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WO2008139574A1 - Forme cristalline d'un composé lactame et son procédé de production - Google Patents

Forme cristalline d'un composé lactame et son procédé de production Download PDF

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Publication number
WO2008139574A1
WO2008139574A1 PCT/JP2007/059540 JP2007059540W WO2008139574A1 WO 2008139574 A1 WO2008139574 A1 WO 2008139574A1 JP 2007059540 W JP2007059540 W JP 2007059540W WO 2008139574 A1 WO2008139574 A1 WO 2008139574A1
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WIPO (PCT)
Prior art keywords
crystal
formula
crystals
powder
crystal according
Prior art date
Application number
PCT/JP2007/059540
Other languages
English (en)
Japanese (ja)
Inventor
Shinichiro Takahashi
Yukako Sakio
Keiko Hamajima
Tatsuya Ishikawa
Junko Koizumi
Kouji Haga
Haruya Sato
Yuuji Ikegaya
Original Assignee
Ajinomoto Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ajinomoto Co., Inc. filed Critical Ajinomoto Co., Inc.
Priority to PCT/JP2007/059540 priority Critical patent/WO2008139574A1/fr
Priority to PCT/JP2008/058037 priority patent/WO2008136393A1/fr
Priority to PCT/JP2008/058036 priority patent/WO2008136392A1/fr
Priority to PCT/JP2008/058038 priority patent/WO2008136394A1/fr
Publication of WO2008139574A1 publication Critical patent/WO2008139574A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to a crystal of a ratata compound excellent in storage stability and the like, a medicament containing the crystal, a method for producing the crystal, and the like.
  • the compound represented by the formula (I) is useful as a pharmaceutical agent such as a therapeutic agent for diabetes.
  • the crystal form of the compound is often preferable to amorphous in terms of characteristics such as storage stability.
  • compounds that are active pharmaceutical ingredients have important properties that are further desired in addition to biological activity, and stable crystal forms can meet these requirements.
  • Important properties include, for example, purity, storage stability (eg to avoid the production of pharmaceutical formulations containing degradation products), stability during the manufacturing process of the pharmaceutical formulation (eg grinding process), final formulation Stability (for example, is important because it affects the shelf life), and low hygroscopicity (for example, high hygroscopicity causes fluctuations in the content of active ingredients per weight).
  • purity e.g to avoid the production of pharmaceutical formulations containing degradation products
  • stability during the manufacturing process of the pharmaceutical formulation eg grinding process
  • final formulation Stability for example, is important because it affects the shelf life
  • low hygroscopicity for example, high hygroscopicity causes fluctuations in the content of active ingredients per weight.
  • purification can be facilitated by recrystallization. Disclosure of the invention
  • the present inventors have succeeded in obtaining a crystal containing a compound represented by the formula (I). Furthermore, the inventors have found that the obtained crystal is excellent in storage stability, and have completed the present invention.
  • the present invention provides crystals of a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, a medicament containing the same, a method for producing the same, and the like.
  • the present invention is as follows.
  • a medicament comprising the crystal according to any one of (1) to (1 3) above.
  • a crystal of a compound represented by '1/2 C 6 H 5 OCH 3 A crystal of a compound represented by '1/2 C 6 H 5 OCH 3 .
  • crystallization in any one of said (7)-(13) including the process of adding a poor solvent to the solution containing the compound represented by these.
  • the method for producing a crystal according to any one of the above (7) to (13), the crystal of the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof has high storage stability. Therefore, a drug containing the compound represented by the above formula (I) excellent in stability or a drug substance or standard substance for manufacturing a drug excellent in stability is provided.
  • the type I crystal (described later) of the present invention is an anhydrous crystal, it is very easy to handle, for example, when used as a drug substance or a standard substance for pharmaceutical production.
  • the type I crystal (described later) of the present invention has little change in water content within a certain range of water content, it is very easy to handle, for example, when used as a drug substance in pharmaceutical production.
  • the I-type crystal of the present invention does not change its crystal form even when water is added, it is possible to provide a drug substance suitable for a preparation using water in the production process.
  • FIG. 1 is a diagram showing a powder X-ray diffraction spectrum of an ethyl acetate hydrate crystal obtained in Example 2 and a crystal after desolvating it (measured by apparatus B (described later)).
  • FIG. 2 is a graph showing a powder X-ray diffraction spectrum of the anisosolvate crystal obtained in Example 3 and the crystal after desolvation of the crystal (measured by apparatus B).
  • FIG. 3 is a diagram showing a powder X-ray diffraction spectrum of the benzonitrile hydrate crystal obtained in Example 4 after removing the solvent (measured by apparatus B).
  • FIG. 4 is a diagram showing a powder X-ray diffraction spectrum of the tetrahydrofuran solvate crystal obtained in Example 20 (measured with apparatus A (described later)).
  • FIG. 5 is a diagram showing a powder X-ray diffraction spectrum of the toluene solvate crystal obtained in Example 21 (measured by apparatus A).
  • FIG. 6 shows a powder X-ray spectrum of the type I crystal (measured by apparatus A).
  • FIG. 7 is a diagram showing a differential scanning calorimetry (DSC) chart of the I-type crystal.
  • FIG. 8 is a diagram showing the results of water vapor adsorption / desorption measurement of the type I crystal.
