Anti-inflammatory compounds, pharmaceutical compositions, and methods for treating hemochromatosis and other diseases

Abstract

The pharmaceutical compound has anti-inflammatory activity. The pharmaceutical composition may comprise a therapeutically effective amount of the compound and a pharmaceutically acceptable vehicle. A method for treating hemochromatosis, hyperammonemia, or a disease associated with chronic inflammation or cancer comprises administering the pharmaceutical composition to an individual in need thereof. In another aspect, a method for inhibiting the formation of metal oxides or reducing the reactivity of a metal comprises contacting the metal with an effective amount of the compound.

Description

[Background technology]

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application claims priority under 35 U.S.C. § 119 to U.S. Provisional Application No. 63 / 458,611, filed April 11, 2023, and U.S. Provisional Application No. 63 / 403,536, filed September 2, 2022, the contents of which are incorporated herein by reference in their entireties.

[0002] Metal overload or imbalance is associated with various diseases and pathological conditions. For example, hereditary hemochromatosis (HH) is a primary iron overload (IO) disorder. Mutations in the HFE (Hereditary Hemochromatosis) protein cause increased intestinal absorption of iron despite normal dietary intake, leading to excessive iron deposition in the body, particularly in the liver, pancreas, heart, thyroid, pituitary gland, and joints. If left untreated, excessive iron deposition can lead to tissue damage and fibrosis, with the potential for liver cirrhosis, diabetes, arthropathy, congestive heart failure, hypogonadism, and skin hyperpigmentation. Excessive iron deposition is also associated with inflammatory diseases, chronic kidney disease, rheumatoid arthritis, autoimmune diseases, acute infections, cancer, anemia of chronic disease, type 2 diabetes, metabolic syndrome, atherosclerosis, fatty liver disease, anorexia, Graves' disease, cardiac arrhythmias, and chronic hepatitis C infection.

[0003] The current standard of care for HH is phlebotomy. By harvesting red blood cells, the body's primary iron mobilizer, iron toxicity can be minimized. Patients require more than 100 500 mL phlebotomies to reduce iron levels to normal.

[0004] In addition to HH, there is another form of hemochromatosis known as secondary hemochromatosis, which can occur in patients with hemoglobinopathies (e.g., sickle cell disease, thalassemia, and sideroblastic anemia), congenital hemolytic anemia, and myelodysplasia. In patients with secondary hemochromatosis (also known as secondary iron overload), iron overload results from increased iron absorption, exogenous iron administration to treat anemia, and repeated blood transfusions.

[0005] Secondary hemochromatosis is typically treated with iron chelators, such as deferoxamine or deferasirox; unfortunately, these treatments can be complicated to administer, impose unusual time burdens on patients, and / or are associated with side effects such as hypotension, GI problems, vision and hearing loss, and liver and kidney dysfunction. Therefore, alternative treatment approaches for patients with secondary hemochromatosis are also needed.

[0006] Absolute telomere length (ATL) shortening is a key molecular hallmark of cellular senescence and DNA damage, which are associated with chronic disease and death. Indeed, telomere shortening has been found to be a major cause of human aging. In particular, ATL reduction is associated with nearly all chronic diseases associated with aging, including cancer, heart disease, diabetes, and autoimmune diseases.

[0007] Telomeres are the ends of chromosomes that protect DNA, similar to the tips of shoelaces, preventing the laces from unraveling. When telomeres shorten to a critical length, DNA is no longer protected during replication, resulting in DNA damage and chromosomal rearrangements, which can lead to somatic cell senescence, apoptosis, or oncogenic transformation. Therefore, therapeutic approaches to prevent ATL shortening and lengthen telomeres are needed.

[0008] Hyperammonemia is a metabolic disorder characterized by excess ammonia in the blood. It is a dangerous condition that can lead to brain damage and death. It can be primary or secondary. Treatment of severe hyperammonemia (serum ammonia levels greater than 1000 μmol / L) should begin with hemodialysis, if medically appropriate and tolerated.

[0009] Ammonia is a nitrogenous product resulting from protein catabolism. Before being excreted in the urine, it is converted by the kidneys to the less toxic substance urea. The metabolic pathway that synthesizes urea involves reactions that begin in the mitochondria and then move to the cytoplasm. This process, known as the urea cycle, involves several enzymes that work in sequence. Hyperammonemia is greatly exacerbated by common zinc deficiency, which further elevates ammonia levels.

[0010] Hyperammonemia, one of the metabolic disorders that causes hepatic encephalopathy, can lead to astrocyte swelling and stimulation of NMDA receptors in the brain, which induces excitotoxicity.

[0011] Acquired hyperammonemia is usually caused by diseases that result in either acute liver failure, such as severe hepatitis B or exposure to hepatotoxins, or chronic liver failure leading to cirrhosis. Chronic hepatitis B, chronic hepatitis C, and excessive alcohol consumption are common causes of cirrhosis. The physiological consequences of cirrhosis include shunting of blood from the liver to the inferior vena cava, resulting in decreased blood filtration and hepatic removal of nitrogen-containing toxins, leading to hyperammonemia. This type of hyperammonemia can be initially treated with antibiotics to kill ammonia-producing bacteria, but this is not as effective as removing protein from the colon before it is digested into ammonia, which can be achieved by administering lactulose to encourage frequent bowel movements (3–4 times daily).

[0012] Drug-induced hyperammonemia can occur with valproate overdose and is due to carnitine deficiency. Treatment is carnitine supplementation.

[0013] Hyperammonemia can also be a serious side effect of cancer chemotherapy.

[0014] Severe dehydration and small intestinal bacterial overgrowth can also lead to acquired hyperammonemia.

[0015] Glycine toxicity can lead to hyperammonemia, manifested by central nervous system symptoms and nausea. Transient blindness may also occur.

[0016] Congenital hyperammonemia usually results from a genetic defect in one of the enzymes of the urea cycle, for example ornithine transcarbamylase deficiency, which results in reduced production of urea from ammonia.

[0017] The mainstay of treatment is to restrict ammonia intake and increase its excretion. Dietary protein, the metabolic source of ammonium, is restricted, and caloric intake is met by glucose and fat. Intravenous arginine (argininosuccinase deficiency), sodium phenylbutyrate, and sodium benzoate (ornithine transcarbamoylase deficiency) are commonly used as adjunctive therapies to treat hyperammonemia in patients with urea cycle enzyme deficiencies. Sodium phenylbutyrate and sodium benzoate can function as waste nitrogen excretors, replacing urea. Phenylebutyrate, a product of phenylacetic acid, conjugates with glutamine to form phenylacetylglutamine, which is excreted by the kidney. Similarly, sodium benzoate combines with glycine to form hippuric acid, which is rapidly excreted by the kidney, thereby reducing blood ammonia levels. Formulations containing sodium phenylacetate and sodium benzoate are available under the trade name Ammonul. Acidification of the intestinal lumen with lactulose can reduce ammonia levels by protonating ammonia and trapping it in the feces, a treatment for hepatic encephalopathy.

[0018] Many common over-the-counter and prescription medications can also contribute to increased ammonia levels, typically as a result of increased nitrite production. It would be desirable to develop anti-inflammatory compounds that are effective in lowering individual ammonia levels. It would be particularly desirable to develop therapeutic therapies that are effective in treating not only hyperammonemia, but also other disorders related to chronic inflammation and cancer.

[0019] The present invention addresses the need for alternative therapeutic approaches to treat conditions associated with metal overload, autoimmune or anti-inflammatory diseases, hemochromatosis, telomere shortening, hyperammonemia, cancer, and the like. Summary of the Invention

[0020] In one aspect, the present disclosure provides a compound of formula Ia or Ib shown below: [ka] [ka] or a pharmaceutically acceptable ester or solvate thereof, wherein in the above formula, X - is an ion of an acid that forms a pharmaceutically acceptable salt, A1, A2, A3, and A4 are independently selected from nitrogen (N) or carbon (C), and R1, R2, R3, R4, R5, R6, R7, and R8 are independently selected from the group consisting of nothing, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle; when R3 is N, R1 is nothing; when A4 is N, R3 is nothing; alkyl, alkenyl, alkynyl, or acyl is selected from halogen, —OH, alkyl, —O-alkyl, NR A R B optionally substituted with one or more substituents independently selected from the group consisting of -S-alkyl, -SO-alkyl, -SO2-alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle; R A and R Bare each independently hydrogen and C 1-4 alkyl; aryl or heteroaryl, whether alone or as part of a substituent, are selected from halogen, —OH, alkyl, —O-alkyl, —COOH, —C(O)—C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, NR C R D optionally substituted with one or more substituents independently selected from the group consisting of -S-alkyl, -SO-alkyl, and -SO2-alkyl; R C and R D are each independently hydrogen and C 1-4 alkyl.

[0021] In some embodiments, R2 and / or R4 are selected from the group consisting of Formula IIa and IIb: [ka] wherein X - , A1, A2, R5, R6, R7, and R8 are defined as above.

[0022] In some embodiments, A1 and A3 are N, A4 is C, and R3 has a structure according to Formula IIa or Formula IIb.

[0023] In some embodiments, A2 is C.

[0024] In some embodiments, A1 is N and / or A3 and / or A4 are N.

[0025] In some embodiments, A2 is C.

[0026] In some embodiments, R2 and R4 have a structure according to Formula IIa or Formula IIb.

[0027] In some embodiments, the compound has the following structure: [ka] or a pharmaceutically acceptable salt, ester or solvate thereof.

[0028] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt, ester or solvate thereof.

[0029] In some embodiments, the compound is: [ka] [ka] [ka] or a pharmaceutically acceptable salt, ester, or solvate thereof.

[0030] According to some embodiments, the anti-inflammatory compound has the following structure: [ka] or a pharmaceutically acceptable salt, ester or solvate thereof.

[0031] In some embodiments, the present disclosure provides compounds of formula IIIa or IIIb shown below: [ka] or a pharmaceutically acceptable ester or solvate thereof, wherein X - is an ion of an acid that forms a pharmaceutically acceptable salt, and R 1 , R 2 and R 3is independently selected from the group consisting of H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle; alkyl, alkenyl, alkynyl, or acyl is independently selected from the group consisting of halogen, —OH, alkyl, —O-alkyl, NR A R B optionally substituted with one or more substituents independently selected from the group consisting of -S-alkyl, -SO-alkyl, -SO2-alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle; R A and R B are each independently hydrogen and C 1-4 alkyl; aryl or heteroaryl, whether alone or as part of a substituent group, are selected from halogen, —OH, alkyl, —O-alkyl, —COOH, —C(O)—C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, NR C R D , -S-alkyl, -SO-alkyl, and -SO2-alkyl; R C and R D are each independently hydrogen and C 1-4 alkyl.

[0032] In some embodiments, the compound has the following structure: [ka] or a pharmaceutically acceptable salt, ester or solvate thereof.

[0033] In some embodiments, the present disclosure provides compounds of Formula IVa or Formula IVb, as set forth below: [ka] wherein X -is an ion of an acid that forms a pharmaceutically acceptable salt, and R1, R2, R3, R4, R5, R6, and R7 are independently selected from the group consisting of H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle; alkyl, alkenyl, alkynyl, or acyl is selected from the group consisting of halogen, -OH, alkyl, -O-alkyl, NR A R B , -S-alkyl, -SO-alkyl, -SO2-alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle; R A and R B are each independently hydrogen and C 1-4 alkyl; aryl or heteroaryl, whether alone or as part of a substituent group, are selected from halogen, —OH, alkyl, —O-alkyl, —COOH, —C(O)—C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, NR C R D optionally substituted with one or more substituents independently selected from the group consisting of -S-alkyl, -SO-alkyl, and -SO2-alkyl; R C and R D are each independently hydrogen and C 1-4 alkyl.

[0034] In some embodiments, the compound has the following structure: [ka] or a pharmaceutically acceptable salt, ester or solvate thereof.

[0035] In another aspect, the present disclosure provides a compound of formula Va or formula Vb shown below: [ka] [ka] or a pharmaceutically acceptable ester or solvate thereof, wherein X - is an ion of an acid that forms a pharmaceutically acceptable salt, A1, A2, A3, A4, A5, and A6 are independently selected from nitrogen (N) or carbon (C), and R1, R2, R3, R4, R5, R6, R7, and R8 are independently selected from the group consisting of nothing, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle; when R3 is N, R1 is nothing; when A4 is N, R3 is nothing; alkyl, alkenyl, alkynyl, or acyl is selected from halogen, —OH, alkyl, —O-alkyl, NR A R B optionally substituted with one or more substituents independently selected from the group consisting of -S-alkyl, -SO-alkyl, -SO2-alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle; R A and R B are each independently hydrogen and C 1-4 alkyl; aryl or heteroaryl, whether alone or as part of a substituent, are selected from halogen, —OH, alkyl, —O-alkyl, —COOH, —C(O)—C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, NR C R D optionally substituted with one or more substituents independently selected from the group consisting of -S-alkyl, -SO-alkyl, and -SO2-alkyl; R C and R D are each independently hydrogen and C 1-4 In some embodiments, R2 and / or R4 have a structure according to Formula IIa or IIb, wherein X is selected from alkyl. -, A1, A2, R5, R6, R7, and R8 are defined as above. In some embodiments, A1 and A3 are N, A4, A5, and A6 are C, and R3 has a structure according to Formula IIa or Formula IIb. In some embodiments, A1 and A3 are N, A4 is C, A5 or A6 is N, and R3 has a structure according to Formula IIa or Formula IIb. In some embodiments, A1, A3, and A4 are N, A5 and A6 are C, and R3 has a structure according to Formula IIa or Formula IIb. In some embodiments, A2 is C. In some embodiments, A1 is N, and / or A3 and / or A4 are N. In some embodiments, R2 and R4 have a structure according to Formula IIa or Formula IIb.

[0036] In some embodiments, the compound according to Formula Va or Vb has the following structure: [ka] or a pharmaceutically acceptable salt, ester or solvate thereof.

[0037] In some embodiments, the compound according to Formula Va or Vb is: [ka] [ka] or a pharmaceutically acceptable salt, ester, or solvate thereof.

[0038] In some embodiments, the compound according to Formula Va or Vb is: [ka] or a pharmaceutically acceptable salt, ester, or solvate thereof.

[0039] In some embodiments, the compound according to Formula Va or Vb is: [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, ester, or solvate thereof.

[0040] In another embodiment, a pharmaceutical composition comprises a therapeutically effective amount of at least one of the above compounds and a pharmaceutically acceptable vehicle therefor.

[0041] In another embodiment, a method of inhibiting the formation of metal oxides, comprising contacting a metal with at least one compound as described above. In one example, the metal is present in a mammalian cell, such as a human cell.

[0042] In another embodiment, a method of treating hyperammonemia comprises administering said pharmaceutical composition to an individual in need thereof.

[0043] In yet another aspect, a method of treating a disorder associated with chronic inflammation comprises administering said pharmaceutical composition to an individual in need thereof. In another aspect, the present disclosure relates to a method of treating a disorder associated with chronic inflammation comprising administering to an individual in need thereof a pharmaceutical composition disclosed herein.

