Thyroid hormone prodrugs and compositions comprising the same

Abstract

A triiodothyronine (T3) prodrug, an ionized form thereof, a salt thereof, a hydrate thereof, or any combination thereof. The T3 prodrug includes phosphoric acid ester or an ionized form of a phosphoric acid ester. Pharmaceutical compositions including a T3 prodrug and methods of administering the same. Methods of making a T3 prodrug.

Description

THYROID HORMONE PRODRUGS AND COMPOSITIONS COMPRISING THE SAMECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 649,530, filed May 20, 2024, which is incorporated herein by reference in its entirety.SUMMARY

[0002] This disclosure describes, in one aspect, a T3 (3,3’5-triiodo-L-thyronine) prodrug of the formula:an ionized form thereof, a salt thereof, a hydrate thereof, or any combination thereof. RAincludes a phosphoric acid ester or an ionized form of a phosphoric acid ester. In one or more embodiments, the T3 prodrug is a sodium salt.

[0003] In one or more embodiments, RAis -O-(PC>3H2) or an ionized form of -O-(PO3H2). In one or more embodiments, R is -O-(C(R1)(R2))-O-(PO3H2) or an ionized form of -O-(C(R1)(R2))- O-(PO3H2) wherein R1and R2 are each independently H or a Cl to C3 alkyl. In one or more embodiments, R is -O-CH2-O-(PO3H2) or an ionized form of -O-CH2-O-(PO3H2). In one or more embodiments, R is -O-(C(CH3)H)-O-(PO3H2) or an ionized form of -O-(C(CH3)H)-O-(PO3H2).In one or more embodiments, R is -O-(C(CH3)2)-O-(PO3H2) or an ionized form of -O-(C(CH3)2)- O-(PO3H2).

[0004] In one or more embodiments, the T3 prodrug is of Formula (la):an ionized form thereof, a salt thereof, hydrate thereof, or any combination thereof. In one or more embodiments, the T3 prodrug is the sodium salt of Formula (la).

[0005] In one or more embodiments, the T3 prodrug is of Formula T3P1 :T3P1

[0006] In one or more embodiments, the T3 prodrug is of Formula (lb):an ionized form thereof, a salt thereof, hydrate thereof, or any combination thereof. In one or more embodiments, the T3 prodrug is the sodium salt of Formula (Ib).In one or more embodiments, the T3 prodrug is of Formula T3P2:T3P2

[0007] In another aspect, the present disclosure describes a pharmaceutical composition that includes the prodrug of any previous aspect or embodiment and a carrier. In one or more embodiments, the pharmaceutical composition is a solid. In one or more embodiments, the pharmaceutical composition is a liquid. In one or more embodiments, the pharmaceuticalcomposition is aerosolized. In one or more embodiments, the pharmaceutical composition is nebulized.

[0008] In one or more embodiments, the carrier includes water. In one or more embodiments, the carrier includes an aqueous buffer. In one or more embodiments, the pharmaceutical composition has a pH of 2 to 11. In one or more embodiments, the pharmaceutical composition has a pH of 5.5 to 8.5. In one or more embodiments, the pharmaceutical composition has a pH of 4 to 8. In one or more embodiments, the pharmaceutical composition has a pH of 2 to 6. In one or more embodiments, the pharmaceutical composition has a pH of 3 to 6.

[0009] In another aspect, the present disclosure describes a method of administering the pharmaceutical composition of any previous aspect or embodiment to a subject. In one or more embodiments, the subject is a human.

[0010] In one or more embodiments the subject has or is at risk of having a pulmonary and / or a cardiac disease, condition, or disorder. In one or more embodiments, the subject has or is at risk of having lung inflammation, lung edema, or both. In one or more embodiments, the pharmaceutical composition is administered prior to the subject manifesting any symptom or clinical sign of a pulmonary and / or cardiac disease, condition, or disorder. In one or more embodiments, the pharmaceutical composition is administered after the subject manifesting any symptom or clinical sign of a pulmonary and / or cardiac disease, condition, or disorder.

[0011] In one or more embodiments, the pharmaceutical composition is administered directly to the pulmonary tract of the subject. In one or more embodiments, the pharmaceutical composition is administered by pulmonary instillation. In one or more embodiments, the pharmaceutical composition is administered by intratracheal instillation. In one or more embodiments, the pharmaceutical composition is administered by inhalation of an aerosolized pharmaceutical composition. In one or more embodiments, the pharmaceutical composition is administered by inhalation of an aerosolized particulate pharmaceutical composition. In one or more embodiments, the pharmaceutical composition is administered by inhalation of a nebulized pharmaceutical composition.

[0012] In another aspect, the present disclosure describes a method of making a T3 prodrug of the present disclosure.BRIEF DESCRIPTION OF DRAWINGS

[0013] FIG. 1 is a plot of T3 concentration observed after various T3 prodrugs (T3P1 and T3P2) where incubated in the presence and absence of alkaline phosphatase (Aik. Phos.).

[0014] FIG. 2 is a synthetic scheme for synthesizing the T3 prodrug T3P1 sodium salt.

[0015] FIG. 3 is a synthetic scheme for synthesizing the T3 prodrug T3P2 sodium salt.DETAILED DESCRIPTION

[0016] This disclosure describes 3,3’,5-triiodo-L-thyronine (T3) prodrugs, compositions including the same, methods of administering such compositions, and methods of making the T3 prodrugs. A T3 prodrugs may be effective for treating a pulmonary and / or a cardiac disease, disorder, or condition. For example, a T3 prodrugs may be effective for treating pulmonary edema, acute or infant respiratory distress syndrome, lung inflammation of multiple primary causes, pre- or post-lung transplantation, acute coronary syndrome or myocardial ischemia, heart failure, or any combination thereof. A T3 prodrug containing compositions may be formulated to be administered directly into the lung, whether in a liquid form or as an aerosol. For example, a T3 prodrug or composition containing the same, can be administered by lung instillation or pulmonary delivery.

[0017] Triiodothyronine (T3; 3,3',5'-triiodo-L-thyronine) and thyroxine (T4; 3, 5,3', 5'- tetraiodothyronine) are tyrosine based thyroid hormones. T4 is a less active agent and is converted to T3 in the thyroid gland pre-secretion or in peripheral body tissue cells by deiodinase enzymes. T3 affects lung development, lung function, and repair of injury to lung tissues and a variety of cardiac-related functions. Low serum concentrations of T3 are associated with a variety of thyroid disorders and low serum levels are observed in chronic and critical illness.

[0018] Clinically, thyroid disorders are associated with diverse pulmonary symptoms. Both hypothyroidism and hyperthyroidism may cause respiratory muscle weakness and / or decreased pulmonary function. Hypothyroidism reduces respiratory drive and can also cause obstructive sleep apnea or pleural effusions. Conversely, hyperthyroidism increases respiratory drive and can cause dyspnea on exertion. Either hypothyroidism or hyperthyroidism, can be associated with idiopathic primary pulmonary arterial hypertension (IPPAH). Further, treating the underlyingthyroid disorder may reverse pulmonary hypertension, although the exact mechanism involved in the pathogenesis is not established.

[0019] At the cellular level, T3 concentration affects alveolar number, the number and size of alveolar type II pneumocyte cells, and their surfactant production. T3 stimulation of alveolar fluid clearance occurs locally and rapidly in the lung. For example, T3 increases alveolar fluid clearance (AFC) in alveolar epithelial cells through augmented Na,K-ATPase activity. Active sodium resorption is involved in surfactant production, clearing pulmonary (alveolar) edema in lungs at birth, in acute lung injury (ALI), in acute respiratory distress syndrome (ARDS), and in cardiogenic edema, such as congestive heart failure. Conversely, reducing T3 levels in the lung can exacerbate alveolar edema.

[0020] In one or more embodiments, a T3 prodrug of the present disclosure or compositions including a prodrug of the present disclosure may be used to treat a pulmonary disease, disorder, or condition. In one or more embodiments, a T3 prodrug of the present disclosure or a composition including the same, may be used to treat alveolar edema, lung inflammation, pre- or post-transplantation lung transplant, lung fibrosis, or any combination thereof. Exemplary causes of lung inflammation or alveolar edema that may be treatable using the prodrugs and methods described herein include, for example, acute respiratory distress syndrome (ARDS), infant RDS (IRDS) seen with premature birth, chest trauma, acute / chronic congestive heart failure, dilated cardiomyopathies, pre- and / or post-lung transplant, pre- and / or post- lung cancer radiotherapy or chemotherapy, pneumonia, sepsis, drug and substance-induced lung diseases such as smoking (including vaping and whether tobacco or THC), exposure to pollutants (whether environmental or occupational, e.g., asbestosis, silicosis, berylliosis, Coal Worker’s, pneumoconiosis, gas exposure, thermal injury, or other pneumoconiosis), hypersensitivity pneumonitis, reactive or obstructive lung diseases (e.g., asthma, chronic bronchitis, reactive airway dysfunction syndrome, or other reactive airway diseases), aspiration chemical pneumonitis or pneumonia, pneumonia or an infection of nasosinus, intratracheal, intrabronchial or alveolar airspace (e.g., bacterial, viral, fungal), connective tissue and vasculitic diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, scleroderma, sarcoidosis, and other related diseases), Wegener’s granulomatosis, Goodpasture disease, acute or chronic eosinophilic pneumonia, medication- related lung injury (e.g., injury from use of amiodarone, bleomycin, busulfan, mitomycin C,methotrexate, apomorphine, nitrofurantoin, or other pneumotoxic drugs), cryptogenic organizing pneumonia, pulmonary hemorrhage such as exercise induced pulmonary hemorrhage, Churg- Strauss syndrome, or congenital or structural lung disease (e.g., cystic fibrosis, bronchiectasis).

[0021] Acute respiratory distress syndrome (ARDS) is characterized, at least in part, by a lack of T3 in lung tissue. The T3 deficiency results in a decreased capability of the lung to remove fluids when inflamed or in a disease state. Further, both oxygen therapy and mechanical ventilation, each of which assists sick patients to be able to breathe and have proper blood oxygen levels, can be injurious to lung tissue (e g., ventilator-associated lung injury, VALI), further compounding the ARDS lung injury. As such, the lack of T3 in lung tissue and the concomitant use of oxygen and ventilator therapy in ARDS patients create a difficult problem for clinicians to treat.

[0022] Congestive heart failure (CHF, acute and chronic) is characterized, at least in part, by a deficit of T3 in both heart and lung tissue. Patients with CHF often have inflammation and edema in the lungs. Delivering T3 directly to the lung can allow the drug to immediately and directly act on cellular pump mechanisms to remove the excess fluid buildup in the lungs. In addition, after the lung has absorbed the T3, its next delivery path is the heart, where T3 improves heart function (i.e., contractility).

[0023] Infant respiratory distress syndrome (IRDS) is characterized, at least in part, by a deficit of T3, often due to a premature birth. Incomplete gestation shortens the maternal-to-baby development cycle, such that lung development is incomplete with underdeveloped lung epithelium. The immature epithelium has deficiency in surfactant production / release and in the fluid absorption system. Fetal thyroid hormone levels normally increase shortly prior to birth and this is required for clearance of the airspace fluid in order for breathing to be effective in maintaining oxygen levels after birth. Thus, infants with IRDS often experience pulmonary edema, decreased gas exchange, and resulting hypoxemia.

