JP2012521964A - Novel salt of 1,3,5-triazine-2,4,6-triamine derivative - Google Patents

Novel salt of 1,3,5-triazine-2,4,6-triamine derivative Download PDF

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JP2012521964A
JP2012521964A JP2011541013A JP2011541013A JP2012521964A JP 2012521964 A JP2012521964 A JP 2012521964A JP 2011541013 A JP2011541013 A JP 2011541013A JP 2011541013 A JP2011541013 A JP 2011541013A JP 2012521964 A JP2012521964 A JP 2012521964A
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淳弥 大森
良 笠井
武徳 木村
憲孝 ▲浜▼田
亮 溝口
聡 宮本
則征 河野
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Abstract

【課題】N-(4-フルオロフェニル)- N'-フェニル-N''- (ピリミジン-2-イルメチル)- 1,3,5-トリアジン-2,4,6-トリアミン（化合物A）及び／又はN, N'-ビス(4-フルオロフェニル)-N''- (ピリミジン-2-イルメチル)- 1,3,5-トリアジン-2,4,6-トリアミン（化合物B）を、医薬品又は医薬品の原体として使用するための、安定的に単一の結晶が得られ、安定性に優れた化合物A及び／又は化合物Bのフマル塩及びその新規結晶が提供される。
【解決手段】化合物A及び／又は化合物Bのフマル酸との塩は、安定的に単一の結晶が得られ、安定性に優れた医薬品又は医薬品原体としてきわめて有用な化合物である。
【選択図】なしThe present invention relates to N- (4-fluorophenyl) -N′-phenyl-N ″-(pyrimidin-2-ylmethyl) -1,3,5-triazine-2,4,6-triamine (compound A) and / or Or N, N'-bis (4-fluorophenyl) -N ''-(pyrimidin-2-ylmethyl) -1,3,5-triazine-2,4,6-triamine (compound B) Thus, compound A and / or compound B fumarate excellent in stability and a novel crystal thereof are obtained.
A salt of compound A and / or compound B with fumaric acid is a very useful compound as a pharmaceutical or drug substance having a stable single crystal and having excellent stability.
[Selection figure] None

Description

本発明は、医薬、特に特定のカリウムチャネル阻害剤として有用な、N-(4-フルオロフェニル)- N'-フェニル-N''- (ピリミジン-2-イルメチル)- 1,3,5-トリアジン-2,4,6-トリアミン（以下、化合物Aと言う。）及び／又はN, N'-ビス(4-フルオロフェニル)-N''- (ピリミジン-2-イルメチル)- 1,3,5-トリアジン-2,4,6-トリアミン（以下、化合物Bと言う。）の新規な塩に関する。   The present invention relates to N- (4-fluorophenyl) -N′-phenyl-N ″-(pyrimidin-2-ylmethyl) -1,3,5-triazines useful as pharmaceuticals, particularly certain potassium channel inhibitors. -2,4,6-triamine (hereinafter referred to as Compound A) and / or N, N′-bis (4-fluorophenyl) -N ″-(pyrimidin-2-ylmethyl) -1,3,5 -It relates to a novel salt of triazine-2,4,6-triamine (hereinafter referred to as Compound B).

化合物A及び／又は化合物Bは、以下の化学構造を有し、特定のカリウムチャネル（BEC1カリウムチャネル）を阻害する作用と抗うつ作用を有すること及び認知症の治療に有用であることが知られている（米国特許第7375222号）。   Compound A and / or Compound B has the following chemical structure and is known to have an action and an antidepressant action to inhibit a specific potassium channel (BEC1 potassium channel) and to be useful for the treatment of dementia. (US Pat. No. 7,372,522).

Figure 2012521964
Figure 2012521964

化合物Aは、具体的に、化合物A・2HCl・0.3H2O・0.1酢酸エチルの組成物として単離されており（米国特許第7375222号）、他の製薬学的に許容される酸付加塩の具体的な報告はない。また、化合物Bは架空実施例として記載されているのみである（米国特許第7375222号）。 Compound A is specifically isolated as a composition of Compound A · 2HCl · 0.3H 2 O · 0.1 ethyl acetate (US Pat. No. 7,372,522) and other pharmaceutically acceptable acid addition salts. There is no specific report. Compound B is only described as a fictitious example (US Pat. No. 7,372,522).

化合物AのpKa値は3.9であり塩基性が弱いことから、一般的には強酸との塩が好ましい。代表的な強酸の1つである塩酸を対イオンとした公知化合物である化合物Aの2塩酸塩は、付着溶媒のない無水物の結晶として得られるものの、DSCを測定すると複数の吸熱ピークが得られることから、複数の結晶が存在する可能性があった。構造式が同一の化合物であっても、結晶形が異なれば、化合物の溶解性や安定性が異なることはよく知られた事実である。医薬品の品質の同一性や安定性を確保するためには、同一の結晶形が安定的に得られる化合物及びその製造法を選択することが好ましい。
化合物Ｂについては、具体的な化合物が得られているわけではない。しかし、医薬品の品質の同一性や安定性を確保するためには、同一の結晶形が安定的に得られる化合物（フリー体又は特定の酸付加塩）及びその製造法を選択することが好ましい点、更に、溶媒和物が得られる場合には、製薬学的に許容できる溶媒和物であることが好ましい点は、化合物Aと同様である。 Since the pKa value of Compound A is 3.9 and its basicity is weak, a salt with a strong acid is generally preferred. Although the dihydrochloride of Compound A, a known compound with hydrochloric acid as one of the representative strong acids as a counter ion, is obtained as an anhydrous crystal without an attached solvent, multiple endothermic peaks are obtained when DSC is measured. Therefore, there is a possibility that a plurality of crystals exist. It is a well-known fact that even if the compounds have the same structural formula, the solubility and stability of the compounds differ if the crystal forms are different. In order to ensure the identity and stability of the quality of pharmaceuticals, it is preferable to select a compound that can stably obtain the same crystal form and a production method thereof.
For compound B, no specific compound has been obtained. However, it is preferable to select a compound (free form or specific acid addition salt) that can stably obtain the same crystal form and a method for producing the same in order to ensure the same quality and stability of pharmaceutical products. Furthermore, when a solvate is obtained, the pharmaceutically acceptable solvate is preferably the same as Compound A.

本発明者らは、化合物A及び／又はBについて、それらのフリー体やそれらの酸付加塩について検討を行った結果、化合物A及び／又はBの特定の不揮発性の酸付加塩が、単一の結晶として安定的に得られること、及び、当該結晶が優れた安定性を有することを見出し、本発明を完成させた。   As a result of examining the free forms and acid addition salts of compounds A and / or B, the present inventors have found that a specific nonvolatile acid addition salt of compound A and / or B is a single compound. The present invention has been completed by finding that it can be stably obtained as a crystal and that the crystal has excellent stability.

即ち、本発明の目的は、式（Ｉ）

Figure 2012521964
（ここでR1：H又はF）
の化合物とフマル酸からなる塩を提供することである。 That is, the object of the present invention is to formula (I)
Figure 2012521964
 (Where R 1 is H or F)
And a salt comprising fumaric acid.

本発明の他の目的は、式（Ｉ）の化合物の結晶を提供することである。   Another object of the present invention is to provide crystals of the compound of formula (I).

本発明の他の目的は、式（Ｉ）の化合物を有効量を含有し、更に製薬学的に許容される担体を含む医薬組成物を提供することである。   Another object of the present invention is to provide a pharmaceutical composition comprising an effective amount of a compound of formula (I) and further comprising a pharmaceutically acceptable carrier.

本発明の、化合物A（式IにおいてR1がHである化合物）のフマル酸塩は、公知化合物である化合物A・2塩酸塩と比較して、安定的に単一の結晶が得られる点で有利であり、優れた安定性を有する医薬品又は活性医薬成分としてきわめて有用な化合物である。また、化合物B（式IにおいてR1がFである化合物）のフマル酸塩も、安定的に単一の結晶が得られ、安定性に優れた医薬品又は活性医薬成分としてきわめて有用な化合物である。
特に、安定的に単一の結晶が得られるという点においては、公知化合物である化合物A・2塩酸塩は単一の結晶形が得られていないことが明らかとなっており、開発品として選択する場合には、一定の規格の範囲の溶解性や安定性を有する結晶を安定的に製造しなければならない点で不利である。化合物A及び／又はBのフマル酸塩は、単一の結晶として安定的に得られること、及び、当該結晶が優れた安定性を示すことから優れた医薬品の提供に資するものである。
化合物A及び／又は化合物Bは、統合失調症の動物モデルにおいて、メタンフェタミン誘発運動亢進を抑制した。すなわち、これら２化合物は認知症の改善効果のみならず、統合失調症の症状を改善する作用があることが見出された。 The fumarate salt of the compound A (compound in which R 1 is H in the formula I) of the present invention is more stable than the known compound A · 2 hydrochloride salt, and a single crystal can be obtained stably. And is a very useful compound as a pharmaceutical or active pharmaceutical ingredient having excellent stability. In addition, the fumarate salt of Compound B (the compound in which R 1 is F in Formula I) is also a very useful compound as an active pharmaceutical ingredient or an active pharmaceutical ingredient that can stably obtain a single crystal. .
In particular, it is clear that compound A • 2 hydrochloride, which is a known compound, has not obtained a single crystal form in that stable single crystals can be obtained. In this case, it is disadvantageous in that crystals having solubility and stability within a certain standard range must be stably produced. The fumarate salt of compound A and / or B contributes to the provision of an excellent pharmaceutical because it is stably obtained as a single crystal and the crystal exhibits excellent stability.
Compound A and / or Compound B suppressed methamphetamine-induced hyperactivity in an animal model of schizophrenia. That is, it was found that these two compounds have not only an effect of improving dementia but also an effect of improving symptoms of schizophrenia.

