S1P receptor modulator

Abstract

The present invention relates to a compound of formula (I): The S1P receptor modulator compound shown in JPEG2023515612000054.jpg39160 is based on a determination that the S1P receptor modulator compound reduces the heart rate of a subject to which it is administered by about 5 beats / min or less per day, or by about 4 beats / min or less per day, or by about 3 beats / min or less per day, or by about 2 beats / min or less per day, wherein the S1P receptor modulator compound is administered at an initial daily dose substantially the same as a standard daily therapeutic dose.

Description

[Technical Field]

[0001] This disclosure relates to methods for treating or preventing diseases or disorders, particularly inflammation, immune-mediated disorders, and vascular and neurological disorders. The method of the present invention involves administering a pharmaceutical product containing an S1P receptor modulator that results in minimization of bradycardia and lymphopenia. [Background technology]

[0002] The relationship between the S1P receptor axis and disease inflammation. S1P receptors are a family of G protein-coupled receptors widely expressed across major organ systems such as the immune, nervous, and vascular systems. There are five receptors known as sphingosine 1-phosphate receptors (S1P1-5), and the common endogenous ligand S1P has various downstream effects (Cooke et al, Annual Reports in Medicinal Chemistry, 2007, 42, pp 245-263, and references therein). S1P receptors, particularly the type 1 receptor S1P1, are involved in immune responses, endothelial barrier enhancement (Wilkerson BA et al, J Biol Chem, 2012, Vol.287, 44645), cytoprotection (Rutherford C et al, Cell Death and Disease, 2013, 4, e927; doi:10.1038 / cddis, 455), cell differentiation, and cell recruitment / chemotaxis.

[0003] Downstream effects mediated by the S1P receptor are known to be involved in mTOR regulation and immunomodulation (Liu G. et al, Nat Immunol, 2010, 11, 1047). The involvement of the S1P receptor is well documented in the inhibition of STAT3, a target known to be involved in inflammation and cancer (Garris CS et al, Nat Immunol, 2013, Vol 14, 1166). The S1P receptor is also well known to modulate pain (Welch SP et al, Biochem Pharmacol, 2012, 84, 1551). Furthermore, the S1P receptor is involved in stem cell chemotaxis (Kimura A. et al., Stem Cell, 2007, 25, 115) and regeneration (Leronimakis et al. Skeletal Muscle, 2013, 3, 20), and the S1P axis is involved in neuroprotection (Asle RM et al, EXCLI Journal, 2013, 12, 449). Regulation of the S1P receptor is involved in the expression of cytokines such as TNFα, IL6, IL12, and VEGF (Bolick DT et al, Arterioscler Thromb Vasc Biol, 2005, 25, 976; Sanchez T, et al, J Biol Chem 2003, 278 (47), 47281). The S1P receptor has been shown to be significantly involved in serious diseases such as acute lung injury and influenza. Endothelial cells, which make up the inner lining of blood vessels, express S1P receptors, and S1P1 agonists are well known to strengthen the vascular barrier, prevent vascular leakage, and enhance the maturation of vascular structures (McVerry BJ et al. J. et al, J Cell Biochem, 2004, 92, 1075; Allende ML et al, Blood, 2003, 102, 3665; Paik J. et al, Genes Dev, 2004, 18, 2392; Garcia JGN et al, J Clin Invest, 2001, 108(5), 689).The S1P receptor axis is involved in inflammation and cancer (Kunkel GT et al, Drug Discovery, 2013, 12, 688).

[0004] Inflammation is an immune response to injury or infection. Symptoms include redness, warmth, swelling, and pain. While controlling inflammation is important for regeneration and wound healing, uncontrolled inflammation can lead to long-term adverse responses and potentially chronic diseases. Inflammation can be localized or organ-specific, or it can spread throughout the body and cause systemic diseases.

[0005] Inflammatory sites overexpress pro-inflammatory cytokines and factors, such as interleukins (IL-1, IL-6, IL-17), tumor necrosis factor (TNFα), inducible nitroxide synthase (iNOS), cyclooxygenase-2 (COX-2), myeloperoxidase (MPO), and vascular endothelial growth factor (VEGF). These cytokines and factors are involved in the recruitment of immune cells, altered immune responses, disruption of the endothelial barrier, altered differentiation, and abnormal proliferation patterns within inflammation. Blood vessels become abnormal, dilated, leaky, and tortuous, leading to fluid accumulation and edema. Distant areas are deprived of blood supply, progressing to hypoxia and potentially leading to cancer development. Cell survival patterns change, and degeneration occurs.

[0006] Growing scientific data reveals that inflammation is involved in almost all diseases. Multiple diseases of inflammatory origin are common in various organ systems, including the cardiovascular system (i.e., atherosclerosis, ischemic disease, venous disease), the nervous system (i.e., multiple sclerosis, epilepsy, ALS, neuropathy), and immune-mediated diseases (i.e., rheumatoid arthritis, asthma, psoriasis, atopic dermatitis, acne, vitiligo). Inflammation plays an underlying role in ischemic injury, atherosclerotic lesions (Galkina E. et al, Annu Rev Immunol, 2009, 27, 165), and cancerous tumors (Landskron G. et al, J Immunol Res, 2014, Article ID 149185, 19 pages http: / / dx.doi.org / 10.1155 / 2014 / 149185).

[0007] Diseases such as rheumatoid arthritis, arthralgia, muscle inflammation, psoriasis, dermatitis, uveitis, and atherosclerosis are accompanied by inflammation, along with other co-pathologies such as pain, itching, and degeneration. The S1P receptor is known as a target of the S1P1 receptor axis in multiple pathological conditions occurring in inflammatory signs, particularly in inflammation and immunomodulation.

[0008] Cancers of various origins share common pathological features, including inflammation, vascular abnormalities (leakage, angiogenesis), hypoxia, abnormal differentiation, cell exudation from the primary cancer site, and metastasis. By modulating the S1P receptor, a single treatment can alleviate multiple pathological features seen in various cancers by reducing inflammation, strengthening the barrier, avoiding metastasis, and promoting cell differentiation. Cell clamping mediated by the S1P receptor has been reported to enhance cell-cell adhesion, thereby blocking the invasion of tumor cells into blood vessels from cancer points (Feng H, Cancer Cell, 2010, 18(4), 353-366).

[0009] Vascular diseases such as vascular abnormalities, leakage and fluid exudation, and edema-hypervascularization are also thought to be the result of underlying inflammation. Neurodegeneration, inflammation, vascular leakage, and hypervascularization are common in macular degeneration, glaucoma, and retinopathy. Lung inflammation is a central cause of various lung problems, including asthma, chronic obstructive pulmonary disease (COPD), acute lung injury, and influenza.

[0010] Myocardial infarction, spinal cord injury, and ischemic injury are associated with inflammation, cell death, and dysfunction of vital organs. Modulation of the S1P receptor can mitigate the pathology by stopping inflammation, rescuing cell death (Schabbauer G. et al., Arterioscler Thromb Vasc Biol, 2004, 24, 1963; Wang J. et al., Biomaterials, 2015, 62, 76), improving blood flow, and attracting stem cells to the site of injury, differentiation, and regeneration (Leronimakis et al, Skeletal Muscle, 2013, 3, 20). The use of S1P receptor modulators can be extended to wound healing and regeneration of muscle, bone, and other organs, including successful transplantation (Lia L et al, Cornea, 2014, 33 (4), 398).

[0011] Modulation of the S1P receptor can address several pathological events common to various diseases in humans, animals, and other species (Figure 1). However, its potential as an important drug target is hampered by the occurrence of significant clinical side effects such as lymphopenia and bradycardia. In S1P receptor modulator therapy, there is no causal relationship between lymphopenia and positive treatment outcomes.

[0012] Many multiple sclerosis disease-modifying therapies result in corresponding decreases in circulating T lymphocytes and B lymphocytes. However, the degree of lymphopenia in peripheral blood was not associated with positive treatment outcomes of FTY720 in patients with relapsing-remitting multiple sclerosis (RRMS) (Fragoso YD et al, Multiple Sclerosis and Related Diseases, 2018, 19, 105-108 and references therein).

[0013] Another study in an animal model of multiple sclerosis (MS) showed no association between lymphopenia and treatment outcomes. Immediately after discontinuation of FTY720 administration, disease scores improved, while the severity of lymphopenia persisted. After discontinuation of drug treatment, clinical signs reappeared in mice several days later, and disease scores relapsed to similar levels as seen in untreated controls (M. Webb et al., Journal of Neuroimmunology, 2004, 153, pp 108-121). Therefore, high levels of lymphopenia observed after treatment of autoimmune diseases such as multiple sclerosis with S1P modulators appear to be unrelated and an undesirable side effect.

[0014] Lymphopenia can lead to changes in the immune system, contributing to undesirable adverse effects (Pierre-Eric Juifa PE. et al, Expert opinion on drug metabolism & toxicology, 2016, 12, (8), 879-895). This can ultimately lead to the discontinuation or cessation of S1P drug therapy (Johnson TA, Clinical Immunology, 2010, 137, 15-20), and subsequently, an increased risk of disease symptom recurrence or rebound in disease activity (Joachim B. Havla et al, Arch Neurol, Feb 2012, Vol 69, No.2).

[0015] Separately, recent studies suggest that the effect is not related to lymphocytes or immune cells, but rather to the direct effects of modulation of S1P1 receptors and / or activation of S1P receptors in various cells and organs that appear to be associated with therapeutic efficacy.

[0016] In animal models of kidney disease, disease symptoms were significantly reduced by both S1P1 modulators FTY720 and SEW2871, but only FTY720 was associated with a decrease in total lymphocyte levels, suggesting that its effect is independent of lymphopenia (Awad A et al, Kidney Int., 2011, 79(10), 1090-1098). In another animal model of acute kidney disease (AKI), endothelial S1P1 activation was found to be necessary to protect against IRI and enable recovery from AKI (Perry HM et al, Am Soc Nephrol, 2016, 27, 3383-3393). Similarly, in animal models of neuropathy, the direct effect of S1P1 modulation on astrocytes is associated with the efficacy of neuropathy. The cellular and molecular mechanisms involving the S1PR1 axis in neuropathic pain establish S1PR1 as an important target for therapeutic intervention through S1PR1 modulation as a class of non-narcotic analgesics (Chen Z et al, PNAS, 2019, vol. 116, no. 21, 10557-0562).

[0017] Another study linked the direct effect of S1P1 modulation on astrocytes to efficacy in multiple sclerosis. This data identifies a non-immunological CNS mechanism of FTY720 efficacy and suggests that the S1P signaling pathway within the CNS is a target for multiple sclerosis treatment (Choi JW et al, PNAS, 2011, vol. 108, no. 2, 751-756). S1P1 receptor activity is associated with FTY720-mediated myelination processes and MS disease relief (Sheridan GK et al, GLIA, 2012, 60:382-392; Cho JW et al, PNAS, 2011, 108, 2, 751). Local administration of FTY720 achieved the opposite effect, promoting demyelination, and the drug was unsuccessful in primary progressive multiple sclerosis, a more neurodegenerative form of MS (Hu Y et al, Molecular and Cellular Neuroscience, 2011, 48, 72-81; Lublin F et al, Lancet, 2016, 387, 1075-84). This adverse effect may be due to potent S1P1 receptor degradation by FTY720.

[0018] Direct effects on endothelial cells were associated with efficacy in animal models of influenza. Cytokine storms during viral infection are predictors of morbidity and mortality, but their cellular source remains undefined. The S1P1 receptor is expressed in endothelial cells and lymphocytes in lung tissue, and in this study, S1P1 regulation in these cells suppressed cytokine release and innate immune cell recruitment in wild-type lymphocyte-deficient mice, identifying endothelial cells as the central regulator of cytokine storms (Teijaro JW et al, Cell, 2011, 146, 980-991).

[0019] Suppression of the S1P1 receptor in cytokine storms may also be valuable in managing viral symptoms. S1P modulator therapy alone has been shown to have higher clinical efficacy compared to antiviral therapy alone against pathogenic influenza virus in mice (82% mortality vs. 50% mortality). Furthermore, a combination of both S1P1 modulation and antiviral therapy nearly completely prevented mortality (96%) (Walsh KB, PNAS, 2011, 12018-12023).

[0020] The modulation of S1P1 receptors is also involved in bone regeneration (Yang-Hee Kim et al, Biomaterials, 2014, 35 (1), 214-224), muscle healing (Nicholas Ieronimakis et al, Ieronimakis et al. Skeletal Muscle 2013, 3:20), nerve regeneration (Safarian et al, J Mol Neurosci, 2015, 56, 177), and pain relief (Stockstill et al, J Pain, 2014, 15(4), S60).

[0021] S1P1 modulation is desirable in several cardiovascular and neurological diseases due to its ability to exert a direct effect on endothelial cells and / or nerve cells, but lymphopenia is another undesirable side effect, as it does not play a role in treating these conditions and instead hinders continued treatment.

[0022] Therefore, there is a need for improved S1P1 modulators that cause only low levels of lymphopenia and can thus be safely used, for example, in immune-mediated and / or cardiovascular and / or neurological symptoms.

