Metalloenzyme inhibitors used to treat cancer, Alzheimer's disease, hemochromatosis, and other conditions.

Abstract

The pharmaceutical compound possesses anti-inflammatory activity and, in some respects, can act as a metalloenzyme inhibitor for the beneficial regulation of metalloproteins. The pharmaceutical composition may comprise a therapeutically effective amount of the compound and a pharmaceutically acceptable mediator. The pharmaceutical composition may be used to treat conditions associated with chronic inflammation and / or metalloenzyme dysregulation, including hemochromatosis, cancers such as breast cancer, or neurodegenerative diseases such as Alzheimer's disease.

Description

[0001] Cross-reference of related applications

[0002] This application claims priority to U.S. Application No. 63 / 092,594, filed October 16, 2020, pursuant to 35 U.S. SC §119(e), the disclosure of which is hereby incorporated herein by reference in its entirety. Background Technology

[0003] Metalloproteins perform a variety of functions in the body, including regulating blood pH, promoting matrix degradation, and regulating DNA transcription. Dysregulation of metalloproteinases can lead to a range of disease states, including cancer, heart disease, Alzheimer's disease, and hemochromatosis. Inhibition of metalloproteinases therefore presents a promising target for various therapeutic approaches.

[0004] Conventional metalloenzyme inhibitors are typically small molecules with metal-binding groups (MBGs) incorporated into their active sites to coordinate with metal ions. MBGs are linked to the drug-like "backbone" group via linkers. Hydroxamic acid is the most common MBG among metalloenzyme inhibitors, followed by carboxylic acids, thiols, and phosphonates.

[0005] For cancers (such as breast cancer) and other conditions associated with metalloenzyme dysregulation (such as hemochromatosis and Alzheimer's disease), alternative metalloenzyme inhibitors and therapeutic treatments are still needed. Summary of the Invention

[0006] According to one aspect, a compound has the following structure:

[0007]

[0008] Or its pharmaceutically acceptable salts, esters or solvates.

[0009] In another aspect, a pharmaceutical composition comprises a therapeutically effective amount of the compound described above and a pharmaceutically acceptable mediator for said compound.

[0010] On the other hand, one approach to treating conditions associated with chronic inflammation involves administering a pharmaceutical composition to an individual in need.

[0011] On another front, a method of treating conditions associated with metalloenzyme dysregulation involves administering a pharmaceutical composition to an individual in need. In some respects, the condition is cancer, such as breast cancer. In others, the condition is hemochromatosis. In still others, the condition is a neurodegenerative disease, such as Alzheimer's disease.

[0012] This article also describes various other pharmaceutical compounds, pharmaceutical compositions, and related treatment methods. Attached Figure Description

[0013] The following figures illustrate a non-limiting and non-exhaustive embodiment, wherein similar reference numerals are used throughout the figures to indicate similar parts unless otherwise specified.

[0014] Figure 1 The nuclear magnetic resonance (NMR) spectrum of a compound synthesized according to one aspect of this disclosure is shown.

[0015] Figure 2 It is an NMR spectrum like Figure 1 The mass spectrum of the compound shown.

[0016] Figure 3 It is an NMR spectrum like Figure 1 High-performance liquid chromatography (HPLC) of the compound shown.

[0017] Figure 4 It is an NMR spectrum like Figure 1 The Diversity PLUS panel plot of the compound shown.

[0018] Figure 5 It demonstrates TNF-α convertase (TACE), which requires Zn 2+ It also cleaved TNF-α, IL-6, and IL-17 into their soluble forms of metalloproteinases.

[0019] Figure 6 This demonstrates phosphoinositol 3-kinase (PI3K) activated via the insulin receptor (InsR) in cells exposed to insulin; Cu 2+ and Zn 2+ (Not shown) Stimulation of PI3K and Ser / Thr kinase Akt PI3K-dependent activation. Detailed Implementation

[0020] In some respects, the pharmaceutical compounds disclosed herein can act as inhibitors of metalloenzymes. While not wishing to be bound by theory, it is believed that the compounds can beneficially modulate metalloproteins and / or inhibit metalloenzymes to treat conditions associated with overexpression, enhanced activation, or dysregulation of endogenous metalloenzymes. More broadly, the compounds can interact with one or more metalloenzyme targets, as described in Chen et al., Targeting Metalloenzymes for Therapeutic Intervention, Chem Rev. 2019 Jan 23; 119(2):1323–1455, doi:10.1021 / acs.chemrev.8b00201, the contents of which are hereby incorporated by reference. Zinc enzymes, as part of zinc metalloproteins, play a crucial role in this field.

