAT2 (L-type amino acid transporter 2) is known to be widely expressed in normal cells. Therefore, a compound having a selective inhibitory activity on LAT1 can be an antitumor drug with few 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).
Figure JPOXMLDOC01-appb-C000001
　また、化合物Ａ、ｐＨ調整剤、およびシクロデキストリン類を含む注射剤が知られている（特許文献２）。 In addition, injections containing compound A, a pH adjusting agent, and cyclodextrins are known (Patent Document 2).
国際公開２００８／０８１５３７号International Publication No. 2008/081537 特開２０１７－１５５０２３号Japanese Patent Laid-Open No. 2017-155023
　本発明は、高純度で乾燥時に塊化しにくく、溶解性に優れ、原薬としての取り扱い性に優れた化合物Ａの塩酸塩を提供することを目的とする。 An object of the present invention is to provide a hydrochloride salt of Compound A which has high purity, is hard to agglomerate during drying, has excellent solubility, and is easy to handle as a drug substance.
　本発明者らは、鋭意研究を重ねた結果、高純度で乾燥時に塊化しにくく、凍結乾燥製剤を製造する際の調製溶液に対する溶解性に優れる化合物Ａの新規な化合物フォームとして１塩酸塩・１水和物の結晶を見出した。また、化合物Ａ・１塩酸塩・１水和物には、擬似結晶多形である無水物の結晶が存在することを見出した。さらに、本発明者らは、化合物Ａ・１塩酸塩・１水和物の結晶を選択的に製造可能な製造条件を見出し、本発明を完成した。 As a result of intensive studies, the present inventors have found that monohydrochloride. Hydrate crystals were found. In addition, it was found that in the compound A.1 hydrochloride monohydrate, there are anhydrous crystals that are pseudo-crystalline polymorphs. Furthermore, the inventors of the present invention have completed the present invention by finding out the production conditions under which the crystals of compound A.1 hydrochloride monohydrate can be selectively produced.
　即ち、本発明は、以下を提供する。 That is, the present invention provides the following.
［１］化合物Ａ・１塩酸塩。
［２］化合物Ａ・１塩酸塩・１水和物。
［３］化合物Ａ・１塩酸塩・無水物。
［４］化合物Ａ・１塩酸塩・１水和物の結晶。
［５］化合物Ａ・１塩酸塩・無水物の結晶。
［６］含水有機溶媒中で、化合物Ａに塩酸を加えてｐＨを調整することによる、化合物Ａ・１塩酸塩・１水和物の製造方法。
［７］含水有機溶媒中で、化合物Ａと塩基とからなる塩に塩酸を加えてｐＨを調整することによる、化合物Ａ・１塩酸塩・１水和物の製造方法。
［８］化合物Ａと塩基とからなる塩が、化合物Ａのアルカリ金属塩である、［７］に記載の製造方法。
［９］含水有機溶媒中で、化合物Ａと酸とからなる塩に塩酸または塩基を加えてｐＨを調整することによる、化合物Ａ・１塩酸塩・１水和物の製造方法。
［１０］化合物Ａと酸とからなる塩が、化合物Ａの塩酸塩である、［９］に記載の製造方法。
［１１］化合物Ａと酸とからなる塩が、化合物Ａ・１塩酸塩・無水物である、［１０］に記載の製造方法。
［１２］ｐＨを調整するのに使用される塩基が、無機塩基である、［９］～［１１］に記載の製造方法。
［１３］ｐＨを調整するのに使用される塩基が、水酸化ナトリウム、炭酸ナトリウム、炭酸水素ナトリウムから選ばれる１種類以上の塩基である、［９］～［１２］に記載の製造方法。
［１４］含水有機溶媒の水分活性が０．５～１．０であり、かつ、ｐＨを１～２の範囲に調整する、［６］～［１３］のいずれか一つに記載の製造方法。
［１５］有機溶媒中で、化合物Ａと塩酸とを反応させることによる、化合物Ａ・１塩酸塩・無水物の製造方法。
［１６］有機溶媒の水分活性が０．５未満であり、かつ、化合物Ａに対し、０．８～１．２モル当量の塩酸を反応させる、［１５］に記載の製造方法。
［１７］化合物Ａ・１塩酸塩・１水和物を有機溶媒中で懸濁撹拌し、水和水を除去する、化合物Ａ・１塩酸塩・無水物の製造方法。 [1] Compound A · 1 hydrochloride.
[2] Compound A.1 hydrochloride monohydrate.
[3] Compound A / 1-hydrochloride / anhydrous.
[4] A crystal of Compound A / 1 hydrochloride / monohydrate.
[5] Crystals of Compound A / 1-hydrochloride / anhydrous.
[6] A method for producing compound A · monohydrochloride · monohydrate by adding hydrochloric acid to compound A in a water-containing organic solvent to adjust the pH.
[7] A method for producing compound A · monohydrochloride · monohydrate by adding hydrochloric acid to a salt consisting of compound A and a base in a water-containing organic solvent to adjust the pH.
[8] The production method according to [7], wherein the salt consisting 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 a water-containing organic solvent to adjust the pH.
[10] The production method according to [9], wherein the salt consisting of compound A and an acid is the hydrochloride salt of compound A.
[11] The production method according to [10], wherein the salt consisting of the compound A and the acid is compound A / 1-hydrochloride / anhydride.
[12] The production method according to [9] to [11], wherein the base used for adjusting the pH is an inorganic base.
[13] The production method according to [9] to [12], wherein the base used for adjusting the pH is at least one kind of base selected from sodium hydroxide, sodium carbonate and sodium hydrogen carbonate.
[14] The production method according to any one of [6] to [13], wherein the water-containing organic solvent has a water activity of 0.5 to 1.0 and the pH is adjusted to a 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 equivalent of hydrochloric acid is reacted with the compound A.
[17] A method for producing Compound A · 1 hydrochloride / anhydrous, which comprises suspending and stirring Compound A · 1 hydrochloride · monohydrate in an organic solvent to remove water of hydration.
　更に、本発明は、以下を提供する。
［１８］粉末Ｘ線回折において、２θで表される７．１、９．５、１８．９、２１．６および２４．２°の回折角度を有することを特徴とする、［４］に記載の結晶。
［１９］赤外吸収スペクトルにおいて、１３９３、１３８１、１３４２、１３２９および１２６７ｃｍ－１にピークを有することを特徴とする、［４］に記載の結晶。
［２０］粉末Ｘ線回折において、２θで表される１０．５、１４．５、１７．１、２２．５および２３．０°の回折角度を有することを特徴とする、［５］に記載の結晶。
［２１］赤外吸収スペクトルにおいて、１６０１、１５５６、１５４７、１４０４および１２６９ｃｍ－１にピークを有することを特徴とする、［５］に記載の結晶。
［２２］［１］又は［２］に記載の化合物、又は、［４］、［１８］又は［１９］のいずれかの結晶、及び薬学的に許容される担体、を含む医薬組成物。
［２３］がんの治療用である［２２］に記載の医薬組成物。
［２４］［２２］又は［２３］に記載の医薬組成物と、抗がん性アルキル化剤、抗がん性代謝拮抗剤、抗がん性抗生物質、植物由来抗がん剤、抗がん性白金配位化合物、抗がん性カンプトテシン誘導体、抗がん性チロシンキナーゼ阻害剤、モノクローナル抗体及びインターフェロンからなる群から選択される抗がん剤よりなる群から選択される少なくとも１つの抗がん剤とを組み合わせた、医薬。 Further, the present invention provides the following.
[18] The powder X-ray diffraction according to [4], which has diffraction angles of 7.1, 9.5, 18.9, 21.6 and 24.2 ° represented by 2θ. Crystals.
[19] The crystal according to [4], which has peaks at 1393, 1381, 1342, 1329 and 1267 cm −1 in the infrared absorption spectrum.
[20] The powder X-ray diffraction according to [5], which has diffraction angles of 10.5, 14.5, 17.1, 22.5 and 23.0 ° represented by 2θ. Crystals.
[21] The crystal according to [5], which has peaks at 1601, 1556, 1547, 1404 and 1269 cm −1 in the infrared absorption spectrum.
[22] A pharmaceutical composition comprising the compound according to [1] or [2], or the crystal of any of [4], [18] or [19], and a pharmaceutically acceptable carrier.
[23] The pharmaceutical composition according to [22], which is used for treating cancer.
[24] The pharmaceutical composition according to [22] or [23], an anticancer alkylating agent, an anticancer antimetabolite, an anticancer antibiotic, a plant-derived anticancer agent, and an anticancer agent. At least one antitumor agent selected from the group consisting of anticancer agents selected from the group consisting of a cancerous platinum coordination compound, an anticancer camptothecin derivative, an anticancer tyrosine kinase inhibitor, a monoclonal antibody and interferon. A drug that combines a drug.
　本発明は、化合物Ａ・１塩酸塩・１水和物とその製造法を提供する。化合物Ａ・１塩酸塩・１水和物は、高純度で乾燥時に塊化しにくく、凍結乾燥製剤を製造する際の調製溶液に対する溶解性に優れるため、医薬の原薬として有用である。 The present invention provides compound A.1 hydrochloride monohydrate and a method for producing the same. Compound A / 1-hydrochloride / monohydrate is of high purity, hardly clumps during drying, and has excellent solubility in a prepared solution when producing a freeze-dried preparation, and thus is useful as a drug substance for a drug.
　さらに本発明は、化合物Ａ・１塩酸塩・無水物とその製造法を提供する。化合物Ａ・１塩酸塩・無水物は、化合物Ａ・１塩酸塩・１水和物を製造するための原料として有用である。 Further, the present invention provides compound A / 1 hydrochloride / anhydride and a method for producing the same. Compound A · 1 hydrochloride · anhydride is useful as a raw material for producing compound A · 1 hydrochloride · monohydrate.
化合物Ａ・２塩酸塩の光学顕微鏡像を示す図である。It is a figure which shows the optical microscope image of compound A * 2 hydrochloride. 化合物Ａ・塩酸塩の酸解離平衡を示す図である。It is a figure which shows the acid dissociation equilibrium of compound A * hydrochloride. 各ｐＨにおける化合物Ａの解離平衡の状態を示す図である。It is a figure which shows the state of dissociation equilibrium of the compound A in each pH. 化合物Ａ・１塩酸塩・１水和物の光学顕微鏡像を示す図である。It is a figure which shows the optical microscope image of compound A * 1 monohydrochloride * monohydrate. 化合物Ａ・１塩酸塩・無水物の光学顕微鏡像を示す図である。It is a figure which shows the optical microscope image of compound A * 1 hydrochloride * anhydrous. 化合物Ａ・２塩酸塩の赤外吸収スペクトル（ＡＴＲ法）の一例を示す図である。It is a figure which shows an example of the infrared absorption spectrum (ATR method) of compound A * 2 hydrochloride. 化合物Ａ・２塩酸塩の粉末Ｘ線回折パターンの一例を示す図である。It is a figure which shows an example of the powder X-ray-diffraction pattern of compound A * 2 hydrochloride. 化合物Ａ・１塩酸塩・１水和物の赤外吸収スペクトル（ＡＴＲ法）の一例を示す図である。It is a figure which shows an example of the infrared absorption spectrum (ATR method) of compound A * 1 hydrochloride monohydrate. 化合物Ａ・１塩酸塩・１水和物の粉末Ｘ線回折パターンの一例を示す図である。It is a figure which shows an example of the powder X-ray-diffraction pattern of compound A * 1 hydrochloride monohydrate. 化合物Ａ・１塩酸塩・無水物の赤外吸収スペクトル（ＡＴＲ法）の一例を示す図である。It is a figure which shows an example of the infrared absorption spectrum (ATR method) of compound A * 1 hydrochloride / anhydrous. 化合物Ａ・１塩酸塩・無水物の粉末Ｘ線回折パターンの一例を示す図である。It is a figure which shows an example of the powder X-ray-diffraction pattern of compound A * 1 monohydrochloride * anhydrous. 塊状の化合物Ａ・２塩酸塩の外観を示す図である。It is a figure which shows the external appearance of a massive compound A * 2 hydrochloride. 微粉末状の化合物Ａ・２塩酸塩の外観を示す図である。It is a figure which shows the external appearance of compound A * 2 hydrochloride of a fine powder form. 粉末状の化合物Ａ・１塩酸塩・１水和物の外観を示す図である。It is a figure which shows the external appearance of a powdery compound A * 1 hydrochloride * 1 hydrate.
　以下に本発明について詳細に説明する。 The present invention will be described in detail below.
　本明細書において、特に断らない限り、各用語は、以下の意味を有する。 Unless otherwise specified, each term used herein has the following meaning.
　本発明において、「原薬」とは、医薬の有効成分を意味する。 In the present invention, the “drug substance” means an active ingredient of a medicine.
　化合物Ａとは、（Ｓ）－２－アミノ－３－｛４－［（５－アミノ－２－フェニルベンゾ［ｄ］オキサゾール－７－イル）メトキシ］－３，５－ジクロロフェニル｝プロパン酸である。 Compound A is (S) -2-amino-3- {4-[(5-amino-2-phenylbenzo [d] oxazol-7-yl) methoxy] -3,5-dichlorophenyl} propanoic acid ..
