Metalloenzyme inhibitors for treating cancer, Alzheimer's disease, hemochromatosis and other disorders

Abstract

The pharmaceutical compounds have anti-inflammatory activity and, in some embodiments, can function as metalloenzyme inhibitors for beneficial modulation of metalloproteins. The pharmaceutical compositions can include a therapeutically effective amount of the compound and a pharmaceutically acceptable vehicle. The pharmaceutical compositions can be useful for treating disorders associated with chronic inflammation and / or misregulation of metalloenzymes, including hemochromatosis, cancers such as breast cancer, or neurodegenerative diseases such as Alzheimer's disease.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 119(e) to U.S. Application No. 63 / 092,594, filed October 16, 2020, the disclosure of which is incorporated herein by reference in its entirety. [Background technology]

[0002] Metalloproteins perform many functions in vivo, including regulating blood pH, promoting matrix degradation, and regulating DNA transcription. Misregulation of metalloenzymes contributes to a variety of disease states, including cancer, heart disease, Alzheimer's disease, and hemochromatosis. Therefore, inhibition of metalloenzymes represents a promising target for various therapeutic approaches.

[0003] Traditional metalloenzyme inhibitors are typically small molecules that incorporate a metal binding group (MBG) that coordinates the metal ion at the active site. The MBG is attached to a drug-like "backbone" group via a linker. For metalloenzyme inhibitors, hydroxamic acids are the most common MBGs, followed by carboxylic acids, thiols, and phosphonates.

[0004] There remains a need for alternative metalloenzyme inhibitors and treatments for cancers such as breast cancer, and other disorders associated with misregulation of metalloenzymes such as hemochromatosis and Alzheimer's disease. Summary of the Invention

[0005] According to one embodiment, the compound has the structure:

[0006] [ka] or a pharmaceutically acceptable salt, ester, or solvate thereof.

[0007] In another embodiment, a pharmaceutical composition comprises a therapeutically effective amount of the compound described above and a pharmaceutically acceptable vehicle therefor.

[0008] In another embodiment, a method of treating a disorder associated with chronic inflammation comprises administering the pharmaceutical composition to an individual in need thereof.

[0009] In yet another aspect, a method for treating a disorder associated with misregulation of metalloenzymes comprises administering the pharmaceutical composition to an individual in need thereof. In some aspects, the disorder is cancer, such as breast cancer. In other aspects, the disorder is hemochromatosis. In yet other aspects, the disorder is a neurodegenerative disorder, such as Alzheimer's disease.

[0010] Various other pharmaceutical compounds, pharmaceutical compositions, and related methods of treatment are also described herein.

[0011] Non-limiting and non-exhaustive embodiments are described with reference to the following drawings, in which like reference numerals refer to like parts throughout the several views unless otherwise specified. [Brief explanation of the drawings]

[0012] [Figure 1] 1 is a nuclear magnetic resonance (NMR) spectrum of a compound synthetically prepared according to one embodiment of the present disclosure. [Figure 2] The NMR spectrum is the mass spectrum for the compound shown in FIG. [Figure 3] The NMR spectrum is shown in Figure 1. This is a high performance liquid chromatogram (HPLC) of the compound. [Figure 4] The NMR spectrum is a Diversity PLUS Panel profile of the compound shown in Figure 1. [Figure 5] FIG. 1 illustrates TNF-α converting enzyme (TACE), a metalloprotease that requires Zn2+ and cleaves TNF-α, IL-6, and IL-17 into soluble forms. [Figure 6]Figure 1 shows that phosphoinositide 3-kinase (PI3K) is activated in cells exposed to insulin via the insulin receptor (InsR); Cu2+ and Zn2+ (not shown) stimulate activation of PI3K and the PI3K-dependent Ser / Thr kinase Akt. DETAILED DESCRIPTION OF THE INVENTION

[0013] In some embodiments, the pharmaceutical compounds disclosed herein can function as metalloenzyme inhibitors. Without wishing to be bound by theory, it is believed that the compounds can beneficially regulate metalloproteins and / or inhibit metalloenzymes to treat disorders associated with overexpression, increased activation, or misregulation of endogenous metalloenzymes. Broadly speaking, the compounds may interact with one or more metalloenzyme targets, as described in Chen et al., Targeting Metalloenzymes for Therapeutic Intervention, Chem Rev. 2019 January 23; 119(2)1323-1455, doi:10.1021 / acs.chemrev.8b00201, the disclosure of which is incorporated herein by reference. Zinc enzymes, as part of zinc metalloproteins, occupy a very important position in this field.

