JPH10316677A - Crystal - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a high purity crystal easy in handling and excellent in solid stability by crystallizing a compound having bradykinin antagonism, and useful as a preventive and/or treating agent for allergies, inflammations, etc. SOLUTION: This crystal is a crystal of the hydrate of 8-[3-[N-[(E)-3-(6- acetoamidopyridin-3-yl)acryloylglycidyl]-N-methylamino-2,6-dichloroben zyloxy]-2- methylquinoline (called FR173657) and preferably being three kinds of crystals of A-type crystal in which powdery X-ray diffraction pattern has peculiar peaks at about 5.66 deg., 9.27 deg., 21.73 deg., 24.64 deg., and 24.90 deg., B-type crystal which has peculiar peaks at about 9.78 deg., 12.92 deg., 21.64 deg., 28.95 deg. and 29.21 deg., and C-type crystal which has peculiar peaks at about 4.38 deg., 8.73 deg., 21.85 deg. and 27.97 deg..

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to 8- [3- [N-
[(E) -3- (6-acetamidopyridin-3-yl) acryloylglycyl] -N-methylamino]-
2,6-Dichlorobenzyloxy] -2-methylquinoline (hereinafter, FR173657) hydrate crystals and a pharmaceutical composition containing the same.
Used in the medical field.

[0002]

BACKGROUND OF THE INVENTION Problems to be Solved by the Invention
173657 corresponds to the following formula [I] disclosed in JP-A-7-2780.

[0003]

Embedded image

The compound has activity as a bradykinin antagonist represented by, for example, allergy, inflammation, autoimmune disease,
It is a compound useful as a prophylactic and / or therapeutic agent for shock, pain and the like. FR173657 has excellent activity as a bradykinin antagonist, but it can be produced only in an amorphous form so far, and this amorphous solid has insufficient solid stability and a low filtration rate during production. Due to the drawbacks, there is a problem in manufacturing and supplying pharmaceuticals having a certain quality. The inventors of the present invention have intensively studied to obtain FR173657 as a crystal having good solid stability and easy to handle in drug production, and as a result, it has been confirmed that FR173657 has high purity and excellent solid stability.
The present inventors have found crystals of the hydrate of 173657 and completed the present invention.

[0005]

Means for Solving the Problems FR17365 of the present invention
The hydrate crystal of 7 is a state in which water molecules are included as a part of the crystal lattice of the FR173657 crystal, a state in which water molecules are included in the crystal lattice of the FR173657 crystal, Or all states such as a state of being attached or a combination thereof.

The crystal of the hydrate of FR173657 may change depending on the relative humidity, but is usually 2 to 12% by weight.
Containing water. Of the crystals of the hydrate of FR173657,
Three types of crystals having the following physicochemical properties (referred to as A-type crystals, B-type crystals, and C-type crystals, respectively) are preferred. Measurement conditions Water content: Measurement by Karl-Fisher method Powder X-ray diffraction: Anti-cathode: Cu Filter: Ni Tube voltage: 30 kV Tube current: 10 mA Detector: Scintillation counter Infrared absorption spectrum: Measurement by Nujol method Thermal analysis (TG / DTA): Heating rate: 10 ° C./min

(1) Physicochemical properties of A-type crystal (a) Water content It varies within a range of about 3.5 to 8.5% depending on relative humidity. (B) Characteristic diffraction peak (2θ) in powder X-ray diffraction
Value) 5.66 °, 9.27 °, 21.73 °, 24.64 ° and around 24.90 ° The powder X-ray diffraction pattern is shown in FIG. (C) Characteristic absorption in infrared absorption spectrum 3265, 1703, 1529, 1234 and 835
FIG. 2 shows the cm ^-1 infrared absorption spectrum. (D) Thermal analysis (TG / DTA) From room temperature to 154 ° C, a weight loss (6.32%) based on desorption of water is shown, and at 132 ° C, an endothermic peak (peak apex: 138 ° C) based on glass transition. After 25
At 9 ° C. there was a weight loss due to decomposition. Thermal analysis (TG /
The DTA) profile is shown in FIG.

