JP2007509125A - N−〔(r)−2,3−ジヒドロキシ−プロポキシ〕−3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−ベンズアミドの多形 - Google Patents
N−〔(r)−2,3−ジヒドロキシ−プロポキシ〕−3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−ベンズアミドの多形 Download PDFInfo
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- JP2007509125A JP2007509125A JP2006536192A JP2006536192A JP2007509125A JP 2007509125 A JP2007509125 A JP 2007509125A JP 2006536192 A JP2006536192 A JP 2006536192A JP 2006536192 A JP2006536192 A JP 2006536192A JP 2007509125 A JP2007509125 A JP 2007509125A
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- fluoro
- difluoro
- iodo
- phenylamino
- benzamide
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Abstract
Description
本発明は、N−〔(R)−2,3−ジヒドロキシ−プロポキシ〕−3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−ベンズアミドの新規多形IV形、並びに当該多形の製法、並びに当該多形を利用する医薬組成物及び治療方法を提供する。
N−(2,3−ジヒドロキシプロポキシ)−3,4−ジフルオロ−2−〔(2−フルオロ−4−ヨードフェニル)アミノ〕−ベンズアミドは、WO 2002 006213 A2(Barrett et al.)及びEP 1262176 A1(Baragi et al.)に記載される。
本発明は、約4.6,7.2,14.6,19.9,23.2、及び26.5に角度2θで表される特徴的なピークをもつX線粉末回折パターンを示す、以下の式:
当業者は、年齢、体重、一般健康状態、投与される化合物、投与経路、疼痛のタイプ又は処置を必要とする症状、及び他の投薬の存在を考慮して、知られた方法に従って、患者に投与される本発明に係る化合物の適当な治療的有効量又は投与量を、決定することができるであろう。一般に、N−〔(R)−2,3−ジヒドロキシ−プロポキシ〕−3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−ベンズアミドの上記多形IV形の有効量又は治療的有効量は、約0.1〜約1000mg/kg/日、好ましくは、約1〜約300mg/kg体重であろうし、そして日用量は、正常体重の成人患者について約1〜約500mg、好ましくは約1mg〜50mgであろう。医療専門家により決定されるように、成人ヒトについての日用投与量は、単一投与又は分割投与において、約1mg〜約20mgでありうる。例えば、0.25mg、0.5mg、1mg、5mg、10mg、25mg、50mg、100mg、200mg,300mg、又は400mgの商業的に入手しうるカプセル又は他の配合品(例えば、液体及びフィルム被覆錠剤)が、開示された方法に従って投与されうる。
N−〔(R)−2,3−ジヒドロキシ−プロポキシ〕−3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−ベンズアミド(I形)
ステップA:窒素雰囲気下、乾燥テトラヒドロフラン(500mL、0.2M)中3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−安息香酸(39.3g、100.0mmol)の溶液に、(R)−O−(2,2−ジメチル−〔1,3〕ジオキソラン−4−イルメチル)−ヒドロキシルアミン(14.7g、100.0mmol)、その後、N−メチルモルフォリン(27.5mL、0.25モル)を添加した。オレンジ色の溶液を、氷水浴で冷却した。ジフェニルホスフィニック・クロライド(22.9mL、0.12モル)を滴下した。いくらかの固体が形成した。この混合物を周囲温度まで温ため、そして18時間撹拌した。水を添加して、反応を終了させ、そしてテトラヒドロフランを真空下で蒸発させた。残存油を、酢酸エチル(500mL)に溶解し、飽和ブラインと飽和重炭酸ナトリウムの混合液(1:1)で2回洗浄した。酢酸エチルを留去し、そして粗油固形物をフラッシュ・クロマトグラフィー(シリカゲル、ヘキサン−アセトン/2:1)により精製して、20時間40℃で真空オーブン内で乾燥させた後、くすんだ白色固体として、N−〔(R)−2,2−ジメチル−〔1,3〕ジオキソラン−4−イルメトキシ)−3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−ベンズアミドを得た:41.7g(79.8%)、融点124〜125℃。不純フラクションを併合し、そして同一条件を用いた第2のカラム・クロマトグラフィーにより精製して、6.4g(12.3%)、融点124〜125℃、総収量48.1g(92.1%)の第2バッチを得た。
N−〔(R)−2,3−ジヒドロキシ−プロポキシ〕−3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−ベンズアミド(II形)
ステップA:−15℃で窒素雰囲気下、乾燥テトラヒドロフラン中3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−安息香酸ジフェニルホスフィニック・クロリド(1.26mL、6.63モル)の溶液に、ジフェニルホスフィニック・クロライド(1.26mL、6.63モル)を滴下した。20分間撹拌した後、N−メチル・モルフォリン(0.70mL、6.375mmol)を添加し、そして反応物をさらに20分間撹拌した。(R)−O−(2,2−ジメチル−〔1,3〕ジオキソラン−4−イルメチル)−ヒドロキシルアミン(0.748g、5.1mmol)を添加し、そして反応物を1時間撹拌し、この時点で、N−メチルモルフォリン(0.7mL、6.37mmol)を添加した。この混合物を周囲温度まで温め、そして12時間撹拌した。この反応物を真空下で濃縮し、そしてその後、EtOAcで希釈した。有機層を、飽和NaHCO3(2×)、ブライン(1×)で洗浄し、Na2SO4上で乾燥させ、濾過し、そして濃縮した。粗生成物を溶出液として4:1ヘキサン/EtOAcを用いてSiO2上で精製して1.82g(68%)の茶褐色の固体を得た。
