Methods of treating cytokine release syndrome

Abstract

Disclosed are a composition for preventing and / or treating cytokine release syndrome and a method of preventing and / or treating cytokine release syndrome. The composition includes an arylethylene compound, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. The method includes administering an effective amount of the arylethylene compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject in need. The cytokine release syndrome can be caused by a toxic infection. The administration of the compound reduces the level of proinflammatory cytokines in the subject.

Description

[0001] Cross-referencing related applications

[0002] This application claims priority and benefits based on U.S. Provisional Patent Application No. 63 / 060,779, filed August 4, 2020, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] This invention discloses treatment methods including cytokine release syndrome. In one aspect, the invention relates to the use of a molecule to reduce or prevent excessive production of cytokines in macrophages following toxic infection. This molecule helps prevent mitochondrial dysfunction caused by pro-inflammatory responses mediated by estrogen-associated receptor gamma (ERRg) in macrophages. The invention also relates to a method of treating mammals suffering from cytokine release syndrome by administering this molecule. Background Technology

[0004] Inflammatory diseases are fundamental to many human illnesses, characterized by an excessive immune response leading to the secretion of large amounts of circulating pro-inflammatory cytokines in response to infection with virulent pathogens. This response activates receptors on immune effector cells, including T cells and macrophages. For example, according to the Centers for Disease Control and Prevention (CDC), sepsis is an extreme immune response to infection that occurs when an existing infection—such as a skin, lung, or urinary tract infection—triggers a “chain reaction” in the body, resulting in widespread inflammation. A recent study published in the Lancet (Kempker and Martin, A global accounting of sepsis, Lancet, Vol. 395, Publication No. 10219, pp. 168-170, January 18, 2020) projected that 49 million people developed sepsis in 2017, and 11 million died from the disease. A key feature of these infectious diseases is a burst of cytokine release from pro-inflammatory cells, including macrophages, lymphocytes, and polymorphonuclear leukocytes (PMNs), known as a cytokine storm. In many cases, an excessive cytokine storm (hypercytokinemia) can lead to a fatal immune response. The constant activation of immune effector cells produces persistent and supraphysiological levels of cytokines, including TNFα, IFNb, IL-1β, and IL-6, which can cause severe tissue damage. These pro-inflammatory cytokines are produced by several different cell types, most importantly immune cells (e.g., monocytes, macrophages, and neutrophils), as well as non-immune cells such as fibroblasts, osteoblasts, smooth muscle cells, epithelial cells, and neurons (56). Pro-inflammatory cytokines contribute to a variety of conditions, particularly sepsis, through their release during inflammatory cytokine cascades.

[0005] The nuclear receptor (NR) superfamily represents a large class of ligand-dependent transcription factors. The NR family differs uniquely from other types of receptors in their ability to directly interact and control genomic DNA expression. Therefore, NRs play a crucial role in embryonic development and adult metabolic homeostasis. Estrogen-associated receptors (ERRs) were the first orphan members of the NR superfamily to be identified, and the subfamily is now known to contain three related isoforms: ERRα (also known as NR3B1, Esrra, ERRa), β (also known as NR3B2, Esrr, ERRb), and γ (also known as NR3B3, Esrrg, ERRg). Although named after estrogen receptors due to their structural homology, ERRs are not activated by estrogen (the ligand of the estrogen receptor) or any known natural compounds. ERRs play a vital role in the transcriptional control of metabolic genes involved in cellular energy production and utilization, and thus play a crucial role in key aspects of organ development and cellular homeostasis. ERRs are primarily expressed in the heart, skeletal muscle, brain, kidney, pancreas, placenta, and liver, and are predicted to exhibit significant differences in their synthetic ligand binding preferences.

[0006] Recent findings in various mammalian experimental models indicate that ERRg, as a downstream mediator of multiple extracellular signals, plays a crucial role in coordinating endocrine and metabolic signaling, leading to changes in glucose, alcohol, lipid, and iron metabolism. Therefore, ERRg dysregulation contributes to the pathogenesis of metabolic diseases such as hyperglycemia, insulin resistance, and alcoholic liver injury. Interestingly, ERRg has also been shown to be involved in the pathogenesis of bacterial infections. These findings highlight the importance of ERRg in the endocrine and metabolic control of metabolism and suggest that ERRg may be a promising therapeutic target for various diseases.

[0007] U.S. Patent Applications 16 / 313,360 (Publication No. 2019 / 0167820A1) and 16 / 677,596 (Publication No. 20200078476A1), the entire contents of which are incorporated herein by reference, disclose novel arylethane derivatives as inhibitors of estrogen-associated receptor gamma (ERRg).

[0008] This invention is based on the new discovery that certain compounds with ERRg inhibitory activity can be used to treat cytokine release syndrome caused by toxic infections. Summary of the Invention

[0009] Generally, the present invention relates to methods and / or applications for treating, preventing, or controlling cytokine release syndrome, including administration of an arylethylene compound represented by formula (I), its isomers, its prodrugs, its pharmaceutically acceptable salts, or solvates thereof. In one embodiment, cytokine release syndrome is caused by a toxic infection. The infection may be viral or bacterial. Treatment, prevention, or control of cytokine release syndrome may include normalizing and / or reducing supraphysiological levels of pro-inflammatory cytokines in the patient. Pro-inflammatory cytokines include IFNb, IL1b, TNFα, and / or IL6, etc.

[0010] This invention relates to a method for preventing, treating, or controlling cytokine release syndrome in a subject in need, comprising administering to the subject an aryl vinyl compound represented by the following chemical formula 1, or a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof:

[0011]

[0012] Wherein, L is (C6-C20) arylene, (C3-C20) heteroarylene, or (C3-C20) fused heterocycle;

[0013] R 1 It is (C3-C20) heterocyclic alkyl, (C3-C20) heteroaryl, -O-(CH2) m -R 11 -(CH2) m -R 12 -NH-(CH2) m -R 13 -NHCO-(CH2) n -R 14 or -SiR 16 R 17 -(CH2) m -R 15 ;

[0014] R 11 To R 15 Each is an independent (C3-C20) heterocyclic alkyl group;

[0015] R 16 and R 17 Each is an independent (C1-C20) alkyl group;

[0016] m is an integer from 1 to 3; and

[0017] n is 0 or 1;

