JP4005731B2 - Crystal polymorphs of aminoethylphenoxyacetic acid derivatives - Google Patents

Description

【０００１】
【発明の属する技術分野】
本発明は、医薬品として有用な新規なアミノエチルフェノキシ酢酸誘導体の結晶多形に関するものである。
【０００２】
さらに詳しく述べれば、本発明は、強力なβ₂ −アドレナリン受容体刺激作用およびβ₃ −アドレナリン受容体刺激作用を有し、尿路結石症の疼痛緩解および排石促進剤等として有用な、式
【０００３】
【化１】

【０００４】
で表されるアミノエチルフェノキシ酢酸誘導体（化学名：２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸）の結晶多形（β形結晶）に関するものである。
【０００５】
【従来の技術】
２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸は、文献未記載の新規な化合物であり、その物性や薬理活性については何ら知られていない。
【０００６】
【発明が解決しようとする課題】
本発明者らは、２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸に関して研究したところ、当該化合物には数種類の結晶多形が存在し、製造方法及び製造条件の相違により、得られる結晶多形の種類やその存在比率が変動し、一定の品質のものが得られないという知見を得た。
【０００７】
通常、結晶多形が存在する化合物は、結晶多形毎に種々性質が相違するため、たとえ同一化合物であっても全く異なる作用効果を示すことがある。特に医薬品においては溶解度、溶解速度、安定性等に差異が見られることが知られており、同一化合物を使用した場合であっても、結晶多形の相違により所期の作用効果が得られなかったり、また、予測と異なる作用効果を生じ、不測の事態を招くことが考えられる。それ故、常に一定の作用効果が期待できるような同一品質の化合物を提供することが必要とされている。従って、結晶多形が存在する化合物を医薬品として用いる場合、医薬品として要求される均一な品質及び一定の作用効果を確保するためには、一定の結晶性を有する化合物を安定して提供できることが要請され、また保存上においても、同一品質を維持できる安定した結晶多形が望まれる。
【０００８】
２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸は数種類の結晶多形が存在する化合物であり、しかも製造方法によって複数の結晶多形が混在することがある。更にある結晶多形においては保存時の外部環境により変化し、一定の品質のものが得られないことがある。それ故、医薬品としての必須要件である一定の作用効果と品質を確保するために、当該化合物の安定な結晶多形を見出し、さらにその結晶多形を常に一定して得るための製造方法を確立することが切望されていた。
【０００９】
【発明の実施の形態】
本発明者らは、尿路結石症の疼痛緩解および排石促進剤等として有用な２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸の結晶多形に関し鋭意検討した結果、本発明の結晶多形が下記の方法に従い一定の品質で製造できること、また本発明の結晶多形が耐湿性等において優れており、医薬品として極めて有用であることを見出し、本発明をなすに至った。
【００１０】
本発明は、粉末Ｘ線回折図形で、回折角（２θ±０．１度）において、１０．１、１０．４、１５．５、１７．０、２０．０および２０．２度に強い回折ピークを示す新規な２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸の結晶多形（β形結晶）に関するものである。
【００１１】
本発明の結晶多形は、２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸を水とメタノールの混合溶媒（容量比で７：３〜９：１）に溶解後、高温下を避けて減圧濃縮し、析出した結晶をろ取後、室温〜６０℃で数時間以上減圧乾燥し、メタノール中懸濁状態にて室温〜還流温度下、数十分〜数時間撹拌することにより製造することができる。撹拌温度、撹拌時間は処理する量、使用溶媒の量などにより適宜加減して実施することができる。また、メタノール中懸濁させる化合物の乾燥時間は化合物の量、状態、乾燥温度により適宜加減して実施することができる。
【００１２】
本発明の結晶多形以外の結晶多形としては、例えば、粉末Ｘ線回折図形で、回折角（２θ±０．１度）において、１８．１、１９．７、２０．３、２１．２および２２．４度に強い回折ピークを示す結晶多形（γ形結晶）、同様に１０．２、１３．２、１７．６、１９．８および２０．６度に強い回折ピークを示す結晶多形（δ形結晶）が存在するが、これらの結晶多形が吸湿してその水和物へ変化するのに対し、本発明の結晶多形は耐湿性に優れており、保存上望ましい。また、本発明の結晶多形は水（３７℃）における溶解度が３．０ｍｇ／ｍＬであり、δ形結晶の溶解度が１．８ｍｇ／ｍＬであるのに比し優れた溶解性を示すため、経口投与製剤において使用した場合薬物吸収性に優れるものである。また、本発明の結晶多形は、注射剤等の液剤において使用する場合製剤化効率がよい。