a)一定量のN−〔(R)−2,3−ジヒドロキシ−プロポキシ〕−3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−ベンズアミドを、一定体積のC1−C4低級アルカノールと水であって、当該低級アルカノールの量と水の量は約1:7から約1:13までの比にあるものに、約30℃から約40℃までの温度で、入れ;
b)上記ステップa)の成分を撹拌して、アルカノールと水中の、N−〔(R)−2,3−ジヒドロキシ−プロポキシ〕−3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−ベンズアミドの混合物を作り;
c)上記アルカノールと水中の、N−〔(R)−2,3−ジヒドロキシ−プロポキシ〕−3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−ベンズアミドの混合物を、約20℃から約30℃未満までの温度に冷却し;
d)上記アルカノールと水から当該N−〔(R)−2,3−ジヒドロキシ−プロポキシ〕−3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−ベンズアミドを分離する、
を含む方法により製造されうる。
a)一定量のN−〔(R)−2,3−ジヒドロキシ−プロポキシ〕−3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−ベンズアミドを、一定体積のC1−C4低級アルカノールと水であって、当該エタノールの量と水の量は約1:9から約1:11までの比にあるものに、約32℃から約38℃までの温度で、入れ;
b)上記ステップa)の成分を撹拌して、アルカノールと水中の、N−〔(R)−2,3−ジヒドロキシ−プロポキシ〕−3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−ベンズアミドの混合物を作り;
c)上記アルカノールと水中の、N−〔(R)−2,3−ジヒドロキシ−プロポキシ〕−3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−ベンズアミドの混合物を、約22℃から約28℃未満までの温度に冷却し;
d)上記アルカノールと水から当該N−〔(R)−2,3−ジヒドロキシ−プロポキシ〕−3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−ベンズアミドを分離する、
により多形IV形を製造するステップが存在する。
N−〔(R)−2,3−ジヒドロキシ−プロポキシ〕−3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−ベンズアミド(IV形)
窒素雰囲気下、3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−安息香酸(2.6kg、6.6mol)とN,N′−カルボニルジイミダゾール(1.1kg、6.8mol)を入れたフラスコに、12Lの乾燥アセトニトリルを添加した。約90分間22±5℃で撹拌した後、トルエン中(R)−O−(2,2−ジメチル−〔1,3〕ジオキソラン−4−イルメチル)−ヒドロキシルアミンの溶液を添加した(8.5L合計量、約8モルのアミン)。この溶液を、22±5℃で少なくとも6時間撹拌した。水性塩酸(9L、1.5M)を添加し、そして約5分間撹拌した後、層分離させた。水性塩酸(9L、1.5M)を残存上層に添加し、そして約20時間撹拌した後、層分離させた。残存上層を真空蒸留により濃縮し、そしてその後、15Lのトルエンと2Lのエタノールで希釈した。この混合物を、37〜45℃に温め、そして20Lの温水で希釈し、その後、0〜5℃に冷却した。生成物を、濾過により回収し、そして2Lのトルエンで洗浄した。生成物を、12Lのトルエンと2Lのエタノール(50±5℃)中に溶解させることにより再結晶化し、10Lの水を添加し、そして0〜5℃に冷却した。濾過による上記生成物の回収及びトルエンによる洗浄後、当該生成物を真空オーブン内で乾燥させることで、2.6kgのN−〔(R)−2,3−ジヒドロキシプロポキシ〕−3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−ベンズアミドが得られた。
本発明に係る結晶形のX線回折パターンを、Rigaku Ultima+Cuka照射による回折図上で計測した。
Rigaku Ultima+回折計、IBM互換インターフェース、6位置オートサンプラー装備、ソフトウェア=RigMeas v2.0(Rigaku,December 1995)及びJADE 3.1(Materials Data,Inc.)。
Cuka照射(40mA、40kV、λ=1.5419Å)。
0.5にスリットIとII、0.3°にスリットIII。
方法
連続θ/2θ結合スキャン:2θにおいて3.00°〜45.00°、0.2°/分のスキャン速度:15.0秒/0.05°ステップ。
サンプルを、バイアルから残らず取り出し、そしてアルミニウム・ホルダー内のゼロ−バックグラウンド・ケイ素上に圧縮した。サンプルは5mm幅であった。
サンプルを保存し、そして室温で実行した。
サンプルを、データ収集の間、垂直軸の廻りに40rpmで回転させた。
Claims (5)
- 約4.6,7.2,14.6,19.9,23.2、及び26.5に角度2θで表される特徴的ピークをもつX線粉末回折パターンを示すN−〔(R)−2,3−ジヒドロキシ−プロポキシ〕−3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−ベンズアミドの結晶多形。
- 約4.6,7.2,14.6,19.1,19.9,20.7,22.0,22.2,23.2,23.6,23.9,25.0,26.5,28.1,28.3,30.0,30.4,32.7,33.0,34.1,36.6,40.1,42.1,43.4、及び44.6に角度2θで表されるX線粉末回折パターンを示す、請求項1に記載のN−〔(R)−2,3−ジヒドロキシ−プロポキシ〕−3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−ベンズアミドの結晶多形。
- N−〔(R)−2,3−ジヒドロキシ−プロポキシ〕−3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−ベンズアミドIV形の製造方法であって、以下のステップ:
a)一定量のN−〔(R)−2,3−ジヒドロキシ−プロポキシ〕−3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−ベンズアミドを、一定体積のエタノールと水であって、当該エタノールの量と水の量は約1:7から約1:13までの比にあるものに、約30℃から約40℃までの温度で、入れ;
b)上記ステップa)の成分を撹拌して、エタノールと水中の、N−〔(R)−2,3−ジヒドロキシ−プロポキシ〕−3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−ベンズアミドの混合物を作り;
c)上記エタノールと水中の、N−〔(R)−2,3−ジヒドロキシ−プロポキシ〕−3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−ベンズアミドの混合物を、約20℃から約30℃未満までの温度に冷却し;
d)上記エタノールと水から当該N−〔(R)−2,3−ジヒドロキシ−プロポキシ〕−3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−ベンズアミドを分離する、
を含む前記方法。 - 以下のステップ:
a)一定量のN−〔(R)−2,3−ジヒドロキシ−プロポキシ〕−3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−ベンズアミドを、一定体積のエタノールと水であって、当該エタノールの量と水の量は約1:7から約1:13までの比にあるものに、約30℃から約40℃までの温度で、入れ;
b)上記ステップa)の成分を撹拌して、エタノールと水中の、N−〔(R)−2,3−ジヒドロキシ−プロポキシ〕−3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−ベンズアミドの混合物を作り;
c)上記エタノールと水中の、N−〔(R)−2,3−ジヒドロキシ−プロポキシ〕−3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−ベンズアミドの混合物を、約20℃から約30℃未満までの温度に冷却し;
d)上記エタノールと水から当該N−〔(R)−2,3−ジヒドロキシ−プロポキシ〕−3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−ベンズアミドを分離する、
により製造されるN−〔(R)−2,3−ジヒドロキシ−プロポキシ〕−3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−ベンズアミドの多形を含む物。 - 医薬として有効な量のN−〔(R)−2,3−ジヒドロキシ−プロポキシ〕−3,4−ジフルオロ−2−(2−フルオロ−4−ヨード−フェニルアミノ)−ベンズアミドIV形、及び医薬として許容される担体を含む医薬製剤。
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AU5785900A (en) | 1999-07-16 | 2001-02-05 | Warner-Lambert Company | Method for treating chronic pain using mek inhibitors |
WO2001047921A1 (en) | 1999-12-28 | 2001-07-05 | Pharmacopeia, Inc. | Pyrimidine and triazine kinase inhibitors |
AU2001247372A1 (en) | 2000-03-15 | 2001-09-24 | Warner Lambert Company | 5-amide substituted diarylamines as mex inhibitors |
DE10017480A1 (de) * | 2000-04-07 | 2001-10-11 | Transmit Technologietransfer | Verwendung von Substanzen, die als MEK Inhibitor wirken, zur Herstellung eines Arneimittels gegen DNA- und RNA-Viren |
CA2420003A1 (en) | 2000-08-25 | 2002-03-07 | Derick Dale Winkle | Process for making n-aryl-anthranilic acids and their derivatives |
WO2002069960A2 (en) | 2001-03-06 | 2002-09-12 | Axxima Pharmaceuticals Ag | Use of mek inhibitors for treating inflammation and virus induced hemorrhagic shock |
AU2002255852B2 (en) | 2001-03-22 | 2006-11-09 | Van Andel Research Institute | Anthrax lethal factor inhibits tumor growth and angiogenesis |
CA2473545A1 (en) | 2002-01-23 | 2003-07-31 | Warner-Lambert Company Llc | N-(4-substituted phenyl)-anthranilic acid hydroxamate esters |
DOP2003000556A (es) | 2002-01-23 | 2003-10-31 | Warner Lambert Co | Esteres hidroxamato de acido n-(4-fenil-sustituido)-antranilico. |
MXPA05003431A (es) * | 2002-11-15 | 2005-07-05 | Warner Lambert Co | Quimioterapia de combinacion. |
-
2004
- 2004-10-11 AU AU2004283148A patent/AU2004283148A1/en not_active Abandoned
- 2004-10-11 EP EP04769603A patent/EP1682495A1/en not_active Withdrawn
