US20190276405A1

US20190276405A1 - Crystal of quinoline derivative

Info

Publication number: US20190276405A1
Application number: US16/302,553
Authority: US
Inventors: Donald John Daley; John Gary Montana; George Hynd; Mitsuru Teramoto; Takahiro Ito; Taro Tameyama
Original assignee: Teijin Pharma Ltd; GB001 Inc
Current assignee: Teijin Pharma Ltd; GB001 Inc
Priority date: 2016-05-16
Filing date: 2017-05-15
Publication date: 2019-09-12
Also published as: EP3476835A1; WO2017199903A1; BR112018073667A2; JP6906510B2; JPWO2017199903A1; RU2018144286A3; US20200017447A1; US10626089B2; AU2017267768A1; RU2018144286A; EP3476835A4; MX2018013764A; CA3025049A1; KR20190018643A; TW201808910A; CN109415323A

Abstract

Crystals of [8-chloro-3-(4-chlorobenzyl)-4-difluoromethoxy-2-ethylquinolin-5-yloxy]acetic acid L-lysine salt, i.e., a crystal A which has peaks at diffraction angles 2θ=6.0°, 10.0°, 10.7°, 12.1°, 18.4°, 19.2° and 20.1° in powder X-ray diffraction spectra and a crystal B which has peaks at diffraction angles 2θ=6.0°, 11.7°, 12.4°, 15.2°, 16.4°, 20.3° and 22.6° in powder X-ray diffraction spectra. These crystals are chemically stable and have excellent thermal stability and physical properties, and are therefore suitable as medicinal substances.

Description

TECHNICAL FIELD

The present invention relates to crystals of [8-chloro-3-(4-chlorobenzyl)-4-difluoromethoxy-2-ethylquinolin-5-yloxy]acetic acid L-lysine salt.

BACKGROUND TECHNOLOGY

The compound [8-chloro-3-(4-chlorobenzyl)-4-difluoro-methoxy-2-ethylquinolin-5-yloxy]acetic acid is described in example 39 of patent citation 1. Patent citation 1 also states that this compound is useful in the treatment and prevention of diseases in which CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) receptors participate, such as bronchial asthma, chronic obstructive pulmonary disease, allergic airway syndrome, bronchitis, cystic fibrosis, emphysema, rhinitis, etc., and psoriasis, atopic and nonatopic dermatitis, Crohn's disease, ulcerative colitis, and irritable bowel disease, etc.
From that described in patent citation 1 and technical common sense, it can also be understood that this compound is useful in the treatment and prevention of perennial allergic rhinitis, seasonal allergic rhinitis, chronic eosinophilic rhinosinusitis, chronic noneosinophilic rhinosinusitis, chronic spontaneous urticaria, and eosinophilic gastrointestinal disease.
However, patent citation 1 does not mention crystals of [8-chloro-3-(4-chlorobenzyl)-4-difluoromethoxy-2-ethylquinolin-5-yloxy]acetic acid or of the L-lysine salt thereof.

CITATIONS OF THE PRIOR ART

Patent Citations

Patent citation 1: International patent publication WO2007/036743

SUMMARY OF THE INVENTION

Problem to be Solved by the Invention

The aim of the present invention is to provide crystals of [8-chloro-3-(4-chlorobenzyl)-4-difluoromethoxy-2-ethylquinolin-5-yloxy]acetic acid that are chemically stable and suitable as a pharmaceutical drug substance.

