JP5496080B2 - (e)−1−(4−((1r,2s,3r)−1,2,3,4−テトラヒドロキシブチル)−1h−イミダゾール−2−イル)エタノンオキシムの固体形態 - Google Patents
(e)−1−(4−((1r,2s,3r)−1,2,3,4−テトラヒドロキシブチル)−1h−イミダゾール−2−イル)エタノンオキシムの固体形態 Download PDFInfo
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- JP5496080B2 JP5496080B2 JP2010503233A JP2010503233A JP5496080B2 JP 5496080 B2 JP5496080 B2 JP 5496080B2 JP 2010503233 A JP2010503233 A JP 2010503233A JP 2010503233 A JP2010503233 A JP 2010503233A JP 5496080 B2 JP5496080 B2 JP 5496080B2
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- Prior art keywords
- imidazol
- tetrahydroxybutyl
- crystalline
- ethanone oxime
- disease
- Prior art date
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Description
本発明は、(E)−1−(4−((1R,2S,3R)−1,2,3,4−テトラヒドロキシブチル)−1H−イミダゾール−2−イル)エタノンオキシムの固体形態、並びに、様々な疾患及び障害の治療、予防及び管理のためのそれらの使用方法に関する。
[関連出願の相互参照]
本願は、2007年4月12日に出願された米国仮出願第60/923,037号
明細書(この全体は参照により本明細書中に援用される)に対する優先権を主張する。
同じ化合物の種々の固体形態は、実質的に異なる特性を有し得る。例えば、或る薬剤の無定形形態は、結晶形態(複数可)と異なる溶解性、及び異なるバイオアベイラビリティパターン、すなわち、最適な効果を達成するための薬剤の投与方法に影響を及ぼし得る特性を示すことがある。薬剤の無定形形態及び結晶形態はまた、異なる取扱特性(例えば、流動性、圧縮性)、溶解速度、溶解性及び安定性を有する場合があり、これらは全て、剤形の製造に影響を及ぼし得る。結果として、薬剤の複数の形態の利用が様々な理由から望まれている。さらに、規制当局(例えば、米国食品医薬品局)が、新たな薬剤物質を含有する製品を認可するのに先立って、新たな薬剤物質の全ての固体(例えば、多形)形態の特定を要求する可能性がある。非特許文献1。
本発明は、一つには、(E)−1−(4−((1R,2S,3R)−1,2,3,4−テトラヒドロキシブチル)−1H−イミダゾール−2−イル)エタノンオキシム:
本発明はまた、固体形態を含む剤形、及び様々な疾患及び障害を管理、治療及び予防するためのそれらの使用方法を包含する。
本発明の或る態様は、以下の図を参照して理解することができる。
本発明は、ひとつには、循環リンパ球の強力な抑制因子である、(E)−1−(4−((1R,2S,3R)−1,2,3,4−テトラヒドロキシブチル)−1H−イミダゾール−2−イル)エタノンオキシムの新規な固体形態を対象とする。
特に明示のない限り、「管理する(manage)」、「管理すること(managing)」及び「管理(management)」という用語は、特定の疾患又は障害を既に患っている患者において疾患若しくは障害の再発を予防すること、及び/又は疾患若しくは障害を患っている患者が寛解を保つ時間を長くすることを包含する。この用語は、疾患又は障害の閾値、発症、及び/又は継続期間を調節すること、或いは患者の疾患又は障害に対する応答の仕方を変化させることを包含する。
本発明は、(E)−1−(4−((1R,2S,3R)−1,2,3,4−テトラヒドロキシブチル)−1H−イミダゾール−2−イル)エタノンオキシムの固体形態を包含する。
本発明は、S1P量を、必要な患者(例えば、マウス、ラット、イヌ、ネコ又はヒト)において調節する(例えば、増加させる)方法を包含し、これは、患者に本発明の化合物(即ち、本明細書中に開示される化合物)の有効量を投与することを含む。