[0023] Bradycardia is another common and serious side effect of current S1P therapy. Human clinical trials evaluating S1P1 modulators, including the drug FTY720, have frequently reported induction of bradycardia upon first administration (Bigaud M. et all, Biochimica et Biophysica Acta 2014, 1841, 745-758 and references therein; Pierre Eric J et al, Expert Opinion on Drug Metabolism & Toxicology, 2016, VOL. 12, NO. 8, 879-895; Pierre Eric J et al, Int. J. Mol. Sci. 2017, 18, 2636; Tran JQ et al, The Journal of Clinical Pharmacology, 2017, 00(0), 1-9; US 2019 / 0091180 A1; Siponimod: USOO8492441 B2, July 2013; Abstract Presented at the 13th Congress of the European Crohn's and Colitis Organization (ECCO), February 14-17, 2018, Vienna, Austria).

[0024] Therefore, to mitigate or reduce potential side effects, a dose titration strategy is typically required, starting with a low dose below the therapeutic dose during the initial days of administration, and then steadily increasing the dose level to the standard daily therapeutic dose after several days. However, this dose titration strategy wastes a total of treatment days at the therapeutic dose level.

[0025] Observation of bradycardia after S1P receptor therapy may lead to the prohibition of use in patients with a history of heart failure, arrhythmias, high-grade atrioventricular block, sick sinus syndrome, syncope episodes, or those who do not experience these conditions during antiarrhythmic treatment. Furthermore, dose escalation is not a reasonable option for patients with acute symptoms requiring urgent therapeutic doses, such as those in emergency situations, sepsis, stroke, or organ injury.

[0026] Bradycardia and lymphopenia are evident in S1P1 modifier therapy, but these two events are independent and unrelated, as demonstrated in studies using the clinical compound GSK2018682. In single-dose sessions, doses of 2 mg or less of GSK2018682 induced minimal or no lymphopenia beyond the normal range of diurnal variation (up to approximately 20%), but bradycardia was evident at this dose level, with heart rate decreasing by 10 beats or more. (Xu J et al, Clinical Pharmacology in Drug Development, 2014, 3(3) 170-178).

[0027] Furthermore, it has been reported that the observation of bradycardia by S1P1-selective agonists exhibits species specificity. S1P1 receptor-selective agonists do not induce bradycardia in rodents, but S1P1-selective agonists tested in humans caused significant bradycardia in patients (Juif PE. et al, Int. J. Mol. Sci. 2017, 18, 2636; doi:10.3390 / ijms18122636; Pali L. et al, Pharmacol Res Perspect, 2017; e00370. wileyonlinelibrary.com / journal / prp2 | 1 of 12; Rey M et al, PLOS ONE, September 2013 | Volume 8 | Issue 9 | e74285). This suggests that the behavior of S1P modulators in humans is unpredictable, and results from animal experiments cannot be easily applied to humans.

[0028] Therefore, there is a need for improved administration regimens of S1P receptor modulators that do not cause serious side effects such as bradycardia and / or lymphopenia, even with long-term administration.

[0029] There are further unmet needs for improved administration and safer use of S1P receptor modulators in the treatment of diseases, particularly inflammation, immune-mediated disorders, and vascular or neurological disorders. This disclosure addresses one or more of these unmet needs.

[0030] References in this Specified Publication (or information derived therefrom) or known matters shall not, and should not, be construed as, an endorsement, permission, or any suggestion in any way that such prior publication (or information derived therefrom) or known matters form part of the common general knowledge in the field of the efforts relating to this Specified Publication. [Overview of the Initiative]

[0031] This disclosure relates to pharmaceuticals comprising S1P receptor modulators for the treatment of diseases, particularly inflammatory, immune-mediated disorders, vascular disorders, and neurological disorders, as well as advantageous administration regimens for such pharmaceuticals. While S1P receptor modulators are currently used to treat inflammatory or painful diseases or disorders, administrations and regimens associated with such modulators cause serious side effects, such as bradycardia and prolonged moderate to severe lymphopenia.

[0032] Bradycardia, as understood by those skilled in the art, is a heart rate slower than normal. It may vary from person to person, for example, as a result of age or physical condition. However, a skilled professional, such as a physician, would be able to easily determine if a patient has bradycardia. A normal adult's resting heart rate is 60–100 beats per minute (bpm). In a patient with average bradycardia and good health and physical condition, the heart rate is less than 60 beats per minute.

[0033] Lymphopenia, also known as lymphocytopenia, is a condition in which the number of lymphocytes in the bloodstream is lower than normal. As is understood by those skilled in the art, when adjusted for age, a diagnosis of lymphopenia means a blood lymphocyte count of less than 1,500 cells / microliter. Infants and children have a higher lymphocyte count, so in this case, a count of less than 3,000 cells / microliter is considered too low.

[0034] While prior art S1P receptor modulator therapies frequently require dose escalation strategies, the methods and pharmaceuticals comprising S1P receptor modulators disclosed herein can advantageously initiate treatment immediately at therapeutic dose levels and offer other benefits, including improved clinical safety, patient satisfaction, and compliance. Furthermore, the methods and pharmaceuticals comprising S1P receptor modulators disclosed herein can mitigate or reduce lymphopenia, thereby avoiding undesirable immunosuppression that could pose a threat to opportunistic infections or cancer.

[0035] Furthermore, concerns regarding the side effects of prior art S1P receptor modulators or agonists may limit the safer use of S1P modulators for non-autoimmune signs, such as vascular or neurological signs. Prior art S1P receptor modulators or agonists may reduce cardiac rhythm and induce bradycardia that persists for several hours after administration. As a result of this side effect, S1P receptor modulator or agonist therapy may need to be initiated under strict medical supervision to ensure that cardiac rhythm is maintained at an acceptable level. This may involve hospitalization of the patient and make the treatment more expensive and complex. In the treatment of other signs, topical or other applicable routes of administration of prior art S1P receptor modulators or agonists may be limited to sub-therapeutic levels due to these side effects (e.g., limited area and / or limited dose level).

[0036] One aspect of the present disclosure provides a method for treating or preventing a disease or disorder, comprising administering to a patient in need of treatment or prevention a medicament comprising a therapeutically effective amount of an S1P receptor modulator, wherein the medicament reduces the heart rate of the subject by approximately 5 beats / min or less per day, or approximately 4 beats / min or less per day, or approximately 3 beats / min or less per day, or approximately 2 beats / min or less per day, and the S1P receptor modulator is administered in an initial daily dose substantially identical to a standard daily therapeutic dose.

[0037] In another aspect of the present disclosure, a therapeutically effective amount of an S1P receptor modulator for use in the treatment or prevention of a disease or disorder is provided, wherein the pharmacopoeia reduces the target heart rate by approximately 5 beats / min or less per day, or by approximately 4 beats / min or less per day, or by approximately 3 beats / min or less per day, or by approximately 2 beats / min or less per day, wherein the S1P receptor modulator is administered in an initial daily dose substantially identical to a standard daily therapeutic dose.

[0038] In a further embodiment, a use is provided for the use of a therapeutically effective amount of an S1P receptor modulator in the preparation of a medicament for treating or preventing a disease or disorder, wherein the medicament reduces the target heart rate by about 5 beats / min or less per day, or by about 4 beats / min or less per day, or by about 3 beats / min or less per day, or by about 2 beats / min or less per day, wherein the S1P receptor modulator is formulated for administration at an initial daily dose substantially identical to a standard daily therapeutic dose.

[0039] Preferably, the SIP receptor modulator is a compound represented by formula (I) shown herein, most preferably, [ka] That is the case.

[0040] As used herein in each aspect and embodiment described throughout, the term “initial daily dose” means the first dose level to which the S1P receptor modulator is administered to a patient. As used herein, the term “standard daily therapeutic dose” means a dose level sufficient to deliver a therapeutically effective amount of the S1P receptor modulator to a patient.

[0041] The standard daily therapeutic dose may be delivered by injection, orally, topically, or via medical devices involving various systemic exposures to the patient. The standard daily therapeutic dose may also mean a dose level sufficient to control symptoms or effectively halt disease progression in a patient. The term “substantially identical” means two values ​​that are similar or identical, but is understood to encompass a normal range of acceptable values ​​in the art. For example, this may be within two standard deviations of the mean dose.

[0042] In some embodiments, the difference between the initial daily dose and the standard daily therapeutic dose is less than 25%, less than 15%, less than 10%, or less than 5%.

[0043] In some embodiments, the initial daily dose is the same as the standard daily therapeutic dose.

[0044] Typically, in prior art S1P receptor modulators, the initial daily dose may be much lower than the standard therapeutic dose and may be increased stepwise or only once until the standard therapeutic dose is reached. Advantageously, this disclosure provides a method for initiating a dose at or slightly below the standard therapeutic dose without the occurrence of side effects associated with prior art S1P receptor modulator therapy.

[0045] In some embodiments, the standard daily therapeutic dose of the S1P receptor modulator is up to 70 mg via oral or injectable administration, and up to 3 g topically.

[0046] In some embodiments, the standard daily therapeutic dose of the S1P receptor modulator is up to 24 mg, administered orally or by injection.

[0047] In some embodiments, the standard daily therapeutic dose of the S1P receptor modulator is 0.5 mg to 12 mg via oral administration or injection, preferably ≤ 6 mg per day orally.

[0048] In some embodiments, the administration of the drug does not cause a substantial decrease in heart rate.

[0049] In some embodiments, the administration of the pharmacopoeia does not cause bradycardia. Accordingly, in another embodiment of the present invention, a method is provided for preventing or improving the risk of bradycardia in a subject who has received a pharmacopoeia comprising a therapeutically effective amount of an S1P receptor modulator, wherein the pharmacopoeia reduces the subject's heart rate by about 5 beats / min or less per day, or about 4 beats / min or less per day, or about 3 beats / min or less per day, or about 2 beats / min or less per day, wherein the S1P receptor modulator is administered in an initial daily dose substantially identical to a standard daily therapeutic dose.

[0050] In a further embodiment of the present invention, a method is provided for preventing or reducing lymphopenia in a subject who has received a pharmacopoeia comprising a therapeutically effective amount of an S1P receptor modulator, wherein the pharmacopoeia reduces the subject's heart rate by approximately 5 beats / min or less per day, or approximately 4 beats / min or less per day, or approximately 3 beats / min or less per day, or approximately 2 beats / min or less per day, wherein the S1P receptor modulator is administered in an initial daily dose substantially identical to a standard daily therapeutic dose.

[0051] In some embodiments, the level of lymphopenia is ≤25%.

[0052] In some embodiments, the level of lymphopenia is ≤50%.

[0053] In some embodiments, the level of lymphopenia is ≤70%.

[0054] Preferably, the SIP receptor modulator in the above-described aspects and embodiments of the present invention is a compound represented by formula (I) shown herein, most preferably, [ka] That is the case.

[0055] Furthermore, the compounds represented by formula (I) of the present invention are effective in treating or preventing pruritus. Pruritus, as understood by those skilled in the art, is itching, particularly of the skin, which can have many causes particularly relevant to the present invention and may be pruritus as a result of psoriasis, dermatitis, nodular prurigo and other conditions. Accordingly, a method is provided for preventing or treating pruritus, comprising administering a pharmacopoeia, preferably as a topical pharmacopoeia, containing an effective amount of an S1P receptor modulator to a subject in need thereof. More preferably, the SIP receptor modulator is a compound represented by formula (I) as shown herein, most preferably, [ka] If the treatment is successful, the itching in the affected area will be improved, reduced in severity, or disappear. Prophylactic administration of a drug containing an effective amount of S1P receptor modulator can prevent the onset or progression of itching.

[0056] Furthermore, the compounds represented by formula (I) of the present invention are effective in treating or preventing pain, particularly neuropathic pain, arthritis pain, and wound pain. Accordingly, a method is also provided for preventing or treating pain, preferably neuropathic pain, myalgia, and wound pain, comprising administering to a subject in need a pharmacopoeia, preferably orally or topically, containing an effective amount of an S1P receptor modulator. More preferably, the SIP receptor modulator is a compound represented by formula (I) as shown herein, most preferably, [ka] That is the case.

[0057] The compounds represented by formula (I) of the present invention have also been found to be useful in the treatment of acne and rosacea. Acne, also known as acne vulgaris, is characterized by inflammatory papules and pustules on the skin as a result of clogged hair follicles. Rosacea may be characterized by similar, pus-filled bumps. The inventors have demonstrated that the compounds represented by formula (I) of the present invention are effective in the treatment of acne and / or rosacea. Accordingly, a method for treating either or both acne and rosacea is also provided, comprising administering a pharmacopoeia, preferably as a topical pharmacopoeia, containing an effective amount of an S1P receptor modulator to a subject in need thereof. More preferably, the SIP receptor modulator is a compound represented by formula (I) as shown herein, most preferably, [ka] That is the case.