Means of Solving the Problem

As a result of diligent research into achieving the abovementioned aim, the present inventors discovered that [8-chloro-3-(4-chlorobenzyl)-4-difluoromethoxy-2-ethylquinolin-5-yloxy]acetic acid L-lysine salt (hereafter also referred to as “compound (I)”) can be crystallized, and that it has at least two crystal polymorphs. Also, they arrived at the present invention upon discovering that the resulting crystals have a higher melting point, better thermal stability and physical properties than the free form of [8-chloro-3-(4-chlorobenzyl)-4-difluoromethoxy-2-ethylquinolin-5-yloxy]acetic acid (hereafter also referred to simply as “free form”; melting point 141° C.) which is not in salt form, and are very useful as a pharmaceutical drug substance.
Specifically, the present invention is:
[1] crystals of [8-chloro-3-(4-chlorobenzyl)-4-difluoromethoxy-2-ethylquinolin-5-yloxy]acetic acid L-lysine salt;
[2] the crystals described in [1], which are crystals A;
[3] the crystals described in [1] (crystals A), which, in their powder X-ray diffraction spectrum, have peaks at diffraction angles 2θ=6.0°, 10.0°, 10.7°, 12.1°, 18.4°, 19.2°, and 20.1°;
[4] the crystals described in [1] (crystals A), which have the powder X-ray diffraction spectrum pattern shown in FIG. 1;
[5] the crystals described in [1] (crystals A), which, in their infrared absorption spectrum, have peaks at wavenumbers 673 cm⁻¹, 810 cm⁻¹, 872 cm⁻¹, 1010 cm⁻¹, 1051 cm⁻¹, 1413 cm⁻¹, and 1568 cm⁻¹;
[6] the crystals described in [1] (crystals A), which have the infrared absorption spectrum pattern shown in FIG. 3;
[7] the crystals described in [1] (crystals A), which, in their solid-state ¹³C-NMR spectrum, have chemical shift peaks at 107.1 ppm, 115.9 ppm, 127.5 ppm, 136.5 ppm, 145.7 ppm, 152.7 ppm, 153.8 ppm, 165.8 ppm, 175.8 ppm, 177.3 ppm, and 179.5 ppm;
[8] the crystals described in [1] (crystals A), which have the solid-state ¹³C-NMR spectrum pattern shown in FIG. 5;
[9] the crystals described in [1] (crystals A), which, in their solid-state ¹⁹F-NMR spectrum, have chemical shift peaks at −77.0 ppm, and −72.3 ppm;
[10] the crystals described in [1] (crystals A), which have the solid-state ¹⁹F-NMR spectrum pattern shown in FIG. 6;
[11] the crystals described in [1] (crystals A), which, in their solid-state ¹⁵N-NMR spectrum, have a chemical shift peak at −347.2 ppm;
[12] the crystals described in [1] (crystals A), which have the solid-state ¹⁵N-NMR spectrum pattern shown in FIG. 7;
[13] the crystals described in [1], which are crystals B;
[14] the crystals described in [1] (crystals B), which, in their powder X-ray diffraction spectrum, have peaks at diffraction angles 2θ=6.0°, 11.7°, 12.4°, 15.2°, 16.4°, 20.3°, and 22.6°;
[15] the crystals described in [1] (crystals B), which have the powder X-ray diffraction spectrum pattern shown in FIG. 2;
[16] the crystals described in [1] (crystals B), which, in their infrared absorption spectrum, have peaks at wavenumbers 667 cm⁻¹, 803 cm⁻¹, 885 cm⁻¹, 1012 cm⁻¹, 1032 cm⁻¹, 1402 cm⁻¹, and 1597 cm⁻¹;
[17] the crystals described in [1] (crystals B), which have the infrared absorption spectrum pattern shown in FIG. 4;
[18] a pharmaceutical composition containing the crystals described in any of [1]-[17] and pharmaceutically acceptable carrier;
[19] a CRTH2 antagonist containing, as active ingredient, the crystals described in any of [1]-[17];
[20] a therapeutic drug or preventive drug for one or more diseases chosen from the group consisting of bronchial asthma, chronic obstructive pulmonary disease, bronchitis, cystic fibrosis, perennial allergic rhinitis, seasonal allergic rhinitis, chronic eosinophilic rhinosinusitis, and chronic noneosinophilic rhinosinusitis, containing, as active ingredient, the crystals described in any of [1]-[17]; and
[21] a therapeutic drug or preventive drug for one or more diseases chosen from the group consisting of psoriasis, atopic and nonatopic dermatitis, chronic spontaneous urticaria, Crohn's disease, ulcerative colitis, eosinophilic gastrointestinal disease, and irritable bowel disease, containing, as active ingredient, the crystals described in any of [1]-[17].

Advantages of the Invention

The present invention provides crystals of [8-chloro-3-(4-chlorobenzyl)-4-difluoromethoxy-2-ethylquinolin-5-yloxy]acetic acid L-lysine salt that are chemically stable, have superior thermal stability and physical properties, and are suitable as a pharmaceutical drug substance.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 Powder X-ray diffraction spectrum of crystals A of compound (I)

FIG. 2 Powder X-ray diffraction spectrum of crystals B of compound (I)

FIG. 3 Infrared absorption spectrum of crystals A of compound (I)

FIG. 4 Infrared absorption spectrum of crystals B of compound (I)

FIG. 5 Solid-state ¹³C-NMR spectrum of crystals A of compound (I)

FIG. 6 Solid-state ¹⁹F-NMR spectrum of crystals A of compound (I)

FIG. 7 Solid-state ¹⁵N-NMR spectrum of crystals A of compound (I)

