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KR-20260064237-A - NOVEL COMPOUND AS A FUNCTIONAL ANTAGONIST FOR S1PR1 AND S1PR4

KR20260064237AKR 20260064237 AKR20260064237 AKR 20260064237AKR-20260064237-A

Abstract

The present invention relates to a novel compound acting as a functional inhibitor for S1PR1 and S1PR4 and its uses. The compound according to the present invention has the advantage of exhibiting excellent effects in the prevention or treatment of inflammatory bowel disease, alopecia areata, autoimmune diseases, etc., due to its significantly superior binding affinity to S1PR1 and S1PR4 receptors.

Inventors

  • 이봉용
  • 박양혜
  • 김은정
  • 최호중

Assignees

  • 주식회사 넥스트젠바이오사이언스

Dates

Publication Date
20260507
Application Date
20241031

Claims (17)

  1. Compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] Here, R is a C 1-15 alkyl.
  2. In paragraph 1, A compound characterized by being represented by the above chemical formula 1 being any one selected from the group of compounds below, or a pharmaceutically acceptable salt thereof: (1) 2-amino-4-(1-hexyl-1H-1,2,3-triazol-4-yl)-2-(hydroxymethyl)butyl dihydrogen phosphate (2) 2-amino-2-(hydroxymethyl)-4-(1-octyl-1H-1,2,3-triazol-4-yl)butyl dihydrogen phosphate (3) 2-amino-2-(hydroxymethyl)-4-(1-nonyl-1H-1,2,3-triazol-4-yl)butyl dihydrogen phosphate (4) 2-amino-4-(1-decyl-1H-1,2,3-triazol-4-yl)-2-(hydroxymethyl)butyl dihydrogen phosphate (5) 2-amino-2-(hydroxymethyl)-4-(1-undecyl-1H-1,2,3-triazol-4-yl)butyl dihydrogen phosphate (6) 2-amino-4-(1-dodecyl-1H-1,2,3-triazol-4-yl)-2-(hydroxymethyl)butyl dihydrogen phosphate
  3. In paragraph 1, A compound characterized in that the compound represented by the above chemical formula 1 is represented by the following chemical formula 1a, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1a]
  4. S1PR1 and S1PR4 inhibitors represented by the following chemical formula 1: [Chemical Formula 1] Here, R is a C 1-15 alkyl.
  5. In claim 4, the compound represented by Chemical Formula 1 is an S1PR1 and S1PR4 inhibitor having an S1PR1 and S1PR4 binding activity increased by more than 10 times compared to the compound represented by Chemical Formula 2 below: [Chemical Formula 2] Here, R is a C 1-15 alkyl.
  6. In paragraph 4, S1PR1 and S1PR4 inhibitors characterized in that the compound represented by the above chemical formula 1 is represented by the following chemical formula 1a: [Chemical Formula 1a]
  7. A pharmaceutical composition for the prevention or treatment of inflammatory bowel disease containing the compound of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.
  8. A pharmaceutical composition according to claim 7, wherein the inflammatory bowel disease is ulcerative colitis (UC) or Crohn's disease (CD).
  9. A pharmaceutical composition for the prevention or treatment of alopecia areata (AA) containing, as an active ingredient, a compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.
  10. A pharmaceutical composition for the prevention or treatment of an autoimmune disease containing, as an active ingredient, a compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.
  11. In paragraph 10, the above-mentioned autoimmune diseases are asthma, type 1 diabetes mellitus, rheumatoid arthritis, polymyalgia rheumatica, ankylosing spondylitis, psoriatic arthritis, multiple sclerosis, interleukin-17 (IL-17)-induced dementia, peripheral neuritis, uveitis, autoimmune cytopenia, autoimmune myocarditis, primary cirrhosis, dry eye syndrome, fibromyalgia, Good-Feitzer syndrome, autoimmune meningitis, Sjögren's syndrome, Addison's disease, alopecia areata, autoimmune hepatitis, autoimmune parotitis, epididymitis, glomerulonephritis, Graves' disease, celiac disease, Guillain-Barré syndrome, Hashimoto's disease, hemolytic anemia, myasthenia gravis, amyotrophic lateral sclerosis, sarcoidosis, spondyloarthritis, thyroiditis, vasculitis, myxedema, pernicious anemia, antiphospholipid syndrome, A pharmaceutical composition for the prevention or treatment of an autoimmune disease, comprising one or more selected from the group consisting of late solid organ transplantation and chronic rejection, and graft-versus-host disease.
  12. A pharmaceutical composition according to any one of claims 7 to 11, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers, diluents, and/or excipients.
  13. A pharmaceutical composition according to any one of claims 7 to 11, wherein the pharmaceutical composition does not cause cardiovascular disease side effects.
  14. A pharmaceutical composition according to any one of claims 7 to 11, wherein the pharmaceutical composition is administered intraperitoneally.
  15. A method for preparing a compound represented by the following chemical formula 1, comprising the following steps: [Chemical Formula 1] Here, R is a C 1-15 alkyl (a) a step of synthesizing a compound represented by the following chemical formula 3 by reacting a compound represented by the following chemical formula 2 with sodium bicarbonate and benzyl chloroformate; [Chemical Formula 2] Here, R is a C 1-15 alkyl [Chemical Formula 3] Here, R is a C 1-15 alkyl (b) a step of synthesizing a compound represented by the following chemical formula 4 by reacting tetrabenzyl pyrophosphate with a compound represented by the above chemical formula 3; and [Chemical Formula 4] Here, R is a C 1-15 alkyl (c) A step of synthesizing a compound represented by Chemical Formula 1 by reacting hydrogen ( H₂ ) with a compound represented by Chemical Formula 4.
  16. A method for preparing a compound represented by Formula 1, wherein step (b) above involves reacting N,N-diisopropylethylamine and titanium(IV)butoxide.
  17. In claim 15, the above step (c) is a method for preparing a compound represented by Formula 1, wherein the reaction is carried out under a palladium/carbon catalyst.

