JP2020530835A - Rorガンマの阻害剤 - Google Patents
Rorガンマの阻害剤 Download PDFInfo
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- JP2020530835A JP2020530835A JP2020503929A JP2020503929A JP2020530835A JP 2020530835 A JP2020530835 A JP 2020530835A JP 2020503929 A JP2020503929 A JP 2020503929A JP 2020503929 A JP2020503929 A JP 2020503929A JP 2020530835 A JP2020530835 A JP 2020530835A
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A61K31/33—Heterocyclic compounds
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A61P19/00—Drugs for skeletal disorders
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
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Abstract
Description
[0001]本出願は、その全内容が参照により本明細書に組み込まれる、2017年7月24日出願の国際出願番号PCT/CN2017/094043への優先権の利益を主張する。
[0006]一態様では、本明細書において、化合物1の安定な臭化水素塩形態が提供される。他の塩形態と異なり、開示されたHBr塩は、分解の懸念が最小限で、または酸素不含雰囲気中での作業などの特別な予防措置の必要性が最低限で調製され得る。例えば、以下の実施例項目を参照されたい。
[0039]さらに他の態様では、本明細書に記載した塩および結晶形態のうちの1つまたは複数を製造する方法が明細書に記載される。
[0040]用語「形態A」は、単独で使用されている場合、化合物1の結晶多形体Aを指す。用語「形態A」、「化合物1の形態A」および「化合物1の結晶形態A」は、互換的に使用される。同様に、用語「形態B」は、単独で使用されている場合、化合物1の結晶多形体Bを指す。用語「形態B」、「化合物1の形態B」および「化合物1の結晶形態B」は、互換的に使用される。同様に、用語「形態C」は、単独で使用されている場合、化合物1の結晶多形体Cを指す。用語「形態C」、「化合物1の形態C」および「化合物1の結晶形態C」は、互換的に使用される。同様に、用語「形態D」は、単独で使用されている場合、化合物1の結晶多形体Dを指す。用語「形態D」、「化合物1の形態D」および「化合物1の結晶形態D」は、互換的に使用される。同様に、用語「形態E」は、単独で使用されている場合、化合物1の結晶多形体Eを指す。用語「形態E」、「化合物1の形態E」および「化合物1の結晶形態E」は、互換的に使用される。
[0048]一態様では、本開示は、化合物1の結晶形態A、結晶形態B、結晶形態C、結晶形態Dおよび結晶形態Eを提供する。
[0055]一態様では、結晶形態A、C、DまたはEは、それぞれ独立して、例えば水と溶媒和されている(すなわち、水和物)などの、溶媒和物であってもよい。
[0056]一態様では、化合物1の開示した形態の複数のうちの1種または化合物1の開示した形態の複数のうちの1種、および薬学的に許容される担体を含む組成物を使用する、RORγによって媒介される疾患または障害を有する対象(例えば、ヒト)を処置する方法が提供される。一態様では、開示された形態の量は、生物学的試料または対象において、RORγに対してインバースアゴニストまたはアンタゴニストとして有効となるような量である。ある種の態様では、提供された組成物は、このような組成物を必要とする対象に投与するために製剤化される。一部の態様では、提供された組成物は、対象に経口投与するために製剤化される。
[0065]一態様では、上で列挙した疾患および障害のうちの1つまたは複数を処置する際に使用するための、化合物1の開示した形態が提供される。