MODE OF THE INVENTION

The inventive crystals are characterized by their powder X-ray diffraction spectra, infrared absorption spectra, solid-state NMR spectra, or a combination of these means. The powder X-ray diffraction (XRD) spectra, infrared absorption spectra, and solid-state NMR spectra of these crystals have unique patterns.
The powder X-ray diffraction spectrum of crystals A of inventive compound (I) has peaks at diffraction angles 2θ=6.0°, 10.0°, 10.7°, 12.1°, 18.4°, 19.2°, and 20.1°. Also, the powder X-ray diffraction spectrum of crystals A of inventive compound (I) has the pattern shown in FIG. 1.
The infrared absorption spectrum of crystals A of inventive compound (I) has absorption peaks at wavenumbers 673 cm⁻¹, 810 cm⁻¹, 872 cm⁻¹, 1010 cm⁻¹, 1051 cm⁻¹, 1413 cm⁻¹, and 1568 cm⁻¹. Also, the infrared absorption spectrum of crystals A of inventive compound (I) has the pattern shown in FIG. 3.
The solid-state ¹³C-NMR spectrum of crystals A of inventive compound (I) has chemical shift peaks at 107.1 ppm, 115.9 ppm, 127.5 ppm, 136.5 ppm, 145.7 ppm, 152.7 ppm, 153.8 ppm, 165.8 ppm, 175.8 ppm, 177.3 ppm, and 179.5 ppm. Also, the solid-state ¹³C-NMR spectrum of crystals A of inventive compound (I) has the pattern shown in FIG. 5.
The solid-state 19F-NMR spectrum of crystals A of inventive compound (I) has chemical shift peaks at −77.0 ppm and −72.3 ppm. Also, the solid-state ¹⁹F-NMR spectrum of crystals A of inventive compound (I) has the pattern shown in FIG. 6.
The solid-state ¹⁵N-NMR spectrum of crystals A of inventive compound (I) has a chemical shift peak at −347.2 ppm. Also, the solid-state ¹⁵N-NMR spectrum of crystals A of inventive compound (I) has the pattern shown in FIG. 7.
Furthermore, crystals A of inventive compound (I) have a melting point of 200° C.
The powder X-ray diffraction spectrum of crystals B of inventive compound (I) has peaks at diffraction angles 2θ=6.00, 11.7°, 12.40, 15.20, 16.40, 20.30, and 22.60. Also, the powder X-ray diffraction spectrum of crystals B of inventive compound (I) has the pattern shown in FIG. 2.
The infrared absorption spectrum of crystals B of inventive compound (I) has absorption peaks at wavenumbers 667 cm⁻¹, 803 cm⁻¹, 885 cm⁻¹, 1012 cm⁻¹, 1032 cm⁻¹, 1402 cm⁻¹, and 1597 cm⁻¹. Also, the infrared absorption spectrum of crystals B of inventive compound (I) has the pattern shown in FIG. 4.
It should be noted that when measurement conditions are good, for example when a high performance measuring instrument is used and the sample is of high purity, other unique peaks in addition to those described above can be found on the powder X-ray diffraction spectra, infrared absorption spectra, and/or solid-state NMR spectra of crystals A and B of inventive compound (I).
For example, on the powder X-ray diffraction spectrum of crystals A of inventive compound (I), one or a plurality of peaks at diffraction angles 2θ=9.1°, 21.1°, 24.5°, and 28.4° can also sometimes be observed simultaneously, and on the powder X-ray diffraction spectrum of crystals B of inventive compound (I), a peak at diffraction angle 2θ=24.4° can also sometimes be observed.
Conversely, when measurement conditions are inadequate, for example with a low purity sample, it is sometimes not possible to observe all of the abovementioned peaks on the powder X-ray diffraction spectra, infrared absorption spectra, and/or solid-state NMR spectra of crystals A and B of inventive compound (I). Even in such cases, if the plurality of peaks that can be found are the same as the peak values described above, those skilled in the art can, on overall consideration, sometimes verify that the sample contains crystals A or B of inventive compound (I). In other words, identification of suspected infringing substance and crystals A or B of inventive compound (I) depends ultimately on “whether the crystal is the same or not”, and this decision is based not on whether all the peaks on the powder X-ray diffraction spectra, infrared absorption spectra or solid-state NMR spectra the are the same, but on whether the overall pattern is the same.
The values of the diffraction angle 2θ peaks on a powder X-ray diffraction spectrum can vary slightly depending on measurement conditions such as the measurement error of the instrument and the condition of the sample being measured and so even if there are small differences in the 2θ values, whether or not the crystal form is the same should be decided by examining the overall pattern of the appropriate spectrum; crystals within the error range are included the present invention. The 2θ value error is thought to be ±0.50. Specifically, for a crystal identified from the abovementioned diffraction angles, within a ±0.50 range is deemed “the same”. Though in accordance with the 16^thedition of the Japanese Pharmacopoeia, powder X-ray diffraction spectra peaks that are within ±0.20 can be said to be the same, and this can also be deemed common knowledge to those skilled in the art.
For example, a powder X-ray diffraction spectrum obtained under ordinary measurement conditions is said to “have a peak at a diffraction angle 2θ value of 6.0°” if the diffraction angle 2θ value is in the range of from 5.5° to 6.5°, i.e., 6.0±0.5°; however a powder X-ray diffraction spectrum obtained under particularly rigorously controlled measurement conditions is said to “have a peak at a diffraction angle 2θ value of 6.0°” if the diffraction angle 2θ value is in the range of from 5.8° to 6.2°. The same applies to the other peaks.
It should be noted that the measurement values in the following examples are within these error ranges.
