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EP-4736858-A1 - TETRAORGANOPHOSPHONIUM COMPOUNDS FOR USE IN THE PREVENTION AND TREATMENT OF METABOLIC DISEASES

EP4736858A1EP 4736858 A1EP4736858 A1EP 4736858A1EP-4736858-A1

Abstract

The present invention relates to the use of compounds of formula I for treatment of metabolic disease, wherein R 1 , R 2 , R 3 are independently selected from the group consisting of phenyl, benzyl, and cyclohexyl; Z is a linear alkylene, alkenylene or alkynylene chain with the number of carbon atoms in the range of from 6 to 20, wherein one or more -CH 2 - groups may optionally be substituted with one or more O atoms; R 4 is selected from the group consisting of H, OH, halogen atom, and (C1 to C10)alkoxy group, which may optionally be substituted with one or more -OH groups; and A - is a pharmaceutically acceptable anion of an organic or inorganic acid.

Inventors

  • Stemberkova-Hubackova, Sona
  • STURSA, JAN
  • WERNER, LUKAS
  • HALUZIK, Martin

Assignees

  • Institiute of Clinical and Experimental Medicine

Dates

Publication Date
20260506
Application Date
20241104

Claims (14)

  1. Phosphonium compounds of general formula I for use in the treatment of metabolic diseases; wherein R 1 , R 2 , R 3 are independently selected from the group consisting of phenyl, benzyl, and cyclohexyl; Z is a linear alkylene, alkenylene or alkynylene chain with the number of carbon atoms in the range of from 6 to 20, wherein one or more -CH 2 - groups may optionally be substituted with one or more O atoms; R 4 is selected from the group consisting of H, OH, halogen atom, and (C1 to C10)alkoxy group, which may optionally be substituted with one or more -OH groups; A - is a pharmaceutically acceptable anion.
  2. Phosphonium compounds of general formula I for use according to claim 1, wherein A - is selected from the group comprising Cl - , Br - , I - , carbonate, bicarbonate, nitrate, sulphate, phosphate, hexafluorophosphate, tetrafluoroborate, acetate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bitartrate, camsylate, citrate, decanoate, edetate, esylate, formiate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl sulfate, methansulfonate, mucate, napsylate, octanoate, oleate, oxalate, pamoate, pantothenate, polygalacturonate, propionate, salicylate, stearate, succinate, tartrate, teoclate, and tosylate.
  3. Phosphonium compounds of general formula I for use according to claim 1 or 2, wherein all of R 1 , R 2 and R 3 are the same, preferably selected from phenyl and cyclohexyl.
  4. Phosphonium compounds of general formula I for use according to claim 1, 2 or 3, wherein R 4 is selected from the group consisting of H, OH, and halogen atom.
  5. Phosphonium compounds of general formula I for use according to any one of claims 1 to 4, wherein Z is a linear alkylene linker of formula -(CH 2 ) n -, wherein n is an integer in the range of from 6 to 20, wherein one or more -CH 2 - groups may optionally be substituted with one or more O atoms.
  6. Phosphonium compounds of general formula I for use according to any one of claims 1 to 5, wherein Z is a linear (C6 to C20)alkenylene linker, preferably containing one double bond, wherein one or more -CH 2 - groups may optionally be substituted with one or more O atoms.
  7. Phosphonium compounds of general formula I for use according to any one of claims 1 to 6, wherein the phosphonium compounds of general formula I are selected from: (18-hydroxyoctadec-9-en-1-yl)triphenylphosphonium; (10-bromodecyl)tricyclohexylphosphonium; Tricyclohexyl(16-hydroxyhexadecyl)phosphonium methansulfonate (16-hydroxyhexadecyl)triphenylphosphonium.
  8. Phosphonium compounds of general formula I for use according to any one of claims 1 to 7, wherein the metabolic diseases are selected from the group comprising type 2 diabetes mellitus, obesity, cardiorenal diseases, respiratory diseases, neurodegenerative diseases, and cancer.
  9. Phosphonium compounds of general formula for use according to any one of claims 1 to 8, wherein the metabolic diseases are selected from the group comprising obesity, type 2 diabetes mellitus, liver steatosis, pancreatic tumour, pancreatic fibrosis, and/or pulmonary fibrosis.
  10. Phosphonium compounds of general formula I for use according to any one of the preceding claims 1 to 9, wherein the metabolic diseases are selected from the group comprising type 2 diabetes mellitus, obesity, chronic/diabetic kidney disease, metabolic dysfunction-associated fatty liver disease, metabolic dysfunction-associated steatohepatitis, atherosclerosis, cardiac ischemia, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, idiopatic pulmonary disease, chronic obstructive pulmonary disease, diabetic neuropathy, and pancreatic cancer.
  11. Phosphonium compounds of general formula I as defined in any one of the preceding claims 1 to 7 for use in a prophylactic treatment, preferably for the prevention of metabolic diseases in individuals suffering from obesity or in overweight individuals.
  12. Phosphonium compounds of general formula I as defined in any one of the preceding claims 1 to 7, for use in a prevention of obesity in overweight individuals.
  13. Use of phosphonium compounds of general formula I as defined in claims 1 to 7 as a food supplement to reduce overweight and/or to improve overweight-induced metabolic complications in overweight individuals.
  14. A pharmaceutical composition characterized in that it contains at least one phosphonium compound of general formula I, as defined in any one of the preceding claims 1 to 7, as the active pharmaceutical ingredient, and at least one pharmaceutically acceptable excipient.

