JP2019514922A - N−{6−(2−ヒドロキシプロパン−2−イル)−2−[2−(メチルスルホニル)エチル]−2h−インダゾール−5−イル}−6−(トリフルオロメチル)ピリジン−2−カルボキサミドの多形体 - Google Patents
N−{6−(2−ヒドロキシプロパン−2−イル)−2−[2−(メチルスルホニル)エチル]−2h−インダゾール−5−イル}−6−(トリフルオロメチル)ピリジン−2−カルボキサミドの多形体 Download PDFInfo
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 to ring carbon atoms
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- C07D213/81—Amides; Imides
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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
- C07D401/02—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 two hetero rings
- C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/86—Hydrazides; Thio or imino analogues thereof
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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Abstract
Description
・製造方法のスケールアップ/スケーラビリティ
・N2−アルキル化反応における高い位置選択性
・クロマトグラフィー分離および精製ステップの回避
・結晶化を介した最終処理
・クラス3溶媒(FDAガイドラインによる)を使用した多形変態の最終調整
図1:化合物(I)の多形体Bの粉末X線ディフラクトグラム
図2:化合物(I)の多形体Aの粉末X線ディフラクトグラム
図3:化合物(I)の1,7−水和物の粉末X線ディフラクトグラム
図4:化合物(I)の多形体BのDSC−およびTGA−サーモグラム
図5:化合物(I)の多形体AのDSC−およびTGA−サーモグラム
図6:化合物(I)の1,7−水和物のDSC−およびTGA−サーモグラム
N2での驚くほど高度に選択的なアルキル化を介した化合物(I)の調製は、以下に記載される:
N−[6−(2−ヒドロキシプロパン−2−イル)−1H−インダゾール−5−イル]−6−(トリフルオロメチル)ピリジン−2−カルボキサミド(中間体5−1)160mg(0.44mmol)を、炭酸カリウム182mgおよびヨウ化カリウム36mgと一緒に、DMF1.0mlに懸濁し、混合物を室温で15分間撹拌した。次いで、2−ブロモエチルメチルスルホン123mgを添加し、混合物を室温で一晩撹拌した。水を添加し、混合物を酢酸エチルで2回抽出し、抽出物を飽和塩化ナトリウム水溶液で洗浄し、疎水性フィルタを通して濾過し、濃縮した。残渣を分取HPLCによって精製すると、標記化合物20mg(収率9.7%)が得られた。
R1は2−(メチルスルホニル)エチルであり;
R4はジフルオロメチル、トリフルオロメチルまたはメチルであり;
R5は水素またはフッ素であり;
好ましくはR4=トリフルオロメチルおよびR5=Hである):
一般式(II)ならびに(V)による化合物の調製は、国際公開第2015/091426号パンフレットに記載されている。この新規な発明の方法は、式(V)で示される化合物に焦点を当てている:
スキーム2は、式(VIII)のアニリン様化合物からの式(I)の純粋な生成物の合成全体を示す。式(I)の生成物は、99面積%(HPLC)超の純度で得られる。各ステップで達成された最良の収率で計算すると、50%の全収率が得られる。これには、最終的な結晶形態の設置も含まれる。
1.アミドカップリング(式(VI)による化合物の調製):収率84%;
2.グリニャール反応、引き続いてクロマトグラフィー精製:収率45%;
3.文献で公知の方法と同様に2−ブロモエチルメチルスルホンでアルキル化し、引き続いてクロマトグラフィー精製:収率9.68%;