[0024] Exercise induced pulmonary hemorrhage (EIPH) is characterized by blood in the airways associated with exercise. EPIH is commonly observed in horses such as racehorses but has also been observed in humans.

[0025] Other pulmonary and cardiac conditions involve T3 deficits. Myocardial infarction (MI) patients also have an acute absence of T3 in infarcted myocardium. Often these patients are intubated, enabling a direct instill approach during the most critical post-MI phase of disease.

[0026] In one or more embodiments, a pharmaceutical composition of the present disclosure may be used to treat a cardiac disease, disorder, or condition. Heart failure, acute coronary syndrome, acute valvular heart disease, Takotsubo’s Syndrome, and cardiac surgery / hemodynamics can result in decreased pumping efficiency of the heart. The force of contraction by the heart muscle (myocardium), is known as inotropy. Myocardial inotropy is influenced by the active form of T3. For example, T3 contributes to myocardial gene expression by increasing the synthesis of the intracellular mechanisms that increase inotropic contractility. Decreased cardiac T3 levels may result in decreased myocardial inotropy seen in congestive heart failure, acute coronary syndrome, and in both children and adults following cardiac surgery such as cardiac bypass, cardiac valvular replacement, and heart transplant. These conditions can result in myocardial failure due to decreased inotropy and increase in systemic vascular resistance.

[0027] T3 replacement therapy for the heart has been limited to either oral or intravenous (IV) administration. Unfortunately, in critical illness there is poor absorption due to bowel wall edema, thus, blunting / delaying the effect of T3 replacement. The IV T3 replacement, although direct and immediate, results in high serum T3 spikes, which is systemically circulated affecting all other organs and can trigger undesired side-effects (i.e., atrial arrhythmias, hypertension).

[0028] In one or more embodiments, a pharmaceutical composition of the present disclosure may be used to treat a cardiac disease, disorder, or condition such as. Examples of such disease, disorders, and conditions include acute coronary syndromes including unstable angina, myocardial ischemia, ST-segment elevation myocardial infarction (STEMI), Takotsubo’s Syndrome, and non-ST-segment elevation myocardial infarction (NSTEMI); acute valvular heart disease; heart failure including acute heart failure, chronic heart failure, dilated cardiomyopathies, decompensated chronic heart failure, left-sided heart failure, right-sided heart failure, and biventricular heart failure; or any combination. In one or more embodiments, a pharmaceutical composition of the present disclosure may be administered to a subject before, during, or after cardiac surgery, hemodynamics, or both.

[0029] Acute Coronary Syndromes (ACS, e.g., unstable angina, NSTEMI and STEMI), can cause post-ischemia myocardial damage. Even with early reperfusion (i.e., primary PCI angiography), further myocardial injury and inflammation (e.g., IL-6), can occur, resulting in cardiac remodeling and heart failure. Cardiac cell death following ACS is propagated by dysfunctional mitochondrial potassium channels, which normally provide an antioxidant and protective role to the myocardium. T3 is a regulator of this mitochondrion, providing what is termed, a T3-dependent cardioprotective action. ACS results in rapid destruction of cardiac tissue T3 concentrations due to acute expression of deiodinase type 3 (D3), which inactivates T3 creating a local hypothyroid condition. Consequently, patients with an acute decrease in cardiac tissue T3 have an increased risk of major cardiac events, including cardiogenic shock, ventricular arrhythmias, and death. Replacing cardiac T3 in ACS may be beneficial. However, previous studies administered T3 intravenously resulting atrial fibrillation, an undesirable side-effect difficult to avoid when using intravenous administration (Pantos, et al Effects of Acute Triiodothyronine Treatment in Patients with Anterior Myocardial Infarction Undergoing Primary Angioplasty: Evidence from a Pilot Randomized Clinical Trial- ThyRepair Study. Thyroid. 2022 Nov 6; 32:714-724.).

[0030] In heart failure (acute / chronic), there is altered T3 thyroid hormone metabolism. Low serum T3 represents a strong, independent predictor of poor outcomes in heart failure. Local cardiac tissue T3 is decreased due to expression of the inactivating enzyme, deiodinase type 3 which can result in an inflammatory cytokine (i.e., IL-6, TNF-alpha) increase in heart failure altering local biochemical changes driving disease progression. Thus, it is common practice among heart failure programs to screen for subclinical hypothyroidism (SCH, TSH>7 mIU / L). SCH is characterized by decreased myocardial inotropy, impaired myocardial relaxation, decreased heart rate, resulting in decreased cardiac output. As such, SCH is an independent risk factor for heart failure among older patients. Current SCH treatment is the initiation of oral thyroid replacement for chronic heart failure (CHF). In the acute setting, a clinical trial showed hemodynamic benefits of IV T3 replacement as salvage therapy after failing conventional pharmacological and mechanical support. However, to date, no thyroid replacement is currently recommended for acute heart failure, or decompensated CHF, due to the undesired atrial arrhythmias (e.g., atrial fibrillation), which can further worsen the heart failure.

[0031] In cardiac surgery (e.g., CABG, transplant), and hemodynamics (e.g., mechanical cardiac support- ECMO, IABP), T3 may play a significant role. T3 increases the sensitivity of the heart and peripheral vascular receptors to catecholamines (e.g., epinephrine, norepinephrine, dopamine), increasing both the heart rate and blood pressure. In contrast, for profound hypothyroid state, such as in myxedema coma, patients present with bradycardia and hypotension. Treating with catecholamines alone provides only transient correction, but homeostasis may be restored when the synergistic effect of thyroid hormone replacement is added. During cardiac surgery (e.g., CABG), T3 levels decline contributing to postoperative bradycardia and hypotension. In a randomized control trial, perioperative IV T3 resulted in higher heart rate and cardiac output, and lower systemic vascular resistance. As such, cardiac surgeons may give perioperative IV T3 to hasten liberation from cardiopulmonary bypass. Children after cardiac surgery are at a specific risk of developing perioperative hypothyroid state; however, no T3 replacement is recommended due risk of atrial arrhythmias. Finally, multiple clinical studies of brain-dead potential organ donors with hemodynamic instability were given IV T3, resulting in significant reduction in the total vasopressor (catecholamine) requirement, with increased viability of solid organs for transplant.

[0032] It is thought that T3 can be used to treat various pulmonary and / or cardiac diseases, disorders, or conditions by direct pulmonary administration. However, the aqueous solubility of T3 is relatively low. For example, the solubility of T3 in an aqueous solution at a physiologically relevant pH (e.g., 7.4) is about 7 micromolar. The low aqueous solubility of T3 may make developing a T3 therapy that can be delivered as an aerosol to the lungs in pharmaceutically effective amounts challenging. The solubility of T3 can be increased by formulating it with dimethyl sulfoxide (DMSO) or in an aqueous solution having a high pH, for example a pH of 10. However, T3 formulations that include DMSO or a high pH can potentially cause unwanted side effects when delivered to the lungs. The T3 prodrugs of the present disclosure may increase aqueous solubility compared to T3 when formulated in an aqueous composition at physiological relevant pH values. For example, in one or more embodiments, the T3 prodrugs of the present disclosure may have improved aqueous solubility compared to T3 when formulated in an aqueous solution at neutral pH (i.e., a pH that is ± 1.5 units from pH 7).

[0033] In one aspect, this disclosure describes T3 prodrugs. A prodrug is an inactive or less active compound that is transformed in vitro or in vivo into a more active compound capable of having a pharmacological effect. A T3 prodrug is converted to T3 in vitro or in vivo. For example, a T3 prodrug is converted to T3 within the body of a subject to which the T3 prodrug was administered. Prodrugs can be chemically activated or enzymatically activated. In one or more embodiments, the T3 prodrugs are enzymatically activated. For example, the T3 prodrug can be converted to T3 in vitro or in vivo by an enzyme.

[0034] T3 has the structure

[0035] Relative to the structure of T3, the T3 prodrugs of the present disclosure replace the hydroxyl (OH) of T3 with a chemical group that can be removed in vitro or in vivo to produce T3. The hydroxyl of T3 may be replaced by a group that includes a phosphoric acid ester (-O- (PO3H2)) or an ionized form of a phosphoric ester (e.g., (-O-(PO3H)1-) and -O-((PO3)2)) to form an enzymatically activated T3 prodrug. The ionized form of a phosphoric acid ester is a phosphate ester. As used herein, the term phosphate includes all negatively charged forms of a phosphoric acid ester including -O-(PO3H)1_and -O-((PO3)2), unless otherwise specified. Phosphoric acid esters or phosphate esters can be cleaved to reveal a hydroxyl group, for example, by an alkaline phosphatase.

[0036] A T3 prodrug may be a neutral compound or an ion, a hydrate, a solvate, a salt, or any combination thereof. In the context of compositions including a T3 prodrug that include a liquid carrier, the neutral compound, hydrate, solvate, or salt forms of a T3 prodrug may be ionized,and as such, the composition may include ions that were previously bound to the T3 prodrug via a covalent or ionic bond. Unless otherwise stated, a T3 prodrug is described as its form before formulation into a composition. Additionally, unless otherwise stated, the term “T3 prodrug” includes the prodrug provided as a neutral compound, an ionized compound, a hydrate, a solvate, a salt, or any combination thereof.

[0037] A salt of a T3 prodrug is an ionized or ionizable compound that has at least one charge that has one or more ionic bonds to an appropriate counterion. In one or more embodiments, the counterion is a cation. For example, a T3 prodrug that is acidic and has a negative charge, for example, through a phosphate ester, a carboxylate, or both, can be made into a salt through reaction with a base. In instances where a T3 prodrug is a salt, the counterion may be classified in view of the neutral form of the atom or compound or the charged form of the compound. For example, it is understood that a sodium salt of a T3 prodrug includes sodium atoms having a positive charge. The identity of a T3 prodrug salt can be expressed, for example, as “X T3 prodrug salt;” “X salt of a / the T3 prodrug;” or as “T3 prodrug X salt” where X is the neutral form of the atom or compound counterion or the charged form of the compound counterion. For example, a T3 prodrug that includes one or more sodium counterions can be called a sodium T3 prodrug salt, a sodium salt of a T3 prodrug, or a T3 prodrug sodium salt.

[0038] In one or more embodiments, a T3 prodrug is a T3 prodrug salt that includes one or more counterions. Example counterions include, but are not limited to, the cations of sodium, magnesium, calcium, lysine, lithium, meglumine, potassium, procaine, tri ethyl amine, zinc, aluminum, arginine, benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, and the ammonium ion. In one or more embodiments, a T3 prodrug is a T3 prodrug sodium salt. The number of counterions per a single T3 prodrug molecule may or may not be an integer.

[0039] In one or more embodiments, a T3 prodrug is of Formula (I):an ionized form thereof, salt thereof, a hydrate thereof, or any combination thereof. In Formula (I), RAincludes a phosphoric acid ester or an ionized form of a phosphoric acid (i.e., phosphate ester). When the phosphoric acid ester exists in an ionized form (phosphate ester), the carboxylic acid may exist in an ionized form (carboxylate), the amine may exit in an ionized form, or any combination thereof, the T3 prodrug of Formula (I) can be a salt.

