JP2022048388A - 代謝機能不全によって引き起こされる腫瘍の治療 - Google Patents
代謝機能不全によって引き起こされる腫瘍の治療 Download PDFInfo
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Abstract
Description
本開示は、癌などの、代謝機能不全を併発する増殖性疾患を有する患者の治療のための化合物、医薬組成物、及び方法を提供する。本開示は、生体臨床医学、薬学、及び分子生物学の分野に関する。
本出願は、2016年1月11日に提出された米国特許出願第62/277293号明細書、2016年9月13日に提出された米国特許出願第62/393929号明細書、及び2016年9月16日に提出された米国特許出願第62/395446号明細書に対する優先権及び利益を主張する。各出願の内容の全てはここに参照により援用される。
肥満及び代謝機能不全が人の癌発症の危険因子であることはゆるぎないことである。しかし、一旦癌又は増殖に関連した疾患と診断されると、代謝機能不全な人に対する具体的な治療計画はない。癌研究において、ある種の癌患者の内分泌の健全性と、代謝因子、脂肪組織由来のホルモン、及び過剰な内臓肥満症をともなう慢性的炎症を中心とする癌の進行との間に複雑な相互作用のあることが、最近の発見により明らかにされた。ある種の癌において、脂肪組織由来のホルモンは、特定の発がん過程を刺激し、それにより癌細胞の増殖と侵襲性を増加させ、ついにそれらの代謝因子が正常値である癌患者より早く、患者を死に至らしめる。その他の内臓脂肪細胞由来ホルモンは、癌において防御的役割を果たし、しばしば過剰な内臓肥満を抑制する。この癌/代謝の関係が、米国一国で年8万人以上の死亡者に直結している事実にも拘らず、この疾病関係と患者に対する特別な治療計画は未だない。
本開示は、治療を必要とする対象において、癌などの増殖性疾患の少なくとも一つの症状を治療する又は改善する方法であり、その対象は代謝機能不全であるが、その対象に、増殖性疾患を治療するため本開示の化合物の少なくとも一つを、治療効果のある量で投与することを含む方法を提供する。
R4はH又はC1-C6アルキル、
R5はH又はC1-C6アルキル、
R6はC2-C6ヒドロキシアルキル、
Zは-NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L又は-NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-Q-X-Y-C(O)-Wであり
AA1はグリシン、アラニン、又はH2N(CH)2mCO2Hであり、mは2、3、4、又は5である、
AA2は結合又はアラニン、システイン、アスパラギン酸、グルタミン酸、フェニルアラニン、グリシン、ヒスチジン、イソロイシン、リシン、ロイシン、メチオニン、アスパラギン、プロリン、グルタミン、アルギニン、セリン、スレオニン、バリン、トリプトファン又はチロシンであり、
AA3は結合又はアラニン、システイン、アスパラギン酸、グルタミン酸、フェニルアラニン、グリシン、ヒスチジン、イソロイシン、リシン、ロイシン、メチオニン、アスパラギン、プロリン、グルタミン、アルギニン、セリン、スレオニン、バリン、トリプトファン又はチロシンであり、
AA4は結合又はアラニン、システイン、アスパラギン酸、グルタミン酸、フェニルアラニン、グリシン、ヒスチジン、イソロイシン、リシン、ロイシン、メチオニン、アスパラギン、プロリン、グルタミン、アルギニン、セリン、スレオニン、バリン、トリプトファン又はチロシンであり、
AA5は結合又はグリシン、バリン、チロシン、トリプトファン、フェニルアラニン、メチオニン、ロイシン、イソロイシン又はアスパラギンであり、
AA6は結合又はアラニン、アスパラギン、シトルリン、グルタミン、グリシン、ロイシン、メチオニン、フェニルアラニン、セリン、スレオニン、トリプトファン、チロシン、バリン又はH2N(CH2)mCO2Hであり、mは2、3、4又は5である、
Lは、-OH、-O-スクシンイミド、-O-スルホスクシンイミド、アルコキシ、アリールオキシ、アシロキシ、アロイルオキシ、アルコキシカルボニルオキシ、アリールオキシカルボニルオキシ、-NH2、-NH(C2-C6ヒドロキシアルキル)、ハライド又はパーフルオロアルキルオキシであり、
QはNR、O又はSであり、
XはM-(C(R)2)p-M-J-M-(C(R)2)p-M-Vであり、
Mは結合又はC(O)であり、
Jは結合又は((CH2)qQ)r、C5-C8シクロアルキル、アリール、ヘテロアリール、NR、O又はSであり、
