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 of related applications] This application claims priority under U.S. Provisional Application No. 63 / 458,611, filed on 11 April 2023, and U.S. Provisional Application No. 63 / 403,536, filed on 2 September 2022, both of which are incorporated herein by reference in their entirety.

[0002] Metal overload or imbalance is associated with a variety of diseases and pathological conditions. For example, hereditary hemochromatosis (HH) is a form of primary iron overload (IO). 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, potentially resulting in cirrhosis, diabetes, arthropathy, congestive heart failure, hypogonadism, and hyperpigmentation of the skin. Excessive iron deposition is also associated with inflammatory diseases, chronic kidney disease, rheumatoid arthritis, autoimmune diseases, acute infections, cancer, anemia in chronic diseases, type 2 diabetes, metabolic syndrome, atherosclerosis, fatty liver disease, loss of appetite, Graves' disease, arrhythmias, and chronic hepatitis C infection.

[0003] The current standard treatment for HH is phlebotomy. By removing red blood cells, which are the primary mobilizers of iron in the body, iron toxicity can be minimized. Patients require more than 100 phlebotomies of 500 mL each to lower their 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 hemoglobin disorders (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 occurs due to increased iron absorption, exogenous iron administration for the treatment of anemia, and repeated blood transfusions.

[0005] Secondary hemochromatosis is typically treated with iron chelators such as deferoxamine or deferasirox. Unfortunately, these treatments are complex to administer, can impose an unusual time burden on patients, and / or are associated with side effects such as hypotension, impaired GI, vision and hearing loss, and impaired liver and kidney function. Therefore, alternative treatment approaches are needed for patients with secondary hemochromatosis.

[0006] Shortening of absolute telomere length (ATL) is a key molecular feature of cellular senescence and DNA damage associated with chronic diseases and mortality. In fact, telomere shortening has been found to be a major cause of aging in humans. In particular, a decrease in ATL is associated with almost all age-related chronic diseases, including cancer, heart disease, diabetes, and autoimmune diseases.

[0007] Telomeres are the ends of chromosomes and, like the tips of shoelaces that prevent them from coming undone, they play a role in protecting DNA. When telomeres shorten to a critical length, DNA is no longer protected during replication, resulting in DNA damage and chromosomal rearrangement, which can lead to somatic cell aging, apoptosis, or oncogenic transformation. Therefore, therapeutic approaches are needed to prevent ATL shortening and lengthen telomeres.

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

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

[0010] Hyperammonemia is one of the metabolic disorders that can cause hepatic encephalopathy, leading to astrocyte swelling and stimulation of NMDA receptors in the brain. Excessive stimulation of NMDA receptors induces excitotoxicity.

[0011] Acquired hyperammonemia is usually caused by a disease that leads to either acute liver failure, such as severe hepatitis B or exposure to hepatoxin, or cirrhosis with chronic liver failure. Chronic hepatitis B, chronic hepatitis C, and excessive alcohol consumption are common causes of cirrhosis. A physiological consequence of cirrhosis is the shunting of blood from the liver to the inferior vena cava, resulting in decreased blood filtration and removal of nitrogen-containing toxins by the liver, leading to hyperammonemia. This type of hyperammonemia can initially be treated with antibiotics that kill ammonia-producing bacteria, but this is less effective than the removal of proteins from the colon before digestion into ammonia, which is achieved by administering lactulose to induce frequent (3-4 times per day) bowel movements.

[0012] Drug-induced hyperammonemia can occur with excessive valproic acid intake and is caused by carnitine deficiency. Treatment involves carnitine supplementation.

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

[0014] Severe dehydration and excessive bacterial growth in the small intestine can also lead to acquired hyperammonemia.

[0015] Glycine toxicity causes hyperammonemia, which manifests as central nervous system symptoms and nausea. Transient blindness may also occur.

[0016] Congenital hyperammonemia is usually caused by a genetic defect in one of the enzymes of the urea cycle, such as ornithine transcarbamylase deficiency, which leads to reduced urea production from ammonia.

[0017] The focus of treatment is on restricting ammonia intake and increasing its excretion. Dietary protein, a metabolic source of ammonium, is also restricted, and calorie intake is supplied by glucose and fat. Intravenously administered arginine (for argininosuccinase deficiency), sodium phenylbutyrate, and sodium benzoate (for ornithine transcarbamoylase deficiency) are commonly used pharmaceutical agents as adjunctive therapies for treating hyperammonemia in patients with urea cycle enzyme deficiencies. Sodium phenylbutyrate and sodium benzoate can function as urea substitutes and excretort agents of waste nitrogen. Phenylbutyrate is a product of phenylacetic acid, which conjugates with glutamine to form phenylacetylglutamine, which is excreted by the kidneys. Similarly, sodium benzoate conjugates with glycine to form hippuric acid, which is rapidly excreted by the kidneys, thereby reducing ammonia levels in the blood. Preparations containing sodium phenylacetate and sodium benzoate are available under the trade name Ammonul. Acidifying the intestinal lumen with lactulose can lower ammonia levels by protonating ammonia and capturing it in the feces. This is a treatment for hepatic encephalopathy.

[0018] Many common over-the-counter and prescription medications can also contribute to elevated ammonia levels, typically as a result of increased nitrite production. It is desirable to develop anti-inflammatory compounds that have the effect of lowering individual ammonia levels. In particular, it is desirable to develop effective therapeutic therapies not only for hyperammonemia but also for other disorders associated with chronic inflammation and cancer.

[0019] This 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. [Overview of the project]

[0020] In one embodiment, this disclosure relates to formula Ia or formula Ib shown below: [ka] [ka] This relates to compounds having the structure of, or a pharmaceutically acceptable ester or solvate thereof. Here, in the above formula, X - R1 is an ion of an acid that forms a pharmaceutically acceptable salt, where 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 no, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocyclic; when R3 is N, R1 is no; when A4 is N, R3 is no; alkyl, alkenyl, alkynyl, or acyl are 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 Bis independently selected from hydrogen and C 1-4 alkyl; aryl or heteroaryl, whether alone or as part of a substituent, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, alkyl, -O-alkyl, -COOH, -C(O)-C 1-4 alkyl, -C(O)O-C 1-4 alkyl, NR C R D , -S-alkyl, -SO-alkyl, and -SO2-alkyl; R C and R D are each independently selected from hydrogen and C[[ID=..]] 1-4 alkyl.

[0021] In some embodiments, R2 and / or R4 have the structure according to the following Formula IIa or Formula IIb:

Chemical formula

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

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

[0028] In some embodiments, the compound is [ka] It is not a pharmaceutically acceptable salt, ester, or solvate thereof.

[0029] In some embodiments, the compound is as follows: [ka] [ka] [ka] It has a structure selected from the group consisting of the following, or a pharmaceutically acceptable salt, ester, or solvate thereof.

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

[0031] In some embodiments, this disclosure relates to Formula IIIa or Formula IIIb as shown below: [ka] This relates to compounds having the structure of, or a pharmaceutically acceptable ester or solvate thereof. Here, X - R is an acid ion that forms a pharmaceutically acceptable salt, 1 , R 2 and R 3The group is independently selected from the group consisting of H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocyclic; alkyl, alkenyl, alkynyl, or acyl may be 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 heterocycles; R A and R B These are, independently, hydrogen and C 1-4 Selected from alkyl groups; aryl or heteroaryl, whether alone or as part of a group of substituents, halogen, -OH, alkyl, -O-alkyl, -COOH, -C(O)-C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, NR C R D These are -S-alkyl, -SO-alkyl, and -SO2-alkyl; R C and R D These are, independently, hydrogen and C 1-4 Selected from alkyl groups.

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

[0033] In some aspects, this disclosure relates to formula IVa or formula IVb described below: [ka] This relates to compounds having the structure of . Here, in the formula, X -R1, R2, R3, R4, R5, R6, and R7 are ions of acids that form pharmaceutically acceptable salts, 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 heterocyclic; alkyl, alkenyl, alkynyl, or acyl may be 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 heterocycles; R A and R B These are, independently, hydrogen and C 1-4 Selected from alkyl groups; aryl or heteroaryl groups, whether alone or as part of a group of substituents, include halogens, -OH, alkyl, -O-alkyl, -COOH, and -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 These are, independently, hydrogen and C 1-4 Selected from alkyl groups.

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

[0035] In another aspect, this disclosure relates to the following formula Va or formula Vb: [ka] [ka] This relates to compounds having the structure of, or a pharmaceutically acceptable ester or solvate thereof. Here, X - R1 is an ion of an acid that forms a pharmaceutically acceptable salt, where 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 no, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocyclic; when R3 is N, R1 is no; when A4 is N, R3 is no; alkyl, alkenyl, alkynyl, or acyl are 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 These are, independently, hydrogen and C 1-4 Selected from alkyl; aryl or heteroaryl, whether alone or as part of a substituent, 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 These are, independently, hydrogen and C 1-4 Selected from alkyl groups. In some embodiments, R2 and / or R4 have a structure according to formula IIa or formula IIb, where X -A1, A2, R5, R6, R7, and R8 are defined as described 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 is N. In some embodiments, R2 and R4 have a structure according to formula IIa or formula IIb.

[0036] In some embodiments, compounds with formula Va or Vb have the following structure: [ka] or having a pharmaceutically acceptable salt, ester, or solvate thereof.

[0037] In some embodiments, compounds with formula Va or Vb are as follows: [ka] [ka] It has a structure selected from the group consisting of the following, or a pharmaceutically acceptable salt, ester, or solvate thereof.

[0038] In some embodiments, compounds with formula Va or Vb are as follows: [ka] It has the structure of, or a pharmaceutically acceptable salt, ester, or solvate thereof.

[0039] In some embodiments, compounds with formula Va or Vb are as follows: [ka] [ka] [ka] [ka] [ka] It has a structure selected from the group consisting of the following, or a pharmaceutically acceptable salt, ester, or solvate thereof.

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

[0041] In another embodiment, a method for inhibiting the formation of a metal oxide, comprising contacting a metal with at least one of the above-mentioned compounds. For example, the metal is present in mammalian cells such as human cells.

[0042] In another embodiment, a method for treating hyperammonemia includes administering the pharmaceutical composition to an individual in need thereof.

[0043] In yet another embodiment, a method for treating a disorder associated with chronic inflammation includes administering the pharmaceutical composition to an individual in need. In yet another embodiment, the present disclosure relates to a method for treating a disorder associated with chronic inflammation, and includes administering the pharmaceutical composition disclosed herein to an individual in need.

[0044] In another embodiment, the present disclosure relates to a method for treating subjects suffering from 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 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 fibrotic tissue, wherein the method comprises administering the pharmaceutical compositions disclosed herein to the subject.

[0045] In some embodiments, subjects suffer from chronic inflammatory diseases, vasculitis, restenosis, allergies, asthma, ulcerative colitis, atherosclerosis, rheumatoid arthritis, metabolic disorders, organ transplant-associated reactions, psoriasis, Crohn's disease, and hematological neoplastic diseases or conditions due to inflammation, pulmonary fibrosis, exacerbations of chronic obstructive pulmonary disease (COPD), sarcoidosis, pulmonary responses to respiratory infections, or Th1 type cutaneous inflammatory reactions to mechanical, chemical, or infectious agents.

[0046] In some embodiments, Th1-type vascular inflammatory diseases include chronic inflammatory diseases, vascular inflammation, or restenosis.

[0047] In some embodiments, Th2-type vascular inflammatory diseases or conditions include allergies, asthma, or ulcerative colitis.

[0048] In some embodiments, Th1-type chronic inflammation and / or monocyte-activated responses include atherosclerosis, restenosis, rheumatoid arthritis, or metabolic disorders.

[0049] In some aspects, vascular inflammatory diseases or conditions include organ transplant-associated reactions, rheumatoid arthritis, psoriasis, Crohn's disease, and Caused by inflammation Blood malignant disease or illness attitude include.

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

[0051] In some embodiments, Th2 type pneumonia or conditions include asthma, pulmonary fibrosis, or exacerbations of chronic obstructive pulmonary disease (COPD).

[0052] In some embodiments, Th1 type pneumonia or conditions include sarcoidosis and pulmonary responses to respiratory infections.

[0053] In some embodiments, Th1-type inflammatory diseases or conditions include fibrosis, rheumatoid arthritis, dermatitis, or psoriasis.

