JP2014521654A - デニブリン二塩酸塩 - Google Patents
デニブリン二塩酸塩 Download PDFInfo
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- JP2014521654A JP2014521654A JP2014523062A JP2014523062A JP2014521654A JP 2014521654 A JP2014521654 A JP 2014521654A JP 2014523062 A JP2014523062 A JP 2014523062A JP 2014523062 A JP2014523062 A JP 2014523062A JP 2014521654 A JP2014521654 A JP 2014521654A
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- dihydrochloride
- monohydrochloride
- pharmaceutically acceptable
- solubility
- compound
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- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/30—Nitrogen atoms not forming part of a nitro radical
- C07D235/32—Benzimidazole-2-carbamic acids, unsubstituted or substituted; Esters thereof; Thio-analogues thereof
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
本発明は、二塩酸塩MN−029の合成と特性評価とその医薬的に許容できる配合の製剤に焦点を当てている。病気の進行のために血管新生による新生血管系の生成に依存する病気の治療に化合物とその製剤を使用する方法を開示する。
【選択図】図3
Description
本発明によるMN−029二塩酸塩の試料の結晶化度パーセントは、少なくとも約90%結晶質であることが好ましく、約95%結晶質であることがより好ましく、更には約99%結晶質であることがより好ましく、約99%又は100%結晶質であることが最も好ましい。
平衡状態においておき、その後に残留固体を濾過し、得られる濾過液に溶解した化合物があるかHPLCにより分析する。
[医薬組成物と投薬量]
本発明のMN−029・2HCl塩は、強力な血管破壊剤と考えられている。したがって、正常な成熟した血管系には被害を与えずに、新しく形成された血管系を破壊することができると考えられている。したがって、化合物、又は同物質の組成物は、癌、乾癬、関節リウマチ、黄斑変性、アテローム性動脈硬化プラークのような血管新生による新生血管系が病気の発生進行の重要な病理段階となる病気に対する治療法として有効である。
[実験]
[MN−029・2HClの調合と特性評価]
[A.MN−029二塩酸塩の合成]
本発明のMN−029・2HCl塩は、MN−029の遊離塩基から従来のやり方で作ることができる。例えば、MN−029遊離塩基を水又は水と適切な有機溶媒の混合物に分散させ、その懸濁液を氷浴によって冷却した。この懸濁液に、二当量の濃塩酸を一滴ずつ加えた。酸の付加は溶解を促し、その結果溶液は透明になる。その後、MN−029・2HClを沈殿させるため、反応混合物を真空中で濃縮する。得られた固体物質を濾過により回収し乾燥させた。
XRPDにより固体物質の特性評価をした。CuKu放射線(40kV、40mA)、8−8ゴニオメーター、自動発散・受光スリット、グラファイト・セカンダリ・モノクロメータ、シンチレーション計数機を使用し、シーメンスD5000回折計で粉体X線回折パターンを集めた。装置性能は、認定コランダム標準(NIST 1976)を使用して確認を行った。
最終的な最大濃度が化合物の親遊離型1mLあたり10mg以上となるように、十分な量の化合物を0.25mLの水に懸濁して水溶解度を測定した。懸濁液は、25℃で24時間平衡状態におき、その後pHを測定した。懸濁液を濾過し、濾過液を101倍に希釈した。標準溶液を基準にHPLCによる定量分析を行った。標準溶液、希釈溶液及び非希釈溶液の様々な量を注射し、標準溶液の主要ピークと同時に検出されたピークを積分し溶解度を算出した。
pH範囲2から7をカバーするように緩衝液を準備した。薬をおよそ5から10ミリグラム計量しHPLCのバイアルに入れ、そこに適切な緩衝液1.00mLを加えた。溶液を短時間ボルテックスし、その後オービタルシェーカーで5日間振とうさせた。MN−029の他の塩の形態での初期製剤研究中に平衡に達するまで速度の遅さが観察されていたために、振とうを長時間行った。
10mLメスフラスコにMN−029二塩酸塩を計量して入れ溶液を作った。薬を水にボルテックスで溶解させ、試料を水で希釈した。このやり方で1、2、4、6、8mg/mLの溶液を作った。pHとモル浸透圧濃度の測定の前に、試料を室温で一晩そのまま置いておいた。
XRPDにより固体物質の特性評価をした。CuKα放射線(40kV、40mA)、θ−θゴニオメーター、自動発散・受光スリット、グラファイト・セカンダリ・モノクロメータ、シンチレーション計数機を使用し、シーメンスD5000回折計で粉体X線回折パターンを集めた。装置性能は、認定コランダム標準(NIST 1976)を使用して確認を行った。
Claims (7)
- 固体形態において、放射線源としてCuKα線を使用し得られる粉体X線回折パターンが、角度2θで15.01、20.98、21.49、22.52、23.15、24.27、25.80、及び26.57にピークが現れる、化学式2の化合物。
- 前記粉体X線回折パターンにおいて、角度2θで更に11.10、15.9、18.03、21.25及び27.43にピークが現れる、請求項1に記載の化合物。
- 化学式2の化合物と、1つ又は複数の医薬的に許容できる添加剤とを含む医薬組成物。
- 凍結乾燥製剤である、請求項3に記載の医薬組成物。
- デニブリン二塩酸塩を有効量投与することを含む、哺乳類の細胞増殖性疾患を治療する方法。
- 前記細胞増殖性疾患は、癌、乾癬、関節リウマチ、黄斑変性及びアテローム性動脈硬化プラークからなるグループから選択される、請求項5に記載の方法。
- 前記化学式2の化合物と、1つ又は複数の医薬的に許容できる添加剤、および