Similarly, the relative intensities at diffraction angles 2θ on powder X-ray diffraction spectra also vary somewhat, in accordance with the error of the measurement instrument used and the effects of low crystallinity due to the size, shape, orientation, and pulverization of the crystal particles in the sample measured; therefore even when the relative intensities of the peaks on the powder X-ray diffraction spectra differ somewhat from those shown in FIG. 1 and FIG. 2, those skilled in the art can, by making an overall judgement of the positions of the peaks, sometimes verify that these are spectra of crystals A and B of inventive compound (I).
The infrared absorption spectra shown in FIG. 3 and FIG. 4 were measured by the total reflection method (ATR method). Known special features of the total reflection method are that, compared to the transmission method and the diffuse reflectance method (referred to as transmission methods; in these measurement methods the sample is often diluted using KBr powder and then measured), there is usually higher absorption intensity on the low wavenumber side, and the absorption peaks shift from several cm⁻¹to several tens of cm⁻¹to the low wavenumber side. In response to the absorption peak shifts, total reflection-measuring devices are often provided with a function known as “ATR correction”, which converts total reflection method measurement results to transmission method measurement results based on more data than is used in the total reflection method and transmission methods.
The absorption peak values differ greatly, and so whether the results were obtained with or without “ATR correction” must be noted. The infrared absorption spectra shown in FIG. 3 and FIG. 4 were obtained without “ATR correction”.
In infrared absorption spectra, absorption peak errors are common even when the same measurement method is used (even when the total reflection measurement method used is the same in terms of whether or not “ATR correction” is applied). These errors are usually in the range of ±0.5 cm⁻¹. Therefore the crystal form identified from the abovementioned wavenumbers includes those that match in the range of ±0.5 cm⁻¹.
Errors in the chemical shifts in solid-state NMR spectra are also common. These errors are usually in the range of ±0.5 ppm, and there can be additional ±0.5 ppm errors depending on the condition of the solid-state sample. Therefore the crystal form identified from the abovementioned chemical shifts includes those that match in the range of from ±0.5 ppm to ±1.0 ppm.
[8-Chloro-3-(4-chlorobenzyl)-4-difluoromethoxy-2-ethyl-quinolin-5-yloxy]acetic acid can be produced by the production method described in abovementioned patent citation 1, for example. Compound (I) is obtained, for example, by adding L-lysine to a mixed solution of [8-chloro-3-(4-chlorobenzyl)-4-difluoromethoxy-2-ethyl-quinolin-5-yloxy]acetic acid and solvent.
In this specification, melting point refers to that measured using a differential scanning calorimeter.
Generally, a pharmaceutical drug substance needs to be stable at the temperatures and pressures employed during tabletting, and on long-term storage, and so crystals must have a high melting point and excellent thermal stability.
Inventive crystals of compound (I) can be obtained by various production methods; typical examples are shown below.
Crystals of compound (I) can be obtained by dissolving or suspending compound (I) in solvent, or dissolving or suspending [8-chloro-3-(4-chlorobenzyl)-4-difluoro-methoxy-2-ethylquinolin-5-yloxy]acetic acid and L-lysine in solvent, and then crystallizing by concentration, refrigeration or the addition of a poor solvent.
More specifically, if the solution is unsaturated a solution of compound (I) is obtained, and if the solution is super-saturated the compound may precipitate out directly as crystals or remain in solution, depending on the conditions such as the type, concentration, and temperature of the solvent. Those skilled in the art can select the conditions such as solvent, concentration, and temperature in order to obtain a super-saturated or unsaturated solution, as appropriate. Compound (I) can be precipitated out of solution as crystals by methods such as concentrating or cooling the solution, or adding a poor solvent. Stable crystals can be obtained from suspension as described above and by solvent-mediated transition; that is, using the principle of transition to the most stable form of crystals at that solvent composition and temperature.
Examples of solvents that can be used are N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, chloroform, acetonitrile, ethanol, methyl formate, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, isobutyl alcohol, 2-butanol, t-butyl alcohol, 1-pentanol, 3-methyl-1-butanol, neopentyl alcohol, 2-ethoxymethanol, 2-ethoxyethanol, 2,2,2-trifluorodiethyl ether, 1,1,1,3,3,3-hexafluoro-2-propanol, diisopropyl ether, t-butyl methyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, anisole, acetone, 2-butanone, 4-methyl-2-pentanone, cyclohexanone, pentane, hexane, heptane, cyclohexane, methylcyclohexane, tetralin, toluene, xylene, water, and mixed solvents comprising two or more selected from these. From an economic perspective and from an industrial perspective, the more preferred solvents are acetonitrile, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, methanol, ethanol, 1-propanol, 2-propanol, tetrahydrofuran, 1,4-dioxane, acetone, 2-butanone, hexane, heptane, water, and mixed solvents comprising two or more selected from these.
There are no particular limitations regarding the amount of solvent used, and 5-100×volume is preferred, ≤50×volume is more preferred, and ≤20×volume is even more preferred. Hereafter, 1×volume refers to 1 mL of solvent per 1 g of [8-chloro-3-(4-chlorobenzyl)-4-difluoromethoxy-2-ethylquinolin-5-yloxy]acetic acid or compound (I). Preferred solvents for minimizing the amount of solvent are ethanol, 1-propanol, 2-propanol, tetrahydrofuran, and 1,4-dioxane, which are solvents in which [8-chloro-3-(4-chlorobenzyl)-4-difluoromethoxy-2-ethylquinolin-5-yloxy]acetic acid is highly soluble.