  • FIG. 9 is a diagram showing a powder X-ray diffraction spectrum of a type II crystal (measured by apparatus B).
  • FIG. 10 is a diagram showing a differential scanning calorimetry (DSC) chart of a type II crystal.
  • Fig. 11 shows the powder X-ray diffraction spectrum of I-type crystals measured under vacuum (measured with apparatus B).
  • FIG. 12 is a diagram showing the results of water vapor adsorption / desorption measurement of II type crystals.
  • FIG. 13 is a diagram showing the change over time in the water content of the I-type crystal.
  • the present invention relates to a crystal of a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical containing the same, a production method thereof, and the like.
  • a crystal of a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof a pharmaceutical containing the same, a production method thereof, and the like.
  • the first aspect of the present invention relates to a crystal of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof (sometimes referred to as “the crystal of the present invention”).
  • the present invention also relates to a method for producing the crystal of the present invention.
  • the crystal of the present invention introduces a solution containing a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof (sometimes referred to as “compound of the present invention”) to a supersaturated state, It can be manufactured by analyzing.
  • the compound of the present invention, the crystal of the present invention, and the production method thereof will be described in detail.
  • Formula (I) Is a compound disclosed in US Patent Application Publication No. 2 0 0 4/0 0 4 8 8 4 7, and has excellent sputum transport enhancing action, clot lowering action and the like.
  • the compound represented by the formula (I) may be a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt means a salt that can be used as a medicine. However, those which do not take the salt form are preferred.
  • Examples of the salt of the compound represented by the formula (I) include acid addition salts such as inorganic acid salts, organic acid salts, and sulfonic acid salts; Al force metal salts, Al force earth metal salts, metal salts, ammonia salts And base addition salts.
  • Examples of inorganic acid salts include hydrochloride, hydrobromide, sulfate, phosphate, and the like.
  • Examples of the organic acid salt include carbonate, acetate, benzoate, oxalate, maleate, fumarate, tartrate, kenate, and the like.
  • Examples of the sulfonate include methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like.
  • Examples of alkali metal salts include sodium salts, potassium salts, and lithium salts.
  • Examples of alkaline earth metal salts include calcium salts and magnesium salts.
  • Examples of the metal salt include an aluminum salt.
  • the compound represented by the formula ( ⁇ ) can be produced according to the method disclosed in US Patent Application Publication No. 2 0 0 4/0 0 4 8 8 4 7 or a method analogous thereto. More specifically, it can be produced, for example, according to the method disclosed in Reference Example 1 described later or a method analogous thereto. .
  • the crystal of the compound represented by or a pharmaceutically acceptable salt thereof is a hydrate or a solution. It may be a solvate. Such a hydrate or solvate is also included in the “crystal of the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof”. Examples of the hydrate include a compound represented by the formula (1-2).
  • solvate examples include an ethyl acetate solvate, a carsol solvate, a benzo-tolyl solvate, a tetrahydrofuran solvate, a toluene solvate, and the like, and a compound represented by the formula (I-13) Ethyl acetate solvate), compound represented by formula (I 1-4) (anisolate solvate), compound represented by formula (I 1-5) (benzonitrile solvate), formula (I 1-6) A compound represented by the formula (tetrahydrofuran solvate) and a compound represented by the formula (1-7) (toluene solvate) are preferred.
  • the crystal of the present invention which is a hydrate crystal not only contains moisture as water of crystallization, but can also contain moisture as adhering water due to moisture absorption, for example. Such a water-containing crystal is also included in the crystal of the present invention.
  • the crystal of the present invention which is not a hydrate crystal is, for example, an anhydrous crystal, it can be converted to a water-containing crystal containing water as adhering water due to moisture absorption.
  • a water-containing crystal is also included in the crystal of the present invention.
  • the water content of the crystal of the present invention is not necessarily constant depending on drying conditions, storage conditions, and the like. However, regardless of the water content, all are included in the crystal of the present invention.
  • the water content can be measured in accordance with a known method such as a forceful Fischer method.
  • the crystal of the present invention can be produced, for example, by a method including the following steps.
  • a compound represented by formula (I) or a pharmaceutically acceptable salt thereof is used as an appropriate solvent.
  • the method leads to a supersaturated state and precipitates crystals.
  • the crystals precipitated in step 2 are isolated and dried.
  • Anhydrous crystals can also be produced by desolvating solvate crystals.
  • Solvent removal can be performed by heating, reduced pressure, or the like, but is preferably by heating.
  • the good solvent for the compound represented by the formula (I) or a salt thereof means a solvent that dissolves the compound of the present invention well within the range of room temperature to boiling point.
  • the good solvent preferably includes a solvent having a saturated solubility at room temperature of about 0.1 mg / m or more, and more preferably a solvent of about l mg Zm 1 or more.
  • examples of such a good solvent include methanol, ethanol, propanol, butanol, octanol and the like having 1 to 8 carbon atoms.
  • dimethylenolesulphoxide dimethylenolenolemamide, formamide, benzonitrile, acetonitrile, ethyl acetate, acetone, 2-butanone, tetrahydrofuran, diisopropylamine, dichloromethane, etc., preferably ethanolol, Propanol, butanol, dimethinolesnoreoxide, dimethenolenole amide, formamide or benzonitrile.
  • the poor solvent of the compound represented by the formula (I) or a salt thereof is defined in relation to the good solvent used and can be miscible with the good solvent, but the compound of the present invention is dissolved in comparison with the good solvent. It means a solvent that is difficult to understand.