Description

Field of Art The present invention is related to the use of phosphonium compounds for the treatment of metabolic diseases, in particular obesity and type 2 diabetes mellitus and their complications like liver steatosis, chronic/diabetic kidney disease, cardiovascular diseases, pancreatic tumour, pancreatic fibrosis, and/or pulmonary fibrosis. Background Art The increasing prevalence of metabolic diseases and their chronic debilitating complications represent one of the most significant health threats worldwide. Obesity, type 2 diabetes mellitus (T2DM), and its complications, currently affecting 422 million people worldwide, are expected to become the seventh leading cause of death by 2030. This is particularly evident in elderly patients, where it can affect as many as 30-40 % of the population, compared to approximately 6-25 % of patients under 65 years of age. Bariatric surgery (also called metabolic surgery, reflecting its outstanding beneficial metabolic effects) is currently the most efficient approach for the treatment of obesity, resulting in substantial and sustained weight loss and improvement of metabolic complications of obesity. In addition to its weight-reducing effects, bariatric surgery markedly improves diabetes control, with a high percentage of patients achieving diabetes remission. The improvement of metabolic health goes beyond the expected effect of weight loss suggesting the involvement of other mechanisms in addition to weight reduction triggered by bariatric surgery including alleviation of low-grade inflammation, alterations in gut hormone secretion profiles and bile acids, neural mechanisms as well as changes in gut microbiota. However, none of these mechanisms can fully explain the profound and long-lasting metabolic effects of bariatric surgery. Cellular senescence can occur in all dividing cells in response to excessive extracellular or intracellular stress, leading to cell cycle arrest. Despite being locked in cell cycle arrest, senescent cells remain metabolically active and secrete a wide range of pro-inflammatory cyto- and chemokines, growth factors and extracellular matrix modulators collectively called "senescence-associated secretory phenotype" (SASP). SASP is primarily responsible for the attraction and activation of immune cells that remove senescent cells and restore tissue homeostasis. However, the inability of immune cells to eliminate senescent cells may lead to inflammation or the development of age-related diseases. Due to their significant accumulation in the adipose tissue of patients with obesity and T2DM, cellular senescence, with its emerging role in the pathogenesis of obesity, T2DM, and related complications, might offer a novel mechanism underlying bariatric surgery-associated metabolic improvements. However, not all patients can undergo bariatric surgery, thus relying on pharmacotherapy for obesity, T2DM, and related complications. GLP-1 receptor agonists and SGLT2-inhibitors (gliflozins) currently represent the most promising classes of glucose-lowering therapies, affecting not only glucose control but also chronic complications, at least in part, independently of the improvement of diabetes control. Despite these significant advances, many patients develop chronic complications. Moreover, the landscape of treatment still primarily focuses on symptom management rather than addressing the underlying causes. Novel complementary treatment approaches, such as targeting senescence that can prevent metabolic diseases and their chronic complications, are still needed. Senolytics reduce the number of senescent cells in an organism. Their positive metabolic effect was suggested based on animal experiments, where the administration of senolytics was associated with improved glucose control and other obesity- and diabetes-related metabolic disturbances (Kulkarni, A.S., et al., Aging Cell, 2018. 17(2), Hickson, L.J., et al., Ebiomedicine, 2019. 47: p. 446-456, Palmer, A.K., et al., Aging Cell, 2019. 18(3)). Clinical testing of the anti-diabetic agent Metformin on human aging and the development of aging-related complications is currently underway (registration number: NCT04264897). Despite these promising results, all currently available agents target specific proteins or pathways that are not expressed in all types of senescent cells. This limited efficacy has prompted a search for novel therapeutic targets. Mitochondrial dysfunction is an important determinant of the aging process and plays a critical role in the pathogenesis of a wide array of metabolic disorders, impacting energy metabolism, insulin resistance, and accumulation of metabolic intermediates. This has spurred interest in directly targeting mitochondrial dysfunction as a novel therapeutic approach. Alkyl triphenylphosphonium (ATPP) salts have been utilized in a range of scientific and industrial domains owing to their unique chemical properties. In the realm of biochemistry and cell biology, these co