- 2004-10-11 KR KR1020067007613A patent/KR101013932B1/ko not_active IP Right Cessation
- 2004-10-11 MX MXPA06004363A patent/MXPA06004363A/es unknown
- 2004-10-11 CA CA002542210A patent/CA2542210A1/en not_active Abandoned
- 2004-10-11 JP JP2006536192A patent/JP2007509125A/ja active Pending
- 2004-10-11 WO PCT/IB2004/003309 patent/WO2005040098A1/en active Application Filing
- 2004-10-11 BR BRPI0415710-9A patent/BRPI0415710A/pt not_active IP Right Cessation
- 2004-10-11 RU RU2006113437/04A patent/RU2352558C2/ru not_active IP Right Cessation
- 2004-10-11 CN CN200480030534A patent/CN100594212C/zh not_active Expired - Fee Related
- 2004-10-11 NZ NZ546011A patent/NZ546011A/en unknown
- 2004-10-19 AR ARP040103782A patent/AR046124A1/es not_active Application Discontinuation
- 2004-10-20 TW TW093131810A patent/TW200524584A/zh unknown
- 2004-10-20 US US10/969,681 patent/US7060856B2/en not_active Expired - Fee Related
-
2006
- 2006-03-16 IL IL174367A patent/IL174367A0/en unknown
- 2006-03-17 ZA ZA200602250A patent/ZA200602250B/en unknown
- 2006-04-20 CO CO06037639A patent/CO5690569A2/es not_active Application Discontinuation
- 2006-05-09 NO NO20062090A patent/NO20062090L/no not_active Application Discontinuation
-
2007
- 2007-01-03 HK HK07100071.5A patent/HK1093483A1/xx not_active IP Right Cessation
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2002006213A2 (en) * | 2000-07-19 | 2002-01-24 | Warner-Lambert Company | Oxygenated esters of 4-iodo phenylamino benzhydroxamic acids |
WO2002020467A1 (fr) * | 2000-09-08 | 2002-03-14 | Ono Pharmaceutical Co., Ltd. | Nouveaux cristaux de n-hydroxy-2(s)-methyl-5-ethoxymethoxy-4(s)-[n-(4-phenoxyphenylcarbonyl)amino]pentanamide, leur procede de production et medicaments contenant ces cristaux en tant que substance active |
JP2002332247A (ja) * | 2001-05-09 | 2002-11-22 | Warner Lambert Co | Mek阻害剤の投与による好中球化学走性の治療または抑制方法 |
WO2003054180A1 (en) * | 2001-12-21 | 2003-07-03 | Warner-Lambert Company Llc | Modified mek1 and mek2, crystal of a peptide: ligand: cofactor complex containing such modified mek1 or mek2, and methods of use thereof |
Also Published As
Publication number | Publication date |
---|---|
CN100594212C (zh) | 2010-03-17 |
NZ546011A (en) | 2009-09-25 |
RU2352558C2 (ru) | 2009-04-20 |
BRPI0415710A (pt) | 2006-12-19 |
CO5690569A2 (es) | 2006-10-31 |
CA2542210A1 (en) | 2005-05-06 |
AU2004283148A1 (en) | 2005-05-06 |
NO20062090L (no) | 2006-07-12 |
AR046124A1 (es) | 2005-11-23 |
TW200524584A (en) | 2005-08-01 |
US20050085550A1 (en) | 2005-04-21 |
IL174367A0 (en) | 2006-08-01 |
KR20060080230A (ko) | 2006-07-07 |
MXPA06004363A (es) | 2006-06-14 |
EP1682495A1 (en) | 2006-07-26 |
ZA200602250B (en) | 2007-05-30 |
CN1867543A (zh) | 2006-11-22 |
US7060856B2 (en) | 2006-06-13 |
RU2006113437A (ru) | 2006-08-27 |
WO2005040098A1 (en) | 2005-05-06 |
KR101013932B1 (ko) | 2011-02-14 |
HK1093483A1 (en) | 2007-03-02 |
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