JP2000212168A - New crystal of hexahydro-1,4-diazepine derivative salt hydrate - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject crystal which has an activity to inhibit the activated blood coagulation factor X, can easily be purified, when produced in a large amount, can extremely easily be handled, when processed into preparations, etc., is thermally stable, and has excellent storage stability and high solubility. SOLUTION: The crystal of N-[4-(4-acetimidolylhexahydro-1H-1,4-diazepin-1- yl)phenyl]-N-[(7-amidino-2-naphthyl)methyl]sulfamoyl}acetic acid salt hydrate. The crystal is obtained, for example, by dissolving the amorphous solid of N-[4-(4-acetimidolylhexahydro-1H-1,4-diazepin-1-y1)phenyl]-N-[(7-amidi no-2- naphthyl)methyl]sulfamoyl}acetic acid hydrochloric acid salt or the hydrochloric acid salt crystal in water in the presence of hydrobromic acid or the hydrobromic acid and a hydrobromide (NaBr, etc.), and then crystallize the compound at a pH value of about 5.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to [N- [4- (4
-Acetimidoylhexahydro-1H-1,4-diazepin-1-yl) phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] acetic acid salt hydrate The present invention relates to α-form crystals, β-form crystals of monohydrobromide hydrate and crystals of the same ethanesulfonate hydrate.

[0002]

Activated blood coagulation factor X is located at the junction of extrinsic and intrinsic coagulation cascade reactions.
zyme, and inhibition of this factor may be more efficient than thrombin inhibition and may specifically inhibit the coagulation system [T
HROMBOSIS RESEARCH (19), 339-349, 1980]. Therefore, it is thought that an agent that specifically inhibits activated blood coagulation factor X can be an anticoagulant or an effective agent for preventing or treating diseases caused by thrombus or embolus.
Amidinonaphthyl derivatives and the like have been reported as compounds exhibiting activated blood coagulation factor X inhibitory activity [JP-A-5-208946 / Thrombosis Haemostasis, 71].
(3), 314-319, 1994 / Thrombosis Haemostasis, 72 (3),
393-396, 1994 or WO 96/16940]. However, [N- [4- (4-acetimidoylhexahydro-1) has excellent activated blood coagulation factor X inhibitory activity.
H-1,4-diazepin-1-yl) phenyl] -N-
A series of hexahydro-1,4-diazepine derivatives, including [(7-amidino-2-naphthyl) methyl] sulfamoyl] acetic acid, or a pharmaceutically acceptable salt thereof, has not been reported previously.

[0003]

Under such a state of the art, the present inventors have conducted intensive studies for the purpose of providing a medicament having an activated blood coagulation factor X inhibitory activity.
[4- (4-acetimidoylhexahydro-1H-
1,4-diazepin-1-yl) phenyl] -N-
A series of hexahydro-1,4-diazepine derivatives, including [(7-amidino-2-naphthyl) methyl] sulfamoyl] acetic acid, or a pharmaceutically acceptable salt thereof, provides excellent activated blood coagulation X It has been found for the first time that it has factor inhibitory activity, and a patent application has already been filed (PCT / JP98 / 03267). Example 33 of the publication discloses "ethyl [N- [4- (4-acetimidoylhexahydro-1H-1,4-diazepine-1).
-Yl) phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] acetate dihydrochloride
450 mg was dissolved in concentrated hydrochloric acid (8 ml) and stirred at room temperature for 14 hours. The residue obtained by evaporating the reaction solution was dissolved in 8 ml of concentrated hydrochloric acid and stirred at room temperature for 4 hours. The residue obtained by evaporating the reaction solution was purified by ODS column chromatography using acetonitrile: water (10:90) as an elution solvent. After adding a small amount of 1N hydrochloric acid and freeze-drying, [N- [4- (4-acetimidoylhexahydro-1H-1,4-diazepin-1-yl) phenyl] -N-[(7-amidino-2- Naphthyl) methyl] sulfamoyl] acetic acid dihydrochloride
302 mg were obtained. Is described. However, the dihydrochloride was an amorphous solid (amorphous) and was not separated as crystals. Then, [N- [4-
(4-acetimidoylhexahydro-1H-1,4-
Diazepin-1-yl) phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] acetic acid is easy to purify in mass production,
It has been desired to find highly soluble salt hydrate crystals that are extremely easy to handle in formulation and the like, are thermally stable, and have excellent storage stability.

