JP-7856707-B2 - organic compound

Inventors

• スナイダー，グレッチェン
• ウェノグル，ローレンス ピー
• オブライエン，ジェニファー
• ヘンドリック，ジョゼフ
• デイビス，ロバート

Assignees

• イントラ－セルラー・セラピーズ・インコーポレイテッド

Dates

Publication Date

20260511

Application Date

20240821

Priority Date

20190107

Claims (8)

1. A pharmaceutical agent for suppressing macrophage recruitment or microglia recruitment to metastatic cells, wherein the pharmaceutical agent comprises a PDE1 inhibitor, and the PDE1 inhibitor is (1) Formula II, in free form or pharmaceutically acceptable salt form: Formula II [In the formula, (i) X is methylene; (ii) Y is either allirene; (iii) Z is aryl, pyridyl, -C(O)-R 1 ; (iv) R1 is a C1-6 alkyl , a halo C1-6 alkyl , an -OH or -OC1-6 alkyl ; (v) R4 is H, and R5 is an aryl which may be substituted with a halo; (vi) Here, Z may be replaced by a halo; (2) Formula 1a: in free form or pharmaceutically acceptable salt form Equation Ia [In the formula, (i) R2 and R3 are each methyl, and R4 and R5 are each H; (ii) R 6 is a phenylamino acid (which may be halosubstituted); (iii) R 10 is C1-4 alkyl , methylcarbonyl, hydroxyethyl, carboxylic acid, (halosubstituted) phenyl or (halosubstituted) pyridyl; (iv) X and Y are C or N. A pharmaceutical compound selected from among these .
2. The pharmaceutical agent according to claim 1, wherein macrophage or microglia recruitment to metastatic cells is at least partially mediated by CCL2.
3. The pharmaceutical product according to claim 1 or 2, administered in combination with a checkpoint inhibitor.
4. The pharmaceutical product according to claim 3, wherein the checkpoint inhibitor is an inhibitor of CTLA-4, PD-1, and/or PD-L1.
5. The pharmaceutical product according to claim 3, wherein the checkpoint inhibitor comprises one or more members selected from nivolumab, pembrolizumab, semiprimab, ipilimumab, avelumab, durvalumab, atezolizumab, and spartalizumab.
6. PDE1 inhibitors, in free form or pharmaceutically acceptable salt form, as follows: A pharmaceutical product according to any one of claims 1 to 5 , selected from the above.
7. PDE1 inhibitors are available in free form or in pharmaceutically acceptable salt form, such as monophosphate form. The pharmaceutical product according to any one of claims 1 to 5 .
8. PDE1 inhibitors, in free form or pharmaceutically acceptable salt form, The pharmaceutical product according to any one of claims 1 to 5 .

Description

This field relates to the use of phosphodiesterase 1 (PDE1) inhibitors for the treatment of cancer and tumors, including inhibiting the recruitment of macrophages and other cells to tumors or cancer cells; for inhibiting tumor cell migration and preventing tumor metastasis; for complementing and enhancing checkpoint inhibitor therapy, genome editing therapy, and chimeric antigen receptor T cell (CAR-T) therapy; for preventing or reversing the immunosuppressive tumor microenvironment; and for mitigating side effects (i.e., inflammatory adverse events) associated with immunotherapy, including checkpoint inhibitor therapy, and cellular immunotherapy, including CAR-T therapy. It is estimated that 90% of cancer-related deaths worldwide are due to metastasis. In most cases, metastatic tumor cells develop ways to evade the immune response and become resistant to treatment. While resistance to cancer treatment can be inherent in tumor cells, it is often conferred or enhanced by non-malignant cells that make up the tumor microenvironment (TME). The TME consists of tissue-resident cells, stromal cells, and other cells recruited by the tumor, and therefore may include endothelial cells, pericytes, fibroblasts, mesenchymal stem cells, as well as a variety of immune cells, including regulatory T ( Treg ) cells, mast cells, neutrophils, myeloid-derived suppressor cells, and tumor-associated macrophages. These cells promote tumor angiogenesis and cancer cell invasion, and/or disrupt immune surveillance. Macrophages are one of the most common types of tumor-associated cells. Researchers initially assumed these immune cells were part of the body's rejection of tumors, and indeed, the primary checks for cancer development are the surveillance of the immune system and its response to the presence of cancer by cells of the innate immune system (e.g., macrophages, neutrophils) and cells associated with adaptive immune responses (e.g., T cells and B cells). However, in some cases, cancer can evade and utilize the immune system, so these immune system cells become part of the tumor's support and defense system rather than attacking the tumor. Immune TMEs can be modified to support tumors and promote their progression while suppressing immune cell-mediated cytotoxicity. Substantial clinical and experimental evidence indicates that macrophages (abundant in most tumor types) play a major regulatory role in promoting tumor progression to malignancy. Macrophages in primary tumors (tumor-associated macrophages or TAMs) and macrophages in metastatic tumors (metastasis-associated macrophages or MAMs) are both abundant in most solid tumors and may be associated with tumor metastasis. The accumulation of TAMs, MAMs, and their progenitor cells appears to be driven by chemokine ligands released by tumor and stromal cells. For example, there is evidence that TAMs and MAMs originate, at least in part, from CCR2-expressing monocytes recruited by CCL2-expressing tumor cells and/or CCL2-expressing stromal cells. However, the exact mechanism is not fully defined, and other CCR2 ligands such as CCL12, cytokines such as VEGF and CSF1, as well as other chemoattractant signals such as CCL5-CCR5, CCL20-CCR6, and CXCL12-CXCR4 may provide alternative or additional chemoattractant pathways for TAM recruitment. Therefore, efforts to target specific chemoattractant receptors or ligands, such as efforts to specifically block the CCR2-CCL2 interaction, have not been entirely effective, presumably because cancer can utilize alternative pathways. Immune activation is primarily T-cell mediated and regulated by stimulative, co-stimulative, and inhibitory (checkpoint) signaling. When T cells encounter self-cells, there are crucial receptor-ligand interactions that provide a check on activation, preventing immune cells from attacking the body's normal cells. While cancer cells possess genetic and epigenetic alterations that can lead to antigen expression that can trigger immune activation, they can also utilize these immune checkpoint interactions, such as PD-1/PD-L1 and CTLA4/B7-1/B7-2, to inactivate immune cells, rendering the immune system ineffective against cancer destruction. Immune checkpoint inhibitors have been effective in many patients with various types of cancer because they allow the patient's own immune system to destroy the cancer. However, immunotherapy-related adverse events can limit the use of checkpoint inhibitor therapy and can cause serious adverse events. Inhibition of immune checkpoints allows the immune system to attack normal tissue. This can lead to inflammatory conditions such as dermatitis, colitis, arthritis, nephritis, myositis, polymyalgia-like syndrome, and cytokine release syndrome (CRS), caused by the rapid and massive release of cytokines into the bloodstream from immune cells affected by immunotherapy. These side effects can be very serious and sometimes fatal. Thus, despite the significant benefits of immune checkpoint inhibit