JP2005179272A - Malonate crystal of carboxamide derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new crystal of new salt useful as a raw material for producing an activated hemocoagulation factor X inhibitor. <P>SOLUTION: A stable crystal of N-(4-bromo-2-ä[(5-chloropyridin-2-yl)amino]carbonyl}-6-hydroxyphenyl)-1-isopropylpiperidine-4-carboxamide malonate is useful as a raw material in the extensive synthesis in the industrial production of pharmaceuticals since it does not show hygroscopicity and is excellent in stability. Moreover, a stable solid composition comprising the malonate crystal of the present invention and a pharmaceutically acceptable carrier, in particular an activated hemocoagulation factor X inhibitor, is useful as a stable medicine having a good activity. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to N- (4-bromo-2-{[(5-chloropyridin-2-yl) amino] carbonyl} -6-hydroxyphenyl) -1 useful as an activated blood coagulation factor X inhibitor -Isopropylpiperidine-4-carboxamide malonate crystals and a medicament containing the crystals.

しかしながら、この塩酸塩には吸湿性があるため、医薬品としての使用には今なお問題があった。即ち、医薬品は、湿度、温度、光等に長期間安定であるほか、製剤化工程における安定性も求められる。医薬品が吸湿性を有すると物理的化学的性質が変化することが考えられ、また周囲の湿度変化によって水分量が大きく異なるといった不都合を生じる。従って、この塩酸塩を医薬品の製造原体に用いるためには、乾燥剤の使用を検討するなどして、常に湿度に対する保存環境に留意することが必要となり、工業的使用には好適でない。
更に、この塩酸塩には、少なくとも２種類の結晶多形が存在することが判明しており、この観点からも医薬品の製造原体として好適でない。 We have 4′-bromo-2 ′-[(5-chloro-2-pyridyl) carbamoyl] -6′-hydroxy-1-isopropylpiperidine-4-carboxanilide hydrochloride represented by the following structural formula: It has been previously reported that it is a useful compound as an activated blood coagulation factor X inhibitor (Example 19 of WO 02/42270 (Patent Document 1)).

However, since this hydrochloride salt is hygroscopic, there are still problems in its use as a pharmaceutical product. In other words, pharmaceutical products are required to be stable in humidity, temperature, light, etc. for a long period of time and also in the formulation process. If a pharmaceutical product has hygroscopicity, the physical and chemical properties may change, and the amount of water varies greatly depending on changes in ambient humidity. Therefore, in order to use this hydrochloride as a drug substance, it is necessary to always pay attention to the storage environment against humidity, for example, by considering the use of a desiccant, which is not suitable for industrial use.
Furthermore, it has been found that at least two types of crystal polymorphs exist in this hydrochloride, and from this point of view, it is not suitable as a drug substance.

In addition, “4′-bromo-2 ′-[(5-chloro-2-pyridyl) carbamoyl] -6′-hydroxy-1-isopropylpiperidine-4-carboxanilide” and “N- (4-bromo-2- “[[(5-chloropyridin-2-yl) amino] carbonyl} -6-hydroxyphenyl) -1-isopropylpiperidine-4-carboxamide” means compounds having the same structural formula. Hereinafter, the present invention will be described with the latter naming unified.
International Publication No. 02/42270 Pamphlet

 The inventors have identified N- (4-bromo-2-{[(5-chloropyridin-2-yl) amino] carbonyl, which is useful as a drug substance, in particular as an active ingredient of an activated blood coagulation factor X inhibitor. } -6-Hydroxyphenyl) -1-isopropylpiperidine-4-carboxamide was studied for the purpose of providing new crystals suitable for industrial production, that is, stable crystals that do not exhibit hygroscopicity.