[0018] Ar is (C6-C20) aryl or (C3-C20) heteroaryl, wherein the aryl or heteroaryl group of Ar may be further composed of one or more elements selected from hydroxyl, halogen, (C1-C20) alkyl, halo(C1-C20) alkyl, (C1-C20) alkoxy, nitro, cyano, -NR 21 R 22 (C1-C20)alkylcarbonyloxy, (C1-C20)alkylcarbonylamino, guanidinyl, -SO2-R 23 and -OSO2-R 24 Substitution of groups;

[0019] R 21 and R 22 Each is independently hydrogen, (C1-C20) alkylsulfonyl or (C3-C20) cycloalkylsulfonyl;

[0020] R 23 and R 24 Each can be independently classified as (C1-C20) alkyl, halo(C1-C20) alkyl, or (C3-C20) cycloalkyl;

[0021] R 2 It can be hydroxyl, halogen, (C1-C20) alkyl carbonyloxy or (C1-C20) alkyl sulfonyloxy;

[0022] R 1 heterocyclic alkyl or heteroaryl and R 11 -R 15 The heterocyclic alkyl group may be further substituted with one or more groups selected from (C1-C20)alkyl, (C3-C20)cycloalkyl, (C2-C20)alkenyl, amidine, (C1-C20)alkoxycarbonyl, hydroxy, hydroxy(C1-C20)alkyl, and di(C1-C20)alkylamino(C1-C20)alkyl; and

[0023] Heterocyclic alkyl and heteroaryl groups contain one or more heteroatoms selected from N, O and S, and the heterocyclic alkyl group is a saturated or unsaturated mono-, bi-, or spirocyclic ring having a carbon or nitrogen atom as a binding site in the ring.

[0024] In one implementation, cytokine release syndrome is a syndrome caused by an excessive immune response in the host (subject) to a toxic infection. Treatment, prevention, or control of cytokine release syndrome may include normalizing and / or reducing supraphysiological levels of pro-inflammatory cytokines in the patient. Pro-inflammatory cytokines include IFNb, IL1β, TNFα, and / or IL6, etc.

[0025] Another aspect of the present invention is a method for treating and / or preventing and / or controlling cytokine release syndrome in a subject infected with a virus, comprising administering a compound of chemical formula 2 or a pharmaceutically acceptable salt thereof or a solvate thereof.

[0026]

[0027] in,

[0028] R 1 It is a (C3-C10) heterocyclic alkyl group or -O-(CH2). m -R 11 ;

[0029] R 11 It is a (C3-C10) heterocyclic alkyl group;

[0030] m is an integer from 1 to 3;

[0031] R 1 and R 11 The heterocyclic alkyl group may be further substituted with one or more groups selected from (C1-C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl, amidine, (C1-C10)alkoxycarbonyl, hydroxy(C1-C10)alkyl and di(C1-C20)alkylamino(C1-C20)alkyl;

[0032] Ar is (C6-C12)aryl or (C3-C12)heteroaryl, wherein the aryl or heteroaryl group of Ar may be further substituted by one or more groups selected from hydroxyl, halogen, (C1-C10)alkyl, halo(C1-C10)alkyl, (C1-C10)alkoxy, nitro, cyano, amino, (C1-C10)alkylsulfonylamino, (C3-C10)cycloalkylsulfonylamino, di((C1-C10)alkylsulfonyl)amino, (C1-C10)alkylcarbonyloxy, (C1-C10)alkylcarbonylamino, guanidinyl, (C1-C10)alkylsulfonyl, (C1-C10)alkylsulfonyloxy, halo(C1-C10)alkylsulfonyloxy, and (C3-C10)cycloalkylsulfonyloxy; and

[0033] R 2The molecule is hydroxyl, fluorine, (C1-C10)alkylcarbonyloxy, or (C1-C10)alkylsulfonyloxy. In one embodiment, cytokine release syndrome is a syndrome caused by an excessive immune response in a subject to a toxic infection. In one aspect, the excessive immune response can be a burst of cytokine release (cytokine storm). Therefore, treatment, prevention, or control of cytokine release syndrome may include normalizing and / or reducing supraphysiological levels of pro-inflammatory cytokines in the patient. Pro-inflammatory cytokines include IFNb, IL1β, TNFα, and / or IL6, etc.

[0034] Another aspect of the present invention is a method for treating and / or preventing and / or controlling cytokine release syndrome in a subject in need, said method comprising administering a compound of formula 6 or a pharmaceutically acceptable salt thereof or a solvate thereof.

[0035]

[0036] in,

[0037] R 1 It is a (C3-C10) heterocyclic alkyl group or -O-(CH2). m -R 11 ;

[0038] R 11 It is a (C3-C10) heterocyclic alkyl group;

[0039] m is an integer from 1 to 3;

[0040] Ar is (C6-C12) aryl or (C3-C12) heteroaryl.

[0041] The heterocyclic alkyl group, the aryl group, or the heteroaryl group may be further substituted with one or more groups selected from hydroxyl, halogen, (Cl-C10)alkyl, halo(Cl-C10)alkyl, (Cl-C10)alkoxy, nitro, cyano, amino, (Cl-C10)alkylsulfonylamino, (C3-C10)cycloalkylsulfonylamino, di((Cl-C10)alkylsulfonyl)amino, (Cl-C10)alkylcarbonyloxy, (Cl-C10)alkylcarbonylamino, guanidinyl, (Cl-C10)alkylsulfonyl, (Cl-C10)alkylsulfonyloxy, halo(Cl-C10)alkylsulfonyloxy, and (C3-C10)cycloalkylsulfonyloxy; and

[0042] R 2The cytokine is a hydroxyl, halogen, (C1-C10)alkylcarbonyloxy, or (C1-C10)alkylsulfonyloxy. In one embodiment, cytokine release syndrome is a syndrome caused by an excessive immune response in a subject to a toxic infection. In one aspect, the excessive immune response can be a burst of cytokine release (cytokine storm). Therefore, treatment, prevention, or control of cytokine release syndrome may include normalizing and / or reducing supraphysiological levels of pro-inflammatory cytokines in the patient. Pro-inflammatory cytokines include IFNb, IL1b, TNFα, and / or IL6.

[0043] According to one embodiment, the compound represented by chemical formula 1 is selected from the following compounds 18a, 18k, 22i, and 22r:

[0044]

[0045] In one respect, cytokine release syndrome can be caused by toxic infections. These infections can be viral or bacterial. Treatment, prevention, or control of cytokine release syndrome may include normalizing and / or reducing supraphysiological levels of pro-inflammatory cytokines in the patient. These pro-inflammatory cytokines include IFNb, IL1β, TNFα, and / or IL6.

