JP2018528949A - Pi3k阻害剤およびmdm2阻害剤を使用する組み合わせ療法 - Google Patents
Pi3k阻害剤およびmdm2阻害剤を使用する組み合わせ療法 Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
Description
(a)式(I)の構造を有する化合物
またはその薬学的に許容される塩と、
(b)MDM2阻害剤と
を含む医薬組み合わせ物が、本明細書において提供される。
式(II)の構造を有する化合物
からなる群から選択される。
(a)式(I)の構造を有する化合物
(b)MDM2阻害剤と
を含む医薬組成物が、本明細書において提供される。
(a)式(I)の構造を有する化合物
(b)MDM2阻害剤と
を含む医薬組み合わせ物が、本明細書において提供される。
がんを、それを必要とする対象において治療または予防する方法であって、治療有効量の本発明の組み合わせ物、すなわち、(a)化合物(I)またはその薬学的に許容される塩と、(b)MDM2阻害剤および任意選択で(c)BLC−2阻害剤とを含む医薬組み合わせ物を対象に投与することを含む方法が、本明細書において提供される。
I.(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−{[5−(2−tert−ブチル−ピリジン−4−イル)−4−メチル−チアゾール−2−イル]−アミド}の合成
表題化合物は、上記に記載された手順に類似しているが、以下の修正を伴って調製される。ステップ1.1では、反応混合物を還流下で14時間撹拌する。ステップ1.2では、反応混合物を85℃で1時間撹拌し、クエンチした後、EtOAcで抽出する。ステップ1.3では、反応混合物を120℃で2.5時間撹拌する。ステップ1.4では、反応混合物を83℃で1時間撹拌し、クエンチした後、EtOAcで抽出する。ステップ1.5では、反応混合物を65℃で1時間撹拌し、MeOH中でのすり混ぜは実施しない。ステップ1.6では、粗生成物を精製しない。ステップ1.7では、3,3,3−トリフルオロ−2,2−ジメチル−プロピオニルクロリドを使用する。
化合物AおよびBを100%DMSO(Sigma、カタログ番号D2650)に20mMの濃度で溶解し、使用するまで−20℃で保存した。化合物を薬物マスタープレート(drug master plate)(Greiner、カタログ番号788876)に配列し、2000×濃度で3倍に連続希釈(7ステップ)した。
I=1−xnorm
I:阻害
xnorm:正規化細胞計数(3回の複製の中央値)
C=Σ濃度(Iデータ *(Iデータ−Iモデル))
Iデータ:測定阻害値
Iモデル:HSA帰無仮説による阻害値
zC=C/mad(Cゼロ)
Cゼロ:非相互作用組み合わせ物の組み合わせスコア
zC≧3:相乗作用
3>zC≧2:弱い相乗作用
zC<2:相乗作用なし
化合物A、B、およびCを100%DMSO(Sigma、カタログ番号D2650)に20mMの濃度で溶解し、使用するまで−20℃で保存した。化合物を薬物マスタープレート(drug master plate)(Greiner、カタログ番号788876)に配列し、2000×濃度で3倍に連続希釈(7ステップ)した。
I=1−xnorm
I:阻害
xnorm:正規化細胞計数(3回の複製の中央値)
C=Σ濃度(Iデータ *(Iデータ−Iモデル))
Iデータ:測定阻害値
Iモデル:HSA帰無仮説による阻害値
zC=C/mad(Cゼロ)
Cゼロ:非相互作用組み合わせ物の組み合わせスコア
zC≧3:相乗作用
3>zC≧2:弱い相乗作用
zC<2:相乗作用なし
Claims (42)
- (a)式(I)の構造を有する化合物
(b)MDM2阻害剤と
