JP2018534289A - Egfr阻害剤の塩、結晶形及びその使用 - Google Patents
Egfr阻害剤の塩、結晶形及びその使用 Download PDFInfo
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- JP2018534289A JP2018534289A JP2018519750A JP2018519750A JP2018534289A JP 2018534289 A JP2018534289 A JP 2018534289A JP 2018519750 A JP2018519750 A JP 2018519750A JP 2018519750 A JP2018519750 A JP 2018519750A JP 2018534289 A JP2018534289 A JP 2018534289A
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- 150000003751 zinc Chemical class 0.000 description 1
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Abstract
【選択図】 なし
Description
i)2θの度で表して14.88°±0.2°,18.05°±0.2°,20.84°±0.2°,21.34°±0.2°,24.39°±0.2°及び25.18°±0.2°におけるピークを含む粉末X線回折(XRPD)パターン;及び/又は
ii)単結晶から分析される以下の構造パラメータ:
結晶系:単斜晶系、
空間群:C2/c、
セル定数:a=27.3004(5) Å,α=90°、
b=16.2882(3) Å,β=103.3439(17)°、
c=14.3529(2) Å,γ=90°、
体積:6210.01(18) Å3、
各単位セルの分子数(Z):8。
別段定義されない限り、本明細書で使用される全ての技術的用語及び科学的用語は、本発明が属する技術分野の当業者によって通常理解されるものと同じ意味を有する。本明細書で言及される全ての特許及び刊行物は、その全体が参照により援用される。本明細書に記載されたものと類似又は同等の多くの方法及び材料が本発明の実施又は試験に使用され得るが、好ましい方法、器具及び材料が本発明に記載される。
上に記載したように、本明細書に開示された薬学的に許容され得る組成物は、本明細書に開示された化合物、水和物又は結晶形、或いはその組み合わせ、及び任意に薬学的に許容され得る担体、アジュバント、又はビヒクルを含み、それは、本明細書で使用されるとき、所望の個々の剤形に適したあらゆる溶媒、希釈剤、希釈剤、又は他の液状ビヒクル、分散又は懸濁化助剤、界面活性剤、等張剤、増稠又は乳化剤、防腐剤、固体バインダー、潤滑剤等を含む。医薬組成物における活性成分の含量は、1〜99wt%、1〜95wt%、1〜90wt%、1〜85wt%、1〜80wt%、1〜75wt%、1〜70wt%、1〜65wt%、1〜60wt%、1〜55wt%、1〜50wt%、1〜45wt%、1〜40wt%、1〜35wt%、1〜30wt% %、1〜25wt%、1〜20wt%、1〜15wt%、1〜10wt%、1〜5wt%の量である。記載されるように、両方が参照によりその全てが本明細書に援用されるRemington:The Science and Practice of Pharmacy, 21st ed., 2005, Lippincott Williams & Wilkins, Philadelphia、及びSwarbrick et al., Encyclopedia of Pharmaceutical Technology, eds. 1988-1999, Marcel Dekker, New Yorkには、薬学的に許容され得る組成物を処方する上で使用される種々の担体及びその調製のための既知の技術が開示されている。いずれかの通常の担体媒体が、例えばいずれかの望ましくない生物学的効果を生じるか又は薬学的に許容され得る組成物のいずれかの他の成分と有害な様式で相互作用することにより、本明細書に開示された化合物、水和物又は結晶形化合物と相容性でないことを除いて、その使用が本発明の範囲内であることが企図されている。
本発明を以下の実施例によってさらに説明するが、これらは本発明の範囲を限定するように解釈されるものではない。
1. 4−[(3−クロロ−4−フルオロフェニル)アミノ]−7−メトキシ−6−[3−[(1R,6S)−2,5−ジオキサ−8−アザビシクロ[4.3.0]ノナン−8−イル]プロポキシ]キナゾリンジメタンスルホナート一水和物の結晶形Iの調製