[0046] On the other hand, cytokine release syndrome caused by toxic infection can include septic shock, pneumonia, and other inflammatory conditions.

[0047] In another respect, the subjects were mammals, particularly humans.

[0048] One aspect of the invention further relates to a pharmaceutical composition for the prevention and / or treatment and / or control of cytokine release syndrome, comprising a therapeutically effective amount of a compound of formula 1 as an active ingredient, a solvate thereof, an isomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0049] One aspect of the invention further relates to a pharmaceutical composition for the prevention and / or treatment and / or control of cytokine release syndrome, comprising a therapeutically effective amount of a compound of formula 2 as an active ingredient, a solvate thereof, an isomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0050] One aspect of the invention further relates to a pharmaceutical composition for the prevention and / or treatment and / or control of cytokine release syndrome, comprising a therapeutically effective amount of a compound of formula 6 as an active ingredient, a solvate thereof, an isomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0051] In the aforementioned respects, cytokine release syndrome is a syndrome caused by an excessive immune response in a subject to a toxic infection. In one aspect, this excessive immune response can be a burst of cytokine release (cytokine storm). Treatment, prevention, or control of cytokine release syndrome may include normalizing and / or reducing supraphysiological levels of pro-inflammatory cytokines in the patient. These pro-inflammatory cytokines include IFNb, IL1β, TNFα, and / or IL6, among others.

[0052] In one embodiment, the composition comprises a compound selected from compounds 18a, 18k, 22i, and 22r, its solvates, its isomers, or pharmaceutically acceptable salts thereof.

[0053] Another aspect of the invention relates to the use of compounds of Formula 1, their solvates, isomers, or pharmaceutically acceptable salts thereof in the preparation of medicaments for the prevention and / or treatment and / or control of cytokine release syndrome. In one embodiment, cytokine release syndrome may be caused by a toxic infection and may include a cytokine release burst (cytokine storm). Treatment, prevention, or control of cytokine release syndrome may include normalizing and / or reducing supraphysiological levels of pro-inflammatory cytokines in patients. Pro-inflammatory cytokines include IFNb, IL1b, TNFα, and / or IL6, etc.

[0054] Another aspect of the invention is the use of the compound represented by Formula 2 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention and / or treatment and / or control of cytokine release syndrome. In one embodiment, cytokine release syndrome is a syndrome caused by an excessive immune response in a subject to a toxic infection. In one aspect, the excessive immune response can be a burst of cytokine release (cytokine storm). Therefore, treatment, prevention, or control of cytokine release syndrome may include normalizing and / or reducing supraphysiological levels of pro-inflammatory cytokines in a patient. Pro-inflammatory cytokines include IFNb, IL1b, TNFα, and / or IL6, etc.

[0055] Another aspect of the invention is the use of the compound represented by Formula 6 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention and / or treatment and / or control of cytokine release syndrome. In one embodiment, cytokine release syndrome is a syndrome caused by an excessive immune response in a subject to a toxic infection. In one aspect, the excessive immune response can be a burst of cytokine release (cytokine storm). Therefore, treatment, prevention, or control of cytokine release syndrome may include normalizing and / or reducing supraphysiological levels of pro-inflammatory cytokines in a patient. Pro-inflammatory cytokines include IFNb, IL1b, TNFα, and / or IL6, etc.

[0056] Another aspect of this embodiment is the use of compounds 18a, 18k, 22i, or 22r, or pharmaceutically acceptable salts thereof, or solvates thereof, or isomers thereof, in the preparation of a medicament for the prevention and / or treatment of cytokine release syndrome. In one embodiment, cytokine release syndrome is a syndrome caused by an excessive immune response in a subject to a toxic infection. In one aspect, the excessive immune response can be a burst of cytokine release (cytokine storm). Treatment, prevention, or control of cytokine release syndrome may include normalizing and / or reducing supraphysiological levels of pro-inflammatory cytokines in the patient. Pro-inflammatory cytokines include IFNb, IL1b, TNFα, and / or IL6, etc. Attached Figure Description

[0057] Figures 1A-1C The compound represented by Formula 1 was shown to exert its anti-inflammatory effect by inhibiting the expression of inflammatory surface markers (CD40, CD80, CD86) in LPS-treated macrophages.

[0058] Figure 2 The efficacy of the compound of Formula 1 in vivo in an LPS-induced endotoxemia model was demonstrated. To evaluate the effect of the compound of Formula 1 in an LPS-induced endotoxemia model, the model was treated with DMRC200434, which resulted in a significant delay in endotoxin-mediated death. This result indicates that the compound of Formula 1 can treat cytokine release syndrome. Detailed Implementation

[0059] This invention relates to a method for preventing and / or treating cytokine release syndrome, comprising administering an arylethylene compound of formula 1, or a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof:

[0060]

[0061] All symbols have the same meaning as those defined in the aforementioned Chemical Formula 1.

[0062] According to one embodiment, the compound may be a compound represented by chemical formula 2, or a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof:

[0063]

[0064] All symbols have the same meaning as those defined in the aforementioned chemical formula 2.

[0065] According to one embodiment, the compound can be a pharmaceutically acceptable salt of the compound represented by Chemical Formula 6 or a solvation thereof:

[0066]

[0067] All symbols have the same meaning as those defined in the aforementioned chemical formula 6.

[0068] According to another embodiment, the compound represented by chemical formula 1 may be selected from one of the following compounds:

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075] In another embodiment, the compound represented by Formula 1 can be any of the following compounds:

[0076] Compound 18a (=DMRC200434)

[0077] (E)-5-(4-hydroxyphenyl)-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-4-phenylpent-4-en-1-ol

[0078] Compound 18k (=DMRC2001000)

[0079] (E)-5-(5-hydroxyphenyl)-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-4-phenylpent-4-en-1-ol

[0080] Compound 22i (DMRC200699)

[0081] (E)-5-(4-hydroxyphenyl)-5-(4-(N-cyclopropylpiperidin-4-yl)phenyl)-4-phenylpent-4-en-1-ol

[0082]

[0083] Compound 22r (DMRC200996)

[0084] (E)-5-(5-hydroxyphenyl)-5-(4-(N-cyclopropylpiperidin-4-yl)phenyl)-4-phenylpent-4-en-1-ol

[0085] A pharmaceutical composition according to one embodiment comprises, as an active ingredient, the compound described above, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or an isomer thereof. The pharmaceutical composition may include pharmaceutically acceptable carriers, excipients, or additives known in the art.