 As shown in the test examples described later, the hydrochloride crystal described in Example 19 of Patent Document 1 increases in weight as the humidity increases, retains about 2% of moisture at a relative humidity of 95%, and has a hygroscopic property. I had it. The present inventors have conducted research to obtain stable crystals of the hydrochloride, and have found that crystal polymorphism exists. However, the newly found crystal also retains about 5% of moisture at a relative humidity of 95% and exhibits strong hygroscopicity, and is not suitable for industrial use. As a result of further studies by the present inventors in search of new crystals that do not exhibit hygroscopicity, the inventors have unexpectedly found for the first time stable crystals that do not exhibit hygroscopic properties in malonates. That is, the present invention provides a novel N- (4-bromo-2-{[(5-chloropyridin-2-yl) amino] carbonyl} -6-hydroxyphenyl) -1-isopropylpiperidine-4-carboxamide malonate The present invention relates to stable new crystals. The malonate of the present invention is a stable crystal that does not exhibit hygroscopicity (less than 0.2%) in the entire range of 5% to 95% relative humidity, and is a suitable production base for pharmaceutical products, particularly solid compositions. is there. The invention also relates to a stable solid composition containing the crystals, in particular an activated blood coagulation factor X inhibitor.

 The N- (4-bromo-2-{[(5-chloropyridin-2-yl) amino] carbonyl} -6-hydroxyphenyl) -1-isopropylpiperidine-4-carboxamide malonate crystals of the present invention are hygroscopic. Therefore, it is useful as a manufacturing base in mass synthesis in industrial production of pharmaceuticals. Furthermore, a stable solid composition comprising the malonate crystal of the present invention and a pharmaceutically acceptable carrier, particularly an activated blood coagulation factor X inhibitor, is useful as a stable drug having good activity. is there.

（比較例：塩酸塩結晶Ａ）

（比較例：塩酸塩結晶Ｂ）

更にＤＳＣ分析の結果、マロン酸塩結晶は214〜220℃に、塩酸塩結晶Ａは264〜270℃に、塩酸塩結晶Ｂは261〜267℃に、それぞれ熱吸収ピークを有した。 The malonate crystal of the present invention is characterized by the crystal lattice spacing [2θ (°)] of the powder X-ray diffraction spectrum shown in Table 1 below, the heat absorption peak of DSC analysis, or both. Tables 2 and 3 show the known hydrochloride crystals (hereinafter referred to as “hydrochloride crystals A”) and polymorphs thereof (hereinafter referred to as “hydrochloride crystals B”) described in Example 19 of Patent Document 1 for comparison. Data).
Powder X-ray diffraction is based on the nature of the data, and the crystal lattice spacing and overall pattern are important in identifying the identity of the crystal. The relative intensity depends somewhat on the crystal growth direction, particle size, and measurement conditions. Since it can change, it should not be interpreted strictly.


(Malonate crystal of the present invention)

(Comparative example: hydrochloride crystal A)

(Comparative example: hydrochloride crystal B)

As a result of DSC analysis, the malonate crystal had a heat absorption peak at 214 to 220 ° C, the hydrochloride crystal A at 264 to 270 ° C, and the hydrochloride crystal B at 261 to 267 ° C.

For measurement of powder X-ray diffraction, MAC Science MXP18TAHF22 was used. Tube: Cu, tube current: 40 mA, tube voltage: 160 kV, sampling width: 0.020 °, scanning speed: 3 ° / min, wavelength: 1.54056Å Measurement diffraction angle range (2θ): Measured under conditions of 3 to 40 °.
Thermal analysis (DSC and TGA) was measured under the following conditions.

DSC: TA Instruments DSC 2910 Differential Scanning Calorimeter, room temperature to 300 ° C. (10 ° C./min), N ₂ (50 ml / min), aluminum sample pan. TGA: TA Instruments TGA 2950 Thermogravimetric Analyzer, room temperature to 300 ° C. (10 ° C./min), N ₂ (50 ml / min), platinum sample pan.
Nuclear magnetic resonance spectra (NMR) were measured using JEOL JNM-LA400 and JEOL JNM-A500, and tetramethylsilane (TMS) was used as an internal standard.
Mass spectrometry spectra were measured using JEOL DX-300 and JEOL LX-2000.