There are no particular limitations regarding the temperature conditions, agitation conditions, or time to filtration after crystallization has started; these conditions affect the yield, chemical purity, particle size, etc., of the crystals and so it is preferable to set an appropriate combination of conditions in accordance with the target.
When crystallization from solution is performed, is it is effective to add seed crystals of the same crystal form as the target crystals. The amount thereof is usually from around 0.01% by weight to 20% by weight, preferably 0.1% by weight to 10% by weight, of the drug substance [8-chloro-3-(4-chlorobenzyl)-4-difluoromethoxy-2-ethylquinolin-5-yloxy]acetic acid or compound (I), and it is preferably already pulverized. At the time of addition, the crystals to be obtained are preferably in the region of super-saturation; it is not necessary for them to be already super-saturated at the time of addition, but it is important that the system is such that the added crystals do not all dissolve.
Inventive crystals A of compound (I) are relatively easy to obtain, and can be crystallized by the production methods described above under a wide range of conditions (combinations of various solvents). The crystals obtained from the resulting suspension are filtered and dried to obtain crystals A. The filtration can be performed by a common method; examples of methods that can be used are natural filtration, filtration under increased pressure, filtration under reduced pressure, and centrifugation. The drying can be performed by a common method; examples of methods that can be used are natural drying, drying under reduced pressure, heated drying, and heated drying under reduced pressure.
Inventive crystals B of compound (I) are hydrate crystals, and can be obtained using a combination of solvents that includes water. Alcohols such as ethanol and 2-propanol are preferred as the solvent used in combination with water. For example, the crystals can be obtained by dissolving compound (I) in a mixed solvent containing ethanol and water at a ratio of 1:1 (80×volume), concentrating and then drying. The drying can comprise natural drying, drying under reduced pressure, heated drying, or heated drying under reduced pressure. In heated drying under reduced pressure it is confirmed that no water of crystallization is lost even at 80° C., but at higher temperatures caution is required.
The inventive crystals of compound (I) can be used as the active ingredient in pharmaceuticals. It is also possible to use not only a single crystal, but also mixtures of two or more crystal forms.
The inventive crystals of compound (I) are advantageous in terms of ease of handling during production, reproducibility, stability, storage stability, etc., compared to when non-crystalline.
Also, the inventive crystals of compound (I) are crystals of L-lysine salt and have better storage stability than crystals of the free form.
The inventive crystals of compound (I) can be used to obtain pharmaceutical compositions using pharmaceutically acceptable carrier.
Formulations containing inventive crystals of compound (I) are prepared using additives commonly used in formulation preparation. Examples of these additives for solid formulations include excipients such as lactose, white sugar, glucose, corn starch, potato starch, crystalline cellulose, light anhydrous silicic acid, synthetic aluminum silicate, magnesium metasilicate aluminate, and calcium hydrogen phosphate; binders such as crystalline cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose sodium and polyvinylpyrrolidone; disintegrating agents such as starch, carboxymethylcellulose sodium, carboxymethylcellulose calcium, croscarmellose sodium, and carboxymethylstarch sodium; lubricants such as talc and stearates; coatings such as hydroxymethylpropyl cellulose, hydroxypropyl methyl cellulose phthalate, and ethyl cellulose; and colorants. For semi-solid formulations, they include base such as white vaseline; and for liquid formulations they include solvents such as ethanol; solubilizing agents such as ethanol; preservatives such as para-oxybenzoic acid esters; isotonizing agents such as glucose; buffers such as citrates; antioxidants such as L-ascorbates; chelating agents such as EDTA; and suspending agents and emulsifiers such as polysorbate 80.
The inventive crystals of compound (I) can be used in any dosage form, such as solid formulations, semi-solid formulations and liquid formulations, and in any appropriate oral or non-oral formulation (injection agent, transdermal agent, eyedrops, suppository, nasal agent, inhalant, etc.).
Pharmaceutical compositions containing inventive crystals of compound (I) as active ingredient can be used as drugs for the treatment or prevention of diseases in which CRTH2 receptors participate, such as bronchial asthma, chronic obstructive pulmonary disease, bronchitis, cystic fibrosis, perennial allergic rhinitis, seasonal allergic rhinitis, chronic eosinophilic rhinosinusitis, chronic noneosinophilic rhinosinusitis, psoriasis, atopic and nonatopic dermatitis, chronic spontaneous urticaria, Crohn's disease, ulcerative colitis, eosinophilic gastrointestinal disease, and irritable bowel disease. Here, “prevention” refers to the prevention of disease or symptoms in an individual who does not yet exhibit disease or symptoms, and “treatment” refers to affecting cure, inhibition or improvement of disease or symptoms in an individual who already exhibits disease or symptoms.

