JP2016525109A - Process for producing 1- (5-halonaphthalene-1-sulfonyl) -1H-hexahydro-1,4-diazepine and composition containing the same - Google Patents

Process for producing 1- (5-halonaphthalene-1-sulfonyl) -1H-hexahydro-1,4-diazepine and composition containing the same Download PDF

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JP2016525109A
JP2016525109A JP2016526659A JP2016526659A JP2016525109A JP 2016525109 A JP2016525109 A JP 2016525109A JP 2016526659 A JP2016526659 A JP 2016526659A JP 2016526659 A JP2016526659 A JP 2016526659A JP 2016525109 A JP2016525109 A JP 2016525109A
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ブロー，エリック
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Abstract

本発明は、下記式（Ｉ）：（式中、Ｘはハロゲン原子である）で示される化合物を合成する方法に関する。本方法により、化合物ＭＬ７（Ｘ＝Ｉ）及びＭＬ９（Ｘ＝Ｃｌ）が製造される。The present invention relates to a method for synthesizing a compound represented by the following formula (I): (wherein X is a halogen atom). This method produces compounds ML7 (X = I) and ML9 (X = Cl).

Description

本発明は、ＭＬ７分子、又は、ＭＬ９分子のようなその１つの誘導体を製造する方法に関する。   The present invention relates to a method for producing the ML7 molecule or one of its derivatives, such as the ML9 molecule.

ＭＬ７分子、即ち１−（５−ヨードナフタレン−１−スルホニル）−１Ｈ−ヘキサヒドロ−１，４−ジアゼピンは、Saitoh et al., J. Biol. Chem 1987, 262(16), p. 7796に記載された。これはＭＬ９（１−（５−クロロ−１−スルホニル）−１Ｈ−ヘキサヒドロ−１，４−ジアゼピン）の誘導体分子であり、ミオシン軽鎖キナーゼ（ＭＬＣＫ）の触媒活性を選択的に阻害することができる。   The ML7 molecule, 1- (5-iodonaphthalene-1-sulfonyl) -1H-hexahydro-1,4-diazepine, is described in Saitoh et al., J. Biol. Chem 1987, 262 (16), p. 7796. It was done. This is a derivative molecule of ML9 (1- (5-chloro-1-sulfonyl) -1H-hexahydro-1,4-diazepine), which selectively inhibits the catalytic activity of myosin light chain kinase (MLCK). it can.

現在、ＭＬ７の合成は不十分である。それゆえ本発明者らは、従来技術において直面する問題を克服する、ＭＬ７化合物及びその誘導体を合成するための新規な方法を開発した。   Currently, the synthesis of ML7 is inadequate. We have therefore developed a novel method for synthesizing ML7 compounds and derivatives thereof that overcomes the problems encountered in the prior art.

本発明は更に、ＭＬ７又はＭＬ９化合物を含む点眼剤であって、安定な、前記化合物の刺激効果の緩和された、眼の障害の処置のための治療的用途に適合し得る濃度での前記化合物の溶解を可能にする点眼剤の提供に関する。   The present invention further comprises an eye drop comprising an ML7 or ML9 compound, wherein said compound is in a concentration that is stable, less irritating to said compound and compatible with therapeutic use for the treatment of ocular disorders. It is related with provision of the eye drop which enables melt | dissolution.

本発明は、下記式（Ｉ）：

Figure 2016525109

（式中、Ｘはハロゲン原子である）
で示される化合物を合成する方法であって、
ａ）下記式（ＩＩ）：
Figure 2016525109
で示される化合物のアミノ基をハロゲン原子で置換して、下記式（ＩＩＩ）：
Figure 2016525109
で示される化合物を与える工程；
ｂ）前記式（ＩＩＩ）で示される化合物のスルホン基をハロゲン化して、下記式（ＩＶ）：
Figure 2016525109
（式中、Ｒ１はハロゲン原子、より具体的には塩素原子、である）
で示されるハロゲン化スルホニルを生成する工程；及び
ｃ）前記式（ＩＶ）で示される化合物のハロゲン化スルホニル基をホモピペラジン基で置換して、前記式（Ｉ）で示される化合物を得る工程
を含む方法に関する。 The present invention relates to the following formula (I):
Figure 2016525109
(Wherein X is a halogen atom)
A method for synthesizing a compound represented by
a) The following formula (II):
Figure 2016525109
The amino group of the compound represented by formula (III) is substituted with a halogen atom, and the following formula (III):
Figure 2016525109
Providing a compound of formula;
b) The sulfone group of the compound represented by the formula (III) is halogenated to form the following formula (IV):
Figure 2016525109
(Wherein R 1 is a halogen atom, more specifically a chlorine atom)
And c) a step of obtaining the compound represented by the formula (I) by substituting the sulfonyl halide group of the compound represented by the formula (IV) with a homopiperazine group. Relates to the method of including.