　中間体１とは、（Ｓ）－２－アミノ－３－｛４－［（５－アミノ－２－フェニルベンゾ［ｄ］オキサゾール－７－イル）メトキシ］－３，５－ジクロロフェニル｝－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］プロパン酸である。 Intermediate 1 means (S) -2-amino-3- {4-[(5-amino-2-phenylbenzo [d] oxazol-7-yl) methoxy] -3,5-dichlorophenyl} -2- [(Tert-Butoxycarbonyl) amino] propanoic acid.
　脂肪族炭化水素類としては、例えば、ペンタン、ヘキサン、シクロヘキサンまたはヘプタンが挙げられる。 Examples of the aliphatic hydrocarbons include pentane, hexane, cyclohexane or heptane.
　芳香族炭化水素類としては、例えば、ベンゼン、トルエンまたはキシレンが挙げられる。 Examples of aromatic hydrocarbons include benzene, toluene or xylene.
　ハロゲン化炭化水素類としては、例えば、ジクロロメタン、クロロホルムまたはジクロロエタンが挙げられる。 Examples of halogenated hydrocarbons include dichloromethane, chloroform or dichloroethane.
　アルコール類としては、例えば、メタノール、エタノール、１－プロパノール、２－プロパノール、ブタノールまたは２－メチル－２－プロパノールが挙げられる。 Examples of alcohols include methanol, ethanol, 1-propanol, 2-propanol, butanol or 2-methyl-2-propanol.
　エーテル類としては、例えば、ジエチルエーテル、ジイソプロピルエーテル、ジオキサン、テトラヒドロフラン、アニソール、エチレングリコールジメチルエーテル、ジエチレングリコールジメチルエーテルまたはジエチレングリコールジエチルエーテルが挙げられる。 Examples of ethers include diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether or diethylene glycol diethyl ether.
　ケトン類としては、例えば、アセトン、２－ブタノンまたは４－メチル－２－ペンタノンが挙げられる。 Examples of the ketones include acetone, 2-butanone and 4-methyl-2-pentanone.
　エステル類としては、例えば、酢酸メチル、酢酸エチル、酢酸プロピル、酢酸イソプロピルまたは酢酸ブチルが挙げられる。 Examples of the esters include methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate or butyl acetate.
　アミド類としては、例えば、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミドまたは１－メチル－２－ピロリドンが挙げられる。 Examples of the amides include N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone.
　ニトリル類としては、例えば、アセトニトリルまたはプロピオニトリルが挙げられる。 Examples of nitriles include acetonitrile and propionitrile.
　スルホキシド類としては、例えば、ジメチルスルホキシドが挙げられる。 Examples of sulfoxides include dimethyl sulfoxide.
　一般に、赤外吸収スペクトル（ＡＴＲ法）における波数（ｃｍ－１）の値は、±２ｃｍ－１の範囲内で誤差が生じ得る。従って、本発明で「波数Ｙ」というときは、特に記載した場合を除き、「波数（（Ｙ－２）～（Ｙ＋２））ｃｍ－１」を意味する。従って、赤外吸収スペクトル（ＡＴＲ法）における吸収ピークの波数が完全に一致する結晶だけでなく、吸収ピークの波数が±２ｃｍ－１の誤差範囲内で一致する結晶も本発明に含まれる。 In general, the wave number (cm −1 ) value in the infrared absorption spectrum (ATR method) may have an error within a range of ± 2 cm −1 . Therefore, in the present invention, “wave number Y” means “wave number ((Y-2) to (Y + 2)) cm −1 ”, unless otherwise specified. Therefore, the present invention includes not only crystals in which the wave numbers of absorption peaks in the infrared absorption spectrum (ATR method) completely match, but also crystals in which the wave numbers of absorption peaks match within an error range of ± 2 cm −1 .
　一般に、粉末Ｘ線回折における回折角度（２θ）は、±０．２°の範囲内で誤差が生じ得る。従って、本発明で「回折角度（２θ）Ｘ°」というときは、特に記載した場合を除き、「回折角度（２θ）（（Ｘ－０．２）～（Ｘ＋０．２））°」を意味する。従って、粉末Ｘ線回折における回折角度（２θ）が完全に一致する結晶だけでなく、回折角度（２θ）が±０．２°の誤差範囲内で一致する結晶も本発明に含まれる。 Generally, the diffraction angle (2θ) in powder X-ray diffraction may have an error within a range of ± 0.2 °. Therefore, the term “diffraction angle (2θ) X °” in the present invention means “diffraction angle (2θ) ((X−0.2) to (X + 0.2)) °”, unless otherwise specified. To do. Therefore, the present invention includes not only a crystal whose diffraction angle (2θ) in powder X-ray diffraction completely matches, but also a crystal whose diffraction angle (2θ) matches within an error range of ± 0.2 °.
［化合物Ａ］
　化合物Ａは、特許文献１に記載の方法で製造することができる。化合物Ａは、種々の有機溶媒に対して難溶性であり、抽出などの操作によって単離することは難しい。そのため、化合物Ａは、例えば、含水溶媒中、中和晶析などの方法によって単離される。 [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 operations such as extraction. Therefore, the compound A is isolated by a method such as neutralization crystallization in a water-containing solvent.
［化合物Ａ・２塩酸塩］
　特許文献１によれば、化合物Ａの塩酸塩は、化合物Ａを常法に従い塩酸塩とすることで製造できる。 [Compound A / Dihydrochloride]
According to Patent Document 1, the hydrochloride salt of Compound A can be produced by converting Compound A into a hydrochloride salt according to a conventional method.
　本発明者らは、特許文献１に記載の方法を参考とし、（Ｓ）－２－アミノ－３－｛４－［（５－アミノ－２－フェニルベンゾ［ｄ］オキサゾール－７－イル）メトキシ］－３，５－ジクロロフェニル｝－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］プロパン酸（以下、中間体１と称することもある）を、定法に従い脱保護し、微細な結晶性固体（図１）として、化合物Ａ・２塩酸塩を得た。 The present inventors refer to the method described in Patent Document 1 and refer to (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) was deprotected by a conventional method to give a fine crystalline solid (Fig. 1). ) Was obtained as the compound A.2 hydrochloride.
　化合物Ａ・２塩酸塩は、粉末Ｘ線回折において、２θで表される８．０、８．８、１９．６、２２．２、２３．８および２６．１°の回折角度を有することを特徴とする。図７は、化合物Ａ・２塩酸塩の粉末Ｘ線回折チャートを示す。 Compound A · 2 hydrochloride has a diffraction angle represented by 2θ of 8.0, 8.8, 19.6, 22.2, 23.8 and 26.1 ° in powder X-ray diffraction. Characterize. FIG. 7 shows a powder X-ray diffraction chart of compound A · 2 hydrochloride.
　また、化合物Ａ・２塩酸塩は、赤外吸収スペクトルにおいて、１７３６、１４８３、１４７４および１２４０ｃｍ－１に特徴的なピークを有することを特徴とする。図６は、化合物Ａ・２塩酸塩の赤外吸収スペクトルチャートを示す。 Further, Compound A · 2 hydrochloride is characterized by having characteristic peaks at 1736, 1483, 1474 and 1240 cm −1 in the infrared absorption spectrum. FIG. 6 shows an infrared absorption spectrum chart of Compound A · 2 hydrochloride.
Figure JPOXMLDOC01-appb-C000002
Figure JPOXMLDOC01-appb-C000002
［化合物Ａの酸解離平衡］
　化合物Ａは、塩酸と塩を形成しうる塩基性部位を２つ以上有し、図２に示す平衡が成り立つ。化合物Ａの酸解離定数（ｐＫａ）を、中和滴定により実験的に求めたところ、第一酸解離定数（ｐＫａ１）は１．０、第２酸解離定数（ｐＫａ２）は２．２であった。 [Acid dissociation equilibrium of compound A]
Compound A has two or more basic sites capable of forming a salt with hydrochloric acid, and the equilibrium shown in FIG. 2 is established. When the acid dissociation constant (pK a ) of Compound A was experimentally determined by neutralization titration, the first acid dissociation constant (pK a1 ) was 1.0 and the second acid dissociation constant (pK a2 ) was 2.2. Met.
　ここで、化合物Ａの各成分のモル分率を、それぞれ、［化合物Ａ・２塩酸塩］、［化合物Ａ・１塩酸塩］、［化合物Ａ］と表し、水素イオン濃度を［Ｈ＋］と表すと、式１～式３が成り立つ。 Here, the molar fraction of each component of the compound A is expressed as [compound A · dihydrochloride], [compound A · monohydrochloride], [compound A], and the hydrogen ion concentration is [H + ]. If expressed, Equations 1 to 3 hold.
（式１）Ｋａ１＝［化合物Ａ・１塩酸塩］×［Ｈ＋］／［化合物Ａ・２塩酸塩］
（式２）Ｋａ2＝［化合物Ａ］×［Ｈ＋］／［化合物Ａ・１塩酸塩］
（式３）［化合物Ａ・２塩酸塩］＋［化合物Ａ・１塩酸塩］＋［化合物Ａ］＝１ (Formula 1) K a1 = [Compound A · 1 Hydrochloride] × [H + ] / [Compound A · 2 Hydrochloride]
(Formula 2) K a2 = [compound A] × [H + ] / [compound A · monohydrochloride]
(Formula 3) [Compound A · Dihydrochloride] + [Compound A · 1 Hydrochloride] + [Compound A] = 1
　さらに、式１～式３に対し、任意のｐＨにおける［Ｈ＋］の値を代入することで、図３に示す平衡状態のグラフを作成した。図３は、各ｐＨにおける化合物Ａの解離平衡の状態を示す図である。 Further, by substituting the value of [H + ] at an arbitrary pH into the equations 1 to 3, the equilibrium state graph shown in FIG. 3 was created. FIG. 3 is a diagram showing a state of dissociation equilibrium of compound A at each pH.
　図３からわかるとおり、ｐＨが１．０（＝ｐＫａ１）未満の範囲では、化合物Ａ・２塩酸塩が優位となり、ｐＨが２．２（＝ｐＫａ２）よりも大きい範囲では、化合物Ａが優位となる。さらに、ｐＨが１．０（＝ｐＫａ１）～２．２（＝ｐＫａ２）の範囲では、化合物Ａ・１塩酸塩が優位となり、ｐＨが１．６（＝（ｐＫａ１＋ｐＫａ２）／２）のとき、モル分率が極大となることが明らかである。 As can be seen from FIG. 3, in the range where the pH is lower than 1.0 (= pK a1 ), the compound A.2 hydrochloride is dominant, and in the range where the pH is higher than 2.2 (= pK a2 ), the compound A is Take an advantage. Further, in the range of pH 1.0 (= pK a1 ) to 2.2 (= pK a2 ), Compound A · 1 hydrochloride is dominant, and pH is 1.6 (= (pK a1 + pK a2 ) / 2. ), It is clear that the mole fraction becomes maximum.
　このように、化合物Ａの塩酸塩を形成する際、ｐＨの範囲を制御することで、任意の価数の塩酸塩を得ることが可能となる。 In this way, when forming the hydrochloride salt of compound A, it is possible to obtain the hydrochloride salt of any valence by controlling the pH range.
［水分活性と化合物Ａ・１塩酸塩の水和との相関関係］
　医薬の分野においては、溶解度などの物理化学的性質を改善する上で水和物は極めて重要な物質である。水和物は、結晶構造中に水分子を含むことを特徴とすることから、一般的に自由水を含まない溶液中から得ることは難しい。 [Correlation between Water Activity and Hydration of Compound A / 1 Hydrochloride]
In the field of medicine, hydrates are extremely important substances for improving physicochemical properties such as solubility. Since hydrates are characterized by containing water molecules in their crystal structures, it is generally difficult to obtain hydrates from a solution containing no free water.
　例えば、Ｓｉｍｏｎらの報告（Ｏｒｇ．　Ｐｒｏｃｅｓｓ　Ｒｅｓ．　Ｄｅｖ．，２００９，１３（１），ｐｐ７８－８３）や、国際公開２０１５／０７３４７６号では、系の水分活性（以下、ａｗと称することもある）によって、無水物や、価数の異なる水和物が得られることを示している。 For example, in the report of Simon et al. (Org. Process Res. Dev., 2009, 13 (1), pp78-83) and International Publication No. 2015/073476, the water activity of the system (hereinafter sometimes referred to as aw ). ) Indicates that anhydrate and hydrates having different valences can be obtained.
　ここで、水分活性ａｗは、任意の物質に含まれる自由水の割合を表す指標であり、式４に示す通り、水の活量係数γｗと水のモル分率ｘｗの積で表すことができる。 Here, the water activity a w is an index representing the ratio of free water contained in an arbitrary substance, and is represented by the product of the water activity coefficient γ w and the water mole fraction x w as shown in Equation 4. be able to.
（式４）ａｗ＝γｗ×ｘｗ (Formula 4) a w = γ w × x w
　また、式４中の水の活量係数γｗは、例えば、ＵＮＩＱＵＡＣ式を用いて推算することができる（Ａｂｒａｍｓ，Ｄ．Ｓ．ら：ＡＩＣｈＥ　Ｊ．，１９７５，２１，ｐｐ１１６－１２８）。 Further, the water activity coefficient γ w in Equation 4 can be estimated using, for example, the UNIQUAC equation (Abrams, DS, et al .: AIChE J., 1975, 21, pp116-128).