  The pharmaceutical product using the malonate crystal of the present invention as the active ingredient for producing a pharmaceutical may be in any form of oral administration such as tablets, pills, capsules, granules, powders, or parenteral administration such as inhalants. Good. As a solid composition for oral administration, tablets, powders, granules and the like are used. In such solid compositions, one or more active substances are present in at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicate. Mixed with magnesium aluminate acid. The composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, a stabilizer, and a solubilizing agent according to a conventional method. If necessary, tablets or pills may be coated with a sugar coating or a gastric or enteric coating agent. The dose is appropriately determined according to the individual case in consideration of symptoms, age of the administration subject, sex, etc., but is usually about 0.01 mg / kg to 100 mg / kg per adult for oral administration. Is administered once or divided into 2 to 4 times.

EXAMPLES Hereinafter, although this invention is demonstrated concretely by Examples 1-2, these do not limit the scope of the present invention. Since some raw material compounds are produced by a method different from the method described in Patent Document 1, they are shown as Reference Examples 1 to 6.
Moreover, although the synthetic route is illustrated in the following as a general synthetic method of the present invention, these are not limited to Reference Examples 1 to 6 and Examples 1 and 2, but are described in Patent Document 1 and obvious to those skilled in the art. This can be done by an improved method.

Reference example 1
A mixture of 24.50 kg of isonipecotic acid, 50 L of methanol, 120 L of acetone, and 5.22 kg of wet 10% palladium carbon catalyst (wet rate 52.1%) was heated and stirred at 65 ° C. for 2 days in a hydrogen stream. The catalyst was removed from the reaction solution by filtration, and the catalyst was washed with 50 L of methanol. To the reaction solution was added 25 L of methanol and concentrated under reduced pressure, and then 70 L of isopropanol was added and concentrated again under reduced pressure. To the residue, 245 L of isopropanol was added and dissolved by heating (81 ° C.), followed by cooling. After adding 60.64 kg of 4N hydrogen chloride / ethyl acetate solution, the mixture was stirred at 0 ° C. overnight. The resulting crystals were collected by filtration and washed with 80 L of isopropanol. Vacuum drying gave 39.40 kg of 1-isopropylpiperidine-4-carboxylic acid hydrochloride.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm) = 1.25 (6H, d, J = 6.4 Hz), 1.91-2.02 (4H, m), 2.57 (1H, br), 2.96 (2H, br ), 3.24 (2H, br), 3.37 (1H, m). FAB-MS m / z: 172 (M + H) +.

Reference example 2
A mixture of 47.50 kg of 3-hydroxy-2-nitrobenzoic acid, 190 L of acetonitrile, 2.11 kg of pyridine, and 34.41 kg of acetic anhydride was stirred at 55 ° C. for 3 hours. 950 L of water was added to the reaction solution, cooled to 5 ° C., and stirred overnight. The resulting crystals were collected by filtration and washed with 180 L of water. Vacuum drying gave 48.86 kg of 3-acetoxy-2-nitrobenzoic acid.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm) = 2.30 (3H, s), 7.77 (2H, m), 7.90 (1H, m). FAB-MS m / z: 224 (MH)- .