[0058] Most preferably, represented by formula (I) shown herein. [ka] SIP receptor modulators can also be used in pharmaceuticals for treating or preventing pruritus, or for treating or preventing pain, or for treating acne and / or rosacea. Similarly, in the preparation of pharmaceuticals for treating or preventing pruritus, or pharmaceuticals for treating or preventing pain, or pharmaceuticals for treating acne and / or rosacea, compounds represented by formula (I) shown herein, most preferably [ka] The use of SIP receptor modulators is provided.

[0059] The inventors have also made the surprising finding that the compound represented by formula (I) of the present invention can inhibit mold growth. Accordingly, in an alternative embodiment of the present invention, a method is provided for inhibiting or preventing mold growth, comprising administering a composition comprising an effective amount of an S1P receptor modulator. The composition may be administered to an animal or plant subject on which mold growth occurs. In one embodiment of this aspect of the present invention, the method treats or prevents a condition or disease caused by mold, which is inhibited by the compound of the present invention. The disease or condition may be that of an animal or a plant. The mold may be, for example, Rhizopus stolonifera.

[0060] In some embodiments, as described above, the S1P receptor modulator is of formula (I): [ka] [In the formula, R1 is selected from the group consisting of hydrogen, deuterium, halogen, CN, CF3, -COOH, amide, sulfonamide, alkoxy, aryloxy, nitro, and C1-6 alkyl groups, wherein the alkyl group may be deuterium, O, S, NR'(R'=H, alkyl, cycloalkyl), halogen, carbon-carbon double bond, carbon-carbon triple bond, carbon-nitrogen double bond, carbon-nitrogen triple bond, heterocycle, aryl, alkyl and cycloalkyl(C 3-7) including one or more of the following; R2 is selected from the group consisting of hydrogen, deuterium, halogen, CN, CF3, nitro, alkoxy, aryloxy, and C1-4 alkyl groups, wherein the alkyl group may include deuterium, O, S, NR' (R'=H, alkyl, cycloalkyl), halogen, carbon-carbon double bond, carbon-carbon triple bond, carbon-nitrogen double bond, carbon-nitrogen triple bond, heterocycle, aryl, and C 3-7 Containing one or more cycloalkyl groups; R3 is hydrogen, deuterium, halogen, alkoxy, aryloxy, C 1-6 Selected from the group consisting of alkyl groups, the alkyl group may include one or more of deuterium, O, S, NR' (R'=H, alkyl, cycloalkyl), halogen, carbon-carbon double bond, carbon-carbon triple bond, carbon-nitrogen double bond, carbon-nitrogen triple bond, heterocycle, aryl, alkyl, and C3-7 cycloalkyl; R4 is hydrogen, deuterium, halogen, CN, CF3, C 1-4 Selected from the group consisting of alkyl groups, the alkyl group may include deuterium, O, S, NR' (R'=H, alkyl, cycloalkyl), halogen, carbon-carbon double bond, carbon-carbon triple bond, carbon-nitrogen double bond, carbon-nitrogen triple bond, heterocycle, aryl, alkyl, and C 3-7 Containing one or more cycloalkyl groups; A independently represents a carbon or nitrogen atom in each appearance, provided that a single ring has up to two nitrogen atoms; L is hydrogen, deuterium, F, Cl, Br, and C 1-3 Selected from the group consisting of alkyl groups; R is H, COOH, C1-4 alkyl and C 1-4 Selected from the group consisting of hydroxyalkyl groups; R' and R'' are independent of H and C 1-4 Selected from alkyl groups; R''' is selected from OH, -OPO3H2, and physiologically acceptable salts; symbol: [ka] represents an arbitrary crosslinking group] and is a compound represented by or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, R3 is selected from the group consisting of Me, OMe, OEt, OPr, O-iPr, O-isobutyl, O-isopentyl, O-cyclopentyl, O-allyl and O-benzyl.

[0062] In some embodiments, the S1P receptor modulator is of formula (II): [Chemical formula] [wherein, R1 is selected from hydrogen, deuterium, halogen, CN, CF3, -COOH, amide, sulfonamide, alkoxy, aryloxy, nitro and an alkyl chain (C1-5), and the alkyl chain may optionally contain one or more of deuterium, O, S, NR' (R' = H, alkyl, cycloalkyl), halogen, multiple bonds, heterocycles, aryl, cycloalkyl (C 3-7 ) and one or more of carbocyclic rings; [[ID=2​​​​​​​​​3-7 ) including one or more of the following; L is hydrogen, deuterium, F, Cl, Br and alkyl(C) 1-3 ) Selected from] It is a compound represented by [the formula shown].

[0063] In some embodiments, in the compound represented by formula (II), R1 is selected from F, Cl, Br, CN, CF3, NO2, Me, OMe, OEt, OPr, O-iPr, O-isobutyl, O-isopentyl, O-cyclopentyl, O-allyl, O-benzyl; R2 is selected from H, deuterium, F, Cl, Br, CN, CF3, NO2, Me, OMe, OEt, OPr, O-iPr, O-isobutyl, O-isopentyl, O-cyclopentyl, O-allyl, O-benzyl; R3 is selected from H, deuterium, Pr, butyl, OMe, OEt, OPr, OiPr, O-isobutyl, O-isopentyl, O-butyl, O-pentyl, O-cyclopentyl, O-allyl, O-benzyl; R4 is selected from H, deuterium, Me and Et; and L is selected from H, deuterium, Me, and Cl.

[0064] In some embodiments, in the compound represented by formula (II), R1 is selected from F, Cl, Br, CN, CF3, Me, NO2, OMe, OEt, OPr, O-iPr, O-isobutyl, O-isopentyl, O-cyclopentyl, O-allyl, O-benzyl; R2 is H; R3 is selected from H, deuterium, Pr, butyl, OMe, OEt, OPr, OiPr, O-isobutyl, O-isopentyl, O-butyl, O-pentyl, O-cyclopentyl, O-allyl, O-benzyl; R4 is selected from H, deuterium, Me and Et; and L is H.

[0065] In some embodiments, the subject is a mammal or a bird, preferably a human.

[0066] In some embodiments, the pharmaceutical agent is administered to a subject who has previously received treatment with another S1P1 modulator or agonist, and / or the patient has now discontinued or stopped treatment with the other S1P modulator or agonist.

[0067] In some embodiments, the interruption or cessation of the procedure is due to bradycardia and / or lymphopenia events.

[0068] In some embodiments, the pharmaceutical product is in the form of a topical formulation selected from, for example, a solid, patch, powder, liquid, semi-solid, ointment, gel, spray, aerosol, inhaler, and lotion.

[0069] In some embodiments, the pharmaceutical product is, for example, an oral formulation, an injectable formulation, or a systemic formulation selected from pills, tablets, capsules, solutions, and syrups.

[0070] In some embodiments, the disease or disorder is an inflammatory-mediated or immune-mediated disorder selected from the group consisting of, for example, psoriasis, eczema, vitiligo, nodular prurigo, acne, rosacea, alopecia, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, gout, stroke, hemorrhoids, lung injury, liver injury, acute kidney injury, asthma, chronic obstructive pulmonary disease (COPD), uveitis, macular degeneration, glaucoma, otitis, allergy, sepsis, influenza, rhinitis, itch, and pruritus.

[0071] In some embodiments, the disease or disorder is pruritus, and preferably the pharmacopoeia is an oral or topical formulation of a compound represented by formula (I) as shown herein.

[0072] In some embodiments, the disease or disorder is acne, and preferably the pharmaceutical is a topical formulation of a compound represented by formula (I) as shown herein.

[0073] In some embodiments, the disease or disorder is rosacea, and preferably the pharmacopoeia is a topical formulation of a compound represented by formula (I) as shown herein.

[0074] In some embodiments, the disease or disorder is a vascular disorder selected from the group consisting of, for example, aneurysms, strokes, retinopathy, nephropathy, sepsis, kidney injury or liver injury, and dilated blood vessels.

[0075] In some embodiments, the disease or disorder is an autoimmune disorder selected from the group consisting of, for example, multiple sclerosis and psoriasis.

[0076] In some embodiments, the disease or disorder is selected from the group consisting of vascular disorders or central nervous system (CNS) disorders, such as Parkinson's disease, Alzheimer's disease, motor neuron disorders, Huntington's disease, multiple sclerosis, and neuropathy.

[0077] In some embodiments, the subjects are prone to heart failure, arrhythmias, high-grade atrioventricular block, sick sinus syndrome, and have a history of syncope episodes or a combination thereof.

[0078] In some embodiments, the subject is receiving antiarrhythmic treatment by administering a beta-blocker or an antiarrhythmic drug.

[0079] In some embodiments, the subject has previously undergone interruption or discontinuation of treatment with another S1P receptor modulator / agonist. Such discontinuation may last for more than 4, 6, 8, 10, 12, or 14 days.

[0080] In some embodiments, the pharmaceutical product is administered topically, orally, transdermally, non-enterally, intranasally, into the eye, or rectally.

[0081] In some embodiments, the pharmaceutical product is a sustained-release formulation administered topically by implantation, injection, or via a medical device.

[0082] In some embodiments, the pharmaceutical product is applied topically.

[0083] In some embodiments, the pharmaceutical product contains the S1P receptor modulator in an amount of 0.01% to 30% by weight.

[0084] In one particular embodiment, the pharmaceutical product contains an S1P receptor modulator in an amount of about 3% by weight.

[0085] In some embodiments, the pharmaceutical product contains up to 300 cm³ per gram of pharmaceutical formulation with varying potencies (i.e., 0.1% to 30% ww of active S1P receptor modulators). 2 This applies to the body surface area, where the standard daily therapeutic dose of the S1P receptor modulator is ≤3 g. In a particular embodiment, the standard daily therapeutic dose of the S1P receptor modulator is ≤1.5 g. In another embodiment, the drug provides up to 1000 cm³ per gram of pharmaceutical formulations with varying potencies (i.e., 0.1% to 30% ww of active S1P receptor modulator). 2 It applies to the body surface area.

[0086] In some embodiments, the pharmaceutical agent is used to treat pain selected from the group consisting of joint pain, arthritis pain, gout pain, back pain, muscle pain, neuropathic pain, neuralgia, migraine, cancer pain, sports injury pain, and wound pain.

[0087] In some embodiments, the pharmaceutical comprises, as a composition, an S1P receptor modulator together with one or more other pharmaceutically active compounds selected from, or not limited to, immunosuppressants / immunomodulators, pain modulators, pruritus modulators, neuromodulators, anti-inflammatory substances, antipathogens, antibacterial substances, antiviral substances, and antifungal substances.

[0088] All prior art S1P1 modulators tested in clinical trials or approved as drugs induce bradycardia in humans after initial administration (Bigaud M. et all, Biochimica et Biophysica Acta 2014, 1841, 745-758 and references therein; Pierre Eric J et al, Expert Opinion on Drug Metabolism & Toxicology, 2016, VOL. 12, NO. 8, 879-895; Pierre Eric J et al, Int. J. Mol. Sci. 2017, 18, 2636). The medicaments according to this disclosure may, advantageously, not substantially affect heart rate after single or multiple administrations to humans and may therefore have advantages in treating certain symptoms.

[0089] Accordingly, embodiments of the present disclosure provide a method for treating or preventing a disease or disorder, comprising administering to a subject in need of such treatment or prevention a pharmacopoeia comprising a therapeutically effective amount of an S1P receptor modulator, wherein the administration of the pharmacopoeia does not cause a substantial decrease in heart rate. Preferably, the administration of the pharmacopoeia does not cause bradycardia.

[0090] Further embodiments of the present disclosure provide a method for treating or preventing a disease or disorder, comprising administering to a subject in need thereof a medicament comprising a therapeutically effective amount of an S1P receptor modulator, wherein the level of lymphopenia is between 25% and 70%. In alternative embodiments, the lymphocyte level remains constant.

[0091] According to embodiments of this disclosure, for example, a level of lymphopenia equivalent to 25% means a 25% decrease in peripheral blood lymphocytes from the baseline value before initiating the initial daily dose.

[0092] Severe lymphopenia is a significant side effect of S1P receptor modulator therapy, leading to weakened immune systems and other undesirable side effects (Pierre-Eric Juifa PE. et al, Expert opinion on drug metabolism & toxicology, 2016, 12, (8), 879-895), (Johnson TA, Clinical Immunology (2010) 137, 15-20). Since S1P1 modulators may be useful in other non-autoimmune diseases such as cardiovascular and neurological diseases due to their direct effects on endothelial and neuronal cells, lymphopenia is an undesirable side effect unrelated to treatment outcomes in these conditions, and therefore, S1P modulators that do not cause lymphopenia are needed. The method according to this disclosure results in lymphopenia-free or reduced levels and can be safely used in immune-mediated signs and / or cardiovascular signs and / or neurological signs and / or pruritic signs and / or pain signs, where the preferred daily oral dose for treatment is ≤6 mg.

[0093] In any of the embodiments disclosed herein, the compound represented by formula (I) may be administered in combination with other therapeutically active compounds, such as small molecules, biological substances, antiviral substances, antimicrobial substances, pain modifiers, pruritus modifiers, anticancer drugs, or anti-inflammatory substances.

[0094] Representative examples of compounds represented by formula (I) used in the above-described aspects and embodiments of the present invention include, for example, [ka] [ka] [ka] There is.