YはNR、O又はSであり、
RはH又はアルキルであり、
Vは結合又は
R9はアルキル、アリール、アラルキル又は結合、又はR9はYと結合し複素環を形成する、
R10はアミノ又は結合であり、
R11はH又はアルキルであり、
WはMetAP2阻害剤部分又はアルキルであり
xは1からおよそ450の範囲内
yは1から約30の範囲内
nは1から約100の範囲内
pは0から20、
qは2又は3
rは1、2、3、4、5又は6である。
Z-Q-X-Y-C(O)-W、
式中、Zは-H、-H2N-AA3-AA4-AA5-AA6-C(O)-又は、ZはH2N-AA5-AA6-C(O)であり、
AA3は結合、又はアラニン、システイン、アスパラギン酸、グルタミン酸、フェニルアラニン、グリシン、ヒスチジン、イソロイシン、リシン、ロイシン、メチオニン、アスパラギン、プロリン、グルタミン、アルギニン、セリン、スレオニン、バリン、トリプトファン、又はチロシンであり、
AA4は結合、又はアラニン、システイン、アスパラギン酸、グルタミン酸、フェニルアラニン、グリシン、ヒスチジン、イソロイシン、リシン、ロイシン、メチオニン、アスパラギン、プロリン、グルタミン、アルギニン、セリン、スレオニン、バリン、トリプトファン、又はチロシンであり、
AA5は結合、又はグリシン、バリン、チロシン、トリプトファン、フェニルアラニン、メチオニン、ロイシン、イソロイシン又はアスパラギンであり、
AA6はアラニン、アスパラギン、シトルリン、グルタミン、グリシン、ロイシン、メチオニン、フェニルアラニン、セリン、スレオニン、トリプトファン、チロシン、バリン、又はH2N(CH2)mCO2Hであり、mは2、3、4又は5である、
QはNR、O又はSであり、
XはM-(C(R)2)p-M-J-M-(C(R)2)p-M-Vであり、
Mは結合又はC(O)であり、
Jは結合又は((CH2)qQ)r、C5-C8シクロアルキル、アリール、ヘテロアリール、NR、O又はSであり、
YはNR、O又はSであり、
RはH又はアルキルであり、
Vは結合又は
R9はアルキル、アリール、アラルキル又は結合、又はR9はYと結合し複素環を形成する、
R10はアミノ又は結合であり、
R11はH又はアルキルであり、
WはMetAP2阻害剤部分であり
pは0から20、
qは0又は3、及び
rは1、2、3、4、5、又は6である。
適用の方法
本開示は、治療を必要とする対象において、癌などの増殖性疾患の少なくとも一つの症状を治療する又は改善する方法であり、その対象は代謝機能不全であるが、その対象に、増殖性疾患を治療するため少なくとも一つのMetAP2阻害剤を治療効果のある量で投与することを含む方法を提供する。好ましい態様において、増殖性疾患は癌である。前記癌は、閉経後HR+/Her2乳がん、去勢抵抗性前立腺癌、食道癌、結腸直腸腺癌、子宮頸癌、子宮内膜癌、卵巣癌、膵臓腺癌、胆のう癌、肝臓癌、乳頭状腎細胞がん、メラノーマ、多発性骨髄腫、又はこれらの組み合わせである。前記代謝機能不全は、過剰な内臓脂肪症、高レプチン値、低アディポネクチン値、アディポネクチンに対する高レプチン比、慢性炎症を伴う高空腹時インスリン値、又はそれらの組み合わせを含んでいる。好ましくは、代謝機能不全は、低アディポネクチン値、高レプチン値、高空腹時インスリン値、又はそれらの組み合わせである。本開示の方法は、増殖性疾患の少なくとも一つの症状を治療する又は改善することに加え、代謝機能不全の少なくとも一つの症状を治療する又は改善することも含んでいてもよい。
本開示は、修飾された活性部分、複合体部分、及び切断可能なリンカー、該リンカーの切断は実質的に標的の組織内で起こり、非修飾の活性部分と比べると標的組織からの流失が抑えられる修飾された活性部分を生成する、を含む組成物及び薬剤複合体組成物を提供する。本開示はまた、修飾された活性部分を含む組成物を提供する。
好ましくは、構造:
2-[((S)-1-エチルピロリジン-2-イル)カルボニル-アミノメチル]-4-フルオロベンゼン-スルフォニルアミノ}-1,1a,2,7b-テトラヒドロシクロプロパ[c]クロメン-4-カルボン酸;(1aRS,7bSR)-5-[2-(4-ジメチルアミノブチリルアミノ)-4-フルオロベンゼンスルフォニル-アミノ]-1,1a,2,7b-テトラヒドロシクロプロパ-[c]クロメン-4-カルボン酸;(1aRS,7bSR)-5-[2-((S)-1-エチル-ピロリジン-3-イルメチル)-4-フルオロベンゼンスルフォニル-アミノ]-1,1a,2,7b-テトラヒドロシクロプロパ[c]クロメン-4-カルボン酸;(1aRS,7bSR)-5-[2-(3-ジメチルアミノプロピルカルバモイル)ベンゼン-スルフォニルアミノ]-1,1a,2,7