Reference example 3
A mixture of 3-acetoxy-2-nitrobenzoic acid 48.80 kg, ethyl acetate 240 L, N, N-dimethylformamide 2.49 kg, thionyl chloride 38.71 kg was stirred at 50 ° C. for 3 hours and then concentrated under reduced pressure. After adding 100 L of acetonitrile and concentrating again under reduced pressure, 100 L of acetonitrile was added to the residue and dissolved. This solution was added dropwise at 4 to 16 ° C. to a mixture of 27.90 kg of 2-amino-5-chloropyridine, 340 L of acetonitrile, and 20.60 kg of pyridine. After adding 50 L of acetonitrile to the reaction solution, the mixture was stirred at 10 ° C. overnight. After adding 390 L of water to the reaction solution, a solution of 30.30 kg of sodium hydroxide and 390 L of water was added dropwise and stirred at 10 ° C. for 2 hours. The reaction solution was crystallized by adding 54.14 kg of 38% hydrochloric acid and stirred at 3 ° C. overnight. The crystals were collected by filtration and washed with 150 L of water. Vacuum drying gave 49.42 kg of N- (5-chloro-2-pyridyl) -3-hydroxy-2-nitrobenzamide.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm) = 7.25 (2 H, m), 7.50 (1 H, t, J = 7.8 Hz), 7.95 (1 H, dd, J = 2.8 Hz, 8.8 Hz) , 8.08 (1H, d, J = 8.8Hz), 8.44 (1H, d, J = 2.8Hz), 11.22 (1H, br), 11.36 (1H, s). FAB-MS m / z: 294 (M + H) +.

Reference example 4
A mixture of N- (5-chloro-2-pyridyl) -3-hydroxy-2-nitrobenzamide 25.00 kg, N, N-dimethylformamide 220 L, Raney nickel catalyst 5.01 kg in a hydrogen stream until hydrogen absorption is complete Stir. The catalyst was removed from the reaction solution by filtration, and the catalyst was washed with 50 L of N, N-dimethylformamide (reaction solution A).
N- (5-chloro-2-pyridyl) -3-hydroxy-2-nitrobenzamide 24.30 kg, N, N-dimethylformamide 220 L, Raney nickel catalyst 4.90 kg in a hydrogen stream until hydrogen absorption is complete Stir. The catalyst was removed from the reaction solution by filtration, and the catalyst was washed with 48 L of N, N-dimethylformamide.

(Reaction solution B).
Reaction liquids A and B were mixed, and a mixture of 300 L of methanol and 300 L of water was added dropwise thereto, followed by stirring at 25 ° C. overnight. The crystals were collected by filtration and washed with 150 L of water. Vacuum drying gave 40.89 kg of 2-amino-N- (5-chloro-2-pyridyl) -3-hydroxybenzamide.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm) = 5.93 (2H, s), 6.45 (1H, t, J = 8.0 Hz), 6.82 (1H, d, J = 8.0 Hz), 7.28 ( 1H, d, J = 8.0Hz), 7.92 (1H, m), 8.14 (1H, d, J = 8.0Hz), 8.40 (1H, s), 9.59 (1H, s), 10.45 (1H, s). FAB-MS m / z: 264 (M) +.

Reference Example 5
A mixture of 2-amino-N- (5-chloro-2-pyridyl) -3-hydroxybenzamide 40.50 kg, N, N-dimethylacetamide 400 L, 38% hydrochloric acid 17.72 kg was distilled under reduced pressure to remove water. To this solution, a solution of 26.00 kg of N-bromosuccinimide and 120 L of N, N-dimethylacetamide was added dropwise at -7 ° C. or lower, and 40 L of N, N-dimethylacetamide was further added. To the reaction solution were added 570 L of water and 12.90 kg of sodium hydrogen carbonate, and the mixture was stirred at 20 ° C. overnight. The crystals were collected by filtration and washed with 120 L of water. Vacuum drying gave 52.25 kg of crude crystals of 2-amino-5-bromo-N- (5-chloro-2-pyridyl) -3-hydroxybenzamide.
2-amino-5-bromo-N- (5-chloro-2-pyridyl) -3-hydroxybenzamide crude crystal 52.00 kg, N, N-dimethylformamide 160 L, activated carbon 5.20 kg, ethyl acetate 520 L Was stirred at 25 ° C. overnight, and the reaction solution was filtered to remove activated carbon. To the filtrate were added 52 L of ethyl acetate and 46.27 kg of 4N hydrogen chloride / ethyl acetate solution, and the mixture was stirred at 20 ° C. overnight. The resulting crystals were collected by filtration and washed with 130 L of ethyl acetate. Vacuum drying gave 2-amino-5-bromo-N- (5-chloro-2-pyridyl) -3-hydroxybenzamide hydrochloride 57.53 kg.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm) = 7.13 (1H, d, J = 2.0 Hz), 7.48 (1H, d, J = 1.6 Hz), 7.96 (1H, dd, J = 2.6 Hz, 9.0Hz), 8.11 (1H, d, J = 8.8Hz), 8.42 (1H, dd, J = 2.8Hz, 12.0Hz), 7.5-8.5 (3H, br). FAB-MS m / z: 344 (M + H) +.