  • the poor solvent include a solvent in which the saturation solubility of the target compound at room temperature is 1/10 or less of the good solvent, and a solvent in which 1100 or less is more preferable.
  • examples of such a poor solvent include water, ether, isoptinole acetate, butinoreamine, toluene, Examples include anisol, black mouth form, mouth hexane, hexane and the like.
  • the supersaturated state is obtained by, for example, dissolving a compound represented by the formula (I) in a solvent heated (for example, 60 to 90 ° C.) and concentrating as necessary to obtain a saturated solution. This can be achieved by gradually cooling the liquid (eg, from 0 to 30 ° C.).
  • a solvent heated for example, 60 to 90 ° C.
  • concentration may be any concentration that can be brought to a supersaturated state by cooling even if it does not reach a saturated state, but is preferably a saturated state.
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is dissolved in a good solvent to obtain a saturated solution, and the resulting saturated solution is gradually added with a poor solvent to be supersaturated. It can also be in a state.
  • the crystal of the compound represented by formula (I) is an anhydrous crystal of the compound represented by the formula (I).
  • the crystal has an endothermic signal in the range of about 210 to 250 ° C. in the differential scanning calorimetry (DSC), and the endothermic peak temperature is about 228 to 234 ° C.
  • DSC differential scanning calorimetry
  • Such a crystal of a compound represented by the formula (I 1 1) may be referred to as “type I crystal”.
  • Type I crystals are anhydrous crystals, but may contain water as adhering water depending on storage conditions.
  • the amount of water is not always constant depending on drying conditions and storage conditions.
  • the water content of type I crystals is usually in the range of about 0-2.5% at room temperature.
  • Such I-type crystals are included in the crystal represented by the formula (I-1) of the present invention regardless of the amount of water.
  • Type I crystals are, for example, heated compounds represented by formula (I) (for example, about 60 ° C) Dissolved in dichloromethane to obtain a saturated solution, and the obtained saturated solution was gradually cooled.
  • formula (I) for example, about 60 ° C
  • the type I crystal is produced, for example, by removing the solvate crystal of the compound represented by the formula (I) by a method such as heating (for example, 1550-220 ° C). It can also be done.
  • a method such as heating (for example, 1550-220 ° C).
  • the solvate crystal for example, an ethyl acetate solvate crystal, an anisol solvate crystal, a benzo-tolyl solvate crystal and the like can be suitably used.
  • a crystal, a crystal of a compound represented by the formula (1-4), or a crystal of a compound represented by the formula (1-5) is preferable.
  • Solvate crystals can be produced according to the method described below. Examples of the solvent removal method include methods such as heating and reduced pressure, and a method using heating is preferred.
  • the heating temperature is usually about 1550 to 2200 ° C, preferably about 1600 to 1700 ° C.
  • the degree of crystallinity can be increased by a method such as heating (for example, about 2 10 ° C).
  • the type I crystal is obtained by, for example, adding a poor solvent (for example, heptane) to a solution obtained by dissolving the compound represented by the formula (I) in ethanol (preferably a saturated solution) at 30 ° C. or less. It can also be produced by adding crystallization.
  • type I crystals have high storage stability, they can be suitably used, for example, as drugs (for example, sugar transport enhancing agents, hypoglycemic agents, antidiabetic agents, etc.), drug substances, and the like.
  • drugs for example, sugar transport enhancing agents, hypoglycemic agents, antidiabetic agents, etc.
  • drug substances for example, sugar transport enhancing agents, hypoglycemic agents, antidiabetic agents, etc.
  • drug substances for example, sugar transport enhancing agents, hypoglycemic agents, antidiabetic agents, etc.
  • drug substances for example, sugar transport enhancing agents, hypoglycemic agents, antidiabetic agents, etc.
  • the type I crystal can be rapidly transferred to the type I I crystal by adding water, it can also be used for the production of the type I I crystal.
  • the crystal of the compound represented by formula (I) is a hydrate crystal of the compound represented by the formula (I).
  • Diffraction angle (2 0) 1 3.6, 1 6. 1 to 1 6. 2 and 2 7.4 have characteristic peaks (measured using device ⁇ ⁇ described later, hereinafter simply “device ⁇ ” May be indicated).
  • DSC differential scanning calorimetry
  • it has an endothermic signal in the range of about 190 to 240 ° C, and the endothermic peak temperature is about 204 to 210 ° C.
  • Such a crystal of the compound represented by the formula (1-2) may be referred to as “II type crystal”.
  • type I crystals are hydrate crystals, the crystal water is relatively easy to enter and exit, and the value of X in formula (1-2) is not necessarily constant depending on the drying conditions and storage conditions.
  • X is preferably 0.6-1 and more preferably 0.7-0.9.
  • Such a water-containing crystal of type I I crystal is also included in the type I I crystal of the present invention.
  • the water content of type I crystals is usually about 0% to 12%, more preferably about 0 to 7%, and particularly preferably about 3 to 5%.
  • I Type I crystals stabilize at room temperature at a relative humidity of about 40-80% and a moisture content of about 3-5% (ie, X is about 0.6-1).