[0054] In some embodiments, Th1-type inflammatory diseases or conditions include a Th1-type cutaneous inflammatory response to mechanical, chemical, or infectious factors.

[0055] In some embodiments, diseases or conditions associated with macrophage activation responses include atherosclerosis, restenosis, or rheumatoid arthritis.

[0056] In some aspects, the Disclosure relates to a method for treating cancer in a subject requiring treatment, comprising administering a therapeutically effective amount of a compound or a therapeutically effective amount of a pharmaceutical composition disclosed herein to the subject requiring treatment. In some aspects, the cancer is adrenal 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, chromophobic renal cell carcinoma, clear cell carcinoma, colon cancer,Colorectal cancer, benign fibrous histiocytoma, fibroplastic 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 lipomatous tumor, liposarcoma / malignant lipomatous tumor, liver cancer, lymphoma, lung cancer, medulloblastoma, melanoma, meningioma, multiple endocrine tumors The group consists of ulcers, multiple myeloma, myelodysplastic syndrome, neuroblastoma, neuroendocrine tumors, ovarian cancer, pancreatic cancer, papillary thyroid carcinoma, parathyroid tumors, childhood cancers, peripheral nerve sheath tumors, pheochromocytoma, pituitary tumors, prostate cancer, posterior uveal melanoma, rare hematological disorders, renal metastasis, rhabdoid tumors, 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, 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 small lymphocytic lymphoma (SLL), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma, systemic mastocytosis, or Burkitt lymphoma.

[0058] In another embodiment, the Disclosure relates to a method for treating or preventing an iron overload condition or disease, comprising administering a pharmaceutical composition containing the compounds disclosed herein to an individual in need thereof.

[0059] In some embodiments, iron overload conditions or diseases include hemochromatosis disorders or pathologies.

[0060] In some embodiments, iron overload conditions or diseases include liver disease, inflammatory diseases, chronic kidney disease, hyperthyroidism, anemia, diabetes, metabolic syndrome, Graves' disease (also known as Graves' disease), arrhythmias, and chronic hepatitis C infection, or cancer.

[0061] In some embodiments, inflammatory diseases include rheumatoid arthritis, autoimmune diseases, acute infections, or atherosclerosis.

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

[0063] In another embodiment, the disclosure relates to a method for reversing or preventing aging-related processes, diseases, or conditions, the method comprising administering a pharmaceutical composition comprising the compounds disclosed herein to an individual in need thereof.

[0064] In some embodiments, aging-related processes include hair loss, loss of vitality, or telomere shortening.

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

[0066] In one embodiment, the present disclosure relates to a method for reducing VCAM-1 levels, which includes administering a pharmaceutical composition comprising the compound disclosed herein to an individual in need of such reduction.

[0067] In one embodiment, the present disclosure relates to a method for 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 embodiment, 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; 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.

[0069] In another embodiment, the present disclosure relates to a method for reducing or improving the reactivity, toxicity, or biodistribution of a metal in an object requiring such reduction, comprising administering a compound or pharmaceutical composition disclosed herein to an individual requiring such reduction. In some embodiments, the compound binds to the metal.

[0070] In some embodiments, the compound is bonded to the metal at two or more bonding sites.

[0071] In some embodiments, two or more compounds are bonded to a metal.

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

[0073] In some embodiments, the compound is activated by an enzyme and then binds to the metal.

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

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

[0076] In some embodiments, the subjects suffer from a metal overload disease or condition.

[0077] In some embodiments, metal overload disorders or conditions include iron, copper, or zinc overload disorders or conditions.

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

[0079] In some embodiments, the transition metal includes 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 human.

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

[0083] In some embodiments, mammals include primates, dogs, horses, cats, cattle, or pigs.

[0084] In some embodiments, the subjects include non-human animals.

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

[0086] [Figure 1] Figure 1 shows the 1H NMR (proton nuclear magnetic resonance) spectra of two different lots of 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine synthesized according to the protocol described in Example 5 of this specification. The 1H NMR spectra confirmed the identity and purity of 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine. [Figure 2] Figure 2 shows the 1H NMR spectra of two different lots of 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine synthesized according to the protocol described in Example 5 of this specification. The 1H NMR spectra confirmed the identity and purity of 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine. [Figure 3] Figure 3 shows the 1H NMR spectra of two different lots of 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine synthesized according to the protocol described in Example 5 of this specification. The 1H NMR spectra confirmed the identity and purity of 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine. [Figure 4]Figure 4 shows the 1H NMR spectra of two different lots of 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine synthesized according to the protocol described in Example 5 of this specification. The 1H NMR spectra confirmed the identity and purity of 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine. [Figure 5] Figure 5 shows the IR (infrared) spectrum of an exemplary lot of 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine synthesized according to the protocol described in Example 5 of this specification. The IR spectrum confirmed the identity and purity of 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine. [Figure 6] Figure 6 shows the IR spectrum of an exemplary lot of 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine synthesized according to the protocol described in Example 5 of this specification. The IR spectrum confirmed the identity and purity of 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine. [Figure 7] Figure 7 shows the IR spectrum of an exemplary lot of 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine synthesized according to the protocol described in Example 5 of this specification. The IR spectrum confirmed the identity and purity of 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine. [Figure 8] Figure 8 shows the IR spectrum of an exemplary lot of 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine synthesized according to the protocol described in Example 5 of this specification. The IR spectrum confirmed the identity and purity of 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine. [Figure 9] Figure 9 shows the superposition of the IR spectra shown in Figures 5-8. [Figure 10]Figure 10 shows the results of long-term liquid chromatography-mass spectrometry (LC-MS) of 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine synthesized according to the protocol described in Example 5 of this specification. The LC-MS results further confirm that both the major and minor peaks from HPLC of compound 8 produced 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine. [Figure 11] Figure 11 shows the results of long-time liquid chromatography-mass spectrometry of 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine synthesized according to the protocol described in Example 5 of this specification. The [M+H]+ from LC-MS analysis of both peaks from HPLC purification corresponds to the product mass [LC-MS calculated value: 281.3, measured value: 281.3] for [M+H]+ of C17H21N4 in m / z. Figure 11 shows images of 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine obtained from both peaks of isolated compound 8. [Figure 12] Figure 12 shows the results of conventional HPLC (A) and chiral HPLC (B) of the same lot of synthesized 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine. [Figure 13] Figure 13 shows a photograph of the crystals of 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine synthesized from both HPLC peaks. [Figure 14] Figure 14 shows photographs comparing aged mice treated with 10 mg / day of 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine on day 1 and day 8. [Figure 15] Figure 15 shows the inhibition of VCAM activity by 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine (Tri-Iso-1) in comparison with doxycycline. [Figure 16]Figure 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-pyrrole-2-yl)pyridine of Example 8. [Figure 17] Figure 17 shows the HPLC chromatogram of 2,4,6-pyridinetricaldehyde. [Figure 18] Figure 18 shows the 1H NMR spectrum of Stage 1 (DMSO, 400 MHz) in the synthesis scheme III of 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine of Example 8. [Figure 19] Figure 19 shows the HPLC chromatogram of the Stage 1 product in the synthesis scheme III of 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine in Example 8. [Figure 20] Figure 20 shows the 1H NMR spectrum of the Stage 2 product in the synthesis scheme III of 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine in Example 8. [Figure 21] Figure 21 shows the HPLC chromatogram of the Stage 2 product in the synthesis scheme III of 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine in Example 8. [Figure 22] Figure 22 shows the 1H NMR spectrum of the Stage 3 product in the synthesis scheme III of 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine in Example 8. [Figure 23] Figure 23 shows the HPLC chromatogram of the Stage 3 product in the synthesis scheme III of 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine in Example 8. [Figure 24] Figure 24 shows the structure optimization without explicit water molecules. [Figure 25] Figure 25 shows the complex formation of 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine, Fe2+, and six water molecules. [Modes for carrying out the invention]

[0087] The pharmaceutical compounds disclosed herein possess anti-inflammatory and anticancer activities and are useful in the treatment of hemochromatosis. The compounds disclosed herein can also function as metalloenzyme inhibitors, preventing enzymatic activity that leads 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] Accordingly, in some embodiments, the Disclosure relates to a method for reducing or improving the reactivity, toxicity, or biodistribution of a metal in an object requiring it, the method comprising administering a compound or pharmaceutical composition disclosed herein to an individual requiring it. 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] Therefore, in some embodiments, a therapeutically effective amount of the compound described herein is administered to an individual in need, where the therapeutically effective amount reduces metal reactivity, toxicity, or improves the biodistribution of the metal. In some embodiments, a therapeutically effective amount of the compound does not interfere with the normal and healthy metal state in the individual. In some embodiments, the compound does not exhibit cytotoxicity to normal and healthy cells, tissues, or organs. Exemplary therapeutically effective amounts are disclosed elsewhere in this specification.

[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 metals 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%.

[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 the biodistribution of metals 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%.

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

[0095] The compounds disclosed herein can be designed to preferentially bind to metals under specific cellular conditions or during enzyme activation. For example, a compound can be modified to bind to a metal only under oxidative stress, such as in the presence of hydrogen peroxide. The modified compound activated by oxidative stress may be a boronate. Oxidative stress is associated with many diseases disclosed herein, such as inflammatory diseases, gastrointestinal diseases, autoimmune diseases, or cancers. In some embodiments, the compounds target organs or tissues through modification of the compound. For example, the incorporation of N-acetyl-galactosamine helps target hepatocytes.

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

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

[0098] In some embodiments, 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, preferably the transition metals are 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 subjects suffer from a metal overload disease or condition.

[0101] In some embodiments, metal overload disorders or conditions include iron, copper, or zinc overload disorders or conditions.

[0102] For example, compounds such as 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine disclosed herein may help balance the levels of intracellular iron and circulating iron in iron overload (IO) conditions. One type of IO condition is hereditary hemochromatosis (HH), caused by mutations in the iron storage protein ferritin. Iron overload conditions also include secondary hemochromatosis, which can occur in patients with abnormal hemoglobin disorders (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. Excess iron deposition is also associated with inflammatory diseases, chronic kidney disease, rheumatoid arthritis, autoimmune diseases, acute infections, cancer, anemia of chronic diseases, type 2 diabetes, metabolic syndrome, atherosclerosis, fatty liver disease, anorexia, Graves' disease, arrhythmias, and chronic hepatitis C infection. In some embodiments, the iron overload condition or disease includes hemochromatosis disease or pathology. In some embodiments, the iron overload condition or disease includes liver disease, inflammatory diseases, chronic kidney disease, hyperthyroidism, anemia, diabetes, metabolic syndrome, Graves' disease, arrhythmias, and chronic hepatitis C infection, or cancer.

[0104] In some embodiments, inflammatory diseases include rheumatoid arthritis, autoimmune diseases, acute infections, or atherosclerosis.

[0105] The compounds disclosed herein can also prevent or reverse absolute telomere length (ATL) shortening, a key molecular feature of cellular senescence and DNA damage associated with chronic diseases and death. In fact, telomere shortening has been found to be a major cause of human aging. In particular, a decrease in ATL is associated with almost all age-related chronic diseases, including cancer, heart disease, diabetes, and autoimmune diseases.

[0106] Telomeres are the ends of chromosomes and, much like the ends of shoelaces that prevent them from coming undone, they play a role in protecting DNA. When telomeres shorten to a critical length, DNA is no longer protected during replication, resulting in DNA damage and chromosomal rearrangement, which in turn leads to somatic cell aging, apoptosis, or oncogenic transformation.

[0107] In another embodiment, the Disclosure relates to a method for treating or preventing an iron overload condition or disease, which involves administering to an individual in need a pharmaceutical composition comprising a compound disclosed herein.

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

[0109] In another embodiment, the Disclosure relates to a method for reversing or preventing age-related processes, diseases, or conditions, which involves administering a pharmaceutical composition comprising the compounds disclosed herein to an individual in need thereof.