例により、及び、明細書の記載をより明確にするため、図に従って説明する。
化合物Aとフマル酸の比が2:1の塩の無水物の結晶（I型結晶）の粉末X線回折パターンを示す図である。 化合物Aとフマル酸の比が2:1の塩であって、化合物Aと水の比が2:1である水和物の結晶（II型結晶）の粉末X線回折パターンを示す図である。 化合物Aとフマル酸の比が1:1の塩（化合物Aと付着溶媒であるメチルエチルケトン、EtOH及び水の比=1:0.1：0.007：0.3）の結晶（III型結晶）の粉末X線回折パターンを示す図である。 化合物Aと塩酸の比が1:2の塩の無水物の結晶の粉末X線回折パターンを示す図である。 化合物Bとフマル酸の比が1:1の塩の結晶（I型結晶）の粉末X線回折パターンを示す図である。 化合物Bと塩酸の比が1:2の塩の結晶（I型結晶）の粉末X線回折パターンを示す図である。 化合物Aとフマル酸の比が2:1の塩の無水物の結晶（I型結晶）のDSC曲線を示す図である。 化合物Aとフマル酸の比が2:1の塩であって、化合物Aと水の比が2:1である水和物の結晶（II型結晶）のDSC曲線を示す図である。 化合物Aとフマル酸の比が1:1の塩（化合物Aと付着溶媒であるメチルエチルケトン、EtOH及び水の比=1:0.1：0.007：0.3）の結晶（III型結晶）のDSC曲線を示す図である。 化合物Aと塩酸の比が1:2の塩の無水物の結晶のDSC曲線を示す図である。 化合物Bとフマル酸の比が1:1の塩の結晶（I型結晶）のDSC曲線を示す図である。 化合物Bと塩酸の比が1:2の塩の結晶（I型結晶）のDSC曲線を示す図である。 化合物Aのフリー体の結晶の粉末Ｘ線回折パターンを示す図である。この結晶は、線源としてCuを用いた粉末Ｘ線解析において、２θ（°）が、7.7付近，19.5付近，21.8付近，及び28.6付近にピークを示すことを特徴とする。 化合物Aのフリー体の結晶のDSC曲線を示す図である。DSCにおける吸熱オンセット温度が約185℃である。 In order to make the description of the specification clearer by way of example, description will be made according to the drawings.
FIG. 4 is a diagram showing a powder X-ray diffraction pattern of an anhydride crystal (type I crystal) of a salt having a ratio of compound A to fumaric acid of 2: 1. FIG. 3 is a graph showing a powder X-ray diffraction pattern of a hydrate crystal (type II crystal) in which the ratio of compound A to fumaric acid is 2: 1 and the ratio of compound A to water is 2: 1. . Powder X-ray diffraction pattern of a crystal (type III crystal) of a salt having a ratio of compound A to fumaric acid of 1: 1 (ratio of compound A and adhering solvent methyl ethyl ketone, EtOH and water = 1: 0.1: 0.007: 0.3) FIG. FIG. 3 is a graph showing a powder X-ray diffraction pattern of an anhydride crystal of a salt having a ratio of Compound A to hydrochloric acid of 1: 2. FIG. 3 is a graph showing a powder X-ray diffraction pattern of a salt crystal (type I crystal) having a ratio of compound B to fumaric acid of 1: 1. FIG. 3 is a diagram showing a powder X-ray diffraction pattern of a salt crystal (type I crystal) having a ratio of compound B to hydrochloric acid of 1: 2. FIG. 2 is a diagram showing a DSC curve of an anhydride crystal (type I crystal) of a salt having a ratio of compound A to fumaric acid of 2: 1. FIG. 3 is a diagram showing a DSC curve of a hydrate crystal (type II crystal) in which the ratio of compound A to fumaric acid is 2: 1 and the ratio of compound A to water is 2: 1. A diagram showing a DSC curve of a crystal (type III crystal) of a salt having a ratio of compound A to fumaric acid of 1: 1 (ratio of compound A and adhering solvent methyl ethyl ketone, EtOH and water = 1: 0.1: 0.007: 0.3) It is. FIG. 3 is a diagram showing a DSC curve of an anhydrous crystal of a salt having a ratio of Compound A to hydrochloric acid of 1: 2. FIG. 3 is a diagram showing a DSC curve of a salt crystal (type I crystal) in which the ratio of compound B to fumaric acid is 1: 1. FIG. 3 is a diagram showing a DSC curve of a salt crystal (type I crystal) having a ratio of Compound B to hydrochloric acid of 1: 2. FIG. 3 is a graph showing a powder X-ray diffraction pattern of a free form crystal of Compound A. This crystal is characterized in that 2θ (°) peaks in the vicinity of 7.7, 19.5, 21.8, and 28.6 in powder X-ray analysis using Cu as a radiation source. FIG. 3 is a diagram showing a DSC curve of a free crystal of Compound A. The endothermic onset temperature in DSC is about 185 ° C.

本発明の化合物Aのフマル酸塩及び／又は化合物Bのフマル酸塩は、単一の結晶として安定的に得られ、当該結晶は優れた安定性を示す。従って、本発明のいずれの塩又はそれらの結晶も医薬品又は活性医薬成分として好適であるが、特に好ましくは、化合物A とフマル酸の比が2:1である塩及び／又は化合物Bとフマル酸の比が1:1である塩又はそれらの結晶である。   The fumarate salt of Compound A and / or the fumarate salt of Compound B of the present invention is stably obtained as a single crystal, and the crystal exhibits excellent stability. Accordingly, any salt of the present invention or a crystal thereof is suitable as a pharmaceutical or active pharmaceutical ingredient, but particularly preferably a salt and / or a compound B and fumaric acid in which the ratio of compound A to fumaric acid is 2: 1. Is a salt or a crystal thereof.