[0068]化合物1の一臭化水素塩およびビス臭化水素塩を調製する方法が、本明細書において提供される。化合物1および前駆体物質を調製するための出発材料および合成方法は、例えば、その内容が参照により本明細書に組み込まれている米国特許第9,266,886号の一般手順Bに見いだすことができる。
[0069]化合物1のビス臭化水素塩を形成させるため、2段階法を最初に開発した。例えば、実施例項目中のスキーム5を参照されたい。この一部は、スキーム1としてここに図示されている。この方法は、まず、化合物1の一臭化水素塩を最初に形成して単離し、次いで、化合物1の一臭化水素塩をビス臭化水素塩に変換することで構成される。
[0071]一態様では、工程iv)における溶液に、種晶が添加される。一態様では、化合物1の結晶形態Dであるビス臭化水素塩は、冷却すると(例えば、30分/5〜6時間で5℃まで)、工程iv)における溶液から沈殿し、ろ過される。
B.1工程法
[0081]化合物1のビス臭化水素塩を調製するための1工程法も特定した。この例では、還元アミノ化反応において、溶媒をCH2Cl2からEtOHに交換し、次いで還元アミノ化混合物を中和し、得られた遊離塩基を沈殿させると、高度に純粋な遊離塩基生成物を、または少なくとも、一臭化水素塩を単離する個別の工程なしにそれをビス臭化水素塩に直接変換することが可能なほど十分に純粋な形態の遊離塩基生成物が得られることを見いだした。この方法は、以下のスキーム6に図示されており、この一部は、ここではスキーム3として示されている。
材料/方法
示差走査熱量測定(DSC)
[0095]DSCは、TA Instruments2920示差走査熱量測定を使用して行った。温度較正は、NISTにより追跡可能なインジウム金属を使用して行った。試料をアルミニウム製のTzero圧着パン(T0C)内に置き、その重量を正確に記録した。試料用パンとして構成される秤量済みのアルミニウム製パンを、セルの参照側に置いた。各サーモグラムに関するデータアクイジションパラメーターおよびパン構成は、図中の画像に表示される。サーモグラム上の方法コードは、開始温度および終了温度、ならびに加熱速度の略称である。例えば、(−30)−250−10は、「−30℃から10℃/分で250℃まで」を意味する。
[0096]TG分析は、TA Instruments Q5000 IR熱重量分析器を使用して行った。温度較正は、ニッケルおよびAlumel(商標)を使用して行った。各試料を白金製パンに置いた。この試料を気密密閉し、蓋に穴を開けて、次に、TG炉に挿入した。炉を窒素下で加熱した。各サーモグラムに関するデータアクイジションパラメーターは、図中に表示される。サーモグラム上の方法コードは、開始温度および終了温度、ならびに加熱速度の略称である。例えば、00−350−10は、「周囲℃から10℃/分で350℃まで」を意味する。
[0097]XRPDパターンは、Optix長高精度焦点源(Optix long,fine−focus source)を使用して発生させたCu照射線の入射ビームを使用する、PANalytical X‘Pert PRO MPD回折計を用いて収集した。楕円状傾斜多層ミラーを使用して、試験体を通して検出器表面にCu Kα X線の焦点を合わせた。分析前に、ケイ素試験体(NIST SRM 640e)を分析し、Si 111ピークの観察位置が、NISTによる認証位置と一致していることを検証した。試料の試験体を、3μmの厚みのフィルムの間に挟んで、透過幾何学で分析した。ビームストップ、短い散乱防止エクステンション(short antiscatter extension)、散乱防止ナイフエッジを使用して、空気により発生するバックグラウンドを最小限にした。入射ビームおよび回折ビームに対するソラースリットを使用して、軸発散に起因する広がりを最小限にした。回折パターンは、試験体から240nmに位置する走査型位置高感度検出器(X’Celerator)およびデータ収集ソフトウェアv.2.2bを使用して収集した。各パターンのデータアクイジションパラメーターは、ミラーの前の発散スリット(DS)を含む、この報告書のデータ項目における画像の上に表示する。
[0098]化合物1は、特に溶液中で、非常に酸化され易いので、この化合物の安定な塩形態を生成するのは著しく困難であった。