[0044] In another aspect, the present disclosure relates to a method of treating a subject suffering from a vascular inflammatory disease or condition, a Th1-type vascular inflammatory disease or condition, a Th2-type vascular inflammatory disease or condition, a condition or disease associated with Th1-type inflammation, a monocyte activation response, T cell-dependent B cell proliferation, activation, and class switching in germinal centers of secondary lymphoid organs, a Th2-type pulmonary inflammatory disease or condition, a Th1-type pulmonary inflammatory disease or condition, multiple fibrosis disease or condition, or an inflammation-related response in fibrotic tissue, a disease or condition associated with a macrophage activation response, wherein the method comprises administering to the subject a pharmaceutical composition disclosed herein.

[0045] In some embodiments, the subject suffers from chronic inflammatory disease, vascular inflammation, restenosis, allergy, asthma, ulcerative colitis, atherosclerosis, rheumatoid arthritis, metabolic disease, organ transplant-related reaction, psoriasis, Crohn's disease and inflammatory hematological neoplastic diseases or conditions, pulmonary fibrosis, chronic obstructive pulmonary disease (COPD) exacerbation, sarcoidosis, pulmonary response to respiratory infection, or a Th1-type skin inflammatory response to a mechanical, chemical, or infectious agent.

[0046] In some embodiments, the Th1-type vascular inflammatory disease comprises a chronic inflammatory disease, vascular inflammation, or restenosis.

[0047] In some embodiments, the Th2-type vascular inflammatory disease or condition comprises allergy, asthma, or ulcerative colitis.

[0048] In some embodiments, the Th1-type chronic inflammatory and / or monocyte activation response comprises atherosclerosis, restenosis, rheumatoid arthritis, or metabolic disease.

[0049] In some embodiments, the vascular inflammatory disease or condition includes inflammation causing organ transplant-related reactions, rheumatoid arthritis, psoriasis, Crohn's disease, and hematological oncological diseases or conditions.

[0050] In some embodiments, the pathology or disease associated with T cell-dependent B cell proliferation, activation, and class switching in the germinal centers of secondary lymphoid organs comprises systemic lupus erythematosus (SLE), hematological oncology, autoimmune conditions, asthma, or allergies.

[0051] In some embodiments, the Th2-type pulmonary inflammatory disease or condition comprises asthma, pulmonary fibrosis, or chronic obstructive pulmonary disease (COPD) exacerbation.

[0052] In some embodiments, the Th1-type pulmonary inflammatory disease or condition includes sarcoidosis and pulmonary responses to respiratory infections.

[0053] In some embodiments, the Th1-type inflammatory disease or condition comprises fibrosis, rheumatoid arthritis, dermatitis or psoriasis.

[0054] In some embodiments, the Th1-type inflammatory disease or condition comprises a Th1-type cutaneous inflammatory response to a mechanical, chemical, or infectious agent.

[0055] In some embodiments, the disease or condition associated with a macrophage activation response comprises atherosclerosis, restenosis, or rheumatoid arthritis.

[0056] In some embodiments, the present disclosure relates to a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a therapeutically effective amount of a pharmaceutical composition disclosed herein. In some embodiments, the cancer is selected from the group consisting of adrenal gland tumor, AIDS-related cancer, alveolar soft tissue sarcoma, astrocytic tumor, bladder cancer, bone cancer, brain and spinal cord cancer, metastatic brain tumor, breast cancer, carotid body tumor, cervical cancer, chondrosarcoma, chordoma, chromophobe renal cell carcinoma, clear cell carcinoma, colorectal cancer, cutaneous benign fibrous histiocytoma, desmoplastic small round cell tumor, ependymoma, Ewing's tumor, extraskeletal myxoid chondrosarcoma, osteogenesis imperfecta, fibrous dysplasia, gallbladder or bile duct cancer, gastric cancer, gestational trophoblastic tumor, germ cell tumor, head and neck cancer, hepatocellular carcinoma, pancreatic islet cell tumor, Kaposi's sarcoma, kidney cancer, leukemia, lipoma / benign lipoma Selected from the group consisting of lipomatous tumor, liposarcoma / malignant lipomatous tumor, liver cancer, lymphoma, lung cancer, medulloblastoma, melanoma, meningioma, multiple endocrine neoplasia, multiple myeloma, myelodysplastic syndrome, neuroblastoma, neuroendocrine tumor, ovarian cancer, pancreatic cancer, papillary thyroid cancer, parathyroid tumor, pediatric cancer, peripheral nerve sheath tumor, pheochromocytoma, pituitary tumor, prostate cancer, posterior uveal melanoma, rare blood disorders, renal metastatic cancer, rhabdoid tumor, rhabdomyosarcoma, sarcoma, skin cancer, soft tissue sarcoma, squamous cell carcinoma, gastric cancer, synovial sarcoma, testicular cancer, thymic carcinoma, thymoma, metastatic thyroid cancer, and uterine cancer.

[0057] In some embodiments, the cancer is selected from the group consisting of colorectal cancer, hepatocellular carcinoma, glioma, renal cancer, breast cancer, multiple myeloma, bladder cancer, neuroblastoma; sarcoma, non-Hodgkin's lymphoma, non-small cell lung cancer, ovarian cancer, pancreatic cancer, rectal cancer, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute B-lymphoblastic leukemia (B-ALL), chronic lymphocytic leukemia (CLL), hairy cell leukemia (HCL), non-Hodgkin's lymphoma (NHL), including blastic plasmacytoid dendritic cell neoplasm (BPDCN), Mantel cell leukemia (MCL), and small lymphocytic lymphoma (SLL), Hodgkin's lymphoma, systemic mastocytosis, or Burkitt's lymphoma.

[0058] In another aspect, the present disclosure relates to a method of treating or preventing an iron overload condition or disease, comprising administering to an individual in need thereof a pharmaceutical composition comprising a compound disclosed herein.

[0059] In some embodiments, the iron overload condition or disease comprises a hemochromatosis disease or condition.

[0060] In some embodiments, the iron overload condition or disease comprises liver disease, inflammatory disease, chronic kidney disease, hyperthyroidism, anemia, diabetes, metabolic syndrome, Graves' disease (also known as Graves' disease), cardiac arrhythmia, and chronic hepatitis C infection, or cancer.

[0061] In some embodiments, the inflammatory disease comprises rheumatoid arthritis, an autoimmune disease, an acute infection, or atherosclerosis.

[0062] In another aspect, the present disclosure relates to a method of preventing or reversing telomere shortening, comprising administering to an individual in need thereof a pharmaceutical composition comprising a compound disclosed herein.

[0063] In another aspect, the present disclosure relates to a method of reversing or preventing an aging-related process, disease, or condition, comprising administering to an individual in need thereof a pharmaceutical composition comprising a compound disclosed herein.

[0064] In some embodiments, the aging-associated process is hair loss, loss of vitality, or telomere shortening.

[0065] In some embodiments, administration of a pharmaceutical composition comprising a compound disclosed herein results in a decrease in VCAM-1 levels.

[0066] In one aspect, the present disclosure relates to a method of reducing VCAM-1 levels, comprising administering to an individual in need thereof a pharmaceutical composition comprising a compound disclosed herein.

[0067] In one aspect, the present disclosure relates to a method of treating a gastrointestinal disease or disorder, comprising administering to an individual in need thereof a pharmaceutical composition comprising a compound disclosed herein. In some embodiments, the gastrointestinal disease or disorder is selected from the group consisting of achalasia, Barrett's esophagus, colorectal cancer, gastric cancer, esophageal cancer, celiac disease, colitis, Crohn's disease, diverticulosis, diverticulitis, gastritis, inflammatory bowel disease, ulcerative colitis, irritable bowel syndrome, microscopic colitis, collagenous colitis, lymphocytic colitis, pancreatitis, reflux esophagitis, and ulcerative colitis.

[0068] In another aspect, the present disclosure relates to a method for treating an autoimmune disease, comprising administering to an individual in need thereof a pharmaceutical composition comprising a compound disclosed herein. In some embodiments, the autoimmune disease is selected from the group consisting of lupus erythematosus; Wiskott-Aldrich syndrome; autoimmune lymphoproliferative syndrome; myasthenia gravis; rheumatoid arthritis (RA); lupus nephritis; multiple sclerosis; systemic lupus erythematosus, cutaneous lupus erythematosus including subacute cutaneous lupus erythematosus, chilblain lupus erythematosus, chronic arthritis, Sjogren's syndrome, autoimmune nephritis, autoimmune vasculitis, autoimmune hepatitis, autoimmune carditis, autoimmune encephalitis, autoimmune blood disease, inflammatory chronic rhinosinusitis, colitis, celiac disease, inflammatory bowel disease, Barrett's esophagus, and / or inflammatory gastritis.

[0069] In another aspect, the present disclosure relates to methods of reducing or ameliorating the reactivity, toxicity, or biodistribution of a metal in a subject in need thereof, comprising administering to an individual in need thereof a compound or pharmaceutical composition disclosed herein, hi some embodiments, the compound binds to the metal.

[0070] In some embodiments, the compound binds to the metal at more than one binding site.

[0071] In some embodiments, two or more compounds bind to the metal.

[0072] In some embodiments, the compound binds to the metal only under conditions such as the presence of oxidative stress.

[0073] In some embodiments, the compound is activated by an enzyme to bind to a metal.

[0074] In some embodiments, the compound targets an organ or tissue.

[0075] In some embodiments, the compound alters the concentration or biodistribution of a metal in a subject.

[0076] In some embodiments, the subject is suffering from a metal overload disease or condition.

[0077] In some embodiments, the metal overload disease or condition comprises an iron, copper, or zinc overload disease or condition.

[0078] In some embodiments, the metal is a transition metal.

[0079] In some embodiments, the transition metal comprises scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, silver, cadmium, hafnium, tantalum, tungsten, rhenium, osmium, iridium, platinum, and / or gold; preferably, the transition metal is iron, copper, and / or zinc.

[0080] In some embodiments, the metal is a trivalent metal ion, a divalent metal ion, and / or a monovalent metal ion.

[0081] In some embodiments, the subject is a human.

[0082] In some embodiments, the subject is a mammal.

[0083] In some embodiments, the mammal comprises a primate, dog, horse, cat, cow, or pig.

[0084] In some embodiments, the subject comprises a non-human animal.

[0085] In some embodiments, the non-human animal is a bird or a reptile. [Brief explanation of the drawings]

[0086] [Figure 1] Figure 1 shows the H NMR (proton nuclear magnetic resonance) spectra for two different lots of 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine synthesized according to the protocol described herein in Example 5. The H NMR spectra confirmed the identity and purity of the 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine. [Figure 2] Figure 2 shows the H NMR spectra for two different lots of 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine synthesized according to the protocol described herein in Example 5. The H NMR spectra confirmed the identity and purity of the 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine. [Figure 3] 3 shows the H NMR spectra for two different lots of 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine synthesized according to the protocol described herein in Example 5. The H NMR spectra confirmed the identity and purity of the 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine. [Figure 4]4 shows the H NMR spectra for two different lots of 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine synthesized according to the protocol described herein in Example 5. The H NMR spectra confirmed the identity and purity of the 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine. [Figure 5] 5 shows the IR (infrared) spectrum of an exemplary lot of 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine synthesized according to the protocol described herein in Example 5. The IR spectrum confirmed the identity and purity of the 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine. [Figure 6] 6 shows the IR spectrum of an exemplary lot of 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine synthesized according to the protocol described herein in Example 5. The IR spectrum confirmed the identity and purity of the 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine. [Figure 7] 7 shows the IR spectrum of an exemplary lot of 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine synthesized according to the protocol described herein in Example 5. The IR spectrum confirmed the identity and purity of the 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine. [Figure 8] 8 shows the IR spectrum of an exemplary lot of 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine synthesized according to the protocol described herein in Example 5. The IR spectrum confirmed the identity and purity of the 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine. [Figure 9] FIG. 9 shows an overlay of the IR spectra shown in FIGS. [Figure 10]10 shows the results of long-term liquid chromatography mass spectrometry (LC-MS) of 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine synthesized according to the protocol described in Example 5 herein. The LC-MS results further confirm that both the main and minor peaks from HPLC of compound 8 produced 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine. [Figure 11] Figure 11 shows the results of long-term liquid chromatography mass spectrometry analysis of 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine synthesized according to the protocol described in Example 5 herein. The [M+H]+ from LCMS analysis for both peaks from HPLC purification corresponds to the product mass [LC-MS calculated for m / z of [M+H]+ for CHN4: 281.3, found: 281.3]. Figure 11 shows images of 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine obtained from both peaks of isolated compound 8. [Figure 12] FIG. 12 shows the normal HPLC (A) and chiral HPLC (B) of the same lot of synthesized 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine. [Figure 13] FIG. 13 shows a photograph of the crystals of 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine synthesized from both HPLC peaks. [Figure 14] FIG. 14 shows photographs comparing days 1 and 8 of old mice treated with 10 mg / day of 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine. [Figure 15] FIG. 15 shows the inhibition of VCAM activity by 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine (Tri-Iso-1) in comparison to doxycycline. [Figure 16]FIG. 16 shows the 1H NMR spectrum of 2,4,6-pyridinetricarbaldehyde (CDCl3, 400 MHz) in Synthesis Scheme III of 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine in Example 8. [Figure 17] FIG. 17 shows the HPLC chromatogram of 2,4,6-pyridinetricarbaldehyde. [Figure 18] FIG. 18 shows the 1H NMR spectrum of Stage 1 (DMSO, 400 MHz) in Synthesis Scheme III of 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine in Example 8. [Figure 19] FIG. 19 shows an HPLC chromatogram of the Stage 1 product in Synthesis Scheme III of 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine of Example 8. [Figure 20] FIG. 20 shows the 1H NMR spectrum of the Stage 2 product in Synthesis Scheme III of 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine in Example 8. [Figure 21] FIG. 21 shows an HPLC chromatogram of the Stage 2 product in the synthetic scheme III of 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine in Example 8. [Figure 22] FIG. 22 shows the 1H NMR spectrum of the Stage 3 product in Synthesis Scheme III of 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine in Example 8. [Figure 23] FIG. 23 shows an HPLC chromatogram of the Stage 3 product in the synthetic scheme III of 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine in Example 8. [Figure 24] FIG. 24 shows the geometry optimization without explicit water molecules. [Figure 25] FIG. 25 shows the complexation of 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine, Fe 2+ , and six water molecules. DETAILED DESCRIPTION OF THE INVENTION

[0087] The pharmaceutical compounds disclosed herein have anti-inflammatory and anti-cancer activity and are useful for the treatment of hemochromatosis. The compounds disclosed herein can also function as metalloenzyme inhibitors, preventing the action of enzymes that lead to cellular metal imbalance and telomere shortening. Furthermore, the compounds disclosed herein can prevent, reverse, or slow down aging-related processes, as shown in Examples 6 and 7 herein.