b-テトラヒドロシクロプロパ[c]クロメン-4-カルボン酸;(1aRS,7bSR)-5-(2-{[N-((S)-1-エチル-ピロリジン-3-イル)-N-メチルカルバモイル]メチル}-4-フルオロ-ベンゼンスルフォニルアミノ)-1,1a,2,7b-テトラヒドロシクロプロパ-[c]クロメン-4-カルボン酸;(1aRS,7bSR)-5-(2-{[N-((R)-1-エチル-ピロリジン-3-イル)-N-メチルカルバモイル]メチル}-4-フルオロ-ベンゼンスルフォニルアミノ)-1,1a,2,7b-テトラヒドロシクロプロパ-[c]クロメン-4-カルボン酸;(1aRS,7bSR)-5-{2-[2-((S)-1-エチルピロリジン-2-イル)エチルアミノ]-ベンゼンスルフォニル-アミノ}-1,1a,2,7b-テトラヒドロシクロプロパ-[c]クロメン-4-カルボン酸;(1aRS,7bSR)-5-{2-[2-((R)-1-エチルピロリジン-2-イル)エチルアミノ]-ベンゼンスルフォニル-アミノ}-1,1a,2,7b-テトラヒドロシクロプロパ-[c]クロメン-4-カルボン酸;(1aRS,7bSR)-5-[2-(3-N,N,-ジエチルアミノプロピルアミノ)ベンゼン-スルフォニルアミノ]-1,1a,2,7b-テトラヒドロシクロプロパ[c]クロメン-4-カルボン酸;(1aRS,7bSR)-5-(2-{[((R)-1-エチルピロリジン-2-イル)カルボニル-アミノ]メチル}-4-フルオロベンゼンスルフォニルアミノ)-1,1a,2,7b-テトラヒドロシクロプロパ[c]クロメン-4-カルボン酸;(1aRS,7bSR)-5-{2-[(1-エチルアゼピジン-3-イルメチル)アミノ]ベンゼン-スルフォニルアミノ}-1,1a,2,7b-テトラヒドロシクロプロパ[c]クロメン-4-カルボン酸;(1 aS,7bR)-5-[2-((Z)-3-ジエチルアミプロピ-1-エニル)ベンゼンスルフォニルアミノ]-1,1a,2,7b-テトラヒドロシクロプロパ[c]クロメン-4-カルボン酸;(1 aR,7bS)-5-[2-((Z)-3-ジエチルアミプロピ-1-エニル)ベンゼンスルフォニルアミノ]-1,1a,2,7b-テトラヒドロシクロプロパ[c]クロメン-4-カルボン酸;(1aRS,7bSR)-5-(2-(N-[((R)-1-エチルピロリジン-2-イル)カルボニル]-N-メチル-アミノメチル)-4-フルオロベンゼンスルフォニルアミノ)-1,1a,2,7b-テトラヒドロシクロプロパ[c]クロメン-4-カルボン酸;(1aRS,7bSR)-5-(2-{N-[((S)-1-エチルピロリジン-2-イル)カルボニル]-N-メチルアミノ-メチル}-4-フルオロベンゼンスルフォニルアミノ)-1,1a,2,7b-テトラヒドロシクロプロパ[c]クロメン-4-カルボン酸;(1aRS,7bSR)-5-[2-(4-ジメチルアミノブチルアミノ)-4-フルオロベンゼンスルフォニル-アミノ]-1,1a,2,7b-テトラヒドロシクロプロパ[c]クロメン-4-カルボン酸;(1aRS,7bSR)-5-{2-[((R)-1-エチルピロリジン-3-イルメチル)アミノ]-ベンゼンスルフォニルアミノ}-1,1a,2,7b-テトラヒドロシクロプロパ-[c]クロメン-4-カルボン酸;(1aRS,7bSR)-5-{2-[((S)-1-エチルピロリジン-3-イルメチル)アミノ]-ベンゼンスルフォニルアミノ}-1,1a,2,7b-テトラヒドロシクロプロパ-[c]クロメン-4-カルボン酸;(1aRS,7bSR)-5-[2-(4-エチル-2-オキソピペラジン-1-イルメチル)-4-フルオロベンゼン-スルフォニルアミノ]-1,1a,2,7b-テトラヒドロシクロプロパ[c]クロメン-4-カルボン酸;(1aRS,7bSR)-5-[2-(1-エチルピペラジン-4-イルメチル)-4-フルオロ-ベンゼンスルフォニルアミノ]-1,1a,2,7b-テトラヒドロシクロプロパ-[c]クロメン-4-カルボン酸;(1aRS,7bSR)-5-{2-[2-(1-エチルアゼピジン-3-イル)エチル]-4-フルオロ-ベンゼンスルフォニル-アミノ}-1,1a,2,7b-テトラヒドロシクロプロパ[c]クロメン-4-カルボン酸;(1aRS,7bSR)-5-{2-[((S)-1-アザビシクロ[2.2.2]オクチ-3-イル)アミノ]ベンゼンスルフォニル-アミノ}-1,1a,2,7b-テトラヒドロシクロプロパ[c]クロメン-4-カルボン酸;(1aRS,7bSR)-5-{2-[((R)-1-アザビシクロ-[2.2.2]オクチ-3-イル)アミノ]ベンゼンスルフォニル-アミノ}-1,1a,2,7b-テトラヒドロシクロプロパ[c]クロメン-4-カルボン酸;(1aRS,7bSR)-5