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

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

[0112] In some aspects, processes associated with aging include hair loss, decreased vitality, or telomere shortening. As used herein, the term “vitality” refers to vitality as defined by the World Health Organization (WHO): “the complex 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 for mental vitality include the 10-item Geriatric Depression Scale (GDS), which is 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 stand-up tests. In some aspects, vitality includes an individual’s biophysiological state and his ability to maintain homeostasis when faced with daily exposures or more extreme, unusual, or unexpected challenges such as injury or infection. In some aspects, vitality can be considered the amount of inherent capacity that can be retained, which underlies an individual’s vitality, stamina, and resilience to challenges. The main characteristics of vitality are hormonal function, energy metabolism, and cardiovascular function. Other characteristics of vitality include nutrition, body composition, depression, fatigue, metabolism, immune system response, respiratory function, or muscular endurance.

[0113] Fatigue can include measurements of muscle endurance, self-perceived fatigue assessment, and daytime fatigue. Metabolic fatigue can be measured by insulin sensitivity, glycosylated hemoglobin, serum albumin, fasting blood glucose, or hormonal status of the hypothalamic-pituitary-adrenal system. Body composition can be measured by anthropometric measurements, 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 post-lying response, blood pressure, cardiovascular health status, or maximal oxygen consumption. Nutrition can be assessed by measuring or evaluating appetite, weight loss, malnutrition, undernutrition, or a brief nutritional status assessment. Immune or stress responses can be assessed by inflammation, perceived immune status, oxygen saturation, or circulating biomarkers of autonomic nervous system function. Other measurable features of vitality include self-esteem assessment, mitochondrial function, sedentary behavior, sleep quantity and quality, methylation clock, or electrolyte balance.

[0114] For example, a compound may have anti-inflammatory activity that can reduce the levels of inflammation-inducing molecules. While we do not wish to be bound by theory, it is conceivable that the disclosed compounds may have anti-inflammatory activity that can reduce the levels of substance P (SP), calcitonin gene-related peptide (CGRP), glutamate, or combinations thereof. A compound may have anti-inflammatory activity that can reduce the levels of SP, CGRP, glutamate, or combinations thereof released from sensory neurons by, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%.

[0115] Prostaglandins mediate local inflammatory responses and are involved in all inflammatory functions through their action on prostaglandin receptors, mediating inflammatory signaling including chemotaxis (macrophages, neutrophils, and eosinophils), vasodilation, and hyperalgesia. However, PG-mediated inflammatory responses are self-limiting (dissipate). The major dissipation 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 levels of Th1 pro-inflammatory cytokines, and 2) promotes the differentiation of monocytes into macrophage M2 cells. Macrophage M2 cells produce and release Th2 anti-inflammatory cytokines.

[0116] The compounds disclosed herein may have anti-inflammatory activity that can reduce the levels of inflammation-inducing prostaglandins. The compounds may have anti-inflammatory activity that can reduce the levels of inflammation-inducing 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 reduces the levels of inflammation-inducing prostaglandins released from sensory neurons, for example, from approximately 10% to 100%, 20% to 100%, 30% to 100%, 40% to 100%, 50% to 100%, 60% to 100%, 70% to 100%, 80% to 100%, 10% to 90%, 20% to 90%, 30% to 90%, 40% to 90%, and so on. It may have anti-inflammatory activity that can reduce inflammation by approximately 50% to 90%, approximately 60% to 90%, approximately 70% to 90%, approximately 10% to 80%, approximately 20% to 80%, approximately 30% to 80%, approximately 40% to 80%, approximately 50% to 80%, or approximately 60% to 80%, approximately 10% to 70%, approximately 20% to 70%, approximately 30% to 70%, approximately 40% to 70%, or approximately 50% to 70%.

[0117] Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating gene expression. All PPARs are known to heterodimerize with retinoid X receptors (RXRs) and bind to specific regions on the DNA of target genes called peroxisome proliferator-activated elements (PPREs). PPARs play crucial roles in regulating cell differentiation, development, and metabolism (carbohydrates, lipids, and proteins), as well as tumorigenesis, in higher organisms. This family includes three members: PPAR-α, PPAR-γ, and PPAR-δ (also known as PPAR-β). PPAR-α is expressed in the liver, kidneys, heart, muscle, adipose tissue, and other tissues. PPAR-δ is expressed in many tissues, but is particularly prominent in the brain, adipose tissue, and skin. PPAR-γ includes three alternative splicing forms, each with a different expression pattern. PPAR-γ1 is expressed in almost all tissues, including the heart, muscle, colon, kidney, pancreas, and spleen. PPAR-γ2 is primarily expressed in adipose tissue. PPAR-γ3 is expressed in macrophages, the colon, and white adipose tissue. Endogenous ligands for PPAR include free fatty acids and eicosanoids. PPAR-γ is activated by PGD2 (prostaglandin), and PPAR-α is activated by leukotriene B4.

[0118] The compound may possess anti-inflammatory activity that can reduce the levels of IFN-γ, TNF-α, IL-12, or combinations thereof released from Th1 cells, and increase the level 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 combinations thereof released from th1 cells by, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%, and may have anti-inflammatory activity that can increase the levels 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%.

[0119] The compounds may possess anti-inflammatory activity that can stimulate some or all of the PPAR signaling pathways. Therefore, such compounds are intended to act as PPAR panagonists, or possibly selective PPAR agonists.

[0120] The compound may have anti-inflammatory activity that can modulate 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 combinations 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 in the range of, 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, a compound may have anti-inflammatory activity that can reduce the levels of IFN-γ, TNF-α, IL-12, or combinations thereof released from Th1 cells 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%. A compound may have anti-inflammatory activity that can reduce the levels of IFN-γ, TNF-α, IL-12, or combinations thereof released from Th1 cells by, for example, in the range of about 5% to about 100%, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, or about 10% to about 90%.

[0122] Compounds such as 2,4,6-tris(3,4-dihydro-2H-pyrrole-2-yl)pyridine, comprising ethanol as a carrier, may possess anti-inflammatory activity capable of modulating inflammatory molecules. The compounds may have anti-inflammatory activity capable of reducing 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 capable of reducing the levels of CD40, sIgG, sIL-10, HLA-DR, sIL-17A, CD38, sIL-6, sIL-17F, sIL-2, or combinations 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 possess 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 to approximately 5% to 100%, 10% to 100%, 20% to 100%, 30% to 100%, 40% to 100%, 50% to 100%, 60% to 100%, 70% to 100%, 80% to 100%, or approximately 10% to 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 the levels of eotaxin 3, MCP-1, VCAM-1, MIG, IL-6, and / or P-selectin to approximately 5% to approximately 100%, approximately 10% to approximately 100%, approximately 20% to approximately 100%, approximately 30% to approximately 100%, approximately 40% to approximately 100%, approximately 50% to approximately 100%, approximately 60% to approximately 100%, approximately 70% to approximately 100%, approximately 80% to approximately 100%, or approximately 10% to approximately 90%.

[0124] The compound may have anti-inflammatory activity that can reduce 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 that can reduce 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 may have anti-inflammatory activity that can reduce the levels of eotaxin 3, MCP-1, MIP-1α, I-TAC, MIG, IP-10, IL-6, VCAM-1, SAA, IL-1α, and / or P-selectin to approximately 5% to approximately 100%, approximately 10% to approximately 100%, approximately 20% to approximately 100%, approximately 30% to approximately 100%, approximately 40% to approximately 100%, approximately 50% to approximately 100%, approximately 60% to approximately 100%, approximately 70% to approximately 100%, approximately 80% to approximately 100%, or approximately 10% to approximately 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 reducing TIMP-1, collagen IV, PAI-1, and / or collagen III. The compounds may have tissue remodeling activity that can reduce the levels of TIMP-1, collagen IV, PAI-1, and / or collagen III, or combinations 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 compounds may possess tissue remodeling activity that can reduce the levels of TIMP-1, collagen IV, PAI-1, and / or collagen III to approximately 5% to approximately 100%, approximately 10% to approximately 100%, approximately 20% to approximately 100%, approximately 30% to approximately 100%, approximately 40% to approximately 100%, approximately 50% to approximately 100%, approximately 60% to approximately 100%, approximately 70% to approximately 100%, approximately 80% to approximately 100%, or approximately 10% to approximately 90%.

[0127] The compounds disclosed herein can also affect tissue remodeling activity by reducing TIMP-1, collagen IV, MMP-1, PAI-1, uPAR, αSMA, and / or MMP-9. The compounds may 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 combinations 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 compounds may possess tissue remodeling activity that can reduce the levels of TIMP-1, collagen IV, MMP-1, PAI-1, uPAR, αSMA, and / or MMP-9 to approximately 5% to approximately 100%, approximately 10% to approximately 100%, approximately 20% to approximately 100%, approximately 30% to approximately 100%, approximately 40% to approximately 100%, approximately 50% to approximately 100%, approximately 60% to approximately 100%, approximately 70% to approximately 100%, approximately 80% to approximately 100%, or approximately 10% to approximately 90%.

[0128] The compounds disclosed herein may also affect tissue remodeling activity by reducing 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 combinations 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 compounds may possess 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 to approximately 5% to approximately 100%, approximately 10% to approximately 100%, approximately 20% to approximately 100%, approximately 30% to approximately 100%, approximately 40% to approximately 100%, approximately 50% to approximately 100%, approximately 60% to approximately 100%, approximately 70% to approximately 100%, approximately 80% to approximately 100%, or approximately 10% to approximately 90%.

[0129] The compounds disclosed herein may affect hemostatic activity, as demonstrated by a decrease in TM (thrombomodulin) and an increase in TF (tissue factor). The compounds disclosed herein may 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 may 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 hemostatic activity that can reduce the level 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 hemostatic activity that can increase the TF level 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] Therefore, 2,4,6-tris(3,4-dihydro-2H-pyrrole-2-yl)pyridine, comprising ethanol as a carrier, can be used in methods to treat subjects suffering from vascular inflammatory diseases or conditions, Th1 type vascular inflammatory diseases or conditions, Th2 type vascular inflammatory diseases or conditions, Th1 type vascular inflammatory diseases or conditions, Th1 type vascular inflammatory diseases or conditions, Th1 type inflammation, monocyte activation response, T cell-dependent B cell proliferation, activation, and class switching in 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 and macrophage activation responses in fibrous tissues.

[0131] In some embodiments, subjects suffer from chronic inflammatory diseases, vasculitis, restenosis, allergies, asthma, ulcerative colitis, atherosclerosis, rheumatoid arthritis, metabolic diseases, organ transplant-associated reactions, psoriasis, Crohn's disease, and hematological neoplastic diseases 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.

[0132] In some embodiments, Th1-type vascular inflammatory diseases include chronic inflammatory diseases, vascular inflammation, or restenosis.

[0133] In some embodiments, Th2-type vascular inflammatory diseases or conditions include allergies, asthma, or ulcerative colitis.

[0134] In some embodiments, Th1-type chronic inflammation and / or monocyte-activated responses include atherosclerosis, restenosis, rheumatoid arthritis, or metabolic disorders.

[0135] In some aspects, vascular inflammatory diseases or conditions include organ transplant-associated reactions, rheumatoid arthritis, psoriasis, Crohn's disease, and Caused by inflammation Blood malignant disease or illness attitude include.

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

[0137] In some embodiments, Th2 type pneumonia or conditions include asthma, pulmonary fibrosis, or exacerbations of chronic obstructive pulmonary disease (COPD).

[0138] In some aspects, Th1 type pneumonia or conditions include sarcoidosis and pulmonary responses to respiratory infections.

[0139] In some embodiments, Th1-type inflammatory diseases or conditions include fibrosis, rheumatoid arthritis, dermatitis, or psoriasis.

[0140] In some embodiments, Th1-type inflammatory diseases or conditions include a Th1-type cutaneous inflammatory response to mechanical, chemical, or infectious factors.

[0141] In some embodiments, diseases or conditions associated with macrophage activation responses include atherosclerosis, restenosis, or rheumatoid arthritis.