メタノール(10mL)中のメタンスルホン酸(0.173g、1.803mmol)の溶液に、メタノール(30mL)中の4−[(3−クロロ−4−フルオロフェニル)アミノ]−7−メトキシ−6−[3−[(1R,6S)−2,5−ジオキサ−8−アザビシクロ[4.3.0]ノナン−8−イル]プロポキシ]キナゾリン(0.40g、0.819mmol)の溶液をrtで加えた。混合物を60℃で一晩撹拌した。混合物を真空濃縮し溶媒を取り除いた。残分を大量の酢酸エチルで摩砕し、白色固体を得た(519mg、93.01%)。
1)塩形成比は1H NMRによって決定し、1:2であった。
式(II)の化合物及び本発明の結晶形Iの薬物動態学的特性をビーグル犬で評価した。3匹のビーグル犬を有する各グループには、カプセルの形態で経口的に投与した。結晶形Iの投与量は、式(II)の化合物に従って5mg/kgの投薬量に変更し、決定した。結果を以下に示す。
1.器具: 百万電子天秤、種類:XP205DR、製造元:Mettler。
5)吸湿性の特徴及び吸湿性の重量増加の定義は、表3にまとめられている(中国薬局方2010、付録XIX J:医薬品吸湿試験の指針、試験条件:25℃±1℃、相対湿度80%±2%)。
結果を表4に示す。
「原材料及び製剤の安定性試験の指針」(中国薬局方2015、第4編、一般的なルール9001)に従い、結晶形Iの安定性を以下のように試験した。
「原材料及び製剤の安定性試験の指針」(中国薬局方2015、第4編、一般的なルール9001)に従い、結晶形Iの加速試験を以下のように実施した。
(1)不純物は加速試験の進行において明らかな変化はなく、試料の特性は包装条件下で劣化がなく、安定であった。
Claims (21)
- 前記水和物は、式(I)を有する化合物の一水和物である請求項2に記載の水和物。
- 式(I):
を有する化合物の一水和物の結晶形であって、
前記結晶形は、以下の特性:
i)2θの度で表して14.88°±0.2°,18.05°±0.2°,20.84°±0.2°,21.34°±0.2°,24.39°±0.2°及び25.18°±0.2°におけるピークを含む粉末X線回折(XRPD)パターン;及び/又は
ii)単結晶から分析された以下の構造パラメータ:
結晶系:単斜晶系
空間群:C2/c、
セル定数:a=27.3004(5) Å,α=90°、
b=16.2882(3) Å,β=103.3439(17)°、
c=14.3529(2) Å,γ=90°、
体積:6210.01(18) Å3、
各単位セルの分子数(Z):8
の1つ以上を有する形Iである結晶形。 - 2θの度で表して9.47°±0.2°,14.88°±0.2°,16.58°±0.2°,17.15°±0.2°,17.46°±0.2°,18.05°±0.2°,20.46°±0.2°,20.84°±0.2°,21.34°±0.2°,22.71°±0.2°,23.16°±0.2°,24.39°±0.2°,25.18°±0.2°,25.46°±0.2°,26.29°±0.2°及び28.01°±0.2°におけるピークを含む粉末X線回折(XRPD)パターンを有する請求項4に記載の結晶形。
- 2θの度で表して6.36°±0.2°,6.66°±0.2°,9.47°±0.2°,10.82°±0.2°,11.70°±0.2°,13.31°± 0.2°,14.88°±0.2°,15.86°±0.2°,16.58°±0.2°,17.15°±0.2°,17.46°±0.2°,18.05°±0.2°,19.30°±0.2°,20.46°±0.2°,20.84°±0.2°,21.34°±0.2°,21.76°±0.2°,22.28°±0.2°,22.71°±0.2°,23.16°±0.2°,24.07°±0.2°,24.39°±0.2°,25.18°±0.2°,25.46°±0.2°,26.29°±0.2°,26.78°±0.2°,27.15°±0.2°,28.01°±0.2°,28.80°±0.2°,29.77°±0.2°,30.44°±0.2°,31.06°±0.2°,32.05°±0.2°,33.01°±0.2°,33.51°±0.2°,33.84°±0.2°,34.90°±0.2°,38.03°±0.2°,38.58°±0.2°及び39.48°±0.2°におけるピークを含む粉末X線回折(XRPD)パターンを有する請求項4に記載の結晶形。
- 図1に示される粉末X線回折(XRPD)パターンを有する請求項4に記載の結晶形。
- 図3に示される単結晶構造を有する請求項4に記載の結晶形。
- 請求項1に記載の化合物、請求項2又は3に記載の水和物、又は請求項4〜8の何れか1項に記載の結晶形、又はその組み合わせを含む医薬組成物。
