Once-daily aldosterone synthase inhibitor (R)-(+)-5-(P-cyanophenyl)-5,6,7,8-tetrahydroimidazo[L,5-A]pyridine

Abstract

The present invention relates to a composition for use in the treatment of a disease or disorder, preferably a disease or disorder in which excessive exposure to aldosterone contributes to the symptoms of the disease or disorder, said composition comprising a compound which is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, preferably (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, said compound having an enantiomeric excess (ee) of the (R) form of 99% or greater, said composition being administered once daily for at least 8 weeks to a patient in need thereof.

Description

[Technical Field]

[0001] The present invention relates to a composition for use in treating a disease or disorder, preferably a disease or disorder in which excessive exposure to aldosterone contributes to the symptoms of the disease or disorder, the composition comprising a compound which is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, preferably (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, the compound having an enantiomeric excess (ee) of the (R) form of 99% or greater, the composition being administered once daily for at least 8 weeks to a patient in need thereof. Diseases of aldosterone overexposure can be diagnosed biochemically and include, in decreasing order of severity, primary aldosteronism resulting from aldosterone-producing adrenal adenomas or nodules, or from adrenal cortical hyperplasia, or from apparently normal glands.

[0002] Related technologies Aldosterone excess can be associated with or accompanied by a variety of adverse metabolic and cardiovascular structural effects, including sodium and water retention, hypokalemia, hypomagnesemia, hypertension, left ventricular hypertrophy, and cardiac fibrosis. Primary aldosteronism has substantially adverse outcomes compared with essential hypertension. Therefore, medical therapy that is effective in both lowering blood pressure and antagonizing the excessive activation of mineralocorticoid receptors is an important therapeutic goal (Parthasarathy et al., 2011, J Hypertens 29:980-990).

[0003] Primary aldosteronism (PA) is defined as a group of disorders in which aldosterone production is inappropriately high relative to sodium status, is relatively autonomous from the primary regulators of secretion (angiotensin II, plasma potassium concentration), and is unsuppressed by sodium loading. Such inappropriate aldosterone production leads to hypertension, cardiovascular damage, sodium retention, suppression of plasma renin, and (if prolonged or severe) increased potassium excretion, which can lead to hypokalemia. PA is commonly caused by benign adrenal adenomas, adrenal nodules, unilateral or bilateral adrenal hyperplasia (BAH), or, rarely, adrenal carcinoma or the inherited condition familial hyperaldosteronism. PA is also known as Conn's syndrome (Funder et al., 2016, J Clin Endocrinol Metab 101:1889-1916).

[0004] Aldosterone levels can be measured in blood and urine. The Endocrine Society Clinical Practice Guidelines for the Management of Primary Aldosteronism detail the process and methods for measuring the aldosterone-to-renin ratio (ARR) in blood samples (Funder et al., 2016, J Clin Endocrinol Metab 101:1889-1916). The guidelines also recommend diagnostic cutoff levels for abnormal values. A more accurate method for measuring aldosterone levels involves collecting a 24-hour urine sample and determining the content of tetrahydroaldosterone, the main metabolic product of aldosterone, in urine (Funder and Carey, 2022, Hypertens 79:726-735). The authors provide diagnostic cutoff levels for abnormal values.

[0005] Furthermore, the Endocrine Society Clinical Practice Guidelines for the Management of Primary Aldosteronism recommend and describe an invasive process, aided by CT imaging, to subtype patients and lateralize the adrenal source of excess aldosterone. Unilateral adrenal adenomas can be surgically removed by adrenalectomy, whereas bilateral disease requires medical treatment (Funder et al., 2016, J Clin Endocrinol Metab 101:1889-1916).

[0006] The ability of adrenal glomerulosa cells to produce aldosterone is primarily controlled by the regulated transcription of CYP11B2, the gene encoding aldosterone synthase. Inhibition of aldosterone synthase has emerged as a treatment option for hypertension, heart failure, and renal disorders. The goal is to reduce aldosterone concentrations in both plasma and tissues, thereby reducing MR-dependent and MR-independent effects in target organs: the heart, blood vessels, and kidney.

[0007] (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine is a small molecule capable of inhibiting aldosterone synthase. International Publication No. 2018 / 078049 teaches the preparation of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine and its pharmaceutically acceptable salts (e.g., (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, also known as dexfadrostat phosphate) with an enantiomeric excess (ee) of 99% or greater for the (R) form. The high enantiomeric excess values ​​achieved by the methods described in WO 2018 / 078049 result in potent (i.e., low nanomolar) and selective inhibition of aldosterone synthase by (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine.

[0008] WO 2019 / 211394 teaches the results of a phase I clinical trial studying the use of dexfadrostat phosphate in healthy subjects.

[0009] Summary of the Invention In a prospective, double-blind, randomized Phase II efficacy study in patients diagnosed with primary aldosteronism, the present inventors surprisingly found that a preferred compound of the present invention, at a dose of 4 mg once daily, can effectively normalize the aldosterone-to-renin ratio in the patients compared with baseline values ​​by suppressing aldosterone synthesis.This finding is particularly noteworthy because a previous Phase I clinical trial in healthy subjects with normal aldosterone levels showed that the aldosterone suppression efficacy of a dose of 4 mg once daily was limited.

[0010] Furthermore, the present inventors surprisingly demonstrated that preferred compounds of the present invention were able to normalize plasma aldosterone levels in patients at doses of 4 mg, 8 mg, and 12 mg once daily, regardless of underlying adrenal pathology, such as unilateral or bilateral adenomas, unilateral or bilateral nodules, unilateral or bilateral hyperplasia, and normal-appearing adrenal glands. This finding is particularly noteworthy because patients with primary aldosteronism due to adenoma are characterized by extreme aldosterone and potassium levels that require adrenal surgery for management.

[0011] Furthermore, the inventors surprisingly observed that preferred compounds of the present invention, at doses of 4 mg, 8 mg, and 12 mg once daily, were able to normalize plasma aldosterone levels in the patients with a rapid response, i.e., within a short treatment period of 14 days, thereby leading to a rapid normalization of blood pressure and hypokalemia. This finding is particularly noteworthy because a clinical response to surgery and current medical treatments can take 3 to 12 months to occur.

[0012] Furthermore, the inventors surprisingly observed that preferred compounds of the present invention, at doses of 4 mg, 8 mg, and 12 mg once daily, were able to normalize plasma aldosterone levels in the patients with a rapid response that was maintained throughout the treatment period without dose adjustment, thereby leading to sustained normalization of blood pressure and hypokalemia, indicating long-term cardiovascular protection. This finding is particularly noteworthy because current medical treatments require biweekly dose escalation to balance efficacy and tolerability.

[0013] Furthermore, the inventors surprisingly observed that the preferred compounds of the present invention were able to normalize urinary aldosterone secretion in the patients at doses of 4 mg, 8 mg, and 12 mg once daily, which broadens the utility of the compounds to diseases characterized by abnormal urinary aldosterone content, such as essential hypertension, resistant hypertension, and heart failure and renal failure. This finding is particularly noteworthy because diseases following current medical treatment (e.g., mineralocorticoid receptor antagonists) further induce aldosterone production as a result of the treatment.

[0014] In one aspect, the invention provides a composition for use in treating a disease or disorder, wherein the composition is administered once daily to a subject in need thereof for at least 8 weeks, and the composition comprises a compound that is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, wherein the compound has an enantiomeric excess (ee) of the (R) form of about 99% or greater.

[0015] Accordingly, in one aspect, the present invention provides a composition for use in treating a disease or disorder, said composition comprising a compound that is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or dexfadrostat (Formula (I)) or a pharmaceutically acceptable salt thereof, wherein said compound has an enantiomeric excess (ee) of the (R) form of 99% or greater, and said composition is administered once daily to a patient in need thereof at a dose of 1 to 8 mg.

[0016] In a further aspect, the present invention provides a composition for use in treating a disease or disorder, preferably primary aldosteronism, more preferably various pathological subtypes of primary aldosteronism such as unilateral or bilateral adenoma, unilateral or bilateral nodules, unilateral bilateral adrenal hyperplasia, and normal-appearing adrenals.

[0017] In a further aspect, the invention provides a composition for use in treating a disease or disorder, wherein the disease or disorder is primary aldosteronism, in which excessive aldosterone exposure contributes to debilitating symptoms and events, and in which patients require rapid correction of underlying biochemical (hyperaldosteronism, hypokalemia) and clinical (systolic and diastolic blood pressure) health risk adverse events.

[0018] In a further aspect, the present invention provides a composition for use in treating a disease or disorder, wherein the disease or disorder is primary aldosteronism, in which excessive aldosterone exposure contributes to debilitating symptoms and events, and in which patients require sustained and reliable correction of underlying biochemical (hyperaldosteronism, hypokalemia) and clinical (systolic and diastolic blood pressure) health risk adverse events.

[0019] In a further aspect, the present invention provides a composition for use in treating a disease or disorder characterized by abnormal or inappropriate aldosterone content in the urine, such as primary aldosteronism, secondary aldosteronism, heart failure, renal failure, resistant hypertension, essential hypertension, nephropathy, edema, coronary heart disease, hypokalemia, and cardiac arrhythmias.

[0020] In one aspect, the invention provides a composition for use in treating a disease or disorder, the composition being administered once daily to a subject, preferably a human, in need thereof, the composition comprising a compound that is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, the compound having an enantiomeric excess (ee) of the (R) form of about 99% or greater.

[0021] In some embodiments, the composition is administered once daily to a subject in need thereof for at least 8 weeks.

[0022] In some embodiments, the disease or disorder is a chronic disease or disorder, preferably a chronic cardiovascular disease or disorder.

[0023] In some embodiments, the composition is administered to the subject once daily at a dosage of about 1 mg to about 12 mg of the compound. In some embodiments, the compound is administered at a dosage of about 4 mg. In some embodiments, the compound is administered at a dosage of about 8 mg.

[0024] In some embodiments, the compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, and preferably, the (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate has an enantiomeric excess (ee) of the (R) form of about 99.5% or greater, more preferably about 99.9% or greater.

[0025] In some aspects, the disease or disorder is selected from the group consisting of primary aldosteronism, secondary aldosteronism, heart failure, chronic renal failure, hypertension, restenosis, obesity, nephropathy, post-myocardial infarction, renal fibrosis, coronary heart disease, sodium retention, water retention, hypokalemia, hypomagnesemia, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular injury, suppression of plasma renin, renal fibrosis, arrhythmias, nephropathy, edema, muscle weakness due to hypokalemia, cardiac fibrillation and weakened myocardial contractility; Preferably, the disease or disorder is selected from the group consisting of primary aldosteronism, secondary aldosteronism, heart failure, chronic renal failure, hypertension, restenosis, obesity, nephropathy, post-myocardial infarction, renal fibrosis, coronary heart disease, sodium retention, water retention, hypokalemia, hypomagnesemia, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular injury, plasma renin suppression, renal fibrosis, arrhythmia, nephropathy, and edema.

[0026] In some aspects, the disease or disorder is primary aldosteronism.

[0027] In some aspects, the disease or disorder is bilateral primary aldosteronism.

[0028] In some aspects, the disease or disorder is unilateral primary aldosteronism, preferably, the unilateral primary aldosteronism is caused by a unilateral adenoma, a unilateral nodule, or a unilateral hyperplasia.

[0029] In some embodiments, the disease or disorder is essential hypertension and / or resistant hypertension, preferably, the disease or disorder is essential hypertension and / or resistant hypertension associated with hypokalemia.

[0030] In some embodiments, the disease or disorder is hypokalemia.

[0031] In some embodiments, the once-daily dose does not require dose adjustment.

[0032] In some embodiments, the subject exhibits a clinical response within about 14 days of treatment, preferably wherein the clinical response is selected from a decrease in plasma aldosterone levels, a normalization of plasma aldosterone levels, a decrease in blood pressure, a normalization of blood pressure, a reduction in hypokalemia, a normalization of potassium levels, and a decrease in urinary THA.