EXAMPLES

Powder X-Ray Diffraction Measurement Method
The powder X-ray diffraction of the inventive crystals was measured under the following conditions.
Measurement instrument: Shimadzu Corporation
Measurement conditions: Source Cu-Kα, 40 kV-40 mA, scan 5-400, scan time 35 seconds
Infrared Absorption Measurement Method
The infrared absorption spectrum of the inventive crystals was measured under the following conditions in accordance with the ATR infrared absorption spectra measurement method described in the common test methods section of the Japanese Pharmacopoeia.
Conditions 1
Measurement instrument: Perkin Elmer Spectrum Two
Measurement conditions: 4000-400 cm⁻¹, resolution 4 cm⁻¹, accumulation 64 times
Conditions 2
Measurement instrument: Bruker-Optics Alpha
Measurement conditions: 4000-400 cm⁻¹, resolution 4 cm⁻¹, accumulation 24 times
Solid-State ¹³C-NMR Measurement Method
The solid-state ¹³C-NMR of the inventive crystals was measured under the following conditions.
Measurement instrument: Bruker Avance III HD400
Measurement conditions: Pulse mode CP/MAS measurement, pulse repeat time 20 seconds, chemical shift standard hexamethylbenzene (external standard: 17.35 ppm)
Solid-State 19F-NMR Measurement Method
The solid-state ¹⁹F-NMR of the inventive crystals was measured under the following conditions.
Measurement instrument: Bruker Avance III HD400
Measurement conditions: Pulse mode CP/MAS measurement, pulse repeat time 55 seconds, chemical shift standard hexafluorobenzene (external standard: −163.0 ppm)
Solid-State ¹⁵N-NMR Measurement Method
The solid-state ¹⁵N-NMR of the inventive crystals was measured under the following conditions.
Measurement instrument: Bruker Avance 400
Measurement conditions: Pulse mode CP/MAS measurement, pulse repeat time 15 seconds, chemical shift standard ammonium chloride (external standard: −341.2 ppm)
Melting Point Measurement Method
The melting point of the inventive crystals was measured under the following conditions.
Measurement instrument: TA Instruments Japan Q2000
Measurement conditions: Measurement range 30-320° C., temperature elevation rate 20° C./minute, on set value
Solution NMR Measurement Method
The measured solution ¹H-NMR spectrum (400 mHz, DMSO-d₆or CDCI₃) shows the chemical shifts (δ: ppm) and coupling constants (J: Hz). The symbols used below are as follows.
s=singlet, d=doublet, t=triplet, q=quartet, brs=broad singlet, m=multiplet
Measurement instrument: Bruker BioSpin AV-400M

Example 1

Production of [8-chloro-3-(4-chlorobenzyl)-4-difluoro-methoxy-2-ethylquinolin-5-yloxy]acetic acid L-lysine Salt Crystals A