　本発明者らは、化合物Ａ・１塩酸塩・１水和物を、水分活性の異なる種々のアルコール水中で懸濁撹拌した結果、化合物Ａ・１塩酸塩は、系の水分活性によって化合物Ａ・１塩酸塩・１水和物、および、化合物Ａ・１塩酸塩・無水物となることを見出した。その結果を表１に示す。 As a result of suspending and stirring Compound A · 1 hydrochloride monohydrate in various alcoholic waters having different water activities, the present inventors have found that Compound A · 1 hydrochloride is compound A · 1 hydrochloride depending on the water activity of the system. It has been found that it is a monohydrochloride monohydrate and a compound A monohydrochloride anhydrate. The results are shown in Table 1.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
　即ち、表１に示すように、系の水分活性が０．４５以下の範囲では化合物Ａ・１塩酸塩・無水物が、系の水分活性が０．６５以上の範囲では化合物Ａ・１塩酸塩・１水和物が得られる。 That is, as shown in Table 1, in the range where the water activity of the system is 0.45 or less, the compound A · 1 hydrochloride / anhydride is obtained, and in the range where the water activity of the system is 0.65 or more, the compound A · 1 hydrochloride is obtained. -A monohydrate is obtained.
　このように、水分活性の範囲を制御することで、化合物Ａ・１塩酸塩・無水物、および、化合物Ａ・１塩酸塩・１水和物を、それぞれ選択的に得ることが可能となる。 By thus controlling the range of water activity, it becomes possible to selectively obtain Compound A.1 hydrochloride / anhydrate and Compound A.1 hydrochloride / monohydrate.
［化合物Ａ・１塩酸塩・１水和物］
　化合物Ａ・１塩酸塩・１水和物は、本発明者らが見出した化合物である。 [Compound A-1 Hydrochloride Monohydrate]
The compound A-1 monohydrochloride monohydrate is a compound found by the present inventors.
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004
　化合物Ａ・１塩酸塩・１水和物は、アスペクト比が大きな針～柱状の結晶性固体（図４）であり、粉末Ｘ線回折において、２θで表される７．１、９．５、１８．９、２１．６および２４．２°の回折角度を有することを特徴とする。図９には、化合物Ａ・１塩酸塩・１水和物の粉末Ｘ線回折チャートを示す。 Compound A · 1 hydrochloride · monohydrate is a needle-to-columnar crystalline solid having a large aspect ratio (FIG. 4), and is represented by 2θ in powder X-ray diffraction of 7.1, 9.5, It is characterized by having diffraction angles of 18.9, 21.6 and 24.2 °. FIG. 9 shows a powder X-ray diffraction chart of compound A / 1 hydrochloride / monohydrate.
　また、化合物Ａ・１塩酸塩・１水和物は、赤外吸収スペクトルにおいて、１３９３、１３８１、１３４２、１３２９および１２６７ｃｍ－１に特徴的なピークを有することを特徴とする。図８には、化合物Ａ・１塩酸塩・１水和物の赤外吸収スペクトルチャートを示す。 In addition, Compound A · 1 hydrochloride · monohydrate is characterized by having characteristic peaks at 1393, 1381, 1342, 1329 and 1267 cm −1 in the infrared absorption spectrum. FIG. 8 shows an infrared absorption spectrum chart of compound A / 1 hydrochloride / monohydrate.
　化合物Ａ・１塩酸塩・１水和物には、化合物Ａに対し、１モル当量の塩化水素が含まれ、０．８～１．２モル当量の範囲で含まれていてもよい。 The compound A monohydrochloride monohydrate contains 1 molar equivalent of hydrogen chloride with respect to the compound A, and may be contained in the range of 0.8 to 1.2 molar equivalents.
　さらに、化合物Ａ・１塩酸塩・１水和物には、３．４ｗｔ％の水が含まれ、２．８～４．１ｗｔ％の範囲で含まれていてもよい。 Further, the compound A / 1 hydrochloride / monohydrate contains 3.4 wt% of water, and may be contained in the range of 2.8 to 4.1 wt%.
［化合物Ａ・１塩酸塩・１水和物の製造法］
　化合物Ａ・１塩酸塩・１水和物は、含水有機溶媒中、化合物Ａに塩酸を加えてｐＨを調整することにより製造することができる。 [Production Method of Compound A / 1 Hydrochloride Monohydrate]
Compound A · hydrochloride monohydrate can be produced by adding hydrochloric acid to compound A in a water-containing organic solvent to adjust the pH.
　この反応に使用される溶媒としては、反応に影響を及ぼさないものであれば特に限定されないが、例えば、アルコール類、エーテル類、ケトン類、エステル類、アミド類、ニトリル類、スルホキシド類が挙げられ、これらは混合して使用してもよい。好ましい溶媒としては、アルコール類、エーテル類、ケトン類、ニトリル類が挙げられ、アルコール類がより好ましく、メタノール、エタノール、１－プロパノール、２－プロパノールがさらに好ましい。 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. These may be mixed and used. Preferable solvents include alcohols, ethers, ketones and nitriles, alcohols are more preferable, and methanol, ethanol, 1-propanol and 2-propanol are further preferable.
　含水有機溶媒における溶媒の水分活性は、０．５以上であればよく、０．６５以上が好ましい。 The water activity of the solvent in the water-containing organic solvent may be 0.5 or more, preferably 0.65 or more.
　溶媒の使用量は、化合物Ａに対して１～５０倍量（ｖ／ｗ）であればよく、５～２０倍量（ｖ／ｗ）が好ましい。 The amount of the solvent used may be 1 to 50 times (v / w) the amount of Compound A, preferably 5 to 20 times (v / w).
　化合物Ａ・１塩酸塩・１水和物を調製する際のｐＨの範囲は、１～２の範囲であればよく、１．０～２．２の範囲が好ましく、１．２～２．０の範囲がより好ましい。 The pH range for preparing the compound A / 1-hydrochloride / monohydrate may be in the range of 1-2, preferably 1.0-2.2, and 1.2-2.0. Is more preferable.
　反応温度は、０～６０℃であればよく、０～３０℃が好ましい。 The reaction temperature may be 0 to 60 ° C, preferably 0 to 30 ° C.
　反応時間は、１分間～５０時間であればよく、３０分間～１２時間が好ましい。 The reaction time may be 1 minute to 50 hours, preferably 30 minutes to 12 hours.
　反応雰囲気は特に制限されないが、不活性ガス雰囲気下で行うことが好ましい。不活性ガス雰囲気としては、例えば、アルゴンガス雰囲気、窒素ガス雰囲気などが挙げられる。 The reaction atmosphere is not particularly limited, but it is preferable to carry out under an inert gas atmosphere. Examples of the inert gas atmosphere include an argon gas atmosphere and a nitrogen gas atmosphere.
　また、この反応に用いる化合物Ａとして、化合物Ａと塩基とからなる塩を用いてもよい。化合物Ａと塩基とからなる塩の種類としては、反応に影響を及ぼさないものであれば特に限定されないが、例えば、無機塩基、有機塩基との塩が挙げられる。好ましい塩としては、無機塩基との塩が挙げられ、アルカリ金属との塩がより好ましい。 As the compound A used in this reaction, a salt composed of the compound A and a base may be used. The type of salt composed of the compound A and the base is not particularly limited as long as it does not affect the reaction, and examples thereof include salts with an inorganic base and an organic base. Preferred salts include salts with inorganic bases, and salts with alkali metals are more preferred.
　さらに、この反応に用いる化合物Ａとして、化合物Ａと酸とからなる塩を用い、塩酸または塩基を加えることでｐＨを調整してもよい。 Further, as the compound A used in this reaction, a salt of the compound A and an acid may be used, and the pH may be adjusted by adding hydrochloric acid or a base.
　化合物Ａと酸とからなる塩の種類としては、反応に影響を及ぼさないものであれば特に限定されないが、例えば、鉱酸、カルボン酸との塩が挙げられる。好ましい塩としては、鉱酸との塩が挙げられ、塩酸塩がより好ましい。すなわち、この反応に用いる化合物Ａの塩酸塩は、化合物Ａ・１塩酸塩・無水物であってもよい。 The type of salt composed of 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, with the hydrochloride salt being more preferred. That is, the hydrochloride salt of Compound A used in this reaction may be Compound A · 1 hydrochloride · anhydride.
　ｐＨ調整に用いられる塩基の種類としては、無機塩基が挙げられ、アルカリ金属の塩基が好ましく、水酸化ナトリウム、炭酸ナトリウム、炭酸水素ナトリウムがより好ましい。これらは、１種単独でも、２種類以上を混合して用いてもよい。 Examples of the type of base used for pH adjustment include inorganic bases, alkali metal bases are preferable, and sodium hydroxide, sodium carbonate, and sodium hydrogen carbonate are more preferable. These may be used alone or in combination of two or more.
［化合物Ａ・１塩酸塩・無水物］
　化合物Ａ・１塩酸塩・無水物は、本発明者らが見出した化合物である。 [Compound A-1 monohydrochloride / anhydride]
The compound A-1 monohydrochloride / anhydride is a compound found by the present inventors.
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
　化合物Ａ・１塩酸塩・無水物は、微細な結晶性固体であり、粉末Ｘ線回折において、２θで表される１０．５、１４．５、１７．１、２２．５および２３．０°の回折角度を有することを特徴とする。図１１には、化合物Ａ・１塩酸塩・１水和物の粉末Ｘ線回折チャートを示す。 Compound A / 1 hydrochloride / anhydrous is a fine crystalline solid, and is 10.5, 14.5, 17.1, 22.5 and 23.0 ° represented by 2θ in powder X-ray diffraction. It has a diffraction angle of. FIG. 11 shows a powder X-ray diffraction chart of compound A / 1 hydrochloride / monohydrate.
　また、化合物Ａ・１塩酸塩・無水物は、赤外吸収スペクトルにおいて、１６０１、１５５６、１５４７、１４０４および１２６９ｃｍ－１に特徴的なピークを有することを特徴とする。図１０には、化合物Ａ・１塩酸塩・無水物の赤外吸収スペクトルチャートを示す。 In addition, Compound A / 1-hydrochloride / anhydride is characterized by having characteristic peaks at 1601, 1556, 1547, 1404 and 1269 cm −1 in the infrared absorption spectrum. FIG. 10 shows an infrared absorption spectrum chart of compound A / 1-hydrochloride / anhydrous.
　化合物Ａ・１塩酸塩・無水物には、化合物Ａに対し、１モル当量の塩化水素が含まれ、０．８～１．２モル当量の範囲で含まれていてもよい。 The compound A / 1-hydrochloride / anhydride contains 1 molar equivalent of hydrogen chloride with respect to the compound A, and may be contained in the range of 0.8 to 1.2 molar equivalents.
［化合物Ａ・１塩酸塩・無水物の製造法］
　化合物Ａ・１塩酸塩・無水物は、有機溶媒中で、化合物Ａと、１モル当量の塩化水素とを反応させることで製造することができる。 [Production Method of Compound A / 1 Hydrochloride / Anhydrous]
Compound A / 1 hydrochloride / anhydrous can be produced by reacting compound A with 1 molar equivalent of hydrogen chloride in an organic solvent.
　この反応に使用される溶媒としては、反応に影響を及ぼさないものであれば特に限定されないが、例えば、アルコール類、エーテル類、ケトン類、エステル類、ニトリル類が挙げられ、これらは混合して使用してもよい。好ましい溶媒としては、アルコール類、エーテル類、エステル類が挙げられ、メタノール、エタノール、酢酸エチル、テトラヒドロフラン、ジオキサンがより好ましい。 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 are mixed. May be used. Preferable solvents include alcohols, ethers and esters, with methanol, ethanol, ethyl acetate, tetrahydrofuran and dioxane being more preferable.
　溶媒の水分活性は、０．５未満であればよく、０．３以下が好ましい。 The water activity of the solvent should be less than 0.5, preferably 0.3 or less.
　溶媒の使用量は、化合物Ａに対して１～５０倍量（ｖ／ｗ）であればよく、５～２０倍量（ｖ／ｗ）が好ましい。 The amount of the solvent used may be 1 to 50 times (v / w) the amount of Compound A, preferably 5 to 20 times (v / w).
　反応させる塩化水素の量は、１モル当量であればよく、０．８～１．２モル当量がより好ましく、０．９～１．１モル当量がさらに好ましい。 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.
　反応温度は、０～６０℃であればよく、０～３０℃が好ましい。 The reaction temperature may be 0 to 60 ° C, preferably 0 to 30 ° C.
　反応時間は、１分間～５０時間であればよく、３０分間～１２時間が好ましい。 The reaction time may be 1 minute to 50 hours, preferably 30 minutes to 12 hours.
　反応雰囲気は特に制限されないが、不活性ガス雰囲気下で行うことが好ましい。不活性ガス雰囲気としては、例えば、アルゴンガス雰囲気、窒素ガス雰囲気などが挙げられる。 The reaction atmosphere is not particularly limited, but it is preferable to carry out under an inert gas atmosphere. Examples of the inert gas atmosphere include an argon gas atmosphere and a nitrogen gas atmosphere.
　化合物Ａ・１塩酸塩・無水物は、化合物Ａ・１塩酸塩・１水和物を有機溶媒中で懸濁撹拌し、水和水を除去することによっても製造することができる。 The compound A / 1-hydrochloride / anhydrous can also be produced by suspending and stirring Compound A / 1-hydrochloride / monohydrate in an organic solvent and removing water of hydration.