[0086] Methods of use

[0087] Generally, the present invention relates to a method or application for treating cytokine release syndrome, particularly cytokine release syndrome caused by toxic infection, comprising administering an arylethylene compound of formula 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0088] A treatment method according to one embodiment includes administering a therapeutically effective amount of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a patient in need. Various embodiments include methods of treating cytokine release syndrome by administering a therapeutically effective amount of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a patient in need.

[0089] In one embodiment, the compounds disclosed herein can be used to treat inflammatory conditions, particularly those mediated by cytokine release, especially cytokine storms. For example, the compounds disclosed herein can be used to treat inflammatory diseases that are the basis of a variety of human diseases characterized by a highly activated immune system that, upon infection with a virulent pathogen, leads to the secretion of large amounts of circulating pro-inflammatory cytokines in response to host cell damage or related stimuli, activating receptors on immune effector cells, including T cells, macrophages, and the like. A key feature of these infectious diseases is a burst of cytokine release from pro-inflammatory cells, including macrophages, lymphocytes, and polymorphonuclear leukocytes (PMNs), i.e., a cytokine storm.

[0090] Cytokine storms can be excessive (hypercytokineemia) and lead to lethal immune responses, with persistent activation of immune effector cells producing sustained and supraphysiological levels of TNFα, IFNb, IL-1β, and IL-6, resulting in severe tissue damage. The compounds disclosed herein can inhibit the release of pro-inflammatory cytokines such as TNFα, IFNb, IL-1β, and / or IL-6.

[0091] In some embodiments, the compounds disclosed herein are fully reactive to many harmful cytokines. For example, the compounds disclosed herein can inhibit hypercytokineemia and / or prevent or reduce supraphysiological levels of TNFα, IFNb, IL-1β, and / or IL-6 or related harmful molecules.

[0092] Inflammatory conditions treatable by the compounds disclosed herein include any condition having an inflammatory component. Exemplary inflammatory conditions include acute and chronic inflammatory conditions such as asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, localized pneumonia (including hypersensitivity pneumonitis and radiation pneumonitis), acute pneumonia, human immunodeficiency virus-related inflammation, sepsis, vasculitis, bursitis, viral or influenza-induced inflammation or edema. The compounds disclosed herein are effective in treating sepsis, pneumonia, viral infection-induced inflammation (e.g., influenza-induced inflammation), edema, etc. The compounds disclosed herein can be used to treat inflammation and tissue damage caused by pathogenic infections. In one embodiment, the pathogenic infection may be a toxic infection. The compounds disclosed herein are effective in treating sepsis or pneumonia.

[0093] Another embodiment disclosed herein is a method for inhibiting the production of pro-inflammatory cytokines in a subject, the method comprising administering to the subject a compound disclosed herein as an anti-ERRg inhibitor. The pro-inflammatory cytokines include TNFα, IFNb, IL-1β, and / or IL-6 or related harmful molecules.

[0094] Another embodiment disclosed herein is a method for reducing supraphysiological levels of pro-inflammatory cytokines in a subject, comprising administering to the subject a compound disclosed herein as an anti-ERRg inhibitor. The pro-inflammatory cytokines include TNFα, IFNb, IL-1β, and / or IL-6 or related harmful molecules.

[0095] As used herein, “treatment” in relation to a condition means: (1) improving the condition or one or more biological manifestations of the condition; (2) intervening in (a): one or more points in a biological cascade that lead to or cause the condition; or (b): one or more biological manifestations of the condition; (3) alleviating one or more symptoms or effects associated with the condition; or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

[0096] In the context of disease, the term "treatment" can include prevention or avoidance of the condition. The term "prevention" refers to the preventive administration of medication to adequately reduce the likelihood or severity of the condition or its biological manifestations, or to delay the onset of such condition or its biological manifestations.

[0097] As used herein, the term "effective amount" for compounds of Formula 1 or their pharmaceutically acceptable salts or other pharmaceutically active agents means an amount of compound sufficient to treat a patient's condition within the bounds of reasonable medical judgment. The effective amount of a compound will vary depending on the specific compound chosen (e.g., the compound's potency, efficacy, and half-life will be considered); the chosen route of administration; the condition being treated; the severity of the condition being treated; the age, body type, weight, and physical condition of the patient being treated; the patient's medical history; the duration of treatment; the nature of concurrent treatments; the desired therapeutic effect; and similar factors, but may still be routinely determined by those skilled in the art.

[0098] As used herein, the terms "patient" or "subject" refer to a human or other mammal. A mammal can be any type of mammal, including but not limited to mice, rats, dogs, cats, horses, sheep, goats, cattle, pigs, monkeys, or humans. In one embodiment, "patient" refers to a human.

[0099] One embodiment of this disclosure also provides a method for treating cytokine release syndrome, the method comprising administering to a patient in need an effective amount of a compound of formula 1, a pharmaceutically acceptable salt thereof, or a solvation thereof. In one embodiment, cytokine release syndrome is induced by a toxic infection. The infection may be a viral or bacterial infection.

[0100] In one embodiment, a method is provided for treating, preventing, or controlling cytokine release syndrome induced by toxic infection, the method comprising administering to a patient in need a therapeutically effective amount of a compound of Formula 1, a pharmaceutically acceptable salt thereof, or a solvation thereof.

[0101] In one embodiment, a method for treating cytokine release syndrome is provided, the method comprising administering to a patient in need a therapeutically effective amount of (E)-5-(4-hydroxyphenyl)-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-4-phenylpent-4-en-1-ol (compound DMRC200344 or 18a) or a pharmaceutically acceptable salt thereof or a solvate thereof. In one embodiment, cytokine release syndrome is caused by a toxic infection. The infection may be viral or bacterial.

[0102] In another embodiment, a method for treating cytokine release syndrome is provided, comprising administering to a patient in need a therapeutically effective amount of (E)-5-(5-hydroxyphenyl)-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-4-phenylpent-4-en-1-ol (compound DMRC2001000 or 18k), a pharmaceutically acceptable salt thereof, or a solvation thereof. In one embodiment, cytokine release syndrome is caused by a toxic infection. The infection may be viral or bacterial.

[0103] In another embodiment, a method for treating cytokine release syndrome is provided, comprising administering to a patient in need a therapeutically effective amount of (E)-5-(4-hydroxyphenyl)-5-(4-(N-cyclopropylpiperidin-4-yl)phenyl)-4-phenylpent-4-en-1-ol (compound DMRC200699 or 22i), a pharmaceutically acceptable salt thereof, or a solvation thereof. In one embodiment, cytokine release syndrome is caused by a toxic infection. The infection may be viral or bacterial.

