WO2020096041A1 - Acide (s)-2-amino-3-{4-[(5-amino-2-phénylbenzo[d]oxazol-7-yl)méthoxy]-3,5-dichlorophényl}propanoïque · monochlorure, monohydrate de celui-ci, cristal correspondant et procédé de production associé - Google Patents

Acide (s)-2-amino-3-{4-[(5-amino-2-phénylbenzo[d]oxazol-7-yl)méthoxy]-3,5-dichlorophényl}propanoïque · monochlorure, monohydrate de celui-ci, cristal correspondant et procédé de production associé 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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English (en)
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/ja
Publication of WO2020096041A1 publication Critical patent/WO2020096041A1/fr

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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

L'invention concerne l'acide (S)-2-amino-3-{4-[(5-amino-2-phénylbenzo[d]oxazol-7-yl)méthoxy]-3,5-dichlorophényl}propanoïque · monochlorure, un monohydrate de celui-ci, un cristal correspondant, et un procédé de production associé. L'invention concerne en outre une composition pharmaceutique contenant ledit composé, utile en tant qu'agent anticancéreux.
PCT/JP2019/043856 2018-11-09 2019-11-08 Acide (s)-2-amino-3-{4-[(5-amino-2-phénylbenzo[d]oxazol-7-yl)méthoxy]-3,5-dichlorophényl}propanoïque · monochlorure, monohydrate de celui-ci, cristal correspondant et procédé de production associé WO2020096041A1 (fr)

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JP2015040179A (ja) * 2013-08-20 2015-03-02 ジェイファーマ株式会社 免疫抑制剤
WO2015173970A1 (fr) * 2014-05-15 2015-11-19 ジェイファーマ株式会社 Composition d'agent anti-tumeur maligne
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CN114652718A (zh) * 2022-03-08 2022-06-24 浙江大学 Lat1抑制剂和奥沙利铂在制备肾细胞癌治疗药物中的应用
CN114652718B (zh) * 2022-03-08 2024-03-12 浙江大学 Lat1抑制剂和奥沙利铂在制备肾细胞癌治疗药物中的应用

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