[0033] The excessive increase in aldosterone production in primary aldosteronism is believed to be the result of the escape of cell clusters in the adrenal zona glomerulosa from normal physiological control.Therefore, it is further believed that aldosterone synthase inhibitors, when given at appropriate doses and for an appropriate duration of action, may prevent the sequelae of excessive aldosterone synthesis.In a preferred embodiment, the disease or disorder treated according to the present invention is a condition that occurs after or as a result of excessive exposure to aldosterone. [Brief explanation of the drawings]

[0034] [Figure 1] FIG. 1 is a schematic diagram of the study design for the Phase II clinical trial described in Example 1. [Figure 2A] Plot of aldosterone-to-renin ratio (ARR) (ng / dL) / (mU / L) for all patients obtained on days 1 and 56. The lognormal LSM change from baseline was -2.54 (95% CI -2.9 to -2.2). *p<0.0001. [Figure 2B] Plot of mean (SEM) 24-hour ambulatory SBP (aSBP) (mmHg) for all patients obtained on days 1 and 56. The LSM change from baseline was -10.7 mmHg (95% CI -13.6 to -7.9). *p<0.0001. [Figure 3A] Plot of aldosterone-to-renin ratio (ARR) (ng / dL) / (mU / L) for patients with unilateral PA obtained on days 1, 14, 28, 42, and 56. [Figure 3B]Plots of aldosterone-to-renin ratio (ARR) (ng / dL) / (mU / L) for patients with bilateral PA or PA of unknown cause (idiopathic PA) obtained on days 1, 14, 28, 42, and 56. [Figure 4A] Figure 1 shows plots of LSM change in lognormal aldosterone-to-renin ratio (ARR) (ng / dL) / (mU / L) in patients treated with 4 mg dexfadrostat (n=10) obtained on days 1 and 56. Box plots show median, first and third quartiles, and range. *p<0.0005. [Figure 4B] Figure 1 shows plots of LSM changes in lognormal values ​​of aldosterone-to-renin ratio (ARR) (ng / dL) / (mU / L) in patients treated with 8 mg dexafadrostat (n=12) obtained on days 1 and 56. Box plots show median, first and third quartiles, and range. *p<0.0005. [Figure 4C] Figure 1 shows plots of LSM changes in lognormal values ​​of aldosterone-to-renin ratio (ARR) (ng / dL) / (mU / L) in patients treated with 12 mg dexafadrostat (n=13) obtained on days 1 and 56. Box plots show median, first and third quartiles, and range. *p<0.0005. [Figure 4D] Plot of LSM change in 24-hour ambulatory SBP (aSBP) (mmHg) in patients treated with 4 mg dexafadrostat (n=10) obtained on days 1 and 56. *p<0.0005. [Figure 4E] Plot of LSM change in 24-hour ambulatory SBP (aSBP) (mmHg) in patients treated with 8 mg dexafadrostat (n=12) obtained on days 1 and 56. *p<0.0005. [Figure 4F] Plot of LSM change in 24-hour ambulatory SBP (aSBP) (mmHg) in patients treated with 8 mg dexafadrostat (n=13) obtained on days 1 and 56. *p<0.0005. [Figure 4G] Plots of LSM changes in urinary tetrahydroaldosterone (THA) (μg / 24h) in patients treated with 4 mg dexafadrostat (n=10) obtained on days 1 and 56. Box plots show median, 1st and 3rd quartiles, and range. *p<0.0001. [Figure 4H] Plots of LSM changes in urinary tetrahydroaldosterone (THA) (μg / 24 h) in patients treated with 8 mg dexafadrostat (n=12) obtained on days 1 and 56. Box plots show median, 1st and 3rd quartiles, and range. *p<0.0001. [Figure 4I] Plots of LSM changes in urinary tetrahydroaldosterone (THA) (μg / 24h) in patients treated with 12 mg dexafadrostat (n=13) obtained on days 1 and 56. Box plots show median, 1st and 3rd quartiles, and range. *p<0.0001. [Figure 5A] Figure 1 shows plots of the aldosterone-to-renin ratio (ARR) (ng / dL) / (mU / L) measured in log-normal LSM change from baseline for patients treated with 4 mg dexafadrostat (n=10) at days 14, 28, 42, 56, and 70. Box plots show median, first and third quartiles, and range. *p≦0.0008. [Figure 5B] Plot of office systolic blood pressure (oSBP) (mmHg) measured in LSM change from baseline for patients treated with 4 mg dexfadrostat (n=10) at days 14, 28, 42, 56, and 70. *p≦0.0008. [Figure 5C] Plot of mean (SEM) plasma potassium concentrations (mmol / L) measured in LSM change from baseline for patients treated with 4 mg dexfadrostat (n=10) at days 14, 28, 42, 56, and 70. *p≦0.0008. [Figure 5D]Figure 1 shows plots of the aldosterone-to-renin ratio (ARR) (ng / dL) / (mU / L) measured in log-normal LSM change from baseline for patients treated with 8 mg dexafadrostat (n=12) at days 14, 28, 42, 56, and 70. Box plots show median, first and third quartiles, and range. *p<0.0001, **p<0.05. [Figure 5E] Plot of office systolic blood pressure (oSBP) (mmHg) measured in LSM change from baseline in patients treated with 8 mg dexfadrostat (n=12) at days 14, 28, 42, 56, and 70. *p<0.0001, **p<0.05. [Figure 5F] Plot of mean (SEM) plasma potassium concentrations (mmol / L) measured in LSM change from baseline for patients treated with 8 mg dexfadrostat (n=12) at days 14, 28, 42, 56, and 70. *p<0.0001, **p<0.05.

[0035] Detailed Description of the Invention Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0036] When the term "about" is used, unless otherwise indicated, it specifically means ±10%, ±5%, or ±3%, each of which refers to a given numerical value. In various embodiments of the present invention, "about" can be omitted. All ranges of values ​​disclosed herein refer to and encompass any and all values ​​contained within said range, including the values ​​defining the range. For clarity, for example, a value of 12 to 13 refers to a value of 12 or 13 or any and all values ​​contained within the range of 12 to 13; for example, a daily dose of 1 mg to 16 mg refers to a daily dose of 1 mg or 16 mg or any and all values ​​contained within the range of 1 mg to 16 mg.

[0037] As used herein, the term "adenoma" is a type of non-cancerous or benign tumor that can affect various organs.

[0038] As used herein, the term "adrenal vein sampling," abbreviated as "AVS," refers to a procedure used in conjunction with computed tomography (CT) scanning to subtype primary aldosteronism (PA). Blood leaves each adrenal gland and circulates through the adrenal veins (AVs), eventually draining into the inferior vena cava (VC). (The right AV drains directly into the VC, while the left AV drains into the left renal vein and then into the inferior VC.) AVS is considered the most reliable method for subtyping PA.

[0039] Intravenous (IV) cannulation is the technique of placing a cannula (thin tube) into a vein to establish venous access, which allows for blood sampling and the administration of fluids, medications, parenteral nutrition, chemotherapy, and blood products. The right adrenal vein is the most difficult to cannulate due to its location and small diameter.

[0040] As used herein, the term "aldosterone-producing cell clusters (APCCs)" refers to cell clusters that strongly express aldosterone synthase (CYP11B2). They are frequently found in the adult adrenal gland and can be found in aldosterone-producing adenomas.

[0041] As used herein, the term "aldosterone synthase" refers to the steroid hydroxylase cytochrome P450 enzyme CYP11B2. Thus, aldosterone synthase inhibition is equivalent to CYP11B2 inhibition.

[0042] As used herein, the term "chiral purity" is defined by the enantiomeric excess (ee) as determined by chiral HPLC (see examples for details) and calculated by the following formula: ee=(A R -A S ) / (A R +A S )×100% [In the formula, A R is the area of ​​the peak of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine in the HPLC chromatogram of the sample solution, and A S is the area of ​​the peak of (S)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine in the HPLC chromatogram of the sample solution.

[0043] The terms "disease" and "disorder" are used interchangeably herein and refer to any deranged or abnormal state or function or pathological physical or mental condition, particularly an abnormal medical condition such as a disease or injury in which a tissue, organ, or individual can no longer perform its function efficiently. th (ed., 1988). Typically, although not necessarily, a disease may be associated with or accompanied by specific symptoms or signs that indicate the presence of such disease. Thus, the presence of such symptoms or signs may be indicative of a tissue, organ, or individual that is afflicted with the disease. Preferably, a tissue, organ, or individual that is "at risk of developing" indicates that the possibility of the disease emerging is encompassed within the term "disease" or "disorder." Typically, the risk of developing a disease is associated with early or mild signs or symptoms of such disease.

[0044] As used herein, the expression "diseases or disorders in which excessive exposure to aldosterone contributes to the symptoms of the disease or disorder" preferably refers to diseases or disorders caused by abnormal or inappropriate activity / expression of aldosterone synthase and biological activities or processes associated with abnormal or inappropriate expression of aldosterone synthase. Typical examples of diseases or disorders caused by abnormal or inappropriate activity / expression of aldosterone synthase are primary aldosteronism, secondary aldosteronism, heart failure, chronic renal failure, hypertension, restenosis, obesity, nephropathy, post-myocardial infarction, renal fibrosis, coronary heart disease, sodium retention, water retention, hypokalemia, hypomagnesemia, hypertension, left ventricular hypertrophy and cardiac fibrosis, cardiovascular damage, suppression of plasma renin, renal fibrosis, arrhythmia, nephropathy, edema, and muscle weakness, cardiac fibrillation, and weakened myocardial contraction caused by hypokalemia. Preferably, said disease or disorder caused by abnormal or inappropriate activity / expression of aldosterone synthase is primary aldosteronism, secondary aldosteronism, heart failure, chronic renal failure, hypertension, restenosis, obesity, nephropathy, post-myocardial infarction, renal fibrosis, coronary heart disease, sodium retention, water retention, hypokalemia, hypomagnesemia, hypertension, left ventricular hypertrophy and cardiac fibrosis, cardiovascular damage, suppression of plasma renin, renal fibrosis, arrhythmias, nephropathy, edema.

[0045] As used herein, the term "nodule" refers to an abnormal tissue growth that can be found anywhere in the body. While they are often benign, some nodules are symptoms of an underlying disease.

[0046] The term "pharmaceutically acceptable salt" as used herein refers to a pharmaceutically acceptable salt that has the desired pharmacological activity of the parent compound.Such salts include acid addition salts formed with inorganic or organic acids known to those skilled in the art (P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor); Handbook of Pharmaceutical Salts Properties, Selection, and Use, 2nd Revised Edition, March 2011, Wiley-VCH, ISBN: 978-3-90639-051-2).Particularly preferred pharmaceutically acceptable salts in the present invention are acid addition salts such as hydrochloride or phosphate salts formed with phosphoric acid, i.e., dihydrogen phosphate salt.

[0047] The term "phosphate salt" as used in this application refers to a compound comprising the protonated form of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, i.e., the (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine cation, and further comprising an anion derived from phosphoric acid, wherein said anion is typically and preferably the dihydrogen phosphate anion [H2PO4]. - or hydrogen phosphate anion [HPO4] 2- Preferably, the term "phosphate" as used in this application refers to the dihydrogen phosphate salt of formula (I), i.e., the compound of formula (I) is once protonated and the counter ion is [H2PO4] - Therefore, the stoichiometry of monoprotonated (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine to dihydrogen phosphate anion is 1:1. The latter compound is referred to herein as (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate.