【００１３】
尚、γ形結晶は、２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸を水酸化ナトリウム溶液に溶解した後、氷冷下塩酸を用いて中和し、析出する結晶をろ取し、４０〜６０℃で数時間減圧乾燥することにより製造することができる。また、δ形結晶は、２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸を水とメタノール（容積比で約７：３）に溶解後、高温を避けて減圧濃縮し、析出した結晶をろ取し、４０〜６０℃で１０〜２０時間程度減圧乾燥することにより製造することができる。
【００１４】
本発明の内容を以下の参考例、実施例、比較例及び試験例を用いて詳細に説明する。尚、各種結晶多形の融点は株式会社リガクの示差熱熱重量同時測定装置（ＴＧ／ＤＴＡ）Ｔｈｅｒｍｏ ｐｌｕｓ ＴＧ８１２０を用いて昇温速度１０℃／分で測定し、補外融解開始温度で示した。また、各種結晶多形の粉末Ｘ線回折データは株式会社リガクのＸ線回折装置ＲＩＮＴ１４００によりＣｕＫα線（１．５４１Å）を用いて測定した。
【００１５】
参考例１
２−〔４−（２−ヒドロキシエチル）フェノキシ〕酢酸エチル
４−（２−ヒドロキシエチル）フェノール（５ｇ）のアセトン（45mL）溶液に、室温で無水炭酸カリウム（ 6.5ｇ）を加え、30分間撹拌した。混合物に内温40〜45℃でブロモ酢酸エチル（ 4.4mL）を滴下し、40℃で更に８時間撹拌した。不溶物をろ去し、ろ液を減圧下に濃縮した後、残留物をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル）で精製して、２−〔４−（２−ヒドロキシエチル）フェノキシ〕酢酸エチル（ 5.8ｇ）を得た。
【００１６】
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃ ）δ ｐｐｍ：
1.28(3H, t, J=7.1Hz), 2.32(1H, br), 2.76(2H, t, J=5.8Hz), 3.84(2H, m), 4.24(2H, q, J=7.1Hz), 4.57(2H, s), 6.88(2H, d, J=7.8Hz), 7.12(2H, d, J=7.8Hz)
【００１７】
参考例２
２−〔４−（２−メタンスルホニルオキシエチル）フェノキシ〕酢酸エチル
２−〔４−（２−ヒドロキシエチル）フェノキシ〕酢酸エチル（ 7.3ｇ）の酢酸エチル（22mL）溶液に窒素気流下、室温でトリエチルアミン（ 5.9mL）を加え撹拌した。この混合物に内温０〜15℃でメタンスルホニルクロリド（ 2.8mL）を滴下し、室温で30分間撹拌した。反応混合物に水を加え、水層を分液し、水層を酢酸エチルで抽出した後、有機層を合わせて飽和炭酸水素ナトリウム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した。溶媒を減圧下に留去した後、残留物に酢酸エチル（ 8.6mL）及び２−プロパノール（23mL）を加え、加熱して溶解し、室温まで冷却後、析出した結晶をろ取して、２−〔４−（２−メタンスルホニルオキシエチル）フェノキシ〕酢酸エチル（ 7.2ｇ）を得た。
【００１８】
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃ ）δ ｐｐｍ：
1.29(3H, t, J=7.1Hz), 2.84(3H, s), 2.99(2H, t, J=6.9Hz), 4.26(2H, q, J=7.1Hz), 4.37(2H, t, J=6.9Hz), 4.60(2H, s), 6.87(2H, d, J=8.7Hz), 7.15(2H, d, J=8.7Hz)
【００１９】
参考例３
２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸エチル・リン酸塩
（１Ｒ，２Ｓ）−２−アミノ−１−（４−ヒドロキシフェニル）プロパン−１−オール（ 8.8ｇ）、２−〔４−（２−メタンスルホニルオキシエチル）フェノキシ〕酢酸エチル（15.9ｇ）、ジイソプロピルアミン（11mL）及びＮ，Ｎ−ジメチルアセトアミド（61mL）の混合物を窒素気流下、75℃で 3.5時間撹拌した。反応混合物を室温まで冷却し、酢酸エチル／トルエン（９／１）の混合液と水を加えた後、水層を分液し、水層を酢酸エチル／トルエン（９／１）の混合液で抽出した。有機層を合わせて水及び18％食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、溶媒を減圧下に留去した。残留物に酢酸エチル（14mL）及びエタノール（92mL）を加えた後、撹拌下室温で16％リン酸−エタノール溶液（32ｇ）を滴下し、析出した結晶をろ取して、２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸エチル・リン酸塩（12.4ｇ）を得た。
