JP2009292771A

JP2009292771A - Orally applicable pharmaceutical composition containing hydrophilic surfactant

Info

Publication number: JP2009292771A
Application number: JP2008148009A
Authority: JP
Inventors: Tatsuya Nakai; 達也中井; Masa Hirano; 雅平野; Tetsuya Ishikawa; 哲也石川; Naohiro Ito; 尚浩伊東
Original assignee: Kowa Co Ltd
Current assignee: Kowa Co Ltd
Priority date: 2008-06-05
Filing date: 2008-06-05
Publication date: 2009-12-17

Abstract

<P>PROBLEM TO BE SOLVED: To provide an orally applicable pharmaceutical composition containing (+)-4-[[2-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethylamino]methyl]-N-isopropylaniline-1 fumaric acid salt having excellent absorbability. <P>SOLUTION: The orally applicable pharmaceutical composition contains a (+)-4-[[2-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethylamino]methyl]-N-isopropylaniline-1 fumaric acid salt or its solvate, and a hydrophilic surfactant. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

本発明は、アレルギー性鼻炎の治療及び／又は予防効果を有する（＋）−４−［［２−［６−フルオロ−３−（４−フルオロベンジル）−３，４−ジヒドロイソキノリン−２（１Ｈ）−イル］エチルアミノ］メチル］−Ｎ−イソプロピルアニリン・１フマル酸塩に親水性界面活性剤を配合した経口医薬組成物に関する。 The present invention relates to (+)-4-[[2- [6-fluoro-3- (4-fluorobenzyl) -3,4-dihydroisoquinoline-2 (1H) having therapeutic and / or preventive effects on allergic rhinitis. ) -Yl] ethylamino] methyl] -N-isopropylaniline monofumarate and an oral pharmaceutical composition comprising a hydrophilic surfactant.

バイオアベイラビリティー（以下、ＢＡという。）は、全身循環血中に到達する薬物の投与薬物に対する相対的な量とその速度を表す指標であり、薬効や毒性と密接に関連する臨床的に重要なパラメーターである。一般に、経口投与時のＢＡが低い薬物は、期待される薬効が得られなかったり、個体内および個体間変動が大きくなるため、薬効や毒性の予測、制御が困難になる。特に、用量−効果曲線がシャープであったり、安全域が狭い薬物では、血中薬物濃度の制御が困難となるため、開発にあたって、ＢＡを向上させる努力が必要となる。ＢＡは初回通過効果や消化管内における代謝安定性等の諸要因によってその大きさが決まるが、消化管からの薬物の吸収性を改善することにより、ＢＡが向上することが知られている。 Bioavailability (hereinafter referred to as BA) is an index representing the relative amount and rate of a drug that reaches the systemic circulation to the administered drug, and is clinically important that is closely related to drug efficacy and toxicity. It is a parameter. In general, a drug having a low BA at the time of oral administration cannot obtain the expected drug effect, and the intra-individual and inter-individual fluctuations are large, making it difficult to predict and control the drug effect and toxicity. In particular, a drug with a sharp dose-effect curve or a narrow safety range makes it difficult to control the blood drug concentration, and therefore, efforts to improve BA are required for development. The size of BA is determined by various factors such as the first-pass effect and metabolic stability in the gastrointestinal tract, but it is known that the BA is improved by improving the absorbability of the drug from the gastrointestinal tract.

薬物の吸収性改善のための方法として、界面活性剤を配合する方法が知られており、例えば、非晶質の難溶性薬物（ベンゾジアゼピン誘導体）に非イオン性界面活性剤（ポリオキシエチレン硬化ヒマシ油６０）及び高分子基剤（ヒドロキシプロピルメチルセルロース）を組み合わせた技術（特許文献１）、難溶性薬物（タクロリムス）に２種以上の界面活性（ポリオキシエチレン硬化ヒマシ油６０及びモノカプリル酸プロピレングリコール）を組み合わせた技術（特許文献２）、難溶性のプロピオン酸系ＮＳＡＩＤｓ（イブプロフェン）に水溶性高分子基剤（ヒドロキシプロピルメチルセルロース）及び非イオン性界面活性剤（ポリオキシエチレン硬化ヒマシ油６０）を組み合わせた技術（特許文献３）等が開示されている。
しかし、本発明記載のようなテトラヒドロイソキノリン骨格を有する化合物における吸収性の改善については、これまでに報告がない。
国際公開第９６／１９２３９号パンフレット国際公開第９８／４６２６８号パンフレット国際公開第００／０４８９６号パンフレット As a method for improving the absorption of a drug, a method of adding a surfactant is known. For example, a non-ionic surfactant (polyoxyethylene cured castor) is added to an amorphous poorly soluble drug (benzodiazepine derivative). Oil 60) and a polymer base (hydroxypropylmethylcellulose) in combination (Patent Document 1), a poorly soluble drug (tacrolimus), and two or more types of surface activity (polyoxyethylene hydrogenated castor oil 60 and propylene glycol monocaprylate) ), A combination of a poorly soluble propionic acid-based NSAIDs (ibuprofen), a water-soluble polymer base (hydroxypropylmethylcellulose) and a nonionic surfactant (polyoxyethylene hydrogenated castor oil 60) A combined technique (Patent Document 3) and the like are disclosed.
However, there has been no report on improvement in absorbability in a compound having a tetrahydroisoquinoline skeleton as described in the present invention.
International Publication No. 96/19239 Pamphlet International Publication No. 98/46268 Pamphlet International Publication No. 00/04896 Pamphlet

本発明は、アレルギー性鼻炎治療薬として有用な（＋）−４−［［２−［６−フルオロ−３−（４−フルオロベンジル）−３，４−ジヒドロイソキノリン−２（１Ｈ）−イル］エチルアミノ］メチル］−Ｎ−イソプロピルアニリン・１フマル酸塩を有効成分とする、吸収性の優れた経口医薬組成物を提供することを目的とする。 The present invention relates to (+)-4-[[2- [6-fluoro-3- (4-fluorobenzyl) -3,4-dihydroisoquinolin-2 (1H) -yl] useful as a therapeutic agent for allergic rhinitis. An object of the present invention is to provide an oral pharmaceutical composition excellent in absorbability comprising ethylamino] methyl] -N-isopropylaniline monofumarate as an active ingredient.

本発明者らは、新たなアレルギー性鼻炎治療薬の創製を目指して鋭意検討を行った結果、下式（１）に示す（＋）−４−［［２−［６−フルオロ−３−（４−フルオロベンジル）−３，４−ジヒドロイソキノリン−２（１Ｈ）−イル］エチルアミノ］メチル］−Ｎ−イソプロピルアニリン・１フマル酸塩（１）が、アレルギー性鼻炎における鼻づまり症状を改善する作用を有することを見出した。 As a result of intensive studies aiming at the creation of a new therapeutic agent for allergic rhinitis, the present inventors have shown (+)-4-[[2- [6-fluoro-3- ( 4-Fluorobenzyl) -3,4-dihydroisoquinolin-2 (1H) -yl] ethylamino] methyl] -N-isopropylaniline monofumarate (1) improves nasal congestion in allergic rhinitis It was found to have an action.

そして、さらに本発明者らは、上記化合物（１）を有効成分とする医薬組成物について種々検討を行ったところ、化合物（１）に親水性界面活性剤を配合することにより、消化管からの吸収性に優れた経口医薬組成物が得られることを見出し、本発明を完成した。 Further, the present inventors have conducted various studies on pharmaceutical compositions containing the compound (1) as an active ingredient. As a result, by incorporating a hydrophilic surfactant into the compound (1), It was found that an oral pharmaceutical composition excellent in absorbability was obtained, and the present invention was completed.

すなわち、本発明は、
［１］（＋）−４−［［２−［６−フルオロ−３−（４−フルオロベンジル）−３，４−ジヒドロイソキノリン−２（１Ｈ）−イル］エチルアミノ］メチル］−Ｎ−イソプロピルアニリン・１フマル酸塩又はその溶媒和物と、親水性界面活性剤を含有する経口医薬組成物、
［２］親水性界面活性剤がＨＬＢ値１０以上の非イオン性界面活性剤である前記［１］に記載の経口医薬組成物、
［３］親水性界面活性剤がポリオキシエチレン硬化ヒマシ油である前記［１］に記載の経口医薬組成物、
を提供するものである。 That is, the present invention
[1] (+)-4-[[2- [6-Fluoro-3- (4-fluorobenzyl) -3,4-dihydroisoquinolin-2 (1H) -yl] ethylamino] methyl] -N-isopropyl An oral pharmaceutical composition containing aniline monofumarate or a solvate thereof and a hydrophilic surfactant,
[2] The oral pharmaceutical composition according to the above [1], wherein the hydrophilic surfactant is a nonionic surfactant having an HLB value of 10 or more,
[3] The oral pharmaceutical composition according to the above [1], wherein the hydrophilic surfactant is polyoxyethylene hydrogenated castor oil,
Is to provide.

本発明によれば、（＋）−４−［［２−［６−フルオロ−３−（４−フルオロベンジル）−３，４−ジヒドロイソキノリン−２（１Ｈ）−イル］エチルアミノ］メチル］−Ｎ−イソプロピルアニリン・１フマル酸塩を含有する、消化管からの吸収性に優れ、高いＢＡを発揮する経口医薬組成物を提供することができる。また、当該化合物のＢＡが向上すれば、投与量を少なくすることができ、さらに安全性を確保することもできる。 According to the invention, (+)-4-[[2- [6-Fluoro-3- (4-fluorobenzyl) -3,4-dihydroisoquinolin-2 (1H) -yl] ethylamino] methyl]- An oral pharmaceutical composition containing N-isopropylaniline and 1 fumarate, excellent in absorbability from the digestive tract and exhibiting high BA can be provided. In addition, if the BA of the compound is improved, the dose can be reduced and further safety can be ensured.

本発明の（＋）−４−［［２−［６−フルオロ−３−（４−フルオロベンジル）−３，４−ジヒドロイソキノリン−２（１Ｈ）−イル］エチルアミノ］メチル］−Ｎ−イソプロピルアニリン（１’）及びそのフマル酸塩（１）は、例えば、後記実施例に示すように下記工程に従い製造することができる。なお、反応工程図中の＊印は不斉炭素を示す。 (+)-4-[[2- [6-Fluoro-3- (4-fluorobenzyl) -3,4-dihydroisoquinolin-2 (1H) -yl] ethylamino] methyl] -N-isopropyl of the present invention Aniline (1 ′) and its fumarate salt (1) can be produced, for example, according to the following steps as shown in Examples below. In addition, * mark in a reaction process figure shows asymmetric carbon.

すなわち、反応工程Ａにより得られる化合物（２）と、反応工程Ｂにより得られる化合物（３）とを反応させて化合物（４）を得、これを還元し、次いでイソプロピル化した後、還元することにより、（＋）−４−［［２−［６−フルオロ−３−（４−フルオロベンジル）−３，４−ジヒドロイソキノリン−２（１Ｈ）−イル］エチルアミノ］メチル］−Ｎ−イソプロピルアニリン（１’）が得られ、さらに、後記実施例のごとく化合物（１’）にフマル酸を作用させることでフマル酸塩（１）が得られる。 That is, the compound (2) obtained by the reaction step A and the compound (3) obtained by the reaction step B are reacted to obtain a compound (4), which is reduced, then isopropylated and then reduced. (+)-4-[[2- [6-Fluoro-3- (4-fluorobenzyl) -3,4-dihydroisoquinolin-2 (1H) -yl] ethylamino] methyl] -N-isopropylaniline (1 ') is obtained, and further, the fumaric acid salt (1) is obtained by allowing fumaric acid to act on the compound (1') as in Examples described later.

また、本発明の化合物（１）は、水和物に代表される溶媒和物としても使用することができる。 Moreover, the compound (1) of this invention can be used also as a solvate represented by the hydrate.

