JP2022534428A - カスパーゼ阻害剤プロドラッグの注射用組成物 - Google Patents
カスパーゼ阻害剤プロドラッグの注射用組成物 Download PDFInfo
- Publication number
- JP2022534428A JP2022534428A JP2021570951A JP2021570951A JP2022534428A JP 2022534428 A JP2022534428 A JP 2022534428A JP 2021570951 A JP2021570951 A JP 2021570951A JP 2021570951 A JP2021570951 A JP 2021570951A JP 2022534428 A JP2022534428 A JP 2022534428A
- Authority
- JP
- Japan
- Prior art keywords
- dihydroisoxazole
- isopropyl
- carboxamide
- isoquinolin
- fluoromethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- 229910052736 halogen Inorganic materials 0.000 description 1
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- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
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- 238000007151 ring opening polymerisation reaction Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
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- 239000006228 supernatant Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
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- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000005199 ultracentrifugation Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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Abstract
Description
(2S,3S)-2-(フルオロメチル)-3-((R)-5-イソプロピル-3-(イソキノリン-1-イル)-4,5-ジヒドロイソオキサゾール-5-カルボキサミド)-5-オキソテトラヒドロフラン-2-イルアセテート;
(2S,3S)-2-(フルオロメチル)-3-((R)-5-イソプロピル-3-(イソキノリン-1-イル)-4,5-ジヒドロイソオキサゾール-5-カルボキサミド)-5-オキソテトラヒドロフラン-2-イルプロピオネート;
(2R,3S)-2-(フルオロメチル)-3-((R)-5-イソプロピル-3-(イソキノリン-1-イル)-4,5-ジヒドロイソオキサゾール-5-カルボキサミド)-5-オキソテトラヒドロフラン-2-イルイソブチレート;
(2R,3S)-2-(フルオロメチル)-3-((R)-5-イソプロピル-3-(イソキノリン-1-イル)-4,5-ジヒドロイソオキサゾール-5-カルボキサミド)-5-オキソテトラヒドロフラン-2-イルピバレート;
(2R,3S)-2-(フルオロメチル)-3-((R)-5-イソプロピル-3-(イソキノリン-1-イル)-4,5-ジヒドロイソオキサゾール-5-カルボキサミド)-5-オキソテトラヒドロフラン-2-イル3-メチルブタノエート;
(2R,3S)-2-(フルオロメチル)-3-((R)-5-イソプロピル-3-(イソキノリン-1-イル)-4,5-ジヒドロイソオキサゾール-5-カルボキサミド)-5-オキソテトラヒドロフラン-2-イル3,3-ジメチルブタノエート;
(2S,3S)-2-(フルオロメチル)-3-((R)-5-イソプロピル-3-(イソキノリン-1-イル)-4,5-ジヒドロイソオキサゾール-5-カルボキサミド)-5-オキソテトラヒドロフラン-2-イルパルミテート;
(2S,3S)-2-(フルオロメチル)-3-((R)-5-イソプロピル-3-(イソキノリン-1-イル)-4,5-ジヒドロイソオキサゾール-5-カルボキサミド)-5-オキソテトラヒドロフラン-2-イルベンゾエート;
(2S,3S)-2-(フルオロメチル)-3-((R)-5-イソプロピル-3-(イソキノリン-1-イル)-4,5-ジヒドロイソオキサゾール-5-カルボキサミド)-5-オキソテトラヒドロフラン-2-イル4-(トリフルオロメチル)ベンゾエート;
(2S,3S)-2-(フルオロメチル)-3-((R)-5-イソプロピル-3-(イソキノリン-1-イル)-4,5-ジヒドロイソオキサゾール-5-カルボキサミド)-5-オキソテトラヒドロフラン-2-イル2-フェニルアセテート;
(5R)-N-((3S)-2-エトキシ-2-(フルオロメチル)-5-オキソテトラヒドロフラン-3-イル)-5-イソプロピル-3-(イソキノリン-1-イル)-4,5-ジヒドロイソオキサゾール-5-カルボキサミド;及び
(5R)-N-((3S)-2-(フルオロメチル)-2-メトキシ-5-オキソテトラヒドロフラン-3-イル)-5-イソプロピル-3-(イソキノリン-1-イル)-4,5-ジヒドロイソオキサゾール-5-カルボキサミド
下記表1の組成に従ってカスパーゼ阻害剤プロドラッグがカプセル化されたミクロスフェアを調製した。
下記表2の組成に従ってニボカサンがカプセル化されたミクロスフェアを調製した。
