JP2022547208A - ニコチニルアルコールエーテル誘導体のマレイン酸塩、その結晶形、及びその使用 - Google Patents
ニコチニルアルコールエーテル誘導体のマレイン酸塩、その結晶形、及びその使用 Download PDFInfo
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Abstract
Description
イソプロピル (S)-N-(2-(ピリジン-3-イル-メトキシ)-4-(2-ブロモ-3-フェニルベンジルオキシ)-5-クロロベンジル)セリネートをマレイン酸と溶媒中で反応させて塩を形成する工程であって、最も好ましくは、上記溶媒がイソプロピルアルコール、テトラヒドロフラン又はアセトンである工程、
得られたイソプロピル (S)-N-(2-(ピリジン-3-イル-メトキシ)-4-(2-ブロモ-3-フェニルベンジルオキシ)-5-クロロベンジル)セリネートマレイン酸塩を、アセトン及び水の混合溶媒中で結晶化する工程であって、アセトンと水の比は200:1~1:1の範囲にあり、好ましくは上記比は50:1~5:1の範囲にあり、最も好ましくは上記比は25:1~10:1の範囲にある工程。式(I)の化合物並びにその溶媒和物及び塩の調製プロセス中に、異なる結晶化条件下で多結晶が出現してもよい。
実施例1:イソプロピル (S)-N-[2-(ピリジン-3-イル-メトキシ)-4-(2-ブロモ-3-(フェニル)ベンジルオキシ)-5-クロロベンジル]セリネート塩酸塩(本実施例は比較例であり、本化合物は公知化合物であり、その調製方法は、国際出願PCT/CN2017/085418号の実施例6と全く同じである)。
室温で、イソプロピル (S)-N-[2-(ピリジン-3-イル-メトキシ)-4-(2-ブロモ-3-(フェニル)ベンジルオキシ)-5-クロロベンジル]セリネート(2.6g)及びイソプロパノール(9ml)を50ml反応フラスコに添加した。この混合物を40℃に加熱し、0.5時間撹拌し、マレイン酸(0.594g)-イソプロパノール(4ml)溶液を滴下しながら加えた。温度を35~45℃に制御し、固体を析出させた後、その混合物をその温度で0.5時間撹拌し、自然に室温まで冷却し、一晩撹拌した。翌日、この混合物を吸引濾過し、濾過ケーキを0.5mlのイソプロパノール及び0.5mlのアセトンで順次洗浄し、淡黄色固体を得たが、これがイソプロピル (S)-N-(2-(ピリジン-3-イル-メトキシ)-4-(2-ブロモ-3-フェニルベンジルオキシ)-5-クロロベンジル)セリネートマレイン酸塩の粗生成物である。室温で、この粗生成物及びアセトン(26ml)を50ml反応フラスコに加え、加熱して還流させ、1.4mlの精製水を滴下して加えた。完全に溶解させた後、混合物を熱濾過にかけた。濾過後、濾過ケーキを50mlの反応フラスコに移し、自然に室温まで冷却し、晶析のために一晩撹拌した。翌日、この混合物を5~15℃に冷却し、2時間撹拌した後、吸引濾過した。濾過ケーキを0.5mlのアセトンで洗浄し、45℃で恒量まで強制風乾し、純品(0.73g)を白色固体として得た。
1)元素分析:
(1)試験装置:微量元素分析装置FLASH1112及び百万分の一天秤MX-5。
(2)試験方法:炭素、水素及び窒素を並行して2回測定した。
(3)測定結果:
(1)試験装置:島津製作所UV-2700紫外可視分光光度計
(2)試験方法:試料を所定濃度の溶液に調製し、同じバッチの溶媒をブランク対照として使用し、1cm吸収セルを用いて190~400nmの範囲で吸収値を測定した。
溶媒:水-メタノール(1:1)、0.1mol/Lの塩酸-メタノール(1:1)、0.1mol/Lの水酸化ナトリウム-メタノール(1:1)
試験溶液濃度:20μl/ml。
(3)実測データ
(1)試験装置:Bruker AVANCE III 500型高分解能超伝導核磁気共鳴分光計
(2)試験条件:溶媒はDMSO-d6であり、内部標準はTMSであった。
(1)試験装置:米国PE製343型旋光計。
(2)試験方法:本発明の生成物を正確に秤量し、DMSOに溶解し、1mlあたり約50mgを含む溶液となるように定量的に希釈し、比旋光度を測定した。
