JPH09221479A - Aminobenzenesulfonic acid derivative monohydrate and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce a new aminobenzenesulfonic acid derivative monohydrate useful for producing a medicinal composition effective in preventing or treating ischemic cardiopathy, cardiac failure and hypertension, etc. SOLUTION: This new aminobenzenesulfonic acid derivative monohydrate is represented by the formula [R<1> is H, an alkyl, a halogen, etc.; R<2> is H, an alkyl or cyano, an aralkyl, etc.; (n) is an integer of 1-4], e.g. 2-(1-piperazinyl)-5- methylbenzenesulfonic acid monohydrate. The compound represented by formula I is obtained by suspending an aminobenzenesulfonic acid derivative anhydride in water or a hydrous organic solvent or carrying out the crystallizing treatment of the dissolved solution and drying the formed crystal. The organic solvent to be used is a water-soluble organic solvent such as methanol or ethanol. The suspending treatment of the anhydride is preferably conducted by stirring the mixture at normal temperature for >=2hr.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an aminobenzenesulfonic acid derivative monohydrate, a pharmaceutical composition containing the hydrate as an active ingredient, and a method for producing an aminobenzenesulfonic acid derivative monohydrate. .

[0002]

PRIOR ART The following general formula (I):

Embedded image (In the formula, R ¹ is a hydrogen atom, a C _{1 to} C ₆ alkyl group, a C _{3 to} C ₇ cycloalkyl group, a C _{1 to} C ₄ halogenated alkyl group, a halogen atom, or a C _{6 to} C ₁₂ Represents an aryl group; R ² represents a hydrogen atom, a C _{1 to} C ₆ alkyl group, or a cyano group, a nitro group, a C _{1 to} C ₆ alkoxy group, a halogen atom, a C _{1 to} C ₆ alkyl group, and amino; An aminobenzenesulfonic acid represented by a C _{7 to} C ₁₂ aralkyl group which may have one or more substituents selected from the group consisting of groups; and n represents an integer of 1 to 4). Derivatives are known to have an action of suppressing intracellular Ca ^{2+ hyperaccumulation} . (JP-A-3-
7263). It has been clarified that these compounds are useful for the prevention and treatment of ischemic heart disease (such as myocardial infarction and angina), heart failure, hypertension or arrhythmia (Japanese Patent Application Laid-Open No. 3-7263 and Patent Publication No. (Kaihei 4-139127 publication).

Among these compounds, 2- (1-piperazinyl) -5-methylbenzenesulfonic acid (disclosed in Example 1 of JP-A-3-7263 and Synthesis example 1 of JP-A-4-139127). Compound No. 12), which significantly suppresses the excessive inflow of calcium ions into myocardial cells and has high safety, is an active ingredient of a therapeutic and / or prophylactic agent for heart disease. It is expected to be extremely useful.

A method for producing these compounds is disclosed in Japanese Patent Publication No. 6-864.
According to that method, the compound of the above-mentioned general formula (I) is obtained as an anhydride. However, according to the research conducted by the present inventors, this anhydride may have hygroscopicity, and if left as it is, it may absorb moisture gradually and increase in weight to become a monohydrate. There was found. In particular, when a formulation study was conducted to provide 2- (1-piperazinyl) -5-methylbenzenesulfonic acid as a therapeutic and / or preventive agent for heart disease, this substance gradually absorbs moisture during the formulation process. Since this causes a weight change, it is difficult to accurately weigh the preparation, and the content of the active ingredient varies among lots of the preparation, which makes it impossible to stably supply a uniform preparation. In producing a formulation containing the above aminobenzene sulfonic acid derivative as an active ingredient, it is desirable to use a monohydrate rather than an anhydride from the viewpoint of producing and supplying a formulation that guarantees stable and constant quality. .

Japanese Patent Laid-Open Nos. 3-7263 and 4-139127 teach the existence of acid addition salts and base addition salts for the above-mentioned aminobenzenesulfonic acid derivatives. There is no suggestion or teaching about having the property of forming a Japanese product. Further, the above-mentioned publication specifically discloses 2- (1-piperazinyl) -5-methylbenzenesulfonic acid (anhydride) in a free form, but whether this compound forms a monohydrate or not. There is no suggestion or teaching about this.

[0006]

Generally, as a method for producing a hydrate from an anhydride, (1) a method of allowing an anhydride to stand in a humidified steam chamber to adjust the humidity, (2) an anhydrous humidified steam The method of positively injecting and controlling the humidity is used. However, in the case of producing a large amount of hydrate, the method of (1) requires a long time to control the humidity, and water droplets adhere to the steam chamber or the container to cause unevenness of the humidity control partially, resulting in a uniform humidity control. There is a problem that it is difficult to produce a hydrate. Also,
The method (2) has a problem that when the anhydride is insufficiently dispersed, uneven humidity control occurs partially and a uniform hydrate cannot be produced. Furthermore, in common with the methods of (1) and (2), it is difficult to control the humidification conditions, so there is a high risk of absorbing more than the desired equivalent amount of hydrate, and in that case again. There is the problem that the anhydride has to be prepared again. The present inventors have tried to produce a monohydrate by a method corresponding to (1), as shown in Reference Examples described later,
It was confirmed that there are problems that it takes a long time to produce a monohydrate, and that water droplets adhere to the inside of the steam chamber or the container, which often necessitates wiping.