[0088] Thus, in some embodiments, the present disclosure relates to a method of reducing or ameliorating the reactivity, toxicity, or biodistribution of a metal in a subject in need thereof, comprising administering to an individual in need thereof a compound or pharmaceutical composition disclosed herein. In some embodiments, the compound binds to the metal. In some embodiments, the compound binds to the metal at two or more binding sites. In some embodiments, two or more compounds bind to the metal.

[0089] Thus, in some embodiments, a therapeutically effective amount of a compound herein is administered to an individual in need thereof, where the therapeutically effective amount reduces metal reactivity, toxicity, or improves metal biodistribution. In some embodiments, the therapeutically effective amount of the compound does not interfere with normal, healthy metal status in the individual. In some embodiments, the compound is not cytotoxic to normal, healthy cells, tissues, or organs. Exemplary therapeutically effective amounts are disclosed elsewhere herein.

[0090] In some embodiments, the compounds disclosed herein reduce the level of metal reactivity 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%.

[0091] In some embodiments, the compounds disclosed herein reduce the cytotoxicity of a metal 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%.

[0092] In some embodiments, the compounds disclosed herein improve metal reactivity 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%.

[0093] In some embodiments, the compounds disclosed herein improve metal biodistribution 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%.

[0094] In some embodiments, the compounds disclosed herein improve or reduce metalloenzyme activity, e.g., by 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%.

[0095] The compounds disclosed herein can be designed to preferentially bind to metals under specific cellular conditions or upon enzyme activation. For example, the compounds can be modified to bind to metals only under oxidative stress, such as in the presence of hydrogen peroxide. The modified compounds activated by oxidative stress can be boronates. Oxidative stress is associated with many diseases, such as inflammatory diseases, gastrointestinal diseases, autoimmune diseases, or cancer diseases, as disclosed herein. In some embodiments, the compounds target organs or tissues by modifying the compounds. For example, the incorporation of N-acetyl-galactosamine aids in targeting hepatocytes.

[0096] In some embodiments, the compound alters the concentration or biodistribution of a metal in a subject.

[0097] In some embodiments, the metal is a transition metal.

[0098] In some embodiments, the transition metal comprises scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, silver, cadmium, hafnium, tantalum, tungsten, rhenium, osmium, iridium, platinum, and / or gold; preferably, the transition metal is iron, copper, and / or zinc.

[0099] In some embodiments, the metal is a trivalent metal ion, a divalent metal ion, and / or a monovalent metal ion.

[0100] In some embodiments, the subject is suffering from a metal overload disease or condition.

[0101] In some embodiments, the metal overload disease or condition comprises an iron, copper, or zinc overload disease or condition.

[0102] For example, compounds such as 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine disclosed herein may help balance intracellular and circulating iron levels in iron overload (IO) conditions. One IO condition is hereditary hemochromatosis (HH), which is caused by mutations in the iron storage protein ferritin. Iron overload conditions also include secondary hemochromatosis, which can occur in patients with hemoglobinopathies (e.g., sickle cell disease, thalassemia, and sideroblastic anemia), congenital hemolytic anemia, and myelodysplasia.

[0103] Conditions associated with iron overload may also include liver disease, rheumatoid arthritis or other inflammatory diseases, hyperthyroidism, or cancers such as pancreatic cancer, colorectal cancer, lung cancer, T-cell lymphoma, and hepatocellular carcinoma. Excessive iron deposition is also associated with inflammatory diseases, chronic kidney disease, rheumatoid arthritis, autoimmune diseases, acute infections, cancer, anemia of chronic disease, type 2 diabetes, metabolic syndrome, atherosclerosis, fatty liver disease, anorexia, Graves' disease, cardiac arrhythmia, and chronic hepatitis C infection. In some embodiments, the iron overload condition or disease includes hemochromatosis disease or condition. In some embodiments, the iron overload condition or disease includes liver disease, inflammatory diseases, chronic kidney disease, hyperthyroidism, anemia, diabetes, metabolic syndrome, Graves' disease, cardiac arrhythmia, and chronic hepatitis C infection, or cancer.

[0104] In some embodiments, the inflammatory disease comprises rheumatoid arthritis, an autoimmune disease, an acute infection, or atherosclerosis.

[0105] The compounds disclosed herein can also prevent or reverse absolute telomere length (ATL) shortening, which is an important molecular characteristic of cellular senescence and DNA damage associated with chronic disease and death.In fact, it has been discovered that telomere shortening is the main cause of human aging.In particular, ATL reduction is associated with almost all chronic diseases associated with aging, such as cancer, heart disease, diabetes, and autoimmune diseases.

[0106] Telomeres are the ends of chromosomes that protect DNA, similar to the tips of shoelaces that prevent the laces from unraveling. When telomeres are shortened to a critical length, DNA is no longer protected during replication, resulting in DNA damage and chromosomal rearrangements, which in turn lead to somatic cell senescence, apoptosis, or oncogenic transformation.

[0107] In another aspect, the present disclosure relates to a method of treating or preventing an iron overload condition or disease, comprising administering to an individual in need thereof a pharmaceutical composition comprising a compound disclosed herein.

[0108] In another aspect, the present disclosure relates to a method of preventing or reversing telomere shortening, comprising administering to an individual in need thereof a pharmaceutical composition comprising a compound disclosed herein.

[0109] In another aspect, the present disclosure relates to a method of reversing or preventing an age-related process, disease, or condition, comprising administering to an individual in need thereof a pharmaceutical composition comprising a compound disclosed herein.

[0110] In some embodiments, administration of a pharmaceutical composition comprising a compound disclosed herein results in a decrease in VCAM-1 levels.

[0111] In one aspect, the present disclosure relates to a method of reducing VCAM-1 levels, comprising administering to an individual in need thereof a pharmaceutical composition comprising a compound disclosed herein.

[0112] In some embodiments, the aging-related process is hair loss, loss of vitality, or telomere shortening. As used herein, the term "vitality" refers to vitality as defined by the World Health Organization (WHO): "the composite of all physical and mental capabilities available to an individual at any given time." Thus, vitality includes mental vitality, physical vitality, and / or a combination of both mental and physical vitality. Many measures of mental vitality, including the 10-item Geriatric Depression Scale (GDS), are known in the art. Physical vitality can be measured by a number of different physical exercises, such as grip strength (HGS), walking speed, knee extensor strength, or the stand-up test. In some embodiments, vitality includes an individual's biophysical state and their ability to maintain homeostasis in the face of everyday exposures or more extreme, unusual, or unexpected challenges, such as injury or infection. In some embodiments, vitality is the amount of intrinsic capacity that can be retained and can be considered to underlie an individual's vitality, stamina, and resilience to challenges. The main aspects of vitality are hormonal function, energy metabolism, and cardiovascular function. Other aspects of vitality are nutrition, body composition, depression, fatigue, metabolism, immune system response, respiratory function, or muscular endurance.

[0113] Fatigue can include measures of muscle endurance, assessment of self-perceived fatigue, and daytime fatigue. Metabolic fatigue can be measured by insulin sensitivity, glycosylated hemoglobin, serum albumin, fasting glucose, or hormonal status of the hypothalamic-pituitary-adrenal axis. Body composition can be measured by anthropometry, weight, BMI, waist circumference, and muscle mass. Cardiovascular function can be measured by heart rate during physical activity, heart rate variability, oxygen saturation, orthostatic hypotension or recumbency response, blood pressure, cardiovascular fitness, or maximal oxygen consumption. Nutrition can be assessed by measuring or assessing appetite, weight loss, malnutrition, undernutrition, or a simplified nutritional status assessment. Immune or stress responses can be assessed by circulating biomarkers of inflammation, perceived immune status, oxygen saturation, or autonomic function. Other measurable aspects of vitality include self-esteem, mitochondrial function, sedentary behavior, sleep quantity and quality, the methylation clock, or electrolyte balance.

[0114] For example, the compound may have anti-inflammatory activity, which can reduce the level of inflammation-inducing molecules. Without wishing to be bound by theory, it is believed that the disclosed compound can have anti-inflammatory activity, which can reduce the level of substance P (SP), calcitonin gene-related peptide (CGRP), glutamic acid (glutamate), or a combination thereof. The compound can have anti-inflammatory activity, which can reduce the level of SP, CGRP, glutamic acid, 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%.

[0115] 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 primary resolution 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.

[0116] 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 inflammation-induced 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%, about 40% to about 90%, about The anti-inflammatory activity can be reduced by 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 about 70%, or about 50% to about 70%.

[0117] 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 response elements (PPREs). PPARs play important roles in regulating cellular differentiation, development, and metabolism (carbohydrates, lipids, and proteins) in higher organisms, as well as tumorigenesis. This 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 includes three alternatively spliced ​​forms, each with a distinct expression pattern. PPAR-γ1 is expressed in almost all tissues, including the heart, muscle, colon, kidney, pancreas, and spleen. PPAR-γ2 is mainly 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.

[0118] The compounds may have anti-inflammatory activity, which 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 have anti-inflammatory activity that 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%.

[0119] The compounds may have anti-inflammatory activity that can stimulate some or all of the PPAR signaling pathways. It is therefore contemplated that such compounds may act as pan-PPAR agonists, or perhaps as selective PPAR agonists.

[0120] 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 inflammatory molecules released from Th1 or Th2 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 inflammatory molecules released from Th1 or Th2 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%.

[0121] For example, the compound may have anti-inflammatory activity capable of reducing the levels of IFN-γ, TNF-α, IL-12, or a combination 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 capable of reducing 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%.

[0122] Compounds such as 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine and 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine with ethanol as a carrier may have anti-inflammatory activity that can modulate inflammatory molecules. The compounds may have anti-inflammatory activity that can reduce the levels of CD40, sIgG, sIL-10, HLA-DR, sIL-17A, CD38, sIL-6, sIL-17F, and sIL-2. The compounds may have anti-inflammatory activity that can reduce the levels of CD40, sIgG, sIL-10, HLA-DR, sIL-17A, CD38, sIL-6, sIL-17F, sIL-2, or a combination thereof 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 levels of CD40, sIgG, sIL-10, HLA-DR, sIL-17A, CD38, sIL-6, sIL-17F, or sIL-2 by 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%.

[0123] The compound may have anti-inflammatory activity that can reduce the levels of eotaxin 3, MCP-1, VCAM-1, MIG, IL-6, and / or P-selectin. The compound may have anti-inflammatory activity that can reduce the levels of eotaxin 3, MCP-1, VCAM-1, MIG, IL-6, P-selectin, or a combination thereof, 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 levels of eotaxin 3, MCP-1, VCAM-1, MIG, IL-6, and / or P-selectin by 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%.

[0124] The compound may have anti-inflammatory activity capable of reducing the levels of eotaxin 3, MCP-1, MIP-1α, I-TAC, MIG, IP-10, IL-6, VCAM-1, SAA, IL-1α, and P-selectin. The compound may have anti-inflammatory activity capable of reducing the levels of eotaxin 3, MCP-1, MIP-1α, I-TAC, MIG, IP-10, IL-6, VCAM-1, SAA, IL-1α, P-selectin, or a combination thereof, 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 can have anti-inflammatory activity that can reduce levels of eotaxin 3, MCP-1, MIP-1α, I-TAC, MIG, IP-10, IL-6, VCAM-1, SAA, IL-1α, and / or P-selectin by 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%.

[0125] 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%.

[0126] The compounds disclosed herein can also affect tissue remodeling activity by decreasing TIMP-1, collagen IV, PAI-1, and / or collagen III. The compounds can have tissue remodeling activity that can reduce the levels of TIMP-1, collagen IV, PAI-1, and / or collagen III, or a combination thereof, 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 tissue remodeling activity that can reduce levels of TIMP-1, collagen IV, PAI-1, and / or collagen III by 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%.

[0127] The compounds disclosed herein can also affect tissue remodeling activity by decreasing TIMP-1, collagen IV, MMP-1, PAI-1, uPAR, αSMA, and / or MMP-9. The compounds can have tissue remodeling activity that can reduce the levels of TIMP-1, collagen IV, MMP-1, PAI-1, uPAR, αSMA, and / or MMP-9, or a combination thereof, 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 tissue remodeling activity capable of reducing levels of TIMP-1, collagen IV, MMP-1, PAI-1, uPAR, αSMA, and / or MMP-9 by 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%.

[0128] The compounds disclosed herein may also affect tissue remodeling activity by decreasing collagen I, TIMP-2, TIMP-1, collagen IV, tPA, collagen III, αSMA, bFGF, MMP-1, PAI-1, Ker8 / 18, and / or MMP-9. The compounds may have tissue remodeling activity that can reduce the levels of collagen I, TIMP-2, TIMP-1, collagen IV, tPA, collagen III, αSMA, bFGF, MMP-1, PAI-1, Ker8 / 18, and / or MMP-9, or a combination thereof, 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 tissue remodeling activity that can reduce levels of collagen I, TIMP-2, TIMP-1, collagen IV, tPA, collagen III, αSMA, bFGF, MMP-1, PAI-1, Ker8 / 18, and / or MMP-9 by 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%.

[0129] The compounds disclosed herein can affect hemostasis-related activity, as demonstrated by a decrease in TM (thrombomodulin) and an increase in TF (tissue factor). The compounds disclosed herein can decrease TM 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 compounds disclosed herein can increase TF 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 compounds disclosed herein may have hemostasis-related activity that can reduce levels of TM by 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%. The compounds disclosed herein may have hemostasis-related activity that can increase the level of TF by 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%.

[0130] Thus, 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine and 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine with ethanol as a carrier can be used in methods of treating a subject suffering from a vascular inflammatory disease or condition, a Th1-type vascular inflammatory disease or condition, a Th2-type vascular inflammatory disease or condition, a Th1-type vascular inflammatory disease or condition, a condition or disease associated with Th1-type inflammation, a monocyte activation response, T cell-dependent B cell proliferation, activation, and class switching in germinal centers of secondary lymphoid organs, a Th2-type pulmonary inflammatory disease or condition, a Th1-type pulmonary inflammatory disease or condition, multiple fibrosis disease or condition, or an inflammation-related response in fibrotic tissue, a disease or condition associated with a macrophage activation response.

[0131] In some embodiments, the subject is suffering from a chronic inflammatory disease, vascular inflammation, restenosis, allergy, asthma, ulcerative colitis, atherosclerosis, rheumatoid arthritis, metabolic disease, organ transplant-related reaction, psoriasis, Crohn's disease and hematological neoplastic disease or condition caused by inflammation, pulmonary fibrosis, exacerbation of chronic obstructive pulmonary disease (COPD), sarcoidosis, a pulmonary response to a respiratory infection, or a Th1-type skin inflammatory response to a mechanical, chemical, or infectious agent.

[0132] In some embodiments, the Th1-type vascular inflammatory disease comprises a chronic inflammatory disease, vascular inflammation, or restenosis.

[0133] In some embodiments, the Th2-type vascular inflammatory disease or condition comprises allergy, asthma, or ulcerative colitis.

[0134] In some embodiments, the Th1-type chronic inflammatory and / or monocyte activation response comprises atherosclerosis, restenosis, rheumatoid arthritis, or metabolic disease.