Reference Example 6
A mixture of 33.00 kg of 1-isopropylpiperidine-4-carboxylic acid, 340 L of acetonitrile, 0.56 kg of N, N-dimethylformamide, and 28.73 kg of thionyl chloride was stirred at 55 ° C. for 2 hours and then concentrated under reduced pressure. After adding 190 L of acetonitrile and concentrating again under reduced pressure, 140 L of acetonitrile was added to the residue and dissolved. This solution was added to a mixture of 48.20 kg of 2-amino-5-bromo-N- (5-chloro-2-pyridyl) -3-hydroxybenzamide hydrochloride, 290 L of acetonitrile and 57.49 kg of diisopropylethylamine at 4-8 ° C. And dripped. 50 L of acetonitrile was added to the reaction solution, and the mixture was stirred at 50 ° C. for 2 hours. Then, 480 L of methanol was added and stirred at 20 ° C. overnight. The crystals were collected by filtration and washed with 80 L of methanol. Vacuum drying gave N- (4-bromo-2-{[(5-chloropyridin-2-yl) amino] carbonyl} -6-hydroxyphenyl) -1-isopropylpiperidine-4-carboxamide hydrochloride 53.50 kg It was.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm) = 0.9-1.3 (6H, br), 1.6-2.1 (4H, br), 2.6-3.5 (6H, br), 7.17 (1H, m) , 7.25 (1H, m), 7.93 (1H, m), 8.11 (1H, m), 8.38 (1H, m), 9.42 (0.3H, br), 10.62 (0.7H, br). FAB-MS m / z: 497 (M + H) +.

Example 1 (Production of free body crystals)
N- (4-Bromo-2-{[(5-chloropyridin-2-yl) amino] carbonyl} -6-hydroxyphenyl) -1-isopropylpiperidine-4-carboxamide hydrochloride 53.40 kg, water 210 L and ethanol To a 640 L mixture, a solution of sodium bicarbonate 10.10 kg and water 210 L was added dropwise. The reaction solution was heated and stirred at 70 ° C. for 6 hours, then cooled and stirred at 25 ° C. overnight. The crystals were collected by filtration and washed with 80 L of 50% ethanol water. Vacuum drying gave 48.65 kg of N- (4-bromo-2-{[(5-chloropyridin-2-yl) amino] carbonyl} -6-hydroxyphenyl) -1-isopropylpiperidine-4-carboxamide.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm) = 0.97 (6H, br), 1.52 (2H, br), 1.71 (2H, br), 2.23 (2H, br), 2.41 (1H, br ), 2.82 (2H, br), 3.51 (1H, br), 7.18 (2H, m), 7.93 (1H, m), 8.12 (1H, m), 8.38 (1H, m). FAB-MS m / z : 497 (M + H) ⁺ .