[0014] Zinc is a transition metal ion and micronutrient essential for life, required for the activity of over 300 enzymes. Intracellular zinc concentrations are quite high, nearly as high as those of ATP. Zinc is the second most abundant metal in biology and is the only metal known to be present in all six classes of enzymes. Zinc is the major metallocoenzyme for metalloproteins, and zinc-containing proteins (up to 3,000) represent the largest category of metalloproteins, accounting for between one-quarter and one-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 stabilization, and redox regulation and apoptosis. Accumulating evidence suggests that zinc metalloproteins play a fundamental role in the pathophysiology and development of a wide range of human diseases, from cancer to infectious diseases. See Hou et al., "Zinc enzymes in medicinal Chemistry," Euro. J. of Med. Chem. 226 (2021) 113877.

[0015] Zinc is also one of the most common and essential elements involved in brain function, playing a role in both physiological and pathophysiological processes. 2+ Neurons containing zinc (Zn) are found in various regions of the brain, including the cerebral cortex, amygdala, olfactory bulb, and hippocampal neurons, and are thought to have the highest zinc concentrations in the brain. Zinc is involved in the biological activity of enzymes, proteins, and signaling transcription factors, as well as maintaining various homeostatic mechanisms, acting as a structural, regulatory, and catalytic cofactor for various enzymes, including DNA and RNA polymerases, histone deacetylases, and DNA ligases. Zinc is also important for cell proliferation and genomic stability. See Choi et al., "Zinc in the Brain: Friend or Foe?" Int. J. Mol. Sci. 2020, 21, 8941; doi:10.3390 / ijms21238941.

[0016] The pharmaceutical compounds disclosed herein have anti-inflammatory activity. For example, the compounds may have anti-inflammatory activity that can reduce the level of inflammation-inducing molecules. Without wishing to be bound by theory, it is believed that the disclosed compounds may have anti-inflammatory activity that can reduce the level of substance P (SP), calcitonin gene-related peptide (CGRP), glutamate, or a combination thereof. The compounds may have anti-inflammatory activity that can reduce the level of SP, CGRP, glutamate, or a combination 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%.

[0017] Prostaglandins mediate local inflammatory responses and are involved in all inflammatory functions through their actions on prostaglandin receptors, mediating inflammatory signaling, including chemotaxis (macrophages, neutrophils, and eosinophils), vasodilation, and hyperalgesia. However, PG-mediated inflammatory responses are self-limiting (resolving). The main resolving factor is a prostaglandin called 15dPGJ2, which is an endogenous agonist of peroxisome proliferator-activator receptor-γ (PPAR-γ) signaling. The PPAR-γ signaling pathway 1) induces apoptosis of macrophage M1 cells, thereby reducing the levels of Th1 proinflammatory cytokines, and 2) promotes the differentiation of monocytes into macrophage M2 cells. Macrophage M2 cells then produce and release Th2 anti-inflammatory cytokines.

[0018] The compounds disclosed herein can have anti-inflammatory activity, which can reduce the level of inflammation-induced prostaglandins.The compounds can have anti-inflammatory activity, which 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 can reduce the level of proinflammatory prostaglandins released from sensory neurons by, for example, 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 90%, or about 40% to about 90%. , about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to 70%, or about 50% to about 70%.