本発明で使用する親水性界面活性剤としては、例えば、ジＰＯＥ（１０）ラウリルエーテルリン酸ナトリウム、ジＰＯＥ（８）オレイルエーテルリン酸ナトリウム、ジＰＯＥ（４）（Ｃ１２−１５）アルキルエーテルリン酸、ジＰＯＥ（６）（Ｃ１２−１５）アルキルエーテルリン酸、ジＰＯＥ（８）（Ｃ１２−１５）アルキルエーテルリン酸、ジＰＯＥ（１０）（Ｃ１２−１５）アルキルエーテルリン酸、トリＰＯＥ（４）ラウリルエーテルリン酸、トリＰＯＥ（５）セチルエーテルリン酸、トリＰＯＥ（８）（Ｃ１２−１５）アルキルエーテルリン酸、トリＰＯＥ（１０）（Ｃ１２−１５）アルキルエーテルリン酸等のポリオキシエチレンアルキルエーテルリン酸・リン酸塩；ＰＯＥ（５）ステアリルアミン、ＰＯＥ（１０）ステアリルアミン、ＰＯＥ（１５）ステアリルアミン、ＰＯＥ（５）オレイルアミン、ＰＯＥ（１５）オレイルアミン、ＰＯＥ（４）ステアリン酸アミド、ＰＯＥ（１５）ステアリン酸アミド、ＰＯＥ（５）オレイン酸アミド等のポリオキシエチレンアルキルアミン・脂肪酸アミド；モノラウリン酸ヘキサグリセリル、モノステアリン酸ヘキサグリセリル、モノオレイン酸ヘキサグリセリル、モノミリスチン酸ヘキサグリセリル、モノラウリン酸デカグリセリル、モノミリスチン酸デカグリセリル、モノステアリン酸デカグリセリル、モノイソステアリン酸デカグリセリル、モノオレイン酸デカグリセリル、モノリノール酸デカグリセリル、ジイソステアリン酸デカグリセリル、ジステアリン酸デカグリセリル等のポリグリセリン脂肪酸エステル；モノステアリン酸ＰＯＥ（５）グリセリル、モノステアリン酸ＰＯＥ（１５）グリセリル、モノオレイン酸ＰＯＥ（５）グリセリル、モノオレイン酸ＰＯＥ（１５）グリセリル等のポリオキシエチレングリセリン脂肪酸エステル；ポリソルベート４０、ポリソルベート６０、ポリソルベート６５、ポリソルベート８０、ポリソルベート８５、モノヤシ油脂肪酸ＰＯＥ（２０）ソルビタン、モノステアリン酸ＰＯＥ（６）ソルビタン、モノイソステアリン酸ＰＯＥ（２０）ソルビタン、モノオレイン酸ＰＯＥ（６）ソルビタン等のポリオキシエチレンソルビタン脂肪酸エステル；モノラウリン酸ＰＯＥ（６）ソルビット、テトラステアリン酸ＰＯＥ（６０）ソルビット、テトラオレイン酸ＰＯＥ（３０）ソルビット、テトラオレイン酸ＰＯＥ（４０）ソルビット、テトラオレイン酸ＰＯＥ（６０）ソルビット等のポリオキシエチレンソルビット脂肪酸エステル；ＰＥＧ−１０ラノリン、ＰＥＧ−２０ラノリン、ＰＥＧ−３０ラノリン、ＰＯＥ（５）ラノリンアルコール、ＰＯＥ（１０）ラノリンアルコール、ＰＯＥ（２０）ラノリンアルコール、ＰＯＥ（４０）ラノリンアルコール、ＰＯＥ（２０）ソルビットミツロウ等のポリオキシエチレンラノリン・ラノリンアルコール・ミツロウ誘導体；ＰＯＥ（２０）ヒマシ油、ＰＯＥ（４０）ヒマシ油、ＰＯＥ（５０）ヒマシ油、ＰＯＥ（６０）ヒマシ油、ＰＯＥ（２０）硬化ヒマシ油、ＰＯＥ（３０）硬化ヒマシ油、ＰＯＥ（４０）硬化ヒマシ油、ＰＯＥ（５０）硬化ヒマシ油、ＰＯＥ（６０）硬化ヒマシ油、ＰＯＥ（８０）硬化ヒマシ油、ＰＯＥ（１００）硬化ヒマシ油等のポリオキシエチレンヒマシ油・硬化ヒマシ油；ＰＯＥ（５）フィトステロール、ＰＯＥ（１０）フィトステロール、ＰＯＥ（２０）フィトステロール、ＰＯＥ（３０）フィトステロール、ＰＯＥ（２５）フィトスタノール、ＰＯＥ（３０）コレスタノール等のポリオキシエチレンステロール・水素添加ステロール；ＰＯＥ（２）ラウリルエーテル、ＰＯＥ（４．２）ラウリルエーテル、ＰＯＥ（９）ラウリルエーテル、ＰＯＥ（２１）ラウリルエーテル、ＰＯＥ（２５）ラウリルエーテル、ＰＯＥ（２）セチルエーテル、ＰＯＥ（５．５）セチルエーテル、ＰＯＥ（７）セチルエーテル、ＰＯＥ（１０）セチルエーテル、ＰＯＥ（１５）セチルエーテル、ＰＯＥ（２０）セチルエーテル、ＰＯＥ（２３）セチルエーテル、ＰＯＥ（２５）セチルエーテル、ＰＯＥ（３０）セチルエーテル、ＰＯＥ（４０）セチルエーテル、ＰＯＥ（４）ステアリルエーテル、ＰＯＥ（２０）ステアリルエーテル、ＰＯＥ（７）オレイルエーテル、ＰＯＥ（１０）オレイルエーテル、ＰＯＥ（１５）オレイルエーテル、ＰＯＥ（２０）オレイルエーテル、ＰＯＥ（５０）オレイルエーテル、ＰＯＥ（１０）ベヘニルエーテル、ＰＯＥ（２０）ベヘニルエーテル、ＰＯＥ（３０）ベヘニルエーテル、ＰＯＥ（２）（Ｃ１２−１５）アルキルエーテル、ＰＯＥ（４）（Ｃ１２−１５）アルキルエーテル、ＰＯＥ（１０）（Ｃ１２−１５）アルキルエーテル、ＰＯＥ（５）２級アルキルエーテル、ＰＯＥ（７）２級アルキルエーテル、ＰＯＥ（９）２級アルキルエーテル、ＰＯＥ（１２）２級アルキルエーテル等のポリオキシエチレンアルキルエーテル；ＰＯＥ（１）ＰＯＰ（４）セチルエーテル、ＰＯＥ（１）ＰＯＰ（８）セチルエーテル、ＰＯＥ（１０）ＰＯＰ（４）セチルエーテル、ＰＯＥ（２０）ＰＯＰ（４）セチルエーテル、ＰＯＥ（２０）ＰＯＰ（８）セチルエーテル、ＰＯＥ（２０）ＰＯＰ（６）デシルテトラデシルエーテル、ＰＯＥ（３０）ＰＯＰ（６）デシルテトラデシルエーテル等のポリオキシエチレンポリオキシプロピレンアルキルエーテル；モノラウリン酸ポリエチレングリコール（１０Ｅ．Ｏ．）、モノステアリン酸ポリエチレングリコール（１０Ｅ．Ｏ．）、モノステアリン酸ポリエチレングリコール（２５Ｅ．Ｏ．）、モノステアリン酸ポリエチレングリコール（４０Ｅ．Ｏ．）、モノステアリン酸ポリエチレングリコール（４５Ｅ．Ｏ．）、モノステアリン酸ポリエチレングリコール（５５Ｅ．Ｏ．）、モノオレイン酸ポリエチレングリコール（１０Ｅ．Ｏ．）、ジステアリン酸ＰＥＧ−８、ジステアリン酸ＰＥＧ−１５０等のポリオキシエチレン脂肪酸エステル等が挙げられる。これらは１種又は２種以上を組み合わせて用いることができる。 Examples of the hydrophilic surfactant used in the present invention include diPOE (10) sodium lauryl ether phosphate, diPOE (8) sodium oleyl ether phosphate, diPOE (4) (C12-15) alkyl ether phosphorus. Acid, di-POE (6) (C12-15) alkyl ether phosphoric acid, di-POE (8) (C12-15) alkyl ether phosphoric acid, di-POE (10) (C12-15) alkyl ether phosphoric acid, tri-POE ( 4) Polyoxy such as lauryl ether phosphoric acid, tri-POE (5) cetyl ether phosphoric acid, tri-POE (8) (C12-15) alkyl ether phosphoric acid, tri-POE (10) (C12-15) alkyl ether phosphoric acid Ethylene alkyl ether phosphate / phosphate; POE (5) stearylamine, POE (10) stearyl Polyoxyethylene alkyl such as min, POE (15) stearylamine, POE (5) oleylamine, POE (15) oleylamine, POE (4) stearamide, POE (15) stearamide, POE (5) oleamide Amines and fatty acid amides; hexaglyceryl monolaurate, hexaglyceryl monostearate, hexaglyceryl monooleate, hexaglyceryl monomyristate, decaglyceryl monolaurate, decaglyceryl monomyristate, decaglyceryl monostearate, decaglyceryl monoisostearate Monoglyceryl fatty acid esters such as decaglyceryl monooleate, decaglyceryl monolinoleate, decaglyceryl diisostearate, decaglyceryl distearate; mono Polyoxyethylene glycerin fatty acid esters such as POE (5) glyceryl thetearate, POE (15) glyceryl monostearate, POE (5) glyceryl monooleate, POE (15) glyceryl monooleate; polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, monococonut oil fatty acid POE (20) sorbitan, monostearic acid POE (6) sorbitan, monoisostearic acid POE (20) sorbitan, monooleic acid POE (6) sorbitan, polyoxyethylene sorbitan fatty acid Esters: monolauric acid POE (6) sorbite, tetrastearic acid POE (60) sorbite, tetraoleic acid POE (30) sorbite, tetraoleic acid POE (40) Polyoxyethylene sorbite fatty acid esters such as sorbit, tetraoleic acid POE (60) sorbit; PEG-10 lanolin, PEG-20 lanolin, PEG-30 lanolin, POE (5) lanolin alcohol, POE (10) lanolin alcohol, POE ( 20) polyoxyethylene lanolin, lanolin alcohol, beeswax derivatives such as lanolin alcohol, POE (40) lanolin alcohol, POE (20) sorbit beeswax; POE (20) castor oil, POE (40) castor oil, POE (50) castor Oil, POE (60) castor oil, POE (20) hydrogenated castor oil, POE (30) hydrogenated castor oil, POE (40) hydrogenated castor oil, POE (50) hydrogenated castor oil, POE (60) hydrogenated castor oil, POE (80) Hardened castor oil, P Polyoxyethylene castor oil / hardened castor oil such as E (100) hydrogenated castor oil; POE (5) phytosterol, POE (10) phytosterol, POE (20) phytosterol, POE (30) phytosterol, POE (25) phytostanol, Polyoxyethylene sterol / hydrogenated sterol such as POE (30) cholestanol; POE (2) lauryl ether, POE (4.2) lauryl ether, POE (9) lauryl ether, POE (21) lauryl ether, POE (25 ) Lauryl ether, POE (2) cetyl ether, POE (5.5) cetyl ether, POE (7) cetyl ether, POE (10) cetyl ether, POE (15) cetyl ether, POE (20) cetyl ether, POE ( 23) Seti Ether, POE (25) cetyl ether, POE (30) cetyl ether, POE (40) cetyl ether, POE (4) stearyl ether, POE (20) stearyl ether, POE (7) oleyl ether, POE (10) oleyl ether , POE (15) oleyl ether, POE (20) oleyl ether, POE (50) oleyl ether, POE (10) behenyl ether, POE (20) behenyl ether, POE (30) behenyl ether, POE (2) (C12- 15) Alkyl ether, POE (4) (C12-15) alkyl ether, POE (10) (C12-15) alkyl ether, POE (5) secondary alkyl ether, POE (7) secondary alkyl ether, POE (9 ) Secondary alkyl ether, PO E (12) Polyoxyethylene alkyl ethers such as secondary alkyl ethers; POE (1) POP (4) cetyl ether, POE (1) POP (8) cetyl ether, POE (10) POP (4) cetyl ether, POE (20) POP (4) cetyl ether, POE (20) POP (8) cetyl ether, POE (20) POP (6) decyl tetradecyl ether, POE (30) POP (6) decyl tetradecyl ether, etc. Ethylene polyoxypropylene alkyl ether; polyethylene glycol monolaurate (10E. O. ), Polyethylene glycol monostearate (10E.O.), polyethylene glycol monostearate (25E.O.), polyethylene glycol monostearate (40E.O.), polyethylene glycol monostearate (45E.O.), Examples thereof include polyoxyethylene fatty acid esters such as polyethylene glycol monostearate (55EO), polyethylene glycol monooleate (10EO), PEG-8 distearate, PEG-150 distearate, and the like. These can be used alone or in combination of two or more.