[0135] In some embodiments, vascular inflammatory diseases or conditions include inflammation causing organ transplant-related reactions, rheumatoid arthritis, psoriasis, Crohn's disease, and hemato-oncological diseases or conditions.

[0136] In some embodiments, the condition or disease associated with T cell-dependent B cell proliferation, activation, and class switching in the germinal centers of secondary lymphoid organs comprises systemic lupus erythematosus (SLE), hematological oncology, autoimmune indications, asthma, or allergies.

[0137] In some embodiments, the Th2-type pulmonary inflammatory disease or condition comprises an exacerbation of asthma, pulmonary fibrosis, or chronic obstructive pulmonary disease (COPD).

[0138] In some embodiments, the Th1-type pulmonary inflammatory disease or condition includes sarcoidosis and the pulmonary response to respiratory infections.

[0139] In some embodiments, the Th1-type inflammatory disease or condition comprises fibrosis, rheumatoid arthritis, dermatitis or psoriasis.

[0140] In some embodiments, the Th1-type inflammatory disease or condition comprises a Th1-type cutaneous inflammatory response to a mechanical, chemical, or infectious agent.

[0141] In some embodiments, the disease or condition associated with a macrophage activation response comprises atherosclerosis, restenosis, or rheumatoid arthritis.

[0142] 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 diseases, as demonstrated in both allergic reactions and some muscle disorders, and many immune system disorders result in abnormal inflammation. Non-immune diseases that contribute to chronic inflammatory processes include cancer, atherosclerosis, and ischemic heart disease.Non-limiting examples of diseases that manifest 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, chorioamnionitis, chronic obstructive pulmonary disease (COPD), Liver cirrhosis, colitis, congestive heart failure, conjunctivitis, Crohn's disease, cyclophosphamide-induced cystitis, cystic fibrosis, cystitis, cold, dacryoadenitis, dementia, dermatitis, dermatomyositis, diabetes, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic ulcer, digestive system disease, eczema, emphysema, encephalitis, endocarditis, endometritis, enteritis, epicondylitis, epididymitis, fasciitis, fibromyalgia, fibrosis, fibrositis, gastritis, gastroenteritis, gingivitis, glomerulonephritis, glossitis, heart disease, heart valve dysfunction, hepatitis, hidradenitis suppurativa, Huntington's disease, hyperlipidemia Pancreatitis, 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, osteomyelitis, osteoporosis, osteitis, otitis media, pancreatitis, Parkinson's disease, parotitis, pelvic inflammation Diseases, exonuclear pemphigus, pericarditis, peritonitis, pharyngitis, phlebitis, pleuritis, pneumonia, polycystic nephritis, proctitis, prostatitis, psoriasis, pulpitis, pyelonephritis, pyelophlebitis, renal failure, reperfusion injury, retinitis, rheumatic fever, rhinitis, salpingitis, sarcoidosis, sialadenitis, sinusitis, spastic colon, stenosis, stomatitis, stroke, surgical complications, synovitis, tendinitis, tendinosis, tenosynovitis, thrombophlebitis, tonsillitis, trauma, traumatic brain injury, transplant rejection, trigonitis, tuberculosis, tumor, urethritis, urinary tract inflammation, uveitis, vaginitis, vasculitis, and vulvitis.

[0143] In one aspect, the present disclosure relates to a method of treating a gastrointestinal disease or disorder, comprising administering to an individual in need thereof a pharmaceutical composition comprising a compound disclosed herein. In some embodiments, the gastrointestinal disease or disorder is selected from the group consisting of achalasia, Barrett's esophagus, colorectal cancer, gastric cancer, esophageal cancer, celiac disease, colitis, Crohn's disease, diverticulosis, diverticulitis, gastritis, inflammatory bowel disease, ulcerative colitis, irritable bowel syndrome, microscopic colitis, collagenous colitis, lymphocytic colitis, pancreatitis, reflux esophagitis, and ulcerative colitis.

[0144] In another aspect, the present disclosure relates to a method for treating an autoimmune disease, comprising administering to an individual in need thereof a pharmaceutical composition comprising a compound disclosed herein. In some embodiments, the autoimmune disease is selected from the group consisting of lupus erythematosus; Wiskott-Aldrich syndrome; autoimmune lymphoproliferative syndrome; myasthenia gravis; rheumatoid arthritis (RA); lupus nephritis; multiple sclerosis; systemic lupus erythematosus; cutaneous lupus erythematosus, including subacute cutaneous lupus erythematosus, chilblain lupus erythematosus, chronic arthritis, Sjogren's syndrome, autoimmune nephritis, autoimmune vasculitis, autoimmune hepatitis, autoimmune carditis, autoimmune encephalitis, autoimmune blood disease, inflammatory chronic rhinosinusitis, colitis, celiac disease, inflammatory bowel disease, Barrett's esophagus, and / or inflammatory gastritis.

[0145] In another aspect, the present disclosure relates to a method of treating cancer in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein.

[0146] In some embodiments, the cancer is an adrenal gland tumor, AIDS-related cancer, alveolar soft tissue sarcoma, astrocytic tumor, bladder cancer, bone cancer, brain and spinal cord cancer, metastatic brain tumor, breast cancer, carotid body tumor, cervical cancer, chondrosarcoma, chordoma, chromophobe renal cell carcinoma, clear cell carcinoma, colorectal cancer, cutaneous benign fibrous histiocytoma, desmoplastic small round cell tumor, ependymoma, Ewing's tumor, extraskeletal myxoid chondrosarcoma, osteogenesis imperfecta, fibrous dysplasia, gallbladder or bile duct cancer, gastric cancer, gestational trophoblastic tumor, germ cell tumor, head and neck cancer, hepatocellular carcinoma, pancreatic islet cell tumor, Kaposi's sarcoma, kidney cancer, leukemia, lipoma / benign lipid Selected from the group consisting of lipomatous tumor, liposarcoma / malignant lipomatous tumor, liver cancer, lymphoma, lung cancer, medulloblastoma, melanoma, meningioma, multiple endocrine neoplasia, multiple myeloma, myelodysplastic syndrome, neuroblastoma, neuroendocrine tumor, ovarian cancer, pancreatic cancer, papillary thyroid cancer, parathyroid tumor, pediatric cancer, peripheral nerve sheath tumor, pheochromocytoma, pituitary tumor, prostate cancer, posterior uveal melanoma, rare blood disorders, renal metastatic cancer, rhabdoid tumor, rhabdomyosarcoma, sarcoma, skin cancer, soft tissue sarcoma, squamous cell carcinoma, gastric cancer, synovial sarcoma, testicular cancer, thymic carcinoma, thymoma, metastatic thyroid cancer, and uterine cancer.

[0147] In some embodiments, the cancer is selected from the group consisting of colorectal cancer, hepatocellular carcinoma, glioma, renal cancer, breast cancer, multiple myeloma, bladder cancer, neuroblastoma; sarcoma, non-Hodgkin's lymphoma, non-small cell lung cancer, ovarian cancer, pancreatic cancer, rectal cancer, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute B-lymphoblastic leukemia (B-ALL), chronic lymphocytic leukemia (CLL), hairy cell leukemia (HCL), non-Hodgkin's lymphoma (NHL), including blastic plasmacytoid dendritic cell neoplasm (BPDCN), Mantel cell leukemia (MCL), and small lymphocytic lymphoma (SLL), Hodgkin's lymphoma, systemic mastocytosis, or Burkitt's lymphoma.

[0148] As used herein, "treatment" refers to clinical intervention in an attempt to change the natural course of the subject or cell being treated, and can be performed for preventive purposes or during clinical pathology. Desirable therapeutic effects include preventing the onset or recurrence of disease, alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, slowing the rate of disease progression, improving or delaying the disease state, and remission or improving prognosis. In some embodiments, the onset of disease or disorder is delayed using the pharmaceutical composition of the present invention.

[0149] As used herein, "inhibiting the growth" of a tumor or cancer cell can refer to slowing the rate of growth of the tumor or cancer cell or to stopping the growth of the tumor or cancer cell altogether.

[0150] As used herein, "tumor" refers to the growth and proliferation of all neoplastic cells (malignant or benign), and all pre-cancerous and cancerous cells and tissues. The terms "cancer," "cancerous," "cell proliferative disorder," "proliferative disorder," and "tumor" referred to herein are not mutually exclusive.

[0151] The terms "cancer" and "cancerous" refer to or describe a physiological condition in mammals that is typically characterized by uncontrolled cell growth / proliferation. Examples of cancer include, but are not limited to, carcinoma, lymphoma (such as Hodgkin's lymphoma and non-Hodgkin's lymphoma), blastoma, sarcoma, and leukemia. More specific examples of such cancers include squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, leukemia, and other lymphoproliferative disorders, as well as various types of head and neck cancer.

[0152] As used herein, "tumor regression" or "regression" of a tumor can refer to a decrease in the size or maximum size of a tumor. Tumor size can be determined, for example, by a bioluminescence-based assay.

[0153] compound In one aspect, the present disclosure provides a compound of formula Ia or Ib shown below: [ka] [ka] or a pharmaceutically acceptable ester or solvate thereof, wherein in the above formula, X - is an ion of an acid that forms a pharmaceutically acceptable salt, A1, A2, A3, and A4 are independently selected from nitrogen (N) or carbon (C), and R1, R2, R3, R4, R5, R6, R7, and R8 are independently selected from the group consisting of nothing, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle; when R3 is N, R1 is nothing; when A4 is N, R3 is nothing; alkyl, alkenyl, alkynyl, or acyl is selected from halogen, —OH, alkyl, —O-alkyl, NR A R B optionally substituted with one or more substituents independently selected from the group consisting of -S-alkyl, -SO-alkyl, -SO2-alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle; R A and R B are each independently hydrogen and C 1-4 alkyl; aryl or heteroaryl, whether alone or as part of a substituent, are selected from halogen, —OH, alkyl, —O-alkyl, —COOH, —C(O)—C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, NR C R Doptionally substituted with one or more substituents independently selected from the group consisting of -S-alkyl, -SO-alkyl, and -SO2-alkyl; R C and R D are each independently hydrogen and C 1-4 alkyl.

[0154] In some embodiments, R2 and / or R4 are selected from the group consisting of Formula IIa and IIb: [ka] wherein X - , A1, A2, R5, R6, R7, and R8 are defined as above.

[0155] In some embodiments, A1 and A3 are N, A4 is C, and R3 has a structure according to Formula IIa or Formula IIb.

[0156] In some embodiments, A2 is C.

[0157] In some embodiments, A1 is N and / or A3 and / or A4 are N.

[0158] In some embodiments, A2 is C.

[0159] In some embodiments, R2 and R4 have a structure according to Formula IIa or Formula IIb.

[0160] In some embodiments, the compound is: [ka] [ka] or a pharmaceutically acceptable salt, ester, or solvate thereof.

[0161] According to one embodiment, the anti-inflammatory compound has the following structure: [ka] or a pharmaceutically acceptable salt, ester or solvate thereof.

[0162] In one aspect, the present disclosure provides a compound having the following structure: [ka] 2,4,6-Tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine or a pharmaceutically acceptable salt, ester, or solvate thereof.

[0163] In some embodiments, the present disclosure provides compounds of formula IIIa or IIIb shown below: [ka] or a pharmaceutically acceptable ester or solvate thereof, wherein X - is an ion of an acid that forms a pharmaceutically acceptable salt, and R 1 , R 2 and R 3 is independently selected from the group consisting of H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle; alkyl, alkenyl, alkynyl, or acyl is independently selected from the group consisting of halogen, —OH, alkyl, —O-alkyl, NR A R B optionally substituted with one or more substituents independently selected from the group consisting of -S-alkyl, -SO-alkyl, -SO2-alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle; R A and R B are each independently hydrogen and C 1-4alkyl; aryl or heteroaryl, whether alone or as part of a substituent group, are selected from halogen, —OH, alkyl, —O-alkyl, —COOH, —C(O)—C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, NR C R D , -S-alkyl, -SO-alkyl, and -SO2-alkyl; R C and R D are each independently hydrogen and C 1-4 alkyl.

[0164] In some embodiments, the compound has the following structure: [ka] or a pharmaceutically acceptable salt, ester or solvate thereof.

[0165] In some embodiments, the present disclosure provides compounds of Formula IVa or Formula IVb, as set forth below: [ka] wherein X - is an ion of an acid that forms a pharmaceutically acceptable salt, and R1, R2, R3, R4, R5, R6, and R7 are independently selected from the group consisting of H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle; alkyl, alkenyl, alkynyl, or acyl is selected from the group consisting of halogen, -OH, alkyl, -O-alkyl, NR A R B , -S-alkyl, -SO-alkyl, -SO2-alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle; R A and R B are each independently hydrogen and C 1-4alkyl; aryl or heteroaryl, whether alone or as part of a substituent group, are selected from halogen, —OH, alkyl, —O-alkyl, —COOH, —C(O)—C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, NR C R D optionally substituted with one or more substituents independently selected from the group consisting of -S-alkyl, -SO-alkyl, and -SO2-alkyl; R C and R D are each independently hydrogen and C 1-4 alkyl.

[0166] In some embodiments, the compound has the following structure: [ka] or a pharmaceutically acceptable salt, ester or solvate thereof.

[0167] In another aspect, the present disclosure provides a compound of formula Va or formula Vb shown below: [ka] [ka] or a pharmaceutically acceptable ester or solvate thereof, wherein X - is an ion of an acid that forms a pharmaceutically acceptable salt, A1, A2, A3, A4, A5, and A6 are independently selected from nitrogen (N) or carbon (C), and R1, R2, R3, R4, R5, R6, R7, and R8 are independently selected from the group consisting of nothing, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle; when R3 is N, R1 is nothing; when A4 is N, R3 is nothing; alkyl, alkenyl, alkynyl, or acyl is selected from halogen, —OH, alkyl, —O-alkyl, NR AR B optionally substituted with one or more substituents independently selected from the group consisting of -S-alkyl, -SO-alkyl, -SO2-alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle; R A and R B are each independently hydrogen and C 1-4 alkyl; aryl or heteroaryl, whether alone or as part of a substituent, are selected from halogen, —OH, alkyl, —O-alkyl, —COOH, —C(O)—C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, NR C R D optionally substituted with one or more substituents independently selected from the group consisting of -S-alkyl, -SO-alkyl, and -SO2-alkyl; R C and R D are each independently hydrogen and C 1-4 In some embodiments, R2 and / or R4 have a structure according to Formula IIa or IIb, wherein X is selected from alkyl. - , A1, A2, R5, R6, R7, and R8 are defined as above. In some embodiments, A1 and A3 are N, A4, A5, and A6 are C, and R3 has a structure according to Formula IIa or Formula IIb. In some embodiments, A1 and A3 are N, A4 is C, A5 or A6 is N, and R3 has a structure according to Formula IIa or Formula IIb. In some embodiments, A1, A3, and A4 are N, A5 and A6 are C, and R3 has a structure according to Formula IIa or Formula IIb. In some embodiments, A2 is C. In some embodiments, A1 is N, and / or A3 and / or A4 are N. In some embodiments, R2 and R4 have a structure according to Formula IIa or Formula IIb.