[0019] Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating gene expression. All PPARs heterodimerize with retinoid X receptors (RXRs) and bind to specific regions on the DNA of target genes called peroxisome proliferator hormone response elements (PPREs). PPARs play important roles in regulating cell differentiation, development, and metabolism (carbohydrates, lipids, and proteins) in higher organisms, as well as tumorigenesis. The family includes three members: PPAR-α, PPAR-γ, and PPAR-δ (also known as PPAR-β). PPAR-α is expressed in the liver, kidney, heart, muscle, adipose tissue, and other tissues. PPAR-δ is expressed in many tissues, but is predominantly expressed in the brain, adipose tissue, and skin. PPAR-γ contains three alternative splicing forms, each with distinct expression patterns. PPAR-γ1 is expressed in virtually all tissues, including the heart, muscle, colon, kidney, pancreas, and spleen. PPAR-γ2 is primarily expressed in adipose tissue. PPAR-γ3 is expressed in macrophages, the colon, and white adipose tissue. Endogenous ligands for PPARs include free fatty acids and eicosanoids. PPAR-γ is activated by PGD2 (prostaglandin), and PPAR-α is activated by leukotriene B4.

[0020] The compounds may have anti-inflammatory activity that can reduce the levels of IFN-γ, TNF-α, IL-12, or a combination thereof, released from Th1 cells and increase the levels of IL-10 released from Th2 cells. The compound may have anti-inflammatory activity that can reduce the levels of IFN-γ, TNF-α, IL-12, or a combination thereof released from Th1 cells by, e.g., 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 can increase the levels of IL-10 released from Th2 cells by, e.g., 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%.

[0021] The compound may have anti-inflammatory activity that can stimulate some or all of the PPAR signaling pathways. Thus, it is contemplated that such a compound may act as a PPAR pan-agonist or, in some cases, as a selective PPAR agonist.

[0022] The compound may have anti-inflammatory activity that can regulate Th1 and Th2 cytokines. The compound may have anti-inflammatory activity that can reduce the levels of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-12 (IL-12), or a combination thereof, released from Th1 cells. The compound may have anti-inflammatory activity that can reduce the levels of IFN-γ, TNF-α, IL-12, or a combination thereof, released from Th1 cells, for example, by 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 a combination thereof released from Th1 cells by, for example, 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%.

[0023] The compound may have anti-inflammatory activity that can increase the level of IL-10 released from Th2 cells. The compound may have anti-inflammatory activity that can increase 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%.

[0024] According to one embodiment, the compound has the structure:

[0025] [ka] or a pharmaceutically acceptable salt, ester, or solvate thereof.

[0026] Another compound disclosed herein, 5-(5-(3,4-dihydro-2H-pyrrol-2-yl)pyridin-3-yl)-1-methylpyrrolidin-2-one, has the structure:

[0027] [ka] or a pharmaceutically acceptable salt, ester, or solvate thereof.

[0028] In other embodiments, the compound is selected from the group consisting of:

[0029] [ka] or a pharmaceutically acceptable salt, ester, or solvate thereof.

[0030] Pharmaceutical compositions may contain pharmaceutically acceptable carriers that facilitate the processing of active ingredients into pharmaceutically acceptable compositions. As used herein, the term "pharmaceutically acceptable carrier" is synonymous with "pharmaceutical carrier" and refers to any carrier that has substantially no long-term or permanent adverse effects when administered, including terms such as "pharmaceutically acceptable vehicle," "stabilizer," "diluent," "additive," "auxiliary agent," or "excipient." Such carriers are generally acceptable for mixing with, diluting, or encapsulating active compounds, and may be solid, semi-solid, or liquid. It is understood that the active ingredient may be soluble or may be delivered as a suspension in a 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, talcum, cellulose, glucose, sucrose, magnesium carbonate, etc.; solvents; dispersion media; coatings; antibacterial and antifungal agents; isotonic and absorption delaying agents; or any other inactive ingredients. The choice of pharmaceutically acceptable carrier can depend on the mode of administration. Except where a pharmaceutically acceptable carrier is incompatible with the active ingredient, its use in the pharmaceutically acceptable composition is contemplated.Non-limiting examples of specific uses of such pharmaceutical carriers can be found in Pharmaceutical Dosage Forms and Drug Delivery Systems (eds. Howard C. Ansel et al., Lippincott Williams & Wilkins Publishers, 7th ed. 1999); REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (eds. Alfonso R. Gennaro, Lippincott, Williams & Wilkins, 20th ed. 2000); Goodman & Gilman's The Pharmacological Basis of Therapeutics (eds. Joel G. Hardman et al., McGraw-Hill Professiona, 10th ed. 2001), and Handbook of Pharmaceutical Excipients (Raymond C. Rowe et al., APhA Publications, 4th edition 2003). These protocols are routine procedures, and any modifications are within the skill of those in the art and possible from the teachings herein.