- 薬学的に許容され得る担体、賦形剤、希釈剤、アジュバント、ビヒクル又はその組み合わせを更に含む請求項9に記載の医薬組成物。
- 治療剤を更に含み、前記治療剤は、増殖性疾患又は癌を治療するために使用される化学療法剤、抗増殖剤、細胞毒性薬、シグナル伝達阻害剤、非小細胞肺癌又は皮膚癌を治療するために用いられる薬剤又はその組み合わせである請求項9に記載の医薬組成物。
- 前記治療剤は、アドリアマイシン、ラパマイシン、テムシロリムス、エベロリムス、イクサベピロン、ゲムシタビン、シクロホスファミド、デキサメタゾン、エトポシド、フルオロウラシル、イマチニブメシル酸塩、ダサチニブ、ニロチニブ、エルロチニブ、ラパチニブ、ゲフィチニブ、ソラフェニブ、スニチニブ、インターフェロン、カルボプラチン、トポテカン、パクリタキセル、ビンブラスチン、ビンクリスチン、テモゾロマイド、トシツモマブ、トラベデクチン、ベバシズマブ、トラスツズマブ、セツキシマブ、パニツムマブ、イコチニブ、イコチニブ塩酸塩、マツズマブ、ネラチニブ、カネルチニブ、バンデタニブ、セディラニブ、バタラニブ、アキシチニブ、モテサニブ、ニモツズマブ、テリアチニブ、エピチニブ、シモチニブ、ポジオチニブ、バルリチニブ、ロシレチニブ、ペリチニブ、オシメルチニブ、PKI−166、PD158780、MDX447、Mab425、HM−61713、TAS−121、セリバンツマブ、ナコチニブ、又はその組み合わせである請求項11に記載の医薬組成物。
- EGFRを阻害するための医薬の製造における請求項1に記載の化合物、又は請求項2若しくは3に記載の水和物、又は請求項4〜8の何れか1項に記載の結晶形、又は請求項9〜12の何れか1項に記載の医薬組成物の使用。
- 罹患体における増殖性疾患を予防し、又は治療し、又は重症度を軽減するための医薬の製造における、請求項1に記載の化合物、又は請求項2若しくは3に記載の水和物、又は請求項4〜8の何れか1項に記載の結晶形、又は請求項9〜12の何れか1項に記載の医薬組成物の使用。
- 前記増殖性疾患は、転移性癌、皮膚癌、結腸癌、胃癌、膀胱癌、乳癌、腎臓癌、肝臓癌、肺癌、甲状腺癌、脳腫瘍、子宮頸癌、前立腺癌、膵臓癌、中枢神経系癌、悪性神経膠腫、骨髄過形成、アテローム性動脈硬化症、又は肺線維症である請求項14に記載の使用。
- EGFRの阻害における使用のための請求項1に記載の化合物、又は請求項2若しくは3に記載の水和物、又は請求項4〜8の何れか1項に記載の結晶形、又は請求項9〜12の何れか1項に記載の医薬組成物。
- 罹患体における増殖性疾患を予防し、又は治療し、又は重症度を軽減することにおける使用のための、請求項1に記載の化合物、又は請求項2若しくは3に記載の水和物、又は請求項4〜8の何れか1項に記載の結晶形、又は請求項9〜12の何れか1項に記載の医薬組成物。
- 前記増殖性疾患は、転移性癌、皮膚癌、結腸癌、胃癌、膀胱癌、乳癌、腎臓癌、肝臓癌、肺癌、甲状腺癌、脳腫瘍、子宮頸癌、前立腺癌、膵臓癌、中枢神経系癌、悪性神経膠腫、骨髄過形成、アテローム性動脈硬化症、又は肺線維症である請求項17に記載の化合物、水和物、結晶形、又は医薬組成物。
- 請求項1に記載の化合物、又は請求項2若しくは3に記載の水和物、又は請求項4〜8の何れか1項に記載の結晶形、又は請求項9〜12の何れか1項に記載の医薬組成物の治療有効量を治療対象体に投与することを含む治療対象体におけるEGFRを阻害する方法。
- 請求項1に記載の化合物、又は請求項2若しくは3に記載の水和物、又は請求項4〜8の何れか1項に記載の結晶形、又は請求項9〜12の何れか1項に記載の医薬組成物の治療有効量を罹患体に投与することを含む、罹患体における増殖性疾患を予防し、又は治療し、又は重症度を軽減するための方法。
- 前記増殖性疾患は、転移性癌、皮膚癌、結腸癌、胃癌、膀胱癌、乳癌、腎臓癌、肝臓癌、肺癌、甲状腺癌、脳腫瘍、子宮頸癌、前立腺癌、膵臓癌、中枢神経系癌、悪性神経膠腫、骨髄過形成、アテローム性動脈硬化症、又は肺線維症である請求項20に記載の方法。
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JP2022537758A (ja) * | 2019-06-19 | 2022-08-29 | シェンチェン・ジンルイ・ファウンデーション・バイオテック・カンパニー・リミテッド | キナゾリン系化合物の結晶体、塩およびその調製方法 |
JP7350374B2 (ja) | 2019-06-19 | 2023-09-26 | チェンドゥ・ジンルイ・ファウンデーション・バイオテック・カンパニー・リミテッド | キナゾリン系化合物の結晶体、塩およびその調製方法 |
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