JPWO2018003980A1 - Crystal of acid addition salt of aminocarboxylic acid and method for producing the same - Google Patents

Abstract

The object of the present invention is to provide crystals of pharmacologically acceptable salts of bicyclic aminocarboxylic acid derivatives. The solution consists of crystals of [(1R, 5S, 6S) -6- (aminomethyl) -3-ethylbicyclo [3.2.0] hept-3-en-6-yl] acetic acid mono (benzenesulfonic acid) salt. is there.

Description

The present invention is a pharmacologically acceptable salt of a bicyclic aminocarboxylic acid derivative, which has an activity as an α ₂ δ ligand and has affinity for the α ₂ δ subunit of a voltage-gated calcium channel The present invention relates to a crystal of a pharmacologically acceptable salt and a process for producing the same.

So far, α ₂ δ ligands have been known as therapeutic agents for neuropathic pain, and examples of such α ₂ δ ligands include gabapentin, pregabalin and the like (Patent Documents 1-4).

In addition, the applicant is [(1R, 5S, 6S) -6- (aminomethyl) -3-ethylbicyclo [3.2.0], which is a pharmacologically acceptable salt having activity as an α ₂ δ ligand. Patent documents 5-7 are reported as hept-3-en-6-yl] acetic acid mono (benzenesulfonic acid) salt (salt (I) of the compound shown below) and a method for producing the same.

  In the industrialization of pharmaceuticals, a drug substance having stable quality and storage stability and capable of stably supplying a large amount is generally required for its production and development. Therefore, even in the industrialization of the salt (I) of the compound, a drug substance suitable therefor is required, and in order to obtain the drug substance, it is necessary to obtain crystals suitable for industrialization.

  The “crystal suitable for industrialization” means that a single crystal having a certain quality can be reproducibly obtained, and can be stably supplied as a crystal of a drug substance used for the preparation of a drug, and it is suitable for mass synthesis in industrial production. It is desirable to be a suitable crystal. Furthermore, it is desirable that the obtained crystals have low hygroscopicity and excellent light stability and therefore excellent storage stability.

US 2006/154929 US 2003/220397 US 2004/152779 US 2003/78300 US 2010/249229 US 2012/71685 US 2015/218123

  The object of the present invention is to provide novel crystals of the salt (I) of the compounds and a process for their preparation.

  As a result of intensive research conducted over many years to obtain novel crystals of the salt (I) of the compound, the present inventors have obtained several novel crystals by the method described in the specification. did it. The novel crystals of salt (I) of the compounds of the present invention are hereinafter described as "Form I crystals", "Form II crystals" and "Form III crystals".