[0031] Chronic inflammatory conditions can be associated with a large group of otherwise unrelated disorders, underlying a variety of diseases and disorders.The immune system is often involved in chronic inflammatory disorders, as manifested by both allergic reactions and some myopathies, and many immune system disorders result in abnormal inflammation.Non-immune diseases that have a pathogenesis in chronic inflammatory processes include cancer, atherosclerosis, and ischemic heart disease.Non-limiting examples of disorders that exhibit chronic inflammation as a symptom include, but are not limited to, acne, acid reflux / heartburn, age-related macular degeneration (AMD), allergies, allergic rhinitis, Alzheimer's disease, amyotrophic lateral sclerosis, anemia, appendicitis, arteritis, arthritis, asthma, atherosclerosis, autoimmune diseases, balanitis, blepharitis, bronchiolitis, bronchitis, bullous pemphigoid, burns, bursitis, cancer, cardiac arrest, carditis, celiac disease, cellulitis, cervicitis, cholangitis, cholecystitis, amnionitis, chronic obstructive pulmonary disease (COPD), cirrhosis of the liver, and colitis. , congestive heart failure, conjunctivitis, Crohn's disease, cyclophosphamide-induced cystitis, cystic fibrosis, cystitis, cold, dacryocystitis, dementia, dermatitis, dermatomyositis, diabetes, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic ulcer, digestive disease, eczema, emphysema, encephalitis, endocarditis, endometritis, enteritis, small intestine colitis, epicondylitis, epididymitis, fasciitis, fibromyalgia, fibrosis, fibrositis, gastritis, gastroenteritis, gingivitis, glomerulonephritis, glossitis, heart disease, heart valve dysfunction, hepatitis, hidradenitis, Huntington's disease, hyperlipidemia, hypertension, ileitis, infection , inflammatory bowel disease, inflammatory cardiac hypertrophy, 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, osteopenia, periostitis, osteoporosis, osteitis, otitis, pancreatitis, Parkinson's disease, parotitis, pelvic inflammatory disease, pemphigus vulgaris, heart These include: meningitis, peritonitis, pharyngitis, phlebitis, pleuritis, pneumonia, polycystic kidney disease, proctitis, prostatitis, psoriasis, pulpitis, pyelonephritis, phlebitis, renal failure, reperfusion injury, retinitis, rheumatic fever, rhinitis, salpinitis, sarcoidosis, sarcopenia, sialadenitis, sinusitis, spastic colon, stenosis, stomatitis, stroke, surgical complications, synovitis, tendonitis, tendinosis, tenosynovitis, thrombophlebitis, tonsillitis, trauma, traumatic brain injury, transplant rejection, trigonitis, tuberculosis, tumor, urethritis, ursitis, uveitis, vaginitis, vasculitis, and vulvitis.

[0032] Compounds intended for administration to humans and other mammals generally need to 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, the purity level is at least about 95%, more usually at least about 96%, about 97%, about 98%, or higher. For example, the purity level may 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.

[0033] Compounds described herein that exist in more than one optical isomeric form (enantiomer) may be provided as a racemic mixture or by separating one of the enantiomers, in which case the purity described above may refer to enantiomeric purity.

[0034] The compounds described herein can be synthetically prepared using techniques such as those described in 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, with appropriate modifications to the reagents to obtain the disclosed structures, as would be apparent to one of ordinary skill in the art, without the aid of more than routine experimentation.

[0035] In some embodiments, compounds can be converted into pharmaceutically acceptable salts by using techniques well known to those skilled in the art.For example, salts such as sodium salts and potassium salts can be prepared by treating compounds with suitable sodium bases or potassium bases, such as sodium hydroxide or potassium hydroxide, respectively.Esters and ethers of compounds can be prepared, for example, as described in Advanced Organic Chemistry, 1992, 4th Edition, J. March, John Wiley & Sons or J.Med.Chemistry, 1992, 35, 145-151.

[0036] The compositions described herein may be administered orally, nasally, topically, subcutaneously, intramuscularly, intravenously, or by other modes of administration known to those skilled in the art.