新しい方法の利点が極めて明確になる:
(式中、Rはアルキル基、例えばメチル基、エチル基またはn−プロピル基、またはアリール基、例えばフェニル基を表し、芳香族炭化水素溶媒は例えばトルエンまたはキシレンなどの溶媒である)。
以下のステップ(A):
(式(V)の化合物:
と、場合により芳香族炭化水素溶媒、例えばトルエンまたはキシレン中、好ましくは前記溶媒の還流温度で反応させ、
それによって、式(I)の前記化合物を得る)
を含む方法に関する。
(式(VI)の化合物:
場合によりアルカリ金属ハロゲン化物、例えば塩化リチウムの存在下で反応させ、
それによって、式(V)の前記化合物を得る)
によって調製される、上記の式(I)の化合物を調製する方法に関する。
(式(VIII)の化合物:
場合によりカップリング剤、例えば2,4,6−トリプロピル−1,3,5,2,4,6−トリオキサトリホスフィナン2,4,6−三酸化物(T3P)の存在下で反応させ、
それによって、式(VI)の前記化合物を得る)
によって調製される、上記の式(I)の化合物を調製する方法に関する。
第3の態様によると、本発明は、式(I)の化合物:
以下から選択される化合物:
式(IX’)のビニルスルホン化合物:
の使用に関する。
本発明による式(I)の化合物の結晶形態、好ましくは多形体Bは、有用な薬理学的特性を有し得るので、ヒトおよび動物の障害を予防および治療するために使用することができる。本発明による式(I)の化合物の形態は、さらなる治療代替を切り開くことができるので、薬学の強化となり得る。
上記のものに加えて、本発明のIRAK4阻害剤を以下の有効成分と組み合わせることもできる:
サルタン)、利尿薬(例えば、ヒドロクロロチアジド)、カルシウムチャネル遮断薬(例えば、ニフェジピン)、スタチン(例えば、シンバスタチン、フルバスタチン);抗糖尿病薬、例えばメトホルミン、グリニド(例えば、ナテグリニド)、DPP−4(ジペプチジルペプチダーゼ−4)阻害剤(例えば、リナグリプチン、サキサグリプチン、シタグリプチン、ビルダグリプチン)、SGLT2(ナトリウム/グルコース共輸送体2)阻害剤/グリフロジン(例えば、ダパグリフロジン、エンパグリフロジン)、インクレチン模倣薬(ホルモングルコース依存性インスリン分泌性ペプチド(GIP)およびグルカゴン様ペプチド1(GLP−1)アナログ/アゴニスト)(例えば、エキセナチド、リラグルチド、リキシセナチド)、α−グルコシダーゼ阻害剤(例えば、アカルボース、ミグリトール、ボグリボース)およびスルホニルウレア(例えば、グリベンクラミド、トルブタミド)、インスリン増感剤(例えば、ピオグリタゾン)およびインスリン療法(例えば、NPHインスリン、インスリンリスプロ)、低血糖を治療するため、糖尿病およびメタボリックシンドロームを治療するための物質。脂質低下薬、例えばフィブラート系薬剤(例えば、ベザフィブラート、エトフィブラート、フェノフィブラート、ゲムフィブロジル)、ニコチン酸誘導体(例えば、ニコチン酸/ラロピプラント)、エゼチニブ、スタチン(例えば、シンバスタチン、フルバスタチン)、アニオン交換輸送体(例えば、コレスチラミン、コレスチポール、コレセベラム)。慢性炎症性腸疾患を治療するための有効成分(メサラジン、スルファラジン、アザチオプリン、6−メルカプトプリンまたはメトトレキサートなど)、プロバイオティクス細菌(Mutaflor、VSL#3(登録商標)、ラクトバチルスGG(Lactobacillus GG)、ラクトバチルス・プランタルム(Lactobacillus L.acidophilus)、カゼイ菌(L.casei)、ビフィドバクテリウム・インファンティス(Bifidobacterium infantis)35624、エンテロコッカス・フェシウム(Enterococcus fecium)SF68、ビフィドバクテリウム・ロンガム(Bifidobacterium longum)、大腸菌(Escherichia coli)Nissle 1917)、抗生物質(例えば、シプロフロキサシンおよびメトロニダゾールなど)、止瀉薬(例えば、ロペラミドまたはレキサチブ(ビサコジル)など)。エリテマトーデスを治療するための免疫抑制剤(グルココルチコイドなど)および非ステロイド系抗炎症薬(NSAID)、コルチゾン、クロロキン、シクロスポリン、アザチオプリン、ベリムマブ、リツキシマブ、シクロホスファミド。例として、排他的でないが、臓器移植用のカルシニューリン阻害薬(例えば、タクロリムスおよびシクロスポリン)、細胞分裂阻害薬(例えば、アザチオプリン、ミコフェノール酸モフェチル、ミコフェノール酸、エベロリムスまたはシロリムス)、ラパマイシン、バシリキシマブ、ダクリズマブ、抗CD3抗体、抗Tリンパ球グロブリン/抗リンパ球グロブリン。皮膚科学的障害のための、ビタミンD3類似体、例えばカルシポトリオール、タカルシトールまたはカルシトリオール、サリチル酸、尿素、シクロスポリン、メトトレキサート、エファリズマブ。