本発明において、用語「ハロゲン」はフッ素、塩素、臭素又はヨウ素原子をいう。   In the present invention, the term “halogen” refers to a fluorine, chlorine, bromine or iodine atom.

工程ａ）は、式（ＩＩ）で示される化合物をハロゲン化化合物、好ましくはアルカリ金属ハロゲン化物、例えばヨウ化カリウム、と接触させることによって行われる。置換は、好ましくは亜硝酸塩、例えば亜硝酸ナトリウム、の存在下で行われる。特定の一実施態様において、置換は好ましくは酸性媒体中、特に塩酸ＨＣｌの存在下、で行われる。反応は、好ましくは５℃と周囲温度（これは、約２０＋／−３℃と定義される）の間の温度で行われる。
特定の一実施態様によれば、１．１当量の亜硝酸ナトリウム、３当量のヨウ化カリウム及び１５容の強酸（特にＨＣｌ又はＨ２ＳＯ４）、特に６Ｎ ＨＣｌ、の存在下で、式（ＩＩ）で示される化合物を反応させるのであるが、これらの試薬の添加は、周囲温度を超えないように温度を制御しつつ５℃で行われる。反応は特に、約４時間と約３６時間の間、特に約１０時間と約２４時間の間、具体的には約２０時間、行うことができる。 Step a) is carried out by contacting the compound of formula (II) with a halogenated compound, preferably an alkali metal halide, such as potassium iodide. The substitution is preferably performed in the presence of a nitrite such as sodium nitrite. In one particular embodiment, the substitution is preferably carried out in an acidic medium, in particular in the presence of HCl HCl. The reaction is preferably carried out at a temperature between 5 ° C. and ambient temperature (which is defined as about 20 +/− 3 ° C.).
According to one particular embodiment, in the presence of 1.1 equivalents of sodium nitrite, 3 equivalents of potassium iodide and 15 volumes of strong acid (especially HCl or H 2 SO 4 ), in particular 6N HCl, the formula ( The compound represented by II) is reacted, and the addition of these reagents is performed at 5 ° C. while controlling the temperature so as not to exceed the ambient temperature. The reaction can in particular be carried out between about 4 hours and about 36 hours, in particular between about 10 hours and about 24 hours, in particular about 20 hours.

工程ｂ）は、好ましくは、式（ＩＩＩ）で示される化合物を、塩化チオニル（ＳＯＣｌ２）と接触させることによって行われる。好ましくは、反応は有機溶媒、特にトルエン、の存在下に、ＤＭＦで触媒されて行われる。反応は、好ましくは溶媒の還流下で行われる。
本発明の特定の一実施態様によれば、工程ｂ）は、トルエン中、特に１５容のトルエン中、０．１当量のＤＭＦの存在下における、式（ＩＩＩ）で示される化合物の、１．３〜２当量の、特に２当量の、ＳＯＣｌ２との反応を含む。反応は還流下で、特に１時間と１５時間の間、特に５時間、行われる。 Step b) is preferably carried out by contacting the compound of formula (III) with thionyl chloride (SOCl 2 ). Preferably, the reaction is carried out catalyzed by DMF in the presence of an organic solvent, in particular toluene. The reaction is preferably carried out under reflux of the solvent.
According to one particular embodiment of the present invention, step b) is carried out by subjecting compound 1.III of compound of formula (III) in the presence of 0.1 equivalents of DMF in toluene, in particular in 15 volumes of toluene. Comprising reaction with 3 to 2 equivalents, in particular 2 equivalents, of SOCl 2 . The reaction is carried out under reflux, in particular between 1 and 15 hours, in particular 5 hours.