上記の親水性界面活性剤の中でも、化合物（１）のＢＡ向上の点から、親水性の非イオン性界面活性剤が好ましく、ＨＬＢ値１０以上の非イオン性界面活性剤がより好ましい。ここで、ＨＬＢとは親水親油バランス（ｈｙｄｒｏｐｈｉｌｅ−ｌｉｐｏｐｈｉｌｅｂａｌａｎｃｅ）の略称であり、界面活性剤が果たす効果を表す指標の一つとして知られ、ＨＬＢ値が大きいほど親水性が高くなる。本発明において、非イオン性界面活性剤のＨＬＢ値は１０〜２０が好ましく、さらに１１〜１８が好ましく、特に１２〜１６が好ましい。なお、ＨＬＢ値は以下の方法で求めることができる。
（ＨＬＢ値の測定法）
１．乳化剤の標準物質として、モノステアリン酸ソルビタン（ニッコールＳＳ−１０，ＨＬＢ値：４．７）とモノステアリン酸ポリオキシエチレンソルビタン（ニッコールＴＳ−１０、ＨＬＢ値：１４．９）を用いて、流動パラフィンを乳化する。なお、乳化の処方は流動パラフィンを４０質量％、水を５６質量％、乳化剤の全量を４質量％とする。乳化剤の全量を一定とし、２種の乳化剤の配合割合を０．１質量％ずつ変えて乳化する。
２．１で調製した乳化物を水で１質量％に希釈したものを共栓付き試験管に入れ、約３０分静置する。
３．外観評価から最も安定性の良い配合割合を見出し、以下の式より流動パラフィンの所要ＨＬＢ値を求める。

流動パラフィンの所要ＨＬＢ値＝（（ＴＳ−１０のＨＬＢ値×ＴＳ−１０の配合率）＋（ＳＳ−１０のＨＬＢ値×ＳＳ−１０の配合率））／１００
※）配合率：乳化剤全量を１００質量％とした場合の質量百分率

４．未知の乳化剤が親水性であればＳＳ−１０と、親油性であればＴＳ−１０と組み合わせて、乳化剤の全量を一定とし、２種の乳化剤の配合割合を０．１質量％ずつ変えて流動パラフィンを乳化する。処方は１と同様とする。
５．４で調製した乳化物を水で１質量％に希釈したものを共栓付き試験管に入れ、約３０分静置する。
６．外観評価から最も安定性の良い配合割合を見出し、以下の式より未知の乳化剤のＨＬＢ値を求める。

未知の乳化剤のＨＬＢ値＝（（流動パラフィンの所要ＨＬＢ値×１００）−（ＴＳ−１０またはＳＳ−１０のＨＬＢ値×ＴＳ−１０またはＳＳ−１０の配合率））／未知の乳化剤の配合率
※）配合率：乳化剤全量を１００質量％とした場合の質量百分率 Among the above hydrophilic surfactants, a hydrophilic nonionic surfactant is preferable from the viewpoint of improving the BA of the compound (1), and a nonionic surfactant having an HLB value of 10 or more is more preferable. Here, HLB is an abbreviation for hydrophile-lipophile balance, and is known as one of the indexes representing the effect of surfactants. The higher the HLB value, the higher the hydrophilicity. In the present invention, the HLB value of the nonionic surfactant is preferably 10 to 20, more preferably 11 to 18, and particularly preferably 12 to 16. The HLB value can be obtained by the following method.
(Measurement method of HLB value)
1. As a standard substance of the emulsifier, sorbitan monostearate (Nikkor SS-10, HLB value: 4.7) and polyoxyethylene sorbitan monostearate (Nikkor TS-10, HLB value: 14.9) Liquid paraffin is emulsified. The prescription for emulsification is 40% by mass of liquid paraffin, 56% by mass of water, and 4% by mass of the total amount of emulsifier. The emulsifier is emulsified with the total amount of the emulsifier being constant and the blending ratio of the two emulsifiers being changed by 0.1 mass%.
The emulsion prepared in 2.1, diluted to 1% by mass with water, is placed in a test tube with a stopper and allowed to stand for about 30 minutes.
3. The most stable blending ratio is found from the appearance evaluation, and the required HLB value of liquid paraffin is obtained from the following formula.

Required HLB value of liquid paraffin = ((HLB value of TS-10 × TS-10 blending ratio) + (SS-10 HLB value × SS-10 blending ratio)) / 100
*) Mixing ratio: Mass percentage when the total amount of emulsifier is 100% by mass

4). If the unknown emulsifier is hydrophilic, combine it with SS-10, and if it is oleophilic, TS-10, change the total amount of the emulsifier and change the blending ratio of the two emulsifiers by 0.1% by mass. Liquid paraffin is emulsified. The prescription is the same as in 1.
The emulsion prepared in 5.4 diluted to 1% by mass with water is placed in a test tube with a stopper and allowed to stand for about 30 minutes.
6). From the appearance evaluation, the most stable blending ratio is found, and the HL B value of the unknown emulsifier is obtained from the following formula.

HLB value of unknown emulsifier = ((required HLB value of liquid paraffin × 100) − (HLB value of TS-10 or SS-10 × mixing ratio of TS-10 or SS-10)) / mixing ratio of unknown emulsifier *) Mixing ratio: Mass percentage when the total amount of emulsifier is 100% by mass

ＨＬＢ値１０以上の非イオン性界面活性剤としては、例えば、モノラウリン酸ヘキサグリセリル、モノミリスチン酸ヘキサグリセリル、モノラウリン酸デカグリセリル、モノミリスチン酸デカグリセリル、モノステアリン酸デカグリセリル、モノイソステアリン酸デカグリセリル、モノオレイン酸デカグリセリル、モノリノール酸デカグリセリル、ジイソステアリン酸デカグリセリル等のポリグリセリン脂肪酸エステル；モノステアリン酸ＰＯＥ（１５）グリセリル、モノオレイン酸ＰＯＥ（１５）グリセリル等のポリオキシエチレングリセリン脂肪酸エステル；ポリソルベート４０、ポリソルベート６０、ポリソルベート６５、ポリソルベート８０、ポリソルベート８５、モノヤシ油脂肪酸ＰＯＥ（２０）ソルビタン、モノイソステアリン酸ＰＯＥ（２０）ソルビタン、モノオレイン酸ＰＯＥ（６）ソルビタン等のポリオキシエチレンソルビタン脂肪酸エステル；モノラウリン酸ＰＯＥ（６）ソルビット、テトラステアリン酸ＰＯＥ（６０）ソルビット、テトラオレイン酸ＰＯＥ（３０）ソルビット、テトラオレイン酸ＰＯＥ（４０）ソルビット、テトラオレイン酸ＰＯＥ（６０）ソルビット等のポリオキシエチレンソルビット脂肪酸エステル；ＰＥＧ−１０ラノリン、ＰＥＧ−２０ラノリン、ＰＥＧ−３０ラノリン、ＰＯＥ（５）ラノリンアルコール、ＰＯＥ（１０）ラノリンアルコール、ＰＯＥ（２０）ラノリンアルコール、ＰＯＥ（４０）ラノリンアルコール等のポリオキシエチレンラノリン・ラノリンアルコール；ＰＯＥ（２０）ヒマシ油、ＰＯＥ（４０）ヒマシ油、ＰＯＥ（５０）ヒマシ油、ＰＯＥ（６０）ヒマシ油、ＰＯＥ（２０）硬化ヒマシ油、ＰＯＥ（３０）硬化ヒマシ油、ＰＯＥ（４０）硬化ヒマシ油、ＰＯＥ（５０）硬化ヒマシ油、ＰＯＥ（６０）硬化ヒマシ油、ＰＯＥ（８０）硬化ヒマシ油、ＰＯＥ（１００）硬化ヒマシ油等のポリオキシエチレンヒマシ油・硬化ヒマシ油；ＰＯＥ（１０）フィトステロール、ＰＯＥ（２０）フィトステロール、ＰＯＥ（３０）フィトステロール、ＰＯＥ（２５）フィトスタノール、ＰＯＥ（３０）コレスタノール等のポリオキシエチレンステロール・水素添加ステロール；ＰＯＥ（４．２）ラウリルエーテル、ＰＯＥ（９）ラウリルエーテル、ＰＯＥ（２１）ラウリルエーテル、ＰＯＥ（２５）ラウリルエーテル、ＰＯＥ（５．５）セチルエーテル、ＰＯＥ（７）セチルエーテル、ＰＯＥ（１０）セチルエーテル、ＰＯＥ（１５）セチルエーテル、ＰＯＥ（２０）セチルエーテル、ＰＯＥ（２３）セチルエーテル、ＰＯＥ（２５）セチルエーテル、ＰＯＥ（３０）セチルエーテル、ＰＯＥ（４０）セチルエーテル、ＰＯＥ（２０）ステアリルエーテル、ＰＯＥ（７）オレイルエーテル、ＰＯＥ（１０）オレイルエーテル、ＰＯＥ（１５）オレイルエーテル、ＰＯＥ（２０）オレイルエーテル、ＰＯＥ（５０）オレイルエーテル、ＰＯＥ（１０）ベヘニルエーテル、ＰＯＥ（２０）ベヘニルエーテル、ＰＯＥ（３０）ベヘニルエーテル、ＰＯＥ（４）（Ｃ１２−１５）アルキルエーテル、ＰＯＥ（１０）（Ｃ１２−１５）アルキルエーテル、ＰＯＥ（５）２級アルキルエーテル、ＰＯＥ（７）２級アルキルエーテル、ＰＯＥ（９）２級アルキルエーテル、ＰＯＥ（１２）２級アルキルエーテル等のポリオキシエチレンアルキルエーテル；ＰＯＥ（１０）ＰＯＰ（４）セチルエーテル、ＰＯＥ（２０）ＰＯＰ（４）セチルエーテル、ＰＯＥ（２０）ＰＯＰ（８）セチルエーテル、ＰＯＥ（２０）ＰＯＰ（６）デシルテトラデシルエーテル、ＰＯＥ（３０）ＰＯＰ（６）デシルテトラデシルエーテル等のポリオキシエチレンポリオキシプロピレンアルキルエーテル；モノラウリン酸ポリエチレングリコール（１０Ｅ．Ｏ．）、モノステアリン酸ポリエチレングリコール（１０Ｅ．Ｏ．）、モノステアリン酸ポリエチレングリコール（２５Ｅ．Ｏ．）、モノステアリン酸ポリエチレングリコール（４０Ｅ．Ｏ．）、モノステアリン酸ポリエチレングリコール（４５Ｅ．Ｏ．）、モノステアリン酸ポリエチレングリコール（５５Ｅ．Ｏ．）、モノオレイン酸ポリエチレングリコール（１０Ｅ．Ｏ．）、ジステアリン酸ＰＥＧ−１５０等のポリオキシエチレン脂肪酸エステル等が挙げられる。
これらのなかで、ポリオキシエチレンヒマシ油・硬化ヒマシ油が好ましく、ポリオキシエチレン硬化ヒマシ油が特に好ましい。 Examples of the nonionic surfactant having an HLB value of 10 or more include hexaglyceryl monolaurate, hexaglyceryl monomyristate, decaglyceryl monolaurate, decaglyceryl monomyristate, decaglyceryl monostearate, decaglyceryl monoisostearate, Polyglycerin fatty acid esters such as decaglyceryl monooleate, decaglyceryl monolinoleate, decaglyceryl diisostearate; polyoxyethylene glycerin fatty acid esters such as POE (15) glyceryl monostearate and POE (15) glyceryl monooleate; polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, monococonut oil fatty acid POE (20) sorbitan, monoisostearin Polyoxyethylene sorbitan fatty acid esters such as POE (20) sorbitan, monooleic acid POE (6) sorbitan; monolauric acid POE (6) sorbitol, tetrastearic acid POE (60) sorbitol, tetraoleic acid POE (30) sorbitol, tetra Polyoxyethylene sorbite fatty acid esters such as oleic acid POE (40) sorbit, tetraoleic acid POE (60) sorbit; PEG-10 lanolin, PEG-20 lanolin, PEG-30 lanolin, POE (5) lanolin alcohol, POE (10 ) Polyoxyethylene lanolin / lanolin alcohol such as lanolin alcohol, POE (20) lanolin alcohol, POE (40) lanolin alcohol; POE (20) castor oil, POE (40) castor oil, P E (50) castor oil, POE (60) castor oil, POE (20) hydrogenated castor oil, POE (30) hydrogenated castor oil, POE (40) hydrogenated castor oil, POE (50) hydrogenated castor oil, POE (60) Hydrogenated castor oil, POE (80) hydrogenated castor oil, polyoxyethylene castor oil and hydrogenated castor oil such as POE (100) hydrogenated castor oil; POE (10) phytosterol, POE (20) phytosterol, POE (30) phytosterol, POE (25) Polyoxyethylene sterol / hydrogenated sterol such as phytostanol, POE (30) cholestanol; POE (4.2) lauryl ether, POE (9) lauryl ether, POE (21) lauryl ether, POE (25) Lauryl ether, POE (5.5) cetyl ether, POE (7 ) Cetyl ether, POE (10) cetyl ether, POE (15) cetyl ether, POE (20) cetyl ether, POE (23) cetyl ether, POE (25) cetyl ether, POE (30) cetyl ether, POE (40) Cetyl ether, POE (20) stearyl ether, POE (7) oleyl ether, POE (10) oleyl ether, POE (15) oleyl ether, POE (20) oleyl ether, POE (50) oleyl ether, POE (10) behenyl Ether, POE (20) behenyl ether, POE (30) behenyl ether, POE (4) (C12-15) alkyl ether, POE (10) (C12-15) alkyl ether, POE (5) secondary alkyl ether, POE (7) 2nd class Archi Polyoxyethylene alkyl ethers such as ether, POE (9) secondary alkyl ether, POE (12) secondary alkyl ether; POE (10) POP (4) cetyl ether, POE (20) POP (4) cetyl ether, POE (20) Polyoxyethylene polyoxypropylene alkyl ethers such as POP (8) cetyl ether, POE (20) POP (6) decyl tetradecyl ether, POE (30) POP (6) decyl tetradecyl ether; polyethylene glycol monolaurate (10E. O. ), Polyethylene glycol monostearate (10E.O.), polyethylene glycol monostearate (25E.O.), polyethylene glycol monostearate (40E.O.), polyethylene glycol monostearate (45E.O.), Examples thereof include polyoxyethylene fatty acid esters such as polyethylene glycol monostearate (55EO), polyethylene glycol monooleate (10EO), and PEG-150 distearate.
Among these, polyoxyethylene castor oil / hardened castor oil is preferable, and polyoxyethylene hydrogenated castor oil is particularly preferable.

