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EP-4739655-A2 - SUBSTITUTED 2-PHENYLPIPERIDINE COMPOUNDS FOR USE IN THE DIAGNOSIS, TREATMENT AND/OR PREVENTION OF CANCER

EP4739655A2EP 4739655 A2EP4739655 A2EP 4739655A2EP-4739655-A2

Abstract

The disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, a method for preparation thereof as well as use thereof in the treatment and/or diagnosis of cancer such as neuroblastoma, prostate cancer, pancreatic cancer, leukemia, osteosarcoma, hepatoblastoma, lung cancer, colon cancer, breast cancer, skin cancer, thyroid cancer and/or rhabdoid cancer.

Inventors

  • BENGTSSON, CHRISTOFFER
  • YNGVE, ULRIKA
  • BEGNINI, Fabio
  • Jha, Preeti
  • ROSENSTRÖM, Ulrika
  • NESTOR, Marika

Assignees

  • Nestor, Marika

Dates

Publication Date
20260513
Application Date
20240703

Claims (20)

  1. 1. A compound of Formula I: Formula I wherein : R 1 is H or (CH 2 ) P Z; R 2 is H, OH or F; R 3 is H or Ci-Csalkyl; R 4 is selected from the group consisting of H, CF3, OCi-Cealkyl, OCF3, CN, F and NO 2 ; R 5 is selected from the group consisting of H, CF3, OCi-Cealkyl, OCF3, CN, F and NO 2 ; Q is C or N; X is O or NH; Y is selected from the group consisting of 127 I, 123 I, 124 I, 125 I, 131 I and 211 At; Z is a five- or six-membered heterocycle comprising 1, 2 or 3 nitrogen atoms and/or an N-oxide, said heterocycle being substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, I, OH, Ci-Csalkyl, oxo and (CH2) q NHR 6 ; R 6 is a chelating moiety or a radionuclide complex thereof; n is 0 or 1; m is 0 or 1; p is 0, 1, 2, or 3; q is 2, 3, 4 or 5; the substituents are located cis with respect to each other; with the proviso that: n + m = l; P90727PC or a pharmaceutically acceptable salt thereof.
  2. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, with the further proviso that when R 2 is H then m is 1.
  3. 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Q is C thereby providing a compound of Formula la: Formula la
  4. 4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Q is N thereby providing a compound of Formula lb: Formula lb
  5. 5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula lb is a compound of Formula Ibl, Formula Ib2 or Formula Ib3 : P90727PC
  6. 6. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the piperidine ring has S configuration at carbons 2 and 3, or /? configuration at carbons 2 and 3.
  7. 7. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 1 is H.
  8. 8. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R 1 is (CH2) P Z.
  9. 9. The compound according to any one of claims 1-6 or 8, or a pharmaceutically acceptable salt thereof, wherein Z is selected from the group consisting of
  10. 10. The compound according to any one of claims 1-6, 8 or 9, or a pharmaceutically acceptable salt thereof, wherein p is 1.
  11. 11. The compound according to any one of claims 1-6 or 8-10, or a pharmaceutically acceptable salt thereof, wherein R 6 is a chelating moiety selected from the group consisting of P90727PC
  12. 12. The compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein R 6 is a chelating moiety comprising or consisting of
  13. 13. The compound according to any one of claims 1-6 or 8-12, or a pharmaceutically acceptable salt thereof, wherein q is 4.
  14. 14. The compound according to any one of claims 1-6 or 8-13, or a pharmaceutically acceptable salt thereof, wherein R 6 is a radionuclide complex comprising the chelating moiety and a radionuclide.
  15. 15. The compound according to claim 14, or a pharmaceutically acceptable salt thereof, wherein the radionuclide is selected from the group consisting of 68 Ga, 18 F, 64 Cu, 4 4 Sc, 89 Zr, in In, 67 Ga, 99m Tc, Gd, 177 Lu, 86 / 90 Y, 225 Ac, 161/155 Tb, 226/227 Th, and an ion thereof. P90727PC
  16. 16. The compound according to claim 15, or a pharmaceutically acceptable salt thereof, wherein the radionuclide is 177 Lu such as 177 Lu 3+ .
  17. 17. The compound according to any one of claims 1-6 or 8-16, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of
  18. 18. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 1 is
  19. 19. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 2 is H or OH.
  20. 20. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 3 is H or CH3.