[0007]

[Means for Solving the Problems] The inventors of the present invention, while searching for the cause of these problems, found that the anhydride of 2- (1-piperazinyl) -5-methylbenzenesulfonic acid was found to cause moisture in the air and formulation. By contacting with water used in the liquefaction process,
It was found that one molecule of water was taken in as crystal water and gradually changed to a monohydrate. Further, the present inventors have found that the above-obtained monohydrate is stable and has no weight change due to moisture absorption, and that the use of this hydrate in the formulation process enables accurate weighing. Therefore, it has been found that a pharmaceutical composition having a uniform active ingredient content can be provided.
The present invention has been completed based on the above findings.
Further, the inventors of the present invention have conducted extensive studies on a simple method for producing a monohydrate of an aminobenzenesulfonic acid derivative, and as a result, completed the present invention.

That is, the present invention provides the following general formula (I):

Embedded image (In the formula, R ¹ is a hydrogen atom, a C _{1 to} C ₆ alkyl group, a C _{3 to} C ₇ cycloalkyl group, a C _{1 to} C ₄ halogenated alkyl group, a halogen atom, or a C _{6 to} C ₁₂ Represents an aryl group; R ² represents a hydrogen atom, a C _{1 to} C ₆ alkyl group, or a cyano group, a nitro group, a C _{1 to} C ₆ alkoxy group, a halogen atom, a C _{1 to} C ₆ alkyl group, and amino; An aminobenzenesulfonic acid represented by a C _{7 to} C ₁₂ aralkyl group which may have one or more substituents selected from the group consisting of groups; and n represents an integer of 1 to 4). A monohydrate of the derivative is provided. According to a preferred embodiment of the present invention, there is provided an aminobenzenesulfonic acid derivative monohydrate wherein R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group, R ² is a hydrogen atom, and n is 2. (In the present specification, the term “monohydrate” means a monohydrate crystal). 2- (1-Piperazinyl) -5-methylbenzenesulfonic acid monohydrate is provided as a particularly preferred embodiment of the present invention.

According to another aspect of the invention, the above formula (I)
A method for producing a monohydrate of an aminobenzenesulfonic acid derivative represented by the formula (1), wherein an anhydride of the aminobenzenesulfonic acid derivative (in the present specification, “anhydride” means an anhydrous crystal (non-crystal)). (Which means) is suspended in water or a water-containing organic solvent, or a solution obtained by dissolving the anhydride in water or a water-containing organic solvent is subjected to a crystallization treatment, and then the obtained crystals are dried. A method is provided that includes the steps of: According to a preferred embodiment of this method, R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group, R ² is a hydrogen atom, and n is 2. Production method: A method for producing the above-mentioned aminobenzenesulfonic acid derivative monohydrate, wherein R ¹ is a methyl group, R ² is a hydrogen atom, and n is 2.

According to another embodiment of the present invention, after crystallite of 2- (1-piperazinyl) -5-methylbenzenesulfonic acid is suspended in water or a water-containing organic solvent, or the anhydride is water or water-containing. The solution obtained by dissolving in an organic solvent is subjected to a crystallization treatment, and the obtained crystal can be obtained by a method including a step of drying 2- (1-piperazinyl) -5-methylbenzenesulfonic acid Hydrate; and the above formula
(I) A pharmaceutical composition comprising an aminobenzenesulfonic acid derivative monohydrate represented by formula (I) as an active ingredient; and the active ingredient comprising 2- (1-piperazinyl) -5-methylbenzenesulfonic acid monohydrate. The above-mentioned pharmaceutical composition which is a product is provided.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The monohydrate of the aminobenzenesulfonic acid derivative provided by the present invention has the above general formula (I).
It is a monohydrate of the compound represented by: In the formula, as the C _{1 to} C ₆ alkyl group defined by R ¹ , for example, a methyl group,
Examples thereof include ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, hexyl group and isohexyl group. C ₃ ~
As the cycloalkyl group of C _7, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group,
Examples thereof include a cycloheptyl group. As the C _{1 to} C ₄ halogenated alkyl group, for example, a trifluoromethyl group,
Examples thereof include trifluoroethyl group and pentafluoroethyl group. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and the like. Examples of the C _{6 to} C ₁₂ aryl group include a phenyl group and a naphthyl group.

The C ₁ -C ₆ alkyl group defined by R ² includes, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, t
Examples thereof include ert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, hexyl group, and isohexyl group. As the C _{7 to} C ₁₂ aralkyl group,
Examples thereof include a benzyl group, a phenethyl group and a naphthylmethyl group. This aralkyl group is a cyano group; a nitro group; a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a tert-butoxy group, a pentyloxy group, an isopentyloxy group, t
ert-C _{1 to} C ₆ alkoxy group such as pentyloxy group and hexyloxy group; halogen atom such as fluorine atom, chlorine atom and bromine atom; methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group , Sec-butyl group, t
ert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, hexyl group, one or more substitutions selected from the group consisting of C _{1 to} C ₆ alkyl groups such as isohexyl group and amino group It may have a group.

As a preferred example of the monohydrate of the present invention, for example, in the above-mentioned general formula (I), R ¹ is a hydrogen atom or C ₁
To C ₆ alkyl group, R ² is a hydrogen atom, and n is 2
And a monohydrate of the compound Specific preferred examples of the monohydrate of the present invention include the monohydrates of the compounds shown in Table 1 below.