【００２０】
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆ ）δ ｐｐｍ：
0.89(3H, d, J=6.6Hz), 1.23(3H, t, J=7.1Hz), 2.80-3.15(5H, m), 4.16(2H, q, J=7.1Hz), 4.73(2H, s), 4.92(1H, br s), 6.71(2H, d, J=8.6Hz), 6.85(2H, d, J=8.6Hz), 7.13(2H, d, J=8.6Hz), 7.16(2H, d, J=8.6Hz), 7.92(4H, br)
【００２１】
参考例４
２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸（α形結晶）
２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸エチル・リン酸塩 (62.0ｇ）に２モル／Ｌ水酸化ナトリウム水溶液（ 393mL）を加え、撹拌下に内温を40℃まで加温して溶かした。内温40〜46℃で４モル／Ｌリン酸水溶液（ 115mL）を滴下し、室温で一晩撹拌後、析出した結晶をろ取し、水で洗浄して白色結晶を得た。得られた結晶を水／メタノール（１／８）の混合液（ 200mL）に懸濁し、懸濁状態にて30分間加熱還流させた後、室温まで冷却し、結晶をろ取後、40〜50℃で３時間減圧乾燥して、２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸（α形結晶） (50.0ｇ）を得た。
【００２２】
融点：２３５．１℃（分解）
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆ ）δ ｐｐｍ：
0.91(3H, d, J=6.6Hz), 2.55-2.75(2H, m), 2.90-3.05(2H, m), 3.15-3.25(1H, m), 4.25-4.40(2H, m), 5.00-5.10(1H, m), 6.65-6.80(4H, m), 6.91(2H, d, J=8.6Hz), 7.13(2H, d, J=8.6Hz), 9.40(1H, br)
比旋光度：〔α〕_D ²⁵ ＝−１０．０°（ｃ＝１．００，１モル／Ｌ塩酸）
【００２３】
実施例１
２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸（β形結晶）
２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸（α形結晶）（ 2.0ｇ）をメタノール（30mL）および水（70mL）の混合液に加熱して溶かし、室温まで冷却した。不溶物をろ去後、ろ液を減圧下に濃縮し、室温で30分間放置した。析出した結晶をろ取した後、40℃で18時間減圧乾燥した。得られた結晶にメタノール（25mL）を加え、室温で約20分間撹拌し、結晶をろ取した後、40℃で２時間減圧乾燥して、２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸（β形結晶）（ 1.6ｇ）を得た。
【００２４】
融点：２３７．２℃（分解）
【００２５】
２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕フェノキシ〕酢酸の結晶多形（β形結晶）の粉末Ｘ線回折図形は、以下の図１に示す通りである。
【００２６】
【図１】
【００２７】
実施例２
２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸（β形結晶）
２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸（α形結晶）（ 1.0ｇ）をメタノール（８mL）および水（72mL）の混合液に加熱して溶かし、室温まで冷却した。不溶物をろ去後、ろ液を減圧下に濃縮した。析出した結晶をろ取した後、40℃で２時間減圧乾燥した。得られた結晶にメタノール（12mL）を加え、室温で約20分間撹拌し、結晶をろ取した後、40℃で３時間減圧乾燥して、２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸（β形結晶）（0.72ｇ）を得た。尚、各種物性値は実施例１と同様であった。
【００２８】
比較例１
２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸（γ形結晶）