[0095] A preferred example of the compound represented by formula (I) is: [ka] That is the case.

[0096] The S1P receptor modulator, for example, the compound of formula (I), may also be in the form of a salt. The salt may be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be obvious to those skilled in the art and include acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, boric acid, or phosphoric acid; and organic acids, such as succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, or naphthalenesulfonic acid, as described in J Pharm Sci, 1977, 66, 1-19. A particular S1P receptor modulator, for example, the compound represented by formula (I), may form an acid addition salt with one or more equivalent amounts of acid. This disclosure includes, within its scope, all possible stoichiometric and non-stoichiometric forms, as well as the free base form.

[0097] The S1P receptor modulators, for example, the compound represented by formula (I), may be prepared in crystalline or amorphous form, and in the case of crystalline forms, they may optionally be hydrates or solvates. The disclosure includes, within its scope, S1P receptor modulators, for example, stoichiometric hydrates or solvates of the compound represented by formula (I), as well as formulations containing variable amounts of water and / or solvent, and all salts, solvates, hydrates, complexes, polymorphs, prodrugs, radiolabeled derivatives, stereoisomers and optical isomers.

[0098] The currently disclosed pharmaceuticals contain an S1P receptor modulator, for example, a compound represented by formula (I), as the sole active ingredient, and may optionally contain one or more inactive ingredients. Alternatively, the pharmaceuticals may contain a composition in which the compound represented by formula (I) is combined with one or more other active ingredients, and optionally inactive ingredients.

[0099] In some embodiments, the pharmacopoeia may include various delivery vehicles, such as pharmacoexistential excipients including stabilizers, carriers, or encapsulated formulations for systemic use (i.e., oral, injection, device) or topical or targeted use (i.e., topical, ear, eye, nasal, oral, non-enteral, rectal). The composition may provide a preferred combination effect between the delivery vehicle and at least one compound selected from one or more groups consisting of, for example, steroids, opioids, and nonsteroidal anti-inflammatory drugs, and cannabinoids such as cannabidiol (CBD). The combined effect may improve treatment and / or prevention and / or immunotherapy compared to S1P receptor modulators, for example, the compound represented by formula (I) alone.

[0100] Other active and inactive ingredients or excipients include, but are not limited to, ointments, gels, hydrogels, solutions, drops, topical patches, transdermal patches, topical liquid preparations, sprays, aerosols, lotions, foams, degradation-controlled polymers, patches, tablets, capsules, oral liquid preparations, powders, granules, lozenges, microparticles, liposomes, nanoemulsions, polymers, microsponges or release-controlled particles such as fullerenes, or injectable or injectable solutions, suspensions or suppositories.

[0101] In another aspect of the present disclosure, a method is provided for treating or preventing a disease or disorder, comprising administering a pharmacopoeia comprising a therapeutically effective amount of an S1P receptor modulator to a subject in need thereof, wherein the pharmacopoeia is administered to a patient who has previously received treatment with another S1P1 modulator or agonist, and / or the patient has now discontinued or stopped treatment with the other S1P modulator or agonist.

[0102] In another aspect of the present disclosure, a therapeutically effective amount of an S1P receptor modulator is provided for use in the treatment or prevention of a disease or disorder, wherein the pharmacopoeia is administered to a patient who has previously received treatment with another S1P1 modulator or agonist, and / or the patient has now discontinued or stopped treatment with the other S1P modulator or agonist.

[0103] In another aspect of the present disclosure, a use is provided for the use of a therapeutically effective amount of an S1P receptor modulator in the preparation of a medicament for treating or preventing a disease or disorder, wherein the medicament is for a patient who has previously received treatment with another S1P1 modulator or agonist, and / or the patient has now interrupted or discontinued treatment with the other S1P modulator or agonist.

[0104] As previously stated, other S1P modifier therapies may result in the occurrence of additional side effects, including cardiovascular abnormalities and lymphopenia. The occurrence of these side effects may necessitate discontinuation of treatment with the S1P modifier or agonist, during which control of the disease or disorder may worsen. Such patients may be treated by the methods described herein instead during this discontinuation period, as the observation of side effects is reduced or none of the side effects are present.

[0105] In some embodiments of this model, the interruption or cessation of the procedure is due to a bradycardia event or a lymphopenia event. In some embodiments, the interruption or cessation of the procedure is due to the occurrence of both a bradycardia event and a lymphopenia event.

[0106] Accordingly, a method is provided for preventing or improving the risk of bradycardia in a subject receiving a pharmacopoeia comprising a therapeutically effective amount of an S1P receptor modulator, wherein the pharmacopoeia is administered to a subject who has previously received treatment with another S1P1 modulator or agonist, and / or the patient has now discontinued or stopped treatment with the other S1P modulator or agonist.

[0107] A method is provided for preventing or reducing lymphopenia in a subject receiving a therapeutically effective dose of a pharmacopoeia containing an S1P receptor modulator, wherein the pharmacopoeia is administered to a subject who has previously received treatment with another S1P1 modulator or agonist, and / or the patient has now discontinued or stopped treatment with the other S1P modulator or agonist.

[0108] Preferably, in each of the above embodiments of the present invention, the pharmacopoeia reduces the heart rate of the subject by about 5 beats / min or less per day, or by about 4 beats / min or less per day, or by about 3 beats / min or less per day, or by about 2 beats / min or less per day, and more preferably, the S1P receptor modulator is administered in an initial daily dose substantially the same as the standard daily therapeutic dose.

[0109] In any of the methods disclosed herein, the pharmaceutical product is for topical use and may be in the form of a liquid formulation, e.g., lotions and solutions (but not limited thereto), a semi-solid formulation, e.g., ointments, gels, foams or creams, sprays and aerosols (but not limited thereto), or a solid formulation, e.g., topical patches (but not limited thereto). The topical delivery system may also include aerosol foams, liposomes, nanoemulsions, polymers, microsponges or fullerenes (Pharma Innovation, 2012, 1(9), 18-31). The topical composition may include a skin penetration enhancer.Examples of skin penetration enhancers include short-chain alcohols, such as dimethyl sulfoxide, dimethyl isosorbide, stearic acid, ethanol, propylene glycol, and isopropanol; long-chain alcohols, such as decanol, hexanol, lauryl alcohol, myristyl alcohol, octanol, octyldodecanol, cetyl alcohol, stearyl alcohol, and oleyl alcohol; cyclic amides, such as azon; and esters, such as ethyl acetate, octyl salicylate, padimate O, ethyl oleate, glyceryl stearate, glyceryl monolate, glyceryl monocaprylate, glyceryl tricaprylate, isopropyl myristate, isopropyl palmitate, and propylene glycol monolaurate. , or propylene glycol monocaprylate; fatty acids, e.g., lauric acid, linoleic acid, myristic acid, oleic acid, palmitic acid, stearic acid, or isostearic acid; glycols, e.g., dipropylene, propylene, 1,2-butylene glycol, or 1,3-butylene glycol; pyrrolidones, e.g., N-methyl-2-pyrrolidone, or 2-pyrrolidone; sulfoxides, e.g., decyl methyl sulfoxide or dimethyl sulfoxide; anionic surfactants, e.g., sodium lauryl sulfate; cationic surfactants, e.g., alkyldimethylbenzylammonium halides, alkyltrimethylammonium halides, alkylpyridinium halides; nonionic surfactants, e.g., Brij 36T or Tween 80; monoterpenes, e.g., eugenol, d-limonene, menthol, menthone; sesquiterpenes, e.g., farnesol or neridol.

[0110] In some embodiments of the present disclosure, inflammation-mediated or immune-mediated disorders may be selected from the group consisting of, but not limited to, psoriasis, eczema, vitiligo, nodular prurigo, alopecia, rheumatoid arthritis, osteoarthritis, gout, hemorrhoids, asthma, chronic obstructive pulmonary disease (COPD), uveitis, retinopathy, nephropathy, macular degeneration, glaucoma, otitis, allergies, sepsis, influenza, rhinitis, and pruritus. In one preferred embodiment of the present disclosure, the disease or disorder is pruritus.

[0111] In some embodiments of this disclosure, the method may be used for transplantation purposes, for example, for transplantation of the cornea, kidney, and liver.

[0112] In some embodiments of this disclosure, vascular disorders may be selected from the group consisting of, but not limited to, aneurysms, vasculitis, stroke, heart attack, ischemic injury, peripheral artery disease, lung injury, liver injury, kidney injury, retinopathy, nephropathy, hemorrhoids, vascular abnormalities, and vasculitis, vascular disorders, aneurysms, chronic wounds, or lower extremity ulcers.

[0113] In some embodiments of this disclosure, the vascular or central nervous system (CNS) disorder may be selected from the group consisting of, but not limited to, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, motor neuron disorders, epilepsy, tension headache, anxiety, ALS, neuromuscular diseases, and neuropathy.

[0114] The disclosure also provides a method for treating or preventing pain, comprising administering a pharmacopoeia to a subject in need of treatment or prevention, wherein the pharmacopoeia comprises a therapeutically effective amount of an S1P receptor modulator according to any one of the embodiments disclosed herein.

[0115] This disclosure also provides therapeutically effective amounts of S1P receptor modulators according to any one embodiment disclosed herein for use in methods of treating or preventing pain.

[0116] This disclosure also provides the use of a therapeutically effective amount of an S1P receptor modulator in any one embodiment disclosed herein in the preparation of a medicament for treating or preventing pain.

[0117] In some embodiments, the disease or disorder is selected from a group consisting of, but not limited to, susceptible heart failure, arrhythmia, high-grade atrioventricular block, sick sinus syndrome, a history of syncope episodes, or a combination thereof.

[0118] In this embodiment, the subject is receiving antiarrhythmic treatment by administering a beta-blocker or an antiarrhythmic drug.

[0119] In this embodiment, the patient is one who has experienced an interruption or discontinuation of treatment from another S1P receptor modulator / agonist. The discontinuation of treatment may exceed 4, 6, 8, 10, 12, or 14 days.

[0120] Prior art S1P receptor modulators / agonists are known to cause bradycardia or lymphopenia, so patients may be required to discontinue treatment to reduce bradycardia or lymphopenia before treatment can be continued. Advantageously, the pharmacopoeia of this disclosure does not cause bradycardia and / or significant lymphopenia, so these patients may subsequently continue treatment with the pharmacopoeia.

[0121] In any of the methods disclosed herein, the pharmaceutical product may be administered in any acceptable mode of administration, for example, topically, orally, intravenously, non-enterally, intranasally, into the eye, or rectally.

[0122] Some embodiments of the methods disclosed herein may be used to treat gastrointestinal problems such as (but not limited to) intestinal inflammation, vascular disorders, wounds, ulcers, hemorrhoids, anal pruritus, ulcerative colitis, and Crohn's disease.

[0123] In any of the methods disclosed herein, the pharmaceutical product may be a sustained-release formulation administered topically, by implantation or injection, or via a medical device. The sustained-release pharmaceutical product may have a desired therapeutic level of S1P receptor modulator at a systemic or topical level. Furthermore, the sustained-release pharmaceutical product may be applied in situ or to the periphery of affected areas, for example, in inflammation, ischemic injury, cancer, tumor, or atherosclerotic lesions.

[0124] When applied topically, sustained-release drugs can be administered without the increased exposure associated with systemic exposure. This process can enhance the overall therapeutic window that might otherwise not be possible through systemic treatment. For example, skin lesions of psoriasis or atopic dermatitis (eczema) may receive the necessary exposure to S1P receptor modulators through direct administration of the drug according to this disclosure to the lesion, whereas systemic treatment may not achieve sufficient therapeutic exposure to S1P receptor modulators.

[0125] The methods described herein may be used, via sustained-release formulations, for example, to treat orally, systemically, or topically to the skin, eyes, ears, nose, lungs, mouth, rectum and anus, or digestive organs. For example, treatment of hypoxia by topical administration of an effective amount of the disclosed medicament to a target requiring treatment, such as in a distant site of cancer. Transplant rejection is often accompanied by inflammation (Lutz et al, J Inflamm (Lond), 2010, 7, 27; Liang J et al, Cornea, 2014, 33 (4), 398). Modulation of the S1P receptor is involved in immune tolerance and correction of vascular structure, and topical administration and optimal exposure, with or without the use of other immunomodulators, may be a promising approach for transplant success. Therefore, a method is provided for treating transplant rejection by topical administration, comprising administering a medicament containing a therapeutically effective amount of an S1P receptor modulator to a target requiring treatment. Modulation of the S1P receptor can yield effective and appropriate responses ranging from immunity against infection (Pinschewer DD et al, Neurology, 2011, 76 (Suppl 3): S15-S19) or cancer (Marcus A et al, Blood, 2011, 118(4), 975) to immune tolerance (Liu G. et al, J Immunol, 2014, 192; Yoshida Y. et al, Biol Pharm Bull, 2011, 34(6), 933) and successful transplantation.

[0126] Topical formulations, tablets, and capsules according to this disclosure for oral administration may be in unit dose form and may contain conventional excipients, such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, hydroxyethyl or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); tableting lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); and acceptable wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated according to methods well known in the field of ordinary medicine. Tablets may be released in a specific organ, such as the stomach or intestine, to deliver an S1P receptor modulator, such as a compound represented by formula (I).