Description

P90727PC SUBSTITUTED 2-PHENYLPIPERIDINE COMPOUNDS FOR USE IN THE DIAGNOSIS, TREATMENT AND/OR PREVENTION OF CANCER Technical field The present disclosure concerns novel substituted 2-phenylpiperidine compounds, methods for preparation thereof as well as their use in the diagnosis, treatment and/or prevention of cancer. In particular, the disclosure concerns novel substituted 2- phenylpiperidine compounds, methods for preparation thereof as well as their use in the diagnosis, treatment and/or prevention of neuroblastoma. Background Cancer is a generic term for a large group of diseases that can affect any part of the body. One defining feature of cancer is the rapid creation of abnormal cells that grow beyond their usual boundaries, which can invade adjoining parts of the body and spread to other organs; the latter process is referred to as metastasis. Widespread metastases are the primary cause of death from cancer. Approximately 1 in every 6 deaths worldwide are caused by cancer. Currently, it is the second-leading cause of death (following cardiovascular diseases) worldwide and in high- and very high Human Development Index countries. It has been estimated that by 2040 the global burden is expected to grow to 27.5 million new cancer cases and 16.3 million cancer deaths each year, due to the growth and ageing of the population. G protein-coupled receptors (GPCRs) belong to the largest superfamily of integral cell membrane proteins and play diverse roles in cellular signalling. The neurokinin 1 receptor (commonly abbreviated as NK1R, and also known as the tachykinin 1 receptor) belongs to the tachykinin receptor subfamily of GPCRs. Two isoforms of the NK1R have been reported: a truncated form (311 amino acids), containing a very short C-terminal sequence, and a full-length sequence (407 amino acids). After binding to the NK1R, the peptide substance P (SP), which is widely distributed in both the central and peripheral nervous systems, triggers a variety of functions. Antagonists against the NK1R are known to have anti-inflammatory, analgesic, anxiolytic, antidepressant, and antiemetic effects. It has been found that the SP/NK1R system can strongly influence the microenvironment of a tumour, having implications in processes related to P90727PC oncogenesis, such as mitogenesis, angiogenesis, cell migration and metastasis. While NK1R levels typically display limited peripheral expression in normal tissues, it has been shown to be upregulated in several cancer types. Subsequently, it has been demonstrated that SP acts through the NK1R as a mitogen in several human cancer cell lines, including astrocytoma, melanoma, prostate, glioma, retinoblastoma, leukaemia and pancreatic, laryngeal, colon, gastric and breast cancers. NK1R inhibitors have demonstrated cancer growth inhibition in a number of in vitro and in vivo models. Consequently, the NK1R/SP system is seen as a promising target for cancer diagnostics and therapeutics, including the concept of selectively imaging and targeting tumour cells overexpressing NK1R. NK1R is highly expressed in neuroblastoma (NBL), which is the most common extracranial solid tumour in children. NBL tumours are characterised by significant biologic heterogeneity. While some tumours show very aggressive, therapy-resistant behaviour, others regress spontaneously. To account for this diversity, current treatment strategies are uniquely guided by pre-treatment risk stratification based on a large range of clinical, histological, molecular and biological markers. Thus, the prognosis and treatment for NBL are highly dependent on molecular, genetic, and pathologic tests. Following risk stratification, NBL treatment approaches range from observation or resection for tumours considered low risk to intensive multimodal therapy for high-risk tumours including, induction chemotherapy (administered at the beginning of the cancer treatment), surgery, radiation, consolidation therapy (administered after the initial treatment to target remaining cancer cells) and immunotherapy. Current treatments are not fully effective, and NBL remains a major therapeutic challenge in paediatric oncology. Although multimodal therapy is often able to drastically reduce the tumour burden, leading to an apparent complete remission of the disease (referred to as minimal residual disease), patients diagnosed with high- risk tumours have a survival rate of only 40-50% and, in addition to frequently suffering from long-term side effects, approximately 50% of patients who complete therapy experience disease recurrence. Radiopharmaceuticals are pharmaceuticals comprising radioisotopes which are designed to target specific cells, organs or tissues and are being increasingly used for both the diagnosis and treatment of a number of cancers. P90727PC Radiopharmaceuticals are administered systemically and, unlike conventional therapies (e.g., radiation therapy, chemotherapy, surgery), bind to a specific cancer cell transmemb