-(2-{[((S)-1-エチルピロリジン-3-カルボニル)アミノ]メチル}-4-フルオロ-ベンゼンスルフォニルアミノ)-1,1a,2,7b-テトラヒドロシクロプロパ[c]クロメン-4-カルボン酸;(1aRS,7bSR)-5-{2-[2-((R)-1-エチルピロリジン-3-イルアミノ)エチル]-4-フルオロ-ベンゼンスルフォニルアミノ}-1,1a,2,7b-テトラヒドロシクロプロパ-[c]クロメン-4-カルボン酸;(1aRS,7bSR)-5-{2-[((R)-1-エチルピロリジン-3-イル)アミノ]-ベンゼンスルフォニルアミノ}-1,1a,2,7b-テトラヒドロシクロプロパ-[c]クロメン-4-カルボン酸;(1aRS,7bSR)-5-{2-[((S)-1-エチルピロリジン-3-イル)アミノ]-ベンゼンスルフォニルアミノ}-1,1a,2,7b-テトラヒドロシクロプロパ-[c]クロメン-4-カルボン酸;(1aRS,7bSR)-5-(2-{[((R)-1-エチルピロリジン-3-カルボニル)アミノ]-メチル)}-4-フルオロ-ベンゼンスルフォニルアミノ)-1,1a,2,7b-テトラヒドロ-シクロプロパ[c]クロメン-4-カルボン酸;(1aRS,7bSR)-5-[2-((Z)-3-ジエチルアミノ-2-メチルプロプ-1-エニル)-4-フルオロベンゼン-スルフォニルアミノ]-1,1a,2,7b-テトラヒドロシクロプロパ[c]クロメン-4-カルボン酸;(1aRS,7bSR)-5-{2-[2-((R)-1-エチルピロリジン-3-イル)エチルアミノ]-ベンゼンスルフォニルアミノ}-1,1a,2,7b-テトラヒドロシクロプロパ-[c]クロメン-4-カルボン酸;(1aRS,7bSR)-5-{2-[2-((S)-1-エチルピロリジン-3-イル)エチルアミノ]-ベンゼンスルフォニル-アミノ}-1,1a,2,7b-テトラヒドロシクロプロパ-[c]クロメン-4-カルボン酸;(1aR,7bS)-5-[2-((S)-1-エチルピロリジン-3-イルオキシメチル)-4-フルオロ-ベンゼンスルフォニルアミノ]-1,1a,2,7b-テトラヒドロシクロプロパ-[c]クロメン-4-カルボン酸;(1 aR,7bS)-5-[2-((R)-1-エチルピロリジン-3-イルオキシメチル)-4-フルオロ-ベンゼンスルフォニルアミノ]-1,1a,2,7b-テトラヒドロシクロプロパ-[c]クロメン-4-カルボン酸;(1aR,7bS)-5-[2-(1-エチルピペラジン-3-イルメチル)-4-フルオロベンゼン-スルフォニルアミノ]-1,1a,2,7b-テトラヒドロシクロプロパ[c]クロメン-4-カルボン酸;(1aR,7bS)-5-{2-[2-((R)-1-エチルピロリジン-2-イル)エチル]-4-フルオロベンゼンスルフォニル-アミノ}-1,1a,2,7b-テトラヒドロシクロプロパ-[c]クロメン-4-カルボン酸;及びこれらの医薬的に許容される塩、ステレオイソマー、エステル、及びプロドラッグである。
・ 高度に難治性又は末期の固形腫瘍を持つ患者における、化合物1の安全性及び耐薬性の測定
・ 高度に難治性又は末期の固形腫瘍を持つ患者における、化合物1の最大耐薬性の用量の測定
・ 高度に難治性又は末期の固形腫瘍を持つ患者における、化合物1の推奨するフェーズ2用量(RP2D)の測定
・ 高度に難治性又は末期の固形腫瘍を持つ患者における、化合物5、化合物1の活性部分及び代謝物、の薬物動態(PK)の評価
・ 高度に難治性又は末期の固形腫瘍を持つ患者における、化合物1の抗腫瘍活性の証明を記録する。
・ 高度に難治性又は末期の固形腫瘍を持つ患者における、バイオマーカー分析及びPET走査画像(研究者及び医療観察者に臨床的に妥当であり承認されたもの)による化合物1の効果を評価する。
・ 高度に難治性又は末期の固形腫瘍を持つ患者における、MetAP2分析及びDCEMRI画像(研究者及び医療観察者に臨床的に妥当であり承認されたもの)による化合物1の薬物動態(PD)効果を評価する。
・ 高度に難治性又は末期の固形腫瘍を持つ患者における、代謝因子への化合物1の効果を記録する。
・ 選択された患者における、体内筋肉及び脂肪細胞量をMRI又はCT画像で評価する。
・ 臨床的応答がある場合、又は
・ C2、C4、C6、及その後の毎3周期後の画像研究に基づく評価で安定した疾病がある場合、又は
・ 研究者及び医療観察者が治療から利益を受けていると同意する場合。
DLTは臨床的に有意な、以下の有害事象のいずれかとして定義され、最大の医療支持にも拘らず、研究者が、恐らく、たぶん、又は明らかに頑固に続く化合物1の投与に関連すると見なされる。
・ グレード3又はより高い非血液毒性のいずれか;7日間続く、又は