(2) Physicochemical characteristics of B-type crystal (a) Water content The water content varies within a range of about 2.5 to 5% depending on relative humidity. (B) Characteristic diffraction peak (2θ) in powder X-ray diffraction
Value) 9.78 ゜, 12.92２１, 21.64 ゜, 28.95
゜ and around 29.21 ゜ The powder X-ray diffraction pattern is shown in FIG. (C) Characteristic absorption in infrared absorption spectrum FIG. 5 shows the infrared absorption spectra of 3588, 3498, 1682, 1537, 1238 and 833 cm ^-1 . (D) Thermal analysis (TG / DTA) From room temperature to 110 ° C., a weight loss (2.88%) due to desorption of water was shown, and an endothermic peak (peak apex: 209 ° C.) due to melting was shown at 203 ° C. . Thermal analysis (TG
/ DTA) profile is shown in FIG.

(3) Physicochemical properties of the C-type crystal (a) Water content It varies within a range of about 5 to 11% depending on relative humidity. (B) Characteristic diffraction peak (2θ) in powder X-ray diffraction
Values) 4.38, 8.73, 21.85, and 27.9
The powder X-ray diffraction pattern around 7 ° is shown in FIG. (C) Characteristic absorption in infrared absorption spectrum 3300, 1683, 1535, 1245 and 839
FIG. 8 shows the cm ^-1 infrared absorption spectrum. (D) Thermal analysis (TG / DTA) From room temperature to 100 ° C., a weight loss (5.47%) due to desorption of water and an endothermic peak (peak apex: 92 ° C.) were shown.
Endothermic peak due to melting at 7 ° C. (peak apex: 145
° C). The thermal analysis (TG / DTA) profile is shown in FIG.

[0010] The crystal of the hydrate of FR173657 is prepared by producing FR173657 by a known method disclosed in, for example, JP-A-7-2780, and then stirring the FR173657 in a solvent under heating or heating, followed by cooling. A method of dissolving FR173657 in a solvent under acidic conditions, followed by adding a base and, if necessary, water or a water-containing solvent to neutralize the solution, thereby precipitating crystals.
The FR173657 crystal can be produced by exposing the crystal to water vapor or organic solvent vapor, or by combining them.

[0011] As a solvent used for the precipitation of crystals,
Water, for example, alcohols such as methanol, ethanol, isopropyl alcohol and the like, acetone, N, N-dimethylformamide, dioxane, tetrahydrofuran, ethyl acetate, acetonitrile, dimethyl sulfoxide and the like, or a common organic solvent such as dimethyl sulfoxide, or a mixed solvent thereof, is more preferable. Examples include water-containing alcohols such as water-containing methanol and water-containing ethanol, water-containing acetone, and a mixed solvent of water and an organic solvent such as a combination of water and ethyl acetate.

Further, the crystals of each of the above-mentioned A-type, B-type and C-type can more preferably be produced by the method described in the following Examples or a method similar thereto. The crystal of the hydrate of FR173657 of the present invention has potent activity as a bradykinin antagonist, and is a disease induced by bradykinin or an analog thereof in humans or animals, such as allergy, inflammation, autoimmune disease, shock, and pain. It is useful for treatment and / or prevention.

[0013] For treatment, the FR17365 of the present invention
Oral administration of hydrate crystal of 7 as an active ingredient; parenteral administration such as intravenous injection, intramuscular injection, subcutaneous injection or intraarticular injection; external use such as transdermal, enteral administration, rectal administration, transdermal administration It may be used in the form of a pharmaceutical preparation containing it together with a pharmaceutically acceptable carrier such as an organic or inorganic solid, semi-solid or liquid excipient suitable for vaginal administration, inhalation, ophthalmic, nasal, sublingual administration and the like. it can.