　この反応に使用される溶媒としては、反応に影響を及ぼさないものであれば特に限定されないが、例えば、アルコール類、エーテル類、ケトン類、エステル類、ニトリル類が挙げられ、これらは混合して使用してもよい。好ましい溶媒としては、アルコール類、ケトン類、エステル類が挙げられ、メタノール、エタノール、１－プロパノール、２－プロパノール、アセトン、酢酸エチルがより好ましい。 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 are mixed. May be used. Preferable solvents include alcohols, ketones and esters, with methanol, ethanol, 1-propanol, 2-propanol, acetone and ethyl acetate being more preferable.
　溶媒の水分活性は、０．５未満であればよく、０．３以下が好ましい。 The water activity of the solvent should be less than 0.5, preferably 0.3 or less.
　溶媒の使用量は、化合物Ａに対して１～５０倍量（ｖ／ｗ）であればよく、５～２０倍量（ｖ／ｗ）が好ましい。 The amount of the solvent used may be 1 to 50 times (v / w) the amount of Compound A, preferably 5 to 20 times (v / w).
　反応温度は、０～６０℃であればよく、０～３０℃が好ましい。 The reaction temperature may be 0 to 60 ° C, preferably 0 to 30 ° C.
　反応時間は、１分間～５０時間であればよく、３０分間～１２時間が好ましい。 The reaction time may be 1 minute to 50 hours, preferably 30 minutes to 12 hours.
　反応雰囲気は特に制限されないが、不活性ガス雰囲気下で行うことが好ましい。不活性ガス雰囲気としては、例えば、アルゴンガス雰囲気、窒素ガス雰囲気などが挙げられる。 The reaction atmosphere is not particularly limited, but it is preferable to carry out under an inert gas atmosphere. Examples of the inert gas atmosphere include an argon gas atmosphere and a nitrogen gas atmosphere.
　即ち、上記方法により、化合物Ａ・１塩酸塩・無水物、および、化合物Ａ・１塩酸塩・１水和物を、それぞれ選択的に得ることが可能となる。更には、化合物Ａ・１塩酸塩・無水物から化合物Ａ・１塩酸塩・１水和物が調製可能となった。そして、以下に述べる医薬組成物の調製には化合物Ａ・１塩酸塩・１水和物の利用が有利となる。 That is, according to the method described above, it is possible to selectively obtain Compound A · 1 hydrochloride / anhydrate and Compound A · 1 hydrochloride / monohydrate. Furthermore, it has become possible to prepare compound A · 1 hydrochloride · monohydrate from compound A · 1 hydrochloride · anhydride. Then, the use of Compound A.1 hydrochloride monohydrate is advantageous for the preparation of the pharmaceutical composition described below.
投与対象
　本発明において、投与対象（患者）は、温血動物であり、ヒトまたは非ヒト哺乳動物である。一実施形態では、投与対象はヒトである。 Subject of Administration In the present invention, the subject of administration (patient) is a warm-blooded animal, which is a human or non-human mammal. In one embodiment, the administration subject is a human.
医薬組成物
　本発明の化合物Ａ・１塩酸塩は、薬学的に許容される希釈剤、賦形剤または担体（本明細書ではこれらを総称して「担体」と呼ぶ）とともに、医薬組成物として患者に投与される。前記薬学的に許容される希釈剤、賦形剤または担体は、所定の投与形、例えば、錠剤、丸剤、カプセル、粉末、顆粒、滅菌溶液もしくは懸濁液、エアロゾルもしくは液体スプレー、滴剤、注射剤または坐剤などの単位剤形である。前記医薬組成物は、経口、非経口、鼻腔内、舌下もしくは直腸内投与、または吸入による投与のためのものである。本発明の医薬組成物の調合は、当該技術から公知の方法によって行うことができる。ここで、「薬学的に許容される」とは、投与対象（患者）に対して無毒なことを意図する。 Pharmaceutical Composition The compound A · 1 hydrochloride of the present invention is used as a pharmaceutical composition together with a pharmaceutically acceptable diluent, excipient or carrier (these are collectively referred to as “carrier” in the present specification). Administered to patients. Said pharmaceutically acceptable diluent, excipient or carrier can be in the form of a prescribed dosage form, for example tablets, pills, capsules, powders, granules, sterile solutions or suspensions, aerosols or liquid sprays, drops, A unit dosage form such as an injection or a suppository. Said 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, the term "pharmaceutically acceptable" means non-toxic to administration subjects (patients).
　さらに、本発明の化合物Ａ・１塩酸塩は、好適な鼻腔内賦形剤の局所使用によって鼻腔内形で投与することができ、または当業者に周知の経皮皮膚パッチの形を用いて経皮経路によって投与することができる。 In addition, the Compound A • 1 hydrochloride salt of the invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patch forms well known to those of ordinary skill in that art. It can be administered by the dermal route.
　さらに、本発明の化合物Ａ・１塩酸塩は、好適な鼻腔内賦形剤の局所使用によって鼻腔内形で投与することができ、または当業者に周知の経皮皮膚パッチの形を用いて経皮経路によって投与することができる。経皮送達系の形で投与するための用量投与は、その投薬計画を通して継続的であろう。 In addition, the Compound A • 1 hydrochloride salt of the invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patch forms well known to those of ordinary skill in that art. It can be administered by the dermal route. Dose administration for administration in the form of transdermal delivery systems will be continuous throughout the dosing schedule.
　一実施形態において、前記医薬組成物は、治療有効量の本発明の化合物Ａ・１塩酸塩・１水和物を薬学的に許容され得る担体との混合物で含む。 In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of compound A.1 hydrochloride monohydrate of the invention in admixture with a pharmaceutically acceptable carrier.
　一実施形態において、前記医薬組成物中の化合物Ａ・１塩酸塩・１水和物は結晶形態である。一実施形態において、前記結晶形態は、原薬の約５重量％から約１００重量％で存在する。別の実施形態において、前記結晶形態は、原薬の約１０重量％から約１００重量％で存在する。別の実施形態において、前記結晶形態は、原薬の約２５重量％から約１００重量％で存在する。別の実施形態において、前記結晶形態は、原薬の約５０重量％から約１００重量％で存在する。さらに別の実施形態において、原薬の実質的にすべてが前記結晶形態である。 In one embodiment, Compound A.1 hydrochloride monohydrate in the pharmaceutical composition is in crystalline form. In one embodiment, the crystalline form is present at about 5% to about 100% by weight of the drug substance. In another embodiment, the crystalline form is present at about 10% to about 100% by weight of the drug substance. In another embodiment, the crystalline form is present at about 25% to about 100% by weight of the drug substance. In another embodiment, the crystalline form is present at about 50% to about 100% by weight of the drug substance. In yet another embodiment, substantially all of the drug substance is in said crystalline form.
　本発明の意図する効果を得るための本発明の有効成分である原薬の投薬量は、１日につき体重１ｋｇあたり約０．０１ｍｇ（ｍｇ／ｋｇ／日）から約１００ｍｇ／ｋｇ／日、好ましくは０．０１から１０ｍｇ／ｋｇ／日、および最も好ましくは０．１から５．０ｍｇ／ｋｇ／日の範囲であろう。経口投与については、好ましくは、処置すべき患者に対する投薬量の調整のために０．０１、０．０５、０．１、０．５、１．０、２．５、５．０、１０．０、１５．０、２５．０、５０．０、１００および５００ミリグラムの有効成分を含有する錠剤の形態での医薬組成物を提供する。医薬組成物は、典型的には約０．０１ｍｇから約５００ｍｇの有効成分、好ましくは約１ｍｇから約２００ｍｇの有効成分を含有する。静脈内投与における用量は、約０．１から約１０ｍｇ／ｋｇの範囲であろう。本発明の結晶を単一日用量してもよく、または全日用量を１日２、３もしくは４回の用量に分割して投与してもよい。 The dose of the drug substance, which is the active ingredient of the present invention, for obtaining the intended effect of the present invention is about 0.01 mg / kg body weight per day (mg / kg / day) to about 100 mg / kg / day, preferably Will range from 0.01 to 10 mg / kg / day, and most preferably 0.1 to 5.0 mg / kg / day. For oral administration, preferably 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10. There is provided a pharmaceutical composition in the form of a tablet containing 0, 15.0, 25.0, 50.0, 100 and 500 milligrams of active ingredient. Pharmaceutical compositions typically contain from about 0.01 mg to about 500 mg of active ingredient, preferably from about 1 mg to about 200 mg. The dose for intravenous administration will be in the range of about 0.1 to about 10 mg / kg. The crystals of the invention may be given in a single daily dose, or the total daily dose may be administered in divided doses of 2, 3 or 4 times daily.
　或いは、本発明の医薬組成物は、治療有効量の本発明の有効成分を薬学的に許容され得る担体との混合物で含み、この場合の有効成分は、約１重量％から約１００重量％、約５重量％から約１００重量％、約１０重量％から約１００重量％、約５０重量％から約１００重量％、約７０重量％から約１００重量％、約８０重量％から約１００重量％の化合物Ａ・１塩酸塩・１水和物を含む。 Alternatively, the pharmaceutical composition of the present invention comprises a therapeutically effective amount of the active ingredient of the present invention in admixture with a pharmaceutically acceptable carrier, wherein the active ingredient is from about 1% to about 100% by weight, From about 5% to about 100%, about 10% to about 100%, about 50% to about 100%, about 70% to about 100%, about 80% to about 100% Includes Compound A.1 Hydrochloride Monohydrate.
　例えば、錠剤またはカプセルの形での経口投与については、活性薬物成分を経口用の非毒性で薬理学的に許容され得る不活性担体、例えば、ラクトース、デンプン、スクロース、グルコース、メチルセルロース、ステアリン酸マグネシウム、リン酸二カルシウム、硫酸カルシウム、マンニトール、ソルビトール等併用することができ；液体形での経口投与については、経口薬物成分を任意の経口用の非毒性で薬理学的に許容され得る不活性担体、例えば、エタノール、グリセロール、水等と併用することができる。さらに、必要な場合には、好適な結合剤、滑沢剤、崩壊剤および着色剤もその組成物に組み込むことができる。好適な結合剤としては、デンプン、ゼラチン、天然糖、例えばグルコースまたはβ－ラクトース、トウモロコシ甘味料、天然および合成ゴム、例えばアラビアゴム、トラガカントゴムまたはアルギン酸ナトリウム、カルボキシメチルセルロース、ポリエチレングリコール、蝋等が挙げられる。これらの剤形に使用される滑沢剤としては、オレイン酸ナトリウム、ステアリン酸ナトリウム、ステアリン酸マグネシウム、安息香酸ナトリウム、酢酸ナトリウム、塩化ナトリウム等が挙げられる。崩壊剤としては、限定されるものではないが、デンプン、メチルセルロース、寒天、ベントナイト、キサンタンガム等が挙げられる。 For example, for oral administration in the form of tablets or capsules, the active drug component can be an oral, non-toxic, pharmaceutically 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, any oral non-toxic pharmacologically acceptable inert carrier for oral drug component , For example, it can be used in combination with ethanol, glycerol, water and the like. Moreover, when desired, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the composition. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. .. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
　特に、本発明の化合物Ａ・１塩酸塩・１水和物は、抗がん剤として使用可能であることから、好ましくは注射剤として製剤することができる。そのような注射剤としては、本発明の化合物Ａ・１塩酸塩・１水和物、ｐＨ調整剤及びシクロデキストリン類を含むものである。 In particular, since the compound A / 1 monohydrochloride / monohydrate of the present invention can be used as an anticancer agent, it can be preferably formulated as an injection. Such an injection includes the compound A · monohydrochloride · monohydrate of the present invention, a pH adjuster and cyclodextrins.
　注射剤としては、例えば、静脈、皮下、筋肉内注射剤、点滴静注剤が挙げられる。 Examples of the injection include intravenous, subcutaneous, intramuscular injection, and intravenous drip infusion.
　本発明に係る注射剤に配合することができるｐＨ調整剤としては、例えば、炭酸ナトリウム、炭酸カリウム、水酸化ナトリウム、水酸化カリウムのようなアルカリ金属水酸化物、水素化ナトリウム、水素化カリウムのようなアルカリ金属水素化物、アルカリ金属又はアルカリ土類金属の炭酸塩等が挙げられ、特に、水酸化ナトリウム及び炭酸ナトリウムが好ましく、水酸化ナトリウムがより好ましい。 Examples of the pH adjuster that can be added to the injection according to the present invention include alkali metal hydroxides such as sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide, sodium hydride and potassium hydride. Examples thereof include alkali metal hydrides, carbonates of alkali metals or alkaline earth metals, and the like. Particularly, sodium hydroxide and sodium carbonate are preferable, and sodium hydroxide is more preferable.