[0104] In another embodiment, a method for treating cytokine release syndrome is provided, comprising administering to a patient in need a therapeutically effective amount of (E)-5-(5-hydroxyphenyl)-5-(4-(N-cyclopropylpiperidin-4-yl)phenyl)-4-phenylpent-4-en-1-ol (compound DMRC200699 or 22r), a pharmaceutically acceptable salt of or solvation thereof. In one embodiment, cytokine release syndrome is caused by a toxic infection. The infection may be viral or bacterial.

[0105] On the other hand, compounds of Formula 1, pharmaceutically acceptable salts thereof, or solvates thereof are provided for reducing cytokine levels in subjects infected with pathogens. Cytokine levels are serum cytokine levels. These cytokines include IFNb, IL1β, TNFα, and / or IL6, etc.

[0106] In one embodiment, a compound of Formula 1, a pharmaceutically acceptable salt thereof, or a solvation thereof is provided for treating cytokine release syndrome. In one embodiment, cytokine release syndrome is caused by a toxic infection. The infection may be viral or bacterial. Treatment of cytokine release syndrome may include normalizing the patient's serum cytokine levels. Cytokines include IFNb, IL1b, TNFα, and / or IL6, etc.

[0107] In one embodiment, the use of a compound of Formula 1, a pharmaceutically acceptable salt thereof, or a solvate thereof in the preparation of a medicament for treating cytokine release syndrome is provided. In one embodiment, cytokine release syndrome is caused by a toxic infection. The infection may be viral or bacterial. Treatment of cytokine release syndrome may include normalizing the patient's serum cytokine levels. Cytokines include IFNb, IL1β, TNFα, and / or IL6, etc.

[0108] In one embodiment, the use of (E)-5-(4-hydroxyphenyl)-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-4-phenylpent-4-en-1-ol (DMRC200344 or 18a), a pharmaceutically acceptable salt thereof, or a solvate thereof in the preparation of a medicament for treating cytokine release syndrome is provided. In one embodiment, cytokine release syndrome is caused by a toxic infection. The infection may be viral or bacterial. Treatment of cytokine release syndrome may include normalizing the patient's serum cytokine levels. Cytokines include IFNb, IL1b, TNFα, and / or IL6, etc.

[0109] In one embodiment, the use of (E)-5-(5-hydroxyphenyl)-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-4-phenylpent-4-en-1-ol (DMRC2001000 or 18k), a pharmaceutically acceptable salt thereof, or a solvate thereof in the preparation of a medicament for treating cytokine release syndrome is provided. In one embodiment, cytokine release syndrome is caused by a toxic infection. The infection may be viral or bacterial. Treatment of cytokine release syndrome may include normalizing the patient's serum cytokine levels. Cytokines include IFNb, IL1b, TNFα, and / or IL6, etc.

[0110] In one embodiment, the use of (E)-5-(4-hydroxyphenyl)-5-(4-(N-cyclopropylpiperidin-4-yl)phenyl)-4-phenylpent-4-en-1-ol (DMRC200699 or 22i), a pharmaceutically acceptable salt thereof, or a solvate thereof in the preparation of a medicament for treating cytokine release syndrome is provided. In one embodiment, cytokine release syndrome is caused by a toxic infection. The infection may be viral or bacterial. Treatment of cytokine release syndrome may include normalizing the patient's serum cytokine levels. Cytokines include IFNb, IL1b, TNFα, and / or IL6, etc.

[0111] In one embodiment, the use of (E)-5-(5-hydroxyphenyl)-5-(4-(N-cyclopropylpiperidin-4-yl)phenyl)-4-phenylpent-4-en-1-ol (DMRC200699 or 22r), a pharmaceutically acceptable salt thereof, or a solvate thereof in the preparation of a medicament for treating cytokine release syndrome is provided. In one embodiment, cytokine release syndrome is caused by a toxic infection. The infection may be viral or bacterial. Treatment of cytokine release syndrome may include normalizing the patient's serum cytokine levels. Cytokines include IFNb, IL1b, TNFα, and / or IL6, etc.

[0112] In one aspect, the present invention relates to a method or application for treating cytokine release syndrome, comprising administering to a patient in need a compound of formula 6, a pharmaceutically acceptable salt thereof, or a solvation thereof:

[0113]

[0114] In this embodiment, all symbols have the same meaning as defined in the aforementioned Chemical Formula 6. In one implementation, cytokine release syndrome is caused by a toxic infection. The infection can be viral or bacterial. Treatment of cytokine release syndrome may include normalizing the patient's serum cytokine levels. Cytokines include IFNb, IL1β, TNFα, and / or IL6, etc.

[0115] In another aspect, the present invention relates to a method or application for treating cytokine release syndrome, comprising administering to a patient in need a compound of formula 6, a pharmaceutically acceptable salt thereof, or a solvation thereof, wherein R 2 For hydroxyl group, R 1 It is a heterocyclic alkyl group selected from the following structures:

[0116]

[0117] Among them, R 31 and R 32 Each of these can be independently hydrogen, (C1-C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl, amidine, (C1-C10)alkoxycarbonyl, hydroxy(C1-C10)alkyl, or di(C1-C10)alkylamino(C1-C10)alkyl; and

[0118] L represents O or S.

[0119] In one implementation, cytokine release syndrome is caused by a toxic infection. The infection can be viral or bacterial. Treatment for cytokine release syndrome may include normalizing the patient's serum cytokine levels. These cytokines include IFNb, IL1β, TNFα, and / or IL6, etc.

[0120] In another aspect, the present invention relates to a method or application for treating cytokine release syndrome, comprising administering to a patient in need a compound selected from the above-mentioned compounds, a pharmaceutically acceptable salt thereof, or a solvation thereof. In one embodiment, cytokine release syndrome is caused by a toxic infection. The infection may be a viral or bacterial infection. Treatment of cytokine release syndrome may include normalizing the patient's serum cytokine levels. Cytokines include IFNb, IL1b, TNFα, and / or IL6, etc.