[0021] Zinc is an essential transition metal ion and micronutrient for life, and is required for the activity of more than 300 enzymes. Zinc concentrations in cells are quite high, almost as high as ATP concentrations. In biology, zinc is the second most common metal and the only known metal present in all six classes of enzymes. Zinc is a major metal cofactor of metalloproteins, and zinc-containing proteins (up to 3,000 species) constitute the largest class of metalloproteins, accounting for a quarter to half of all metalloproteins. Zinc metalloproteins are involved in many important biological functions, including cell proliferation and differentiation, RNA and DNA synthesis, cell structure / membrane stability, redox regulation, and apoptosis. Increasing evidence suggests that zinc metalloproteins play a fundamental role in the pathophysiology and pathogenesis of a wide range of human diseases, from cancer to infection. See Hou et al., “Zinc enzymes in medicinal chemistry,” Euro. J. of Med. Chem. 226(2021) 113877.

[0022] Zinc is also one of the most common and important elements involved in brain function, playing a role in both physiological and pathophysiological processes. It contains "free zinc ions" (Zn). 2+Neurons containing zinc are present in various regions of the brain, including cortical, amygdala, olfactory bulb, and hippocampal neurons, and these neurons appear to have the highest zinc concentration in the brain. Zinc acts as a structural, regulatory, and catalytic cofactor for various enzymes (such as DNA and RNA polymerases, histone deacetylases, and DNA ligases) and is involved in the biological activity of enzymes, proteins, and signaling transcription factors, as well as the maintenance of various homeostatic mechanisms. Zinc is also important for cell growth and genome stability. See Choi et al., “Zinc in the Brain: Friend or Foe?”, International Journal of Molecular Sciences (Int. J. Mol. Sci), 2020, 21, 8941; doi:10.3390 / ijms21238941.

[0023] The pharmaceutical compounds disclosed herein possess anti-inflammatory activity. For example, the compounds may possess anti-inflammatory activity that reduces the level of inflammation-inducing molecules. While not wishing to be bound by theory, it is believed that the disclosed compounds may possess anti-inflammatory activity that reduces the level of substance P (SP), calcitonin gene-related peptide (CGRP), glutamate, or combinations thereof. The compounds may possess anti-inflammatory activity that reduces the level of SP, CGRP, glutamate, or combinations thereof released from sensory neurons by, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%.

[0024] Prostaglandins mediate local inflammatory responses and participate in all inflammatory functions through their action on prostaglandin receptors, mediating inflammatory signaling including chemotaxis (macrophages, neutrophils, and eosinophils), vasodilation, and hyperalgesia. However, the PG-mediated inflammatory response is self-limiting (naturally curative). The primary degradation factor is a prostaglandin called 15dPGJ2, which is an endogenous agonist of peroxisome proliferator-activated receptor-γ (PPAR-γ) signaling. The PPAR-γ signaling pathway 1) induces apoptosis in macrophage M1 cells, thereby reducing the levels of Th1 pro-inflammatory cytokines, and 2) promotes the differentiation of monocytes into macrophage M2 cells. Macrophage M2 cells produce and release Th2 anti-inflammatory cytokines.

[0025] The compounds disclosed herein may possess anti-inflammatory activity, which can reduce the level of inflammation-induced prostaglandins. The compounds may possess anti-inflammatory activity that can reduce the level of inflammation-induced prostaglandins released from sensory neurons by, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. The compound may possess anti-inflammatory activity, which is capable of reducing the level of inflammation-induced prostaglandins released from sensory neurons, for example, by about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 100%. The range of approximately 90%, approximately 40% to approximately 90%, approximately 50% to approximately 90%, approximately 60% to approximately 90%, approximately 70% to approximately 90%, approximately 10% to approximately 80%, approximately 20% to approximately 80%, approximately 30% to approximately 80%, approximately 40% to approximately 80%, approximately 50% to approximately 80%, or approximately 60% to approximately 80%, approximately 10% to approximately 70%, approximately 20% to approximately 70%, approximately 30% to approximately 70%, approximately 40% to approximately 70%, or approximately 50% to approximately 70%.

[0026] Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptor proteins that act as transcription factors regulating gene expression. All PPARs are known to heterodimerize with the retinol X receptor (RXR) and bind to specific regions on target gene DNA called peroxisome proliferator-hormone response elements (PPREs). PPARs play important roles in the regulation of cell differentiation, development, and metabolism (carbohydrates, lipids, proteins) and tumorigenesis in higher organisms. This family includes three members: PPAR-α, PPAR-γ, and PPAR-δ (also known as PPAR-β). PPAR-α is expressed in the liver, kidneys, heart, muscle, adipose tissue, and other tissues. PPAR-δ is expressed in many tissues, but is prominently expressed in the brain, adipose tissue, and skin. PPAR-γ comprises three alternating splice forms, each with a distinct expression pattern. PPAR-γ1 is expressed in almost all tissues, including the heart, muscle, colon, kidneys, pancreas, and spleen. PPAR-γ2 is primarily expressed in adipose tissue. PPAR-γ3 is expressed in macrophages, colon, and white adipose tissue. The endogenous ligands of PPAR include free fatty acids and eicosanoids. PPAR-γ is activated by PGD2 (a prostaglandin), while PPAR-α is activated by leukotriene B4.