ポリオキシエチレン硬化ヒマシ油としては、ニッコールＨＣＯ−２０、ニッコールＨＣＯ−３０、ニッコールＨＣＯ−４０、ニッコールＨＣＯ−５０、ニッコールＨＣＯ−６０、ニッコールＨＣＯ−８０、ニッコールＨＣＯ−１００（日光ケミカルズ製）、ユニオックス、ユニオックスＨＣ−２０、ユニオックスＨＣ−４０、ユニオックスＨＣ−５０、ユニオックスＨＣ−６０、ユニオックスＨＣ−１００（日本油脂製）等が市販品として入手することができる。 As the polyoxyethylene hydrogenated castor oil, Nikkor HCO-20, Nikkor HCO-30, Nikkor HCO-40, Nikkor HCO-50, Nikkor HCO-60, Nikkor HCO-80, Nikkor HCO-100 (manufactured by Nikko Chemicals), Unico Ox, UNIOX HC-20, UNIOX HC-40, UNIOX HC-50, UNIOX HC-60, UNIOX HC-100 (manufactured by NOF Corporation) and the like are commercially available.

本発明の経口医薬組成物において、上記化合物（１）と親水性界面活性剤の質量比は、化合物（１）のＢＡ向上の点から１：１００〜１００：１が好ましく、１：５０〜５０：１がより好ましく、１：２０〜２０：１が特に好ましい。 In the oral pharmaceutical composition of the present invention, the mass ratio of the compound (1) to the hydrophilic surfactant is preferably 1: 100 to 100: 1, and preferably 1:50 to 50 from the viewpoint of improving the BA of the compound (1). : 1 is more preferable, and 1:20 to 20: 1 is particularly preferable.

本発明の経口医薬組成物には、本発明の効果を損なわない範囲で、通常、医薬組成物に使用される他の任意成分を加えることができる。このような任意成分としては、結晶セルロース、白糖、乳糖、マンニトール、軽質無水ケイ酸、リン酸水素カルシウム等の賦形剤、ヒドロキシプロピルメチルセルロース、メチルセルロース、ヒドロキシプロピルセルロース、ゼラチン、ポリビニルピロリドン、プルラン等の結合剤、クロスカルメロースナトリウム、クロスポビドン等の崩壊剤、ステアリン酸マグネシウム、タルク等の滑沢剤、タール色素、三二酸化鉄等の着色剤、アスパルテーム、ステビア等の矯味剤等が挙げられる。 To the oral pharmaceutical composition of the present invention, other optional components usually used in pharmaceutical compositions can be added within a range not impairing the effects of the present invention. Such optional components include crystalline cellulose, sucrose, lactose, mannitol, light anhydrous silicic acid, calcium hydrogen phosphate and other excipients, hydroxypropyl methylcellulose, methylcellulose, hydroxypropylcellulose, gelatin, polyvinylpyrrolidone, pullulan and the like. Examples include binders, disintegrants such as croscarmellose sodium and crospovidone, lubricants such as magnesium stearate and talc, colorants such as tar dyes and iron sesquioxide, and flavoring agents such as aspartame and stevia.

本発明の医薬組成物の形態は、経口医薬組成物であれば特に限定されるものではないが、カプセル剤、錠剤、顆粒剤、細粒剤等の経口固形医薬組成物が好ましい。 Although the form of the pharmaceutical composition of this invention will not be specifically limited if it is an oral pharmaceutical composition, Oral solid pharmaceutical compositions, such as a capsule, a tablet, a granule, a fine granule, are preferable.

上記化合物（１）の投与量は、ヒトの場合、成人１日当り通常０．１〜１０００ｍｇ、好ましくは、１〜３００ｍｇの範囲内で、１日量を１日１回又は数回に分けて経口投与するのが好ましい。 In the case of humans, the dose of the above compound (1) is usually 0.1 to 1000 mg per day for an adult, preferably 1 to 300 mg, and the daily dose is orally divided into once or several times a day. Administration is preferred.

次に実施例を挙げて本発明を具体的に説明するが、本発明は何らこれらによって限定されるものではない。 EXAMPLES Next, the present invention will be specifically described with reference to examples, but the present invention is not limited to these examples.

［製造例］（＋）−４−［［２−［６−フルオロ−３−（４−フルオロベンジル）−３，４−ジヒドロイソキノリン−２（１Ｈ）−イル］エチルアミノ］メチル］−Ｎ−イソプロピルアニリン・１フマル酸塩の製造
a）４−メチルフェニル[１−（メチルチオ）−２−（３−フルオロフェニル）エチル]スルホンの製造 [Production Example] (+)-4-[[2- [6-Fluoro-3- (4-fluorobenzyl) -3,4-dihydroisoquinolin-2 (1H) -yl] ethylamino] methyl] -N- Production of isopropylaniline monofumarate
a) Preparation of 4-methylphenyl [1- (methylthio) -2- (3-fluorophenyl) ethyl] sulfone

メチルチオメチルｐ−トリルスルホン３５０ｇをトルエン５００ｍＬに溶解し、室温下攪拌した。これに３−フルオロベンジルブロマイド３５２ｇ、トリオクチルメチルアンモニウムクロライド２６ｇを順次加えた。次いで５０％水酸化ナトリウム水溶液５００ｇを加え、室温下二日攪拌を続けた。
反応終了後、反応液に水５００ｍＬを加え、有機層を分離した。更に酢酸エチルで抽出し、有機層を併せ、１Ｎ塩酸水、飽和食塩水で順次洗浄した。有機層を無水硫酸ナトリウムで乾燥後溶媒を留去し、黄白色固体の粗生成物７３２ｇを得た。
得られた粗生成物をジエチルエーテル：ヘキサン＝１：４混合溶液５００ｍＬで攪拌し縣濁液を濾取、ヘキサンで洗浄し表題化合物４２９ｇ（収率８２％）を淡黄色固体として得た。
¹H-NMR (CDCl₃)δ：2.14 (3H, s), 2.48 (3H, s), 2.63 (1H, dd, J = 11.7, 14.4 Hz), 3.59 (1H, dd, J = 2.8, 14.4 Hz), 3.84 (1H, dd, J = 2.8, 11.7 Hz), 6.88-6.99 (3H, m), 7.23-7.30 (1H, m), 7.39 (2H, d, J = 8.1 Hz), 7.88 (2H, d, J = 8.1 Hz).
元素分析（C₁₆H₁₇O₂S₂F）
理論値 C, 59.23; H, 5.28; F, 5.86
実測値 C, 59.42; H, 5.31; F, 5.69 350 g of methylthiomethyl p-tolylsulfone was dissolved in 500 mL of toluene and stirred at room temperature. To this, 352 g of 3-fluorobenzyl bromide and 26 g of trioctylmethylammonium chloride were sequentially added. Next, 500 g of a 50% aqueous sodium hydroxide solution was added, and stirring was continued at room temperature for 2 days.
After completion of the reaction, 500 mL of water was added to the reaction solution, and the organic layer was separated. The mixture was further extracted with ethyl acetate, and the organic layers were combined and washed successively with 1N hydrochloric acid and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off to obtain 732 g of a crude product as a yellowish white solid.
The obtained crude product was stirred with 500 mL of a mixed solution of diethyl ether: hexane = 1: 4, and the suspension was collected by filtration and washed with hexane to obtain 429 g (yield 82%) of the title compound as a pale yellow solid.
¹ H-NMR (CDCl ₃ ) δ: 2.14 (3H, s), 2.48 (3H, s), 2.63 (1H, dd, J = 11.7, 14.4 Hz), 3.59 (1H, dd, J = 2.8, 14.4 Hz ), 3.84 (1H, dd, J = 2.8, 11.7 Hz), 6.88-6.99 (3H, m), 7.23-7.30 (1H, m), 7.39 (2H, d, J = 8.1 Hz), 7.88 (2H, d, J = 8.1 Hz).
Elemental analysis (C ₁₆ H ₁₇ O ₂ S ₂ F)
Theoretical C, 59.23; H, 5.28; F, 5.86
Found C, 59.42; H, 5.31; F, 5.69

b)４−メチルフェニル[１−（４−フルオロベンジル）−１−（メチルチオ）−２−（３−フルオロフェニル）エチル]スルホンの製造 b) Preparation of 4-methylphenyl [1- (4-fluorobenzyl) -1- (methylthio) -2- (3-fluorophenyl) ethyl] sulfone

４−メチルフェニル[１−（メチルチオ）−２−（３−フルオロフェニル）エチル]スルホン４００gを無水テトラヒドロフラン（以下、「ＴＨＦ」と称す）１．２Ｌに溶解し、アルゴン雰囲気下、室温下攪拌した。反応液を−１０〜−１２℃まで冷却し、これにｎ−ブチルリチウム／ヘキサン溶液４０４ｍＬ（２．６２ｍｏｌ／Ｌ）を５０分かけてゆっくり加えた。次いで無水ＴＨＦ４００ｍＬに溶解した４−フルオロベンジルブロマイド２７９ｇを２０分かけてゆっくり加え、２時間攪拌を続けた。反応液を氷冷冷却に変更し２時間攪拌し、次いで室温下一晩攪拌を続けた。 400 g of 4-methylphenyl [1- (methylthio) -2- (3-fluorophenyl) ethyl] sulfone was dissolved in 1.2 L of anhydrous tetrahydrofuran (hereinafter referred to as “THF”) and stirred at room temperature under an argon atmosphere. . The reaction solution was cooled to −10 to −12 ° C., and 404 mL (2.62 mol / L) of an n-butyllithium / hexane solution was slowly added thereto over 50 minutes. Next, 279 g of 4-fluorobenzyl bromide dissolved in 400 mL of anhydrous THF was slowly added over 20 minutes, and stirring was continued for 2 hours. The reaction solution was changed to ice cooling and stirred for 2 hours, and then stirred at room temperature overnight.