本発明は、1つ又は複数の本発明の化合物を含む薬学的組成物を包含する。或る薬学的組成物は、患者への経口、粘膜(例えば鼻、舌下、膣、頬側、若しくは直腸)、非経口(例えば皮下、静脈内、ボーラス注射、筋肉内、若しくは動脈内)、又は経皮投与に好適な単回単位剤形(single unit dosage forms)である。剤形の例としては、錠剤;カプレット;軟ゼラチンカプセル等のカプセル剤;カシェ剤;トローチ;ロゼンジ;分散液;坐剤;軟膏剤;パップ(湿布);ペースト;散剤;包帯;クリーム;硬膏剤;液剤;パッチ;エアロゾル(例えば経鼻スプレー又は吸入器);ゲル;懸濁液(例えば、水性又は非水性の液体懸濁液、水中油型乳濁液、又は油中水型液体乳濁液)、溶液、及びエリキシルを含む、患者への経口投与又は粘膜投与に好適な液体剤形;患者への非経口投与に好適な液体剤形;並びに患者への非経口投与に好適な液体剤形を提供するために再構成され得る滅菌固体(例えば結晶性又は無定形の固体)が挙げられるが、これらに限定されない。
経口投与に好適な本発明の薬学的組成物は、錠剤(例えばチュアブル錠)、カプレット、カプセル及び液剤(例えば、香りのするシロップ)等(これらに限定されない)の別個の剤形として提供され得る。かかる剤形は所定量の有効成分を含有し、当業者に既知の製薬法によって調製され得る。例えば、「レミントンの薬学」、第18版、Mack Publishing、Easton PA(1990)を参照されたい。
非経口剤形は、皮下、静脈内(ボーラス注射を含む)、筋肉内、及び動脈内を含む(これらに限定されない)各種経路によって患者に投与され得る。典型的には汚染物質に対する患者の自然防御を回避して投与されるため、非経口剤形は具体的には滅菌されているか、又は患者に投与する前に滅菌可能である。非経口剤形の例としては、すぐに注射することができる溶液、注射用の薬学的に許容されるビヒクル(vehicle)にすぐに溶解又は懸濁することができる乾燥品、すぐに注射できる懸濁液、及び乳濁液が挙げられるが、これらに限定されない。
経皮剤形、局所剤形、及び粘膜剤形としては、点眼液、スプレー、エアロゾル、クリーム、ローション、軟膏、ゲル、溶液、乳濁液、懸濁液、又は当業者に既知の他の形態が挙げられるが、これらに限定されない。例えば、「レミントンの薬学」、第16版及び第18版、Mack Publishing, Easton PA(1980 & 1990)、及び「医薬品剤形序論(Introduction to Pharmaceutical Dosage Forms)」、第4版、Lea & Febiger, Philadelphia(1985)を参照されたい。経皮剤形としては、皮膚に貼付し、所定時間装用することにより、所望量の有効成分の透過が可能となり得る、「リザーバ型」パッチ又は「マトリクス型」パッチが挙げられる。
本発明の態様は、以下の実施例から理解され得るが、その範囲を限定するものではない。
メカニカルスターラー、温度調節器及び冷却器を備えた3L容三口丸底フラスコに、1−(4−((1R,2S,3R)−1,2,3,4−テトラヒドロキシブチル)−1H−イミダゾール−2−イル)エタノン(100.0g、434.4mmol)、ヒドロキシルアミン塩酸塩(45.2g、1.5当量)、酢酸ナトリウム(53.4g、1.5当量)及びメタノール(HPLCグレード、1.0L、10×)を投入した。上記溶液を、攪拌しながら65℃で2時間加熱した。
実施例1からの固体をEtOH(800ml、8×)でスラリーにし、75℃で1時間加熱した。得られた混合物を0℃に冷却し、0℃で1時間攪拌させた。この白色固体を濾過により回収し、EtOH(0℃、100ml、1×、2回)で洗浄し、50℃真空下で恒量まで乾燥させて、表題の化合物を得た。
表題の化合物は、実施例1からの結晶性二水和物を真空下50℃で約2日間乾燥させることによって得た。
(E)−1−(4−((1R,2S,3R)−1,2,3,4−テトラヒドロキシブチル)−1H−イミダゾール−2−イル)−エタノンオキシム二水和物の単結晶構造は、照射源としてファインフォーカスシールド管(MoKα)を備えるSMART 1K CCDエリアディテクタを用いて得た。構造解は、SHELXS−97(Sheldrick, 1990)ソフトフェアを用いて得られ、SHELXL−97(Sheldrick, 1997)を改良プログラムとして使用した。改良手法は、F2に基づくフルマトリクス最小二乗法(full-matrix least-squares)であった。F2に基づく適合度は1.037であった。
Claims (13)
- 結晶性の無水(E)−1−(4−((1R,2S,3R)−1,2,3,4−テトラヒドロキシブチル)−1H−イミダゾール−2−イル)−エタノンオキシム。
- 約4.7、8.2及び12.5度(2θ)でのピークを含む粉末X線回折スペクトルを有する、請求項1に記載の結晶性の無水(E)−1−(4−((1R,2S,3R)−1,2,3,4−テトラヒドロキシブチル)−1H−イミダゾール−2−イル)−エタノンオキシム。
- 約17.1、19.9及び20.8度(2θ)でのピークを含む粉末X線回折スペクトルを有する、請求項1に記載の結晶性の無水(E)−1−(4−((1R,2S,3R)−1,2,3,4−テトラヒドロキシブチル)−1H−イミダゾール−2−イル)−エタノンオキシム。
- 約29.3、32.0及び33.1度(2θ)でのピークを含む粉末X線回折スペクトルを有する、請求項1に記載の結晶性の無水(E)−1−(4−((1R,2S,3R)−1,2,3,4−テトラヒドロキシブチル)−1H−イミダゾール−2−イル)−エタノンオキシム。