[0168] In some embodiments, the compound according to Formula Va or Vb has the following structure: [ka] or a pharmaceutically acceptable salt, ester or solvate thereof.

[0169] In some embodiments, the compound according to Formula Va or Vb is: [ka] [ka] or a pharmaceutically acceptable salt, ester, or solvate thereof.

[0170] In some embodiments, the compound according to Formula Va or Vb is: [ka] or a pharmaceutically acceptable salt, ester, or solvate thereof.

[0171] In some embodiments, the compound according to Formula Va or Vb is: [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, ester, or solvate thereof.

[0172] Pharmaceutical Composition Pharmaceutical compositions may include 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 does not cause substantial long-term or permanent adverse effects when administered, including terms such as "pharmaceutically acceptable vehicle," "stabilizer," "diluent," "additive," "auxiliary agent," or "additive." Pharmaceutically acceptable carriers are generally safe and non-toxic, and include vehicles that are acceptable for veterinary use and human pharmaceutical use. Such carriers are generally capable of being mixed with, or diluting or encapsulating, the active compound, and may be solid, semi-solid, or liquid agents. It is 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; coating agents; antibacterial and antifungal agents; isotonic and absorption delaying agents; or any other inactive ingredients. The choice of pharmaceutically acceptable carrier can depend on the method of administration. Any pharmaceutically acceptable carrier is contemplated for use in the pharmaceutically acceptable composition, except insofar as it is incompatible with the active ingredient.Non-limiting examples of specific uses of such pharmaceutical carriers are described in Pharmaceutical Dosage Forms and Drug Delivery Systems (Howard C. Ansel et al., eds., Lippincott Williams & Wilkins Publishers, 7th ed. 1999); REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (Alfonso R. Gennaro ed., Lippincott, Williams & Wilkins, 20th ed. 2000); Goodman & Gilman's The Pharmacological Basis of Therapeutics (Joel G. Hardman et al., eds., McGraw-Hill Professional, 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 well within the skill of those in the art and will be readily apparent from the teachings herein.

[0173] In various embodiments, the present invention provides kits for treating, preventing, reducing the severity, and / or delaying the progression of a condition or disease described herein in a subject. The kit is a collection of materials or components, including at least one of the compounds disclosed herein. Thus, in some embodiments, the kit contains a composition comprising a drug delivery molecule conjugated to a therapeutic compound, as described above. The exact nature of the components comprised in the kits of the present invention will depend on their intended purpose. In one embodiment, the kit is specifically configured for treating mammalian subjects. In another embodiment, the kit is specifically configured for treating human subjects. In a further embodiment, the kit is specifically configured for veterinary use, treating subjects such as, but not limited to, farm animals, domestic animals, and laboratory animals. The kit may also include instructions for use. "Instructions" typically include specific language describing the techniques to be employed in using the kit components to achieve the desired result. Optionally, the kit also includes other useful components, such as diluents, buffers, pharmaceutically acceptable carriers, syringes, catheters, applicators, pipettes or measuring tools, bandages, or other useful devices readily recognizable to those skilled in the art. The materials or components incorporated into the kit can be stored and provided to the physician in any convenient and appropriate manner that maintains their operability and usefulness. For example, the components may be in dissolved, dehydrated, or lyophilized form and may be provided at room temperature, refrigerated, or frozen temperature. The components are typically contained in suitable packaging material(s). As used herein, the term "packaging material" refers to one or more physical structures used to contain the contents of the kit, such as the composition of the present invention. The packaging material is preferably constructed by well-known methods to provide a sterile, contaminant-free environment. As used herein, the term "package" refers to a suitable solid matrix or material, such as glass, plastic, paper, or foil, capable of holding individual kit components.

[0174] Compounds intended for administration to humans or other mammals should generally have a very high purity. Purity refers to the ratio of the mass of the compound after any purification step to the total mass of the sample. Typically, the purity level is at least about 95%, more usually at least about 96%, about 97%, about 98%, or more. For example, the purity level 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 more.

[0175] Compounds described herein that exist in multiple optically isomeric forms (enantiomers) can be provided as racemic mixtures or by isolating one of the enantiomers, in which case purity as described above may refer to enantiomeric purity. The present disclosure is meant to include all possible optical isomers or enantiomers of the disclosed compounds, mixtures of such enantiomers with enantiomerically pure forms or racemic mixtures, or enantiomerically enriched mixtures, or (if one or more chiral centers are present) diastereomerically pure compounds, or compositions containing diastereomeric mixtures in any relative proportions.

[0176] Enantiomers can be prepared or isolated, for example, by chiral synthesis from appropriate optically pure precursors, or by resolution of a racemate (or a racemate of a salt or derivative), for example, using chiral high-pressure liquid chromatography (HPLC). "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. A mixture of enantiomers in a ratio other than 1:1 is a "scalemic" mixture. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms or axes of chirality but are not mirror images of each other. "Tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. The present disclosure includes tautomers of any compound provided herein.

[0177] "Isolated optical isomer" means a compound that has been substantially purified from the corresponding optical isomer of the same formula. Preferably, the isolated isomer is at least about 80% by weight pure, more preferably at least 90% by weight pure, even more preferably at least 98% by weight pure, and most preferably at least about 99% by weight pure. The compounds of the present invention may be provided with any of these degrees of enantiomeric purity, such as a racemic mixture of enantiomers (50% enantiomeric purity), or 60% enantiomeric purity, 70% enantiomeric purity, 80% enantiomeric purity, or 90% enantiomeric purity, or 98% enantiomeric purity, or 99+% enantiomeric purity.

[0178] A "solvate" is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds provided herein are also provided. Hydrates of the compounds provided herein are also provided.

[0179] A "prodrug" is a biologically inactive derivative of a drug that, upon administration to the human body, is converted into the biologically active parent drug following some chemical or enzymatic pathway.

[0180] The compounds described herein can be synthetically prepared using techniques such as those described in M. ELLIS, “PART I: THE TOTAL SYNTHESIS OF MYOSMINE AND APOFERROROSAMINE, PART II: STUDIES ON THE POTENTIAL OF ISOXAZOLES AS GENERAL SYNTHETIC INTERMEDIATES,” (1971) Diss., Rice University, (hdl.handle.net / 1911 / 14718), with appropriate modification of reagents as would be apparent to one skilled in the art without more than routine experimentation to obtain the disclosed structures.

[0181] In some embodiments, compounds can be converted into pharmaceutically acceptable salts by 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.

[0182] The compositions described herein can be administered orally, nasally, topically, subcutaneously, intramuscularly, intravenously, or by other methods of administration known to those of skill in the art.

[0183] Pharmaceutical compositions may optionally contain other pharmaceutically acceptable ingredients (or pharmaceutical components), including, but not limited to, buffers, preservatives, tonicity adjusters, salts, antioxidants, osmotic pressure adjusters, physiological substances, pharmaceutical substances, bulking agents, emulsifiers, wetting agents, sweeteners, or flavoring agents. Various buffers and pH-adjusting means can be used to prepare the pharmaceutical compositions disclosed herein, so long as the resulting preparation is pharmaceutically acceptable. Examples of 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, and other pharmaceutically acceptable tonicity adjusters. Pharmaceutical compositions can 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 art of pharmacology can be included in pharmaceutical compositions.

[0184] Examples of adjuvants and / or excipients include cremophor, poloxamer, benzalkonium chloride, sodium lauryl sulfate, dextrose, glycerin, magnesium stearate, polyethylene glycol, starch, dextrin, lactose, cellulose, sodium carboxymethylcellulose, talc, agar, agar, mineral oil, animal oil, vegetable oil, organic and mineral wax, paraffin, gel, propylene glycol, benzyl alcohol, dimethylacetamide, ethanol, polyglycol, Tween 80, Solutol HS15, and water. The active substance can also be administered in a suitable form without a vehicle or diluent, such as, for example, a capsule.

[0185] The pharmaceutical composition may contain a sufficient amount of therapeutic compound to allow for normal 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 therapeutic compound. In other embodiments, a 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 therapeutic compound. In still 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 composition disclosed herein may be administered in a dosage form containing, 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 1 The dosage may include about 00 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.

[0186] The pharmaceutical compositions described herein may contain a pharmaceutically acceptable solvent. A solvent is a liquid, solid, or gas that dissolves another solid, liquid, or gas (solute) to form 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-pyrilidone (NMP), and diethyl ether.

[0187] The administration method and dosage range suitable in a particular case depend on the species being treated and the respective condition or disease state, and can be optimized using techniques known in the art. In most cases, the daily dose of the active compound for a patient can range from 0.0005 mg / kg to 15 mg / kg, or from 0.001 mg / kg to 7.5 mg / kg. The therapeutically effective amount of the therapeutic compounds disclosed herein can generally range from about 0.001 mg / kg / day to about 100 mg / kg / day. An effective amount can be, for example, at least 0.001 mg / kg / day, at least 0.01 mg / kg / day, at least 0.1 mg / kg / day, at least 1.0 mg / kg / day, at least 5.0 mg / kg / day, at least 10 mg / kg / day, at least 15 mg / kg / day, at least 20 mg / kg / day, at least 25 mg / kg / day, at least 30 mg / kg / day, at least 35 mg / kg / day, at least 40 mg / kg / day, at least 45 mg / kg / day, or at least 50 mg / kg / day. In some examples, an effective amount of a therapeutic compound is from about 0.001 mg / kg / day to about 10 mg / kg / day, from about 0.001 mg / kg / day to about 15 mg / kg / day, from about 0.001 mg / kg / day to about 20 mg / kg / day, from about 0.001 mg / kg / day to about 25 mg / kg / day, from about 0.001 mg / kg / day to about 30 mg / kg / day, from about 0.001 mg / kg / day to about 30 mg / kg / day, or from about 0.001 mg / kg / day to about 30 mg / kg / day. g / day, about 0.001 mg / kg / day to about 35 mg / kg / day, about 0.001 mg / kg / day to about 40 mg / kg / day, about 0.001 mg / kg / day to about 45 mg / kg / day, about 0.001 mg / kg / day to about 50 mg / kg / day, about 0.001 mg / kg / day to about 75 mg / kg / day, or about 0.001 mg / kg / day to about 100 mg / kg / day.In other examples, an effective amount of a therapeutic compound disclosed herein can be in the range of, for example, about 0.01 mg / kg / day to about 10 mg / kg / day, about 0.01 mg / kg / day to about 15 mg / kg / day, about 0.01 mg / kg / day to about 20 mg / kg / day, about 0.01 mg / kg / day to about 25 mg / kg / day, about 0.01 mg / kg / day to about 30 mg / kg / day, about 0.01 mg / kg / day to about 35 mg / kg / day, about 0.01 mg / kg / day to about 40 mg / kg / day, about 0.01 mg / kg / day to about 45 mg / kg / day, about 0.01 mg / kg / day to about 50 mg / kg / day, about 0.01 mg / kg / day to about 75 mg / kg / day, or about 0.01 mg / kg / day to about 100 mg / kg / day.

[0188] Dosing can be a single dose or cumulative (continuous) dosing, and can be easily determined by one skilled in the art. For example, treatment can include a single administration of an effective amount of the pharmaceutical composition disclosed herein. Alternatively, treatment can include multiple administrations of an effective amount of the pharmaceutical composition over a period of time, such as once daily, twice daily, three times daily, once every few days, or once weekly. The timing of administration can vary from individual to individual depending on factors such as the severity of individual symptoms. For example, an effective amount of the pharmaceutical composition disclosed herein can 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.

[0189] Pharmaceutical compositions can contain any conventional non-toxic pharmaceutically acceptable carrier, adjuvant or vehicle.In some cases, the pH of formulation can be adjusted with acceptable pharmaceutical or food grade acid, base or buffer to enhance the stability of formulated composition or its delivery form.

[0190] Liquid dosage forms for oral administration include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs of acceptable pharmaceutical or food grade.In addition to the active compound, 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, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions can also contain auxiliary agents such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0191] Solid dosage forms for oral administration include capsules, tablets, lozenges, pills, powders, and granules, etc. In such solid dosage forms, the active compound is mixed with at least one inert and 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 silicic acid, b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) agar, calcium carbonate, potato or They are mixed with disintegrating agents such as tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) dissolution 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, and j) sweeteners, flavors, fragrances, and mixtures thereof. In the case of capsules, troches, tablets, and pills, the dosage form may also contain buffering agents.

[0192] Solid dosage forms such as tablets, capsules, pills, and granules can be prepared with coatings or shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and may be composed so as to release the active ingredient only, or preferentially, in a certain part of the intestinal tract, or optionally in a delayed or extended 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.

[0193] Compositions can contain the compounds disclosed herein alone or in combination with other therapeutic compounds(s). Therapeutic compounds are compounds that provide pharmaceutical 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 compound can have anti-inflammatory activity, such as a nonsteroidal anti-inflammatory drug (NSAID). NSAIDs are a large group of therapeutic compounds that have analgesic, anti-inflammatory, and antipyretic effects. NSAIDs reduce inflammation by blocking cyclooxygenase.NSAIDs include aceclofenac, acemetacin, actarit, alcofenac, alminoprofen, amfenac, aloxipirin, aminophenazone, anthraphenine, aspirin, azapropazone, benorylate, benoxaprofen, benzydamine, butibufen, celecoxib, chlortenoxacin, choline salicylate, clometacin, dexketoprofen, diclofenac, diflunisal, emorfazone, epirizole; etodolac, etoricoxib, feclobuzone, felbinac, fenbufen, fenclofenac, flurbiprofen, glafenine, hydroxyethyl salicylate, These include, but are not limited to, 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.

[0194] 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 also 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 NSAID include but are not limited to alminoprofen, benoxaprofen, dexketoprofen, fenoprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, loxoprofen, naproxen, oxaprozin, pranoprofen and suprofen.Examples of suitable acetic acid derivative NSAID 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.

[0195] In some instances, the compounds and compositions described herein can be administered to an individual to prevent the formation of metal oxides, hi other instances, the compounds can be used to prevent the formation of metal oxides in industrial applications such as descaling, pickling, and surface treatments, including the removal of surface deposits and corrosion products.

[0196] The description of the embodiments of the present disclosure is not intended to be exhaustive or to limit the disclosure to the precise form disclosed. While specific embodiments and examples of the present disclosure have been described herein for illustrative purposes, those skilled in the art will recognize that various equivalent modifications are possible within the scope of the present disclosure. For example, while method steps or functions are presented in a given order, alternative embodiments may perform the functions in a different order, or may perform the functions substantially simultaneously. The teachings of the disclosure provided herein can be applied to other procedures or methods, as appropriate. The various embodiments described herein can be combined to provide further embodiments. Aspects of the present disclosure can be modified, as appropriate, to employ compositions, functions, and concepts from the above references and applications to provide further embodiments of the present disclosure. Furthermore, in consideration of biological functional equivalence, some changes can be made to protein structures without affecting the type or amount of biological or chemical activity. These and other changes can be made to the present disclosure in light of the detailed description. All such modifications are intended to be within the scope of the appended claims.

