WO2020171055A1 - Alcoolate dérivé de benzazépine ou cristal de celui-ci - Google Patents

Alcoolate dérivé de benzazépine ou cristal de celui-ci Download PDF

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WO2020171055A1
WO2020171055A1 PCT/JP2020/006243 JP2020006243W WO2020171055A1 WO 2020171055 A1 WO2020171055 A1 WO 2020171055A1 JP 2020006243 W JP2020006243 W JP 2020006243W WO 2020171055 A1 WO2020171055 A1 WO 2020171055A1
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crystal
compound
characteristic peaks
alcohol
characteristic
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PCT/JP2020/006243
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English (en)
Japanese (ja)
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宣慶 春日井
和包 長井
齊藤　幸治
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株式会社 三和化学研究所
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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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • 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
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to an alcoholate of a benzazepine derivative or a crystal thereof.
  • N-[(S)-1-hydroxypropan-2-yl]-4-methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-2,3 4,5-Tetrahydro-1H-benzo[b]azepine-4-carboxamide is a compound having a V2 receptor agonistic action, and is effective in preventing or treating nocturia.
  • a chiral compound of the compound and a method for producing the same are disclosed in Patent Document 1. Further, intermediates of the compound are reported in Patent Document 2, Patent Document 3 and Non-Patent Document 1.
  • Patent Document 1 N-[(S)-1-hydroxypropan-2-yl]-4-methyl-1-[2-methyl-4-(3-methyl-1H).
  • -Pyrazol-1-yl)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxamide chiral compound was prepared and analyzed.
  • the compound was amorphous (amorphous).
  • Amorphous is known to be in a thermodynamically non-equilibrium metastable state, and generally has a high solubility and a high dissolution rate, but is low in stability and is often unfavorable in terms of drug development.
  • an object of the present invention is to increase the applicability as a drug substance to (S)-N-[(S)-1-hydroxypropan-2-yl]-4 represented by the formula (I).
  • -Methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxamide It is to provide an alcohol solvate or a crystal thereof.
  • the inventors of the present invention have made extensive studies, and found that when the optically active benzazepine derivative represented by the formula (I) was used as a specific alcohol solvate, it could be isolated as a crystal, and the present invention was made. It came to completion.
  • the main configuration of the present invention is as follows.
  • an alcoholate and a crystal could not be obtained.
  • Formula (I) An alcoholate of the compound shown by or a crystal thereof.
  • Infrared absorption spectrum as wavenumber ( ⁇ 0.5%), or shows a characteristic absorption peak at 1535cm -1 and 1635 cm -1, or 948cm -1, 1096cm -1, 1240cm -1 and 1384cm -
  • the alcohol solvate crystal according to any one of [4] to [6], which exhibits a characteristic absorption peak in 1 .
  • the spacing d is 10.0 ⁇ 0.33 ⁇ , 7.3 ⁇ 0.18 ⁇ , 6.2 ⁇ 0.13 ⁇ , 4.9. Shows characteristic peaks at ⁇ 0.08 ⁇ and 4.1 ⁇ 0.06 ⁇ , or 10.0 ⁇ 0.33 ⁇ , 9.4 ⁇ 0.30 ⁇ , 7.3 ⁇ 0.18 ⁇ , 6.2 ⁇ 0.13 ⁇ , 5.9 ⁇ 0.12 ⁇ , 4.9 ⁇ 0.08 ⁇ , 4.3 ⁇ 0.06 ⁇ , 4.1 ⁇ 0.06 ⁇ and 3.9 ⁇ 0.05 ⁇
  • Infrared absorption spectrum as wavenumber ( ⁇ 0.5%), or shows a characteristic absorption peak at 1535cm -1 and 1623cm -1, or 1084cm -1, 1241cm -1, and 1384cm -1, wherein The crystal of the alcohol solvate according to any of [8] to [10], which exhibits a specific absorption peak.
  • [15] In the infrared absorption spectrum, as wavenumber ( ⁇ 0.5%), or shows a characteristic absorption peak at 1535cm -1 and 1580 cm -1, or 966cm -1, characteristic of 1094 cm -1 and 1384cm -1
  • a pharmaceutical composition comprising the alcoholate or the crystal thereof according to any one of [1] to [15].
