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KR-20260066411-A - NOVEL TRIAZOLOPYRIMIDINE DERIVATIVES AND USES THEREOF

KR20260066411AKR 20260066411 AKR20260066411 AKR 20260066411AKR-20260066411-A

Abstract

The present invention relates to a novel compound and a pharmaceutical composition for the prevention or treatment of neuroinflammatory diseases containing the same, and more specifically, to a novel compound and a pharmaceutical composition for the prevention or treatment of neuroinflammatory diseases containing the same, which can be usefully utilized for the prevention or treatment of neuroinflammatory diseases while minimizing taste-related side effects by confirming the P2X3 receptor antagonistic effect and high antagonistic selectivity of a novel tetrazolopyrimidine derivative and a triazolopyrimidine derivative.

Inventors

  • 김용철
  • 김가람

Assignees

  • 광주과학기술원

Dates

Publication Date
20260512
Application Date
20241104

Claims (10)

  1. A compound represented by the following chemical formula 1, a pharmaceutically acceptable salt thereof, or a solvate thereof: [Chemical Formula 1] (In the formula, R1 is -N or -CR6 , and R 2 and R3 are each independently -H, a halogen group, a hydroxyl group, an amino group, a cyano group, a straight-chain or branched C2 - C8 alkyl group, a C2 - C8 alkenyl group, a C1 - C8 hydroxyalkyl group, a C2 - C8 carbonyl group, a C2 - C8 acyl group, a C1 - C8 alkoxy group, a C2 - C8 ester group, a C2 - C8 carboxyl group, a sulfonyl group, a C3 - C10 cycloalkyl group, a C4 - C10 heterocycloalkyl group, a C6 - C15 aryl group, a C4 - C15 heteroaryl group, or And, R4 is -H, a halogen group, a hydroxyl group, an amino group, a cyano group, a straight-chain or branched C2 - C8 alkyl group, a C2 - C8 alkenyl group, a C1 - C8 hydroxyalkyl group, a C2 - C8 acyl group, a C1 - C8 alkoxy group, a C2 - C8 ester group, a C2 - C8 carboxyl group, a sulfonyl group, a C3 - C10 cycloalkyl group, a C4 - C10 heterocycloalkyl group, or a C4 - C15 heteroaryl group, and R 5 is or And, R6 is a C3 - C10 cycloalkyl group, a C2 - C10 heterocycloalkyl group, a C6 - C15 aryl group, or a C4 - C15 heteroaryl group, and R 7 and R 13 are each independently -H, a straight-chain or branched C 1 -C 8 alkyl group, a C 3 -C 10 cycloalkyl group, or a C 2 -C 10 heterocycloalkyl group, and R8 to R12 are each independently -H, a halogen group, a hydroxyl group, an amino group, a cyano group, a straight-chain or branched-chain C1 - C8 alkyl group or a C1 - C5 alkoxy group, and R 14 and R 15 are each independently a straight-chain or branched-chain C 2 -C 8 alkyl group or a C 2 -C 8 alkenyl group, and R 16 is -H, a halogen group, a hydroxyl group, an amino group, a cyano group, a straight-chain or branched C 1 -C 8 alkyl group, a C 3 -C 10 cycloalkyl group, a C 2 -C 10 heterocycloalkyl group, a C 2 -C 8 carbonyl group, a C 2 -C 8 acyl group, a C 2 -C 8 ester group, a C 2 -C 8 carboxyl group, or a C 1 -C 8 amide group).
  2. In claim 1, in the formula 1 R 1 is -N, and R2 is -H, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, an isopropyl group, or an isobutyl group, and R 3 is or And, R 4 is -H, a methyl group, an ethyl group, a propyl group, a butyl group, an isopropyl group, or an isobutyl group, and R5 is a halogen group or And, R 7 and R 13 is independently -H, methyl group, ethyl group, propyl group, isopropyl group, isobutyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, or cyclohexyl group, and R8 to R12 are each independently -H, a halogen group, or a C1 - C5 alkoxy group, and R 16 is a compound, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 16 is a methyl group, an ethyl group, a C 2 - C 8 carbonyl group, a C 2 -C 8 acyl group, a C 2-C 8 ester group, a C 2-C 8 carboxyl group, or a C 1 -C 8 amide group.