[0197] Specific elements of any of the foregoing embodiments may be combined with or substituted for elements of other embodiments. Additionally, although advantages associated with particular embodiments of the present disclosure have been described in the context of those embodiments, other embodiments may also exhibit such advantages, and not all embodiments necessarily need to exhibit such advantages to fall within the scope of the present disclosure.

[0198] definition For convenience, the meanings of some terms and phrases used in the specification, examples, and appended claims are provided below. Unless otherwise specified or implied from the context, the following terms and phrases have the meanings provided below. The definitions are provided to assist in the description of particular embodiments and are not intended to limit the claimed subject matter, as the scope of the present technology is limited only by the claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this technology belongs. If there is an apparent discrepancy between the usage of a term in the art and its definition provided herein, the definition provided herein shall prevail.

[0199] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. For example, reference to "a cell" includes a combination of two or more cells, and the like.

[0200] As used herein, the term "approximately" or "about" when used in connection with a value or parameter is generally interpreted to include numbers within 5%, 10%, 15%, or 20% of that number in either direction (greater or less), unless otherwise specified or clear from the context (unless such number is less than 0% or greater than 100% of a possible value). When a value or parameter is expressed herein as "approximately" or "about," embodiments directed to that value or parameter are included (and described). For example, a description that refers to "about X" includes a description of "X."

[0201] As used herein, the word "or" means "and / or." As used herein in phrases such as "A and / or B," the term "and / or" is intended to include both A and B, A or B, A alone, and B alone. Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to encompass each of the following: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A alone; B alone; and C alone.

[0202] As used herein, the term "comprising" means that other elements may be present in addition to the defined elements that are presented. The use of "comprising" indicates inclusion rather than limitation.

[0203] The term "consisting of" refers to compositions, methods, and their respective components described herein, excluding any element not recited in that description of an embodiment.

[0204] As used herein, the term "consisting essentially of" refers to elements required for a given embodiment. The term permits the presence of additional elements that do not materially affect the basic and novel or functional characteristics of that embodiment of the technology.

[0205] The terms "individual," "subject," or "patient" are used interchangeably herein. In some embodiments, a patient or subject is a vertebrate. The term subject can be a human or a veterinary subject. In certain embodiments, a vertebrate is a mammal. The term "mammal" for therapeutic purposes refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sport, or pet animals, such as dogs, horses, cats, cows, etc. In certain embodiments, a mammal is a human. In certain embodiments, a vertebrate is a non-mammal, such as a bird, reptile, or amphibian. Thus, a subject or patient can include, but is not limited to, farm animals (such as cows), laboratory animals (such as mice, rats, pigs, primates, guinea pigs, rabbits, etc.), sport animals, livestock, or pets (such as cats, dogs, and horses). In certain embodiments, a subject or patient is a human. In some embodiments, a mammal includes a primate, dog, horse, cat, cow, or pig. In some embodiments, the subject comprises a non-human animal. In some embodiments, the non-human animal is a bird or a reptile. In some embodiments, the non-human animal is a chicken.

[0206] While the present invention has been described in terms of 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. [Example]

[0207] Example 1: BioMAP® System The BioMAP® system was used to predict the safety, efficacy, and function of test agents in models of human tissue and disease biology consisting of vascular, skin, lung, and inflamed tissues.

[0208] The BioMAP® panel consists of human primary cell-based systems designed to model various aspects of the human body in an in vitro format. BioMAP® systems are configured using one or more primary cell types derived from healthy human donors and stimuli (e.g., cytokines or growth factors) to capture the relevant signaling networks that naturally occur in human tissues or pathological conditions. Vascular biology is modeled in both Th1 (3C system) and Th2 (4H system) inflammatory environments, as well as in 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 (Mphg system), and T cell-dependent activation of B cells occurring in germinal centers (BT system). The BE3C system (Th1) and the BF4T system (Th2) represent pulmonary airway inflammation, while the MyoF system models myofibroblast-induced 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. A subset of eight of these BioMAP systems has previously been used in the U.S. Environmental Protection Agency's (EPA) ToxCast™ program to characterize environmental chemicals, define mechanisms of toxicity, and develop predictive toxicity signatures.

[0209] The diseases and pathologies modeled by the above cellular systems are shown in Table 1 below. [Table 1]

[0210] Table 2 provides further description of the above-mentioned markers and the associated BioMAP® system. [Table 2]

[0211] Each test agent generates a signature BioMAP® profile, created from changes in protein biomarker readouts within the individual system environment. Biomarker readouts (7–17 per system) are selected based on therapeutic and biological relevance, predict disease outcome or specific drug effects, and are validated using agents with known mechanisms of action (MoA). Each readout is quantitatively measured by immunological methods that detect proteins (e.g., ELISA) or functional assays that measure proliferation and viability. BioMAP® readouts are diverse and include cell surface receptors, cytokines, chemokines, matrix molecules, and enzymes. In total, the Diversity PLUS panel contains 148 biomarker readouts that capture biological changes occurring within the physiological context of a specific BioMAP® system.

[0212] Custom-designed software, including data mining tools, allows BioMAP® profiles to be compared to a proprietary reference database of over 4,000 BioMAP® profiles of bioactive agents (biologics, approved drugs, chemicals, and experimental agents) to classify and identify the most similar profiles. This robust data platform enables rapid evaluation and interpretation of BioMAP® profiles by unbiased mathematical identification of similar activities. Specific BioMAP® activities are correlated with in vivo biology, and multiparameter BioMAP® profiles have been used to differentiate compounds based on MoA and target selectivity, providing predictive signatures of in vivo toxicity outcomes (e.g., vascular toxicity, developmental toxicity, etc.) across various physiological systems.

[0213] Human primary cells in the BioMAP® system are used at an early subculture stage (passage 4 or earlier) to minimize adaptation to cell culture conditions and maintain physiological signal responses. All cells are collected from a pool of multiple donors (n = 2–6), commercially purchased, and handled according to the manufacturer's recommendations. Human blood-derived CD14+ monocytes are differentiated in vitro into macrophages before being added to the Mphg system. The following abbreviations are used: human umbilical vein endothelial cells (HUVECs), peripheral blood mononuclear cells (PBMCs), human neonatal dermal fibroblasts (HDFn), B cell receptor (BCR), T cell receptor (TCR), and Toll-like receptor (TLR). The cell types and stimuli used in each system are as follows: 3C system [HUVEC+ (IL-1β, TNFα, and IFNγ)], 4H system [HUVEC+ (IL-4 and histamine)], LPS system [PBMC and HUVEC+TLRS (TLR4 ligand)], SAg system [PBMC and HUVEC+TCR ligand], BT system [CD19+ B cells and PBMC+ (α-IgM and TCR ligand)], BF4T system [bronchial epithelial cells and HDFn+ (TNFα and IL-4)], BE3C system [tracheal The following systems were used: the CASM3C system [coronary artery smooth muscle cells + (IL-1β, TNFα, and IFN)], the HDF3CGF system [HDFn + (IL-1β, TNFα, IFNγ, EGF, bFGF, PDGF-BB)], the KF3CT system [keratinocytes and HDFn + (IL-1β, TNFα, IFNγ, and TGFβ)], the MyoF system [differentiated pulmonary myofibroblasts + (TNFα and TGFβ)], and the lMphg system [HUVECs and M1 macrophages + zymosan (TLR2 ligand)]. The systems were derived from either single cell types or coculture systems. Adherent cell types were cultured to confluence in 96- or 384-well plates, followed by the addition of PBMCs (Sag and LPS systems). The BT system consists of CD19+ B cells co-cultured with PBMCs and stimulated with BCR activators and low concentrations of TCR stimuli.Test agents prepared in either DMSO (small molecules; final concentration ≤0.1%) or PBS (biologicals) are added at the indicated concentrations 1 hour before stimulation and cultured for 24 hours or the indicated time (48 hours, MyoF system; 72 hours, BT system (soluble readout); 168 hours, BT system (secreted IgG)). Each plate includes a drug control appropriate for each system (e.g., the conventional control test agent colchicine 1.1 μM), a negative control (e.g., unstimulated conditions), and a vehicle control (e.g., 0.1% DMSO). Direct ELISAs are used to measure biomarker levels of cell-associated and plasma membrane targets. Soluble factors from the supernatant are quantified using either HTRF® detection, bead-based multiplex immunoassays, or capture ELISAs. Significant adverse effects of test agents on cell proliferation and viability (cytotoxicity) are detected by sulforhodamine B (SRB) staining for adherent cells and by AlamarBlue® reduction for cells in suspension. For proliferation assays, individual cell types are cultured at subconfluence and measured at time points optimized for each system (48 h: 3C and CASM3C systems; 72 h: BT and HDF3CGF systems; 96 h: SAg system). Cytotoxicity of adherent cells is measured by SRB (24 h: 3C, 4H, LPS, SAg, BF4T, BE3C, CASM3C, HDF3CGF, KF3CT, and lMphg systems; 48 h: MyoF system) and Alamar Blue staining of cells in suspension (24 h: SAg system; 42 h: BT system) at the indicated time points.

[0214] Data analysis is performed by dividing the test drug measurement by the mean value of the control samples (at least six vehicle controls from the same plate) to generate a ratio, followed by log10 transformation. Significance prediction envelopes are calculated using historical vehicle control data, with 95% confidence intervals.

[0215] Biomarker activity was annotated when two or more consecutive concentrations changed in the same direction relative to the vehicle control, were outside the significance envelope, and had at least one concentration with an effect size greater than 20% (|log10 ratio|>0.1). Primary biomarker activity was described as modulated when these activities increased in one system but decreased in another. A cytotoxic state was observed when total protein levels were reduced by 50% or more (log10 ratio of SRB or AlamarBlue concentrations <-0.3) and is indicated by a thin black arrow on the x-axis. Compounds were considered to have broad cytotoxicity if cytotoxicity was detected in three or more systems. Test agent concentrations capable of detecting broad cytotoxicity were excluded from biomarker activity annotation and downstream benchmarking, similarity searches, and cluster analyses. Antiproliferative effects were defined by SRB or AlamarBlue® log10 ratio values ​​less than -0.1 from cells seeded at lower densities and are indicated by a gray arrow on the x-axis. For the cytotoxic and antiproliferative arrows, only one concentration is required to meet the indicated threshold for profile annotation.

[0216] Example 2: Analysis of Test Substance 2: 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine A BioMAP® profile was generated for 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine as described in Example 1.

[0217] 2,4,6-Tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine was found to have no cytotoxicity at the concentrations tested in this study. 2,4,6-Tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine was found to have antiproliferative effects on human primary endothelial cells (100 μM, 33 μM, 11 μM), T cells (100 μM, 33 μM), B cells (100 μM, 33 μM, 11 μM), and fibroblasts (100 μM).

[0218] 2,4,6-Tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine was found to affect inflammation-related activities as demonstrated by decreases in eotaxin-3, MCP-1, VCAM-1, SAA, I-TAC, MIG, IL-6, and P-selectin; increases in sPGE2; and modulation of sTNFα and IL-8. 2,4,6-Tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine was also found to affect immunomodulatory activities as demonstrated by decreases in CD40, sIgG, sIL-10, HLA-DR, sIL-17A, CD38, sIL-6, sIL-17F, and sIL-2; and increases in CD69. 2,4,6-Tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine was found to affect tissue remodeling activity, as indicated by a decrease in TIMP-1, collagen IV, PAI-1, and collagen III. 2,4,6-Tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine was found to affect hemostasis-related activity, as indicated by a decrease in TM and an increase in TF. Furthermore, 2,4,6-Tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine was found to decrease LDLR.

[0219] See Table 2 for further description of these markers and the associated BioMAP® system.

[0220] Example 3: Analysis of Test Substance 3: 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine in ethanol A BioMAP® profile was generated for 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine in ethanol as carrier, as described in Example 1.

[0221] Ethanol-borne 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine was found to be non-cytotoxic at the concentrations tested in this study.

[0222] 2,4,6-Tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine with ethanol as a carrier was found to have antiproliferative effects on human primary B cells (200 μM, 67 μM, 22 μM, 7.4 μM), T cells (200 μM, 67 μM, 22 μM, 7.4 μM), endothelial cells (200 μM, 67 μM, 22 μM, 7.4 μM), and fibroblasts (22 μM, 7.4 μM).

[0223] 2,4,6-Tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine with ethanol as a carrier was found to affect inflammation-related activities by decreasing eotaxin-3, MCP-1, MIP-1α, I-TAC, MIG, IP-10, IL-6, VCAM-1, SAA, IL-1α, and P-selectin, increasing sPGE2, and modulating IL-8 and sTNFα. 2,4,6-Tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine with ethanol as a carrier was found to affect immunomodulatory activities, as indicated by decreases in CD40, sIgG, sIL-17A, sIL-6, sIL-17F, sIL-2, sIL-10, HLA-DR, and CD38; and increases in CD69. 2,4,6-Tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine with ethanol as a carrier was found to affect tissue remodeling activity, as indicated by decreases in collagen I, TIMP-2, TIMP-1, collagen IV, tPA, collagen III, αSMA, bFGF, MMP-1, PAI-1, Ker8 / 18, and MMP-9, and increases in uPAR. 2,4,6-Tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine with ethanol as a carrier was found to affect hemostasis-related activity, as indicated by decreases in TM and increases in TF. 2,4,6-Tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine with ethanol as a carrier was found to decrease VEGFR2.

[0224] See Table 2 for further description of these markers and the associated BioMAP® system. Example 4: Synthesis of 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine [ka]

[0225] 2,4,6-Tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine was synthesized according to the following synthetic scheme I.

number

[0226] Step 3 of the above synthesis scheme I was carried out using sodium borohydride (NaBH4 (10.0 equivalents)) and methanol at 0 °C to room temperature (RT) for approximately 16 hours. The resulting compound 4 was isolated using silica gel column chromatography. The yield was approximately 95%, with 34 g of compound 4 obtained from 38 g of compound 3. The structure of compound 4 was consistent with the standard.

[0227] Step 4 of Synthetic Scheme I was carried out using 6N hydrogen chloride (HCl) at 0 °C to RT, and compound 5 was isolated by silica gel column chromatography. The yield of this reaction was approximately 66%, and 9.6 g of compound 5 was obtained. The structure of compound 5 matched the standard.

[0228] Step 5 of Synthetic Scheme I was carried out using Dess-Martin periodinane (4.5 equivalents) and dichloromethane (DCM) at room temperature for 16 hours. The reaction yielded 8.4 g of crude compound 6, which was not purified further. The structure of compound 6 matched the standard.

[0229] Step 6 of Synthetic Scheme I was carried out using (S)-(-)-2-methyl-2-propanesulfinamide (3.2 equivalents) and para-toluenesulfonic acid (PTSA) (0.3 equivalents). The yield of this reaction was 95% or 24 g. Compound 7 matched the standard and was isolated using silica gel column chromatography.