[0027] The compound may have anti-inflammatory activity, which can reduce the levels of IFN-γ, TNF-α, IL-12 or combinations thereof released from Th1 cells and increase the levels of IL-10 released from Th2 cells. The compound may have anti-inflammatory activity capable of reducing the levels of IFN-γ, TNF-α, IL-12, or combinations thereof released from Th1 cells by, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%, and capable of increasing the level of IL-10 released from Th2 cells by, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%.

[0028] The compound may possess anti-inflammatory activity, which can stimulate some or all of the PPAR signaling pathway. Therefore, this compound could potentially act as a pan-PPAR agonist or a selective PPAR agonist.

[0029] The compound may possess anti-inflammatory activity that modulates Th1 and Th2 cytokines. The compound may possess anti-inflammatory activity that reduces the levels of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-12 (IL-12), or combinations thereof released from Th1 cells. The compound may possess anti-inflammatory activity that reduces the levels of IFN-γ, TNF-α, IL-12, or combinations thereof released from Th1 cells by, for example, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. The compound may have anti-inflammatory activity that can reduce the levels of IFN-γ, TNF-α, IL-12, or combinations thereof released from Th1 cells, for example, in the range of about 5% to about 100%, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, or about 10% to about 90%.

[0030] The compound may possess anti-inflammatory activity capable of increasing the level of IL-10 released from Th2 cells. The compound may possess anti-inflammatory activity capable of increasing the level of IL-10 released from Th2 cells by, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%.

[0031] According to one aspect, a compound has the following structure:

[0032]

[0033] Or its pharmaceutically acceptable salts, esters or solvates.

[0034] Another compound disclosed herein, 5-(5-(3,4-dihydro-2H-pyrrolo-2-yl)pyridin-3-yl)-1-methylpyrrolidin-2-one, has the following structure:

[0035]

[0036] Or its pharmaceutically acceptable salts, esters or solvates.

[0037] In other respects, the compound has a structure selected from the group consisting of:

[0038]

[0039] Or its pharmaceutically acceptable salts, esters or solvates.

[0040] Pharmaceutical compositions may comprise a pharmaceutically acceptable carrier that facilitates the formulation of the active ingredient into a pharmaceutically acceptable composition. As used herein, the term "pharmacologically acceptable carrier" is synonymous with "pharmacological carrier" and means any carrier that has substantially no long-term or permanent harmful effects when administered, and encompasses terms such as "pharmacologically acceptable mediator," "stabilizer," "diluent," "additive," "excipient," or "component." This carrier is typically mixed with the active compound or allows for the dilution or blocking of the active compound, and may be a solid, semi-solid, or liquid formulation. It should be understood that the active ingredient may be soluble or may be delivered as a suspension in the desired carrier or diluent. Any of a variety of pharmaceutically acceptable carriers can be used, including, but not limited to, aqueous media such as water, saline, glycine, hyaluronic acid, etc.; solid carriers such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, etc.; solvents; dispersion media; coatings; antibacterial and antifungal agents; isotonic and absorption delay agents; or any other inactive ingredient. The choice of a pharmacologically acceptable carrier may depend on the route of administration. The use of this carrier in a pharmaceutically acceptable composition is envisioned, except to the extent that any pharmacologically acceptable carrier is incompatible with the active ingredient.Non-limiting examples of specific uses of such drug delivery systems can be found in the following literature: Pharmaceutical Dosage Forms and Drug Delivery Systems (edited by Howard C. Ansel et al., Lippincott Williams & Wilkins Publishers, 7th edition, 1999); Remington: The Science and Practice of Pharmaceuticals (edited by Alfonso R. Gennaro, Lippincott Williams & Wilkins Publishers, 20th edition, 2000); and Goodman & Gilman: The Pharmacological Basis of Therapeutics (edited by Joel G. Hardman et al., McGraw-Hill Professional Publishers). Professional (10th edition, 2001); and Handbook of Pharmaceutical Excipients (Raymond C. Rowe et al., APhA Publications, 4th edition, 2003). These protocols are standard procedures, and any modifications are entirely within the scope of those skilled in the art and are made in accordance with the teachings herein.

