Novel compound as functional inhibitor against s1PR1 and s1PR4

Abstract

The present invention relates to a novel compound acting as a functional inhibitor against S1PR1 and S1PR4, and a use thereof. The compound according to the present invention has a remarkably excellent ability to bind to S1PR1 and S1PR4 receptors, and thus has the advantage of exhibiting an excellent effect of preventing or treating inflammatory bowel disease, alopecia areata, autoimmune diseases, and the like.

Description

Novel compounds as functional inhibitors of S1PR1 and S1PR4

[0001] The present invention relates to a novel compound that acts as a functional inhibitor for S1PR1 and S1PR4 and its use.

[0002] 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.

[0003] 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.

[0004] 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.

[0005] 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.

[0006] 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.

[0007] 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.

[0008] 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).

[0009] 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.

[0010] 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 receptors.

[0011] Accordingly, while the inventors were making diligent efforts to develop an independent compound that selectively acts on S1P subtype receptors among sphingolipid compounds, they completed the present invention by confirming that the compound according to the present invention specifically binds to S1PR1 and S1PR4 receptors and acts as a functional inhibitor (antagonist), and at the same time, its effect is significantly superior to that of conventional specific inhibitors.

[0012] The present invention aims to provide a novel compound having significantly superior binding affinity to S1PR1 and S1PR4 receptors, its uses, and a method for manufacturing.

[0013] To achieve the above objective, the present invention provides a compound represented by the following chemical formula 1:

[0014] [Chemical Formula 1]

[0015]

[0016] Here, R is C 1-15 It is an alkyl of.

[0017] The compound represented by the above chemical formula 1 may be any one compound selected from the group of compounds below.

[0018] (1) 2-amino-4-(1-hexyl-1H-1,2,3-triazol-4-yl)-2-(hydroxymethyl)butyl dihydrogen phosphate

[0019] (2) 2-amino-2-(hydroxymethyl)-4-(1-octyl-1H-1,2,3-triazol-4-yl)butyl dihydrogen phosphate

[0020] (3) 2-amino-2-(hydroxymethyl)-4-(1-nonyl-1H-1,2,3-triazol-4-yl)butyl dihydrogen phosphate

[0021] (4) 2-amino-4-(1-decyl-1H-1,2,3-triazol-4-yl)-2-(hydroxymethyl)butyl dihydrogen phosphate

[0022] (5) 2-amino-2-(hydroxymethyl)-4-(1-undecyl-1H-1,2,3-triazol-4-yl)butyl dihydrogen phosphate

[0023] (6) 2-amino-4-(1-dodecyl-1H-1,2,3-triazol-4-yl)-2-(hydroxymethyl)butyl dihydrogen phosphate

[0024] The compound represented by the above chemical formula 1 may be a compound represented by the following chemical formula 1a.

[0025] [Chemical Formula 1a]

[0026]

[0027] The present invention also provides S1PR1 and S1PR4 inhibitors represented by the following chemical formula 1:

[0028] [Chemical Formula 1]

[0029]

[0030] Here, R is C 1-15 It is an alkyl of.

[0031] In the present invention, the compound represented by Formula 1 may have a binding activity for S1PR1 and S1PR4 that is increased by more than 10 times compared to the compound represented by Formula 2 below:

[0032] [Chemical Formula 2]

[0033]

[0034] Here, R is C 1-15 It is an alkyl of.

[0035] The present invention also provides a pharmaceutical composition for the prevention or treatment of inflammatory bowel disease containing the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0036] In the present invention, the inflammatory bowel disease may be ulcerative colitis (UC) or Crohn's disease (CD).

[0037] The present invention also provides a pharmaceutical composition for the prevention or treatment of alopecia areata (AA) containing the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0038] The present invention also provides a pharmaceutical composition for the prevention or treatment of an autoimmune disease containing the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0039] In the present invention, the autoimmune disease is asthma, type 1 diabetes, rheumatoid arthritis, rheumatic polymyalgia, 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-Fitzer 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, solid organ transplantation It may be one or more selected from the group consisting of late and chronic rejection and graft-versus-host disease.

[0040] In the present invention, the pharmaceutical composition may further comprise one or more pharmaceutically acceptable carriers, diluents, and / or excipients.

[0041] In the present invention, the pharmaceutical composition may not cause cardiovascular disease side effects.

[0042] In the present invention, the pharmaceutical composition may be administered into the abdominal cavity.

[0043] The present invention also provides a method for preparing a compound represented by the following chemical formula 1, comprising the following steps:

[0044] [Chemical Formula 1]

[0045]

[0046] Here, R is C 1-15 It is an alkyl of

[0047] (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;

[0048] [Chemical Formula 2]

[0049]

[0050] Here, R is C 1-15 It is an alkyl of

[0051] [Chemical Formula 3]

[0052]

[0053] Here, R is C 1-15 It is an alkyl of;

[0054] (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

[0055] [Chemical Formula 4]

[0056]

[0057] Here, R is C 1-15 It is an alkyl of

[0058] (c) A step of synthesizing a compound represented by Chemical Formula 1 by reacting hydrogen (H2) with a compound represented by Chemical Formula 4.

[0059] In the present invention, step (b) may involve adding and reacting N,N-diisopropylethylamine and titanium(IV)butoxide.

[0060] In the present invention, step (c) may be carried out under a palladium / carbon catalyst.

[0061] The compound represented by Formula 1 according to the present invention has the advantage of exhibiting excellent effects in the prevention or treatment of inflammatory bowel disease, alopecia areata, and autoimmune diseases, by significantly improving the binding affinity between S1PR1 and S1PR4 compared to the compound represented by Formula 2, which is known as a functional inhibitor of S1PR1 and S1PR4.

[0062]

[0063] Figure 1 is the result of confirming the activity of S1PR1, S1PR2, S1PR3, and S1PR4 by measuring the degree of arrestin binding of one compound (compound 1a) according to the present invention.

[0064] Figure 2 shows the results of confirming the pharmacokinetics in plasma after intraperitoneal administration (10 mg / kg) of a compound (compound 1a) according to the present invention to mice.