[0004]

Means for Solving the Problems The present inventors [N-
[4- (4-acetimidoylhexahydro-1H-
1,4-diazepin-1-yl) phenyl] -N-
[(7-Amidino-2-naphthyl) methyl] sulfamoyl] acetic acid salt hydrate, particularly α-form crystal, β-form crystal of the same monohydrobromide hydrate and ethanesulfonic acid hydrate of the same Completed the present invention by finding that the new crystal is a highly soluble crystal that is easy to purify during mass production, is extremely easy to handle during formulation, is thermally stable, has excellent storage stability, and is highly soluble. did.

[0005]

DETAILED DESCRIPTION OF THE INVENTION [N- [4- (4-acetimidoylhexahydro-1H-1,4-diazepin-1-yl) phenyl] -N-[(7-amidino-2-naphthyl) methyl Sulfamoyl] Acetic acid
Α- and β-form crystals of monohydrobromide hydrate crystals and [N- [4- (4-acetimidoylhexahydro-
1H-1,4-diazepin-1-yl) phenyl] -N
Table 1 shows the physicochemical properties of the crystals of-[(7-amidino-2-naphthyl) methyl] sulfamoyl] acetic acid 1 ethanesulfonate hydrate.

[0006]

[Table 1]

(Production method) The crystal of the monohydrobromide hydrate of the present invention is [N- [4- (4-acetimidoylhexahydro-1H-1,4-diazepin-1-yl) phenyl]. ] -N-[(7-amidino-2-naphthyl) methyl]
Sulfamoyl] amorphous solid of acetic acid hydrochloride, or hydrochloride crystals in the presence of hydrobromic acid (HBr) or hydrobromic acid and hydrobromic acid salt (NaBr, KBr, etc.)
It is produced by dissolving in water and adjusting the pH to about 5 for crystallization. By repeating the same operation, it is possible to recrystallize and purify again. Further, it can also be purified by a usual recrystallization method in which it is heated and dissolved, and then cooled and crystallized. The crystals of the monohydrate of ethanesulfonate of the present invention are obtained by dissolving the crystals of monohydrate of hydrobromide in water in the presence of ethanesulfonic acid (EtSO ₃ H) and adjusting the pH to about 5. And can be manufactured. By repeating the same operation, it is possible to recrystallize and purify again.

[N- [4- (4-acetimidoylhexahydro-1H-1,4-diazepin-1-yl) phenyl] -N-[(7-amidino-2-naphthyl) methyl] of the present invention Sulfamoyl] Acetic acid
The hydrate salt is a pharmaceutically acceptable salt, specifically, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid,
Inorganic acids such as phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid,
Acid addition salts with organic acids such as ethanesulfonic acid, propanesulfonic acid, toluenesulfonic acid, aspartic acid, glutamic acid, inorganic bases such as sodium, potassium, magnesium, calcium, aluminum, methylamine, ethylamine, ethanolamine, lysine, Examples thereof include salts with an organic base such as ornithine and the like, and ammonium salts. Among these, monohydrobromide and ethanesulfonate are preferred. Further, the salt hydrate of the present invention becomes a 4 to 6 hydrate in a normal storage state, but may become another hydrate under drying and humidification. Further, a pharmaceutical composition containing the crystal of the present invention as an active ingredient, a carrier or excipient for a commonly used formulation, using other additives, tablets,
It is prepared into powders, fine granules, granules, capsules, pills, solutions, injections, suppositories, ointments, patches, and the like, and is orally or parenterally administered.

[0009]

The crystal of the present invention is obtained not as an amorphous solid but as a crystal, so that it is easy to purify during mass production, and it is very easy to handle such as formulation. Further, it is a crystal having high solubility, which is thermally stable and excellent in storage stability. For example, the solubility of the crystals of 1-ethanesulfonate hydrate of the present invention in water is 10 mg / ml or more. Also,
All of the crystals of the present invention showed high stability in a stability test at 60 ° C. room humidity. For example, the residual ratio of the α-form crystal of the monohydrobromide hydrate of the present invention was 99.6% at 60 ° C. and room humidity. This indicates that these crystals are extremely useful as pharmaceuticals.
The crystal of the present invention specifically inhibits activated blood coagulation factor X and has a strong anticoagulant effect.
/ JP98 / 03267.

[0010]

The method for producing the crystal of the present invention will be specifically described below. The starting compounds of the crystals of the present invention also include novel compounds, and a method for producing these compounds will be described as a reference example. In the measurement of the powder X-ray diffraction of the crystal of the present invention, copper (Cu) was used as a radiation source.