  • the moisture content of the compound represented by the formula (I 1 2) changes, the relative intensity of the peak in powder X-ray diffraction, the diffraction angle (2 ⁇ ), etc. change continuously. Is reversible. The extent of this change The crystal structure is stable to changes in the amount of water, even though they all show almost the same pattern.
  • the diffraction angle (26) 9.8,13.6, 16.
  • the diffraction angle (2 ⁇ ) 9.7, 1 3. 6, 14. ⁇ , 16. 2, 19. 4, 19. 9, 20. 9. 2
  • Such II type crystals are included in the crystal of the compound represented by the formula (I-2) of the present invention regardless of the amount of water.
  • Type II crystals can be obtained by, for example, heating a compound represented by the formula (I) (eg, about 70 to 80 ° C.) or alcohol having 1 to 8 carbon atoms (eg, ethanol, absolute ethanol, butanol). ) To obtain a saturated solution, and the resulting saturated solution is gradually cooled (for example, to 0 to 30 ° C.) and allowed to stand in the cooled state (for example, 1 to 60 days). it can. After cooling the solution containing the compound represented by the formula (I), a poor solvent may be added.
  • a compound represented by the formula (I) eg, about 70 to 80 ° C.
  • alcohol having 1 to 8 carbon atoms eg, ethanol, absolute ethanol, butanol
  • the I-type crystal can be produced, for example, by dissolving the compound represented by the formula (I) in a good solvent to obtain a saturated solution, and gradually adding a poor solvent to the obtained saturated solution.
  • the solution may be cooled (for example, 0 to 10 ° C.), and is preferably cooled.
  • the good solvent used methanol, ethanol, propanol, dimethyl sulfoxide, dimethylformamide, formamide, or the like is preferable.
  • the poor solvent water, ether, isobutyl acetate and the like are preferable.
  • the type II crystal can also be produced, for example, by adding water to the type I crystal to form a slurry to be transferred to the type II crystal.
  • the type II crystal can also be produced, for example, by adding water to a toluene solvate crystal of the compound represented by the formula (I) to form a slurry and transferring it to a type II crystal.
  • the type II crystal is obtained by, for example, adding a poor solvent (eg, heptane) at 60 ° C. to a solution (preferably a saturated solution) obtained by dissolving the compound represented by the formula (I) in ethanol. It can also be produced by adding crystallization and cooling crystallization to 10 ° C.
  • a poor solvent eg, heptane
  • a solution preferably a saturated solution
  • the I type I crystal can also be produced, for example, by removing a suitable solvate crystal of the compound represented by the formula (I) by a method such as heating. Furthermore, a type II crystal having a preferred moisture content is obtained by allowing a type II crystal from which water has been removed by, for example, heat drying to store and absorb moisture under normal conditions, preferably under humidified conditions. Therefore, it can be suitably manufactured.
  • a type II crystal having a preferred moisture content can be suitably obtained by storing and releasing moisture of a type II crystal having a higher moisture content under normal conditions, preferably under low humidity conditions. Can be manufactured.
  • a type I I crystal having a preferred water content can be suitably produced by heating and drying a type I I crystal having a higher water content to an appropriate level.
  • type I crystals have high storage stability, they can be suitably used, for example, as pharmaceuticals (for example, sugar transport enhancing agents, hypoglycemic agents, antidiabetic agents, etc.), active pharmaceutical ingredients, and the like.
  • pharmaceuticals for example, sugar transport enhancing agents, hypoglycemic agents, antidiabetic agents, etc.
  • active pharmaceutical ingredients for example, active pharmaceutical ingredients, and the like.
  • type II crystals have a particularly favorable water content.
  • Type II crystals have little change in water content under normal conditions (for example, in the environment during pharmaceutical production).
  • Agents, antihyperglycemic agents, antidiabetic agents, etc.), and active pharmaceutical ingredients are particularly favorable.
  • the water content of the crystal of the compound represented by the formula (I-13) is not necessarily constant depending on the drying conditions and storage conditions.
  • the crystal of the compound represented by the formula (I 1 3) is obtained by, for example, dissolving a compound represented by the formula (I) in ethyl acetate heated (for example, about 50 to 80 ° C.) to obtain a saturated solution.
  • the obtained saturated solution is gradually cooled (for example, to 0 to 30 ° C.) and allowed to stand in the cooled state (for example, 1 to 7 days).
  • the crystal of the compound represented by the formula (I-13) is desolvated by heating (for example, about 160 ° C.) and transitions to the I-type crystal. Therefore, it can be used for the production of the I-type crystal. .
  • the crystal of the compound represented by formula (I) is a solvate crystal of the compound represented by formula (I).
  • the water content of the crystal of the compound represented by the formula (I-14) is not necessarily constant depending on the drying conditions and storage conditions.
  • the crystal of the compound represented by formula (I-14) is prepared by, for example, dissolving the compound represented by formula (I) in a good solvent to form a saturated solution, and gradually adding anisol to the obtained saturated solution.
  • a good solvent for example, 0 to 10 ° C. for 1 to 60 days.
  • the good solvent used is preferably dimethylformamide.
  • the crystal of the compound represented by the formula (1-3) is desolvated by heating (for example, about 170 ° C.) and transitions to the I-type crystal. Therefore, it can be used for the production of the I-type crystal. it can.
  • the water content of the crystal of the compound represented by the formula (I 1-5) is not necessarily constant depending on the drying conditions and storage conditions.