２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸（α形結晶）（ 1.4ｇ）を１モル／Ｌ水酸化ナトリウム水溶液（20mL）および水（ 125mL）の混合液に溶かし、氷冷撹拌下、１モル／Ｌ塩酸（20mL）を加えた。氷冷下、30分間撹拌した後、析出した結晶をろ取し、水洗後、50℃で３時間減圧乾燥して、２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸（γ形結晶）（0.78ｇ）を得た。
【００２９】
融点：１８９．８℃（分解）
【００３０】
２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸の結晶多形（γ形結晶）の粉末Ｘ線回折図形は、以下の図２に示す通りである。
【００３１】
【図２】
【００３２】
比較例２
２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸（δ形結晶）
２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸（α形結晶）（ 2.0ｇ）をメタノール（30mL）及び水（70mL）の混合液に加熱して溶かし、室温まで冷却した。不溶物をろ去後、ろ液を減圧下に濃縮し、室温で30分間放置した。析出した結晶をろ取した後、40℃で18時間減圧乾燥して、２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸（δ形結晶）（ 1.8ｇ）を得た。
【００３３】
融点：２３６．３℃（分解）
【００３４】
２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸の結晶多形（δ形結晶）の粉末Ｘ線回折図形は、以下の図３に示す通りである。
【００３５】
【図３】
【００３６】
試験例１
β₂ −アドレナリン受容体刺激作用
ＳＤ系妊娠ラット（妊娠２１日目）の子宮を摘出し、胎盤付着部を避けて、縦走筋方向に幅約５ｍｍ、長さ約１５ｍｍの標本を作成し、Ｍａｇｎｕｓ法に準じて実験を行った。標本は３７℃で９５％の酸素と５％の炭酸ガスを含む混合ガスを通気したＬｏｃｋｅ−Ｒｉｎｇｅｒ液中に懸垂し、１ｇの負荷をかけた。子宮自動運動は、張力トランスデューサーを介して等尺性に導出し、レクチグラフにより記録した。２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸は５分毎に累積的にＭａｇｎｕｓ管内に添加した。本化合物の薬物評価は、本化合物の添加前５分間の子宮収縮高の和を１００％とし、本化合物を各種濃度で添加後５分間の子宮収縮高の和を比較して行い、３．１×１０^-8（Ｍ）で子宮収縮高の和を５０％抑制する薬物濃度（ＥＣ₅₀値）を示した。
【００３７】
試験例２
β₃ −アドレナリン受容体刺激作用
雄性フェレット（体重１１００〜１４００ｇ）の尿管を摘出し、結合組織を除去した後、縦軸方向に約２０ｍｍの標本を作成し、Ｍａｇｎｕｓ法に準じて実験を行った。標本は３７℃で９５％の酸素と５％の炭酸ガスを含む混合ガスを通気したＫｒｅｂｓ−Ｈｅｎｓｅｌｅｉｔ液中に懸垂し、０．５ｇの負荷をかけた。尿管自動運動は、張力トランスデューサーを介して等尺性に導出し、レクチグラフにより記録した。２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸は３分毎に累積的にＭａｇｎｕｓ管内に添加した。本化合物の薬物評価は、本化合物の添加前３分間の尿管収縮高の和を１００％とし、本化合物を各種濃度で添加後３分間の尿管収縮高の和を比較して行い、１．４×１０^-8（Ｍ）で尿管収縮高の和を５０％抑制する薬物濃度（ＥＣ₅₀値）を示した。
【図面の簡単な説明】
【図１】本発明の２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸の結晶多形（β形結晶）の粉末Ｘ線回折データ（モノクロメーターを使用した）。尚、縦軸はＸ線の強度（ｋｃｐｓ）を示し、横軸は回折角（２θ）を示す。
【図２】２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸の結晶多形（γ形結晶）の粉末Ｘ線回折データ（モノクロメーターを使用した）。尚、縦軸はＸ線の強度（ｋｃｐｓ）を示し、横軸は回折角（２θ）を示す。
【図３】２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸の結晶多形（δ形結晶）の粉末Ｘ線回折データ（モノクロメーターを使用した）。尚、縦軸はＸ線の強度（ｋｃｐｓ）を示し、横軸は回折角（２θ）を示す。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a crystalline polymorph of a novel aminoethylphenoxyacetic acid derivative useful as a pharmaceutical product.