[0065] Figure 3 shows the results of determining the percentage of lymphocytes among white blood cells after administering one compound (compound 1a) according to the present invention intraperitoneally to mice (10 mg / kg).

[0066] Figure 4 shows the results of confirming the area under the disease activity index curve (AUC) following oral administration (5 mg / kg, 10 mg / kg) of one compound (compound 1a) according to the present invention in mice with DSS-induced colitis.

[0067] Figure 5 shows the results of confirming the effect of restoring colon length following oral administration (5 mg / kg, 10 mg / kg) of one compound (compound 1a) according to the present invention in mice with DSS-induced colitis.

[0068]

[0069] The present invention will be described in detail below.

[0070] In the present invention, we aimed to develop a novel compound that specifically binds to S1PR1 and S1PR4 receptors and acts as a functional antagonist. It was confirmed that the compound represented by Chemical Formula 1 below can act as a functional antagonist by specifically binding to S1PR1 and S1PR4 receptors with an activity approximately 300 to 1000 times higher than that of the compound represented by Chemical Formula 2 below, which is known as a functional antagonist that specifically binds to S1PR1 and S1PR4 receptors.

[0071] [Chemical Formula 1]

[0072]

[0073] Here, R is C 1-15 It is an alkyl of.

[0074] [Chemical Formula 2]

[0075]

[0076] Here, R is C 1-15 It is an alkyl of.

[0077] Accordingly, in one aspect, the present invention relates to a novel compound represented by the following chemical formula 1:

[0078] [Chemical Formula 1]

[0079]

[0080] Here, R is C 1-15 It is an alkyl of.

[0081] In the present invention, the compound represented by the chemical formula 1 may be any one of the compounds selected from the group of compounds below.

[0082] (1) 2-amino-4-(1-hexyl-1H-1,2,3-triazol-4-yl)-2-(hydroxymethyl)butyl dihydrogen phosphate

[0083] (2) 2-amino-2-(hydroxymethyl)-4-(1-octyl-1H-1,2,3-triazol-4-yl)butyl dihydrogen phosphate

[0084] (3) 2-amino-2-(hydroxymethyl)-4-(1-nonyl-1H-1,2,3-triazol-4-yl)butyl dihydrogen phosphate

[0085] (4) 2-amino-4-(1-decyl-1H-1,2,3-triazol-4-yl)-2-(hydroxymethyl)butyl dihydrogen phosphate

[0086] (5) 2-amino-2-(hydroxymethyl)-4-(1-undecyl-1H-1,2,3-triazol-4-yl)butyl dihydrogen phosphate

[0087] (6) 2-amino-4-(1-dodecyl-1H-1,2,3-triazol-4-yl)-2-(hydroxymethyl)butyl dihydrogen phosphate

[0088] Preferably, the compound represented by the above chemical formula 1 may be 2-amino-4-(1-decyl-1H-1,2,3-triazol-4-yl)-2-(hydroxymethyl)butyl dihydrogen phosphate, which is the compound represented by the following chemical formula 1a.

[0089] [Chemical Formula 1a]

[0090] .

[0091] In addition, the present invention relates, in another aspect, to S1PR1 and S1PR4 inhibitors represented by the following chemical formula 1:

[0092] [Chemical Formula 1]

[0093]

[0094] Here, R is C 1-15 It is an alkyl of.

[0095] In the present invention, the compound of Formula 1 may be characterized by having S1PR1 and S1PR4 binding activity increased by more than 10 times compared to the compound represented by Formula 2 below:

[0096] [Chemical Formula 2]

[0097]

[0098] Here, R is C 1-15 It is an alkyl of.

[0099] In one embodiment, the compound represented by the following formula 1a according to the present invention may have a binding activity for S1PR1 and S1PR4 increased by more than 10 times compared to the compound represented by the following formula 2a:

[0100] [Chemical Formula 1a]

[0101]

[0102] [Chemical Formula 2a]

[0103] .

[0104] In the present invention, 'binding affinity' can be expressed as the ability to bind to S1PR1 and / or S1PR4, i.e., binding affinity, and can be expressed as the activity of binding to S1PR1 and / or S1PR4 and inhibiting the in vivo function of the receptor.

[0105] In one embodiment, the binding activity is EC in the competitive inhibition reaction for S1P. 50 It can be a value compared as.

[0106] In another embodiment, the binding activity may be the ability to recruit β-Arrestin by activating S1PR1 and / or S1PR4, and β-Arrestin recruitment can be measured by fluorescently labeling β-Arrestin and analyzing the increase in fluorescence expression.

[0107] The compound represented by Formula 1 (e.g., Formula 1a) according to the present invention may have an ability to recruit β-Arrestin by activating S1PR1 and / or S1PR4 (i.e., fluorescence expression intensity) increased by about 300 to 1000 times compared to the compound represented by Formula 2 (e.g., Formula 2a).

[0108] In the present invention, the compound represented by Formula 1 (e.g., Formula 1a) has a binding activity for S1PR1 that is about 10 times, about 20 times, about 30 times, about 40 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, about 110 times, about 120 times, about 130 times, about 140 times, about 150 times, about 160 times, about 170 times, about 180 times, about 190 times, about 200 times, about 210 times, about 220 times, about 230 times, about 240 times, about 250 times, about 260 times, about 270 times, about 280 times, about 290 times, about 300 times, approx. 310 times, approx. 320 times, approx. 330 times, approx. 340 times, approx. 350 times, approx. 360 times, approx. 370 times, approx. 380 times, approx. 390 times, approx. 400 times, approx. 410 times, approx. 420 times, approx. 430 times, approx. 440 times, approx. 450 times, approx. 460 times, approx. 470 times, approx. 480 times, approx. 490 times, approx. 500 times, approx. 510 times, approx. 520 times, approx. 530 times, approx. 540 times, approx. 550 times, approx. 560 times, approx. 570 times, approx. 580 times, approx. 590 times, approx. 600 times, approx. 610 times, approx. 620 times, approx. 630 times, approx. 640 times, approx. 650 times, approx. 660 times, approx. 670 times, approx. 680 times, approx. 690 times, approx. 700 times, approx. 710 times, approx. 720 times, approx. 730 times, approx. 740 times, approx. 750 times, approx. 760 times, approx. 770 times, approx. 780 times, approx. 790 times, approx. 800 times, approx. 810 times, approx. 820 times, approx. 830 times, approx. 840 times, approx. 850 times, approx. 860 times, approx. 870 times, approx. 880 times, approx. 890 times, approx. 900 times, approx. 910 times, approx. 920 times, approx. 930 times, approx. 940 times, approx. 950 times, approx. 960 times, approx. 970 times, approx. 980 times, approx. 990 times or approx. It may have increased by more than 1,000 times.