[0040] The phosphoric acid ester or ionized form of the phosphoric acid ester can be directly attached to a T3 parent scaffold or can be attached to the parent scaffold through a dialkyl linker. The dialkyl linker can be, for example, a Cl, C2, or C3 linker. In one or more embodiments, the dialkyl linker is a Cl linker. In one or more embodiments, the dialkyl linker is a C2 linker. In one or more embodiments, the dialkyl linker is a C3 linker. In one or more embodiments, the dialkyl linker may be substituted with one or more C l to C3 alkyl groups.

[0041] In one or more embodiments, RAcan be -O- PChFb), -O-(C(R1)(R2))-O-(PO3H2), or an ionized form thereof. R1and R2are each independently H or a Cl to C3 alkyl. In one or more embodiments, R1and R2are H. In one or more embodiments, R1and R2are -CH3. In one or more embodiments, R1is -CH3 and R2is H. In one or more embodiments R can be -O-(CH2)-O- (PO3H2), -O-(C(CH3)H)-O-(PO3H2), -O-(C(CH3)2)-O-(PO3H2), or an ionized form thereof. The ionized form of -O-(PC>3H2) and -O-(C(R1)(R2))-O-(PO3H2) include monohydrate phosphate esters and dihydrate phosphate esters. For example, the ionized forms of -O- PChFb) include -O- (PO3H) and -O-(PO3)2-. The ionized forms of -O-(C(R1)(R2))-O-(PO3H2) include -O- (C(R1)(R2))-O-(PO3H)- and -O-(C(R1)(R2))-O-(PO3)2'. The ionized forms of -O-(PO3H2) and -O- (C(R1)(R2))-O-(PO3H2) may include an ionic bond to one or more counterions.

[0042] In one or more embodiments, a T3 prodrug is of Formula (la):an ionized form thereof, a salt thereof, hydrate thereof, or any combination thereof. In one or more embodiments, a T3 prodrug is the sodium salt of Formula (la).

[0043] In one or more embodiments, a T3 prodrug is of Formula T3P1 :T3P1

[0044] In embodiment of T3P1, there can be between 0 and 3 Na atoms, including nonintegers.

[0045] In one or more embodiments, a T3 prodrug is of Formula (lb):an ionized form thereof, a salt thereof, hydrate thereof, or any combination thereof. In one or more embodiments, a T3 prodrug is the sodium salt of Formula (lb).

[0046] In one or more embodiments, a T3 prodrug is of Formula T3P2:

[0047] In embodiment of T3P2, there can be between 0 and three Na atoms, including nonintegers.

[0048] T3 prodrugs T3P1 and T3P2 have improved aqueous solubility compared to T3.Table 1 shows the solubility of T3, T3P1, and T3P2 in an aqueous solution of phosphate bufferedsaline a pH of 7.4. T3P1 and T3P2 are at least 35 times more soluble than T3 in the conditions tested.Table 1: Aqueous solubility of T3 and T3 prodrugs

[0049] T3 prodrugs T3P1 and T3P2 can be converted to T3 in vitro by alkaline phosphatase. For example, incubation of T3P1 and T3P2 with alkaline phosphatase resulted in the production of T3 (FIG. 1; see the Example for experimental conditions). In contrast, control T3P1 and T3P2 samples incubated without alkaline phosphates showed no conversion to T3 (FIG. 1).

[0050] T3 prodrugs T3P1 and T3P2 can be converted to T3 in vivo. Prodrugs T3P1 and T3P2 were administered intravenously to Sprague-Dawley rats and blood samples were collected at various time points after administration. T3 content in plasma samples, as determined by liquid chromatography mass spectrometry, indicates that both T3P1 and T3P2 prodrugs are converted to T3 in vivo. Conversion appears to be more efficient for T3P2 than T3P1.

[0051] The T3 prodrugs described herein may have different in vivo properties than T3. For example, the T3 prodrugs may have a different in vivo half-life and / or biodistribution than T3. For example, the T3 prodrugs may less readily diffuse into the circulatory system as compared to T3.

[0052] In another aspect, the present disclosure describes compositions comprising a T3 prodrug described herein. The composition may be a pharmaceutical composition. The pharmaceutical composition may be administered to a subject in need thereof.

[0053] The pharmaceutical composition including a T3 prodrug may be formulated with any suitable pharmaceutically acceptable carrier. As used herein, the term “carrier” includes any solvent, dispersion medium, vehicle, diluent, carrier solution, suspension, colloid, and the like. The use of such media and / or agents is well known in the art. Except insofar as any conventionalmedia or agent is incompatible with the T3 prodrug, its use in pharmaceutical composition is contemplated.

[0054] In one or more embodiments, a carrier includes water. In one or more embodiments, a carrier is a buffered aqueous solution, that is, the solution includes one or more agents that allow the solution to resist change in pH when exposed to certain amounts of acid and / or base. A buffered aqueous solution includes at least one weak acid and its conjugate base or at least one weak base and its conjugate acid. The weak acid and its conjugate base or the weak base and its conjugate acid are derived from buffering agents that are weak acids, weak bases, or salts thereof. As such, in one or more embodiments, a pharmaceutical composition comprises one or more buffering agents and the ions thereof. Buffering agents are salts of weak acids and / or salts of weak bases. Examples of buffering agents include, but are not limited to, acetic acid or salts thereof (e.g., acetate salts); monosodium and / or disodium phosphate or other phosphate salts; maleic acid or salts thereof (e.g., maleate salts); citric acid or salts thereof (e.g., citrate salts); histidine or salts thereof (e.g., histidine sodium salt); tartaric acid or salts thereof (e.g., tartrate salts); lactic acid or salts thereof (e.g., lactate salts); succinic acid or salts thereof (e.g., succinate salts); gluconic acid or salts thereof (e.g., gluconate salts); fumaric acid or salts thereof (e.g., fumarate salts); carbonic acid or salts thereof (e.g., bicarbonate salts), tromethamine and salts thereof; and phthalic acid and salts thereof (e.g., hydrogen phthalate salts).

[0055] In one or more embodiments, a pharmaceutical composition may include one or more salts that are not buffering agents. Example salts include, but are not limited to, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and sodium hydroxide.

[0056] The conventional T3 liquid formulation is FDA-approved for clinical use to treat myxedema coma / precoma by intravenous administration directly into the bloodstream. The conventional formulation is not pH adjusted because intravenous administration to the bloodstream causes the T3 to be rapidly diluted and buffered by the buffering capacity of serum proteins and other blood components. When the conventional T3 formulation is administered directly into the lung, its concentration is not diluted immediately and the degree of buffering capacity of the lung, both tracheobronchial tree and alveolar lining fluids, is uncertain. Thus, instilling or inhaling T3 into the airway and lung directly from the manufacturer’s vial (i.e., without adjusting the pH) may be toxic to the mucosa and airspaces.

[0057] A pharmaceutical composition may be at a pH of 2 to 13. A pharmaceutical composition may be at a pH of 2 to 11. In embodiment, a pharmaceutical composition may be at a pH of 2 or greater, 3 or greater, 4 or greater, 5.5 or greater, 6 or greater, 6.5 or greater, 7 or greater, 7.5 or greater, 8 or greater, 8.5 or greater, 9 or greater, 10 or greater, 11 or greater, or 12 or greater. In embodiment, a pharmaceutical composition may be at a pH of 13 or less, 12 or less, 11 or less, 10 or less, 9 or less, 8.5 or less, 8 or less, 7.5 or less, 7 or less, 6.5 or less, 6 or less, 5.5 or less 5 or less, 4 or less, or 3 or less. In one or more embodiments, a pharmaceutical composition may be at a pH that falls within a range having endpoints defined by any minimum pH value listed above and any maximum pH value listed above that is greater than the minimum pH value. Thus, for example, a pharmaceutical composition may be at a pH of 4 to 11, such as, for example, 4 to 10 or 5 to 9. In one or more embodiments, a pharmaceutical composition has a pH of 3 to 10. In one or more embodiments, a pharmaceutical composition has a pH of 3 to 8. In one or more embodiments, a pharmaceutical composition has a pH of 3 to 7. In one or more embodiments, a pharmaceutical composition has a pH of 2 to 6. In one or more embodiments, a pharmaceutical composition has a pH of 3 to 6. In one or more embodiments, a pharmaceutical composition has a pH of 4 to 8. In one or more embodiments, a pharmaceutical composition has a pH of 4 to 6. In one or more embodiments, a pharmaceutical composition has a pH of 4 to 7. In one or more embodiments, a pharmaceutical composition has a pH of 4.5 to 8. In one or more embodiments, a pharmaceutical composition has a pH of 4.5 to 7.5.

[0058] In one or more embodiments, a pharmaceutical composition may be at a neutral pH. As used herein, the term “neutral pH” refers to a pH that is pH 7.0 + 1.5 (i.e., a pH of 5.5 to 8.5). In one or more embodiments, a pharmaceutical composition may have a minimum pH of 5.5 or greater, 6.0 or greater, 6.5 or greater, 7.0 or greater, 7.5 or greater, or 8.0 or greater. In one or more embodiments, a pharmaceutical composition may have a maximum pH of 8.5 or less, 8.0 or less, 7.5 or less, 7.0 or less, 6.5 or less, or 6.0 or less. In one or more embodiments, a pharmaceutical composition may have a pH that falls within a range having endpoints defined by any minimum pH and any maximum pH that is greater than the minimum pH. Thus, for example, a pharmaceutical composition may have a pH from 5.5 to 8.5, such as, for example, a pH of 5.5 to 7.0, a pH of 6.0 to 8.0, a pH of 6.0 to7.0, or a pH of 6.5 to 7.5.

[0059] Various acids and / or bases may be used to adjust the pH of a pharmaceutical composition. In the case that the pH of a pharmaceutical composition is adjusted using an acid and / or base or salt thereof, the pharmaceutical composition includes the ions of the acid and / or base or salt thereof used to adjust the pH. Examples of acids and / or bases that may be used to adjust the pH of the pharmaceutical composition include, but are not limited to, strong acids and / or strong bases or salts thereof, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, strontium hydroxide, barium hydroxide, calcium hydroxide, cesium hydroxide, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, chloric acid, hydrobromic acid, hydroiodic acid; or weak acids and / or weak basis or salts thereof such as those described relative to the buffering agents herein.

[0060] In one or more embodiments, a carrier may include saline. In one or more embodiments, a carrier includes normal saline that includes about 0.9% (w / v) sodium chloride. In one or more embodiments, a carrier includes saline that includes from about 0.2% (w / v) to about 0.9 (w / v) sodium chloride, for example, from about 0.2% (w / v) to about 0.6 (w / v) or 0.2% (w / v) to about 0.4% (w / v) sodium chloride.

[0061] In one or more embodiments, a carrier includes dextrose. In one or more embodiments, a carrier includes from about 1% (w / v) to about 5% (w / v) dextrose. For example, in one or more embodiments, a carrier includes about 1% (w / v) to about 4 % (w / v) or about 2% (w / v) to about 5% (w / v) dextrose. In one or more embodiments, a carrier includes about 5% (w / v) dextrose.

[0062] In one or more embodiments, a carrier includes both sodium chloride and dextrose. In one or more embodiments, a carrier includes half-normal saline which includes about 0.45% (w / v) sodium chloride and about 5% (w / v) dextrose. In one or more embodiments, a carrier includes quarter-normal saline which includes about 0.22% (w / v) sodium chloride and about 5% (w / v) dextrose.