を含む、医薬組み合わせ物。 - 前記MDM2阻害剤が、
式(II)の構造を有する化合物
からなる群から選択される、請求項1に記載の医薬組み合わせ物。 - 前記MDM2阻害剤が、式(II)の構造を有する化合物、またはその薬学的に許容される塩である、請求項2に記載の医薬組み合わせ物。
- 前記MDM2阻害剤が、式(III)の構造を有する化合物、またはその薬学的に許容される塩である、請求項2に記載の医薬組み合わせ物。
- 式(I)の構造を有する前記化合物および前記MDM2阻害剤が、同じ製剤の中にある、請求項1から4のいずれか一項に記載の医薬組み合わせ物。
- 式(I)の構造を有する前記化合物および前記MDM2阻害剤が、別々の製剤の中にある、請求項1から4のいずれか一項に記載の医薬組み合わせ物。
- 同時または順次投与のためのものである、請求項1から4のいずれか一項に記載の医薬組み合わせ物。
- BCL−2阻害剤を更に含む、請求項1から4のいずれか一項に記載の医薬組み合わせ物。
- 前記BCL−2阻害剤が、4−[4−[[2−(4−クロロフェニル)−5,5−ジメチル−1−シクロヘキセン−1−イル]メチル]−1−ピペラジニル]−N−[[4−[[(1R)−3−(4−モルホリニル)−1−[(フェニルチオ)メチル]プロピル]アミノ]−3−[(トリフルオロメチル)スルホニル]フェニル]スルホニル]ベンズアミドまたはナビトクラックス、テトロカルシンA、アンチマイシン、ゴシポール、オバトクラックス、2−アミノ−6−ブロモ−4(S)−[1(S)−シアノ−2−エトキシ−2−オキソエチル]−4H−1−ベンゾピラン−3−カルボン酸エチルエステル、オブリメルセン、Bak BH3ペプチド、(−)−ゴシポール酢酸、4−[4−[(4’−クロロ[1,1’−ビフェニル]−2−イル)メチル]−1−ピペラジニル]−N−[[4−[[(1R)−3−(ジメチルアミノ)−1−[(フェニルチオ)メチル]プロピル]アミノ]−3−ニトロフェニル]スルホニル]−ベンズアミド、およびこれらの薬学的に許容される塩からなる群から選択される、請求項8に記載の医薬組み合わせ物。
- 前記BCL−2阻害剤がナビトクラックスである、請求項8に記載の医薬組み合わせ物。
- 式(I)の構造を有する前記化合物、前記MDM2阻害剤、および前記BCL−2阻害剤が、同じ製剤の中にある、請求項8から10のいずれか一項に記載の医薬組み合わせ物。
- 式(I)の構造を有する前記化合物、前記MDM2阻害剤、および前記BCL−2阻害剤が、2つ以上の別々の製剤の中にある、請求項8から10のいずれか一項に記載の医薬組み合わせ物。
- 同時または順次投与のためのものである、請求項8から10のいずれか一項に記載の医薬組み合わせ物。
- それを必要とする対象においてがんを治療または予防する方法であって、治療有効量の請求項1から13のいずれか一項に記載の医薬組み合わせ物を前記対象に投与することを含む、方法。
- 前記がんが固形腫瘍である、請求項14に記載の方法。
- 前記がんが、肺(小細胞肺がん、および非小細胞肺がんを含む)、気管支、前立腺、乳房(散発性乳がん、およびカウデン病罹患者を含む)、膵臓、胃腸、結腸、直腸、結腸癌、結腸直腸がん、甲状腺、肝臓、胆道、肝内胆管、肝細胞、副腎、胃部、胃、神経膠腫、神経膠芽腫、子宮内膜、黒色腫、腎臓、腎盂、膀胱、子宮、子宮頸部、膣、卵巣、多発性骨髄腫、食道、頸部または頭部、脳、口腔および咽頭、喉頭、小腸の良性または悪性腫瘍、黒色腫、絨毛結腸腺腫、肉腫(軟部組織肉腫、脂肪肉腫、横紋筋肉腫、または骨がん、例えば骨肉腫を含む)、新生物、上皮性新生物、乳癌、基底細胞癌、扁平上皮細胞癌、光線角化症、真性赤血球増加症、本態性血小板血症、白血病(急性骨髄性白血病、慢性骨髄性白血病、リンパ球性白血病、および骨髄球性白血病を含む)、リンパ腫(非ホジキンリンパ腫およびホジキンリンパ腫を含む)、骨髄様転移を有する骨髄線維症、ならびにワルデンシュトレーム病からなる群から選択される、請求項14に記載の方法。
