WO2015163447A1 - 4環性化合物の新規結晶 - Google Patents
4環性化合物の新規結晶 Download PDFInfo
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- WO2015163447A1 WO2015163447A1 PCT/JP2015/062516 JP2015062516W WO2015163447A1 WO 2015163447 A1 WO2015163447 A1 WO 2015163447A1 JP 2015062516 W JP2015062516 W JP 2015062516W WO 2015163447 A1 WO2015163447 A1 WO 2015163447A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- 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
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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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the present invention relates to a novel crystal of a tetracyclic compound or a salt or hydrate thereof.
- Anaplastic Lymphoma Kinase is one of receptor tyrosine kinases belonging to the insulin receptor family (Non-patent Document 1, Non-patent Document 2).
- ALK gene abnormalities have been reported to cause the generation of abnormal kinases fused to other genes.
- cancer and cancer metastasis Non-patent Document 1, Patent Document 1,
- depression depression
- cognitive dysfunction Non-patent Document 2
- an ALK inhibitor is provided. Provides effective therapeutic and preventive drugs for those diseases.
- JP2009100783 (A) JP 2008-280352 A Japanese Patent No. 4588121 Japanese Patent No. 4918630 JP2012-126711
- the compound represented by the formula (I) is known to have ALK inhibitory activity, but a new crystal that is pharmaceutically useful has been demanded.
- crystals (1) to (5) are provided.
- novel crystal according to the present invention may be useful for pharmaceutical purposes.
- the type II crystal of monohydrochloride of the compound of formula (I) according to the present invention can be obtained by drying the type III crystal described below at about 40 ° C. under reduced pressure.
- Type II crystals have a diffraction angle (2 ⁇ ) of 9.2 °, 10.2 °, 16.2 °, 20.5 ° and 21.6 ° in the powder X-ray diffraction pattern, more specifically, It has peaks at diffraction angles (2 ⁇ ) of 9.2 °, 10.2 °, 16.2 °, 17.5 °, 19.5 °, 20.5 °, 21.6 ° and 22.8 °. It is characterized by.
- An example of the measurement result of the powder X-ray diffraction of the type II crystal is shown in FIG. 1, and an example of the peak in the powder X-ray diffraction pattern is shown in Table 1.
- the type II crystal is a monohydrate.
- the monohydrate is not particularly limited as long as it is a crystal that stably holds about 1 equivalent of water in an environment (temperature, relative humidity, etc.) in which a pharmaceutical is normally stored and used.
- the monohydrochloride type III crystal of the compound of formula (I) according to the present invention is obtained by mixing a solution containing the compound of formula (I) with a mixture of ethanol and hydrochloric acid (1 equivalent or more of the compound of formula (I) It can be obtained by adding dropwise to a solution containing hydrochloric acid while keeping the temperature of the mixture at around 15 ° C.
- Type III crystals have diffraction angles (2 ⁇ ) of 12.7 °, 14.3 °, 15.0 °, 18.5 ° and 25.7 ° in the powder X-ray diffraction pattern, more specifically 7 It has peaks at diffraction angles (2 ⁇ ) of .5 °, 12.7 °, 14.3 °, 15.0 °, 18.5 °, 20.3 °, 21.0 ° and 25.7 °.
- An example of the powder X-ray diffraction measurement result of the type III crystal is shown in FIG. 2, and an example of the peak in the powder X-ray diffraction pattern is shown in Table 2.
- analysis by powder X-ray diffraction can be performed according to a conventional method such as “powder X-ray diffraction measurement method” described in Japanese Pharmacopoeia (15th revision), for example.
- Japanese Pharmacopoeia it is generally explained that the diffraction angle 2 ⁇ coincides within a range of ⁇ 0.2 degrees in the same crystal form. Therefore, the present invention includes not only crystals in which the diffraction angle of the peak in powder X-ray diffraction completely matches but also crystals in which the diffraction angle of the peak matches with an error of about ⁇ 0.2 degrees.
- the moisture content of the crystal can be measured by a conventional method, for example, a dynamic moisture adsorption temperature apparatus or the Karl Fischer method.
- a dynamic moisture adsorption temperature apparatus An example of the measurement conditions of the dynamic moisture adsorption temperature apparatus is shown below: Dynamic moisture adsorption isotherm: DVS-1 (Surface Measurement Systems) Temperature: Constant temperature around 25 ° C.