[0121] In another aspect, the present invention relates to a method or application for treating cytokine release syndrome, comprising administering to a patient in need (E)-5-(4-hydroxyphenyl)-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-4-phenylpent-4-en-1-ol (compound 18a, DMRC200434), (E)-5-(5-hydroxyphenyl)-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-4-phenylpent-4-en-1-ol (compound 18k, ... DMRC2001000), (E)-5-(4-hydroxyphenyl)-5-(4-(N-cyclopropylpiperidin-4-yl)phenyl)-4-phenylpent-4-en-1-ol (compound 22i, DMRC200699) or (E)-5-(5-hydroxyphenyl)-5-(4-(N-cyclopropylpiperidin-4-yl)phenyl)-4-phenylpent-4-en-1-ol (compound 22r, DMRC200996), pharmaceutically acceptable salts thereof, or solvates thereof. In one embodiment, cytokine release syndrome is caused by a toxic infection. The infection may be viral or bacterial. Treatment, prevention, or control of cytokine release syndrome may include normalizing the patient's serum cytokine levels. Cytokines include IFNb, IL1b, TNFα, and / or IL6, etc.

[0122] In one aspect, the compound represented by Formula 1 can be present in amounts from about 0.01 mg / kg body weight to about 1000 mg / kg body weight, from about 0.01 mg / kg to about 500 mg / kg, from about 0.01 mg to about 400 mg / kg, from about 0.01 mg / kg to 300 mg / kg, from about 0.01 mg / kg to 200 mg / kg, from about 0.01 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to 50 mg / kg, or from about 0.01 mg / kg. / kg to 30mg / kg, about 0.01mg / kg to 20mg / kg, about 0.05mg / kg to about 1000mg / kg body weight, about 0.05mg / kg to about 500mg / kg, about 0.05mg to about 400mg / kg, about 0.05mg / kg to 300mg / kg, about 0.05mg / kg to 200mg / kg, about 0.05mg / kg to about 100mg / kg, about 0.05mg / kg to about 0.05m g / kg, about 0.05 mg / kg to about 0.20 mg / kg, about 0.05 mg / kg to about 5 mg / kg, about 0.5 mg / kg to about 100 mg / kg, about 0.5 mg / kg to about 50 mg / kg, about 0.5 mg / kg to about 20 mg / kg, about 0.2 mg / kg to 500 mg / kg, about 0.2 mg / kg to 400 mg / kg, about 0.2 mg / kg to about 300 mg / kg, about 0.2 mg / kg Administered at doses of about 200 mg / kg, about 0.2 mg / kg to about 100 mg / kg, about 0.1 mg / kg to 500 mg / kg, about 0.1 mg / kg to 400 mg / kg, about 0.1 mg / kg to about 300 mg / kg, about 0.1 mg / kg to about 200 mg / kg, about 0.1 mg / kg to about 100 mg / kg, about 0.1 mg / kg to about 50 mg / kg, or about 0.1 mg / kg to about 20 mg / kg.

[0123] Compositions

[0124] The compounds of the present invention may, but are not necessarily, formulated into pharmaceutical compositions prior to administration to a patient. Thus, in one aspect, a pharmaceutical composition is provided comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof or a solvate thereof, and one or more pharmaceutically acceptable excipients or carriers. This pharmaceutical composition may be prepared by mixing and is suitably adapted for oral, parenteral, or rectal administration at ambient temperature and atmospheric pressure, and therefore may be in the form of tablets, capsules, oral liquid formulations, powders, granules, lozenges, reconfigurable powders, injectable or non-injectable solutions or suspensions, or suppositories.

[0125] Suitable pharmaceutically acceptable excipients or carriers will vary depending on the specific dosage form chosen. Furthermore, suitable pharmaceutically acceptable excipients or carriers can be selected for a specific function that can play a role in the composition. For example, certain pharmaceutically acceptable excipients or carriers can be selected because they facilitate the production of a uniform dosage form. Certain pharmaceutically acceptable excipients or carriers can be selected because they facilitate the production of a stable dosage form. Certain pharmaceutically acceptable excipients or carriers can be selected because, once administered to a patient, they facilitate the transport or translocation of the compound represented by Formula 1 or its pharmaceutically acceptable salt from one organ or part of the body to another organ or part of the body. Certain pharmaceutically acceptable excipients or carriers can be selected because they enhance patient compliance.

[0126] Suitable pharmaceutically acceptable excipients or carriers include the following types of excipients or carriers: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, solubilizers, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, coloring agents, anti-caking agents, wetting agents, chelating agents, plasticizers, thickeners, antioxidants, preservatives, stabilizers, surfactants, and buffers. Those skilled in the art will understand that some pharmaceutically acceptable excipients can provide more than one function and can provide alternative functions, depending on the amount of excipient present in the formulation and what other excipients are present in the formulation.

[0127] Those skilled in the art possess the knowledge and skills to select appropriate amounts of suitable pharmaceutically acceptable excipients or carriers.

[0128] The pharmaceutical composition according to one embodiment is prepared using techniques and methods known to those skilled in the art.

[0129] According to one embodiment, a pharmaceutical composition can be prepared by mixing, and is generally suitable for oral, parenteral, or rectal administration at ambient temperature and atmospheric pressure. Therefore, it can be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconfigurable powders, injectable or non-injectable solutions or suspensions, or suppositories.

[0130] The pharmaceutical composition may contain 0.1 wt% to 99 wt% of the active substance, depending on the method of administration. The dosage of the compound used to treat the aforementioned conditions or diseases will vary in the usual manner depending on the severity of the condition or disease, the subject's weight, and other similar factors. However, as a general guideline, suitable unit doses may be 0.05 to 5000 mg, 1.0 to 500 mg, or 1.0 to 200 mg, and such unit doses may be administered more than once daily, for example, twice or three times daily. This treatment may continue for weeks, months, or years.

[0131] In one embodiment, the pharmaceutical composition is formulated as an injectable or non-injectable solution, or a reconfigurable powder.

[0132] In one embodiment, the pharmaceutical composition is suitable for oral formulation.

[0133] Tablets and capsules for oral administration may be in unit dose form and may contain conventional excipients, such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate); compression 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 known in routine pharmaceutical practice.

[0134] Oral liquid formulations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be in the form of a dried product reconstituted with water or other suitable media prior to use. Such liquid formulations may contain conventional additives, such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats), emulsifiers (e.g., lecithin or gum arabic), non-aqueous carriers (which may include edible oils such as almond oil, esters, ethanol, or fractionated vegetable oils), preservatives (e.g., methylparaben or propylparaben or sorbic acid), and, if desired, conventional flavoring or coloring agents, buffer salts, and sweeteners. Oral dosage forms may be suitably formulated to provide controlled release of the active compound.