工程ｃ）は、好ましくは、式（ＩＶ）で示される化合物を、ホモピペラジンと接触させることによって行われる。好ましくは、反応は有機溶媒、特にトルエン、の存在下で行われる。反応は、好ましくは５℃と周囲温度の間の温度で行われる。
他の一実施態様によれば、工程ｃ）は、トルエン中（特に１５容のトルエン中）、２〜１０当量の、特に４当量の、ホモピペラジンと式（ＩＶ）で示される化合物を反応させる工程を含む。この工程は、０℃と１００℃の間の温度で、より具体的には５℃と周囲温度の間の温度で、特に１６時間行われる。 Step c) is preferably carried out by contacting the compound of formula (IV) with homopiperazine. Preferably, the reaction is carried out in the presence of an organic solvent, especially toluene. The reaction is preferably carried out at a temperature between 5 ° C. and ambient temperature.
According to another embodiment, step c) comprises reacting a compound of formula (IV) with 2-10 equivalents, in particular 4 equivalents, of homopiperazine in toluene (especially in 15 volumes of toluene). Process. This step is carried out at a temperature between 0 ° C. and 100 ° C., more specifically at a temperature between 5 ° C. and ambient temperature, in particular for 16 hours.

本方法は更に、式（Ｉ）で示される化合物の塩、特に塩酸塩、を形成する工程を含んでいてよい。式（Ｉ）で示される化合物の塩は特に、式（Ｉ）で示される化合物を酸と反応させることにより得ることができる。反応はこのようにして、好ましくは塩酸ＨＣｌの存在下で、特に約１当量の塩酸の存在下で、行われる。反応は特に有機溶媒、例えばアルコール、例えばイソプロパノール、の存在下で行われる。反応は、好ましくは５℃と周囲温度の間の温度で行われる。
特定の一実施態様によれば、式（Ｉ）で示される化合物を、５容のイソプロピルアルコール中１当量の６Ｎ ＨＣｌと、これらの試薬を可溶化するため約７０℃の温度で１時間反応させる。温度を周囲温度まで下げることにより、沈殿を起こさせる。 The method may further comprise the step of forming a salt of the compound of formula (I), in particular the hydrochloride. The salt of the compound of formula (I) can in particular be obtained by reacting the compound of formula (I) with an acid. The reaction is thus carried out preferably in the presence of hydrochloric acid HCl, in particular in the presence of about 1 equivalent of hydrochloric acid. The reaction is in particular carried out in the presence of an organic solvent, for example an alcohol such as isopropanol. The reaction is preferably carried out at a temperature between 5 ° C. and ambient temperature.
According to one particular embodiment, the compound of formula (I) is reacted with 1 equivalent of 6N HCl in 5 volumes of isopropyl alcohol for 1 hour at a temperature of about 70 ° C. to solubilize these reagents. . Precipitation occurs by lowering the temperature to ambient temperature.

好ましい一実施態様によれば、本発明は、化合物ＭＬ７の塩化物塩を製造する方法であって、それにより工程ａ）が、式（ＩＩ）で示される化合物の、ヨウ化カリウムとの反応を含む方法に関する。   According to one preferred embodiment, the present invention provides a process for preparing the chloride salt of compound ML7, whereby step a) comprises reacting the compound of formula (II) with potassium iodide. Relates to the method of including.

他の一つの態様によれば、本発明は、ＭＬ７化合物を含む医薬組成物に関し、この組成物は、
−組成物の総重量に対して０．００１重量％と０．５重量％の間のＭＬ７又はＭＬ９；
−組成物の総重量に対して０．１重量％と１０重量％の間のシクロデキストリン；及び
−組成物の総重量に対して０．０１重量％と０．５重量％の間の、ヒドロキシプロピルメチルセルロース、ヒドロキシエチルセルロース、ＰＶＰ又はＰＶＡ
を含む。
本組成物は、生理的に許容し得る賦形剤、特に水、を用いて全体を１００％とすることができる。 According to another aspect, the invention relates to a pharmaceutical composition comprising an ML7 compound, the composition comprising:
-ML7 or ML9 between 0.001% and 0.5% by weight relative to the total weight of the composition;
Between 0.1% and 10% by weight of cyclodextrin, based on the total weight of the composition; and between 0.01% and 0.5% by weight of hydroxy, based on the total weight of the composition Propylmethylcellulose, hydroxyethylcellulose, PVP or PVA
including.
The composition can be made up to 100% overall with a physiologically acceptable excipient, particularly water.

シクロデキストリンは特に、ヒドロキシプロピル−β−シクロデキストリンとすることができる。   The cyclodextrin can in particular be hydroxypropyl-β-cyclodextrin.

製剤のｐＨは、６と７．５の間、特に６．８と７．２の間、とすることができる。   The pH of the formulation can be between 6 and 7.5, in particular between 6.8 and 7.2.