[0063] A pharmaceutical composition may be formulated in a variety of forms adapted for delivery to the nasosinus, intratracheal, intrabronchial, or alveolar space. A pharmaceutical composition can be administered to a mucosal surface, such as by administration to, for example, respiratory mucosa (e.g., by spray, aerosol, nebulization, instillation, inhalation of aerosol or particulates). As such, a pharmaceutical composition may be sprayed, aerosolized, or nebulized.A pharmaceutical composition also can be administered via a sustained or delayed release. Sustained or delayed release may be accomplished through conventional, general technologies for sustained or delayed drug delivery. As such, sustained release also may be accomplished by combining the T3 prodrug with a second drug that inhibits a mechanism that degrades or clears T3 from the lung.

[0064] A pharmaceutical composition may include a second pharmaceutically active drug in addition to a T3 prodrug. An example of a second pharmaceutically active drug that may be included is an iodothyronine deiodinase type-III (D3) inhibitor (D3). D3 inactivates T3 and T4. Inhibiting D3 to limit its ability to inactivate T3 can increase the local concentration (or increase the T3 ratio), potency, and / or duration of action of T3, for example, produced from a T3 prodrug. Exemplary D3 inhibitors include, but are not limited to; iopanoic acid (IOP); iopanoate; ipodate; propylthiourea (PTU); propylthiouracil; 6-propylthiouracil; propranolol; D-propranolol; dexamethasone; cortisol; a glucocorticoid; amiodarone; desethlaminodarone (DEA); dronedarone (Dron); (3’),4’,4,6-(tetra)trihydroxyaurone; PBENZ-dibromomaleic anhydride (PBENZ-DBRMD); ITYR-dibromomaleic anhydride (ITYR-DBRMD); insulin; 3',5'-cyclic adenosine monophosphate; butyrate; phenolphthalein dyes (e.g., chlorophenol red, thymol blue; cresol red; bromocresol purple; 2-bromophenol, 2-iodophenol) or environmental halogenated chemicals (e.g., a hydroxylated PCB, a hydroxylated PBDE, an agrichemical, an antiparasitic, a pharmaceutical, or a food colorant).

[0065] A pharmaceutical composition may include one or more excipients. Exemplary suitable excipients include, but are not limited to, dextrose and ammonium hydroxide. A pharmaceutical composition may further include one or more additives including such as, for example, an adjuvant, a colorant, a fragrance, a flavoring, and the like.

[0066] A formulation may be conveniently presented in unit dosage form and may be prepared by methods well known in the art of pharmacy. Methods of preparing a composition with a pharmaceutically acceptable carrier include the step of bringing a T3 prodrug into association with a carrier and one or more accessory ingredients (if included). In general, a formulation may be prepared by uniformly and / or intimately bringing the active compound into association with a liquid carrier, a finely divided solid carrier, or both. A pharmaceutical composition may be provided in any suitable form including, but not limited to, a solution, asuspension, an emulsion, a spray, an aerosol, or any form of mixture. For example, A formulation may be configured for direct delivery to the lungs such as, for example, as an aerosol, a non-aerosol spray, a solution, a liquid suspension, and the like. An aerosol may be a solid or a liquid.

[0067] In one or more embodiments, a pharmaceutical composition is formulated as a solid. A solid may be administered as a non-liquid aerosol. For example, a pharmaceutical composition can be formulated as an inhalable dry powder.

[0068] In one or more embodiments, a pharmaceutical composition is formulated as a liquid. A liquid may be administered as a solution, as an aerosol, as a non-spray aerosol, liquid suspension.

[0069] In another aspect, the present disclosure describes a method of administering a pharmaceutical composition of the present disclosure to a subject. The subject can be a human or a non-human animal such as, for example, a livestock animal, a laboratory animal, or a companion animal. Exemplary non-human animal subjects include, but are not limited to, animals that are hominid (including, for example chimpanzees, gorillas, or orangutans), bovine (including, for instance, cattle), caprine (including, for instance, goats), ovine (including, for instance, sheep), porcine (including, for instance, swine), equine (including, for instance, horses), members of the family Cervidae (including, for instance, deer, elk, moose, caribou, or reindeer), members of the family Bison (including, for instance, bison), feline (including, for example, domesticated cats, tigers, lions, etc.), canine (including, for example, domesticated dogs, wolves, etc.), avian (including, for example, turkeys, chickens, ducks, geese, etc.), a rodent (including, for example, mice, rats, etc.), a member of the family Leporidae (including, for example, rabbits or hares), members of the family Mustelidae (including, for example ferrets), or member of the order Chiroptera (including, for example, bats).

[0070] The subject can be a human or a non-human animal such as, for example, a livestock animal, a laboratory animal, or a companion animal. The subject may have or is at risk of having a pulmonary and / or cardiac disease, disorder, or condition. The subject may have or is at risk of having, for example, any pulmonary and / or cardiac disease, disorder, or condition described herein. As such, in one or more embodiments, the method comprises administering a pharmaceutical composition to a subject to treat a pulmonary disease, disorder, or condition. Inone or more embodiments, a pharmaceutical composition may be administered to treat a subject that has or is at risk of lung inflammation or pulmonary edema such as alveolar edema. In one or more embodiments, the method comprises administering a pharmaceutical composition to a subject to treat a cardiac disease, disorder, or condition. In one or more embodiments, a pharmaceutical composition may be administered to treat a subject before, during, or after cardiac surgery, hemodynamic treatment, or both.

[0071] In one or more embodiments, the subject has or at risk of having exercise induced pulmonary hemorrhage (EIPH). For example, the subject may be a horse that has or is at risk of having EIPH.

[0072] “Treat” or variations thereof refer to reducing, limiting progression, ameliorating, or resolving, to any extent, the symptoms or signs related to a condition. A “treatment” may be therapeutic or prophylactic. “Therapeutic” and variations thereof refer to a treatment that ameliorates one or more existing symptoms or clinical signs associated with a condition. “Prophylactic” and variations thereof refer to a treatment that limits, to any extent, the development and / or appearance of a symptom or clinical sign of a condition. Generally, a “therapeutic” treatment is initiated after the condition manifests in a subject, while “prophylactic” treatment is initiated before a condition manifests in a subject.

[0073] Treating a pulmonary and / or cardiac condition can be prophylactic or, alternatively, can be initiated after the subject exhibits the onset of a pulmonary and / or cardiac condition or the associated symptoms or clinical signs of a condition. Treatment that is prophylactic — e.g., initiated before a subject experiences an event (e.g., cancer radiotherapy) or manifests a symptom or clinical sign of the condition (e.g., while an infection remains subclinical) — is referred to herein as treatment of a subject that is “at risk” of having the condition. As used herein, the term “at risk” refers to a subject that may or may not actually possess the described risk. Thus, for example, a subject “at risk” of infectious condition is a subject present in an area where other individuals have been identified as having the infectious condition and / or is likely to be exposed to the infectious agent even if the subject has not yet manifested any detectable indication of infection by the microbe and regardless of whether the subject may harbor a subclinical amount of the microbe. As another example, a subject “at risk” of a non-infectiouscondition is a subject possessing one or more risk factors associated with the condition such as, for example, genetic predisposition, ancestry, age, sex, geographical location, or medical history.

[0074] Accordingly, a pharmaceutical composition can be administered before, during, or after the subject first exhibits a pulmonary condition (e.g., pulmonary edema, lung inflammation) and / or a cardiac condition, or other symptom or clinical sign of associated conditions or, in the case of infectious conditions, before, during, or after the subject first comes in contact with the infectious agent. Treatment initiated before the subject first exhibits a symptom or clinical sign clinical sign of a condition may result in decreasing the likelihood that the subject experiences clinical consequences compared to a subject to whom the composition is not administered, decreasing the severity and / or completely resolving the lung and / or cardiac abnormality.Treatment initiated after the subject first exhibits clinical manifestations may result in decreasing the severity and / or complete resolution of pulmonary edema and / or lung inflammation experienced by the subject compared to a subject to whom the composition is not administered. Treatment initiated after the subject first exhibits clinical manifestations may result in decreasing the severity and / or complete resolution of the cardiac condition experienced by the subject compared to a subject to whom the composition is not administered.

[0075] For example, hyperoxic injury to rats in vivo and to alveolar type II cells in vitro is decreased when T3 is given in advance of or coincident with injurious hyperoxic exposure. In vitro, alveolar type II cell death was significantly reduced. In vivo, lung inflammation, lung injury, neutrophil infiltration and protein leakage into the alveolar space were significantly reduced.

[0076] Thus, the method includes administering an effective amount of a composition to a subject having, or at risk of having, a particular condition such as, for example, a pulmonary and / or cardiac disease, disorder, or condition. In this aspect, an “effective amount” is an amount effective to reduce, limit progression, ameliorate, or resolve, to any extent, the particular condition. For example, an “effective amount’ of a T3 prodrug pharmaceutical composition may increase alveolar fluid clearance, increase surfactant production, increase the population of alveolar type II pneumocytes, increase the size of alveolar type II pneumocytes, increase Na,K- ATPase activity in alveolar epithelial cells, decrease or repair alveolar damage, decrease hypoxemia, and / or decrease in inflammation throughout the respiratory tract (e.g., nasosinus,intratracheal, intrabronchial and alveolar airspace ). Accordingly, a composition can be administered before, during, or after the subject first exhibits a symptom or clinical sign of the condition or, in the case of infectious conditions, before, during, or after the subject first comes in contact with the infectious agent.

[0077] In one or more embodiments, the method includes identifying a subject that has a pulmonary and / or cardiac disease, disorder, or condition. A subject that has a pulmonary and / or a cardiac disease, disorder, or condition, may display one or more symptoms or clinical signs associated with a pulmonary and / or cardiac disease, disorder, or condition; may have a genetic signature associated with a pulmonary and / or cardiac disease, disorder, or condition; or both. A subject that has a pulmonary and / or cardiac disease, disorder, or condition may have low levels of serum T3 or T3 in the blood.

[0078] Identification of a subject having a pulmonary and / or cardiac disease, disorder, or condition may include diagnosing the subject with a pulmonary and / or cardiac disease, disorder, or condition. Diagnosis of a pulmonary and / or cardiac disease, disorder, or condition may be by way of a physician or other health care provider conducting tests and exams to identify a cause for symptoms displayed by a subject.

[0079] A pharmaceutical composition may be administered through any suitable route. Example routes of administration include enteral administration and parenteral administration. Enteral administration includes oral administration of tablets, capsules, or liquids. Parenteral administration includes intravenous infusions and injections.

[0080] In one or more embodiments, a pharmaceutical composition that includes a T3 prodrug is administered directly to the pulmonary tract of the subject; that is, direct pulmonary tract administration is used introduce the pharmaceutical composition to the subject.

[0081] As used herein, the terms 'directly to the pulmonary track" and “direct pulmonary tract administration” refer to local delivery of a pharmaceutical composition first to the tissues and / or cavities of the pulmonary tract. It is understood that following local delivery to the tissues of the pulmonary tract, an active ingredient can enter the circulatory system. Direct pulmonary tract administration can include depositing an active ingredient or a composition including the same on a mucosal surface, such as a respiratory mucosa (e.g., by spray, aerosol, nebulization,instillation, inhalation of aerosol or particulates). Direct pulmonary tract administration can include depositing an active ingredient or composition including the same directly within the nasosinus, intratracheal, intrabronchial, or alveolar space. Routes of direct pulmonary administration include, but are not limited to, pulmonary installation, inhalation, nebulization, or any combination thereof. Pulmonary administration may include invasive mechanical ventilation or non-invasive mechanical ventilation (BIPAP, CPAP, AV APS, BiLevel; Helmet ventilation or negative pressure ventilation). Pulmonary administration may include methods of oxygen delivery (e.g., Heated-High-Flow Nasal Cannula, High-Flow Nasal Cannula, Nasal Cannula) or ambient air.