[0002]
More specifically, the present invention has a powerful β ₂ -adrenergic receptor stimulating action and β ₃ -adrenergic receptor stimulating action, and is useful as a pain relieving and calculus promoting agent for urolithiasis. [0003]
[Chemical 1]

[0004]
Aminoethylphenoxyacetic acid derivative represented by the formula (chemical name: 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl) ] Phenoxy] acetic acid) polymorph (β-type crystal).
[0005]
[Prior art]
2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid is a novel compound not described in any literature Nothing is known about its physical properties and pharmacological activity.
[0006]
[Problems to be solved by the invention]
The inventors have studied on 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid. However, there are several types of crystal polymorphs in the compound, and the knowledge that the types of crystal polymorphs obtained and the abundance of the polymorphs vary due to differences in production methods and production conditions, and a certain quality cannot be obtained. Got.
[0007]
In general, a compound in which a crystal polymorph exists has different properties depending on the crystal polymorph, so that even if it is the same compound, it may exhibit completely different effects. Especially in pharmaceutical products, it is known that there are differences in solubility, dissolution rate, stability, etc. Even if the same compound is used, the expected action and effect cannot be obtained due to differences in crystal polymorphism. In addition, it may cause an unexpected effect by causing an operational effect different from the prediction. Therefore, there is a need to provide compounds of the same quality that can always be expected to have a certain effect. Therefore, when a compound having a crystalline polymorph is used as a pharmaceutical, it is required to stably provide a compound having a certain crystallinity in order to ensure the uniform quality and certain effects that are required as a pharmaceutical. In addition, a stable crystal polymorph that can maintain the same quality in storage is desired.
[0008]
2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid has several crystalline polymorphs It is a compound, and a plurality of crystal polymorphs may be mixed depending on the production method. Furthermore, some crystal polymorphs change depending on the external environment during storage, and a certain quality may not be obtained. Therefore, in order to ensure certain effects and quality, which are essential requirements for pharmaceuticals, we have found a stable crystal polymorph of the compound and established a manufacturing method to always obtain the crystal polymorph constantly. It was anxious to do.
[0009]
DETAILED DESCRIPTION OF THE INVENTION
The present inventors have developed 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl)] useful as an agent for ameliorating pain in urinary calculus and a stone excretion promoter. As a result of intensive studies on the crystalline polymorph of -1-methylethyl] amino] ethyl] phenoxy] acetic acid, the crystalline polymorph of the present invention can be produced with a certain quality according to the following method, and the crystalline polymorph of the present invention is resistant to moisture. The present invention has been found out that it is excellent in properties and is extremely useful as a pharmaceutical product.
[0010]
The present invention is a powder X-ray diffraction pattern with strong diffraction at 10.1, 10.4, 15.5, 17.0, 20.0 and 20.2 degrees at a diffraction angle (2θ ± 0.1 degrees). Novel 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid polymorph showing a peak (Β-type crystal).
[0011]
The crystalline polymorph of the present invention comprises 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid. After dissolving in a mixed solvent of water and methanol (7: 3 to 9: 1 by volume), concentrate under reduced pressure avoiding high temperature, filter the precipitated crystals, and dry under reduced pressure at room temperature to 60 ° C for several hours or more. It can be produced by stirring in a suspension state in methanol at room temperature to reflux temperature for several tens of minutes to several hours. The stirring temperature and stirring time can be appropriately adjusted depending on the amount to be treated, the amount of solvent used and the like. Further, the drying time of the compound suspended in methanol can be appropriately adjusted depending on the amount, state and drying temperature of the compound.
[0012]
Examples of the crystal polymorph other than the crystal polymorph of the present invention include, for example, a powder X-ray diffraction pattern, and a diffraction angle (2θ ± 0.1 degrees) of 18.1, 19.7, 20.3, 21.2. And polymorphs exhibiting strong diffraction peaks at 22.4 degrees (γ-form crystals), as well as crystal polymorphs exhibiting strong diffraction peaks at 10.2, 13.2, 17.6, 19.8 and 20.6 degrees Although there is a form (δ form crystal), these crystal polymorphs absorb moisture and change to their hydrates, whereas the crystal polymorph of the present invention is excellent in moisture resistance and is desirable for storage. In addition, since the crystal polymorph of the present invention has a solubility in water (37 ° C.) of 3.0 mg / mL, and the solubility of the δ-form crystal is 1.8 mg / mL, it exhibits excellent solubility. When used in an orally administered preparation, it has excellent drug absorbability. In addition, the crystalline polymorph of the present invention has good formulation efficiency when used in a liquid such as an injection.