凍結乾燥医薬製剤に医薬的に許容できる溶媒を有効量加え、溶液を提供することを含む 、 前記凍結乾燥医薬製剤をもどす方法。
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002534452A (ja) * | 1999-01-15 | 2002-10-15 | アンジオジーン ファーマスーティカルズ リミテッド | ベンズイミダゾール血管損傷薬剤 |
JP2003519698A (ja) * | 2000-01-07 | 2003-06-24 | トランスフォーム ファーマスーティカルズ,インコーポレイテッド | 多様な固体形態のハイスループットでの形成、同定および分析 |
WO2006076376A1 (en) * | 2005-01-11 | 2006-07-20 | Medicinova, Inc. | Topical treatment of solid tumors and ocular neovascularization |
Family Cites Families (6)
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US20050267148A1 (en) | 1998-07-15 | 2005-12-01 | Teijin Limited | Benzimidazole derivative |
GB9900334D0 (en) | 1999-01-07 | 1999-02-24 | Angiogene Pharm Ltd | Tricylic vascular damaging agents |
US9016221B2 (en) * | 2004-02-17 | 2015-04-28 | University Of Florida Research Foundation, Inc. | Surface topographies for non-toxic bioadhesion control |
GB0410817D0 (en) | 2004-05-14 | 2004-06-16 | Angiogene Pharm Ltd | Vascular damaging therapy |
GB0509979D0 (en) | 2005-05-17 | 2005-06-22 | Mcguinness Keir | Sanitary product |
ES2587847T3 (es) * | 2011-07-29 | 2016-10-27 | Medicinova, Inc. | Di-hidrocloruro de denibulina |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002534452A (ja) * | 1999-01-15 | 2002-10-15 | アンジオジーン ファーマスーティカルズ リミテッド | ベンズイミダゾール血管損傷薬剤 |
JP2003519698A (ja) * | 2000-01-07 | 2003-06-24 | トランスフォーム ファーマスーティカルズ,インコーポレイテッド | 多様な固体形態のハイスループットでの形成、同定および分析 |
WO2006076376A1 (en) * | 2005-01-11 | 2006-07-20 | Medicinova, Inc. | Topical treatment of solid tumors and ocular neovascularization |
Non-Patent Citations (7)
Title |
---|
"新医薬品の規格及び試験方法の設定について", 医薬審発第568号, JPN6010021254, 2001, ISSN: 0002838730 * |
ANTICANCER RESEARCH, vol. 25, JPN6014025907, 2005, pages 3899 - 3904, ISSN: 0002838727 * |
BERGE,S. M.: "Pharmaceutical salts", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 66, no. 1, JPN5004004439, 1977, US, pages 1 - 19, ISSN: 0002838728 * |
大島寛: "結晶多形・擬多形の析出挙動と制御", PHARM STAGE, vol. 6, no. 10, JPN6011001457, 15 January 2007 (2007-01-15), pages 48 - 53, ISSN: 0002838731 * |
山野光久: "医薬品のプロセス研究における結晶多形現象への取り組み", 有機合成化学協会誌, vol. 65, no. 9, JPN6010003277, 1 September 2007 (2007-09-01), pages 907 - 69, ISSN: 0002838733 * |
生活工学研究, vol. 4, JPN6014015069, 2002, pages 310 - 317, ISSN: 0002838729 * |
高田則幸: "創薬段階における原薬Formスクリーニングと選択", PHARM STAGE, vol. 6, no. 10, JPN6009053755, 15 January 2007 (2007-01-15), pages 20 - 25, ISSN: 0002838732 * |
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BR112014001965A2 (pt) | 2017-02-21 |
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EP2736334A4 (en) | 2015-04-15 |
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ES2587847T3 (es) | 2016-10-27 |
EP2736334A1 (en) | 2014-06-04 |
US8633324B2 (en) | 2014-01-21 |
CN103841828A (zh) | 2014-06-04 |
US20140045909A1 (en) | 2014-02-13 |
US20130041002A1 (en) | 2013-02-14 |
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