[0109] That is, in the present invention, the compound represented by Formula 1 (e.g., Formula 1a) has an EC in the competitive inhibition reaction with S1P for S1PR1 compared to the compound represented by Formula 2 (e.g., Formula 2a). 50approx. 1 / 10, approx. 1 / 20, approx. 1 / 30, approx. 1 / 40, approx. 1 / 50, approx. 1 / 60, approx. 1 / 70, approx. 1 / 80, approx. 1 / 90, approx. 1 / 100, approx. 1 / 110, approx. 1 / 120, approx. 1 / 130, approx. 1 / 140, approx. 1 / 150, approx. 1 / 160, approx. 1 / 170, approx. 1 / 180, approx. 1 / 190, approx. 1 / 200, approx. 1 / 210, approx. 1 / 220, approx. 1 / 230, approx. 1 / 240, approx. 1 / 250, approx. 1 / 260, approx. 1 / 270, approx. 1 / 280, approx. 1 / 290, approx. 1 / 300, approx. 1 / 310, approx. 1 / 320, approx. 1 / 330, approx. 1 / 340, approx. 1 / 350, approx. 1 / 360, approx. 1 / 370, approx. 1 / 380, approx. 1 / 390, approx. 1 / 400, approx. 1 / 410, approx. 1 / 420, approx. 1 / 430, approx. 1 / 440, approx. 1 / 450, approx. 1 / 460, approx. 1 / 470, approx. 1 / 480, approx. 1 / 490, approx. 1 / 500, approx. 1 / 510, approx. 1 / 520, approx. 1 / 530, approx. 1 / 540, approx. 1 / 550, approx. 1 / 560, approx. 1 / 570, approx. 1 / 580, approx. 1 / 590, approx. 1 / 600, approx. 1 / 610, approx. 1 / 620, approx. 1 / 630, approx. 1 / 640, approx. 1 / 650, approx. 1 / 660, approx. 1 / 670, approx. 1 / 680, approx. 1 / 690, approx. 1 / 700, approx. 1 / 710, approx. 1 / 720, approx. 1 / 730, approx. 1 / 740, approx. 1 / 750, approx. 1 / 760, approx. 1 / 770, approx. 1 / 780, approx. 1 / 790, approx. 1 / 800, approx. 1 / 810, approx. 1 / 820, approx. 1 / 830, approx. 1 / 840, approx. 1 / 850, approx. 1 / 860, approx. 1 / 870, approx. 1 / 880, approx. 1 / 890, approx. 1 / 900, approx. 1 / 910, approx. It may be reduced to 1 / 920, approximately 1 / 930, approximately 1 / 940, approximately 1 / 950, approximately 1 / 960, approximately 1 / 970, approximately 1 / 980, approximately 1 / 990, or approximately 1 / 1000 or less.

[0110] In the present invention, the compound represented by Formula 1 (e.g., Formula 1a) has a binding activity for S1PR4 approximately 10 times, approximately 20 times, approximately 30 times, approximately 40 times, approximately 50 times, approximately 60 times, approximately 70 times, approximately 80 times, approximately 90 times, approximately 100 times, approximately 110 times, approximately 120 times, approximately 130 times, approximately 140 times, approximately 150 times, approximately 160 times, approximately 170 times, approximately 180 times, approximately 190 times, approximately 200 times, approximately 210 times, approximately 220 times, approximately 230 times, approximately 240 times, approximately 250 times, approximately 260 times, approximately 270 times, approximately 280 times, approximately 290 times, approximately It may have increased by 300 times, about 310 times, about 320 times, about 330 times, about 340 times, about 350 times, about 360 times, or about 370 times or more.

[0111] That is, in the present invention, the compound represented by Formula 1 (e.g., Formula 1a) has an EC in the competitive inhibition reaction with S1P for S1PR4 compared to the compound represented by Formula 2 (e.g., Formula 2a). 50 approx. 1 / 10, approx. 1 / 20, approx. 1 / 30, approx. 1 / 40, approx. 1 / 50, approx. 1 / 60, approx. 1 / 70, approx. 1 / 80, approx. 1 / 90, approx. 1 / 100, approx. 1 / 110, approx. 1 / 120, approx. 1 / 130, approx. 1 / 140, approx. 1 / 150, approx. 1 / 160, approx. 1 / 170, approx. 1 / 180, approx. 1 / 190, approx. 1 / 200, approx. 1 / 210, approx. 1 / 220, approx. 1 / 230, approx. 1 / 240, approx. 1 / 250, approx. 1 / 260, approx. 1 / 270, approx. 1 / 280, approx. 1 / 290, approx. 1 / 300, approx. 1 / 310, approx. It may be reduced to 1 / 320, approximately 1 / 330, approximately 1 / 340, approximately 1 / 350, approximately 1 / 360, or approximately 1 / 370 or less.

[0112] In one embodiment, the binding activity is EC according to the β-Arrestin Recruitment Assay. 50 It can be evaluated as.

[0113] In another aspect, the present invention relates to a composition comprising a compound represented by the following chemical formula 1 (e.g., chemical formula 1a), specifically a composition for inhibiting S1PR1 and S1PR4 comprising a compound represented by the following chemical formula 1 (e.g., chemical formula 1a):

[0114] [Chemical Formula 1]

[0115]

[0116] Here, R is C 1-15 It is an alkyl of.

[0117] In another aspect, the present invention relates to a pharmaceutical composition for the prevention or treatment of inflammatory bowel disease containing a compound represented by Formula 1 (e.g., Formula 1a) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0118] In another aspect, the present invention relates to the use of a compound represented by Formula 1 (e.g., Formula 1a) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the prevention or treatment of inflammatory bowel disease.