Reference Example 1 Hexahydro-1H-1,4-diazepine (21.4 g) was dissolved in DMF (214 ml), and thereto was added 4-fluoronitrobenzene (10.1 g) and potassium carbonate (19.7 g), followed by stirring at 90 ° C. for 7 hours. The reaction solution was distilled off, chloroform was added to the obtained residue, and the mixture was washed successively with a 10% aqueous potassium hydrogen carbonate solution and saturated saline, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The obtained residue is
-Dissolved in 210 ml of dichloroethane, and 86.5 g of triethylamine, 9-di-t-butyl dicarbonate 9
3.4 g was added, and the mixture was stirred at room temperature for 13 hours. The reaction solution was washed with water, dried over anhydrous sodium sulfate, and evaporated. The residue was washed with ether and 4-tert-butoxycarbonyl-1-.
(4-nitrophenyl) hexahydro-1H-1,4-
14.12 g of diazepine were obtained.

Reference Example 2 14.12 g of the obtained 4-t-butoxycarbonyl-1- (4-nitrophenyl) hexahydro-1H-1,4-diazepine was suspended in 44 ml of ethanol, and 700 mg of 10% palladium-carbon was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The reaction solution was filtered and then distilled off. The resulting residue was dissolved in 440 ml of 1,2-dichloroethane, then 7.95 g of 7-formyl-2-naphthalenecarbonitrile, 26 ml of acetic acid, and sodium triacetoxyborohydride. 5 g were sequentially added, and the mixture was stirred at room temperature for 2 hours. Further, 0.8 g of 7-formyl-2-naphthalenecarbonitrile and sodium triacetoxyborohydride 1.
9 g was added and stirred for 1 hour. Furthermore, 7-formyl-2-
0.8 g of naphthalenecarbonitrile and 1.9 g of sodium triacetoxyborohydride were added, and the mixture was stirred for 2 hours.
The reaction solution was washed successively with a 10% aqueous potassium carbonate solution and saturated saline, dried over anhydrous sodium sulfate, and evaporated. Of the obtained residue (25.01 g), 7.04 g was purified by silica gel column chromatography using hexane: ethyl acetate (3: 1) as an eluting solvent to give 7-[[4- (4
-T-butoxycarbonylhexahydro-1H-1,4
-Diazepin-1-yl) anilino] methyl] -2-naphthalenecarbonitrile 4.45 g was obtained.

Reference Example 3 7-[[4- (4-t-Butoxycarbonylhexahydro-1H-1,4-diazepin-1-yl) anilino] methyl] -2-naphthalenecarbonitrile 57 obtained
0 mg was dissolved in 1,2-dichloroethane (13 ml).
Stirred at ° C. Add 296 mg of pyridine and ethyl
After adding (chlorosulfonyl) acetate (350 mg), the mixture was stirred at room temperature for 12 hours. Chloroform was added to the reaction solution, washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and evaporated. The obtained residue was purified by silica gel column chromatography using hexane: ethyl acetate (50:50) as an eluting solvent,
[N- [4- (4-t-butoxycarbonylhexahydro-1H-1,4-diazepin-1-yl) phenyl]
660 mg of -N-[(7-cyano-2-naphthyl) methyl] sulfamoyl] acetate were obtained.

Reference Example 4 The obtained ethyl [N- [4- (4-tert-butoxycarbonylhexahydro-1H-1,4-diazepine-1-)
5.19 g of yl) phenyl] -N-[(7-cyano-2-naphthyl) methyl] sulfamoyl] acetate was dissolved in a mixture of 9 ml of chloroform and 9 ml of ethanol. The solution was cooled to −20 ° C. with stirring, and saturated by introducing hydrogen chloride. After the reaction solution was stirred at 5 ° C. for 23 hours, the reaction solution was distilled off. The obtained residue was dissolved in 18 ml of ethanol, 6.6 g of ammonium acetate was added thereto, and the mixture was stirred at room temperature for 28 hours. The reaction solution was distilled off, and the obtained residue was purified by ODS column chromatography using ethanol: water (10:90) as an elution solvent. Add a small amount of 1N hydrochloric acid, freeze-dry and add ethyl [N-
[(7-amidino-2-naphthyl) methyl] -N- [4
1.02 g of-(hexahydro-1H-1,4-diazepin-1-yl) phenyl] sulfamoyl] acetate dihydrochloride was obtained.