・ グレード3又はより高い3日続く吐き気、下痢及び/又は嘔吐のいずれか、患者は最大の医療介入及び/又は予防的抗嘔吐治療をした場合、又は、
・ グレード3又はより高い血液毒性のいずれか;3日間続く、又は
・ グレード3又はより高い発熱性好中球減少症のいずれか。
・ 血液学:ANC >1500細胞/mm3、血小板数>100000 細胞/mm3及びヘモグロビン>9g/dL。
・ 検尿:臨床的に有意な異常なし。
・ 凝固:INR及びPTT正常値内。
・ HIV陽性患者は、以下の基準に合っていれば適格である:CD4数≧100/mm3、過去3か月以内のウィルス量が検出限界以下、研究参加前4週間以上、抗レトロウィルス治療を受けている。
臓器移植手術を受けた患者。
・ 細胞障害性又は細胞増殖抑制化学療法、モノクロナール抗体治療、放射線治療、分子標的治療、ホルモン剤、TKI(チロシンキナーゼ阻害剤)、血管新生及びVEGF阻害剤に依るすべての治療。
・ 研究薬剤の最初の投与前、4週間以内の大きな手術。
・ 研究薬剤の最初の投与前、12週間以内の放射線免疫治療による全ての治療。
・ 署名された同意説明書
・ 既往歴
・ 身体検査(全身); もし臨床的に示されていない場合、直腸内及び生殖器試験は遅らせてもよい
・ 身長及び体重
・ ECOGパフォーマンスステータス
・ バイタルサイン(体温、血圧、脈拍、及び呼吸数)
・ 併用薬の評価
・ 12-リード心電図(三つ組)
・ 血清妊娠テスト(妊娠の可能性のある、不妊ではない女性のため)
・ 血液学
・ 臨床化学、血液凝固、脂質、及び尿検査(ディップスティックで陽性ならば、顕微鏡検査)
・ RECIST1.1基準を用いた放射線学的評価に依る腫瘍負荷評価(もし治療第1日目のわずか30日以内に見つかったなら、CTスキャンを用いてよい。)
・ 研究者及び医療観察者によって承認され、臨床的に示された時、PET及びDCE MRIスキャン
・ 身体組成分析のため、研究者及び医療観察者によって承認された選択された患者へのMRI又はCTスキャン、参照画像マニュアル
・ 患者の特定の腫瘍タイプに関連するタンパクバイオマーカーに帰着する利用可能な臨床的に許された分析記録(例えば、PSA、CA-125、AFP、CEA、beta-hCG、Ca19-9、等)
・ 既往歴
・ 体重(研究薬剤の計算のため毎治療日前投与-前回の訪問からの体重を研究薬剤投与計算のため用いてよい)。
・ 食事習慣、摂食、及び身体活動に関する問診
・ ECOGパフォーマンスステータス(各周期の投与前第1日)
・ バイタルサイン(体温、血圧、脈拍、及び呼吸数)
・ 併用薬の評価
・ 12-リード心電図(三つ組)
・ 皮下治療注入部の局所耐性
・ 血清妊娠テスト(妊娠の可能性のある、不妊ではない女性のため)(投与前第1日)
・ 血液学
・ 臨床化学、血液凝固、脂質、及び尿検査(ディップスティックで陽性ならば、顕微鏡検査)
・ PK及びPD分析用の血液サンプルの収集
・ 診査用のバイオマーカー及び保持のための血液サンプルの収集
・ 研究者及び医療観察者によって承認され、臨床的に示された時、PET及びDCE MRIスキャン
・ 身体組成分析のため、研究者及び医療観察者によって承認された選択された患者へのMRI又はCTスキャン、参照画像マニュアル
・ RECIST1.1を用いて、一回置きの周期で(すなわち、Cycles2、4,6)行われる腫瘍負荷評価。周期6が完了した後、腫瘍負荷評価は毎3周期で行われる。もし安定した又は積極的な応答が明らかとなった場合は、フォローアップ(4週間)の確証的放射線評価が行われる。
・ 患者の特定の腫瘍タイプに関連するタンパクバイオマーカーに帰着する利用可能な臨床的に許された分析記録(例えば、PSA、CA-125、AFP、CEA、beta-hCG、Ca19-9、等)
・ 有害事象の見直し(症状の見直しを含む)
・ 体重
・ 摂食、食事習慣、身体活動に関する質問
・ ECOGパフォーマンスステータス(各周期の投与前第1日)
・ バイタルサイン(体温、血圧、脈拍、及び呼吸数)
・ 併用薬の評価
・ 12-リード心電図(三つ組)
・ 皮下治療注入部の局所耐性
・ 血液学
・ 臨床化学、血液凝固、脂質、及び尿検査(顕微鏡検査)
・ PK及びPD分析用の血液サンプルの収集
・ バイオマーカー及び保持のための血液サンプルの収集
・ RECIST1.1基準を用いた放射線学的評価に依る腫瘍負荷評価
・ 患者の特定の腫瘍タイプに関連するタンパクバイオマーカーに帰着する利用可能な臨床的に許された分析記録(例えば、PSA、CA-125、AFP、CEA、beta-hCG、Ca19-9、等)
・ 有害事象の見直し(症状の見直しを含む)
・ 身体検査
・ 身長及び体重