本発明の好ましい態様を以下に示す。
（１）化合物A とフマル酸の比が2:1の塩の無水物。
（２）化合物A とフマル酸の比が2:1の塩の無水物の結晶。
（３）DSCにおける吸熱オンセット温度が190℃付近である（２）に記載の結晶。
（４）線源としてCuを用いた粉末Ｘ線解析において、２θ（°）が、5.3付近，8.2付近，10.5付近，及び16.4付近にピークを示すことを特徴とする（２）に記載の結晶。
（５）線源としてCuを用いた粉末Ｘ線解析において、２θ（°）が、5.3付近，8.2付近，9.8付近，10.5付近，11.7付近，16.4付近，18.6付近及び，26.6付近にピークを示すことを特徴とする（２）に記載の結晶。
（６）DSCにおける吸熱オンセット温度が180-200℃であり、粉末Ｘ線解析において線源としてCuを用いた粉末Ｘ線解析において、２θ（°）が、5.3付近，8.2付近，10.5付近，及び16.4付近にピークを示すことを特徴とする（２）に記載の結晶。
（７）DSCにおける吸熱オンセット温度が180-200℃であり、粉末Ｘ線解析において線源としてCuを用いた粉末Ｘ線解析において、２θ（°）が、5.3付近，8.2付近，9.8付近，10.5付近，11.7付近，16.4付近，18.6付近及び，26.6付近にピークを示すことを特徴とする（２）に記載の結晶。
（８）（２）〜（７）に記載された結晶がI型結晶である結晶。
（９）化合物Aとフマル酸から成る塩を有効成分として含有し、さらに製薬学的に許容される担体を含有する医薬組成物。
（１０）有効成分が化合物A とフマル酸の比が2:1の塩である（９）に記載の医薬組成物。
（１１）有効成分が化合物A とフマル酸の比が2:1の塩の無水物である（９）に記載の医薬組成物。
（１２）（２）〜（７）に記載の結晶を有効成分として含有し、さらに製薬学的に許容される担体を含有する医薬組成物。
（１３）化合物A とフマル酸の比が2:1の塩であって、化合物Aと水の比が2:１である水和物。
（１４）（１３）に記載の化合物の結晶。
（１５）DSCにおける吸熱オンセット温度が150℃付近である（１４）に記載の結晶。
（１６）線源としてCuを用いた粉末Ｘ線解析において、２θ（°）が、6.7付近，7.8付近，20.1付近，及び20.5付近にピークを示すことを特徴とする（１４）に記載の結晶。
（１７）線源としてCuを用いた粉末Ｘ線解析において、２θ（°）が、6.7付近，7.8付近，8.1付近，10.5付近，13.9付近，20.1付近，20.5付近及び，21.6付近にピークを示すことを特徴とする（１４）に記載の結晶。
（１８）DSCにおける吸熱オンセット温度が140-160℃であり、粉末Ｘ線解析において線源としてCuを用いた粉末Ｘ線解析において、２θ（°）が、6.7付近，7.8付近，20.1付近，及び20.5付近にピークを示すことを特徴とする（１４）に記載の結晶。
（１９）DSCにおける吸熱オンセット温度が140-160℃であり、粉末Ｘ線解析において線源としてCuを用いた粉末Ｘ線解析において、２θ（°）が、6.7付近，7.8付近，8.1付近，10.5付近，13.9付近，20.1付近，20.5付近及び，21.6付近にピークを示すことを特徴とする（１４）に記載の結晶。
（２０）（１４）〜（１９）から選択される結晶がII型結晶である結晶。
（２１）（１３）に記載の塩化合物を有効成分として含有し、さらに製薬学的に許容される担体を含有する医薬組成物。
（２２）（１４）〜（２０）に記載の結晶から選択された結晶を有効成分として含有し、さらに製薬学的に許容される担体を含有する医薬組成物。
（２３）化合物A とフマル酸の比が1:1の塩。
（２４）化合物A とフマル酸の比が1:1の塩の無水物。
（２５）（２３）又は（２４）に記載の化合物の結晶。
（２６）DSCにおける吸熱オンセット温度が160℃付近である（２５）に記載の結晶。
（２７）線源としてCuを用いた粉末Ｘ線解析において、２θ（°）が、6.7付近，17.7付近，22.3付近，及び26.3付近にピークを示すことを特徴とする（２５）に記載の結晶。
（２８）線源としてCuを用いた粉末Ｘ線解析において、２θ（°）が、6.7付近，9.5付近，11.5付近，13.4付近，16.4付近，17.7付近，22.3付近及び，26.3付近にピークを示すことを特徴とする（２５）に記載の結晶。
（２９）DSCにおける吸熱オンセット温度が150-170℃であり、粉末Ｘ線解析において線源としてCuを用いた粉末Ｘ線解析において、２θ（°）が、6.7付近，17.7付近，22.3付近，及び26.3付近にピークを示すことを特徴とする（２５）に記載の結晶。
（３０）DSCにおける吸熱オンセット温度が150-170℃であり、粉末Ｘ線解析において線源としてCuを用いた粉末Ｘ線解析において、２θ（°）が、6.7付近，9.5付近，11.5付近，13.4付近，16.4付近，17.7付近，22.3付近及び，26.3付近にピークを示すことを特徴とする（２５）に記載の結晶。
（３１）（２５）〜（３０）に記載される結晶がIII型結晶である結晶。
（３２）（２３）に記載の化合物を有効成分として含有し、さらに製薬学的に許容される担体を含有する医薬組成物。
（３３）（２４）に記載の化合物を有効成分として含有し、さらに製薬学的に許容される担体を含有する医薬組成物。
（３４）（２５）〜（３１）に記載の結晶から選択された結晶を有効成分として含有し、さらに製薬学的に許容される担体を含有する医薬組成物。
（３５）化合物B とフマル酸の比が1:1の塩の無水物。
（３６）（３５）に記載の化合物の結晶。
（３７）DSCにおける吸熱オンセット温度が215℃付近である（３６）に記載の結晶。
（３８）線源としてCuを用いた粉末Ｘ線解析において、２θ（°）が、6.6付近，8.2付近，15.7付近，及び26.5付近にピークを示すことを特徴とする（３６）に記載の結晶。
（３９）線源としてCuを用いた粉末Ｘ線解析において、２θ（°）が、6.6付近，8.2付近，9.2付近，10.9付近，13.6付近，15.7付近，20.5付近及び，26.5付近にピークを示すことを特徴とする（３６）に記載の結晶。
（４０）DSCにおける吸熱オンセット温度が200-220℃であり、粉末Ｘ線解析において線源としてCuを用いた粉末Ｘ線解析において、２θ（°）が、6.6付近，8.2付近，15.7付近，及び26.5付近にピークを示すことを特徴とする（３６）に記載の結晶。
（４１）DSCにおける吸熱オンセット温度が205-225℃であり、粉末Ｘ線解析において線源としてCuを用いた粉末Ｘ線解析において、２θ（°）が、6.6付近，8.2付近，9.2付近，10.9付近，13.6付近，15.7付近，20.5付近及び，26.5付近にピークを示すことを特徴とする（３６）に記載の結晶。
（４２）（３６）〜（４１）から選択される結晶がI型結晶である結晶。
（４３）化合物Bとフマル酸から成る塩を有効成分として含有し、さらに製薬学的に許容される担体を含有する医薬組成物。
（４４）化合物A とフマル酸の比が1:1の塩を有効成分として含有し、さらに製薬学的に許容される担体を含有する医薬組成物。
（４５）（３５）に記載の化合物を有効成分として含有し、さらに製薬学的に許容される担体を含有する医薬組成物。
（４６）（３６）〜（４２）に記載の結晶から選択された結晶を有効成分として含有し、さらに製薬学的に許容される担体を含有する医薬組成物。 Preferred embodiments of the present invention are shown below.
(1) A salt anhydride having a ratio of compound A to fumaric acid of 2: 1.
(2) Anhydrous crystals of salt with a ratio of compound A to fumaric acid of 2: 1.
(3) The crystal according to (2), wherein the endothermic onset temperature in DSC is around 190 ° C.
(4) In the powder X-ray analysis using Cu as the radiation source, 2θ (°) shows peaks in the vicinity of 5.3, 8.2, 10.5, and 16.4. .
(5) In powder X-ray analysis using Cu as the radiation source, 2θ (°) shows peaks near 5.3, 8.2, 9.8, 10.5, 11.7, 16.4, 18.6, and 26.6. The crystal according to (2), which is characterized in that
(6) The endothermic onset temperature in DSC is 180-200 ° C, and in the powder X-ray analysis using Cu as the radiation source in the powder X-ray analysis, 2θ (°) is around 5.3, around 8.2, around 10.5, And the crystal according to (2), which shows a peak in the vicinity of 16.4.
(7) Endothermic onset temperature in DSC is 180-200 ° C, and in powder X-ray analysis using Cu as a radiation source in powder X-ray analysis, 2θ (°) is around 5.3, around 8.2, around 9.8, The crystal according to (2), characterized by having peaks in the vicinity of 10.5, 11.7, 16.4, 18.6 and 26.6.
(8) A crystal in which the crystals described in (2) to (7) are I-type crystals.
(9) A pharmaceutical composition comprising a salt comprising compound A and fumaric acid as an active ingredient, and further comprising a pharmaceutically acceptable carrier.
(10) The pharmaceutical composition according to (9), wherein the active ingredient is a salt having a ratio of compound A to fumaric acid of 2: 1.
(11) The pharmaceutical composition according to (9), wherein the active ingredient is a salt anhydride having a ratio of compound A to fumaric acid of 2: 1.
(12) A pharmaceutical composition comprising the crystal according to (2) to (7) as an active ingredient and further containing a pharmaceutically acceptable carrier.
(13) A hydrate wherein the ratio of compound A to fumaric acid is 2: 1 and the ratio of compound A to water is 2: 1.
(14) A crystal of the compound according to (13).
(15) The crystal according to (14), wherein the endothermic onset temperature in DSC is around 150 ° C.
(16) In the powder X-ray analysis using Cu as the radiation source, 2θ (°) has peaks at around 6.7, 7.8, 20.1, and 20.5, .
(17) In powder X-ray analysis using Cu as the radiation source, 2θ (°) shows peaks at around 6.7, 7.8, 8.1, 10.5, 13.9, 20.1, 20.5, and 21.6. The crystal according to (14), which is characterized in that
(18) The endothermic onset temperature in DSC is 140-160 ° C, and in the powder X-ray analysis using Cu as the radiation source in the powder X-ray analysis, 2θ (°) is around 6.7, around 7.8, around 20.1, And the crystal according to (14), which shows a peak in the vicinity of 20.5.
(19) The endothermic onset temperature in DSC is 140-160 ° C., and in powder X-ray analysis using Cu as a radiation source in powder X-ray analysis, 2θ (°) is around 6.7, around 7.8, around 8.1, The crystal according to (14), characterized by having peaks in the vicinity of 10.5, 13.9, 20.1, 20.5, and 21.6.
(20) A crystal wherein the crystal selected from (14) to (19) is a type II crystal.
(21) A pharmaceutical composition comprising the salt compound according to (13) as an active ingredient and further containing a pharmaceutically acceptable carrier.
(22) A pharmaceutical composition comprising a crystal selected from the crystals according to (14) to (20) as an active ingredient and further containing a pharmaceutically acceptable carrier.
(23) A salt having a 1: 1 ratio of Compound A to fumaric acid.
(24) A salt anhydride having a 1: 1 ratio of Compound A to fumaric acid.
(25) A crystal of the compound according to (23) or (24).
(26) The crystal according to (25), wherein the endothermic onset temperature in DSC is around 160 ° C.
(27) In the powder X-ray analysis using Cu as the radiation source, 2θ (°) shows peaks at around 6.7, 17.7, 22.3, and 26.3, and the crystal according to (25) .
(28) In powder X-ray analysis using Cu as the radiation source, 2θ (°) shows peaks near 6.7, 9.5, 11.5, 13.4, 16.4, 17.7, 22.3, and 26.3. The crystal according to (25), which is characterized in that
(29) Endothermic onset temperature in DSC is 150-170 ° C., and in powder X-ray analysis using Cu as a radiation source in powder X-ray analysis, 2θ (°) is around 6.7, around 17.7, around 22.3, And the crystal according to (25), which shows a peak in the vicinity of 26.3.
(30) Endothermic onset temperature in DSC is 150-170 ° C, and in powder X-ray analysis using Cu as a radiation source in powder X-ray analysis, 2θ (°) is around 6.7, around 9.5, around 11.5, The crystal as described in (25), which has peaks near 13.4, 16.4, 17.7, 22.3, and 26.3.
(31) A crystal in which the crystals described in (25) to (30) are type III crystals.
(32) A pharmaceutical composition comprising the compound according to (23) as an active ingredient and further containing a pharmaceutically acceptable carrier.
(33) A pharmaceutical composition comprising the compound according to (24) as an active ingredient and further containing a pharmaceutically acceptable carrier.
(34) A pharmaceutical composition comprising a crystal selected from the crystals according to (25) to (31) as an active ingredient, and further comprising a pharmaceutically acceptable carrier.
(35) A salt anhydride in which the ratio of compound B to fumaric acid is 1: 1.
(36) A crystal of the compound according to (35).
(37) The crystal according to (36), wherein the endothermic onset temperature in DSC is around 215 ° C.
(38) In the powder X-ray analysis using Cu as a radiation source, 2θ (°) has peaks at around 6.6, around 8.2, around 15.7, and around 26.5. .
(39) In powder X-ray analysis using Cu as the radiation source, 2θ (°) shows peaks at around 6.6, 8.2, 9.2, 10.9, 13.6, 15.7, 20.5, and 26.5. The crystal according to (36), which is characterized in that
(40) Endothermic onset temperature in DSC is 200-220 ° C, and in powder X-ray analysis using Cu as a radiation source in powder X-ray analysis, 2θ (°) is around 6.6, around 8.2, around 15.7, And the crystal according to (36), which shows a peak around 26.5.
(41) Endothermic onset temperature in DSC is 205-225 ° C, and in powder X-ray analysis using Cu as a radiation source in powder X-ray analysis, 2θ (°) is around 6.6, around 8.2, around 9.2, The crystal as described in (36), which has peaks near 10.9, 13.6, 15.7, 20.5, and 26.5.
(42) A crystal wherein the crystal selected from (36) to (41) is an I-type crystal.
(43) A pharmaceutical composition comprising a salt comprising compound B and fumaric acid as an active ingredient, and further comprising a pharmaceutically acceptable carrier.
(44) A pharmaceutical composition comprising a salt having a ratio of Compound A to fumaric acid of 1: 1 as an active ingredient and further containing a pharmaceutically acceptable carrier.
(45) A pharmaceutical composition comprising the compound according to (35) as an active ingredient and further containing a pharmaceutically acceptable carrier.
(46) A pharmaceutical composition comprising a crystal selected from the crystals according to (36) to (42) as an active ingredient, and further comprising a pharmaceutically acceptable carrier.

式（Ｉ）の化合物のフマル酸塩は溶媒和物を形成し得る。従って、本明細書では、便宜上、特定の溶媒と溶媒和物を形成しない塩をその塩の無水物と記載する。   The fumarate salt of the compound of formula (I) may form a solvate. Therefore, in this specification, for convenience, a salt that does not form a solvate with a specific solvent is referred to as an anhydride of the salt.

式（Ｉ）の化合物とフマル酸は、種々の比率で酸付加塩を形成し得、種々の比率の酸付加塩の結晶が得られる場合がある。元素分析や粉末Ｘ線回折パターン、DSCなどの分析結果から総合的に判断されるべきでないから、塩及び結晶における同一性の認定においては、式（Ｉ）の化合物とフマル酸との比率は、厳密に解されるべきではない。これらの溶媒和物についても同様である。   The compound of formula (I) and fumaric acid may form acid addition salts in various ratios, and crystals of acid addition salts in various ratios may be obtained. Since it should not be judged comprehensively from analysis results such as elemental analysis, powder X-ray diffraction pattern, DSC, etc., in the identification of identity in salts and crystals, the ratio of the compound of formula (I) to fumaric acid is: It should not be interpreted strictly. The same applies to these solvates.

尚、粉末Ｘ線回折パターンは、データの性質上、結晶の同一性認定においては、回折角や全体的なパターンが重要であり、相対強度は結晶成長の方向、粒子の大きさ、測定条件によって多少変動し得るものであるから、厳密に解されるべきではない。また、本発明には、純粋な化合物A フマル酸塩のI型結晶、II型結晶及び、III型結晶、化合物Aの結晶、化合物B フマル酸塩のI型結晶、化合物B 2塩酸塩のI型結晶に関するものが含まれるが、これらの純粋な結晶と本質的に同一視される混合物もまた、本発明に含まれる。   The powder X-ray diffraction pattern is important for the identification of the crystal due to the nature of the data, and the diffraction angle and the overall pattern are important. The relative intensity depends on the crystal growth direction, particle size, and measurement conditions. Since it can vary somewhat, it should not be interpreted strictly. The present invention also includes pure compound A fumarate type I crystal, type II crystal and type III crystal, compound A crystal, compound B fumarate type I crystal, compound B dihydrochloride I Mixtures that are essentially identical to these pure crystals are also included in the present invention, including those related to type crystals.

各種スペクトルから得られる数値は、その結晶成長の方向、粒子の大きさ、測定条件によって、多少の誤差が生じる場合がある。従って、本明細書中、粉末Ｘ線回折スペクトルにおける回折角（２θ）の値に用いられる「付近」の語は、おおよその値であることを意味し、好ましくはその値の前後0.2（°）の範囲にあればよいことを意味する。更に好ましくは、その値の前後0.1（°）の範囲にあればよいことを意味する。   The numerical values obtained from various spectra may have some errors depending on the crystal growth direction, particle size, and measurement conditions. Therefore, in the present specification, the term “near” used for the value of the diffraction angle (2θ) in the powder X-ray diffraction spectrum means an approximate value, preferably 0.2 (°) before and after that value. It means that it should be in the range. More preferably, it means that it may be within a range of 0.1 (°) before and after that value.