[0135] For parenteral administration, fluid unit dosage forms are prepared using the compounds of the present invention or pharmaceutically acceptable salts thereof and sterile media. Injectable formulations may be in unit dosage forms, such as ampoules or multiple doses, using the compounds of the present invention or pharmaceutically acceptable salts thereof and sterile media, optionally with the addition of preservatives. The composition may be in the form of a suspension, solution, or emulsion, for example, in an oily or aqueous media, and may contain formulations such as suspending agents, stabilizers, and / or dispersants. Alternatively, the active ingredient may be in powder form, reconstituted with a suitable media, such as sterile pyrogen-free water, prior to use. Depending on the media used and the concentration, the compound may be suspended or dissolved in the media. In preparing solutions, the compound may be dissolved, sterilized by injection and filtration, and then filled into suitable vials or ampoules and sealed. Advantageously, adjuvants such as local anesthetics, preservatives, and buffers are dissolved in the media. To improve stability, the composition may be frozen after being filled into vials and water removed under vacuum. The parenteral suspension is prepared in essentially the same manner, except that the compound is suspended in the medium rather than dissolved, and sterilization cannot be achieved by filtration. The compound can be sterilized by exposure to ethylene oxide before suspension in a sterile medium. Advantageously, the composition includes a surfactant or wetting agent to promote uniform distribution of the compound.

[0136] Lotions can be formulated with aqueous or oil-based bases and typically contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners, or colorants. Drops can be formulated with aqueous or non-aqueous bases and also contain one or more dispersants, stabilizers, solubilizers, or suspending agents. They may also contain preservatives.

[0137] The pharmaceutical composition can also be formulated into rectal compositions, such as suppositories or retention enemas, for example, containing a conventional suppository base, such as cocoa butter or other glycerides.

[0138] The pharmaceutical compositions can also be formulated into reservoir formulations. Such long-acting formulations can be administered via implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Thus, for example, the compounds of the present invention can be formulated with suitable polymers or hydrophobic materials (e.g., as emulsions in acceptable oils) or ion exchange resins, or as slightly soluble derivatives, such as slightly soluble salts.

[0139] For intranasal administration, the compounds of the present invention can be formulated as solutions and administered via suitable metering or single-dose devices, or as powders mixed with suitable carriers and administered using suitable delivery devices. Thus, the compounds of formula (I) can be formulated for oral, oral, parenteral, topical (including ocular and nasal), receptacle, or rectal administration, or for administration via inhalation or blowing (through the mouth or nose).

[0140] Pharmaceutical compositions can be formulated as ointments, creams, gels, lotions, vaginal suppositories, aerosols, or drops (e.g., eye drops, ear drops, or nasal drops) for topical administration. Ointments and creams can be formulated, for example, using an aqueous or oil-based base with the addition of suitable thickeners and / or gelling agents. Ointments for ocular administration can be prepared aseptically using sterile ingredients.

[0141] One aspect of the present invention provides a pharmaceutical composition for treating, preventing, or controlling cytokine release syndrome, comprising a compound of Formula 1, a pharmaceutically acceptable salt thereof, or a solvation thereof, and one or more pharmaceutically acceptable excipients or carriers. In one embodiment, cytokine release syndrome is caused by a toxic infection. The infection may be viral or bacterial. Treatment, prevention, or control of cytokine release syndrome may include normalizing the patient's serum cytokine levels. The cytokines include IFNb, IL1b, TNFα, and / or IL6, etc.

[0142] Reference Preparation

[0143] The compound represented by Formula 1 can be prepared according to the method described in U.S. Patent Application No. 16 / 313,360, the entire contents of which are incorporated herein by reference.

[0144] Reference Preparation Example 1: Preparation of (E)-5-(4-(2-(aziridin-1-yl)ethoxy)phenyl)-5-(4-bromophenyl)-4-phenylpent-4-en-1-ol hydrochloride (compound 18t)

[0145] Compound 18t was prepared using the following reaction procedure:

[0146]

[0147] Step 1: Preparation of methyl 5-(4-(neovaleroxy)phenyl)pentan-4-acetylic acid (C-1)

[0148] 4-Iodophenyl neopentanoate (2 g, 6.6 mmol), copper chloride (I) (0.13 g, 0.66 mmol), bis(triphenylphosphine)palladium(II) dichloride (PdCl2(PPh3)2, 0.23 g, 0.33 mmol), and methyl pentyl-4-acetylacetic acid (0.74 g, 0.66 mmol) were dissolved in trimethylamine (15 mL) and reacted at 50 °C for 12 hours. The reaction solution was concentrated under reduced pressure and column chromatography was used to obtain 1.1 g of the desired compound C-1 (58%).

[0149] Step 2: Preparation of (E)-3-(4-(5-methoxy-5-oxo-2-phenyl-1-(4-(neovaleroxy)phenyl)pent-1-en-1-yl)phenyl)azacyclobutane-1-carboxylic acid tert-butyl ester (C-2)

[0150] 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxacycloboroxane-2-yl)phenyl)azacyclobutane-1-carboxylic acid tert-butyl ester (0.27 g, 0.75 mmol), compound C-1 (0.14 g, 0.5 mmol), and iodobenzene (84 μL, 0.75 mmol) were dissolved in DMF (8 mL) and water (4 mL). 0.025 M PdCl₂(PhCN)₂ (0.2 mL, 5 μmol) was added, and the mixture was heated at 45 °C for 10 min. Cesium carbonate (0.24 g, 0.75 mmol) was added, and the mixture was heated at 45 °C for 12 h. When the reaction was complete, brine and ethyl acetate were added to the reaction solution, and the organic layer was extracted. The organic layer was dried over anhydrous Na₂SO₄ and filtered. The residue was obtained by vacuum distillation and purified by column chromatography to give 81 mg of the desired compound C-2 (27%).

[0151] Step 3: Preparation of (E)-3-(4-(5-hydroxy-1-(4-hydroxyphenyl)-2-phenylpent-1-en-1-yl)phenyl)azacyclobutane-1-carboxylic acid tert-butyl ester (18t)

[0152] Compound C-2 (0.021 mmol) was added to tetrahydrofuran (2 mL), the temperature was lowered to 0 °C, and 1 M lithium aluminum hydride, diisobutylaluminum hydride, or lithium borohydride (0.024 mL, 0.024 mmol) were added. The temperature was raised to room temperature and stirred for 1 hour. Water and ethyl acetate were added to the reaction solution to extract the organic layer. The organic layer was dried over anhydrous Na₂SO₄ and filtered. The solvent was distilled under reduced pressure to obtain the residue, which was purified by column chromatography and then dissolved in methanol:dichloromethane (1:1). The temperature was lowered to 0 °C, and 1 M aqueous HCl solution was slowly added. The mixture was then distilled under reduced pressure to obtain 24 mg of the desired compound 18t (78%).