・ 摂食、食事習慣、身体活動に関する質問
・ ECOGパフォーマンスステータス
・ バイタルサイン(体温、血圧、脈拍、及び呼吸数)
・ 併用薬の評価
・ 12-リード心電図(三つ組)
・ 皮下治療注入部の局所耐性
・ 血清妊娠テスト(妊娠の可能性のある、不妊ではない女性のため)
・ 血液学
・ 臨床化学、血液凝固、脂質、及び尿検査(顕微鏡検査)
・ PK及びPD分析用の血液サンプルの収集
・ バイオマーカー及び保持のための血液サンプルの収集
・ RECIST1.1を用いた腫瘍負荷評価がなされる
・ 患者の特定の腫瘍タイプに関連するタンパクバイオマーカーに帰着する利用可能な臨床的に許された分析記録(例えば、PSA、CA-125、AFP、CEA、beta-hCG、Ca19-9、等)
・ 有害事象の見直し(症状の見直しを含む)
・ AEの発生率、グレード、及び期間
・ 全体及び限られた場所での容認性評価
・ 実験室での評価
・ 健康診断、バイタルサイン、及びECGパラメータ
・ 患者がもはや研究薬剤を取らなくなるまで、投与1からPKプロファイル
・ 疾病状態の変化、全体的応答の速さ(CR+PR)、及び疾病制御速さ(CR+PR+SD)
・ PET及びDCE MRI評価
・ 患者がもはや研究薬剤を取らなくなるまで、投与1からPD(MetAP2)プロファイル
・ 身体組成における変化のMRI又はCT評価
・ 患者がもはや研究薬剤を取らなくなるまで、投与1からバイオマーカー評価(TNF-α、IL-6、MCP-1,IGF-1、hsCRP、レプチン、インスリン、SHBG(選択された患者用)VEGF、bFGF、及びアディポネクチン)
・ 患者がもはや研究薬剤を取らなくなるまで、投与1から代謝評価(グルコース、総コレステロール、LDL、HDL、遊離脂肪酸、脂質、トリグリセリド、及びVLDL)、及び食事及び栄養評価
Claims (51)
- 癌の少なくとも一つの症状を治療又は改善を必要とする対象に、下記式:
R4はH又はC1-C6アルキル、
R5はH又はC1-C6アルキル、
R6はC2-C6ヒドロキシアルキル、
Zは-NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L又は-NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-Q-X-Y-C(O)-Wであり
AA1はグリシン、アラニン、又はH2N(CH2)mCO2Hであり、mは2,3,4、又は5である、
AA2は結合又はアラニン、システイン、アスパラギン酸、グルタミン酸、フェニルアラニン、グリシン、ヒスチジン、イソロイシン、リシン、ロイシン、メチオニン、アスパラギン、プロリン、グルタミン、アルギニン、セリン、スレオニン、バリン、トリプトファン又はチロシンであり、
AA3は結合又はアラニン、システイン、アスパラギン酸、グルタミン酸、フェニルアラニン、グリシン、ヒスチジン、イソロイシン、リシン、ロイシン、メチオニン、アスパラギン、プロリン、グルタミン、アルギニン、セリン、スレオニン、バリン、トリプトファン又はチロシンであり、
AA4は結合又はアラニン、システイン、アスパラギン酸、グルタミン酸、フェニルアラニン、グリシン、ヒスチジン、イソロイシン、リシン、ロイシン、メチオニン、アスパラギン、プロリン、グルタミン、アルギニン、セリン、スレオニン、バリン、トリプトファン又はチロシンであり、
AA5は結合又はグリシン、バリン、チロシン、トリプトファン、フェニルアラニン、メチオニン、ロイシン、イソロイシン又はアスパラギンであり、
AA6は結合又はアラニン、アスパラギン、シトルリン、グルタミン、グリシン、ロイシン、メチオニン、フェニルアラニン、セリン、スレオニン、トリプトファン、チロシン、バリン又はH2N(CH2)mCO2Hであり、mは2、3、4又は5である、
Lは、-OH、-O-スクシンイミド、-O-スルホスクシンイミド、アルコキシ、アリールオキシ、アシロキシ、アロイルオキシ、アルコキシカルボニルオキシ、アリールオキシカルボニルオキシ、-NH2、-NH(C2-C6ヒドロキシアルキル)、ハライド又はパーフルオロアルキルオキシ、
QはNR、O又はS、
XはM-(C(R)2)p-M-J-M-(C(R)2)p-M-V、
Mは結合又はC(O)、
Jは結合又は((CH2)qQ)r、C5-C8シクロアルキル、アリール、ヘテロアリール、NR、O又はS、
YはNR、O又はS、
RはH又はアルキル、
Vは結合又は
R10はアミノ又は結合、
R11はH又はアルキル、
WはMetAP2阻害剤部分又はアルキル
Xは1からおよそ450の範囲内
Yは1からおよそ30の範囲内
nは1からおよそ100の範囲内