また、DSCにおける吸熱オンセット温度の値に用いられる「付近」の語は、おおよそその吸熱オンセット（補外開始）の温度の値であることを意味し、好ましくはその値の前後２℃の範囲にあればよいことを意味し、さらに好ましくはその値の前後１℃の範囲にあればよいことを意味する。   In addition, the word “near” used for the endothermic onset temperature value in DSC means that it is approximately the temperature value of the endothermic onset (extrapolation start), and preferably 2 ° C. before and after that value. It means that it suffices to be in the range, and more preferably, it should be in the range of 1 ° C. before and after the value.

本発明の「化合物A とフマル酸の比が2:1の塩の無水物の結晶」は、１）化合物Aに対して0.9-1.1mol等量のフマル酸を用いて再結晶を行なうことによって化合物A 1フマル酸塩結晶を単離する工程、２）得られた「化合物A とフマル酸の比が1:1の塩」を、溶媒中の水分量を0.5%以下に制御しながら溶媒中で加熱懸濁する工程、から成る製造方法によって得ることができる。   According to the present invention, “anhydride crystals of a salt having a ratio of compound A to fumaric acid of 2: 1” are obtained by 1) recrystallization using 0.9-1.1 mol equivalent of fumaric acid to compound A. Step of isolating compound A 1 fumarate crystals, 2) The obtained “salt with a ratio of compound A to fumaric acid of 1: 1” in the solvent while controlling the water content in the solvent to 0.5% or less. It can be obtained by a production method comprising a step of suspending by heating.

１）化合物Aに対して等mol量のフマル酸を用いて再結晶を行なうことによって「化合物A とフマル酸の比が2:1の塩の無水物の結晶」を単離する工程で用いられる再結晶用溶媒としては、例えば、エタノール-メチルエチルケトンの混合溶媒、メチルエチルケトン，アセトン-DMSOの混合溶媒，アセトン-DMSO-エタノールの混合溶媒が好ましい。再結晶用の溶媒量としては、エタノール-メチルエチルケトン混合溶媒の場合、用いる化合物Aに対して21-30重量部を用いればよい。エタノールとメチルエチルケトンの量の比率は、1：1.7-4.3が好ましい。メチルエチルケトンを単独で用いる場合には、用いる化合物Aに対して16-35重量部を用いればよい。アセトン-DMSO混合溶媒の場合、用いる化合物Aに対して約50重量部を用いればよい。アセトンとDMSOの比率は、50：1程度が好ましい。アセトン-DMSO-エタノールの混合溶媒の場合、用いる化合物Aに対して32-33重量部を用いればよい。DMSOに対して、アセトンは約10倍量、エタノールは約11倍量用いるのが好ましい。再結晶は、公知の方法により行なうことができる。   1) Used in the process of isolating "anhydride crystals of a salt with a ratio of compound A to fumaric acid of 2: 1" by recrystallizing compound A with equimolar amounts of fumaric acid. As the recrystallization solvent, for example, a mixed solvent of ethanol-methyl ethyl ketone, a mixed solvent of methyl ethyl ketone, acetone-DMSO, and a mixed solvent of acetone-DMSO-ethanol are preferable. As the amount of solvent for recrystallization, in the case of an ethanol-methylethylketone mixed solvent, 21-30 parts by weight with respect to the compound A to be used may be used. The ratio of the amount of ethanol and methyl ethyl ketone is preferably 1: 1.7-4.3. When methyl ethyl ketone is used alone, 16 to 35 parts by weight may be used with respect to compound A to be used. In the case of an acetone-DMSO mixed solvent, about 50 parts by weight may be used for Compound A to be used. The ratio of acetone to DMSO is preferably about 50: 1. In the case of a mixed solvent of acetone-DMSO-ethanol, 32-33 parts by weight may be used for compound A to be used. About 10 times the amount of acetone and about 11 times the amount of ethanol are preferably used with respect to DMSO. Recrystallization can be performed by a known method.

２）得られた「化合物A とフマル酸の比が1:1の塩」を、溶媒中の水分量を0.5%以下に制御しながら溶媒中で加熱懸濁する工程で用いられる加熱懸濁用の溶媒としては、例えば、エタノールが好ましい。加熱懸濁用の溶媒量としては、エタノールの場合、用いる化合物Aに対して10-20重量部を用いればよく、加熱温度としては50℃−75℃が好ましい。   2) For heating suspension used in the process of heating and suspending the obtained “salt in which the ratio of compound A and fumaric acid is 1: 1” in the solvent while controlling the water content in the solvent to 0.5% or less. As the solvent, for example, ethanol is preferable. In the case of ethanol, the solvent amount for the heating suspension may be 10-20 parts by weight with respect to the compound A used, and the heating temperature is preferably 50 ° C-75 ° C.

本発明の「化合物A とフマル酸の比が2:1の塩の無水物の結晶」は、化合物Aに対して0.9-1.1mol等量のフマル酸と共に、溶媒中の水分量を0.5%以下に制御しながら溶媒中で加熱懸濁する製造方法によっても得ることができる。加熱懸濁用の溶媒としては、例えば、エタノールが好ましい。溶媒量としては、エタノールの場合、用いる化合物Aに対して20重量部程度を用いればよく、加熱温度としては60℃−70℃が好ましい。   In the present invention, “anhydrous crystals of a salt having a ratio of compound A to fumaric acid of 2: 1” is 0.9 to 1.1 mol equivalent of fumaric acid with respect to compound A, and the water content in the solvent is 0.5% or less. It can also be obtained by a production method in which the suspension is heated and suspended in a solvent while being controlled at a low temperature. As the solvent for heating suspension, for example, ethanol is preferable. As the amount of solvent, in the case of ethanol, about 20 parts by weight may be used with respect to the compound A to be used, and the heating temperature is preferably 60 ° C to 70 ° C.

本発明の「化合物A とフマル酸の比が2:1の塩であって、化合物Aと水の比が2:１である水和物の結晶」は、１）化合物Aに対して0.9-1.1mol等量のフマル酸を用いて再結晶を行なうことによって「化合物A とフマル酸の比が1:1の塩の結晶」を単離する工程、２）得られた「化合物A とフマル酸の比が1:1の塩の結晶」を、溶媒中の水分量を5%以上に制御しながら溶媒中で加熱懸濁する工程、から成る製造方法によって得ることができる。   According to the present invention, “a hydrate crystal in which the ratio of compound A to fumaric acid is 2: 1 and the ratio of compound A to water is 2: 1” is 1) 0.9- A step of isolating “a salt crystal having a 1: 1 ratio of compound A to fumaric acid” by recrystallization using 1.1 mol equivalent of fumaric acid, 2) the obtained “compound A and fumaric acid” Can be obtained by a production method comprising a step of heating and suspending in a solvent while controlling the amount of water in the solvent to 5% or more.

１）化合物Aに対して等mol量のフマル酸を用いて再結晶を行なうことによって「化合物A とフマル酸の比が1:1の塩の結晶」を単離する工程において用いられる溶媒などの条件は、上述の通りである。   1) Solvents used in the process of isolating “crystals of salt with a 1: 1 ratio of compound A to fumaric acid” by recrystallizing compound A with equimolar amounts of fumaric acid The conditions are as described above.

２）得られた「化合物A とフマル酸の比が1:1の塩の結晶」を、溶媒中の水分量を5%以上に制御しながら溶媒中で加熱懸濁する工程で用いられる加熱懸濁用の溶媒としては、例えば、エタノールが好ましい。加熱懸濁用の溶媒量としては、エタノールの場合、用いる化合物A とフマル酸の比が1:1の塩の結晶に対して10重量部程度を用いればよく、加熱温度としては55℃−65℃が好ましい。   2) The heating suspension used in the process of heating and suspending the obtained “crystal of salt with a ratio of compound A and fumaric acid of 1: 1” in the solvent while controlling the water content in the solvent to 5% or more. As the turbid solvent, for example, ethanol is preferable. As for the amount of the solvent for the heating suspension, in the case of ethanol, it is sufficient to use about 10 parts by weight with respect to the salt crystals having a ratio of the compound A to fumaric acid of 1: 1, and the heating temperature is 55 ° C.-65 ° C is preferred.

本発明の「化合物A とフマル酸の比が2:1の塩であって、化合物Aと水の比が2:１である水和物の結晶」は、化合物A の結晶を、化合物Aに対して0.5-0.6mol等量のフマル酸と共に、溶媒中の水分量を1%以上に制御しながら再結晶を行う工程によっても得ることができる。再結晶は、公知の方法により行なうことができる。   According to the present invention, “a hydrate crystal having a ratio of compound A to fumaric acid of 2: 1 and a ratio of compound A to water of 2: 1”, compound A is converted to compound A. On the other hand, it can also be obtained by a step of recrystallization while controlling the water content in the solvent to 1% or more together with 0.5-0.6 mol equivalent of fumaric acid. Recrystallization can be performed by a known method.

化合物Aに対して0.5-0.6mol等量のフマル酸を用いて再結晶を行なうことによって「化合物A とフマル酸の比が2:1の塩であって、化合物Aと水の比が2:１である水和物の結晶」を単離する工程で用いられる再結晶用溶媒としては、例えば、エタノール、DMSO-水の混合溶媒、DMSO-アセトン-水の混合溶媒、DMSO-アセトニトリル-水の混合溶媒が好ましい。再結晶用の溶媒量としては、水分量1%のエタノールの場合、用いる化合物Aに対して55重量部程度を用いるのが好ましい。再結晶用の溶媒量としては、DMSO-水の混合溶媒の場合、用いる化合物Aに対して8重量部程度を用いればよい。DMSOと水の量の比率は、3：1程度が好ましい。DMSO-アセトン-水の混合溶媒の場合、用いる化合物Aに対して23重量部程度を用いればよい。DMSOとアセトンと水の量の比率は、1：2.5：2.3程度が好ましい。DMSO-アセトニトリル-水の混合溶媒の混合溶媒の場合、用いる化合物Aに対して15重量部程度を用いればよい。DMSOとアセトニトリルと水の量の比率は、1：2.5：0.25程度が好ましい。   By recrystallization using 0.5-0.6 mol equivalent of fumaric acid with respect to compound A, a “salt with a ratio of compound A to fumaric acid of 2: 1 and a ratio of compound A to water of 2: Examples of the recrystallization solvent used in the step of isolating “hydrate crystal 1” include, for example, ethanol, DMSO-water mixed solvent, DMSO-acetone-water mixed solvent, DMSO-acetonitrile-water. Mixed solvents are preferred. As the amount of the solvent for recrystallization, in the case of ethanol having a water content of 1%, it is preferable to use about 55 parts by weight with respect to the compound A to be used. As the amount of solvent for recrystallization, in the case of a mixed solvent of DMSO-water, about 8 parts by weight may be used with respect to Compound A to be used. The ratio of DMSO to water is preferably about 3: 1. In the case of a mixed solvent of DMSO-acetone-water, about 23 parts by weight may be used for Compound A to be used. The ratio of the amount of DMSO, acetone, and water is preferably about 1: 2.5: 2.3. In the case of a mixed solvent of DMSO-acetonitrile-water, about 15 parts by weight may be used with respect to Compound A to be used. The ratio of the amount of DMSO, acetonitrile, and water is preferably about 1: 2.5: 0.25.