(3)試験温度:20℃
(4)結果
DMSOを溶媒とし、測定濃度を50mg/mlとした場合、実施例2の化合物の比旋光度は+5.5°であった。[α]20 589=+5.5°(C=5、DMSO)。
1)粉末X線回折分析:
(1)試験装置:D8-Advance X線回折計
(2)試験条件:動作電圧:40kV、動作電流:40mA、Cuターゲット。走査速度:0.02度/ステップ、データ取り込み時間:0.1秒/ステップ。
(3)試験結果(図3参照):
2)示差走査熱量測定/熱重量分析(DSC/TG):
(1)試験装置:スイスのMettlerのTGA/DSC3+熱分析計
(2)パラメータ設定:開始温度:35℃;終了温度:250℃;昇温速度:10℃/分。
(3)実測データ:DSC:ピーク温度:174.68℃(吸熱)。
TGA:170℃付近で重量減少が始まり、175℃で重量減少が明らかになった。
(4)分析:DSCは、174.68℃に吸熱ピークがあることを示し、この吸熱ピークは実施例2の化合物の融解から吸収された熱に起因するはずである。TGAは、160℃までは基本的に熱重量曲線に変化はなく、重量減少もないことを示し、これは、実施例2の化合物は結晶化溶媒を含まないことを示唆した。DSC吸熱ピークの頂点(約175℃)まで温度が上昇すると、重量減少が明らかになり、これは、試料の溶融分解に伴う重量減少であった。このDSC吸熱ピークは、実施例2の化合物の分解点であった。
1)実施例1の化合物の安定性
(1)物理的及び化学的な特性
外観:オフホワイトの粉末
融点:119.36℃(DSC法)(図1参照)
純度:99.5%(HPLC規格化法)
logP=2.4
(2)影響因子試験
実験の目的:
マウスメラノーマB16F10に対するPD-L1阻害剤としての実施例1の化合物及び実施例2の化合物のインビボ抗腫瘍効果を、マウスの皮下移植腫瘍モデルで評価した。
実験的解決手段:
動物群分け:実験動物を溶媒対照群、シクロホスファミド80mg/kg群(CTX)、実施例1の化合物5mg/kg群及び10mg/kg群、並びに実施例2の化合物5mg/kg群及び10mg/kg群にそれぞれ分けた。
実験手順:継代培養したB16F10腫瘍株をホモジナイザで粉砕し、滅菌した普通食塩水で2回洗浄し、計数し、腫瘍細胞懸濁液の細胞濃度を普通食塩水で9×106/mlに調整した。この細胞懸濁液0.2mlをC57BL/6Jマウスの右脇の下に接種し、その日を0日目と記録した。接種の翌日、動物を無作為に群分けし、体重測定して投与した。溶媒対照群のマウスには、0.5%CMCを毎日経口投与した。シクロホスファミドは腹腔内投与した。試験対象となる化合物は1日1回経口投与した。処理の過程で、動物を体重測定し、殺処分した。腫瘍組織を剥離し、重量測定し、写真を撮った。最後に、抗腫瘍効果の強さを評価するために、腫瘍抑制率を計算した。
計算及び統計の方法:腫瘍増殖抑制率TGI(%):TGI=(1-T/C)×100 (T:処理群における腫瘍重量、C:陰性対照群における腫瘍重量)。
統計方法:データの統計解析にはGraphpad(グラフパッド)を使用し、一元配置ANOVA検定を使用した、* P<0.05、** P<0.01、*** P<0.001。
投与後、動物を実行し、腫瘍の重量を測定した。マウスメラノーマB16F10に対する実施例1の化合物及び実施例2の化合物の抗腫瘍効果を下記表に示した。
実験の目的:
マウス大腸癌MC38に対するPD-L1阻害剤としての実施例1の化合物及び実施例2の化合物のインビボ抗腫瘍効果を、マウスの皮下移植腫瘍モデルで評価した。
実験的解決手段:
動物群分け:実験動物を溶媒対照群、シクロホスファミド80mg/kg群(CTX)、実施例1の化合物5mg/kg群及び10mg/kg群、並びに実施例2の化合物5mg/kg群及び10mg/kg群にそれぞれ分けた。
実験手順:継代培養したMC38腫瘍株をホモジナイザで粉砕し、滅菌した普通食塩水で2回洗浄し、計数し、腫瘍細胞懸濁液の細胞濃度を普通食塩水で9×106/mlに調整し、この細胞懸濁液0.2mlをC57BL/6Jマウスの右脇の下に接種し、その日を0日目と記録した。接種の翌日、動物を無作為に群分けし、体重測定して投与した。溶媒対照群のマウスには、0.5%CMCを毎日経口投与した。シクロホスファミドは腹腔内投与した。試験対象となる化合物は1日1回経口投与した。処理の過程で、動物を体重測定し、殺処分した。腫瘍組織を剥離し、重量測定し、写真を撮った。最後に、抗腫瘍効果の強さを評価するために、腫瘍抑制率を計算した。
