WO2011115173A1 - Monomaleate of benzothiazine compound - Google Patents

Abstract

Provided is an agent for the treatment and/or prevention of allergic disorders and inflammatory disorders, having good photostability, thermal stability, non-hygroscopic properties and solubility. A monomaleate of a benzothiazine compound is represented by formula (2) (in the formula, l represents an integer of 1 or 2, m represents an integer of 1 or 2, and n represents an integer of 1 to 4).

Description

Monomaleic acid salt of benzothiazine compound

The present invention relates to a monomaleate salt of a benzothiazine compound and a method for producing the same, and an agent for preventing and / or treating an allergic disease or an inflammatory disease containing the compound.

The following equation (1):

(Wherein, l is an integer of 1 or 2; m is an integer of 1 or 2; n is an integer of 1 to 4)
The benzothiazine compound represented by the formula has antihistamine action and anti-leukotriene action, and prevents allergic diseases such as allergic rhinitis and allergic conjunctivitis, or inflammatory diseases such as asthma, psoriasis, rheumatism and inflammatory colitis It is useful as a therapeutic agent (Patent Document 1).

Further, since the benzothiazine compound has three basic nitrogen atoms in its structure, it is in the form of various acid addition salts, and is isolated as a dimaleate in Patent Document 1 (Patent Document 1) Example 28).

On the other hand, it is desirable that drug substances have certain reproducibility that they can always be produced with the same level of yield and purity, even when the production scale etc. changes, in addition to the ease of drug production. . And, in addition to that, it is required to satisfy various conditions such as crystallinity, non-hygroscopicity, water solubility, stability against visible light and ultraviolet light, low degree of decomposition against temperature and humidity, etc. of drug substance . If the pharmaceutically active compound does not have suitable physicochemical properties as such drug substance, various improvement studies are usually made. That is, for the purpose of improving crystallization, water solubility, bioavailability, light stability, storage stability, non-hygroscopicity, etc., salts, hydrates and crystal forms of compounds are often studied, and compounds As an improved result, it is used in the manufacture of medicine as a drug substance having appropriate physicochemical properties.

For example, crystallization of oils and amorphous compounds makes them easy to handle, thus facilitating quality control, but it has been reported that there is a difference in the solubility and bioavailability of the compounds (non-patented) Reference 1). Also, if the crystalline form of the compound is a stable form, then the risk of crystalline form change in the formulation process is reduced. In addition, if crystallization of the compound is easy, purification yield of the target compound by recrystallization can be improved, and quality control in the production process can be advantageously advanced (Non-patent Document 2). The improvement of the water solubility of the compound can improve the bioavailability of the oral preparation and can facilitate the manufacturing process of injections and eye drops. The improvement of the heat and light stability of the compound is useful for guaranteeing the quality of medicine, and the non-hygroscopicity of the compound is advantageous in the storage and formulation process of the drug substance. From these facts, it is very important to find a drug substance having optimum physicochemical properties in the manufacture of a drug, and for that reason, it is desirable to thoroughly examine various drug substance forms. ing. However, it is difficult to predict in advance what physicochemical properties of the newly formed salt, hydrate and crystal form have.

Patent No. 3588126 gazette

The present invention exhibits excellent photostability, heat stability, non-hygroscopicity and solubility, and can be efficiently produced with purification, and is further effective for the treatment or prevention of allergic diseases and inflammatory diseases. An object of the present invention is to provide a novel form of the benzothiazine compound represented by the formula (1).

Means for Solving the Invention

Then, the present inventors variously examined about the salt of the said benzothiazine compound. For the benzothiazine compound (1), a dimaleate salt is reported in Patent Document 1, but this salt was considered to be a stable form in terms of chemical structure. That is, since the basicity of the two nitrogen atoms incorporated into the piperazine skeleton located at the center among the compounds (1) is the strongest, it is most structurally stable that the compound takes the form of dimaleate. When it was attempted to produce the maleate salt of the compound (1) according to a general production method, it was thought that a dimaleate salt was formed as reported in the same document.

However, when the salts are formed using a small amount of maleic acid, which is not commonly used in the formation of salts of compound (1), the monomaleate salt of compound (1) is obtained, which is surprising. Also, the monomaleate has excellent photostability, heat stability, non-hygroscopicity and solubility, and the monomaleate is very good as compared to other salt compounds of the compound (1). It has been found that purification efficiency can be obtained. Furthermore, the present inventors confirmed that the monomaleate salt of the compound has a therapeutic or preventive effect on allergic diseases (particularly allergic conjunctivitis), and completed the present invention.

That is, according to the present invention, the following equation (2)

(Wherein, l is an integer of 1 or 2; m is an integer of 1 or 2; n is an integer of 1 to 4)
To provide a monomaleate salt of a benzothiazine compound represented by
The present invention also provides a preventive and / or therapeutic agent for allergic diseases, which comprises the monomaleate salt (2) of the benzothiazine compound as an active ingredient.
Furthermore, according to the present invention, the above benzothiazine compound (1) and maleic acid of 1 equivalent or less relative to the benzothiazine compound (1) are reacted by heating in a solvent, and the reaction solution is cooled to -20 to 20 ° C after heating. The present invention provides a process for producing the monomaleate salt (2) of the benzothiazine compound, which is characterized by the following.

The present invention also provides a method for preventing and / or treating allergic diseases, which comprises administering an effective amount of the monomaleate salt (2) of the above benzothiazine compound.
Furthermore, the present invention provides monomaleate salt (2) of the above-mentioned benzothiazine compound for use in the prevention and / or treatment of allergic diseases.
Furthermore, the present invention provides the use of a monomaleate salt of the above benzothiazine compound for producing an agent for preventing and / or treating allergic diseases.

The monomaleate salt (2) (hereinafter sometimes referred to simply as monomaleate salt (2)) of the benzothiazine compound of the present invention has very excellent photostability and thermal stability, as shown in the examples described later. Compared with the dimaleate salt of compound (1) having non-hygroscopicity and solubility and further having a similar chemical structure, it has very excellent purification efficiency. The compound has a therapeutic effect equivalent to that of the compound (1) against allergic diseases or inflammatory diseases despite showing significant points in such physicochemical properties and production processes. Is a drug substance that is less irritating to the human body.

It is a chart which shows the thermal analysis data (TG-DTA measurement) of monomaleic acid salt (2a). It is a figure which shows the absorption peak of the infrared absorption spectrum (ATR method) by the infrared spectrophotometer of monomaleate salt (2a). It is a figure which shows the powder X-ray-diffraction pattern of monomaleate salt (2a). It is a figure which shows the HPLC chart of monomaleate salt (2a). It is a figure which shows the HPLC chart of the dimaleic acid salt of benzothiazine compound (1a). It is a figure which shows the antihistamine effect of the dimaleate salt of monomaleate salt (2a) and a benzothiazine compound (1a). It is a figure which shows the therapeutic effect of the dimaleate salt of monomaleate salt (2a) and a benzothiazine compound (1a) of allergic conjunctivitis.

The compound of the present invention is a monomaleate represented by the following formula (2). Although l in Formula (2) shows the integer of 1 or 2, 1 is preferable. Also, m is an integer of 1 or 2, preferably 1. Also, n is an integer of 1 to 4, preferably 2 to 4, and particularly preferably 3. Among monomaleic acid salts represented by the formula (2), compounds in which l = 1, m = 1, n = 3, ie, 7- [3- {4- (N-ethoxyethyl benzimidazol-2-ylmethyl) ) -L-Piperazinyl} propoxy] -3,4-dihydro-2H-1,4-benzothiazin-3-one monomaleate (2a) is particularly preferred.