  • the crystal of the compound represented by the formula (I 1-5) is, for example, dissolved in benzonitrile obtained by heating (for example, about 70 to 90 ° C.) the compound represented by the formula (I) to form a saturated solution,
  • the obtained saturated solution can be gradually cooled (for example, to 0 to 10 ° C.) and allowed to stand in the cooled state (for example, for 1 to 30 days).
  • the crystal of the compound represented by the formula (1-5) is desolvated by heating (for example, about 170 ° C.) and transitions to the type I crystal. Therefore, it can be used for the production of the type I crystal. it can.
  • the crystal of the compound represented by formula (I) is a tetrahydrofuran hydrate crystal of the compound represented by formula (I).
  • Diffraction angle (2 ⁇ ) 7.1, 14.4, 19.9, 21.3, 22.5 and 23.7 have characteristic peaks (apparatus ⁇ ).
  • the amount of water in the crystal of the compound represented by formula (1-6) is not necessarily constant depending on the drying conditions and storage conditions.
  • the crystal of the compound represented by the formula (1-6) is, for example, dissolved in benzonitrile obtained by heating the compound represented by the formula (I) (for example, about 55 to 75 ° C) to form a saturated solution.
  • the obtained saturated solution can be gradually cooled (for example, to 0 to 30 ° C.) and allowed to stand in the cooled state (for example, for 1 to 30 days).
  • the moisture content of the crystal of the compound represented by the formula (I-7) is not necessarily constant depending on the drying conditions and storage conditions.
  • Crystals of the compound represented by the formula (I-7) are obtained by adding toluene to a solution (preferably a saturated solution) obtained by dissolving the compound represented by the formula (I) in ethanol. Then, it can be produced by cooling crystallization (for example, up to 10 ° C.).
  • the crystal of the compound represented by the formula (I 17) can be transferred to the II type crystal by adding water, it can be used for the production of the II type crystal.
  • the peak value and the relative intensity value of the diffraction angle. (2 ⁇ ) of the powder X-ray diffraction pattern can allow an experimental error. More specifically, the 20 values described in the present invention are accurate in the range of 0.2 under the same measurement conditions. That is, when determining whether or not a crystal is a crystal according to the present invention, the range of ⁇ 0.2 of the 26 values of the characteristic peak of 2 ⁇ 1S crystal of the present invention obtained experimentally for the crystal. If it is within the range, it is recognized as the same peak.
  • the crystal of the present invention has a sugar transport enhancing action.
  • Agent; hypoglycemic agent; diabetes, diabetic peripheral neuropathy, diabetic nephropathy, diabetes It is useful as a medicine for the prevention and / or treatment of pathologic retinopathy, diabetic macroangiopathy, impaired glucose tolerance, or obesity.
  • compositions for oral administration include tablets (including sugar-coated tablets, coated tablets, dry-coated tablets, sublingual tablets, intraoral patches, orally disintegrating tablets), pills, capsules (hard capsules, soft capsules) , Capsules, microcapsules), powders, granules, fine granules, troches, liquids (including syrups, emulsions and suspensions).
  • Examples of the pharmaceutical composition for parenteral administration include injections, creams, ointments, suppositories and the like.
  • Such a pharmaceutical composition can be produced, for example, by mixing with a pharmaceutically acceptable excipient, carrier, etc. according to a conventional method.
  • excipients and carriers examples include, for example, excipients in solid preparations, binders, disintegrating agents, lubricants; solvents in liquid preparations, solubilizers, suspending agents. , Buffers, thickeners, emulsifiers, etc.
  • formulation additives such as coloring agents, seasonings, and antioxidants can be used as necessary.
  • excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, arsenic starch, dextrin, crystalline cellulose (for example, microcrystalline cellulose), low-substituted hydroxypropylcellulose, carboxy
  • excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, arsenic starch, dextrin, crystalline cellulose (for example, microcrystalline cellulose), low-substituted hydroxypropylcellulose, carboxy
  • examples include methylcellulose sodium, gum arabic, dextrin, pullulan, light anhydrous carboxylic acid, synthetic aluminum silicate and magnesium aluminate metasilicate.
  • binders include pregelatinized starch, sucrose, gelatin, macrogol, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydrange Droxypropylcellulose (HPC), Hydroxypropylmethylcellulose (HP MC), Polyvinylpyrrolidone ( ⁇
  • Disintegrants include, for example, lactose, sucrose, starch, carboxymethyl cellulose, canolepoxymethinorescenellose calcium, cross-linked polyvinylino pyrrolidone, force norellose sodium, croscarmellose sodium, canoleboxoxymethinorester These include sodium sodium, light anhydrous caustic acid, low-substituted hydroxypropyl cellulose, cation exchange resin, partially pregelatinized starch, and corn starch.
  • lubricant examples include stearic acid, magnesium stearate, calcium stearate, tanolec, waxes, colloidal silica, DL-leucine, sodium lauryl sulfate, magnesium lauryl sulfate, macrogol, and aerosil.
  • Solvents include, for example, water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, medium chain fatty acid triglyceride (MCT), vegetable oil (eg safflower oil, sesame oil, corn oil, olive oil) Cottonseed oil, soy lecithin, etc.).
  • physiological saline Ringer's solution
  • alcohol propylene glycol
  • polyethylene glycol polyethylene glycol
  • MCT medium chain fatty acid triglyceride
  • vegetable oil eg safflower oil, sesame oil, corn oil, olive oil
  • Cottonseed oil soy lecithin, etc.