[0127] The topical and oral liquid formulations of this disclosure may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or in the form of dry products for reconstitution with water or other suitable vehicles before use. Such liquid formulations may appropriately contain conventional additives, e.g., suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifiers (e.g., lecithin or acacia), non-aqueous vehicles (which may include edible oils, e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g., methyl-p-hydroxybenzoate or propyl-p-hydroxybenzoate or sorbic acid), and, if necessary, conventional flavorings or colorants, buffer salts and sweeteners. Formulations for topical administration and formulations for oral administration may be appropriately formulated to control the release of S1P receptor modulators.

[0128] For non-enteral administration, a fluid unit dosage form can be prepared using the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a sterile vehicle. The injectable formulation may exist, for example, in ampoules or multi-dose unit dosage forms using the compound represented by formula (I) or a pharmaceutically acceptable derivative thereof and a sterile vehicle, and may optionally contain preservatives. The composition may take the form of a suspension, solution or emulsion in an oily or aqueous vehicle and may contain compounding agents, such as suspenders, stabilizers and / or dispersants. Alternatively, the active ingredient may be in powder form for composition with a suitable vehicle, such as sterile pyrogenic substance-removed water, before use. When preparing a solution, the compound represented by formula (I) can be dissolved for injection, filtered and sterilized, and then filled and sealed in a suitable vial or ampoule. Advantageously, adjuvants, such as local anesthetics, preservatives and buffers, may be dissolved in the vehicle. Surfactants or wetting agents may be included in the composition to promote the uniform distribution of the compound.

[0129] The lotion may be formulated using an aqueous or oily base and may contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners, or colorants. The dropper may be formulated using an aqueous or non-aqueous base and may contain one or more dispersants, stabilizers, solubilizers, or suspending agents. It may also contain preservatives.

[0130] In any of the methods disclosed herein, the pharmaceutical product may also be formulated into a rectal composition such as a suppository or retaining enema, comprising, for example, a conventional suppository base such as cocoa butter or other glycerides. As a depot preparation, such a long-acting formulation may be administered by implantation (e.g., subcutaneous or intramuscular, in situ or peripheral to the site of inflammation and / or injury) or intramuscular injection. It may be formulated with a suitable polymer or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion exchange resin, or as a sparingly soluble derivative, such as a sparingly soluble salt.

[0131] For formulations as controlled-release particles, the required amount of the compound represented by formula (I) may be treated with a polymer, in particular a biodegradable polymer that degrades in vivo enzymatically, non-enzymatically, or both, to produce biocompatible and toxicologically safe byproducts that are further removed by normal metabolic pathways. Such biodegradable polymer options include, but are not limited to, polylactic acid-coglycolic acid (PLGA) polyanhydride, PLAGA, polycaprolactone (PCL), complex sugars (hyaluronan, hitosan), and inorganic compounds (hydroxyapatite). For better delivery formulations, the compound represented by formula (I) may be encapsulated in various types of copolymers of polyester and polyethylene glycol (PEG). PLGA / PEG block copolymers may be used as diblocks (PLGA-PEG) or triblock molecules containing both ABA (PLGA-PEG-PLGA) and BAB (PEG-PLGA-PEG). These drug delivery devices avoid the cumbersome surgical insertion of large implants and can employ injectable, biodegradable, biocompatible PLGA particles (microspheres, microcapsules, nanocapsules, nanospheres) in a controlled-release dosage form. The active ingredient can be released from the polymer device by either diffusion across a polymer barrier, erosion of the polymer material, or a combination of both diffusion and erosion mechanisms.

[0132] For intranasal administration, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof may be formulated alone or as a composition containing other active ingredients, as a solution for administration via a suitable measuring device or unit-dose device, or as a powder mixture with a suitable carrier for administration using a suitable delivery device. Accordingly, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and / or combination thereof may be formulated in a form suitable for oral administration, buccal administration, non-enteral administration, topical administration (including ocular and nasal), depot administration or rectal administration, or for administration by inhalation or blown (either orally or nasally).

[0133] The compound represented by formula (I) or a pharmaceutically acceptable salt thereof may be formulated for topical administration, either alone or in composition with other active ingredients, in the form of ointments, creams, gels, lotions, pessaries, aerosols, or drops (e.g., eye drops, ear drops, or nasal drops). Ointments and creams may be formulated, for example, by adding a suitable thickener and / or gelling agent to an aqueous or oily base. Ointments for ocular administration may be manufactured aseptically using a sterilizing component. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof may be used alone or with other therapeutically active compounds, such as cyclosporine A, methotrexate, steroids, corticosteroids, nonsteroidal anti-inflammatory drugs, inflammatory cytokine inhibitors, kinase inhibitors (e.g., JAK kinase), immunomodulators including biological substances, antiviral substances including or not limited to acyclovir, 5-fluorouracil, ganciclovir, valacyclovir, vidaraamine or zidovudine, and broad-spectrum antiviral substances (Front Microbiol, 2015; 6: 517) It may be used as a combination compound with antibiotics, including but not limited to amoxicillin, cephthaloline, colistin, daptomycin, ertapenem, fosfomycin, penicillin, rapamycin, or tigecycline; or with antifungal substances, including but not limited to amphotericin, liposomal amphotericin B, fluconazole, flucytosine, micafungin, posaconazole, and viriconazole.

[0134] The compound represented by formula (I) or a pharmaceutically acceptable salt thereof may be used alone or in combination preparations according to the present disclosure for the treatment of other diseases or disorders, including but not limited to arteriosclerotic lesions, tumors, kidneys (nephropathy), prostates (prostatitis), urinary tracts (inflammation), pancreas (pancreatitis), colons (colitis), liver (liver disease), deep tissues (neuropathy, inflammation, degeneration), ulcers, wounds, ischemic injuries, bone regeneration, muscle regeneration, treatment of epithelial ulcers, wound healing, therapeutic angiogenesis, and gangrene. The preparation may be administered to the affected area or the area surrounding the affected area.

[0135] The pharmaceuticals according to this disclosure may contain an S1P receptor modulator in an amount of about 0.05% to about 10% by weight, or about 0.5% to about 10% by weight, preferably about 1.0% to about 4.5% by weight, or preferably about 1.5% to about 4.5% by weight. Treatment with a 3% ww topical formulation of 2 g per day for 3 weeks provided an average systemic exposure of about 2.5 ng / mL, while oral administration at 8 mg per day for 1 week provided an average systemic exposure of about 53 ng / mL without events of bradycardia and significant lymphopenia. The dose of the S1P receptor modulator used to treat the disorder typically varies depending on the severity of the disorder, the body weight of the person suffering, and other similar factors. In a preferred embodiment, the pharmaceutical contains 100 cm³ per gram of pharmaceutical. 2 Applies to the surface area of ​​the body, with a maximum of 1000 cm² per gram of medicine. 2 The drug is applied to the body surface area. The drug can be applied so that the standard daily therapeutic dose of the active compound is ≤3 g. The local administration level and potency of the formulation having the compound represented by formula (I) can be extended to higher levels without the risk of bradycardia and lymphopenia. For example, the administration levels of the drug by the method of this disclosure may include up to the following: 1. A 10g daily dose can contain up to 30% ww potency, and 1g can contain up to 300cm³. 2 surface area 2. A 10g daily dose can contain up to 30% ww potency, and 1g can contain up to 1000cm³. 2 surface area 3. A 10g daily dose can contain up to 3% ww potency, and 1g can contain up to 300cm³. 2 surface area 4. A 10g daily dose can contain up to 3% ww potency, with a maximum of 1000cm³ per gram. 2 surface area 5. Maximum daily dose of 300g is 1% ww potency, with a maximum of 300cm³ per 1g. 2 surface area. 6. A 300g daily dose can contain up to 1% ww potency, with a maximum of 1g containing 1000cm³ of active ingredient. 2 surface area

[0136] According to the method of this disclosure, the disease or disorder may be pain selected from the group consisting of, but not limited to, neuralgia, migraine, nociceptive pain, neuropathic pain, inflammatory pain, wound pain, tension headache, herpes neuralgia, myalgia, arthralgia, back pain, wound pain, sports injury pain, etc.

[0137] The aforementioned pharmaceutical product can be formulated as a sustained-release formulation to release up to 70 mg of the active compound per day. [Brief explanation of the drawing]

[0138] [Figure 1] Figure 1 shows various S1P receptor regulatory pathways.

[0139] [Figure 2] Figure 2 shows the effect of the compound represented by formula I on markers of inflammation and pruritus.

[0140] [Figure 3] Figure 3 shows the effect of the compound represented by formula I on the pruritus score.

[0141] [Figure 4] Figure 4 shows the effect of a 12 mg dose of the compound represented by formula I on human heart rate over 72 hours.

[0142] [Figure 5] Figure 5 shows the antifungal activity of a solution of the compound represented by formula I.

[0143] [Figure 6] Figure 6 shows the effects of the compound represented by formula I on the secretion of cytokines TNFα and IL6.

[0144] [Figure 7] Figure 7 confirms that the compound represented by formula (I) did not inhibit or impair wound healing.

[0145] Detailed description of the embodiment The following is a detailed description of the disclosure provided to assist those skilled in the art in implementing this disclosure. Those skilled in the art can modify and adapt the embodiments described herein without departing from the spirit or scope of the disclosure.

[0146] Any methods and compositions similar or equivalent to those described herein may also be used in the implementation or testing of this disclosure. Preferred methods and compositions are described herein.

[0147] Furthermore, it should be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include multiple references unless otherwise specified. Therefore, for example, a reference to "S1P receptor modulator" may include more than one S1P receptor modulator.

[0148] Throughout this specification, the use of the terms “comprises” or “comprising” or their grammatical variations thereof is deemed to identify the presence of the features, integers, processes, or components described, but does not preclude the presence or addition of one or more other features, integers, processes, components, or groups thereof that are not identified.

[0149] Unless otherwise specified or made clear from the context, the term “about” as used herein is understood to mean within the normal tolerance range in the art, for example, within two standard deviations of the mean. “About” may be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless made clear from the context, all numerical values ​​provided herein and in the claims may be modified by the term “about.”

[0150] Any method provided herein may be combined with any one or more of the other methods provided herein.

[0151] The ranges provided herein are understood to be abbreviations for all values ​​within that range. For example, the range 1–50 is understood to include any number, combination of numbers, or subrange from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.

[0152] Next, exemplary embodiments of the Disclosure will be described in detail. The detailed examples and embodiments described herein are given illustratively for illustrative purposes only and should not be considered to limit the Disclosure. [Examples]

[0153] The compound represented by formula (I) used in the following examples is: [ka] That's what I decided.

[0154] Example 1: Activity in the sphingosine-1-phosphate (S1P) receptor The compound represented by formula (I) showed S1P receptor activity, particularly type 1 receptor agonist activity. The S1P1 assay system used membrane-bound GTPgama-S from CHO K1 cells expressing the human S1P1 receptor. 35 The compounds were tested, and concentration-response (administration response) curves were created for these receptors. The analysis showed that the efficacy of the selected compound represented by equation (I) for S1P was (E max ) and effect (EC 50 ) provides EC in the S1P1 receptor 50It was demonstrated that the concentration is <2nM. The compound represented by formula (I) has a low tendency to degrade the S1P1 receptor. The compound represented by formula (I) is selective for S1P2, S1P3, S1P4, and S1P5 receptors.

[0155] In comparison, the endogenous ligand S1P and the drug FTY-720 are active on the S1P1 receptor, with EC50 nM values ​​of 1.2 nM and 2 nM, respectively, in the GTPγS assay, while their receptor degradation capabilities are 302 nM and 0.34 nM, respectively (Lucas et al, Journal of Biomolecular Screening, 2013, 1-10 pp). Known S1P receptor modulators have low activity vs. degradation margins (FTY720=0.17; BAF-312=2.95, ponesimod<2), while the compound represented by formula (I) has a margin of over 100 (Samuvel J et al, PLOS ONE, 2015, | DOI:10.1371 / journal.pone.0141781; Piali L et, JPET, 2011, 337, 547-556; Lucas S et al, Journal of Biomolecular Screening, 2014, Vol. 19(3) 407 -416; Gatfield J et al, Immunomodulation, 28th ECTRIM, 10-13 October, 2012, Lyon, France).

[0156] Example 2: Correlation between lymphopenia and systemic exposure of the compound represented by formula (I) in humans and mice. In humans, treatment with the compound represented by formula (I) (at a dose of approximately 0.17 mg / kg) resulted in a systemic exposure of 18.8 ng / mL, without inducing significant lymphopenia. In contrast, in mice, treatment with the compound represented by formula (I) (at a dose of 0.3 mg / kg) resulted in a systemic exposure of 6.36 ng / mL, and a 40% lymphopenia was measured 6 hours after administration. This is surprising and suggests that the association between lymphopenia and systemic exposure to S1P receptor modulators such as the compound represented by formula (I) differs between mice and humans.