The present invention relates to the following.
[1]
Crystals of [(1R, 5S, 6S) -6- (aminomethyl) -3-ethylbicyclo [3.2.0] hept-3-en-6-yl] acetic acid mono (benzenesulfonic acid) salt.
[2]
The crystal according to [1] (Form I crystal), having peaks at about 10.9, 17.1, 22.0, 24.0, 27.6, and 33.3 as diffraction angles (2θ (°)) in powder X-ray diffraction.
[3]
The crystal according to [1] according to [1], having peaks at about 5.46, 10.94, 17.14, 18.66, 22.02, 24.62, 28.86, 33.32, and 33.94 as diffraction angles (2θ (°)) in powder X-ray diffraction .
[Four]
The crystal (Form I crystal) according to [1], having an X-ray diffraction pattern shown in FIG.
[Five]
In thermogravimetry / differential thermal analysis, any of [1]-[4] crystals having endothermic peaks at around 140 ° C. and at around 185 ° C. and having a mass reduction to the melting temperature of less than 0-1% The crystal according to item 1 (Form I crystal).
[6]
The crystal according to [1] (Form II crystal) having peaks at about 16.3, 17.8, 18.6, 23.3, 23.7 and 24.7 as diffraction angles (2θ (°)) in powder X-ray diffraction.
[7]
The crystal according to [1] (Form II crystal), having peaks at about 5.32, 16.30, 17.40, 17.80, 18.60, 19.74, 20.90, 23.34, 23.66 and 24.72 as diffraction angles (2θ (°)) in powder X-ray diffraction.
[8]
The crystal (Form II crystal) according to [1], having an X-ray diffraction pattern shown in FIG.
[9]
In thermogravimetry / differential thermal analysis, it has an endothermic peak around 180 ° C., and the mass loss to the melting temperature is less than 0-1%, as described in any one of [1] or [6]-[8] Crystals (Form II crystals).
[Ten]
The crystal according to [1] (Form III crystal), having peaks at about 10.7, 21.5, 23.3, 27.0, 32.5, 33.8 and 38.2 as diffraction angles (2θ (°)) in powder X-ray diffraction.
[11]
The crystal according to [1], which has peaks at about 4.84, 5.34, 5.62, 5.90, 10.70, 21.52, 23.12, 27.00, 28.48, 32.54, 33.80 and 38.16 as diffraction angles (2θ (°)) in powder X-ray diffraction Form III crystal).
[12]
The crystal (Form III crystal) according to [1], having an X-ray diffraction pattern shown in FIG.
[13]
In thermogravimetry / differential thermal analysis, it has an endothermic peak near 180 ° C., and the mass loss to the melting temperature is less than 0-1%, as described in any one of [1] or [10]-[12] Crystals (Form III crystals).
[14]
The pharmaceutical composition which contains the crystal as described in any one of [1]-[13] as an active ingredient.
[15]
The pharmaceutical composition according to [14], which is a pharmaceutical composition for the treatment of pain.
[16]
The pharmaceutical composition according to [15], wherein the pain is neuropathic pain and / or pain associated with fibromyalgia.
[17]
The crystal according to any one of [1]-[13] for the treatment of pain.
[18]
A method of treating pain comprising administering to a patient an effective amount of the crystal according to any one of [1]-[13].

  According to the present invention, there are provided novel crystals of salt (I) of the compound and a process for their preparation.

1 shows a powder X-ray diffraction pattern of Form I crystals. The ordinate represents intensity (cps) and the abscissa represents a diffraction angle (2θ (°)). The characteristic peaks (2θ (°)), d values (Å) and relative intensities (%) of powder X-ray diffraction of Form I crystals are shown. The DTA profile and the TG profile of Form I crystals are shown. In the diagram of DTA, the vertical axis represents heat quantity (μV) and the horizontal axis represents temperature (° C.). The graph of TG shows weight change (%) on the vertical axis and temperature (° C.) on the horizontal axis. Elemental analysis values of Form I crystals are shown. 1 shows a powder X-ray diffraction pattern of Form II crystals. The ordinate represents intensity (cps) and the abscissa represents a diffraction angle (2θ (°)). The characteristic peak (2θ (°)), d value (Å) and relative intensity (%) of powder X-ray diffraction of Form II crystals are shown. The DTA profile and the TG profile of Form II crystals are shown. In the diagram of DTA, the vertical axis represents heat quantity (μV) and the horizontal axis represents temperature (° C.). The graph of TG shows weight change (%) on the vertical axis and temperature (° C.) on the horizontal axis. Elemental analysis values of Form II crystals are shown. 1 shows a powder X-ray diffraction pattern of Form III crystals. The ordinate represents intensity (cps) and the abscissa represents a diffraction angle (2θ (°)). The characteristic peaks (2θ (°)), d values (Å) and relative intensities (%) of powder X-ray diffraction of Form III crystals are shown. The DTA profile and the TG profile of Form III crystals are shown. In the diagram of DTA, the vertical axis represents heat quantity (μV) and the horizontal axis represents temperature (° C.). The graph of TG shows weight change (%) on the vertical axis and temperature (° C.) on the horizontal axis. The elemental analysis value of Form III crystal is shown.

  Hereinafter, the present invention will be described in detail.

  The salt (I) of the compound is [(1R, 5S, 6S) -6- (aminomethyl) -3-ethylbicyclo [3.2.0] hept-3-en-6-yl] acetic acid (benzenesulfonic acid) It is a salt and is described in Patent Documents 5-7 and the like, and its use as a therapeutic drug for neuropathic pain is expected.