pは0から20、
qは2又は3
rは1、2、3、4、5又は6である。]
で表される化合物の少なくとも一つ、その医薬的に許容される塩、プロドラッグ、代謝物、又は類似物もしくは誘導体の治療有効量を投与することを含む、癌の少なくとも一つの症状を治療する又は改善する方法であって、前記対象は代謝機能不全を有し、癌は治療される、方法。 - R4がメチル基である、請求項1に記載の方法。
- R5がメチル基である、請求項1に記載の方法。
- R6が2-ヒドロキシプロピル基である、請求項1に記載の方法。
- Zが-NH-AA6-C(O)-Q-X-Y-C(O)-Wである、請求項1に記載の方法。
- AA6がグリシンである、請求項7に記載の方法。
- Zが-NH-AA5-AA6-C(O)-Q-X-Y-C(O)-Wである、請求項1に記載の方法。
- AA5がロイシンであり、AA6がグリシンである、請求項9に記載の方法。
- AA5がバリンであり、AA6がグリシンである、請求項9に記載の方法。
- AA5がフェニルアラニンでありAA6がグリシンである、請求項9に記載の方法。
- AA5がグリシンであり、AA6がグリシンである、請求項9に記載の方法。
- Zが-NH-AA3-AA4-AA5-AA6-C(O)-Q-X-Y-C(O)-Wである、請求項1に記載の方法。
- AA5がロイシンであり、AA3、AA4、又はAA6は各々グリシンである、請求項14に記載の方法。
- AA5がバリンであり、AA3、AA4、又はAA6は各々グリシンである、請求項14に記載の方法。
- AA5がフェニルアラニンであり、AA3、AA4、又はAA6は各々グリシンである、請求項14に記載の方法。
- AA3がグリシンであり、AA4がフェニルアラニンであり、AA5がロイシンであり、AA6がグリシンである、請求項14に記載の方法。
- AA3、AA4、AA5及びAA6は各々グリシンである、請求項14に記載の方法。
- 前記比x:yが約30:1~約3:1の範囲である、請求項1に記載の方法。
- 前記比x:yが約11:1である、請求項1に記載の方法。
- 下記式:
Z-Q-X-Y-C(O)-W
[式中、
Zは-H、-H2N-AA3-AA4-AA5-AA6-C(O)-又は、ZはH2N-AA5-AA6-C(O)であり、
AA3は結合又はアラニン、システイン、アスパラギン酸、グルタミン酸、フェニルアラニン、グリシン、ヒスチジン、イソロイシン、リシン、ロイシン、メチオニン、アスパラギン、プロリン、グルタミン、アルギニン、セリン、スレオニン、バリン、トリプトファン、又はチロシンであり、
AA4は結合又はアラニン、システイン、アスパラギン酸、グルタミン酸、フェニルアラニン、グリシン、ヒスチジン、イソロイシン、リシン、ロイシン、メチオニン、アスパラギン、プロリン、グルタミン、アルギニン、セリン、スレオニン、バリン、トリプトファン、又はチロシンであり、
AA5は結合又はグリシン、バリン、チロシン、トリプトファン、フェニルアラニン、メチオニン、ロイシン、イソロイシン又はアスパラギンであり、
AA6は結合又はアラニン、アスパラギン、シトルリン、グルタミン、グリシン、ロイシン、メチオニン、フェニルアラニン、セリン、スレオニン、トリプトファン、チロシン、バリン又はH2N(CH2)mCO2Hであり、mは2、3、4又は5である、
QはNR、O又はS、
XはM-(C(R)2)p-M-J-M-(C(R)2)p-M-V、
Mは結合又はC(O)、
Jは結合又は((CH2)qQ)r、C5-C8シクロアルキル、アリール、ヘテロアリール、NR、O又はS、
YはNR、O又はS、
RはH又はアルキル、
Vは結合又は
R10はアミノ又は結合、
R11はH又はアルキル、
WはMetAP2阻害剤部分、
pは0から20、
qは2又は3、
rは1、2、3、4、5又は6である。]
で表わされる化合物の少なくとも一つ、又はその医薬的に許容される塩、プロドラッグ、代謝物、又はその類似物もしくは誘導体の治療有効量を、癌の少なくとも一つの症状の治療又は改善を必要とする対象に投与することを含む、癌の少なくとも一つの症状を治療する又は改善する方法であって、前記対象は代謝機能不全を有し、癌は治療される、方法。 - Zが-NH-AA5-AA6-C(O)-Q-X-Y-C(O)-W、AA5はロイシン、AA6はグリシンである、請求項24に記載の方法。
- Zが-NH-AA5-AA6-C(O)-Q-X-Y-C(O)-W、AA5 はバリン、AA6はグリシンである、請求項24に記載の方法。
- Zが-NH-AA5-AA6-C(O)-Q-X-Y-C(O)-W、AA5はフェニルアラニン、AA6はグリシンである、請求項24に記載の方法。