[00102]異なる水分活性を有する様々な溶媒中、化合物1のアモルファス臭化水素塩を用いて開始したスラリー実験を行った。合計で5種の結晶性臭化水素塩形態(一HBr塩およびビスHBr塩両方)が見いだされ、形態A、形態B、形態C、形態Dおよび形態Eとして分類した。これらの5種の形態の各々の要約を以下に議論する。化合物1のアモルファス臭化水素塩は、その内容が参照により本明細書に組み込まれている米国特許第9,266,886号において、化合物2に関して記載されている一般手順Bに準拠して調製した。
[00106]化合物1のアモルファスHBr塩を、様々な溶媒中でスラリー形成させた。アモルファスHBr塩50mgを、酢酸エチル(EA)、エタノール(EtOH)、メチル−tert−ブチル−エーテル(MtBEまたはMTBE)、酢酸イソプロピル(IPAc)、メチルエチルケトン(MEK)およびメチルイソブチルケトン(MIBK)溶媒(約10体積分)中、10℃で20時間、懸濁させた。窒素保護下で、懸濁液から試料を採取し、50℃で10分間、乾燥した。残留固体はすべて、依然としてアモルファスであった。
[00115]上で説明した通り、形態Aに関する結晶化実験中に、この物質は、最初に、油状物へと変換された。数時間、油状物をスラリー形成させた後に、この油状物は、固体へと徐々に変換された。ここで課題を決定しなかったが、プラント中での操作のために、油状物段階に経由すると、大規模での生成物形成に問題が生じる恐れがあった。この潜在的な問題を克服するため、新しいな形態である形態Cの知見に最終的に至る他の溶媒系を探索した。
[00124]形態Dを調製するため、1gのアモルファス一臭化水素塩形態Bを反応器に投入する。固体が完全に溶解するまで、室温で5体積分のMeOHを加える。室温で40%HBr/水溶液(1.2当量)、次いで8〜9体積分のMtBE、および種晶を加える。この混合物を30分間〜1時間、保持し、30分/5〜6時間(2つの個別の実験;速い/遅い冷却速度)で5℃まで冷却し、一晩、スラリー形成させた。2〜3時間で、14〜15体積分のMtBEを加え、この混合物を2〜3時間スラリー形成させて、ろ過し、次に、45℃で乾燥する。
[00128]形態Dに到達する2工程形成が、以下のスキーム5に示される。中間体2は、その内容が参照により本明細書に組み込まれている、米国特許第9,266,886号における一般手順Bに準拠して調製した。
[00135]用いた1工程手法が、以下のスキーム6に示される。中間体2は、米国特許第9,266,886号の一般手順Bに準拠してやはり調製した。
[00140]代替として、1工程法および2工程法の一部をやはり組み合わせることができる。例えば、残留臭化メチルを除去するIPAc/水の再スラリー化手順を、2段階法に由来する一臭化水素塩およびビス臭化水素塩形態の両方の生成物形成に使用することができる。還元アミノ化のための溶媒は、塩化メチレンの代わりにやはりEtOHとすることができ、塩基はiPr2Netとすることができる。代表的な手法が、以下のスキーム3に示される。
Claims (41)
- ビス臭化水素塩が結晶性であり、結晶形態が、結晶形態A、C、DまたはEである、請求項2に記載のビス臭化水素塩。
- 結晶形態が、14.90°、20.28°、20.70°、22.00°、23.34°および26.46°から選択される2θの角度における、少なくとも3本のX線粉末回折ピークを特徴とする、請求項3に記載の結晶形態A。
- 結晶形態が、14.90°、20.28°、20.70°、22.00°、23.34°および26.46°から選択される2θの角度における、少なくとも4本のX線粉末回折ピークを特徴とする、請求項3または4に記載の結晶形態A。
- 結晶形態が、14.90°、20.28°、20.70°、22.00°、23.34°および26.46°から選択される2θの角度における、少なくとも5本のX線粉末回折ピークを特徴とする、請求項3から5のいずれか一項に記載の結晶形態A。
- 結晶形態が、14.90°、20.28°、20.70°、22.00°、23.34°および26.46°での2θの角度におけるX線粉末回折ピークを特徴とする、請求項3から6のいずれか一項に記載の結晶形態A。