- Atmospheric gas Dry nitrogen Atmospheric gas flow rate: 200 sccm (mL / min) Minimum waiting time: 10 min Maximum waiting time: 1200 min
- Analytical method coulometric titration method
- KF analyzer Trace moisture analyzer Model KF-100 (Mitsubishi Chemical Corporation)
- Anolyte Aquamicron AX (Mitsubishi Chemical)
- Catholyte Aquamicron CXU (Mitsubishi Chemical).
- the present inventors further identified a crystal of the compound of the above formula (II) (hereinafter referred to as “I-type crystal”) different from the II-type crystal and the III-type crystal.
- I-type crystal a crystal of the compound of the above formula (II)
- a solution containing the compound of formula (I) is transferred to a mixture of ethanol and hydrochloric acid (containing 1 molar equivalent or more of hydrochloric acid with respect to the compound of formula (I)), and the temperature of the mixture is about 35 ° C. It can be obtained by dripping while keeping.
- Type I crystals are characterized by having peaks at diffraction angles (2 ⁇ ) of 8.4 °, 14.0 °, 16.7 °, 18.8 ° and 23.3 ° in the powder X-ray diffraction pattern. To do.
- An example of the measurement result of the powder X-ray diffraction of the type I crystal is shown in FIG. 3, and an example of the peak in the powder X-ray
- the compound represented by the formula (I) and its hydrochloride can be produced according to the methods described in Patent Documents 3 to 5, but are not limited thereto.
- Example 3 9-ethyl-6,6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo-6,11-dihydro-5H-benzo [b] carbazole-3-carbonitrile
- Type II crystal of monohydrochloride The type III crystal obtained in Example 2 was washed with ethanol (90 ml) and dried under reduced pressure at 40 ° C. for about 16 hours to give the type II crystal of monohydrochloride of the title compound.
- This solution was added dropwise to a mixed solution (stirred at 15 ° C.) of ethanol (40 ml) and 2N hydrochloric acid (8.00 ml) while maintaining the mixed solution temperature at 15 ° C.
- a mixed solvent of methyl ethyl ketone (8.00 ml), distilled water (2.80 ml), and acetic acid (2.40 ml) was added dropwise while keeping the temperature of the mixture at 15 ° C. Subsequently, the mixture was stirred at 15 ° C. The precipitated solid was collected by filtration, washed with ethanol (40 ml), and then dried under reduced pressure at 40 ° C. to give type II crystals of the monohydrochloride of the title compound (2.4805 g).
- This solution was added dropwise to a mixed solution (stirred at 15 ° C.) of ethanol (40 ml) and 2N hydrochloric acid (8.00 ml) while maintaining the mixed solution temperature at 15 ° C.
- a mixed solvent of methyl ethyl ketone (8.00 ml), distilled water (2.80 ml), and acetic acid (2.40 ml) was added dropwise while keeping the temperature of the mixture at 15 ° C. Subsequently, the mixture was stirred at 15 ° C. The precipitated solid was collected by filtration to obtain the monohydrochloride type III crystal (7.8435 g) of the title compound.
- Measuring device X'Pert-Pro MPD (manufactured by PANalytical) Counter cathode: Cu Tube voltage: 45kV Tube current: 40 mA Step width: 0.02 Scanning axis: 2 ⁇ Sampling time per step: 43 seconds Scan range: 3-40 °
- Test condition 1 (confirmation of crystal form transition of type II crystals under low humidity) Sample amount: Approximately 17mg Temperature: Constant temperature around 25 ° C. Atmospheric gas: Dry nitrogen Atmospheric gas flow rate: 200 sccm (mL / min) Mass change rate: 0.002 dm / dt (% / min) Relative humidity: The sample was placed under a relative humidity of 0% RH. Minimum waiting time: 10 min Maximum waiting time: 1200 min
- Test condition 2 (Confirmation of crystal form transition of type II crystals under high humidity) Sample amount: about 16mg Temperature: Constant temperature around 25 ° C. Atmospheric gas: Dry nitrogen Atmospheric gas flow rate: 200 sccm (mL / min) Mass change rate: 0.002 dm / dt (% / min) Relative humidity: The sample was placed under a relative humidity of 70% RH. Minimum waiting time: 10 min Maximum waiting time: 1200 min
- this crystal When this crystal was left in the air and powder X-ray diffraction was measured over time, it returned to the original type II crystal in the measurement after 4 hours. From this, it is considered that the type II crystal absorbs moisture in a high humidity environment (relative humidity of 65% RH or more) and becomes another crystal form having crystal water.
