JP2022525579A - 医薬化合物、その製造方法、及び薬剤としての使用 - Google Patents
医薬化合物、その製造方法、及び薬剤としての使用 Download PDFInfo
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
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- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
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Abstract
Description
(i)化合物(I)をジメチルスルホキシドに溶解して、化合物(I)のジメチルスルホキシド溶液を得るステップと、
(ii)この化合物(I)のジメチルスルホキシド溶液を水に加えて、化合物(I)の懸濁液を得るステップと、
(iii)化合物(I)の懸濁液中に懸濁された化合物(I)を析出させて、本明細書に記載の結晶形態を得るステップ
を含む方法を提供する。
(i)化合物(I)をジメチルスルホキシドに溶解し、化合物(I)のジメチルスルホキシド溶液を得るステップと、
(ii)この化合物(I)のジメチルスルホキシド溶液を水に加え、化合物(I)の懸濁液を得るステップと、
(iii)化合物(I)の懸濁液中に懸濁された化合物(I)を析出させ、本明細書に記載の結晶形態を得るステップ
を含む方法を提供する。
実験の項
粉末X線回析試験は、≪Siemens D500≫回折計(銅放射線、二次ビームにおけるグラファイトモノクロメータ、Bragg-Brentanoジオメトリー)を使用して行われた。
以下の非限定的な例は本発明をさらに例証する。
化合物(I)をウクライナ特許第108246号及びWO 2018/067102に記載される通りに調製した。
ウクライナ特許第108246号及びWO 2018/067102に記載される通りに調製された化合物(I)のサンプルをジメチルスルホキシドに溶解する。具体的には、室温(約20℃)で、ジメチルスルホキシド10ml当たり化合物(I)のサンプル1gを溶解する。得られた溶液を、激しい撹拌下の水にゆっくりと室温で加え(水100ml当たり溶液10ml)、形成された懸濁液を30分間混合する。その後、撹拌を停止して析出のために懸濁液を3時間静置する。分散された析出物を濾紙を使用して真空濾過し、精製水(毎回100ml)で3回洗浄して、120℃の乾燥及び加熱チャンバー(universal drying and heating chamber FD-115、Binder Gmbh、Germanyから入手可能)内で乾燥させる。
化合物Iの形態I及び形態IIに関する基本的な結晶学的データ及び構造の精密化(単結晶データ)。
化合物(I)の多形形態における平均致死量(LD50)の決定
前記化合物の急性毒性を量的に特徴付ける指標-集団の50%に致死作用をもたらす物質の用量(LD50)に基づいて、物質を特定の毒性クラスへ予備的に割り当てる。実験動物の種類のうちの1種におけるこの指標の決定は、他の種における指標の推定を可能にし、治験の第I相における用量限界の根拠とすることができる。
温痛覚のモデルにおける化合物(I)の結晶形態の鎮痛活性(「テールフリック」試験)
ラットに収束光線を使用して、ラットの尾「テールフリック」モデルにおける抗侵害受容(鎮痛)活性を評価した。潜時は、尾が光線源から離れることによって決定され、秒で表記された。指標が4~12秒である潜伏期の初期値に関して動物を無作為化した。抗侵害受容性効果の大きさは、潜伏期の長さ(疼痛感受性閾値、PST)の延長によって示された。PSTの初期の指標と試験化合物の投与2時間後のその変化を比較した。最小二乗法を使用して、ED50(ラットのこのモデルにおける鎮痛活性の平均有効用量)の算出を行った。
マウスの酢酸誘発疼痛(痙攣)のモデルにおける化合物(I)の結晶形態の鎮痛活性
内臓及び身体の急性深部痛(侵害受容性疼痛)を再現するため、「酢酸誘発疼痛(痙攣)」の方法をマウスに用いた。試験化合物の投与2時間後、マウスに0.75%酢酸溶液(0.1ml/体重10gの用量)を腹腔内投与した。病理学的状態をモニターした後の1分目~20分目(両端値含む)の痙攣回数を計数した。ED50(マウスのこのモデルにおける鎮痛活性に関する平均有効用量)の算出は、最小二乗法を使用して行われた。
Claims (19)
- 粉末X線回折パターンにおいて、2θ値として表される17.8±0.2°、19.4±0.2°、20.9±0.2°、及び27.5±0.2°のうちの1つ以上で、1つ以上の反射をさらに示す、請求項1に記載の結晶形態。
- 粉末X線回折パターンが、2θ値として表される15.1±0.2°で反射を示さない、請求項1又は請求項2に記載の結晶形態。
- 融点が186℃~191℃である、請求項1から3のいずれか一項に記載の結晶形態。
- 融点が187℃~190℃である、請求項1から4のいずれか一項に記載の結晶形態。
- 請求項1から5のいずれか一項で定義された結晶形態を製造する方法であって、
(i)化合物(I)をジメチルスルホキシドに溶解して、化合物(I)のジメチルスルホキシド溶液を得るステップと、
(ii)前記化合物(I)のジメチルスルホキシド溶液を水に加えて、化合物(I)の懸濁液を得るステップと、
(iii)前記化合物(I)の懸濁液中に懸濁された化合物(I)を析出させ、請求項1で定義された結晶形態を得るステップ
を含む方法。 - 前記化合物(I)のジメチルスルホキシド溶液が、化合物(I)の飽和ジメチルスルホキシド溶液である、請求項6に記載の方法。
- 前記化合物(I)のジメチルスルホキシド溶液を水に加えることが、15℃~25℃の温度で行われる、請求項6又は請求項7に記載の方法。
- 前記化合物(I)の懸濁液中に懸濁された化合物(I)を析出させることが、15℃~25℃の温度で行われる、請求項6から8のいずれか一項に記載の方法。
- 請求項1から5のいずれか一項に記載の結晶形態及び少なくとも1種の薬学的に許容される賦形剤を含む医薬組成物。
- 1つ以上のさらなる薬学的に活性な薬剤を含む、請求項10に記載の医薬組成物。
- 療法で使用するための、請求項1から5のいずれか一項に記載の結晶形態又は請求項10若しくは11に記載の医薬組成物。
- 医薬として使用するための、請求項1から5のいずれか一項に記載の結晶形態又は請求項10若しくは11に記載の医薬組成物。
- 神経障害性疼痛の治療又は予防に使用するための、請求項1から5のいずれか一項に記載の結晶形態又は請求項10若しくは11に記載の医薬組成物。
- 侵害受容性疼痛の治療又は予防に使用するための、請求項1から5のいずれか一項に記載の結晶形態又は請求項10若しくは11に記載の医薬組成物。
- 糖尿病性ニューロパチーの治療又は予防に使用するための、請求項1から5のいずれか一項に記載の結晶形態又は請求項10若しくは11に記載の医薬組成物。
- ヒト又は動物の治療対象における神経障害性疼痛を治療又は予防する方法であって、治療又は予防を必要とする治療対象に、請求項1から5のいずれか一項に記載の結晶形態又は請求項10若しくは請求項11に記載の医薬組成物の有効量を投与することを含む方法。
- ヒト又は動物の治療対象における侵害受容性疼痛を治療又は予防する方法であって、治療又は予防を必要とする治療対象に、請求項1から5のいずれか一項に記載の結晶形態又は請求項10若しくは請求項11に記載の医薬組成物の有効量を投与することを含む方法。
- ヒト又は動物の治療対象における糖尿病性ニューロパチーを治療又は予防する方法であって、治療又は予防を必要とする治療対象に、請求項1から5のいずれか一項に記載の結晶形態又は請求項10若しくは請求項11に記載の医薬組成物の有効量を投与することを含む方法。
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