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EP-4739668-A1 - 1,3-ISOINDOLINEDIONE DERIVATIVES AND HETEROAROMATIC ANALOGUES FOR STIMULATING ENDOTHELIAL CELL-PERICYTE INTERACTION

EP4739668A1EP 4739668 A1EP4739668 A1EP 4739668A1EP-4739668-A1

Abstract

The present invention relates to pharmaceutical compound, and formulations comprising the compound, wherein the compound has a structure according to formula I or II: The compound and formulations are suitable for use as a medicament in the prevention or treatment of a disease or a disorder characterized by pericyte dysfunction, detachment and/or loss, in a therapeutic treatment for blood vessel stabilization, in a treatment of promoting, restoring or preserving pericyte attachment to blood vessels, and/or in a treatment of a vascular-associated disease in a patient.

Inventors

  • LEBRIN, Franck Patrice Gérard
  • THALGOTT, Jérémy Hervé
  • DEKKERS, Sebastian
  • IJZERMAN, ADRIAAN

Assignees

  • Academisch Ziekenhuis Leiden (h.o.d.n. LUMC)
  • Universiteit Leiden

Dates

Publication Date
20260513
Application Date
20240703

Claims (20)

  1. 1. A formulation comprising a pharmaceutical compound and a pharmaceutically acceptable excipient, adjuvant, diluent and/or carrier, wherein the pharmaceutical compound has a structure according to formula I or II: wherein A 1 , A 2 , A 3 and A 4 each individually represent CR 1 or N; A 5 and A 6 each individually represent S, CR 1 or N; wherein R 1 represents hydrogen, halogen, OH, Ci-Cs alkyl, NO2, or NR 2 R 3 , wherein R 2 and R 3 are each independently selected from H, Ci-Cs alkyl, Ci-Cs-alkyl-carbonyl, and Ci-Cs- alkoxy-carbonyl; wherein R x represents Y or CHR 4 R 5 , wherein Y represents a 4-, 5-, or 6-membered heterocycle comprising 1 , 2, or 3 nitrogen atoms, wherein Y is optionally substituted with one or more substituents selected from the group consisting of halide, saturated or unsaturated Ci-Cs hydrocarbon, Ci-Cs-alkoxy-carbonyl, or Ci-Cs-alkyl-carbonyl, preferably acetyl or propionyl; wherein R 4 represents H, Ci-Cs-alkyl, Ci-Cs-cycloalkyl, Ci-Cs-cycloalkylalkyl, heteroaryl, Ci-Cs- heteroaralkyl, Ci-Cs-heterocycloalkyl, or Ci-Cs-heterocycloalkylalkyl, optionally substituted at one or more carbon atoms with one or more groups selected from halogen, amino, sulfinyl and sulfonyl, wherein R 5 represents H, OH, COOH, or Ci-Cs-alkyl optionally substituted at one or more carbon atoms with one or more groups selected from halogen, amino, sulfinyl and sulfonyl, preferably COOH, i-propyl or t-butyl; with the proviso that R 4 and R 5 are not both H.
  2. 2. The formulation according to claim 1 , wherein A 1 or A 2 represents C-NH2 or C-NHC(O)CH3, preferably wherein A 1 represents C-NH2, and A 2 , A 3 and A 4 each individually represent CH, C-CH3 or C-CI, preferably CH, or wherein A 2 represents C-NH2, and A 1 , A 3 and A 4 each individually represent CH, C-CH3 or C-CI, preferably C.
  3. 3. The formulation according to claim 1 , wherein A 1 represents C-NH2 and A 2 , A 3 and A 4 each individually represent CH, CH3 or CCI, preferably CH.
  4. 4. The formulation according to claim 1 or 2, wherein R x represents wherein R 6 represents Ci-Cs-alkyl, C2-Cs-alkenyl, C2-Cs-alkynyl, Ci-Cs-alkoxyalkyl, Ci-Cs-alkoxy-carbonyl, aryl, or Ci-Cs-alkyl-carbonyl, preferably acetyl or propionyl.