[0014] The pharmaceutical preparation may be a capsule, tablet, dragee, granule, suppository, solution, lotion, suspension, emulsion, ointment, gel, cream or the like.
If necessary, the above-mentioned preparations may be mixed with auxiliary agents, stabilizers, wetting or emulsifying agents, buffers and other commonly used additives. The dose of FR173657 hydrate crystals will vary with the age and condition of the patient, but for the prevention and / or treatment of the aforementioned diseases, FR17365
About 0.1 mg, 1 m
g, 10 mg, 50 mg, 100 mg, 250 mg, 5
It may be used as 00 mg and 1000 mg. Generally, 0.1 mg / individual to 1,00 mg / day
A dose of 0 mg / individual may be used.

[0015]

The crystal of the hydrate of FR173657 according to the present invention has higher purity and better solid stability than known FR173657, and substantially contains a residual organic solvent unsuitable as a medicament. Since it is not available, it is useful for producing and supplying pharmaceuticals having a certain quality.

In addition to these effects, A type, B type and C type
Each type of crystal is particularly useful because there is no transition to another crystal form under heating or humidification conditions, and among them, type B crystal is particularly useful under any conditions. No metastasis is observed and is more useful.

[0017]

EXAMPLES The present invention will be described more specifically with reference to the following production examples and examples, but the present invention is not limited to these examples. Production Example 1 8- [3- (N-glycyl-N-methylamino) -2,
6-Dichlorobenzyloxy] -2-methylquinoline (100 mg), a mixture of (E) -3- (6-acetamidopyridin-3-yl) acrylic acid (56.1 mg) and N, N-dimethylformamide (2 ml) 1 in
-Hydroxybenzotriazole (43.4 mg) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (56.9 mg) in a nitrogen stream at 0 ° C.
And the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with chloroform. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate, water and brine,
After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by preparative thin-layer chromatography (methanol: dichloromethane = 1: 10, v / v), solidified with diethyl ether and ethyl acetate, and treated with 8- [3- [N-
[(E) -3- (6-acetamidopyridin-3-yl) acryloylglycyl] -N-methylamino]-
2,6-Dichlorobenzyloxy] -2-methylquinoline (FR173657) (78.8 mg) was obtained as an off-white solid. mp: 133-139 ° C NMR (CDCl ₃ , δ): 2.22 (3H, s), 2.74 (3H, s), 3.27
(3H, s), 3.67 (1H, dd, J = 16.5, 5.5 Hz), 3.96 (1H, d
d, J = 16.5, 5.5Hz), 5.62 (1H, d, J = 11.0Hz), 5.67 (1
H, d, J = 11.0Hz), 6.46 (1H, d, J = 16.0Hz), 6.73 (1H,
brt, J = 5.5 Hz), 7.21-7.33 (3H, m), 7.38-7.51 (3H,
m), 7.52 (1H, d, J = 16.0 Hz), 7.82 (1H, dd, J = 8.5,
1.5Hz), 8.03 (1H, d, J = 8.5Hz), 8.13-8.25 (2H, m),
8.33 (1H, d, J = 1.5Hz)

Production Example 2 FR173657 (7 g) in methanol (720 ml)
Was added at 60 ° C., and the mixture was stirred under reflux for 5 minutes. Mix 30
After cooling to 20 ° C or lower, the mixture was stirred at 20 to 30 ° C for 2 hours to be crystallized. The crystallized solution was filtered and the crystallized product was methanol (14 ml).
, And vacuum dried at 40 ° C to obtain FR173657.
(6.3 g) of crude anhydrous crystals (hereinafter referred to as crude FR173657 crystals) was obtained. The crystals were crystals containing about 5% methanol.

