Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-28
2001-10-30
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S238000
Reexamination Certificate
active
06310065
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a 3/2-hydrochloride of a pyridazinone compound having a bronchodilation function, an antiallergy function and/or an antiplatelet function, and a method for producing the same.
BACKGROUND ART
A pyridazinone compound of the formula (1), i.e. 4-chloro-5-[3-(4-benzylpiperazin-1-yl) carbonylmethoxy-4-methoxybenzylamino]-3(2H)-pyridazinone is disclosed in WO95/01343 laid open on Jan. 12, 1995 and JP-A-8-041033 laid open on Feb. 13, 1996, and is a compound useful as a pharmaceutical product having a bronchodilation function, an antiallergy function or an antiplatelet function.
The above patent publications disclose a hydrochloride of the pyridazinone compound (1) and a method for producing the same, and a 2-hydrochloride (see Reference Example 1) obtained by the above preparation method has an excellent pharmaceutical effect. However, the 2-hydrochloride is highly hygroscopic and is easily decomposed and is rapidly decomposed in a methanol solvent. Thus, the 2-hydrochloride is unstable, and is therefore not suitable as a starting material for a pharmaceutical product.
DISCLOSURE OF THE INVENTION
In order to solve the above-mentioned problems, the present inventors have intensively studied, and have discovered that the pyridazinone compound (1) takes a 3/2-hydrochloride form (2) in addition to a 2-hydrochloride form. Further, as proved by the following Test Example 1, the present inventors have discovered that the pyridazinone compound (1) in the form of 3/2-hydrochloride (2) is clearly excellent in hygroscopicity and stability.
Further, the compound (1) and its 3/2-hydrochloride (2) were compared with regard to biological dynamics in a dog. As this result, it was found that as compared with the compound (1), the 3/2-hydrochloride has 5.4 times higher maximum concentration in blood (Cmax) and is 2.3 times more preferable in respect of area under the curve (AUC) of time-concentration in blood (0-∞). Thus, it was proved that the 3/2-hydrochloride (2) is excellent as a starting material for a pharmaceutical product as compared with the compound (1). Result: (10 mg/kg oral administration by capsules)
TABLE 1
Compound
Cmax (ng/ml)
AUC (0-∞) (ng/ml · hr)
1
249.7
844.3
2
1349.0
1998.3
Further, it was found that the 3/2-hydrochloride achieves a pharmaceutical effect equivalent to that of 2-hydrochloride, and it was therefore confirmed that the 3/2-hydrochloride has a satisfactory applicability as a starting material for a pharmaceutical product. The present invention has been completed on the basis of the above-mentioned discovery.
On the other hand, as shown in Reference Example 3, a method for producing a 1-hydrochloride has been discovered. However, this compound is hardly decomposed, but has a high hygroscopicity, and its crystal is easily electrostatically charged, and this compound is poor in solubility and is colored by light. Thus, in view of its physical properties, this compound is not suitable as a starting material for a pharmaceutical product. Still further, according to powder X-ray diffraction analysis, it was proved that the 3/2-hydrochloride is not a mixture of 2-hydrochloride and 1-hydrochloride (see Test Example 2 and
FIG. 1
showing powder X-ray diffraction data).
Thus, the present invention relates to a 3/2-hydrochloride (2) of a pyridazinone compound (1) and a method for producing the same.
The method for producing the 3/2-hydrochloride (2) includes the following features
(1) A method characterized by crystallizing a pyridazinone compound (1) in an alcohol type solvent or an alcohol type-ester type mixture solvent in the presence of hydrogen chloride and water.
(2) A method characterized by crystallizing a 2-hydrochloride of a pyridazinone compound (1) in an alcohol type solvent or an alcohol type-ester type mixture solvent in the presence of hydrogen chloride and water.
(3) A method characterized by crystallizing a 1-hydrochloride of a pyridazinone compound (1) in an alcohol type solvent or an alcohol type-ester type mixture solvent in the presence of hydrogen chloride and water.