Example 2 (Production of malonate crystals)
N- (4-Bromo-2-{[(5-chloropyridin-2-yl) amino] carbonyl} -6-hydroxyphenyl) -1-isopropylpiperidine-4-carboxamide 23.40 kg, malonic acid 7.40 kg, water 206 A mixture of L and 309 L of 1-propanol was heated and dissolved (81 ° C.), then cooled and stirred at 0 ° C. overnight. The crystals were collected by filtration and washed with 100 L of 1-propanol. Vacuum-dried N- (4-bromo-2-{[(5-chloropyridin-2-yl) amino] carbonyl} -6-hydroxyphenyl) -1-isopropylpiperidine-4-carboxamide malonate 21.89 kg Obtained.
A powder X-ray diffraction diagram and a thermal analysis diagram of malonate crystals are shown in FIGS.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm) = 1.15 (6H, br), 1.77 (2H, br), 1.90 (2H, br), 2.67 (1H, br), 2.77 (2H, s ), 2.84 (2H, br), 3.23 (3H, br), 7.20 (2H, m), 7.93 (1H, m), 8.11 (1H, m), 8.39 (1H, m), 9.42 (0.4H, br ), 10.65 (0.6H, br) .FAB-MS m / z: 497 (M + H) ⁺ .

Reference Example 7 (Production of hydrochloride crystal B)
N- (4-Bromo-2-{[(5-chloropyridin-2-yl) amino] carbonyl} -6-hydroxyphenyl) -1-isopropylpiperidine-4-carboxamide hydrochloride 0.46 g, ethanol 7 ml and water 3 ml of the mixture was dissolved by heating, then cooled and stirred at 0 ° C. overnight. The crystals were collected by filtration and washed with 2 ml of ethanol. Vacuum drying gave 0.24 g of N- (4-bromo-2-{[(5-chloropyridin-2-yl) amino] carbonyl} -6-hydroxyphenyl) -1-isopropylpiperidine-4-carboxamide hydrochloride It was.

(Test example)
The usefulness of the malonate crystal of the present invention as a drug manufacturing substance and the usefulness as a drug were confirmed by the following tests.

1. Hygroscopicity test VTI SGA-100 was used for the measurement of hygroscopicity under the conditions of temperature: 25 ° C., measurement range: relative humidity 5 to 95%, measurement interval: relative humidity 5%.
As a result, N- (4-bromo-2-{[(5-chloropyridin-2-yl) amino] carbonyl} -6-hydroxyphenyl) -1-isopropylpiperidine-4-carboxamide hydrochloride crystal A The humidity increased from about 5%, and the relative humidity of 95% retained moisture of about 2% and exhibited hygroscopicity (see FIG. 8). Further, the hydrochloride crystal B showed an increase in weight from a relative humidity of about 5%, and showed a strong hygroscopicity while holding about 5% of water at a relative humidity of 95% (see FIG. 9). N- (4-Bromo-2-{[(5-chloropyridin-2-yl) amino] carbonyl} -6-hydroxyphenyl) -1-isopropylpiperidine-4-carboxamide hydrochloride crystal A and hydrochloride crystal B Both showed hygroscopicity and were not suitable as a drug substance.
On the other hand, the malonate crystal of the present invention did not exhibit hygroscopicity in the entire range of 5% to 95% relative humidity (see FIG. 7). Therefore, it was shown to be useful as a medicine, particularly as a solid composition.

2. Coagulation time measurement test for human activated blood coagulation factor Xa (in vitro)
Add 10 μl of drug or physiological saline and 50 μl of human factor Xa (Enzyme Research Labs) to 90 μl of human plasma, incubate at 37 ° C. for 3 minutes, and then add 100 μl of 20 mM CaCl ₂ previously warmed to 37 ° C. The time until solidification was performed using a coagulometer (Amelung: KC10) was measured. For human plasma, 45 ml of blood is collected from a healthy person (6 people) from the cubital vein with 5 ml of 3.8% sodium citrate and pooled by centrifugation at 4 ° C, 3000 rpm, 15 minutes, What was cryopreserved was used. The concentration of human factor Xa was selected so that the clotting time was about 30-40 seconds when physiological saline (control) was added. The CT ₂ value (concentration that doubles the clotting time of the control) was obtained by plotting a relative value (fold) of the clotting time with respect to the control and the drug concentration and performing linear regression.

As a result, the malonate crystal of the present invention showed a strong activity of 0.094 μM in a human activated blood coagulation factor X coagulation time measurement test.