本発明の化合物Aのフマル酸塩及び／又は化合物Bのフマル酸塩は、医薬品の活性成分として用いることができ、即ち、本発明の化合物Aのフマル酸塩又は化合物Bのフマル酸塩含む配合は、医製薬学的に許容される担体、賦形剤等と組み合わせて、医薬品の製造に使用することができる。医薬品の製造は、当分野にて通常使用されている方法によって行うことができる。
本発明の化合物Aのフマル酸塩及び／又は化合物Bのフマル酸塩を含有する医薬品としては、錠剤、丸剤、カプセル剤、顆粒剤、散剤、液剤等による経口投与製剤、又は、関節内、静脈内、筋肉内等の注射剤、坐剤、経皮用液剤、軟膏剤、経皮用貼付剤、経粘膜液剤、経粘膜貼付剤、吸入剤等の非経口投与製剤のいずれの形態であってもよい。特に、化合物Aの酸付加塩の結晶を製造原体とする、経口投与用の錠剤、丸剤、カプセル剤、顆粒剤、散剤は、安定な固形製剤として有利である。 The fumarate salt of the compound A and / or the fumarate salt of the compound B of the present invention can be used as an active ingredient of a pharmaceutical product, that is, a compound containing the fumarate salt of the compound A or fumarate salt of the compound B of the present invention. Can be used in the manufacture of a pharmaceutical in combination with a pharmaceutically acceptable carrier, excipient or the like. The production of a pharmaceutical can be performed by a method usually used in the art.
As a pharmaceutical containing the fumarate of compound A and / or fumarate of compound B of the present invention, an orally administered preparation such as a tablet, a pill, a capsule, a granule, a powder, a liquid, or the like, It is in the form of parenteral preparations such as intravenous and intramuscular injections, suppositories, transdermal solutions, ointments, transdermal patches, transmucosal solutions, transmucosal patches, inhalants, etc. May be. In particular, tablets, pills, capsules, granules, and powders for oral administration, which are based on crystals of the acid addition salt of Compound A, are advantageous as stable solid preparations.

経口投与のための本発明の固体組成物においては、1種以上の活性物質が、少なくとも1種の不活性な希釈剤、例えば乳糖、マンニトール、ブドウ糖、ヒドロキシプロピルセルロース、微結晶セルロース、デンプン、ポリビニルピロリドン、メタケイ酸アルミン酸マグネシウム等と混合される。組成物は、常法に従って、不活性な希釈剤以外の添加剤、例えばステアリン酸マグネシウム等の滑沢剤、繊維素グリコール酸カルシウム等の崩壊剤、安定化剤、溶解補助剤等を含有していてもよい。錠剤又は丸剤は必要によりショ糖、ゼラチン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロースフタレート等の糖衣又は胃溶性若しくは腸溶性のフィルムで被覆してもよい。   In the solid composition of the invention for oral administration, one or more active substances are at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinyl Mixed with pyrrolidone, magnesium aluminate metasilicate and the like. The composition contains additives other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium calcium glycolate, a stabilizer, a solubilizing agent and the like according to a conventional method. May be. If necessary, tablets or pills may be coated with sugar coating such as sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, etc., or a gastric or enteric film.

経口投与のための液体組成物は、薬剤的に許容される乳濁剤、溶液剤、懸濁剤、シロップ剤、エリキシル剤等を含み、一般的に用いられる不活性な希釈剤、例えば精製水、エタノールを含む。この組成物は不活性な希釈剤以外に湿潤剤、懸濁剤のような補助剤、甘味剤、風味剤、芳香剤、防腐剤を含有していてもよい。
非経口投与のための注射剤としては、無菌の水性又は非水性の溶液剤、懸濁剤、乳濁剤を含有する。水性の溶液剤、懸濁剤としては、例えば注射用蒸留水及び生理食塩水が含まれる。非水性の溶液剤、懸濁剤としては、例えばプロピレングリコール、ポリエチレングリコール、オリーブ油等の植物油、エタノール等のアルコール類、ポリソルベート80等がある。このような組成物は、さらに防腐剤、湿潤剤、乳化剤、分散剤、安定剤、溶解補助剤等の補助剤を含んでいてもよい。これらは例えばバクテリア保留フィルターを通す濾過、殺菌剤の配合又は照射によって無菌化される。これらはまた無菌の固体組成物を製造し、使用前に無菌水又は無菌の注射用溶媒に溶解して使用することもできる。 Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and commonly used inert diluents such as purified water. Contains ethanol. In addition to the inert diluent, the composition may contain adjuvants such as wetting agents and suspending agents, sweeteners, flavors, fragrances and preservatives.
Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of the aqueous solution and suspension include distilled water for injection and physiological saline. Examples of non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate 80, and the like. Such a composition may further contain auxiliary agents such as preservatives, wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving it in sterile water or a sterile solvent for injection before use.

本発明の医薬組成物は、その有効成分としてBEC1カリウムチャネル阻害剤である本発明の化合物Aのフマル酸塩及び／又は化合物Bのフマル酸塩を含有しているため、BEC1カリウムチャネル阻害剤が用いられる種々の疾患の治療や予防に供することができる。即ち、本発明の医薬組成物は、具体的には例えば、認知症の治療剤若しくは予防剤として有用である。   Since the pharmaceutical composition of the present invention contains the fumarate salt of the compound A of the present invention and / or the fumarate salt of the compound B which is a BEC1 potassium channel inhibitor as its active ingredient, the BEC1 potassium channel inhibitor is It can be used for the treatment and prevention of various diseases used. That is, the pharmaceutical composition of the present invention is specifically useful, for example, as a therapeutic or prophylactic agent for dementia.

本発明に用いられる薬剤は、認知症を有する患者に対し投与され、１日の投与量は、通常経口投与の場合、体重当たり約０．００１乃至１００ｍｇ／ｋｇが適当であり、一日１回で、あるいは２乃至４回に分けて投与する。静脈内投与される場合は、１日の投与量は、体重当たり約０．０００１乃至１０ｍｇ／ｋｇが適当で、１日１回乃至複数回に分けて投与する。また、経粘膜剤としては、体重当たり約０．００１乃至１００ｍｇ／ｋｇを１日１回乃至複数回に分けて投与する。投与量は症状、年令、性別等を考慮して個々の場合に応じて適宜決定される。   The drug used in the present invention is administered to patients with dementia, and the daily dose is usually about 0.001 to 100 mg / kg per body weight in the case of oral administration, and once a day. Or in 2 to 4 divided doses. In the case of intravenous administration, the daily dose is suitably about 0.0001 to 10 mg / kg per body weight, and is administered once to several times a day. As a transmucosal agent, about 0.001 to 100 mg / kg per body weight is administered once to several times a day. The dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.

以下、実施例により本発明を具体的に説明するが、本発明はこれらの実施例により何ら制限されるものではなく、本発明の範囲を限定するものでもない。
なお、熱分析及び粉末X線回折は以下の方法により行った。 EXAMPLES Hereinafter, the present invention will be specifically described with reference to examples. However, the present invention is not limited to these examples and does not limit the scope of the present invention.
Thermal analysis and powder X-ray diffraction were performed by the following methods.

（１）熱分析
（DSC）
試料およそ3 mgを専用のアルミニウム製サンプルパンに充填し、窒素雰囲気下（50 mL/min）において、測定範囲を室温〜300 ℃とし、昇温速度10 ℃/minで試料とリファレンス（空のアルミニウム製サンプルパン）との間に発生する熱量変化を連続的に測定し記録した。なお、データ処理を含む装置の取り扱いは、各装置で指示された方法及び手順に従った。（装置：TA Instrument製 Hi-Res DSC 2910，DSC Q20）
（TG）
試料およそ5 mgを専用の白金製サンプルパンに充填し、窒素雰囲気下（50 mL/min）において、測定範囲を室温〜300 ℃とし、昇温速度10 ℃/minで試料の重量変化を連続的に測定し記録した。なお、データ処理を含む装置の取り扱いは、各装置で指示された方法及び手順に従った。（装置：TA Instrument製 Hi-Res TGA 2950，TGA Q50）
（２）粉末X線回折
試料およそ10 mgを専用のサンプルホルダー（横5 mm、縦18 mm、深さ0.2 mm）に充填し、以下の条件下で試料の粉末X線回折を測定し記録した。なお、データ処理を含む装置の取り扱いは、各装置で指示された方法及び手順に従った。（装置：MAC Science（現Bruker）製 MXP18TAHF22）
（条件）
図３及び１３
線源：Cu、波長：1.54056 Å、測定範囲：2.50 〜 40.00 °、サンプリング間隔：0.02 °、スキャン速度：4.00 °/min、管電圧：40 kV、管電流：200 mA、発散スリット：可変 (照射幅5.00 mm)、散乱スリット：可変 (照射幅 5.00 mm)、受光スリット：0.15 mm

図１，２，４，５，及び６
線源：Cu、波長：1.54056 Å、測定範囲：3.02 〜 40.00 °、サンプリング間隔：0.02 °、スキャン速度：3.00 °/min、管電圧：40 kV、管電流：200 mA、発散スリット：可変 (照射幅1.00 mm)、散乱スリット：可変 (照射幅 1.00 mm)、受光スリット：0.15 mm

なお、回折角および回折強度は、その結晶成長の方向、粒子の大きさ、測定条件等によって多少の変動がある場合がある。従って、それらの数値は厳密に解されるべきではない。 (1) Thermal analysis (DSC)
Approximately 3 mg of the sample is filled in a dedicated aluminum sample pan, and the measurement range is room temperature to 300 ° C under a nitrogen atmosphere (50 mL / min), and the sample and reference (empty aluminum are used at a heating rate of 10 ° C / min. The amount of heat generated between the sample pan and the sample pan was continuously measured and recorded. In addition, the handling of the apparatus including data processing followed the method and procedure instructed by each apparatus. (Device: Hi-Res DSC 2910, DSC Q20 manufactured by TA Instrument)
(TG)
Approximately 5 mg of the sample is filled in a dedicated platinum sample pan, and in a nitrogen atmosphere (50 mL / min), the measurement range is set to room temperature to 300 ° C, and the weight change of the sample is continuously performed at a heating rate of 10 ° C / min. Measured and recorded. In addition, the handling of the apparatus including data processing followed the method and procedure instructed by each apparatus. (Device: Hi-Res TGA 2950, TGA Q50 manufactured by TA Instrument)
(2) Powder X-ray diffraction Approximately 10 mg of the sample was filled in a dedicated sample holder (5 mm wide, 18 mm long, 0.2 mm deep), and the powder X-ray diffraction of the sample was measured and recorded under the following conditions. . In addition, the handling of the apparatus including data processing followed the method and procedure instructed by each apparatus. (Device: MXP18TAHF22 manufactured by MAC Science (now Bruker))
(conditions)
3 and 13
Radiation source: Cu, wavelength: 1.54056 mm, measurement range: 2.50 to 40.00 °, sampling interval: 0.02 °, scan speed: 4.00 ° / min, tube voltage: 40 kV, tube current: 200 mA, diverging slit: variable (irradiation Width 5.00 mm), scattering slit: variable (irradiation width 5.00 mm), receiving slit: 0.15 mm

1, 2, 4, 5, and 6
Radiation source: Cu, wavelength: 1.54056 mm, measurement range: 3.02 to 40.00 °, sampling interval: 0.02 °, scan speed: 3.00 ° / min, tube voltage: 40 kV, tube current: 200 mA, diverging slit: variable (irradiation Width 1.00 mm), scattering slit: variable (irradiation width 1.00 mm), light receiving slit: 0.15 mm

The diffraction angle and diffraction intensity may vary slightly depending on the crystal growth direction, particle size, measurement conditions, and the like. Therefore, those numbers should not be interpreted exactly.