  • solubilizers include polyethylene glycol, propylene glycol, D-mannitol, trenosylose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium tamate, sodium salicylate, Examples thereof include sodium acetate.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; Hydrophilic polymers such as Polyvinylenopyrrolidone, Canoleboxymethinoresenorelose sodium, Metinorece / Rerose, Hydroxymethy / Recenorelose, Hydroxy Shetinorecellulose, Hydroxypropyl Cellulose; Polysorbates And polyoxyethylene hydrogenated castor oil.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate
  • Hydrophilic polymers such as Polyvinylenopyrrolidone, Canoleboxymet
  • buffer solutions such as phosphate, acetate, carbonate, citrate, and the like.
  • Examples of the thickener include natural gums and cellulose derivatives.
  • Examples of the emulsifier include fatty acid esters (for example, sucrose fatty acid ester, glycerin fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester, etc.), wax (for example, beeswax, rapeseed hydrogenated oil, safra-hydrogenated oil, palm Hydrogenated oil, sitosterol, stigmasterol, force mpesterol, brush casterol, cacao butter powder, carnauba wax, rice wax, molasses, paraffin, etc.), lecithin (eg egg yolk lecithin, large Bean lecithin).
  • fatty acid esters for example, sucrose fatty acid ester, glycerin fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester, etc.
  • wax for example, beeswax, rapeseed hydrogen
  • colorants examples include water-soluble edible tar dyes (eg, edible red No. 2 oppi 3, edible yellow No. 4 and 5, edible blue No. 1 oppi No. 2, etc., water insoluble Lake pigments (eg, aluminum salts of the above-mentioned water-soluble edible tar pigments), natural pigments (eg, J3—power rotin, chlorophyll, bengara, etc.).
  • water-soluble edible tar dyes eg, edible red No. 2 oppi 3, edible yellow No. 4 and 5, edible blue No. 1 oppi No. 2, etc.
  • water insoluble Lake pigments eg, aluminum salts of the above-mentioned water-soluble edible tar pigments
  • natural pigments eg, J3—power rotin, chlorophyll, bengara, etc.
  • sweetening agent examples include sucrose, lactose, sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia and the like.
  • antioxidant examples include sulfite, ascorbic acid and alkali metal salts thereof, alkaline earth metal salts, and the like.
  • Tablets, granules, fine granules, etc. can be coated by a known method using a coating substrate for the purpose of masking taste, improving light stability, improving appearance or enteric properties, etc. Good.
  • the coating base include a sugar coating base, a water-soluble film coating base, and an enteric film coating base.
  • sugar coating base examples include sucrose, and one or more kinds selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.
  • water-soluble film coating bases examples include celluloses such as hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), ethinore senorelose, hydroxenochinoselenose, and methino lech dorochichinenoselenose.
  • Polymers Polyvinylacetal Jetylaminoacetate, Aminoalkyl methacrylate copolymer E (Eudragit E (registered trademark)) Synthetic polymers such as polyvinylpyrrolidone; Polysaccharides such as pullulan I can get lost.
  • enteric film coating bases include cellulosic polymers such as hydroxypropylmethylenorerose phthalate, hydroxypropinoremethylolosenolose acetate succinate, carboxymethylethyl cellulose, and cellulose acetate phthalate; Methacrylic acid copolymer L (Eudragit L (registered trademark)), Methacrylic acid copolymer LD (Eudragit L 1 3 0 D 5 5 (registered trademark)) Methacrylic acid copolymer S (Eudragit S (registered trademark)), etc. Talaric acid polymers; natural products such as shellac.
  • These coating bases may be coated singly or as a mixture of two or more kinds in an appropriate ratio, or two or more kinds may be sequentially coated.
  • the content of the crystal of the present invention in the medicament of the present invention is usually 0.01 to 100% by weight, preferably 1 to 99% by weight.
  • the proportion of the compound of the present invention that takes the form of crystals is preferably 50% or more, more preferably 95% or more. Particularly preferably, it is 98% or more.
  • the dose of the crystal of the present invention may be within the range of the effective amount of the crystal of the present invention, such as a sugar transport enhancing action and a hypoglycemic action, and also varies depending on the target disease, administration subject, administration method, symptoms, etc. However, it is usually from about 0.001 to about 100 Omg per day per kilogram of body weight.
  • the crystals of the present invention when administered orally to a diabetic patient for the purpose of treating diabetes, about 0.01 to 100 mg of crystals of the present invention per day per kg of body weight, Preferably, 0.05 to 50 mg, more preferably 0.:! To 10 mg is applied.
  • the crystals of the present invention are about 0.001 to 5 Omg, preferably 0.005 to 2 Omg, more preferably 0.01 to 1 Omg. Administer. Example.
  • Humidity controller Shinei Co., Ltd. SRH-1R
  • Drying conditions measured while drying the sample under reduced pressure
  • Humidity conditions Measure humidity by placing saturated salt solution
  • the filtrate was concentrated under reduced pressure until the liquid volume reached 27.3 L, 22.5 L of methanol was added, and the filtrate was concentrated under reduced pressure until the liquid volume reached 13.5 L. Further, 22.5 L of methanol was added, and after concentration under reduced pressure until the liquid volume became 15 L, 31.06 L of methanol was added. To this solution was added 5.48 L (26.98 mol) of a 28% sodium methoxide / methanol solution at 60 ° C, and the mixture was washed with 10.62 L of methanol. After stirring at 64 ° C for 5 hours, the mixture was cooled to 30 ° C and 15.96 L (31. 89 mol) of 2M hydrochloric acid was added.
