Search

JP-7854973-B2 - 3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione as a MEK inhibitor

JP7854973B2JP 7854973 B2JP7854973 B2JP 7854973B2JP-7854973-B2

Inventors

  • シェリー アレン
  • エレン マーガレット クナップ
  • デヴィッド オースティン モレノ
  • ジェイコブ マシュー オリーリ
  • リー レン
  • フェイス エリザベス ウィトコス
  • ジェニファー リン フルトン
  • ジェームズ フランシス ブレイク
  • シドニー テイラー ブランシェ
  • マーク ローレンス ボーイズ
  • ウェズリー デウィット クラーク
  • コナー ジェームズ カウドリ
  • ジョシュア ライアン ダールケ
  • パトリック マイケル デルナー バーバー
  • アレックス アンドリュー ケラム

Assignees

  • ファイザー・インク

Dates

Publication Date
20260507
Application Date
20230922
Priority Date
20220926

Claims (20)

  1. structure A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof that is 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione having the above characteristics.
  2. structure A pharmaceutical composition comprising a compound which is 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione having the following characteristics.
  3. A pharmaceutical composition containing crystals comprising 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione.
  4. A pharmaceutical composition containing crystals of anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione.
  5. The pharmaceutical composition according to claim 4, comprising crystals of anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, characterized by having PXRD peaks at 5.0, 8.7, 9.3, 10.8, 14.5, 15.3, 18.8, and 20.5 degrees 2-theta (±0.2 degrees 2-theta).
  6. The pharmaceutical composition according to claim 4, comprising crystals of anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, having a PXRD pattern including characteristic peaks at 7.1, 9.4, 12.4, 12.8, 14.3, 15.6, 16.4, 17.4, 18.5, 18.9, 19.5, 21.1, 21.4, 23.2, 23.7, 24.8, 25.6, 27.6, 30.3, 33.2, 33.5, and 37.5 degrees 2 theta (±0.2 degrees 2 theta).
  7. A pharmaceutical composition containing crystals of 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione monohydrate.
  8. A pharmaceutical composition comprising crystals of 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione monohydrate according to claim 7, characterized by having PXRD peaks at 13.7, 18.0, and 18.3 degrees 2-theta (±0.2 degrees 2-theta).
  9. A pharmaceutical composition containing an amorphous solid of 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione.
  10. A pharmaceutical composition according to any one of claims 1 to 9, for use in treating MEK-related tumors.
  11. The pharmaceutical composition according to claim 10, wherein the tumor has a BRAF V600 mutation selected from V600E, V600K, V600D, V600R, and V600S.
  12. The pharmaceutical composition according to claim 10, wherein the tumor has the BRAF V600E mutation.
  13. The pharmaceutical composition according to claim 10, wherein the tumor is a CNS tumor.
  14. The pharmaceutical composition according to claim 13, wherein the CNS tumor is an intracranial tumor.
  15. The pharmaceutical composition according to claim 14, wherein the intracranial tumor is a brain tumor.
  16. The pharmaceutical composition according to claim 15 , wherein the brain tumor is a metastatic brain tumor.
  17. The pharmaceutical composition according to claim 16, wherein the metastatic brain tumor is selected from metastatic melanoma, metastatic colorectal cancer, metastatic non-small cell lung cancer, metastatic thyroid cancer, and metastatic ovarian cancer.
  18. The pharmaceutical composition according to claim 13, wherein the CNS tumor is an intracranial LMD or an extracranial LMD.
  19. The pharmaceutical composition according to claim 18, wherein LMD is selected from metastatic melanoma, metastatic colorectal cancer, and metastatic non-small cell lung cancer.
  20. The pharmaceutical composition according to claim 14, wherein the intracranial tumor is a primary tumor.

