JP2011144182A - 2,5−ジオン−3−(1−メチル−1h−インドール−3−イル)−4−[1−(ピリジン−2−イルメチル)ピペリジン−4−イル]−1h−インドール−3−イル]−1h−ピロール一塩酸塩の結晶 - Google Patents
2,5−ジオン−3−(1−メチル−1h−インドール−3−イル)−4−[1−(ピリジン−2−イルメチル)ピペリジン−4−イル]−1h−インドール−3−イル]−1h−ピロール一塩酸塩の結晶 Download PDFInfo
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- JP2011144182A JP2011144182A JP2011033310A JP2011033310A JP2011144182A JP 2011144182 A JP2011144182 A JP 2011144182A JP 2011033310 A JP2011033310 A JP 2011033310A JP 2011033310 A JP2011033310 A JP 2011033310A JP 2011144182 A JP2011144182 A JP 2011144182A
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- 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
Abstract
【解決手段】銅放射源(CuKα、λ=1.54056Å)からX線回折パターンを得る場合、2θ=6.8±0.1、10.9±0.1、14.2±0.1および16.6±0.1°のピークを含むパターンを有する、2,5-ジオン-3-(1-メチル-1H-インドール-3-イル)-4-[1-(ピリジン-2-イル-メチル)ピペリジン-4-イル]-1H-インドール-3-イル]-1H-ピロール一塩酸塩もしくはその水和物の結晶、および前記塩を含む医薬製剤。
【選択図】なし
Description
メタノールから生成したクエン酸塩は水に不溶である。メシル酸塩は吸湿性であり、70%RHで2%までの重量増、また95%RHで15%を超える重量増を示す。リン酸塩は初期時点で素早い溶解および高溶解度を示すが、長期のインキュベーションにより、リン酸塩の溶解度は71μg/mLにまで低下する。リン酸塩もまたいくらか吸湿性があり、水解離にヒステリシスを示し、これは水和物の形成があり得ることを示唆する。
FB-2HClの水性溶解度を種々の状態において分析した結果、FB-2HCl溶液は、10mg/mLまでの濃度においては、室温で10日までの間安定である。しかし、50℃に保った溶液では、第一の時点(6日)より前に厄介な沈殿が現れた。40mg/mL以上の濃度においては、室温で数分以内に素早い沈殿が見られた。沈殿した結晶のXRD分析およびイオンクロマトグラフィー(塩化物量を決定するため)により、この沈殿物はFB-HClであることを確認した。
下記の調製例に記載する合成の生成物は、概してFBの非溶媒和結晶型である。この非溶媒和型(以後FBI型と言及する)は、反応中十分に結晶化し、素早く濾過でき、高純度の産物(総関連物質(TRS)約0.77%)が得られるので好ましい。ところが、これらのまさに同じ反応条件において、テトラヒドロフラン(THF)を含む溶媒和物もまた時折(発生頻度約10-20%)単離される。この溶媒和物の結晶は非常にゆっくり濾過器を通り、いくらかの不純物を取り込む結果、産物に対してTRSがより高くなる(2.42-4.78%)。この溶媒和物に付随する高いTRSのために、単離溶媒和物が存在する場合は再生成の必要が生じた。かなりの研究がなされたにもかかわらず、THFを含む溶媒和物が時折形成される理由は未知である。FBI型の調製における管理欠如によって、最終活性医薬成分(API)としてのその発展可能性が制限されてきた。