[0041] Chronic inflammatory symptoms can be associated with a large class of conditions that are otherwise unrelated, and these conditions form the basis of many diseases and symptoms. The immune system is often involved in chronic inflammatory conditions, as seen in both allergic reactions and some myopathies, many of which lead to abnormal inflammation. Non-immune diseases with etiological origins in the chronic inflammatory process include cancer, atherosclerosis, and ischemic heart disease.Non-limiting examples of conditions presenting with chronic inflammation include, but are not limited to, acne, acid reflux / heartburn, age-related macular degeneration (AMD), allergies, allergic rhinitis, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), anemia, appendicitis, arteritis, arthritis, asthma, atherosclerosis, autoimmune diseases, balanitis, blepharitis, bronchiolitis, tracheitis, bullous pemphigoid, burns, bursitis, cancer, cardiac arrest, carditis, celiac disease, cellulitis, cervicitis, cholangitis, cholecystitis, chorioamnionitis, chronic obstructive pulmonary disease (COPD), cirrhosis, colitis, congestive heart failure, conjunctivitis, and Crohn's disease. Diseases, cyclophosphamide-induced cystitis, cystic fibrosis, cystitis, common cold, dacryoadenitis, dementia, dermatitis, dermatomyositis, diabetes, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic ulcer, digestive system diseases, eczema, emphysema, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibromyalgia, fibrosis, fibrositis, gastritis, gastroenteritis, gingivitis, glomerulonephritis, glossitis, heart disease, valvular heart dysfunction, hepatitis, suppurative hand-foot-and-mouth disease, Huntington's disease Diseases, hyperlipidemic pancreatitis, hypertension, ileitis, infection, inflammatory bowel disease, inflammatory hypertrophic cardiomyopathy, inflammatory neuropathy, insulin resistance, interstitial cystitis, interstitial nephritis, iritis, ischemia, ischemic heart disease, keratitis, keratoconjunctivitis, laryngitis, lupus nephritis, mastitis, mastoiditis, meningitis, metabolic syndrome (Syndrome X), migraine, multiple sclerosis, myelitis, myocarditis, myositis, nephritis, non-alcoholic steatohepatitis, obesity, omphalitis, oophoritis, orchitis, osteochondritis, osteoporosis, osteomyelitis, osteoporosis, osteitis, otitis, pancreatitis, Parkinson's disease. Diseases, mumps, pelvic inflammatory disease, pemphigus vulgaris, pericarditis, peritonitis, pharyngitis, phlebitis, pleurisy, pneumonia, polycystic nephritis, proctitis, prostatitis, psoriasis, pulpitis, pyelonephritis, glomerulonephritis, renal failure, reperfusion injury, retinitis, rheumatic fever, rhinitis, salpingitis, sarcoidosis, sarcopenia, salivary gland inflammation, sinusitis, spastic colon, stenosis, stomatitis, stroke, surgical complications, synovitis, myositis, tendinitis, tendinous synovitis, thrombophlebitis, tonsillitis, trauma, traumatic brain injury, transplant rejection, triangle inflammation, tuberculosis, tumors, urethritis, bursitis, uveitis, vaginitis, vasculitis, and vulvitis.

[0042] Compounds intended for administration to humans or other mammals should generally have very high purity. Purity refers to the ratio of the mass of the compound to the total mass of the sample after any purification steps. Typically, purity levels are at least about 95%, and more commonly at least about 96%, about 97%, about 98%, or higher. For example, purity levels can be about 98.5%, 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or higher.

[0043] The compounds described herein, which exist in more than one optical isomer (enantiomer), can be provided as racemic mixtures or by isolating one enantiomer. In the latter case, purity, as described above, can refer to enantiomer purity.

[0044] The compounds described herein can be synthesized using techniques as described in the following literature: Riah et al., “Synthesis of Cotinine and Cotinine N-oxide: Evaluation of their Interaction with Nicotine in the Insecticidal Activity”, J. Nat. Prod. Letters, Vol. 11 (1997), https: / / doi.org / 10.1080 / 10575639708043755, wherein the disclosed structures can be obtained by appropriate modification of the reagents with the aid of routine experiments, which will be apparent to those skilled in the art.

[0045] In some respects, the compound can be converted into a pharmaceutically acceptable salt using techniques well known to those skilled in the art. For example, salts (such as sodium and potassium salts) can be prepared by treating the compound, respectively, with a suitable sodium or potassium base (such as sodium hydroxide or potassium hydroxide). Esters and ethers of the compound can be prepared, for example, as described in the following literature: Advanced Organic Chemistry, 1992, 4th edition, J. March, John Wiley & Sons, or Journal of Med. Chemistry, 1992, 35, 145-151.

[0046] The compositions described herein can be administered orally, nasally, topically, subcutaneously, intramuscularly, intravenously, or by other means of administration known to those skilled in the art.