反応終了後、反応液に水５００ｍＬを追加し、酢酸エチルで抽出した。有機層を飽和重曹水、１Ｎ塩酸水、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥後溶媒を留去し、黄色固化物５３２ｇを得た。
¹H-NMR (CDCl₃)δ：2.31 (3H, s), 2.46 (3H, s), 3.33 (1H, d, J = 15.1 Hz), 3.35 (1H, d, J = 15.1 Hz), 3.39 (1H, d, J = 15.1 Hz), 3.40 (1H, d, J = 15.1 Hz), 6.78-6.91 (5H, m), 7.02-7.08 (2H, m), 7.11 (1H, ddd, J = 6.1, 8.1, 8.3 Hz), 7.30 (2H, d, J = 8.2 Hz), 7.77 (2H, d, J = 8.2 Hz). After completion of the reaction, 500 mL of water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, 1N aqueous hydrochloric acid and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off to obtain 532 g of a yellow solid product.
¹ H-NMR (CDCl ₃ ) δ: 2.31 (3H, s), 2.46 (3H, s), 3.33 (1H, d, J = 15.1 Hz), 3.35 (1H, d, J = 15.1 Hz), 3.39 ( 1H, d, J = 15.1 Hz), 3.40 (1H, d, J = 15.1 Hz), 6.78-6.91 (5H, m), 7.02-7.08 (2H, m), 7.11 (1H, ddd, J = 6.1, 8.1, 8.3 Hz), 7.30 (2H, d, J = 8.2 Hz), 7.77 (2H, d, J = 8.2 Hz).

c)１−（３−フルオロフェニル）−３−（４−フルオロフェニル）−プロパン−２−オンの製造 c) Preparation of 1- (3-fluorophenyl) -3- (4-fluorophenyl) -propan-2-one

４−メチルフェニル[１−（４−フルオロベンジル）−１−（メチルチオ）−２−（３−フルオロフェニル）エチル]スルホン５３２ｇをメタノール５５０ｍＬに溶解し攪拌した。反応液に９Ｎ塩酸２７５ｍＬを加え、還流下、３時間攪拌を続けた。
反応終了後、反応液を減圧濃縮し、水５００ｍＬを追加し、クロロホルムで抽出した。有機層を水、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥後溶媒を留去し、黄色油状物４９５ｇを得た。
¹H-NMR (CDCl₃)δ：3.71 (2H, s), 3.72 (2H, s), 6.84-6.88 (1H, m), 6.91 (1H, d, J = 7.6 Hz), 6.95 (1H, dd, J = 2.4, 8.6 Hz), 7.01 (2H, ddd, J = 2.2, 6.4, 8.6 Hz), 7.09-7.13 (2H, m), 7.26-7.31 (1H, m). 532 g of 4-methylphenyl [1- (4-fluorobenzyl) -1- (methylthio) -2- (3-fluorophenyl) ethyl] sulfone was dissolved in 550 mL of methanol and stirred. 275 mL of 9N hydrochloric acid was added to the reaction solution, and stirring was continued for 3 hours under reflux.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, 500 mL of water was added, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off to obtain 495 g of a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 3.71 (2H, s), 3.72 (2H, s), 6.84-6.88 (1H, m), 6.91 (1H, d, J = 7.6 Hz), 6.95 (1H, dd , J = 2.4, 8.6 Hz), 7.01 (2H, ddd, J = 2.2, 6.4, 8.6 Hz), 7.09-7.13 (2H, m), 7.26-7.31 (1H, m).

d)１−（３−フルオロフェニル）−３−（４−フルオロフェニル）−プロパン−２−アミンの製造 d) Preparation of 1- (3-fluorophenyl) -3- (4-fluorophenyl) -propane-2-amine

１−（３−フルオロフェニル）−３−（４−フルオロフェニル）−プロパン−２−オン４９０ｇと酢酸アンモニウム７６４ｇにメタノール２．６Ｌを加え溶解した。次いで反応液にシアノトリヒドロホウ酸ナトリウム８５ｇを加え、還流下３０分攪拌した。
反応終了後、反応液を室温まで冷却し飽和重曹水２００ｍＬをゆっくり加えた。その後、減圧濃縮し、残渣に水酸化ナトリウム水を加えクロロホルムで抽出した。有機層を水酸化ナトリウム水、飽和食塩水で洗い、無水硫酸ナトリウムで乾燥後溶媒を留去し、４８４ｇの橙色油状物を得た。
この粗生成物をメタノールに溶解し、フマル酸１４３ｇを加え加熱溶解した。その後、室温下、ジエチルエーテルを加え室温下攪拌しながら結晶を析出させた。得られた結晶を濾取し、ヘキサンで洗浄し１フマル酸塩の粗結晶３２０ｇを得た。
粗結晶を再度メタノールに加温して溶解し、室温下ジエチルエーテルを加え一晩攪拌して結晶を析出させた。得られた結晶を濾取し、ヘキサンで洗浄し１フマル酸塩を微黄色固体として得た。この固体をクロロホルムに溶解し、水酸化ナトリウム水で洗浄した。水層を再度クロロホルムで抽出し、有機層を水酸化ナトリウム水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後溶媒を留去し、目的物２２６ｇ（３工程、収率７４％）を黄色油状物として得た。
１フマル酸塩
¹H-NMR (DMSO-d₆)δ：3.10-3.70 (4H, m), 3.64 (1H, m), 6.57 (2H, s), 7.03-7.18 (6H, m), 7.24-7.36 (2H, m).
元素分析（C₁₉H₁₉ N₁O₄F₂）
理論値 C, 62.80; H, 5.27; N, 3.85; F, 10.46
実測値 C, 62.84; H, 5.31; N, 3.83; F, 10.73
遊離塩基
¹H-NMR (CDCl₃)δ：2.64 (1H, dd, J = 4.2, 8.1 Hz), 2.67(1H, dd, J = 3.9, 8.1 Hz), 2.76-2.85 (2H, m), 3.24-3.32 (1H, m), 3.38-3.52 (2H, br), 6.87-7.01 (4H, m), 7.12-7.16 (2H, m), 7.23-7.28 (2H, m). 2.6 L of methanol was dissolved in 490 g of 1- (3-fluorophenyl) -3- (4-fluorophenyl) -propan-2-one and 764 g of ammonium acetate. Next, 85 g of sodium cyanotrihydroborate was added to the reaction solution, and the mixture was stirred for 30 minutes under reflux.
After completion of the reaction, the reaction solution was cooled to room temperature and 200 mL of saturated aqueous sodium bicarbonate was slowly added. Thereafter, the mixture was concentrated under reduced pressure, aqueous sodium hydroxide was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with aqueous sodium hydroxide and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain 484 g of an orange oil.
This crude product was dissolved in methanol, and 143 g of fumaric acid was added and dissolved by heating. Thereafter, diethyl ether was added at room temperature, and crystals were precipitated while stirring at room temperature. The obtained crystals were collected by filtration and washed with hexane to obtain 320 g of 1 fumarate crude crystals.
The crude crystals were dissolved again by heating in methanol, and diethyl ether was added at room temperature and stirred overnight to precipitate crystals. The obtained crystals were collected by filtration and washed with hexane to obtain the 1 fumarate salt as a slightly yellow solid. This solid was dissolved in chloroform and washed with aqueous sodium hydroxide. The aqueous layer was extracted again with chloroform, the organic layer was washed with aqueous sodium hydroxide and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The target product (226 g, 3 steps, yield 74%) was yellow. Obtained as an oil.
1 fumarate
¹ H-NMR (DMSO-d ₆ ) δ: 3.10-3.70 (4H, m), 3.64 (1H, m), 6.57 (2H, s), 7.03-7.18 (6H, m), 7.24-7.36 (2H, m).
Elemental analysis (C ₁₉ H ₁₉ N ₁ O ₄ F ₂ )
Theoretical C, 62.80; H, 5.27; N, 3.85; F, 10.46
Found C, 62.84; H, 5.31; N, 3.83; F, 10.73
Free base
¹ H-NMR (CDCl ₃ ) δ: 2.64 (1H, dd, J = 4.2, 8.1 Hz), 2.67 (1H, dd, J = 3.9, 8.1 Hz), 2.76-2.85 (2H, m), 3.24-3.32 (1H, m), 3.38-3.52 (2H, br), 6.87-7.01 (4H, m), 7.12-7.16 (2H, m), 7.23-7.28 (2H, m).

e)６−フルオロ−３−（４−フルオロベンジル）−１,２,３,４−テトラヒドロイソキノリンの製造 e) Preparation of 6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline

１−（３−フルオロフェニル）−３−（４−フルオロフェニル）−プロパン−２−アミン８４ｇをトリフルオロ酢酸６７２ｍＬに溶解し、ホルムアルデヒド水溶液５３．９ｇを加え、７０℃で１２時間攪拌した。反応液を減圧濃縮し、残渣を酢酸エチルに溶解し、飽和重曹水、飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後溶媒を留去し、８４ｇの粗生成物を黄色油状物として得た。
¹H-NMR (CDCl₃)δ：2.80 (1H, dd, J = 4.2, 16.8 Hz), 2.92 (1H, dd, J = 10.0, 16.8 Hz), 2.95 (1H, dd, J = 9.2, 13.2 Hz), 3.33 (1H, dd, J = 5.1, 13.2 Hz), 3.34-3.44 (1H, m), 4.19 (1H, m), 4.31 (1H, m), 6.76 (1H, dd, J = 2.4, 9.3 Hz), 6.88 (1H, ddd, J = 2.4, 8.5, 8.5 Hz), 6.98-7.07 (3H, m), 7.18-7.24 (2H, m). 84 g of 1- (3-fluorophenyl) -3- (4-fluorophenyl) -propan-2-amine was dissolved in 672 mL of trifluoroacetic acid, 53.9 g of an aqueous formaldehyde solution was added, and the mixture was stirred at 70 ° C. for 12 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off to obtain 84 g of a crude product as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 2.80 (1H, dd, J = 4.2, 16.8 Hz), 2.92 (1H, dd, J = 10.0, 16.8 Hz), 2.95 (1H, dd, J = 9.2, 13.2 Hz ), 3.33 (1H, dd, J = 5.1, 13.2 Hz), 3.34-3.44 (1H, m), 4.19 (1H, m), 4.31 (1H, m), 6.76 (1H, dd, J = 2.4, 9.3 Hz), 6.88 (1H, ddd, J = 2.4, 8.5, 8.5 Hz), 6.98-7.07 (3H, m), 7.18-7.24 (2H, m).

f)（−）−６−フルオロ−３−（４−フルオロベンジル）−１,２,３,４−テトラヒドロイソキノリンの製造 f) Preparation of (−)-6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline

６−フルオロ−３−（４−フルオロベンジル）−１,２,３,４−テトラヒドロイソキノリンの粗生成物１２ｇとＬ−ジベンゾイル酒石酸１８．３ｇをエタノール：水＝９：１の混合溶液２４０ｍＬに溶解し、７０℃で２０時間攪拌した。更に５５℃で２時間、４０℃で２時間攪拌し、次いで室温で１時間３０分攪拌した。析出物を濾取し、エタノール：水＝９：１の混合溶液５０ｍＬで洗浄し（−）−６−フルオロ−３−（４−フルオロベンジル）−１,２,３,４−テトラヒドロイソキノリンのＬ−ジベンゾイル酒石酸塩８．９ｇ（収率３０％）を得た。得られた塩をＨＰＬＣ分析（カラム：ＣｈｉｒａｌｐａｋＡＤダイセル化学工業株式会社製, １０μｍ, ４．６×２５０ｍｍ, カラム温度４０℃, 移動相；メタノール：ジエチルアミン＝１０００：１,０．９ｍＬ／分, 検出：ＵＶ２６８ｎｍ）した結果、光学純度は９８．８％ｅｅであった［保持時間：（−）体４．６分, （＋）体５．３分］。
Ｌ−ジベンゾイル酒石酸塩
¹H-NMR (DMSO-d₆)δ：2.70-2.84 (3H, m), 3.06 (1H, dd, J = 4.2, 12.0 Hz), 3.55-3.66 (1H, m), 4.16 (1H, d, J = 16.1 Hz), 4.23 (1H, d, J = 16.1 Hz), 5.67 (2H, brs), 6.98-7.04 (2H, m), 7.12-7.24 (3H, m), 7.306.76 (1H, dd, J = 2.4, 9.3 Hz), 6.88 (1H, ddd, J = 2.4, 8.5, 8.5 Hz), 6.98-7.07 (3H, m), 7.18-7.24 (2H, m).
元素分析（C₃₄H₂₉ N₁O₈F₂）
理論値 C, 66.12; H, 4.73; N, 2.27; F, 6.15.
実測値 C, 66.20; H, 4.78; N, 2.32; F, 6.13. 12 g of a crude product of 6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline and 18.3 g of L-dibenzoyltartaric acid are dissolved in 240 mL of a mixed solution of ethanol: water = 9: 1. And stirred at 70 ° C. for 20 hours. The mixture was further stirred at 55 ° C. for 2 hours and at 40 ° C. for 2 hours, and then stirred at room temperature for 1 hour and 30 minutes. The precipitate was collected by filtration, washed with 50 mL of a mixed solution of ethanol: water = 9: 1, and (-)-6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline L -8.9 g (yield 30%) of dibenzoyl tartrate was obtained. HPLC analysis (column: Chiralpak AD, manufactured by Daicel Chemical Industries, 10 μm, 4.6 × 250 mm, column temperature 40 ° C., mobile phase; methanol: diethylamine = 1000: 1, 0.9 mL / min, detection : UV 268 nm), as a result, the optical purity was 98.8% ee [retention time: (−) body 4.6 minutes, (+) body 5.3 minutes].
L-Dibenzoyl tartrate
¹ H-NMR (DMSO-d ₆ ) δ: 2.70-2.84 (3H, m), 3.06 (1H, dd, J = 4.2, 12.0 Hz), 3.55-3.66 (1H, m), 4.16 (1H, d, J = 16.1 Hz), 4.23 (1H, d, J = 16.1 Hz), 5.67 (2H, brs), 6.98-7.04 (2H, m), 7.12-7.24 (3H, m), 7.306.76 (1H, dd , J = 2.4, 9.3 Hz), 6.88 (1H, ddd, J = 2.4, 8.5, 8.5 Hz), 6.98-7.07 (3H, m), 7.18-7.24 (2H, m).
Elemental analysis (C ₃₄ H ₂₉ N ₁ O ₈ F ₂ )
Theoretical C, 66.12; H, 4.73; N, 2.27; F, 6.15.
Found C, 66.20; H, 4.78; N, 2.32; F, 6.13.