[0014]

[Table 1] ───────────────────────────── Compound number R ¹ R ² n ─────────── ─────────────────── 1 HH 2 2 CH ₃ H 2 3 CH ₂ CH ₃ H 2 4 (CH ₂ ) ₂ CH ₃ H 2 5 CH (CH ₃ ) ₂ H 2 6 (CH ₂ ) ₃ CH ₃ H 2 7 (CH ₂ ) ₄ CH ₃ H 2 8 (CH ₂ ) ₅ CH ₃ H 2 9 Phenyl H 2 10 HH 3 11 CH ₃ H 3 12 CH ₂ CH ₃ H 3 13 (CH ₂ ) ₂ CH ₃ H 3 14 CH (CH ₃ ) ₂ H 3 15 (CH ₂ ) ₃ CH ₃ H 3 16 (CH ₂ ) ₄ CH ₃ H 3 17 (CH ₂ ) ₅ CH ₃ H 3 18 Phenyl H 3 19 H CH ₃ 2 20 CH ₃ CH ₃ 2 21 CH ₂ CH ₃ CH ₃ 2 22 (CH ₂ ) ₂ CH ₃ CH ₃ 2 23 CH (CH ₃ ) ₂ CH ₃ 2 24 Phenyl CH ₃ 2 25 H (CH ₂ ) ₂ CH ₃ 2 26 CH ₃ (CH ₂ ) ₂ CH ₃ 2 27 CH ₂ CH ₃ (CH ₂ ) ₂ CH ₃ 2 28 (CH ₂ ) ₂ CH ₃ (CH ₂ ) ₂ CH ₃ 2 29 CH (CH ₃ ) ₂ (CH ₂ ) ₂ CH ₃ 2 30 Phenyl (CH ₂ ) ₂ CH ₃ 2 31 H benzyl 2 32 CH ₃ benzyl 2 33 CH ₂ CH ₃ benzyl 2 34 (CH ₂ ) ₂ CH ₃ benzyl 2 35 CH (CH ₃ ) ₂ benzyl 2 36 CH ₃ 2-cyanobenzyl 2 37 (CH ₂ ) ₂ CH ₃ 2-cyanobenzyl 2 38 CH ₃ 3-nitrobenzyl 2 39 (CH ₂ ) ₂ CH ₃ 3-nitrobenzyl 2 40 CH ₃ 4-methoxybenzyl 3 41 (CH ₂ ) ₂ CH ₃ 4-methoxybenzyl 3 42 CH ₃ 3,4-dimethoxybenzyl 3 43 (CH ₂ ) ₂ CH ₃ 3,4-dimethoxybenzyl 3 44 CH ₃ 2-fluorobenzyl 3 45 (CH ₂ ) ₂ CH ₃ 3-chlorobenzyl 3 46 CH ₃ 4-Bromobenzyl 3 47 (CH ₂ ) ₂ CH ₃ 2-Methylbenzyl 3 48 CH ₃ 3-Ethylbenzyl 3 49 (CH ₂ ) ₂ CH ₃ 4-Propylbenzyl 2 50 CH ₃ 3-Aminobenzyl 2 51 (CH ₂ ) ₂ CH ₃ 4-Aminobenzyl 2 ──────────────────────────────

The monohydrate of pharmaceutically acceptable salts of the above compounds is also included in the scope of the present invention. Examples of such salts include alkali metal salts or alkaline earth metal salts such as sodium salts, potassium salts, magnesium salts, calcium salts and aluminum salts; lower alkylamine salts such as ammonium salts and triethylamine salts, 2-
Hydroxyethylamine salts, bis- (2-hydroxyethyl) amine salts, tris (hydroxymethyl) aminomethane salts, hydroxy lower alkylamine salts such as N-methyl-D-glucamine salts, cycloalkylamine salts such as dicyclohexylamine salts, Benzylamine salt such as N, N-dibenzylethylenediamine salt, amine salt such as dibenzylamine salt; inorganic acid salt such as hydrochloride, hydrobromide, sulfate, phosphate; or fumarate Examples thereof include organic acid salts such as succinate, oxalate, and lactate.

Further preferred monohydrates are the monohydrates of the compounds of the above general formula (I) in which R ¹ is a methyl group, R ² is a hydrogen atom and n is 2. To be Crystals of 2- (1-piperazinyl) -5-methylbenzenesulfonic acid monohydrate provided as a particularly preferred embodiment of the present invention are described in Example 1 of JP-A No. 3-7263, Compound No. 12 It is a crystal different from the amorphous crystal of 2- (1-piperazinyl) -5-methylbenzenesulfonic acid described as. The monohydrate is stable at room temperature for a long period of time, and generally, even if it is dried at room temperature, water of crystallization is not eliminated. However,
By heating at a temperature of 60 ° C. or higher, for example, a temperature of about 100 to 120 ° C. under normal pressure or reduced pressure, the water of crystallization is gradually desorbed to remove the water of crystallization described in Example 1 of JP-A-3-7263. Give a crystal.