[0047] The pharmaceutical composition may optionally include, but is not limited to, other pharmaceutically acceptable components (or pharmaceutical components), including, but not limited to, buffers, preservatives, tonic modifiers, salts, antioxidants, osmotic modifiers, physiological substances, pharmacological substances, fillers, emulsifiers, wetting agents, sweeteners, or flavoring agents. The pharmaceutical compositions disclosed herein can be prepared using various buffers and means for adjusting pH, provided that the resulting formulation is pharmaceutically acceptable. Such buffers include, but are not limited to, acetate buffers, citrate buffers, phosphate buffers, neutral buffered saline, phosphate buffered saline, and borate buffers. It should be understood that acids or bases may be used to adjust the pH of the composition as needed. Pharmaceutically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene. Useful preservatives include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, stable oxychloride compositions, and chelating agents such as DTPA or DTPA-diamide, calcium DTPA, and CaNaDTPA-diamide. Tonic modifiers that can be used in pharmaceutical compositions include, but are not limited to, salts such as sodium chloride, potassium chloride, mannitol, or glycerol, and other pharmaceutically acceptable tonic modifiers. Pharmaceutical compositions may be provided in the form of salts and may be formed from a number of acids, including, but not limited to, hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, etc. Salts tend to be more soluble in aqueous or other protic solvents than their corresponding free base forms. It should be understood that these substances, and other substances known in the field of pharmacology, may be included in pharmaceutical compositions.

[0048] Examples of adjuvants and / or excipients that may be mentioned include cremophor, poloxamer, benzalkonium chloride, sodium lauryl sulfate, dextrose, glycerin, magnesium stearate, polyethylene glycol, starch, dextrin, lactose, cellulose, sodium carboxymethyl cellulose, talc, agar, mineral oil, animal oil, vegetable oil, organic and mineral waxes, paraffin, gels, propylene glycol, benzyl alcohol, dimethylacetamide, ethanol, polyethylene glycol, Tween 80, Soluto HS15, and water. The active substance can also be administered in a suitable form (e.g., capsules) without a mordant or diluent.

[0049] The pharmaceutical composition may include a therapeutic compound in an amount sufficient to allow for routine administration to an individual. The unit dosage form may have, for example, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of the therapeutic compound. In other aspects, the unit dosage form may have, for example, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1,000 mg, at least 1,100 mg, at least 1,200 mg, at least 1,300 mg, at least 1,400 mg, or at least 1,500 mg of the therapeutic compound. In other aspects of this embodiment, the pharmaceutical compositions disclosed herein may comprise, for example, a therapeutic compound of about 5 mg to about 100 mg, about 10 mg to about 100 mg, about 50 mg to about 150 mg, about 100 mg to about 250 mg, about 150 mg to about 350 mg, about 250 mg to about 500 mg, about 350 mg to about 600 mg, about 500 mg to about 750 mg, about 600 mg to about 900 mg, about 750 mg to about 1,000 mg, about 850 mg to about 1,200 mg, or about 1,000 mg to about 1,500 mg. In other aspects of this embodiment, the pharmaceutical composition disclosed herein may contain, for example, about 10 mg to about 250 mg, about 10 mg to about 500 mg, about 10 mg to about 750 mg, about 10 mg to about 1,000 mg, about 10 mg to about 1,500 mg, about 50 mg to about 250 mg, about 50 mg to about 500 mg, about 50 mg to about 750 mg, about 50 mg to about 1,000 mg, about 50 mg to about 1,500 mg, about 100 mg to... Therapeutic compounds of about 250 mg, about 100 mg to about 500 mg, about 100 mg to about 750 mg, about 100 mg to about 1,000 mg, about 100 mg to about 1,500 mg, about 200 mg to about 500 mg, about 200 mg to about 750 mg, about 200 mg to about 1,000 mg, about 200 mg to about 1,500 mg, about 5 mg to about 1,500 mg, about 5 mg to about 1,000 mg, or about 5 mg to about 250 mg.

[0050] The pharmaceutical compositions described herein may contain pharmaceutically acceptable solvents. A solvent is a liquid, solid, or gas that dissolves another solid, liquid, or gas (solute) to form a solution. Solvents that can be used in pharmaceutical compositions include, but are not limited to, pharmaceutically acceptable polar aprotic solvents, pharmaceutically acceptable polar protic solvents, and pharmaceutically acceptable nonpolar solvents. Pharmaceutically acceptable polar aprotic solvents include, but are not limited to, dichloromethane (DCM), tetrahydrofuran (THF), ethyl acetate, acetone, dimethylformamide (DMF), acetonitrile (MeCN), and dimethyl sulfoxide (DMSO). Pharmaceutically acceptable polar protic solvents include, but are not limited to, acetic acid, formic acid, ethanol, n-butanol, 1-butanol, 2-butanol, isobutanol, sec-butanol, tert-butanol, n-propanol, isopropanol, 1,2-propanediol, methanol, glycerol, and water. Pharmaceutically acceptable nonpolar solvents include, but are not limited to, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, chloroform, n-methylpyrrolidone (NMP), and diethyl ether.