- 結晶形態が、20.28°、20.70°、23.18°、23.34°、25.24°および26.46°から選択される2θの角度における、少なくとも3本のX線粉末回折ピークを特徴とする、請求項3に記載の結晶形態C。
- 結晶形態が、20.28°、20.70°、23.18°、23.34°、25.24°および26.46から選択される2θの角度における、少なくとも4本のX線粉末回折ピークを特徴とする、請求項3または8に記載の結晶形態C。
- 結晶形態が、20.28°、20.70°、23.18°、23.34°、25.24°および26.46から選択される2θの角度における、少なくとも5本のX線粉末回折ピークを特徴とする、請求項3、8および9のいずれか一項に記載の結晶形態C。
- 結晶形態が、20.28°、20.70°、23.18°、23.34°、25.24°および26.46°での2θの角度におけるX線粉末回折ピークを特徴とする、請求項3および8から10のいずれか一項に記載の結晶形態C。
- 結晶形態が、14.24°、15.24°、15.90°、18.54°、18.82°および22.46°から選択される2θの角度における、少なくとも3本のX線粉末回折ピークを特徴とする、請求項3に記載の結晶形態D。
- 結晶形態が、14.24°、15.24°、15.90°、18.54°、18.82°および22.46°から選択される2θの角度における、少なくとも4本のX線粉末回折ピークを特徴とする、請求項3または12に記載の結晶形態D。
- 結晶形態が、14.24°、15.24°、15.90°、18.54°、18.82°および22.46°から選択される2θの角度における、少なくとも5本のX線粉末回折ピークを特徴とする、請求項3、12および13のいずれか一項に記載の結晶形態D。
- 結晶形態が、14.24°、15.24°、15.90°、18.54°、18.82°および22.46°での2θの角度におけるX線粉末回折ピークを特徴とする、請求項3および12から14のいずれか一項に記載の結晶形態D。
- 結晶形態が、4.1°、8.3°、12.70°、16.64°、16.98°および21.32°から選択される2θの角度における、少なくとも3本のX線粉末回折ピークを特徴とする、請求項3に記載の結晶形態E。
- 結晶形態が、4.1°、8.3°、12.70°、16.64°、16.98°および21.32°から選択される2θの角度における、少なくとも4本のX線粉末回折ピークを特徴とする、請求項3または16に記載の結晶形態E。
- 結晶形態が、4.1°、8.3°、12.70°、16.64°、16.98°および21.32°から選択される2θの角度における、少なくとも5本のX線粉末回折ピークを特徴とする、請求項3、16および17のいずれか一項に記載の結晶形態E。
- 結晶形態が、4.1°、8.3°、12.70°、16.64°、16.98°および21.32°での2θの角度におけるX線粉末回折ピークを特徴とする、請求項3および16から18のいずれか一項に記載の結晶形態E。
- 結晶形態が溶媒和物である、請求項3から19のいずれか一項に記載の結晶形態A、C、DまたはE。
- 結晶形態が水和物である、請求項3から20のいずれか一項に記載の結晶形態A、C、DまたはE。
- 一臭化水素塩が結晶性であり、結晶形態が結晶形態Bである、請求項1に記載の一臭化水素塩。
- 結晶形態が、5.24°、7.98°、12.12°、19.42°、21.18°および21.52°から選択される2θの角度における、少なくとも3本のX線粉末回折ピークを特徴とする、請求項22に記載の結晶形態B。
- 結晶形態が、5.24°、7.98°、12.12°、19.42°、21.18°および21.52°から選択される2θの角度における、少なくとも4本のX線粉末回折ピークを特徴とする、請求項22または23に記載の結晶形態B。
- 結晶形態が、5.24°、7.98°、12.12°、19.42°、21.18°および21.52°から選択される2θの角度における、少なくとも5本のX線粉末回折ピークを特徴とする、請求項22から24のいずれか一項に記載の結晶形態B。
- 結晶形態が、5.24°、7.98°、12.12°、19.42°、21.18°および21.52°の2θの角度におけるX線粉末回折ピークを特徴とする、請求項22から25のいずれか一項に記載の結晶形態B。