In the examples below, various physicochemical properties of the above-mentioned 2- (1-piperazinyl) -5-methylbenzenesulfonic acid monohydrate, which is a particularly preferred embodiment of the present invention, were experimentally investigated. It is to be understood that although shown as numerical values and spectra, these experimental numerical values and spectra are provided for reference only. Whether or not a crystal corresponds to the monohydrate of the present invention is determined by whether or not the crystal gives an experimental value and spectrum which are completely the same as the experimental value and spectrum shown in the present specification. should not do. It is easily understood by those skilled in the art that experimental numerical values and spectra include experimental errors due to factors such as measurement equipment and measurement method, or measurement conditions, and after considering such experimental errors, Needless to say, the judgment should be made based on whether or not it has the following physicochemical properties. The method for producing the monohydrate of the present invention is not particularly limited, but generally, according to the method described in Example 1 of JP-A No. 3-7263, the amorphous compound of the above formula (I) Then, the crystal-free crystal may be contacted with water, water in a solvent, or water in the air for an appropriate time. However, in order to produce the monohydrate of the present invention, it is preferable to use the production method of the present invention described below.

According to another aspect of the invention, the above formula (I)
A method for producing a monohydrate of an aminobenzenesulfonic acid derivative represented by the following, wherein the anhydride of the aminobenzenesulfonic acid derivative is suspended in water or a water-containing organic solvent, or the anhydride is water or There is provided a method including a step of subjecting a solution dissolved in a water-containing organic solvent to a crystallization treatment and then drying the obtained crystal. The aminobenzenesulfonic acid derivative of the above general formula (I) used as a raw material for the production of this method can be produced according to a known method (Japanese Patent Publication No. 6-86438). For example, when 2-fluoro-5-methylbenzenesulfonic acid and piperazine are reacted by heating in a sealed tube in the presence of cuprous iodide and copper powder, 5-methyl-2- (1-piperazinyl) benzenesulfonic acid is produced. can get. This compound
In the above general formula (I), R ¹ is a methyl group, R ² is a hydrogen atom, and n is 2 (Compound No. 2 in Table 1).

The aminobenzenesulfonic acid monohydrate of the present invention is prepared by suspending the aminobenzenesulfonic acid derivative represented by the general formula (I) in water or a water-containing organic solvent, and collecting the obtained crystals by filtration and drying. It can be manufactured. As the organic solvent, for example, a water-soluble organic solvent such as methanol, ethanol, 2-propanol, acetone or tetrahydrofuran can be used. The suspension treatment is preferably carried out under stirring conditions, and the treatment temperature is room temperature or under heating, preferably 35 ° C. or lower, and room temperature is also sufficient. The amount of water or water-containing organic solvent is not particularly limited, the above general formula (I)
The amount may be such that the aminobenzene sulfonic acid derivative (1) can be sufficiently immersed. Usually, 1 to 50 times amount (V / W) with respect to the weight of the aminobenzenesulfonic acid derivative of the above general formula (I).
Can be used. The proportion of water in the water-containing organic solvent is not particularly limited, but it is necessary to use water in an equimolar amount or more with respect to the aminobenzenesulfonic acid derivative of the above general formula (I). The suspension time may be short, but is usually 1 hour or longer, preferably 2 hours or longer. After the suspension is completed, the crystals can be collected by filtration and dried to obtain the monohydrate of the present invention. The pressure and temperature at the time of drying may be appropriately determined in consideration of the bond strength (stability of the monohydrate) of the crystal water constituting the monohydrate to the crystal. The end of drying can also be judged by stopping the weight change (reduction) of the crystals.

The aminobenzenesulfonic acid monohydrate of the present invention is obtained by dissolving the aminobenzenesulfonic acid derivative of the above general formula (I) in water or a water-containing organic solvent and subjecting it to crystallization treatment. After that, it can also be produced by filtering the obtained crystals and drying. As the crystallization treatment, for example, (a) dissolving the aminobenzenesulfonic acid derivative of the above general formula (I) in water or a water-containing organic solvent under heating or reflux stirring conditions, and then cooling the obtained solution. (B) The aminobenzenesulfonic acid derivative of the above general formula (I) is dissolved in a basic or acidic aqueous solution or a water-containing organic solvent, and the hydrogen ion concentration of the resulting solution is adjusted to acid. Alternatively, a method of precipitating and aging crystals by adjusting with a base; or (c) the aminobenzenesulfonic acid derivative of the above general formula (I) is dissolved in water or a water-containing organic solvent to obtain a solution. Examples thereof include a method of precipitating and aging crystals by adding a solvent that reduces the solubility of the aminobenzenesulfonic acid derivative of the general formula (I).

As the organic solvent, water-soluble organic solvents such as methanol, ethanol, 2-propanol, acetone and tetrahydrofuran can be used. As the acid,
Mineral acids such as hydrochloric acid and sulfuric acid, or organic acids such as acetic acid, methanesulfonic acid and paratoluenesulfonic acid are used, and the bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide. Alkali metal and alkaline earth metal salts such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate, or organic bases such as pyridine and triethylamine are used. Further, these acids and bases may be used as a solution diluted or dissolved with water or an organic solvent.
Temperature at which the aminobenzenesulfonic acid derivative of the above general formula (I) is dissolved; water, water-containing organic solvent, basic solvent, or acidic solvent amount; amount of acid or base used to adjust hydrogen ion concentration; Alternatively, the temperature at which the precipitated crystals are aged can be appropriately determined in consideration of the solubility of the aminobenzenesulfonic acid derivative of the general formula (I) in the solvent.