The monomaleate salt (2) can be produced, for example, according to the reaction step described below. In addition, when performing the following reaction, functional groups other than the reactive site may be protected in advance, if necessary, and then deprotected at an appropriate stage. The protection and deprotection conditions can be carried out with reference to generally used methods (for example, methods described in Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc., 1999). Furthermore, in each step, the reaction may be carried out by a method which is usually carried out (for example, the method described in Comprehensive Organic Transformations Second Edition, John Wiley & Sons, Inc; 1999), and the isolation and purification are crystallization and recrystallization. Alternatively, conventional methods such as chromatography may be appropriately selected or combined.

[Production of monomaleate (2)]
[Reaction route diagram 1]

[Wherein, X ¹ represents a leaving group such as a halogen atom or a sulfonyloxy group, and l, m and n are as defined above] ]

[Reaction step 1]
Reaction step 1 is a step of producing compound (1), and compound (I) in the presence or absence of a base, in the presence or absence of a reaction accelerator, in one equivalent or an excess amount of compound (II The compound (1) can be produced by reacting with the compound (1) in a solvent.

The solvent is not particularly limited, but for example, halogenated alkyl solvents such as dichloromethane and chloroform, ether solvents such as tetrahydrofuran, diethyl ether and dioxane, aromatic hydrocarbon solvents such as benzene, toluene and xylene, methanol, Alcohol solvents such as ethanol, ester solvents such as ethyl acetate, nitrile solvents such as acetonitrile and propionitrile, aprotic polar solvents such as dimethylformamide and dimethylsulfoxide, water and the like may be used alone or in combination it can.

The base is not particularly limited. For example, organic bases such as pyridine, collidine, lutidine, triethylamine and diisopropylethylamine, alkali metals such as lithium hydride, sodium hydride and potassium hydride, potassium hydrogencarbonate And inorganic bases such as alkali metal hydrogencarbonates such as sodium hydrogencarbonate, alkali metal carbonates such as potassium carbonate and sodium carbonate, and alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and lithium hydroxide. .

Although there is no restriction | limiting in particular as a reaction promoter, For example, potassium iodide is mentioned. The reaction conditions are not particularly limited, and for example, -30 to 130 ° C., preferably 0 to 50 ° C., for 30 minutes to 3 days, preferably 1 hour to 1 day.

[Reaction step 2]
The monomaleate salt (2) can be produced by heating the compound (1) obtained by the above reaction with 1 equivalent or less of maleic acid in a solvent and then cooling the reaction solution. The amount of maleic acid used in the reaction is preferably less than 1 equivalent, more preferably 0.95 equivalents or less, and 0.70 to 0.95 equivalents relative to the compound (1). Is more preferred.

The solvent is not particularly limited, but, for example, ether solvents such as tetrahydrofuran, diethyl ether and dioxane, aromatic hydrocarbon solvents such as benzene, toluene and xylene, alcohol solvents such as methanol and ethanol, ethyl acetate and the like These ester solvents, nitrile solvents such as acetonitrile and propionitrile, acetone, water and the like can be used alone or in combination. Among them, alcohol solvents are preferably used, and ethanol is more preferably used.

The reaction conditions are not particularly limited, and the reaction conditions are, for example, 20 to 100 ° C., preferably 40 to 80 ° C., for 5 minutes to 5 days, preferably 30 minutes to 1 day. After completion of the reaction, the resulting reaction solution is stirred at -20 to 40 ° C, preferably -20 to 20 ° C, more preferably -10 to 10 ° C, for 30 minutes to 3 days, preferably 1 hour to 1 day By leaving still, monomaleate (2) can be produced. In addition, it is also possible to use monomaleate (2) seed crystals separately prepared to promote crystallization in this step. In particular, after crystallization on a large scale, in order to crystallize monomaleate (2) from the reaction solution, seed crystals of monomaleate (2) separately prepared are used more easily. It is possible to crystallize monomaleate (2) efficiently. When crystallization is performed, it is preferable to use 4 to 24 times as much solvent as the compound (1) and maleic acid in terms of weight, and it is more preferable to use 4 to 10 times as much solvent. The solvent used for crystallization is preferably ethanol. The method of crystallization of monomaleate (2) in this step may be crystallization, but recrystallization may be used as another means.

[Production of Intermediate (I)]
[Reaction route diagram 2]

[Wherein, X ² and X ^{3 each} represent a halogen atom, a leaving group such as a sulfonyloxy group, or a hydroxyl group, P ¹ represents a protective group for an amino group, and m and n are as defined above. ]

[Reaction step 3]
The reaction step 3 is a step of producing a compound (V), and the compound (III) is used in an amount of 1 equivalent or less of the compound (IV) in the presence or absence of a base, in the presence or absence of a reaction accelerator. The compound (V) can be produced by reacting it with a compound in a solvent.

Here, the solvent is not particularly limited, but for example, halogenated alkyl solvents such as dichloromethane and chloroform, ether solvents such as tetrahydrofuran, diethyl ether and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene Solvent, alcohol solvents such as methanol and ethanol, ester solvents such as ethyl acetate, nitrile solvents such as acetonitrile and propionitrile, aprotic polar solvents such as dimethylformamide and dimethyl sulfoxide, water, etc. alone or in combination It can be used.

The base is not particularly limited, but, for example, alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, alkali metal hydrogencarbonates such as potassium hydrogencarbonate and sodium hydrogencarbonate, potassium carbonate and carbonic acid Inorganic bases such as alkali metal carbonates such as sodium and alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and lithium hydroxide can be mentioned.

The reaction accelerator is not particularly limited, and examples thereof include potassium iodide and the like. The reaction conditions are not particularly limited, and for example, 30 to 180 ° C., preferably 50 to 120 ° C., for 30 minutes to 5 days, preferably 1 hour to 1 day.

Further, according to a method known as Mitsunobu reaction (Synthesis, p 1-28, 1981), compound (III) and an equivalent or excess amount of compound (IV) in a solvent in the presence of a phosphine reagent and an azo reagent The compound (V) can also be produced by reacting at

Here, the phosphine reagent is not particularly limited, but, for example, trialkyl phosphines such as trimethyl phosphine, triethyl phosphine, tripropyl phosphine, triisopropyl phosphine, tributyl phosphine, triisobutyl phosphine, tricyclohexyl phosphine and the like, triphenyl phosphine Etc. Triaryl phosphines etc. can be used.

The azo reagent is not particularly limited. For example, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), di-tert-butyl azodicarboxylate (DBAD), 1,1- (azodicarbonyl) Piperidine (ADDP), 1,1′-azobis (N, N′-diisopropylamide) (TIPA), 1,6-dimethyl-1,5,7-hexahydro-1,4,6-tetrazocine-2,5- Diones (DHAD) and the like can be used. Also, instead of the azo reagent, an ethylene dicarboxylic acid reagent may be used. The ethylenedicarboxylic acid reagent is not particularly limited, and, for example, dimethylmaleate, diethylmaleate, dimethyl fumarate, diethyl fumarate and the like can be used.

The solvent is not particularly limited, and examples thereof include halogenated alkyl solvents such as dichloromethane and chloroform, ether solvents such as tetrahydrofuran, diethyl ether and dioxane, aromatic hydrocarbon solvents such as benzene, toluene and xylene, methanol Alcohol solvents such as ethanol, aprotic polar solvents such as dimethylformamide may be used alone or in combination.