上記得られた（−）−６−フルオロ−３−（４−フルオロベンジル）−１,２,３,４−テトラヒドロイソキノリンのＬ−ジベンゾイル酒石酸塩は水酸化ナトリウム水で中和後、酢酸エチル抽出し、更に飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥後、溶媒を留去し、（−）−６−フルオロ−３−（４−フルオロベンジル）−１,２,３,４−テトラヒドロイソキノリンを無色固化物として定量的に回収した。
遊離塩基
¹H-NMR (CDCl₃)δ：2.80 (1H, dd, J = 4.2, 16.8 Hz), 2.92 (1H, dd, J = 10.0, 16.8 Hz), 2.95 (1H, dd, J = 9.2, 13.2 Hz), 3.33 (1H, dd, J = 5.1, 13.2 Hz),3.34-3.44 (1H, m), 4.19 (1H, m), 4.31 (1H, m), 6.76 (1H, dd, J = 2.4, 9.3 Hz), 6.88 (1H, ddd, J = 2.4, 8.5, 8.5 Hz), 6.98-7.07 (3H, m), 7.18-7.24 (2H, m).
[α]²⁷ _D-70°（c 1.0, MeOH） The obtained L-dibenzoyl tartrate of (−)-6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline was neutralized with aqueous sodium hydroxide and extracted with ethyl acetate. And further washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and (-)-6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline was quantitatively determined as a colorless solid. Recovered.
Free base
¹ H-NMR (CDCl ₃ ) δ: 2.80 (1H, dd, J = 4.2, 16.8 Hz), 2.92 (1H, dd, J = 10.0, 16.8 Hz), 2.95 (1H, dd, J = 9.2, 13.2 Hz ), 3.33 (1H, dd, J = 5.1, 13.2 Hz), 3.34-3.44 (1H, m), 4.19 (1H, m), 4.31 (1H, m), 6.76 (1H, dd, J = 2.4, 9.3 Hz), 6.88 (1H, ddd, J = 2.4, 8.5, 8.5 Hz), 6.98-7.07 (3H, m), 7.18-7.24 (2H, m).
[α] ²⁷ _D -70 ° (c 1.0, MeOH)

g)Ｎ−（４−ニトロベンジル）−２−ブロモアセトアミドの製造 g) Preparation of N- (4-nitrobenzyl) -2-bromoacetamide

４−ニトロベンジルアミン・１塩酸塩１０ｇをアセトニトリル５０ｍＬ中で攪拌した。反応液を氷冷冷却し、ジメチルアニリン１３．１ｇをゆっくり加えた。反応液にブロモアセチルブロマイド１２ｇをゆっくり加え、そのまま１５分攪拌を続けた。反応終了後、反応液に水を加え、酢酸エチルで抽出し、水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し減圧濃縮した。粗生成物を酢酸エチル−トルエン混合液より析出し濾取することで目的物１４．４ｇ（９９％）を微黄色固体として得た。
¹H-NMR (CDCl₃)δ：3.98 (2H, s), 4.59 (2H, d, J = 6.1 Hz), 6.94 (1H, brs), 7.46 (2H, d, J = 8.1 Hz), 8.21 (2H, d, J = 8.1 Hz). 10 g of 4-nitrobenzylamine monohydrochloride was stirred in 50 mL of acetonitrile. The reaction solution was cooled with ice and 13.1 g of dimethylaniline was slowly added. 12 g of bromoacetyl bromide was slowly added to the reaction solution, and stirring was continued for 15 minutes. After completion of the reaction, water was added to the reaction mixture, extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was precipitated from an ethyl acetate-toluene mixture and collected by filtration to obtain 14.4 g (99%) of the desired product as a slightly yellow solid.
¹ H-NMR (CDCl ₃ ) δ: 3.98 (2H, s), 4.59 (2H, d, J = 6.1 Hz), 6.94 (1H, brs), 7.46 (2H, d, J = 8.1 Hz), 8.21 ( (2H, d, J = 8.1 Hz).

h)Ｎ−（４−ニトロベンジル）−［６−フルオロ−３−（４−フルオロベンジル）−１,２,３,４−テトラヒドロイソキノリン−２（１Ｈ）−イル］アセトアミドの製造 h) Preparation of N- (4-nitrobenzyl)-[6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinolin-2 (1H) -yl] acetamide

６−フルオロ−３−（４−フルオロベンジル）−１,２,３,４−テトラヒドロイソキノリン６０．０ｇをアセトニトリル３６０ｍＬに溶解した。反応液に室温下、Ｎ−（４−ニトロベンジル）−２−ブロモアセトアミド６９．６ｇ、炭酸カリウム９５．７ｇを順次加え、６０℃にて一晩攪拌した。反応液を吸引ろ過し、濾液を減圧濃縮した。濃縮液を酢酸エチルに溶解し、水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を留去した。残渣を酢酸エチルに溶解し、氷冷下、４Ｎ塩酸／酢酸エチルを加え、室温で１時間攪拌した。反応液を減圧濃縮し、残渣に酢酸エチルを加えて加熱溶解し、室温下攪拌しながらヘキサンを加えた。析出物を濾取し、ヘキサン洗浄し目的物の塩酸塩を微黄色固体として１０５．８ｇ（収率９５％）得た。
得られた塩酸塩をクロロホルムに溶解し、飽和重曹水、飽和食塩水の順に洗浄し無水硫酸ナトリウムで乾燥後、溶媒を留去した。残渣にメタノールを加え溶解させ、ヘキサンを加え室温下２時間攪拌した。析出物を濾取、ヘキサン洗浄し目的物を微黄色固体として１００．９ｇ（収率８５％）得た。 60.0 g of 6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline was dissolved in 360 mL of acetonitrile. To the reaction solution, 69.6 g of N- (4-nitrobenzyl) -2-bromoacetamide and 95.7 g of potassium carbonate were sequentially added at room temperature, followed by stirring at 60 ° C. overnight. The reaction solution was suction filtered, and the filtrate was concentrated under reduced pressure. The concentrated solution was dissolved in ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dissolved in ethyl acetate, 4N hydrochloric acid / ethyl acetate was added under ice cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue and dissolved by heating, and hexane was added with stirring at room temperature. The precipitate was collected by filtration and washed with hexane to obtain 105.8 g (yield 95%) of the target hydrochloride as a slightly yellow solid.
The obtained hydrochloride was dissolved in chloroform, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. Methanol was added to the residue for dissolution, hexane was added, and the mixture was stirred at room temperature for 2 hours. The precipitate was collected by filtration and washed with hexane to obtain 100.9 g (yield 85%) of the target product as a slightly yellow solid.

遊離塩基
¹H-NMR (CDCl₃)δ：2.55 (1H, dd, J = 3.9, 16.4 Hz), 2.62 (1H, dd, J = 7.6, 13.2 Hz), 2.70-2.90 (2H, m), 3.20 (1H, d, J = 16.8 Hz), 3.22-3.28 (1H, m), 3.38 (1H, d, J = 16.8 Hz), 3.78 (1H, d, J = 16.4 Hz), 3.90 (1H, d, J = 16.4 Hz), 4.42 (1H, d, J = 7.2 Hz), 4.45 (1H, d, J = 7.2 Hz), 6.80 (1H, dd, J = 2.4, 9.5 Hz), 6.92 (1H, ddd, J = 2.4, 8.5, 8.5 Hz), 6.95-7.11 (4H, m), 7.35 (2H, dd, J = 1.9, 7.0 Hz), 7.40-7.46 (1H, m), 8.18 (2H, dd, J = 1.9, 7.0 Hz). Free base
¹ H-NMR (CDCl ₃ ) δ: 2.55 (1H, dd, J = 3.9, 16.4 Hz), 2.62 (1H, dd, J = 7.6, 13.2 Hz), 2.70-2.90 (2H, m), 3.20 (1H , d, J = 16.8 Hz), 3.22-3.28 (1H, m), 3.38 (1H, d, J = 16.8 Hz), 3.78 (1H, d, J = 16.4 Hz), 3.90 (1H, d, J = 16.4 Hz), 4.42 (1H, d, J = 7.2 Hz), 4.45 (1H, d, J = 7.2 Hz), 6.80 (1H, dd, J = 2.4, 9.5 Hz), 6.92 (1H, ddd, J = 2.4, 8.5, 8.5 Hz), 6.95-7.11 (4H, m), 7.35 (2H, dd, J = 1.9, 7.0 Hz), 7.40-7.46 (1H, m), 8.18 (2H, dd, J = 1.9, 7.0 Hz).

i)Ｎ−（４−アミノベンジル）−［６−フルオロ−３−（４−フルオロベンジル）−１,２,３,４−テトラヒドロイソキノリン−２（１Ｈ）−イル］アセトアミドの製造 i) Preparation of N- (4-aminobenzyl)-[6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinolin-2 (1H) -yl] acetamide

Ｎ−（４−ニトロベンジル）−［６−フルオロ−３−（４−フルオロベンジル）−１,２,３,４−テトラヒドロイソキノリン−２（１Ｈ）−イル］アセトアミド８７．５ｇをメタノールに縣濁し、１０％Ｐｄ−Ｃ（ｗｅｔ.）４．５ｇを加えた。反応系内を水素置換し、室温下２時間反応を続けた。反応終了後、反応液をセライトろ過し、濾液を濃縮し目的物を白色泡沫状固体として定量的に得た。
¹H-NMR (CDCl₃)δ： 2.52-2.54 (2H, m), 2.72-2.86 (2H, m), 3.13 (1H, d, J = 16.4 Hz), 3.13-3.22 (1H, m), 3.33 (1H, d, J = 16.4 Hz), 3.74 (1H, d, J = 16.2 Hz), 3.80 (1H, d, J = 16.2 Hz), 4.20-4.32 (2H, m), 6.63 (2H, d, J = 8.5 Hz), 6.81 (1H, dd, J = 2.4, 9.2 Hz), 6.88 (1H, ddd, J = 2.4, 8.5, 8.5 Hz), 6.90 (2H, dd, J = 8.5, 8.5 Hz), 6.98 (1H, dd, J = 5.9, 8.5 Hz), 6.98-7.20 (5H, m). 87.5 g of N- (4-nitrobenzyl)-[6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinolin-2 (1H) -yl] acetamide was suspended in methanol. 4.5 g of 10% Pd-C (wet.) Was added. The reaction system was purged with hydrogen, and the reaction was continued at room temperature for 2 hours. After completion of the reaction, the reaction solution was filtered through Celite, and the filtrate was concentrated to quantitatively obtain the target product as a white foamy solid.
¹ H-NMR (CDCl ₃ ) δ: 2.52-2.54 (2H, m), 2.72-2.86 (2H, m), 3.13 (1H, d, J = 16.4 Hz), 3.13-3.22 (1H, m), 3.33 (1H, d, J = 16.4 Hz), 3.74 (1H, d, J = 16.2 Hz), 3.80 (1H, d, J = 16.2 Hz), 4.20-4.32 (2H, m), 6.63 (2H, d, J = 8.5 Hz), 6.81 (1H, dd, J = 2.4, 9.2 Hz), 6.88 (1H, ddd, J = 2.4, 8.5, 8.5 Hz), 6.90 (2H, dd, J = 8.5, 8.5 Hz), 6.98 (1H, dd, J = 5.9, 8.5 Hz), 6.98-7.20 (5H, m).