　本発明に係る注射剤は、ｐＨ調整剤を用いて適当なｐＨに適宜調整されうる。本実施形態に係る注射剤のｐＨは、３～６であることが好ましく、３～５であることがより好ましく、３～４．５であることがさらに好ましく、３．５～４．５であることが特に好ましい。 The injection according to the present invention can be appropriately adjusted to a suitable pH using a pH adjuster. The pH of the injection according to the present embodiment is preferably 3 to 6, more preferably 3 to 5, further preferably 3 to 4.5, and 3.5 to 4.5. It is particularly preferable that
　本発明に係る注射剤に配合することができるシクロデキストリン類としては、例えば、未修飾シクロデキストリン、修飾シクロデキストリンが挙げられる。未修飾シクロデキストリンとして、例えば、α－シクロデキストリン、β－シクロデキストリン、γ－シクロデキストリン等が挙げられる。また修飾シクロデキストリンとして、例えば、ジメチル－α－シクロデキストリン、ジメチル－β－シクロデキストリン、ジメチル－γ－シクロデキストリン、ヒドロキシプロピル－α－シクロデキストリン、ヒドロキシプロピル－β－シクロデキストリン、ヒドロキシプロピル－γ－シクロデキストリン、スルホブチルエーテル－α－シクロデキストリン、スルホブチルエーテル－β－シクロデキストリン、スルホブチルエーテル－γ－シクロデキストリン、マルトシル－α－シクロデキストリン等が挙げられ、これらは、単独で又は組み合わせて使用可能である。 Examples of cyclodextrins that can be added to the injection according to the present invention include unmodified cyclodextrin and modified cyclodextrin. Examples of the unmodified cyclodextrin include α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin and the like. Examples of the modified cyclodextrin include dimethyl-α-cyclodextrin, dimethyl-β-cyclodextrin, dimethyl-γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ- Examples thereof include cyclodextrin, sulfobutyl ether-α-cyclodextrin, sulfobutyl ether-β-cyclodextrin, sulfobutyl ether-γ-cyclodextrin, and maltosyl-α-cyclodextrin, which can be used alone or in combination. ..
　本発明に係る注射剤に配合されるシクロデキストリン類としては、好ましくは、ヒドロキシプロピル－β－シクロデキストリン、スルホブチルエーテル－β－シクロデキストリンが好ましく、スルホブチルエーテル－β－シクロデキストリンがより好ましい。 The cyclodextrins to be added to the injection according to the present invention are preferably hydroxypropyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin, more preferably sulfobutylether-β-cyclodextrin.
　本発明に係る注射剤には、必要により緩衝剤、懸濁化剤、溶解補助剤、安定化剤、等張化剤、保存剤等を添加してもよい。 If necessary, a buffer, 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.
　緩衝剤としては、例えば、ホウ酸緩衝剤、リン酸緩衝剤、クエン酸緩衝剤、酢酸緩衝剤、トリス緩衝剤等が挙げられる。 Examples of the buffer include borate buffer, phosphate buffer, citrate buffer, acetate buffer, Tris buffer and the like.
　懸濁化剤としては、例えば、メチルセルロース、ポリソルベート８０、ヒドロキシエチルセルロース、アラビアゴム、トラガント末、カルボキシメチルセルロースナトリウム、ポリオキシエチレンソルビタンモノラウレートなどが挙げられる。 Examples of the suspending agent include methyl cellulose, polysorbate 80, hydroxyethyl cellulose, gum arabic, tragacanth powder, sodium carboxymethyl cellulose, polyoxyethylene sorbitan monolaurate and the like.
　溶解補助剤としては、例えば、ポリオキシエチレン硬化ヒマシ油、ポリソルベート８０、ニコチン酸アミド、ポリオキシエチレンソルビタンモノラウレート、マクロゴール、グリセリン脂肪酸エステルなどが挙げられる。 Examples of the solubilizing agent include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinic acid amide, polyoxyethylene sorbitan monolaurate, macrogol, and glycerin fatty acid ester.
　安定化剤としては、亜硫酸ナトリウム、メタ亜硫酸ナトリウムなどが挙げられ、等張化剤としては、グリセリン、塩化ナトリウムなどが挙げられ、そして保存剤としては、パラオキシ安息香酸メチル、パラオキシ安息香酸エチル、ソルビン酸などが挙げられる。 Stabilizers include sodium sulfite, sodium metasulfite, etc., isotonic agents include glycerin, sodium chloride, etc., and preservatives include methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbin. Acid etc. are mentioned.
　本発明に係る注射剤は、凍結乾燥製剤であってもよい。このような凍結乾燥製剤は、用時に、例えば、注射用蒸留水、輸液、電解液の１種又はこれら２種以上の溶媒に溶解して用時溶解型注射剤として使用することができる。 The injection according to the present invention may be a freeze-dried preparation. Such a lyophilized preparation can be used as a ready-to-use injection for injection by dissolving it in one or more solvents of distilled water for injection, infusion solution, and electrolytic solution at the time of use.
　凍結乾燥製剤を水に溶解した時のｐＨとして、３～６であることが好ましく、３～５であることがより好ましく、３～４．５であることがさらに好ましく、３．５～４．５であることが特に好ましい。 The pH of the freeze-dried preparation when dissolved in water is preferably 3 to 6, more preferably 3 to 5, further preferably 3 to 4.5, and 3.5 to 4. 5 is particularly preferable.
　前記凍結乾燥製剤は、従来公知の凍結乾燥製剤の製造方法により作製することができ、例えば、－２５℃以下の温度で凍結後、真空度を約２０Ｐａ以下に保ちながら、室温に到達するまで昇温させつつ乾燥させる方法等が挙げられる。 The freeze-dried preparation can be produced by a conventionally known method for producing a freeze-dried preparation. For example, the freeze-dried preparation is frozen at a temperature of −25 ° C. or lower, and then heated to room temperature while maintaining the vacuum degree at about 20 Pa or less. Examples include a method of drying while heating.
　本発明の医薬組成物が適用される投薬レジメは、患者のタイプ、人種、年齢、体重、性別および医学的状態；処置すべき状態の重症度；投与経路；ならびに患者の肝および腎機能をはじめとする様々な要因に従って選択される。医師、獣医または臨床医は、その症状の進行を予防、阻止または停止させるために必要な薬物の有効量を容易に決定し、処方することができる。 The dosing regimen to which the pharmaceutical composition of the present invention is applied depends on 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 liver and renal function of the patient. It is selected according to various factors including the above. A doctor, 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.
　本発明の本発明の化合物Ａ・１塩酸塩、特に、化合物Ａ・１塩酸塩・１水和物は、選択的ＬＡＴ１阻害剤として作用し、腫瘍の増殖を抑制し、有効な抗がん剤となり得る。 The compound A.1 hydrochloride of the present invention of the present invention, particularly the compound A.1 hydrochloride monohydrate acts as a selective LAT1 inhibitor, suppresses tumor growth, and is an effective anticancer agent. Can be.
　本発明の医薬組成物の治療対象となるがんの種類は、特に限定されず、例えば、線維腫、脂肪腫、粘液腫、軟骨腫、骨腫、血管腫、血管内皮腫、リンパ腫、骨髄腫、骨髄肉腫、細網腫、細網肉腫、黒色腫、筋腫、神経腫、神経膠腫、神経鞘腫、肉腫、骨肉種、筋種、線維肉腫、乳頭腫、腺腫、嚢腫、脳腫瘍、頚癌、舌癌、咽頭癌、喉頭癌、甲状腺癌、食道癌、肺癌、乳癌、膵癌、胃癌、十二指腸・空腸・回腸等の小腸癌、結腸・盲腸・直腸等の大腸癌、膀胱癌、腎癌、肝癌、胆嚢癌、前立腺癌、子宮体癌、子宮頸癌、卵巣癌、等の癌腫、およびこれらの混合腫瘍や転移腫瘍等を挙げることができる。特に、ＬＡＴ１ががん細胞上に高度に発現しているという観点から、膵癌、膀胱癌、乳癌および胃癌の予防剤又は治療剤であることが好ましい。 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, hemangioma, hemangioendothelioma, lymphoma, and myeloma. , Myelosarcoma, reticulomatous, reticulosarcoma, melanoma, myoma, neuroma, glioma, schwannoma, sarcoma, osteosarcoma, myeloma, 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 intestine cancer such as duodenum / jejunum / ileum, colon cancer such as colon / cecum / rectum, bladder cancer, renal cancer, Examples thereof include liver cancer, gallbladder cancer, prostate cancer, endometrial cancer, cervical cancer, ovarian cancer, and other carcinomas, and mixed tumors and metastatic tumors thereof. Particularly, from the viewpoint that LAT1 is highly expressed on cancer cells, it is preferably a preventive or therapeutic agent for pancreatic cancer, bladder cancer, breast cancer and gastric cancer.
併用治療
　本発明の実施において、本発明の医薬組成物は、他の抗がん剤と同時に投与してもよい。また、本発明の医薬組成物を投与してから連続して他の抗がん剤を投与してもよいし、他の抗がん剤を投与してから本発明の医薬組成物を連続して投与してもよい。さらに、本発明の医薬組成物を投与し、時間をおいて別々に他の抗がん剤を投与してもよいし、他の抗がん剤を投与し、時間を置いて別々に本発明の医薬組成物を投与してもよい。かかる投与順序及び投与間隔は、用いられる本発明の医薬組成物を含む製剤、及びそれと併用される抗がん剤を含む製剤、治療すべきがん細胞の種類、患者の状態などに応じて、当業者が適宜選択することができる。 Combination Therapy In practicing the present invention, the pharmaceutical compositions of the present invention may be administered concurrently with other anticancer agents. Further, other anticancer agents may be continuously administered after administration of the pharmaceutical composition of the present invention, or the pharmaceutical composition of the present invention may be continuously administered after administration of the other anticancer agent. May be administered. Furthermore, the pharmaceutical composition of the present invention may be administered, and the other anticancer agent may be administered separately at a certain time, or the other anticancer agent may be administered and the present invention may be separately provided at a certain time. May be administered. Such administration sequence and administration interval, depending on the formulation containing the pharmaceutical composition of the present invention to be used, and the formulation containing an anticancer agent used in combination therewith, the type of cancer cells to be treated, the condition of the patient, etc. A person skilled in the art can appropriately select.
　また、本明細書で用いる「同時に」とは、ほぼ同じ時間に治療に使用することをいい、「別々に」とは、異なった時間に別々に治療に使用することをいい、例えば、１日目に１つの薬剤、２日目にもう１つの薬剤を治療に使用するような場合をいう。「順次に」とは、順番に従って使用することをいい、例えば、最初に１つの薬剤を使用し、次いで、決められた時間後に、他の薬剤を治療に使用するような場合をいう。 Further, as used herein, “simultaneously” means to be used for treatment at almost the same time, and “separately” means to be used for treatment separately at different times, for example, one day. When one drug is used for the eye and another drug is used for treatment on the second day. “Sequentially” means to be used in order, for example, one drug is used first, and then another drug is used for treatment after a predetermined time.
　本明細書で用いる「抗がん性アルキル化剤」は、抗がん活性を有するアルキル化剤を意味し、例えば、ナイトロジェン　マスタード　Ｎ－オキシド、シクロホスファミド、メルファラン、ブスルファン、ミトブロニトール、カルボコン、チオテバ又はテモゾロミドなどが挙げられる。 As used herein, “anticancer alkylating agent” means an alkylating agent having anticancer activity, and includes, for example, nitrogen mustard N-oxide, cyclophosphamide, melphalan, busulfan, mitbronitol, Carbocon, thioteva, temozolomide and the like can be mentioned.
　本明細書で用いる「抗がん性代謝拮抗物質」は、抗がん活性を有する代謝拮抗物質をいい、例えば、メトトレキサート、６－メルカプトプリンリボシド、メルカプトプリン、５－フルオロウラシル、テガフール、ドキシフルリジン、シタラビン、シタラビンオクホスファート、エノシタビン、ゲムシタビン又はフルダラビンなどが挙げられる。 As used herein, "anticancer antimetabolite" refers to an antimetabolite having anticancer activity, and includes, for example, methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil, tegafur, doxyfluridine, Examples include cytarabine, cytarabine ocfosfate, enocitabine, gemcitabine or fludarabine.
　本明細書で用いる「抗がん性抗生物質」は、抗がん活性を有する抗生物質をいい、例えば、アクチノマイシンＤ、ドキソルビシン、ダウノルビシン、ネオカルチノスタチン、ブレオマイシン、マイトマイシンＣ、アクラルビシン、イダルビシン又はシロリムスなどが挙げられる。 As used herein, "anticancer antibiotic" refers to an antibiotic having anticancer activity, and includes, for example, actinomycin D, doxorubicin, daunorubicin, neocarzinostatin, bleomycin, mitomycin C, aclarubicin, idarubicin or Examples include sirolimus.
　本明細書で用いる「植物由来抗がん剤」は、植物を起源として見いだされた抗がん活性を有する化合物又はその化合物の化学修飾物を包含する。「植物由来抗がん剤」には、例えば、ビンクリスチン、ビンブラスチン、ビンデシン、エトポシド、ソブゾキサン、ドセタキセル、パクリタキセルなどが挙げられる。 As used herein, the “plant-derived anticancer agent” includes a compound having an anticancer activity found from a plant or a chemically modified product of the compound. Examples of the “plant-derived anticancer agent” include vincristine, vinblastine, vindesine, etoposide, sobuzoxane, docetaxel, paclitaxel and the like.
　本明細書で用いる「抗がん性カンプトテシン誘導体」は、カンプトテシン自身を含み、構造的にカンプトテシンに関連するがん細胞増殖阻害性化合物を意味し、例えば、カンプトテシン、トポテカン及びイリノテカンなどが挙げられる。 “Anticancer camptothecin derivative” as used herein means a cancer cell growth inhibitory compound that includes camptothecin itself and is structurally related to camptothecin, and examples thereof include camptothecin, topotecan, and irinotecan.