  The "Form I crystals", "Form II crystals" and "Form III crystals" of the salt (I) of the compound of the present invention are reproducible as single crystals having a certain quality under certain controllable conditions. It is obtained well. In addition, these crystals can be stably supplied, and are crystals suitable for industrialization of the salt (I) of the compound.

[Form I crystal]
It is a crystal having peaks at about 10.9, 17.1, 22.0, 24.0, 27.6, and 33.3 as diffraction angles (2θ (°)) of powder X-ray diffraction obtained using Cu-Kα rays, preferably The crystals have peaks at about 5.46, 10.94, 17.14, 18.66, 22.02, 24.02, 27.64, 28.86, 33.32, and 33.94.

  In thermogravimetry / differential thermal analysis, it is a crystal showing an endothermic peak attributable to crystal conversion to Form II at around 140 ° C. and an endothermic peak at around 185 ° C. due to melting and subsequent decomposition. It is a crystal which shows no mass loss up to the melting temperature, or as little as 1%.

(Method of manufacturing Form I crystal)
[(1R, 5S, 6S) -6- (aminomethyl) -3-ethylbicyclo [3,2,0] hept-3-en-6-yl] acetic acid is suspended or dissolved in a solvent. As the solvent in this case, t-butyl methyl ether, acetone, water, acetonitrile, anisole, acetic acid or the like, or a mixed solvent thereof is used. More preferred solvents include anisole.

  Benzene sulfone slowly into a suspension or solution of [(1R, 5S, 6S) -6- (aminomethyl) -3-ethylbicyclo [3,2,0] hept-3-en-6-yl] acetic acid Add the acid solution. As the solvent in this case, t-butyl methyl ether, acetone, water, acetonitrile, anisole, acetic acid or the like, or a mixed solvent thereof is used. More preferred solvents include anisole.

  The equivalent weight of benzenesulfonic acid added is, relative to [(1R, 5S, 6S) -6- (aminomethyl) -3-ethylbicyclo [3,2,0] hept-3-en-6-yl] acetic acid: 1.00-1.1 is preferable, and 1.02-1.06 is more preferable.

  In addition, if necessary, add solvent and continue stirring.

  Furthermore, if necessary, reduce the temperature and continue stirring.

  The precipitated crystals are separated by filtration, washed with a solvent and dried under reduced pressure to obtain crystals.

[Form II crystal]
Crystals having peaks at about 16.3, 17.8, 18.6, 23.3, 23.7 and 24.7 as a diffraction angle (2θ (°)) of powder X-ray diffraction obtained using Cu-Kα radiation, preferably about 5.32, It is a crystal having peaks at 16.30, 17.40, 17.80, 18.60, 19.74, 20.90, 23.34, 23.66 and 24.72.

  In thermogravimetry / differential thermal analysis, it is a crystal that exhibits an endothermic peak at around 180 ° C. due to melting and decomposition that occurs subsequently to melting. The mass loss up to the melting temperature was about 0.3%, which indicated that Form II crystals were non-solvate.

(Method of producing Form II crystal)
The Form I crystals obtained in Example 1 are heated to about 140 ° C. to 185 ° C. to obtain Form II crystals. Preferably, the temperature is gradually raised from room temperature to about 160 ° C. to 185 ° C. More preferably, heating is performed at about 10 ° C./min to about 180 ° C. Thereafter, the temperature is returned to room temperature to obtain Form II crystals. The heating method is not particularly limited, but preferably, the heating operation is performed using a differential scanning calorimeter (DSC).

[Form III crystal]
It is a crystal having peaks at about 10.7, 21.5, 23.3, 27.0, 32.5, 33.8 and 38.2 as diffraction angles (2θ (°)) of powder X-ray diffraction obtained using Cu-Kα rays, preferably Crystals having peaks at about 4.84, 5.34, 5.62, 5.90, 10.70, 21.52, 23.32, 27.00, 28.48, 32.54, 33.80 and 38.16.

  In thermogravimetry / differential thermal analysis, it is a crystal showing an endothermic peak at about 180 ° C. due to melting and subsequent decomposition. The mass reduction to the melting temperature was about 0.4%, and it was supported that Form III was a non-solvate.