実施例及び比較例で調製されたミクロスフェアの特性は、調製中の薬物の析出、凍結乾燥ミクロスフェアの性状、及び再分散時の水相における浮遊よって確認した。
-カプセル化率=(測定された薬物の重量)/(測定されたミクロスフェア(MS)の重量)×100(%)
-カプセル化効率=(測定された薬物の重量)/(添加した薬物の重量)×100(%)
測定された結果をまとめて下記表3に示した。
実施例4及び5で調製されたミクロスフェアのインビトロ溶出試験を行った。ミクロスフェアをリン酸緩衝生理食塩水(PBS、37℃)で振とうし、特定の時間に溶出液を収集及びろ過した後、放出された薬物の量をHPLCで分析した。プロドラッグは水溶液中での加水分解により親薬物であるカスパーゼ阻害剤に変換されるため、HPLCで測定されるカスパーゼ阻害剤の量から放出された薬物の量を確認した。
Claims (13)
- 有効成分として、下記式(1)
生体適合性ポリマー;
を含む注射用医薬組成物。 - R1は、C1-C8アルキル又は-C(O)R2を表し、ここで、R2は、C1-C20アルキル、C6-C10アリール又はC6-C10アリール-C1-C7アルキルであることを特徴とする請求項1に記載の注射用医薬組成物。
- R1は、C1-C5アルキル又は-C(O)R2を表し、ここで、R2は、C1-C15アルキル、C6-C10アリール又はC6-C10アリール-C1-C5アルキルを表し、置換基は、アルキル又はハロアルキルであることを特徴とする請求項1に記載の注射用医薬組成物。
- 前記一般式(1)の化合物が以下の群からから選ばれることを特徴とする請求項1に記載の注射用医薬組成物:
(2S,3S)-2-(フルオロメチル)-3-((R)-5-イソプロピル-3-(イソキノリン-1-イル)-4,5-ジヒドロイソオキサゾール-5-カルボキサミド)-5-オキソテトラヒドロフラン-2-イルアセテート;
(2S,3S)-2-(フルオロメチル)-3-((R)-5-イソプロピル-3-(イソキノリン-1-イル)-4,5-ジヒドロイソオキサゾール-5-カルボキサミド)-5-オキソテトラヒドロフラン-2-イルプロピオネート;
(2R,3S)-2-(フルオロメチル)-3-((R)-5-イソプロピル-3-(イソキノリン-1-イル)-4,5-ジヒドロイソオキサゾール-5-カルボキサミド)-5-オキソテトラヒドロフラン-2-イルイソブチレート;
(2R,3S)-2-(フルオロメチル)-3-((R)-5-イソプロピル-3-(イソキノリン-1-イル)-4,5-ジヒドロイソオキサゾール-5-カルボキサミド)-5-オキソテトラヒドロフラン-2-イルピバレート;
(2R,3S)-2-(フルオロメチル)-3-((R)-5-イソプロピル-3-(イソキノリン-1-イル)-4,5-ジヒドロイソオキサゾール-5-カルボキサミド)-5-オキソテトラヒドロフラン-2-イル3-メチルブタノエート;
(2R,3S)-2-(フルオロメチル)-3-((R)-5-イソプロピル-3-(イソキノリン-1-イル)-4,5-ジヒドロイソオキサゾール-5-カルボキサミド)-5-オキソテトラヒドロフラン-2-イル3,3-ジメチルブタノエート;
(2S,3S)-2-(フルオロメチル)-3-((R)-5-イソプロピル-3-(イソキノリン-1-イル)-4,5-ジヒドロイソオキサゾール-5-カルボキサミド)-5-オキソテトラヒドロフラン-2-イルパルミテート;
(2S,3S)-2-(フルオロメチル)-3-((R)-5-イソプロピル-3-(イソキノリン-1-イル)-4,5-ジヒドロイソオキサゾール-5-カルボキサミド)-5-オキソテトラヒドロフラン-2-イルベンゾエート;
(2S,3S)-2-(フルオロメチル)-3-((R)-5-イソプロピル-3-(イソキノリン-1-イル)-4,5-ジヒドロイソオキサゾール-5-カルボキサミド)-5-オキソテトラヒドロフラン-2-イル4-(トリフルオロメチル)ベンゾエート;
(2S,3S)-2-(フルオロメチル)-3-((R)-5-イソプロピル-3-(イソキノリン-1-イル)-4,5-ジヒドロイソオキサゾール-5-カルボキサミド)-5-オキソテトラヒドロフラン-2-イル2-フェニルアセテート;
(5R)-N-((3S)-2-エトキシ-2-(フルオロメチル)-5-オキソテトラヒドロフラン-3-イル)-5-イソプロピル-3-(イソキノリン-1-イル)-4,5-ジヒドロイソオキサゾール-5-カルボキサミド;及び
(5R)-N-((3S)-2-(フルオロメチル)-2-メトキシ-5-オキソテトラヒドロフラン-3-イル)-5-イソプロピル-3-(イソキノリン-1-イル)-4,5-ジヒドロイソオキサゾール-5-カルボキサミド - 前記生体適合性ポリマーが、ポリラクチド、ポリグリコリド及びポリ(ラクチド-co-グリコリド)、ポリカプロラクトン、ポリオルトエステル及びポリホスファジンからなる群から選ばれる一つ以上であることを特徴とする請求項1に記載の注射用医薬組成物。
- 前記生体適合性ポリマーが、ポリ(ラクチド-co-グリコリド)であることを特徴とする請求項5に記載の注射用医薬組成物。
- 前記ポリ(ラクチド-co-グリコリド)のラクチド対グリコリドのモル比が、90:10~10:90であることを特徴とする請求項6に記載の注射用医薬組成物。
- 前記ポリ(ラクチド-co-グリコリド)のラクチド対グリコリドのモル比が、90:10~40:60であることを特徴とする請求項7に記載の注射用医薬組成物。
- 前記ポリ(ラクチド-co-グリコリド)のラクチド対グリコリドのモル比が、85:15~50:50であることを特徴とする請求項8に記載の注射用医薬組成物。
- 溶媒をさらに含むことを特徴とする請求項1に記載の注射用医薬組成物。
- 前記溶媒が、水、生理食塩水又はリン酸緩衝食塩水であることを特徴とする請求項10に記載の注射用医薬組成物。
- アポとシース関連疾患、炎症疾患、骨関節炎、リウマチ性関節炎、変性性関節炎及び破壊性骨障害から選ばれる疾患の予防又は治療のためであることを特徴とする請求項1に記載の注射用医薬組成物。
- 骨関節炎の予防、治療又は疼痛緩和のためであることを特徴とする請求項12に記載の注射用医薬組成物。
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