[0119] In another aspect, the present invention relates to a compound represented by Formula 1 (e.g., Formula 1a) or a pharmaceutically acceptable salt thereof for the prevention or treatment of inflammatory bowel disease, or a pharmaceutical composition comprising a compound represented by Formula 1 (e.g., Formula 1a) or a pharmaceutically acceptable salt thereof.

[0120] In another aspect, the present invention relates to a method for preventing or treating inflammatory bowel disease comprising the step of administering a compound represented by Formula 1 (e.g., Formula 1a) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to an individual in need thereof.

[0121] In another aspect, the present invention relates to the use of a compound represented by Formula 1 (e.g., Formula 1a) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a drug for the prevention or treatment of inflammatory bowel disease.

[0122] In the present invention, the inflammatory bowel disease may be ulcerative colitis (UC) or Crohn's disease (CD), but is not limited thereto.

[0123] In another aspect, the present invention relates to a pharmaceutical composition for the prevention or treatment of alopecia areata (AA) containing, as an active ingredient, a compound represented by the above formula 1 (e.g., formula 1a) or a pharmaceutically acceptable salt thereof.

[0124] In another aspect, the present invention relates to the use of a compound represented by Formula 1 (e.g., Formula 1a) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition said to be for the prevention or treatment of alopecia areata (AA).

[0125] In another aspect, the present invention relates to a compound represented by Formula 1 (e.g., Formula 1a) or a pharmaceutically acceptable salt thereof for the prevention or treatment of alopecia areata (AA), or a pharmaceutical composition comprising a compound represented by Formula 1 (e.g., Formula 1a) or a pharmaceutically acceptable salt thereof.

[0126] In another aspect, the present invention relates to a method for preventing or treating alopecia areata (AA), comprising the step of administering a compound represented by Formula 1 (e.g., Formula 1a), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to an individual in need thereof.

[0127] In another aspect, the present invention relates to the use of a compound represented by Formula 1 (e.g., Formula 1a) or a pharmaceutically acceptable salt thereof or said pharmaceutical composition for the manufacture of a drug for the prevention or treatment of alopecia areata (AA).

[0128] In another aspect, the present invention relates to a pharmaceutical composition for the prevention or treatment of an autoimmune disease containing, as an active ingredient, a compound represented by Formula 1 (e.g., Formula 1a) or a pharmaceutically acceptable salt thereof or said pharmaceutical composition.

[0129] In another aspect, the present invention relates to the use of a compound represented by Formula 1 (e.g., Formula 1a), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the prevention or treatment of an autoimmune disease.

[0130] In another aspect, the present invention relates to a compound represented by Formula 1 (e.g., Formula 1a) or a pharmaceutically acceptable salt thereof for the prevention or treatment of an autoimmune disease, or a pharmaceutical composition comprising a compound represented by Formula 1 (e.g., Formula 1a) or a pharmaceutically acceptable salt thereof.

[0131] In another aspect, the present invention relates to a method for preventing or treating an autoimmune disease comprising the step of administering a compound represented by Formula 1 (e.g., Formula 1a), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to an individual in need thereof.

[0132] In another aspect, the present invention relates to the use of a compound represented by Formula 1 (e.g., Formula 1a) or a pharmaceutically acceptable salt thereof for the manufacture of a drug for the prevention or treatment of an autoimmune disease.

[0133] In the present invention, the autoimmune disease is asthma, type 1 diabetes, rheumatoid arthritis, rheumatic polymyalgia, 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-Fitzer 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, solid organ transplantation It may be one or more selected from the group consisting of late and chronic rejection and graft-versus-host disease, but is not limited thereto.

[0134] In another aspect, the present invention relates to a pharmaceutical composition for the prevention or treatment of focal segmental glomerulosclerosis (FSGS) containing, as an active ingredient, a compound represented by the above formula 1 (e.g., formula 1a) or a pharmaceutically acceptable salt thereof.

[0135] In another aspect, the present invention relates to the use of a compound represented by Formula 1 (e.g., Formula 1a) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition said to be for the prevention or treatment of focal segmental glomerulosclerosis (FSGS).

[0136] In another aspect, the present invention relates to a compound represented by Formula 1 (e.g., Formula 1a) or a pharmaceutically acceptable salt thereof for the prevention or treatment of focal segmental glomerulosclerosis (FSGS), or a pharmaceutical composition comprising a compound represented by Formula 1 (e.g., Formula 1a) or a pharmaceutically acceptable salt thereof.

[0137] In another aspect, the present invention relates to a method for preventing or treating focal segmental glomerulosclerosis (FSGS), comprising the step of administering a compound represented by Formula 1 (e.g., Formula 1a), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to an individual in need thereof.

[0138] In another aspect, the present invention relates to the use of a compound represented by Formula 1 (e.g., Formula 1a), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the preparation of a drug for the prevention or treatment of focal segmental glomerulosclerosis (FSGS).

[0139] In another aspect, the present invention relates to a pharmaceutical composition for the prevention or treatment of interstitial fibrosis and tubular atrophy (IFTA) containing, as an active ingredient, a compound represented by the above formula 1 (e.g., formula 1a) or a pharmaceutically acceptable salt thereof.

[0140] In another aspect, the present invention relates to the use of a compound represented by Formula 1 (e.g., Formula 1a) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition said to be for the prevention or treatment of interstitial fibrosis and tubular atrophy (IFTA).

[0141] In another aspect, the present invention relates to a compound represented by Formula 1 (e.g., Formula 1a) or a pharmaceutically acceptable salt thereof for the prevention or treatment of interstitial fibrosis and tubular atrophy (IFTA), or a pharmaceutical composition comprising a compound represented by Formula 1 (e.g., Formula 1a) or a pharmaceutically acceptable salt thereof.

[0142] In another aspect, the present invention relates to a method for preventing or treating interstitial fibrosis and tubular atrophy (IFTA), comprising the step of administering a compound represented by Formula 1 (e.g., Formula 1a), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to an individual in need thereof.