また、参考例、実施例、及び後記表中以下の略号を用いる。
mp：融点、FAB+：FAB-MS(M+H)+、EI：EI-MS(M)+、ESI+：ESI-MS(M+H)+、NMR-DMSOd6：DMSO-d6中の1H NMRにおけるピークのδ(ppm)）、DMF：N,N-ジメチルホルムアミド、DMSO：ジメチルスルホキシド、THF：テトラヒドロフラン、4M 塩化水素/ジオキサン溶液：４mol / l 塩化水素ジオキサン溶液、MeCN：アセトニトリル、MeOH：メタノール、EtOH：エタノール。 In addition, the following abbreviations are used in Reference Examples, Examples, and Tables below.
mp: melting point, FAB +: FAB-MS ( M + H) +, EI: EI-MS (M) +, ESI +: ESI-MS (M + H) +, NMR-DMSOd6: 1 H in DMSO-d 6 Δ (ppm) of NMR peak), DMF: N, N-dimethylformamide, DMSO: dimethyl sulfoxide, THF: tetrahydrofuran, 4M hydrogen chloride / dioxane solution: 4 mol / l hydrogen chloride dioxane solution, MeCN: acetonitrile, MeOH: methanol EtOH: ethanol.

参考例１ 実施例１及び２の原料化合物である、化合物Aの製造
2Lフラスコにシアヌル酸クロリド75.0g、THF680mLを加え、攪拌しながら-19℃にて炭酸カリウム51.10gを加えた。-12.4℃以下にてTHF75mLで希釈したp-フルオロアニリン41.08g、THF75mLを加えた。-12.8〜-14.4℃にて1時間反応を行い、水450mLを加えた。室温にて分液を行い、水層を分離後に水300mLを加え再度分液を行い水層を分離した。有機層に、１）THF600mL、及び、２）炭酸カリウム1.1gを水308mLに加えて調製した水溶液、を加えた後に分液を行い、水層を分離した。有機層に水150mLを加えて分液を行い、水層を分離し、有機層を溶液残量280mLになるまで減圧にて濃縮した。濃縮液にMeCN750mLを加えて減圧にて溶液残量280mLになるまで濃縮する操作を3回行った。続いてMeCN600mLを加えて冷却後、アニリン34.43g、MeCN75mLを-5.9℃以下で加え、N,N-ジイソプロピルエチルアミン47.79g、MeCN38mLを-9.2℃にて加えた。その後室温まで昇温し，12時間攪拌後に2-アミノメチルピリミジン48.42g、MeCN75mLを室温にて加えた後、N,N-ジイソプロピルエチルアミン57.35g、MeCN38mLを室温にて加えた。内温82.4℃に昇温し4.5時間撹拌後、内温70℃以上で水560mLを加えた後冷却した。内温65.8℃にて結晶析出を確認後、室温にて終夜攪拌し濾過を行った。得られた結晶をMeCN：水=2：1の混合溶液にて洗浄し、続いて水300mLで洗浄した。得られた結晶を50℃にて1日減圧乾燥を行い、108.54gの化合物Aのフリー体の結晶を得た。

NMR-DMSOd6
4.71-4.73 (2H,m), 6.91-7.26 (5H,m), 7.37 (1H,dd, J=5.2Hz, 4.8Hz), 7.44-7.80 (5H,m), 8.78 (2H,d, J=4.8Hz), 9.01-9.05 (2H,m).
FAB+：389
Elemental Analysis. Calcd for C20H17FN8 : C, 61.85; H, 4,41; N, 28.85; F, 4.89; Cl, 0.00. Found: C, 61.78; H, 4.43; N, 28.81; F, 4.95; Cl, 0.00.
Reference Example 1 Production of Compound A, which is a raw material compound of Examples 1 and 2
Cyanuric chloride 75.0 g and THF 680 mL were added to a 2 L flask, and 51.10 g of potassium carbonate was added at −19 ° C. with stirring. 41.08 g of p-fluoroaniline diluted with 75 mL of THF at -12.4 ° C. or lower and 75 mL of THF were added. The reaction was performed at -12.8 to -14.4 ° C for 1 hour, and 450 mL of water was added. Liquid separation was performed at room temperature, and after separating the aqueous layer, 300 mL of water was added and liquid separation was performed to separate the aqueous layer. To the organic layer, 1) 600 mL of THF and 2) an aqueous solution prepared by adding 1.1 g of potassium carbonate to 308 mL of water were added, followed by liquid separation, and the aqueous layer was separated. The organic layer was separated by adding 150 mL of water, the aqueous layer was separated, and the organic layer was concentrated under reduced pressure until the remaining amount of the solution was 280 mL. The operation of adding 750 mL of MeCN to the concentrated liquid and concentrating it under reduced pressure until the remaining amount of the solution was 280 mL was performed three times. Subsequently, 600 mL of MeCN was added and cooled, and then 34.43 g of aniline and 75 mL of MeCN were added at −5.9 ° C. or less, and 47.79 g of N, N-diisopropylethylamine and 38 mL of MeCN were added at −9.2 ° C. Thereafter, the temperature was raised to room temperature, and after stirring for 12 hours, 48.42 g of 2-aminomethylpyrimidine and 75 mL of MeCN were added at room temperature, and then 57.35 g of N, N-diisopropylethylamine and 38 mL of MeCN were added at room temperature. The temperature was raised to 82.4 ° C. and stirred for 4.5 hours, and then 560 mL of water was added at an internal temperature of 70 ° C. or higher, followed by cooling. After confirming crystal precipitation at an internal temperature of 65.8 ° C., the mixture was stirred overnight at room temperature and filtered. The obtained crystals were washed with a mixed solution of MeCN: water = 2: 1, followed by washing with 300 mL of water. The obtained crystals were dried under reduced pressure at 50 ° C. for 1 day to obtain 108.54 g of a compound A free form crystal.

NMR-DMSOd6
4.71-4.73 (2H, m), 6.91-7.26 (5H, m), 7.37 (1H, dd, J = 5.2Hz, 4.8Hz), 7.44-7.80 (5H, m), 8.78 (2H, d, J = 4.8Hz), 9.01-9.05 (2H, m).
FAB +: 389
Elemental Analysis.Calcd for C20H17FN8: C, 61.85; H, 4,41; N, 28.85; F, 4.89; Cl, 0.00.Found: C, 61.78; H, 4.43; N, 28.81; F, 4.95; Cl, 0.00 .

実施例１ 「化合物Aとフマル酸の比が2:1の塩の無水物」の製造
メチルエチルケトン414L、化合物Aの結晶23.00kgを反応容器1へ加え、内温65.0℃にて溶解させた。濾過を行い、反応容器2へ移送後、再度加熱した。別に、反応容器1にフマル酸6.90kg、EtOH 115Lを加え内温58.3℃にて溶解させ、反応容器2へと移送した。冷却後、内温54.2℃にて結晶析出を確認後、0℃にて終夜攪拌した。濾過を行った後、EtOH 46Lにて結晶を洗浄後、得られた「化合物A とフマル酸の比が1:1の塩の結晶」（III型結晶：wet）30.34kgとEtOH 460Lを反応容器2に加えた。内温52.4〜69.2℃にて懸濁状態で42時間攪拌し、冷却し室温にて終夜攪拌した。濾過を行いEtOH 46Lで結晶を洗浄後、60℃にて4日間減圧乾燥を行い「化合物Aとフマル酸の比が2:1の塩の無水物の結晶」(I型)20.97kgを得た。

化合物Aとフマル酸の比が2:1の塩の無水物の結晶（I型結晶）
NMR-DMSOd6
4.71-4.73 (2H,m), 6.64 (1H,s), 6.91-7.23 (5H,m), 7.37 (1H,dd, J=5.2Hz, 4.8Hz), 7.44-7.80 (5H,m), 8.78 (2H,d, J=4.8Hz), 9.01-9.06 (2H,m),13.06 (1H,br)
FAB+：389
Elemental Analysis. Calcd for C20H17FN8・0.5C4H4O4: C, 59.19; H, 4,29; N, 25.10; F, 4.26; O, 7.17. Found: C, 59.09; H, 4.36; N, 25.19; F, 4.31.
DSCにおける吸熱オンセット温度： 約190℃
実施例１の化合物(I型結晶)の粉末X線回折パターンを図１に示す。

化合物Aとフマル酸の比が1:1の塩（化合物Aと付着溶媒であるメチルエチルケトン、EtOH及び水の比=1:0.1：0.007：0.3）の結晶（III型結晶）
NMR-DMSOd6
4.71 (2H,m), 6.64 (2H,s), 6.90-7.29 (5H,m), 7.38 (1H, dd, J=4.8Hz, 4.8Hz), 7.57-7.81 (5H,m), 8.79 (2H,d, J=4.8Hz), 9.05-9.11 (2H,m), 13.09 (2H,br)
ESI+：389
Elemental Analysis. Calcd for C20H17FN8・C4H4O4・0.1 C4H8O・0.007 C2H6O・0.3 H2O : C, 56.67; H, 4,37; N, 21.66; F, 3.67; O, 13.63. Found: C, 56.56; H, 4.47; N, 21.68; F, 3.63.
DSCにおける吸熱オンセット温度： 約160℃
実施例１の化合物（III型結晶）の粉末X線回折パターンを図３に示す。
Example 1 Production of “Salt Anhydride with a Ratio of Compound A to Fumaric Acid of 2: 1” 414 L of methyl ethyl ketone and 23.00 kg of crystals of Compound A were added to the reaction vessel 1 and dissolved at an internal temperature of 65.0 ° C. Filtration was performed, and the mixture was transferred to the reaction vessel 2 and then heated again. Separately, 6.90 kg of fumaric acid and 115 L of EtOH were added to the reaction vessel 1 and dissolved at an internal temperature of 58.3 ° C. and transferred to the reaction vessel 2. After cooling, after confirming crystal precipitation at an internal temperature of 54.2 ° C., the mixture was stirred at 0 ° C. overnight. After filtration, the crystals were washed with EtOH 46L, and the obtained “crystal of the salt with a 1: 1 ratio of compound A to fumaric acid” (type III crystal: wet) 30.34 kg and EtOH 460 L were placed in a reaction vessel. Added to 2. The suspension was stirred for 42 hours at an internal temperature of 52.4 to 69.2 ° C., cooled, and stirred overnight at room temperature. After filtration, the crystals were washed with EtOH 46L, and dried under reduced pressure at 60 ° C for 4 days to obtain 20.97 kg of "anhydride crystals of a salt with a ratio of compound A and fumaric acid of 2: 1" (form I) .