- 図1に示されるものと実質的に同様の粉末X線回折スペクトルを有する、請求項1に記載の結晶性の無水(E)−1−(4−((1R,2S,3R)−1,2,3,4−テトラヒドロキシブチル)−1H−イミダゾール−2−イル)−エタノンオキシム。
- 図2に示されるものと実質的に同様のラマンスペクトルを有する、請求項1に記載の結晶性の無水(E)−1−(4−((1R,2S,3R)−1,2,3,4−テトラヒドロキシブチル)−1H−イミダゾール−2−イル)−エタノンオキシム。
- 結晶性の(E)−1−(4−((1R,2S,3R)−1,2,3,4−テトラヒドロキシブチル)−1H−イミダゾール−2−イル)−エタノンオキシム一水和物。
- 結晶性の(E)−1−(4−((1R,2S,3R)−1,2,3,4−テトラヒドロキシブチル)−1H−イミダゾール−2−イル)−エタノンオキシム二水和物。
- 約12.5、14.1又は16.9度(2θ)でのピークを含む粉末X線回折スペクトルを有する、請求項8に記載の結晶性の(E)−1−(4−((1R,2S,3R)−1,2,3,4−テトラヒドロキシブチル)−1H−イミダゾール−2−イル)−エタノンオキシム二水和物。
- 約20.4、25.2及び27.0度(2θ)でのピークを含む粉末X線回折スペクトルを有する、請求項8に記載の結晶性の(E)−1−(4−((1R,2S,3R)−1,2,3,4−テトラヒドロキシブチル)−1H−イミダゾール−2−イル)−エタノンオキシム二水和物。
- 図3に示されるものと実質的に同様の粉末X線回折スペクトルを有する、請求項8に記載の結晶性の(E)−1−(4−((1R,2S,3R)−1,2,3,4−テトラヒドロキシブチル)−1H−イミダゾール−2−イル)−エタノンオキシム二水和物。
- 図4に示されるものと実質的に同様のラマンスペクトルを有する、請求項8に記載の結晶性の(E)−1−(4−((1R,2S,3R)−1,2,3,4−テトラヒドロキシブチル)−1H−イミダゾール−2−イル)−エタノンオキシム二水和物。
- 三斜晶系であり、且つP1空間群をとる、請求項8に記載の結晶性の(E)−1−(4−((1R,2S,3R)−1,2,3,4−テトラヒドロキシブチル)−1H−イミダゾール−2−イル)−エタノンオキシム二水和物。
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NZ (1) | NZ579689A (ja) |
PE (1) | PE20090072A1 (ja) |
TW (1) | TWI412362B (ja) |
UY (1) | UY31012A1 (ja) |
WO (1) | WO2008128045A1 (ja) |
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Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
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US7649098B2 (en) * | 2006-02-24 | 2010-01-19 | Lexicon Pharmaceuticals, Inc. | Imidazole-based compounds, compositions comprising them and methods of their use |
TW200848029A (en) | 2007-03-01 | 2008-12-16 | Lexicon Pharmaceuticals Inc | Heterocyclic compounds, compositions comprising them and methods of their use |
AR065980A1 (es) | 2007-04-12 | 2009-07-15 | Lexicon Pharmaceuticals Inc | Metodos para preparar compuestos basados en imidazol |
TW200920355A (en) * | 2007-09-06 | 2009-05-16 | Lexicon Pharmaceuticals Inc | Compositions and methods for treating immunological and inflammatory diseases and disorders |
CN102131803A (zh) * | 2008-06-18 | 2011-07-20 | 莱西肯医药有限公司 | (1r,2s,3r)-1-(2-(异噁唑-3-基)-1h-咪唑-4-基)丁烷-1,2,3,4-四醇的固体形式及其使用方法 |