In the above method (a), the above general formula (I)
As the temperature at which the aminobenzenesulfonic acid derivative of is dissolved, for example, the reflux temperature of the solvent is preferable, and as the amount of water or the water-containing organic solvent, for example, the aminobenzenesulfonic acid of the above general formula (I) is used at the reflux temperature of the solvent. The minimum amount required for complete dissolution of the derivative is preferred. The temperature for aging the precipitated crystals is preferably room temperature or lower, more preferably 25 ° C or lower. The proportion of water in the water-containing organic solvent is not particularly limited, and is appropriately determined in consideration of the solubility of the aminobenzenesulfonic acid derivative of the general formula (I) in the solvent. The aging time of the precipitated crystals is usually 1 hour or longer, preferably 2 hours or longer.
After completion of the aging, the monohydrate of the present invention can be obtained by filtering the crystals and drying them. The drying step may be performed by the method described above.

When the monohydrate of the present invention is a monohydrate of a salt of the compound represented by the above formula (I), the monohydrate of the present invention can be prepared by I) A method for preparing a salt of an aminobenzenesulfonic acid derivative represented by the formula, and then producing a monohydrate of the salt according to the above method; producing a monohydrate of the compound in a free form according to the method of the present invention And then converting into a monohydrate salt according to a conventional method;
Or, when producing a monohydrate according to the method of the present invention,
It can be produced by a method such as simultaneous conversion into salts by a conventional method.

The monohydrate of the present invention is characterized by having substantially no water absorption and / or hygroscopicity. Therefore, for example, 2- (1) described in Example 1 of Japanese Patent Application Laid-Open No. 3-7263
-Piperazinyl) -5-methylbenzenesulfonic acid in place of crystal, 2- (1-piperazinyl) -5-methylbenzenesulfonic acid monohydrate of the present invention as an active ingredient of a pharmaceutical composition, effective Accurate weighing of the components is possible, and a pharmaceutical composition having a uniform active ingredient content can be provided.

The monohydrate of the present invention is useful for producing a pharmaceutical composition useful for the prevention or treatment of ischemic heart disease (myocardial infarction, angina, etc.), heart failure, hypertension or arrhythmia. . The form of such a pharmaceutical composition is not particularly limited, but tablets, capsules, powders that are administered orally,
Examples thereof include pharmaceutical compositions such as fine granules, granules, liquids, and syrups, and parenterally administered injections, infusions, suppositories, inhalants, patches and the like.

In the production of the above-mentioned pharmaceutical composition, appropriate pharmacologically and pharmaceutically acceptable additives can be used. Formulations suitable for oral administration, or transdermal or transmucosal administration include, for example, excipients such as glucose, lactose, D-mannitol, starch, or crystalline cellulose; disintegrating agents such as carboxymethyl cellulose, starch, or carboxymethyl cellulose calcium. Or a disintegration aid; a binder such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, or gelatin; a lubricant such as magnesium stearate or talc; a coating agent such as hydroxypropylmethylcellulose, sucrose, polyethylene glycol, or titanium oxide; A base such as petrolatum, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water, or hard fat can be used. In addition, propellants such as CFCs, diethyl ether, or compressed gas; adhesives such as sodium polyacrylate, polyvinyl alcohol, methyl cellulose, polyisobutylene, polybutene; additives for formulations such as cotton cloth or plastic cloth base cloth. Can be used.

Formulations suitable for injection or infusion include, for example, distilled water for injection, physiological saline, and solubilizers or solubilizers that can be dissolved in water before use, such as propylene glycol, or solubilizers; glucose, sodium chloride, Tonicity agents such as D-mannitol and glycerin; pharmaceutical additives such as pH adjusting agents such as inorganic acids, organic acids, inorganic bases or organic bases may be added. Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to the following Examples.

[0028]

【Example】

Example 1: Production of monohydrate of the present invention (a) According to the method described in Example 1 of JP-A-3-7263, 2-fluoro-5-methylbenzenesulfonic acid 0.76
g and piperazine (3.44 g) were reacted in the presence of copper iodide (0.76 g) and copper powder (0.26 g) in a sealed tube at 160 ° C. for 8 hours, and the reaction product was subjected to silica gel column chromatography (developing solvent; chloroform: methanol: Acetic acid = 100: 10
Purification at 0: 3) yielded amorphous 2- (1-piperazinyl) -5-methylbenzenesulfonic acid (0.67 g, 65.0% yield).