- a high humidity environment relative humidity of 65% RH or more
- Atmospheric gas Dry nitrogen Atmospheric gas flow rate: 200 sccm (mL / min) Minimum waiting time: 10 min Maximum waiting time: 1200 min Mass change rate: 0.002 dm / dt (% min), except for 5, 10, 15, 55, 60, 65% RH, 0.001 dm / dt (% min)
- Relative humidity 0, 5, 10, 15, 20, 30, 40, 50, 55, 60, 65, 70, 80, 90, 80, 70, 65, 60, 55, 50, 40, 30, 20, 15 , 10, 5, 0% RH in order. This was defined as 1 cycle and 3 cycles were performed.
- the measurement results are shown in FIG.
- the weight change rate (%) of the type II crystal is 3.7% in the range of 0% RH to 15% RH when the temperature environment is changed from 0% RH to 90% RH at around 25 ° C. , 0.05% in the range of 15% RH to 55% RH, 11% in the range of 55% RH to 65% RH, 0.04% in the range of 65% RH to 90% RH there were.
- the molecular weight is 537.0928. From the molecular weight and mass change rate (%), it is considered that type II crystals are monohydrochloride monohydrate, dehydrated and transferred to monohydrochloride when stored in an atmosphere of 0% RH. In addition, it is considered that the type II crystal absorbs moisture in a high humidity environment with a humidity of 65% RH or more and is transferred to monohydrochloride tetrahydrate.
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Abstract
Description
ALKの異常を伴う疾患として、例えばがんおよびがん転移(非特許文献1、特許文献1、)、うつ、認知機能障害(非特許文献2)等が知られており、ALK阻害剤の提供はそれらの疾患の有効な治療および予防薬を提供する。
ALK阻害作用を有する化合物として、式(I)により表わされる化合物(化合物名:9-エチル-6,6-ジメチル-8-(4-モルホリン-4-イル-ピペリジン-1-イル)-11-オキソ-6,11-ジヒドロ-5H-ベンゾ[b]カルバゾール-3-カルボニトリル)等が知られている(特許文献3、特許文献4、特許文献5)。
しかしながら、これまで、式(I)の結晶形態については報告されていなかった。
すなわち、本発明の1つの側面によれば、以下の(1)~(5)の結晶が提供される。
(1)粉末X線回折パターンにおいて、9.2°±0.2°、10.2°±0.2°、16.2°±0.2°、20.5°±0.2°、および21.6°±0.2°の回折角(2θ)にピークを有する、式(I)で表される化合物の一塩酸塩の結晶。
(2)粉末X線回折パターンにおいて、9.2°±0.2°、10.2°±0.2°、16.2°±0.2°、17.5°±0.2°、19.5°±0.2°、20.5°±0.2°、21.6°±0.2°、および22.8°±0.2°の回折角(2θ)にピークを有する(1)に記載の結晶。
(3)1水和物結晶である、(1)または(2)に記載の結晶。
(4)粉末X線回折パターンにおいて、12.7°±0.2°、14.3°±0.2°、15.0°±0.2°、18.5°±0.2°および25.7°±0.2°の回折角(2θ)にピークを有する、式(I)で表される化合物の一塩酸塩の結晶。
(5)粉末X線回折パターンにおいて、7.5°±0.2°、12.7°±0.2°、14.3°±0.2°、15.0°±0.2°、18.5°±0.2°、20.3°±0.2°、21.0°±0.2°および25.7°±0.2°の回折角(2θ)にピークを有する、(4)に記載の結晶。
