JP2021063081A - β−ニコチンアミドモノヌクレオチドの結晶形態 - Google Patents
β−ニコチンアミドモノヌクレオチドの結晶形態 Download PDFInfo
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Abstract
Description
本出願は、その全体が参照により本明細書に組み込まれている、2015年10月2日出願の、米国仮特許出願第62/236,657号への優先権の利益を主張する。
ある種の実施形態では、本発明は、a)溶媒中の式(I)の化合物の混合物を提供するステップ、及びb)式(I)の化合物を含む混合物から式(I)の化合物を結晶化するステップを含む、式(I)の構造を有する結晶性化合物の製造の方法に関する。
NMNは、Namptによって触媒される反応である、NAD生合成経路においてニコチンアミドから産生される。NMNは、NAD生合成経路において、NADにさらに変換され、この反応はNmnatによって触媒される。以下の構造に相当する「ニコチンアミドアデニンジヌクレオチド」(NAD)
軸索変性は、神経変性疾患及び末梢性ニューロパシーにおいて頻繁に起こる。切断軸索の変性は、ニコチンアミドアデニンジヌクレオチド(NAD+)合成酵素、ニコチンアミドモノヌクレオチドアデニルイルトランスフェラーゼ(Nmnat1)を含む融合タンパク質の過剰発現を有するウォラー変性遅延(Wlds)マウスでは遅延する。WldとNmnat1のどちらも、それ自体、ニューロンの培養物中の軸索変性を防止する機能がある。
哺乳動物において、血中グルコースの濃度を調節する方法が、本明細書において提供される。本明細書において利用される通り、血中グルコースの濃度の調節とは、既に決定されているレベルに比べた、血中グルコースの濃度の上昇、低下及び/又は維持のいずれかを指す。
一部の実施形態では、本発明は、副作用を予防する及び毒性から細胞を保護するための、NMNの使用に関する。毒性は、照射、又は身体の細胞に及ぼす外因性化学品の副作用とすることができる。毒素の例は、医薬品、薬物乱用、UV又はX線光などの照射である。放射毒性と化学毒性の両方が、DNAなどの生物分子を損傷する可能性を有する。この損傷は、通常、外因性薬剤の化学反応若しくは生物分子によるその代謝産物によって、又は反応性酸素種(例えば、スーパーオキシド、過酸化物、ヒドロキシルラジカル)の刺激生成により間接的に起こる。細胞における修復システムが、毒素によって引き起こされた損傷を排除して修復する。
ある種の実施形態では、本発明は、細胞をNMN及び/又はNAD+に接触させることによる、細胞寿命の延長、細胞の増殖能力の延長、細胞の加齢の減速、細胞の生存の促進、細胞における細胞老化の遅延、カロリー制限効果の模倣、細胞のストレスへの耐性の上昇、又は細胞のアポトーシスの防止の方法を提供する。最近の検討により、加齢過程、並びに加齢に関連する疾患及び状態において、NAD+が役割を果たすことが実証されている。例えば、Imaiら、「NAD+ and sirtuins in aging and disease」、Trends in Cell Biol. 2014年、24巻(8号):464〜471頁;及びGomesら、「Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging」、Cell 2013年、155巻:1624〜1638頁を参照されたい。
ある種の実施形態では、本発明は、細胞内NAD+のレベルを増加させる量のNMNをそれを必要とする対象に投与することによる、心血管疾患を処置及び/又は予防する方法を提供する。心血管疾患を処置する際のNAD+の有益性は、Borradaileら、「NAD+, Sirtuins, and Cardiovascular Disease」、Current Pharmaceutical Design 2016年、15巻(1号):110〜117頁などのいくつかの研究に記載されている。
概日時計は、行動及び代謝を明-暗周期と同期する、転写翻訳フィードバックループによってコードされる。哺乳動物のNAD+生合成における律速酵素であるニコチンアミドホスホリボシルトランスフェラーゼ(NAMPT)とNAD+のレベルの両方が、マウスにおけるコアクロック機構(core clock machinery)によって調節される、概日振動を示すことが予期せず発見された。NAMPTを阻害すると、SIRT1による抑制からCLOCK:BMAL1を放出することにより、時計遺伝子Per2の振動が促進される。ひいては、概日転写因子CLOCKは、Namptに結合して上方調節し、こうして、NAMPT/NAD+及びSIRT1/CLOCK:BMAL1を含むフィードバックループを完了する。例えば、Ramseyら、「Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis」、Science 2009年、324巻:651〜654頁を参照されたい。