[0153] Reference Preparation 2-3

[0154] Compounds 18a and 18t were prepared according to the method of Reference Preparation Example 1, and the identification data of compounds 18a and 18t prepared therefrom are shown in Table 1 below.

[0155] Table 1

[0156]

[0157] Reference Preparation 4

[0158] Preparation of (E)-4-(5-hydroxy-1-(4-(1-isopropylazacyclobutane-3-yl)phenyl)-2-phenylpent-1-en-1-yl)phenol (compound 22a)

[0159] Compound 22a was prepared using the following reaction procedure:

[0160]

[0161] Step 1: Preparation of methyl (E)-5-(4-(1-isopropylazacyclobutane-3-yl)phenyl)-4-phenyl-5-(4-(neovaleroxy)phenyl)pent-4-enoate (E-2)

[0162] Compound E-1 (0.03 g, 0.06 mmol), acetone (0.14 mL, 1.9 mmol), and sodium triacetoxyborohydride (NaBH(OAc)3, 41 mg, 0.19 mmol) were added to dichloroethane (3 mL) and stirred at room temperature for 1 hour. Water and ethyl acetate were then added to the reaction solution, and the organic layer was extracted. The organic layer was dried over anhydrous Na₂SO₄ and filtered. The solvent was distilled under reduced pressure to obtain the residue, which was purified by column chromatography to yield 18 mg of the desired compound E-2 (54%).

[0163] Step 2: Preparation of (E)-4-(5-hydroxy-1-(4-(1-isopropylazacyclobutane-3-yl)phenyl)-2-phenylpent-1-en-1-yl)phenol (22a)

[0164] Using compound E-2, 4 mg of the desired compound 22a (27%) was obtained by following the same method as step 3 in Preparation Example 4.

[0165] Reference Preparation 5-6

[0166] Compounds 22i and 22r were prepared according to the method of Reference Preparation Example 4, and the identification data of compounds 22i and 22r prepared therefrom are shown in Table 2 below.

[0167] Table 2

[0168]

[0169]

[0170] Biological Examples

[0171] Animal model. Six- to eight-week-old female C57BL / 6 mice (Jackson Laboratory) were used, following an animal protocol approved by the Animal Care and Use Committee of Kyungook National University.

[0172] Biological Example 1 The anti-inflammatory effect of the compound shown in Formula 1 on macrophages

[0173] Dysregulation of immune activation in innate immune cells is a major factor contributing to cytokine release syndrome. The immunomodulatory effects of compound 1 (DMRC200434) on macrophages were evaluated using compound 18a (DMRC200434). Activated macrophages were treated with 5 μM DMRC200434 with 100 ng / mL lipopolysaccharide (LPS) (Sigma-Aldrich). After 24 hours of LPS treatment, activation markers (CD40, CD80, CD86) were measured by flow cytometry.

[0174] When LPS is triggered on macrophages, the expression of inflammatory surface markers (CD40, CD80, CD86) is upregulated, and their expression is downregulated after treatment with the compound shown in Formula 1. Figures 1A-1C This result indicates that DMRC200434 may have the potential to treat cytokine release syndrome.

[0175] Biological Example 2 LPS-induced endotoxemia model

[0176] The compound represented by Formula 1 (DMRC200434, 30 mg / kg) was dissolved in a solution of 5% DMSO: 95%-20% PEG400 (saline) and injected at two points—24 hours before and at the start of LPS (50 mg / kg) injection. Survival was observed for 50 hours after LPS injection.

[0177] The inventors used DMRC200434 to analyze the efficacy of the compound of Formula 1 in vivo against an LPS-induced endotoxemia model. To evaluate the effect of DMRC200434 on endotoxemia, the LPS-induced endotoxemia model was treated with DMRC200434. DMRC200434 significantly delayed endotoxin-mediated death (…). Figure 2 This result indicates that DMRC200434 may have the potential to treat cytokine release syndrome.

[0178] Given the many possible embodiments in which the principles of the disclosed invention can be applied, it should be recognized that the embodiments shown are merely preferred embodiments of the invention and should not be considered as limiting the scope of the invention.

Claims

1. The use of a pharmaceutical composition in the preparation of a medicament for treating, preventing, or controlling cytokine release syndrome caused by macrophage activation in a subject of need, said pharmaceutical composition comprising an effective amount of the following compound as an active ingredient, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier:

2. The application according to claim 1, wherein, The cytokine release syndrome is caused by a viral infection.

3. The application according to claim 1, wherein, Cytokine release syndrome is an inflammatory disease.

4. The application according to claim 3, wherein, The inflammatory disease mentioned is sepsis.

5. The application according to claim 3, wherein, The inflammatory disease mentioned is pneumonia.

6. The application according to claim 1, wherein, Administration of the compound reduced the levels of pro-inflammatory cytokines in the serum of the subjects.

7. The application according to claim 6, wherein, The pro-inflammatory cytokines are IFNb, IL1b, TNFα and / or IL6.

8. The application according to claim 1, wherein, The compound is (E)-5-(4-hydroxyphenyl)-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-4-phenylpent-4-en-1-ol, as shown in the following chemical formula: Or its pharmaceutically acceptable salt.

9. The use of a pharmaceutical composition in the preparation of a medicament for the prevention, treatment, or control of cytokine release syndrome caused by macrophage activation in a subject of need, said pharmaceutical composition comprising an effective amount as an active ingredient (E)-5-(4-hydroxyphenyl)-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-4-phenylpent-4-en-1-ol, represented by the following chemical formula: Or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.

10. The application according to claim 9, wherein, The cytokine release syndrome is caused by a viral infection.

11. Use of a pharmaceutical composition in the preparation of a medicament for treating endotoxemia in a subject of need, said pharmaceutical composition comprising an effective amount of the following compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier:

12. The application according to claim 11, wherein, The compound is (E)-5-(4-hydroxyphenyl)-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-4-phenylpent-4-en-1-ol, as shown in the following chemical formula:

13. The application according to claim 12, wherein, The subject had a viral infection.

14. The use of the following compounds in the preparation of any one of the following (a)-(b): (a) For the treatment, prevention or control of cytokine release syndrome caused by macrophage activation in subjects in need, (b) For the treatment of endotoxemia in subjects in need.

Images