- Zが-NH-AA5-AA6-C(O)-Q-X-Y-C(O)-W、AA5はグリシン、AA6はグリシンである、請求項24に記載の方法。
- Zが-NH-AA3-AA4-AA5-AA6-C(O)-Q-X-Y-C(O)-W、AA5はロイシン、AA3、AA4、又はAA6の各々はグリシンである、請求項24に記載の方法。
- Zが-NH-AA3-AA4-AA5-AA6-C(O)-Q-X-Y-C(O)-W、AA5はバリン、AA3、AA4、又はAA6の各々はグリシンである、請求項24に記載の方法。
- Zが-NH-AA3-AA4-AA5-AA6-C(O)-Q-X-Y-C(O)-W、AA5はフェニルアラニン、AA3、AA4、又はAA6の各々はグリシンである、請求項24に記載の方法。
- Zが-NH-AA3-AA4-AA5-AA6-C(O)-Q-X-Y-C(O)-W、AA5はグリシン、AA4はフェニルアラニン、AA5はロイシン、AA6はグリシンである、請求項24に記載の方法。
- Zが-NH-AA3-AA4-AA5-AA6-C(O)-Q-X-Y-C(O)-W、AA3、AA4、AA5、又はAA6の各々はグリシンである、請求項24に記載の方法。
- 前記癌が、閉経後HR+/Her2-乳癌、去勢抵抗性前立腺癌、食道癌、結腸直腸腺癌、子宮頸癌、子宮内膜癌、卵巣癌、膵臓腺癌、胆のう癌、肝臓癌、乳頭状腎細胞癌、メラノーマ、多発性骨髄腫、及びこれらの組み合わせである、請求項1又は24に記載の方法。
- 前記代謝機能不全が、過剰な内臓脂肪症、高レプチン値、低アディポネクチン値、アディポネクチンに対する高レプチン比、慢性炎症を伴う高空腹時インスリン値、又はそれらの組み合わせである、請求項1又は24に記載の方法。
- 前記対象における代謝機能不全の少なくとも一つの症状を治療すること又は改善することを更に含む、請求項1又は24に記載の方法。
- 前記対象において、アディポネクチンを増加させること、レプチンを下げること、空腹時インスリンを下げること、又はこれらの組み合わせを更に含む、請求項1又は24に記載の方法。
- 前記治療有効量が、約0.0001mg/kg~約5mg/体重kg/日である、請求項1又は24に記載の方法。
- 前記治療有効量が、約0.001~約0.005mg/体重kg/日である、請求項1又は24に記載の方法。
- 前記化合物が、約1~約5回/週服用される、請求項1又は24に記載の方法。
- 前記化合物が4日毎の予定で服用される、請求項1又は24に記載の方法。
- 前記化合物が7日毎の予定で服用される、請求項1又は24に記載の方法。
- 前記対象が少なくとも約6か月間治療される、請求項1又は24に記載の方法。
- 前記対象が少なくとも約1年間治療される、請求項1又は24に記載の方法。
- 前記化合物が非経口的に服用される、請求項1又は24に記載の方法。
- 前記化合物が皮下的に服用される、請求項1又は24に記載の方法。
- 第二の活性薬剤を服用することを更に含む、請求項1又は24に記載の方法。
- 前記化合物が、前記化合物と医薬的に許容される担体を含む医薬組成物として提供される、請求項1又は24に記載の方法。
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WO2017123603A1 (en) | 2017-07-20 |
CN114225045A (zh) | 2022-03-25 |
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CN108697807A (zh) | 2018-10-23 |
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US20210077452A1 (en) | 2021-03-18 |
AU2021286420A1 (en) | 2022-01-20 |
CA3008960A1 (en) | 2017-07-20 |
US20220280470A1 (en) | 2022-09-08 |
MX2023002076A (es) | 2023-03-17 |
KR20180100663A (ko) | 2018-09-11 |
MX2018008321A (es) | 2018-09-21 |
US10646463B2 (en) | 2020-05-12 |
JP7022066B2 (ja) | 2022-02-17 |
EP3402529A1 (en) | 2018-11-21 |
CN108697807B (zh) | 2021-11-26 |
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