概日リズムの調節、及び細胞死からの神経細胞の保護に加えて、SIRT3、SIRT4及びSIRT5などのサーチュインが、ミトコンドリア中で見いだされる。SIRT3は、代謝活性組織中に高いレベルで発現する。SIRT3のモジュレートは、カロリー制限又は運動の模倣、ミトコンドリア生合成又は代謝の上昇、細胞のグルコース取り込みへの感作、脂肪酸酸化の上昇、及び反応性酸素種の減少を含む、筋細胞のための様々な生理学的用途を有する。さらに、SIRT3は、遺伝毒性ストレス中の、細胞生存の促進に関与していることが本明細書において実証されている。したがって、SIRT3レベルのモジュレートはまた、細胞生存の媒介に適用される。
光受容体のニューロン細胞死及び視力は、NMN投与によってレスキューされ得る。ある種の実施形態では、ニコチンアミドホスホリボシルトランスフェラーゼ(NAMPT)媒介性NAD生合成は、桿体及び/又は錐体PRニューロン生存においてある役割を果たすことができる。ある種の実施形態では、NADレベルの低下は、PRニューロンにおけるミトコンドリア機能の障害、TCAサイクル代謝産物の変質を引き起こす恐れがあり、細胞死及び失明に至る恐れがある。
ある種の実施形態では、本発明は、式(I)の結晶性化合物及び1種以上の薬学的に許容される賦形剤、並びに、このような結晶性化合物を使用して製造される製剤及び1種以上の薬学的に許容される賦形剤を含む医薬組成物に関する。ある種の実施形態では、医薬調製物は、本明細書に記載されている状態又は疾患を処置又は防止するのに使用してもよい。ある種の実施形態では、医薬調製物は、ヒト患者の静脈への使用に好適であるほどに、十分に低いパイロジェン活性を有する。ある種の実施形態では、本発明はまた、栄養補助食品、獣医学及び農業に関連性のある使用に好適な調製物に関する。
X線粉末回折
X線粉末回折パターンは、Cu Kα線(40kV、40mA)、θ-2θ角度計、並びにV4及び受光スリットの発散を使用するBruker D8回折計、Geモノクロメータ、並びにLynxeye検出器で採集した。機器の性能は、認定コランダム標準(NIST 1976)を使用して確認を行った。データ採集のために使用されたソフトウェアは、Diffrac Plus XRD Commander v2.6.1であり、データは、Diffrac Plus EVA v15.0.0.0を使用して分析し、提示した。
- 角度範囲:2〜42°2θ
- ステップサイズ:0.05°2θ
- 採集時間:0.5秒/ステップ
純度分析は、ダイオードアレイ検出器を備え、ChemStationソフトウェアvB.04.03を使用するAgilent HP1100シリーズのシステムにおいて、表1で以下に詳述する方法を使用して実行した。
試料は、画像取込のためにデジタルビデオカメラを備えたLeica LM/DM偏光顕微鏡によって調べた。少量の各試料を、スライドガラスの上に置き、浸漬油で固定し、ガラススリップで覆い、個別の粒子を可能な限り分離させた。試料は、適切な拡大率及び部分偏光で、γ偽色フィルタを接続させて観察した。
メタノールからの結晶化による形態1の合成
アモルファス性のニコチンアミドモノヌクレオチド(565mg)は、ガラスバイアルで計量し、メタノール(10.0mL)を添加した。得られるスラリーは、室温で4時間、撹拌し、次に、さらに一部のMeOH(10.0mL)を添加した。存在する白色固体は、ろ過により単離され、次に、真空下、室温でおよそ16時間、乾燥させると、XRPD分析によって示されたように、結晶化β-ニコチンアミドモノヌクレオチド形態1が得られた。(459mg、81%回収)。
水からの結晶化による形態1の合成
アモルファス性のβ-ニコチンアミドモノヌクレオチド(605mg)は、ガラスバイアルで計量し、脱イオン水(600μL)を添加した。短時間のボルテックスの後、透明の溶液が形成された。一部のこの溶液(およそ200μL)を別々のバイアルに分配し、5℃でおよそ16時間、冷却した。発生した白色固体は、ろ過により単離され、XRPD分析によって示されると、結晶化β-ニコチンアミドモノヌクレオチド形態1であった(収率は決定せず)。
SCXRDのための蒸気拡散による形態1の合成
アモルファス性のβ-ニコチンアミドモノヌクレオチド(605mg)は、ガラスバイアルで計量し、脱イオン水(600μL)を添加した。短時間のボルテックスの後、透明の溶液が形成された。一部のこの溶液(100μL)を別々のバイアルに分配し、これ自体は、蒸気が両バイアルの間を自由に拡散できるような、メタノール(500μL)を含有するより大きなバイアルに入れた。より大きなバイアルは、密封し、白色固体が発生した時間からおよそ16時間、室温で保管した。この固体をサンプリングし、SCXRDによって示されると、結晶化β-ニコチンアミドモノヌクレオチド形態1であった。
形態2の合成
アモルファス性のβ-ニコチンアミドモノヌクレオチド(568mg)は、ガラスバイアルで計量し、DMSO(10.0mL)を添加した。得られるスラリーは、室温でおよそ20時間、撹拌した。次に、存在する白色固体は、ろ過により単離され、アセトン(3×1mL)で洗浄され、真空下、室温でおよそ16時間、乾燥させると、結晶化β-ニコチンアミドモノヌクレオチド形態2が得られた(501mg、72%回収*)。
* 物質がDMSOモノ溶媒和物であるという仮説に基づく
アモルファス性及び結晶性NMNに対する、3か月の安定性試験及び強制分解研究