[0143] In another aspect, the present invention relates to the use of a compound represented by Formula 1 (e.g., Formula 1a), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a drug for the prevention or treatment of interstitial fibrosis and tubular atrophy (IFTA).

[0144] In the present invention, the pharmaceutical composition may further comprise one or more pharmaceutically acceptable carriers, diluents, and / or excipients.

[0145] In the present invention, the compound represented by Formula 1 (e.g., Formula 1a) or a pharmaceutically acceptable salt thereof may be included in an amount of 0.1 to 90 weight percent relative to the total weight of the pharmaceutical composition.

[0146] In the present invention, the compound represented by Formula 1 (e.g., Formula 1a), the pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof may not cause cardiovascular disease side effects.

[0147] In the present invention, the compound represented by Formula 1 (e.g., Formula 1a) or a pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof may be administered intraperitoneally, but is not limited thereto.

[0148] In the present invention, "prevention" refers to any act of administering a pharmaceutical composition to an individual to suppress or delay the onset of a target disease.

[0149] In the present invention, "treatment" means any act of administering a pharmaceutical composition to an individual to improve or benefit the symptoms of a target disease.

[0150] The compound represented by the above chemical formula 1 (e.g., chemical formula 1a) may be used in the form of a pharmaceutically acceptable salt. In this case, the salt may be an acid addition salt formed by a pharmaceutically acceptable free acid.

[0151] More specifically, acid addition salts can be obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromide, hydroiodide, nitrous acid, phosphoric acid, etc., aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkandioates, aromatic acids, aliphatic and aromatic sulfonic acids, etc., non-toxic organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc.

[0152] In addition, pharmaceutically non-toxic salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphate chloride, bromides, iodides, fluorides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caprates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, malieates, butyne-1,4-dioate, hexane-1,6-dioate, benzoates, chlorobenzoates, methyl benzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, and phthalates. It may include terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, etc.

[0153] Acid addition salts can be prepared by conventional methods. For example, a derivative of a compound represented by Chemical Formula 1 (e.g., Chemical Formula 1a) can be prepared by dissolving it in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc., adding an organic or inorganic acid, and filtering and drying the resulting precipitate, or by vacuum distilling the solvent and excess acid, drying, and crystallizing under an organic solvent.

[0154] In addition, pharmaceutically acceptable metal salts can be prepared using a base. For example, a compound represented by Formula 1 (e.g., Formula 1a) can be dissolved in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, the undissolved compound salt can be filtered, and the filtrate can be evaporated and dried to obtain the salt. It is preferable to prepare sodium, potassium, or calcium salts as metal salts. In addition, the corresponding salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0155] In addition, the pharmaceutical composition according to the present invention may not only contain a compound represented by Formula 1 (e.g., Formula 1a) and a pharmaceutically acceptable salt thereof as an active ingredient, but may also contain a substance selected from solvates, optical isomers, hydrates, etc. that can be prepared therefrom as an active ingredient.

[0156] A pharmaceutical composition comprising a compound represented by Chemical Formula 1 (e.g., Chemical Formula 1a), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient can be changed into an oral administration formulation and other types of formulations within the range of pharmacological activity.

[0157] Oral formulations may be in the form of troches, lozenges, tablets, water-soluble suspensions, oily suspensions, prepared powders, granules, emulsions, hard capsules, soft capsules, syrups, or elixirs, but are not limited thereto.

[0158] In addition, to formulate the pharmaceutical composition according to the present invention into an oral administration formulation, binders such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose, or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch or sweet potato starch; lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate, or polyethylene glycol wax; sweeteners; flavorings; syrups; etc. may be used. Furthermore, in the case of capsule formulations, in addition to the materials mentioned above, liquid carriers such as fatty oils may be additionally used.

[0159] A pharmaceutical composition comprising a compound represented by Chemical Formula 1 (e.g., Chemical Formula 1a), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient can be formulated into various suitable formulations for parenteral administration and used.

[0160] Preparations for parenteral administration include, but are not limited to, injectable solutions, suppositories, powders for respiratory inhalation, aerosols for spray, ointments, powders for topical application, oils, creams, etc.

[0161] In addition, to formulate the pharmaceutical composition according to the present invention into a parenteral administration formulation, sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, topical formulations, etc. may be used. Specifically, for non-aqueous solvents and suspensions, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, etc. may be used.

[0162] When the pharmaceutical composition according to the present invention is formulated as an injectable solution, the pharmaceutical composition may be mixed in water with a stabilizer or a buffer to prepare a solution or suspension, and formulated for unit administration in ampoules or vials. Additionally, when the pharmaceutical composition according to the present invention is formulated as an aerosol, a propellant or the like may be combined with additives to disperse the water-dispersed concentrate or wet powder. Furthermore, when the pharmaceutical composition according to the present invention is formulated as an ointment, cream, etc., it may be formulated using animal oil, vegetable oil, wax, paraffin, starch, tracanth, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc, zinc oxide, etc. as a carrier.

[0163] The pharmaceutical composition according to the present invention may additionally include one or more other therapeutic agents suitable for the treatment of the said disease.

[0164] One or more other therapeutic agents suitable for treating the above disease may be administered together or separately. If administered separately, they may be administered simultaneously or sequentially in any order. The dosage and timing of administration of the compound represented by Formula 1 (e.g., Formula 1a) or its pharmaceutically acceptable salt and other therapeutic agents may be selected to achieve the desired combination therapeutic effect.

[0165] The pharmaceutical composition according to the present invention may further comprise a pharmaceutically acceptable carrier. "Pharmaceutically acceptable" means that it is commonly used in the pharmaceutical field and does not impair the biological activity and properties of the administered compound without stimulating the organism when the compound is administered.

[0166] The type of carrier is not particularly limited, and any carrier commonly used in the relevant technical field may be used. Non-limiting examples of carriers include saline solution, sterile water, Ringer's solution, buffered saline solution, albumin injection solution, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, maltodextrin, glycerol, ethanol, etc. These may be used alone or in a mixture of two or more types.