(Method of manufacturing Form III crystal)
The Form I crystals obtained in Example 1 are lyophilized as an aqueous solution. The concentration of the aqueous solution is not particularly limited, but preferably about 10 mg / mL.

As for the lyophilization conditions, after pre-drying below the melting temperature, it is sufficiently dried near room temperature. After drying desirably at a low temperature, it is dried while gradually raising the temperature, and finally it is sufficiently dried above room temperature.
For example, by gradually raising the temperature little by little with -40 ° C for 600 minutes, -20 ° C for 1200 minutes, -5 ° C for 1200 minutes and finally leaving at about 25 ° C to -30 ° C for about 1440 minutes or more , Form III crystals are obtained.

  In the present specification, unless otherwise stated, values of powder X-ray diffraction analysis are values obtained using Cu-Kα radiation. When X-rays other than Cu-Kα rays are used, 2θ (°) varies according to the equation 2d sin θ = nλ (d is the distance between two surfaces, n is an arbitrary integer, λ is the wavelength of X-rays) However, these are merely expressions of the crystals of the present invention by substantially equivalent alternative expression methods and are included in the scope of the present invention, which can be easily understood by those skilled in the crystal arts. Also, the relative intensities of the peaks shown by these charts may vary depending on, for example, the degree of crystallization of the sample or the method of preparation. 2θ (°) does not vary substantially, but can vary within an error range (generally ± 0.2 ° range) recognized by those skilled in the crystal arts. In the characteristic peak of powder X-ray diffraction represented by the angle 2θ, “about” indicates ± 0.2 °, and in another embodiment ± 0.1 °.

  Due to the nature of the data, the value of powder X-ray diffraction analysis indicates the crystal lattice spacing and the overall pattern in determining the identity of crystals, and the relative strength depends somewhat on the direction of crystal growth, particle size, and measurement conditions. Because it is a variable, it should not be interpreted strictly.

  In the endothermic peak in thermogravimetry / differential thermal analysis, “in the vicinity” means ± 5 ° C., and in another embodiment means ± 2 ° C. For example, the endothermic peak of Form III crystals means around 180 ° C., ie 175-185 ° C.

  In mass reduction to melting temperature in thermogravimetry / differential thermal analysis, "degree" means ± 0.05%. For example, the mass loss of Form III crystals to the melting temperature is about 0.4%, which means 0.35 to 0.45%.

  Each crystal can be concluded also in the results of thermogravimetry / differential thermal analysis, but it should not be understood exactly because it may be somewhat changed by the measuring equipment, heating rate and data analysis.

  Further, the present invention relates to "Form I crystal", "Form II crystal" and "Form III crystal" of the salt (I) of pure compound, but "Form I crystal" and "Form II crystal" of compound salt (I) And mixtures of "Form III crystals" are also encompassed by the present invention.

(Formulation example 1)
FormI crystals (4.39 mg), mannitol (83.51 mg), carmellose calcium (10 mg), magnesium stearate (10.7 mg), a coating agent (appropriate amount), and coated tablets are manufactured according to a known method.

(Formulation example 2)
Form II crystals (4.39 mg), mannitol (83.51 mg), carmellose calcium (10 mg), magnesium stearate (10.7 mg), a coating agent (appropriate amount), and coated tablets are manufactured according to a known method.

(Formulation example 3)
Coated tablets are prepared according to known methods, FormIII crystals (4.39 mg), mannitol (83.51 mg), carmellose calcium (10 mg), magnesium stearate (10.7 mg), a coating agent (appropriate amount).

  The invention also relates to a pharmaceutical composition comprising the crystals of the invention. The pharmaceutical composition of the present invention partially comprises at least Form I crystals, Form II crystals or Form III crystals.