　本明細書で用いる「抗がん性白金配位化合物」は、抗がん活性を有する白金配位化合物をいい、例えば、シスプラチン；シス－ジアンミンジアコ白金（ＩＩ）－イオン；クロロ（ジエチレントリアミン）－白金（ＩＩ）クロリド；ジクロロ（エチレンジアミン）－白金（ＩＩ）；ジアンミン（１，１－シクロブタンジカルボキシラト）白金（ＩＩ）（カルボプラチン）；スピロプラチン；イプロプラチン；（１，２－ジアミノシクロヘキサン）オキサラト白金（ＩＩ）；オルマプラチン；カルボプラチン；オキザリプラチンなどが挙げられる。 As used herein, "anticancer platinum coordination compound" refers to a platinum coordination compound having anticancer activity, for example, cisplatin; cis-diamminediacoplatinum (II) -ion; chloro (diethylenetriamine) -Platinum (II) chloride; dichloro (ethylenediamine) -platinum (II); diammine (1,1-cyclobutanedicarboxylato) platinum (II) (carboplatin); spiroplatin; iproplatin; (1,2-diaminocyclohexane) oxalato Platinum (II); ormaplatin; carboplatin; oxaliplatin and the like.
　本明細書で用いる「抗がん性チロシンキナーゼ阻害剤」とは、抗がん活性を有するチロシンキナーゼ阻害剤をいい、例えば、ゲフィチニブ、イマチニブ、ソラフェニブ、スニチニブ、ダザチニブ、エルロチニブなどが挙げられる。 As used herein, the “anticancer tyrosine kinase inhibitor” refers to a tyrosine kinase inhibitor having anticancer activity, and examples thereof include gefitinib, imatinib, sorafenib, sunitinib, dazatinib, erlotinib and the like.
　本明細書で用いる「モノクローナル抗体」とは、単一クローンの抗体産生細胞が産生する抗体をいい、例えば、セツキシマブ、ベバシズマブ、リツキシマブ、アレムツズマブ、トラスツズマブ、イピリムマブ、ニボルマブ、ペンブロリズマブ、アテゾリズマブ、アベルマブ、ヂュルバルマブなどが挙げられる。 As used herein, the term "monoclonal antibody" refers to an antibody produced by antibody-producing cells of a single clone, for example, cetuximab, bevacizumab, rituximab, alemtuzumab, trastuzumab, ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, etc. Is mentioned.
　本明細書で用いる「インターフェロン」とは、抗がん活性を有するインターフェロンをいい、例えば、インターフェロンα、インターフェロンα－２ａ、インターフェロンα－２ｂ、インターフェロンβ、インターフェロンγ－１ａ、インターフェロンγ－ｎ１などが挙げられる。 As used herein, the term "interferon" refers to interferon having anticancer activity, and examples thereof include interferon α, interferon α-2a, interferon α-2b, interferon β, interferon γ-1a, interferon γ-n1 and the like. Can be mentioned.
　よって、本発明においては、本発明の医薬組成物と、抗がん性アルキル化剤、抗がん性代謝拮抗剤、抗がん性抗生物質、植物由来抗がん剤、抗がん性白金配位化合物、抗がん性カンプトテシン誘導体、抗がん性チロシンキナーゼ阻害剤、モノクローナル抗体、インターフェロンからなる群から選択される抗がん剤よりなる群から選択される少なくとも１つの抗がん剤とを組み合わせた、医薬が提供される。これらは、同一のパッケージの製剤で又は別個のパッケージの製剤として投与される。 Therefore, in the present invention, the pharmaceutical composition of the present invention, an anticancer alkylating agent, an anticancer antimetabolite, an anticancer antibiotic, a plant-derived anticancer agent, an anticancer platinum At least one anticancer agent selected from the group consisting of a coordination compound, an anticancer camptothecin derivative, an anticancer tyrosine kinase inhibitor, a monoclonal antibody, and an interferon; A pharmaceutical product in which the above are combined is provided. They are administered in the same packaged formulation or as separate packaged formulations.
　また、本発明に係る２つの別個の製剤からなる組み合わせ製剤において、好ましくは、２つの別個の製剤のいずれか一方又は両方が、非経口製剤であり、さらに好ましくは、２つの別個の製剤のいずれか一方又は両方が、注射剤又は点滴剤である。 In addition, in the combination preparation comprising two separate preparations according to the present invention, preferably one or both of the two separate preparations is a parenteral preparation, and more preferably one of the two separate preparations. One or both is an injection or drip.
実施例
　次に、本発明を試験例、参考例および実施例を挙げて説明するが、本発明はこれらに限定されるものではない。 EXAMPLES Next, the present invention will be described with reference to Test Examples, Reference Examples and Examples, but the present invention is not limited thereto.
　粉末Ｘ線回折は、株式会社リガクの粉末Ｘ線回折装置ＲＩＮＴ２１００を用いて測定した。 The powder X-ray diffraction was measured using a powder X-ray diffractometer RINT2100 manufactured by Rigaku Corporation.
［粉末Ｘ線回折の測定条件］
対陰極：Ｃｕ
管電圧：４０ｋＶ
管電流：３０ｍＡ
走査軸：２θ [Powder X-ray diffraction measurement conditions]
Anticathode: Cu
Tube voltage: 40kV
Tube current: 30mA
Scan axis: 2θ
　赤外吸収スペクトルは、株式会社島津製作所の赤外分光光度計ＩＲ　Ｐｒｅｓｔｉｇｅ－２１を用いて測定した。 The infrared absorption spectrum was measured using an infrared spectrophotometer IR Prestige-21 manufactured by Shimadzu Corporation.
［赤外吸収スペクトルの測定条件］
ＡＴＲ法 [Infrared absorption spectrum measurement conditions]
ATR method
　核磁気共鳴スペクトル（ＮＭＲスペクトル）は、ＢＲＵＫＥＲの核磁気共鳴装置ＡＶ４００を用いて測定した。
［核磁気共鳴スペクトルの測定条件］
４００ＭＨｚ The nuclear magnetic resonance spectrum (NMR spectrum) was measured using a nuclear magnetic resonance apparatus AV400 manufactured by BRUKER.
[Nuclear magnetic resonance spectrum measurement conditions]
400 MHz
　水分は、三菱ケミカルアナリティックの水分測定装置ＣＡ－２００／ＫＦ－２００を用いて定量法により測定した。 The water content was measured by a quantitative method using a water content measuring device CA-200 / KF-200 manufactured by Mitsubishi Chemical Analytic.
参考例１：化合物Ａ・２塩酸塩の製造例
　特許文献１に記載の方法を参考に、化合物Ａ・塩酸塩を製造した。
　窒素雰囲気下、中間体１（１０．０ｇ、１７．５ｍｍｏｌ）のテトラヒドロフラン（２００ｍＬ、２０ｖｏｌ／ｗｔ）に、４Ｎ塩化水素／酢酸エチル溶液（２００ｍＬ、２０ｖｏｌ／ｗｔ）を１５～２２℃で４５分間かけて滴下し、２２～２４℃で４．５時間撹拌した。減圧下で反応溶液が２００ｍＬ以下になるまで濃縮し、酢酸エチル（２００ｍＬ、２０ｖｏｌ／ｗｔ）を加え、再度、減圧下で反応溶液が２５０ｍＬ以下まで濃縮した。濃縮した反応溶液に、エタノール（３００ｍＬ、３０ｖｏｌ／ｗｔ）を４５℃で加え、４５～５０℃で１．５時間撹拌した後、反応溶液を２５℃に冷却し、２０～２５℃で１時間撹拌した。析出した固体を濾過し、濾過残渣をエタノール（５０ｍＬ、５ｖｏｌ／ｗｔ）で洗浄し、淡黄色の湿固体（１７．８ｇ）を得た。 Reference Example 1: Production Example of Compound A · Dihydrochloride A compound A · hydrochloride was produced with reference to the method described in Patent Document 1.
Under a nitrogen atmosphere, tetrahydrofuran (200 mL, 20 vol / wt) of Intermediate 1 (10.0 g, 17.5 mmol) was treated with 4N hydrogen chloride / ethyl acetate solution (200 mL, 20 vol / wt) at 15 to 22 ° C. for 45 minutes. And added dropwise, and the mixture was stirred at 22 to 24 ° C. for 4.5 hours. The reaction solution was concentrated under reduced pressure to 200 mL or less, ethyl acetate (200 mL, 20 vol / wt) was added, and the reaction solution was concentrated again under reduced pressure to 250 mL or less. Ethanol (300 mL, 30 vol / wt) was added to the concentrated reaction solution at 45 ° C. and stirred at 45 to 50 ° C. for 1.5 hours, then the reaction solution was cooled to 25 ° C. and stirred at 20 to 25 ° C. for 1 hour. did. The precipitated solid was filtered and the filtration residue was washed with ethanol (50 mL, 5 vol / wt) to obtain a pale yellow wet solid (17.8 g).
　窒素雰囲気下、得られた湿固体（１７．８ｇ）をエタノール（３００ｍＬ、３０ｖｏｌ／ｗｔ）に懸濁させて６０℃まで加熱し、６０～６５℃で１時間懸濁撹拌した。懸濁液を２５℃に冷却し、２０～２５℃で１時間撹拌した。固体を濾過し、濾過残渣をエタノール（５０ｍＬ、５ｖｏｌ／ｗｔ）で洗浄し、白色の湿固体（１７．５ｇ）を得た。得られた湿固体を５０℃で１５時間かけて真空乾燥し、白色固体として、化合物Ａ・２塩酸塩（７．４ｇ、１３．６ｍｍｏｌ）を得た。
収率：７８％
水分：１．５％
塩化物（中和滴定）：１．８２モル当量 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 suspended and stirred at 60 to 65 ° C. for 1 hour. The suspension was cooled to 25 ° C and stirred at 20-25 ° C for 1 hour. The solid was filtered and the filter residue was washed with ethanol (50 mL, 5 vol / wt) to give a white wet solid (17.5 g). The obtained wet solid was vacuum dried at 50 ° C. for 15 hours to obtain Compound A.2 hydrochloride (7.4 g, 13.6 mmol) as a white solid.
Yield: 78%
Water content: 1.5%
Chloride (neutralization titration): 1.82 molar equivalents
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）σ値：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）．
赤外吸収スペクトル：図６に示す。
粉末Ｘ線回折パターン：図７に示す。 1 H-NMR (DMSO-d 6 ) σ value: 8.20 to 8.14 (2H, m), 7.79 (1H, d, J = 1.6 Hz), 7.70 to 7.62 (3H , M), 7.57 (1H, d, J = 1.6 Hz), 7.52 (2H, s), 5.40 (2H, s), 4.30 to 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. 7.
実施例１：化合物Ａ・１塩酸塩・１水和物の製造例１
　化合物Ａ・２塩酸塩（１０．０ｇ、１８．３ｍｍｏｌ）の２－プロパノール（２５ｍＬ、２．５ｖｏｌ／ｗｔ）／水（７５ｍＬ、７．５ｖｏｌ／ｗｔ）懸濁液に、濃塩酸（０．４６ｇ、４．６ｍｍｏｌ）を加え、５０℃に加熱して溶解させた。この時、反応溶液のｐＨは１．２であった。反応溶液を５０分間かけて２３℃に徐冷し、固体の析出を確認した。懸濁液を５℃に冷却し、２～５℃で１時間撹拌した。固体を濾過し、濾過残渣を２－プロパノール（３０ｍＬ、３．０ｖｏｌ／ｗｔ）で洗浄し、白色の湿固体（１１．６ｇ）を得た。得られた湿固体を１６時間ドラフト内で風乾し、化合物Ａ・１塩酸塩・１水和物（９．３ｇ）を得た。この固体の水分を測定したところ、１９．４％であった。 Example 1: Preparation example 1 of compound A monohydrochloride monohydrate
A suspension of Compound A · 2 hydrochloride (10.0 g, 18.3 mmol) in 2-propanol (25 mL, 2.5 vol / wt) / water (75 mL, 7.5 vol / wt) was added with concentrated hydrochloric acid (0.46 g). 4.6 mmol) was added and heated to 50 ° C. to dissolve. At this time, the pH of the reaction solution was 1.2. The reaction solution was gradually cooled to 23 ° C. over 50 minutes, and solid precipitation 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 give a white wet solid (11.6 g). The obtained wet solid was air-dried in a draft for 16 hours to obtain compound A.1 hydrochloride monohydrate (9.3 g). The water content of this solid was measured and found to be 19.4%.
　得られた化合物Ａ・１塩酸塩・１水和物の一部（１．００ｇ）を、４５℃、２ｋＰａで１時間真空乾燥し、化合物Ａ・１塩酸塩・１水和物（０．８４ｇ、１．６ｍｍｏｌ）を得た。この固体の水分を測定したところ、４．０％であった。
収率：８１％
水分：４．０％
塩化物（中和滴定）：０．８７モル当量 A part (1.00 g) of the obtained compound A.1 hydrochloride monohydrate was vacuum dried at 45 ° C. and 2 kPa for 1 hour to obtain a compound A.1 hydrochloride monohydrate (0.84 g). , 1.6 mmol) was obtained. The water content of this solid was measured and found to be 4.0%.
Yield: 81%
Water content: 4.0%
Chloride (neutralization titration): 0.87 molar equivalent
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）σ値：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）．
赤外吸収スペクトル：図８に示す。
粉末Ｘ線回折パターン：図９に示す。 1 H-NMR (DMSO-d 6 ) σ value: 8.17 to 8.07 (2H, m), 7.68 to 7.55 (3H, m), 7.50 (2H, s), 6. 96 (1H, d, J = 2.1 Hz), 6.90 (1H, d, J = 2.1 Hz), 5.23 (2H, s), 4.28 to 4.17 (1H, m), 3.19 (1H, dd, J = 14.4, 5.9 Hz), 3.10 (1H, dd, J = 14.4, 7.0 Hz).