ＭＬ７化合物の改良された合成
１−（５−ヨードナフタレン−１−スルホニル）−１，４−ジアゼパンの塩酸塩を合成するための改良された方法を以下に記載する。 Improved Synthesis of ML7 Compound An improved method for synthesizing 1- (5-iodonaphthalene-1-sulfonyl) -1,4-diazepane hydrochloride is described below.

原料試薬はいずれも市販の製品である。   All of the raw material reagents are commercially available products.

第１工程では、６Ｎ ＨＣｌ、ＮａＮＯ２及びＫＩの存在下、２３℃±２℃で５−アミノ−１−ナフタレンスルホン酸のヨウ素化を行い、５−ヨード−１−ナフタレンスルホン酸を得る。 In the first step, 5-amino-1-naphthalenesulfonic acid is iodinated at 23 ° C. ± 2 ° C. in the presence of 6N HCl, NaNO 2 and KI to obtain 5-iodo-1-naphthalenesulfonic acid.

第２工程は、５−ヨード−１−ナフタレンスルホニルクロリドを得るための、ＤＭＦの存在下における、５−ヨード−１−ナフタレンスルホン酸のＳＯＣｌ２による処理を含む。 The second step involves treatment of 5-iodo-1-naphthalenesulfonic acid with SOCl 2 in the presence of DMF to obtain 5-iodo-1-naphthalenesulfonyl chloride.

その後、トルエン中で５−ヨード−１−ナフタレンスルホニルクロリドがホモピペラジンと反応して、１−（５−ヨードナフタレン−１−スルホニル）−１，４−ジアゼパンを与える。   Thereafter, 5-iodo-1-naphthalenesulfonyl chloride reacts with homopiperazine in toluene to give 1- (5-iodonaphthalene-1-sulfonyl) -1,4-diazepane.

最後に、イソプロパノール中で１−（５−ヨードナフタレン−１−スルホニル）−１，４−ジアゼパンを６Ｎ ＨＣｌで塩にして、１−（５−ヨードナフタレン−１−スルホニル）−１，４−ジアゼパン塩酸塩を与える。   Finally, 1- (5-iodonaphthalene-1-sulfonyl) -1,4-diazepane is salted with 6N HCl in isopropanol to give 1- (5-iodonaphthalene-1-sulfonyl) -1,4-diazepane. Give the hydrochloride salt.