[0230] Step 7 of Synthetic Scheme I was carried out using 2-(2-bromoethyl)-1,3-dioxolane (10 equivalents), magnesium (Mg) (13 equivalents), iodine (catalyst), and tetrahydrofuran (THF) (50 V) at -20 °C for 2 h. THF (10 V) was then added and the reaction continued at 0 °C for 16 h. The yield was 37%, giving 15 g of compound 8. The structure of compound 8 was confirmed by LCMS and HNMR. Compound 8 was isolated using silica gel column chromatography followed by reverse-phase column chromatography on a 15 g scale with an LCMS purity of 99% (20.7% + 78.3%). The split observed by LC is believed to be due to isomer formation.

[0231] Step 8 of Synthesis Scheme I was carried out using 10% H2SO4 (10 V) and DCM (5 V) at 0-5 °C for 6 h. The yield was 92%, and 7.0 g of compound 9 was obtained. The structure of compound 9 was confirmed by LCMS and NMR. Compound 9 was isolated on a 7 g scale with an HPLC purity of 95.6% (59.4% + 36.2%). Compound 9 was confirmed to be 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine. The physical properties of compound 9 include a light brown color, a low melting point, and a foamy solid.

[0232] Example 5: Synthesis of 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine The synthesis of 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine was carried out according to the following synthetic scheme II.

number

[0233] Steps 1 to 5 of Synthesis Scheme II were carried out in the same manner as in Example 4 to produce Compound 6.

[0234] Compound 6 of Synthesis Scheme II was reacted with (S)-(-)-2-methyl-2-propanesulfinamide, para-toluenesulfonic acid (PTSA), and dichloromethane (DCM) at 25°C for 6 hours to produce compound 7.

[0235] Next, according to Synthesis Scheme II, compound 7 was reacted with 2-(2-bromoethyl)-1,3-dioxolane, magnesium (Mg), and tetrahydrofuran (THF) at 35°C, followed by conventional column purification and then reverse column purification to produce compound 8.

[0236] Compound 8 was purified by HPLC (high performance liquid chromatography) to give a major peak (500 mg, 71% purity) and a minor peak (500 mg, 81% purity). Both purified peaks were used separately in the final reaction.

[0237] Finally, compound 8 (both peaks) was exposed to H2SO4 and DCM at 0-10 °C according to synthetic scheme II to give 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine (trisomine).

[0238] 1 The structure and purity of the synthesized 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine were determined using H NMR (proton nuclear magnetic resonance). Overlays of H NMR spectra for multiple lots of 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine prepared according to the above synthesis are shown in Figures 1-4, demonstrating consistent synthesis of trisomine.

[0239] Infrared (IR) spectroscopy was used to confirm the identity of the synthesized 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine. Figures 5-8 show IR spectra for multiple lots of 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine synthesized, and Figure 9 shows an overlay of these spectra. The overlay in Figure 9 shows that the IR spectra were similar for all lots.

[0240] Long-term liquid chromatography-mass spectrometry (LC-MS) was performed and confirmed that both peaks from HPLC corresponded to 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine, as shown in Figures 10 and 11.

[0241] Chiral HPLC was also performed and two peaks similar to those observed in conventional HPLC were observed, as shown for one lot of synthesized 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine in Figure 12. The peak table below shows the data plotted in Figure 12. [Table 3] [Table 4]

[0242] FIG. 13 shows the images of trisomine finally obtained from peak 1 (or main peak) and peak 2 (or minor peak) isolated from compound 8.

[0243] In summary, this example demonstrates the successful synthesis and purification of 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine.

[0244] Example 6: Methods of Treating, Reversing, Slowing, or Preventing the Aging Process in a Subject Example 6 demonstrated reduced hair loss and increased vitality in aging mice. The method involved administering a therapeutically effective amount of 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine to aged mice. 12-month-old mice were given 10 mg / day of 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine. Experiments were conducted on 20 mice. By day 10, the outward signs of aging in the mice (hair loss, decreased energy, and decreased vitality) were reversed, and the treated mice had lush, thick hair, improved vitality, and were highly energetic, as evidenced in Figure 14.

[0245] Thus, this example demonstrates that administration of 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine can treat, reverse, slow, or prevent the aging process in a subject.

[0246] Example 7: 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine can reduce VCAM-1 levels. 2,4,6-Tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine is 2000 times more effective than doxycycline at reducing VCAM-1 levels, as shown in Figure 15. VCAM-1 is a key cell adhesion molecule involved in inflammation, which is closely related to various immunological diseases (including rheumatoid arthritis and asthma), aging, and cancer. Doxycycline is an antibiotic that also has anti-inflammatory properties and is FDA-approved for the treatment of periodontitis and an inflammatory skin disease called rosacea.

[0247] This example demonstrated that 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine is an effective anti-inflammatory agent and can treat immunological diseases (including rheumatoid arthritis and asthma), aging, and cancer.

[0248] Example 8: Synthesis of 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine This example shows an exemplary scheme for synthesizing 2,4,6-tri(3,4-dihydro-2H-pyrrol-2-yl)pyridine / trisomine.

[0249] In this example, trisomine was synthesized using a four-step synthetic protocol as shown in Scheme III below. Trimethylpyridine was oxidized with SeO to give the 2,4,6-pyridinetricarbaldehyde intermediate. 2,4,6-pyridinetricarbaldehyde was then treated with S-(-)-2-methyl-2-propanesulfinamide to give the Stage 1 product. A Grignard reaction was performed using Stage 1 and 2-(2-bromoethyl)-1,3-dioxolane to give the Stage 2 product. Stage 2 was treated with HSO to give trisomine.

[0250] The synthesis scheme III of trisomine according to this example is as follows:

number

[0251] 2,4,6-Pyridinetricarbaldehyde (RSM) was synthesized as follows.

number

[0252] A typical synthesis protocol for 2,4,6-pyridinetricarbaldehyde was carried out by adding selenium dioxide (4.12 kg, 4.5 equiv.) to a stirred solution of 2,4,6-trimethylpyridine (1.0 kg, 1 equiv.) in chlorobenzene (10.0 L, 10.0 vol.) at 25-30°C.

[0253] The reaction was gradually heated to 125±5°C and stirred at 125±5°C for 8 hours. The progress of the reaction was monitored by TLC (5% MeOH in DCM). After completion of the reaction, the reaction was filtered through a bed of Celite and the bed was washed with chlorobenzene (1.0 L, 1.0 vol.). The filtrate was completely concentrated and dried under reduced pressure at 45±5°C to give a brown solid. Yield: 97.3 g, 7.2%. The structure is shown in Figure 16. 1 Confirmed using H NMR: (400 MHz, CDCl): δ 10.21 (s, 1H), δ 10.20 (s, 2H), 8.52 (s, 2H). Purity was determined using HPLC: 90.6 (% area), as shown in Figure 17 and Table 5 below.

[0254] Table 5: HPLC results of synthesized 2,4,6-pyridinetricarbaldehyde [Table 5]

[0255] Stage 1 of Synthetic Scheme III was carried out as follows. 2,4,6-Pyridinetricarbaldehyde (120.0 g, 1.0 equiv.) and DCM (2.4 L, 20.0 vol.) were charged to a reactor at 25 ± 5 °C and cooled to 0–5 °C. S-(−)-2-methyl-2-propanesulfinamide (276.4 g, 3.1 equiv.) and PTSA (38.0 g, 0.3 equiv.) were charged at 0 °C. The reaction was brought to 25 ± 5 °C and stirred at 25 ± 5 °C for 20 h. The reaction progress was monitored by TLC (10% MeOH in DCM). After completion of the reaction, the reaction was completely concentrated and diluted with EtOAc (1.8 L, 15.0 vol.). To the diluted material was added saturated sodium bicarbonate solution (1.2 L, 10.0 vol.) and stirred for 10 min. The layers were separated, and the aqueous layer was washed with EtOAc (360.0 mL, 3.0 vol.). The combined organic layers were washed with 10% aqueous sodium chloride solution (1.2 L, 10.0 vol.). Charcoal (2% w / w) was added to the organic layer and slurried at 25±5°C for 2 hours. It was filtered through a bed of Celite, and the bed was washed with ethyl acetate (240.0 mL, 2.0 vol.). The filtrate was completely concentrated under reduced pressure at 45°C. To this was added hexane (1.2 L, 10.0 vol.), and stirring was continued at 25±5°C for 30 minutes. The solid was filtered and washed with hexane (360.0 mL, 3.0 vol.). The solid was removed and dried under reduced pressure at 45°C for 2 hours to give a pale yellow solid. Stage 1 completion: 238.8 g, 68.6%. 1 The structure was confirmed using H NMR, as shown in Figure 18: 1 H NMR (400 MHz, DMSO): δ 8.81 (s, 1H), 8.64 (s, 2H), 8.58 (s, 2H), 1.23-1.19 (m, 27H). Purity was assessed using HPLC: 98.9 (% area), as shown in Figure 19 and Table 6 below. Table 6: HPLC determination of purity of product of Stage 1 in Synthesis Scheme III: [Table 6]

[0256] Stage 2 Reaction of Synthetic Scheme III: Under a nitrogen atmosphere, magnesium turnings (56.6 g, 11.0 equiv.) and iodine (catalyst) were charged to dry THF (1.0 L, 10.0 vol.) at 25 ± 5 °C. The mixture was heated to 35 °C, and 1,2-dibromoethane (3.97 g, 0.1 equiv.) was added at 35 ± 5 °C and stirred for 30 minutes. A solution of 2-(2-bromoethyl)-1,3-dioxolane (383.0 g, 10.0 equiv.) in dry THF (500.0 mL, 5.0 vol.) was added to the mixture at 35 ± 5 °C and stirred for 2 hours at the same temperature. A solution of Stage 1 (100.0 g, 1.0 equiv.) in dry THF (500.0 mL, 5.0 vol.) was added over 2 hours at 35 ± 5 °C, and stirring was continued for an additional 16 hours at 30 ± 5 °C. The progress of the reaction was monitored by TLC (10% MeOH in DCM). After completion of the reaction, it was cooled to 5-10°C. The reaction was quenched below 20°C with saturated aqueous ammonium chloride (1.0 L, 10.0 vol.). The reaction mixture was stirred at 25±5°C for 30 minutes. The mixture was diluted with ethyl acetate (1.0 L, 10.0 vol.) and filtered through a bed of Celite. The layers were separated, and the aqueous layer was re-extracted twice with ethyl acetate (1.0 L, 10.0 vol.). The layers were separated, and the combined organic layers were concentrated and dried under reduced pressure for 1 hour to give a brown syrup. The crude compound was purified by column chromatography using ethyl acetate and methanol. Yield of Stage 2: 100 g (60.6%). 1 The structure was confirmed using H NMR: as shown in Figure 20. 1 H NMR (300 MHz, DMSO): δ 7.33 (s, 2H), 5.83 (s, 7.8 Hz, 1H), 5.68 (s, 6.9 Hz, 2H), 4.76 (br, 3H), 4.35-4.22 (m, 3H), 3.84-3.71 (m, 12H), 1.83-1.47 (s, 12H), 1.20-1.10 (s, 27H). Purity was assessed using HPLC and was 94% area (peak 1 + peak 2), as shown in Figure 21 and Table 7 below. Table 7: Purity of Stage 2 product in Synthesis Scheme III [Table 7]

[0257] The Stage 3 reaction of Synthetic Scheme III was carried out as follows: The Stage 2 product (20.0 g, 1.0 equiv.) was dissolved in DCM (100.0 mL, 5.0 vol.) at 25±5°C. The solution was cooled to 0-5°C, and 10% aqueous sulfuric acid (600.0 mL, 30.0 vol.) was added slowly at 0-5°C. The reaction was stirred at 0±5°C for 4 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was separated into an organic layer and an aqueous layer, and the aqueous layer was washed five times with DCM (200.0 mL, 10.0 vol.). The aqueous layer was added to 20% sodium hydroxide solution (400.0 mL, 20.0 vol.) over 1 hour at 5-10°C. The pH of the reaction mixture was adjusted to approximately 12.6 using 20% ​​sodium hydroxide solution (40.0 mL, 2.0 vol.). The aqueous layer was extracted five times with cold DCM (200.0 mL, 10.0 vol.). The organic layers, concentrated below 28° C., were combined to give a light brown solid. Stage 3 yield: 5.9 g (82.0%). 1 The structure was confirmed using H NMR, as shown in Figure 22. 1 H NMR (400 MHz, CDCl): δ 7.81-7.80 (m, 3H), 7.07-7.00 (m, 2H), 5.18-5.24 (m, 2H), 5.06-5.01 (m, 1H), 2.75-2.67 (m, 3H), 2.64-2.55 (m, 3H), 2.44-2.33 (m, 3H), 2.44-2.33 (m, 3H), 1.95-1.80 (m, 2H), 1.65-1.50 (m, 1H). Purity was determined using HPLC: 92.9% area (peak 1 + peak 2), as shown in Figure 23 and Table 8 below. Table 8: Purity of Stage 3 Product (Trisomine) [Table 8]

[0258] Example 9: 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine and Fe in aqueous solution 2+ Calculation of Ion Affinity introduction Water is a complex environment that can interact in a variety of ways with solutes, especially charged molecules.

[0259] NIST SRD46: A database of carefully selected stability constants for metal complexes, Fe 2+ Several affinity constants for the complex were obtained, and for this study, the dissociation constant pK = 6.33, or equivalently, ΔG 0 = 36.11 kJ / mol, the iron complex of diethylenetriamine [dien‐Fe] 2+ , record 3201, was selected. The structures of the two test compounds are shown below. [ka] [ka]

[0260] "2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine" is sometimes referred to herein as "D102," and these two terms are synonymous.

[0261] method: All calculations were carried out in parallel for 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine and diethylenetriamine.

[0262] For each complex and its dissociation products, calculations were performed at different levels of approximation in different phases as described in "A Chemist's Guide to Density Functional Theory, 2nd Edition, Wolfram Koch, Max C. Holthausen, ISBN: 978-3-527-30372-4." The calculations were performed using the following model: 1. Hartree Fock-3c (HF-3c) is a lower level of theory, does not consider solvent, but includes some empirical corrections to HF. The resulting geometries are usually good, which is the main reason for this type of calculation. It is based on a three-term correction of the HF calculation in the smallest MINIX basis set. 2. Density Functional Theory (DFT) - B3LYP def2-TZVP: Standard good theory level with binding affinity estimated to within 8 kJ / mol in vacuum. This gives a good idea of ​​the process and allows validating the geometry obtained in the first step. However, it does not take into account solvent effects. 3. DFT-B3LYP def2-TZVP CPCM SMD: The solvent is treated as a continuous dielectric, and electrostatic effects are largely accurate, but chemically specific solvent effects are not considered. In this model, the molecules are surrounded by a polarizable medium outside the excluded volume. Therefore, the charge distribution of the solute induces an apparent polarization charge on the separating surface, which in turn generates an electrostatic force on the solute. See Sure, et al., Comput. Chem. 2013, 34, 1672-1685. DOI: 10.1002 / jcc.23317, and Barone, et al., (1998) J. Phys. Chem. A, 102, 1995.