[0082] For some pulmonary disease, disorder, or condition, direct pulmonary administration of a therapeutic may allow for a more effective treatment than systemic administration of the same therapeutic. Systemic administration, in some cases, may not achieve effective concentrations of therapeutics in the pulmonary tract due in part to systemic clearance mechanisms. Direct pulmonary administration may avoid, mitigate, or circumvent one or more systemic clearance mechanisms. Various blood-pulmonary system barriers may hinder a therapeutic from penetrating into the lungs or reaching portions of the pulmonary tract at a therapeutically relevant concentration when systemically administered. Additionally, direct pulmonary administration may result in fewer side effects than systemic administration of a therapeutic because direct pulmonary tract administration provides local delivery of the therapeutic to the location to be treated.

[0083] For some cardiac diseases, disorders, or conditions, direct pulmonary administration of a therapeutic may allow for a more effective treatment than systemic administration of the same therapeutic. Following direct pulmonary administration, the therapeutic can diffuse into the circulatory system where it interacts with heart tissue. In contrast to intravenous administration of a therapeutic to treat a heart disease, disorder, or condition, direct pulmonary administration may avoid high serum T3 spikes commonly associated with intravenous administration of T3 therapeutics.

[0084] In one or more embodiments, a pharmaceutical composition is directly delivered to the pulmonary tract via pulmonary tract instillation. Pulmonary tract installation is the administration of a liquid pharmaceutical composition to a tissue or cavity of the pulmonarytract. Pulmonary tract installation is typically accomplished in the lower respiratory tract. For example, pulmonary tract instillation includes intratracheal instillation and intrabronchial instillation.

[0085] In one or more embodiments, a pharmaceutical composition is directly delivered to the pulmonary tract by inhalation. Administration by inhalation includes inhalation by a subject of a sprayed, aerosolized, nebulized, pharmaceutical composition. Administration by inhalation may be facilitated by an inhaler device such as a metered dose inhaler, dry powder inhaler, soft- mist inhaler, or nebulizer. Administration by inhalation may be facilitated by heated high flow via a nasal cannula.

[0086] The amount of a T3 prodrug administered can vary depending on various factors including, but not limited to, the weight, physical condition, and / or age of the subject; the particular clinical signs or symptoms exhibited by the subject; the type or cause of lung inflammation or pulmonary edema; and / or the method of administration. Thus, the absolute amount of a T3 prodrug included in a given unit dosage form can vary widely, and depends upon factors such as the species, age, weight and physical condition of the subject, and / or the method of administration. Accordingly, it is not practical to set forth generally the amount that constitutes an amount of T3 prodrug effective for all possible applications. The physiologically active T3 concentration at the cellular level has been determined and varies depending upon the cell type and the specific hormonal target effect. Dosing of a T3 prodrug can be designed to achieve either physiologic or pharmacologic local tissue T3 levels. Those of ordinary skill in the art, however, can determine the appropriate amount with due consideration of such factors.

[0087] For example, a T3 prodrug may be administered to treat pulmonary edema or lung inflammation at the same T3 equivalent dose and frequency for which T3 has already received regulatory approval. In other cases, a T3 prodrug may be administered for treating alveolar edema or lung inflammation at the same dose and frequency at which the T3 prodrug is being evaluated in clinical or preclinical studies. One can alter the dosages and / or frequency as needed to achieve a desired level of T3 prodrug and / or T3 formed from the T3 prodrug. Thus, one can use standard / known dosing regimens and / or customize dosing as needed.

[0088] The primary active form of T3 — i.e., the form in which it has the greatest physiological activity — is when the T3 is “free” — e.g., not bound to large proteins such asalbumin. Therefore, the physiologic effect of a given amount of T3 may be influenced by the proteins and other aspects of the environment that it is introduced into. Thus, a smaller amount of a T3 prodrug may be required to achieve an effective T3 prodrug delivered dose for the direct pulmonary administration methods herein than the dose of T3 drug receiving regulatory approval from treating other conditions by intravenous delivery.

[0089] In one or more embodiments, the method can include administering sufficient T3 to provide a deposited dose of, for example, from about 0.5 pg to about 5.0 mg to the subject, although in one or more embodiments the methods may be performed by administering T3 prodrug in a dose outside this range. In one or more of these embodiments, the method includes administering sufficient T3 to provide a deposited dose of from about 5 pg to about 200 pg to the subject. On a pg / kg basis, the calculated administered T3 dose to achieve physiologic effects could range from as low as 2 ng / kg to 1 mg / kg. As one example, a 50 pg dose can provide a pg / kg dosage range of from about 0.03 pg / kg (to a 160 kg person) to as high as 25 pg / kg (to a 2 kg preterm infant). In many instances, however, dosing on a pg / kg basis is less relevant since direct instillation to lung tissue is not as subject to systemic dilution as, for example, intravenous administration. Lung size in adults does not vary significantly with weight, so mass of T3 delivered is often the more relevant measure of an appropriate dose.

[0090] As used herein, the term “deposited dose” or “lung-delivered” dose refers to the amount of T3 prodrug deposited to the surface of the respiratory tract. For instillation, the deposited dose is essentially the full dose being instilled. In an aerosol or nebulized formulation, however, the deposited dose is conventionally 10% or less of the drug being aerosolized or nebulized. 90% of the drug is expected to be lost in the delivery apparatus and / or exhaled. This may be greater in the injured ARDS lung. Thus, one may aerosolize or nebulize 500 pg of T3 prodrug to achieve an aerosolized or nebulized deposited dose of 50 pg. The use the term “deposited dose” or “lung-delivered” dose normalizes the dose across different routes of administration.

[0091] A sufficient deposited dose or lung-delivered dose can provide delivery of a minimum amount of T3 prodrug of 5 ng or greater such as, for example, 100 ng or greater, 1 pg or greater, 10 pg or greater, 50 pg or greater, 100 pg or greater, 250 pg or greater, 500 pg orgreater, 1 mg or greater, 1 .5 mg or greater, 2 mg or greater, 5 mg or greater, 10 mg or greater, 15 mg or greater, 20 mg or greater, or at least 25 or greater.

[0092] A sufficient deposited dose or lung-delivered dose can provide delivery of a maximum amount of T3 prodrug of 50 mg or less such as, for example, 30 mg or less, 20 mg or less, 15 mg or less, 10 mg or less, 5 mg or less, 4 mg or less, 3 mg or less, 2 mg or less, 1.5 mg or less, 1 mg or less, 500 pg of less, 300 pg or less, 200 pg or less, 100 pg or less, 50 pg or less, 30 pg or less, 20 pg, or less or 10 pg or less. A sufficient deposited dose or lung-delivered dose also can be characterized by any range that includes, as endpoints, any combination of a minimum deposited dose or lung-delivered dose and any maximum deposited dose or lung- delivered dose that is greater than the minimum deposited dose or lung-delivered dose. For example, in one or more embodiments, the deposited dose or lung-delivered dose can be from 1 pg to 2 mg such as, for example, from 5 pg to 50 pg.

[0093] In one or more embodiments where administration is done via lung instillation, the volume of a pharmaceutical composition delivered may be from 0.02 mL / g or wet lung weight per dose to 2 mL / g wet lung weight per dose. In one or more embodiments, a pharmaceutical composition delivered to the pulmonary tract may have a maximum volume of 2 mL / g wet lung weight per dose or less, 1.75 mL / g wet lung weight per dose or less, 1.5 mL / g wet lung weight per dose or less, 1.25 mL / g wet lung weight per dose, 1.0 mL / g wet lung weight per dose or less, 0.8 mL / g wet lung weight per dose or less, 0.6 mL / g wet lung weight per dose or less, 0.4 mL / g wet lung weight per dose or less, 0.2 mL / g wet lung weight per dose or less, 0.08 mL / g wet lung weight per dose or less, 0.06 mL / g wet lung weight per dose or less, or 0.04 mL / g wet lung weight per dose. In one or more embodiments, a pharmaceutical composition delivered to the pulmonary tract may have a minimum volume of 0.02 mL / g wet lung weight per dose or greater, 0.04 mL / g wet lung weight per dose or greater, 0.06 mL / g wet lung weight per dose or greater, 0.08 mL / g wet lung weight per dose or greater, 0.2 mL / g wet lung weight per dose or greater, 0.4 mL / g wet lung weight per dose or greater, 0.6 mL / g wet lung weight per dose or greater, 0.8 mL / g wet lung weight per dose or greater, 1.0 mL / g wet lung weight per dose or greater, 1.25 mL / g wet lung weight per dose or greater, 1.5 mL / g wet lung weight per dose or greater, or 1.75 mL / g wet lung weight per dose or greater. The maximum volume per wet lung weight per dose can be characterized by any range that includes, as endpoints, any combination of a minimumwet lung weight per dose and any maximum wet lung weight per dose that is greater than the minimum wet lung weight per dose. For example, in one or more embodiments, the volume of a liquid pharmaceutical composition delivered by lung instillation can be from 0.02 mL / g or wet lung weight per dose to 2 mL / g or wet lung weight per dose, for example, from 0.1 mL / g or wet lung weight per dose to 1 mL / g or wet lung weight per dose or 0.1 mL / g or wet lung weight per dose to 0.5 mL / g or wet lung weight per dose.

[0094] In one or more embodiments, a T3 prodrug may be administered, for example, from a single dose to multiple doses per day, although in one or more embodiments the method can be performed by administering a T3 prodrug at a frequency outside this range. When multiple doses are used within a certain period, the amount of each dose may be the same or different. For example, a dose of 50 pg in a day may be administered as a single dose of 50 pg, two 25 pg doses, or in multiple unequal doses. Also, when multiple doses are used within a certain period, the interval between doses may be the same or be different. In certain embodiments, a T3 prodrug may be administered from about once per day, four times per day, or continuously.

[0095] In one or more embodiments, a T3 prodrug may be administered, for example, from a single dose to a duration of multiple days, although in one or more embodiments the method can be performed by administering a T3 prodrug for a period outside this range. In certain embodiments, a T3 prodrug may be administered once, over a period of three days, or over a period of seven days. In certain embodiments, a T3 prodrug may be administered from about once per day, four times per day, or continuously. Usually, thyroid hormone replacement for human clinical hypothyroidism is given daily with either thyroxine T4 or combination T4 and T3. A recent study using a single oral dose of 50 micrograms of liothyronine resulted in peak serum concentration at 2.5 hours with a mean half-life of 22.5 hours. There was a lag between the peak serum concentration and the physiologic effect of increased heart rate at five hours. (Jonklaas et al., Ther Drug Monit. 37(1): 110-118, 2015). For acute severe human illness with myxedema coma, there is a wide recommended frequency of intravenous T3 administration, from every four hours to every 12-24 hours. Thus, in one or more embodiments, T3 prodrug may be administered once daily by intratracheal instillation at escalating doses with frequent physiologic measurement of hemodynamic parameters and less frequently extravascular lung water (EVLW).