(B) To a 5 ml eggplant-shaped flask, 0.4506 g of the crystal-free crystal obtained in (a) above and 1.35 ml of distilled water were added, and the mixture was kept at 5 ° C.
For 2 hours. Crystals were recovered from the suspension by suction filtration, and then the crystals remaining in the eggplant-shaped flask were washed with the filtrate and collected. The combined crystals were dried at 50 ° C. and 90 mmHg for 3 hours to obtain 0.4485 g (yield 93.0%) of white 5-methyl-2- (1-piperazinyl) benzenesulfonic acid monohydrate. From the results of the elemental analysis shown below, it was confirmed that the present compound was a monohydrate. Elemental analysis: Monohydrate crystal Theoretical value: C: 48.16, H: 6.61, N: 10.21, S: 11.69 Actual value: C: 48.16, H: 6.55, N: 10.09, S: 11.87 (reference) Anhydrous crystal Theoretical: C: 51.54, H: 6.29, N: 10.93, S: 12.51

Example 2: Thermal analysis of the monohydrate of the invention (TG-DT
A) About 10 mg of a sample was taken, and using a thermal analyzer (RIGAKU TAS-200) in a dry nitrogen atmosphere, the amorphous crystal described in Example 1 of JP-A-3-7263 and the monohydrate of the present invention. Thermal analysis of the product was performed. The heating rate was 5 ° C / min, and the measurement was performed in the range of 50 to 400 ° C. As for crystal-free, the one obtained in (a) above was used.

Regarding the monohydrate of the present invention, a weight reduction and an endothermic peak due to desorption of water of crystallization were observed at around 60 ° C. The weight loss at this time was 6.57%, which was equivalent to one molecule of water. Furthermore, endothermic peaks accompanied by weight loss were observed around 300 ° C and 320 ° C (Fig. 1). On the other hand, crystal-free crystals gave endothermic peaks with weight loss around 300 ° C and 320 ° C, but neither weight loss nor endothermic peaks below 100 ° C due to desorption of water of crystallization were observed (Fig. 2). The monohydrate obtained in (b) of Example 1 was heated to 110 ° C. in a thermal analyzer to remove the water of crystallization of the monohydrate, and was prepared before use. When cooled and subjected to thermal analysis after cooling, the same data as that of the anhydride (FIG. 2) was obtained.

Example 3 X-Ray Diffraction Analysis of the Monohydrate of the Present Invention Using the X-ray diffractometer (Philips, PW 1700), the monohydrate of the present invention at room temperature under a stream of dry nitrogen (50 ml / min). Japanese powder X
Line diffraction analysis was performed. The powder diffraction pattern obtained is shown in FIG. Further, under the same conditions, the powder X-ray diffraction analysis of the crystal-free crystal obtained in (a) of Example 1 was performed. The obtained powder diffraction pattern is shown in FIG. Different powder diffractograms were given for monohydrate and amorphous, confirming that they are different crystalline powders. After analysis of the monohydrate, the temperature of the sample was raised to 110 ° C to prepare the quartz-free sample, and after cooling to 25 ° C, powder X-ray diffraction analysis was performed. A powder diffractogram was obtained.

Example 4: Hygroscopicity of the monohydrate of the invention The sample of the monohydrate of the invention was placed in a desiccator adjusted to 57% and 98% relative humidity and stored at 20 ° C for 16 days, during which time The change in weight was measured. As a control, the crystal-free crystal obtained in (a) of Example 1 was stored in a desiccator adjusted to a relative humidity of 57% and 98%, and the weight change was measured. Table 2 shows the results
(The numerical value (%) in the table indicates weight increase). The monohydrate did not show any substantial weight change compared with that before storage at any relative humidity. On the other hand, regarding non-crystal, a weight increase of about 7% corresponding to about 1 mol of water of crystallization was observed.

[0034]

[Table 2]

Example 5: Plasma concentration (1)

Embedded image 1 mg of the labeled body of 2- (1-piperazinyl) -5-methylbenzenesulfonic acid monohydrate represented by the above formula (II) (hereinafter abbreviated as “label body”) in male rats (n = 3) / kg [2- (1-piperazinyl) -5-methylbenzenesulfonic acid anhydride (hereinafter referred to as "anhydride") 0.94 mg / kg equivalent dose is orally administered to measure plasma radioactivity concentration AUC _0- ∞ (1039.86
ng eq · h / ml). AUC _0- ∞ was also administered to male rats (n = 3) intravenously at a dose of 0.3 mg / kg (0.28 mg / kg in terms of anhydride) of labeled body and the plasma radioactivity concentration was measured.
(816.28 ng eq.h / ml) was calculated. From these values of AUC _0- ∞ and the dose at that time, the absorption rate was calculated by the following formula 1. The absorption rate was 38%.

[0036]

(Equation 1)

Example 6: Plasma concentration (2) Male rats (n = 5) were labeled with 0.1 mg / kg and 0.3 mg / k.
g, 1 mg / kg and 3 mg / kg (0.094 in terms of anhydride)
mg / kg, 0.28 mg / kg, 0.94 mg / kg and 2.8 mg / kg) were orally administered, and the radioactivity concentration in plasma was measured. Tmax, Cmax, calculated from these changes in plasma radioactivity concentration
t1 / 2 and AUC are shown in Table 3. The correlation between AUC and Cmax and the dose is shown in FIGS. 5 and 6, respectively.