[0048] The term "primary aldosteronism" and abbreviation PA are defined herein as a group of disorders characterized by autonomous aldosterone excess leading to suppressed renin levels. A proposed screening test is the aldosterone-to-renin ratio, which is pathologically increased in PA. PA therefore encompasses disorders in which aldosterone production is inappropriately high given sodium status, is relatively autonomous from the primary regulators of secretion (angiotensin II, plasma potassium concentration), and is non-suppressible by sodium loading. The term "primary aldosteronism" also encompasses hyperaldosteronism and diseases and disorders that are the result of inadequate production of aldosterone, which are typically and preferably selected from hypertension, cardiovascular damage, sodium retention, water retention, suppression of plasma renin, and increased potassium excretion and hypokalemia, hypomagnesemia, left ventricular hypertrophy, cardiac and renal fibrosis, heart failure, arrhythmias, nephropathy, edema, and muscle weakness, cardiac fibrillation, weakened myocardial contractility, and cardiac failure due to hypokalemia. The term "primary aldosteronism" also encompasses diseases or disorders that cause PA, typically and preferably including adrenal adenoma, unilateral and bilateral adrenal hyperplasia (BAH) (e.g., bilateral idiopathic (nodular) adrenal hyperplasia and primary (unilateral) adrenal hyperplasia), adrenal carcinoma (e.g., aldosterone-producing adrenocortical carcinoma and ectopic aldosterone-producing adenoma or carcinoma), glucocorticoid-responsive aldosteronism, the inherited condition of familial hyperaldosteronism, and FH type II. PA is also known as Conn's syndrome. Excessively increased aldosterone production in PA results from the escape of cell clusters in the adrenal zona glomerulosa from the normal aldosterone-renin-aldosterone regulatory control. In some embodiments, hyperaldosteronism is defined as a blood aldosterone concentration of 416 pmol / L (i.e., 15 ng / dL) or greater. In some embodiments, hyperaldosteronism is defined as a urinary aldosterone concentration of 10 μg / 24 hours or greater. In some embodiments, hyperaldosteronism is defined as a blood aldosterone concentration of 416 pmol / L (i.e., 15 ng / dL) or greater or a urinary aldosterone concentration of 10 μg / 24 hours or greater.In a preferred embodiment, the hyperaldosteronism is blood pressure independent hyperaldosteronism.

[0049] As used herein, the term "unilateral PA" refers to a specific subtype of primary aldosteronism in which only one adrenal gland is the apparent cause of the uncontrolled overproduction of aldosterone that is the primary feature of PA. Unilateral disease is typically caused by aldosterone-producing adenomas (benign tumors) and less commonly by adrenal carcinoma or hyperplasia (when the entire gland is overactive). In a preferred embodiment, subtyping is performed using a combination of computed tomography (CT) scans and adrenal venous sampling (AVS).

[0050] As used herein, the term "bilateral PA" refers to a specific subtype of primary aldosteronism in which both adrenal glands appear to be involved in the uncontrolled overproduction of aldosterone, a primary feature of PA. This may be caused by bilateral growth in both adrenal glands (known as bilateral adrenal hyperplasia). In a preferred embodiment, subtype classification is performed using a combination of computed tomography (CT) scans and adrenal venous sampling (AVS).

[0051] As used herein, the term "hyperplastic PA" or "adrenal hyperplasia" refers to another form of primary aldosteronism caused by the abnormal or unusual proliferation of extra cells within the adrenal glands. Hyperplastic PA can be present in either unilateral or bilateral disease.

[0052] As used herein, the term "idiopathic PA" refers to primary aldosteronism of unknown cause.

[0053] As used herein, the term "genetic PA" refers to primary aldosteronism resulting from genetic factors. Familial hyperaldosteronism is a genetic cause of PA defined by a family history of two or more affected family members that is not explained by another genetic mechanism.

[0054] As used herein, the term "rapid response" refers to the body's involuntary reaction(s) to a stimulus. In this context, "rapid" response refers to a response that occurs faster than the expected, defined stimulus and response mechanistic pathway.

[0055] As used herein, the term "sustained response" refers to a response that remains stable over time, i.e., that is maintained for an extended period of time without interruption or decline. Thus, a sustained response is a long-lasting or prolonged response.

[0056] As used herein, the term "secondary aldosteronism" (SA) (also hyperreninism, or high-renin hyperaldosteronism) refers to the excessive secretion of aldosterone secondary to stimulation from extra-adrenal sources. An extra-adrenal stimulus is, for example, renal hypoperfusion. SA results from hyperactivity of the renin-angiotensin-aldosterone system. The term "secondary aldosteronism" encompasses diseases and disorders that are the result of inadequate production of aldosterone and renin, and is typically and preferably selected from high plasma aldosterone levels, high plasma renin levels, hypertension, hypokalemic alkalosis causing temporary weakness, paresthesia, transient paralysis, tetany, and peripheral edema. The term "secondary aldosteronism" also encompasses diseases or disorders that cause SA, such as reduced renal blood flow, obstructive renal artery disease (e.g., atheroma, stenosis), renal vasoconstriction, edematous diseases (e.g., heart failure, liver cirrhosis with ascites, nephrotic syndrome), renin-producing tumors, juxtaglomerular tumors, fibromuscular dysplasia, reduced sodium reabsorption (e.g., as seen in Bartter and Gitelman syndromes), and hypovolemia / hypotension. The term "secondary aldosteronism" also encompasses secondary hyperaldosteronism.

[0057] The term "subtyping," as used herein in the context of primary aldosteronism, refers to the process of identifying whether one or both adrenal glands are thought to be involved in uncontrolled aldosterone overproduction. Subtyping requires the use of computed tomography (CT) scans in combination with adrenal venous sampling (AVS) to distinguish between unilateral and bilateral disease. This is currently considered the most accurate diagnostic method.

[0058] As used herein, aldosterone-to-renin ratio (ARR) is understood to mean the plasma aldosterone concentration divided by either the blood renin concentration or renin activity. Aldosterone is measured as the plasma (plasma is the liquid portion of blood, i.e., cell-free) aldosterone concentration (PAC). Renin is measured as plasma renin activity (PRA) or plasma renin concentration (PRC). To determine the ARR, a blood sample is taken from a patient, and the PAC is divided by either the PRA or PRC to determine the ARR. Without wishing to be bound by theory, in a preferred embodiment, the ARR is used as a screening test to identify patients at risk of primary aldosteronism (PA).

[0059] Systolic blood pressure (SBP) as used herein is understood as the pressure developed by the heart on the arteries during ventricular contraction.

[0060] As used herein, diastolic blood pressure is understood to be the arterial pressure between heartbeats. Without wishing to be bound by theory, SBP is more closely correlated with cardiovascular events such as stroke and myocardial infarction. Both systolic and diastolic blood pressure are usually determined using a blood pressure cuff placed on the brachial artery (near the elbow). In primary aldosteronism (PA), blood pressure rises due to increased sodium and water retention in the body. Sodium and water are retained by excessive and uncontrolled production of aldosterone, a steroid hormone primarily responsible for sodium and subsequent water retention in the body. Therefore, hypertension is considered a clinical marker of PA.

[0061] As used herein, "office systolic blood pressure (oSBP)" refers to a blood pressure measurement taken in a doctor's office. The blood pressure measurement indicates the patient's blood pressure at the time of the patient's arrival at the office.

[0062] As used herein, "ambulatory systolic blood pressure (aSBP)" is a collection of blood pressure measurements taken over (generally) a 24-hour period. As used herein, blood pressure measurements were taken 3x / hour or every 20 minutes throughout the 24-hour period (for Study DP13C201). Blood pressure monitors were worn by subjects, and the subjects maintained their daily routines. Without wishing to be bound by theory, a 24-hour blood pressure measurement record is considered a more reflective, and therefore more accurate, measurement of a person's blood pressure because it is recorded continuously over a 24-hour period.

[0063] As used herein, the term "symptom" refers to any manifestation of an abnormal condition, disease, or disorder, and includes any deviation from normal function or normal sensation that is either noticed by a subject, preferably a patient, or that can be observed objectively (effects or symptoms) and that reflects the presence of an abnormal condition, disorder, or disease.

[0064] As used herein, the term "day" or "daily" refers to either a calendar day or a single 24-hour period, preferably the term "day" or "daily" refers to either a calendar day.

[0065] As used herein, the term "abnormal activity of aldosterone synthase" refers to activity of aldosterone synthase that differs from the activity of the wild-type or native gene or protein, or that differs from the activity of the gene or protein in a healthy subject. The abnormal activity may be stronger or weaker than the normal activity.

[0066] As used herein, the term "normal" or "normalization" in the context of clinical parameters such as plasma aldosterone concentration (PAC), plasma renin activity (PRA), plasma renin concentration (PRC, also known as direct renin concentration (DRC)), plasma aldosterone-to-renin ratio (ARR), plasma potassium concentration, urinary content of tetrahydroaldosterone (THA), ambulatory systolic blood pressure (aSBP), and office systolic blood pressure (oSBP) refers to a cutoff value, threshold, or range defined by a medical or clinical consensus publication regarding reference values ​​as values ​​characteristic of healthy individuals. Therefore, subjects who exhibit "normal" clinical parameters typically do not require additional clinical intervention to treat the parameters. The Endocrine Society Clinical Practice Guidelines suggest the following cutoff values ​​for detecting patients with primary aldosteronism (Funder et al., J Clin Endocrinol Metab 2016;101:1889-1916), with ARR cutoff values ​​depending on the assay and whether PAC, PRA, and PRC (DRC) are measured in conventional or SI units: [Table 1]

[0067] As used herein, normal PAC is understood to be <15 ng / dL (<410 pmol / L) for patients with adenomatous PA and <10 ng / dL (<275 pmol / L) for patients with bilateral PA.

[0068] As used herein, a normal PRA for a patient with unilateral PA is understood to be >0.5 ng / mL / h and a PRC >5 ng / L, using a highly sensitive assay that can detect a PRA as low as 0.2-0.3 ng / mL / h or a PRC as low as 2 mU / L. As used herein, a normal PRA value for a patient with bilateral PA is understood to be >1.0 ng / mL / h and a PRC >10 ng / L.

[0069] As used herein, a normal ARR is understood to be less than 3.7 (ng / dL) / (mU / L) (ie, PAC / DRC).

[0070] As used herein, normal urinary aldosterone excretion is understood to be less than 12 μg / 24 hours as measured by tetrahydroaldosterone content in a 24 hour urine sample.

[0071] As used herein, normal office or ambulatory blood pressure is understood to be a systolic blood pressure <140 mmHg and a diastolic blood pressure <90 mmHg.

[0072] As used herein, normal ambulatory blood pressure is understood to be a systolic blood pressure <135 mmHg and a diastolic blood pressure <85 mmHg, preferably a systolic blood pressure <130 mmHg and a diastolic blood pressure <80 mmHg), and normal 24-hour ambulatory blood pressure monitoring is understood to be a systolic blood pressure <130 mmHg and a diastolic blood pressure <80 mmHg. Without wishing to be bound, these values ​​are consistent with the 2013 ESH / ESC guidelines for the management of arterial hypertension. J. Hypertens 2013;31:1281-1357.

[0073] As used herein, a normal blood potassium level is understood to be a potassium level of 3.6 mmol / L to 5.2 mmol / L (Mayo Clinic). As used herein, a level below 3.6 mmol / L is understood to define a state of hypokalemia, while a level above 5.2 mmol / L is understood to be a state of hyperkalemia. As used herein, a level (i.e., potassium level) below 3.0 mmol / L is understood to define a state of severe hypokalemia.

[0074] As used herein, potassium-resistant hypokalemia refers to a state of hypokalemia in which the hypokalemia cannot be treated by administering potassium, e.g., dietary potassium, to a subject with the potassium-resistant hypokalemia. In some embodiments, potassium-resistant hypokalemia is understood to mean that severe hypokalemia remains unchanged (i.e., the blood potassium level remains below 3.0 mmol / L) even after potassium, e.g., dietary potassium, is administered to the subject. In some embodiments, potassium-resistant hypokalemia is understood to mean that severe hypokalemia remains unchanged (i.e., the blood potassium level remains above 3.0 mmol / L but below 3.6 mmol / L) even after potassium, e.g., dietary potassium, is administered to the subject. In some embodiments, potassium-resistant hypokalemia is understood to mean that hypokalemia remains unchanged (i.e., the blood potassium level remains below 3.6 mmol / L) even after potassium, e.g., dietary potassium, is administered to the subject.