The reaction conditions are not particularly limited, and for example, -80 to 100 ° C., preferably -30 to 60 ° C., for 1 minute to 5 days, preferably 15 minutes to 1 day.

[Reaction step 4]
The compound (V) obtained by the above reaction is reacted in the solvent with one equivalent or an excess of the compound (VI) in the presence or absence of a base, in the presence or absence of a reaction accelerator Compound (VII) can be produced.

Here, the solvent is not particularly limited, but for example, halogenated alkyl solvents such as dichloromethane and chloroform, ether solvents such as tetrahydrofuran, diethyl ether and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene Solvent, alcohol solvents such as methanol and ethanol, ester solvents such as ethyl acetate, nitrile solvents such as acetonitrile and propionitrile, aprotic polar solvents such as dimethylformamide and dimethyl sulfoxide, water, etc. alone or in combination It can be used.

The base is not particularly limited, but, for example, alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, alkali metal hydrogencarbonates such as potassium hydrogencarbonate and sodium hydrogencarbonate, potassium carbonate and carbonic acid Inorganic bases such as alkali metal carbonates such as sodium and alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and lithium hydroxide can be mentioned.

The reaction accelerator is not particularly limited, and examples thereof include potassium iodide and the like. The reaction conditions are not particularly limited, and for example, 30 to 180 ° C., preferably 50 to 120 ° C., for 30 minutes to 5 days, preferably 3 hours to 1 day.

[Reaction step 5]
The reaction step 5 is a step of deprotecting the compound (VII) to produce a compound (I). Here, an example in the case where P ¹ is a tert-butoxycarbonyl group (Boc), a benzyl group (Bn) or a benzyloxycarbonyl group (Z) is shown below. In the case of other protective groups, for example, conventional deprotection methods described in Protective Groups in Organic Synthesis Forth Edition, John Wiley & Sons, Inc., can be used.

(When P ¹ is a tert-butoxycarbonyl group (Boc))
Compound (I) can be produced by reacting compound (VII) obtained by the above reaction in the presence or absence of one equivalent or an excess of an acid and a solvent.

At this time, the solvent is not particularly limited, but for example, halogenated alkyl solvents such as dichloromethane and chloroform, ether solvents such as tetrahydrofuran, diethyl ether and dioxane, alcohol solvents such as methanol and ethanol, acetonitrile, pro Nitrile solvents such as peonitrile, water and the like can be used alone or in combination.

The acid is not particularly limited, and examples thereof include hydrochloric acid, sulfuric acid and trifluoroacetic acid. The reaction conditions are not particularly limited, and for example, -80 to 180 ° C., preferably -30 to 100 ° C., for 1 minute to 3 days, preferably 30 minutes to 1 day.

(When P ¹ is benzyl group (Bn), benzyloxycarbonyl group (Z))
Compound (I) can be produced by subjecting compound (VII) obtained by the above reaction to catalytic hydrogenation reaction using a hydrogen source and a catalyst.

The hydrogen source is not particularly limited, and, for example, hydrogen, formic acid, ammonium formate, cyclohexadiene and the like can be used. The catalyst is not particularly limited, and, for example, palladium, palladium black, palladium carbon, platinum carbon, platinum, platinum oxide, copper chromite, Raney nickel and the like can be used alone or in combination.

The solvent is not particularly limited. For example, ether solvents such as tetrahydrofuran, diethyl ether and dioxane, alcohol solvents such as methanol, ethanol, propanol, ethylene glycol and propanediol, ester solvents such as ethyl acetate, acetonitrile Nitrile solvents such as propionitrile, aprotic polar solvents such as dimethylformamide, water and the like can be used alone or in combination.

The hydrogen pressure in the catalytic hydrogenation reaction is usually normal pressure to 50 atm, preferably normal pressure to 10 atm, but is not particularly limited. The reaction conditions are not particularly limited, and for example, -80 to 180 ° C., preferably -30 to 100 ° C., for 30 minutes to 5 days, preferably 1 hour to 1 day.

The intermediate and the desired product obtained in each of the above reactions are required to be subjected to purification methods commonly used in organic synthesis chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, etc. It can be isolated and purified according to In addition, intermediates can also be subjected to the next reaction without purification.

Furthermore, various isomers can be isolated by applying a conventional method utilizing differences in physicochemical properties between the isomers. The racemic mixture is optically pure by a general racemate resolution method such as a method of converting into a diastereomer salt with a general optically active acid such as tartaric acid or optical resolution or a method using optically active column chromatography. It can be converted to the isomer. In addition, diastereomer mixtures can be separated by, for example, fractional crystallization or various chromatography. An optically active compound can also be produced by using an appropriate optically active raw material.

The monomaleate salt (2) of the present invention obtained as described above has good crystallinity, and can be stably stored in the crystalline state.
Further, among the monomaleate salts (2) of the present invention, 7- [3- {4- (N-ethoxyethylbenzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4-dihydro-2H- Particularly preferred is 1,4-benzothiazin-3-one monomaleate (2a). 7- [3- {4- (N-Ethoxyethyl benzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4-dihydro-2H-1,4-benzothiazin-3-one monomaleic acid The salt (2a) has the following properties.

(1) Powder X-ray diffraction pattern (see FIG. 3)
It has peaks near the diffraction angle (2θ) 16.7 and 24.7. More specifically, it has peaks at diffraction angles (2θ) of 16.7, 20.3, 23.7 and 24.7.
(2) Infrared spectrum (see Figure 2)
Having a peak 1669cm around ^-1, 1492Cm around ^-1, around 868Cm ^-1 and around 754cm ^-1. More particularly having a peak near 1669cm ^-1, 1492cm around ^-1, 1231Cm around ^-1, 1208Cm around ^-1, around 868Cm ^-1 and around 754cm ^-1.
(3) Melting point 147 to 150 ° C

The monomaleate salt (2) of the present invention has excellent photostability, heat stability, non-hygroscopicity and water solubility as shown in the Examples below, and is also a dimaleate salt of compound (1) It has excellent purification efficiency compared to. Furthermore, it has low eye mucous membrane irritation and has excellent antiallergic action. Therefore, the monomaleate salt (2) of the present invention is useful as a pharmaceutical for animals or humans represented by agents for preventing and / or treating allergic diseases.

As a medicament containing the monomaleate salt (2) of the present invention as an active ingredient, this active ingredient may be used alone, but usually it is used in combination with a pharmaceutically acceptable carrier, additive, etc. It is also good. The administration mode of the pharmaceutical composition is not particularly limited, and can be appropriately selected according to the therapeutic purpose. For example, oral agents, injections, suppositories, ointments, inhalants, eye drops, nasal drops, patches and the like may be used. Pharmaceutical compositions suitable for these administration forms can be prepared by known formulation methods. The monomaleate salt (2) of the present invention can also be used in combination with other compounds effective for the treatment of diseases, such as other compounds effective for the treatment of allergic diseases.

When preparing a solid preparation for oral use, after adding an excipient and, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent, a flavoring agent, etc. to monomaleate (2) Tablets, coated tablets, granules, powders, capsules and the like can be produced by conventional methods. The additives may be those commonly used in the art.

When preparing a liquid preparation for oral use, a flavoring agent, a buffer, a stabilizer, a flavoring agent, etc. are added to monomaleate (2) to produce an internal solution liquid, a syrup, an elixir etc. by a conventional method. Can.