- 前記がんが、結腸直腸がん、乳がん、肺がん、軟部組織肉腫、脂肪肉腫、または扁平上皮細胞癌である、請求項14に記載の方法。
- 前記がんが、BRAF突然変異、KRAS突然変異、MDM2増幅、PIK3CA突然変異、およびPIK3CA過剰発現のうちの1つまたは複数により特徴付けられる、請求項14から17のいずれか一項に記載の方法。
- 前記がんが、MDM2阻害剤による治療に対して抵抗性がある、または難治性である、請求項14から18のいずれか一項に記載の方法。
- 前記MDM2阻害剤が、式(II)の構造を有する化合物、式(III)の構造を有する化合物、およびこれらの薬学的に許容される塩からなる群から選択される、請求項19に記載の方法。
- がんの治療または予防における使用のための、請求項1から13のいずれか一項に記載の医薬組み合わせ物。
- がんの治療または予防のための医薬の調製における使用のための、請求項1から13のいずれか一項に記載の医薬組み合わせ物。
- 前記がんが固形腫瘍である、請求項21または22に記載の医薬組み合わせ物。
- 前記がんが、肺(小細胞肺がん、および非小細胞肺がんを含む)、気管支、前立腺、乳房(散発性乳がん、およびカウデン病罹患者を含む)、膵臓、胃腸、結腸、直腸、結腸癌、結腸直腸がん、甲状腺、肝臓、胆道、肝内胆管、肝細胞、副腎、胃部、胃、神経膠腫、神経膠芽腫、子宮内膜、腎臓、腎盂、膀胱、子宮、子宮頸部、膣、卵巣、多発性骨髄腫、食道、頸部または頭部、脳、口腔および咽頭、喉頭、小腸の良性または悪性腫瘍、黒色腫、絨毛結腸腺腫、肉腫(軟部組織肉腫、脂肪肉腫、横紋筋肉腫、または骨がん、例えば骨肉腫を含む)、新生物、上皮性新生物、乳癌、基底細胞癌、扁平上皮細胞癌、光線角化症、真性赤血球増加症、本態性血小板血症、白血病(急性骨髄性白血病、慢性骨髄性白血病、リンパ球性白血病、および骨髄球性白血病を含む)、リンパ腫(非ホジキンリンパ腫およびホジキンリンパ腫を含む)、骨髄様転移を有する骨髄線維症、ならびにワルデンシュトレーム病からなる群から選択される、請求項21または22に記載の医薬組み合わせ物。
- 前記がんが、結腸直腸がん、乳がん、肺がん、軟部組織肉腫、脂肪肉腫、または扁平上皮細胞癌である、請求項21または22に記載の医薬組み合わせ物。
- 前記がんが、BRAF突然変異、KRAS突然変異、MDM2増幅、PIK3CA突然変異、およびPIK3CA過剰発現のうちの1つまたは複数により特徴付けられる、請求項21から25のいずれか一項に記載の医薬組み合わせ物。
- 前記がんが、MDM2阻害剤による治療に対して抵抗性がある、または難治性である、請求項21から26のいずれか一項に記載の医薬組み合わせ物。
- 前記MDM2阻害剤が、式(II)の構造を有する化合物、式(III)の構造を有する化合物、およびこれらの薬学的に許容される塩からなる群から選択される、請求項27に記載の医薬組み合わせ物。
- がんの治療または予防のための医薬の製造のための、請求項1から13のいずれか一項に記載の医薬組み合わせ物の使用。
- がんの治療または予防のための、請求項1から13のいずれか一項に記載の医薬組み合わせ物の使用。
- 前記がんが固形腫瘍である、請求項29または30に記載の使用。