[0037] Pharmaceutical compositions may optionally contain other pharmaceutically acceptable components (or pharmaceutical ingredients), including, but not limited to, buffers, preservatives, tonicity adjusters, salts, antioxidants, osmolality adjusting agents, physiological substances, pharmacological substances, bulking agents, emulsifiers, humectants, sweeteners, or flavoring agents. Various buffers and means for adjusting pH may be used to prepare the pharmaceutical compositions disclosed herein, provided the resulting preparation is pharmaceutically acceptable. Such buffers include, but are not limited to, acetate buffer, citrate buffer, phosphate buffer, neutral buffered saline, phosphate buffered saline, and borate buffer. It is understood that acids or bases can 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, stabilized oxychloro compositions, and chelating agents, such as DTPA or DTPA-bisamide, calcium DTPA, and CaNaDTPA-bisamide. Tonicity adjusters useful in pharmaceutical compositions include, but are not limited to, salts such as sodium chloride, potassium chloride, mannitol, or glycerin, as well as other pharmaceutically acceptable tonicity adjusters. Pharmaceutical compositions may be provided as salts, which can be formed with many acids, including, but not limited to, hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like. Salts tend to be more soluble in aqueous or other protic solvents than the corresponding free base forms. It is understood that these and other substances known in the pharmaceutical arts can be included in pharmaceutical compositions.

[0038] Examples of adjuvants and / or excipients which may be mentioned are cremophor, poloxamer, benzalkonium chloride, sodium lauryl sulfate, dextrose, glycerin, magnesium stearate, polyethylene glycol, starch, dextrin, lactose, cellulose, sodium carboxymethylcellulose, talc, agar, mineral oil, animal oil, vegetable oil, organic and mineral waxes, paraffin, gel, propylene glycol, benzyl alcohol, dimethylacetamide, ethanol, polyglycol, Tween 80, solutol HS 15, and water. It is also possible to administer the active substance as it is, in a suitable form such as, for example, a capsule, without using a vehicle or diluent.

[0039] The pharmaceutical composition may contain a sufficient amount of the therapeutic compound to allow routine administration to an individual. A 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 embodiments, 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 yet other aspects of this embodiment, the pharmaceutical compositions disclosed herein can contain, for example, 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 of a therapeutic compound.In yet another aspect of this embodiment, the pharmaceutical compositions disclosed herein may be administered in amounts of, 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 The therapeutic compound may comprise about 100 mg to 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.

[0040] The pharmaceutical compositions described herein may contain a pharmaceutically acceptable solvent. A solvent is a liquid, solid, or gas that dissolves other solids, liquids, or gases (solutes), resulting in a solution. Solvents useful 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 non-polar solvents include, but are not limited to, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, chloroform, n-methyl-pyrrolidone (NMP), and diethyl ether.

[0041] The preferred method of administration and dosage range for a particular case will depend on the species being treated and the state of the respective condition or disease, and can be optimized using techniques known in the art. Most frequently, the daily dosage of the active compound in a patient will range from 0.0005 mg to 15 mg per kg, more usually from 0.001 mg to 7.5 mg per kg. Administration may be single or cumulative (continuous) and can be readily determined by one of ordinary skill in the art. For example, treatment may involve a single administration of an effective amount of the pharmaceutical composition disclosed herein. Alternatively, treatment may involve multiple administrations of an effective amount of the pharmaceutical composition administered over a range of time periods, such as once daily, twice daily, three times daily, once every few days, or once weekly. The timing of administration may vary from individual to individual, depending on factors such as the severity of the individual's symptoms. For example, an effective amount of the pharmaceutical composition disclosed herein may be administered to an individual once daily for an indefinite 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 course of treatment and the effective amount of the pharmaceutical composition disclosed herein administered can be adjusted accordingly.

[0042] Pharmaceutical compositions can contain any conventional non-toxic pharmaceutically acceptable carrier, adjuvant or vehicle.In some cases, the pH of the formulation can be adjusted with acceptable pharmaceutical or food grade acid, base or buffer to enhance the stability of the formulated composition or its delivery form.