  For example, when Form I crystals are contained in the pharmaceutical composition, crystal forms (eg, Form II crystals and / or Form III) other than Form I crystals may be present. The proportion of Form I crystals contained in the pharmaceutical composition is in the range of 0.01% by weight to 99.9% by weight, for example, 0.01% by weight or more, 0.1% by weight or more, with respect to the entire active ingredient contained in the pharmaceutical composition. 1 wt% or more, 10 wt% or more, 50 wt% or more, 90 wt% or more, 95 wt% or more, 98 wt% or more, 99 wt% or more, 99.5 wt% or more, 99.6 wt% or more, 99.7 wt% or more, 99.8 wt% or more or 99.9 wt% or more may be contained. Whether Form I crystals are included in the pharmaceutical composition can be confirmed by the instrumental analysis method (eg, powder X-ray diffraction, thermal analysis, etc.) described herein.

  The medicament comprising the crystal of the present invention as an active ingredient is preferably provided in the form of a pharmaceutical composition comprising the crystal of the present invention and one or more pharmaceutically acceptable carriers. The administration form of the medicament of the present invention is not particularly limited and can be administered orally or parenterally, but is preferably administered orally.

  As the pharmaceutically acceptable carrier used for the production of the above-mentioned pharmaceutical composition, for example, excipients, disintegrants or disintegrants, binders, lubricants, coatings, dyes, diluents, bases, There may be mentioned, but not limited to, solubilizers or solubilizers, tonicity agents, pH adjusters, stabilizers, propellants or adhesives.

  Examples of preparations suitable for oral administration include tablets, powders, granules, capsules, solutions, syrups, elixirs, oily and aqueous suspensions, and the like. In addition, as preparations suitable for parenteral administration, for example, injections, drops, suppositories, inhalants or patches can be mentioned.

  The dosage of the crystal of the present invention is not particularly limited, and can be appropriately selected according to various conditions such as the patient's age, body weight, symptoms, etc. For example, the following administration methods can be considered.

  When used for the treatment of neuropathic pain and pain associated with fibromyalgia, the active ingredient (as a free form) is usually divided into 1-50 mg twice daily as an initial dose for adults. After oral administration, the dose is gradually increased to about 5-50 mg as a daily dose over one week. The dosage may be adjusted according to the age and symptoms, but the daily maximum dose does not exceed a certain level.

  Examples are described below, but the present invention is not limited thereto.

  The following shows the equipment used for various analyzes and measurements and their conditions.

X-ray diffraction measurement (XRD, X-ray diffraction)
Equipment used for measurement: Rigaku Corporation RINT TTR-III
X-ray source: CuKα
Method: Reflection method Tube voltage: 50 kV
Tube current: 300 mA
Scanning range: 2 ° -40 °
Scanning speed: 2 ° / min
Sampling width: 0.02 °
Rotation speed: 120 rpm
Sample amount: about 10 mg

Thermogravimetry / differential thermal analysis (TG / DTA, Thermo Gravimetry / Differential Thermal Analysis)
Equipment used for measurement: TG / DTA6200 manufactured by Hitachi High-Tech Science Co., Ltd.
Measurement temperature range: 30 ° C-250 ° C
Heating rate: 10 ° C / min
Atmosphere gas: Nitrogen Nitrogen gas flow rate: 200 mL / min
Sample amount: 3-5 mg

Elemental analysis Equipment used for measurement
CHN: J Science Lab Co., Ltd. Elemental analyzer JM10
S: Thermo Fisher Scientific Co., Ltd. Dionex ICS-1500

Example 1 Preparation of Form I Crystals
[(1R, 5S, 6S) -6- (aminomethyl) -3-ethylbicyclo [3,2,0] hept-3-en-6-yl] acetic acid (8.0 g, 38.2 mmol) in anisole (156 mL) To which benzenesulfonic acid (6.29 g, 39.78 mmol) dissolved in anisole (20 mL) was added dropwise over 2 hours.

  After adding anisole (8 mL) to this suspension, it stirred at room temperature for 1.5 hours. Acetone (40 mL) was added, and the mixture was further stirred for 1.5 hours, and then cooled to 2 ° C. The suspension was filtered, and the filtered solid was washed with cold acetone (28 mL) and dried under reduced pressure to obtain the target crystals (13.16 g, 93.7% (target HPLC area% 99.89%)).