[0013]
The γ-form crystal is 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid in water. After dissolving in a sodium oxide solution, it can be neutralized with hydrochloric acid under ice cooling, and the precipitated crystals are collected by filtration and dried under reduced pressure at 40 to 60 ° C. for several hours. In addition, the δ-form crystal is 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid in water. And dissolved in methanol (approximately 7: 3 by volume), concentrated under reduced pressure avoiding high temperature, and the precipitated crystals are collected by filtration and dried under reduced pressure at 40-60 ° C. for about 10-20 hours. it can.
[0014]
The contents of the present invention will be described in detail using the following reference examples, examples, comparative examples and test examples. The melting points of various crystal polymorphs were measured at a heating rate of 10 ° C./min using a differential thermal thermogravimetric simultaneous measurement apparatus (TG / DTA) Thermo plus TG8120 manufactured by Rigaku Corporation, and indicated as an extrapolated melting start temperature. . Further, powder X-ray diffraction data of various crystal polymorphs were measured using CuKα rays (1.541 Å) by an R-ray diffraction apparatus RINT1400 manufactured by Rigaku Corporation.
[0015]
Reference example 1
2- [4- (2-hydroxyethyl) phenoxy] ethyl acetate 4- (2-hydroxyethyl) phenol (5 g) in acetone (45 mL) was added anhydrous potassium carbonate (6.5 g) at room temperature and stirred for 30 minutes. did. Ethyl bromoacetate (4.4 mL) was added dropwise to the mixture at an internal temperature of 40 to 45 ° C., and the mixture was further stirred at 40 ° C. for 8 hours. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give 2- [4- (2-hydroxyethyl) phenoxy. Ethyl acetate (5.8 g) was obtained.
[0016]
¹ H-NMR (CDCl ₃ ) δ ppm:
1.28 (3H, t, J = 7.1Hz), 2.32 (1H, br), 2.76 (2H, t, J = 5.8Hz), 3.84 (2H, m), 4.24 (2H, q, J = 7.1Hz), 4.57 (2H, s), 6.88 (2H, d, J = 7.8Hz), 7.12 (2H, d, J = 7.8Hz)
[0017]
Reference example 2
2- [4- (2-Methanesulfonyloxyethyl) phenoxy] ethyl acetate A solution of ethyl 2- [4- (2-hydroxyethyl) phenoxy] acetate (7.3 g) in ethyl acetate (22 mL) at room temperature under a nitrogen stream. Triethylamine (5.9 mL) was added and stirred. Methanesulfonyl chloride (2.8 mL) was added dropwise to the mixture at an internal temperature of 0 to 15 ° C., and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, the aqueous layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, ethyl acetate (8.6 mL) and 2-propanol (23 mL) were added to the residue, dissolved by heating, cooled to room temperature, and the precipitated crystals were collected by filtration. -[4- (2-Methanesulfonyloxyethyl) phenoxy] ethyl acetate (7.2 g) was obtained.
[0018]
¹ H-NMR (CDCl ₃ ) δ ppm:
1.29 (3H, t, J = 7.1Hz), 2.84 (3H, s), 2.99 (2H, t, J = 6.9Hz), 4.26 (2H, q, J = 7.1Hz), 4.37 (2H, t, J = 6.9Hz), 4.60 (2H, s), 6.87 (2H, d, J = 8.7Hz), 7.15 (2H, d, J = 8.7Hz)
[0019]
Reference example 3
2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid ethyl phosphate (1R, 2S ) -2-Amino-1- (4-hydroxyphenyl) propan-1-ol (8.8 g), ethyl 2- [4- (2-methanesulfonyloxyethyl) phenoxy] acetate (15.9 g), diisopropylamine (11 mL) ) And N, N-dimethylacetamide (61 mL) were stirred at 75 ° C. for 3.5 hours under a nitrogen stream. The reaction mixture was cooled to room temperature, a mixture of ethyl acetate / toluene (9/1) and water were added, the aqueous layer was separated, and the aqueous layer was separated with a mixture of ethyl acetate / toluene (9/1). Extracted. The organic layers were combined, washed with water and 18% brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. After adding ethyl acetate (14 mL) and ethanol (92 mL) to the residue, a 16% phosphoric acid-ethanol solution (32 g) was added dropwise at room temperature with stirring, and the precipitated crystals were collected by filtration to give 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid ethyl phosphate (12.4 g) was obtained.