Anhydrous crystals of salt with a ratio of compound A to fumaric acid of 2: 1 (type I crystals)
NMR-DMSOd6
4.71-4.73 (2H, m), 6.64 (1H, s), 6.91-7.23 (5H, m), 7.37 (1H, dd, J = 5.2Hz, 4.8Hz), 7.44-7.80 (5H, m), 8.78 (2H, d, J = 4.8Hz), 9.01-9.06 (2H, m), 13.06 (1H, br)
FAB +: 389
Elemental Analysis.Calcd for C20H17FN8 ・ 0.5C4H4O4: C, 59.19; H, 4,29; N, 25.10; F, 4.26; O, 7.17.
Endothermic onset temperature at DSC: about 190 ° C
The powder X-ray diffraction pattern of the compound of Example 1 (type I crystal) is shown in FIG.

Crystal of a salt having a ratio of compound A to fumaric acid of 1: 1 (compound A and the adhering solvent methyl ethyl ketone, EtOH and water = 1: 0.1: 0.007: 0.3) (type III crystal)
NMR-DMSOd6
4.71 (2H, m), 6.64 (2H, s), 6.90-7.29 (5H, m), 7.38 (1H, dd, J = 4.8Hz, 4.8Hz), 7.57-7.81 (5H, m), 8.79 (2H , d, J = 4.8Hz), 9.05-9.11 (2H, m), 13.09 (2H, br)
ESI +: 389
Elemental Analysis.Calcd for C20H17FN8 ・ C4H4O4 ・ 0.1 C4H8O ・ 0.007 C2H6O ・ 0.3 H2O: C, 56.67; H, 4,37; N, 21.66; F, 3.67; O, 13.63. N, 21.68; F, 3.63.
Endothermic onset temperature in DSC: approx. 160 ° C
The powder X-ray diffraction pattern of the compound of Example 1 (type III crystal) is shown in FIG.

実施例２ 「化合物Aとフマル酸の比が2:1の塩であって、化合物Aと水の比が2:1である水和物」の製造（II型結晶）
200mLフラスコに化合物A 結晶3.0g、エタノール120mL、水30mLを加え、内温を76℃に加熱し溶解させた。続いてフマル酸448mgを加え、内温80℃にて溶解を確認した。冷却し、室温にて終夜攪拌を行った。濾過を行い40℃にて乾燥を行い、「化合物Aとフマル酸の比が2:1の塩であって、化合物Aと水の比が2:1である水和物の結晶」3.2g（II型結晶）を得た。
NMR-DMSOd6
4.72-4.74 (2H,m), 6.65 (1H,s), 6.91-7.27 (5H,m), 7.37 (1H,dd, J=4.8Hz, 4.8Hz), 7.45-7.81 (5H,m), 8.78 (2H,d, J=4.8Hz), 9.02-9.06 (2H,m), 13.06 (1H,br)
FAB+：389
Elemental Analysis. Calcd for C20H17FN8・0.5C4H4O4・0.5H2O : C, 58.02; H, 4,43; N, 24.60; F, 4.17; O, 8.78. Found: C, 58.20; H, 4.46; N, 24.77; F, 4.33.
DSCにおける吸熱オンセット温度： 約150℃
実施例２の化合物（II型結晶）の粉末X線回折パターンを図２に示す。
Example 2 Production of “Hydrate with Compound A / Fumaric Acid 2: 1 Ratio and Compound A / Water Ratio 2: 1” (Type II Crystal)
Compound A crystals (3.0 g), ethanol (120 mL), and water (30 mL) were added to a 200 mL flask, and the internal temperature was heated to 76 ° C. for dissolution. Subsequently, 448 mg of fumaric acid was added, and dissolution was confirmed at an internal temperature of 80 ° C. Cooled and stirred at room temperature overnight. After filtration and drying at 40 ° C., “a hydrate crystal having a ratio of compound A to fumaric acid of 2: 1 and a ratio of compound A to water of 2: 1” 3.2 g ( II type crystal) was obtained.
NMR-DMSOd6
4.72-4.74 (2H, m), 6.65 (1H, s), 6.91-7.27 (5H, m), 7.37 (1H, dd, J = 4.8Hz, 4.8Hz), 7.45-7.81 (5H, m), 8.78 (2H, d, J = 4.8Hz), 9.02-9.06 (2H, m), 13.06 (1H, br)
FAB +: 389
Elemental Analysis.Calcd for C20H17FN8 ・ 0.5C4H4O4 ・ 0.5H2O: C, 58.02; H, 4,43; N, 24.60; F, 4.17; O, 8.78. Found: C, 58.20; H, 4.46; N, 24.77; F , 4.33.
Endothermic onset temperature in DSC: about 150 ° C
The powder X-ray diffraction pattern of the compound of Example 2 (type II crystal) is shown in FIG.

実施例３ 化合物Bと塩酸の比が1:2の塩の製造
6-クロロ-N,N'-ビス(4-フルオロフェニル)-1,3,5-トリアジン-2,4-ジアミン 10.0g のMeCN 100mL 懸濁液に、1-ピリミジン-2-イルメチルアミン酢酸塩6.0g 及び N,N-ジイソプロピルエチルアミン 11.5mL を加えて、85℃で12時間攪拌した。反応液を室温まで冷却した後、溶媒を留去して得られた残渣に酢酸エチルを加えて、有機層を5%クエン酸水溶液及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム:MeOH=100:0〜95:5)で精製して 10.8g の微黄色アモルファスを得た。このものをEtOH 200mL に溶解し、活性炭2gを加えて10分間加熱還流した後、活性炭をセライトを用いた濾過により除去し、溶媒を留去して得られた残渣を80%含水EtOH 400mL を用いて固体化させて固体を濾取し、7.5g の無色固体を得た。このものを70%含水MeCN 150mlに加熱して溶解し、室温まで放冷しながら攪拌した後、析出している固体を濾取し、化合物B 7.08g を得た。
得られた化合物B 7.05g をMeOH 200mL、THF 200mL に溶解し、4M 塩化水素/ジオキサン溶液 10mL を加えた後、溶媒を留去して、得られた残渣にEtOHを加えて30分間撹拌して固体を析出させた。固体を濾取して減圧乾燥させた後、MeCNに懸濁させて10分間加熱還流させ、反応液を室温に戻して固体を濾取し、減圧乾燥を行なって、「化合物Bと塩酸の比が1:2の塩」7.25g を無色結晶（I型結晶）として得た。

化合物Bと塩酸の比が1:2の塩の結晶
NMR-DMSOd6
4.78 (2H, m), 7.10 (2H, brs), 7.25 (2H, t, J=8.7Hz), 7.3-7.8 (6H, m), 8.85 (2H, d, J=4.9Hz), 8.9-9.4 (1H, m), 10.45 (1H, brs), 10.88 (1H, brs)
Elemental Analysis. Calcd for C20H16F2N8・2HCl: C, 50.12; H, 3,79; N, 23.38; F, 7.93; Cl, 14.79. Found: C, 50.03; H, 3.92; N, 23.33; F, 7.94; Cl, 14.84.
DSCにおける吸熱オンセット温度： 約160及び約190℃
実施例３の化合物（（I型結晶））の粉末X線回折パターンを図６に示す。

化合物B（フリー体）
NMR-DMSOd6
4.70 (2H, d, J=5.8Hz), 7.00 (2H, m), 7.10 (2H, t, J=8.7Hz), 7.38 (1H, t, J=4.9Hz), 7.57 (3H, brs), 7.80 (2H, brs), 8.79 (2H, d, J=4.9Hz), 9.0-9.2 (2H, m).
FAB+: 407
Example 3 Production of a salt in which the ratio of compound B to hydrochloric acid is 1: 2.
Add 1-pyrimidin-2-ylmethylamine acetic acid to a suspension of 10.0 g of 6-chloro-N, N'-bis (4-fluorophenyl) -1,3,5-triazine-2,4-diamine in 100 mL of MeCN. The salt (6.0 g) and N, N-diisopropylethylamine (11.5 mL) were added, and the mixture was stirred at 85 ° C. for 12 hours. After cooling the reaction solution to room temperature, the solvent was distilled off, ethyl acetate was added to the resulting residue, and the organic layer was washed with 5% aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, Was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform: MeOH = 100: 0 to 95: 5) to obtain 10.8 g of a slightly yellow amorphous substance. Dissolve this in 200 mL of EtOH, add 2 g of activated carbon, heat to reflux for 10 minutes, remove the activated carbon by filtration using Celite, remove the solvent, and use 400 mL of 80% aqueous EtOH to remove the residue. The solid was collected by filtration to obtain 7.5 g of a colorless solid. This was heated and dissolved in 150 ml of 70% water-containing MeCN and stirred while allowing to cool to room temperature. The precipitated solid was collected by filtration to obtain 7.08 g of Compound B.
Dissolve 7.05 g of the obtained compound B in 200 mL of MeOH and 200 mL of THF, add 10 mL of 4M hydrogen chloride / dioxane solution, then evaporate the solvent, add EtOH to the resulting residue and stir for 30 minutes. A solid was precipitated. The solid was collected by filtration and dried under reduced pressure, then suspended in MeCN and heated to reflux for 10 minutes. The reaction solution was returned to room temperature, and the solid was collected by filtration and dried under reduced pressure. Was 7.25 g of 1: 2 salt as colorless crystals (type I crystals).

Salt crystals with a ratio of compound B to hydrochloric acid of 1: 2
NMR-DMSOd6
4.78 (2H, m), 7.10 (2H, brs), 7.25 (2H, t, J = 8.7Hz), 7.3-7.8 (6H, m), 8.85 (2H, d, J = 4.9Hz), 8.9-9.4 (1H, m), 10.45 (1H, brs), 10.88 (1H, brs)
Elemental Analysis.Calcd for C20H16F2N8 ・ 2HCl: C, 50.12; H, 3,79; N, 23.38; F, 7.93; Cl, 14.79. , 14.84.
Endothermic onset temperature in DSC: about 160 and about 190 ° C
The powder X-ray diffraction pattern of the compound of Example 3 ((type I crystal)) is shown in FIG.