５−ヨード−１−ナフタレンスルホン酸の製造
メカニカルスターラーを取り付けた三つ口丸底フラスコに、５−アミノ−１−ナフタレンスルホン酸（５０ｇ、２２４ｍｍｏｌ）を、６Ｎ ＨＣｌ（７５０ｍＬ、１５容）と共に入れる。その懸濁液を５±３℃に冷却し、ＮａＮＯ２（１７ｇ、２４６ｍｍｏｌ）の水（５０ｍＬ、１容）中溶液を、５±３度で１０分間かけて滴下する（発熱反応は観測されない）。その懸濁液を１時間撹拌下におくと、温度が１８±２℃に上昇する（反応のこの時点で、ＬＣ／ＭＳ分析には原料試薬は全く検出されない）。ＫＩ（１１１．５ｇ、６７２ｍｍｏｌ）の水（８０ｍＬ、１．６容）中溶液を、１８±２℃で３０分間かけて滴加する（発熱反応は観測されないが、添加の開始時において顕著な脱気が観測される）。
その反応混合物を２３±２℃で２０時間撹拌し、次いで１８±２℃に冷却する。スルファミン酸アンモニウム（２５．６ｇ、２２４ｍｍｏｌ）の水（１５ｍＬ、０．３容）中溶液を添加し、その反応混合物を１８±２℃で１５分間撹拌する。Ｎａ２Ｓ２Ｏ３の飽和溶液（２００ｍＬ、４容）を添加する（吸熱反応が観測され、反応混合物は２℃に下がる）。その反応混合物を５±３℃に冷却し、次いで１時間撹拌する。形成された沈殿物を、焼結ガラス（直径１０ｃｍ、気孔率＝３、厚さ３．５ｃｍ）を通して濾過し、６Ｎ ＨＣｌ（５０ｍＬ、１容）ですすぎ、５±３℃に冷却する（すすいだ後の厚さ１．５ｃｍ）。
得られた固体を、撹拌下に５００ｍＬ（１０容）のトルエンに添加する。その懸濁液をＤｅａｎ−Ｓｔａｒｃｋ装置中で還流し、水を除去する。次いで、その混合物を１８±２℃に冷却し、焼結ガラス（直径１０ｃｍ、気孔率＝３）を通して減圧濾過する。そのケーク（厚さ＝２ｃｍ）をトルエン１００ｍＬ（２容）で２回トリチュレートし、トルエン１００ｍＬ（１容）で２回洗浄する。得られた褐色固体を、精製することなく以降の工程で用いる。
総重量：１３５．８ｇ
推定乾燥重量：８１．５ｇ
収率：定量的
分析：１Ｈ，１３Ｃ ＮＭＲ；ＨＰＬＣ；ＭＳ Preparation of 5-iodo-1-naphthalenesulfonic acid In a three-necked round bottom flask equipped with a mechanical stirrer, 5-amino-1-naphthalenesulfonic acid (50 g, 224 mmol) is charged with 6N HCl (750 mL, 15 volumes). . The suspension is cooled to 5 ± 3 ° C. and a solution of NaNO 2 (17 g, 246 mmol) in water (50 mL, 1 volume) is added dropwise over 5 minutes at 5 ± 3 degrees (no exothermic reaction is observed). . If the suspension is left under stirring for 1 hour, the temperature rises to 18 ± 2 ° C. (at this point in the reaction no starting reagents are detected in the LC / MS analysis). A solution of KI (111.5 g, 672 mmol) in water (80 mL, 1.6 vol) is added dropwise over 30 minutes at 18 ± 2 ° C. (no exothermic reaction is observed, but significant desorption at the start of the addition). Qi is observed).
The reaction mixture is stirred at 23 ± 2 ° C. for 20 hours and then cooled to 18 ± 2 ° C. A solution of ammonium sulfamate (25.6 g, 224 mmol) in water (15 mL, 0.3 vol) is added and the reaction mixture is stirred at 18 ± 2 ° C. for 15 min. Add a saturated solution of Na 2 S 2 O 3 (200 mL, 4 vol) (endothermic reaction is observed and the reaction mixture drops to 2 ° C.). The reaction mixture is cooled to 5 ± 3 ° C. and then stirred for 1 hour. The precipitate formed was filtered through sintered glass (diameter 10 cm, porosity = 3, thickness 3.5 cm), rinsed with 6N HCl (50 mL, 1 volume) and cooled to 5 ± 3 ° C. (rinse). Later thickness 1.5 cm).
The resulting solid is added to 500 mL (10 vol) of toluene with stirring. The suspension is refluxed in a Dean-Starck apparatus to remove water. The mixture is then cooled to 18 ± 2 ° C. and vacuum filtered through sintered glass (diameter 10 cm, porosity = 3). The cake (thickness = 2 cm) is triturated twice with 100 mL (2 volumes) of toluene and washed twice with 100 mL (1 volume) of toluene. The resulting brown solid is used in subsequent steps without purification.
Total weight: 135.8g
Estimated dry weight: 81.5g
Yield: quantitative analysis: 1 H, 13 C NMR; HPLC; MS

５−ヨード−１−ナフタレンスルホニルクロリドの調製
三つ口丸底フラスコ内に、５−ヨード−１−ナフタレンスルホン酸（１３５．８ｇ（生成物全体、２２４ｍｍｏｌ）とトルエン１．２リットル（期待される重量に対して１５容）を仕込む。その懸濁液を１８±２℃で撹拌し、ＤＭＦ（１．７ｍＬ、２２．４ｍｍｏｌ）を添加する。次に、ＳＯＣｌ２（３２．５ｍＬ、４４８ｍｍｏｌ）を５分間かけて滴加する。その混合物を４時間３０分間還流し、２０±３℃に冷却する。その溶液を、焼結ガラス（直径１０ｃｍ、気孔率＝３、厚さ１ｃｍ）を通して減圧濾過し、その固体を８０ｍＬ（１容）のトルエンで洗浄する。その濾液を減圧下で蒸発させて過剰のＳＯＣｌ２を除去し、推定体積の８００ｍＬ（１０容）まで濃縮する。得られた溶液を、精製することなく以降の工程に用いる。
分析：ＨＰＬＣ、ＭＳ（メチルエステル体） Preparation of 5-iodo-1-naphthalenesulfonyl chloride In a three-neck round bottom flask, 5-iodo-1-naphthalenesulfonic acid (135.8 g (total product, 224 mmol) and 1.2 liters of toluene (expected) The suspension is stirred at 18 ± 2 ° C. and DMF (1.7 mL, 22.4 mmol) is added, followed by SOCl 2 (32.5 mL, 448 mmol). The mixture is refluxed for 4 hours 30 minutes and cooled to 20 ± 3 ° C. The solution is vacuum filtered through sintered glass (diameter 10 cm, porosity = 3, thickness 1 cm). , washing the solids with toluene 80 mL (1 vol). the filtrate was evaporated under reduced pressure to remove excess SOCl 2, concentrated to estimate a volume of 800 mL (10 vol). obtained The solution used in the subsequent step without purification.
Analysis: HPLC, MS (methyl ester)