Reference Example 5 The obtained ethyl [N-[(7-amidino-2-naphthyl) methyl] -N- [4- (hexahydro-1H-1,
590 mg of 4-diazepin-1-yl) phenyl] sulfamoyl] acetate dihydrochloride in ethanol 22
680 ml of ethylacetimidate hydrochloride
g and 555 mg of triethylamine were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was distilled off, and the obtained residue was purified by ODS column chromatography using ethanol: water (10:90) as an elution solvent. After adding a small amount of 1N hydrochloric acid, freeze-drying was performed, and ethyl [N- [4- (4-acetimidoylhexahydro-1H-1,4-diazepine-
118 mg of 1-yl) phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] acetate dihydrochloride was obtained. The obtained ethyl [N- [4-
(4-acetimidoylhexahydro-1H-1,4-
Diazepin-1-yl) phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] acetate dihydrochloride (450 mg) was dissolved in concentrated hydrochloric acid (8 ml) and stirred at room temperature for 14 hours. The reaction solution was distilled off, and the obtained residue was dissolved in 8 ml of concentrated hydrochloric acid and stirred at room temperature for 4 hours. The reaction solution was distilled off, and the obtained residue was treated with acetonitrile: water (1
0:90) as an elution solvent. After adding a small amount of 1N hydrochloric acid, the mixture is freeze-dried and [N- [4- (4-acetimidoylhexahydro-1H-1,4-diazepin-1-yl) phenyl]].
-N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] acetic acid dihydrochloride 302 m
g was obtained.

Example 1 [N- [4- (4-acetimidoylhexahydro-1H-1,4-diazepin-1-yl) obtained in Reference Example]
929 mg of phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] acetic acid dihydrochloride was dissolved in 5 ml of water, and a saturated aqueous sodium hydrogen carbonate solution was added dropwise with stirring to adjust the pH to 5. . After stirring for 3 hours, the resulting crystals were filtered and [N- [4- (4-
Acetimidylhexahydro-1H-1,4-diazepin-1-yl) phenyl] -N-[(7-amidino-
761 mg of 2-naphthyl) methyl] sulfamoyl] acetic acid monohydrochloride hydrate was obtained. [N- [4- (4-acetimidoylhexahydro-1H-1,4-diazepin-1-yl) obtained in this manner.
Phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] acetic acid monohydrochloride hydrate (1.00 g) was suspended in 25 ml of water, and NaBr was added.
After adding 4.12 g and 2.12 ml of a 47% aqueous HBr solution and stirring at room temperature for 2 hours, a saturated aqueous sodium hydrogen carbonate solution was added dropwise to adjust the pH to 5. Stir at room temperature for 20 hours,
The obtained crystals were filtered, washed with water, and dried under reduced pressure.
The obtained crystals were allowed to stand at about 84% humidity for 24 hours and N- [4
-(4-acetimidoylhexahydro-1H-1,4
-Diazepin-1-yl) phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] acetic acid monohydrobromide hydrate α-form crystal 1.00 g was obtained.

Example 2 Ethyl [N-[(7
-Amidino-2-naphthyl) methyl] -N- [4- (hexahydro-1H-1,4-diazepin-1-yl) phenyl] sulfamoyl] acetate oxalate 10
g was dissolved in 50 ml of methanol, 5.03 g of ethylacetoimidate hydrochloride and 5.77 g of triethylamine were added, and the mixture was stirred at room temperature for 3.5 hours. After 200 ml of water was added dropwise over 30 minutes, the mixture was stirred at room temperature for 3 hours. After adding 0.33 g of triethylamine and stirring at room temperature for 1.5 hours, 0.33 g of triethylamine was further added and stirred for 1 hour. 2.52 g of 47% HBr aqueous solution, NaBr16.7
6 g and 50 ml of water were added, and the mixture was heated to 60 ° C. and dissolved, then returned to room temperature and stirred for 18 hours. The obtained crystals are filtered, washed with water, and dried under reduced pressure, and 6.97 g of N- [4- (4-acetimidoylhexahydro-1H-1,4-diazepin-1-yl) phenyl] is obtained. -N-[(7-amidino-2
-Naphthyl) methyl] sulfamoyl] acetic acid monohydrobromide 6.97 g of crude crystals were obtained. After adding 270 ml of water to the crude crystals and raising the temperature to 54 ° C., 1.36 g of activated carbon was added, and the mixture was stirred at 54 ° C. for 1 hour and filtered.
Washed with 68 ml of warm water. NaBr was added to the resulting aqueous solution.
After adding 5.7 g, the mixture was stirred at room temperature for 13 hours, and the resulting crystals were filtered, washed with water, and dried under reduced pressure. Then about 7
By leaving it at 5% humidity for 4 days, N- [4- (4
-Acetimidoylhexahydro-1H-1,4-diazepin-1-yl) phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] acetic acid monohydrobromide hydrate Form β crystals were obtained.