[0142] Chronic inflammatory symptoms can be associated with a large, otherwise unrelated group of disorders that underlie a variety of diseases and disabilities. 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 cause chronic inflammatory processes include cancer, atherosclerosis, and ischemic heart disease.Non-limiting examples of diseases that present with 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), Cirrhosis, colitis, congestive heart failure, conjunctivitis, Crohn's disease, cyclophosphamide-induced cystitis, cystic fibrosis, cystitis, common cold, dacryoadenitis, dementia, dermatitis, dermatomyositis, diabetes, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic ulcer, digestive system diseases, eczema, emphysema, encephalitis, endocarditis, endometritis, enteritis, epicondylitis, epididymitis, fasciitis, fibromyalgia, fibrosis, connective tissue inflammation, gastritis, gastroenteritis, gingivitis, glomerulonephritis, glossitis, heart disease, heart valve dysfunction, hepatitis, hidradenitis suppurativa, Huntington's disease, hyperlipidemia Pancreatitis, hypertension, ileitis, infections, inflammatory bowel disease, inflammatory cardiomegaly, inflammatory neuropathy, insulin resistance, interstitial cystitis, interstitial nephritis, iritis, ischemia, ischemic heart disease, keratitis, keratoconjunctivitis, laryngitis, lupus nephritis, mastitis, mastoiditis, meningitis, metabolic syndrome (X syndrome), migraine, multiple sclerosis, myelitis, myocarditis, myositis, nephritis, non-alcoholic fatty liver disease, obesity, omphalitis, oophoritis, orchitis, osteochondritis, osteopenia, osteomyelitis, osteoporosis, osteitis, otitis media, pancreatitis, Parkinson's disease, mumps, pelvic ulcers These include symptomatic diseases, pemphigus externa, pericarditis, peritonitis, pharyngitis, phlebitis, pleurisy, pneumonia, polycystic glomerulonephritis, proctitis, prostatitis, psoriasis, pulpitis, pyelonephritis, pyelophelitis, renal failure, reperfusion injury, retinitis, rheumatic fever, rhinitis, salpingitis, sarcoidosis, sialadenitis, sinusitis, spastic colon, stenosis, stomatitis, stroke, surgical complications, synovitis, tendinitis, tendinopathy, tenosynovitis, thrombophlebitis, tonsillitis, trauma, traumatic brain injury, transplant rejection, triangular ulcer, tuberculosis, tumors, urethritis, urinary tractitis, uveitis, vaginitis, vasculitis, and vulvitis.

[0143] In one embodiment, the present disclosure relates to a method for 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 embodiment, 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; Wiscott-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 and 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.

[0145] In another embodiment, the Disclosure relates to a method for treating cancer in a subject requiring treatment, comprising administering a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein to a subject requiring treatment.

[0146] In some ways, cancer includes 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, chromophobic renal cell carcinomas, clear cell carcinomas, colon cancer,Colorectal cancer, benign fibrous histiocytoma, fibroplastic 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 lipomatous tumor, liposarcoma / malignant lipomatous tumor, liver cancer, lymphoma, lung cancer, medulloblastoma, melanoma, meningioma, multiple endocrine tumors The group consists of ulcers, multiple myeloma, myelodysplastic syndrome, neuroblastoma, neuroendocrine tumors, ovarian cancer, pancreatic cancer, papillary thyroid carcinoma, parathyroid tumors, childhood cancers, peripheral nerve sheath tumors, pheochromocytoma, pituitary tumors, prostate cancer, posterior uveal melanoma, rare hematological disorders, renal metastasis, rhabdoid tumors, 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, 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 small lymphocytic lymphoma (SLL), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma, systemic mastocytosis, or Burkitt lymphoma.

[0148] As used herein, “treatment” refers to a clinical intervention in an attempt to alter the natural course of the subject or cells being treated, which may be performed for preventive purposes or during clinicopathology. Desired therapeutic effects include prevention of disease onset or recurrence, relief of symptoms, reduction of any direct or indirect pathological consequences of the disease, slowing of the rate of disease progression, improvement or delay of the disease state, and remission or improved prognosis. In some embodiments, the onset of a disease or disorder is delayed by the use of the pharmaceutical compositions of the present invention.

[0149] As used herein, "inhibiting the growth" of tumors or cancer cells may mean slowing down the rate of growth of tumors or cancer cells, or completely stopping the growth of tumors or cancer cells.

[0150] As used herein, “tumor” refers to the growth and proliferation of all neoplastic cells (malignant or benign), as well as all precancerous and cancerous cells and tissues. The terms “cancer,” “cancerous,” “proliferative disorder,” “proliferative disorder,” and “tumor” as used herein are not mutually exclusive.

[0151] The terms "cancer" and "malignant" typically refer to or describe a physiological condition in mammals characterized by uncontrolled cell growth / proliferation. Examples of cancer include, but are not limited to, carcinomas, lymphomas (such as Hodgkin lymphoma and non-Hodgkin lymphoma), blastomas, sarcomas, and leukemias. 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 These include endometrial cancer 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 cancers.

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

[0153] compound In one embodiment, this disclosure relates to formula Ia or formula Ib shown below: [ka] [ka] This relates to compounds having the structure of , or pharmaceutically acceptable esters or solvates thereof. Here, in the above formula, X - R1 is an ion of an acid that forms a pharmaceutically acceptable salt, where 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 no, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocyclic; when R3 is N, R1 is no; when A4 is N, R3 is no; alkyl, alkenyl, alkynyl, or acyl are 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 These are, independently, hydrogen and C 1-4 Selected from alkyl; aryl or heteroaryl, whether alone or as part of a substituent, 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 These are, independently, hydrogen and C 1-4 Selected from alkyl groups.

[0154] In some embodiments, R2 and / or R4 are given by the following formula IIa or formula IIb: [ka] It has a structure such that, in the formula, X -A1, A2, R5, R6, R7, and R8 are defined as described 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 is 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 as follows: [ka] [ka] It has a structure selected from the group consisting of the following, or a pharmaceutically acceptable salt, ester, or solvate thereof.

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

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

[0163] In some embodiments, the present disclosure provides Formula IIIa or Formula IIIb shown below:

Chemical Structure

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

[0165] In some embodiments, the present disclosure relates to a compound having the structure according to Formula IVa or Formula IVb described below: [Chemical formula] 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 heterocyclic ring; alkyl, alkenyl, alkynyl, or acyl is optionally substituted with one or more substituents independently 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 heterocyclic ring; R A and R B are each independently selected from hydrogen and C 1-4 alkyl; aryl or heteroaryl, whether alone or part of a substituent group, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, alkyl, -O-alkyl, -COOH, -C(O)-C 1-4 alkyl, -C(O)O-C 1-4 alkyl, NR C R D 、-S-alkyl, -SO-alkyl, and -SO2-alkyl; R C and R D are each independently selected from hydrogen and C 1-4 alkyl.

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

[0167] In another aspect, this disclosure relates to the following formula Va or formula Vb: [ka] [ka] This relates to compounds having the structure of, or pharmaceutically acceptable esters or solvates thereof. Here, X - R1 is an ion of an acid that forms a pharmaceutically acceptable salt, where 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 no, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocyclic; when R3 is N, R1 is no; when A4 is N, R3 is no; alkyl, alkenyl, alkynyl, or acyl are 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 These are, independently, hydrogen and C 1-4 Selected from alkyl; aryl or heteroaryl, whether alone or as part of a substituent, 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 These are, independently, hydrogen and C 1-4 Selected from alkyl groups. In some embodiments, R2 and / or R4 have a structure according to formula IIa or formula IIb, where X - A1, A2, R5, R6, R7, and R8 are defined as described 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 is N. In some embodiments, R2 and R4 have a structure according to formula IIa or formula IIb.

[0168] In some embodiments, compounds with formula Va or Vb have the following structure: [ka] or having a pharmaceutically acceptable salt, ester, or solvate thereof.

[0169] In some embodiments, compounds with formula Va or Vb are as follows: [ka] [ka] It has a structure selected from the group consisting of the following, or a pharmaceutically acceptable salt, ester, or solvate thereof.

[0170] In some embodiments, the compound according to formula Va or Vb is as follows: [Chemical formula] has the structure of, or a pharmaceutically acceptable salt, ester or solvate thereof.

[0171] In some embodiments, the compound according to formula Va or Vb is as follows: [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula]​​​​​​​​​A pharmaceutical composition may include a pharmaceutically acceptable carrier that facilitates the processing of the active ingredient into a pharmaceutically acceptable composition. As used herein, the term “pharmaceutically acceptable carrier” is synonymous with “pharmaceutically acceptable carrier” and means any carrier that does not cause substantially long-term or permanent adverse effects when administered, and includes terms such as “pharmaceutically acceptable vehicle,” “stabilizer,” “diluent,” “additive,” “auxiliary,” or “excipient.” pharmaceutically acceptable carriers generally include vehicles that are safe, non-toxic, and acceptable for veterinary and human pharmaceutical use. Such carriers are generally capable of being mixed with or diluting / encapsulating the active compound and may be solid, semi-solid, or liquid agents. The active ingredient may be soluble or may be delivered as a suspension in the desired carrier or diluent. Without limiting itself, any of the following pharmaceutically acceptable carriers may be used: 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; antimicrobial and antifungal agents; isotonic and absorption retardants; or any other inert components. The choice of a pharmaceutically acceptable carrier may depend on the method of administration. Any pharmaceutically acceptable carrier is intended for use in a pharmaceutically acceptable composition unless 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 scope of those skilled in the art and are readily available from the teachings herein.

[0173] In various embodiments, the present invention provides kits for treating, preventing, reducing the severity of, and / or delaying the progression of conditions or diseases described herein in a subject. A kit is a collection of materials or components comprising at least one of the compounds disclosed herein. Thus, in some embodiments, a kit contains a composition comprising a drug delivery molecule complexed with a therapeutic compound, as described above. The exact nature of the components comprising a kit of the present invention depends on its intended purpose. In one embodiment, a kit is configured for the purpose of treating a mammalian subject in particular. In another embodiment, a kit is configured for the purpose of treating a human subject in particular. In further embodiments, a kit is configured for veterinary use to treat subjects such as domesticated animals, companion animals, and laboratory animals, but is not limited thereto. A kit may include instructions for use. Instructions for use typically include specific expressions describing the techniques to be employed when using the components of the kit to achieve the desired results. Where necessary, a kit also includes other useful components such as diluents, buffers, pharmaceutically acceptable carriers, syringes, catheters, applicators, pipettes or measuring tools, bandage materials, or other useful devices readily recognizable to those skilled in the art. The materials or components incorporated into the kit can be stored in any convenient and appropriate manner that maintains their operability and usefulness and provided to the physician. For example, components may be in a dissolved, dehydrated, or freeze-dried form and may be provided at room temperature, refrigerated, or frozen temperature. Components are typically housed in suitable packaging material(s). As used herein, “packaging material” refers to one or more physical structures used to house the contents of the kit, such as the compositions of the present invention. The packaging material is preferably constructed by known methods to provide a sterile, contaminant-free environment. As used herein, “packaging” refers to a suitable solid matrix or material, such as glass, plastic, paper, or foil, that can hold the individual components of the kit.

[0174] Compounds intended for administration to humans or other mammals should generally be of very high purity. Purity refers to the ratio of the mass of the compound after any purification steps to the total mass of the sample. Typically, the level of purity is at least about 95%, more commonly at least about 96%, about 97%, about 98%, or higher. For example, the level of purity may be about 98.5%, 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or higher.

[0175] Compounds described herein that exist in the form of multiple optical isomers (enantiomers) may be provided as a racemic mixture or by isolating one of the enantiomers, in the latter case, the purity as described above may refer to the purity of the enantiomer. This disclosure includes all possible optical isomers or enantiomers of the disclosed compounds, mixtures of such enantiomers with the pure form or racemic mixture of the enantiomers, or enantiomerically concentrated mixtures, or diastereomerically pure compounds (in the presence of one or more chiral centers), or compositions containing diastereomer mixtures in any relative proportions.

[0176] Enantiomers can be prepared or isolated, for example, by chiral synthesis from a suitable optically pure precursor, or by decomposition of a racemate (or a racemate of a salt or derivative) using chiral high-pressure liquid chromatography (HPLC). “Enantiomers” are a pair of stereoisomers that are mirror images of each other and cannot be superimposed. 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 “skelemic” mixture. “Diastereoisomers” are stereoisomers that have at least two chiral atoms or chirality axes but are not mirror images of each other. “Tautomerism” refers to a proton shift from one atom of a molecule to another atom of the same molecule. This disclosure includes tautomerisms of any compound provided herein.

[0177] "Isolated optical isomer" means a compound substantially purified from the corresponding optical isomer of the same formula. Preferably, the isolated isomer is at least about 80% by weight, more preferably at least 90% by weight, even more preferably at least 98% by weight, and most preferably at least about 99% by weight pure. The compounds of the present invention are provided in any of these degrees of enantiomer purity, for example, a racemic mixture of enantiomers (50% enantiomer purity), or 60% enantiomer purity, 70% enantiomer purity, 80% enantiomer purity, 90% enantiomer purity, 98% enantiomer purity, or 99+ enantiomer 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 to a biologically active parent drug via several chemical or enzymatic pathways.