8.0 g of [8-chloro-3-(4-chlorobenzyl)-4-difluoro-methoxy-2-ethylquinolin-5-yloxy]acetic acid were dissolved in 96 mL of 2-propanol at 45° C., 24 mL of an aqueous solution of 2.6 g L-lysine were added, and the system was agitated at 45° C. for 1 hour. It was then cooled to 15° C. over a period of 2 hours, and then crystals were obtained by filtration and washed using 24 mL of 2-propanol. The crystals were dried under reduced pressure at 40° C. to obtain 9.0 g of [8-chloro-3-(4-chlorobenzyl)-4-difluoromethoxy-2-ethylquinolin-5-yloxy]acetic acid L-lysine salt crystals. The powder XRD of the resulting crystals is shown in FIG. 1. Peaks were observed at diffraction angles 2θ=6.0°, 10.0°, 10.7°, 12.1°, 18.4°, 19.2°, and 20.1°. The infrared spectrum of the resulting crystals under conditions 1 is shown in FIG. 3. Peaks were observed at wavenumbers 673 cm⁻¹, 810 cm⁻¹, 872 cm⁻¹, 1010 cm⁻¹, 1051 cm⁻¹, 1413 cm⁻¹, and 1568 cm⁻¹.
The solid-state ¹³C-NMR spectrum of the resulting crystals is shown in FIG. 5. Chemical shift peaks were observed at 107.1 ppm, 115.9 ppm, 127.5 ppm, 136.5 ppm, 145.7 ppm, 152.7 ppm, 153.8 ppm, 165.8 ppm, 175.8 ppm, 177.3 ppm, and 179.5 ppm.
The solid-state ¹⁹F-NMR spectrum of the resulting crystals is shown in FIG. 6. Chemical shift peaks were observed at −77.0 ppm and −72.3 ppm.
The solid-state ¹⁵N-NMR spectrum of the resulting crystals is shown in FIG. 7. A chemical shift peak was observed at −347.2 ppm.
The melting point was 200° C.
Solution ¹H-NMR (400 MHz, DMSO-d₆) δ: 1.21 (3H, t, J=7.4 Hz), 1.25-1.75 (6H, m), 2.73 (2H, t, J=7.2 Hz), 2.83 (2H, q, J=7.3 Hz), 3.17 (1H, t, J=6.0 Hz), 4.32 (2H, s), 4.46 (2H, s), 6.89 (1H, d, J=8.8 Hz), 7.12 (1H, d, J=8.8 Hz), 7.33 (1H, d, J=8.8 Hz), 7.81 (1H, d, J=8.8 Hz)

Example 2

Production of [8-chloro-3-(4-chlorobenzyl)-4-difluoro-methoxy-2-ethylquinolin-5-yloxy]acetic acid L-lysine Salt Crystals B

4.8 g of crystals A of compound (I) were dissolved at room temperature in 420 mL of an ethanol/water=1/1 mixed solution, and concentrated under reduced pressure at 40° C. The resulting concentrate was dried under reduced pressure at 65° C. to obtain 4.8 g of [8-chloro-3-(4-chlorobenzyl)-4-difluoromethoxy-2-ethylquinolin-5-yloxy]acetic acid L-lysine salt crystals. The powder XRD of the resulting crystals is shown in FIG. 2. Peaks were observed at diffraction angles 2θ=6.00, 11.7°, 12.40, 15.20, 16.40, 20.30, and 22.60. The infrared spectrum of the resulting crystals under conditions 2 is shown in FIG. 4. Peaks were observed at wavenumbers 667 cm⁻¹, 803 cm⁻¹, 885 cm⁻¹, 1012 cm⁻¹, 1032 cm⁻¹, 1402 cm⁻¹, and 1597 cm⁻¹.
Solution ¹H-NMR (400 MHz, DMSO-ds) δ: 1.21 (3H, t, J=7.4 Hz), 1.25-1.75 (6H, m), 2.73 (2H, t, J=7.2 Hz), 2.83 (2H, q, J=7.3 Hz), 3.22 (1H, t, J=6.0 Hz), 4.32 (2H, s), 4.50 (2H, s), 6.90 (1H, d, J=8.8 Hz), 7.11 (1H, d, J=8.4 Hz), 7.33 (1H, d, J=8.4 Hz), 7.80 (1H, d, J=8.4 Hz)

Comparative Example 1

Production of Free-Form Crystals of [8-chloro-3-(4-chlorobenzyl)-4-difluoromethoxy-2-ethylquinolin-5-yloxy]acetic acid

An aqueous solution obtained by dissolving sodium hydroxide (14 g) in water (350 mL) was added to a methanol (2000 mL) solution of [8-chloro-3-(4-chlorobenzyl)-4-difluoromethoxy-2-ethylquinolin-5-yloxy] acetic acid ethyl ester (100 g) obtained in accordance with the method described in example 39, preparation 39c of international patent publication WO2007/036743, and the resulting system was agitated at 35° C. for 1 hour. It was then cooled to room temperature, 2000 mL of water were added with agitation, and the pH was adjusted to 4 using dilute hydrochloric acid and aqueous sodium hydroxide solution. The precipitated crystals were filtered and then dried under reduced pressure at 42° C. to obtain 95 g of free-form crystals of [8-chloro-3-(4-chlorobenzyl)-4-difluoromethoxy-2-ethylquinolin-5-yloxy]acetic acid. The resulting crystals had a melting point of 141° C.