[0051] The appropriate method of administration and dosage range applicable in a particular situation depends on the species to be treated and the corresponding symptom or disease state, and can be optimized using techniques known in the art. Most commonly, the daily dose of the active compound in the patient can range from 0.0005 mg / kg to 15 mg / kg, and more typically from 0.001 mg / kg to 7.5 mg / kg. Administration can be a single dose or cumulative administration (continuous administration), and can be readily determined by those skilled in the art. For example, treatment may include a single administration of an effective dose of the pharmaceutical composition disclosed herein. Alternatively, treatment may include multiple administrations of an effective dose of the pharmaceutical composition over a series of time periods, such as once daily, twice daily, three times daily, every few days, or weekly. The timing of administration may vary from individual to individual, depending on factors such as the severity of individual symptoms. For example, an effective dose of the pharmaceutical composition disclosed herein may be administered to an individual once daily for an indeterminate period of time or until the individual no longer requires treatment. Those skilled in the art will recognize that an individual's condition can be monitored throughout the treatment process, and the effective amount of the pharmaceutical composition disclosed herein administered can be adjusted accordingly.

[0052] Pharmaceutical compositions may contain any conventionally non-toxic, pharmaceutically acceptable carriers, adjuvants, or mediators. In some cases, the pH of the formulation may be adjusted with acceptable pharmaceutical or food-grade acids, bases, or buffers to enhance the stability of the formulated composition or its delivery form.

[0053] Orally administered liquid dosage forms comprise acceptable pharmaceutical or food-grade emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethyl sulfoxide (DMSO), dimethylformamide, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatizers.

[0054] Oral solid dosage forms include capsules, tablets, lozenges, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with: at least one inert, acceptable pharmaceutical or food-grade excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silica; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; e) solution delayers, such as paraffin; f) absorption enhancers, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glyceryl monostearate; h) absorbents, such as kaolin and bentonite; i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, and mixtures thereof; and j) sweeteners, flavorings, aromas, and mixtures thereof. In the case of capsules, lozenges, tablets, and pills, the dosage form may also include buffers.

[0055] Solid dosage forms of tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the field of pharmaceutical formulation. They may optionally contain emulsifiers and may also be compositions that release only the active ingredient, or preferably the active ingredient in a portion of the intestine, or optionally release the active ingredient in a delayed or prolonged manner. Examples of encapsulation compositions that can be used include polymeric substances and waxes. Tablet formulations for prolonged release are also described in U.S. Patent No. 5,942,244.

[0056] The composition may contain the compounds disclosed herein, alone or in combination with other therapeutic compounds. A therapeutic compound is a compound that provides pharmacological activity or other direct action in the diagnosis, cure, relief, treatment, or prevention of a disease, or affects the structure or any function of the human or animal body. The therapeutic compounds disclosed herein may be used in the form of pharmaceutically acceptable salts, solvates, or solvates of salts (e.g., hydrochlorides). Additionally, the therapeutic compounds disclosed herein may be provided as racemic mixtures or as enantiomers alone, said enantiomers comprising R- or S-enantiomers. Thus, the therapeutic compounds disclosed herein may comprise only the R-enantiomer, only the S-enantiomer, or a combination of both the R-enantiomer and the S-enantiomer. In some aspects, the therapeutic compounds may have anti-inflammatory activity, such as nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs are a large class of therapeutic compounds with analgesic, anti-inflammatory, and antipyretic properties. NSAIDs reduce inflammation by blocking cyclooxygenase. NSAIDs include, but are not limited to, aceclofenac, acemetacin, actarit, alcofenac, alminoprofen, amfenac, aloxipirin, aminophenazone, antraphenine, aspirin, azapropazone, benorilate, benzoxaprofen, benzydamine, butibufen, celecoxib, chlorthenoxacin, choline salicylate, clometacin, dexketoprofen, diclofenac, diflunisal, emorfazone, and epirizole.Etodolac, etoricoxib, feclobuzone, felbinac, fenbufen, fenclofenac, flurbiprofen, glafenine, hydroxylethyl salicylate, ibuprofen, indometacin, indoprofen, ketoprofen, ketorolac, lactyl phenetidin, loxoprofen, lumiracoxib, mefenamic acid meloxicam, metamizole, methazzic acid, mofebutazone, mofezolac, nabumetone, naproxen, nifenazone, niflumic acid, oxametacin, phenacetin, pipebuzone, pranoprofen, propyphenazone, proquazone, protizinic acid The following are listed: rofecoxib, salicylamide, salsalate, sulindac, suprofen, tiaramide, tinoridine, tolfenamic acid, valdecoxib, and zomepirac.