式(I)の化合物の結晶形態が全身および/または局所活性を有することが可能である。この目的のために、これらを適当な様式で、例えば、経口、非経口、肺、経鼻、舌下、舌、頬側、直腸、膣、真皮、経皮、結膜、耳経路を介して、またはインプラントもしくはステントとして投与することができる。
・充填剤および担体(例えば、セルロース、微結晶セルロース(例えば、Avicel(登録商標)など)、ラクトース、マンニトール、デンプン、リン酸カルシウム(例えば、Di−Cafos(登録商標)など))、
・軟膏基剤(例えば、黄色ワセリン、パラフィン、トリグリセリド、蝋、羊毛蝋、羊毛蝋アルコール、ラノリン、親水軟膏、ポリエチレングリコール)、
・坐剤基剤(例えば、ポリエチレングリコール、カカオ脂、硬質脂肪)、
・溶媒(例えば、水、エタノール、イソプロパノール、グリセロール、プロピレングリコール、中鎖トリグリセリド脂肪油、液体ポリエチレングリコール、パラフィン)、
・界面活性剤、乳化剤、分散剤または湿潤剤(例えば、ドデシル硫酸ナトリウム)、レシチン、リン脂質、脂肪アルコール(例えば、Lanette(登録商標)など)、ソルビタン脂肪酸エステル(例えば、Span(登録商標)など)、ポリオキシエチレンソルビタン脂肪酸エステル(例えば、Tween(登録商標)など)、ポリオキシエチレン脂肪酸グリセリド(例えば、Cremophor(登録商標)など)、ポリオキシエチレン脂肪酸エステル、ポリオキシエチレン脂肪アルコールエーテル、グリセロール脂肪酸エステル、ポロキサマー(例えば、Pluronic(登録商標)など))、
・緩衝剤、酸および塩基(例えば、リン酸塩、炭酸塩、クエン酸、酢酸、塩酸、水酸化ナトリウム溶液、炭酸アンモニウム、トロメタモール、トリエタノールアミン)、
・等張剤(例えば、グルコース、塩化ナトリウム)、
・吸着剤(例えば、高分散性シリカ)、
・増粘剤、ゲル形成剤、増ちょう剤および/または結合剤(例えば、ポリビニルピロリドン、メチルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、カルボキシメチルセルロースナトリウム、デンプン、カルボマー、ポリアクリル酸(例えば、Carbopol(登録商標)など);アルギン酸塩、ゼラチン)、
・崩壊剤(例えば、加工デンプン、カルボキシメチルセルロース−ナトリウム、デンプングリコール酸ナトリウム(例えば、Explotab(登録商標)など)、架橋ポリビニルピロリドン、クロスカルメロース−ナトリウム(例えば、AcDiSol(登録商標)など))、
・流動調節剤、潤滑剤、滑剤および離型剤(例えば、ステアリン酸マグネシウム、ステアリン酸、タルク、高分散性シリカ(例えば、Aerosil(登録商標)など))、
・コーティング材料(例えば、糖、シェラック)および迅速にまたは修飾された様式で溶解するフィルムまたは拡散膜のためのフィルム形成剤(例えば、ポリビニルピロリドン(例えば、Kollidon(登録商標)など)、ポリビニルアルコール、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、エチルセルロース、ヒドロキシプロピルメチルセルロースフタレート、酢酸セルロース、セルロースアセテートフタレート、ポリアクリレート、ポリメタクリレート(例えば、Eudragit(登録商標)など))、
・カプセル材料(例えば、ゼラチン、ヒドロキシプロピルメチルセルロース)、
・合成ポリマー(例えば、ポリ乳酸、ポリグリコール酸、ポリアクリレート、ポリメタクリレート(例えば、Eudragit(登録商標)など)、ポリビニルピロリドン(例えば、Kollidon(登録商標)など)、ポリビニルアルコール、ポリ酢酸ビニル、ポリエチレンオキシド、ポリエチレングリコーならびにこれらのコポリマーおよびブロックコポリマー)、