When preparing eye drops, use pH adjuster, buffer, stabilizer, tonicity agent, preservative, antioxidant, thickener, chelating agent, etc. with monomaleate (2) , Can be manufactured by a conventional method.

When preparing an injection, pH adjuster, buffer, stabilizer, isotonic agent, local anesthetic etc. are added to monomaleate (2), and subcutaneous, muscle and intravenous injections are performed according to a conventional method. Can be manufactured.

When preparing a suppository, a suppository carrier known to compounds represented by monomaleate (2), such as polyethylene glycol, lanolin, cacao butter, fatty acid triglyceride and the like, and, if necessary, tween (registered After adding surfactant etc., such as (trademark), it can manufacture by a conventional method.

When preparing an ointment, a base, a stabilizer, a wetting agent, a preservative and the like which are usually used for the compound represented by monomaleate (2) are blended as necessary, and are mixed by a conventional method , Formulated.

In addition to the above, the monomaleate salt (2) can be appropriately formulated into a preferable preparation by using a conventional method, and can also be formed into an inhalant, eye drops and a nasal drop by a conventional method.

The monomaleate salt (2) of the present invention is preferably administered orally or parenterally. The dosage of the medicament of the present invention varies depending on the patient's body weight, age, sex, symptoms and the like, but in the case of adults, it is usually 0.01 to 1000 mg as monomaleate (2) divided into 1 to 4 times a day Can be administered. Preferably, 0.1 to 10 mg can be divided and administered 1 to 4 times a day, and more preferably 0.4 to 2 mg can be divided and administered 1 to 4 times a day.

The monomaleate salt (2) of the present invention has an antihistaminic action and is useful as a preventive and / or therapeutic agent for allergic diseases, as shown in Examples and the like described later. Here, the "allergic disease" in the present invention is not particularly limited, and examples thereof include atopic dermatitis, allergic gastroenteritis, allergic rhinitis, allergic eye disease and the like. The "allergic eye disease" is not particularly limited, and examples thereof include allergic conjunctivitis and the like.

"Allergic conjunctivitis" is an inflammatory disease of the conjunctiva in which type I allergy is involved, which is accompanied by some autonomic symptoms, and is not particularly limited. For example, seasonal allergic conjunctivitis, annual allergic allergy Conjunctivitis, atopic keratoconjunctivitis, spring catarrh, giant papillary conjunctivitis, etc. can be mentioned. If conjunctivitis in which the type I allergic reaction is involved, other types of inflammatory reactions are mixed and it is diagnosed as allergic conjunctivitis. Symptoms include pruritus, eye oil, tears, redness, foreign body, edema, etc., which are the main symptoms of allergic conjunctivitis, but may also indicate corneal or ocular disorders.

EXAMPLES The present invention will be more specifically described below by Examples, Comparative Examples, and Test Examples, but the present invention is not limited thereto. The abbreviations used in the following examples have the following meanings.
s: singlet
d: Doublet (doublet)
t: Triplet (triplet)
q: Quartet (quartet)
m: multiplet
br: Broad
J: Coupling constant
Hz: Hertz
CDCl ₃ : deuterated chloroform ¹ H-NMR: proton nuclear magnetic resonance IR: infrared absorption spectrum

Example 1-1: 7- [3- {4- (N-ethoxyethylbenzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4-dihydro-2H-1,4-benzothiazine-3- Production of ON (1a) (production of free body)

a) 65 g (359 mmol) of 7-hydroxy-3,4-dihydro-2H-1,4-benzothiazin-3-one obtained by the method described in JP-A-60-4176 and JP-A-59-70675 Was suspended in tetrahydrofuran (194 mL) under an argon atmosphere, 104 g (397 mmol) of triphenylphosphine and 32 mL (379 mmol) of 3-chloropropanol were added, and the mixture was cooled to 0.degree. Next, 78 mL (396 mmol) of azodicarboxylic acid diisopropyl ester was added dropwise to the resulting reaction solution at 30 ° C. or less, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated from the resulting solution under reduced pressure, methanol (390 mL) was added, and the mixture was stirred at room temperature for 1 hour. The precipitated crystals are collected by filtration and then dried under reduced pressure at 50 ° C. for 5 hours to give 59 g of 7- (3-chloropropoxy) -3,4-dihydro-2H-1,4-benzothiazin-3-one (yield 64%) ) Was obtained as blue-white crystals.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.12 (2 H, quint, J = 6.2 Hz), 3.28 (2 H, s), 3.76 (2 H, t, J = 6. 2 Hz), 4.03 (2 H, t, J = 5.8 Hz), 6.78 (1 H, dd, J = 2.8, 8.8 Hz), 6.88 (1 H, d, J = 8.8 Hz ), 6.90 (1 H, d, J = 2.8 Hz), 10. 38 (1 H, s)

b) 57 g (221 mmol) of 7- (3-chloropropoxy) -3,4-dihydro-2H-1,4-benzothiazin-3-one is suspended in dimethylformamide (172 mL), 49 g (355 mmol) of potassium carbonate, 40 g (241 mmol) of potassium iodide and 43 g (231 mmol) of Nt-butoxycarbonylpiperazine were added, and the mixture was heated to 100 ° C. and stirred for 4 hours. After water (344 mL) was added to the reaction solution, it was cooled to 0 ° C. and stirred at the same temperature for 1 hour. The precipitated crystals are collected by filtration and then dried under reduced pressure at 50 ° C. for 5 hours, 7- [3- (N-t-butoxycarbonylpiperazinyl) propoxy] -3,4-dihydro-2H-1,4-benzothiazine 89 g (yield 99%) of -3-one were obtained as bluish white crystals.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.39 (9 H, s), 1.83 (2 H, quint, J = 6.8 Hz), 2.31 (4 H, t, J = 4. 8 Hz), 2.39 (2 H, t, J = 7.0 Hz), 3.30 (4 H, t, J = 4.6 Hz), 3.41 (2 H, s), 3.95 (2 H, t, J = 6.4 Hz), 6.78 (1 H, dd, J = 2.8, 8.8 Hz), 6.88 (1 H, d, J = 8.8 Hz), 6.89 (1 H, s), 10.38 (1 H, s)

c) 87 g (214 mmol) of 7- {3- (N-t-butoxycarbonylpiperazinyl) propoxy} -3,4-dihydro-2H-1,4-benzothiazin-3-one was suspended in ethanol (174 mL); A 6N aqueous hydrochloric acid solution (174 mL) was added dropwise at 50 ° C., and the mixture was stirred at the same temperature for 1 hour. After ethanol (522 mL) was added to the reaction mixture, it was cooled to 0 ° C. and stirred at the same temperature for 1 hour. The precipitated crystals are collected by filtration and then dried under reduced pressure at 50 ° C. for 5 hours to give 7- {3- (piperazin-1-yl) propoxy} -3,4-dihydro-2H-1,4-benzothiazin-3-one. -75 g (yield 92%) of dihydrochloride was obtained as pale-white crystals.