  • an alcoholate of an optically active benzazepine derivative represented by the formula (I) can be isolated as crystals.
  • 1 shows a powder X-ray diffraction pattern of the compound obtained in Example 1.
  • 1 shows an infrared absorption spectrum of the compound obtained in Example 1.
  • 3 shows a powder X-ray diffraction pattern of the compound obtained in Example 2.
  • 2 shows an infrared absorption spectrum of the compound obtained in Example 2.
  • 3 shows a powder X-ray diffraction pattern of the compound obtained in Example 3.
  • 3 shows an infrared absorption spectrum of the compound obtained in Example 3.
  • 3 shows a powder X-ray diffraction pattern of the compound of Comparative Example 3.
  • the hygroscopic curve of the compound of Example 1, Example 2 and the reference example 1 in a hygroscopic property test is shown.
  • the vertical axis of the figure shows the amount of moisture absorption (%), and the horizontal axis shows the relative humidity (%RH).
  • One embodiment of the present invention is an alcohol solvate of the compound of formula (I).
  • the compound represented by the formula (I) is a V2 receptor agonist.
  • the compound represented by formula (I) is referred to as compound (I).
  • Compound (I) (free non-solvate) has not been obtained as a crystal at this time, but it can be obtained as a solvate with a specific alcohol.
  • Alcohol solvate refers to a complex formed by compound (I) (solute) and alcohol (solvent).
  • the alcohol is preferably a linear or branched C 1 -C 5 alcohol, more preferably a linear or branched C 1 -C 3 alcohol, and a linear or branched C 2 -C such as ethanol, isopropanol or normal propanol. 3 alcohol is particularly preferred.
  • compound (I) crystals other than alcohol solvate have not been obtained at present.
  • the alcohol content is preferably 0.1-fold to 2-fold, more preferably 0.5- to 1.5-fold, and most preferably 1-fold by molar ratio of compound (I).
  • the content of alcohol in the compound can be specified by a thermogravimetric measuring device, gas chromatography, nuclear magnetic resonance device, or the like.
  • the crystal of the alcoholate of the compound (I) shows the following characteristic peaks in the powder X-ray diffraction as the 2 ⁇ value or the interplanar spacing d.
  • the crystal of the isopropanol solvate of the compound (I) shows a characteristic peak at 17.5° and 18.0° as a 2 ⁇ value in a powder X-ray diffraction spectrum (pattern) using CuK ⁇ radiation, or 8 It preferably exhibits characteristic peaks at 0.5°, 14.8°, 18.0° and 21.0°, and 8.5°, 11.9°, 14.1°, 14.8°, 17 It is more preferable to show characteristic peaks at 0.5°, 18.0° and 21.0°, and 8.5°, 11.9°, 14.1°, 14.8°, 17.5°, More preferably, it exhibits characteristic peaks at 18.0°, 19.0°, 20.7°, 21.0°, 22.8° and 24.6°.
  • characteristic peaks at 5.1 ⁇ and 4.9 ⁇ are shown, or 10.3 ⁇ , 6.0 ⁇ , 4.9 ⁇ and It is preferable to show a characteristic peak at 4.2 ⁇ , 10.3 ⁇ , 7.4 ⁇ , 6.3 ⁇ , 6.0 ⁇ , 5.1 ⁇ , 4.9 ⁇ and 4.2 ⁇ More preferably, 10.3 ⁇ , 7.4 ⁇ , 6.3 ⁇ , 6.0 ⁇ , 5.1 ⁇ , 4.9 ⁇ , 4.7 ⁇ , 4.3 ⁇ , 4.2 ⁇ , 3.9 ⁇ and 3.6 ⁇ More preferably, it exhibits a peak.