[0167] In addition, other pharmaceutically acceptable additives, such as excipients, diluents, antioxidants, buffers, or bacteriostatic agents, may be added to the pharmaceutical composition according to the present invention as needed. In addition, fillers, extenders, wetting agents, disintegrants, dispersants, surfactants, binders, or lubricants may be additionally added to the pharmaceutical composition according to the present invention as needed.

[0168] The pharmacologically effective amount and dosage to be administered to the human body of the pharmaceutical composition according to the present invention may vary depending on the formulation method, administration method, administration time and / or administration route of the pharmaceutical composition. The dosage may vary depending on various factors and similar factors widely known in the pharmaceutical field, including the type and degree of response to be achieved by administering the pharmaceutical composition, the type of individual to be administered, age, body weight, general health condition, symptoms or severity of disease, gender, diet, excretion, and other components of the composition such as drugs used simultaneously or at different times with the individual, and a person with ordinary knowledge in the relevant technical field can easily determine and prescribe a dosage effective for the intended treatment.

[0169] Furthermore, the administration route and method of administration of the pharmaceutical composition according to the present invention may each be independent and are not particularly limited. Any administration route and method may be followed as long as the active ingredient can reach the intended site when the pharmaceutical composition according to the present invention is administered.

[0170] The pharmaceutical composition according to the present invention may be administered orally or parenterally. For example, parenteral administration methods may include intravenous administration, intraperitoneal administration, intramuscular administration, transdermal administration, or subcutaneous administration. Additionally, the pharmaceutical composition according to the present invention may be applied to a diseased area, sprayed, or inhaled, but is not limited thereto. Furthermore, the pharmaceutical composition according to the present invention may be used for the treatment of the said disease in subjects requiring it. In this case, the type of subject is not particularly limited, but may be a mammal, and preferably may be a human.

[0171] The S1PR1 receptor is primarily present in lymphocytes and plays a major role in regulating the release of lymphocytes from immune cells. The S1PR4 receptor is also present in lymphocytes and is involved in inflammatory responses by acting not only on immune cell trafficking but also on T cell regulation. Therefore, the compound of the present invention acts as a functional inhibitor on the S1PR1 receptor, thereby inhibiting the release of lymphocytes, and also acts on S1PR4 to exhibit an effective anti-inflammatory effect, thereby having the effect of preventing or treating the aforementioned diseases.

[0172] Specifically, the compound of the present invention acts as a functional antagonist for these receptors by specifically binding to S1PR1 and S1PR4 and then introducing them into the cell to eliminate them, thereby having the effect of preventing or treating the aforementioned disease. In addition, the pharmaceutical composition according to the present invention acts as a functional inhibitor for S1PR1 and S1PR4 and may not cause cardiovascular disease side effects.

[0173] In another aspect, the present invention relates to a method for preparing a compound represented by the following chemical formula 1, comprising the following steps:

[0174] [Chemical Formula 1]

[0175]

[0176] Here, R is C 1-15 It is an alkyl of

[0177] (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;

[0178] [Chemical Formula 2]

[0179]

[0180] Here, R is C 1-15 It is an alkyl of

[0181] [Chemical Formula 3]

[0182]

[0183] Here, R is C 1-15 It is an alkyl of

[0184] (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

[0185] [Chemical Formula 4]

[0186]

[0187] Here, R is C 1-15 It is an alkyl of

[0188] (c) A step of synthesizing a compound represented by Chemical Formula 1 by reacting hydrogen (H2) with a compound represented by Chemical Formula 4.

[0189] In one embodiment, the present invention relates to a method for preparing a compound represented by the following formula 1a, comprising the following steps:

[0190] [Chemical Formula 1a]

[0191]

[0192] (a) A step of synthesizing a compound represented by the following chemical formula 3a by reacting a compound represented by the following chemical formula 2a with sodium bicarbonate and benzyl chloroformate;

[0193] [Chemical Formula 2a]

[0194]

[0195] [Chemical Formula 3a]

[0196]

[0197] (b) a step of synthesizing a compound represented by the following chemical formula 4a by reacting tetrabenzyl pyrophosphate with a compound represented by the above chemical formula 3a; and

[0198] [Chemical Formula 4a]

[0199]

[0200] (c) A step of synthesizing a compound represented by chemical formula 1a by reacting hydrogen (H2) with a compound represented by chemical formula 4a.

[0201] In the present invention, step (b) may involve adding and reacting N,N-diisopropylethylamine and titanium(IV)butoxide.

[0202] In the present invention, step (c) may be carried out under a palladium / carbon catalyst.

[0203]

[0204] The present invention will be described in more detail below through examples. These examples are intended solely to illustrate the present invention, and it will be obvious to those skilled in the art that the scope of the present invention is not to be interpreted as being limited by these examples.

[0205]

[0206] Preparation Example

[0207] Step 1) Synthesis of Benzyl (4-(1decyl-1H-1,2,3-triazol-4-yl)-1-hydroxy-2-(hydroxymethyl)butan-2-yl)carbamate (3a)

[0208]

[0209] In 90 ml of ethyl acetate, compound 2a (in the compound represented by Chemical Formula 2, R is C 10 2.04 g of a compound characterized as being an alkyl group (refer to Korean Registered Patent Publication No. 10-1830244), 525 mg of sodium bicarbonate, and 50 ml of purified water were added and stirred at room temperature for 30 minutes. 1.6 g of benzyl chloroformate was slowly added at room temperature. After stirring at room temperature for 6 hours, 3 ml of methanol was added and stirred for 30 minutes, after which the layers were separated. The organic layer was washed with 20 ml of saturated saline, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was separated by column to obtain 1.87 g of compound 3a.

[0210] 1H NMR (400 MHz, CDCl3) δ(m, 5H), 7.18(s, 1H), 4.98(br s, 2H), 4.25~4.28 (m, 2H), 4.02~4.15 (m, 4H), 3.48(m, 2H), 2.65~2.62(m, 2H), 1.92(m, 2H),1.80 (m, 2H), 1.28 (m, 14H), 0.86 (t, J = 8.0 Hz, 3H).

[0211] LC-MS [M+H]+ = 461.