¹ H-NMR (400 MHz, D ₂ O) δ: 2.13 (2 H, td, J = 5.9, 15.6 Hz), 3.34 (2 H, s), 3. 35 (2 H, t, J = 8.0 Hz), 3.44-3.64 (8 H, m), 4.02 (2 H, t, J = 5.6 Hz), 6.74 (1 H, dd, J = 2.4, 8. 8 Hz), 6.85 (1 H, d, J = 8.8 Hz), 6. 90 (1 H, d, J = 2.4 Hz)

d) 1- (2-Ethoxyethyl) -2-chloromethyl-1H-benzimidazole obtained by the method described in Journal of Heterocyclic Chemistry (1987), 24 (1), 31-37 with tetrahydrofuran (293 mL) 7- {3- (N-t-Butoxycarbonylpiperazinyl) propoxy} -3,4-dihydro-2H- dissolved in a mixture of water (147 mL) and prepared in step c) of Example 1-1 73 g (192 mmol) of 1,4-benzothiazin-3-one were added. Then, 117 mL (673 mmol) of diisopropylethylamine and 35 g (211 mmol) of potassium iodide were added, and the mixture was stirred at room temperature for 15 hours. Ethyl acetate (293 mL) and water (147 mL) were added to the reaction solution for extraction, and the organic layer was washed with 20% brine (147 mL). The organic layer was concentrated under reduced pressure to give 115 g (two steps, quantitative) of the title compound (1a) as a brown oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.13 (3 H, t, J = 7.0 Hz), 1.93 (2 H, quint, J = 6.9 Hz), 2.40-2.70 ( 8H, m), 2.51 (2H, t, J = 7.2 Hz), 3.41 (2H, s), 3.42 (2H, q, J = 6.8 Hz), 3.76 (2H, 2H, s) t, J = 6.0 Hz), 3.88 (2 H, s), 3. 97 (2 H, t, J = 6.2 Hz), 4.51 (2 H, t, J = 5.8 Hz), 6. 71 (1 H, dd, J = 2.6, 8.6 Hz), 6.77 (1 H, d, J = 8.8 Hz), 6.85 (1 H, d, J = 2.4 Hz), 7.24 -7.28 (2H, m), 7.39 (1 H, ddd, J = 1.2, 6.0, 6.8 Hz), 7.73 (1 H, ddd, J = 1.2, 6.0 , 6.8 Hz) 8.35 (1H, s)

Example 1-2: 7- [3- {4- (N-ethoxyethylbenzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4-dihydro-2H-1,4-benzothiazine-3- Production of on monomaleate (2a) (production of seed crystals)

7- [3- {4- (N-Ethoxyethylbenzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4-dihydro-2H-1,4-benzothiazin-3-one (1a) 1. 0 g (1.96 mmol) was dissolved in ethanol (8 mL) and warmed to 60.degree. After adding 211 mg (1.80 mmol) of maleic acid and stirring at 50 ° C. for 1 hour, the mixture was stirred at room temperature for 16 hours and further stirred at 0 ° C. for 3 hours. The precipitated crystals were collected by filtration and then dried under reduced pressure at 50 ° C. for 5 hours to obtain 1.02 g (yield 91%) of monomaleic acid salt (2a) as pale-white crystals (melting point: 148-151 ° C.).

Example 1-3: 7- [3- {4- (N-ethoxyethylbenzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4-dihydro-2H-1,4-benzothiazine-3- Production of on monomaleate (2a)

7- [3- {4- (N-Ethoxyethylbenzoimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4-dihydro-2H-1,4-benzothiazin-3-one (1a) 7. After dissolving 0 g (13.7 mmol) in ethanol (56 mL) and warming to 60 ° C., 1.46 g (12.6 mmol) of maleic acid was added, cooled to 50 ° C., and obtained in Example 1-2. 0.035 g (0.056 mmol) of the seed crystals were added. The reaction solution was stirred at 50 ° C. for 1 hour, then at room temperature for 1 hour, and further stirred at 0 ° C. for 3 hours. The precipitated crystals were collected by filtration and then dried under reduced pressure at 50 ° C. for 5 hours to obtain 7.08 g (yield 90%) of monomaleic acid salt (2a) as pale-white crystals.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.02 (3 H, t, J = 7.2 Hz), 2.00-2.07 (2 H, m), 2.80-3.61 ( 10H, m), 3.39 (2H, q, J = 6.9 Hz), 3.42 (2H, s), 3.71 (2H, t, J = 5.2 Hz), 3.93 (2H, 2H, s) s), 4.01 (2 H, t, J = 6.2 Hz), 4.50 (2 H, t, J = 5.2 Hz), 6.03 (2 H, s), 6.78 (1 H, dd, J = 2.4, 8.8 Hz), 6.88 (1 H, s), 6. 91 (1 H, dd, J = 2.4, 2.4 Hz), 7.18 (1 H, ddd, J = 1 .2, 7.6, 7.6 Hz), 7.24 (1 H, ddd, J = 1.4, 7.5, 7.5 Hz), 7.59 (2 H, d, J = 8.4 Hz), 10.40 (1 H, s)

Elemental analysis value of monomaleate (2a) obtained in Example 1-3: C ₃₁ H ₃₉ N ₅ O ₇ S Theoretical value: C 59.50%; H 6.28%; N 11.19 %
Found: C 59.33%; H 6.29%; N 11.10%

7- [3- {4- (N-Ethoxyethylbenzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4-dihydro-2H-1,4-benzothiazine obtained in Example 1-3 Thermal analysis measurements of -3-one monomaleate (2a) were performed. For thermal analysis measurement, approximately 5 mg of a sample is accurately weighed in an aluminum pan for thermal analysis, and using Al ₂ O ₃ as a reference substance, the temperature rising rate is 10 ° C./in the presence of atmospheric N ₂ gas (150 mL / min). The thermal analysis was performed by differential thermal analysis (DTA) and thermal mass spectrometry (TG) using a thermal analyzer Thermo Plus 2 system (manufactured by RIGAKU Co., Ltd.). The results of the thermal analysis measurement are shown in FIG. In addition, the melting point of monomaleate (2a) was 147-150 ° C. (manufactured by BUCHI, B-545).

7- [3- {4- (N-Ethoxyethylbenzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4-dihydro-2H-1,4-benzothiazine obtained in Example 1-3 3-infrared absorption spectrum by the infrared spectrophotometer on mono maleate (2a) (Thermo Nicolet Co., AVATAR370; ATR method) exhibits a pattern described in Figure 2, 1669Cm around ^-1, 1492cm around ^-1 had 1231cm around ^-1, 1208Cm around ^-1, an absorption peak specific to around 868Cm ^-1 and around 754cm ^-1.

7- [3- {4- (N-Ethoxyethylbenzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4-dihydro-2H-1,4-benzothiazine obtained in Example 1-3 The powder X-ray diffraction (manufactured by Rigaku Denki Kogyo; Miniflex) of -3-one monomaleate (2a) was measured. In the measurement of powder X-ray crystal diffraction, the sample is filled in the sample holder portion of the silicon nonreflective sample plate for X-ray diffraction, and the scanning range of diffraction angle 2θ is 3.00 by the desktop X-ray diffractometer: MiniFlex (Rigaku). The measurement was performed under the conditions of 4 ° to 40.00 °, sampling width: 0.02 °, scan rate: 2.00 ° / min. The obtained diffraction pattern is shown in FIG. The monomaleate salt (2a) had the characteristic diffraction angles and relative intensities shown in Table 1.