- 前記がんが、肺(小細胞肺がん、および非小細胞肺がんを含む)、気管支、前立腺、乳房(散発性乳がん、およびカウデン病罹患者を含む)、膵臓、胃腸、結腸、直腸、結腸癌、結腸直腸がん、甲状腺、肝臓、胆道、肝内胆管、肝細胞、副腎、胃部、胃、神経膠腫、神経膠芽腫、子宮内膜、腎臓、腎盂、膀胱、子宮、子宮頸部、膣、卵巣、多発性骨髄腫、食道、頸部または頭部、脳、口腔および咽頭、喉頭、小腸の良性または悪性腫瘍、黒色腫、絨毛結腸腺腫、肉腫(軟部組織肉腫、脂肪肉腫、横紋筋肉腫、または骨がん、例えば骨肉腫を含む)、新生物、上皮性新生物、乳癌、基底細胞癌、扁平上皮細胞癌、光線角化症、真性赤血球増加症、本態性血小板血症、白血病(急性骨髄性白血病、慢性骨髄性白血病、リンパ球性白血病、および骨髄球性白血病を含む)、リンパ腫(非ホジキンリンパ腫およびホジキンリンパ腫を含む)、骨髄様転移を有する骨髄線維症、ならびにワルデンシュトレーム病からなる群から選択される、請求項29または30に記載の使用。
- 前記がんが、結腸直腸がん、乳がん、肺がん、軟部組織肉腫、脂肪肉腫、または扁平上皮細胞癌である、請求項29または30に記載の使用。
- 前記がんが、BRAF突然変異、KRAS突然変異、MDM2増幅、PIK3CA突然変異、およびPIK3CA過剰発現のうちの1つまたは複数により特徴付けられる、請求項28から33のいずれか一項に記載の使用。
- 前記がんが、MDM2阻害剤による治療に対して抵抗性がある、または難治性である、請求項29から34のいずれか一項に記載の使用。
- 前記MDM2阻害剤が、式(II)の構造を有する化合物、式(III)の構造を有する化合物、およびこれらの薬学的に許容される塩からなる群から選択される、請求項35に記載の使用。
- (a)式(I)の構造を有する化合物
(b)MDM2阻害剤と
を含む、医薬組成物。 - 前記MDM2阻害剤が、
式(II)の構造を有する化合物
からなる群から選択される、請求項36に記載の医薬組成物。 - BCL−2阻害剤またはその薬学的に許容される塩を更に含む、請求項37または38に記載の医薬組成物。
- 前記BCL−2阻害剤が、4−[4−[[2−(4−クロロフェニル)−5,5−ジメチル−1−シクロヘキセン−1−イル]メチル]−1−ピペラジニル]−N−[[4−[[(1R)−3−(4−モルホリニル)−1−[(フェニルチオ)メチル]プロピル]アミノ]−3−[(トリフルオロメチル)スルホニル]フェニル]スルホニル]ベンズアミドまたはナビトクラックス、テトロカルシンA、アンチマイシン、ゴシポール、オバトクラックス、2−アミノ−6−ブロモ−4(S)−[1(S)−シアノ−2−エトキシ−2−オキソエチル]−4H−1−ベンゾピラン−3−カルボン酸エチルエステル、オブリメルセン、Bak BH3ペプチド、(−)−ゴシポール酢酸、4−[4−[(4’−クロロ[1,1’−ビフェニル]−2−イル)メチル]−1−ピペラジニル]−N−[[4−[[(1R)−3−(ジメチルアミノ)−1−[(フェニルチオ)メチル]プロピル]アミノ]−3−ニトロフェニル]スルホニル]−ベンズアミドからなる群から選択される、請求項39に記載の医薬組成物。
- 前記BCL−2阻害剤がナビトクラックスである、請求項39に記載の医薬組成物。
- 1つまたは複数の添加剤を更に含む、請求項36から41のいずれか一項に記載の医薬組成物。
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PAREJA, FRESIA ET AL.: "PI3K and BCL2 Inhibition Primes Glioblastoma Cells to Apoptosis through Downregulation of Mcl-1 and", MOLECULAR CANCER RESEARCH, vol. 12, no. 7, JPN6020023548, 2014, pages 987 - 1001, ISSN: 0004298311 * |
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