・可塑剤(例えば、ポリエチレングリコール、プロピレングリコール、グリセロール、トリアセチン、クエン酸トリアセチル、フタル酸ジブチル)、
・浸透促進剤、
・安定剤(例えば、抗酸化剤(例えば、アスコルビン酸、パルミチン酸アスコルビル、アスコルビン酸ナトリウム、ブチルヒドロキシアニソール、ブチルヒドロキシトルエン、没食子酸プロピルなど)、
・保存剤(例えば、パラベン、ソルビン酸、チオメルサール、塩化ベンザルコニウム、酢酸クロルヘキシジン、安息香酸ナトリウム)、
・着色剤(例えば、無機顔料(例えば、酸化鉄、二酸化チタンなど))、
・香味剤、甘味剤、香味−および/または臭気マスキング剤。
哺乳動物において上で識別された状態の治療を決定するための薬理学的アッセイ、ならびにこれらの結果とこれらの状態を治療するために使用される既知の医薬品の結果との比較による、障害の治療に有用な化合物を評価するために知られている実験室技術に基づいて、本発明の化合物の有効投与量を各所望の適応症を治療するために容易に決定することができる。これらのうちのある状態の治療で投与されるべき有効成分の量は、使用される特定の化合物および投与量単位、投与様式、治療期間、治療される患者の年齢および性別、ならびに治療される状態の性質および程度などの考慮事項により広く変化し得る。
以下の実施例が本発明を説明する。
Perkin−Elmer製の示差走査熱量計(モデルDSC7、Pyris−1またはDiamond)を用いてDSCサーモグラムを記録した。非気密アルミニウムパンを用いて20K/分の加熱速度で測定を行った。フローガスは窒素とした。試料調製はなかった。
HPLC
方法A
装置:1290 Infinity Sampler&Agilent 1100シリーズを備えたAgilent Technologie 1260 Infinity
Zorbax SB−AQ、50*4,6mm、1,5μm
緩衝液:リン酸二水素アンモニウムpH:2.4
アセトニトリル
0分。5%緩衝液
8.3分。80%緩衝液
11分。80%緩衝液
210 nm/4 nm
1.2ml/分。
装置 1.Agilent Technologies、HPLC 1290 Infinity(DAD付き):超高速液体クロマトグラフサーモスタット制御カラムオーブン、UV検出器およびデータ評価システム
2.ステンレス鋼カラム
長さ:5cm
内径:2.1mm
充填:SB−Aq Rapid Resolution HD、1.8μm
試薬 1.アセトニトリル、HPLC用
2.テトラヒドロフラン、HPLC用
3.水、分析グレード
3.リン酸85%、分析グレード
試験溶液 式(I)の試料化合物を0.5mg/mlの濃度でテトラヒドロフランに溶解する。
(例えば、正確に秤量した式(I)の試料化合物約25mgを、アセトニトリル50mlに溶解する)
較正溶液 参照標準化合物*を、0.5mg/mlの濃度でアセトニトリルに溶解する(例えば、正確に秤量した参照標準物質約25mgを、アセトニトリル50mlに溶解する)
*参照標準化合物とは、高純度の化合物、すなわち97面積%HPLC超として分析されなければならない化合物を意味する
対照溶液 較正溶液と同一の対照溶液を調製する。さらに、対照溶液は少量の有機不純物を含有する。
検出感度溶液 0.76μg/mlの濃度に希釈した成分Solbrol P(CAS番号:94−13−3;プロピル4−ヒドロキシベンゾエート)(室温約2.80分)を含有する溶液を調製する。
HPLC条件 上記条件は、例えば以下である。最適な分離を達成するために、これらを、必要に応じて、クロマトグラフの技術的可能性およびそれぞれのカラムの特性に適合させるべきである。
溶離液 A.水:テトラヒドロフラン(v:v)9:1、次いで、0.1%リン酸85%
B.アセトニトリル:テトラヒドロフラン9:1
流量 0.8mL/分
カラムオーブンの温度 40℃
サンプルチャンバーの温度 室温
検出 測定波長:220 nm
帯域幅:6nm
注入体積 2.0μl
吸引速度 200μL/分
ニードル洗浄 フラッシュポート用溶媒:テトラヒドロフラン
Datenrate 10Hz
細胞寸法 10mm
平衡時間 10分(開始条件で)
勾配
アッセイ(含量)の計算 アッセイを、線形回帰を使用し、有効なクロマトグラフデータシステム(例えば、Empower)を用いて、参照標準の試料重量、アッセイおよび重量を考慮して計算する。