Infrared absorption spectrum: shown in FIG.
Powder X-ray diffraction pattern: shown in FIG.
実施例２：化合物Ａ・１塩酸塩・１水和物の製造例２
　窒素雰囲気下、中間体１（９．０ｇ、１５．７ｍｍｏｌ）の酢酸エチル（８１ｍＬ、９ｖｏｌ／ｗｔ）に、４Ｎ塩化水素／酢酸エチル溶液（２７ｍＬ、３ｖｏｌ／ｗｔ）を２２～２５℃で５０分間かけて滴下し、２２～２８℃で２４時間撹拌した。この反応溶液に、水（３１．５ｍＬ、３．５ｖｏｌ／ｗｔ）を２５～２９℃で３０分間かけて滴下し、次いで、１Ｎ水酸化ナトリウム水溶液（３５ｍＬ、３．５ｖｏｌ／ｗｔ）を２５℃で１時間かけて滴下した。この反応溶液に、酢酸エチル（７２ｍＬ、８ｖｏｌ／ｗｔ）を添加して、分液することで有機層を除去した。得られた水層に、活性炭（０．９０ｇ、０．１０ｗｔ／ｗｔ）、次いで水（９ｍＬ、１．０ｖｏｌ／ｗｔ）を添加し、２５℃で１時間撹拌した後、濾過により活性炭を除去し、濾過ケーキを０．１Ｎ塩酸（１８ｍＬ、２ｖｏｌ／ｗｔ）で洗浄した。得られた濾過溶液に、２－プロパノール（１８ｍＬ、２ｖｏｌ／ｗｔ）を添加した。この時、反応溶液のｐＨは０．７であった。この反応溶液に、１Ｎ水酸化ナトリウム水溶液（２６ｍＬ、２．９ｖｏｌ／ｗｔ）を２５℃で１時間かけて滴下し、２５℃で３０分間撹拌し、固体の析出を確認した。この時、反応溶液のｐＨは１．１であった。この反応溶液に、１Ｎ水酸化ナトリウム水溶液（７ｍＬ、０．８ｖｏｌ／ｗｔ）を添加し、ｐＨを１．３に調整した後、２０～２７℃で１５時間撹拌し、５℃に冷却し、０～５℃で２．５時間撹拌した。固体を濾過し、濾過残渣を、０．１Ｎ塩酸／２－プロパノール混液（９ｖｏｌ／１ｖｏｌ、５０ｍＬ、５．６ｖｏｌ／ｗｔ）、次いで、水／２－プロパノール混液（１ｖｏｌ／９ｖｏｌ、４５ｍＬ、４．５ｖｏｌ／ｗｔ）で洗浄し、乳白色の湿固体（１５．３ｇ）を得た。得られた湿固体を３．５時間ドラフト内で風乾した後、４５℃、２．５ｋＰａで１７時間真空乾燥し、白色固体として化合物Ａ・１塩酸塩・１水和物（７．３ｇ、１３．９ｍｍｏｌ）を得た。
収率：８９％
水分：４．７％ Example 2: Preparation example 2 of compound A · monohydrochloride · monohydrate
Under a nitrogen atmosphere, a 4N hydrogen chloride / ethyl acetate solution (27 mL, 3 vol / wt) was added to Intermediate 1 (9.0 g, 15.7 mmol) in ethyl acetate (81 mL, 9 vol / wt) at 22 to 25 ° C. for 50 minutes. The mixture was added dropwise over 20 minutes and stirred at 22 to 28 ° C. for 24 hours. Water (31.5 mL, 3.5 vol / wt) was added dropwise to this reaction solution at 25 to 29 ° C. over 30 minutes, and then 1N aqueous sodium hydroxide solution (35 mL, 3.5 vol / wt) was added at 25 ° C. It dripped over 1 hour. Ethyl acetate (72 mL, 8 vol / wt) was added to this reaction solution, and the layers were separated to remove the organic layer. Activated carbon (0.90 g, 0.10 wt / wt) and then water (9 mL, 1.0 vol / wt) were added to the obtained aqueous layer, and the mixture was stirred at 25 ° C. for 1 hour and then the activated carbon was removed by filtration. The filter cake was washed with 0.1 N hydrochloric acid (18 mL, 2 vol / wt). 2-Propanol (18 mL, 2 vol / wt) was added to the obtained filtered solution. At this time, the pH of the reaction solution was 0.7. A 1N aqueous sodium hydroxide solution (26 mL, 2.9 vol / wt) was added dropwise to this reaction solution at 25 ° C. over 1 hour, and the mixture was stirred at 25 ° C. for 30 minutes to confirm precipitation of a solid. At this time, the pH of the reaction solution was 1.1. To this reaction solution was added a 1N sodium hydroxide aqueous solution (7 mL, 0.8 vol / wt) to adjust the pH to 1.3, then the mixture was stirred at 20 to 27 ° C. for 15 hours, cooled to 5 ° C., Stir at ~ 5 ° C for 2.5 hours. The solid was filtered, and the filtration residue was mixed with 0.1N hydrochloric acid / 2-propanol (9 vol / 1 vol, 50 mL, 5.6 vol / wt), and then with water / 2-propanol mixed solution (1 vol / 9 vol, 45 mL, 4.5 vol). / Wt) to give a milky white wet solid (15.3 g). The obtained wet solid was air-dried in a draft for 3.5 hours, and then vacuum-dried at 45 ° C. and 2.5 kPa for 17 hours to obtain Compound A.1 hydrochloride monohydrate (7.3 g, 13) as a white solid. .9 mmol) was obtained.
Yield: 89%
Moisture: 4.7%
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）σ値：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）．
赤外吸収スペクトル：図８に示すものに一致した。
粉末Ｘ線回折パターン：図９に示すものに一致した。 1 H-NMR (DMSO-d 6 ) σ value: 8.14 to 8.08 (2H, m), 7.75 to 7.57 (3H, m), 7.50 (2H, s), 6. 94 (1H, d, J = 2.1 Hz), 6.88 (1H, d, J = 2.1 Hz), 5.23 (2H, s), 4.25 to 4.19 (1H, m), 3.20 (1H, dd, J = 14.4, 5.9 Hz), 3.10 (1H, dd, J = 14.4, 6.9 Hz).
Infrared absorption spectrum: coincided with that shown in FIG.
Powder X-ray diffraction pattern: coincided with that shown in FIG.
実施例３：化合物Ａ・１塩酸塩・無水物の製造例
　化合物Ａ・１塩酸塩・１水和物（１．００ｇ、１．９ｍｍｏｌ）をアセトン（２０ｍＬ、２０ｖｏｌ／ｗｔ）に懸濁させ、室温で２２時間撹拌した。固体を濾過し、湿固体（０．９５ｇ）を得た。得られた湿固体を、４５℃、１．３ｋＰａで２時間真空乾燥し、淡褐色の固体として、化合物Ａ・１塩酸塩・無水物（０．６５ｇ、１．３ｍｍｏｌ）を得た。得られた化合物Ａ・１塩酸塩・無水物の１Ｈ－ＮＭＲケミカルシフト値は、化合物Ａ・１塩酸塩・１水和物と一致した。
収率：６７％
水分：０．７％ Example 3: Preparation Example of Compound A · 1 Hydrochloride · Anhydrous Compound A · 1 Hydrochloride · monohydrate (1.00 g, 1.9 mmol) was suspended in acetone (20 mL, 20 vol / wt), The mixture was stirred at room temperature for 22 hours. The solid was filtered to give a wet solid (0.95g). The obtained wet solid was vacuum dried at 45 ° C. and 1.3 kPa for 2 hours to obtain Compound A · 1 hydrochloride · anhydride (0.65 g, 1.3 mmol) as a light brown solid. The 1 H-NMR chemical shift value of the obtained compound A · 1 hydrochloride · anhydride was consistent with that of compound A · 1 hydrochloride · monohydrate.
Yield: 67%
Water content: 0.7%
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）σ値：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）．
赤外吸収スペクトル：図１０に示す。
粉末Ｘ線回折パターン：図１１に示す。 1 H-NMR (DMSO-d 6 ) σ value: 8.14 to 8.08 (2H, m), 7.75 to 7.57 (3H, m), 7.49 (2H, s), 6. 94 (1H, d, J = 2.1 Hz), 6.88 (1H, d, J = 2.1 Hz), 5.23 (2H, s), 4.27 to 4.20 (1H, m), 3.19 (1H, dd, J = 14.4, 5.9 Hz), 3.09 (1H, dd, J = 14.4, 7.0 Hz).
Infrared absorption spectrum: shown in FIG.
Powder X-ray diffraction pattern: shown in FIG.
試験例：シクロデキストリン溶液に対する化合物Ａ・塩酸塩の溶解性評価
　参考例および実施例に従い製造した化合物Ａ・各塩酸塩を、凍結乾燥製剤を製造する際の調製溶液（すなわち、シクロデキストリン溶液）に対する溶解性の評価に付した。試験条件は、特許文献２に記載の処方１９（化合物Ａ濃度：６．２５ｍｇ／ｍＬ、シクロデキストリン濃度：２０％、最終調整ｐＨ：３．５）に準じて実施した。結果を以下に示す。 Test Example: Evaluation of Solubility of Compound A / Hydrochloride in Cyclodextrin Solution Compound A / hydrochloride prepared according to Reference Examples and Examples is used in a preparation solution (ie, cyclodextrin solution) for producing a freeze-dried preparation. The solubility was evaluated. The test conditions were according to the 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.
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
　化合物Ａ・２塩酸塩は、微細結晶で塊になりやすい性質を有しており、塊状の化合物Ａ・２塩酸塩（図１２）が溶解するまでには、１１時間以上を要した。粉末状の化合物Ａ・２塩酸塩（図１３）では、溶解までに要する時間が幾分改善され、３時間で溶解した。その一方、化合物Ａ・１塩酸塩・１水和物は、粉末状で塊になりにくい性質を有しており（図１４）、溶解までに要した時間は０．５時間であった。 Compound A.2-hydrochloride has a property of being fine crystals and easily lumped, and it took 11 hours or more until the lumpy compound A.2-hydrochloride (FIG. 12) was dissolved. In the case of powdered compound A.2 hydrochloride (Fig. 13), the time required for dissolution was somewhat improved, and it was dissolved in 3 hours. On the other hand, the compound A / 1 hydrochloride / monohydrate had a property of being powdery and was unlikely to clump (FIG. 14), and the time required for dissolution was 0.5 hours.
　このように、化合物Ａ・１塩酸塩・１水和物は、化合物Ａ・２塩酸塩と比較して、凍結乾燥製剤を製造する際の調製溶液に対する溶解性に、より優れていた。 As described above, Compound A · 1 hydrochloride monohydrate was superior to Compound A · 2 hydrochloride in solubility in a prepared solution when producing a freeze-dried preparation.
　本発明の（Ｓ）－２－アミノ－３－｛４－［（５－アミノ－２－フェニルベンゾ［ｄ］オキサゾール－７－イル）メトキシ］－３，５－ジクロロフェニル｝プロパン酸・１塩酸塩・１水和物は、高純度で乾燥時に塊化しにくく、凍結乾燥製剤を製造する際の調製溶液に対する溶解性に優れるため、医薬の原薬として有用である。
  (S) -2-Amino-3- {4-[(5-amino-2-phenylbenzo [d] oxazol-7-yl) methoxy] -3,5-dichlorophenyl} propanoic acid monohydrochloride of the present invention Since the monohydrate is highly pure, hardly agglomerates during drying, and has excellent solubility in a prepared solution when producing a freeze-dried preparation, it is useful as a drug substance for medicines.

Claims (24)

  1. 　（Ｓ）－２－アミノ－３－｛４－［（５－アミノ－２－フェニルベンゾ［ｄ］オキサゾール－７－イル）メトキシ］－３，５－ジクロロフェニル｝プロパン酸・１塩酸塩。 (S) -2-amino-3- {4-[(5-amino-2-phenylbenzo [d] oxazol-7-yl) methoxy] -3,5-dichlorophenyl} propanoic acid monohydrochloride.
  2. 　（Ｓ）－２－アミノ－３－｛４－［（５－アミノ－２－フェニルベンゾ［ｄ］オキサゾール－７－イル）メトキシ］－３，５－ジクロロフェニル｝プロパン酸・１塩酸塩・１水和物。 (S) -2-Amino-3- {4-[(5-amino-2-phenylbenzo [d] oxazol-7-yl) methoxy] -3,5-dichlorophenyl} propanoic acid monohydrochloride 1 water Japanese food.
  3. 　（Ｓ）－２－アミノ－３－｛４－［（５－アミノ－２－フェニルベンゾ［ｄ］オキサゾール－７－イル）メトキシ］－３，５－ジクロロフェニル｝プロパン酸・１塩酸塩・無水物。 (S) -2-Amino-3- {4-[(5-amino-2-phenylbenzo [d] oxazol-7-yl) methoxy] -3,5-dichlorophenyl} propanoic acid monohydrochloride / anhydride ..