  5. 5. The formulation according to claim 1-3, wherein R x represents CHR 4 R 5 , wherein R 4 represents hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, neopentyl, isopentyl, cyclopropyl-methyl, or thienyl-methyl.
  6. 6. The formulation according to any one of claims 1-3 or 5, wherein R x represents CHR 4 R 5 , wherein R 5 represents COOH, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, preferably COOH, methyl, i- propyl or t-butyl.
  7. 7. The formulation according to claim 1 , wherein the pharmaceutical compound has a structure according to formula l-a wherein each Z is independently selected from hydrogen, halogen, OH, Ci-Cs alkyl, NO2, and NR 2 R 3 , wherein R 2 and R 3 are each independently selected from H, Ci-Cs alkyl, Ci-Cs-alkyl-carbonyl, and Ci-Cs- alkoxy-carbonyl, preferably wherein each Z is independently selected from H, halogen, NH2, and NHC(O)CH 3 ; wherein m is 1 , 2, 3 or 4, preferably 1 or 2; wherein n is 1 , 2 or 3, and wherein R 6 represents saturated or unsaturated Ci-Cs hydrocarbon, Ci-Cs-alkoxy-carbonyl, or Ci-Cs-alkyl- carbonyl, preferably acetyl or propionyl.
  8. 8. The formulation according to claim 1 , wherein the pharmaceutical compound has a structure according to formula l-b or l-c wherein each Z is independently selected from hydrogen, halogen, OH, Ci-Cs alkyl, and NO2, preferably wherein each Z is independently selected from H, CH3 and Cl; wherein m is 1 , 2, or 3; and wherein R 6 represents saturated or unsaturated Ci-Cs hydrocarbon, Ci-Cs-alkoxy-carbonyl, or Ci-Cs-alkyl- carbonyl, preferably acetyl or propionyl.
  9. 9. The formulation according to any one of claims 1-8, wherein the pharmaceutical compound does not bind to cereblon (CRBN).
  10. 10. The formulation according to any one of claims 1-9, wherein the pharmaceutical compound is selected from
  11. 11 . A pharmaceutical compound, wherein the compound has a structure according to formula I or II: wherein A 1 , A 2 , A 3 and A 4 each individually represent CR 1 or N; A 5 and A 6 each individually represent S, CR 1 or N; wherein R 1 represents hydrogen, halogen, OH, Ci-Cs alkyl, NO2, or NR 2 R 3 , wherein R 2 and R 3 are each independently selected from H, Ci-Cs alkyl, Ci-Cs-alkyl-carbonyl, and Ci-Cs- alkoxy-carbonyl; wherein R x represents CHR 4 R 5 , wherein R 4 represents H, Ci-Cs-alkyl, Ci-Cs-cycloalkyl, Ci-Cs-cycloalkylalkyl, heteroaryl, Ci-Cs- heteroaralkyl, Ci-Cs-heterocycloalkyl, or Ci-Cs-heterocycloalkylalkyl, preferably hydrogen, methyl, ethyl, n- propyl, i-propyl, n-butyl, i-butyl, tert-butyl, neopentyl, isopentyl, cyclopropyl-methyl, or thienyl-methyl; and wherein R 5 represents H, OH, COOH, or Ci-Cs alkyl, preferably OH, COOH, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or tert-butyl, preferably COOH, methyl, i-propyl or t-butyl, with the proviso that R 4 and R 5 are not both H.
  12. 12. A pharmaceutical compound, wherein the compound has a structure according to formula I or II: wherein A 1 , A 2 , A 3 and A 4 each individually represent CR 1 or N; A 5 and A 6 each individually represent S, CR 1 or N; wherein R 1 represents hydrogen, halogen, OH, Ci-Cs alkyl, NO2, or NR 2 R 3 , wherein R 2 and R 3 are each independently selected from H, Ci-Cs alkyl, Ci-Cs-alkyl-carbonyl, and Ci-Cs- alkoxy-carbonyl; wherein R x represents H, Y or CHR 4 R 5 , wherein Y represents a 4-, 5-, or 6-membered heterocycle