ヘッドスペースガスクロマトグラフィー(GC−HS)を介した残留溶媒分析
分割注入およびFID(カラム:Restek Rxi Sil MS;長さ:20μm;内径:0.18mm;df=1μm)を用いるAgilent 6890ガスクロマトグラフ。インジェクター温度160℃、流量1.2ml/分(H2)分割比18、オーブン温度40℃(4.5分)−14℃/分−70℃−90℃/分−220℃(1.69分)。検出器:温度300℃、400ml/分(合成空気)、40ml/分(H2)、30ml/分(N2)、速度20Hz。
試料濃度:DMF2ml中物質20mg
N−{6−(2−ヒドロキシプロパン−2−イル)−2−[2−(メチルスルホニル)エチル]−2H−インダゾール−5−イル}−6−(トリフルオロメチル)ピリジン−2−カルボキサミド(I)の調製
実施例番号1
メチル5−({[6−(トリフルオロメチル)ピリジン−2−イル]カルボニル}アミノ)−1H−インダゾール−6−カルボキシレート(VI)
反応混合物を周囲温度(20℃)に加温する。温度を20〜25℃に保ちながら水3000gを添加する。撹拌を10分間続ける。4N炭酸ナトリウム水溶液を用いて、pHを約7.4(7〜8)に調整する。撹拌を10分間続ける。必要であれば、4N炭酸ナトリウム水溶液を用いて、pHを再び7.4に調整する。
上記の手順に従って、出発物質(メチル5−アミノ−1H−インダゾール−6−カルボキシレート)2kgを使用する4つのバッチを技術実験室で製造した:
収率:
バッチ番号1:3476g(95%)
バッチ番号2:3449g(95%)
バッチ番号3:3476g(95%)
バッチ番号4:3494g(96%)
MS(ESI pos):m/z=365(M+H)+
1H NMR(500 MHz,DMSO−d6):δ[ppm]:3.98(s,3 H),8.21(d,1H),8.25(s,1H),8.31(s,1H),8.39(t,1H),8.48(d,1H),9.16(s,1H),12.57(s,1H),13.45(br s,1H).
1H NMR(300 MHz,DMSO−d6):δ[ppm]=3.97(s,3 H),8.13−8.27(m,2 H),8.30(s,1 H),8.33−8.45(m,1 H),8.45−8.51(m,1 H),9.15(s,1 H),12.57(s,1 H),13.44(br s,1 H).
N−[6−(2−ヒドロキシプロパン−2−イル)−1H−インダゾール−5−イル]−6−(トリフルオロメチル)ピリジン−2−カルボキサミド(V)
以下の節で、反応手順および後処理の様々な変形を記載する。これらの手順は、それぞれの技術プラントの所定の条件で方向づけられる。
メチル5−({[6−(トリフルオロメチル)ピリジン−2−イル]カルボニル}アミノ)−1H−インダゾール−6−カルボキシレート(VI)50g(137.255mmol)をTHF800mlに溶解した。常圧(1気圧)下、THF約300mlを70℃で留去した。次いで、溶液を0〜3℃に冷却した。
収量:39.42g(78.83%、純度97.84面積%HPLC)
MS(ESIpos):m/z=365(M+H)+
1H−NMR(400MHz,DMSO−d6):δ[ppm]=1.63(s,6H),5.99(s,1H),7.50(s,1H),8.06(s,1H),
8.17(d,1H),8.37(t,1H),8.46(d,1H),8.78(s,1H),12.33(s,1H),12.97(br s,1H).
メチル5−({[6−(トリフルオロメチル)ピリジン−2−イル]カルボニル}アミノ)−1H−インダゾール−6−カルボキシレート(VI)30g(82.4mmol)をTHF480mlに溶解した。常圧(1気圧)下、THF約180mlを70℃で留去した。次いで、混合物(わずかな懸濁液)を0〜3℃に冷却した。
HPLC(方法A):Rt=5.8分。
MS(ESI pos):m/z=365(M+H)+
1H−NMR(400MHz,DMSO−d6):δ[ppm]=1.63(s,6H),5.99(s,1H),7.50(s,1H),8.06(s,1H),
8.17(d,1H),8.37(t,1H),8.46(d,1H),8.78(s,1H),12.33(s,1H),12.97(br s,1H).