Example 1-4: 7- [3- {4- (N-ethoxyethyl benzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4-dihydro-2H-1,4-benzothiazine-3- Production of on monomaleate (2a) (examination of reproducibility on a large scale)

7- [3- {4- (N-Ethoxyethyl benzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4-dihydro-2H-1,4-benzothiazin-3-one (1a) 115 g ( 226 mmol) was dissolved in ethanol (293 mL), 5.5 g of activated carbon was added, and the mixture was stirred at room temperature for 1 hour, filtered through celite and washed with ethanol (147 mL). After adding ethanol (147 mL) to the filtrate and heating to 60 ° C., 18.9 g (163 mmol) of maleic acid was added and cooled to 50 ° C. After adding 0.58 g (0.93 mmol) of seed crystals of monomaleic acid salt (2a) obtained in Example 1-3 and stirring at 50 ° C. for 1 hour, stirring at room temperature for 15 hours, further at 0 ° C. Stir for 3 hours. The precipitated crystals were collected by filtration and then dried under reduced pressure at 50 ° C. for 5 hours to obtain 75.2 g (yield 63%) of monomaleic acid salt (2a) as white crystals (melting point: 147-149 ° C.).

Elemental analysis value of monomaleic acid salt (2a) obtained in Example 1-4: as C ₃₁ H ₃₉ N ₅ O ₇ S Theoretical value: C 59.50%; H 6.28%; N 11.19 %
Found: C 59.41%; H 6.29%; N 11.08%

Comparative Example 1: 7- [3- {4- (N-Ethoxyethylbenzoimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4-dihydro-2H-1,4-benzothiazin-3-one. Manufacture of dimaleate

7- [3- {4- (N-Ethoxyethyl benzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4-dihydro-2H-1,4-benzothiazin-3-one 15.9 g (31 .1 mmol) was dissolved in 70 mL of ethanol, and the solution was heated to 60 ° C., and then 8.0 g (68.9 mmol) of maleic acid was added and stirred at room temperature for 15 hours. The precipitated crystals are collected by filtration and then dried under reduced pressure at 50 ° C. for 5 hours to give 7- [3- {4- (N-ethoxyethylbenzoimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4-. 13.3 g of dihydro-2H-1,4-benzothiazin-3-one dimaleate was obtained. The obtained compound was dissolved in methanol (13 mL) and warmed to 60 ° C., THF (52 mL) was added, and the mixture was stirred at room temperature for 20 hours. The obtained crystals are collected by filtration and dried under reduced pressure at 50 ° C. for 5 hours to give 7- [3- {4- (N-ethoxyethylbenzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4. 10.3 g (yield 45%) of -dihydro-2H-1,4-benzothiazin-3-one dimaleate was obtained as pale white crystals.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.01 (3 H, t, J = 7.0 Hz), 2.00-2.07 (2 H, m), 3.00 (4 H, m) , 3.20 (2H, m), 3.37 (2H, q, J = 6.9 Hz), 3.41-3.47 (4H, m), 3.70 (2H, t, J = 5. 2 Hz), 3.95 (2 H, s), 3.99 (2 H, t, J = 5.8 Hz), 4.50 (2 H, t, J = 5.0 Hz), 6. 14 (4 H, s) , 6.76 (1 H, dd, J = 2.4, 8.8 Hz), 6.88 (1 H, s), 6. 90 (1 H, m), 7.19-7.27 (2 H, m) , 7.60 (2 H, d, J = 7.6 Hz), 10. 40 (1 H, s)

Comparative Example 2: 7- [3- {4- (N-Ethoxyethylbenzoimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4-dihydro-2H-1,4-benzothiazin-3-one. Monofumaric acid salt production

7- [3- {4- (N-Ethoxyethylbenzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4-dihydro-2H-1,4-benzothiazin-3-one 6.81 g (13 3 mmol) was dissolved in a mixed solvent of ethanol (60 mL) and (water 6 mL) and the mixture was warmed to 60 ° C. A mixture of ethanol (14 mL) and water (1.5 mL) containing 1.55 g (13.3 mmol) of fumaric acid was added to the mixture, and the mixture was stirred at 40 ° C. for 30 minutes and then at room temperature for 20 hours. . The precipitated crystals are collected by filtration and then dried under reduced pressure at 40 ° C. for 53.5 hours, 7- [3- {4- (N-ethoxyethyl benzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3, 6.16 g (yield 74%) of 4-dihydro-2H-1,4-benzothiazin-3-one monofumaric acid salt was obtained as pale yellow crystals.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.01 (3 H, t, J = 7.0 Hz), 1.81 (2 H, quint, J = 6.6 Hz), 2.40-2. 49 (8 H, m), 3.35-3. 44 (6 H, m), 3.72 (2 H, t, J = 5.6 Hz), 3.78 (2 H, s), 3.93 (2 H, s) t, J = 6.4 Hz), 4.47 (2 H, t, J = 5.2 Hz), 6.60 (2 H, s), 6. 75 (1 H, dd, J = 3.0, 9.0 Hz) ), 6.87 (1 H, d, J = 8.8 Hz), 6.89 (1 H, s), 7.15 (1 H, t, J = 7.6 Hz), 7.20 (1 H, t, J = 7.4 Hz), 7.54 (2 H, t, J = 7.6 Hz), 10. 36 (1 H, s)

Comparative Example 3: 7- [3- {4- (N-Ethoxyethylbenzoimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4-dihydro-2H-1,4-benzothiazin-3-one. Production of disulfate

7- [3- {4- (N-Ethoxyethyl benzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4-dihydro-2H-1,4-benzothiazin-3-one 8.28 g (16 2 mmol) was dissolved in a mixed solvent of ethanol (104 mL) and water (11 mL) and cooled to 0 ° C. A solution of water (11 mL) to which 3.19 g (16.2 mmol) of sulfuric acid was added was added dropwise, and the mixture was stirred at 40 ° C. for 30 minutes and then at room temperature for 20 hours. The precipitated crystals are collected by filtration and then dried under reduced pressure at 40 ° C. for 53.5 hours, 7- [3- {4- (N-ethoxyethyl benzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3, 9.82 g (yield 86%) of 4-dihydro-2H-1,4-benzothiazin-3-one disulfate was obtained as pale yellow crystals.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.02 (3 H, t, J = 6.8 Hz), 2.03 (2 H, m), 2. 65 (2 H, m), 3.00 (4H, m), 3.26 (2H, m), 3.37 (2H, q, J = 6.8 Hz), 3.41-3.47 (4H, m), 3.75 (2H, t , J = 5.0 Hz), 4.01 (2 H, t, J = 5.8 Hz), 4.21 (2 H, brs), 4. 65 (2 H, t, J = 5.0 Hz), 6.78 (1H, dd, J = 2.8, 9.2 Hz), 6.89 (1 H, d, J = 8.8 Hz), 6.90 (1 H, d, J = 3.2 Hz), 7.50- 7.55 (2H, m), 7.79 (1H, d, J = 8.4 Hz), 7.91 (1 H, d, J = 6.0 Hz), 10.41 (1 H, s)

[Presence or absence of crystallization of each product]
The monomaleate (2a) obtained in Example 1-3 and the comparative compounds (dimaleate, monofumarate, disulfate of the title compound (1a)) obtained in Comparative Examples 1 to 3 are , Obtained as crystals as described above. On the other hand, salts of hydrochloric acid, boric acid, phosphoric acid and citric acid were produced as comparative examples using the title compound (1a) in the same manner as in Comparative Example 2, and crystallization was attempted for each of the compounds. In crystallization of each product, methanol or ethanol was used as a crystallization solvent. The results are shown in Table 2.

Crystallization studies have yielded crystalline salts of sulfuric acid, hydrochloric acid, maleic acid, fumaric acid. On the other hand, the borate, phosphate and citrate of the title compound (1a) did not crystallize, the monoborate was an oily substance, and the monophosphate and monocitrate were amorphous. In addition, with respect to the maleate, hydrochloride and sulfate of the title compound (1a), in addition to the 1-fold salt, a 2-fold salt was obtained. The hydrochloride of the title compound (1a) showed obvious deliquescent in both monohydrochloride and dihydrochloride.