[0043] Liquid dosage forms for oral administration include emulsions, microemulsions, solutions, suspensions, syrups and elixirs of acceptable pharmaceutical or food grade.In addition to active compounds, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl sulfoxide (DMSO), dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and their mixtures.In addition to inert diluents, oral compositions can also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings and fragrances.

[0044] The solid dosage form for oral administration includes capsules, tablets, lozenges, pills, powders and granules.In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutical or food-grade excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) filler or extender, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binder, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectant, such as glycerol, d) agar, calcium carbonate, potato or tapioca. Disintegrating agents such as oka starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarders such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof, j) sweeteners, flavoring agents, perfumes, and mixtures thereof. In the case of capsules, lozenges, tablets, and pills, the dosage form may also contain buffering agents.

[0045] Solid dosage forms such as tablets, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They can optionally contain opacifying agents, and can be of a composition that releases the active ingredient only, or preferentially, in a certain part of the intestinal tract, or optionally in a delayed or sustained manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Tablet formulations for sustained release are also described in U.S. Patent No. 5,942,244.

[0046] Compositions can include the compounds disclosed herein alone or in combination with other therapeutic compounds. Therapeutic compounds are compounds that provide pharmacological activity or other direct effects in the diagnosis, cure, mitigation, treatment, or prevention of disease, or that affect the structure or any function of the human or animal body. The therapeutic compounds disclosed herein can be used in the form of pharmaceutically acceptable salts, solvates, or solvates of salts, such as hydrochlorides. Furthermore, the therapeutic compounds disclosed herein can be provided as racemates or as individual enantiomers, including R- or S-enantiomers. Thus, the therapeutic compounds disclosed herein can contain only the R-enantiomer, only the S-enantiomer, or a combination of both the R-enantiomer and the S-enantiomer of the therapeutic compound. In some embodiments, the therapeutic compounds can have anti-inflammatory activity, such as nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs are a large group 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, anthraphenine, aspirin, azapropazone, benorylate, benoxaprofen, benzydamine, butibufen, celecoxib, chlortenoxacin, choline salicylate, clometacin, dextoprofen, diclofenac, diflunisal, emorfazone, epirizole; etodolac, etoricoxib, feclobuzone, felbinac, fenbufen, fenclofenac, flurbiprofen, glafenine, salicylic acid Acid hydroxyl, ibuprofen, indomethacin, indoprofen, ketoprofen, ketorolac, lactylphenetidine, loxoprofen, lumiracoxib, mefenamic acid, meloxicam, metamizole, metiazinic acid, mofebutazone, mofezolac, nabumetone, naproxen, nifenazone, niflumic acid, oxametacin, phenacetin, pipebuzone, pranoprofen, propyphenazone, proquazone, protizinic acid, rofecoxib, salicylamide, salsalate, sulindac, suprofen, tiaramide, tinoridine, tolfenamic acid, valdecoxib, and zomepirac.

[0047] NSAIDs can be classified based on their chemical structure or mechanism of action.Non-limiting examples of NSAIDs include salicylic acid derivative NSAIDs, p-aminophenol derivative NSAIDs, propionic acid derivative NSAIDs, acetic acid derivative NSAIDs, enolic acid derivative NSAIDs, fenamic acid derivative NSAIDs, non-selective cyclooxygenase (COX) inhibitors, selective cyclooxygenase 1 (COX-1) inhibitors, and selective cyclooxygenase 2 (COX-2) inhibitors.NSAIDs may be profen.Suitable examples of salicylic acid derivative NSAIDs include, but are not limited to, acetylsalicylic acid (aspirin), diflunisal, and salsalate.Suitable examples of p-aminophenol derivative NSAIDs include, but are not limited to, paracetamol and phenacetin. Examples of suitable propionic acid derivative NSAIDs include, but are not limited to, aluminoprofen, benoxaprofen, dexketoprofen, fenoprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, loxoprofen, naproxen, oxaprozin, pranoprofen, and suprofen. Examples of suitable acetic acid derivative NSAIDs include, but are not limited to, aceclofenac, acemetacin, actarit, alcofenac, amfenac, clometacin, diclofenac, etodolac, felbinac, fenclofenac, indomethacin, ketorolac, metiazinic acid, mofezolac, nabumetone, naproxen, oxametacin, sulindac, and zomepirac. Examples of suitable enolic acid (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 tolfenamic acid. Examples of suitable selective COX-2 inhibitors include, but are not limited to, celecoxib, etoricoxib, firocoxib, lumiracoxib, meloxicam, parecoxib, rofecoxib, and valdecoxib.