計算及び統計の方法:腫瘍増殖抑制率TGI(%):TGI=(1-T/C)×100 (T:処理群における腫瘍重量、C:陰性対照群における腫瘍重量)。
統計方法:データの統計解析にはGraphpadを使用し、一元配置ANOVA検定を使用した、* P<0.05、** P<0.01、*** P<0.001。
実験結果:
投与後、動物を実行し、腫瘍の重量を測定した。マウス大腸癌MC38に対する実施例1の化合物及び実施例2の化合物の抗腫瘍効果を下記表に示した。
実験の目的:
PD-L1阻害剤としての実施例1の化合物及び実施例2の化合物のインビボ抗腫瘍効果を、ヒト免疫系で再構成したNSG腫瘍保有マウスにおけるヒト肺癌のNCI-H460モデルで評価した。
実験的解決手段:
動物群分け:実験動物を溶媒対照群、シクロホスファミド80mg/kg群(CTX)、実施例1の化合物5mg/kg群及び10mg/kg群、並びに実施例2の化合物5mg/kg群及び実施例2の化合物10mg/kg群にそれぞれ分けた。
実験の手順:新鮮なヒト白血球を分離してPBMCを得た後、尾静脈からNSGマウスに接種し、各マウスには1×107個ずつ接種した。3日目にNCI-H460腫瘍細胞をマウスの脇の下に接種し、各マウスに1×106個ずつ接種した。腫瘍が100~300mm3に成長した後、マウスを群分けして投与した。溶媒対照群のマウスには、0.5%CMCを毎日経口投与した。シクロホスファミドは腹腔内投与した。試験対象となる化合物は1日1回経口投与した。処理の過程で、動物を体重測定し、殺処分した。腫瘍組織を剥離し、重量測定し、写真を撮った。最後に、抗腫瘍効果の強さを評価するために、腫瘍抑制率を計算した。
計算及び統計の方法:腫瘍増殖抑制率TGI(%):TGI=(1-T/C)×100 (T:処理群における腫瘍重量、C:陰性対照群における腫瘍重量)。
統計方法:データの統計解析にはGraphpadを使用し、一元配置ANOVA検定を使用した、* P<0.05、** P<0.01、*** P<0.001。
実験結果:
投与後、動物を実行し、腫瘍の重量を測定した。NCI-H460に対する実施例1の化合物及び実施例2の化合物の抗腫瘍効果を下記表に示した。
マウスメラノーマ高転移性株B16F10の皮下移植腫瘍モデルにおいて、実施例2の化合物の1日経口投与量5mg/kg及び10mg/kgにおける腫瘍抑制率はそれぞれ40%及び55%であり、実施例1の化合物の同じ投与量での腫瘍抑制率はそれぞれ11%及び13%であった。
マウス大腸癌MC38の皮下移植腫瘍モデルにおいて、実施例2の化合物の1日経口投与量5mg/kg及び10mg/kgにおける腫瘍抑制率はそれぞれ75%及び57%であり、実施例1の化合物の同じ投与量での腫瘍抑制率はそれぞれ18%及び27%であった。
ヒト免疫系を再構築したNSG腫瘍保有マウス(NCI-H460)において、実施例2の化合物の1日経口投与量15mg/kgにおける腫瘍抑制率は、実施例1の化合物の腫瘍抑制率より優れていた(腫瘍抑制率:30.6%対24.7%)。
Claims (10)
- 赤外スペクトルによって分析した場合、3059、2984、2841、2761、2519、2170、1988、1968、1807、1741、1716、1623、1602、1580、1505、1481、1460、1446、1425、1401、1389、1368、1309、1262、1242、1205、1171、1111、1095、1069、1040、1004、972、953、924、884、870、864、854、824、788、761、721、703、及び662cm-1±2cm-1の吸収ピークが、前記結晶形A固体物質によって提示される赤外スペクトルの特徴的なピーク位置であることを特徴とする請求項2に記載のイソプロピル (S)-N-(2-(ピリジン-3-イル-メトキシ)-4-(2-ブロモ-3-フェニルベンジルオキシ)-5-クロロベンジル)セリネートマレイン酸塩の結晶形A固体物質。