EP2537831B1 (en) | 2010-02-18 | 2014-12-03 | Daiichi Sankyo Company, Limited | Imidazole derivative |
WO2012002274A1 (ja) | 2010-06-28 | 2012-01-05 | 第一三共株式会社 | 培養細胞を用いたs1pリアーゼ阻害剤のスクリーニング方法 |
JP5960138B2 (ja) * | 2011-06-28 | 2016-08-02 | 第一三共株式会社 | リン酸エステル誘導体 |
Family Cites Families (5)
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US4567194A (en) | 1983-03-10 | 1986-01-28 | The Coca-Cola Company | 2-Acylimidazole compounds, their synthesis and use as medicinal agents |
AU2881797A (en) * | 1996-05-31 | 1998-01-05 | University Of Wollongong, The | Acetyl derivatives of thiazoles and analogues |
CN101395141A (zh) * | 2006-02-24 | 2009-03-25 | 莱西肯医药有限公司 | 咪唑基化合物,包含其的组合物和它们的使用方法 |
US7649098B2 (en) * | 2006-02-24 | 2010-01-19 | Lexicon Pharmaceuticals, Inc. | Imidazole-based compounds, compositions comprising them and methods of their use |
AR065980A1 (es) * | 2007-04-12 | 2009-07-15 | Lexicon Pharmaceuticals Inc | Metodos para preparar compuestos basados en imidazol |
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Also Published As
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UY31012A1 (es) | 2008-09-02 |
BRPI0810197A2 (pt) | 2014-12-30 |
WO2008128045A8 (en) | 2010-01-21 |
WO2008128045A1 (en) | 2008-10-23 |
AR065979A1 (es) | 2009-07-15 |
CN101284818B (zh) | 2012-10-03 |
NZ579689A (en) | 2011-10-28 |
EP2139865B1 (en) | 2014-01-01 |
ES2453543T3 (es) | 2014-04-08 |
EA200970940A1 (ru) | 2010-02-26 |
ECSP099681A (es) | 2009-12-28 |
CN101284818A (zh) | 2008-10-15 |
CA2683963A1 (en) | 2008-10-23 |
MX2009010904A (es) | 2009-10-26 |
US20080275099A1 (en) | 2008-11-06 |
TW200848027A (en) | 2008-12-16 |
EA017042B1 (ru) | 2012-09-28 |
US20090298901A1 (en) | 2009-12-03 |
KR20100015464A (ko) | 2010-02-12 |
PE20090072A1 (es) | 2009-02-18 |
TWI412362B (zh) | 2013-10-21 |
EP2139865A1 (en) | 2010-01-06 |
AU2008240255A1 (en) | 2008-10-23 |
CO6230981A2 (es) | 2010-12-20 |
IL201037A0 (en) | 2010-05-17 |
CL2008001043A1 (es) | 2008-09-26 |
US8658682B2 (en) | 2014-02-25 |
HK1124851A1 (ja) | 2009-07-24 |
AU2008240255B2 (en) | 2013-07-04 |
IL201037A (en) | 2015-08-31 |
JP2010523707A (ja) | 2010-07-15 |
ZA200906493B (en) | 2010-11-24 |
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