[0263] DFT-B3LYP def2-TZVP CPCM SMD + explicit water: Several explicit water molecules were added to the model to measure solvent binding effects. Thermodynamic properties were evaluated using minimum energy conformations and short fixed-temperature quantum molecular (QM) dynamics.

[0264] result During the short phase of HF-3c sampling, [2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine-Fe 2+ ] and [diethylenetriamine-Fe 2+Both [2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine-Fe 2+ The formation of [ ] is hindered by the rigidity of the structure and can only be formed by the system overcoming the transition configuration. In phases 2 and 3, increasing the approximation level did not appreciably change the results. This is expected, as molecular geometry and bonding parameters such as bond lengths are fairly stable to these improvements in theory.

[0265] In phase 4, each complex is prepared with 4, 5, or 6 water molecules, and three of these water molecules are always Fe, as shown in Figure 25. 2+ It was directly coordinated with the ion.

[0266] Of the dissociated parts, iron is in the octahedral complex [Fe-6H2O] 2+ The calculation was performed for spin states S = 0, 1, and 2, and it was confirmed that the iron hydrate has the high-spin configuration S = 2.

[0267] Each of the ligands was calculated with two, three, and four explicit water molecules. In all configurations, one or two water molecules were found to form specific bonds with the nitrogen atoms of the ligand.

[0268] The complexation reaction scheme for a given ligand L is as follows:

number

[0269] When two water molecules specifically bind to the ligand, the reaction is as follows:

number

[0270] The free water energy for stoichiometric equilibrium was estimated from compounds with multiple explicit water contents. Additionally, the zero-point vibrational energy (ZPE) released upon complex dissociation has been reported. The zero-point energy is a contribution that must be considered because quantum systems are never at rest, since it has a minimum vibrational energy. This vibrational energy is released when the system dissociates, typically reducing the dissociation energy.

[0271] From various energy components, the following complex formation of diethylenetriamine is obtained:

number

number

[0272] A good linear relationship was observed between the energy and the number of explicit water molecules. ΔG 0 =ΔU 0 -TΔS 0 TΔS in the equation 0 Even when considering the term, the complex formation energy ΔG 0 was observed to be overestimated by about 25 kJ / mol. This discrepancy may be due to the complex effects of water that cannot be fully explained and the B3LYP treatment of the density function for high-spin iron states, since this density function was primarily optimized based on a large database of ab initio and experimental data on the dissociation energies and structural geometries of organic molecules.

[0273] The complex formation of 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine (D102) can be obtained in a similar manner.

number

[0274] Table 9 below summarizes the results of a single calculation. [Table 9]

[0275] 2,4,6-Tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine is therefore a much more potent Fe ion ... 2+ 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine has a ΔG similar to that of diethylenetriamine. 0 -ΔU 0 The value of TΔS is adopted; 0 Taking into account both the σ and the calculation error μ, the following estimation can be made for 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine:

number

number

[0276] Regarding the complex formation reaction of 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine (D102) with Fe(OH)2, i.e., the reaction scheme of the following formula:

number

number

[0277] Therefore, Fe(OH)2 is a weak binder.

[0278] Finally, using the largest number of explicit waters reported above, we performed short (500 femtosecond) QM dynamics on each of the major species to check whether different nuclear configurations were available and related to the thermodynamic properties of the system. Statistical analysis of the molecular dynamics frames did not reveal any significant modifications to the results reported above.

[0279] conclusion The following reaction was thermodynamically favored by 93.7 kJ / mol:

number

[0280] The pK of this reaction was determined as follows:

number

[0281] According to this pK value, 1 μM Fe 2+ At least 10 μM of 2,4,6-tris(3,4-dihydro-2H-pyrrol-2-yl)pyridine is required for solution complex formation.

Claims

1. Structure: 【Chemistry 1】 Compounds containing 2,4,6-tris(3,4-dihydro-2H-pyrrole-2-yl)pyridine or pharmaceutically acceptable salts or solvates thereof.

2. A pharmaceutical composition comprising an effective amount of the compound described in Claim 1 or a pharmaceutically acceptable salt or solvate thereof.

3. The pharmaceutical composition according to claim 2, further comprising a pharmaceutically acceptable vehicle.

4. The pharmaceutical composition according to claim 2 for treating hyperammonemia.

5. A pharmaceutical composition according to claim 2 for treating diseases related to chronic inflammation.

6. A pharmaceutical composition according to claim 2 for inhibiting the formation of metal oxides.

7. The aforementioned metal is present in mammalian cells. The pharmaceutical composition according to claim 6.

8. The pharmaceutical composition according to claim 2 for treating vascular inflammatory diseases or conditions, Th1 type vascular inflammatory diseases or conditions, Th2 type vascular inflammatory diseases or conditions, Th1 type inflammation, monocyte activation response, conditions or diseases related to the proliferation, activation, and class switching of T cell-dependent B cells in the germinal centers of secondary lymphoid organs, Th2 type pneumonia inflammatory diseases or conditions, Th1 type pneumonia inflammatory diseases or conditions, polyfibrotic diseases or conditions, or diseases or conditions related to inflammation-related responses or macrophage activation responses in fibrous tissue.

9. The pharmaceutical composition according to claim 2 for treating chronic inflammatory diseases, vasculitis, restenosis, allergies, asthma, ulcerative colitis, atherosclerosis, rheumatoid arthritis, metabolic diseases, organ transplant-associated reactions, psoriasis, Crohn's disease, and hematological malignancies or conditions caused by inflammation, pulmonary fibrosis, exacerbations of chronic obstructive pulmonary disease (COPD), sarcoidosis, pulmonary reactions to respiratory infections, or Th1 type cutaneous inflammatory reactions to mechanical, chemical, or infectious factors.

10. The aforementioned Th1 type vascular inflammatory disease includes chronic inflammatory diseases, vascular inflammation, or restenosis. The pharmaceutical composition according to claim 8.

11. The aforementioned Th2 type vascular inflammatory disease or condition includes allergies, asthma, or ulcerative colitis. The pharmaceutical composition according to claim 8.

12. The aforementioned Th1-type chronic inflammation and / or monocyte-activated response includes atherosclerosis, restenosis, rheumatoid arthritis, or metabolic disorders. The pharmaceutical composition according to claim 8.

13. The aforementioned vascular inflammatory diseases or conditions include organ transplant-associated reactions, rheumatoid arthritis, psoriasis, Crohn's disease, and hematological malignancies or conditions caused by inflammation. The pharmaceutical composition according to claim 8.

14. Conditions or diseases associated with the proliferation, activation, and class switching of T cell-dependent B cells in the germinal centers of the secondary lymphoid organs include systemic lupus erythematosus (SLE), hematological oncology, autoimmune conditions, asthma, or allergies. The pharmaceutical composition according to claim 8.

15. The aforementioned Th2 type inflammatory pneumonia or condition includes asthma, pulmonary fibrosis, or exacerbations of chronic obstructive pulmonary disease (COPD). The pharmaceutical composition according to claim 8.

16. The aforementioned Th1 type inflammatory pneumonia or condition includes sarcoidosis and the pulmonary response to respiratory infections. The pharmaceutical composition according to claim 8.

17. The aforementioned Th1 type inflammatory disease or condition includes fibrosis, rheumatoid arthritis, dermatitis, or psoriasis. The pharmaceutical composition according to claim 8.

18. The aforementioned Th1 type inflammatory disease or condition includes a Th1 type cutaneous inflammatory response to mechanical, chemical, or infectious factors. The pharmaceutical composition according to claim 8.

19. The diseases or conditions associated with the macrophage activation response include atherosclerosis, restenosis, or rheumatoid arthritis. The pharmaceutical composition according to claim 8.

20. The pharmaceutical composition according to claim 2 for treating cancer.

21. Cancers include adrenal tumors, AIDS-related cancers, alveolar soft tissue sarcomas, astrocytic tumors, bladder cancers, bone cancers, brain and spinal cord cancers, metastatic brain tumors, breast cancers, carotid body tumors, cervical cancers, chondrosarcomas, chordomas, chromophobe renal cell carcinomas, clear cell carcinomas, colon cancers, colorectal cancers, benign fibrous histiocytomas, fibrinogenic round cell tumors, ependymomas, Ewing's tumors, extraskeletal myxoid chondrosarcomas, osteogenesis imperfecta, fibrous dysplasia, gallbladder or bile duct cancers, gastric cancers, gestational trophoblastic tumors, germ cell tumors, head and neck cancers, hepatocellular carcinomas, pancreatic islet cell tumors, Kaposi's sarcoma, kidney cancers, leukemias, and lipomas / benign lipomas. Selected from the group consisting of ulcers, liposarcoma / malignant lipomatous tumors, liver cancer, lymphoma, lung cancer, medulloblastoma, melanoma, meningioma, multiple endocrine tumors, multiple myeloma, myelodysplastic syndrome, neuroblastoma, neuroendocrine tumors, ovarian cancer, pancreatic cancer, papillary thyroid carcinoma, parathyroid tumor, childhood cancer, peripheral nerve sheath tumor, pheochromocytoma, pituitary tumor, prostate cancer, posterior uveal melanoma, rare hematological disorders, renal metastasis, rhabdoid tumor, rhabdomyosarcoma, sarcoma, skin cancer, soft tissue sarcoma, squamous cell carcinoma, gastric cancer, synovial sarcoma, testicular cancer, thymic carcinoma, thymoma, metastatic thyroid cancer, and uterine cancer. The pharmaceutical composition according to claim 20.

22. Cancer is selected from the group consisting of colorectal cancer, hepatocellular carcinoma, glioma, renal cancer, breast cancer, multiple myeloma, bladder cancer, neuroblastoma; sarcoma, non-Hodgkin lymphoma, non-small cell lung cancer, ovarian cancer, pancreatic cancer, rectal cancer, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute B-lymphoblastic leukemia (B-ALL), chronic lymphocytic leukemia (CLL), hairy cell leukemia (HCL), blastic plasmacytoid dendritic cell neoplasm (BPDCN), Mantel cell leukemia (MCL), and non-Hodgkin lymphoma (NHL), Hodgkin lymphoma, systemic mastocytosis, or Burkitt lymphoma. The pharmaceutical composition according to claim 20.

23. A pharmaceutical composition according to claim 2 for treating or preventing iron overload conditions or diseases.

24. The aforementioned iron overload state or disease includes hemochromatosis, The pharmaceutical composition according to claim 23.

25. The aforementioned iron overload condition or disease includes liver disease, inflammatory disease, chronic kidney disease, hyperthyroidism, anemia, diabetes, metabolic syndrome, Graves' disease, arrhythmia, and chronic hepatitis C infection, or cancer. The pharmaceutical composition according to claim 23.

26. The aforementioned inflammatory diseases include rheumatoid arthritis, autoimmune diseases, acute infections, or atherosclerosis. The pharmaceutical composition according to claim 25.

27. A pharmaceutical composition according to claim 2 for preventing or reversing telomere shortening.

28. A pharmaceutical composition according to claim 2 for preventing telomere shortening.

29. A pharmaceutical composition according to claim 2 for reversing or preventing processes, diseases, or pathological conditions related to aging.

30. The aforementioned aging-related processes include hair loss, loss of vitality, or telomere shortening. The pharmaceutical composition according to claim 29.

31. Administration brings about a decrease in VCAM-1 levels, The pharmaceutical composition according to claim 29.

32. The pharmaceutical composition according to claim 2 for reducing VCAM-1 levels.

33. The pharmaceutical composition according to claim 2 for reducing VCAM-1 levels by administration.

34. A pharmaceutical composition according to claim 2 for treating gastrointestinal diseases or disorders.

35. The aforementioned gastrointestinal disease or disorder is selected from the group consisting of achalasia, Barrett's esophagus, colorectal cancer, gastric cancer, esophageal cancer, celiac disease, colitis, Crohn's disease, diverticulosis, diverticulitis, gastritis, inflammatory bowel disease, ulcerative colitis, irritable bowel syndrome, microscopic colitis, collagenous colitis, lymphocytic colitis, pancreatitis, reflux esophagitis, and ulcerative colitis. The pharmaceutical composition according to claim 34.

36. A pharmaceutical composition according to claim 2 for treating an autoimmune disease.

37. The autoimmune diseases are selected from the group consisting of lupus erythematosus; Wiscott-Aldrich syndrome; autoimmune lymphoproliferative syndrome; myasthenia gravis; rheumatoid arthritis (RA); lupus nephritis; multiple sclerosis; systemic lupus erythematosus, subacute cutaneous lupus erythematosus, cutaneous lupus erythematosus including frostbite-like lupus erythematosus, chronic arthritis, Sjögren's syndrome, autoimmune nephritis, autoimmune vasculitis, autoimmune hepatitis, autoimmune carditis, autoimmune encephalitis, autoimmune hematological disorders, inflammatory chronic rhinosinusitis, colitis, celiac disease, inflammatory bowel disease, Barrett's esophagus, and / or inflammatory gastritis. The pharmaceutical composition according to claim 36.

38. The pharmaceutical composition according to claim 2 for reducing or improving the reactivity, toxicity, or biodistribution of a metal in a target area.

39. The compound bonds to the metal, The pharmaceutical composition according to claim 38.

40. The compound is bonded to the metal at two or more bonding sites. The pharmaceutical composition according to claim 39.

41. Two or more compounds bond to the metal, The pharmaceutical composition according to claim 39.

42. The aforementioned compound bonds to the metal only in the presence of oxidative stress. The pharmaceutical composition according to claim 39.

43. The aforementioned compound is activated by an enzyme and binds to the metal. The pharmaceutical composition according to claim 39.

44. The aforementioned compound targets organs or tissues. The pharmaceutical composition according to claim 39.

45. The compound alters the concentration or biodistribution of the metal in the subject. The pharmaceutical composition according to claim 38.

46. The aforementioned subjects are those suffering from metal overload disease or condition. The pharmaceutical composition according to claim 38.

47. The aforementioned metal overload disease or condition includes iron, copper, or zinc overload disease or condition. The pharmaceutical composition according to claim 46.

48. The aforementioned metal is a transition metal. The pharmaceutical composition according to claim 38.

49. The transition metals include scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, silver, cadmium, hafnium, tantalum, tungsten, rhenium, osmium, iridium, platinum, and / or gold, and preferably the transition metals are iron, copper, and / or zinc. The pharmaceutical composition according to claim 48.

50. The aforementioned metal is a trivalent metal ion, a divalent metal ion, and / or a monovalent metal ion. The pharmaceutical composition according to claim 38.

51. The target of administration is a human, A pharmaceutical composition according to any one of claims 1 to 50.

52. The target of administration is a mammal, A pharmaceutical composition according to any one of claims 1 to 50.

53. The aforementioned mammals include primates, dogs, horses, cats, cattle, or pigs. The pharmaceutical composition according to claim 52.

54. The target of administration includes non-human animals, A pharmaceutical composition according to any one of claims 1 to 50.

55. The aforementioned non-human animal is a bird or a reptile. The pharmaceutical composition according to claim 54.

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