Description

This invention relates to a novel 3,4-dihydro-2,7-naphthirizine-1,6(2H,7H)-dione compound or a pharmaceutically acceptable salt thereof that acts as a MEK inhibitor and is useful for treating abnormal cell growth in patients, such as cancer. The invention also relates to pharmaceutical compositions containing the compound, and to methods of using the compound and compositions in the treatment of abnormal cell growth in subjects requiring it, such as cancer. Furthermore, the invention relates to a solid form of 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthirizine-1,6(2H,7H)-dione, a pharmaceutical composition containing the solid form, and to methods of using the solid form and compositions in the treatment of abnormal cell growth in subjects requiring it, such as cancer. MEK kinase (mitogen-activated protein kinase kinase (MAPKK)) is a key component of the Ras-RAF-MEK-ERK cell survival pathway. The Ras pathway is activated by the binding of growth factors, cytokines, and hormones to their homologous receptors. However, in cancer cells, this pathway is constitutively activated, leading to increased cancer cell survival, proliferation, angiogenesis, and metastasis. Tumors exhibiting constitutive activation of the pathway include, but are not limited to, tumors of the colon, pancreas, breast, brain, ovaries, lungs, and skin. Ras activation (due to upstream signaling or as a result of activation of point mutations in the Ras oncogene) leads to phosphorylation and activation of Raf kinase, which then phosphorylates and activates MEK1 and MEK2 (also known as MAPKK1 and MAPKK2). MEK1 and MEK2 are bispecific kinases that activate ERK1 and ERK2 by phosphorylating and activating ERK1/2 kinase (also known as MAP kinase). This further phosphorylates proteins involved in cell survival and apoptosis, such as Mcl-1, Bim, and Bad, and modulates their function. Therefore, this phosphorylation-mediated cascade results in enhanced cell proliferation, cell survival, and reduced cell death, which are necessary for the initiation and maintenance of tumorigenic phenotypes. Inhibition of this pathway, particularly MEK activity, is known to be beneficial in treating hyperproliferative diseases. MEK inhibitors have shown variable activity in several settings, including BRAF V600-mutated melanoma, NRAS-mutated melanoma, low-grade serous ovarian cancer, plexiform neurofibroma, thyroid cancer, and low-grade glioma, although responses in KRAS-mutated pancreatic or lung cancer are more limited. Cancers with a high frequency of brain metastasis, such as melanoma and non-small cell lung cancer, are known to have MAPK pathway activation alterations, e.g., BRAF V600E and KRAS G12 mutations (Cancer Genome Atlas N., Cell 2015;161:1681-96). Activating mutations can occur at various levels in the classical pathway, but all require mitogen/extracellular signal-regulated kinase (MEK) signaling to enhance proliferation and survival (Schubbert S, Shannon K, Bollag G., Nat Rev Cancer. 2007;7:295-308). Given the MAPK pathway in malignant tumors, and the common activation of MEK at its central and downstream locations, potentially interesting MEK inhibitors are also being used in the treatment of intracranial tumors. The blood-brain interface includes the cerebral microvascular endothelium that forms the blood-brain barrier (BBB) and the choroid plexus epithelium that forms the blood-CSF barrier (BCSFB). The blood-brain barrier (BBB) is a highly selective, physical transport and metabolic barrier that separates the CNS from the blood. The BBB can prevent certain drugs from entering brain tissue and is therefore a limiting factor in the delivery of many peripherally administered drugs to the CNS. The effectiveness of many molecularly targeted drugs in central nervous system tumors is limited by their penetration across the blood-brain barrier (BBB), which consists of a monolayer of endothelial cells connected by tight junctions that act as a physical barrier protecting the brain. In addition, these endothelial cells express multidrug efflux transporters, including P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), which are known to eliminate many anticancer drugs from the brain (Ohtsuki and Terasaki, 2007, Pharm Rez 24:1745-1758; Agarwal et al., 2011, Pharm Rez 24:1745-1758). Similar to the blood-brain barrier, the blood-CSF barrier functions to prevent most blood-derived substances from crossing into the brain, while selectively allowing the passage of certain substances into the brain and promoting the removal of brain metabolites and metabolites into the bloodstream. The powder X-ray diffraction pattern of crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, form 1, is shown.The powder X-ray diffraction pattern of crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-meth