j)Ｎ−（４−イソプロピルアミノベンジル）−［６−フルオロ−３−（４−フルオロベンジル）−１,２,３,４−テトラヒドロイソキノリン−２（１Ｈ）−イル］アセトアミドの製造 j) Preparation of N- (4-isopropylaminobenzyl)-[6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinolin-2 (1H) -yl] acetamide

Ｎ−（４−アミノベンジル）−［６−フルオロ−３−（４−フルオロベンジル）−１，２，３，４−テトラヒドロイソキノリン−２（１Ｈ）−イル］アセトアミド６７．０ｇをトルエン６７０ｍＬに溶解した。これに無水アセトン１０．２ｇを加え、氷冷下、トリアセトキシヒドロホウ酸ナトリウム４７．３ｇ、酢酸１３ｍＬを順次加え、室温で一晩攪拌した。反応終了後、反応液に飽和重曹水、酢酸エチルを加えた。有機層を飽和重曹水、飽和食塩水で順次洗浄した。有機層を無水硫酸ナトリウムで乾燥後、溶媒を留去した。残渣にメタノールを加え加熱溶解し、マレイン酸１８．５ｇのメタノール溶液を加え室温下攪拌した。更に酢酸エチル及びヘキサンを加え攪拌した。析出物を濾取し、目的物８１．８ｇ（収率８８．８％）を微黄色固体として得た。
¹H-NMR (CDCl₃)δ：1.20 (6H, d, J = 6.1 Hz), 2.54 (1H, dd, J = 8.3, 13.9 Hz), 2.55 (1H, dd, J = 5.4, 14.5 Hz), 2.74-2.86 (2H, m), 3.15 (1H, d, J = 16.6 Hz), 3.14-3.22 (1H, m), 3.35 (1H, d, J = 16.6 Hz), 3.47 (1H, brs), 3.56-3.66 (1H, m), 3.76 (1H, d, J = 16.4 Hz), 3.82 (1H, d, J = 16.4 Hz), 4.22 (1H, dd, J = 5.6, 14.4 Hz), 4.31 (1H, dd, J = 5.6, 14.4 Hz), 6.53 (2H, d, J = 8.5 Hz), 6.80 (1H, dd, J = 2.2, 9.3 Hz), 6.86 (1H, ddd, J = 2.7, 8.5, 8.5 Hz), 6.92 (2H, dd, J = 8.6, 8.6 Hz), 6.97 (1H, dd, J = 5.9, 8.5 Hz), 7.00-7.06 (4H, m), 7.20-7.30 (1H, m). 67.0 g of N- (4-aminobenzyl)-[6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinolin-2 (1H) -yl] acetamide is dissolved in 670 mL of toluene. did. To this was added 10.2 g of anhydrous acetone, and 47.3 g of sodium triacetoxyhydroborate and 13 mL of acetic acid were sequentially added under ice cooling, and the mixture was stirred overnight at room temperature. After completion of the reaction, saturated aqueous sodium hydrogen carbonate and ethyl acetate were added to the reaction solution. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. Methanol was added to the residue and dissolved by heating. A methanol solution of 18.5 g of maleic acid was added and stirred at room temperature. Further, ethyl acetate and hexane were added and stirred. The precipitate was collected by filtration to obtain 81.8 g (yield: 88.8%) of the target product as a slightly yellow solid.
¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 6.1 Hz), 2.54 (1H, dd, J = 8.3, 13.9 Hz), 2.55 (1H, dd, J = 5.4, 14.5 Hz), 2.74-2.86 (2H, m), 3.15 (1H, d, J = 16.6 Hz), 3.14-3.22 (1H, m), 3.35 (1H, d, J = 16.6 Hz), 3.47 (1H, brs), 3.56 -3.66 (1H, m), 3.76 (1H, d, J = 16.4 Hz), 3.82 (1H, d, J = 16.4 Hz), 4.22 (1H, dd, J = 5.6, 14.4 Hz), 4.31 (1H, dd, J = 5.6, 14.4 Hz), 6.53 (2H, d, J = 8.5 Hz), 6.80 (1H, dd, J = 2.2, 9.3 Hz), 6.86 (1H, ddd, J = 2.7, 8.5, 8.5 Hz) ), 6.92 (2H, dd, J = 8.6, 8.6 Hz), 6.97 (1H, dd, J = 5.9, 8.5 Hz), 7.00-7.06 (4H, m), 7.20-7.30 (1H, m).

k)（＋）−４−［［２−［６−フルオロ−３−（４−フルオロベンジル）−３，４−ジヒドロイソキノリン−２（１Ｈ）−イル］エチルアミノ］メチル］−Ｎ−イソプロピルアニリンの製造 k) (+)-4-[[2- [6-Fluoro-3- (4-fluorobenzyl) -3,4-dihydroisoquinolin-2 (1H) -yl] ethylamino] methyl] -N-isopropylaniline Manufacturing of

Ｎ−（４−イソプロピルアミノベンジル）−［６−フルオロ−３−（４−フルオロベンジル）−２，３，４−テトラヒドロイソキノリン−２（１Ｈ）−イル］アセトアミドのマレイン酸塩を酢酸エチルに溶解し、２Ｎ水酸化ナトリウム水１００ｍＬで２回、飽和食塩水で順次洗浄し無水硫酸ナトリウムで乾燥後溶媒を留去した。残渣をトルエン共沸しＮ−（４−イソプロピルアミノベンジル）−［６−フルオロ−３−（４−フルオロベンジル）−１，２，３，４−テトラヒドロイソキノリン−２（１Ｈ）−イル］アセトアミドを定量的に回収した。 Dissolve maleate of N- (4-isopropylaminobenzyl)-[6-fluoro-3- (4-fluorobenzyl) -2,3,4-tetrahydroisoquinolin-2 (1H) -yl] acetamide in ethyl acetate The extract was washed twice with 100 mL of 2N aqueous sodium hydroxide and successively with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was azeotroped with toluene to give N- (4-isopropylaminobenzyl)-[6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinolin-2 (1H) -yl] acetamide. Collected quantitatively.

回収したＮ−（４−イソプロピルアミノベンジル）−［６−フルオロ−３−（４−フルオロベンジル）−１，２，３，４−テトラヒドロイソキノリン−２（１Ｈ）−イル］アセトアミド１０．４ｇを無水ＴＨＦ８３ｍＬに溶解した。アルゴンガス雰囲気下、氷冷下、反応液にトリフルオロボレート−ジエチルエーテルコンプレックス９．５ｇを加え、６０℃にて１時間攪拌した。その後、ボラン−ジメチルスルフィドコンプレックス８．５ｇ,１１２ｍＭを加え、そのまま６時間攪拌した。反応終了後、氷冷下にて反応液に５Ｎ塩酸水４４ｍＬを少しずつ加え、６０℃にて１０時間攪拌した。その後、氷冷下にて２Ｎ水酸化ナトリウム水溶液を加え弱塩基性として、酢酸エチルで有機層を分離した。有機層を２Ｎ水酸化ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を留去した。
¹H-NMR( CDCl₃ )δ: 1.20 (6H, d, J = 6.1 Hz), 2.40 (1H, dd, J = 10.0, 13.4 Hz), 2.48 (1H, dd, J = 3.7, 16.6 Hz), 2.73-2.88 (6H, m), 3.13 (1H, m), 3.56-3.68 (1H, m), 3.67 (2H, s), 3.73 (2H, s), 6.53 (2H, d, J = 8.3 Hz), 6.74 (1H, dd, J = 2.4, 9.5 Hz), 6.85 (1H, ddd, J = 2.4, 8.5, 8.5 Hz), 6.94 (2H, dd, J = 8.6, 8.6 Hz), 6.98 (1H, dd, J = 5.6, 8.5 Hz), 7.03 (2H, dd, J = 5.6, 8.6 Hz), 7.07 (2H, d, J = 8.3 Hz).
[α]²⁷ _D+8.9°（c 1.1, MeOH） 10.4 g of the collected N- (4-isopropylaminobenzyl)-[6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinolin-2 (1H) -yl] acetamide is anhydrous Dissolved in 83 mL of THF. Under an argon gas atmosphere and ice cooling, 9.5 g of trifluoroborate-diethyl ether complex was added to the reaction solution, and the mixture was stirred at 60 ° C. for 1 hour. Thereafter, 8.5 g of borane-dimethylsulfide complex and 112 mM were added, and the mixture was stirred as it was for 6 hours. After completion of the reaction, 44 mL of 5N hydrochloric acid was added little by little to the reaction solution under ice cooling, and the mixture was stirred at 60 ° C. for 10 hours. Then, 2N sodium hydroxide aqueous solution was added under ice-cooling to make it weakly basic, and the organic layer was separated with ethyl acetate. The organic layer was washed successively with 2N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated.
¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 6.1 Hz), 2.40 (1H, dd, J = 10.0, 13.4 Hz), 2.48 (1H, dd, J = 3.7, 16.6 Hz), 2.73-2.88 (6H, m), 3.13 (1H, m), 3.56-3.68 (1H, m), 3.67 (2H, s), 3.73 (2H, s), 6.53 (2H, d, J = 8.3 Hz) , 6.74 (1H, dd, J = 2.4, 9.5 Hz), 6.85 (1H, ddd, J = 2.4, 8.5, 8.5 Hz), 6.94 (2H, dd, J = 8.6, 8.6 Hz), 6.98 (1H, dd , J = 5.6, 8.5 Hz), 7.03 (2H, dd, J = 5.6, 8.6 Hz), 7.07 (2H, d, J = 8.3 Hz).
[α] ²⁷ _D + 8.9 ° (c 1.1, MeOH)

l)（＋）−４−［［２−［６−フルオロ−３−（４−フルオロベンジル）−３，４−ジヒドロイソキノリン−２（１Ｈ）−イル］エチルアミノ］メチル］−Ｎ−イソプロピルアニリン・１フマル酸塩の製造 l) (+)-4-[[2- [6-Fluoro-3- (4-fluorobenzyl) -3,4-dihydroisoquinolin-2 (1H) -yl] ethylamino] methyl] -N-isopropylaniline・ Manufacture of 1 fumarate

（＋）−４−［［２−［６−フルオロ−３−（４−フルオロベンジル）−３，４−ジヒドロイソキノリン−２（１Ｈ）−イル］エチルアミノ］メチル］−Ｎ−イソプロピルアニリン１．５９ｇとフマル酸０．４１ｇを６０℃にてエタノール１５．０ｍＬに溶解する。４０℃にて攪拌しながらヘプタン５ｍＬをゆっくり加え、そのまま２時間攪拌し、室温にて更に１８時間攪拌した。析出した結晶を濾取し、減圧下８０℃にて６時間乾燥し、（＋）−４−［［２−［６−フルオロ−３−（４−フルオロベンジル）−３，４−ジヒドロイソキノリン−２（１Ｈ）−イル］エチルアミノ］メチル］−Ｎ−イソプロピルアニリン・１フマル酸塩１．２５ｇ（６２．６％）を無色結晶性粉末として得た。
¹H-NMR (CD₃OD)δ：1.18 (6H, dd, J = 1.3, 6.2 Hz), 2.47 (1H, dd, J = 10.0, 13.4 Hz), 2.53 (1H, dd, J = 3.4, 16.8 Hz), 2.78-2.86 (1H, m), 2.87 (2H, dd, J = 4.9, 14.9 Hz), 2.94-3.02 (1H, m), 3.08-3.20 (3H, m), 3.56-3.64 (1H, m), 3.79 (2H, s), 4.03 (2H, s), 6.62 (2H, dd, J = 2.0, 6.6 Hz), 6.68 (2H, s), 6.80 (1H, dd, J = 2.6, 9.6 Hz), 6.89 (1H, ddd, J = 2.6, 8.5, 8.5 Hz), 7.00 (2H, dd, J = 8.6, 8.6 Hz), 7.07 (1H, dd, J = 5.9, 8.5 Hz), 7.10 (2H, dd, J = 5.5, 8.6 Hz), 7.15 (2H, dd, J = 2.0, 6.6 Hz).
元素分析（C₃₂H₃₇N₃O₄F₂）
理論値 C, 67.95; H, 6.59; N, 7.43; F, 6.72
実測値 C, 67.87; H, 6.63; N, 7.42; F, 6.50. (+)-4-[[2- [6-Fluoro-3- (4-fluorobenzyl) -3,4-dihydroisoquinolin-2 (1H) -yl] ethylamino] methyl] -N-isopropylaniline 59 g and 0.41 g of fumaric acid are dissolved in 15.0 mL of ethanol at 60 ° C. While stirring at 40 ° C., 5 mL of heptane was slowly added, and the mixture was stirred as it was for 2 hours, and further stirred at room temperature for 18 hours. The precipitated crystals were collected by filtration, dried at 80 ° C. under reduced pressure for 6 hours, and (+)-4-[[2- [6-fluoro-3- (4-fluorobenzyl) -3,4-dihydroisoquinoline- 1.25 g (62.6%) of 2 (1H) -yl] ethylamino] methyl] -N-isopropylaniline monofumarate was obtained as a colorless crystalline powder.
¹ H-NMR (CD ₃ OD) δ: 1.18 (6H, dd, J = 1.3, 6.2 Hz), 2.47 (1H, dd, J = 10.0, 13.4 Hz), 2.53 (1H, dd, J = 3.4, 16.8 Hz), 2.78-2.86 (1H, m), 2.87 (2H, dd, J = 4.9, 14.9 Hz), 2.94-3.02 (1H, m), 3.08-3.20 (3H, m), 3.56-3.64 (1H, m), 3.79 (2H, s), 4.03 (2H, s), 6.62 (2H, dd, J = 2.0, 6.6 Hz), 6.68 (2H, s), 6.80 (1H, dd, J = 2.6, 9.6 Hz ), 6.89 (1H, ddd, J = 2.6, 8.5, 8.5 Hz), 7.00 (2H, dd, J = 8.6, 8.6 Hz), 7.07 (1H, dd, J = 5.9, 8.5 Hz), 7.10 (2H, dd, J = 5.5, 8.6 Hz), 7.15 (2H, dd, J = 2.0, 6.6 Hz).
Elemental analysis _{_{_{(C 32 H 37 N 3 O}}} 4 F 2)
Theoretical C, 67.95; H, 6.59; N, 7.43; F, 6.72
Found C, 67.87; H, 6.63; N, 7.42; F, 6.50.