[0212]

[0213] Step 2) Synthesis of Benzyl (1-((bis(benzyloxy)phosphoryl)oxy)-4-(1-decyl-1H-1,2,3-triazol-4-yl)- 2-(hydroxymethyl)butan-2-yl)carbamate (4a)

[0214]

[0215] 1.87 g of compound 3a and 4.24 ml of N,N-diisopropylethylamine were added to 50 ml of tetrahydrofuran and stirred at room temperature for 30 minutes. 2.84 g of tetrabenzyl pyrophosphate and 64.48 mg of titanium(IV) butoxide were added sequentially, followed by stirring at room temperature overnight. 20 ml of saturated sodium bicarbonate and 30 ml of ethyl acetate were added to the reaction mixture and stirred for 10 minutes, after which phase separation occurred. The organic layer was washed with 30 ml of saturated saline solution, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was column-purified to obtain 2.14 g of compound 4a.

[0216] 1H NMR (400 MHz, CDCl3) δ(m, 15H), 7.21(s, 1H), 5.00~5.24(s, 6H), 4.25~4.28 (m, 2H), 4.07~4.17 (m, 2H), 3.52(m, 2H), 2.65~2.69(m, 2H), 2.23-2.38(m, 2H), 1.91~1.95(m, 2H),1.85~1.87 (m, 2H), 1.30 (m, 14H), 0.88 (t, J = 8.0 Hz, 3H).

[0217] LC-MS [M+H]+ = 721.

[0218]

[0219] Step 3) Synthesis of 2-Amino-4-(1-decyl-1H-1,2,3-triazol-4-yl)-2-(hydroxymethyl)butyl dihydrogen phosphate (1a)

[0220]

[0221] 2.14 g of Compound 4a was added to 50 ml of methanol and dissolved, then bubbling with nitrogen for 10 minutes. 0.8 g of 10% palladium / carbon was added, and the reaction was carried out overnight at room temperature using a hydrogen balloon. After filtration through a microfilter and vacuum concentration, 20 ml of an EA / Hexane=1 / 4 solution was added to the concentrated residue and stirred for 1 hour, then filtered and dried to obtain Compound 1a (in the compound represented by Chemical Formula 1, R is C 10 0.82g of a compound characterized as being an alkyl compound was obtained.

[0222] 1H NMR (400 MHz, DMSO-d6) δ(s, 1H), 4.25~4.28 (m, 2H), 3.85(d, 2H), 3.47~3.64 (dd, 2H), 2.67-2.70 (m, 2H), 1.90~1.93 (m, 2H),1.75~1.78 (m, 2H), 1.34 (m, 14H), 0.89 (t, J = 8.0 Hz, 3H).

[0223] LC-MS [M+H]+ = 407.

[0224]

[0225] Experimental Example 1. Arrestin Translocation Assay

[0226] [Formula 1a] 2-amino-4-(1-decyl-1H-1,2,3-triazole-4-yl)-2-(hydroxymethyl)butyl dihydrogen phosphate

[0227]

[0228]

[0229] [Chemical Formula 2a] 2-amino-2-(2-(1-decyl-1H-1,2,3-triazole-4-yl)ethyl)propane-1,3-diol

[0230]

[0231] The compound of the present invention, compound 1a (in the compound represented by Chemical Formula 1, R is C 10 A compound characterized by being an alkyl group) and the comparative example compound 2a (in the compound represented by Chemical Formula 2, R is C 10 The activity of a compound characterized as being an alkyl group against S1PR1, S1PR2, S1PR3, and S1PR4 was compared through the β-Arrestin Recruitment Assay.

[0232] To this end, cell lines overexpressing S1PR1, S1PR2, S1PR3, and S1PR4, respectively (PathHunter ®CHO-K1 eXpress β-Arrestin GPCR cells (DiscoverX, Fremont, USA) were seeded at 5,000 cells / well in 384-well plates and cultured with AssayComplete™ Cell Culture Kit-107 (DiscoverX, Fremont, USA). Compound 1a or Compound 2a was diluted 1 / 3 at 10 µM and treated at 10 points. PathHunter Detection reagent cocktail (DiscoverX, Fremont, USA) was added according to the manufacturer's instructions, and after incubation for 1 hour, the chemiluminescent signal (luminescence reader, 0.1–1 second / well) was measured.

[0233] The types and activities of the control substances are as shown in Table 1.

[0234] Assay formatReference cpdTargetEC 50 AgonismS1PS1PR116.3 nMS1PR217.6 nMS1PR359.2 nMS1PR4229.3 nM

[0235] Compound 1a (in the compound represented by Chemical Formula 1, R is C 10 A compound characterized by being an alkyl group) and compound 2a (in the compound represented by Chemical Formula 2, R is C 10 The results of evaluating the agonosim activity of each S1PR of compounds (characterized by being alkyl) against each S1PR are shown in Table 2 and Figure 1 below. Specifically, both Compound 1a and Compound 2a exhibited selective activity against S1PR1 and S1PR4; in particular, Compound 1a was confirmed to exhibit approximately 300 to 1000 times higher activity compared to Compound 2a (EC for S1PR1). 50 4.3 nM vs 4.2 μM, EC for S1PR4 50 8.1 nM vs 3.0 μM).

[0236] cpd.TargetEC 50 Max response (%) Compound 2aS1PR14.2 uM41.0S1PR2>10 uM4.4S1PR3>10 uM0.0S1PR43.0 uM101.3 Compound 1aS1PR14.3 nM92.8S1PR2>10 uM0S1PR3>10 uM0S1PR48.1 nM102.0

[0237] Experimental Example 2. Pharmacokinetic and pharmacodynamic evaluation of Compound 1a upon intraperitoneal administration to mice

[0238] To analyze the pharmacokinetics of compound 1a, compound 1a dissolved in distilled water was administered once intraperitoneally to ICR mice (Daehan Bio Link Co., Ltd.) (n=12) at a dose of 10 mg / kg. Blood was then collected a total of 10 times at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours, with each collection amount set to 100 μL. The collected blood was placed in heparin-treated (5 IU / mL) tubes and mixed well. The blood was then centrifuged using a centrifuge (MF 300, Hanil Science) at 4°C and 5000 rpm for 10 minutes to separate the plasma. The separated plasma was then dispensed into marked tubes at a rate of approximately 30–40 μL / tube and stored in an ultra-low temperature freezer (approx. -80°C). Afterwards, plasma samples were analyzed using LC-MS / MS (HPLC: Agilent 1200 Series (Agilent, USA) / MS / MS: AB Sciex 4000 QTrap (AB SCIEX, USA)).