[0038]

[Table 3] ─────────────────────────────────── Dose (mg / kg) T max (hr) C max (ng / ml) t 1/2 (hr) AUC (ng ・ hr / ml) ───────────────────────────── ─────── 0.1 2.2 ± 0.5 16.2 ± 2.6 1.77 ± 0.34 64.1 ± 12.3 0.3 2.2 ± 0.5 69.0 ± 17.8 1.33 ± 0.09 270.5 ± 88.4 1 1.8 ± 0.5 171.6 ± 31.1 1.64 ± 0.17 574.4 ± 113.2 3 2.0 ± 0.0 501.5 ± 133.8 1.30 ± 0.08 1769.2 ± 498.4 ─────────────────────────────────── Average ± SD (n = 5)

As is clear from the results of Example 4, a weight change of about 7% was observed for the anhydride [2- (1-piperazinyl)-
In 5-methylbenzenesulfonic acid monohydrate, one molecule of water represents about 7% of the total weight]. In other words, the anhydrate undergoes a weight change of up to about 7% due to hydration due to moisture absorption over time. Therefore, when the crystals obtained as an anhydride are weighed, the degree of hydration due to moisture absorption is not actually known, and therefore, when the crystals are considered to be anhydrate and weighed, the dose of the active substance is 93- Variation occurs in the range of 100%. On the other hand, when the crystals were regarded as monohydrate and weighed, the dose of the active substance was 100 to 10 for the same reason.
Variation occurs in the range of 7%. That is, in the case of weighing anhydrous, the dose of active substance is 93-10 depending on the degree of hydration.
There will be variations in the range of 7%.

As shown in Example 6, the blood concentration of the active form of the monohydrate of the present invention is linearly proportional to the dose.
Therefore, when the crystals were administered by weighing an anhydrous substance, the blood concentration would vary within the range of 14% as described above. Considering the calculation of the oral absorbability in the rat of Example 5, the absorption rate is as shown in the above formula 1. Therefore, when the weighing error occurs in each case of the oral administration and the intravenous administration, the above equation is used. The denominator of 1 and the dose of the numerator will vary independently. 38% average absorption rate
Then, when calculating the range of possible variations,

(Equation 2) Becomes That is, the absorption rate will be expanded to 33.03 to 43.72% (difference: 10.69%).

On the other hand, the monohydrate of the present invention is stable and does not cause the above variations. Therefore, the monohydrate of the present invention has advantages that it is easier to set a medicinal dose and secure a safety margin, and there are also various choices of administration methods. In addition, for example, when the monohydrate of the present invention is used as a medicine for a patient in the state of acute heart failure, the effect of improving cardiac function should be accurately measured, and the dosage should be appropriately controlled according to the improvement situation. Is of great therapeutic importance. By using the monohydrate of the present invention, the plasma concentration of the drug can be appropriately maintained and the onset of action can be controlled.

Example 7: Production of monohydrate in humidified steam chamber A water bath filled with water was heated to 50 ° C. to generate steam in a vinyl house in which the outside air was shut off. 4-886.16 g of 5-methyl-2- (1-piperazinyl) benzenesulfonic acid anhydride prepared by the method described in JP-A No. 3-7263 was spread on a stainless steel metal vat and left in the vinyl house. The crystals were occasionally dispersed, and water droplets adhering to the vinyl house and the stainless steel metal vat were wiped off. After 22.5 hours, the weight gain ceased and a total weight of 5217.65 g of white
5-Methyl-2- (1-piperazinyl) benzenesulfonic acid monohydrate was obtained. From the result of elemental analysis, it was confirmed that this crystal was a monohydrate.

[0043]

[Table 4] [Results of elemental analysis] ────────────────────── Elemental analysis value CHNS ──────────────── ─────── Anhydride calculated 51.54 6.29 10.93 12.51 Calculated monohydrate 48.16 6.61 10.21 11.69 Analytical 47.98 6.77 10.22 11.53 ──────────────── ──────

Example 8: Preparation of monohydrate by suspension in water In a 100 ml round-bottomed flask, 10.00 g of 5-methyl-2- (1-piperazinyl) benzenesulfonic anhydride and distilled water 3
0 ml was added and the mixture was stirred at 5 ° C for 2 hours. Crystals were recovered from the suspension by suction filtration, and then the crystals remaining in the eggplant flask were washed with 3 ml of distilled water to recover. The combined crystals were dried at 50 ° C and 90 mmHg for 3 hours to give white 5-methyl-2.
-(1-Piperazinyl) benzenesulfonic acid monohydrate 10.36
g (yield 96.8%) was obtained. Drying was continued for 27 hours under the same conditions, but no change was observed in the weight and appearance of the monohydrate. 6.96% water content by Karl Fischer moisture meter
And was confirmed to be a monohydrate (theoretical value: 6.
56%).

Example 9: Preparation of monohydrate by crystallization from water In a 200 ml round-bottomed flask, 10.00 g of 5-methyl-2- (1-piperazinyl) benzenesulfonic anhydride and distilled water 7
The crystals were completely dissolved by adding 5 ml and stirring with heating under reflux. Next, this solution was cooled to 5 ° C. under stirring, and stirring was continued at the same temperature for 2 hours. The precipitated crystals were collected by suction filtration and washed with 2 ml of distilled water. Obtained crystals at 50 ℃, 90
After drying at mmHg for 3 hours, 9.40 g of white 5-methyl-2- (1-piperazinyl) benzenesulfonic acid monohydrate (yield 87.
8%). The drying was continued for 27 hours under the same conditions, but the weight and appearance of the monohydrate did not change. The Karl Fischer moisture meter showed a water content of 6.75%, confirming that it was a monohydrate.