EXAMPLE 1 Crude FR173657 crystals (100 g) and purified water (5 g)
Concentrated hydrochloric acid (28.1 ml) was added to the mixture (00 ml) while stirring at 10 ° C. or lower to dissolve the mixture. After adding charcoal powder (5 g) and stirring for 2.5 hours, the charcoal powder was filtered off and purified water (2 g) was added.
00 ml) and concentrated hydrochloric acid (1.4 ml). The obtained filtrate was added to a mixture of acetone (700 ml) and triethylamine (35.87 g) at 55 ° C, and the mixture was stirred at the same temperature for 5 minutes and then refluxed for 20 minutes. After cooling to 40 ° C., the precipitated crystals were collected by filtration. The crystals were washed with 50% acetone and dried under vacuum to obtain FR173657 hydrate crystals (A-type crystals) (88.7 g). Powder X-ray diffraction pattern diagram As shown in FIG. 1 Infrared absorption spectrum diagram As shown in FIG. 2 Thermal analysis (TG / DTA) profile diagram as shown in FIG. 3 As shown in FIG.

Example 2 Crude FR173657 crystals (50 g) and purified water (25
0 ml) to a mixture of concentrated hydrochloric acid (1 ml) while stirring at 5 ° C.
4.1 ml) and dissolved. After adding charcoal dust (2.5 g) and stirring for 30 minutes, the charcoal dust was filtered off and washed with dilute hydrochloric acid. The obtained filtrate was added to a mixture of ethyl acetate (350 ml) and triethylamine (17.93 g) at 70 ° C., and the mixture was stirred under reflux for 2 hours. After cooling to 20 ° C., the mixture was further stirred at the same temperature for 2 hours, and the precipitated crystals were collected by filtration. The crystals were washed with ethyl acetate (100 ml) and purified water (100 ml) and dried in vacuo at 40 ° C. to obtain FR173657 hydrate crystals (B-type crystals) (44.51 g). Powder X-ray diffraction pattern diagram As shown in FIG. 4 Infrared absorption spectrum diagram As shown in FIG. 5 Thermal analysis (TG / DTA) profile diagram As shown in FIG. 6

Example 3 Concentrated hydrochloric acid (2.11 ml) was added to a mixture of crude FR173657 crystals (7.5 g) and 50% ethanol (188 ml) while stirring at 5 ° C., and the mixture was stirred for 5 minutes to dissolve. After filtration, the plate was washed with 50% ethanol (37.5 ml). The obtained filtrate is washed with 50% ethanol (150 ml).
And a mixture of triethylamine (2.56 g)
The mixture was added dropwise at 30 ° C. over 30 minutes and stirred at the same temperature overnight. 25
After cooling to ℃, the mixture was further stirred at the same temperature for 5.5 hours, and the precipitated crystals were collected by filtration. The crystals were washed with 50% ethanol (15 ml) and dried under vacuum to obtain FR173657 hydrate crystals (B-type crystals). The powder X-ray diffraction pattern and the infrared absorption spectrum were the same as those of the crystal obtained in Example 2, respectively.

Example 4 Crude FR173657 crystals (260 g) and purified water (1
Concentrated hydrochloric acid (73 ml) was added to the mixture (300 ml) with stirring at 5 ° C., and the mixture was dissolved by stirring for 10 minutes. After filtration, the resultant was washed with diluted hydrochloric acid. The obtained filtrate is washed with acetone (65
00 ml), purified water (4680 ml) and triethylamine (93.3 g) were added dropwise at 20 ° C. over 30 minutes, and seed crystals of type C crystal (26 mg) were added. The mixture was stirred at the same temperature for 2.5 hours, cooled to 3 ° C.,
Stirred for hours. The precipitated crystals were collected by filtration, washed with 50% acetone (520 ml), dried in vacuo at 40 ° C.
73657 hydrate crystal (C-type crystal) (236.68)
g) was obtained. X-ray powder diffraction pattern diagram Infrared absorption spectrum diagram as shown in Fig. 7 Thermal analysis (TG / DTA) profile diagram as shown in Fig. 8 As shown in Fig. 9