アモルファス性NMN及びNMN結晶形態1の試料は、3か月間、25℃/0%相対湿度(RH)で、及び40℃/75%RHで、固体として保存した。試料は、2週間のオフセットにより2重で調製した。各複製は、異なる容器で保管した。
本明細書に記載された刊行物及び特許はすべて、個別の刊行物又は特許のそれぞれが、具体的かつ個々に、参照により組み込まれるよう示されているかのごとく、それらの全体が参照により本明細書に組み込まれている。抵触の場合、本明細書における定義を含めて、本明細書が支配する。
本発明の具体的な実施形態が考察されている一方で、上記の明細書は、例証であり、限定的ではない。本発明の多くの変形例は、本明細書及び下記の特許請求の範囲により、当業者には明らかになるだろう。本発明の全範囲は、均等物の全範囲に沿って特許請求の範囲及びこのような変形例に沿って明細書を参照することによって決定されるべきである。
Claims (28)
- 無水である、請求項1に記載の結晶性化合物。
- 20.03、20.14、21.83、及び25.73の2θ値を有する、請求項2に記載の結晶性化合物。
- 20.03、20.14、21.03、21.83、23.08、23.39、25.73、及び26.59の2θ値を有する、請求項3に記載の結晶性化合物。
- 7.70、11.54、12.64、16.03、18.99、20.03、20.14、20.83、21.03、21.83、23.08、23.39、25.48、25.73、26.59、及び29.78の2θ値を有する、請求項4に記載の結晶性化合物。
- 7.70、9.95、11.54、12.64、16.03、18.18、18.99、19.16、19.44、20.03、20.14、20.83、21.03、21.83、22.44、23.08、23.39、23.89、24.08、24.53、24.68、25.05、25.48、25.73、26.08、26.59、27.33、27.67、29.78、及び29.92の2θ値を有する、請求項5に記載の結晶性化合物。
- 形態1とラベルを付けた、図1に実質的に示されているXRDパターンを有する、請求項6に記載の結晶性化合物。
- ジメチルスルホキシド溶媒和物である、請求項1に記載の結晶性化合物。
- 8.29、17.39、19.54、22.78、及び22.98の2θ値を有する、請求項8に記載の結晶性化合物。
- 8.29、17.39、19.54、19.74、20.98、21.58、22.03、22.78、22.98、及び25.53の2θ値を有する、請求項9に記載の結晶性化合物。
- 8.29、16.10、17.39、19.24、19.54、19.74、20.33、20.78、20.98、21.18、21.58、22.03、22.78、22.98、25.53、28.48、及び29.48の2θ値を有する、請求項10に記載の結晶性化合物。
- 8.29、13.12、15.79、16.10、16.69、17.39、19.03、19.24、19.54、19.74、20.33、20.78、20.98、21.18、21.58、22.03、22.78、22.98、23.95、24.14、24.48、24.64、25.14、25.53、25.87、26.89、27.18、27.67、28.02、28.13、28.48、28.98、29.34、29.48、及び29.92の2θ値を有する、請求項11に記載の結晶性化合物。
- 形態2とラベルを付けた、図1に実質的に示されているXRDパターンを有する、請求項12に記載の結晶塩。
- 請求項1から13のいずれか一項に記載の塩及び1種以上の薬学的に許容される賦形剤を含む医薬組成物。
- 結晶性化合物が無水である、請求項15に記載の方法。
- 結晶性化合物が溶媒和物である、請求項15に記載の方法。
- 溶媒和物がジメチルスルホキシド溶媒和物である、請求項17に記載の方法。
- 溶媒がメタノール又は水である、請求項15に記載の方法。
- 溶媒がジメチルスルホキシドである、請求項18に記載の方法。
- 式(I)の化合物を含む混合物が溶液であり、混合物から式(I)の化合物を結晶化するステップが、溶液を過飽和として、式(I)の化合物を溶液から沈殿させるステップを含む、請求項15から20のいずれか一項に記載の方法。
- 溶液を過飽和とするステップが、逆溶媒を穏やかに添加するステップ、溶液を冷却するステップ、溶液の体積を低減するステップ、又はこれらの任意の組合せを含む、請求項21に記載の方法。
- 溶液を過飽和とするステップが、溶液を周囲温度以下に冷却するステップを含む、請求項21に記載の方法。
- 式(I)の化合物を含む混合物がスラリーである、請求項15から20のいずれか一項に記載の方法。
- 結晶性化合物を単離するステップをさらに含む、請求項15から24のいずれか一項に記載の方法。
- 結晶性化合物を単離するステップが、結晶性化合物を混合物からろ過するステップを含む、請求項25に記載の方法。
- 減圧下で結晶性化合物を乾燥するステップをさらに含む、請求項25又は請求項26に記載の方法。
- 結晶性化合物が請求項1から13のいずれか一項に記載の結晶性化合物である、請求項15から27のいずれか一項に記載の方法。
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