II型結晶は、粉末X線回折パターンにおいて、9.2°、10.2°、16.2°、20.5°および21.6°の回折角(2θ)に、より具体的には、9.2°、10.2°、16.2°、17.5°、19.5°、20.5°、21.6°および22.8°の回折角(2θ)にピークを有することを特徴とする。II型結晶の粉末X線回折の測定結果の一例を図1に示し、粉末X線回折パターンにおけるピークの一例を表1に示す。
本発明に係る式(I)の化合物の一塩酸塩のIII型結晶は、式(I)の化合物を含む溶液を、エタノールおよび塩酸の混合液(式(I)の化合物に対し1当量以上の塩酸を含む)へ、混合液温度を15℃付近に保ちながら滴下することにより取得することができる。
III型結晶は、粉末X線回折パターンにおいて12.7°、14.3°、15.0°、18.5°および25.7°の回折角(2θ)に、より具体的には、7.5°、12.7°、14.3°、15.0°、18.5°、20.3°、21.0°および25.7°の回折角(2θ)にピークを有することを特徴とする。III型結晶の粉末X線回折の測定結果の一例を図2に示し、粉末X線回折パターンにおけるピークの一例を表2に示す。
測定装置:X’Pert-Pro MPD(PANalytical製)
対陰極:Cu
管電圧:45kV
管電流:40mA
ステップ幅:0.02
走査軸:2θ
ステップあたりのサンプリング時間:43秒
走査範囲:3~40°
動的水分吸着当温装置の測定条件の一例を以下に示す:
動的水分吸着等温装置:DVS-1(Surface Mesurement Systems)
温度:25℃付近の一定温度
雰囲気ガス:乾燥窒素
雰囲気ガスの流量:200sccm(mL/min)
最小待ち時間:10min
最大待ち時間:1200min
カールフィッシャー分析装置を用いた水分測定法の測定条件の一例を以下に示す:
分析法:電量滴定法、
KF分析装置:微量水分測定装置 型式KF-100(三菱化学社製)
陽極液:アクアミクロンAX(三菱化学製)
陰極液:アクアミクロンCXU(三菱化学製)。
9-エチル-6,6-ジメチル-8-(4-モルホリン-4-イル-ピペリジン-1-イル)-11-オキソ-6,11-ジヒドロ-5H-ベンゾ[b]カルバゾール-3-カルボニトリル一塩酸塩のI型結晶
9-エチル-6,6-ジメチル-8-(4-モルホリン-4-イル-ピペリジン-1-イル)-11-オキソ-6,11-ジヒドロ-5H-ベンゾ[b]カルバゾール-3-カルボニトリル400gをメチルエチルケトン4.8L、酢酸1.44Lおよび蒸留水1.68Lの混合溶媒に室温にて溶解しこの溶液をエタノール12Lおよび2N塩酸0.8Lの混合物中に60℃で滴下した。析出した固体を濾取しエタノール2Lで洗浄乾燥し標題の化合物の一塩酸塩のI型結晶357gを得た。
9-エチル-6,6-ジメチル-8-(4-モルホリン-4-イル-ピペリジン-1-イル)-11-オキソ-6,11-ジヒドロ-5H-ベンゾ[b]カルバゾール-3-カルボニトリル一塩酸塩のIII型結晶
9-エチル-6,6-ジメチル-8-(4-モルホリン-4-イル-ピペリジン-1-イル)-11-オキソ-6,11-ジヒドロ-5H-ベンゾ[b]カルバゾール-3-カルボニトリル(9.00g)をメチルエチルケトン(90ml)、蒸留水(31.5ml),および酢酸(27.0ml)の混合溶媒に溶解した。この溶液を、15℃にて撹拌したエタノール(90ml),および2N塩酸(18.00ml)の混合液へ、混合液温度を15℃に保ちながら滴下した。つづいて,メチルエチルケトン(18.00ml)、蒸留水(6.30ml),および酢酸(5.40ml)の混合溶媒にて洗いこみをした後,15℃にて攪拌した。析出した固体を濾取し,標題の化合物の一塩酸塩のIII型結晶を得た。
9-エチル-6,6-ジメチル-8-(4-モルホリン-4-イル-ピペリジン-1-イル)-11-オキソ-6,11-ジヒドロ-5H-ベンゾ[b]カルバゾール-3-カルボニトリル一塩酸塩のII型結晶
実施例2にて得られたIII型結晶を,エタノール(90ml)で洗浄した後に,40℃で約16時間減圧乾燥し、標題の化合物の一塩酸塩のII型結晶を得た。
9-エチル-6,6-ジメチル-8-(4-モルホリン-4-イル-ピペリジン-1-イル)-11-オキソ-6,11-ジヒドロ-5H-ベンゾ[b]カルバゾール-3-カルボニトリル一塩酸塩のII型結晶
9-エチル-6,6-ジメチル-8-(4-モルホリン-4-イル-ピペリジン-1-イル)-11-オキソ-6,11-ジヒドロ-5H-ベンゾ[b]カルバゾール-3-カルボニトリル(4.00g)をメチルエチルケトン(40ml)、蒸留水(14ml),および酢酸(12ml)の混合溶媒に加え,35℃にて溶解した。この溶液を、エタノール(40ml),および2N塩酸(8.00ml)の混合液(15℃にて撹拌)へ、混合液温度を15℃に保ちながら滴下した。この混合液に、さらにメチルエチルケトン(8.00ml)、蒸留水(2.80ml),および酢酸(2.40ml)の混合溶媒を,混合液温度を15℃に保ちながら滴下した。つづいて,混合液を15℃にて攪拌した。析出した固体を濾取し,エタノール(40ml)で洗浄した後に,40℃で減圧乾燥し、標題の化合物の一塩酸塩のII型結晶(2.4805g)を得た。