[0048] The following examples illustrate illustrative aspects of the disclosure and should not be construed as limiting the scope of the invention. [Example]

[0049] This example has the structure:

[0050] [ka] The synthesis of a compound having the formula:

[0051] 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 spectra, mass spectra, and HPLC of the compounds are shown in Figures 1-3, respectively.

[0052] [ka]

[0053] [Table 1] [Example]

[0054] This example describes testing the compound prepared in Example 1 in the BioMAP Diversity PLUS (Eurofins Discovery, Burlingame, California) panel of 12 human primary cell-based systems designed to model different aspects of the human body in an in vitro format. The 12 systems included in the Diversity PLUS panel enable unbiased characterization of test agents in a broad set of systems modeling various human disease states. BioMAP systems are constructed with one or more types of primary cells taken from healthy human donors and stimuli (e.g., cytokines or growth factors) are added to capture relevant signaling networks that naturally occur in human tissues or pathologies. Vascular biology is modeled in both Th1 (3C system) and Th2 (4H system) inflammatory environments, as well as a Th1 inflammatory state specific to arterial smooth muscle cells (CASM3C system). Additional systems recapitulate aspects of the systemic immune response, including monocyte-driven Th1 inflammation (LPS system) or T cell stimulation (SAg system), chronic Th1 inflammation driven by macrophage activation (lMphg system), and T cell-dependent B cell activation occurring in germinal centers (BT system). The BE3C (Th1) and BF4T (Th2) systems represent pulmonary airway inflammation, and the MyoF system models myofibroblast-mediated lung tissue remodeling. Finally, skin biology is addressed with the KF3CT system, which models Th1 skin inflammation, and the HDF3CGF system, which models wound healing.

[0055] Figure 4 shows the Diversity PLUS Panel profiles. The x-axis lists the quantitative protein-based biomarker readouts measured in each system. The y-axis represents the log-transformed ratio of biomarker readouts in drug-treated samples (n = 1) relative to the vehicle control (n ≥ 6). The gray area around the y-axis represents the 95% significance envelope generated from the historical vehicle control. Biomarker activity is annotated when two or more consecutive concentrations change in the same direction relative to the vehicle control, fall outside the significance envelope, and have at least one concentration with an effect size > 20% (|log10 ratio| > 0.1). The primary activity of a biomarker is described as modulated if it increases in one system and decreases in the other. Cytotoxicity is indicated by a thin black arrow above the x-axis on the profile plot, and antiproliferative effects are indicated by a thick gray arrow. Cytotoxicity and antiproliferative arrows require only one concentration to meet the indicated threshold for profile annotation. The compounds exhibited activity across 35 annotated readouts, as summarized in Table 2 below. Specifically, the compounds affected inflammation-related activity (decreased Eotaxin 3, VCAM-1, MCP-1, SAA, sTNFα, MIP-1α; increased IL-1α, IL-6; and IL-8 modulation), immunomodulatory activity (decreased CD40, sIL-10, sIgG, M-CSF, sIL-17A, sIL-6, sIL-17F, sIL-2), tissue remodeling activity (decreased PAI-1, uPAR, αSMA, keratin 8 / 18; increased collagen I, MMP-1), and hemostasis-related activity (increased TF).

[0056] [Table 2]

[0057] At concentrations not associated with cytotoxicity, the compound was antiproliferative 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).

[0058] At the three lowest concentrations tested, the compound was active in 23 annotated readouts. The compound affected inflammation-related activity (decreased Eotaxin 3, VCAM-1, MCP-1, SAA, sTNFα; increased IL-8, IL-1α, IL-6), immunomodulatory activity (decreased sIL-10, sIgG, sIL-17A, sIL-6, sIL-17F, sIL-2), tissue remodeling activity (decreased PAI-1, increased collagen I, MMP-1), and hemostasis-related activity (increased TF).