例えばメタノール、イソプロパノールまたは2-ブタノールなどの低級アルコールもしくは低級アルコール、水の混合物とFBとの混合物に、1当量の濃塩酸または1N塩酸を加えて調製したFB-HClは結晶であり、示差走査熱量測定法(DSC)での測定によると融解開始温度は約256℃である。実施例1に記載の通り生成したFB-HClは、0-70%間のRHでは比較的非吸湿性(95%RHでは2%未満の重量増)である。
熱重量分析(TGA)、DSCおよびXRDなどの様々な方法がFB-HClの性質決定に用いられた。TGAでは重量変化量および重量変化速度を温度関数として測定することが可能である。TGAは、脱溶媒和過程の研究および固体の総揮発体積を量的に決定する際に通常用いられる。ある物質に物理的変化が起こる温度は通常その物質に特有のものなので、DSCは化合物の多形のスクリーニングにしばしば用いられる技術である。DSCは、TGA分析において加熱を制御しながら化合物の物理的変化をスクリーニングする際の補足にしばしば用いられる。XRDは結晶物質内の長距離秩序を検出する技術であり、異なるRHで実行して水分吸収が引き起こすわずかな相変化を検出することができる。
吸湿性および無水両F-Iの様々な水性溶媒における大規模な平衡溶解度決定を室温で試みた。加えて、FBI型の平衡溶解度を室温で測定した。サンプルをそれぞれの溶媒に24時間平衡化した後、高速液体クロマトグラフィー(HPLC)で分析した。結果を表2に集約する。
FBの調製例
段階1 2-ピコリルクロリドヒドロクロリド(7.0g,42.7mmol)、4-ピペリドンモノハイドレートヒドロクロリド(6.88g,44.8mmol)、粉末炭酸ナトリウム(18.3g,173mmol)およびアセトニトリル(70mL)の混合物を、室温で45分、40℃で45分、50℃で45分、60℃で45分間攪拌し、その後激しく攪拌しながら70℃に加熱する。HPLC(Zorbax RX-C8 25cmカラム、pH3.0のアセトニトリル/H3PO4緩衝液、λ=250nm)によって、ピコリルクロリドの消滅に関して反応をモニターする。反応終了時、混合物を室温に冷まし、濾過して不溶固体を除去した後、濾過ケーキをアセトニトリル(2x25ml)で洗浄する。濾液を少容量(約30ml)に濃縮し、溶媒を酢酸エチル41mlに交換する。素早く攪拌し、溶液を55℃に加熱した後、カンファースルホン酸(9.91g,42.67mmol)の酢酸エチル溶液(77mL)で30分以上処理する。生じた懸濁液を室温に冷ました後、3時間攪拌する。沈殿を濾過し、酢酸エチル(2x30ml)で洗浄し、45℃で真空乾燥し、カンファースルホン酸塩15.6g(87%)を得る。
加熱用マントル、コンデンサーおよび蒸留液留去口を備え付けた三つ口フラスコに、FB(59.0g,114.4mol)、2-ブタノール(949ml,16.1体積)、脱イオン水(621.4mL,10.5体積)およびHCl(食品用:12.24mL,14.13g,0.21体積,1.05当量)を加える。反応物を還流温度に加熱し、蒸留によって溶媒の半量を除去する。反応フラスコ中一定の溶媒レベルを保ちながら、2-ブタノール(27体積)を2時間かけてゆっくり加える。反応物を60分かけて室温に冷却した後、0-5℃に冷却し、1-2時間攪拌する。生成物を濾過し、濾過ケーキを2体積の2-ブタノールで洗浄し、その濾過ケーキを真空下50℃で一晩乾燥し、F-Iを得る。元素分析:C32H30N5O2Clの理論値:C,69.62, H,5.48, N,12.69, Cl,6.42。実測値:C,69.29, H,5.49, N,12.52, Cl,6.54。
本発明の塩は好ましくは投与前に単位投与形態に製剤する。従って、本発明のさらなる別の態様は本発明の塩および医薬担体を含む医薬組成物である。本明細書で形容詞として使用する「医薬」なる用語は、受容患者に対して実質的に非有害であることを意味する。