メチル5−({[6−(トリフルオロメチル)ピリジン−2−イル]カルボニル}アミノ)−1H−インダゾール−6−カルボキシレート(VI)30g(82.4mmol)をTHF600mlに溶解した。常圧(1気圧)下、THF約150mlを70℃で留去した。次いで、混合物(わずかな懸濁液)を0〜3℃に冷却した。
HPLC(方法A):Rt=5.8分。
MS(ESI pos):m/z=365 M+H)+
1H−NMR(400MHz,DMSO−d6):δ[ppm]=1.63(s,6H),5.99(s,1H),7.50(s,1H),8.06(s,1H),
8.17(d,1H),8.37(t,1H),8.46(d,1H),8.78(s,1H),12.33(s,1H),12.97(br s,1H).
この変形を、kgスケール(10kg超)の技術的バッチの製造に使用した(表4参照)。
HPLC(方法A):Rt=5.8分。
MS(ESI pos):m/z=365(M+H)+
1H−NMR(400MHz,DMSO−d6):δ[ppm]=1.63(s,6H),5.99(s,1H),7.50(s,1H),8.06(s,1H),
8.17(d,1H),8.37(t,1H),8.46(d,1H),8.78(s,1H),12.33(s,1H),12.97(br s,1H).
イソプロパノール/水中での撹拌を介した精製
粗生成物の純度に応じて、好ましくは1:1のイソプロパノールと水との混合物中での撹拌を介した追加の精製ステップを行うことができる。粗生成物の純度に応じて、粗出発材料に対して2〜10容量の範囲で撹拌を行う。以下の実施例は、3容量のイソプロパノール/水中での撹拌を記載する:
HPLC(方法A):Rt=5.8分。
MS(ESIpos):m/z=365(M+H)+
1H−NMR(400MHz,DMSO−4):δ[ppm]=1.63(s,6H),5.99(s,1H),7.50(s,1H),8.06(s,1H),
8.17(d,1H),8.37(t,1H),8.46(d,1H),8.78(s,1H),12.33(s,1H),12.97(br s,1H).
N−{6−(2−ヒドロキシプロパン−2−イル)−2−[2−(メチルスルホニル)エチル]−2H−インダゾール−5−イル}−6−(トリフルオロメチル)ピリジン−2−カルボキサミド(I)
この変形を、kgスケールの技術的バッチの製造に使用し、これは国際公開第2016/083433号パンフレットに記載されるプロトコルに従う。
HPLC(方法B):Rt=3.07分。
MS(ESI pos):m/z=471(M+H)+
1H NMR(400 MHz,DMSO−d6):δ[ppm]=1.63(s,6 H),2.90(s,3 H),3.85(t,2 H),4.86(t,2 H),5.97(s,1 H),7.59(s,1 H),8.13−8.19(m,1 H),8.37(s,1 H),8.41−8.48(m,2 H),8.74(s,1 H),12.37(s,1 H).
HPLC(方法B):Rt=3.07分。
MS(ESI pos):m/z=471(M+H)+
1H NMR(400 MHz,DMSO−d6):δ[ppm]=1.63(s,6 H),2.90(s,3 H),3.85(t,2 H),4.86(t,2 H),5.97(s,1 H),7.59(s,1 H),8.16(d,1 H),8.37(t,1 H),8.41−8.48(m,2 H),8.74(s,1 H),12.37(s,1 H).
この変形を、kgスケールの技術的バッチの製造に使用した。
HPLC(方法B):Rt=3.07分。
MS(ESI pos):m/z=471(M+H)+
1H NMR(400 MHz,DMSO−d6):δ[ppm]=1.63(s,6 H),2.90(s,3 H),3.85(t,2 H),4.86(t,2 H),5.97(s,1 H),7.59(s,1 H),8.16(d,1 H),8.37(t,1 H),8.41−8.48(m,2 H),8.74(s,1 H),12.37(s,1 H).