  • the crystals of the ethanol solvate of compound (I) have a 2 ⁇ value of 8.9°, 12.1°, 14.3°, 18.2° in the powder X-ray diffraction spectrum (pattern) using CuK ⁇ radiation. And 21.4° are preferable, and 8.9°, 9.4°, 12.1°, 14.3°, 15.1°, 18.2°, 20.9° are preferable. More preferably, it exhibits characteristic peaks at 21.4° and 23.1°. Further, in the powder X-ray diffraction spectrum (pattern) using CuK ⁇ radiation, characteristic peaks are shown as the interplanar spacing d at 10.0 ⁇ , 7.3 ⁇ , 6.2 ⁇ , 4.9 ⁇ and 4.1 ⁇ . Preferably, 10.0 ⁇ , 9.4 ⁇ , 7.3 ⁇ , 6.2 ⁇ , 5.9 ⁇ , 4.9 ⁇ , 4.3 ⁇ , 4.1 ⁇ and 3.9 ⁇ are more preferable.
  • the crystals of the normal propanol solvate of compound (I) are characterized by 2 ⁇ values of 17.3°, 18.0° and 18.8° in a powder X-ray diffraction spectrum (pattern) using CuK ⁇ radiation. It preferably exhibits peaks or characteristic peaks at 8.5°, 14.8°, 18.0° and 21.0°, such as 8.5°, 14.8°, 17.3°, It is more preferable to show characteristic peaks at 18.0°, 18.8° and 21.0°, and 8.5°, 11.9°, 14.3°, 14.8°, 17.3°. , 18.0°, 18.8°, 21.0°, 22.2°, 22.7°, 23.0° and 24.5° are more preferable.
  • characteristic peaks at 5.1 ⁇ , 4.9 ⁇ and 4.7 ⁇ , 10.4 ⁇ , 6.0 ⁇ It is preferable to show characteristic peaks at 4.9 ⁇ and 4.2 ⁇ , and it is preferable to show characteristic peaks at 10.4 ⁇ , 6.0 ⁇ , 5.1 ⁇ , 4.9 ⁇ , 4.7 ⁇ and 4.2 ⁇ . More preferably, 10.4 ⁇ , 7.4 ⁇ , 6.2 ⁇ , 6.0 ⁇ , 5.1 ⁇ , 4.9 ⁇ , 4.7 ⁇ , 4.2 ⁇ , 4.0 ⁇ , 3.9 ⁇ and 3.6 ⁇ More preferably, it exhibits a peak.
  • the 2 ⁇ value and the d-spacing value are selected from the characteristic peaks among the X-ray peaks, and the crystal structure is not necessarily limited to these values, and peaks other than these are included. May be. Further, in general, when crystals are measured by powder X-ray analysis, the peak may have some measurement error depending on the measuring equipment, the measurement conditions, and the like.
  • the 2 ⁇ value is preferably within ⁇ 0.3°, more preferably within ⁇ 0.2°, even more preferably within ⁇ 0.1°.
  • a 2 ⁇ value shows a characteristic peak at 17.5°
  • the error range of the surface spacing d value means a range calculated from the error range of the 2 ⁇ value described above.
  • the surface spacing d shows a characteristic peak at 5.1 ⁇
  • the surface spacing d is 5 It is preferable that "there is a characteristic peak at .01 ⁇ to 5.19 ⁇ ”, and it is more preferable that "there is a characteristic peak at 5.04 ⁇ to 5.16 ⁇ as the inter-spacing d”. It is more preferable that “a characteristic peak appears at 5.07 ⁇ to 5.13 ⁇ ”, and the same applies to other peaks.
  • the crystal of the alcoholate of compound (I) preferably has the following characteristic absorption peak in the infrared absorption spectrum.
  • the crystal of the isopropanol solvate of the compound (I) preferably has characteristic absorption peaks near wave numbers of 1535 cm ⁇ 1 and 1635 cm ⁇ 1 . From another point of view, it is more preferable to have characteristic absorption peaks near the wave numbers of 948 cm -1 , 1096 cm -1 , 1240 cm -1 and 1384 cm -1 .
  • Crystals of the ethanol solvate of compound (I) preferably have characteristic absorption peaks near wave numbers of 1535 cm ⁇ 1 and 1623 cm ⁇ 1 . From another point of view, it is more preferable to have characteristic absorption peaks near the wave numbers of 1084 cm -1 , 1241 cm -1 and 1384 cm -1 .