[0075] In some embodiments, the amount of potassium (e.g., dietary potassium) administered to the subject is insufficient to treat the potassium-resistant hypokalemia and is at least 60 mmol / day, preferably, the amount is at least 70 mmol / day, and more preferably, at least 80 mmol / day.

[0076] As used herein, the term "inappropriate activity of aldosterone synthase" refers to the activity of the wild-type or naturally occurring gene or protein of aldosterone synthase or the activity of the gene or protein in a healthy subject, which is considered appropriate in a healthy subject, but the same activity is considered inappropriate in a diseased subject, i.e., the activity is either too strong or too weak in the diseased subject.

[0077] The terms "treating" and / or "treatment," as used herein, refer to the management and care of a subject, preferably a patient, having a disease or disorder, with the administration of one or more therapeutic compounds or compositions for the disease or disorder, with the goal of eliminating or alleviating the symptoms and complications of such condition. Treating includes administering one or more formulations of the present invention to prevent the onset of symptoms or complications, alleviate symptoms or complications, or eliminate the disease or disorder. As used herein, the term "treatment" (or "therapy," as used interchangeably herein) refers to both therapeutic treatment and prophylactic or preventative measures. Preferably, "treatment" or "therapy" refers to therapeutic treatment.

[0078] As used herein, the term "pharmaceutically acceptable excipient" includes any physiologically inert additive routinely used in pharmaceutical dosage forms. Pharmaceutically acceptable excipients are selected from the group including binders, diluents, carriers, lubricants, glidants, coating additives, or combinations thereof. Additional suitable carriers for the formulation of the active salts of the present invention can be found in Remington, The Science and Practice of Pharmacy, 2006, Lippincott Williams & Wilkins, Philadelphia.

[0079] As used herein, the term "patient" or "subject" is used to mean an animal, preferably a mammal, including a human, suffering from a "disease" or "disorder." Examples of mammals include humans, dogs, cows, horses, pigs, sheep, goats, and cats. In a particularly preferred embodiment, the subject is a human. As used herein, the terms "patient" and "human" are used interchangeably.

[0080] As used herein, the term "administering" means introducing or applying a therapeutic agent into or to the body of a subject, preferably a patient in need thereof, to treat a disease or condition.

[0081] The term "therapeutically effective amount" (therapeutically effective amount) refers to the dosage of an active agent that is considered effective for treating at least one sign or symptom of a disease or disorder, or for producing a particular pharmacological response upon administration of the active agent. The amount of an agent for administration can vary depending on the circumstances, e.g., the subject, preferably the pathological condition of the patient, being treated, the dosage form, the method of administration, subject factors, preferably patient factors, etc. In certain instances, a therapeutically effective amount of an active agent administered to a particular subject will not always be effective in treating the conditions described herein, even if such dosage is considered a therapeutically effective amount by one of skill in the art.

[0082] The term "pharmaceutical composition" refers to a mixture containing at least one therapeutic agent that is administered to a subject, preferably a patient, to prevent or treat a particular disease or condition from which the subject, preferably a patient, suffers.

[0083] As used herein, the term "for use" as used in "a composition for use in the treatment of a disease" is intended to also disclose the corresponding method of treatment and the corresponding use of the preparation for the manufacture of a medicament for the treatment of a disease.

[0084] As used herein, the term "chronic cardiovascular disease or disorder" refers to a disease of the heart or blood vessels, and it is understood that the disease is chronic. As used herein, the term "chronic" is understood as a disease or disorder that lasts for at least 8 weeks, preferably at least 3 months, again more preferably at least half a year, again more preferably at least 1 year, again more preferably at least 2 years, again more preferably at least 5 years, and again more preferably at least 10 years. In a highly preferred embodiment, a chronic disorder is a disorder that lasts for the rest of the patient's life.

[0085] As used herein, "associated with," when used to describe two (or more) diseases or disorders, is understood to mean that a patient suffers from both diseases or disorders simultaneously. Thus, in a preferred embodiment, for example, a chronic cardiovascular disease or disorder associated with hypokalemia is understood to refer to a patient or subject who simultaneously exhibits both a chronic cardiovascular disease or disorder (e.g., primary aldosteronism) and hypokalemia. In some embodiments, the two diseases or disorders that are "associated with" each other may also be related to each other.

[0086] As used herein, the term "associated with" is understood to mean related to or connected to something else. In some embodiments, when two (or more) diseases or disorders are associated with each other, one disease or disorder causes and / or worsens (i.e., exacerbates) the other disease or disorder. So, for example, when a subject has a chronic cardiovascular disease associated with hypokalemia, the chronic cardiovascular disease or disorder (e.g., primary aldosteronism) is caused or worsened by the hypokalemia. In some embodiments, hypokalemia is caused or worsened by the chronic cardiovascular disease or disorder (e.g., primary aldosteronism).

[0087] Compounds of the Invention As used herein, (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine is understood to mean a compound having the structure of formula (I) below, wherein said (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine has an enantiomeric excess (ee) of the (R) form of 99% or greater.

[0088] [ka]

[0089] In some embodiments, the compound according to the present invention is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof. In some embodiments, the compound according to the present invention is selected from the group consisting of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine hydrochloride, (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, and (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine hydrogen phosphate. As used herein, the term "DP13" refers to a compound of Formula (I). In a preferred embodiment, "DP13" refers to (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate.

[0090] In a preferred embodiment, the compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate.

[0091] In some embodiments, the compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, and the compound has an enantiomeric excess (ee) of the (R) form of about 99.5% or greater. In preferred embodiments, the compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, and the compound has an enantiomeric excess (ee) of the (R) form of about 99.9% or greater.

[0092] In some embodiments, the compound is selected from the group consisting of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine hydrochloride, (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, and (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine hydrogen phosphate, wherein the compound has an enantiomeric excess (ee) of the (R) form of about 99.5% or greater. In a preferred embodiment, the compound is selected from the group consisting of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine hydrochloride, (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, and (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine hydrogen phosphate, and the compound has an enantiomeric excess (ee) of the (R) form of about 99.9% or greater.

[0093] In some embodiments, the compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, and the compound has an enantiomeric excess (ee) of the (R) form of about 99.5% or greater. In preferred embodiments, the compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, and the compound has an enantiomeric excess (ee) of the (R) form of about 99.9% or greater.

[0094] In another preferred embodiment, the pharmaceutically acceptable salt is crystalline. In another preferred embodiment, the pharmaceutically acceptable salt is anhydrous. In another preferred embodiment, the pharmaceutically acceptable salt is non-hygroscopic. In another preferred embodiment, the pharmaceutically acceptable salt is non-hygroscopic and anhydrous. In another preferred embodiment, the pharmaceutically acceptable salt is non-hygroscopic and crystalline. In another preferred embodiment, the pharmaceutically acceptable salt is non-hygroscopic, anhydrous, and crystalline.

[0095] In one aspect, a compound according to the present invention is Form I crystal of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, characterized by a powder X-ray diffraction pattern (Bruker AXS D2 PHASER, irradiation: CuKα (30 kV, 10 mA), scan range: 5-45° (2-theta values), sample rotation 5 rpm, 0.5 s / step, 0.010° / step, 3.0 mm detector slit) containing the following 2Θ values ​​measured as described in WO 2019 / 211394: 19.504, 21.919, and 24.159. In one aspect, there is provided Form I crystalline (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate for use in accordance with the present invention, characterized by a powder X-ray diffraction pattern comprising the following measured 2θ values: 19.504, 21.919, and 24.159, where each peak may vary by ±1 degree, or preferably ±0.5 degrees, or more preferably ±0.2 degrees. In a preferred aspect, the powder X-ray diffraction pattern further comprises the following 2θ values: 16.003, 26.101, 27.168, 27.542, and 29.029. In a preferred embodiment, the powder X-ray diffraction pattern further comprises the following 2θ values: 16.003, 26.101, 27.168, 27.542, and 29.029, each peak may vary by ±1 degree, or preferably ±0.5 degrees, or more preferably ±0.2 degrees.In a particularly preferred embodiment, there is provided Form I crystals of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate for use in accordance with the present invention, said Form I crystals having the following 2Θ values: 6.023129, 9.969034, 11.26224, 11.22848, 11.96566, 12.77761, 13.79347, 14.39314, 15.023129, 16.023129, 17.023129, 18.023129, 19.969034, 20.023129, 21.023129, 22.023129, 23.023129, 24.023129, 25.023129, 26.023129, 27.023129, 28.023129, 29.023129, 30.023129, 31.023124, 32.023124, 33.023124, 34.023124, 35.023124, 36.023129, 37.023124, 38.023124, 39.023124, 40.023124, 41.023124, 42.023124, 43.023124, 44.023124, 45.023124, 46.02 .3394, 16.00317, 16.27337, 17.07502, 17.27593, 17.9904, 18.38238, 18.65471, 18.96096, 19.14281, 19.504, 20.01265, 20.58808, 20.43302, 20.72112, 21.12683, 21.91906, 22.59202, 24.44788, 24.15917, 24.48119, 25. 70071, 26.10094, 26.58127, 27.16767, 27.54165, 27.71408, 28.27603, 28.09725, 28.54909, 29.02939, 29.71314, 30.07578, 30.68808, 30.92867, 31.6379, 32.27005, 32.79806, 33.20638, 33.23304, 33.65808, 34.41793, 3 and 40.22464.In another particularly preferred embodiment, there is provided Form I crystals of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate for use in accordance with the present invention, said Form I crystals having the following 2Θ values: 6.023129, 9.969034, 11.26224, 11.22848, 11.96566, 12.77761, 13.79347, 14.39314, 15.3394, 16. 00317, 16.27337, 17.07502, 17.27593, 17.9904, 18.38238, 18.65471, 18.96096, 19.14281, 19.504, 20.01265, 20.58808, 20.43302, 20.72112, 21.12683, 21.91906, 22.59202, 24.44788, 24.15917, 24.48119, 25.70071, 26.10094, 26.581 27, 27.16767, 27.54165, 27.71408, 28.27603, 28.09725, 28.54909, 29.02939, 29.71314, 30.07578, 30.68808, 30.92867, 31.6379, 32.27005, 32.79806, 33.20638, 33.23304, 33.65808, 34.41793, 34.35512, 35.02142, 35.06671, 35.689 and 40.22464, wherein each peak may vary by ±1 degree, or preferably ±0.5 degrees, or even more preferably ±0.2 degrees.In another particularly preferred embodiment, Form I crystals of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate are provided, having the following 2Θ values: 6.023129, 9.969034, 11.26224, 11.22848, 11.96566, 12.77761, 13.79347, 14.39314, 15.3394, 16.00317, and 16.2733 7, 17.07502, 17.27593, 17.9904, 18.38238, 18.65471, 18.96096, 19.14281, 19.504, 20.01265, 20.58808, 20.43302, 20.72112, 21.12683, 21.91906, 22.59202, 24.44788, 24.15917, 24.48119, 25.70071, 26.10094, 26.58127, 2 7.16767, 27.54165, 27.71408, 28.27603, 28.09725, 28.54909, 29.02939, 29.71314, 30.07578, 30.68808, 30.92867, 31.6379, 32.27005, 32.79806, 33.20638, 33.23304, 33.65808, 34.41793, 34.35512, 35.02142, 35.06671, 3 The compound is characterized by a powder X-ray diffraction pattern including at least one, more preferably 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or all of the following peaks: 5.68978, 35.93622, 36.50305, 36.56591, 36.92023, 37.14021, 39.60815, 37.89624, and 40.22464, wherein each peak may vary by ±0.5 degrees, or preferably ±0.2 degrees. In one embodiment, the three largest peaks of crystalline Form I in the XRPD diffractogram have relative intensities of 1 vs. 0.85 vs. 0.55, particularly 1 vs. 0.9 vs. 0.6, more particularly 1 vs. 0.95 vs. 0.65, for example 1 vs. 0.97 vs. 0.68 (obtained by integration of each peak in the XRPD diagram). In certain embodiments, the largest peak is at a 2-theta (θ) value of about 21.919, the second largest peak is at a 2-theta (θ) value of about 19.504, and the third largest peak is at a 2-theta (θ) value of about 24.159, respectively.In further specific embodiments, the largest peak is at a 2-theta (θ) value of about 21.919±0.5 degrees, or preferably ±0.2 degrees, the second largest peak is at a 2-theta (θ) value of about 19.504±0.5 degrees, or preferably ±0.2 degrees, and the third largest peak is at a 2-theta (θ) value of about 24.159±0.5 degrees, or preferably ±0.2 degrees, respectively.