変形番号2として記載される手順に従って、出発材料(V)に関して3.396kgおよび1.699kgのスケールのバッチを製造した:
N−{6−(2−ヒドロキシプロパン−2−イル)−2−[2−(メチルスルホニル)エチル]−2H−インダゾール−5−イル}−6−(トリフルオロメチル)ピリジン−2−カルボキサミド(I)の多形体の調製
N−{6−(2−ヒドロキシプロパン−2−イル)−2−[2−(メチルスルホニル)エチル]−2H−インダゾール−5−イル}−6−(トリフルオロメチル)ピリジン−2−カルボキサミド(I)の多形体Bの調製
cGMPグレード材料の製造および錠剤製造のための結晶形態の調整のために、追加の精製ステップを導入した。
N−{6−(2−ヒドロキシプロパン−2−イル)−2−[2−(メチルスルホニル)エチル]−2H−インダゾール−5−イル}−6−(トリフルオロメチル)ピリジン−2−カルボキサミドの多形体Aの調製
A)N−{6−(2−ヒドロキシプロパン−2−イル)−2−[2−(メチルスルホニル)エチル]−2H−インダゾール−5−イル}−6−(トリフルオロメチル)ピリジン−2−カルボキサミド400mgを還流下でTHF40mLに溶解した。溶液を濾過した。清澄な溶液の蒸発乾固を、室温または冷蔵庫または冷凍庫での貯蔵によって行った。
N−{6−(2−ヒドロキシプロパン−2−イル)−2−[2−(メチルスルホニル)エチル]−2H−インダゾール−5−イル}−6−(トリフルオロメチル)ピリジン−2−カルボキサミドの多形体Bの調製
A)N−{6−(2−ヒドロキシプロパン−2−イル)−2−[2−(メチルスルホニル)エチル]−2H−インダゾール−5−イル}−6−(トリフルオロメチル)ピリジン−2−カルボキサミド400mgを還流下でアセトニトリル40mLに溶解した。溶液を濾過し、清澄な溶液を室温での貯蔵によって蒸発乾固した。
N−{6−(2−ヒドロキシプロパン−2−イル)−2−[2−(メチルスルホニル)エチル]−2H−インダゾール−5−イル}−6−(トリフルオロメチル)ピリジン−2−カルボキサミドの擬似多形体(1,7水和物)の調製
N−{6−(2−ヒドロキシプロパン−2−イル)−2−[2−(メチルスルホニル)エチル]−2H−インダゾール−5−イル}−6−(トリフルオロメチル)ピリジン−2−カルボキサミド100mgを、エタノール/水の1:1混合物1mLに懸濁し、室温で2週間撹拌した。固体を濾別し、室温での貯蔵によって乾燥させた。
アノード材料 Cu
K−α1[Å] 1,54060
発生装置設定 40mA、40kV
一次ビームモノクロメータ 焦点を合わせるX線鏡
試料回転 はい
スキャン軸 ゴニオ
開始位置[2θ°] 2.0066
終了位置[2θ°] 37.9906
N−{6−(2−ヒドロキシプロパン−2−イル)−2−[2−(メチルスルホニル)エチル]−2H−インダゾール−5−イル}−6−(トリフルオロメチル)ピリジン−2−カルボキサミドの多形体AもしくはBまたは擬似多形体(1,7−水和物)の1つを含有する医薬組成物
式(I)の化合物の微粉化形態、ラウリル硫酸ナトリウム、ヒプロメロース3cPおよび精製水をバルクで混合することによって、造粒液を調製する。マンニトール、微結晶セルロースおよびクロスカルメロースナトリウムを混合する。このブレンドを、流動床造粒機中の造粒液で造粒する。顆粒を乾燥させ、ふるい分けする。
N−{6−(2−ヒドロキシプロパン−2−イル)−2−[2−(メチルスルホニル)エチル]−2H−インダゾール−5−イル}−6−(トリフルオロメチル)ピリジン−2−カルボキサミド(原体)の多形体B 15mgまたは120mgを含有するコーティング錠剤を、チャイルドプルーフ型白色ポリプロピレン/ポリエチレンスクリューキャップ栓を備えたHDPE(高密度ポリエチレン)ボトルにパッケージングする。このパッケージング構成は、光および湿気からの十分な保護を提供する。
Claims (18)
- その多形A、その多形Bおよびその1,7−水和物、またはこれらの混合物からなる群から選択される、式(I)
- 多形Bである、請求項1に記載の化合物の形態。
- 2θ値±0.2°として示される少なくとも以下の反射:9.7、10.1、15.4を示す粉末X線回折(25℃および放射線源としての銅Kα1)によって特徴付けられる多形Bである、請求項1に記載の化合物の形態。
- 2θ値±0.2°として示される少なくとも以下の反射:9.7、10.1、15.4、16.1、20.2を示す粉末X線デ回折(25℃および放射線源としてのCu−Kα1)によって特徴付けられる多形Bである、請求項1に記載の化合物の形態。