  • the crystals of the normal propanol solvate of compound (I) preferably have characteristic absorption peaks near wave numbers of 1535 cm -1 and 1580 cm -1 . From another point of view, it is more preferable to have characteristic absorption peaks near the wave numbers of 966 cm -1 , 1094 cm -1 and 1384 cm -1 .
  • the above-mentioned wave number values are selected from characteristic wave number scales, and are not necessarily limited only by these values, and wave number scales other than these may be included.
  • some measurement error may occur due to measurement equipment or measurement conditions, and therefore some error should be taken into account in specifying the wave number.
  • Within ⁇ 0.8% is preferable, and within ⁇ 0.5% is more preferable.
  • the crystal of the alcoholate of the compound (I) of the present invention is not only specified as a characteristic peak as described above in the powder X-ray diffraction as the 2 ⁇ value or the interplanar spacing d, but also the powder X In addition to the characteristic peak in line diffraction, it can be specified as having a characteristic absorption peak as described above in the infrared absorption spectrum.
  • the alcoholate of compound (I) or a crystal thereof can be produced, for example, by the following method.
  • Compound (I) can be produced by the methods described in Patent Documents 1 to 3, and the like.
  • the alcoholate of compound (I) can be obtained by a conventional method for producing an alcoholate. Specifically, the alcoholate of the compound (I) is obtained by mixing the amorphous compound (I) and the alcohol while heating, if necessary, and then cooling the mixture while stirring or leaving it to crystallize. Can be obtained by It is desirable that the cooling be carried out while adjusting the cooling rate as necessary in consideration of the influence on the crystal quality and grain size.
  • cooling at a cooling rate of 20 to 1° C./hour is preferable, and cooling at a cooling rate of 10 to 3° C./hour is more preferable.
  • alcohols used in these methods include ethanol, normal propanol and isopropanol.
  • the alcohol may be hydrous.
  • the amount of alcohol used is preferably 3 to 20 times by mass, more preferably 5 to 10 times by mass, relative to the compound (I).
  • Crystals of the alcoholate of compound (I) can also be obtained by adding seed crystals to an alcohol solution of compound (I). Seed crystals (eg, crystals of isopropanol solvate of compound (I)) may be added during crystallization.
  • the temperature at which the seed crystal is added is not particularly limited, but is preferably 0 to 80°C, more preferably 40 to 70°C, further preferably 50 to 65°C.
  • the amount of seed crystals added is preferably 0.0001 to 0.1 mol, and more preferably 0.005 to 0.01 mol, per 1 mol of compound (I).
  • the crystals obtained above can be isolated by filtration, washed if necessary, and dried according to the usual procedure.
  • the solvent used for washing the crystals the same solvent as used in the crystallization can be used.
  • the alcoholate of compound (I) can be obtained as crystals, it can be easily handled as a medicine. In addition, all of the alcoholates of compound (I) have lower hygroscopicity than the amorphous form of compound (I), and are good as pharmaceuticals in terms of quality control. Therefore, according to the present invention, an alcoholate of compound (I) which is useful as a drug substance can be provided.
  • the pharmaceutical composition according to one embodiment of the present invention can be prepared by mixing a pharmaceutically acceptable additive with an alcoholate of compound (I) or a crystal thereof.
  • the pharmaceutical composition of the present invention can be prepared by a known method, for example, the method described in the general rules for preparation of the 17th edition of the Japanese Pharmacopoeia.
  • the present invention includes a mixture with the compound (I) in an amorphous form as long as it contains an alcoholate of the compound (I) or a crystal thereof in an arbitrary ratio.
  • the content of the alcoholate of the compound (I) or the crystal thereof in the active ingredient is preferably 20% or more, more preferably 30% or more, further preferably 40% or more, and 100%. Is most preferable.
  • the alcoholate of the compound (I) of the present invention or a crystal thereof acts as a V2 receptor agonist, central diabetes insipidus, nocturnal enuresis, nocturia, overactive bladder, hemophilia, or von Wille It can be used as a medicine for the prevention or treatment of Brand's disease.