[0180] The compounds described herein can be synthetically prepared by appropriately modifying the reagents as will be apparent to those skilled in the art without the assistance of ordinary experiments, 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).

[0181] In some embodiments, the compounds can be converted to pharmaceutically acceptable salts using techniques well known to those skilled in the art. For example, salts such as sodium and potassium salts can be prepared by treating the compounds with a suitable sodium or potassium base, such as sodium hydroxide or potassium hydroxide, respectively. Esters and ethers of the 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 may be administered orally, nasally, topically, subcutaneously, intramuscularly, intravenously, or by other methods of administration known to those skilled in the art.

[0183] Pharmaceutical compositions may optionally contain, but are not limited to, buffers, preservatives, tonicity modifiers, salts, antioxidants, osmotic pressure modifiers, physiological substances, pharmaceutical substances, bulking agents, emulsifiers, wetting agents, sweeteners or flavoring agents, and other pharmaceutically acceptable components (or pharmaceutical components). Various buffers and means for adjusting pH may be used to prepare the pharmaceutical compositions disclosed herein, insofar as the resulting preparations are pharmaceutically acceptable. Such buffers include, but are not limited to, acetate buffers, citrate buffers, phosphate buffers, neutral buffered salines, phosphate buffered salines, and borate buffers. It is understood that acids or bases may be used to adjust the pH of the composition as needed. Pharmaceutically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene. Useful preservatives include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercury acetate, phenylmercury nitrate, stabilized oxychloro compositions, and chelating agents such as DTPA or DTPA-bisamide, calcium DTPA, and CaNaDTPA-bisamide. Useful tonic modifiers for pharmaceutical compositions include, but are not limited to, salts of sodium chloride, potassium chloride, mannitol, or glycerin, and other pharmaceutically acceptable tonic modifiers. Pharmaceutical compositions can be provided as salts and 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 others. Salts tend to be more soluble in aqueous or other protic solvents than their corresponding free base forms. It is understood that these and other substances known in the field of pharmacology can be included in pharmaceutical compositions.

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

[0185] The pharmaceutical composition may contain an amount of the therapeutic compound sufficient to enable normal administration to an individual. A unit dose form may contain, for example, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of the therapeutic compound. In other embodiments, a unit dose form may contain, for example, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1,000 mg, at least 1,100 mg, at least 1,200 mg, at least 1,300 mg, at least 1,400 mg, or at least 1,500 mg of the therapeutic compound. In yet another aspect of this embodiment, the pharmaceutical compositions disclosed herein may include, 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 embodiment of this embodiment, the pharmaceutical compositions disclosed herein include, 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, and about 1 It may contain 00mg to approximately 250mg, approximately 100mg to approximately 500mg, approximately 100mg to approximately 750mg, approximately 100mg to approximately 1,000mg, approximately 100mg to approximately 1,500mg, approximately 200mg to approximately 500mg, approximately 200mg to approximately 750mg, approximately 200mg to approximately 1,000mg, approximately 200mg to approximately 1,500mg, approximately 5mg to approximately 1,500mg, approximately 5mg to approximately 1,000mg, or approximately 5mg to approximately 250mg.

[0186] The pharmaceutical compositions described herein may contain pharmaceutically acceptable solvents. A solvent is a liquid, solid, or gas that dissolves another solid, liquid, or gas (solute) to produce a solution. Useful solvents 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. Examples of pharmaceutically acceptable nonpolar solvents include, but are not limited to, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, chloroform, n-methylpyrilidone (NMP), and diethyl ether.

[0187] The preferred administration method and dosage range in specific cases 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 to a patient may be in the range of 0.0005 mg / kg to 15 mg / kg, or 0.001 mg / kg to 7.5 mg / kg. The therapeutically effective dose of the therapeutic compounds disclosed herein may generally be in the range of about 0.001 mg / kg / day to about 100 mg / kg / day. The effective dose may 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 cases, the effective dose of the therapeutic compound is approximately 0.001 mg / kg / day to 10 mg / kg / day, approximately 0.001 mg / kg / day to 15 mg / kg / day, approximately 0.001 mg / kg / day to 20 mg / kg / day, approximately 0.001 mg / kg / day to 25 mg / kg / day, approximately 0.001 mg / kg / day to 30 mg / kg / day, and approximately 0.001 mg / kg / day to 30 mg / kg / day. The dosage may range from g / day, approximately 0.001 mg / kg / day to approximately 35 mg / kg / day, approximately 0.001 mg / kg / day to approximately 40 mg / kg / day, approximately 0.001 mg / kg / day to approximately 45 mg / kg / day, approximately 0.001 mg / kg / day to approximately 50 mg / kg / day, approximately 0.001 mg / kg / day to approximately 75 mg / kg / day, or approximately 0.001 mg / kg / day to approximately 100 mg / kg / day.In other examples, the effective dose of the therapeutic compound disclosed herein may be, for example, in the range of 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] Medication can be administered as a single dose or cumulatively (continuously), and this can be easily determined by those skilled in the art. For example, treatment may consist of a single dose of an effective amount of the pharmaceutical composition disclosed herein. Alternatively, treatment may consist of multiple doses of an effective amount of the pharmaceutical composition administered over a period of time, such as once a day, twice a day, three times a day, once every few days, or once a week. The timing of administration may vary from person to person depending on factors such as the severity of individual symptoms. For example, an effective amount of the pharmaceutical composition disclosed herein may be administered to an individual once a day for an indefinite period, or until the individual no longer requires treatment. Those skilled in the art will recognize that the individual's condition can be monitored throughout the course of treatment, and that the effective amount of the pharmaceutical composition disclosed herein administered can be adjusted accordingly.

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

[0190] Liquid dosage forms for oral administration include acceptable pharmaceutical or food-grade emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may contain, for example, water or other solvents, solubilizers and emulsifiers, and inert diluents commonly used in the art, 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, as well as mixtures thereof. In addition to inert diluents, the oral composition may 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. In such solid dosage forms, the active compound is an inert and acceptable pharmaceutical or food-grade excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or bulking agents 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 It is mixed with disintegrants such as tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) dissolution moderators such as paraffin; f) absorption enhancers 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, lozenges, tablets, and pills, the dosage form may include a buffer.

[0192] Solid dosage forms of tablets, capsules, pills, and granules can be prepared using coatings or shells, such as enteric coatings and other coatings well known in the pharmaceutical technology. They may optionally contain opacifying agents and may be composed to release the active ingredient only to specific parts of the intestinal tract, or preferentially, 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] The composition may contain the compounds disclosed herein alone or in combination with other therapeutic compounds. Therapeutic compounds are compounds that provide pharmaceutically active or other direct effects in the diagnosis, treatment, relief, management, or prevention of a disease, or that affect the structure or any function of the human or animal body. Therapeutic compounds disclosed herein may be used in the form of pharmaceutically acceptable salts, solvates, or solvates of salts, e.g., hydrochloride salts. Furthermore, therapeutic compounds disclosed herein may be provided as racemates or as individual enantiomers containing R- or S-enantiomers. Thus, therapeutic compounds disclosed herein may comprise only the R-enantiomer, only the S-enantiomer, or a combination of both the R-enantiomer and the S-enantiomer. In some embodiments, the therapeutic compounds may have anti-inflammatory activity, such as nonsteroidal anti-inflammatory drugs (NSAIDs). 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, aluminoprofen, amfenac, alloxypyrine, aminophenazone, anthraphenine, aspirin, azapropazon, benolilate, benoxaprofen, benzydamine, butibufen, celecoxib, chlortenoxacin, choline salicylic acid, clometacin, dexketoprofen, diclofenac, diflunisal, emorphazon, epirizole; etodolac, etricoxib, feclobuzon, felbinac, fenbufen, fenclofenac, flurbiprofen, graphenine, hydroxyethyl salicylic acid. This includes, but is not limited to, ibuprofen, indomethacin, indoprofen, ketoprofen, ketrolac, lactylphenetidine, loxoprofen, lumiracoxib, mefenamic acid, meloxicam, metamisole, methiadic acid, mofebutazone, mofezolac, nabumetone, naproxen, nifenazone, niflumic acid, oxamethacin, phenacetin, pipebzone, pranoprofen, propifenazone, proquazone, protidic acid, lofecoxib, salicylamide, sarsalate, 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 profens. 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. Suitable propionic acid derivative NSAIDs include, but are not limited to, aluminoprofen, benoxaprofen, dexketoprofen, fenoprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, loxoprofen, naproxen, oxaprozin, pranoprofen, and suprofen. Suitable acetate derivative NSAIDs include, but are not limited to, aceclofenac, acemetacin, actarit, alcofenac, amfenac, clometacin, diclofenac, etodolac, felbinac, fenclofenac, indomethacin, ketorolac, methiadic acid, mofezolac, nabumetone, naproxen, oxamethacin, 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 cases, the compounds and compositions described herein may be administered to solids to prevent the formation of metal oxides. In other cases, the compounds may be used to prevent the formation of metal oxides in industrial applications such as surface treatments including descaling, pickling, and removal of surface deposits and corrosion products.

[0196] The description of embodiments of this disclosure is not intended to be exhaustive or to limit the disclosure to the exact form disclosed. While specific embodiments and examples of this disclosure are described herein for illustrative purposes, various equivalent modifications are possible within the scope of this disclosure, as will be recognized by those skilled in the art. For example, while the steps or functions of a method are presented in a given order, alternative embodiments may perform the functions in a different order, or the functions may be performed substantially simultaneously. The teachings of the disclosure provided herein may be applied to other procedures or methods as needed. The various embodiments described herein may be combined to provide further embodiments. The aspects of this disclosure may be modified as needed to provide further embodiments of this disclosure by adopting the composition, function, and concepts of the above-mentioned references and applications. Furthermore, considering biofunctional equivalence, several modifications may be made to the protein structure without affecting the type or amount of biological or chemical action. These and other modifications may be made to this disclosure in light of the detailed description. All such modifications are intended to be included in the appended claims.

[0197] Certain elements of any of the embodiments described above can be combined with or replaced by elements of other embodiments. Furthermore, while the advantages associated with specific embodiments of this disclosure have been described in the context of those embodiments, other embodiments may also demonstrate such advantages, and not all embodiments are required to demonstrate such advantages in order to fall within the scope of this disclosure.

[0198] definition For convenience, the meanings of some terms and phrases used herein, in the examples and in the appended claims are provided below. Unless otherwise specified or implied by the context, the following terms and phrases include the meanings provided below. The definitions are provided to aid in the description of specific embodiments and are not intended to limit the subject matter claimed, as the scope of this art is limited only by the claims. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this art belongs. In the event of any apparent conflict between the use of a term in the art and its definition provided herein, the definition provided herein shall prevail.

[0199] As used herein and in the appended claims, the singular nouns “a,” “an,” and “the” refer to multiple subjects unless the context clearly indicates otherwise. For example, a reference to “a cell” includes a combination of two or more cells, etc.

[0200] In this specification, the terms “approximately” or “about” used with respect to a value or parameter are generally interpreted to include numbers that are within the range of 5%, 10%, 15%, or 20% in either direction (greater or less) of a possible value, unless otherwise specified or made clear from the context (except when such a number is less than 0% or greater than 100%). In this specification, when a value or parameter is described as “approximately” or “about,” embodiments relating to that value or parameter are included (and described). For example, a description referring to “about X” includes a description of “X.”

[0201] As used herein, the term "or" means "and / or". In this specification, the term "and / or" as used in phrases such as "A and / or B" 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 include each of the following examples: 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, in addition to the defined elements presented, other elements may also be present. The use of “comprising” indicates inclusion, not limitation.

[0203] The term "consisting of" refers to the compositions, methods, and their respective components described herein, excluding any elements not described in the description of the embodiments.

[0204] As used herein, the term "consisting essentially of" refers to the elements required for a given embodiment. This term allows for the presence of additional elements that do not substantially affect the basic, novel, or functional features of that embodiment of the Art.