[0157] It is noteworthy that the delivery of the compound represented by formula (I) results in dose-proportional systemic exposure. When the compound represented by formula (I) was administered at a dose of 8 mg per day for one week, lymphopenia was measured in a maximum of only 40%, which was 16 times higher than the equivalent FTY720 therapeutic dose in humans.

[0158] Example 3: Effect of the compound shown in formula (I) on heart rate in vivo In humans, treatment with the compound represented by formula I resulted in dose-proportional increases in systemic exposure: 0.5 mg = 0.6 ng / mL; 2 mg = 2.4 ng / mL; 6 mg = 7.1 ng / mL; 12 mg = 18.8 ng / mL. However, there were no dose-proportional or dose-related bradycardia events, which are common side effects observed with prior art S1P1 modulators / agonists, such as a decrease in heart rate that lasts for several hours.

[0159] Species-specificity has been reported in the observation of bradycardia by S1P1-selective agonists. S1P1 receptor-selective agonists do not induce bradycardia in rodents, but S1P1-selective agonists tested in humans caused significant bradycardia in patients (Juif PE. et al, Int. J. Mol. Sci. 2017, 18, 2636; doi:10.3390 / ijms18122636; Pali L. et al, Pharmacol Res Perspect, 2017; e00370. wileyonlinelibrary.com / journal / prp2 | 1 of 12; Rey M et al, PLOS ONE, September 2013 | Volume 8 | Issue 9 | e74285). Surprisingly, the S1P1 receptor modulator represented by formula (I) did not induce bradycardia in humans when tested at different dose levels ranging from 0.5 mg to 12 mg (data for 12 mg shown in Figure 4).

[0160] Example 4: Efficacy of the compound represented by formula (I) in an animal model of excision wounds Two groups, each containing six Wistar rats, were anesthetized with ketamine at a dose of 80 mg / kg (ip), and the backs of the animals were shorn. A total skin thickness of 600-700 mm was shorn from a designated area. 2 A single excision wound was created by cutting off a fragment (with a sterile scalpel). The wound was left exposed in an open environment. Rats in Group 1 were untreated and served as a sham control. Animals in Group 2 were treated with an ointment formulation (3% w / w) of the compound represented by formula (I). The ointment (0.20 g / animal wound) was applied topically twice daily. The compound represented by formula (I) did not inhibit or impair wound healing (Figure 7).

[0161] Example 5: In vitro efficacy of the compound represented by formula (I) against inflammation: Cultured microglia (BV2 cells) and macrophages (raw cells) were treated with the compound shown in formula (I) (1–5 μg / mL) four hours before being treated with 500 ng / mL lipopolysaccharide (LPS). After 16–18 hours of drug treatment, cytokines (TNFα, IL1β, IL6) were measured in the culture medium by ELISA, and the expression levels of cyclooxygenase 2 (Cox-2), inducible nitroxide synthase (iNOS), or β-actin were analyzed by Western blotting in cell homogenates. A significant reduction in pro-inflammatory cytokines was observed after treatment with the compound shown in formula (I) (p<0.05).

[0162] Example 6: In vivo efficacy of the compound represented by formula (I) against pruritus and inflammation: The efficacy of the compound represented by formula (I) was evaluated in an animal model of experimental autoimmune encephalomyelitis (EAE), a widely accepted model of demyelinating diseases such as MS. cDNA was prepared from spleens obtained from vehicle-treated (control), EAE-induced (untreated), and EAE-induced (treated with the compound represented by formula (I)) animals (n=5 in each group) at recovery (days 1 to 27 of MBP immunization). Treatment with the compound represented by formula (I) (3 mg / kg) was initiated on day 11 of MBP immunization. cDNA was synthesized using the Bio-Rad cDNA synthesis kit. RT-PCR was performed for IL-31, IL1β, and IFNγ. Primers were obtained from Qiagen, and samples were analyzed using the Bio-Rad CFX96 real-time analysis system. Administration of the compound represented by formula (I) significantly reduced inflammatory markers (Figure 2). Statistical significance of the data is shown as p-values. * indicates p ≤ 0.05, and ** indicates p ≤ 0.01.

[0163] In models of atopic dermatitis and psoriasis, the compound represented by formula (I) downregulates the cytokines IL17, IL23, and IL2.

[0164] Example 7: Efficacy of the compound represented by formula (I) in a formalin-induced nociceptive (pain) animal model. Forty male Sprague Dawley rats were assigned to different treatment and control groups, each containing eight rats. These groups were treated with different doses of the compound shown in Formula I, administered orally 30 minutes prior to formalin injection at doses of 0.03 mg / kg, 0.3 mg / kg, and 3.0 mg / kg. As a positive control, tramadol hydrochloride (30 mg / kg) was administered orally 30 minutes prior to formalin injection. Deionized water was used as a negative control (vehicle) and administered orally 30 minutes prior to formalin injection. Subsequently, each rat was gently restrained, and formalin (5% v / v in saline, 50 μl, sc) was injected into the sole of the left hind foot using a 27G needle. Foot twitching, a nociceptive behavior following formalin injection, was recorded in 5-minute intervals for 60 minutes. Intraplantar injection of formalin (50 μl, 5% v / v) induced significant ipsilateral rat paw flinching with a typical biphasic response in vehicle / distilled water-treated animals. Oral administration of the compound represented by formula (I) at 0.03 mg / kg, 0.3 mg / kg, and 3 mg / kg 30 minutes prior to formalin treatment inhibited nociceptive behavior. Inhibition of nociceptive behavior at 0.3 mg / kg (33%, p<0.05) and 3.0 mg / kg (45%, p<0.01) was statistically significant compared to vehicle controls.

[0165] Example 8: Efficacy of the compound represented by formula (I) in an animal model of paclitaxel-induced neuropathic pain: Forty-eight male Sprague Dawley rats were assigned to different treatment and control groups, each containing eight animals. All animals except the naive control received four alternating intraperitoneal injections of paclitaxel (2 mg / kg) on ​​D0, D2, D4, and D6. For prophylactic intervention, the compound represented by formula I was orally administered at doses of 0.3 g / kg / day, 1 g / kg / day, and 3 mg / kg / day at the start of treatment with paclitaxel administration, and this dose was continued until day 15 after the first paclitaxel injection. For therapeutic intervention, the compound represented by formula I was orally administered at a dose of 3 mg / kg / day at the start of treatment after the establishment of neuropathic pain, i.e., day 16 after the first paclitaxel injection, and this dose was continued for the next seven days.

[0166] For behavioral testing, each rat was individually acclimatized to a transparent enclosure on a height-adjustable wire mesh for at least 15 minutes. Behavioral testing was performed using an Electronic von Frey Aesthesiometer (IITC Life Science) to assess the paw withdrawal threshold in response to mechanical stimuli. Injection of paclitaxel into negative controls (paclitaxel + vehicle treatment) resulted in a significant decrease in the hind paw withdrawal threshold in response to mechanical stimuli, indicating the progression of paclitaxel-induced neuropathic pain. Treatment with the compound shown in formula (I) was initiated simultaneously with paclitaxel injection (prophylactic treatment), which dose-dependently inhibited the progression of paclitaxel-induced neuropathic pain, with the greatest effect observed at a dose of 3 mg / kg / day. Even when treatment with the compound shown in formula (I) was discontinued 15 days after the initial paclitaxel injection, no reversal of the drug's anti-allodynic effect occurred until 7 days after the last drug treatment (22 days of the study).

[0167] In the prevention model, the score at day 16 decreased by >60% at dose levels of 1 mg / kg and 3 mg / kg (p<0.001), and a similar decrease was observed in the treatment model. In the treatment model, after the establishment of paclitaxel-induced neuropathic pain, treatment with the compound represented by formula (I) was initiated at an oral dose of 3 mg / kg / day, resulting in a time-dependent reversal of neuropathic pain. The maximum effect was recorded after the 1-day dose on day 5, and the effect persisted thereafter. From these findings, it can be concluded that treatment with the compound represented by formula (I) is effective for both prevention and treatment and has an anti-allodynic effect in paclitaxel-induced neuropathic pain.

[0168] Example 9: Efficacy of the compound represented by formula (I) in an animal model of multiple sclerosis In an animal model of multiple sclerosis, oral treatment with the compound shown in formula (I) was performed. Female Lewis rats were induced to develop EAE using guinea pig MBP (25 μg / rat). Rats that developed EAE were divided into three groups (n=6) and administered orally either the compound shown in formula (I) (1.3 mg / kg) or FTY720 (1 mg / kg) daily until day 26. Both the compound shown in formula (I) and FTY720 showed similar effects in reducing the clinical signs of the disease, but lymphopenia was less pronounced in animals treated with the compound shown in formula (I). Furthermore, lymphopenia observed in rats treated with the compound shown in formula (I) recovered quickly in the short term, whereas lymphopenia observed in rats treated with FTY720 was induced at a high level over a long period.

[0169] Example 10: Efficacy of the compound represented by formula (I) in in vivo inflammation The efficacy of the compound represented by formula (I) was determined in animal and inflammatory models of dinitrofluorobenzene (DNFB)-induced delayed-type hypersensitivity (DTH). Animals (n=9) were treated with either the vehicle or the compound represented by formula (I) at a dose of 3 mg / kg twice daily. The efficacy endpoint was measured as ear thickness before and 24 hours after the challenge. Ear weight was measured 24 hours after the challenge. At sacrificial, a right ear sample was taken and subjected to tissue MPO activity testing. Administration of the compound represented by formula (I) significantly reduced ear thickness (approximately 70%, p<0.0001), ear weight (approximately 50%, p<0.01), and MPO activity.

[0170] Example 11: Efficacy of the compound represented by formula (I) in an animal model of stroke The compound represented by formula (I) was evaluated in an animal model of stroke, specifically a middle cerebral artery occlusion (MCAO) model. The effects of the compound represented by formula (I) on 60-minute ischemia and 72-hour reperfusion of infarct (TTC staining) and BBB leakage (Evans blue exudation) were assessed. Oral administration of 1 mg / kg, 3 mg / kg, and 5 mg / kg of the compound represented by formula (I) significantly reduced infarct volume, infarct area, sensorimotor function, and blood-brain barrier leakage.

[0171] Example 12: Efficacy of the compound represented by formula (I) in an animal model of sepsis Sepsis was induced in female Sprague-Dawley rats by administration of LPS (5 mg / kg), and the compound represented by formula (I) (3 mg / kg) was orally treated 1 hour later and then every 24 hours thereafter to determine the effect of the compound represented by formula (I) in this animal model of sepsis (LPS-mediated systemic inflammation). Animals were sacrificed 24 and 72 hours after LPS treatment. There were positive effects on body temperature and organ histopathology.

[0172] Example 13: Efficacy of the compound represented by formula (I) in an animal model of ulcerative colitis The effects of the compound represented by formula (I) in an animal model of ulcerative colitis were evaluated. Twenty-four Balb / C mice were divided into two groups: control and treatment (n=6). Acute colitis was induced in all groups by adding 2.5% w / v dextran sulfate sodium (DSS) treatment in drinking water for 5-7 days. The compound represented by formula (I) was administered orally as repeated doses at a dose of 3 mg / kg body weight for 3 or 6 days. Daily administration of the compound represented by formula (I) resulted in improvement of DSS-induced colitis and a significant reduction in microscopic changes observed in the colon. Macroscopic pathological observations revealed that animals in the group on day 3 were slightly emaciated and had bloody anal sites in both groups. By day 6, these observations had decreased to 16.66% in the control group and 0.00% in the group with the compound represented by formula (I).

[0173] When the length of the colon was measured, the mean colon length of the control group was shorter than that of the treatment group. The mean colon lengths were 9.67 cm, 9.88 cm, 11.20 cm, and 13.02 cm for the control group on day 3, the control group on day 6, the group treated with the compound represented by formula I on day 3, and the group treated with the compound represented by formula I on day 6, respectively. Histopathological evaluation of the colon showed that in the control animals, 2 / 6 showed a severe increase in mucosal thickness, 1 / 6 showed a minimal increase, and 3 / 6 showed a mild increase. In animals treated with the compound represented by formula I, the severity was reduced, and the incidence of increased mucosal thickness was mild in 3 / 6 animals and minimal in 2 / 6 animals. Mucoseal goblet cells were absent in 3 / 6 animals in the control animals, but the number of mucoseal goblet cells increased moderately (4 / 6) in animals treated with the compound represented by formula I. The severity of hemorrhage with sloughed cells in the colon lumen of control animals was reduced in animals treated with the compound shown in formula (I). Histopathological evaluation on day 6 revealed a decrease in MNC infiltration, which was minimal and localized in 5 / 6 animals and moderate in 1 / 6 control animals. In the group treated with the compound shown in formula (I), it was minimal in 2 / 6 animals and mild in 1 / 6 animals. Mucosal thickness was also significantly reduced in animals treated with the compound shown in formula I compared to control animals. Compared to controls, mucosal goblet cells increased from moderate (4 / 6 animals) to minimal (1 / 6 animals) in animals treated with the compound shown in formula I.