Example 3

The storage stability of the compound (I) crystals A obtained in example 1 was compared with that of the free-form crystals obtained in comparative example 1.
The crystals were introduced, respectively, into a glass vessel which was then tightly sealed and stored at 40° C., relative humidity 75° C. for 3 months; the amount of related substances before and after storage was measured by liquid chromatography; the results are shown in Table 1. The values are the total amount of related substances, which are produced impurities, as measured to 20.03%.

	TABLE 1

	At the start	After 3 months

Compound (I) crystals A	0.53%	0.59%
Free-form crystals	1.37%	1.95%

Compound (I) crystals A exhibited better storage stability than the free-form crystals.

INDUSTRIAL APPLICABILITY

The inventive crystals of compound (I) can be used for the production of pharmaceutical products.

Claims

1. Crystals of [8-chloro-3-(4-chlorobenzyl)-4-difluoro-methoxy-2-ethylquinolin-5-yloxy]acetic acid L-lysine salt.

2. The crystals as claimed in claim 1, which are crystals A.

3. The crystals as claimed in claim 1, which, in their powder X-ray diffraction spectrum, have peaks at diffraction angles 2θ=6.0°, 10.0°, 10.7°, 12.1°, 18.4°, 19.2°, and 20.1°.

4. The crystals as claimed in claim 1, which have the powder X-ray diffraction spectrum pattern shown in FIG. 1.

5. The crystals as claimed in claim 1, which, in their infrared absorption spectrum, have absorption peaks at wavenumbers 673 cm⁻¹, 810 cm⁻¹, 872 cm⁻¹, 1010 cm⁻¹, 1051 cm⁻¹, 1413 cm⁻¹, and 1568 cm⁻¹.

6. The crystals as claimed in claim 1, which have the infrared absorption spectrum pattern shown in FIG. 3.

7. The crystals as claimed in claim 1, which, in their solid-state ¹³C-NMR spectrum, have chemical shift peaks at 107.1 ppm, 115.9 ppm, 127.5 ppm, 136.5 ppm, 145.7 ppm, 152.7 ppm, 153.8 ppm, 165.8 ppm, 175.8 ppm, 177.3 ppm, and 179.5 ppm.

8. The crystals as claimed in claim 1, which have the solid-state ¹³C-NMR spectrum pattern shown in FIG. 5.

9. The crystals as claimed in claim 1, which, in their solid-state ¹⁹F-NMR spectrum, have chemical shift peaks at −77.0 ppm, and −72.3 ppm.

10. The crystals as claimed in claim 1, which have the solid-state ¹⁹F-NMR spectrum pattern shown in FIG. 6.

11. The crystals as claimed in claim 1, which, in their solid-state ¹⁵N-NMR spectrum, have a chemical shift peak at −347.2 ppm.

12. The crystals as claimed in claim 1, which have the solid-state ¹⁵N-NMR spectrum pattern shown in FIG. 7.

13. The crystals as claimed in claim 1, which are crystals B.

14. The crystals as claimed in claim 1, which, in their powder X-ray diffraction spectrum, have peaks at diffraction angles 2θ=6.0°, 11.7°, 12.4°, 15.2°, 16.4°, 20.3°, and 22.6°.

15. The crystals as claimed in claim 1, which have the powder X-ray diffraction spectrum pattern shown in FIG. 2.

16. The crystals as claimed in claim 1, which, in their infrared absorption spectrum, have absorption peaks at wavenumbers 667 cm⁻¹, 803 cm⁻¹, 885 cm⁻¹, 1012 cm⁻¹, 1032 cm⁻¹, 1402 cm⁻¹, and 1597 cm⁻¹.

17. The crystals as claimed in claim 1, which have the infrared absorption spectrum pattern shown in FIG. 4.

18. A pharmaceutical composition containing the crystals as claimed in any of claims 1-17 and pharmaceutically acceptable carrier.

19. A CRTH2 antagonist containing, as active ingredient, the crystals as claimed in any of claims 1-17.

20. A therapeutic drug or preventive drug for one or more diseases chosen from the group consisting of bronchial asthma, chronic obstructive pulmonary disease, bronchitis, cystic fibrosis, perennial allergic rhinitis, seasonal allergic rhinitis, chronic eosinophilic rhinosinusitis, and chronic noneosinophilic rhinosinusitis, containing, as active ingredient, the crystals as claimed in any of claims 1-17.

21. A therapeutic drug or preventive drug for one or more diseases chosen from the group consisting of psoriasis, atopic and nonatopic dermatitis, chronic spontaneous urticaria, Crohn's disease, ulcerative colitis, eosinophilic gastrointestinal disease, and irritable bowel disease, containing, as active ingredient, the crystals as claimed in any of claims 1-17.