１−（５−ヨードナフタレン−１−スルホニル）−１，４−ジアゼパンの調製
トルエン１．２リットル（期待される重量に対して１５容）中のホモピペラジン（８９．７ｇ、８９６ｍｍｏｌ）を、三つ口丸底フラスコ内で撹拌する。その混合物を氷浴中で冷却し、５−ヨード−１−ナフタレンスルホニルクロリドの溶液（２２４ｍｍｏｌ、８００ｍＬ）を３０分間かけて添加する（Ｔ０＝７°Ｃ、Ｔｆｉｎａｌ＝１４°Ｃ）。次いで、その反応物を１８±２℃で１６時間撹拌する。その混合物を、焼結ガラス（直径１０ｃｍ、気孔率＝３、厚さ１ｃｍ）を通して減圧濾過し、その固体をトルエン８０ｍＬ（１容）で洗浄する。その濾液を８００ｍＬの水（１０容）で６回洗浄する。その有機相をシリカパッド（２部、直径＝８ｃｍ、シリカ厚さ＝６．５ｃｍ）上で精製し、以下のもの：
−１Ｌのトルエン／ｉＰｒＯＨ（９０：１０）：Ｆ１
−１Ｌのトルエン／ｉＰｒＯＨ（７０：３０）：Ｆ２
−２Ｌのトルエン／ｉＰｒＯＨ（６０：４０）：Ｆ３
−１Ｌのトルエン／ｉＰｒＯＨ（５０：５０）：Ｆ４
で溶出させた。
得られた画分１〜４を減圧下で蒸発させ、得られた固体をイソプロピルアルコール３２０ｍＬ（４容）で結晶化させる。５±２℃に冷却後、固体を濾過し、冷イソプロピルアルコール８０ｍＬ（１容）で洗浄する。その化合物を減圧下で乾燥させて、１−（５−ヨードナフタレン−１−スルホニル）−１，４−ジアゼパンのベージュ色の固体５７．２ｇを得る。
収率：３段階で６１％
分析：１Ｈ、１３Ｃ ＮＭＲ；ＨＰＬＣ；ＭＳ；ＴＬＣ Preparation of 1- (5-iodonaphthalene-1-sulfonyl) -1,4-diazepane Homopiperazine (89.7 g, 896 mmol) in 1.2 liters of toluene (15 vol to expected weight) Stir in a round neck flask. The mixture is cooled in an ice bath and a solution of 5-iodo-1-naphthalenesulfonyl chloride (224 mmol, 800 mL) is added over 30 minutes (T 0 = 7 ° C., T final = 14 ° C.). The reaction is then stirred at 18 ± 2 ° C. for 16 hours. The mixture is filtered under reduced pressure through sintered glass (diameter 10 cm, porosity = 3, thickness 1 cm) and the solid is washed with 80 mL (1 volume) of toluene. The filtrate is washed 6 times with 800 mL water (10 vol). The organic phase was purified on a silica pad (2 parts, diameter = 8 cm, silica thickness = 6.5 cm) and the following:
−1 L of toluene / iPrOH (90:10): F1
-1 L of toluene / iPrOH (70:30): F2
-2 L of toluene / iPrOH (60:40): F3
−1 L of toluene / iPrOH (50:50): F4
And eluted.
The obtained fractions 1 to 4 are evaporated under reduced pressure, and the resulting solid is crystallized with 320 mL (4 volumes) of isopropyl alcohol. After cooling to 5 ± 2 ° C., the solid is filtered and washed with 80 mL (1 volume) of cold isopropyl alcohol. The compound is dried under reduced pressure to give 57.2 g of a beige solid of 1- (5-iodonaphthalene-1-sulfonyl) -1,4-diazepane.
Yield: 61% in 3 steps
Analysis: 1 H, 13 C NMR; HPLC; MS; TLC