9-エチル-6,6-ジメチル-8-(4-モルホリン-4-イル-ピペリジン-1-イル)-11-オキソ-6,11-ジヒドロ-5H-ベンゾ[b]カルバゾール-3-カルボニトリル一塩酸塩のIII型結晶
9-エチル-6,6-ジメチル-8-(4-モルホリン-4-イル-ピペリジン-1-イル)-11-オキソ-6,11-ジヒドロ-5H-ベンゾ[b]カルバゾール-3-カルボニトリル(4.00g)をメチルエチルケトン(40ml)、蒸留水(14ml),および酢酸(12ml)の混合溶媒に加え,35℃にて溶解した。この溶液を、エタノール(40ml),および2N塩酸(8.00ml)の混合液(15℃にて撹拌)へ、混合液温度を15℃に保ちながら滴下した。メチルエチルケトン(8.00ml)、蒸留水(2.80ml),および酢酸(2.40ml)の混合溶媒を,混合液温度を15℃に保ちながら滴下した。つづいて,混合液を15℃にて攪拌した。析出した固体を濾取し,標題の化合物の一塩酸塩のIII型結晶(7.8435g)を得た。
9-エチル-6,6-ジメチル-8-(4-モルホリン-4-イル-ピペリジン-1-イル)-11-オキソ-6,11-ジヒドロ-5H-ベンゾ[b]カルバゾール-3-カルボニトリル一塩酸塩のI型、II型、III型結晶について粉末X線回折を以下の条件により測定した。II型結晶、III型結晶、I型結晶の測定結果を図1、2、3に示す。
測定装置:X’Pert-Pro MPD(PANalytical製)
対陰極:Cu
管電圧:45kV
管電流:40mA
ステップ幅:0.02
走査軸:2θ
ステップあたりのサンプリング時間:43秒
走査範囲:3~40°
9-エチル-6,6-ジメチル-8-(4-モルホリン-4-イル-ピペリジン-1-イル)-11-オキソ-6,11-ジヒドロ-5H-ベンゾ[b]カルバゾール-3-カルボニトリル一塩酸塩のII型結晶について湿度による結晶形転移の確認のために以下の湿度条件に試料を設置し、粉末X線回折を用いて結晶形の変化を確認した。
試料量:約17mg
温度:25℃付近の一定温度
雰囲気ガス:乾燥窒素
雰囲気ガスの流量:200sccm(mL/min)
質量変化率:0.002dm/dt(%/min)
相対湿度:0%RHの相対湿度下に試料を設置した。
最小待ち時間:10min
最大待ち時間:1200min
試料量:約16mg
温度:25℃付近の一定温度
雰囲気ガス:乾燥窒素
雰囲気ガスの流量:200sccm(mL/min)
質量変化率:0.002dm/dt(%/min)
相対湿度:70%RHの相対湿度下に試料を設置した。
最小待ち時間:10min
最大待ち時間:1200min
II型結晶を70%RHで保管したところ、II型結晶の粉末X線回折パターンとは異なる粉末X線回折パターン(図5)を示したことから、II型結晶を高湿度下に保管すると別の結晶形へ転移することが明らかとなった。この結晶を空気中に放置し、経時的に粉末X線回折を測定したところ、4時間後の測定では元のII型結晶へ戻った。このことから、II型結晶は高湿度環境(相対湿度65%RH以上)では吸湿し、結晶水を持つ別の結晶形になると考える。
9-エチル-6,6-ジメチル-8-(4-モルホリン-4-イル-ピペリジン-1-イル)-11-オキソ-6,11-ジヒドロ-5H-ベンゾ[b]カルバゾール-3-カルボニトリル一塩酸塩のII型結晶(約5mg)について、動的水分吸着等温装置:DVS-1(Surface Mesurement Systems)を用いて水分吸着等温線を以下の条件で測定した。
試験条件
温度:25℃付近の一定温度
雰囲気ガス:乾燥窒素
雰囲気ガスの流量:200sccm(mL/min)
最小待ち時間:10min
最大待ち時間:1200min
質量変化率:0.002dm/dt(%min)、ただし、5,10,15,55,60,65%RHでは0.001dm/dt(%min)
II型結晶を式(I)の化合物の1塩酸塩1水和物と仮定すると、分子量は537.0928となる。分子量及び質量変化率(%)から、II型結晶は1塩酸塩1水和物であり、0%RH雰囲気下に保存すると脱水し1塩酸塩に転移すると考える。また、II型結晶は、湿度65%RH以上の高湿度環境では吸湿し、1塩酸塩4水和物に転移すると考える。
Claims (5)
- 粉末X線回折パターンにおいて、9.2°±0.2°、10.2°±0.2°、16.2°±0.2°、17.5°±0.2°、19.5°±0.2°、20.5°±0.2°、21.6°±0.2°、および22.8°±0.2°の回折角(2θ)にピークを有する、請求項1に記載の結晶。