[0020]
¹ H-NMR (DMSO-d ₆ ) δ ppm:
0.89 (3H, d, J = 6.6Hz), 1.23 (3H, t, J = 7.1Hz), 2.80-3.15 (5H, m), 4.16 (2H, q, J = 7.1Hz), 4.73 (2H, s ), 4.92 (1H, br s), 6.71 (2H, d, J = 8.6Hz), 6.85 (2H, d, J = 8.6Hz), 7.13 (2H, d, J = 8.6Hz), 7.16 (2H, d, J = 8.6Hz), 7.92 (4H, br)
[0021]
Reference example 4
2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid (α form crystal)
2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid ethyl phosphate (62.0 g) 2 mol / L aqueous sodium hydroxide solution (393 mL) was added to the solution, and the internal temperature was raised to 40 ° C. with stirring to dissolve. A 4 mol / L phosphoric acid aqueous solution (115 mL) was added dropwise at an internal temperature of 40 to 46 ° C., and the mixture was stirred overnight at room temperature. The precipitated crystals were collected by filtration and washed with water to give white crystals. The obtained crystal was suspended in a mixed solution (200 mL) of water / methanol (1/8), heated and refluxed in a suspended state for 30 minutes, cooled to room temperature, and the crystal was collected by filtration. And dried under reduced pressure at 3 ° C. for 3 hours to give 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid (Α-form crystal) (50.0 g) was obtained.
[0022]
Melting point: 235.1 ° C. (decomposition)
¹ H-NMR (DMSO-d ₆ ) δ ppm:
0.91 (3H, d, J = 6.6Hz), 2.55-2.75 (2H, m), 2.90-3.05 (2H, m), 3.15-3.25 (1H, m), 4.25-4.40 (2H, m), 5.00- 5.10 (1H, m), 6.65-6.80 (4H, m), 6.91 (2H, d, J = 8.6Hz), 7.13 (2H, d, J = 8.6Hz), 9.40 (1H, br)
Specific rotation: [α] _D ²⁵ = -10.0 ° (c = 1.00, 1 mol / L hydrochloric acid)
[0023]
Example 1
2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid (β-form crystal)
2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid (α form crystal) (2.0 g) Was dissolved in a mixture of methanol (30 mL) and water (70 mL) by heating and cooled to room temperature. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure and allowed to stand at room temperature for 30 minutes. The precipitated crystals were collected by filtration and then dried under reduced pressure at 40 ° C. for 18 hours. Methanol (25 mL) was added to the obtained crystals, and the mixture was stirred at room temperature for about 20 minutes. The crystals were collected by filtration and dried under reduced pressure at 40 ° C. for 2 hours to give 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid (β-form crystal) (1.6 g) was obtained.
[0024]
Melting point: 237.2 ° C. (decomposition)
[0025]
2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] phenoxy] acetic acid polymorph (β-form crystal) powder X-ray The diffraction pattern is as shown in FIG.
[0026]
[Figure 1]
[0027]
Example 2
2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid (β-form crystal)
2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid (α form crystal) (1.0 g) Was dissolved in a mixture of methanol (8 mL) and water (72 mL) and cooled to room temperature. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The precipitated crystals were collected by filtration and then dried under reduced pressure at 40 ° C. for 2 hours. Methanol (12 mL) was added to the obtained crystals, and the mixture was stirred at room temperature for about 20 minutes. The crystals were collected by filtration and dried under reduced pressure at 40 ° C. for 3 hours to give 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid (β-form crystal) (0.72 g) was obtained. Various physical property values were the same as those in Example 1.
[0028]
Comparative Example 1
2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid (γ-form crystal)
2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid (α form crystal) (1.4 g) Was dissolved in a mixture of 1 mol / L aqueous sodium hydroxide solution (20 mL) and water (125 mL), and 1 mol / L hydrochloric acid (20 mL) was added with stirring under ice cooling. After stirring for 30 minutes under ice cooling, the precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure at 50 ° C. for 3 hours to give 2- [4- [2-[[(1S, 2R) -2-hydroxy. -2- (4-Hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid (γ-form crystal) (0.78 g) was obtained.