[0096] In another aspect, the present disclosure describes methods of making T3 prodrugs of Formula (I). The method includes installing the RAgroup Formula (I) on a protected T3 starting material. A protected T3 starting material may includes a carboxylic acid protecting group and an amine protecting group. The protecting groups prevent undesirable cross reactions and / or degradation of the chemical moiety they are protecting. A protected T3 starting material may be of Formula (II)where PG2is an amine protecting group and PG1is a carboxylic acid protecting group.

[0097] The protecting groups (PG1and PG2) can be chosen such that they are stable under the RAgroup instillation reaction conditions. The protecting groups may or may not be orthogonal. Orthogonal protecting groups are removable under different conditions. The protecting groups may be base liable; that is, removable under basic conditions. Removal of an amine protecting group results in an amine or a charge form thereof. Example amine protecting groups include acyl, trifluoroacyl, triphenylmethyl, benzyl, benzyloxycarbonyl, 9- fluorenylmethyloxycarbonyl (Fmoc), and t-butyloxycarbonyl (Boc). In one or more embodiments, PG2is trifluoroacyl (-C(O)CF3). Removal of a carboxylic acid protecting group results in a carboxylic acid or carboxylate. Carboxylic acid protecting groups include esters, for example, methyl esters.

[0098] In one or more embodiments, installing the RAgroup includes reacting a T3 protected starting material with one or more reagents in one or more reactions to form an intermediate that includes the RAgroup. In one or more embodiments where two or more reactions are used, the intermediate following each reaction may or may not be isolated prior to the next reaction.

[0099] In one or more embodiments, where the method is being used to synthesize the T3 prodrug of Formula (I) where RAis -O-(POsH2) or an ionized form thereof (the T3 prodrug of Formula (la)), installing the RAgroup includes directly reacting the T3 protected starting material with a phosphorylation agent. A phosphorylation agent installs a phosphoric acid ester or phosphate. Examples of phosphorylation agents include phosphoryl chloride (POCI3), monohydrogen phosphate, and dihydrogen monophosphate. In one or more embodiments where the method is being used to synthesize the T3 prodrug of Formula (la), the phosphorylation agent includes POCI3.

[0100] In one or more embodiments, where the method is being used to synthesize the T3 prodrug of Formula I where RAis -O-(CH2)-O-(PO.3H2) or an ionized form thereof (T3 prodrug of Formula (lb), installing the RAgroup includes one or more reactions prior to the phosphorylation reaction. For example, the T3 protected starting material may be reacted with one or more reagents in one or more reactions to install a -OCH2-J group at the location of the hydroxyl on the starting material. J is a reactive handle capable of reacting with a phosphorylation reagent to result in the -O-CH2-O-(PO3H2) group or an ionized form thereof. Example J reactive handles include halogens. In one or more embodiments, the T3 protected starting material is reacted with one or more reagents to install a -OCH2-Q group. Q is a group that can be reacted with another reagent to result in the -OCH2-J. In one or more embodiments Q is -S-CH3.

[0101] Following installation of the RAgroup, the method includes removing the protecting groups (PG1and PG2) to form the T3 prodrug of Formula (I), or a salt thereof. Removing the protecting groups may be done using various deprotecting agents. The identity of the deprotecting agent depends at least in part on the identity of the protecting group to be deprotected. Example deprotecting agents include inorganic bases, inorganic acids, organic acids, organic bases, or any combination thereof. In one or more embodiments, the deprotecting agent includes an inorganic base such as an inorganic hydroxide (e g., sodium hydroxide, potassium hydroxide, and calcium hydroxide). PG1and PG2may be removed in a single reaction or in two separate reactions.

[0102] Any of the reactions described in the method may be carried out in a reaction solution. The components of a reaction solution may differ depending on the reaction takingplace. A reaction solution includes the reactants of the reaction and a solvent. The solvent may be any suitable solvent for the reaction taking place. Each reaction may independently include, for example, pyridine, tetrahydrofuran, di chloromethane, ethyl acetate, water, methyl ether ketone, acetonitrile, or the like as a reaction solvent. The reaction solution may further include additives such as a catalyst, acids, bases, or the like

[0103] Any of the reactions described in the method may be carried out under various conditions. The reaction conditions of each reaction may depend on the type of reaction. Each reaction may independently include one or more of the following reaction conditions, elevated temperature, mechanical stirring, use of molecular sieves, under pressure, under vacuum, under an inert atmosphere, or any other condition configured to increase the efficiency and / or yield of the reaction.

[0104] The progress of any of the reactions may be monitored using well known methods such as thin layer chromatography.

[0105] The reactions may be allowed to proceed to completion or for length of time. The length of each reaction may depend on the type of reaction. Each reaction may have a reaction time that is, for example, 0.25 hours or greater, 0.5 hours or greater, 1 hour or more, 2 hours or more, 3 hours or more, 4 hours or more, 5 hours or more, 10 hours of more, 15 hours or more, or 20 hours or more. The first reaction time may be, for example, 24 hours less, 20 hours or less, 15 hours or less, 10 hours or less, 5 hours or less, 4 hours or less, 3 hours or less, 2 hours or less, 1 hour or less, or 0.5 hours or less.

[0106] In one or more embodiments the method further includes purifying the T3 prodrug, or a salt thereof. The T3 prodrug of Formula (I), or salt thereof, can be purified using known methods such as, for example, chromatography including high performance liquid chromatography. In cases where a particular salt form of the T3 prodrug of Formula (I) is desired, the method can further include performing a salt exchange. Salt exchange techniques are known and include, for example, ion exchange chromatography.

[0107] In an exemplary embodiment, the T3 prodrug T3P1 sodium salt can be synthesized according to the scheme shown in FIG. 2. Briefly, T3 protected starting material 1 can be reacted with the phosphorylation agent POCh in pyridine to install the -OPO3H2 group resulting inintermediate 2. The T3 protected starting material 1 includes a trifluoroacyl amine protecting group (e.g., PG2in the T3 protected starting material of Formula II is -C(O)CF3) and a methyl ester carboxylic acid protecting group (e.g., PG1in the T3 protected starting material of Formula II is -CH3). The intermediate 2 can be isolated. Next, the protecting groups can be removed. Removal of the protecting groups can be accomplished in a deprotection reaction solution that includes water, sodium hydroxide as the deprotection agent, and the intermediate 2. Following deprotection, the deprotection solution can be acidified by HC1 to form a solid product. The crude solid can be purified using high performance liquid chromatography to afford a T3P1 as an ammonium salt. Ion exchange may be used to prepare a T3P1 sodium salt.

[0108] In an exemplary embodiment, the T3 prodrug T3P2 sodium salt can be synthesized according to the scheme shown in FIG. 3. Briefly, T3 protected starting material 1 can be reacted with chloromethyl sulfide to install a -CH2-SCH3 group resulting in intermediate 3. The first reaction can be carried out in a reaction solution that includes the starting material 1, chloromethyl sulfide, tetrahydrofuran (THF), tetra-n-butylammonium iodide (TBAI), and potassium carbonate (K2CO3). Intermediate 3 can be isolated. In a second reaction, intermediate 3 can be reacted with sulfuryl chloride in dichloromethane to give intermediate 4. Intermediate 4 can be isolated. In a third reaction, intermediate 4 can be reacted with the phosphorylation agent H3PO4 to install the phosphoric acid group. Following phosphorylation, the protecting groups can be removed. Removal of the protecting groups can be accomplished in a deprotection reaction solution that includes water, sodium hydroxide as the deprotection agent, and the phosphorylation reaction product. Following deprotection, the deprotection solution can be acidified by HC1 to form a solid product. The crude solid can be purified using high performance liquid chromatography to afford T3P2 as an ammonium salt. Ion exchange may be used to prepare a T3P2 sodium salt.

[0109] In the preceding description and following claims, the term “and / or” means one or all of the listed elements or a combination of any two or more of the listed elements; the terms “comprises,” “comprising,” and variations thereof are to be construed as open ended — i.e., additional elements or steps are optional and may or may not be present; unless otherwise specified, “a,” “an,” “the,” and “at least one” are used interchangeably and mean one or morethan one; and the recitations of numerical ranges by endpoints include all numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).

[0110] As used herein, the word “exemplary” means to serve as an illustrative example and should not be construed as preferred or advantageous over other embodiments.[OH l] As used herein, the terms “preferred” and “preferably” refer to embodiments of the invention that may afford certain benefits under certain circumstances. However, other embodiments may also be preferred under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful and is not intended to exclude other embodiments from the scope of the invention.

[0112] As used herein, “have,” “has,” “having,” “include,” “includes,” “including,” “comprise,” “comprises,” “comprising” or the like are used in their open-ended inclusive sense, and generally mean “include, but not limited to,” “includes, but not limited to,” or “including, but not limited to.” Further, wherever embodiments are described herein with the language “have,” “has,” “having,” “include,” “includes,” “including,” “comprise,” “comprises,” “comprising” and the like, otherwise analogous embodiments described in terms of “consisting of’ and / or “consisting essentially of’ are also provided. The term “consisting of’ means including, and limited to, that which follows the phrase “consisting of.” That is, “consisting of’ indicates that the listed elements are required or mandatory, and that no other elements may be present. The term “consisting essentially of’ indicates that any elements listed after the phrase are included, and that other elements than those listed may be included provided that those elements do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements.

[0113] In the preceding description, particular embodiments may be described in isolation for clarity. Reference throughout this specification to “one embodiment,” “an embodiment,” “certain embodiments,” “one or more embodiments,” or “some embodiments,” etc., means that a particular feature, configuration, composition, or characteristic described in connection with the embodiment is included in at least one embodiment of the disclosure. Thus, the appearances of such phrases in various places throughout this specification are not necessarily referring to the same embodiment of the disclosure. Furthermore, the particular features, configurations, compositions, or characteristics may be combined in any suitable manner in one or moreembodiments. Thus, features described in the context of one embodiment may be combined with features described in the context of a different embodiment except where the features are necessarily mutually exclusive.

[0114] In several places throughout the above description, guidance is provided through lists of examples, which examples can be used in various combinations. In each instance, the recited list serves only as a representative group and should not be interpreted as an exclusive list.

[0115] For any method disclosed herein that includes discrete steps, the steps may be performed in any feasible order. And, as appropriate, any combination of two or more steps may be performed simultaneously.EXEMPLARY EMBODIMENTS

[0116] The following is a non-limiting list of exemplary embodiments.

[0117] Embodiment 1 is a T3 prodrug of the formulaan ionized form thereof, a salt thereof, a hydrate thereof, or any combination thereof; where RAcomprises a phosphoric acid ester or an ionized form of a phosphoric acid ester.

[0118] Embodiment 2 is the T3 prodrug of Embodiment 1, where RAis -O-(PO3H2) or an ionized form thereof.

[0119] Embodiment 3 is the T3 prodrug of Embodiment 1, where RAis -O-(C(R1)(R2))-O- (PO3H2) or an ionized form thereof wherein R1and R2are each independently H or a Cl to C3 alkyl.

[0120] Embodiment 4 is the T3 prodrug of Embodiment 3, where RAis -O-CFE-CHPChFE) or an ionized form thereof.