[0096] Activity of the compounds of the present invention As shown in Examples 1-5 below, compounds of the present invention successfully corrected both biochemical (e.g., ARR) and clinical dysregulation (e.g., hypertension) caused by primary aldosteronism (i.e., in patients with primary aldosteronism). As shown in Example 2, Tables 1 and 2, and Figures 2A and 2B, treatment with dexfadrostat phosphate reduced median plasma ARR and mean 24-hour aSBP from baseline over a 56-day period at all doses tested (i.e., 4 mg, 8 mg, 12 mg).

[0097] The median ARR decreased from 15.3 to 0.6 (ng / dL) / (mU / L) in patients from baseline to day 56. The mean 24-hour aSBP decreased by 10.7 mmHg from baseline to day 56.

[0098] As shown in Example 2, Table 7, compounds of the present invention successfully treated patients with unilateral disease (e.g., unilateral adenoma or unilateral nodule). Specifically, in each dose group, the treatment outcomes (e.g., ARR) of patients with unilateral PA were similar to those of patients with bilateral PA or PA of undetermined cause (idiopathic PA). Without wishing to be bound by theory, patients with unilateral primary aldosteronism (e.g., unilateral adenoma) are characterized by extreme aldosterone and potassium levels and typically require adrenal surgery for management. As shown in Example 2, Table 7, and Figures 3A and 3B, patients with unilateral PA were effectively treated with compounds of the present invention (e.g., dexfadrostat phosphate) at the tested doses, and patients with unilateral PA responded similarly to patients with bilateral PA or PA of undetermined cause (idiopathic PA).

[0099] As shown in Example 3, Table 8, and Figures 4A, 4B, and 4C, all three doses tested (i.e., 4 mg, 8 mg, and 12 mg) mediated significant reductions (P<0.0001) in ARR from baseline to day 56. The 4 mg dose was only slightly less potent than the 8 mg dose, and the 12 mg dose was less potent than the 8 mg dose.

[0100] As shown in Example 4, Table 10, and Figures 4G, 4H, and 4I, treatment with dexfadrostat phosphate at all three doses tested (i.e., 4 mg, 8 mg, and 12 mg) mediated a significant decrease (P<0.0001) in the content of tetrahydroaldosterone, the major metabolite of aldosterone (24-hour urine samples collected at the end of active treatment were compared with baseline samples). Thus, in some embodiments, the present invention provides the use of compounds of the present invention for treating diseases characterized by abnormal urinary aldosterone content.

[0101] As shown in Example 5, Tables 11-13, and Figures 5A-5F, treatment with dexfadrostat phosphate at all three doses tested mediated rapid and significant (p<0.0001) reductions in ARR, increases in plasma potassium, and decreases in blood pressure from baseline to visits on days 14, 28, 42, and 56. The reductions in ARR, plasma potassium, and blood pressure remained sustained throughout the active treatment period. Surprisingly, for all three clinical endpoints tested, the 4 mg dose was nearly as effective as the 8 mg dose, and the 12 mg dose provided no additional clinical benefit.

[0102] Thus, in some aspects, the present invention provides use of a compound of the present invention for the rapid treatment of a disease or disorder (e.g., a disease or disorder in which excessive aldosterone exposure contributes to the symptoms of the disease or disorder). Preferably, the rapid treatment of the disease comprises treatment within 14 days. Without wishing to be bound by theory, current clinical responses to surgical and medical treatments can take 3 to 12 months to occur.

[0103] Moreover, in some aspects, the present invention provides for the use of compounds of the present invention for continuous treatment over long-term treatment periods (e.g., greater than 8 weeks) without dose adjustment (e.g., at a constant once-daily dose of 4 mg or 8 mg). Without wishing to be bound by theory, current medical treatments require biweekly dose adjustments.

[0104] As shown in the following examples, compounds of the present invention successfully treated hypokalemia, e.g., severe and / or potassium-resistant hypokalemia. Compounds of the present invention were able to treat hypokalemia in patients suffering from chronic cardiovascular disease or disorder (e.g., primary aldosteronism). Without wishing to be bound by theory, in some embodiments, compounds of the present invention can also be used to treat hypokalemia, e.g., severe and / or potassium-resistant hypokalemia, in patients without cardiovascular disease or disorder, e.g., patients without primary aldosteronism.

[0105] Treatment method In one aspect, the invention provides a composition for use in treating a disease or disorder, wherein the composition is administered once daily to a subject in need thereof, and the composition comprises a compound that is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, and the compound has an enantiomeric excess (ee) of the (R) form of about 99% or greater.

[0106] In one aspect, the invention provides a composition for use in treating a disease or disorder, wherein the composition is administered once daily to a subject in need thereof for at least 8 weeks, and the composition comprises a compound that is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, wherein the compound has an enantiomeric excess (ee) of the (R) form of about 99% or greater.

[0107] In preferred embodiments, the subject in need of a composition of the present invention is a mammal. More preferably, the subject is a human. Preferably, the human includes women of childbearing potential and pediatric patients. In preferred embodiments, the human is women of childbearing potential and pediatric patients. In some embodiments, the subject is a human.

[0108] In some embodiments, the compositions are administered orally, preferably in tablet or capsule form, and even more preferably in capsule form.

[0109] In some embodiments, the composition is administered to the subject once daily at a dose of about 1 mg to about 12 mg of the compound. In preferred embodiments, the composition is administered to the subject once daily at a dose of about 1 mg to about 8 mg of the compound. In preferred embodiments, the composition is administered to the subject once daily at a dose of 1 mg to 8 mg of the compound. In some embodiments, the composition is administered to the subject once daily at a dose of about 4 mg or about 8 mg of the compound. In some embodiments, the composition is administered to the subject once daily at a dose of 4 mg or 8 mg of the compound.

[0110] In some embodiments, the composition is administered to the subject once daily at a dosage of about 1 mg of the compound. In some embodiments, the composition is administered to the subject once daily at a dosage of about 2 mg of the compound. In some embodiments, the composition is administered to the subject once daily at a dosage of about 3 mg of the compound. In some embodiments, the composition is administered to the subject once daily at a dosage of about 4 mg of the compound. In some embodiments, the composition is administered to the subject once daily at a dosage of about 5 mg of the compound. In some embodiments, the composition is administered to the subject once daily at a dosage of about 6 mg of the compound. In some embodiments, the composition is administered to the subject once daily at a dosage of about 7 mg of the compound. In some embodiments, the composition is administered to the subject once daily at a dosage of about 8 mg of the compound.

[0111] In a preferred embodiment, the composition is administered to the subject once daily at a dosage of about 1 mg to about 8 mg of the compound, wherein the once daily administration does not require dose adjustment, preferably, the once daily administration does not require dose adjustment for at least 8 weeks, preferably at least 6 months, preferably at least 1 year, preferably at least 5 years, more preferably at least 10 years, and more preferably, the once daily administration does not require dose adjustment at all.

[0112] In a preferred embodiment, the composition is administered to the subject once daily at a once-daily dose of about 4 mg for at least 8 weeks, preferably at least 6 months, preferably at least 1 year, preferably at least 5 years, and more preferably at least 10 years, and more preferably, the once-daily administration does not require any dose adjustment. In a preferred embodiment, the composition is administered to the subject once daily at a once-daily dose of about 8 mg for at least 8 weeks, preferably at least 6 months, preferably at least 1 year, preferably at least 5 years, and more preferably at least 10 years, and more preferably, the once-daily administration does not require any dose adjustment.

[0113] In some embodiments, the subject requires rapid treatment of the disease or disorder. In one aspect, the present invention involves inducing a clinical response in a subject in need thereof, preferably within about 14 days of treatment. In some embodiments, the clinical response is selected from a reduction in plasma aldosterone levels, a normalization of plasma aldosterone levels, a reduction in blood pressure, a normalization of blood pressure, a reduction in hypokalemia, a normalization of potassium levels, and a reduction in urinary THA. Preferably, the reduction in plasma aldosterone levels comprises achieving about <15 ng / dL (about <410 pmol / L) in patients with unilateral PA and about <10 ng / dL (about <275 pmol / L) in patients with bilateral PA. Preferably, the normalization of plasma aldosterone levels comprises achieving about <15 ng / dL (about <410 pmol / L) in patients with unilateral PA and about <10 ng / dL (about <275 pmol / L) in patients with bilateral PA. Preferably, the lowering of blood pressure comprises achieving a systolic blood pressure of about <135 mmHg and a diastolic blood pressure of about <85 mmHg, preferably a systolic blood pressure of about <130 mmHg and a diastolic blood pressure of about <80 mmHg, in the subject. Preferably, the normalization of blood pressure comprises achieving a systolic blood pressure of about <135 mmHg and a diastolic blood pressure of about <85 mmHg, preferably a systolic blood pressure of about <130 mmHg and a diastolic blood pressure of about <80 mmHg, in the subject. Preferably, the alleviation of hypokalemia comprises achieving a plasma potassium concentration of about 3.6 mmol / L to 5.2 mmol / L. Preferably, the normalization of potassium concentration comprises achieving a plasma potassium concentration of about 3.6 mmol / L to 5.2 mmol / L. Preferably, the reduction of urinary THA comprises achieving a urinary tetrahydroaldosterone excretion of less than about 12 μg / 24 hours.In one aspect, the clinical response is a reduction in ARR, preferably the ARR is reduced to less than about 5 (ng / dL) / (mU / L), preferably the ARR is reduced to less than about 4 (ng / dL) / (mU / L), preferably the ARR is reduced to less than about 3.7 (ng / dL) / (mU / L), preferably the ARR is reduced to less than about 3.5 (ng / dL) / (mU / L), preferably the ARR is reduced to less than about 3 (ng / dL) / (mU / L), preferably the ARR is reduced to less than about 2 (ng / dL) / (mU / L), preferably the ARR is reduced to less than about 1 (ng / dL) / (mU / L), preferably the ARR is reduced to less than about 0.55 (ng / dL) / (mU / L).

[0114] In some embodiments, the subject exhibits a clinical response within 14 days of treatment, wherein the clinical response is a decrease in plasma aldosterone levels. Preferably, the decrease in plasma aldosterone levels comprises achieving about <15 ng / dL (about <410 pmol / L) in patients with unilateral PA and about <10 ng / dL (about <275 pmol / L) in patients with bilateral PA. In some embodiments, the subject exhibits a clinical response within 14 days of treatment, wherein the clinical response is a normalization of plasma aldosterone levels. Preferably, the normalization of plasma aldosterone levels comprises achieving about <15 ng / dL (about <410 pmol / L) in patients with unilateral PA and about <10 ng / dL (about <275 pmol / L) in patients with bilateral PA. In some embodiments, the subject exhibits a clinical response within 14 days of treatment, wherein the clinical response is a decrease in blood pressure. Preferably, the reduction in blood pressure comprises achieving in the subject a systolic blood pressure of about <135 mmHg and a diastolic blood pressure of about <85 mmHg, preferably a systolic blood pressure of about <130 mmHg and a diastolic blood pressure of about <80 mmHg. In some embodiments, the subject exhibits a clinical response within 14 days of treatment, wherein the clinical response is a normalization of blood pressure. Preferably, the normalization of blood pressure comprises achieving in the subject a systolic blood pressure of about <135 mmHg and a diastolic blood pressure of about <85 mmHg, preferably a systolic blood pressure of about <130 mmHg and a diastolic blood pressure of about <80 mmHg. In some embodiments, the subject exhibits a clinical response within 14 days of treatment, wherein the clinical response is a reduction in hypokalemia. Preferably, the reduction in hypokalemia comprises achieving a plasma potassium level of about 3.6 mmol / L to 5.2 mmol / L. In some embodiments, the subject exhibits a clinical response within 14 days of treatment, wherein the clinical response is a normalization of potassium levels. Preferably, the normalization of potassium levels comprises achieving a plasma potassium level of about 3.6 mmol / L to 5.2 mmol / L. In some embodiments, the subject exhibits a clinical response within 14 days of treatment, wherein the clinical response is a reduction in urinary THA. Preferably, the reduction in urinary THA comprises achieving a urinary tetrahydroaldosterone excretion of less than about 12 μg / 24 hours.