[0057] NSAIDs can be classified based on their chemical structure or mechanism of action. Non-limiting examples of NSAIDs include salicylate derivative NSAIDs, p-aminophenol derivative NSAIDs, propionic acid derivative NSAIDs, acetic acid derivative NSAIDs, enolate derivative NSAIDs, fenamic acid derivative NSAIDs, non-selective cyclooxygenase (COX) inhibitors, selective cyclooxygenase-1 (COX-1) inhibitors, and selective cyclooxygenase-2 (COX-2) inhibitors. An NSAID can be profen. Suitable examples of salicylate derivative NSAIDs include, but are not limited to, acetylsalicylic acid (aspirin), diflunisal, and bis(salicylic acid). Suitable examples of p-aminophenol derivative NSAIDs include, but are not limited to, acetaminophen and phenacetin. Examples of suitable propionic acid derivative NSAIDs include, but are not limited to, aminprofen, benzoxaprofen, dexketoprofen, fenoprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, loxoprofen, naproxen, oxaprozin, pranoprofen, and sulofen. Examples of suitable acetic acid derivative NSAIDs include, but are not limited to, aceclofenac, acetate, atenolol, amifenac, clomecium, diclofenac, etodoxacin, felbinac, fenclofen, indomethacin, ketorolac, methaqualone, monoxazol, nabumetone, naproxen, oxamethacin, sulinda, and zolmec. Examples of suitable oxicam derivative NSAIDs include, but are not limited to, droxicam, isoxicam, lornoxicam, meloxicam, piroxicam, and tenoxicam. Examples of suitable fenamic acid derivative NSAIDs include, but are not limited to, flufenamic acid, mefenamic acid, meclofenamic acid, and tofenamic acid. Examples of suitable selective COX-2 inhibitors include, but are not limited to, celecoxib, etoricoxib, firocoxib, romecoxib, meloxicam, parecoxib, rofecoxib, and vardicoxib.

[0058] The following examples illustrate aspects of this disclosure and should not be construed as limiting the scope of the invention.

[0059] Example 1

[0060] This example illustrates the synthesis of compounds with the following structure:

[0061]

[0062] The above compounds were prepared according to the following synthetic route. Each of the starting reagents shown is commercially available from various chemical suppliers. The properties of the synthesized products are summarized in Table 1 below. The NMR, mass, and HPLC spectra of the compounds are presented on [Table 1]. Figure 1-3 middle.

[0063]

[0064]

[0065] Table 1

[0066] test Results / References See figure Appearance grayish-white solid not applicable NMR spectrum <![CDATA[ 1 H NMR, 400MHz, dimethyl sulfoxide-d6, continuous 1 mass spectrometry <![CDATA[ESI (multimodal), m / z 214.1 [M+H] + > 2 HPLC 98.9% (area %), Eclipse plus C18, 100 x 4.6 mm, 3.5 μm UV 230 nm detection 3

[0067] Example 2

[0068] This example describes the testing of compounds prepared in Example 1 within the BioMAP Diversity PLUS panel (Eurofins Discovery, Burlingame, California) of 12 human primary cell-based systems designed to model different aspects of the human body in vitro. The 12 systems in the Diversity PLUS panel allow for unbiased characterization of test agents across a broad range of systems modeling various human disease states. BioMAP systems are constructed from one or more primary cell types from healthy human donors, with the addition of stimuli (such as cytokines or growth factors) to capture relevant signaling networks that occur naturally in human tissues or under pathological conditions. Vascular biology is used to model inflammatory environments in Th1 (3C system) and Th2 (4H system) regions, as well as in Th1 inflammatory states specific to arterial smooth muscle cells (CASM3C system). The additional systems encompass various aspects of the systemic immune response, including monocyte-driven Th1 inflammation (LPS system) or T-cell stimulation (SAg system), macrophage activation-driven chronic Th1 inflammation (lMphg system), and T-cell-dependent activation of B cells occurring in germinal centers (BT system). The BE3C system (Th1) and BF4T system (Th2) represent airway inflammation in the lungs, while the MyoF system models myofibroblast-mediated lung tissue remodeling. Finally, skin biology is addressed in the KF3CT system, which models Th1 skin inflammation, and the HDF3CGF system, which models wound healing.

[0069] Figure 4The Diversity PLUS panel plots are shown. The X-axis lists the quantitative readings of the protein-based biomarkers measured in each system. The Y-axis represents the logarithmic transformation ratio of the biomarker readings of the drug-treated sample (n=1) to the mediator control (n≥6). The gray area around the Y-axis represents the 95% significance envelope generated by the historical mediator control. Biomarker activity is annotated when two or more consecutive concentrations change in the same direction relative to the mediator control, outside the significance envelope, and at least one concentration has an effect size >20% (|log10 ratio|>0.1). If the key activities of a biomarker increase in some systems but decrease in others, these key activities are described as modulated activities. Cytotoxicity is represented on the plot by thin black arrows above the X-axis, and antiproliferative activity by thick gray arrows. Only one concentration is required to satisfy the indication threshold for plot annotation for both cytotoxicity and antiproliferative arrows. Compounds exhibiting activity are summarized in Table 2 below, with 35 annotated readings. Specifically, the compounds affect inflammation-related activities (reduced eosinophil chemokine 3 (Eotaxin3), VCAM-1, MCP-1, SAA, sTNFα, MIP-1α; increased IL-1α, IL-6; regulated IL-8), immunomodulatory activities (reduced CD40, sIL-10, sIgG, M-CSF, sIL-17A, sIL-6, sIL-17F, sIL-2), tissue remodeling activities (reduced PAI-1, uPAR, αSMA, keratin 8 / 18; increased collagen I, MMP-1), and hemostatic-related activities (increased TF).