[0121] Embodiment 5 is the T3 prodrug of Embodiment 3, where RAis -O(C(CH3)H)-O- (PO3H2) or an ionized form thereof.

[0122] Embodiment 6 is the T3 prodrug of Embodiment 3, where RAis -O(C(CH3)H)-O- (PO3H2) or an ionized form thereof.

[0123] Embodiment 7 is the T3 prodrug of any of Embodiments 1 to 6, where the T3 prodrug is a sodium salt.

[0124] Embodiment 8 is the T3 prodrug of Embodiment 1, where the T3 prodrug is of Formula (la):

[0125] (la), an ionized form thereof, a salt thereof, hydrate thereof, or any combination thereof.

[0126] Embodiment 9 is the T3 prodrug of Embodiment 8, where the T3 product is a sodium salt.

[0127] Embodiment 10 is the T3 prodrug of Embodiment 1, where the T3 prodrug is of Formula T3P1 :T3P1

[0128] Embodiment 11 is the T3 prodrug of Embodiment 1, where the T3 prodrug is of Formula (lb):an ionized form thereof, a salt thereof, hydrate thereof, or any combination thereof.

[0129] Embodiment 12 is the T3 prodrug of Embodiment 11, wherein the T3 prodrug is a sodium salt.

[0130] Embodiment 13 is the T3 prodrug of Embodiment 1, where the T3 prodrug is ofFormula T3P2:T3P2

[0131] Embodiment 14 is a pharmaceutical composition that includes the prodrug of any of Embodiments 1 to 13.

[0132] Embodiment 15 is the pharmaceutical composition of Embodiment 14, where the pharmaceutical composition further includes a carrier.

[0133] Embodiment 16 is the pharmaceutical composition of any of Embodiments 14 or 15, where the pharmaceutical composition is a solid.

[0134] Embodiment 17 is the pharmaceutical composition of any of Embodiments 14 or 15, where the pharmaceutical composition is a liquid.

[0135] Embodiment 18 is the pharmaceutical composition of any of Embodiments 14, 15, or 17, where the carrier comprises an aqueous buffer.

[0136] Embodiment 19 is the pharmaceutical composition of any of Embodiments 14, 15, 17 or 18, where the pharmaceutical composition has a pH of 2 to 11.

[0137] Embodiment 20A is the pharmaceutical composition of any of Embodiments 14, 15, 17, 18, or 19, where the pharmaceutical composition has a pH of 5.5 to 8.5.

[0138] Embodiment 20B is the pharmaceutical composition of any of Embodiments 14, 15, 17, 18, or 19, where the pharmaceutical composition has a pH of 3 to 8.

[0139] Embodiment 20C is the pharmaceutical composition of any of Embodiments 14, 15, 17, 18, or 19, where the pharmaceutical composition has a pH of 4 to 7.5.

[0140] Embodiment 21 is the pharmaceutical composition of any of Embodiments 14 to 20C, where the pharmaceutical composition is aerosolized.

[0141] Embodiment 22 is the pharmaceutical composition of any of Embodiments 14 to 20C, where the pharmaceutical composition is nebulized.

[0142] Embodiment 23 is a method that includes administering the pharmaceutical composition of any of Embodiment 14 to 22 to a subject.

[0143] Embodiment 24 is the method of Embodiment 23, wherein the subject is a human.

[0144] Embodiment 25 is the method of any of Embodiments 23 or 24, where the subject has or is at risk of having lung inflammation.

[0145] Embodiment 26 is the method of Embodiments 25, where the pharmaceutical composition is administered prior to the subject manifesting any symptom or clinical sign of lung inflammation.

[0146] Embodiment 27 is the method of Embodiments 25, where the pharmaceutical composition is administered after the subject manifesting any symptom or clinical sign of lung inflammation.

[0147] Embodiment 28 is the method of any of Embodiments 23 to 27, where the lung inflammation is a symptom or clinical sign of acute respiratory distress syndrome (ARDS).

[0148] Embodiment 29 is the method of any of Embodiments 23 to 28, where the lung inflammation is a symptom or clinical sign of premature birth, chest trauma, acute / chronic congestive heart failure, dilated cardiomyopathies, pre- and / or post-lung transplant, pre- and / or post- lung cancer radiotherapy or chemotherapy, pneumonia, sepsis, drug and substance-induced lung diseases such as smoking (including vaping and whether tobacco or THC), exposure to pollutants (whether environmental or occupational, e.g., asbestosis, silicosis, berylliosis, Coal Worker’s, pneumoconiosis, gas exposure, thermal injury, or other pneumoconiosis), hypersensitivity pneumonitis, reactive or obstructive lung diseases (e.g., asthma, chronic bronchitis, reactive airway dysfunction syndrome, or other reactive airway diseases), aspiration chemical pneumonitis or pneumonia, pneumonia or an infection of nasosinus, intratracheal, intrabronchial or alveolar airspace (e.g., bacterial, viral, fungal), connective tissue and vasculiticdiseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, scleroderma, sarcoidosis, and other related diseases), Wegener’s granulomatosis, Goodpasture disease, acute or chronic eosinophilic pneumonia, medication-related lung injury (e.g., injury from use of amiodarone, bleomycin, busulfan, mitomycin C, methotrexate, apomorphine, nitrofurantoin, or other pneumotoxic drugs), cryptogenic organizing pneumonia, pulmonary hemorrhage such as exercise induced pulmonary hemorrhage, Churg-Strauss syndrome, or congenital or structural lung disease (e.g., cystic fibrosis, bronchiectasis).

[0149] Embodiment 30 is the method of any of Embodiments 23 to 29, where the subject has or is at risk of having pulmonary edema.

[0150] Embodiment 31 is the method of Embodiment 30, where the pharmaceutical composition is administered prior to the subject manifesting any symptom or clinical sign of pulmonary edema

[0151] Embodiment 32 is the method of Embodiment 30, where the pharmaceutical composition is administered after the subject manifesting any symptom or clinical sign of pulmonary edema.

[0152] Embodiment 33 is the method of any of Embodiments 31 or 32, where the pulmonary edema is a symptom or clinical sign of acute respiratory distress syndrome (ARDS).

[0153] Embodiment 34 is the method of any of Embodiments 31 to 33, where the pulmonary edema is a symptom or clinical sign of premature birth, chest trauma, congestive heart failure, lung transplant, lung cancer radiotherapy, lung cancer chemotherapy, smoking, exposure to a pollutant, hypersensitivity pneumonitis, a reactive / obstructive lung disease, aspiration chemical pneumonitis / pneumonia, pneumonia, an infection of the nasosinus, intratracheal, intrabronchial or alveolar airspace, a connective tissue disease, Wegener’s granulomatosis, Good pasture disease, acute eosinophilic pneumonia, chronic eosinophilic pneumonia, medication-related lung injury, cryptogenic organizing pneumonia, Churg-Strauss syndrome , congenital lung disease, or structural lung disease.

[0154] Embodiment 35 is the method of any of Embodiments 23 or 34, where the subject has or is at risk of having a cardiac disease.

[0155] Embodiment 36 is the method of Embodiments 35, where the cardiac disease is an acute coronary syndrome or heart failure.

[0156] Embodiment 37 is the method of Embodiments 36, where the acute coronary syndrome is unstable angina, ST-segment elevation myocardial infarction (STEMI), or non-ST- segment elevation myocardial infarction (NSTEMI).

[0157] Embodiment 38 is the method of Embodiments 36, where the heart failure acute coronary syndromes including unstable angina, myocardial ischemia, ST-segment elevation myocardial infarction (STEMI), Takotsubo’s Syndreom, and non-ST-segment elevation myocardial infarction (NSTEMI); acute valvular heart disease; heart failure including acute heart failure, chronic heart failure, dilated cardiomyopathies, decompensated chronic heart failure, leftsided heart failure, right-sided heart failure, and biventricular heart failure; or any combination.

[0158] Embodiment 39 is the method of any of Embodiments 23 to 38, where the pharmaceutical composition is administered before, during, or after the subject has cardiac surgery, a hemodynamic treatment, or both.

[0159] Embodiment 40 is the method of any of Embodiments 23 to 39, where the pharmaceutical composition is administered directly to the pulmonary tract of the subject.

[0160] Embodiment 41 is the method of any of Embodiments 23 to 40, where the pharmaceutical composition is administered by pulmonary instillation.

[0161] Embodiment 42 is the method of any of Embodiments 23 to 40, wherein the pharmaceutical composition is administered by intratracheal instillation.

[0162] Embodiment 43 is the method of any of Embodiments 23 to 40, wherein the pharmaceutical composition is administered by inhalation of an aerosolized pharmaceutical composition.

[0163] Embodiment 44 is the method of any of Embodiments 23 to 40, where the pharmaceutical composition is administered by inhalation of a nebulized pharmaceutical composition.

[0164] Embodiment 45 is a method of making the T3 product of any of Embodiments 1 to13, the method including

[0165] installing the RAgroup at the hydroxyl position on a T3 protected starting material, the T3 protected starting material of the structure:

[0166] wherein PG2is an amine protecting group and PG1is a carboxylic acid protecting group; and

[0167] removing the amine protecting group and the carboxylic acid protecting group to result in the T3 prodrug.

[0168] Embodiment 46 the method of Embodiment 45, where PG2is trifluoroacyl (- C(O)CF3).

[0169] Embodiment 47 the method of Embodiment 45 or 46, where PG1is methyl (-CH3).

[0170] Embodiment 48 the method of any of Embodiments 45 to 47, where installing the RAgroup -O-(PO3H2) or an ionized form thereof includes reacting the T3 protected starting material with a phosphorylation agent.

[0171] Embodiment 49 the method of Embodiments 48, where the phosphorylation reagent includes POC13.

[0172] Embodiment 50 the method of any of Embodiments 45 to 49, where installing the RAgroup -O-(CH2)-O-(POSH2) or an ionized form thereof includes reacting the T3 protected starting material with one or more reagents in one or more reactions to install a -OCH2-J group at the hydroxyl position of the T3 starting material, where J is a reactive handle capable of reacting with a phosphorylation reagent to install a phosphoric acid ester or an ionized from thereof.

[0173] Embodiment 51 is the method of Embodiment 50, where J is a halogen.EXAMPLE

[0174] The present invention is illustrated by the following examples. It is to be understood that the particular examples, materials, amounts, and procedures are to be interpreted broadly in accordance with the scope and spirit of the invention as set forth herein.In vitro T3 prodrug conversion to T3 Test

[0175] T3 (1 pg), and the prodrugs T3P1 and T3P2 (1 pg equivalent of T3), were incubated with alkaline phosphatase (0.1 U / ml) for 15 minutes at room temperature (n =3 wells each). Samples were frozen at -80 °C until analyzed for T3 content. T3 content was determined by liquid chromatography mass spectrometry.Synthesis of T3P1 ((5)-2-amino-3-(3,5-diiodo-4-(3-iodo-4- (phosphonatooxy)phenoxy)phenyl)propanoate) sodium salt

[0176] T3P1 sodium salt was synthesized according to the scheme shown in FIG. 2. Specifically, to a solution of methyl (S)-3-(3,5-diiodo-4-(3-iodo-4- ((methylthio)methoxy)phenoxy)phenyl)-2-(2,2,2-trifluoroacetamido)propanoate (compound 1 in FIG. 2, 501.4 mg, 0.659 mmol) in methyl ethyl ketone (11 mL) was added pyridine (0.300 mL, 3.72 mmol) followed by POCI3 (0.250 mL, 2.69 mmol). After stirring for 3 hours, the solution was decanted from some white solid and added to 1 molar (M) HC1. The mixture was then diluted with brine (100 mL) and extracted with ethyl acetate (EtOAc: 3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to afford 689.2 mg of a purple foam.