Compound B (free form)
NMR-DMSOd6
4.70 (2H, d, J = 5.8Hz), 7.00 (2H, m), 7.10 (2H, t, J = 8.7Hz), 7.38 (1H, t, J = 4.9Hz), 7.57 (3H, brs), 7.80 (2H, brs), 8.79 (2H, d, J = 4.9Hz), 9.0-9.2 (2H, m).
FAB +: 407

実施例４ 化合物Bとフマル酸の比が1:1の塩の製造
化合物B 1.0g のエタノール50mL溶液に、フマル酸 285.6mgのエタノール5mL 溶液を加えた。直ぐに固体の析出が始まった。この反応液を加熱還流して固体を完全に溶解させた後、放冷しながら攪拌した。内温が60℃まで下がったところで、化合物Bとフマル酸の比が1:1の塩の結晶を極少量添加し、室温まで放冷しながら12時間攪拌した。析出している結晶を濾取し、エタノールで洗浄した後、60℃で2日間減圧乾燥を行なって、「化合物Bとフマル酸の比が1:1の塩」970mg を無色結晶（I型結晶）として得た。

NMR-DMSOd6
4.70 (2H, d, J=5.7Hz), 6.64 (2H, s), 7.00 (2H, m), 7.10 (2H, t, J=8.7Hz), 7.38 (1H, t, J=4.9Hz), 7.57 (3H, brs), 7.80 (2H, brs), 8.80 (2H, d, J=4.9Hz), 9.0-9.2 (2H, m), 13.13 (2H, brs).
Elemental Analysis. Calcd for C20H16F2N8・C4H4O4: C, 55.17; H, 3.86; N, 21.45; F, 7.27. Found: C, 55.29; H, 4.05; N, 21.64; F, 7.32.
DSCにおける吸熱オンセット温度： 約215℃
実施例４の化合物（I型結晶）の粉末X線回折パターンを図５に示す。
Example 4 Production of a salt having a 1: 1 ratio of Compound B to fumaric acid To a solution of 1.0 g of Compound B in 50 mL of ethanol was added 285.6 mg of fumaric acid in 5 mL of ethanol. Immediately, solid precipitation started. The reaction solution was heated to reflux to completely dissolve the solid, and then stirred while allowing to cool. When the internal temperature dropped to 60 ° C., a very small amount of a salt crystal having a 1: 1 ratio of compound B to fumaric acid was added and stirred for 12 hours while cooling to room temperature. The precipitated crystals are collected by filtration, washed with ethanol, and dried under reduced pressure at 60 ° C. for 2 days. As a result, 970 mg of “a salt having a 1: 1 ratio of compound B to fumaric acid” is obtained as colorless crystals (type I crystals ).

NMR-DMSOd6
4.70 (2H, d, J = 5.7Hz), 6.64 (2H, s), 7.00 (2H, m), 7.10 (2H, t, J = 8.7Hz), 7.38 (1H, t, J = 4.9Hz), 7.57 (3H, brs), 7.80 (2H, brs), 8.80 (2H, d, J = 4.9Hz), 9.0-9.2 (2H, m), 13.13 (2H, brs).
Elemental Analysis.Calcd for C20H16F2N8 ・ C4H4O4: C, 55.17; H, 3.86; N, 21.45; F, 7.27.Found: C, 55.29; H, 4.05; N, 21.64; F, 7.32.
Endothermic onset temperature at DSC: approx. 215 ° C
The powder X-ray diffraction pattern of the compound of Example 4 (type I crystal) is shown in FIG.

本発明の化合物Aの酸付加塩の効果は、以下の試験例によって確認された。   The effect of the acid addition salt of Compound A of the present invention was confirmed by the following test examples.

試験例１ 安定性の評価
保存中の分解物の評価：試料およそ5 mgを10 mLのガラス製メスフラスコに量り取り、以下の保存条件で試験を行った。
条件１：70 ℃−相対湿度75%−開放−２週間
条件２：70 ℃−遮光−密栓−２週間
条件３：25 ℃−D65（3600 lux）−密栓−２週間
保存後の試料の入ったメスフラスコの標線まで溶解溶媒で満たし、溶解したものを試料溶液とし、試料溶液中の化合物Aを定量した。なお、化合物Aと化合物Bの検出は266nmと254nmのUVでそれぞれ行い、データ処理を含む装置の取り扱いは、各装置で指示された方法及び手順に従った。（装置：Agilent 製LC-1100シリーズ）
これらの試験結果を表１に示す。なお定量値とは，試験前の化合物Aに対する試験後の化合物Aの残存率を示している。 Test Example 1 Evaluation of Stability Evaluation of degradation products during storage: Approximately 5 mg of a sample was weighed into a 10 mL glass volumetric flask and tested under the following storage conditions.
Condition 1: 70 ° C-75% relative humidity-Open-2 weeks Condition 2: 70 ° C-Light shielding-Sealed plug-2 weeks Condition 3: 25 ° C-D65 (3600 lux)-Sealed plug-2 weeks Contains sample after storage The volume of the measuring flask was filled with the dissolving solvent, and the dissolved solution was used as a sample solution, and the compound A in the sample solution was quantified. Compound A and compound B were detected by UV at 266 nm and 254 nm, respectively, and handling of the apparatus including data processing was in accordance with the method and procedure instructed by each apparatus. (Device: LC-1100 series manufactured by Agilent)
The test results are shown in Table 1. The quantitative value indicates the residual ratio of compound A after the test with respect to compound A before the test.

Figure 2012521964
Figure 2012521964

表１に示すとおり、化合物Aのフマル酸塩及び／または化合物Bのフマル酸塩は、高温高湿度条件、高温遮光条件、及び光に対する安定性が高いことが明らかとなった（条件１乃至３）。   As shown in Table 1, the fumarate salt of Compound A and / or the fumarate salt of Compound B was found to have high temperature and high humidity conditions, high temperature shading conditions, and high light stability (Conditions 1 to 3). ).

試験例３ 化合物A及び／又はBの統合失調症に対する治療効果
統合失調症に対する治療効果の検証は、メタンフェタミン誘発運動亢進モデルを用いて行った。メタンフェタミンは覚せい剤であり、ドパミン神経系の伝達を亢進することで、統合失調症に類似した症状を引き起こすことが知られており、メタンフェタミンを動物に投与した際に生じる異常行動は、統合失調症治療薬のスクリーニンング方法として汎用されている（Oka et al., 1993, J. Pharmacol. Exp. Ther., 264:158-165）。すなわち、雄性ddyマウスを運動量測定装置に入れ、３０分後にメタンフェタミンを投与した。メタンフェタミン投与後直ちに測定装置に戻し、直後から１時間の運動量を測定した。運動量の測定には、室町機械株式会社のスーパーメックスセンサーを使用した。溶媒、又は、試験化合物をそれぞれ溶媒で複数の濃度に希釈した希釈液を、各群のマウスに経口投与した。溶媒は、０．５％メチルセルロース水溶液を用いた。有意差検定は、Dunnett検定を用い、溶媒投与群と薬物投与群との間で行った。 Test Example 3 Therapeutic Effect of Compound A and / or B on Schizophrenia Verification of the therapeutic effect on schizophrenia was performed using a methamphetamine-induced hyperkinetic model. Methamphetamine is a stimulant and is known to cause symptoms similar to schizophrenia by enhancing transmission in the dopamine nervous system, and abnormal behavior that occurs when methamphetamine is administered to animals is schizophrenia. It is widely used as a screening method for therapeutic drugs (Oka et al., 1993, J. Pharmacol. Exp. Ther., 264: 158-165). That is, male ddy mice were placed in a momentum measuring apparatus, and methamphetamine was administered 30 minutes later. Immediately after the administration of methamphetamine, it was returned to the measuring apparatus, and the momentum for 1 hour was measured immediately after. A super mex sensor from Muromachi Kikai Co., Ltd. was used to measure the momentum. A solvent or a diluted solution obtained by diluting a test compound with a solvent to a plurality of concentrations was orally administered to each group of mice. As the solvent, a 0.5% methylcellulose aqueous solution was used. The significant difference test was performed between the solvent administration group and the drug administration group using Dunnett's test.

試験化合物
化合物（１）：化合物Aとフマル酸の比が2:1の塩の無水物の結晶
化合物（２）：化合物Bと塩酸の比が1:2の塩の結晶 Test compound Compound (1): Crystal of salt anhydride with a ratio of compound A to fumaric acid of 2: 1 Compound (2): Crystal of salt with a ratio of compound B to hydrochloric acid of 1: 2

（結果）
メタンフェタミン誘発運動亢進抑制作用の結果を表２に示す。表中の数値は、各化合物投与群の最小有効用量（溶媒投与群の運動量に対して、運動量が有意に少なかった最も小さい用量）を表す．化合物A及びBははいずれもメタンフェタミン誘発運動亢進を抑制した。すなわち、これら２化合物は統合失調症の症状を改善する作用があることが示された。 (result)
The results of methamphetamine-induced hyperactivity suppression action are shown in Table 2. The numerical values in the table represent the minimum effective dose of each compound administration group (the smallest dose with significantly less exercise than the vehicle administration group). Both compounds A and B inhibited methamphetamine-induced hyperactivity. That is, these two compounds were shown to have an action of improving the symptoms of schizophrenia.

Figure 2012521964
本発明を詳細にまた特定の実施態様を参照して説明してきたが、当業者にとってその発明の範囲から逸脱することなく、様々な変更および修正を行うことができることは明らかである。
Figure 2012521964
 Although the invention has been described in detail and with reference to specific embodiments, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the scope of the invention.

N-(4-フルオロフェニル)- N'-フェニル-N''- (ピリミジン-2-イルメチル)- 1,3,5-トリアジン-2,4,6-トリアミン（化合物A）のフマル酸塩及び／又はN, N'-ビス(4-フルオロフェニル)-N''- (ピリミジン-2-イルメチル)- 1,3,5-トリアジン-2,4,6-トリアミン（化合物B）のフマル酸塩及びそれらの新規結晶は、優れた安定性を有する医薬品又は原料として提供されるものとして有用である。   N- (4-fluorophenyl) -N′-phenyl-N ″-(pyrimidin-2-ylmethyl) -1,3,5-triazine-2,4,6-triamine (compound A) fumarate and / Or fumarate of N, N'-bis (4-fluorophenyl) -N ''-(pyrimidin-2-ylmethyl) -1,3,5-triazine-2,4,6-triamine (compound B) These novel crystals are useful as those provided as pharmaceuticals or raw materials having excellent stability.

Claims (8)

式（Ｉ）
Figure 2012521964
 （R1：H又はF）
の化合物とフマル酸から成る塩。 Formula (I)
Figure 2012521964
 (R 1 : H or F)
A salt consisting of the compound and fumaric acid. R1がHである請求項１に記載の塩。 The salt according to claim 1, wherein R 1 is H. 式（Ｉ）の化合物とフマル酸の比が2：1である請求項２に記載の塩。 The salt according to claim 2, wherein the ratio of the compound of formula (I) to fumaric acid is 2: 1. R1がFである請求項１に記載の塩。 The salt according to claim 1, wherein R 1 is F. 式（Ｉ）の化合物とフマル酸の比が1：1である請求項4に記載の塩。 The salt according to claim 4, wherein the ratio of the compound of formula (I) to fumaric acid is 1: 1. 請求項1乃至５に記載の化合物の結晶。 A crystal of the compound according to claim 1. 請求項1乃至４に記載の化合物の有効量を含有し、更に製薬学的に許容される担体を含む医薬組成物。 A pharmaceutical composition comprising an effective amount of the compound according to claim 1 and further comprising a pharmaceutically acceptable carrier. 請求項６に記載の結晶の有効量を含有し、更に製薬学的に許容される担体を含む医薬組成物。 A pharmaceutical composition comprising an effective amount of the crystals of claim 6 and further comprising a pharmaceutically acceptable carrier.
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