[0174] Example 14: Efficacy of the compound represented by formula (I) in an animal model of epilepsy In an animal model of epilepsy, Sprague Dawley rats (n=6) were treated with the compound shown in formula (I) or a vehicle one hour before administration of kainic acid (10 mg / kg, IP). One hour after kainic acid administration, behavioral changes in the rats (grooming, leering, hindlimb scratching, urination, defecation, wet dog shakes, jaw movements, salivation, infantile spasms), seizure incidence, and latency / approximate mortality were observed up to one hour. A significant reduction in seizures (70%, p<0.005) was observed in the group treated with the compound shown in formula (I). Changes observed in the hippocampal region of control animals included minimal to mild neuronal cell death, particularly in the C3 and C1 regions, including vacuoles in neurons, demonstrating that the compound shown in formula (I) has a neuroprotective effect.

[0175] Example 15: Efficacy of the compound represented by formula (I) in patients with painful arthritis Fifteen arthritis patients experiencing pain were treated topically with the compound represented by formula (I) at 60 mg per day for seven consecutive days. The drug appeared safe and well-tolerated, and no serious or significant adverse events (AEs) were observed (all AEs were in the mild to moderate category). Blood parameters, urine analysis, vital signs, physical examination, and ECG were normal for all subjects. All participants (n=12) treated with the compound represented by formula (I) showed an overall positive response to the Global Patient Assessment of Treatment (PGART) score, observed on day 3 (41.7% of participants) and day 7 (58.3% of participants). In participants with osteoarthritis, a positive PGART response was observed by day 3 (28.6% of participants) and day 7 (57.1% of participants). Placebo participants (n=3) did not show a positive response.

[0176] In the group treated with the compound shown in Formula I (n=12), the numerical rating scale (NRS) for pain decreased from 7.1±1.38 (day 1; baseline) to 5.8±2.12 (day 3) and 4.8±2.72 (day 7). The mean change in NRS score from baseline was -1.3±1.54 (day 3) and -2.3±2.06 (day 7) points in arthritis participants treated with the compound shown in Formula I. In osteoarthritis participants, the 24-hour pain and worst pain scores from day 1 to day 7 were -1.9±1.46 and -1.9±1.57, respectively. The decrease in NRS score in these OA participants was found to be statistically significant (p=0.0153 and 0.0205, respectively). Topical application of the compound shown in Formula I for 7 days to arthritis participants was found to be safe, effective, and well-tolerated, resulting in a significant and rapid decrease in pain scores over time. There were no systemic changes in the absolute lymphocyte count. Systemic exposure on day 7 ranged from 0.42 ng / mL to 2.44 ng / mL (average 0.79 ng / mL).

[0177] Example 16: Efficacy of the compound represented by formula (I) in patients with psoriasis Twelve psoriasis patients were treated with 30 mg of the compound represented by formula (I) daily as a topical treatment under occlusion for 28 consecutive days. A significant reduction in the overall topical psoriasis severity index (LPSI) score compared to baseline was observed in the group treated with the compound represented by formula (I) at each visit from day 7 to day 28. The LPSI score decreased from 5.8 (day 1) to -2.1 (day 28) (p<0.0016), and no significant change was observed in the placebo group. Image analysis of clinical photographs showed a reduction in plaque area in some subjects in the group treated with the compound represented by formula (I). Systemic exposure after topical application was recorded at a limit of quantification (BLQ) <0.400 ng / mL. There were no systemic changes in absolute lymphocyte count. The study drug appeared to be well-tolerated, as evidenced by adverse events, laboratory blood parameters, urine analysis, vital signs, physical examination, and ECG.

[0178] Example 17: Efficacy of the compound represented by formula (I) in patients with atopic dermatitis Patients with atopic dermatitis were treated topically with the compound represented by formula (I) at 60 mg per day for 28 consecutive days. The compound represented by formula (I) resulted in a decrease in the overall eczema area and severity index (EASI) score and pruritus score (Figure 3) compared to baseline. There were no systemic changes in absolute lymphocyte count. The compound represented by formula (I) appears to be well tolerable, as evidenced by adverse events, laboratory blood parameters, urine analysis, vital signs, physical examination, and ECG. Systemic exposure up to week 3 did not result in lymphopenic events, and lymphocyte levels were ≤1–2.5 ng / mL.

[0179] Example 18: Efficacy of the compound represented by formula (I) in healthy human subjects Human subjects were treated with a single oral dose of the compound represented by formula (I) at 0.5 mg, 2 mg, 6 mg, and 12 mg in cohorts with different dose levels (each cohort = 8 human subjects). The drug was safe with no reported bradycardia events at 72 hours after clinical monitoring and ECG (12 mg dose shown in Figure 4 for one of the cohorts).

[0180] One cohort (8 participants) was treated with oral administration of 8 mg daily for 7 consecutive days. Systemic exposure reached an average of 53.3 ng / mL, and only mild lymphopenia was observed (Table 1). [Table 1]

[0181] Example 19: Systemic exposure of the compound represented by formula (I) in human subjects after topical application The surface area of ​​an adult's body is approximately 16,000 cm². 2 ~18,000cm 2 The skin surface area is 10,000 cm². 2 ~20,000cm 2(https: / / hypertextbook.com / facts / 2001 / IgorFridman.shtml, reference cited within this scope). Human subjects have a body surface area of ​​150 cm². 2 In this study, 1 g of a 3% by weight formulation was applied topically twice daily (on the skin) for 21 days. The resulting systemic exposure was approximately 2.2 ng / ml. In another cohort, systemic exposure from topical application of 2 g of a 3% or 6% by weight formulation (60 mg or 120 mg of the compound represented by formula (I)) to joint sites for one week did not exceed 2.5 ng / ml.

[0182] Example 20: Preparation of a tablet formulation of the compound represented by formula (I) Lactose monohydrate was passed through a US mesh #40 and collected in a clean, sterile poly-lined container. Corn starch was then added and passed through a US mesh #100. Next, microcrystalline cellulose was passed through a US mesh #40 and the composition was dry-mixed. Povidone solution (polyvinylpyrrolidone K30) was used as a binder solution and then filtered through a US mesh #100. The granules were dried in a high-temperature oven (55-60°C) for about 25-30 minutes, or until the granules were dry to the desired level. The granules were then sieved through a US mesh #20 and collected in a clean, sterile poly-lined container. Colloidal silicon dioxide was added, and the mixture was sieved through a US mesh #40 and mixed for 3 minutes. Next, magnesium stearate was sieved through a US mesh #60 and mixed for 3 minutes. Finally, this mixture was compressed into the desired tablets. Table 2 shows the components used in the above process. [Table 2]

[0183] Example 21: A 3% w / w ointment composition of a free base, represented by formula (I), of the S1P1 agonist, for topical use. A mixture of petrolatum (30.8 g) and Gelucire 50 / 13 pellet (4 g) was dissolved and stirred at approximately 70°C until homogeneous (approximately 15 minutes). A solution (1.2 g) of the compound represented by formula (I), which is a free base in anhydrous DMSO (4 ml), was added to the mixture while vigorously stirring. The mixture was cooled to room temperature, and the resulting ointment (40 g) contained 3% (w / w) of the free base of the compound represented by formula (I).

[0184] Example 22: 3% w / w gel composition of the HCl salt represented by formula (I) for topical use A mixture of H2O (4.85 g), propylene glycol (4.85 g), and Cerosize PCG10 (0.3 g) was prepared. This mixture was stirred overnight at room temperature to obtain a clear, viscous gel (10 g). This gel (6 g) was mixed with EtOH (4 g), and the resulting mixture was stirred at approximately 70°C for 2 hours. A hydrochloride salt of the compound shown in formula (I) (0.45 g), dissolved in anhydrous DMSO (3 g), was added all at once, and EtOH was added to obtain a final mass of 15 g. The resulting mixture was stirred at approximately 70°C for 1 hour to obtain a colorless, transparent gel with excellent stability and spreadability.

[0185] Example 23: A 3% w / w gel composition of a mesylate represented by formula (I) for topical use. When the hydrochloride salt of the compound represented by formula (I) in Example 7 was replaced with the mesylate salt of the compound represented by formula (I), the title composition was obtained by the same method.

[0186] Example 24: A 3% liquid composition of a mesylate represented by formula (I) for topical use. 0.3 g of the mesylate salt of the compound shown in formula (I) was dissolved in 4 g of 50% aqueous DMSO, and this was diluted to 10 g with EtOH to obtain the formulation described in the title as a colorless liquid (10 g).

[0187] Example 25: A 1% liquid composition of an HCl salt represented by formula (I) containing polyvinylpyrrolidone (PVP) for topical use. 0.05 g of the HCl salt of the compound represented by formula (I) was dissolved in 4.45 ml of 80% aqueous EtOH. 0.5 g of polyvinyl PVP was added to this solution, and the mixture was stirred at room temperature until completely homogeneous (approximately 1 hour) to obtain a stable, colorless solution, which formed a film after application to the skin.

[0188] Example 26. A 0.5% sterile aqueous solution of the mesylate represented by formula (I) for injection / liquid oral formulations / droplets for ocular and ocular administration. A sterile isotonic solution (1 ml) was added to a sterile container (0.005 g) containing the mesylate of the compound shown in formula (I) via a syringe. The resulting mixture was stirred by shaking at room temperature until homogeneous, and prepared for use by injection, eye drops, ear drops, or oral administration.

[0189] Example 27. Topical patch formulation represented by formula (I) The compound represented by formula (I) and other components, including solubility enhancers or penetration enhancers such as DMSO, polyvinylpyrrolidone (PVP), glyciryl laurate, lauryl lactate, aerosols, and eudragit (but not limited to these), can be dissolved in a solvent (ethanol, propanol, isopropanol). An adhesive is added and mixed until homogeneous. The homogeneous slurry may be cast onto a release layer (silicone or fluoropolymer coated polyester film) at an optimal temperature and dried.

[0190] Example 28: A 3% w / w ointment composition for topical use of a free base, the S1P1 agonist represented by formula (I), in combination with 1% nicotinamide and 2% vitamin E. The compound represented by formula (I) (0.6g), nicotinamide (0.2g), vitamin E (d-isomer; 0.4g), Gelucire 50 / 13 pellet (2g), and Polysolve 20 (0.6g) were stirred in anhydrous DMSO (2ml) until homogeneous (about 30 minutes). Dissolved petrolatum was added to a final weight of 20g. This was vigorously stirred at about 50°C for 15 minutes and cooled to room temperature to obtain a grayish-white ointment.

[0191] Example 29: A 3% w / w ointment composition for topical use containing a free base, represented by the S1P1 agonist of formula (I), and 0.05% w / w betamethasone. A mixture of petrolatum (30.78 g) and Gelucire 50 / 13 pellet (4 g) was dissolved and stirred at approximately 70°C until homogeneous (approximately 15 minutes). To this, a solution of the compound represented by formula (I) (1.2 g), which is the free base in anhydrous DMSO (4 g), and betamethasone (0.02 g) was added while vigorously stirring. The mixture was cooled to room temperature to obtain a turbid ointment (40 g) containing 3% (w / w) of the free base of the compound represented by formula (I) and 0.05% betamethasone.

[0192] Example 30: A 2% w / w gel composition for topical use of the HCl salt represented by composition formula (I) and 1% diclofenac. A solution of H2O (4.85 g), propylene glycol (4.85 g), and Cerosize PCG 10 (0.3 g) was prepared. This mixture was stirred overnight at room temperature to obtain a clear, viscous gel (10 g). This gel (6 g) was mixed with EtOH (3.9 g), and the resulting mixture was stirred at approximately 70°C for 2 hours. A mixture of the hydrochloride salt of the compound shown in formula (I) (0.3 g) and diclofenac (0.15 g) (4.5 g), dissolved in anhydrous DMSO, was added all at once, and EtOH was added to obtain a final mass of 15 g. The resulting mixture was stirred at approximately 70°C for 1 hour to obtain the title product as a colorless, transparent gel with excellent stability and spreadability.

[0193] Example 31: Use of a topical formulation of the compound represented by formula (I) in a wound patient A 68-year-old male patient suffered a second-degree burn on the inner surface of his left middle finger, exhibiting swelling, blistering, and pain at the site of the burn. A topical gel formulation of the compound shown in formula (I) was applied topically to the injury site. After 10 minutes, the swelling and blistering were visibly and dramatically reduced, and the patient reported a significant reduction in pain.

[0194] A 49-year-old male patient presented with scratches on his hand sustained while cleaning a drainage ditch. These scratches became inflamed and painful after 3 hours. Topical application of an ointment formulation of the compound shown in formula (I) to the injury site dramatically reduced swelling and pain, and the patient reported significant pain relief. No side effects were reported in either case.

[0195] Example 32: Compound substitute formulation represented by Formula I The compound represented by Formula I is soluble in water in salt forms such as HCl and mesylates, giving stable, clear solutions. The free base (free amine form) of the compound represented by Formula I is insoluble in water. To solubilize this free base in water, a novel technique, AvignaSOL (N,N-dimethylhexaneamide; Patent No.: US9186338B2) and its higher derivatives (octinamide, decamido, etc.), was used to improve the absorption of various poorly soluble drugs. AvignaSOL, at 1-70% ww%, assisted in the solubilization of the free base at 1 gm / 20 mL of water. The solubility of the free base in water is useful for direct use in various formulations such as creams, gels, and solutions, and is utilized to improve skin penetration and / or bioavailability, along with enhancing penetration effects, and to modify the pharmacokinetic and pharmacodynamic profiles of the free base.