１−（５−ヨードナフタレン−１−スルホニル）−１，４−ジアゼパン塩酸塩の調製
１−（５−ヨードナフタレン−１−スルホニル）−１，４−ジアゼパン（５７．２ｇ、１３７ｍｍｏｌ）とイソプロピルアルコール２８６ｍＬ（５容）を、三つ口丸底フラスコ内で撹拌する。混合物が均一になるまでその懸濁液を還流し、次いで２０±２℃に冷却する。次に、漏斗を用いて６Ｎ ＨＣｌ（２２．９ｍＬ、１３７ｍｍｏｌ）を添加する。その混合物を５±２℃に冷却し、次いで濾過し、その固体を冷イソプロピルアルコール（５７ｍＬ、１容）で洗浄する。得られた固体を水１１４ｍＬ（２容）で結晶化する。５±２℃に再冷却後、その固体を濾過し、冷水５７ｍＬ（１容）で洗浄する。その化合物を減圧下７０℃で乾燥させて、１−（５−ヨードナフタレン−１−スルホニル）−１，４−ジアゼパン塩酸塩５２．７ｇを白色固体の形態として得る。
収率：８４％
分析：１Ｈ、１３Ｃ ＮＭＲ；ＨＰＬＣ；ＭＳ；ＴＬＣ Preparation of 1- (5-iodonaphthalene-1-sulfonyl) -1,4-diazepan hydrochloride 1- (5-Iodonaphthalene-1-sulfonyl) -1,4-diazepane (57.2 g, 137 mmol) and isopropyl alcohol 286 mL (5 volumes) is stirred in a three neck round bottom flask. The suspension is refluxed until the mixture is homogeneous and then cooled to 20 ± 2 ° C. Then 6N HCl (22.9 mL, 137 mmol) is added using a funnel. The mixture is cooled to 5 ± 2 ° C., then filtered, and the solid is washed with cold isopropyl alcohol (57 mL, 1 volume). The obtained solid is crystallized with 114 mL (2 volumes) of water. After recooling to 5 ± 2 ° C., the solid is filtered and washed with 57 mL (1 volume) of cold water. The compound is dried at 70 ° C. under reduced pressure to give 52.7 g of 1- (5-iodonaphthalene-1-sulfonyl) -1,4-diazepane hydrochloride in the form of a white solid.
Yield: 84%
Analysis: 1 H, 13 C NMR; HPLC; MS; TLC

ＭＬ７化合物の点眼用製剤
本発明の製剤の例を、下記表に列挙する。

Figure 2016525109

これらの製剤は安定であり、活性化合物の刺激効果の緩和を可能にし、また前記有効成分の、眼の障害の処置のための治療的用途に適合し得る濃度での溶解を可能にする。 Formulations for eye drops of ML7 compound Examples of the formulations of the present invention are listed in the following table.
Figure 2016525109
These formulations are stable, permitting the alleviation of the irritating effect of the active compound and allowing the active ingredient to be dissolved in a concentration that can be adapted for therapeutic use for the treatment of eye disorders.

Claims (11)