[0239] The drug concentrations over time upon intraperitoneal administration of compound 1a are shown in Table 3, and pharmacokinetic data are shown in Table 4 and Figure 2. Specifically, the Cmax of compound 1a was found to be approximately 147 ng / mL and the AUC approximately 185 ng·hr / mL.

[0240] Time(hr) Compound 1a (IP, 10 mg / kg) Compound 1a (ng / mL) 0.08 39 4.38 0.25 146.8 20.55 9.85 134.24 223.73 420.56 68.77 84.48 12 24 ND

[0241] Compound, dose Route Compound 1a, 10 mg / kg, IPPK Parameters Unit Compound 1a AUC last h*ng / mL184.5AUC INF _obsh*ng / mL196.3C max ng / mL146.8T max h0.3t 1 / 2 h1.8

[0242] Meanwhile, to analyze the pharmacodynamics of compound 1a, compound 1a dissolved in distilled water was administered intraperitoneally to ICR mice (Daehan Bio Link Co., Ltd.) (n=3) at a dose of 10 mg / kg. Blood was then collected a total of 8 times at 0.5, 3, 6, 8, 12, 24, 48, and 72 hours, with each collection amounting to 100 μL, and WBC (5 differential count) was measured using an automated hematology counter (Advia 2020i, SIEMENS).

[0243] As a result, as shown in Figure 3, the percentage of lymphocytes among white blood cells (WBC) decreased by more than 50% to 28.5±6.5% at 3 hours after administration of compound 1a compared to before administration of compound 1a (78.4±5.3%), and was found to be 29.2±8.3% at 12 hours after administration of compound 1a, confirming that the decrease in lymphocytes was maintained for up to 12 hours and recovered to the initial ratio level at 24 hours.

[0244] Experimental Example 3. Confirmation of inhibitory efficacy against inflammatory bowel disease using a mouse DSS-induced model

[0245] The efficacy of compound 1a for inflammatory bowel disease was evaluated using a Dextran Sulfate Sodium (DSS)-induced Colitis model.

[0246] In the above mouse model, inflammatory bowel disease was induced in 6-10 week old female C57BL / 6 mice (Coatech Co., Ltd.) by administering DSS at a concentration of 2.5% as a negative fluid. The administration groups consisted of a test group administered compound 1a, a vehicle group [5% DW, 5% Tween 20, 90% 0.1N HCl], and a normal control group, with n=10 in each group. Compound 1a, the compound of the present invention, was orally administered to the above-mentioned inflammatory bowel disease model at doses of 5 and 10 mg / kg once daily for 7 days, respectively.

[0247] The Disease Activity Index (DAI) and the Area Under the Curve (AUC) of DSS-induced colitis mice were determined. The DAI represents the sum of the scores for body weight loss, stool consistency, and the degree of intestinal bleeding compared to the mice's initial body weight. The criteria for calculating the DAI are as shown in Table 5 below, and the DAI was evaluated on days 0, 1, 2, 3, 4, 5, 6, and 7.

[0248] Score Weight Loss Ratio to Initial Body Weight Stool Consistency Intestinal Bleeding 0 None Normal Negative hemoccult 11-5% Soft but still formed Occult blood detected (weak luminol intensity) 26-10% Soft Occult blood detected (strong luminol intensity) 311-18% Very soft; wet Blood visible in stool 4>18% Watery diarrhea Intestinal bleeding

[0249] As a result of the experiment, a statistically significant reduction in the disease activity index compared to the negative control group (Vehicle) was confirmed in both the compound 1a 5 mg / kg and compound 1a 10 mg / kg administration groups. In particular, as a result of administering compound 1a at 10 mg / kg, significant effects were observed in clinical indicators according to body weight loss, stool concentration, and the degree of intestinal bleeding (Fig. 4).

[0250] Meanwhile, colon tissue was excised from DSS-induced colitis mice and its length was measured. Colon length measurement indicates whether damage to the mouse colon tissue was reduced and the degree to which the length was maintained; colon length was evaluated after the administration of the positive control and test substances was completed.

[0251] As a result of the experiment, a statistically significant increase in colon length compared to the negative control (Vehicle) was observed in both the compound 1a 5 mg / kg and compound 1a 10 mg / kg administration groups. In particular, significant results were observed in the reduction of colon tissue damage and maintenance of colon length following the administration of compound 1a 5 mg / kg and compound 1a 10 mg / kg (Fig. 5).

[0252] Statistical analysis was performed between the negative control group and the test group or between the two test groups based on the above evaluation results. An Independent t-test or Repeated Measures ANOVA was used for comparison between the groups, and a p-value of 0.05 or less indicated a significance level.

[0253] Thus, it was confirmed that compound 1a is a substance with an inhibitory effect on inflammatory bowel disease.

Claims

1. A compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] Here, R is C 1-15 It is an alkyl of.

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 C 1-15 It is an alkyl of.

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 at least 10 times compared to the compound represented by Chemical Formula 2 below: [Chemical Formula 2] Here, R is C 1-15 It is an alkyl of.

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 include 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, A pharmaceutical composition for the prevention or treatment of an autoimmune disease, comprising one or more selected from the group consisting of antiphospholipid syndrome, late and chronic rejection of solid organ transplants, 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 C 1-15 It is an alkyl of (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 C 1-15 It is an alkyl of [Chemical Formula 3] Here, R is C 1-15 It is an alkyl of (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 C 1-15 It is an alkyl of (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) of claim 15 involves reacting N,N-diisopropylethylamine and titanium(IV)butoxide.

17. A method for preparing a compound represented by Formula 1, wherein step (c) of claim 15 is reacted under a palladium / carbon catalyst.

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