Example 5 Crude FR173657 crystals (5 g) were dissolved in ethanol (100
ml) and purified water (25 ml) at 70 ° C. or higher. Add charcoal powder (0.25g) and add 3 at the same temperature
After stirring for 0 minutes, the charcoal dust was removed by filtration and washed with 80% ethanol (25 ml). The purified filtrate was added to hot purified water (9
0 ml), and the mixture was adjusted to 50 ° C., and then a seed crystal of a C-type crystal was added. The mixture was stirred at the same temperature for 1.5 hours, cooled to 2 ° C, and further stirred for 3 hours. The precipitated crystals are collected by filtration,
The crystals were washed with 50% ethanol (10 ml), dried in vacuo at 40 ° C., and crystallized as a hydrate of FR173657 (C-type crystal).
(4.31 g) was obtained. The powder X-ray diffraction pattern and the infrared absorption spectrum were the same as those of the crystal obtained in Example 4, respectively.

EXAMPLE 6 Crude FR173657 crystals (80 g) and purified water (40 g)
0 ml) to a mixture of concentrated hydrochloric acid (2 ml) at 3 ° C. with stirring.
2.5 ml) and stirred for 8 minutes to dissolve. Ethyl acetate (400 ml) was added, and the mixture was stirred and separated. The aqueous layer was washed with ethyl acetate (400 ml), charcoal powder (4 g) was added, and the mixture was stirred at 3 ° C. for 40 minutes. The charcoal powder was removed by filtration, and purified water (160 ml) and concentrated hydrochloric acid (1.13 ml). Washed. The obtained filtrate was divided into four parts, which were used in the following (1) to (4). (1) Acetone (140 ml) was added to the obtained filtrate, and triethylamine (7.17 g) was added thereto at 7 ° C. The mixture was stirred at the same temperature for 1 hour and then refluxed for 40 minutes. The mixture was cooled to 25 ° C. and stirred for 1 hour. The precipitated crystals were collected by filtration, washed with 50% acetone (40 ml), and dried in vacuo to obtain FR173657 hydrate crystals (C
(Type crystal) was obtained. The powder X-ray diffraction pattern and the infrared absorption spectrum were the same as those of the crystal obtained in Example 4, respectively. (2) Acetone (140 ml) was added to the obtained filtrate, and triethylamine (7.17 g) was added thereto at 22 ° C. The mixture was stirred at the same temperature for 1 hour and then refluxed for 40 minutes. The mixture was cooled to 25 ° C. and stirred for 1 hour. The precipitated crystals were collected by filtration, washed with 50% acetone (40 ml), and dried in vacuo to obtain FR173657 hydrate crystals (A
(A mixture of type crystals and type C crystals). (3) Acetone (140 ml) was added to the obtained filtrate, and triethylamine (7.17 g) was added thereto at 30 ° C. The mixture was stirred at 50 ° C. for 1 hour, cooled to 25 ° C., and further stirred for 1 hour. The precipitated crystals are collected by filtration, and 50
% Acetone (40 ml), dried under vacuum,
A crystal of 73657 hydrate (A-type crystal) was obtained. Powder X
The line diffraction pattern and the infrared absorption spectrum were identical to those of the crystal obtained in Example 1, respectively. (4) Acetone (140 ml) and triethylamine (7.17 g) were added to the obtained filtrate, and the mixture was added to 43%.
After stirring at 20 ° C. for 20 minutes, the mixture was refluxed for 1 hour. Mixture at 25 ° C
And stirred for 1.5 hours. The precipitated crystals were collected by filtration, washed with 50% acetone (40 ml), and dried in vacuo to obtain FR173657 hydrate crystals (A-type crystals). The powder X-ray diffraction pattern and infrared absorption spectrum
Each of them coincided with the crystal obtained in Example 1.