  4. 　（Ｓ）－２－アミノ－３－｛４－［（５－アミノ－２－フェニルベンゾ［ｄ］オキサゾール－７－イル）メトキシ］－３，５－ジクロロフェニル｝プロパン酸・１塩酸塩・１水和物の結晶。 (S) -2-Amino-3- {4-[(5-amino-2-phenylbenzo [d] oxazol-7-yl) methoxy] -3,5-dichlorophenyl} propanoic acid monohydrochloride 1 water Japanese crystals.
  5. 　（Ｓ）－２－アミノ－３－｛４－［（５－アミノ－２－フェニルベンゾ［ｄ］オキサゾール－７－イル）メトキシ］－３，５－ジクロロフェニル｝プロパン酸・１塩酸塩・無水物の結晶。 (S) -2-Amino-3- {4-[(5-amino-2-phenylbenzo [d] oxazol-7-yl) methoxy] -3,5-dichlorophenyl} propanoic acid monohydrochloride / anhydride Crystals.
  6. 　含水有機溶媒中で、（Ｓ）－２－アミノ－３－｛４－［（５－アミノ－２－フェニルベンゾ［ｄ］オキサゾール－７－イル）メトキシ］－３，５－ジクロロフェニル｝プロパン酸に塩酸を加えてｐＨを調整することによる、（Ｓ）－２－アミノ－３－｛４－［（５－アミノ－２－フェニルベンゾ［ｄ］オキサゾール－７－イル）メトキシ］－３，５－ジクロロフェニル｝プロパン酸・１塩酸塩・１水和物の製造方法。 To give (S) -2-amino-3- {4-[(5-amino-2-phenylbenzo [d] oxazol-7-yl) methoxy] -3,5-dichlorophenyl} propanoic acid in a water-containing organic solvent. By adding hydrochloric acid to adjust the pH, (S) -2-amino-3- {4-[(5-amino-2-phenylbenzo [d] oxazol-7-yl) methoxy] -3,5- Process for producing dichlorophenyl} propanoic acid monohydrochloride monohydrate.
  7. 　含水有機溶媒中で、（Ｓ）－２－アミノ－３－｛４－［（５－アミノ－２－フェニルベンゾ［ｄ］オキサゾール－７－イル）メトキシ］－３，５－ジクロロフェニル｝プロパン酸と塩基とからなる塩に塩酸を加えてｐＨを調整することによる、（Ｓ）－２－アミノ－３－｛４－［（５－アミノ－２－フェニルベンゾ［ｄ］オキサゾール－７－イル）メトキシ］－３，５－ジクロロフェニル｝プロパン酸・１塩酸塩・１水和物の製造方法。 With (S) -2-amino-3- {4-[(5-amino-2-phenylbenzo [d] oxazol-7-yl) methoxy] -3,5-dichlorophenyl} propanoic acid in a water-containing organic solvent. (S) -2-amino-3- {4-[(5-amino-2-phenylbenzo [d] oxazol-7-yl) methoxy by adjusting the pH by adding hydrochloric acid to a salt consisting of a base ] A method for producing -3,5-dichlorophenyl} propanoic acid monohydrochloride monohydrate.
  8. 　（Ｓ）－２－アミノ－３－｛４－［（５－アミノ－２－フェニルベンゾ［ｄ］オキサゾール－７－イル）メトキシ］－３，５－ジクロロフェニル｝プロパン酸と塩基とからなる塩が、（Ｓ）－２－アミノ－３－｛４－［（５－アミノ－２－フェニルベンゾ［ｄ］オキサゾール－７－イル）メトキシ］－３，５－ジクロロフェニル｝プロパン酸のアルカリ金属塩である、請求項７に記載の製造方法。 A salt consisting of (S) -2-amino-3- {4-[(5-amino-2-phenylbenzo [d] oxazol-7-yl) methoxy] -3,5-dichlorophenyl} propanoic acid and a base is , An alkali metal salt of (S) -2-amino-3- {4-[(5-amino-2-phenylbenzo [d] oxazol-7-yl) methoxy] -3,5-dichlorophenyl} propanoic acid. The manufacturing method according to claim 7.
  9. 　含水有機溶媒中で、（Ｓ）－２－アミノ－３－｛４－［（５－アミノ－２－フェニルベンゾ［ｄ］オキサゾール－７－イル）メトキシ］－３，５－ジクロロフェニル｝プロパン酸と酸とからなる塩に塩酸または塩基を加えてｐＨを調整することによる、（Ｓ）－２－アミノ－３－｛４－［（５－アミノ－２－フェニルベンゾ［ｄ］オキサゾール－７－イル）メトキシ］－３，５－ジクロロフェニル｝プロパン酸・１塩酸塩・１水和物の製造方法。 With (S) -2-amino-3- {4-[(5-amino-2-phenylbenzo [d] oxazol-7-yl) methoxy] -3,5-dichlorophenyl} propanoic acid in a water-containing organic solvent. (S) -2-amino-3- {4-[(5-amino-2-phenylbenzo [d] oxazol-7-yl) by adjusting the pH by adding hydrochloric acid or a base to a salt consisting of an acid. ) Methoxy] -3,5-dichlorophenyl} propanoic acid monohydrochloride monohydrate production method.
  10. 　（Ｓ）－２－アミノ－３－｛４－［（５－アミノ－２－フェニルベンゾ［ｄ］オキサゾール－７－イル）メトキシ］－３，５－ジクロロフェニル｝プロパン酸と酸とからなる塩が、（Ｓ）－２－アミノ－３－｛４－［（５－アミノ－２－フェニルベンゾ［ｄ］オキサゾール－７－イル）メトキシ］－３，５－ジクロロフェニル｝プロパン酸の塩酸塩である、請求項９に記載の製造方法。 A salt of (S) -2-amino-3- {4-[(5-amino-2-phenylbenzo [d] oxazol-7-yl) methoxy] -3,5-dichlorophenyl} propanoic acid and an acid is , (S) -2-amino-3- {4-[(5-amino-2-phenylbenzo [d] oxazol-7-yl) methoxy] -3,5-dichlorophenyl} propanoic acid hydrochloride, The manufacturing method according to claim 9.
  11. 　（Ｓ）－２－アミノ－３－｛４－［（５－アミノ－２－フェニルベンゾ［ｄ］オキサゾール－７－イル）メトキシ］－３，５－ジクロロフェニル｝プロパン酸と酸とからなる塩が、（Ｓ）－２－アミノ－３－｛４－［（５－アミノ－２－フェニルベンゾ［ｄ］オキサゾール－７－イル）メトキシ］－３，５－ジクロロフェニル｝プロパン酸・１塩酸塩・無水物である、請求項１０に記載の製造方法。 A salt of (S) -2-amino-3- {4-[(5-amino-2-phenylbenzo [d] oxazol-7-yl) methoxy] -3,5-dichlorophenyl} propanoic acid and an acid is , (S) -2-Amino-3- {4-[(5-amino-2-phenylbenzo [d] oxazol-7-yl) methoxy] -3,5-dichlorophenyl} propanoic acid monohydrochloride / anhydrous The manufacturing method according to claim 10, which is a product.
  12. 　ｐＨを調整するのに使用される塩基が、無機塩基である、請求項９～請求項１１のいずれか一つに記載の製造方法。 The method according to any one of claims 9 to 11, wherein the base used for adjusting the pH is an inorganic base.
  13. 　ｐＨを調整するのに使用される塩基が、水酸化ナトリウム、炭酸ナトリウム、炭酸水素ナトリウムから選ばれる１種類以上の塩基である、請求項９～請求項１２のいずれか一つに記載の製造方法。 The production method according to any one of claims 9 to 12, wherein the base used for adjusting the pH is one or more kinds of bases selected from sodium hydroxide, sodium carbonate and sodium hydrogen carbonate. .
  14. 　含水有機溶媒の水分活性が０．５～１．０であり、かつ、ｐＨを１～２の範囲に調整する、請求項６～請求項１３のいずれか一つに記載の製造方法。 The method according to any one of claims 6 to 13, wherein the water-containing organic solvent has a water activity of 0.5 to 1.0 and the pH is adjusted to a range of 1 to 2.
  15. 　有機溶媒中で、（Ｓ）－２－アミノ－３－｛４－［（５－アミノ－２－フェニルベンゾ［ｄ］オキサゾール－７－イル）メトキシ］－３，５－ジクロロフェニル｝プロパン酸と、塩酸とを反応させることによる、（Ｓ）－２－アミノ－３－｛４－［（５－アミノ－２－フェニルベンゾ［ｄ］オキサゾール－７－イル）メトキシ］－３，５－ジクロロフェニル｝プロパン酸・１塩酸塩・無水物の製造方法。 (S) -2-amino-3- {4-[(5-amino-2-phenylbenzo [d] oxazol-7-yl) methoxy] -3,5-dichlorophenyl} propanoic acid in an organic solvent, (S) -2-Amino-3- {4-[(5-amino-2-phenylbenzo [d] oxazol-7-yl) methoxy] -3,5-dichlorophenyl} propane by reacting with hydrochloric acid Method for producing acid / hydrochloride / anhydride.
  16. 　有機溶媒の水分活性が０．５未満であり、かつ、（Ｓ）－２－アミノ－３－｛４－［（５－アミノ－２－フェニルベンゾ［ｄ］オキサゾール－７－イル）メトキシ］－３，５－ジクロロフェニル｝プロパン酸に対し、０．８～１．２モル当量の塩酸を反応させる、請求項１５に記載の製造方法。 The water activity of the organic solvent is less than 0.5, and (S) -2-amino-3- {4-[(5-amino-2-phenylbenzo [d] oxazol-7-yl) methoxy]- The production method according to claim 15, wherein 0.8 to 1.2 molar equivalents of hydrochloric acid are reacted with 3,5-dichlorophenyl} propanoic acid.
  17. 　（Ｓ）－２－アミノ－３－｛４－［（５－アミノ－２－フェニルベンゾ［ｄ］オキサゾール－７－イル）メトキシ］－３，５－ジクロロフェニル｝プロパン酸・１塩酸塩・１水和物を有機溶媒中で懸濁撹拌し、水和水を除去する、（Ｓ）－２－アミノ－３－｛４－［（５－アミノ－２－フェニルベンゾ［ｄ］オキサゾール－７－イル）メトキシ］－３，５－ジクロロフェニル｝プロパン酸・１塩酸塩・無水物の製造方法。 (S) -2-Amino-3- {4-[(5-amino-2-phenylbenzo [d] oxazol-7-yl) methoxy] -3,5-dichlorophenyl} propanoic acid monohydrochloride monohydrate (S) -2-Amino-3- {4-[(5-amino-2-phenylbenzo [d] oxazol-7-yl) ) Methoxy] -3,5-dichlorophenyl} propanoic acid monohydrochloride / anhydrous production method.
  18. 　粉末Ｘ線回折において、２θで表される７．１、９．５、１８．９、２１．６および２４．２°の回折角度を有することを特徴とする、請求項４に記載の結晶。 The crystal according to claim 4, which has a diffraction angle represented by 2θ of 7.1, 9.5, 18.9, 21.6 and 24.2 ° in powder X-ray diffraction.
  19. 　赤外吸収スペクトルにおいて、１３９３、１３８１、１３４２、１３２９および１２６７ｃｍ－１にピークを有することを特徴とする、請求項４に記載の結晶。 The crystal according to claim 4, which has peaks at 1393, 1381, 1342, 1329 and 1267 cm -1 in an infrared absorption spectrum.
  20. 粉末Ｘ線回折において、２θで表される１０．５、１４．５、１７．１、２２．５および２３．０°の回折角度を有することを特徴とする、請求項５に記載の結晶。 Crystals according to claim 5, characterized in that they have diffraction angles of 10.5, 14.5, 17.1, 22.5 and 23.0 ° represented by 2θ in powder X-ray diffraction.
  21. 　赤外吸収スペクトルにおいて、１６０１、１５５６、１５４７、１４０４および１２６９ｃｍ－１にピークを有することを特徴とする、請求項５に記載の結晶。 The crystal according to claim 5, which has peaks at 1601, 1556, 1547, 1404 and 1269 cm −1 in an infrared absorption spectrum.
  22. 　請求項１又は２に記載の化合物、又は、請求項４、１８又は１９のいずれかの請求項に記載の結晶、及び、薬学的に許容される担体、
    を含む医薬組成物。     A compound according to claim 1 or 2, or a crystal according to any one of claims 4, 18, or 19, and a pharmaceutically acceptable carrier,
    A pharmaceutical composition comprising:
  23. 　がんの治療用である、請求項２２に記載の医薬組成物。 The pharmaceutical composition according to claim 22, which is used for treating cancer.
  24. 　請求項２２又は２３に記載の医薬組成物と、抗がん性アルキル化剤、抗がん性代謝拮抗剤、抗がん性抗生物質、植物由来抗がん剤、抗がん性白金配位化合物、抗がん性カンプトテシン誘導体、抗がん性チロシンキナーゼ阻害剤、モノクローナル抗体及びインターフェロンからなる群から選択される抗がん剤よりなる群から選択される少なくとも１つの抗がん剤とを組み合わせた、医薬。
          The pharmaceutical composition according to claim 22 or 23, and an anticancer alkylating agent, an anticancer antimetabolite, an anticancer antibiotic, a plant-derived anticancer agent, an anticancer platinum coordination. A compound, an anticancer camptothecin derivative, an anticancer tyrosine kinase inhibitor, a monoclonal antibody, and at least one anticancer agent selected from the group consisting of anticancer agents selected from the group consisting of interferons And medicine.
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