[0115] In some embodiments, the disease or disorder is one in which excessive exposure to aldosterone contributes to the symptoms of the disease or disorder. In some embodiments, the disease or disorder is selected from the group consisting of primary aldosteronism, secondary aldosteronism, heart failure, chronic renal failure, hypertension, restenosis, obesity, nephropathy, post-myocardial infarction, renal fibrosis, coronary heart disease, sodium retention, water retention, hypokalemia, hypomagnesemia, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular injury, suppression of plasma renin, renal fibrosis, arrhythmias, nephropathy, edema, muscle weakness due to hypokalemia, cardiac fibrillation, and weakened myocardial contractility; Preferably, the disease or disorder is selected from the group consisting of primary aldosteronism, secondary aldosteronism, heart failure, chronic renal failure, hypertension, restenosis, obesity, nephropathy, post-myocardial infarction, renal fibrosis, coronary heart disease, sodium retention, water retention, hypokalemia, hypomagnesemia, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular injury, plasma renin suppression, renal fibrosis, arrhythmia, nephropathy, and edema.

[0116] In a preferred embodiment, the disease or disorder is selected from the group consisting of primary aldosteronism and secondary aldosteronism. In a preferred embodiment, the disease or disorder is primary aldosteronism. In a preferred embodiment, the disease or disorder is secondary aldosteronism.

[0117] In a preferred embodiment, the disease or disorder is characterized by abnormal urinary aldosterone and / or tetrahydroaldosterone content. Preferably, the disease or disorder characterized by abnormal urinary aldosterone and / or tetrahydroaldosterone content is selected from primary aldosteronism, secondary aldosteronism, heart failure, chronic renal failure, hypertension, restenosis, obesity, nephropathy, post-myocardial infarction, renal fibrosis, coronary heart disease, sodium retention, water retention, hypokalemia, hypomagnesemia, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular damage, plasma renin suppression, renal fibrosis, arrhythmia, nephropathy, edema, muscle weakness due to hypokalemia, cardiac fibrillation, and weakened myocardial contractility.

[0118] Preferably, the disease or disorder characterized by abnormal urinary aldosterone and / or tetrahydroaldosterone content is selected from the group consisting of primary aldosteronism, secondary aldosteronism, heart failure, chronic renal failure, hypertension, restenosis, obesity, nephropathy, post-myocardial infarction, renal fibrosis, coronary heart disease, sodium retention, water retention, hypokalemia, hypomagnesemia, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular injury, plasma renin suppression, renal fibrosis, arrhythmia, nephropathy, and edema.

[0119] In a preferred embodiment, the disease or disorder characterized by abnormal urinary aldosterone and / or tetrahydroaldosterone content is selected from primary aldosteronism, secondary aldosteronism, heart failure, renal failure, resistant hypertension, essential hypertension, nephropathy, edema, coronary heart disease, hypokalemia, and cardiac arrhythmias.

[0120] In a preferred embodiment, the disease or disorder characterized by abnormal urinary aldosterone and / or tetrahydroaldosterone content is selected from heart failure, renal failure, resistant hypertension, and essential hypertension.

[0121] In a preferred embodiment, the disease or disorder is selected from the group consisting of primary aldosteronism and secondary aldosteronism. In a preferred embodiment, the disease or disorder is primary aldosteronism. In a preferred embodiment, the disease or disorder is secondary aldosteronism.

[0122] In some embodiments, the primary aldosteronism is unilateral or bilateral primary aldosteronism, hi some embodiments, the unilateral or bilateral primary aldosteronism is caused by unilateral adenoma, bilateral adenoma, unilateral nodule, bilateral nodule, unilateral hyperplasia, bilateral hyperplasia, or normal-appearing adrenal glands.

[0123] In a highly preferred embodiment, the disease or disorder is unilateral primary aldosteronism. In a preferred embodiment, the disease or disorder is unilateral primary aldosteronism caused by an aldosterone-producing adenoma (benign tumor), a unilateral nodule, adrenal carcinoma, or hyperplasia, preferably unilateral hyperplasia. In a preferred embodiment, the disease or disorder is unilateral primary aldosteronism caused by an aldosterone-producing adenoma (benign tumor). In a preferred embodiment, the disease or disorder is unilateral primary aldosteronism caused by adrenal carcinoma. In a preferred embodiment, the disease or disorder is unilateral primary aldosteronism caused by hyperplasia, preferably unilateral hyperplasia. In a preferred embodiment, the disease or disorder is unilateral primary aldosteronism caused by a unilateral nodule.

[0124] In a preferred embodiment, the primary aldosteronism is unilateral primary aldosteronism, and the unilateral primary aldosteronism is undetected or undiagnosed.

[0125] In some embodiments, the primary aldosteronism is bilateral primary aldosteronism, e.g., bilateral adenomas.

[0126] In a preferred embodiment, the disease or disorder is essential hypertension and / or resistant hypertension, and preferably, the disease or disorder is essential hypertension and / or resistant hypertension accompanied by hypokalemia. In a preferred embodiment, the disease or disorder is hypokalemia.

[0127] In one aspect, the present invention provides a composition for use in treating a disease or disorder, the composition being administered once daily to a subject in need thereof for at least 8 weeks, the composition comprising a compound that is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, the compound having an enantiomeric excess (ee) of the (R) form of about 99% or greater, and the disease or disorder is unilateral primary aldosteronism, preferably, the unilateral primary aldosteronism is caused by an aldosterone-producing adenoma (benign tumor), a unilateral nodule, adrenal carcinoma, or hyperplasia, preferably unilateral hyperplasia.

[0128] In one aspect, the invention provides a composition for use in treating a disease or disorder characterized by abnormal urinary aldosterone content, wherein the composition is administered once daily to a subject in need thereof for at least 8 weeks, the composition comprising a compound that is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, wherein the compound has an enantiomeric excess (ee) of the (R) form of about 99% or greater.

[0129] In one aspect, the present invention provides a composition for use in eliciting a clinical outcome in a subject in need thereof, the composition being administered once daily to the subject for at least 8 weeks, the composition comprising a compound that is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, the compound having an enantiomeric excess (ee) of the (R) form of the compound of about 99% or greater. In some embodiments, the clinical outcome is selected from a reduction in plasma aldosterone levels, a normalization of plasma aldosterone levels, a reduction in blood pressure, a normalization of blood pressure, a reduction in hypokalemia, a normalization of plasma potassium, and a reduction in urinary THA.

[0130] In some embodiments, the present invention provides a composition for use in reducing plasma aldosterone levels in a subject in need thereof, the composition being administered once daily to the subject for at least 8 weeks, the composition comprising a compound that is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, the compound having an enantiomeric excess (ee) of the (R) form of about 99% or greater. Preferably, the plasma aldosterone levels are reduced to normal and / or non-pathological levels.

[0131] In some embodiments, the present invention provides a composition for use in normalizing plasma aldosterone levels in a subject in need thereof, the composition being administered once daily to the subject for at least 8 weeks, the composition comprising a compound that is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, the compound having an enantiomeric excess (ee) of the (R) form of about 99% or greater. Preferably, the plasma aldosterone levels are reduced to normal and / or non-pathological levels.

[0132] In some embodiments, the present invention provides a composition for use in lowering blood pressure in a subject in need thereof, the composition being administered once daily to the subject for at least 8 weeks, the composition comprising a compound that is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, the compound having an enantiomeric excess (ee) of the (R) form of the compound of about 99% or greater. Preferably, the blood pressure is lowered to normal and / or non-pathological levels. In some embodiments, the blood pressure is measured by aSBP. In some embodiments, the blood pressure is measured by oSPB.

[0133] In some embodiments, the present invention provides a composition for use in normalizing blood pressure in a subject in need thereof, the composition being administered once daily to the subject for at least 8 weeks, the composition comprising a compound that is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, the compound having an enantiomeric excess (ee) of the (R) form of the compound of about 99% or greater. Preferably, the blood pressure is reduced to normal and / or non-pathological levels. In some embodiments, the blood pressure is measured by aSBP. In some embodiments, the blood pressure is measured by oSPB.

[0134] In some embodiments, the present invention provides a composition for use in reducing hypokalemia in a subject in need thereof, the composition being administered once daily to the subject for at least 8 weeks, the composition comprising a compound that is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, the compound having an enantiomeric excess (ee) of the (R) form of about 99% or greater. Preferably, the hypokalemia is reduced to normal and / or non-pathological levels.

[0135] In some embodiments, the present invention provides a composition for use in normalizing plasma potassium levels in a subject in need thereof, the composition being administered once daily to the subject for at least 8 weeks, the composition comprising a compound that is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, the compound having an enantiomeric excess (ee) of the (R) form of about 99% or greater. Preferably, the plasma potassium level is increased to a normal and / or non-pathological level.

[0136] In some embodiments, the present invention provides a composition for use in reducing urinary THA levels in a subject in need thereof, the composition being administered once daily to the subject for at least 8 weeks, the composition comprising a compound that is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, the compound having an enantiomeric excess (ee) of the (R) form of about 99% or greater. Preferably, the urinary THA levels are reduced to normal and / or non-pathological levels.

[0137] In one aspect, the invention provides a composition for use in treating a disease or disorder, the composition being administered once daily to a subject in need thereof for at least 8 weeks, the composition comprising a compound that is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, the compound having an enantiomeric excess (ee) of the (R) form of about 99% or greater, and wherein the disease or disorder is The present invention provides a composition for treating a myocardial infarction syndrome, which is selected from the group consisting of primary aldosteronism, secondary aldosteronism, heart failure, chronic renal failure, hypertension, restenosis, obesity, nephropathy, post-myocardial infarction, renal fibrosis, coronary heart disease, sodium retention, water retention, hypokalemia, hypomagnesemia, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular damage, suppression of plasma renin, renal fibrosis, arrhythmia, nephropathy, edema, muscle weakness due to hypokalemia, cardiac fibrillation, and weakened myocardial contraction.

[0138] In one aspect, the invention provides a composition for use in treating a disease or disorder, wherein the composition is administered once daily to a subject in need thereof for at least 8 weeks, the composition comprising a compound that is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, wherein the compound has an enantiomeric excess (ee) of the (R) form of about 99% or greater, and the disease or disorder is selected from the group consisting of primary aldosteronism and secondary aldosteronism.

[0139] In one aspect, the invention provides a composition for use in treating a disease or disorder, wherein the composition is administered once daily to a subject in need thereof for at least 8 weeks, the composition comprising a compound that is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, wherein the compound has an enantiomeric excess (ee) of the (R) form of about 99% or greater, and the disease or disorder is primary aldosteronism.

[0140] In one aspect, the invention provides a composition for use in treating a disease or disorder, wherein the composition is administered once daily to a subject in need thereof for at least 8 weeks, the composition comprising a compound that is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, wherein the compound has an enantiomeric excess (ee) of the (R) form of about 99% or greater, and the disease or disorder is secondary aldosteronism.