[0177] To the resulting residue, 1 M NaOH (15 mL) was added. The reaction mixture was stirred for 3 hours, then acidified with 2 M HC1 and then cooled to 4 °C for 1 hour. The resulting solid was collected by filtration. The crude material was purified by HPLC (5% acetonitrile (ACN) / 10 mM ammonium bicarbonate buffer to 100% ACN, Cis column) to yield, after lyophilization, the desired product as an ammonium salt.

[0178] To prepare the sodium salt, a 1 cm wide column was fdled with 15 cm of DOWEX 50W2 (50-100 mesh, strongly acidic) ion exchange resin. The column was prepared by sequentially washing with ACN / water (1 :3), 1 M aqueous NaHCCh (gas evolution), and then finally ACN / water (1 :3). The reaction product was dissolved and loaded onto the column, which was eluted with ACN / water (1 :3). The product containing fractions were lyophilized to furnish sodium (A)-2-amino-3 -(3 , 5-diiodo-4-(3 -iodo-4-(phosphonatooxy )phenoxy)phenyl)propanoate (T3P1) as a white solid (144.3 mg, 27% yield).

[0179] The product was characterized by!H NMR,13C NMR, and mass spectrometry. 'H NMR, (400 MHz, D2O) 5: 7.81 (s, 2H), 7.28 (d, J= 9.0 Hz, 1H), 7.16 (d, J= 3.0 Hz, 1H), 6.86 (dd, J= 9.0, 3.0 Hz, 1H), 3.89 (dd, J= 8.1, 5.2 Hz, 1H), 3.16 (dd, J= 14.6, 5.2 Hz, 1H), 2.97 (dd, J = 14.8, 8.1 Hz, 1H).13C NMR (100 MHz, D2O) 8: 173.3, 152.6, 151.4, 148.7 (d, J= 5.9 Hz), 141.1, 136.8, 125.0, 120.4, 116.7, 90.8, 90.0 (d, ,7= 7.3 Hz), 55.6, 34.7. The product was further characterized by LC / MS (ESI): m / z calculated for C15H14I3NO7P (M+H+) 731.8, found 731.8.Synthesis of T3P2 ( )-2-amino-3-(3,5-diiodo-4-(3-iodo-4- ((phosphonatooxy)methoxy)phenoxy)phenyl)propanoate sodium salt

[0180] T3P2 sodium salt was synthesized according to the scheme shown in FIG. 3. Specifically, A suspension of methyl (5)-3-(4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)-2- (2,2,2-trifluoroacetamido)propanoate (compound 1 in FIG. 3, 674.5 mg, 0.886 mmol) and K2CO3 (197.2 mg, 1.43 mmol) was stirred in THF (10 mL) for 10 min and then chloromethyl methyl sulfide (0.260 mL, 3.10 mmol) was added by syringe, followed by tetrabutyl ammonium iodide (17 mg, 0.046 mmol) as a solid. After stirring overnight, the reaction mixture was diluted with 1 M HC1 (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography on silica gel (20-55% EtOAc in hexanes as eluent) to obtain methyl (S)-3-(3,5- diiodo-4-(3-iodo-4-((methylthio)methoxy)phenoxy)phenyl)-2-(2,2,2- trifluoroacetamido)propanoate as a white solid (compound 3 in FIG. 3; 394.3 mg, 54% yield).

[0181] Compound 3 was characterized by 'H NMR,13C NMR, and mass spectrometry. 'H NMR (400 MHz, DMSO-d6) 8: 9.90 (d, J= 8.3 Hz, 1H), 7.85 (s, 2H), 7.08 (d, J= 3.2 Hz, 1H), 7.07 (d, .7= 9.3 Hz, 1H), 6.67 (dd, J= 9.0, 2.9 Hz, 1H), 5.30 (s, 2H), 4.76-4.66 (m, 1H), 3.32 (s,3H), 3.22 (dd, J= 13.7, 4.9 Hz, 1H), 2.95 (dd, J= 13.6, 10.9 Hz, 1H), 2.22 (s, 3H).13C NMR (100 MHz, DMSO-D6) 5:170.0, 156.2 (q, J= 36.7 Hz), 151.8, 150.8. 150.7, 140.7, 138.4, 125.0, 115.7 (q, J= 288.3 Hz), 115.5, 115.4, 91.8, 88.3, 73.2, 53.2, 52.4, 33.7, 14.2. LC / MS (ESI): m / z calcd. for C20H16F3I3NO5S (M-H) 819.8, found 819.7.

[0182] To a solution of methyl (5)-3-(3,5-diiodo-4-(3-iodo-4- ((methylthio)methoxy)phenoxy)phenyl)-2-(2,2,2-trifluoroacetamido)propanoate (compound 3 in FIG. 3; 390.9 mg, 0.476 mmol) in DCM (8 mL) was added 1 M sulfuryl chloride in DCM (0.600 mL, 0.600 mmol). After stirring at room temperature for 2 hours, the solvent was removed under reduced pressure to furnish crude methyl (S)-3-(4-(4-(chloromethoxy)-3-iodophenoxy)-3,5- diiodophenyl)-2-(2,2,2-trifluoroacetamido)propanoate (compound 4 in FIG. 3).

[0183] A suspension of H3PO4 (188.7 mg, 1.93 mmol) and 4 A molecular sieves (0.716 g) in ACN (10 mL) was treated with BusN (1.3 mL, 5.5 mmol). The mixture was stirred at rt for Ih, and then added without the sieves to a flask containing crude methyl (S)-3-(4-(4- (chloromethoxy)-3-iodophenoxy)-3,5-diiodophenyl)-2-(2,2,2-trifluoroacetamido)propanoate (compound 4 in FIG. 3) in ACN (2 mL). After stirring overnight, the solvent was removed under reduced pressure. To the resulting residue, 1 M NaOH (20 mL) was added and stirring continued for 2 h. The reaction mixture was acidified with concentrated HC1 and then cooled to 4 °C for 1 h. The aqueous layer was decanted and the precipitate purified by HPLC (5% ACN / 10 mM ammonium bicarbonate buffer to 100% ACN, Cis column) to yield, after lyophilization, the desired product as an ammonium salt.

[0184] To prepare the sodium salt, a 1 cm wide column was filled with 15 cm of DOWEX 50W2 (50-100 mesh, strongly acidic) ion exchange resin. The column was prepared by sequentially washing with ACN / water (1 :3), 1 M aqueous NaHCCh (gas evolution), and then finally ACN / water (1 : 10). The reaction product was dissolved in water and loaded onto the column, which was eluted with ACN / water (1: 10). The product containing fractions were lyophilized to furnish sodium (5)-2-amino-3-(3,5-diiodo-4-(3-iodo-4 ((phosphonatooxy)methoxy)phenoxy)phenyl)propanoate (T3P2) as a white solid (87.8 mg, 22% yield).

[0185] The product was characterized by1H NMR and mass spectrometry. 'H NMR (400 MHz, D2O) 5: 7.81 (s, 2H), 7.22 (d, J= 9.0 Hz, IH), 7.22 (d, J= 3.2 Hz, IH), 6.90 (dd, 9.1,3.0 Hz, 1H), 5.37 (d, J31P = 8.6 Hz, 2H), 3.73 (dd, J= 8.2, 5.3 Hz, 1H), 3.10 (dd, J= 14.4, 5.3 Hz, 1H), 2.88 (dd, J= 14.3, 8.1 Hz, 1H). LC / MS (ESI): m / z calcd. for CieHielsNOsP (M+H+) 761.8, found 761.8.

[0186] The complete disclosure of all patents, patent applications, and publications, and electronically available material cited herein are incorporated by reference in their entirety. In the event that any inconsistency exists between the disclosure of the present application and the disclosure(s) of any document incorporated herein by reference, the disclosure of the present application shall govern. The foregoing detailed description and examples have been given for clarity of understanding only. No unnecessary limitations are to be understood therefrom. The invention is not limited to the exact details shown and described, for variations obvious to one skilled in the art will be included within the invention defined by the claims.

[0187] Unless otherwise indicated, all numbers expressing quantities of components, molecular weights, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless otherwise indicated to the contrary, the numerical parameters set forth in the specification and claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0188] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. All numerical values, however, inherently contain a range necessarily resulting from the standard deviation found in their respective testing measurements.

[0189] All headings are for the convenience of the reader and should not be used to limit the meaning of the text that follows the heading, unless so specified.

Claims

CLAIMSWhat is claimed is:

1. A T3 prodrug of the formulaionized form thereof, a salt thereof, a hydrate thereof, or any combination thereof; wherein RAcomprises a phosphoric acid ester or an ionized form of a phosphoric acid ester.

2. The T3 prodrug of claim 1, wherein RAis -O-(PO3H2), -O-(C(R1)(R2))-O-(PO3H2) or an ionized form thereof wherein R1and R2are each independently H or a Cl to C3 alkyl.

3. The T3 prodrug of any one of claims 1 to 6, wherein the T3 prodrug is a sodium salt.

4. The T3 prodrug of claim 1, wherein the T3 prodrug is of Formula (la):(la), an ionized form thereof, a salt thereof, hydrate thereof, or any combination thereof.

5. The T3 prodrug of claim 1, wherein the T3 prodrug is of Formula T3P1 :T3P16. The T3 prodrug of claim 1, wherein the T3 prodrug is of Formula (lb):an ionized form thereof, a salt thereof, hydrate thereof, or any combination thereof.

7. The T3 prodrug of claim 1, wherein the T3 prodrug is of Formula T3P2:T3P28. A pharmaceutical composition comprising the prodrug of any of claims 1 to 7.

9. The pharmaceutical composition of claim 8, wherein the composition further comprises a carrier.

10. The pharmaceutical composition of claim 8 or 9, wherein the pharmaceutical composition is a solid.

11. The pharmaceutical composition of claim 8 or 9, wherein the pharmaceutical composition is a liquid.

12. The pharmaceutical composition of claim 9 or 11, wherein the carrier comprises an aqueous buffer.

13. The pharmaceutical composition of claim 12, wherein the pharmaceutical composition has a pH of 2 to 8.

14. A method comprising administering the pharmaceutical composition of any one of claims 8 to 12 to a subject.

15. The method of claim 14, wherein the subject has or is at risk of having lung inflammation, pulmonary edema, a cardiac disease, or any combination thereof.

16. The method of claim 14 or 15, wherein the pharmaceutical composition is administered directly to the pulmonary tract of the subject.

17. The method of any of claims 14 to 16 , wherein the pharmaceutical composition is administered by pulmonary instillation.

18. The method of any of claims 14 to 16, wherein the pharmaceutical composition is administered by intratracheal instillation.

19. The method of any of claims 14 to 16, wherein the pharmaceutical composition is administered by inhalation of an aerosolized pharmaceutical composition.

20. The method of any of claims 14 to 16, wherein the pharmaceutical composition is administered by inhalation of a nebulized pharmaceutical composition.

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