[0205] In this specification, the terms “individual,” “subject,” and “patient” are used interchangeably. In some embodiments, the patient or subject is a vertebrate. The term subject may be a human or a veterinary subject. In certain embodiments, vertebrates are mammals. For therapeutic purposes, the term “mammal” refers to any animal classified as a mammal, including humans, livestock and farm animals, as well as zoo, sport, or pet animals, such as dogs, horses, cats, and cows. In certain embodiments, mammals are humans. In certain embodiments, vertebrates are non-mammals such as birds, reptiles, or amphibians. Thus, subjects or patients may include, but are not limited to, farm animals (such as cows), laboratory animals (such as mice, rats, pigs, primates, guinea pigs, and rabbits), sport animals, livestock, or pets (such as cats, dogs, and horses). In certain embodiments, subjects or patients are humans. In some embodiments, mammals include primates, dogs, horses, cats, cows, or pigs. In some embodiments, the subject includes non-human animals. In some embodiments, the non-human animal is a bird or a reptile. In some embodiments, the non-human animal is a chicken.

[0206] Although the present invention has been described in relation to specific embodiments, those skilled in the art will understand that there are numerous variations and substitutions of the above-described systems and technologies that fall within the spirit and scope of the invention as described in the appended claims. [Examples]

[0207] Example 1: BioMAP® System The BioMAP® system was used to predict the safety, efficacy, and function of investigational drugs in human tissue and disease biology models consisting of blood vessels, skin, lungs, and inflammatory tissues.

[0208] The BioMAP® panel consists of human primary cell-based systems designed to model various aspects of the human body in vitro. The BioMAP® system is constructed using one or more primary cell types derived from healthy human donors and, upon stimulation (e.g., cytokines or growth factors), captures 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 Th1 inflammatory conditions specific to arterial smooth muscle cells (CASM3C system). Additional systems replicate aspects of systemic immune responses, 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 lung airway inflammation, while the MyoF system models myofibroblast-lung tissue remodeling. Finally, skin biology is addressed with the KF3CT system, which models Th1 skin inflammation, and the HDF3CGF system, which models wound healing. Eight subsets of these BioMAP systems have been previously used in the U.S. Environmental Protection Agency's (EPA) ToxCast® program for characterizing environmental chemicals, defining toxicity mechanisms, and developing predictive toxicity signatures.

[0209] The diseases and pathological conditions modeled by the above-described cellular systems are shown in Table 1 below. [Table 1]

[0210] Table 2 provides a further description of the markers and related BioMAP® systems mentioned above. [Table 2]

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

[0212] Using custom-designed software, including data mining tools, BioMAP® profiles can be compared against a proprietary reference database of over 4,000 BioMAP® profiles for bioactive agents (biological products, 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 mathematically identifying similar activities without bias. Specific BioMAP® activities correlate with in vivo biology, and multi-parameter BioMAP® profiles are used to distinguish compounds based on MoA and target selectivity, providing predictive signatures for in vivo toxicity outcomes across various physiological systems (e.g., vascular toxicity, developmental toxicity, etc.).

[0213] In the BioMAP® system, primary human cells are used in the early stages of subculturing (passage 4 or earlier) to minimize adaptation to cell culture conditions and maintain physiological signaling 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 into macrophages in vitro before being added to the Mphg system. The following abbreviations are used: human umbilical vein endothelial cells (HUVEC), peripheral blood mononuclear cells (PBMC), 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 systems include: Bronchial epithelial cells + (IL-1β, TNFα, and IFN)], CASM3C system [Coronary artery smooth muscle cells + (IL-1β, TNFα, IFNγ)], HDF3CGF system [HDFn + (IL-1β, TNFα, IFNγ, EGF, bFGF, PDGF-BB)], KF3CT system [Keratinocytes and HDFn + (IL-1β, TNFα, IFNγ, and TGFβ)], MyoF system [Differentiated pulmonary myofibroblasts + (TNFα, TGFβ)], and lMphg system [HUVEC and M1 macrophages + zymosan (TLR2 ligand)]. The systems are derived from either single-cell types or co-culture systems. Adherent cell types are 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 activator and low concentrations of TCR stimulation.The test drug, prepared in either DMSO (small molecule; final concentration ≤0.1%) or PBS (biologic), is added at the specified concentration one hour before stimulation and cultured for 24 hours or the time indicated separately (48 hours, MyoF system; 72 hours, BT system (soluble read); 168 hours, BT system (secreted IgG)). Each plate contains a drug control appropriate for each system (e.g., conventional control drug colchicine 1.1 μM), a negative control (e.g., non-stimulation conditions), and a vehicle control (e.g., 0.1% DMSO). Direct ELISA is used to measure biomarker levels of cell-associated targets and cell membrane targets. Soluble factors derived from the supernatant are quantified using either HTRF® detection, a bead-based multiplex immunoassay, or capture ELISA. Significant adverse effects of the test drug on cell proliferation and viability (cytotoxicity) are detected by sulforhodamine B (SRB) staining for adherent cells and by Alamar Blue® reduction for cells in suspension. In the proliferation assay, individual cell types were cultured in subconfluence and measured at optimized time points for each system (48 hours: 3C and CASM3C systems; 72 hours: BT and HDF3CGF systems; 96 hours: SAg system). Cytotoxicity of adherent cells was measured at indicated time points by SRB (24 hours: 3C, 4H, LPS, SAg, BF4T, BE3C, CASM3C, HDF3CGF, KF3CT, and lMphg systems; 48 hours: MyoF system) and Alamara Blue staining of cells in suspension (24 hours: SAg system; 42 hours: BT system).

[0214] Data analysis is performed by generating ratios by dividing the measured values ​​of the test drug by the mean values ​​of the control samples (at least six vehicle controls from the same plate), and then performing a log10 transformation. The significance prediction envelope is calculated using historical vehicle control data with a 95% confidence interval.

[0215] Biomarker activity is annotated if two or more consecutive concentrations change in the same direction relative to the vehicle control, lie outside the significance envelope, and at least one concentration has an effect size greater than 20% (|log10 ratio|>0.1). Major biomarker activity is described as modulated if these activities increase in some systems but decrease in others. Cytotoxicity is observed when total protein levels decrease by 50% or more (log10 ratio of SRB or Alamablue concentration <-0.3), indicated by a thin black arrow on the X-axis. A compound is considered to have broad cytotoxicity if cytotoxicity is detected in three or more systems. Concentrations of test agents capable of detecting broad cytotoxicity are excluded from biomarker activity annotation and downstream benchmarking, similarity searches, and cluster analysis. Antiproliferative effect is defined by an SRB or Alamablue® log10 ratio value of less than -0.1 from cells seeded at lower densities, indicated by a gray arrow on the X-axis. For cytotoxicity and antiproliferative arrows, only one concentration is required to meet the threshold indicated for profile annotation.

[0216] Example 2: Analysis of test substance 2: 2,4,6-tris(3,4-dihydro-2H-pyrrole-2-yl)pyridine As described in Example 1, a BioMAP® profile was created for 2,4,6-tris(3,4-dihydro-2H-pyrrole-2-yl)pyridine.

[0217] 2,4,6-tris(3,4-dihydro-2H-pyrrole-2-yl)pyridine was found to be non-cytotoxic at the concentrations tested in this study. 2,4,6-tris(3,4-dihydro-2H-pyrrole-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-pyrrole-2-yl)pyridine was found to affect inflammation-related activity, 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-pyrrole-2-yl)pyridine was also found to affect immunomodulatory activity, as indicated 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-pyrrole-2-yl)pyridine was found to affect tissue remodeling activity, as indicated by decreases in TIMP-1, collagen IV, PAI-1, and collagen III. 2,4,6-Tris(3,4-dihydro-2H-pyrrole-2-yl)pyridine was also found to affect hemostatic activity, as indicated by decreases in TM and increases in TF. Furthermore, 2,4,6-Tris(3,4-dihydro-2H-pyrrole-2-yl)pyridine was found to decrease LDLR.

[0219] For further details on these markers and the related BioMAP® system, please refer to Table 2.

[0220] Example 3: Analysis of test substance 3: 2,4,6-tris(3,4-dihydro-2H-pyrrole-2-yl)pyridine supported by ethanol As described in Example 1, a BioMAP® profile was generated for 2,4,6-tris(3,4-dihydro-2H-pyrrole-2-yl)pyridine supported by ethanol.

[0221] 2,4,6-tris(3,4-dihydro-2H-pyrrole-2-yl)pyridine, supported by ethanol, was found not to exhibit cytotoxicity at the concentrations tested in this study.

[0222] 2,4,6-tris(3,4-dihydro-2H-pyrrole-2-yl)pyridine containing ethanol as a carrier was found to have antiproliferative activity against 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-pyrrole-2-yl)pyridine, supported by ethanol, was found to affect inflammation-related activity 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 regulating IL-8 and sTNFα. 2,4,6-tris(3,4-dihydro-2H-pyrrole-2-yl)pyridine, supported by ethanol, was found to affect immunomodulatory activity, 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-pyrrole-2-yl)pyridine, using 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-pyrrole-2-yl)pyridine, using ethanol as a carrier, was found to affect hemostatic activity, as indicated by decreases in TM and increases in TF. 2,4,6-tris(3,4-dihydro-2H-pyrrole-2-yl)pyridine, using ethanol as a carrier, was found to decrease VEGFR2.

[0224] For further details on these markers and the related BioMAP® system, please refer to Table 2. Example 4: Synthesis of 2,4,6-tris(3,4-dihydro-2H-pyrrole-2-yl)pyridine [ka]

[0225] The synthesis of 2,4,6-tris(3,4-dihydro-2H-pyrrole-2-yl)pyridine was carried out according to the following synthesis scheme I.

number

[0226] Step 3 of the above synthesis scheme I was carried out by 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%, and 34 g of compound 4 was obtained from 38 g of compound 3. The structure of compound 4 was consistent with the standard.

[0227] Step 4 of synthesis scheme I was carried out by 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 was consistent with the standard.

[0228] Step 5 of Synthesis Scheme I was carried out using dess-martin periodinane (4.5 equivalents) and dichloromethane (DCM) at room temperature for 16 hours. This reaction yielded 8.4 g of crude compound 6, which was not purified until the next step. The structure of compound 6 was consistent with the standard.

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

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

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

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

number

[0233] Compound 6 was produced by following steps 1-5 of Synthesis Scheme II in the same manner as in Example 4.

[0234] Compound 6 from 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), yielding a main peak (500 mg, 71% purity) and a secondary peak (500 mg, 81% purity). Both purified peaks were used separately in the final reaction.

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

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

[0239] The identity of the synthesized 2,4,6-tris(3,4-dihydro-2H-pyrrole-2-yl)pyridine was confirmed using infrared (IR) spectroscopy. Figures 5-8 show the IR spectra of 2,4,6-tris(3,4-dihydro-2H-pyrrole-2-yl)pyridine from multiple synthesized lots, and Figure 9 shows a superposition of these spectra. The superposition in Figure 9 shows that the IR spectra are similar for all lots.

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

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

[0242] Figure 13 shows an image of the trisomine finally obtained from peak 1 (or primary peak) and peak 2 (or secondary 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-pyrrole-2-yl)pyridine.

[0244] Example 6: Method for treating, reversing, delaying, or preventing a target aging process. In Example 6, we demonstrated that hair loss was reduced and vitality increased in aging mice. This method involved administering a therapeutically effective dose of 2,4,6-tris(3,4-dihydro-2H-pyrrole-2-yl)pyridine to aged mice. 12-month-old mice were given 10 mg / day of 2,4,6-tris(3,4-dihydro-2H-pyrrole-2-yl)pyridine. The experiment was conducted with 20 mice. On day 10, the aging characteristics of the mice (hair loss, decreased energy, decreased vitality) were reversed, and as evidenced in Figure 14, the treated mice had abundant, thick hair, improved vitality, and were very energetic.

[0245] Therefore, this embodiment demonstrates that administration of 2,4,6-tris(3,4-dihydro-2H-pyrrole-2-yl)pyridine can treat, reverse, delay, or prevent the aging process of the target.

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

[0247] This example demonstrates that 2,4,6-tris(3,4-dihydro-2H-pyrrole-2-yl)pyridine is an effective anti-inflammatory agent that 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-pyrrole-2-yl)pyridine This example illustrates an exemplary scheme for synthesizing 2,4,6-tri(3,4-dihydro-2H-pyrrole-2-yl)pyridine / trisomine.