Example 3 N- [4- (4-acetimidoylhexahydro-1H-1,4-diazepin-1-yl) obtained in Example 1
Phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] acetic acid monohydrobromide hydrate α-form crystal, 1.00 g, was suspended in 7 ml of water, and EtSO ₃ H1. A mixture of 72 ml and 3 ml of water was dropped and dissolved. Thereafter, a saturated aqueous sodium hydrogen carbonate solution was added dropwise to adjust the pH to 5. After stirring at room temperature for 5 hours, the obtained crystals were filtered, washed with water, and dried under reduced pressure. The suspension was suspended once again in 7 ml of water, and stirred under EtSO.
₃ was added dropwise a mixture of H1.72ml and water 3ml dissolved. Then, a saturated aqueous solution of sodium hydrogencarbonate is added dropwise to adjust the pH.
Was adjusted to 5. After stirring at room temperature for 15 hours, the obtained crystals were filtered, washed with water, and dried under reduced pressure. The obtained crystal was left at about 84% humidity for 24 hours, and N- [4- (4-acetimidoylhexahydro-1H-1,4-diazepin-1-yl) phenyl] -N-[(7-amidino -2-
965 mg of naphthyl) methyl] sulfamoyl] acetic acid 1 ethanesulfonate hydrate was obtained.

[0019]

[Brief description of the drawings]

FIG. 1. [N- [4- (4-acetimidoylhexahydro-1H-1,4-diazepin-1-yl) phenyl] -N-[(7-amidino-2-naphthyl) methyl]
X-ray diffraction pattern of α-form crystal of sulfamoyl] acetic acid monohydrobromide hydrate

FIG. 2 [N- [4- (4-acetimidoylhexahydro-1H-1,4-diazepin-1-yl) phenyl] -N-[(7-amidino-2-naphthyl) methyl]
X-ray diffraction pattern of β-form crystal of sulfamoyl] acetic acid monohydrobromide hydrate

FIG. 3. [N- [4- (4-acetimidoylhexahydro-1H-1,4-diazepin-1-yl) phenyl] -N-[(7-amidino-2-naphthyl) methyl]
X-Ray Diffraction Diagram of Sulfamoyl] Acetic Acid 1 Ethane Sulfonate Hydrate Crystal

Continued on the front page (72) Inventor Tsukasa Ishihara 21 Miyukigaoka, Tsukuba, Ibaraki Prefecture Yamanouchi Pharmaceutical Co., Ltd. (72) Inventor Sugazawa Keizo 21 Miyukigaoka, Tsukuba City, Ibaraki Pref. Inventor Yoshihiro Akiba 160-2 Matsukubo, Akahama, Takahagi City, Japan Yamanouchi Pharmaceutical Co., Ltd. (72) Inventor Hiroyuki Kaizawa 21 Miyukigaoka, Tsukuba, Ibaraki Prefecture Yamanouchi Pharmaceutical Co., Ltd. 21 Miyukigaoka, Yamanouchi Pharmaceutical Company Limited F term (reference) 4C086 AA03 BC54 GA13 GA15 NA03 ZA54 ZC41

Claims (4)

[Claims] 1. [N- [4- (4-acetimidoylhexahydro-1H-1,4-diazepin-1-yl) phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl ] Acrylic acid salt hydrate crystals. 2. In the powder X-ray diffraction pattern, the lattice spacing is 6.
It shows strong diffraction peaks at 3, 5.0, 4.8, 4.7, 3.8, 3.7 and 3.5 ° [N- [4-
(4-acetimidoylhexahydro-1H-1,4-
Α-form crystal of diazepin-1-yl) phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] acetic acid monohydrobromide hydrate. 3. An X-ray powder diffraction pattern having a lattice spacing of 4.
[N- [4- (4-acetimidoylhexahydro-1H-1,4-diazepin-1-yl) phenyl] -N showing strong diffraction peaks at 7, 4.6, 3.7 and 3.6 °. -[(7-amidino-2-naphthyl) methyl]
Sulfamoyl] β-type crystal of acetic acid monohydrobromide hydrate. 4. An X-ray powder diffraction pattern having a lattice spacing of 14.
[N- [4- (4-acetimidoylhexahydro-1H-1,4-diazepin-1-yl) showing strong diffraction peaks at 4, 5.1, 4.8, 4.7 and 4.2}. Phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] acetic acid
Crystals of 1 ethanesulfonate hydrate.