Example 7 FR173657 hydrate crystal (form A crystal) (2 g)
Was added to purified water (40 ml) at 85 ° C., and the mixture was stirred at the same temperature for 4 hours. The crystals were collected by filtration, washed with purified water (4 ml), and dried in vacuo at 40 ° C. to obtain hydrate crystals of FR173657 (C-type crystals). The powder X-ray diffraction pattern and the infrared absorption spectrum were the same as those of the crystal obtained in Example 4, respectively.

Example 8 FR173657 hydrate crystal (form A crystal) (2 g)
Was added to purified water (40 ml) at 90 ° C. or higher, and the mixture was stirred at the same temperature for 4.5 hours. The crystals were collected by filtration and purified water (4 m
1), vacuum-dried at 40 ° C.
A hydrate crystal (form B crystal) was obtained. The powder X-ray diffraction pattern and the infrared absorption spectrum were the same as those of the crystal obtained in Example 2, respectively.

Example 9 FR173657 hydrate crystal (C-type crystal) was added to acetone at room temperature, and the mixture was stirred at 20 ° C. for 1 hour. The crystals are collected by filtration, washed with acetone and dried in vacuo at 40 ° C.
A crystal of a hydrate of FR173657 (A-type crystal) was obtained.
The powder X-ray diffraction pattern and the infrared absorption spectrum were identical to those of the crystals obtained in Example 1, respectively.

[Brief description of the drawings]

FIG. 1 is a powder X-ray diffraction pattern diagram of a crystal of a hydrate of FR173657 (A-type crystal).

FIG. 2 is an infrared absorption spectrum of a crystal of hydrate of FR173657 (A-type crystal).

FIG. 3 is a thermal analysis (TG / DTA) profile diagram of a crystal (form A crystal) of a hydrate of FR173657.

FIG. 4 is a powder X-ray diffraction pattern diagram of a crystal of hydrate of FR173657 (B-type crystal).

FIG. 5 is an infrared absorption spectrum of a crystal of a hydrate of FR173657 (B-type crystal).

FIG. 6 is a thermal analysis (TG / DTA) profile diagram of a crystal of hydrate of FR173657 (B-type crystal).

FIG. 7 is a powder X-ray diffraction pattern diagram of a crystal of a hydrate of FR173657 (C-type crystal).

FIG. 8 is an infrared absorption spectrum of a crystal (C-type crystal) of a hydrate of FR173657.

FIG. 9 is a thermal analysis (TG / DTA) profile diagram of a crystal (C-type crystal) of a hydrate of FR173657.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI A61K 31/47 AED A61K 31/47 AED (72) Inventor Satoshi Kitamura 45-B-814, Yamada Minami, Suita-shi (72) Inventor I Katsuhiko Fuji 4-20-507 Kumano-cho, Nishinomiya-shi

Claims (7)

[Claims] (1) 8- [3- [N-[(E) -3- (6-acetamidopyridin-3-yl) acryloylglycyl] -N-methylamino] -2,6-dichlorobenzyloxy]- Crystals of 2-methylquinoline hydrate. 2. The crystal according to claim 1, wherein the hydrate comprises 2 to 12% by weight of water. 3. In a powder X-ray diffraction pattern, 5.66.
゜, 9.27 ゜, 21.73 ゜, 24.64 ゜ and 2
3. The crystal according to claim 2, which shows a characteristic peak around 4.90 °. 4. An X-ray powder diffraction pattern of 9.78
3. The crystal according to claim 2, which exhibits characteristic peaks around {, 12.92}, 21.64}, 28.95} and 29.21}. 5. An X-ray powder diffraction pattern of 4.38
The crystal according to claim 2, which exhibits characteristic peaks around {, 8.73}, 21.85} and 27.97%. 6. A pharmaceutical composition comprising the crystal according to claim 1, 2, 3, 4 or 5 as an active ingredient together with a pharmaceutically acceptable and substantially non-toxic carrier or excipient. 7. A preventive and / or therapeutic agent for a disease induced by bradykinin or an analog thereof, comprising the crystal according to claim 1, 2, 3, 4 or 5 as an active ingredient.