[0070] Table 2

[0071]

[0072] At concentrations independent of cytotoxicity, the compound exhibited antiproliferative activity against human primary endothelial cells (670 μM, 220 μM, 74 μM), T cells (670 μM, 220 μM), B cells (670 μM, 220 μM, 74 μM), coronary artery smooth muscle cells (670 μM, 220 μM, 74 μM), and fibroblasts (670 μM).

[0073] The compound was active at the three lower concentrations tested, with 23 annotated readings. The compound affected inflammation-related activities (reduced eosinophil chemokine 3, VCAM-1, MCP-1, SAA, sTNFα; increased IL-8, IL-1α, IL-6), immunomodulatory activities (reduced sIL-10, sIgG, sIL-17A, sIL-6, sIL-17F, sIL-2), tissue remodeling activities (reduced PAI-1; increased collagen I, MMP-1), and hemostatic-related activities (increased TF).

[0074] Notably, the compound in Example 1 simultaneously inhibited the soluble forms of TNF-α, IL-6, and IL-17, and exhibited antiproliferative activity against the following primary human cell types: T cells, B cells, fibroblasts, and endothelial cells. TNF-α is an initiator of acute-phase pro-inflammatory cytokines. An example of a TNF-α inhibitor is adalimumab. IL-6 is activated by TNF-α in the pro-inflammatory cascade. It is a major cytokine associated with depression. An example of a treatment using IL-6 inhibitors is tocilizumab. IL-17 plays a crucial role in the pathogenesis of various autoimmune diseases. An example of a treatment using IL-17 inhibitors is secukinumab.

[0075] A table (see Table 3 below) consisting of the top three similarity matches from an unsupervised search of the BioMAP reference database of >4,500 pharmaceutical agents shows that the compound of Example 1 (2000 μM) is most similar to hexadecylpyridine chloride (1.1 μM) (Pearson's correlation coefficient, r = 0.878). The Pearson correlation coefficient between the two curves is above the established threshold of r = 0.7, indicating that these compounds share mechanically related similarities. Hexadecylpyridine chloride is a cationic quaternary ammonium compound used as a preservative in commercial products. The hexadecylpyridine cation is a pharmaceutical excipient with off-target activity, as reported using the BioMAP DiversityPLUS panel with toxicity characterization analysis (Science, 2020; https: / / doi.org / 10.1126 / science.aaz9906).

[0076] The following systems annotate 18 common activities: SAg (CD40, CD69, Pcyto, Prolif), BT (Prolif, sIgG, sIL-17A, sIL-17F, sIL-2, sIL-6, sTNFα), CASM3C (Prolif), HDF3CGF (collagen III, Prolif72), MyoF (collagen IV), and lMphg (E-selectin, sIL-10, SRB-M).

[0077] The pattern of protein inhibition and stimulation with Zn 2+ and Cu 2+ The stimulation is most similar to PI3K. This means that the chelation of Cu and Zn inhibits PI3K. Therefore, the compound of Example 1 inhibits TNF-α convertase (TACE, also known as ADAM-17), which is a metalloproteinase that cleaves TNF-α, IL-6, and IL-17 into their soluble forms, such as... Figure 5 Schematic illustration. Phosphoinositol 3-kinase (PI3K) is activated via the insulin receptor (InsR) in cells exposed to insulin. 2+ and Zn 2+ (Not shown) Stimulation of PI3K and Ser / Thr kinase Akt PI3K-dependent activation, such as Figure 6 As shown schematically.

[0078] Examples of PI3K inhibitor treatments include idelalisb. It is a drug used to treat certain blood cancers. The substance blocks the delta isoform P110δ of phosphoinositol 3-kinase. Furthermore, Novartis conducted a phase III study of a placebo of the PI3K inhibitor BKM120 / fullvestrant in postmenopausal patients with hormone receptor-positive HER2-negative advanced or metastatic breast cancer resistant to the aromatase inhibitor BELLE-2.

[0079] Table 3

[0080]

[0081] Although the invention has been described with reference to specific examples, those skilled in the art will understand that many variations and arrangements of the systems and techniques described above exist, which fall within the spirit and scope of the invention as set forth in the appended claims.

Claims

1. A compound having the following structure: Or its pharmaceutically acceptable salt.

2. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 and a pharmaceutically acceptable mediator for the compound.

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