  • Compound (I) selectively acts on the V2 receptor and is therefore advantageous from the viewpoint of side effects.
  • the compound (I) has a lower inhibitory effect on the drug-metabolizing enzymes CYP3A4 and CYP2C9 than the conventionally known compounds having a V2 receptor agonistic action, and further has physical properties as a drug such as solubility and membrane permeability. Since it also has excellent properties in terms of surface and dynamic aspects such as plasma clearance and distribution volume, it can be used safely.
  • the amount of the alcohol solvate of the compound (I) of the present invention or its crystal contained as an active ingredient of a drug is not particularly limited and is appropriately selected from a wide range.
  • the dose of the alcohol solvate of Compound (I) or the crystal thereof is appropriately determined depending on the usage, the age of the patient, sex and other conditions, and the degree of the disease. Approximately 1 ⁇ g to 100 mg, preferably approximately 10 ⁇ g to 20 mg, and more preferably approximately 50 ⁇ g to 5 mg per kg, which can be appropriately administered in 1 to 4 divided doses per day. However, since the dose and frequency are determined in consideration of the degree of the condition to be treated, the selection of the compound to be administered and the relevant circumstances including the selected administration route, the above dose range and frequency are not limited to the above. It does not limit the scope of the invention.
  • Compound (I) produces metabolites as shown below when administered to a living body.
  • the powder X-ray diffraction measurement, thermogravimetric measurement, infrared absorption spectrum measurement, and water equilibrium measurement were performed under the following measurement conditions.
  • Thermogravimetric measurement The TGA thermogram was performed using Perkin Elmer (Pyris1-TGA). The measurement conditions were 20 mL/min of nitrogen gas, isothermal for 1 minute at an initial temperature of 80° C., then increased to 170° C. at 5° C./minute, and isothermal for 1 minute at 170° C.
  • the infrared absorption spectrum was measured using Perkin Elmer (Spectrum One). Measurement conditions, the measurement range 4000 ⁇ 400 cm -1, resolution 4.00 cm -1, scan number was 4 times.
  • the moisture equilibrium measurement was performed using TA Instruments (SGA-100).
  • the measurement conditions were a measurement temperature of 25° C., a maximum measurement time of 210 minutes, a water equilibrium weight of 0.005% by weight/5 minutes, and 50 to 95% RH from the start of humidification to the end point.
  • the drying conditions were a drying temperature of 60° C., a temperature rising rate of 5° C./minute, a maximum drying time of 60 minutes, and a water equilibrium weight of 0.01% by weight/2 minutes.
  • FIG. 7 shows the powder X-ray diffraction spectrum of the compound (I) obtained in the first to sixth steps. No clear peak was observed in the X-ray diffraction pattern, and the compound (I) of Reference Example 1 was found to be amorphous.
  • Example 1 Isopropanol solvate of compound (I) To 5.0 g of the amorphous compound (I) of Reference Example 1, 65 mL of isopropanol was added, and the mixture was stirred at room temperature for 30 minutes. The precipitated suspension was heated and dissolved, and then allowed to cool to room temperature and stirred overnight at 5°C. The suspension was filtered, washed with chilled isopropanol and dried overnight at 40° C. to give 4.9 g of a white solid.
  • the powder X-ray diffraction spectrum and infrared absorption spectrum of the compound obtained in Example 1 are shown in FIG. 1 and FIG. 2, respectively.
  • the characteristic peaks shown in Table 1 were shown as the diffraction angle (2 ⁇ ) or as the interplanar spacing d.
  • the obtained compound was crystalline.
  • Example 2 Ethanol solvate of compound (I) To 0.15 g of the amorphous compound (I) of Reference Example 1, 2 mL of ethanol was added, and the mixture was stirred at room temperature for 30 minutes. After the precipitated suspension was dissolved by heating, it was allowed to cool to room temperature and stirred at 5°C overnight. The suspension was filtered, washed with cold ethanol, and dried at 40° C. overnight to give white solid 0.07 g.
  • the powder X-ray diffraction spectrum and infrared absorption spectrum of the compound obtained in Example 2 are shown in FIG. 3 and FIG. 4, respectively.