comprising 1 , 2, or 3 heteroatoms, wherein Y is optionally substituted with one or more substituents selected from the group consisting of halide, saturated or unsaturated Ci-Cs hydrocarbon, Ci-Cs-alkoxy-carbonyl, or Ci-Cs-alkyl-carbonyl, preferably acetyl or propionyl; wherein R 4 represents H, Ci-Cs-alkyl, Ci-Cs-cycloalkyl, Ci-Cs-cycloalkylalkyl, heteroaryl, Ci-Cs- heteroaralkyl, Ci-Cs-heterocycloalkyl, or Ci-Cs-heterocycloalkylalkyl, wherein R 5 represents H, OH, COOH, or Ci-Cs alkyl, preferably COOH, i-propyl or t-butyl, or a formulation comprising such compound and a pharmaceutically acceptable excipient, adjuvant, diluent and/or carrier, for use as a medicament in the treatment of a disease or a disorder characterized by pericyte dysfunction, pericyte detachment and/or pericyte loss.
  13. 13. Compound or formulation for use according to claim 12, wherein the disease or disorder characterized by pericyte dysfunction, detachment and/or loss is selected from diabetes mellitus complications, chronic kidney disease (CKD), small vessel diseases, and Central Nervous System (CNS) diseases.
  14. 14. Compound or formulation for use according to claim 12, wherein the disease or disorder characterized by pericyte dysfunction, detachment and/or loss is selected from diabetic nephropathy (DN), diabetic retinopathy (DR), diabetic cardiomyopathy (DCM), and diabetic neuropathy.
  15. 15. Compound or formulation for use according to claim 12, wherein the disease or disorder characterized by pericyte dysfunction, detachment and/or loss is selected from hypertensive kidney diseases, IgA nephropathy, congenital nephropathy syndrome, lupus nephritis, polycystic kidney disease and allograft nephropathy.
  16. 16. Compound or formulation for use according to claim 12, wherein the disease or disorder characterized by pericyte dysfunction, detachment and/or loss is selected from cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (Cadasil), Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (Carasil), Cerebral Amyloid Angiopathy (CAA), Retinal Vasculopathy with Cerebral Leukoencephalopathy and systemic manifestations (RVCL-S), Hereditary Hemorrhagic Telangiectasia (HHT), and Cerebral Cavernous Malformations (CCM).
  17. 17. Compound or formulation for use according to claim 12, wherein the disease or disorder characterized by pericyte dysfunction, detachment and/or loss is selected from stroke, epilepsy, spinal cord injury, vascular dementia, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, traumatic brain injury, multiple sclerosis, amyotrophic lateral sclerosis, and radiation necrosis.
  18. 18. A pharmaceutical formulation according to any one of claims 1 to 10 for use as a medicament in a treatment of blood vessel stabilization, and/or a treatment of promoting, restoring or preserving pericyte attachment to blood vessels.
  19. 19. The formulation for use according to claim 18, wherein the therapeutic treatment of blood vessel stabilization comprises the protection of blood-brain-barrier integrity, control of blood flow, limitation of inflammation and/or the reduction of tissue damage.
  20. 20. A method for promoting, restoring or preserving pericyte attachment to blood vessels in a patient, the method comprising administering a formulation according to any one of claims 1 to 10 to the patient.