  3. In claim 1, in the formula 1 R 1 is -N, and R 2 and R 4 is -H, and R 3 is , , , , , , or And, R5 is a halogen group, or Phosphorus, compounds, pharmaceutically acceptable salts thereof, or solvates thereof.
  4. In claim 1, in the formula 1 R 1 -CR 6 And, R 2 is -H, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, isopropyl group, or isobutyl group, and R 3 silver or And, R 4 is -H, methyl group, ethyl group, propyl group, butyl group, isopropyl group, or isobutyl group, and R 5 Is And, R 6 C 3 -C 8 Cycloalkyl group, C 2 -C 8 heterocycloalkyl group, C 6 -C 15 aryl group or C 4 -C 15 It is a heteroaryl group, and R 7 and R 13 Each is independently -H, a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, and R 8 to R 12 Each independently -H, a halogen group, or C 1 -C 5 It is an alkoxy period, and R 16 -H, methyl group, ethyl group, propyl group, butyl group, C 2 -C 8 carbonyl group, C 2 -C 8 Asilgi, C 2 -C 8 Ester group, C 2 -C 8 Carboxyl group or C 1 -C 8 Amide, A compound, its pharmaceutically acceptable salt, or its solvate.
  5. In claim 1, in the formula 1 R 1 is -CR 6 , and R 2 and R 4 is -H, and R 3 is And, R 5 is And, R6 is a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, phenyl group, or 4-fluorophenyl group, and R 13 is a methyl group, ethyl group, propyl group, isopropyl group, isobutyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, or cyclohexyl group, and R 16 is a compound, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 16 is a methyl group, ethyl group, propionyl group, methyl carboxylate group, trifluoroacetyl group, C 2 -C 8 carbonyl group, or C 1 -C 8 amide group.
  6. A pharmaceutical composition for the prevention or treatment of neuroinflammatory diseases comprising a compound of any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  7. A pharmaceutical composition for the prevention or treatment of a neuroinflammatory disease according to claim 6, wherein the neuroinflammatory disease is any one selected from the group consisting of chronic cough, neuropathic pain, multiple sclerosis, Guillain-Barré syndrome, autoimmune encephalitis, myelitis, myasthenia gravis, sarcoidosis, chronic inflammatory demyelinating polyneuropathy, neuro Behcet's disease, autoimmune cerebellitis, and viral encephalitis.
  8. A health functional food for the prevention or improvement of neuroinflammatory diseases comprising a compound of any one of claims 1 to 6, a food-grade salt thereof, or a solvate thereof.
  9. A health functional food for preventing or improving neuroinflammatory diseases according to claim 8, wherein the neuroinflammatory disease is any one selected from the group consisting of chronic cough, neuropathic pain, multiple sclerosis, Guillain-Barré syndrome, autoimmune encephalitis, myelitis, myasthenia gravis, sarcoidosis, chronic inflammatory demyelinating polyneuropathy, neuro Behcet's disease, autoimmune cerebellitis, and viral encephalitis.
  10. An antagonist of a P2X3 receptor comprising a compound of any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, or a solvate thereof.