Example 2 Preparation of Form II Crystal The Form I crystal (694. 345 mg) obtained in Example 1 is divided into a plurality of times (20 to 30 mg each), and the following is obtained using a differential scanning calorimeter (DSC): After heating with the temperature program, the temperature was returned to room temperature. The obtained Form II crystals were collectively sieved using No. 100 sieve (671.74 mg, yield: 96.7%).
Equipment used: Hitachi High-Tech Science DSC 6220
Start temperature: 25 ° C, end temperature: 180 ° C, temperature rise rate: 10 ° C / min, hold: 0 min

Example 3 Preparation of Form III Crystals About 80 mL of water was added to the Form I crystals (800.13 mg) obtained in Example 1 to dissolve. The solution was poured into 16 glass bottles. After prefreezing, it was lyophilized according to the following temperature program to obtain Form III crystals (744.81 mg, yield: 93.1%).
1) -40 ° C: 600 minutes
2) -20 ° C: 1200 minutes
3) -5 ° C: 1200 minutes
4) Final temperature (25 ° C-30 ° C) 1440 minutes or more

Claims (18)

Crystals of [(1R, 5S, 6S) -6- (aminomethyl) -3-ethylbicyclo [3.2.0] hept-3-en-6-yl] acetic acid mono (benzenesulfonic acid) salt. The crystal according to claim 1, which has peaks at about 10.9, 17.1, 22.0, 24.0, 27.6, and 33.3 as diffraction angles (2θ (°)) in powder X-ray diffraction (Form I crystal). The crystal according to claim 1, having peaks at about 5.46, 10.94, 17.14, 18.66, 22.02, 24.64, 28.86, 33.32, and 33.94 as diffraction angles (2θ (°)) in powder X-ray diffraction. . The crystal according to claim 1 (Form I crystal) having an X-ray diffraction pattern shown in FIG. The crystal according to any one of claims 1 to 4, which is a crystal having endothermic peaks at around 140 ° C and at around 185 ° C in thermogravimetric / differential thermal analysis and having a mass reduction to the melting temperature of less than 1%. Crystal (Form I crystal). The crystal according to claim 1, having peaks at about 16.3, 17.8, 18.6, 23.3, 23.7 and 24.7 as diffraction angles (2θ (°)) in powder X-ray diffraction. The crystal according to claim 1, having peaks at about 5.32, 16.30, 17.40, 17.80, 18.60, 19.74, 20.90, 23.34, 23.66, and 24.72 as diffraction angles (2θ (°)) in powder X-ray diffraction. The crystal according to claim 1 (Form II crystal) having an X-ray diffraction pattern shown in FIG. The crystal according to any one of claims 1 or 6-8, having an endothermic peak at around 180 ° C in thermogravimetry / differential thermal analysis and having a mass reduction to the melting temperature of less than 1%. . The crystal according to claim 1, which has peaks at about 10.7, 21.5, 23.3, 27.0, 32.5, 33.8 and 38.2 as diffraction angles (2θ (°)) in powder X-ray diffraction. The crystal according to claim 1 having peaks at about 4.84, 5. 34, 5.62, 5. 90, 10. 70, 21. 52, 23. 12, 27.00, 28. 48, 32. 54, 33. 80 and 38. 16 as diffraction angles (2θ (°)) in powder X-ray diffraction. Form III crystal). The crystal (Form III crystal) according to claim 1 having an X-ray diffraction pattern shown in FIG. The crystal according to any one of claims 1 or 10-12, having an endothermic peak at around 180 ° C in thermogravimetry / differential thermal analysis and having a mass reduction to the melting temperature of less than 1%. . A pharmaceutical composition comprising the crystal according to any one of claims 1 to 13 as an active ingredient. The pharmaceutical composition according to claim 14, which is a pharmaceutical composition for the treatment of pain. The pharmaceutical composition according to claim 15, wherein the pain is neuropathic pain and / or pain associated with fibromyalgia. 14. A crystal according to any one of claims 1-13 for use in the treatment of pain. A method of treating pain comprising administering to a patient an effective amount of the crystal according to any one of claims 1-13.