Description

Novel Compound as a Functional Antagonist for S1PR1 and S1PR4 The present invention relates to a novel compound that acts as a functional inhibitor for S1PR1 and S1PR4 and its use. The S1PR1 receptor is primarily found in lymphocytes and plays a role in regulating the release of lymphocytes from immune cells. The S1PR4 receptor is also present in lymphocytes and acts not only on immune cell trafficking but also on T cell regulation, thereby participating in inflammatory responses. Among anti-inflammatory diseases, multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease of the central nervous system (brain, spinal cord, optic nerve). Pathologically, it is characterized by multiple inflammation and demyelination primarily in the white matter of the central nervous system. Although the cause of the disease has not yet been clearly identified, it is thought to be an autoimmune disease triggered by the surrounding environment in genetically predisposed patients. The treatment of multiple sclerosis can be broadly divided into acute treatment, represented by high-dose steroids, long-term disease-modifying therapy, and symptomatic therapy; above all, long-term disease remission to reduce recurring relapses and disability is crucial. Although interferon was conventionally used as a treatment for multiple sclerosis, it presented problems such as persistent disability due to repeated relapses and remissions without complete recovery, diverse neurological symptoms depending on the location of demyelinating lesions, and significant variations in symptoms and disease progression ranging from patients with no specific neurological impairment to those progressing to severe disability. For over 100 years, there has been no distinct treatment to reduce the recurring relapses of multiple sclerosis, but recently, Fingolimod (FTY720, Gilenya), which acts on the sphingosine-1-phospholate (S1P) receptor of T-type leukocytes to effectively block their migration to the site of inflammation and thus exhibits a therapeutic effect, has been marketed and used as the first oral treatment for multiple sclerosis. Specifically, FTY720 is an oral immunomodulatory agent taken once a day, a synthetic analog of sphingosine-1-phosphate (S1P), and is a treatment for multiple sclerosis that has a mechanism of action that inhibits entry into the central nervous system by reversibly capturing some lymphocytes in lymph nodes and isolating them in secondary lymphoid organs, or reduces the number of lymphocytes circulating in the bloodstream, thereby reducing the number of activated lymphocytes reaching the brain and reducing inflammatory destruction. In this case, FTY720 is a compound that acts non-selectively on one or more S1P receptors S1PR1, S1PR2, S1PR3, S1PR4, and S1PR5 as a sphingosine 1-phosphate (S1P) receptor modulator. When it acts, it binds to these S1P receptors, causing intracellular heterotrimeric G-proteins to dissociate into Gα-GTP and Gβγ-GTP, thereby regulating downstream signaling pathways and kinases. It is useful for the treatment or prevention of diseases or disorders mediated by lymphocyte interactions, such as transplant rejection, autoimmune diseases, infectious diseases, and cancer, as well as diseases or disorders mediated by lymphocyte interactions, such as autoimmune diseases, particularly Hashimoto's thyroiditis, peripheral neuropathy, such as Guillain-Barré syndrome (GBS), multifocal motor neuropathy with conduction block (MMN), and paraproteinemic demyelinating peripheral neuropathy (PDN), and for the treatment or prevention of multiple sclerosis. As such, FTY720, approved as an oral drug for multiple sclerosis, is attracting attention for its mechanism of action of modulating immunity by simply regulating lymphocytes without depletion due to lymphocyte death, but it is problematic due to serious side effects centered on the cardiovascular system, such as bradycardia and arrhythmia (Ther Adv Drug Saf. 2013 Jun; 4(3): 119-124). The most commonly reported side effects are nasopharyngitis, headache, and fatigue; more frequently occurring side effects include influenza, diarrhea, back pain, elevated liver enzyme levels, and the common cold; and the most problematic side effects are decreased heart rate, AV conduction block, mild blood pressure elevation, macular edema, and elevated liver enzyme levels occurring during initial treatment. Clinical studies in the prior literature have reported that treatment with FTY720 causes bradycardia during the first 24 hours of treatment. This occurs because FTY720 acts non-selectively on S1P receptor subtypes (S1PR1, S1PR2, S1PR3, S1PR4, and S1PR5), causing side effects such as bradycardia. This has been confirmed through animal experiments using S1P receptor subtype selective agonists, patch clamp experiments using selective inhibitors, and knockout animal models. Consequently, there is a need to develop compounds with greater selectivity for S1P recepto