  • Step 2 4-[(1 R, 2 R) 1 -2-aminocyclohexylamino] 1-3-ringoline 1-one hydrochloride synthesis
  • the procedure of adding 260 mL of 2-propanol and concentrating under reduced pressure was performed in three steps, and then the liquid volume was adjusted to about llOmL.
  • the obtained liquid was kept at 50 ° C for 1 hour, cooled to 10 ° C over about 4 hours, and further kept at 10 ° C for about 10 hours.
  • the precipitated solid was filtered and washed with 84.9 mL of 2-propanol cooled to 10 ° C.
  • the obtained wet solid was dried under reduced pressure at 60 ° C. to obtain 21.40 g (content 88.3%) of the title compound.
  • Acetonitrile was distilled off under reduced pressure, followed by extraction with ethyl acetate, and the organic layer was washed with an aqueous sodium bicarbonate solution (6.9 wt%) and concentrated under reduced pressure. Ethyl acetate was added to the concentrated solution and concentrated under reduced pressure twice, and then ethyl acetate was added so that the liquid volume became about llOmL. After raising the temperature to 55 ° C, add 18 mg of seed crystals of the title compound (for example, obtained in the same manner as this method without using seed crystals), hold for 1 hour at 55 ° C, and then add heptane (5% 2-propanol Contained) 123 mL was added dropwise over 1 hour.
  • heptane 5% 2-propanol Contained
  • a powder X-ray diffraction spectrum (FIG. 1) and 1 H-NMR spectrum of the obtained crystals were measured and confirmed to be about 0.5 ethyl acetate.
  • Step 2 Desolvation of ethyl acetate solvate crystals
  • the ethyl acetate hydrate crystals obtained in Step 1 were heated to about 160 ° C. to remove the solvent. As a result of measuring the powder X-ray diffraction spectrum of the obtained crystal, it was confirmed to be a type I crystal (Fig. 1).
  • Step 1 Manufacture of a solvate crystal.
  • Step 2 Desolvation of solvate crystals
  • the solvate crystals obtained in Step 1 were heated to about 170 ° C to remove the solvent, and the powder X-ray diffraction spectrum of the obtained crystals was measured. It was confirmed to be a type I crystal (Fig. 2).
  • the benzonitrile solvate crystal obtained in Step 1 was heated to about 170 ° C to remove the solvent, and as a result of measuring powder X-ray diffraction, it was confirmed to be a type I crystal (Fig. 3).
  • the obtained crystals were measured by powder X-ray diffraction spectrum (FIG. 4) and 1 H-NMR spectrum, and confirmed to be a tetrahydrofuran solvate.
  • the powder X-ray diffraction spectrum was measured, the dried crystals remained as the Tolen hydrate. 1370 mL of water was added to the dried crystals, and the mixture was stirred in a slurry state at 25 ° C. for 1.5 hours, and then separated by a centrifugal filter.
  • the powder X-ray diffraction spectrum of the crystal obtained by vacuum drying at 60 ° C overnight was measured, and it was confirmed that it was converted to II type crystal. [Example 23].
  • type II with a water content of about 0% was obtained in the same manner as above. Crystals could also be obtained.
  • Fig. 6 shows the powder X-ray diffraction spectrum of the type I crystal
  • Fig. 7 shows the differential scanning calorimetry (DSC) chart.
  • Fig. 9 shows a powder X-ray crystal diffraction spectrum of a type II crystal (water content of about 3-5%), and differential scanning calorimetry (DS C) of the type II crystal obtained by the method described in Example 5
  • Figure 10 shows these charts.
  • a broad endothermic peak with a peak near 90 degrees is considered to correspond to the disappearance of water, and supports the fact that this crystal is a hydrated substance.
  • Fig. 11 shows the results of powder X-ray diffraction measurements after standing for 60 minutes under vacuum.
  • specimen 2 The specimen that was vacuum-dried at 60 ° C for 2 hours was designated as specimen 2, and the water content was measured and confirmed to be 0.2%. After that, it was stored in an open system at about 60% RH (in a constant temperature and humidity chamber of 25 ° C 60% RH) and 84% RH (under a saturated solution of potassium chloride). The water content of each specimen was measured after 1, 6 and 26 hours of storage.
  • the Karl Fischer measurement device (Mitsubishi Chemical Corporation CA-06) was used for the measurement of water content.
  • the specimen with the initial moisture content of 4.4% (Sample 1) is 3-5 ° / at any relative humidity. It was confirmed that the crystal was easy to handle, having a moisture content within a certain range, having little fluctuation in moisture content, and being hardly affected by humidity during weighing. In addition, it was confirmed that the dried crystals became water-containing crystals having a water content in the above range under normal or humid conditions.
  • Type I crystals were stored in a thermostatic chamber at 25 ° C 60% RH and 40 ° C 75% RH. 2 Storage at 5 ° C6 0% RH was performed for up to 12 months.