下記式（Ｉ）：
Figure 2016525109
（式中、Ｘはハロゲン原子である）
で示される化合物を合成する方法であって、
ａ）下記式（ＩＩ）：
Figure 2016525109
で示される化合物のアミノ基をハロゲン原子で置換して、下記式（ＩＩＩ）：
Figure 2016525109
で示される化合物を与える工程；
ｂ）前記式（ＩＩＩ）で示される化合物のスルホン基をハロゲン化して、下記式（ＩＶ）：
Figure 2016525109
（式中、Ｒ１はハロゲン原子である）
で示されるハロゲン化スルホニルを与える工程；及び
ｃ）前記式（ＩＶ）で示される化合物のハロゲン化スルホニル基をホモピペラジン基で置換して、前記式（Ｉ）で示される化合物を得る工程
を含む方法。 The following formula (I):
Figure 2016525109
(Wherein X is a halogen atom)
A method for synthesizing a compound represented by
a) The following formula (II):
Figure 2016525109
The amino group of the compound represented by formula (III) is substituted with a halogen atom, and the following formula (III):
Figure 2016525109
Providing a compound of formula;
b) The sulfone group of the compound represented by the formula (III) is halogenated to form the following formula (IV):
Figure 2016525109
(Wherein R 1 is a halogen atom)
And c) a step of obtaining a compound represented by the formula (I) by substituting a homopiperazine group for the sulfonyl halide group of the compound represented by the formula (IV). Method. Ｘがヨウ素又は塩素原子である、請求項１記載の方法。   The method according to claim 1, wherein X is an iodine or chlorine atom. 工程ａ）が、式（Ｉ）で示される化合物を、アルカリ金属ハロゲン化物、例えばヨウ化カリウム、と接触させることによって行われる、請求項１又は２記載の方法。   The process according to claim 1 or 2, wherein step a) is carried out by contacting the compound of formula (I) with an alkali metal halide, such as potassium iodide. 工程ａ）における置換が酸性媒体中で行われる、請求項１〜３のいずれか一項記載の方法。   The process according to any one of claims 1 to 3, wherein the substitution in step a) is carried out in an acidic medium. 工程ａ）が０℃と１００℃の間の温度で行われる、請求項１〜４のいずれか一項記載の方法。   The process according to any one of claims 1 to 4, wherein step a) is carried out at a temperature between 0 ° C and 100 ° C. 前記式（ＩＩＩ）で示される化合物が、塩化チオニル（ＳＯＣｌ２）と接触させられる、請求項１〜５のいずれか一項記載の方法。 The method according to claim 1, wherein the compound represented by the formula (III) is contacted with thionyl chloride (SOCl 2 ). 工程ｂ）が有機溶媒中、特にＤＭＦとトルエンの混合物中、で行われる、請求項１〜６のいずれか一項記載の方法。   Process according to any one of claims 1 to 6, wherein step b) is carried out in an organic solvent, in particular in a mixture of DMF and toluene. 工程ｃ）が、前記式（ＩＶ）で示される化合物をホモピペラジンと接触させる工程を含む、請求項１〜７のいずれか一項記載の方法。   The method according to any one of claims 1 to 7, wherein step c) comprises a step of contacting the compound represented by the formula (IV) with homopiperazine. 工程ｃ）が、有機溶媒の存在下、特にトルエンの存在下、で行われる、請求項１〜８のいずれか一項記載の方法。   9. A process according to any one of claims 1 to 8, wherein step c) is carried out in the presence of an organic solvent, in particular in the presence of toluene. 式（Ｉ）で示される化合物の塩を形成する工程、特に式（Ｉ）で示される化合物と酸、特に塩酸、との反応により１−（５−ヨードナフタレン−１−スルホニル）−１Ｈ−ヘキサヒドロ−１，４−ジアゼピン化合物の塩酸塩を形成する工程、を更に含む、請求項１〜９のいずれか一項記載の方法。   1- (5-iodonaphthalene-1-sulfonyl) -1H-hexahydro by the step of forming a salt of the compound of formula (I), in particular the reaction of the compound of formula (I) with an acid, in particular hydrochloric acid. The method according to any one of claims 1 to 9, further comprising the step of forming a hydrochloride salt of a -1,4-diazepine compound. 組成物の総重量に対して０．００１重量％と０．５重量％の間のＭＬ７又はＭＬ９；
組成物の総重量に対して０．１重量％と１０重量％の間のシクロデキストリン；及び
組成物の総重量に対して０．０１重量％と０．５重量％の間の、ヒドロキシプロピルメチルセルロース、ヒドロキシエチルセルロース、ＰＶＰ又はＰＶＡ
を含む組成物。 ML7 or ML9 between 0.001% and 0.5% by weight relative to the total weight of the composition;
Between 0.1% and 10% by weight of cyclodextrin relative to the total weight of the composition; and between 0.01% and 0.5% by weight of hydroxypropyl methylcellulose relative to the total weight of the composition , Hydroxyethyl cellulose, PVP or PVA
A composition comprising
JP2016526659A 2013-07-18 2014-07-18 Process for producing 1- (5-halonaphthalene-1-sulfonyl) -1H-hexahydro-1,4-diazepine and composition containing the same Withdrawn JP2016525109A (en)

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JPS6317870A (en) * 1986-07-09 1988-01-25 Hokuriku Seiyaku Co Ltd Naphthalenesulfonamide derivative

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WO2004069181A2 (en) * 2003-02-03 2004-08-19 Pharmacia Corporation Composition for the treatment of intraocular pressure
WO2005102345A1 (en) * 2004-03-30 2005-11-03 Alcon, Inc. Use of rho kinase inhibitors in the treatment of hearing loss, tinnitus and improving body balance
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Title
G. SKOPP ET AL., ARCH. PHARM., vol. Vol. 317, JPN6018003673, 1984, pages p. 649-650 *

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