Powder X-ray diffraction pattern of N- (4-bromo-2-{[(5-chloropyridin-2-yl) amino] carbonyl} -6-hydroxyphenyl) -1-isopropylpiperidine-4-carboxamide malonate crystal . (Invention Crystal) In the figure, Intensity represents strength. same as below. N- (4-Bromo-2-{[(5-chloropyridin-2-yl) amino] carbonyl} -6-hydroxyphenyl) -1-isopropylpiperidine-4-carboxamide Powder X-ray diffraction pattern of hydrochloride crystal A . (Comparative example) N- (4-Bromo-2-{[(5-chloropyridin-2-yl) amino] carbonyl} -6-hydroxyphenyl) -1-isopropylpiperidine-4-carboxamide Powder X-ray diffraction pattern of hydrochloride crystal B . (Comparative example) Thermal analysis of N- (4-bromo-2-{[(5-chloropyridin-2-yl) amino] carbonyl} -6-hydroxyphenyl) -1-isopropylpiperidine-4-carboxamide malonate crystals. (Crystal of the present invention) In the figure, Temperature represents temperature, Heat Flow Exo Up represents heat generation in the positive direction (plus direction), and Weight represents weight. same as below. N- (4-Bromo-2-{[(5-chloropyridin-2-yl) amino] carbonyl} -6-hydroxyphenyl) -1-isopropylpiperidine-4-carboxamide Thermal analysis diagram of hydrochloride crystal A. FIG. (Comparative example) N- (4-Bromo-2-{[(5-chloropyridin-2-yl) amino] carbonyl} -6-hydroxyphenyl) -1-isopropylpiperidine-4-carboxamide Thermal analysis diagram of hydrochloride crystal B. FIG. (Comparative example) FIG. 3 is a hygroscopic curve of N- (4-bromo-2-{[(5-chloropyridin-2-yl) amino] carbonyl} -6-hydroxyphenyl) -1-isopropylpiperidine-4-carboxamide malonate crystal. (Invention Crystal) In the figure, Adsorption represents adsorption, Desorption represents desorption, Isotherm represents an isotherm, and RH represents relative humidity. same as below. N- (4-bromo-2-{[(5-chloropyridin-2-yl) amino] carbonyl} -6-hydroxyphenyl) -1-isopropylpiperidine-4-carboxamide Hygroscopic curve of hydrochloride crystal A. FIG. (Comparative example) N- (4-bromo-2-{[(5-chloropyridin-2-yl) amino] carbonyl} -6-hydroxyphenyl) -1-isopropylpiperidine-4-carboxamide Hygroscopic curve of hydrochloride crystal B. FIG. (Comparative example)

Claims (5)

N- (4-bromo-2-{[(5-chloropyridin-2-yl) amino] carbonyl} -6-hydroxyphenyl) -1-isopropylpiperidine having a heat absorption peak at 214-220 ° C. by DSC analysis -4-carboxamide malonate crystals. N- (4-bromo-2-{[(5) having main peaks in the vicinity of 2θ (°) 7.8, 15.4, 18.8, 19.6, 22.6, 23.6, 24.4, 26.3, 28.3, 31.1 and 32.7 by powder X-ray diffraction. -Chloropyridin-2-yl) amino] carbonyl} -6-hydroxyphenyl) -1-isopropylpiperidine-4-carboxamide malonate crystals. DSC analysis has a heat absorption peak at 214-220 ° C, and X-ray powder diffraction shows 2θ (°) 7.8, 15.4, 18.8, 19.6, 22.6, 23.6, 24.4, 26.3, 28.3, 31.1 and 32.7. N- (4-bromo-2-{[(5-chloropyridin-2-yl) amino] carbonyl} -6-hydroxyphenyl) -1-isopropylpiperidine-4-carboxamide malonate crystals. A solid composition comprising the malonate crystal according to claim 1 and a pharmaceutically acceptable carrier. The solid composition according to claim 4, which is an activated blood coagulation factor X inhibitor.

Images