  • the characteristic peaks shown in Table 2 were shown as the diffraction angle (2 ⁇ ) or as the interplanar spacing d.
  • the obtained compound was crystalline.
  • Example 3 Normal propanol solvate of compound (I) To 5.0 g of amorphous compound (I) of Reference Example 1, 31 mL of normal propanol was added, and the mixture was stirred at room temperature for 15 minutes. The precipitated suspension was heated and dissolved, and then allowed to cool to room temperature and stirred overnight at 5°C. The suspension was filtered, washed with cold normal propanol, and dried at 40° C. overnight to obtain 4.1 g of a white solid.
  • a powder X-ray diffraction spectrum and an infrared absorption spectrum of the compound obtained in Example 3 are shown in FIG. 5 and FIG. 6, respectively.
  • the characteristic peaks shown in Table 3 were shown as the diffraction angle (2 ⁇ ) or as the interplanar spacing d.
  • the obtained compound was crystalline.
  • Comparative compound 1 the compound represented by the above formula (II)
  • Example 93 of Patent Document 1 The compound described in Example 93 of Patent Document 1 (Comparative compound 1: the compound represented by the above formula (II)) was obtained by the production method described in Patent Document 1.
  • the solvent shown in Table 4 was added, and the mixture was stirred at room temperature, dissolved by heating, allowed to cool to room temperature, and allowed to stand at 5° C. overnight.
  • Example 72 of Patent Document 1 The compound described in Example 72 of Patent Document 1 (Comparative compound 2: compound represented by the above formula (III)) was obtained by the production method described in Patent Document 1.
  • the solvent shown in Table 5 was added to 10 mg of the obtained comparative compound 2, and the mixture was stirred at room temperature, dissolved by heating, allowed to cool to room temperature, and allowed to stand at 5° C. overnight. However, it was not possible to obtain a solvate of Comparative Compound 2 or a crystal thereof.
  • Test Example 1 Hygroscopicity Test The compound of Example 1 (isopropanol solvate of compound (I)), the compound of Example 2 (ethanol solvate of compound (I)), and the compound of Reference Example 1 (amorphous compound) The hygroscopicity of (I)) was compared under the following conditions.
  • a quartz sample holder was hooked on a balance, and about 10 mg of the compounds of Examples 1 and 2 and Reference Example 1 were put therein. After registering the sample mass, a test was carried out with a water balance measuring device to measure the rate of change of mass at each relative humidity.
  • Test Example 1 The results of Test Example 1 are shown in FIG. It was confirmed that the compounds of Examples 1 and 2 were less likely to absorb moisture and were excellent in storage stability as compared with the compound of Reference Example 1.
  • an alcoholate of an optically active benzazepine derivative represented by the formula (I) can be isolated as a crystal.

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Abstract

La présente invention concerne un alcoolate de (S)-N-[(S)-1-hydroxypropan-2-yl]-4-méthyl-1-[2-méthyl-4-(3-méthyl-1H-pyrazol-1-yl) benzoyl]-2,3,4,5-tétrahydro-1H-benzo[b]azépine-4-carboxamide représenté par la formule (I), ou un cristal de celui-ci, qui est utilisable en tant que principe actif d'un médicament pharmaceutique.
PCT/JP2020/006243 2019-02-19 2020-02-18 Alcoolate dérivé de benzazépine ou cristal de celui-ci WO2020171055A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014104209A1 (fr) * 2012-12-26 2014-07-03 株式会社 三和化学研究所 Nouveau dérivé de benzazépine et utilisation pharmaceutique associée

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014104209A1 (fr) * 2012-12-26 2014-07-03 株式会社 三和化学研究所 Nouveau dérivé de benzazépine et utilisation pharmaceutique associée

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"About standards for new drugs and setting of a test method", PHARMACEUTICAL AFFAIRS BUREAU NOTIFICATION NO. 568, 2001 *
GRIESSER, U. J.: "The Importance of Solvates", POLYMORPHISM: IN THE PHARMACEUTICAL INDUSTRY, 2006, pages 211 - 233, XP055582446 *

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