[Comparison of purification efficiency of monomaleate and dimaleate of title compound (1a)]
The synthesis of monomaleate and dimaleate of the title compound (1a) was carried out under the same conditions using the same procedure to obtain crystals respectively. The synthetic means of each product is shown below.

(A) Synthesis of monomaleic acid salt of title compound (1a) 7- [3- {4- (N-ethoxyethyl benzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4-dihydro-2H After adding 7.26 g (16.2 mmol) of -1,4-benzothiazin-3-one (1a) to 71.74 g of ethanol, warming to 60 ° C. and adding 1.79 g (15.40 mmol) of maleic acid The mixture was cooled to 50 ° C., and 40 mg (0.064 mmol) of seed crystals were added. The reaction solution was stirred at 50 ° C. for 1 hour and then stirred at room temperature overnight. The reaction was then stirred at 3 ° C. or less for 5 hours. After the completion of stirring, the precipitated crystals were collected by filtration to obtain 6.26 g (yield 62%) of monomaleate of the title compound (1a).

(B) Synthesis of dimaleate salt of title compound (1a) 7- [3- {4- (N-ethoxyethyl benzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4-dihydro-2H- 8.26 g (16.2 mmol) of 1,4-benzothiazin-3-one (1a) was added to 71.74 g of ethanol and heated to 60 ° C., and 4.7 g (40.48 mmol) of maleic acid was added. After confirming that the maleic acid was completely dissolved in the solution, the solution was stirred overnight at room temperature. The reaction was then stirred at 3 ° C. or less for 5 hours. After the completion of stirring, the precipitated crystals were collected by filtration to obtain 8.04 g (yield 67%) of the dimaleate salt of the title compound (1a).

The crystals of monomaleate and dimaleate obtained by the above means (a) and (b) were each dissolved in a small amount of solvent, and the purity of each substance was measured by high performance liquid chromatography (HPLC). The HPLC conditions were as follows, and charts showing the HPLC measurement results are shown in FIG. 4 and FIG. Moreover, what summarized the HPLC measurement result was shown in Table 3.

[High-performance liquid chromatography (HPLC) conditions]
Detector: Ultraviolet absorptiometer (measurement wavelength: 246 nm)
Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 5 cm is packed with 3.5 μm phenylhexylsilylated silica gel for liquid chromatography.
(X Bridgephenyl, 4.6 mmφ × 5 cm, 3.5 μm; Waters)
Column temperature: constant temperature around 40 ° C. gradient condition (B%) 20% → <10 minutes> → 60% (10 minutes) → <10 minutes> → 85% (10 minutes)
Solution A: 0.01 mol / L phosphate buffer, pH 6.0
Liquid B: Methanol Flow rate: 1.0 mL / min
Area measurement range: 40 minutes Injection amount: 3 μL
Sample concentration: 1 mg / mL

[Summary of HPLC measurement results]

As can be seen from Table 3, when the HPLC measurement results of the obtained monomaleate and dimaleate are compared, the peak content of monomaleate is about 99.4% at a retention time (RT) of 16.6 minutes. This indicates that it is higher than about 97.2% of dimaleate. Therefore, it is understood that monomaleate is more efficiently obtained than dimaleate. On the other hand, looking at the by-products, it is confirmed that about 0.4% of the by-products are present on the monomaleate side at RT 19.2-19.6 minutes, On the side, peaks of by-products at RT 20.6-21.6 minutes and 25.7-25.8 minutes were confirmed, and the ratio of by-products was lower with monomaleate as a whole. I understand. From the above results, it was confirmed that monomaleate has a higher purification efficiency of the target compound than dimaleate.

Next, using the monomaleic acid salt (2a) obtained in Example 1-3 and the dimaleic acid salt obtained in Comparative Example 1, comparative measurement with regard to light stability, thermal stability, hygroscopicity and solubility was carried out. went. The detailed conditions of each measurement method and the measurement results are shown below.

To measure the light stability, spread an appropriate amount of sample thinly in a glass container and place it in a light stability tester (Nagano Science, LT-120A-D), and use D65 fluorescent lamp for color comparison and inspection (FLR20S · D- After setting the illuminance of EDL-65 / MNA to 4000lx and exposing it to an integrated illuminance of 1.2 million lx h at 25 ° C, the sample after exposure based on the amount of sample before exposing by high performance liquid chromatography The amount was calculated.

To measure the thermal stability, place an appropriate amount of the sample in a glass container with a lid, store the sample in a compact precision incubator set at 80 ° C. (Asahi Rika Seisakusho, AWC-2 type) for 1 week, The amount of sample after heating was calculated by high performance liquid chromatography based on the amount of sample before application of.

To measure the hygroscopicity, place the appropriate amount of sample thinly in a precisely weighed glass weighing bottle, weigh the sample accurately, and measure 75% relative humidity (saturated solution of sodium chloride) or relative humidity After storing for 1 day at 25 ° C. in a plastic desiccator adjusted to 93% (saturated solution of potassium nitrate), the two weighing bottles containing the sample are accurately weighed respectively, and the moisture absorption of the sample is given by the following formula. The degree was calculated.

[Calculation formula of moisture absorption]
Moisture absorption rate (%) = (W3-W2) / (W2-W1) x 100
W1: Weight of weighing bottle (g)
W2: Weight before storage of the weighing bottle containing the sample (g)
W3: Weight after storage of the weighing bottle containing the sample (g)

About the measurement of solubility, about 100 mg of a sample is weighed in a transparent glass bottle, 10 mL of 0.05 mol / L boric acid solution is added to the glass bottle, and after stirring for 1 hour, pH 5 using a 0.1 mol / L sodium hydroxide solution. The mixture was adjusted to 5 and then the mixture was further stirred for 1 hour and then allowed to stand at 25 ° C. overnight. The supernatant after standing using a centrifuge is centrifuged at 3000 rpm for 10 minutes, and then filtered through a filter (HLC-DISK aqueous & solvent system: pore size 0.45 um), and the concentration is determined using liquid chromatography. It measured.

[Result of measurement of light stability, heat stability, hygroscopicity and solubility]
The measurement results of the monomaleate (2a) obtained in Example 1-3 and the dimaleate obtained in Comparative Example 1 are shown in Table 4 with respect to light stability, heat stability, hygroscopicity and solubility.

As can be seen from the results in Table 4, monomaleate showed better results than dimaleate in all items of thermal stability, light stability, hygroscopicity and solubility. Specifically, the dimaleate crystals showed decomposition upon irradiation with heat or light, whereas the monomaleate crystals did not decompose and showed good stability. Also, although the dimaleate crystals exhibited high hygroscopicity, particularly at 93% relative humidity, the monomaleate crystals did not absorb nearly any water. The monomaleate crystals also showed better values than the dimaleate crystals in terms of solubility, and were shown to be suitable for the preparation of injections, eye drops and the like.

[Examination of eye mucous membrane irritation]
Next, regarding the monomaleate (2a) obtained in the above Example 1-3 and the dimaleate, fumaric acid and sulfate of the title compound (1a) prepared in the above Comparative Examples 1, 2 and 3, The rabbit eye mucous membrane irritation was examined. The test methods and test results are shown below.