[0249] In this example, trisomine was synthesized using a four-step synthesis protocol shown in Synthesis Scheme III below. Trimethylpyridine was oxidized with SeO2 to obtain the 2,4,6-pyridinetricarbaldehyde intermediate. Next, 2,4,6-pyridinetricarbaldehyde was treated with S-(-)-2-methyl-2-propanesulfinamide to obtain the product of Stage 1. A Grignard reaction was carried out using Stage 1 and 2-(2-bromoethyl)-1,3-dioxolane to obtain the product of Stage 2. Stage 2 was treated with H2SO4 to obtain trisomine.

[0250] The synthesis scheme III for trisomine according to this embodiment 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 equivalents) to a solution of 2,4,6-trimethylpyridine (1.0 kg, 1.0 equivalent) in chlorobenzene (10.0 L, 10.0 vol.) while stirring at 25-30°C.

[0253] The reactants were 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 the reaction was complete, the reactants were filtered through a Celite bed, 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 obtain a brown solid. Yield: 97.3 g, 7.2%. The structure is as shown in Figure 16. 1 The purity was confirmed using 1H NMR (400 MHz, CDCl3): δ10.21 (s, 1H), δ10.20 (s, 2H), and 8.52 (s, 2H). Purity was measured using HPLC: 90.6 (% area), as shown in Figure 17 and Table 5 below.

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

[0255] Stage 1 of synthesis scheme III was performed as follows. 2,4,6-Pyridinetricarbaldehyde (120.0 g, 1.0 equivalent) and DCM (2.4 L, 20.0 vol.) were added to the reactor at 25±5°C and cooled to 0-5°C. S-(-)-2-methyl-2-propanesulfinamide (276.4 g, 3.1 equivalents) and PTSA (38.0 g, 0.3 equivalents) were added at 0°C. The reaction mixture was brought to 25±5°C and stirred at 25±5°C for 20 hours. The progress of the reaction was monitored by TLC (10% MeOH in DCM). After the reaction was complete, the reaction mixture was completely concentrated and diluted with ELISA (1.8 L, 15.0 vol.). Saturated sodium bicarbonate solution (1.2 L, 10.0 vol.) was added to the diluted substance and stirred for 10 minutes. The layers were separated, and the aqueous layer was washed with Depositphotos (360.0 mL, 3.0 vol.). The combined organic layers were washed with a 10% sodium chloride aqueous solution (1.2 L, 10.0 vol.). Charcoal (2% w / w) was added to the organic layers and slurryed at 25±5°C for 2 hours. The mixture was filtered through a Celite bed, 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. Hexane (1.2 L, 10.0 vol.) was added, 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 obtain a pale yellow solid. End of Stage 1: 238.8 g, 68.6%. 1 When the structure was confirmed using 1H NMR, it was found to be as shown in Figure 18: 1 ¹H 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 evaluated using HPLC: as shown in Figure 19 and Table 6 below, the purity was 98.9% (per area). Table 6: HPLC measurement of the purity of the Stage 1 product in synthesis scheme III: [Table 6]

[0256] Reaction in Stage 2 of Synthesis Scheme III: Under a nitrogen atmosphere, magnesium shavings (56.6 g, 11.0 equivalents) and iodine (catalyst) were added 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 equivalents) was added at 35±5°C, and the mixture was stirred for 30 minutes. To the above mixture, a solution of 2-(2-bromoethyl)-1,3-dioxolane (383.0 g, 10.0 equivalents) in dry THF (500.0 mL, 5.0 vol.) was added at 35±5°C, and the mixture was stirred at the same temperature for 2 hours. A solution of Stage 1 (100.0 g, 1.0 equivalent) in dry THF (500.0 mL, 5.0 vol.) was added over 2 hours at 35±5°C, and stirring was continued for 16 hours at 30±5°C. The reaction was monitored by TLC (10% MeOH in DCM). After the reaction was complete, the mixture was cooled to 5–10°C. The reactants were rapidly cooled below 20°C with saturated ammonium chloride aqueous solution (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 Celite bed. The layers were separated, and the aqueous layer was re-extracted twice with ethyl acetate (1.0 L, 10.0 hours). The layers were separated, the combined organic layers were concentrated, and dried under reduced pressure for 1 hour to obtain a brown syrup. This 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 1H NMR: as shown in Figure 20, 1 ¹H NMR (300 MHz, DMSO): δ7.33 (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 evaluated using HPLC, and as shown in Figure 21 and Table 7 below, the purity was 94% area (peak 1 + peak 2). Table 7: Purity of Stage 2 product in synthesis scheme III [Table 7]

[0257] The Stage 3 reaction of Synthesis Scheme III was carried out as follows: The Stage 2 product (20.0 g, 1.0 equivalent) was dissolved in DCM (100.0 mL, 5.0 vol.) at 25±5°C. The solution was cooled to 0-5°C, and 10% sulfuric acid aqueous solution (600.0 mL, 30.0 vol.) was gradually added at 0-5°C. The reactants were stirred at 0±5°C for 4 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the reactants were 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 reactants was adjusted using 20% ​​sodium hydroxide solution (40.0 mL, 2.0 vol.) to obtain a pH of approximately 12.6. The aqueous layer was extracted five times with cold DCM (200.0 mL, 10.0 vol.). The concentrated organic layers, kept below 28°C, were combined to obtain a light brown solid. Stage 3 yield: 5.9 g (82.0%). 1 When the structure was confirmed using 1H NMR, as shown in Figure 22, 1 ¹H NMR (400 MHz, CDCl3): δ7.81-7.80 (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 measured using HPLC, and as shown in Figure 23 and Table 8 below, the HPLC purity was 92.9% area (peak 1 + peak 2). Table 8: Purity of Stage 3 product (trisomin) [Table 8]

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

[0259] NIST SRD46: Using a strictly selected database of stability constants for metal complexes, Fe 2+ We obtained several affinity constants for the complex, and for this study, we used the dissociation constant pK = 6.33, or the equivalent ΔG. 0 [dien-Fe] is an iron complex of diethylenetriamine with a concentration of 36.11 kJ / mol. 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-pyrrole-2-yl)pyridine" may be referred to as "D102" in this specification, and these two terms are synonymous.

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

[0262] For each complex and its dissociation products, calculations were performed by applying different levels of approximation at 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 low-level theoretical formula that does not consider solvents, but includes several empirical corrections for HF. The resulting geometry (shape) is usually good, which is the main reason for this type of calculation. This is based on the ternary correction of HF calculations in the MINIX basis set of minimum reductions. 2. Density Functional Theory (DFT)-B3LYP def2-TZVP: This method provides a standard, good theoretical level of binding affinity, estimating accuracy within 8 kJ / mol in vacuum. It offers a good idea of ​​the process and allows verification of the shape obtained in the first step. However, solvent effects are not considered. 3. DFT-B3LYP def2-TZVP CPCM SMD: The solvent is treated as a continuous dielectric, and electrostatic effects are mainly accurate, but chemically specific solvent effects are not considered. In this model, molecules are surrounded by a polarizing medium outside the excluded volume. Therefore, the charge distribution of the solute induces an apparent polarization charge on the separation 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 in the minimum energy conformation using short fixed-temperature quantum molecular (QM) dynamics.

[0264] result In the short phase of HF-3c sampling, [2,4,6-tris(3,4-dihydro-2H-pyrrole-2-yl)pyridine-Fe 2+ ] and [diethylenetriamine-Fe 2+Both of [2,4,6-tris(3,4-dihydro-2H-pyrrole-2-yl)pyridine-Fe] were shown to have stable tridentate conformations, as shown in Figure 24. 2+ The formation of [the bond] 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, there was no noticeable change in the results by increasing the level of approximation. This was expected, as bonding parameters such as molecular structure and bond length are fairly stable to these improvements in the 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 forms an octahedral complex [Fe-6H2O]. 2+ The calculation was performed for spin states S=0, 1, and 2, and it was confirmed that hydrated iron has a high-spin configuration S=2.

[0267] Each ligand was calculated using 2, 3, and 4 explicit water molecules. In all configurations, it was found that one or two water molecules formed specific bonds with the nitrogen atom of the ligand.

[0268] The scheme for the complex formation reaction with respect to a given ligand L is as follows:

number

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

number

[0270] The free water energy for stoichiometric equilibrium was estimated from compounds with multiple explicit water content. Furthermore, the zero-point vibrational energy (ZPE) released during complex dissociation has been reported. The zero-point energy is a contribution that should be considered, as quantum systems never exist in a stationary state because their vibrational energy is minimal. This vibrational energy is released when the system dissociates, usually decreasing the dissociation energy.

[0271] From various energy components, the following diethylenetriamine complexes can be formed.

number

number

[0272] A good linear relationship was observed between energy and the number of explicit water molecules. ΔG 0 =ΔU 0 -TΔS 0 The equation TΔS 0 Even considering the terms, the complex formation energy ΔG 0 It was observed that this value was overestimated by approximately 25 kJ / mol. This discrepancy may be due to the complex interactions of water, which cannot be fully explained, and the B3LYP treatment of the high-spin state density function of iron, as this density function is primarily optimized based on a large database of ab initio and experimental data on the dissociation energies and structural geometry of organic molecules.

[0273] The complex of 2,4,6-tris(3,4-dihydro-2H-pyrrole-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-pyrrole-2-yl)pyridine is therefore far more potent than diethylenetriamine in terms of Fe 2+ It is a complexing agent for 2,4,6-tris(3,4-dihydro-2H-pyrrole-2-yl)pyridine, similar to diethylenetriamine in terms of ΔG 0 -ΔU 0 The value of TΔS is adopted; that is, TΔS 0 Taking both the calculation error μ into account, the following estimation is possible for 2,4,6-tris(3,4-dihydro-2H-pyrrole-2-yl)pyridine.

number

number

[0276] Regarding the complex formation reaction between 2,4,6-tris(3,4-dihydro-2H-pyrrole-2-yl)pyridine (D102) and Fe(OH)2, that is, the reaction scheme shown in the following equation,

number

number

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

[0278] Finally, using the maximum number of explicit water molecules reported above, we performed short-term (500 femtoseconds) QM dynamics for 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 favorable by only 93.7 kJ / mol.