Description

Novel Triazolopyrimidine Derivatives and Uses Thereof The present invention relates to novel tetrazolopyrimidine derivatives and triazolopyrimidine derivatives useful as P2X3 receptor antagonists, and pharmaceutical compositions containing the same for the prevention or treatment of neuroinflammatory diseases. P2X receptors (P2XR) are ligand-gated cation channels activated by extracellular adenosine triphosphate (ATP) and consist of seven subtypes, P2X1R–P2X7R. ATP-mediated opening of P2X receptors is known to induce depolarization of the cell membrane by causing an influx of Na + , K + , and Ca2 + ions into the extracellular space. Among them, P2X3 receptors (P2X3R) play an important role in neuronal hypersensitivity, such as pain detection, as they are primarily located in unmyelinated or thinly myelinated C- and Aδ-fiber primary afferent neurons that reach most tissues and organs. In fact, P2X3R was knocked out or treated with P2X3R antisense oligonucleotides (ASOs) or antagonists, and showed anti-allergic and anti-allodynia effects. Several clinical studies have reported that the overexpression and overactivation of P2X3R are associated with chronic cough. To date, Merck’s Gefapixant, Bayer’s Eliapixant, Bellus’ Camlipixant, and Shionogi’s Sivopixant have been developed as P2X3R antagonists. According to these studies, it is known that higher antagonistic selectivity for homotrimeric P2X3R compared to heterotrimeric P2X2/3R can minimize taste-related side effects such as loss of taste. Accordingly, the inventors of the present invention have completed the present invention regarding novel tetrazolopyrimidine derivatives and triazolopyrimidine derivatives and their uses, as a result of research on P2X3R selective antagonists that are useful for preventing or treating neuroinflammatory diseases such as neuropathic pain or chronic cough while minimizing taste-related side effects. Figures 1 to 8 illustrate the process of synthesizing the compounds of the present invention. Figures 9 and 10 show the results of confirming the anti-allodynia effect following intrathecal injection of compounds 23a and BLU-5937 in an SNL neuropathic pain rat model. Figure 9 shows the withdrawal threshold (g) measured from 15 minutes to 180 minutes after intrathecal injection, where BL is the baseline PWT measured before spinal nerve ligation and C is the control PWT measured before intrathecal injection of the compound. Figure 10 shows the percentage (%MPE) of the maximum possible effect (MPE) of compound 23a and BLU-5937, with data presented as mean ± standard error (SEM) obtained from 6 rats. *P < 0.05, compared to the control group. The present invention provides a novel compound. The present invention provides a novel compound that can be usefully utilized for the prevention or treatment of neuroinflammatory diseases while minimizing taste-related side effects, by confirming the P2X3 receptor antagonistic effect and high antagonistic selectivity of novel tetrazolopyrimidine derivatives and triazolopyrimidine derivatives, and a pharmaceutical composition for the prevention or treatment of neuroinflammatory diseases containing the same. “P2X3 receptors” are signal transduction receptors expressed on sensory nerves that transmit signals from peripheral tissues to the brain; excessive activation of signal transduction through P2X3 receptors can cause neuroinflammatory diseases, including neuropathic pain. If P2X3 receptor antagonists simultaneously bind to other P2X receptor subtypes, such as P2X2/3 receptors, they may cause side effects such as loss of taste. The novel compound of the present invention has high selectivity for the P2X3 receptor compared to the P2X receptor subtype, so it can reduce side effects such as loss of taste. The present invention provides a compound represented by the following chemical formula 1, a pharmaceutically acceptable salt thereof, or a solvate thereof. [Chemical Formula 1] (In the formula, R1 is -N or -CR6 , and R2 and R3 are each independently -H, a halogen group, a hydroxyl group, an amino group, a cyano group, a straight-chain or branched C2 - C8 alkyl group, a C2 - C8 alkenyl group, a C1 - C8 hydroxyalkyl group, a C2 - C8 carbonyl group, a C2 - C8 acyl group, a C1 - C8 alkoxy group, a C2 - C8 ester group, a C2 - C8 carboxyl group, a sulfonyl group, a C3 - C10 cycloalkyl group, a C4 - C10 heterocycloalkyl group, a C6 - C15 aryl group, a C4 - C15 heteroaryl group, or and, R4 is -H, a halogen group, a hydroxyl group, an amino group, a cyano group, a straight-chain or branched C2 - C8 alkyl group, a C2 - C8 alkenyl group, a C1 - C8 hydroxyalkyl group, a C2 - C8 acyl group, a C1 - C8 alkoxy group, a C2 - C8 ester group, a C2 - C8 carboxyl group, a sulfonyl group, a C3 - C10 cycloalkyl group, a C4 - C10 heterocycloalkyl group, or a C4 - C15 heteroaryl group, and R5 is or and, R6 is a C3 - C10 cycloalkyl group, a C2 - C10 heterocycloalkyl group, a C6 - C15 aryl group or a C4 - C15 heteroaryl gr