The details of the test method were as follows. First, 0.5% eye drops were prepared for each of the above-mentioned salt compounds, and damage to the cornea, iris and conjunctiva by eye drops for 2 days, and further closed eye reaction and blink frequency. The evaluation of irritation is based on the Draze method (J. Pharmacol Exp Ther. 1944; 82: 377), indicated by the average value MIOI of IIOI which is the injury score for the cornea, iris and conjunctiva of each individual, 0 to 2.5; No irritation, 2.5 to 15; extremely mild irritation, 15 to 25; mild irritation, 25 to 50; moderate irritation, 50 to 80; intense irritation, 80 to 110; It was evaluated as irritant. The measurement results after instillation are shown in Table 5.

As a result of the rabbit eye mucous membrane irritation test, the sulfate salt of compound (1a) was confirmed to have mild eye mucous membrane irritation, but monomaleate, dimaleate and fumarate of compound (1a) The eye mucous membrane irritation was not confirmed.

The hygroscopicity of the fumaric acid salt of the compound (1a) was also tested by the same method (75% relative humidity) as the above-mentioned hygroscopicity test, but the hygroscopicity was 4.9%. Accordingly, it was found that the fumaric acid salt of compound (1a) is more hygroscopic than monomaleate or dimaleate of compound (1a), and is not suitable for storage or formulation of a drug substance.

Next, using the monomaleate salt (2a) obtained in Example 1-3 and the dimaleate salt obtained in Comparative Example 1, tests on antihistamine action and therapeutic effect on allergic conjunctivitis were conducted. The test methods and the results are shown below.

[Test Example 1: Examination of antihistamine action]
In order to investigate the antihistamine effect possessed by the monomaleate (2a) obtained in Example 1-3 and the dimaleate obtained in Comparative Example 1, a study was conducted using a histamine-induced conjunctivitis model. A male Hartley guinea pig was intravenously administered Evans blue, and immediately 10 μL of a 10 mg / mL histamine solution was instilled to cause vascular hyperpermeability. After 30 minutes, the conjunctiva was excised and the amount of pigment contained was measured. Monomaleic acid salt (2a) and dimaleic acid salt were instilled in an amount of 10 μL one hour before histamine instillation. The results of the obtained antihistaminic action are shown in FIG. Both the monomaleate (2a) and dimaleate had a significant effect of suppressing dye leakage from a concentration of 0.001%, confirming that they have potent antihistaminic effects.

[Test Example 2: Examination of therapeutic effect of allergic conjunctivitis]
The therapeutic effect of allergic conjunctivitis possessed by the monomaleate (2a) obtained in Example 1-3 and the dimaleate obtained in Comparative Example 1 was examined using an antigen-induced conjunctivitis model. Hartley male guinea pigs actively sensitized with OVA and Alum were intravenously administered Evans blue, and immediately 10 μL of 2.5% OVA solution was instilled to cause vascular hyperpermeability. After 30 minutes, the conjunctiva was excised and the amount of pigment contained was measured. Monomaleic acid salt (2a) and dimaleic acid salt were each instilled in a concentration of 10 μL at a concentration of 0.1% one hour before OVA instillation. The obtained antiallergic conjunctivitis action is shown in FIG. Both the monomaleate (2a) and dimaleate have shown strong dye leakage inhibition. Therefore, it was confirmed that both compounds have therapeutic effects on allergic conjunctivitis.

The monomaleate salt (2) of the present invention is a crystal having good non-hygroscopicity, light stability, thermal stability and solubility, and is used as a preventive and / or therapeutic agent for allergic diseases such as allergic eye diseases. It is a useful compound. In addition, the monomaleate salt (2) of the present invention is extremely useful for pharmaceutical use because it can be produced with high purification efficiency compared to the dimaleate salt of the compound.

Claims (25)

1. The following equation (2)
   

   

   (Wherein, l is an integer of 1 or 2; m is an integer of 1 or 2; n is an integer of 1 to 4)
   Monomaleic acid salt of benzothiazine compound represented by
2. The benzothiazine compound represented by the formula (2) is 7- [3- {4- (N-ethoxyethyl benzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4-dihydro-2H-1, The salt according to claim 1, which is 4-benzothiazin-3-one.
3. The monomaleate salt according to claim 1 or 2, which is a crystal.
4. The monomaleate salt according to any one of claims 1 to 3, which shows a powder X-ray diffraction pattern having peaks near the diffraction angles (2θ) 16.7 and 24.7.
5. The thing according to any one of claims 1 to 3, which shows a powder X-ray diffraction pattern having peaks at diffraction angles (2θ) of 16.7, 20.3, 23.7 and 24.7. Maleate.
6. Shown 1669cm around ^-1, 1492Cm around ^-1, the infrared absorption spectrum having a peak near 868Cm ^-1 and near 754Cm ^-1, mono maleate according to any one of claims 1 to 5.
7. 1669cm around ^-1, 1492Cm around ^-1 indicates 1231cm around ^-1, 1208Cm around ^-1, the infrared absorption spectrum having a peak near 868Cm ^-1 and near 754Cm ^-1, any one of claims 1 to 5, Monomaleate as described in.
8. An agent for preventing and / or treating allergic diseases, which comprises the monomaleate salt according to any one of claims 1 to 7 as an active ingredient.
9. The prophylactic and / or therapeutic agent according to claim 8, wherein the allergic disease is allergic eye disease.
10. The agent for preventing and / or treating according to claim 9, wherein the allergic eye disease is allergic conjunctivitis.
11. 

    (Wherein, l is an integer of 1 or 2; m is an integer of 1 or 2; n is an integer of 1 to 4)
    Wherein the benzothiazine compound represented by the formula: and one equivalent or less of maleic acid relative to the benzothiazine compound are heated in a solvent, and the reaction solution is cooled to −20 to 20 ° C. after heating. The manufacturing method of the monomaleic acid salt of the benzothiazine compound represented by 1).
12. The method for producing monomaleate according to claim 11, wherein the amount of maleic acid used for the reaction is 0.70 to 0.95 equivalents with respect to the benzothiazine compound represented by the formula (1).
13. The method for producing monomaleate according to claim 11 or 12, wherein the solvent is ethanol.
14. The method for producing a monomaleate salt according to any one of claims 11 to 13, wherein the heating reaction is carried out by heating the solvent to 40 to 80 属 C.
15. The method for producing a monomaleate according to any one of claims 11 to 14, wherein 4 to 10 times by weight ethanol is used as the solvent in terms of weight relative to the total amount of the benzothiazine compound and maleic acid.
16. The said benzothiazine compound is 7- [3- {4- (N-ethoxyethylbenzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4-dihydro-2H-1,4-benzothiazin-3-one The method for producing a monomaleate salt according to any one of claims 11 to 15, which is
17. The monomaleate salt according to any one of claims 1 to 7 for use in the prevention and / or treatment of allergic diseases.
18. The monomaleate salt according to claim 17, wherein the allergic disease is allergic eye disease.
19. 19. The monomaleate salt of claim 18, wherein the allergic eye disease is allergic conjunctivitis.
20. Use of the monomaleate salt according to any one of claims 1 to 7 for the production of a preventive and / or therapeutic agent for allergic diseases.
21. 21. The use according to claim 20, wherein the allergic disease is allergic eye disease.
22. The use according to claim 21, wherein the allergic eye disease is allergic conjunctivitis.
23. A method for preventing and / or treating allergic diseases, which comprises administering an effective amount of the monomaleate according to any one of claims 1 to 7.
24. The method according to claim 23, wherein the allergic disease is allergic eye disease.
25. 25. The method of claim 24, wherein the allergic eye disease is allergic conjunctivitis.

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