- 2θ値±0.2°として示される少なくとも以下の反射:9.7、10.1、15.4、16.1、20.2、22.3を示す粉末X線回折(25℃および放射線源としてのCu−Kα1)によって特徴付けられる多形Bである、請求項1に記載の化合物の形態。
- 2θ値±0.2°として示される少なくとも以下の反射:9.7、10.1、15.4、16.1、20.2、22.3、25.2を示す粉末X線回折(25℃および放射線源としてのCu−Kα1)によって特徴付けられる多形Bである、請求項1に記載の化合物の形態。
- 主に式(I)の化合物の多形体A、多形体Bおよび1,7−水和物からなる群から選択される結晶形態のただ1つを含み、有意な割合の式(I)の化合物の別の形態を含まない医薬組成物。
- その多形体A、多形体Bおよび1,7−水和物、その非晶形態またはこれらの混合物からなる群から選択される式(I)の化合物の結晶形態と、さらに薬学的に許容される賦形剤とを含む医薬組成物。
- 主に式(I)の化合物の多形体Bのみを含み、有意な割合の式(I)の化合物の別の形態を含まない、請求項8に記載の医薬組成物。
- 組成物中に存在する式(I)の化合物の全ての形態の総量に対して、85重量%超の式(I)の化合物の多形体Bを含む、請求項8に記載の医薬組成物。
- 組成物中に存在する式(I)の化合物の全ての形態の総量に対して、90重量%超の式(I)の化合物の多形体Bを含む、請求項10に記載の医薬組成物。
- 新生物障害、皮膚科学的障害、婦人科障害、心血管障害、肺障害、眼科学的障害、神経障害、代謝障害、肝障害、炎症性障害、自己免疫障害および疼痛の治療および/または予防に使用するための請求項1から6のいずれか一項に記載の化合物の結晶形態。
- リンパ腫、黄斑変性、乾癬、エリテマトーデス、多発性硬化症、COPD、痛風、NASH、肝線維症、インスリン抵抗性、メタボリックシンドローム、脊椎関節炎および関節リウマチ、子宮内膜症および子宮内膜症関連疼痛ならびに他の子宮内膜症関連症状、例えば月経困難症、性交疼痛症、排尿障害および排便障害の治療および/または予防に使用するための請求項1から6のいずれか一項に記載の化合物の結晶形態。
- 新生物障害、皮膚科学的障害、婦人科障害、心血管障害、肺障害、眼科学的障害、神経障害、代謝障害、肝障害、炎症性障害、自己免疫障害および疼痛の治療および/または予防に使用するための請求項7から11のいずれか一項に記載の医薬組成物。
- リンパ腫、黄斑変性、乾癬、エリテマトーデス、多発性硬化症、COPD、痛風、NASH、肝線維症、インスリン抵抗性、メタボリックシンドローム、脊椎関節炎および関節リウマチ、子宮内膜症および子宮内膜症関連疼痛ならびに他の子宮内膜症関連症状、例えば月経困難症、性交疼痛症、排尿障害および排便障害の治療および/または予防に使用するための請求項7から11のいずれか一項に記載の医薬組成物。
- 新生物障害、皮膚科学的障害、婦人科障害、心血管障害、肺障害、眼科学的障害、神経障害、代謝障害、肝障害、炎症性障害、自己免疫障害および疼痛を治療または予防するための医薬組成物を製造するための、請求項1から6のいずれか一項に定義される化合物の使用。
- リンパ腫、黄斑変性、乾癬、エリテマトーデス、多発性硬化症、COPD、痛風、NASH、肝線維症、インスリン抵抗性、メタボリックシンドローム、脊椎関節炎および関節リウマチ、子宮内膜症および子宮内膜症関連疼痛ならびに他の子宮内膜症関連症状、例えば月経困難症、性交疼痛症、排尿障害および排便障害を治療または予防するための医薬組成物を製造するための、請求項1から6のいずれか一項に定義される化合物の使用。
- 安定な医薬組成物を製造するための、請求項1から6のいずれか一項に定義される化合物の使用。
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PCT/EP2017/059767 WO2017186703A1 (en) | 2016-04-29 | 2017-04-25 | Polymorphic form of n-{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulphonyl)ethyl]-2h-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide |
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