Example 10: Preparation of monohydrate by crystallization from hydrous ethanol In a 200 ml round bottom flask, 10.00 g of 5-methyl-2- (1-piperazinyl) benzenesulfonic anhydride and 50% (V /
V) 80 ml of water-containing ethanol was added, and the mixture was heated under reflux with stirring to completely dissolve the crystals. Then, this solution was cooled to 5 ° C. with stirring, and stirring was continued at the same temperature for 2 hours. The precipitated crystals were collected by suction filtration, and 50% (V / V) hydrous ethanol 2
Washed with 0 ml. The obtained crystals were dried at 50 ° C. and 90 mmHg for 3 hours to obtain 9.49 g (yield 88.7%) of white 5-methyl-2- (1-piperazinyl) benzenesulfonic acid monohydrate.
When drying was continued for 27 hours under the same conditions, the weight and appearance of the monohydrate did not change. The water content measured by the Karl Fischer moisture meter was 6.74%, confirming that it was a monohydrate.

[0047]

INDUSTRIAL APPLICABILITY The monohydrate of the aminobenzenesulfonic acid derivative provided by the present invention, preferably 2- (1-piperazinyl) -5-methylbenzenesulfonic acid monohydrate, is a crystal at room temperature for a long period of time. It is stable. Further, since the monohydrate of the present invention has almost no weight change due to moisture absorption, it can be accurately weighed, and an aminobenzenesulfonic acid derivative as an active ingredient, for example, 2- (1-piperazinyl) -5-methylbenzene. It is possible to manufacture a pharmaceutical composition having a uniform sulfonic acid content. Further, according to the manufacturing method of the present invention,
Aminobenzenesulfonic acid derivative monohydrate useful as a prophylactic or therapeutic agent for heart disease can be simply and reliably produced.

[0048]

[Brief description of drawings]

FIG. 1 is a diagram showing the results of thermal analysis of the monohydrate of the present invention. In the figure, TG shows the result of thermogravimetric analysis, and DTA shows the result of differential thermal analysis.

FIG. 2 is a diagram showing a result of thermal analysis of a crystal-free crystal described in Example 1 of JP-A-3-7263. In the figure, TG shows the result of thermogravimetric analysis, and DTA shows the result of differential thermal analysis.

FIG. 3 shows a powder diffractogram of the monohydrate of the present invention. In the figure, the horizontal axis represents the plane spacing (d, angstrom), and the vertical axis represents the intensity (I).

FIG. 4 is a diagram showing a powder diffraction diagram of a crystal-free crystal described in Example 1 of JP-A-3-7263. In the figure, the horizontal axis represents the plane spacing (d, angstrom), and the vertical axis represents the intensity (I).

FIG. 5 is a graph showing the correlation between the dose of a monohydrate labeled body of the present invention orally administered to male rats and the AUC of the change in plasma radioactivity concentration.

FIG. 6 shows the dose and C of the change in plasma radioactivity concentration after a single administration of the labeled body of the monohydrate of the present invention to male rats.
It is a figure which shows the correlation with max.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area C07D 295/08 C07D 295/08 A

Claims (9)

[Claims] 1. The following general formula (I): (In the formula, R ¹ is a hydrogen atom, a C _{1 to} C ₆ alkyl group, a C _{3 to} C ₇ cycloalkyl group, a C _{1 to} C ₄ halogenated alkyl group, a halogen atom, or a C _{6 to} C ₁₂ Represents an aryl group; R ² represents a hydrogen atom, a C _{1 to} C ₆ alkyl group, or a cyano group, a nitro group, a C _{1 to} C ₆ alkoxy group, a halogen atom, a C _{1 to} C ₆ alkyl group, and amino; An aminobenzenesulfonic acid represented by a C _{7 to} C ₁₂ aralkyl group which may have one or more substituents selected from the group consisting of groups; and n represents an integer of 1 to 4). Dehydrate monohydrate. 2. The aminobenzenesulfonic acid derivative monohydrate according to claim 1, wherein R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group, R ² is a hydrogen atom, and n is 2. . 3. 2- (1-Piperazinyl) -5-methylbenzenesulfonic acid monohydrate 4. A pharmaceutical composition containing the monohydrate of the aminobenzenesulfonic acid derivative according to claim 1 as an active ingredient. 5. A pharmaceutical composition comprising 2- (1-piperazinyl) -5-methylbenzenesulfonic acid monohydrate as an active ingredient. 6. The method for producing the monohydrate of the aminobenzenesulfonic acid derivative according to claim 1, wherein the anhydride of the aminobenzenesulfonic acid derivative is suspended in water or a water-containing organic solvent, Alternatively, a method including a step of subjecting a solution obtained by dissolving the anhydride in water or a water-containing organic solvent to a crystallization treatment, and then drying the obtained crystal. 7. The aminobenzenesulfonic acid derivative monohydrate according to claim 6, wherein R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group, R ² is a hydrogen atom, and n is 2. Manufacturing method. 8. The method for producing an aminobenzenesulfonic acid derivative monohydrate according to claim 6, wherein R ¹ is a methyl group, R ² is a hydrogen atom, and n is 2. 9. A suspension of 2- (1-piperazinyl) -5-methylbenzenesulfonic acid anhydride in water or a water-containing organic solvent, or by dissolving the anhydride in water or a water-containing organic solvent. It can be obtained by a method including a step of drying the obtained crystal after subjecting the obtained solution to crystallization treatment 2-
(1-Piperazinyl) -5-methylbenzenesulfonic acid monohydrate.