(4) The method according to the above method (1), (2) or (3), wherein the alcohol type solvent is methanol or ethanol.
(5) The method according to the above method (1), (2) or (3), wherein the alcohol type-ester type mixture solvent is methanol-ethyl acetate mixture solvent.
(6) The method according to the above method (1), (2) or (3), wherein the alcohol type-ester type mixture solvent is ethanol-ethyl acetate mixture solvent.
Now, the method for producing the compound of the present invention is described in more details hereinafter.
A 2-hydrochloride of pyridazinone compound (1) obtained from a three component solvent system of chloroform-methanol-diethyl ether disclosed in WO95/01343 and JP-A-8-041033 can be obtained also from a two component system solvent of ethyl acetate-methanol as shown in Reference Example 2. In this case, hydrogen chloride is added in the form of a methanol solution, but if this is replaced by a solution of 35% hydrochloric acid diluted with methanol, a 3/2-hydrochloride (the compound of the present invention) can be obtained, as shown in Example 1. Thus, the presence of water plays an important role. Under this condition, even when a 2-hydrochloride is added as a seed crystal, a crystal obtained is a 3/2-hydrochloride. As concretely shown in the Examples, the 3/2-hydrochloride could be obtained even when crystallizing conditions were largely varied, and this fact proves that the 3/2-hydrochloride is not a simple mixture of 2-hydrochloride and 1-hydrochloride.
The compound (1) used as a starting material in the production method of the present invention may be a 2-hydrochloride, a 1-hydrochloride or other salts.
Examples of a solvent usable in the present invention include ethyl acetate-ethanol of Example 2 and ethanol alone of Example 3 in view of a production process of a starting material for a pharmaceutical product, but the solvent is not specially limited and other alcohol type or ester type solvents may be used. Examples of the alcohol type solvent include methanol, propanol, isopropanol, ethylene glycol or the like, and examples of the ester type solvent include methyl acetate, isopropyl acetate, ethyl propionate or the like.
An amount of a solvent used is not specially limited, but if the amount of a solvent is smaller, there is a tendency that a time required for crystallization is reduced. However, if the amount of a solvent is smaller than 1.5 times weight to the compound, stirring becomes difficult and causes a problem during mass production.
An amount of hydrogen chloride is necessary to be at least 2 mol time amount (hydrogen chloride) to the compound (1), but the upper limit amount is not specially limited. However, when taking economic conditions, operation efficiency and risk of hydrolysis of the compound into consideration, the amount of hydrogen chloride is generally in the range of from 2 time mol to 8 time mol amounts, preferably from 2.5 time mol to 4 time mol amounts. Hydrogen chloride may be used in the form of a 35% hydrochloric acid solution. As previously mentioned above, water in hydrochloric acid plays an important role in the production method of the present invention.
In order to obtain a 3/2-hydrochloride, the amount of water is preferably in the range of from 0.17 to 1 time weight to 4-chloro-5-[3-(4-benzylpiperazin-l-yl) carbonylmethoxy-4-methoxybenzylamino]-3 (2H) -pyridazinone used as a starting material. The optimum water amount varies depending on a kind and an amount of a solvent used, but concretely a 0.5 time amount is most suitable in the case of ethanol-ethyl acetate type mixture solvent. In the following Examples, 35% hydrochloric acid which is a commercially available concentrated hydrochloric acid was used, but hydrochloric acid used is not necessarily limited thereto.
As described in the following Examples, a relatively long time is required for crystallization. Therefore, such a high crystallization temperature as to cause hydrolysis o
Horiuchi Takashi
Kamikawaji Minako
Matsumoto Hiroo
Matsumoto Sachiko
Bernhardt Emily
Nissan Chemical Industries Ltd.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
LandOfFree
Pyridazinone hydrochloride compound and method for producing... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Pyridazinone hydrochloride compound and method for producing..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Pyridazinone hydrochloride compound and method for producing... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2593050