[0196] AvignaSOL, with a logP of approximately 1.6, inhibits release by increasing the hydrophobicity of the delivery system. Solubilized compounds of formula I-AvignaSOL do not precipitate in phosphate buffer at pH 6.8. Therefore, AvignaSOL can be used, but is not limited to, to increase the bioavailability of compounds represented by formula I via the intestine and / or skin. As a novel formulation technique to improve and / or modify the pharmacokinetic and pharmacodynamic profiles of compounds represented by formula I, combinations of AvignaSOL with other components, including or not including sustained-release enhancers, were prepared.

[0197] To improve the pharmacokinetic profiles such as half-life (T1 / 2) and Cmax, the compounds represented by Formula I were formulated with various components and solvents shown in Table 6. [Table 3-1] [Table 3-2]

[0198] i) Preparation of ointment: White soft paraffin, cetyl alcohol, glyceryl monostearate and light liquid paraffin were heated to 70 - 75 °C with mechanical stirring for 15 minutes to obtain a clear solution (Solution A). Separately, a clear solution of propylene glycol, the compound represented by Formula I and stearic acid (Solution B) was prepared by heating with stirring at 90 - 95 °C using a magnetic stirrer for 15 minutes. This Solution B was added to Solution A (maintained at 90 - 95 °C) with stirring using a mechanical stirrer. Next, this mixture was stirred at 75 - 85 °C at 380 rpm for 15 minutes. Then, this mixture was cooled at 40 - 45 °C at 380 rpm for 30 minutes with stirring using a mechanical stirrer, and then cooled at 25 - 30 °C (ambient conditions) at 300 rpm for 60 minutes to obtain a homogeneous pale grayish-white ointment. [Table 4]

[0199] ii) Preparation of gel or spray: The compound represented by Formula I was added to a mixture of propylene glycol, glycerol, water with or without dimethyl isosorbide and stirred until the solution became clear (60 - 70 °C). Hydroxyethyl cellulose or HPMCK100 or hydroxypropyl cellulose or hydroxymethyl cellulose (Cellosize) was added thereto, and the contents were stirred at 55 °C for 1 hour to obtain a clear gel or solution. [Table 5]

[0200] iii) Preparation of sustained-release granules: The compound shown in formula I was dissolved in AvignaSOL by bath sonication, and then a mixture of isomalt and MCC PH101 was triturated in a mortar. Further ingredients, ethylcellulose, HPMC K100 M, and pregelatinized starch, were added by trituration in a mortar, and then the mixture was sieved three times through a #30 mesh. Next, 5 ml of an IPA:water (80:20) solution containing ethylcellulose was added to form the mixture into granules. In another experiment, the compound shown in formula I was mixed with isomalt, MCCPH101, 7 cps of ethylcellulose, HPMC K100 M, and pregelatinized starch, and then the mixture was sieved three times through a #30 mesh. Next, 5 ml of an IPA:water (80:20) solution containing ethylcellulose was added to form the mixture into granules. These moist granules were sieved through a #20 mesh and dried in a 65°C hot air oven for 2.5 hours. The granules that passed through the #20 mesh and were retained in a #60 mesh were used for an additional elution test at 37-40°C, showing the following in vitro releases: 1 hour (27%) and 19 hours (71.4%).

[0201] Example 33: Antifungal activity of the compound represented by formula I Solutions of the compound represented by formula I as 0% www, 1% www, and 3% www were added as 1 mL aqueous solutions to glass bottles (5 mL) containing fresh wheat flour bread (1 g m). The contents were stored in an open glass cylinder at room temperature and under normal conditions for 14 days, and photographs were taken on day 1 and day 14 (Figures 5A and 5B, respectively).

[0202] The antifungal activity of the compound represented by formula I was demonstrated by preventing mold growth on day 14 in bottles containing the compound represented by formula I, as seen by the blackening of 0% of the bottles. Mold is commonly found in many skin conditions and other human, animal, and plant diseases, such as Rhizopus stolonifera.

[0203] Example 34: Topical efficacy of Freund's adjuvant and the compound represented by Formula I for pain in deep incision wounds in rats. A total of 24 female Sprague Dawley rats were assigned to two test groups of 6 rats each and two control groups. G1 and G2 animals received CFA via an intravascular route on day 1, followed by application of the test substance (0% and 3%, respectively) to the injection site from day 1 to day 7. G3 and G4 animals underwent deep incisions of the plantar skin and fascia, and the test substance (0% and 3%, respectively) was applied to the incision site from day 1 to day 7. Clinical signs, body weight, and pain assessment parameters such as Von Frey estimates and FOB were evaluated, and pain reduction results on day 7 are summarized in Table 7. Treatment with the compound represented by Formula I inhibited CFA-induced and incision wound (neuropathic) pain in rats and exhibited an anti-allodynic effect recorded on day 7 in CFA (complete pain relief) and deep incision-induced neuropathic pain (67% relief). [Table 6]

[0204] Example 35: In vitro efficacy of the compound represented by formula I in acne-induced inflammation. RAW264.7 cell line (monocytes) were challenged with heat-sterilized Propionibacterium acnes (P. acne), incubated for 1 hour, and divided into four groups: G1 = no challenge with P. acne, G2 = challenged with P. acne but untreated, G3 = challenged with P. acne and treated with 1 μM of Formula I, and G3 = challenged with P. acne and treated with 3 μM of Formula I. The effects of the compound shown in Formula I on the secretion of inflammatory cytokines TNFα and IL6 were analyzed using ELISA. The compound shown in Formula I inhibits cytokines in P. acne challenged monocytes. The results are shown in Figure 6 below. The compound shown in Formula I inhibits the secretion of TNFα at 1 μM = approximately 42% and at 3 μM = approximately 69%, and IL6 at 1 μM = approximately 27% and at 3 μM = approximately 42% compared to the untreated P. acne challenged cell line.

[0205] While this disclosure has been described in relation to its specific embodiments, it should be understood that the foregoing description is illustrative and not intended to limit the scope of this disclosure. Other embodiments, advantages, and modifications will be apparent to those skilled in the art to which this disclosure belongs. Accordingly, the following examples are presented to provide a complete disclosure and description of methods for producing and using the disclosed compositions and are not intended to limit the scope of this disclosure.

[0206] All cited documents are fully incorporated herein by reference to the extent that such incorporation is permitted in all jurisdictions and to the extent that such disclosure is consistent with the description in this disclosure. Furthermore, the present invention includes the following embodiments. [Aspect 1] A method of treating or preventing a disease or disorder by administering a pharmaceutical containing an S1P receptor modulator to a subject requiring treatment or prevention, wherein the pharmaceutical reduces the target heart rate by approximately 5 beats / min or less per day, or approximately 4 beats / min or less per day, or approximately 3 beats / min or less per day, or approximately 2 beats / min or less per day. The S1P receptor modulator is administered at an initial daily dose substantially identical to the standard daily therapeutic dose; and The S1P receptor modulator is given by formula (I): [ka] [In the formula, R 1 These are hydrogen, deuterium, halogens, CN, and CF. 3 -COOH, amide, sulfonamide, alkoxy, aryloxy, nitro and C1-6 Selected from the group consisting of alkyl groups, the alkyl group may include deuterium, O, S, NR' (R'=H, alkyl, cycloalkyl), halogen, carbon-carbon double bond, carbon-carbon triple bond, carbon-nitrogen double bond, carbon-nitrogen triple bond, heterocycle, aryl, alkyl, and cycloalkyl (C 3-7 ) including one or more of the following; R 2 These are hydrogen, deuterium, halogens, CN, and CF. 3 alkoxy, aryl oxy and C 1-4 Selected from the group consisting of alkyl groups, the alkyl group may include deuterium, O, S, NR' (R'=H, alkyl, cycloalkyl), halogen, carbon-carbon double bond, carbon-carbon triple bond, carbon-nitrogen double bond, carbon-nitrogen triple bond, heterocycle, aryl, and C 3-7 Containing one or more cycloalkyl groups; R 3 These include hydrogen, deuterium, halogens, alkoxys, aryloxys, and C 1-6 Selected from the group consisting of alkyl groups, the alkyl group may include deuterium, O, S, NR' (R'=H, alkyl, cycloalkyl), halogen, carbon-carbon double bond, carbon-carbon triple bond, carbon-nitrogen double bond, carbon-nitrogen triple bond, heterocycle, aryl, alkyl, and C 3-7 It comprises one or more cycloalkyl groups; preferably, R 3 These include Me, OMe, OEt, OPr, O-iPr, O-isobutyl, O-isopentyl, O-cyclopentyl, O-allyl, O-benzyl and

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

Claims

1. A pharmaceutical product comprising an S1P receptor modulator for treating or preventing a disease or disorder in a human subject, and simultaneously preventing or reducing lymphopenia in a human subject, wherein the pharmaceutical product reduces the heart rate of a human subject by 5 beats / min or less per day. The disease or disorder is selected from the group consisting of pruritus, pain, multiple sclerosis, ulcerative colitis, psoriasis, dermatitis, and acne; The S1P receptor modulator is formulated for administration at an initial daily dose that is less than 25% different from the standard daily therapeutic dose; and The S1P receptor modulator is 【Chemistry 1】 A pharmaceutical product, or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical agent according to claim 1, wherein the pharmaceutical agent reduces the heart rate of a human subject by 4 beats / min or less per day.

3. The pharmaceutical agent according to claim 1, wherein the pharmaceutical agent reduces the heart rate of a human subject by 3 beats / min or less per day.

4. The pharmaceutical agent according to claim 1, wherein the pharmaceutical agent reduces the heart rate of a human subject by 2 beats / min or less per day.

5. The pharmaceutical product according to claim 1, wherein the difference between the initial daily dose and the standard daily therapeutic dose is less than 15%.

6. The pharmaceutical product according to claim 1, wherein the difference between the initial daily dose and the standard daily therapeutic dose is less than 10%.

7. The pharmaceutical product according to claim 1, wherein the difference between the initial daily dose and the standard daily therapeutic dose is less than 5%.

8. The pharmaceutical product according to claim 1, wherein the initial daily dose is the same as the standard daily therapeutic dose.

9. The pharmaceutical product according to any one of claims 1 to 8, wherein the standard daily therapeutic dose of the S1P receptor modulator is up to 70 mg.

10. The pharmaceutical product according to any one of claims 1 to 8, wherein the standard daily therapeutic dose of the S1P receptor modulator is a maximum of 24 mg.

11. The pharmaceutical product according to any one of claims 1 to 8, wherein the standard daily therapeutic dose of the S1P receptor modulator is 0.5 mg to 12 mg.

12. The pharmaceutical product according to any one of claims 1 to 8, wherein administration of the pharmaceutical product does not cause a decrease in heart rate.

13. The pharmaceutical product according to any one of claims 1 to 8, wherein administration of the pharmaceutical product does not cause bradycardia.

14. A pharmaceutical product according to any one of claims 1 to 8, wherein the level of lymphopenia is ≤25%.

15. The pharmaceutical product according to any one of claims 1 to 8, wherein the pharmaceutical product is in the form of a topical formulation selected from a solid, patch, powder, liquid, semi-solid, ointment, gel, spray, aerosol, inhaler, and lotion.

16. The pharmaceutical product according to any one of claims 1 to 8, wherein the pharmaceutical product is an oral or injectable formulation selected from pills, tablets, capsules, solutions, and syrups.

17. The pharmaceutical product according to any one of claims 1 to 8, wherein the human subject is prone to heart failure, arrhythmia, high-grade atrioventricular block, sick sinus syndrome, and has a history of syncope episodes or a combination thereof.

18. The pharmaceutical product according to claim 17, wherein the human subject is receiving antiarrhythmic treatment by administration of a beta-blocker or an antiarrhythmic drug.

19. The pharmaceutical product according to any one of claims 1 to 8, wherein the human subject is undergoing discontinuation or cessation of treatment with another S1P receptor modulator / agonist.

20. The pharmaceutical product according to claim 19, wherein the suspension of the treatment exceeds four days.

21. A pharmaceutical product according to any one of claims 1 to 8, which is a sustained-release formulation administered locally by transplantation or injection, or via a medical device.

22. A pharmaceutical product according to any one of claims 1 to 8, which is applied locally.

23. The pharmaceutical product according to claim 22, comprising an S1P receptor modulator in an amount of 0.01% to 30% by weight.

24. Up to 1000 cm³ per gram of pharmaceutical product 2 The pharmaceutical product according to claim 22, which is applied to the body surface area, where the standard daily therapeutic dose of the S1P receptor modulator is ≤3 g.

25. A pharmaceutical product according to any one of claims 1 to 8, for treating pain selected from the group consisting of joint pain, arthritis pain, gout pain, back pain, muscle pain, neuropathy, neuralgia, migraine, cancer pain, sports injury pain, and wound pain.

Images