[0029]
Melting point: 189.8 ° C (decomposition)
[0030]
2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid polymorph (γ-form crystal) The powder X-ray diffraction pattern is as shown in FIG. 2 below.
[0031]
[Figure 2]
[0032]
Comparative Example 2
2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid (δ-form crystal)
2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid (α form crystal) (2.0 g) Was dissolved in a mixture of methanol (30 mL) and water (70 mL) by heating and cooled to room temperature. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure and allowed to stand at room temperature for 30 minutes. The precipitated crystals were collected by filtration and then dried under reduced pressure at 40 ° C. for 18 hours to give 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1- Methylethyl] amino] ethyl] phenoxy] acetic acid (delta crystal) (1.8 g) was obtained.
[0033]
Melting point: 236.3 ° C. (decomposition)
[0034]
2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid crystal polymorph (δ-form crystal) The powder X-ray diffraction pattern is as shown in FIG.
[0035]
[Fig. 3]
[0036]
Test example 1
β ₂ -Adrenergic receptor stimulation SD uterus of SD pregnant rat (gestation day 21) is removed, and a specimen having a width of about 5 mm and a length of about 15 mm is prepared in the longitudinal muscle direction, avoiding the placenta attachment part, Magnus The experiment was conducted according to the law. The specimen was suspended in a Locke-Ringer solution in which a mixed gas containing 95% oxygen and 5% carbon dioxide gas was passed at 37 ° C., and a load of 1 g was applied. Uterine automatic movements were derived isometrically via a tension transducer and recorded by a rectograph. 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid is accumulated cumulatively every 5 minutes. Added into the tube. Drug evaluation of this compound is performed by comparing the sum of uterine contraction heights for 5 minutes after addition of this compound at various concentrations with the sum of uterine contraction heights for 5 minutes before addition of this compound as 100%. The drug concentration (EC ₅₀ value) that inhibits the sum of the uterine contraction heights by 50% at × 10 ⁻⁸ (M) was shown.
[0037]
Test example 2
β ₃ -adrenergic receptor stimulating action Male ferret (body weight 1100-1400 g) ureter was removed, connective tissue was removed, and a sample of about 20 mm was prepared in the vertical axis direction, and experiments were conducted according to the Magnus method. It was. The specimen was suspended in a Krebs-Henseleit solution in which a mixed gas containing 95% oxygen and 5% carbon dioxide gas was passed at 37 ° C., and a load of 0.5 g was applied. The automatic ureteral movement was derived isometrically via a tension transducer and recorded by a rectograph. 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid is accumulated cumulatively every 3 minutes. Added into the tube. Drug evaluation of this compound is performed by comparing the sum of ureter contraction heights for 3 minutes after addition of this compound at various concentrations with the sum of ureter contraction heights for 3 minutes before addition of this compound being 100%. The drug concentration (EC ₅₀ value) that inhibits the sum of the ureteral contraction height by 50% was shown at 4 × 10 ⁻⁸ (M).
[Brief description of the drawings]
FIG. 1 is a crystal of 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid of the present invention. Powder X-ray diffraction data of polymorph (β-form crystal) (using a monochromator). The vertical axis indicates the X-ray intensity (kcps), and the horizontal axis indicates the diffraction angle (2θ).
FIG. 2 is a crystalline polymorph of 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid ( X-ray powder diffraction data (using a monochromator). The vertical axis indicates the X-ray intensity (kcps), and the horizontal axis indicates the diffraction angle (2θ).
FIG. 3 is a crystalline polymorph of 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid ( X-ray powder diffraction data (using a monochromator). The vertical axis indicates the X-ray intensity (kcps), and the horizontal axis indicates the diffraction angle (2θ).

Claims (1)

粉末Ｘ線回折図形で、回折角（２θ±０．１度）において、１０．１、１０．４、１５．５、１７．０、２０．０および２０．２度に強い回折ピークを示す２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸の結晶。Powder X-ray diffraction pattern 2 showing strong diffraction peaks at 10.1, 10.4, 15.5, 17.0, 20.0 and 20.2 degrees at diffraction angles (2θ ± 0.1 degrees) 2 Crystals of [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid.

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