- 1水和物結晶である請求項1または2に記載の結晶。
- 粉末X線回折パターンにおいて、12.7°±0.2°、14.3°±0.2°、15.0°±0.2°、18.5°±0.2°、および25.7°±0.2°の回折角(2θ)にピークを有する、式(I)で表される化合物の一塩酸塩の結晶。
- 粉末X線回折パターンにおいて、7.5°±0.2°、12.7°±0.2°、14.3°±0.2°、15.0°±0.2°、18.5°±0.2°、20.3°±0.2°、21.0°±0.2°、および25.7±0.2°°の回折角(2θ)にピークを有する、請求項4に記載の結晶。
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EP15782464.0A EP3135671B1 (en) | 2014-04-25 | 2015-04-24 | Novel crystal of tetracyclic compound |
JP2016515222A JP6873698B2 (ja) | 2014-04-25 | 2015-04-24 | 4環性化合物の新規結晶 |
KR1020227009664A KR20220042486A (ko) | 2014-04-25 | 2015-04-24 | 4환성 화합물의 신규 결정 |
CA2946268A CA2946268A1 (en) | 2014-04-25 | 2015-04-24 | Crystal of tetracyclic compound |
MX2016013735A MX2016013735A (es) | 2014-04-25 | 2015-04-24 | Cristales novedosos de compuesto tetraciclico. |
RU2016146119A RU2016146119A (ru) | 2014-04-25 | 2015-04-24 | Новый кристалл тетрациклического соединения |
US15/126,045 US9714229B2 (en) | 2014-04-25 | 2015-04-24 | Crystal of tetracyclic compound |
CN201580020748.0A CN106458967A (zh) | 2014-04-25 | 2015-04-24 | 四环化合物的新结晶 |
KR1020167031032A KR20160142383A (ko) | 2014-04-25 | 2015-04-24 | 4환성 화합물의 신규 결정 |
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CN (2) | CN113416179A (ja) |
CA (1) | CA2946268A1 (ja) |
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WO2023161233A1 (en) | 2022-02-22 | 2023-08-31 | Synthon B.V. | Solid forms of alectinib and alectinib salts |
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WO2023161233A1 (en) | 2022-02-22 | 2023-08-31 | Synthon B.V. | Solid forms of alectinib and alectinib salts |
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US9714229B2 (en) | 2017-07-25 |
RU2016146119A (ru) | 2018-05-29 |
MX2016013735A (es) | 2017-03-09 |
EP3135671A4 (en) | 2017-11-22 |
CN106458967A (zh) | 2017-02-22 |
KR20160142383A (ko) | 2016-12-12 |
JPWO2015163447A1 (ja) | 2017-04-20 |
CN113416179A (zh) | 2021-09-21 |
JP6873698B2 (ja) | 2021-05-19 |
EP3135671B1 (en) | 2019-09-18 |
US20170081306A1 (en) | 2017-03-23 |
RU2016146119A3 (ja) | 2018-07-04 |
CA2946268A1 (en) | 2015-10-29 |
EP3135671A1 (en) | 2017-03-01 |
KR20220042486A (ko) | 2022-04-05 |
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