Description

1 ,3-ISOINDOLINEDIONE DERIVATIVES AND HETEROAROMATIC ANALOGUES FOR STIMULATING ENDOTHELIAL CELL-PERICYTE INTERACTION Field of the Invention The present invention relates to the field of medicine. More particularly, it relates to the use of 1 ,3- isoindolinedione derivatives and heteroaromatic analogues thereof to stimulate endothelial cell-pericyte interaction and pericyte coverage of blood vessels. Background of the invention Blood vessels are intricate networks of hollow tubes that continuously adapt structurally and functionally to ensure optimal delivery of nutrients and oxygen to every cell of the body. They are composed of endothelial cells forming the inner lining of the vessel walls and of mural cells referred to as Vascular Smooth Muscle cells (VSMCs) and pericytes (PCs). VSMCs surround arteries and veins whereas PCs are located within the basal membrane of capillaries, venules and terminal arterioles. PCs have important roles in blood vessel formation and stabilization, regulate endothelial cell survival and control blood barrier to solutes and immune cells as well as blood flow. Many serious diseases affecting millions of people worldwide are caused by or associated with PC death or migration away from blood vessels. These pathological responses can lead to chronic inflammation, excessive vessel growth or/and blood vessel rarefaction that ultimately can lead to hypoperfusion and tissue damage. PC dysfunction has been reported to cause/contribute to the development of a broad range of conditions, such as diabetes (nephropathy and retinopathy), chronic kidney disease (CKD), cardiomyopathy, central nervous system (CNS) disorders such as stroke, epilepsy, spinal cord injury, dementia notably Alzheimer’s disease, Huntington’s disease, multiple sclerosis, amyotrophic lateral sclerosis, radiation necrosis and small inherited vessel diseases such as Cerebral autosomal dominant arteriopathy with (Cadasil) and Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (Carasil), Cerebral Amyloid Angiopathy (CAA), Retinal Vasculopathy with Cerebral Leukoencephalopathy and systemic manifestations (RVCL-S), Hereditary Hemorrhagic Telangiectasia (HHT) and Cerebral Cavernous Malformations (CCM). Most of these conditions currently still lack the availability of effective treatment that is suitable for chronic treatment. The present inventors and others, have previously provided proof of concept data that by promoting PC attachment to blood vessels, they could prevent blood vessel weakness caused by HHT1 or by brain irradiation2-3. Thalidomide was particularly effective in this in both mice and patients suggesting that it may be useful in other diseases with similar underlying pathology. Thalidomide and its analogs lenalidomide and pomalidomide are immunomodulatory imide drugs (IMiDs), which are highly effective treatment modalities for Multiple Myeloma and del(5q) Myelodysplastic Syndrome. The class of compounds exerts pleiotropic effects including immunomodulatory, potent antiinflammatory, anti-angiogenic and direct anti-myeloma activities. Mechanistically, these drugs act as a molecular bridge linking selected neo-substrates to the ubiquitin proteasome system for degradation. All IMiDs are characterized by a glutarimide ring that binds to Cereblon (CRBN), a substrate ofthe E3 ubiquitin ligase CRL4 complex to target proteins for degradation. The glutarimide moiety is responsible for most of their pharmacological activities but also for their adverse teratogenic and hematologic effects. Notably, accumulative evidence indicates that the immuno-modulatory, anti-angiogenic and direct anti-proliferative activities of all IMiDs depend only on the glutarimide motive and not on the phthalimide motive. IMiDs cannot be used to treat chronic diseases. Patients treated with IMiDs can develop serious side effects including possible birth defects, fatigue, weakness, anemia, neuropathy, neutropenia, thrombocytopenia, blood clots causing stroke or heart attack, increase risk of death in people with chronic lymphocytic leukemia (CLL), risk of malignancies, severe liver problems, severe skin reactions, thyroid problems and risk in early death in people who have Mantle Cell Lymphoma (MCL). Hence, it is an object of the present invention to provide compounds and/or treatments to promote endothelial cells-pericyte interaction and pericyte coverage of blood vessels that, unlike currently known IMiDs, can be used in chronic treatments. Summary of the Invention Accordingly, the present invention is directed to a pharmaceutical compound, wherein the compound has a structure according to formula I or II: wherein A1, A2, A3 and A4 each individually represent CR1 or N; A5 and A6 each individually represent S, CR1 or N; wherein R1 represents hydrogen, halogen, OH, Ci-Cs alkyl, NO2, or NR2R3, wherein R2 and R3 are each independently selected from H, Ci-Cs alkyl, Ci-Cs-alkyl-carbonyl, and Ci-Cs- alkoxy-c