[0141] In one aspect, the invention provides a composition for use in treating a disease or disorder, the composition being administered once daily to a subject in need thereof for at least 8 weeks, the composition comprising a compound that is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, the compound having an enantiomeric excess (ee) of the (R) form of about 99.5% or greater, preferably about 99.9% or greater, and the disease or disorder is selected from the group consisting of primary aldosteronism and secondary aldosteronism.

[0142] In one aspect, the present invention provides a composition for use in treating a disease or disorder, the composition being administered at a dose of 4 mg once daily for at least 8 weeks to a subject in need thereof, the composition comprising a compound that is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, the compound having an enantiomeric excess (ee) of the (R) form of about 99.5% or greater, preferably about 99.9% or greater, the disease or disorder being selected from the group consisting of primary aldosteronism and secondary aldosteronism, and preferably the 4 mg once daily dose remaining unchanged for at least 8 weeks.

[0143] In one aspect, the present invention provides a composition for use in treating a disease or disorder, the composition being administered at a dose of 8 mg once daily for at least 8 weeks to a subject in need thereof, the composition comprising a compound that is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, the compound having an enantiomeric excess (ee) of the (R) form of about 99.5% or greater, preferably about 99.9% or greater, the disease or disorder being selected from the group consisting of primary aldosteronism and secondary aldosteronism, and preferably the 8 mg once daily dose remaining unchanged for at least 8 weeks.

[0144] In one aspect, the present invention provides a composition for use in treating a disease or disorder, the composition being administered at a dose of 4 mg once daily for at least 8 weeks to a subject in need thereof, the composition comprising a compound that is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, the compound having an enantiomeric excess (ee) of the (R) form of about 99.5% or greater, preferably about 99.9% or greater, and the disease or disorder is primary aldosteronism, preferably unilateral primary aldosteronism, more preferably, the unilateral primary aldosteronism is caused by an aldosterone-producing adenoma (benign tumor), a unilateral nodule, adrenal carcinoma, or hyperplasia, preferably unilateral hyperplasia.

[0145] In one aspect, the present invention provides a composition for use in treating a disease or disorder, the composition being administered at a dose of 8 mg once daily to a subject in need thereof for at least 8 weeks, the composition comprising a compound that is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, the compound having an enantiomeric excess (ee) of the (R) form of about 99.5% or greater, preferably about 99.9% or greater, and the disease or disorder is primary aldosteronism, preferably unilateral primary aldosteronism, more preferably, the unilateral primary aldosteronism is caused by an aldosterone-producing adenoma (benign tumor), a unilateral nodule, adrenal carcinoma, or hyperplasia, preferably unilateral hyperplasia.

[0146] In one aspect, the present invention provides a composition for use in treating a disease or disorder, the composition being administered once daily to a subject in need thereof for at least 8 weeks, the composition comprising a compound that is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, the compound having an enantiomeric excess (ee) of the (R) form of the compound of about 99% or greater, the disease or disorder being unilateral primary aldosteronism, the composition being orally administered once daily to the subject at a dose of about 4 mg or about 8 mg of the compound, and the once-daily dose not requiring dose adjustment. In a preferred embodiment, the unilateral primary aldosteronism is caused by an aldosterone-producing adenoma (benign tumor), a unilateral nodule, adrenal carcinoma, or hyperplasia, preferably unilateral hyperplasia. In a preferred embodiment, the compound is administered in a dosage of about 4 mg. In a preferred embodiment, the compound is administered in a dosage of about 8 mg. Preferably, the compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate.

[0147] In one aspect, the present invention provides a composition for use in treating unilateral primary aldosteronism, the composition being orally administered once daily at a dose of about 4 mg for at least 8 weeks to a subject in need thereof, the composition comprising a compound that is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, the compound having an enantiomeric excess (ee) of the (R) form of about 99% or greater. In a preferred embodiment, the unilateral primary aldosteronism is caused by an aldosterone-producing adenoma (benign tumor), a unilateral nodule, adrenal carcinoma, or hyperplasia, preferably unilateral hyperplasia.

[0148] In one aspect, the present invention provides a composition for use in treating unilateral primary aldosteronism, the composition being orally administered once daily at a dose of about 8 mg for at least 8 weeks to a subject in need thereof, the composition comprising a compound that is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, the compound having an enantiomeric excess (ee) of the (R) form of about 99% or greater. In a preferred embodiment, the unilateral primary aldosteronism is caused by an aldosterone-producing adenoma (benign tumor), a unilateral nodule, adrenal carcinoma, or hyperplasia, preferably unilateral hyperplasia.

[0149] In one aspect, the invention provides a composition for use in treating a disease or disorder, wherein the disease or disorder is a chronic cardiovascular disease or disorder associated with hypokalemia, wherein the composition is orally administered once daily to a subject in need thereof, preferably for at least 8 weeks, and wherein the composition comprises a compound that is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, and wherein the compound has an enantiomeric excess (ee) of the (R) form of about 99% or greater.

[0150] In one aspect, the invention provides a composition for use in treating a disease or disorder, wherein the disease or disorder is a chronic cardiovascular disease or disorder associated with hypokalemia, wherein the composition is orally administered once daily to a subject in need thereof, preferably for at least 8 weeks, and wherein the composition comprises a compound that is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, and wherein the compound has an enantiomeric excess (ee) of the (R) form of about 99% or greater.

[0151] In some aspects, the chronic cardiovascular disease or disorder associated with hypokalemia is selected from primary aldosteronism, secondary aldosteronism, heart failure, hypertension, restenosis, post-myocardial infarction, coronary heart disease, sodium retention, water retention, hypomagnesemia, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular damage, suppression of plasma renin, arrhythmias, edema, muscle weakness due to hypokalemia, cardiac fibrillation and weakened myocardial contractility; preferably, the chronic cardiovascular disease or disorder associated with hypokalemia is selected from the group consisting of primary aldosteronism, secondary aldosteronism, heart failure, hypertension, restenosis, post-myocardial infarction, coronary heart disease, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular damage, arrhythmias, and edema.

[0152] In some aspects, the chronic cardiovascular disease or disorder associated with hypokalemia is selected from primary aldosteronism, secondary aldosteronism, heart failure, hypertension, restenosis, post-myocardial infarction, coronary heart disease, sodium retention, water retention, hypomagnesemia, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular damage, suppression of plasma renin, arrhythmias, edema, muscle weakness due to hypokalemia, cardiac fibrillation and weakened myocardial contractility; preferably, said chronic cardiovascular disease or disorder associated with hypokalemia is selected from the group consisting of primary aldosteronism, secondary aldosteronism, heart failure, hypertension, restenosis, post-myocardial infarction, coronary heart disease, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular damage, arrhythmias, and edema.

[0153] In some aspects, the chronic cardiovascular disease or disorder associated with hypokalemia is primary aldosteronism with hypokalemia. In some aspects, the chronic cardiovascular disease or disorder associated with hypokalemia is primary aldosteronism associated with hypokalemia.

[0154] In some aspects, the chronic cardiovascular disease or disorder associated with hypokalemia is hyperaldosteronism with hypokalemia. In some aspects, the chronic cardiovascular disease or disorder associated with hypokalemia is hyperaldosteronism associated with hypokalemia.

[0155] In some aspects, the chronic cardiovascular disease or disorder associated with hypokalemia is primary aldosteronism with severe hypokalemia. In some aspects, the chronic cardiovascular disease or disorder associated with hypokalemia is primary aldosteronism associated with severe hypokalemia.

[0156] In some aspects, the chronic cardiovascular disease or disorder associated with hypokalemia is hyperaldosteronism with severe hypokalemia. In some aspects, the chronic cardiovascular disease or disorder associated with hypokalemia is hyperaldosteronism associated with severe hypokalemia.

[0157] In some aspects, the chronic cardiovascular disease or disorder associated with hypokalemia is primary aldosteronism with potassium-resistant hypokalemia. In some aspects, the chronic cardiovascular disease or disorder associated with hypokalemia is primary aldosteronism associated with potassium-resistant hypokalemia.

[0158] In some aspects, the chronic cardiovascular disease or disorder associated with hypokalemia is hyperaldosteronism with potassium-resistant hypokalemia. In some aspects, the chronic cardiovascular disease or disorder associated with hypokalemia is hyperaldosteronism associated with potassium-resistant hypokalemia.

[0159] In some embodiments, the composition is administered to the subject once daily at a dosage of about 1 mg to about 12 mg of the compound. In some embodiments, the compound is administered at a dosage of about 4 mg. In some embodiments, the compound is administered at a dosage of about 8 mg.

[0160] In one aspect, the invention provides a composition for use in treating a disease or disorder, wherein the disease or disorder is hypokalemia, wherein the composition is orally administered once daily to a subject in need thereof, preferably for at least 8 weeks, and wherein the composition comprises a compound that is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, and wherein the compound has an enantiomeric excess (ee) of the (R) form of about 99% or greater.

[0161] In some embodiments, the hypokalemia is severe hypokalemia, hi some embodiments, the hypokalemia is potassium-resistant hypokalemia.

[0162] In some embodiments, the hypokalemia is hypokalemia associated with a chronic cardiovascular disease or disorder. In preferred embodiments, the chronic cardiovascular disease or disorder is selected from primary aldosteronism, secondary aldosteronism, heart failure, hypertension, restenosis, post-myocardial infarction, coronary heart disease, sodium retention, water retention, hypomagnesemia, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular damage, suppression of plasma renin, arrhythmias, edema, muscle weakness due to hypokalemia, cardiac fibrillation, and weakened myocardial contractility; preferably, the chronic cardiovascular disease or disorder is selected from the group consisting of primary aldosteronism, secondary aldosteronism, heart failure, hypertension, restenosis, post-myocardial infarction, coronary heart disease, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular damage, arrhythmias, and edema. In even more preferred embodiments, the hypokalemia is hypokalemia associated with a chronic cardiovascular disease or disorder, and the chronic cardiovascular disease or disorder is primary aldosteronism. In some preferred embodiments, the hypokalemia is hypokalemia associated with a chronic cardiovascular disease or disorder, and the chronic cardiovascular disease or disorder is hyperaldosteronism.

[0163] In some embodiments, the severe hypokalemia is severe hypokalemia associated with a chronic cardiovascular disease or disorder. In preferred embodiments, the chronic cardiovascular disease or disorder is selected from primary aldosteronism, secondary aldosteronism, heart failure, hypertension, restenosis, post-myocardial infarction, coronary heart disease, sodium retention, water retention, hypomagnesemia, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular damage, suppression of plasma renin, arrhythmias, edema, muscle weakness due to hypokalemia, cardiac fibrillation, and weakened myocardial contractility; preferably, the chronic cardiovascular disease or disorder is selected from the group consisting of primary aldosteronism, secondary aldosteronism, heart failure, hypertension, restenosis, post-myocardial infarction, coronary heart disease, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular damage, arrhythmias, and edema. In even more preferred embodiments, the severe hypokalemia is severe hypokalemia associated with a chronic cardiovascular disease or disorder, and the chronic cardiovascular disease or disorder is primary aldosteronism. In some preferred embodiments, the severe hypokalemia is severe hypokalemia associated with a chronic cardiovascular disease or disorder, and the chronic cardiovascular disease or disorder is hyperaldosteronism.