[0059] Importantly, the compound of Example 1 simultaneously inhibited soluble forms of TNF-α, IL-6, and IL-17 and was antiproliferative against human primary cell types: T cells, B cells, fibroblasts, and endothelial cells. TNF-α is an acute-phase pro-inflammatory cytokine initiator. A therapeutic example of a TNF-α inhibitor is adalimumab (Humira®). IL-6 is activated by TNF-α in the pro-inflammatory cascade. It is a key cytokine involved in depression. A therapeutic example of an IL-6 inhibitor is tocilizumab (Actemra®). IL-17 plays an important role in the development of various autoimmune disorders. A therapeutic example of an IL-17 inhibitor is secukinumab (Cosentyx®).

[0060] A table of the top three similarity matches from an unsupervised search of the BioMAP Reference Database of over 4,500 agents (see Table 3 below) showed that the compound of Example 1 (2000 μM) was most similar to cetylpyridinium chloride (1.1 μM) (Pearson correlation coefficient, r = 0.878). The Pearson correlation coefficient between the two profiles exceeded the determined threshold of r = 0.7, indicating that these compounds share mechanistically relevant similarities. Cetylpyridinium chloride is a cationic quaternary ammonium compound used in commercial products as a preservative. Cetylpyridinium is a drug excipient with off-target activity, as reported using the BioMAP Diversity PLUS Panel with Toxicity Signature Analysis (Science, 2020; https: / / doi.org / 10.1126 / science.aaz9906).

[0061] There are 18 common activities annotated within the following systems: SAg (CD40, CD69, Pcyto, Prolif), BT (Prolif, sIgG, sIL-17A, sIL-17F, sIL-2, sIL-6, sTNFα), CASM3C (Prolif), HDF3CGF (Collagen III, Prolif 72), MyoF (Collagen IV) and lMphg (E-selectin, sIL-10, SRB-M).

[0062] The pattern of protein inhibition and stimulation was 2+ and Cu 2+This suggests that Cu and Zn chelation inhibits PI3K. This indicates that the compound of Example 1 inhibits TNF-α converting enzyme (TACE, also known as ADAM-17), a metalloprotease that cleaves TNF-α, IL-6, and IL-17 into soluble forms, as shown schematically in Figure 5. In cells exposed to insulin, phosphoinositide 3-kinase (PI3K) is activated via the insulin receptor (InsR). Cu 2+ and Zn 2+ (not shown) stimulates activation of PI3K as well as the PI3K-dependent Ser / Thr kinase Akt, as shown schematically in FIG.

[0063] An example of a PI3K inhibitor therapy is idelalisib (Zydelig®), a drug used to treat certain blood cancers. This substance blocks P110δ, the delta isoform of the enzyme phosphoinositide 3-kinase. Novartis is also conducting a Phase III trial (BELLE-2) of the PI3K inhibitor BKM120 / placebo versus fulvestrant in postmenopausal patients with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer that is refractory to aromatase inhibitors.

[0064] [Table 3]

[0065] While the present invention has been described with reference to specific embodiments, those skilled in the art will recognize that there are numerous variations and permutations of the above-described systems and techniques that fall within the spirit and scope of the present invention as set forth in the appended claims.

Claims

【Request Item 1】 【Chemistry 1】 1. A compound having a structure selected from the group consisting of:

2. 10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle therefor.

3. structure: 【Chemistry 2】 2. The compound of claim 1, having the formula:

4. structure: 【Transformation 3】 2. The compound of claim 1 having the formula: or a pharmaceutically acceptable salt thereof.

5. 10. Use of an isolated form of the compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 2, for the manufacture of a medicament for use in alleviating symptoms of disorders associated with chronic inflammation and / or misregulation of metalloenzymes, comprising: The use, wherein the disorder is selected from the group consisting of cancer, hemochromatosis, and neurodegenerative disorders.

6. The use according to claim 5, wherein the disorder is cancer.

7. The use according to claim 6, wherein the cancer is breast cancer.

8. The use according to claim 5, wherein the disorder is hemochromatosis.

9. The use according to claim 5, wherein the disorder is a neurodegenerative disorder.

10. 10. The use according to claim 9, wherein the neurodegenerative disorder is Alzheimer's disease.

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