- 示差走査熱量測定によって分析した場合、10℃/分の昇温速度によるDSCスペクトルにおいて、175℃±3℃に吸熱ピークが存在することを特徴とする請求項2に記載のイソプロピル (S)-N-(2-(ピリジン-3-イル-メトキシ)-4-(2-ブロモ-3-フェニルベンジルオキシ)-5-クロロベンジル)セリネートマレイン酸塩の結晶形A固体物質。
- イソプロピル (S)-N-(2-(ピリジン-3-イル-メトキシ)-4-(2-ブロモ-3-フェニルベンジルオキシ)-5-クロロベンジル)セリネートマレイン酸塩の混晶固体物質であって、任意のゼロではない割合の請求項2に記載のイソプロピル (S)-N-(2-(ピリジン-3-イル-メトキシ)-4-(2-ブロモ-3-フェニルベンジルオキシ)-5-クロロベンジル)セリネートマレイン酸塩の結晶形A固体物質を含むことを特徴とするイソプロピル (S)-N-(2-(ピリジン-3-イル-メトキシ)-4-(2-ブロモ-3-フェニルベンジルオキシ)-5-クロロベンジル)セリネートマレイン酸塩の混晶固体物質。
- 請求項1に記載のイソプロピル (S)-N-(2-(ピリジン-3-イル-メトキシ)-4-(2-ブロモ-3-フェニルベンジルオキシ)-5-クロロベンジル)セリネートマレイン酸塩又は請求項2に記載の結晶形A固体物質の調製方法であって、
イソプロピル (S)-N-(2-(ピリジン-3-イル-メトキシ)-4-(2-ブロモ-3-フェニルベンジルオキシ)-5-クロロベンジル)セリネートをマレイン酸と溶媒中で反応させて塩を形成する工程であって、好ましくは、前記溶媒がイソプロピルアルコール、テトラヒドロフラン又はアセトンである工程と、
得られたイソプロピル (S)-N-(2-(ピリジン-3-イル-メトキシ)-4-(2-ブロモ-3-フェニルベンジルオキシ)-5-クロロベンジル)セリネートマレイン酸塩を、アセトン及び水の混合溶媒中で結晶化する工程であって、アセトンと水の比が200:1~1:1の範囲にあり、好ましくは上記比は50:1~5:1の範囲にあり、より好ましくは上記比は25:1~10:1の範囲にある工程と
を含むことを特徴とする方法。 - 有効成分としての請求項1に記載のイソプロピル (S)-N-(2-(ピリジン-3-イル-メトキシ)-4-(2-ブロモ-3-フェニルベンジルオキシ)-5-クロロベンジル)セリネートマレイン酸塩及びその立体異性体又は請求項2から請求項4のいずれか1項に記載の結晶形A固体物質又は請求項5に記載の混晶固体物質と、その薬学的に許容できる担体又は賦形剤とを含むことを特徴とする医薬組成物。
- PD-1/PD-L1シグナル経路に関連する疾患の予防及び/又は治療のための医薬の製造における、請求項1に記載のイソプロピル (S)-N-(2-(ピリジン-3-イル-メトキシ)-4-(2-ブロモ-3-フェニルベンジルオキシ)-5-クロロベンジル)セリネートマレイン酸塩及びその立体異性体又は請求項2から請求項4のいずれか1項に記載の結晶形A固体物質又は請求項5に記載の混晶固体物質の使用。
- 前記PD-1/PD-L1シグナル経路に関連する疾患が、癌、感染症及び自己免疫疾患から選択されることを特徴とする請求項8に記載の使用。
- 前記癌が、皮膚癌、肺癌、泌尿器腫瘍、血液腫瘍、乳癌、神経膠腫、消化器系腫瘍、生殖器系腫瘍、リンパ腫、神経系腫瘍、脳腫瘍、頭頸部癌から選択され、前記感染症が、細菌感染症及びウイルス感染症から選択され、前記自己免疫疾患が、臓器特異的自己免疫疾患、及び全身性自己免疫疾患から選択され、前記臓器特異的自己免疫疾患が、慢性リンパ球性甲状腺炎、甲状腺機能亢進症、インスリン依存性糖尿病、重症筋無力症、潰瘍性大腸炎、慢性萎縮性胃炎による悪性貧血、肺出血性腎炎症候群、原発性胆汁性肝硬変、多発性硬化症、及び急性特発性多発神経炎を含み、前記全身性自己免疫疾患が、関節リウマチ、全身性エリテマトーデス、全身性血管炎、強皮症、天疱瘡、皮膚筋炎、混合性結合組織病、及び自己免疫性溶血性貧血を含むことを特徴とする請求項9に記載の使用。
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