number

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

number

[0281] According to this pK value, at least 10 μM of 2,4,6-tris(3,4-dihydro-2H-pyrrole-2-yl)pyridine is required for complex formation in a 1 μM Fe2+ solution. (Note) (Note 1) Formula Ia or Formula Ib shown below: [ka] [ka] A compound having the structure of, or a pharmaceutically acceptable ester or solvate thereof, wherein X -R1 is an ion of an acid that forms a pharmaceutically acceptable salt, where 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 no, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocyclic; when R3 is N, R1 is no; when A4 is N, R3 is no; and the alkyl, alkenyl, alkynyl, or acyl is 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 These are, independently, hydrogen and C 1-4 Selected from alkyl groups; the aryl or heteroaryl group may be alone or as part of a substituent, including halogens, -OH, alkyl, -O-alkyl, -COOH, and -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 These are, independently, hydrogen and C 1-4 Selected from alkyl groups, compound. (Note 2) The aforementioned R2 and / or R4 are given by the following formula IIa or formula IIb: [ka] It has a structure such that, where X - A1, A2, R5, R6, R7, and R8 are defined as above. The compounds listed in Appendix 1. (Note 3) A1 and A3 are N, A4 is C, and R3 has the structure according to formula IIa or formula IIb. The compounds listed in Appendix 1 or 2. (Note 4) A2 is C. The compounds listed in Appendix 3. (Note 5) A1 is N, and / or A3 and / or A4 is N. The compounds listed in Appendix 1 or 2. (Note 6) A2 is C. The compounds listed in Appendix 5. (Note 7) R2 and R4 have the structure according to formula IIa or formula IIb. The compounds listed in Appendix 6. (Note 8) The compound in question is as follows: [ka] [ka] [ka] A structure selected from the group consisting of, or a pharmaceutically acceptable salt, ester, or solvate thereof, The compounds listed in Appendix 1. (Note 9) The aforementioned structure: [ka] Having 2,4,6-tris(3,4-dihydro-2H-pyrrole-2-yl)pyridine or a pharmaceutically acceptable salt, ester, or solvate thereof, The compounds listed in Appendix 1. (Note 10) The compound in question is [ka] Or, not the pharmaceutically acceptable salt, ester, or solvate thereof. A compound listed in any one of the appendices 1 to 7. (Note 11) Formula IIIa or Formula IIIb shown below: [ka] A compound having the structure thereof, or a pharmaceutically acceptable ester or solvate thereof, Here, in the formula, X - R is an acid ion that forms a pharmaceutically acceptable salt, 1 , R 2 and R 3 The alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocyclic elements are independently selected from the group consisting of H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, 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 heterocycles; R A and R B These are, independently, hydrogen and C 1-4 Selected from alkyl groups; the aryl or heteroaryl may be alone or as part of a group of substituents, including halogens, -OH, alkyl, -O-alkyl, -COOH, and -C(O)-C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, NR C R D These are -S-alkyl, -SO-alkyl, and -SO2-alkyl; R C and R D These are, independently, hydrogen and C 1-4 Selected from alkyl groups, compound. (Note 12) The following structure: [ka] Having, or having a pharmaceutically acceptable salt, ester, or solvate thereof, The compounds listed in Appendix 11. (Note 13) Formula IVa or formula IVb described below: [ka] A compound having the structure of, where X - R1, R2, R3, R4, R5, R6, and R7 are ions 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 heterocyclic; the alkyl, alkenyl, alkynyl, or acyl may be 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 heterocycles; R A and R B These are, independently, hydrogen and C 1-4 Selected from alkyl groups; the aryl or heteroaryl may be alone or as part of a group of substituents, including halogens, -OH, alkyl, -O-alkyl, -COOH, and -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 These are, independently, hydrogen and C 1-4 Selected from alkyl groups, compound. (Note 14) The following structure: [ka] Having, or having a pharmaceutically acceptable salt, ester, or solvate thereof, The compounds listed in Appendix 13. (Note 15) The following formulas Va or Vb: [ka] [ka] A compound having the structure of, or a pharmaceutically acceptable ester or solvate thereof, wherein X - R1 is an ion of an acid that forms a pharmaceutically acceptable salt, where 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 no, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocyclic; when R3 is N, R1 is no; when A4 is N, R3 is no; the alkyl, alkenyl, alkynyl, or acyl may be 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 These are, independently, hydrogen and C 1-4 Selected from alkyl groups; the aryl or heteroaryl group may be alone or as part of a substituent, including halogens, -OH, alkyl, -O-alkyl, -COOH, and -C(O)-C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, NR C RD , 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 These are, independently, hydrogen and C 1-4 Selected from alkyl groups, compound. (Note 16) R2 and / or R4 have the structure according to formula IIa or formula IIb, where X - A1, A2, R5, R6, R7, and R8 are defined as above. The compounds listed in Appendix 15. (Note 17) A1 and A3 are N, A4, A5, and A6 are C, and R3 has the structure according to formula IIa or formula IIb. A compound as described in either item 15 or 16 of the appendix. (Note 18) A1 and A3 are N, A4 is C, A5 or A6 is N, and R3 has the structure according to formula IIa or formula IIb. A compound as described in either item 15 or 16 of the appendix. (Note 19) A1, A3 and A4 are N, A5 and A6 are C, and R3 has the structure according to formula IIa or formula IIb. A compound as described in either item 15 or 16 of the appendix. (Note 20) A2 is C. A compound listed in any one of the appendices 15 to 19. (Note 21) A1 is N, and / or A3 and / or A4 is N. A compound listed in any one of the appendices 15 to 20. (Note 22) R2 and R4 have the structure according to formula IIa or formula IIb. A compound listed in any one of the appendices 15 to 21. (Note 23) The compound in question is as follows: [ka] Having the structure of, or a pharmaceutically acceptable salt, ester, or solvate thereof, The compounds listed in Appendix 17. (Note 24) The compound in question is as follows: [ka] [ka] A structure selected from the group consisting of, or a pharmaceutically acceptable salt, ester, or solvate thereof, The compound described in Appendix 18. (Note 25) The compound has the following structure: [ka] or having a pharmaceutically acceptable salt, ester, or solvate thereof, The compound described in Appendix 19. (Note 26) The compound in question is as follows: [ka] [ka] [ka] A structure selected from the group consisting of, or a pharmaceutically acceptable salt, ester, or solvate thereof, The compounds listed in Appendix 15. (Note 27) A therapeutically effective amount of a compound described in any one of the appendices 1 to 26, and a pharmaceutically acceptable vehicle, Pharmaceutical composition. (Note 28) A treatment method for hyperammonemia, This includes administering to individuals in need of such a compound a pharmaceutical composition containing one of the compounds described in any one of the appendices 1 to 26. method. (Note 29) A treatment method for diseases related to chronic inflammation, This includes administering the pharmaceutical composition described in Appendix 27 to individuals who require it. method. (Note 30) A method for inhibiting the formation of metal oxides, This involves contacting a metal with an effective amount of any one of the compounds described in Appendix 1 to 26. method. (Note 31) The aforementioned metal is present in mammalian cells. The method described in Appendix 30. (Note 32) A method for treating a subject suffering from vascular inflammatory disease or condition, Th1 type vascular inflammatory disease or condition, Th2 type vascular inflammatory disease or condition, Th1 type inflammation, monocyte activation response, conditions or diseases associated with the proliferation, activation, and class switching of T cell-dependent B cells in germinal centers of secondary lymphoid organs, Th2 type pneumonia inflammatory disease or condition, Th1 type pneumonia inflammatory disease or condition, polyfibrotic disease or condition, or diseases or conditions associated with inflammation-related responses or macrophage activation responses in fibrous tissue, This includes administering a compound described in any one of the appendices 1 to 26 or a pharmaceutical composition described in appendice 27 to the target of the drug. method. (Note 33) The aforementioned subjects suffer from 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. The method described in Appendix 32. (Note 34) The aforementioned Th1 type vascular inflammatory disease includes chronic inflammatory diseases, vascular inflammation, or restenosis. The method described in Appendix 32. (Note 35) The aforementioned Th2-type vascular inflammatory diseases or conditions include allergies, asthma, or ulcerative colitis. The method described in Appendix 32. (Note 36) The aforementioned Th1-type chronic inflammation and / or monocyte-activated response includes atherosclerosis, restenosis, rheumatoid arthritis, or metabolic disorders. The method described in Appendix 32. (Note 37) The aforementioned vascular inflammatory diseases or conditions include organ transplant-associated reactions, rheumatoid arthritis, psoriasis, Crohn's disease, and inflammation causing hematological malignancies or conditions. The method described in Appendix 32. (Note 38) 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 method described in Appendix 32. (Note 39) The aforementioned Th2 type inflammatory pneumonia or condition includes asthma, pulmonary fibrosis, or exacerbations of chronic obstructive pulmonary disease (COPD). The method described in Appendix 32. (Note 40) The aforementioned Th1-type inflammatory pneumonia or condition includes sarcoidosis and the pulmonary response to respiratory infections. The method described in Appendix 32. (Note 41) The aforementioned Th1-type inflammatory diseases or conditions include fibrosis, rheumatoid arthritis, dermatitis, or psoriasis. The method described in Appendix 32. (Note 42) The aforementioned Th1-type inflammatory disease or condition includes a Th1-type skin inflammatory response to mechanical, chemical, or infectious factors. The method described in Appendix 32. (Note 43) The diseases or conditions associated with the macrophage activation response include atherosclerosis, restenosis, or rheumatoid arthritis. The method described in Appendix 32. (Note 44) A method for treating cancer in a subject requiring such treatment, comprising administering a therapeutically effective amount of a compound described in any one of Appendix 1 to 26 or a pharmaceutical composition described in Appendix 27 to a subject requiring such treatment. (Note 45) 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, 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, islet cell tumors, Kaposi's sarcoma, kidney cancers, leukemias, lipomas / benign lipomatous tumors, Selected from the group consisting of liposarcoma / malignant lipomatous tumor, 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 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. The method described in Appendix 44. (Note 46) 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), non-Hodgkin lymphoma (NHL) including Mantel cell leukemia (MCL) and small lymphocytic lymphoma (SLL), Hodgkin lymphoma, systemic mastocytosis, or Burkitt lymphoma. The method described in Appendix 44. (Note 47) A method for treating or preventing iron overload or disease, This includes administering to individuals in need of such a compound a pharmaceutical composition containing one of the compounds described in any one of the appendices 1 to 26. method. (Note 48) The aforementioned iron overload state or disease includes hemochromatosis, The method described in Appendix 47. (Note 49) 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 method described in Appendix 47. (Note 50) The aforementioned inflammatory diseases include rheumatoid arthritis, autoimmune diseases, acute infections, or atherosclerosis. The method described in Appendix 48. (Note 51) A method for preventing or reversing telomere shortening, This includes administering a pharmaceutical composition containing the compound disclosed herein to an individual in need thereof. method. (Note 52) A method for preventing or reversing telomere shortening, This includes administering to individuals in need of such a compound a pharmaceutical composition containing one of the compounds described in any one of the appendices 1 to 26. method. (Note 53) A method for reversing or preventing processes, diseases, or conditions related to aging, This includes administering a pharmaceutical composition containing any one of the compounds described in Appendix 1 to 26 to an individual in need of it. method. (Note 54) The aforementioned aging-related processes include hair loss, loss of vitality, or telomere shortening. The method described in Appendix 53. (Note 55) Administration of a pharmaceutical composition containing any one of the compounds described in Appendix 1 to 26 results in a decrease in VCAM-1 levels. The method described in Appendix 53. (Note 56) A method for reducing the VCAM-1 level, This includes administering to individuals in need of such a compound a pharmaceutical composition containing one of the compounds described in any one of the appendices 1 to 26. method. (Note 57) A method for reducing the VCAM-1 level, This includes administering to individuals in need of such a compound a pharmaceutical composition containing one of the compounds described in any one of the appendices 1 to 26. method. (Note 58) A method for treating gastrointestinal diseases or disorders, This includes administering to individuals in need of such a compound a pharmaceutical composition containing one of the compounds described in any one of the appendices 1 to 26. method. (Note 59) 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 method described in Appendix 58. (Note 60) A method for treating autoimmune diseases, This includes administering to individuals in need of such a compound a pharmaceutical composition containing one of the compounds described in any one of the appendices 1 to 26. method. (Note 61) The aforementioned 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 method described in Appendix 60. (Note 62) A method for reducing or improving the reactivity, toxicity, or biodistribution of a metal in a target area, This includes administering to individuals requiring the treatment a compound described in any one of the appendices 1 to 26 or a pharmaceutical composition described in appendice 27. method. (Note 63) The compound bonds to the metal, The method described in Appendix 62. (Note 64) The compound is bonded to the metal at two or more bonding sites. The method described in Appendix 63. (Note 65) Two or more compounds bond to the metal, The method described in any one of the appendices 63 to 64. (Note 66) The aforementioned compound bonds to the metal only under conditions such as the presence of oxidative stress. The method described in any one of the appendices 63 to 65. (Note 67) The aforementioned compound is activated by an enzyme and binds to the metal. The method described in any one of the appendices 63 to 65. (Note 68) The aforementioned compound targets organs or tissues. The method described in any one of the appendices 63 to 67. (Note 69) The compound alters the concentration or biodistribution of the metal in the subject. The method described in any one of the appendices 62 to 68. (Note 70) The aforementioned subjects are those suffering from metal overload disease or condition. The method described in any one of the appendices 62 to 69. (Note 71) The aforementioned metal overload disease or condition includes iron, copper, or zinc overload disease or condition. The method described in Appendix 70. (Note 72) The aforementioned metal is a transition metal. The method described in any one of the appendices 62 to 71. (Note 73) 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 method described in Appendix 72. (Note 74) The aforementioned metal is a trivalent metal ion, a divalent metal ion, and / or a monovalent metal ion. The method described in any one of the appendices 62 to 73. (Note 75) The subject is a human being. The method described in any one of the appendices 28 to 74. (Note 76) The subject is a mammal. The method described in any one of the appendices 28 to 74. (Note 77) The aforementioned mammals include primates, dogs, horses, cats, cattle, or pigs. The method described in Appendix 76. (Note 78) The aforementioned subjects include non-human animals, The method described in any one of the appendices 28 to 74. (Note 79) The aforementioned non-human animal is a bird or a reptile. The method described in Appendix 78.

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 symptoms, 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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