本発明の塩は、血管内皮増殖因子(VEGF)誘導化血管新生の阻害物質である。少なくとも2つの定量法により、これらの薬理学的活性が証明される:即ち、1)F-Iは、F-Iに72時間曝した培養液中のHUVEC細胞において、その細胞のVEGF刺激性増殖の強力な阻害物質である、2)F-Iは、10日間ラットに経口投与した場合、その動物の角膜のマイクロポケットにおけるVEGF誘導化新血管新生の非常に効果的な阻害物質となる。これらの定量法はより完全にWO02/02116に記載されている。このように、本発明の塩は、癌の処置および腫瘍成長の抑制に有効である。
本発明の塩は腫瘍成長阻害物質として、膀胱、脳、乳房、頚部、結腸直腸、食道、腎臓、頭頸部、肝臓、肺、卵巣、膵臓、前立腺および胃の癌の処置に有用である。本発明の塩はまた、軟部組織肉腫および骨肉腫の処置および、ホジキンおよび非ホジキンリンパ腫または血液学的悪性腫瘍(白血病)の処置にも有用である。
当業者は、本発明に従って投与される本発明の塩の量、すなわち治療学的有効量は、抗腫瘍効果の創出、アポトーシスまたは細胞死の誘導、および/または抗血管新生効果の維持に十分な量であることを認識するであろう。
本発明の塩は、経口、直腸、経皮、皮下、局所、静脈内、筋肉内または鼻腔内ルートを含む様々なルートで投与できる。経口ルートが好ましい。
本発明の塩は、腫瘍のある哺乳類、特にヒトを処置するための従来の抗腫瘍治療と併せて用いてもよい。抗腫瘍薬を用いる化学療法および放射線治療などの従来の抗腫瘍治療の手法はすぐに利用でき、当分野で日常的に実施されており、その例として、Harrison’s PRINCIPLES OF INTERNAL MEDICINE 11th edition, McGraw−Hill Book Companyを参照されたい。
Claims (14)
- 2,5-ジオン-3-(1-メチル-1H-インドール-3-イル)-4-[1-(ピリジン-2-イルメチル)ピペリジン-4-イル]-1H-インドール-3-イル]-1H-ピロール一塩酸塩もしくはその水和物の結晶、またはそれらの混合物。
- 銅放射源(CuKα、λ=1.54056Å)からX線回折パターンを得る場合、2θ=6.8±0.1、10.9±0.1、14.2±0.1および16.6±0.1°のピークを含むパターンを有する、2,5-ジオン-3-(1-メチル-1H-インドール-3-イル)-4-[1-(ピリジン-2-イルメチル)ピペリジン-4-イル]-1H-インドール-3-イル]-1H-ピロール一塩酸塩もしくはその水和物の結晶、またはそれらの混合物。
- 2θ=6.3±0.1、7.2±0.1、12.5±0.1および17.0±0.1°のピークをさらに含むX線回折パターンを有する、請求項2記載の一塩酸塩の結晶。
- 請求項1ないし3のいずれか記載の塩および医薬担体を含む医薬組成物。
- 非ホジキンリンパ腫を処置する方法であって、その処置を必要とする哺乳動物に請求項1ないし3のいずれか記載の化合物の有効量を投与する方法。
- グリア芽細胞腫を処置する方法であって、その処置を必要とする哺乳動物に請求項1ないし3のいずれか記載の化合物の有効量を投与する方法。
- 非小細胞肺癌を処置する方法であって、その処置を必要とする哺乳動物に請求項1ないし3のいずれか記載の化合物の有効量を投与する方法。
- 治療により人体を処置する方法に使用するための、請求項1ないし3のいずれか記載の化合物。
- 非ホジキンリンパ腫の処置に用いる、請求項8記載の化合物。
- グリア芽細胞腫の処置に用いる、請求項8記載の化合物。
- 非小細胞肺癌の処置に用いる、請求項8記載の化合物。
- 非ホジキンリンパ腫を処置するための医薬の製造における、請求項1ないし3のいずれか記載の化合物の使用。
- グリア芽細胞腫を処置するための医薬の製造における、請求項1ないし3のいずれか記載の化合物の使用。
- 非小細胞肺癌を処置するための医薬の製造における、請求項1ないし3のいずれか記載の化合物の使用。
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