- 結晶形態がイソプロパノール溶媒和物である、請求項22から26のいずれか一項に記載の結晶形態B。
- 請求項1から27に記載の臭化水素塩のいずれか1つ、および薬学的に許容される担体を含む医薬組成物。
- 対象におけるRORγの発現に関連する疾患または障害を処置する方法であって、対象に請求項1から27に記載の臭化水素塩のいずれか1つ、または請求項28に記載の組成物を投与する工程を含む方法。
- 疾患または障害が、喘息、慢性閉塞性肺疾患(COPD)、気管支炎、アレルギー性鼻炎、アトピー性皮膚炎、接触性皮膚炎、ざ瘡、嚢胞性線維症、同種移植拒絶、多発性硬化症、強皮症、関節炎、関節リウマチ、若年性関節リウマチ、骨関節炎、強直性脊椎炎、全身性エリテマトーデス(SLE)、乾癬、橋本病、すい臓炎、自己免疫性糖尿病、I型糖尿病、自己免疫性眼疾患、潰瘍性大腸炎、クローン病、限局性腸炎、炎症性腸疾患(IBD)、炎症性腸症候群(IBS)、シェーグレン症候群、視神経炎、肥満、脂肪肝、脂肪組織関連炎症、インスリン抵抗性、II型糖尿病、視神経脊髄炎、重症筋無力症、加齢性黄斑変性症、ドライアイ、ブドウ膜炎、ギランバレー症候群、乾癬、乾癬性関節炎(PsA)、ステロイド抵抗性喘息、グレーブス病、強膜炎、大うつ、季節性情動障害、PTSD、双極性障害、自閉症、てんかん、アルツハイマー病、睡眠および/または概日リズムの変化に伴うCNS障害、子宮内膜症、閉塞型無呼吸症候群(OSAS)、ベーチェット病、皮膚筋炎、多発性筋炎、移植片対宿主病、原発性胆汁性肝硬変、肝線維症、非アルコール性脂肪性肝疾患(NAFLD)、サルコイドーシス、原発性硬化性胆管炎、自己免疫性甲状腺疾患、I型多腺性自己免疫症候群、II型多腺性自己免疫症候群、セリアック病、神経脊髄炎、若年性特発性関節炎、全身性硬化症、心筋梗塞、肺高血圧症、骨関節炎、皮膚リーシュマニア症、副鼻腔ポリープおよびがんから選択される、請求項29に記載の方法。
- 疾患または障害が、喘息、アトピー性皮膚炎、ざ瘡、クローン病、限局性腸炎、潰瘍性大腸炎、シェーグレン症候群、ブドウ膜炎、ベーチェット病、皮膚筋炎、多発性硬化症、強直性脊椎炎、全身性エリテマトーデス(SLE)、強皮症、乾癬、乾癬性関節炎(PsA)、ステロイド抵抗性喘息および関節リウマチから選択される、請求項30に記載の方法。
- 工程ii)において、臭化水素酸を添加する前に、化合物1をイソプロパノールと酢酸との混合物に溶解する、請求項32に記載の方法。
- 工程ii)において、化合物1の一臭化水素塩を、臭化水素酸の添加により沈殿させる、請求項32または33に記載の方法。
- アミン化合物が、アミンの酸塩形態を第三級アミン塩基で処理することによってin situで形成される、請求項32から34のいずれか一項に記載の方法。
- アミンが、アミンの二塩酸塩形態をジイソプロピルエチルアミンで処理することによってin situで形成される、請求項32から35のいずれか一項に記載の方法。
- 溶媒がMeOHである、請求項37に記載の方法。
- 臭化水素酸の前記十分な量が、1〜2重量当量の35%〜55%臭化水素酸、または酢酸中の35%〜55%臭化水素を含む、請求項32から38のいずれか一項に記載の方法。
- イミン還元剤がトリアセトキシ水素化ホウ素ナトリウムである、請求項32から39のいずれか一項に記載の方法。
- ビス臭化水素塩が、14.24°、15.24°、15.90°、18.54°、18.82°および22.46°から選択される2θの角度における、少なくとも3本のX線粉末回折ピークを特徴とする結晶形態Dのものである、請求項37から40のいずれか一項に記載の方法。
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WO2019023216A8 (en) | 2019-03-07 |
SG11202000673SA (en) | 2020-02-27 |
UA126814C2 (uk) | 2023-02-08 |
CA3070613A1 (en) | 2019-01-31 |
TW201908315A (zh) | 2019-03-01 |
AU2018307928B2 (en) | 2022-12-08 |
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