［参考例］鼻閉症状の改善試験
実験には、６週齡の雄性ｓｔｄ／Ｈａｒｔｒｅｙモルモット（日本エスエルシー）を用い、被験薬物には、（＋）−４−［［２−［６−フルオロ−３−（４−フルオロベンジル）−３，４−ジヒドロイソキノリン−２（１Ｈ）−イル］エチルアミノ］メチル］−Ｎ−イソプロピルアニリン・１フマル酸塩（以下化合物（１）と称す）を使用した。
モルモットに卵白アルブミン（ＯＶＡ、Ｓｉｇｍａ）１ｍｇ／ｍＬおよび水酸化アルミニウム水和物（和光純薬）１０ｍｇ／ｍＬ生理食塩溶液の１．０ｍＬを背部皮下に投与することで初回感作を行った。初回感作７日後にＯＶＡの１０ｍｇ／ｍＬ生理食塩液を２０μＬずつ両側の鼻腔内に投与することで追加感作を行った。初回感作１４日後にＯＶＡの２０ｍｇ／ｍＬ生理食塩液を１０μＬずつ両側の鼻腔内に投与することによってアレルギー性鼻炎による鼻閉状態を惹起した。惹起後１０分および２時間から６時間まで１時間ごとに、Ｏｓｃｉｌｌａｔｉｏｎ法（ＣＨＥＳＴ．１９９１ＭＡＹ；９９（５）：１２７４−９に記載の方法）により鼻腔抵抗（ｒｅｓｐｉｒａｔｏｒｙｒｅｓｉｓｔａｎｃｅ、以下「Ｒｒｓ」と称す）を測定し、惹起前の初期抵抗値を１００％としたパーセント変化量で示した。
化合物（１）は溶媒として用いた０．５％メチルセルロース（ＭＣ）水溶液に懸濁し、最終惹起の１８時間前および１時間前の２回、１ｍｇ／ｋｇ経口投与した。対照群として、溶媒投与群（Ｃｏｎｔｒｏｌ群）および抗原惹起処置を行わない無処置群（Ｎｏｒｍａｌ群）の測定を行った。 [Reference Example] Improvement test of nasal congestion Symptoms male 6-week-old male std / Hartley guinea pig (Japan SLC) was used in the experiment, and (+)-4-[[2- [6-fluoro -3- (4-Fluorobenzyl) -3,4-dihydroisoquinolin-2 (1H) -yl] ethylamino] methyl] -N-isopropylaniline monofumarate (hereinafter referred to as compound (1)) did.
First sensitization was performed by administering 1.0 mL of ovalbumin (OVA, Sigma) 1 mg / mL and aluminum hydroxide hydrate (Wako Pure Chemical Industries) 10 mg / mL physiological saline to the guinea pig subcutaneously on the back. Additional sensitization was performed 7 days after the first sensitization by administering 20 μL of OVA 10 mg / mL physiological saline into both nasal cavities. 14 days after the first sensitization, 10 μL of OVA 20 mg / mL physiological saline was administered into both nasal cavities to induce nasal congestion due to allergic rhinitis. Oscillation method (method described in CHEST. 1991 MAY; 99 (5): 1274-9) at 10 minutes and every hour from 2 to 6 hours after induction, referred to as “respiratory resistance” (hereinafter referred to as “Rrs”). ) Was measured and expressed as a percent change with the initial resistance value before induction as 100%.
Compound (1) was suspended in a 0.5% aqueous solution of methylcellulose (MC) used as a solvent, and orally administered at 1 mg / kg twice 18 hours and 1 hour before the last induction. As a control group, a solvent administration group (Control group) and an untreated group (Normal group) in which no antigen-inducing treatment was performed were measured.

［結果および統計処理］
結果は、Ｒｒｓの経時変化で示した（図１）。各ポイントは８例の平均±標準誤差である。統計処理にはＳｔｕｄｅｎｔ’ｓｔ−ｔｅｓｔを用い、Ｃｏｎｔｒｏｌ群との比較を行った。
化合物（１）の投与により鼻閉状態の初期反応相（１０分後）では改善傾向が、また、遅発相（２時間〜６時間）では測定ポイントにより有意な改善が見られた（＊：ｐ＜０．０５）。これらの結果から、化合物（１）はアレルギー性鼻炎における鼻閉症状を改善させることが判明した。 [Results and statistical processing]
The results are shown as the time course of Rrs (FIG. 1). Each point is the mean ± standard error of 8 cases. Student's t-test was used for statistical processing, and the comparison with the Control group was performed.
Compound (1) administration showed an improvement trend in the initial reaction phase (after 10 minutes) in the nasal congestion state, and a significant improvement was observed depending on the measurement points in the late phase (2 to 6 hours) (*: p <0.05). From these results, it was found that compound (1) improves nasal congestion symptoms in allergic rhinitis.

［実施例１］（カプセル剤；親水性界面活性剤）
化合物（１）１．０質量部に、ポリオキシエチレン硬化ヒマシ油６０（日光ケミカルズ製：ニッコールＨＣＯ−６０、ＨＬＢ値：１４．０）を９．０質量部添加後、よく攪拌し、投与量が１０ｍｇ／ｋｇとなるようゼラチンカプセル（ＴＯＲＰＡＣ社製：１／４ＯＺ）に封入し、カプセル剤を得た。 [Example 1] (Capsule; hydrophilic surfactant)
After adding 9.0 parts by mass of polyoxyethylene hydrogenated castor oil 60 (manufactured by Nikko Chemicals: Nikkor HCO-60, HLB value: 14.0) to 1.0 part by mass of compound (1), the mixture is well stirred and administered. Was sealed in a gelatin capsule (manufactured by TORAPAC: 1/4 OZ) to give a capsule.

［比較例１］（カプセル剤；界面活性剤なし）
化合物（１）１．０質量部をよく攪拌し、投与量が１０ｍｇ／ｋｇとなるようゼラチンカプセル（ＴＯＲＰＡＣ社製：１／４ＯＺ）に封入し、カプセル剤を得た。 [Comparative Example 1] (Capsule; no surfactant)
1.0 part by mass of compound (1) was sufficiently stirred and sealed in a gelatin capsule (manufactured by TORAPAC: 1/4 OZ) so that the dose was 10 mg / kg to obtain a capsule.

［比較例２］（カプセル剤；親油性界面活性剤）
化合物（１）１．０質量部に、モノステアリン酸グリセリン（日光ケミカルズ製：ニッコールＭＧＳ-Ｆ２０、ＨＬＢ値：７．０）を９．０質量部添加後、よく攪拌し、投与量が１０ｍｇ／ｋｇとなるようゼラチンカプセル（ＴＯＲＰＡＣ社製：１／４ＯＺ）に封入し、カプセル剤を得た。 [Comparative Example 2] (Capsule; Lipophilic surfactant)
After adding 9.0 parts by mass of glyceryl monostearate (manufactured by Nikko Chemicals: Nikkor MGS-F20, HLB value: 7.0) to 1.0 part by mass of compound (1), the mixture was stirred well and the dose was 10 mg / mg. Encapsulated in gelatin capsules (manufactured by TORAPAC: 1/4 OZ) to give kg.

［試験例］
調製したカプセル剤を、１８時間絶食させたビーグル犬（（株）日本医科学動物資材研究所より購入、体重約１０ｋｇ）に、水５０ｍＬとともに経口投与し、投与後０．５、１、２、３、４、６、８及び２４時間で採血した。投与は１０ｍｇ／ｋｇ、例数は２とした。採血後は直ちに遠心分離し、血漿を採取後、逆相カラム（ＩｎｅｒｔｓｉｌＯＤＳ−３(５０ｍｍ×３ｍｍＩ.Ｄ.、５μｍ、ＧＬサイエンス社製)を用いたＬＣ／ＭＳ／ＭＳ（ＡＰＩ４０００ＬＣＭＳシステム：ＡｐｐｌｉｅｄＢｉｏｓｙｓｔｅｍｓ社製）にて血漿中薬物濃度を測定した。２４時間までのＡＵＣ（血漿中濃度時間曲線下面積）及びＢＡを算出し、平均値を表１に示した。 [Test example]
The prepared capsule was orally administered together with 50 mL of water to a beagle dog (purchased from Nippon Medical Science Animal Materials Laboratory, Inc., body weight: about 10 kg) fasted for 18 hours. Blood was collected at 3, 4, 6, 8, and 24 hours. Administration was 10 mg / kg and the number of cases was 2. Immediately after blood collection, the mixture was centrifuged, and after collecting plasma, LC / MS / MS (API4000LCMS system: Applied) using a reverse phase column (Inertsil ODS-3 (50 mm × 3 mm ID., 5 μm, manufactured by GL Science)). The drug concentration in plasma was measured by Biosystems Inc. The AUC (area under the plasma concentration time curve) and BA up to 24 hours were calculated, and the average values are shown in Table 1.

表１から明らかなように、親水性界面活性剤を配合した本発明のカプセル剤（実施例）は、親水性界面活性剤を配合しなかったカプセル剤（比較例１）又は親油性界面活性剤を配合したカプセル剤（比較例２）に比べて高いＢＡを示し、経口吸収性が高かった。 As is clear from Table 1, the capsules of the present invention (Examples) containing a hydrophilic surfactant were capsules (Comparative Example 1) or lipophilic surfactants not containing a hydrophilic surfactant. Compared with the capsule (Comparative example 2) which mix | blended, BA was high and oral absorption was high.

モルモットアレルギー性鼻炎モデルに（＋）−４−［［２−［６−フルオロ−３−（４−フルオロベンジル）−３，４−ジヒドロイソキノリン−２（１Ｈ）−イル］エチルアミノ］メチル］−Ｎ−イソプロピルアニリン・１フマル酸塩を投与した時の鼻閉症状の改善を示す図である。(+)-4-[[2- [6-Fluoro-3- (4-fluorobenzyl) -3,4-dihydroisoquinolin-2 (1H) -yl] ethylamino] methyl]-in a guinea pig allergic rhinitis model It is a figure which shows the improvement of the nasal obstruction symptom when N-isopropyl aniline 1 fumarate is administered.

Claims

(+)-4-[[2- [6-Fluoro-3- (4-fluorobenzyl) -3,4-dihydroisoquinolin-2 (1H) -yl] ethylamino] methyl] -N-isopropylaniline An oral pharmaceutical composition comprising a fumarate salt or a solvate thereof and a hydrophilic surfactant.

The oral pharmaceutical composition according to claim 1, wherein the hydrophilic surfactant is a nonionic surfactant having an HLB value of 10 or more.

The oral pharmaceutical composition according to claim 1, wherein the hydrophilic surfactant is polyoxyethylene hydrogenated castor oil.