  • Type II crystals open in a constant temperature and humidity chamber at 80 ° C / 90% RH, 25 ° C / 40% RH, 60 ° C / 90% RH, or 60 ° CZ Saved with. Storage was performed for up to 3 months. As a result, no significant increase or decrease in impurities was observed after storage under any of the conditions.
  • type II crystals (containing about 3-5% water) have high storage stability, and have a wide range of temperatures as described above. And does not produce impurities under humidity. Although it shows slight changes under high temperature and low humidity conditions, it is basically a stable crystal that does not change its water content or powder X-ray pattern, and is extremely useful for pharmaceutical production.
  • crystal of the compound represented by the formula (I) or the pharmaceutically acceptable salt thereof of the present invention has high storage stability, production of a medicament containing the compound represented by the formula (I), etc. Useful for.
  • crystals of the compound represented by the formula (1-1) of the present invention are anhydrous crystals, they are useful as drug substances and standard substances in pharmaceutical production.
  • the crystal represented by the formula (1-2) of the present invention is extremely useful for pharmaceutical production and the like because the change in water content is small.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Diabetes (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Child & Adolescent Psychology (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un cristal d'un composé lactame présentant une stabilité lors du stockage, une bonne maniabilité ou analogues, qui est approprié en tant que médicament pharmaceutique comme un excellent amplificateur du transport des sucres ou un agent hypoglycémiant. Un cristal d'un composé représenté par la formule (I) de l'invention ou de l'un de ses sels acceptables sur le plan pharmaceutique est utile en tant que médicament pharmaceutique comme un amplificateur du transport des sucres ou un agent hypoglycémiant.
PCT/JP2007/059540 2007-04-27 2007-04-27 Forme cristalline d'un composé lactame et son procédé de production WO2008139574A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
PCT/JP2007/059540 WO2008139574A1 (fr) 2007-04-27 2007-04-27 Forme cristalline d'un composé lactame et son procédé de production
PCT/JP2008/058037 WO2008136393A1 (fr) 2007-04-27 2008-04-25 Cristaux de composé lactame et leur procédé de fabrication
PCT/JP2008/058036 WO2008136392A1 (fr) 2007-04-27 2008-04-25 Préparation pour une administration orale
PCT/JP2008/058038 WO2008136394A1 (fr) 2007-04-27 2008-04-25 Procédé de production d'un composé de lactame et intermédiaire pour le procédé de production

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PCT/JP2007/059540 WO2008139574A1 (fr) 2007-04-27 2007-04-27 Forme cristalline d'un composé lactame et son procédé de production

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002044180A1 (fr) * 2000-12-01 2002-06-06 Ajinomoto Co.,Inc. Composes de lactame et leur utilisation medicale
JP2004010523A (ja) * 2002-06-05 2004-01-15 Ajinomoto Co Inc 縮合多環式化合物およびその医薬用途
WO2004069259A1 (fr) * 2003-02-07 2004-08-19 Ajinomoto Co., Inc. Remede contre le diabete
WO2005042536A1 (fr) * 2003-10-31 2005-05-12 Ajinomoto Co., Inc. Nouveau compose polycyclique condense comprenant un heterocycle et ses applications medicinales
JP2005529933A (ja) * 2002-05-31 2005-10-06 シェーリング　コーポレイション キサンチンホスホジエステラーゼｖインヒビター多形体
JP2006225382A (ja) * 2005-01-24 2006-08-31 Sankyo Co Ltd チアゾリジンジオン化合物の製造方法及びその製造中間体
WO2006118341A1 (fr) * 2005-04-28 2006-11-09 Ajinomoto Co., Inc. Nouveau composé lactame

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002044180A1 (fr) * 2000-12-01 2002-06-06 Ajinomoto Co.,Inc. Composes de lactame et leur utilisation medicale
JP2005529933A (ja) * 2002-05-31 2005-10-06 シェーリング　コーポレイション キサンチンホスホジエステラーゼｖインヒビター多形体
JP2004010523A (ja) * 2002-06-05 2004-01-15 Ajinomoto Co Inc 縮合多環式化合物およびその医薬用途
WO2004069259A1 (fr) * 2003-02-07 2004-08-19 Ajinomoto Co., Inc. Remede contre le diabete
WO2005042536A1 (fr) * 2003-10-31 2005-05-12 Ajinomoto Co., Inc. Nouveau compose polycyclique condense comprenant un heterocycle et ses applications medicinales
JP2006225382A (ja) * 2005-01-24 2006-08-31 Sankyo Co Ltd チアゾリジンジオン化合物の製造方法及びその製造中間体
WO2006118341A1 (fr) * 2005-04-28 2006-11-09 Ajinomoto Co., Inc. Nouveau composé lactame

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CSJ: THE CHEMICAL SOCIETY OF JAPAN: "Jikken Kagaku Koza 1 Kihon Sosa I", vol. 4TH ED., 5 November 1990, MARUZEN CO., LTD., pages: 184 - 186, XP003024077 *
KAGAKU DOJIN HENSHUBU: "Zoku.Jikken no Anzenni Okonau Tameni, new edition", 10 December 1987, KAGAKU-DOJIN PUBLISHING CO., LTD., pages: 82 - 83, XP003024078 *
OKANO T.: "Shin.Yakuzaigaku Soron", NANKODO CO., LTD., 10 April 1987 (1987-04-10), pages 110 - 111 *

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