[0164] In some embodiments, the potassium-resistant hypokalemia is potassium-resistant hypokalemia associated with a chronic cardiovascular disease or disorder. In preferred embodiments, the chronic cardiovascular disease or disorder is selected from primary aldosteronism, secondary aldosteronism, heart failure, hypertension, restenosis, post-myocardial infarction, coronary heart disease, sodium retention, water retention, hypomagnesemia, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular damage, suppression of plasma renin, arrhythmias, edema, muscle weakness due to hypokalemia, cardiac fibrillation, and weakened myocardial contractility; preferably, the chronic cardiovascular disease or disorder is selected from the group consisting of primary aldosteronism, secondary aldosteronism, heart failure, hypertension, restenosis, post-myocardial infarction, coronary heart disease, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular damage, arrhythmias, and edema. In even more preferred embodiments, the potassium-resistant hypokalemia is potassium-resistant hypokalemia associated with a chronic cardiovascular disease or disorder, and the chronic cardiovascular disease or disorder is primary aldosteronism. In some preferred embodiments, the potassium-resistant hypokalemia is potassium-resistant hypokalemia associated with a chronic cardiovascular disease or disorder, and the chronic cardiovascular disease or disorder is hyperaldosteronism.

[0165] In some embodiments, the severe hypokalemia is severe hypokalemia associated with a chronic cardiovascular disease or disorder. In preferred embodiments, the chronic cardiovascular disease or disorder is selected from primary aldosteronism, secondary aldosteronism, heart failure, hypertension, restenosis, post-myocardial infarction, coronary heart disease, sodium retention, water retention, hypomagnesemia, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular damage, suppression of plasma renin, arrhythmias, edema, muscle weakness due to hypokalemia, cardiac fibrillation, and weakened myocardial contractility; preferably, the chronic cardiovascular disease or disorder is selected from the group consisting of primary aldosteronism, secondary aldosteronism, heart failure, hypertension, restenosis, post-myocardial infarction, coronary heart disease, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular damage, arrhythmias, and edema. In even more preferred aspects, the severe hypokalemia is severe hypokalemia associated with a chronic cardiovascular disease or disorder, and the chronic cardiovascular disease or disorder is primary aldosteronism. In some preferred aspects, the severe hypokalemia is severe hypokalemia associated with a chronic cardiovascular disease or disorder, and the chronic cardiovascular disease or disorder is hyperaldosteronism.

[0166] In some embodiments, the potassium-resistant hypokalemia is potassium-resistant hypokalemia associated with a chronic cardiovascular disease or disorder. In preferred embodiments, the chronic cardiovascular disease or disorder is selected from primary aldosteronism, secondary aldosteronism, heart failure, hypertension, restenosis, post-myocardial infarction, coronary heart disease, sodium retention, water retention, hypomagnesemia, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular damage, suppression of plasma renin, arrhythmias, edema, muscle weakness due to hypokalemia, cardiac fibrillation, and weakened myocardial contractility; preferably, the chronic cardiovascular disease or disorder is selected from the group consisting of primary aldosteronism, secondary aldosteronism, heart failure, hypertension, restenosis, post-myocardial infarction, coronary heart disease, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular damage, arrhythmias, and edema. In even more preferred aspects, the potassium-resistant hypokalemia is potassium-resistant hypokalemia associated with a chronic cardiovascular disease or disorder, and the chronic cardiovascular disease or disorder is primary aldosteronism. In some preferred aspects, the potassium-resistant hypokalemia is potassium-resistant hypokalemia associated with a chronic cardiovascular disease or disorder, and the chronic cardiovascular disease or disorder is hyperaldosteronism.

[0167] In some embodiments, the composition is administered to the subject once daily at a dosage of about 1 mg to about 12 mg of the compound. In some embodiments, the compound is administered at a dosage of about 4 mg. In some embodiments, the compound is administered at a dosage of about 8 mg.

[0168] In one aspect, the present invention provides a composition for use in treating a disease or disorder, wherein the disease or disorder is hypokalemia (e.g., severe hypokalemia and / or potassium-resistant hypokalemia), wherein the composition is orally administered once daily to a subject in need thereof, preferably for at least 8 weeks, wherein the composition comprises a compound that is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, wherein the compound has an enantiomeric excess (ee) of the (R) form of the compound of about 99% or greater, and wherein the hypokalemia is not accompanied by or associated with an additional disease or disorder. In some embodiments, the composition is administered once daily to the subject at a dosage of about 1 mg to about 12 mg of the compound. In some embodiments, the compound is administered at a dosage of about 4 mg. In some embodiments, the compound is administered at a dosage of about 8 mg.

[0169] In a preferred embodiment, the composition for use according to the present invention further comprises at least one pharmaceutically acceptable excipient. In one embodiment, the pharmaceutical composition is formulated for oral administration. The oral formulation is preferably solid. More preferably, the oral formulation is selected from the group consisting of tablets, pills, dispersible granules, cachets, capsules, powders, lozenges, suppositories, and retention enemas.

[0170] In one embodiment, the pharmaceutical composition is an oral unit dosage form. In a further embodiment, the pharmaceutical composition is an oral solid unit dosage form, such as a tablet or capsule.

[0171] In a preferred embodiment, the composition for use according to the present invention is orally administered once daily. Also in a preferred embodiment, the composition for use according to the present invention is formulated for oral administration (oral formulation). The oral formulation is preferably solid. More preferably, the oral formulation is selected from the group consisting of tablets, pills, dispersible granules, cachets, capsules, powders, lozenges, suppositories, and retention enemas, most preferably capsules.

[0172] In a preferred embodiment, the composition for use according to the invention is administered for a period of n consecutive days, n preferably being >1. In a preferred embodiment, the composition for use according to the invention is administered once daily continuously for a predetermined period. In a highly preferred embodiment, the composition for use according to the invention is administered long-term. In another preferred embodiment, the composition for use according to the invention is administered for at least 1 month, preferably at least 2 months, more preferably at least 3 months, again more preferably at least 6 months, again more preferably at least 1 year, again more preferably at least 2 years, again more preferably at least 5 years, and again more preferably at least 10 years. In a highly preferred embodiment, the composition for use according to the invention is a lifelong treatment.

[0173] example Equipment, materials and methods (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate (also known as dexfadrostat phosphate) was prepared in >99.9% ee according to the teachings of PCT / EP2017 / 077511 (see WO 2018 / 078049), Example 3.

[0174] Example 1 A double-blind, randomized phase II clinical trial to investigate the efficacy of dexfadrostat phosphate in correcting biochemical (high plasma ARR) and clinical (hypertension) disease parameters in patients with primary aldosteronism Test Design A double-blind, randomized, phase II clinical trial was conducted at 11 centers in Italy, Switzerland, and the Netherlands between November 2019 and June 2022 (NCT04007406). After a 14-day single-blind placebo run-in period, patients were randomized 1:1:1 to receive oral dexfadrostat phosphate capsules once daily for 56 days, followed by a 14-day single-blind placebo washout period (Figure 1). Patients requiring stable-dose antihypertensive therapy continued treatment throughout the study; steroid therapy, β-adrenergic, and renin-angiotensin-aldosterone system blockers were not permitted. At 14-day intervals, office blood pressure was recorded, and blood samples for measurement of steroid and peptide hormones and electrolytes were collected at a central laboratory. Ambulatory blood pressure was recorded over 24 hours and 24-hour urine samples were collected at baseline (day 1) and at the end of active treatment (day 56).

[0175] Examination room blood pressure measurement Blood pressure and pulse rate were measured at each visit after >15 minutes of rest in a seated position. Blood pressure and pulse rate were measured using a locally calibrated and validated automated oscillometric device (e.g., Omron Healthcare). A fitted wrap cuff was placed on the dominant arm. Three repeated measurements were recorded at 10-minute intervals, and the average of the second and third measurements was relevant for the study.

[0176] Ambulatory blood pressure measurement Twenty-four-hour ambulatory blood pressure monitoring (ABPM) included recordings of daytime and nighttime mean systolic and diastolic blood pressure (measured every 20 minutes) along with heart rate measurements, one day before administration of the first dose of dexfadrostat phosphate and 55 days after administration of the second through final doses of dexfadrostat phosphate. A centrally calibrated and validated device (Spacelab Healthcare) was used, which was fitted by medically qualified staff in the hospital outpatient department on days -1 and 55 before supervised patient ingestion. A lightweight digital monitor with a convenient carrying pouch obtained regular blood pressure readings by inflating and subsequently deflating a customized cuff placed around the non-dominant upper arm for a 24-hour recording of approximately 70 readings. Patients engaged in a regular daily routine but refrained from exercise or bathing or showering. Additionally, to ensure proper measurements, patients were seated prior to the reading, with the cuff held at heart level and the arm held steady and still. Patients were also required to keep a diary of their activity, diet, and sleep, recording what they were doing immediately prior to taking the reading. At the end of the 24-hour period, patients were allowed to remove the monitor and cuff, shower or bathe, and return the device to the researcher in the clinic. The machine saved all readings, which were the source data uploaded to the eCRF.

[0177] Analysis of blood samples Plasma aldosterone and plasma renin concentrations were measured in a central laboratory under GCP control using the Liaison® chemiluminescent immunoassay kit supplied by DiaSorin SpA (Italy). The system used specific monoclonal antibodies to prevent cross-reactivity with other potential major reactants in serum samples. The monoclonal antibodies, directed against specific epitopes of the renin molecule, enabled accurate and sensitive quantification. The assays were performed according to the instructions provided by the manufacturer. The aldosterone assay had a wide measurement range of 0.97 to 100 ng / mL and was designed to assess aldosterone for the diagnosis and treatment evaluation of PA. The analytical sensitivity was <0.97 ng / mL. The renin assay had a wide measurement range up to 500 μL U / mL and was designed to assess renin for the diagnosis and treatment evaluation of PA. The analytical sensitivity was <0.53 μL U / mL.

[0178] Analysis of urine samples Urinary tetrahydroaldosterone (THA) content was measured by gas chromatography coupled to mass spectrometry (GC-MS) in a central laboratory.

[0179] Patient Eligibility Key inclusion criteria for patients recruited into the study were (i) age 18–65 years, (ii) diagnosis of PA within 1 year of enrollment according to the Endocrine Society diagnostic criteria, (iii) excessive and autonomous aldosterone production confirmed by ARR before and after suppression testing, and (iv) office systolic blood pressure (oSBP) greater than 145 mmHg and less than 190 mmHg.

[0180] Specifically, the diagnosis of PA was defined by plasma aldosterone levels, plasma renin activity (PRA), or plasma renin concentration (PRC) before and after a 4-hour IV saline infusion or a 2-hour captopril suppression test using the following protocol-specified cutoff values: ARR ≥ 40, plasma aldosterone concentration (PAC) ≥ 15 ng / dL and plasma renin activity (PRA) < 1.0 ng / mL / h. Using a plasma renin concentration (PRC) < 15 mU / L instead of PRA in the denominator resulted in a prescreening ARR ≥ 3.7. An IV saline challenge test (2 L of 0.9% saline infused over 4 hours) was performed, resulting in a PAC >7.0 ng / dL after infusion. For patients at risk for volume expansion, a captopril challenge (50 mg of captopril administered orally) was used instead, resulting in an ARR >30 and a PAC >11 ng / dL (ARR >2.4, respectively, using PRC (mU / L) instead of PRA in the denominator).

[0181] The protocol did not require patients to be further qualified by CT adrenal imaging or adrenal vein sampling.

[0182] Key exclusion criteria were (i) oSBP >190 mmHg, (ii) hyperkalemia, and (iii) prolonged QT interval.

[0183] For the Endocrine Society diagnostic criteria, see Funder, J. Wet al., J. Clin. Endocrinol. Metab., 2016;101:1889-1916.

[0184] Evaluation items Co-primary endpoints were the change from baseline to day 56 in (i) median ARR (for all treatment groups combined, as measured by aldosterone and renin concentrations) and (ii) mean 24-hour ambulatory systolic blood pressure (aSBP) (for all treatment groups combined). Secondary and exploratory endpoints included (i) change from baseline to day 56 in aSBP stratified by dose, (ii) change from baseline to days 14, 28, 42, 56, and 70 in plasma ARR, oSBP, and potassium stratified by dose, (iii) change from baseline to end of treatment on day 56 in 24-hour urinary tetrahydroaldosterone excretion, and (iv) treatment-emergent adverse events (TEAEs) and serious adverse events reported from baseline to day 70.

[0185] statistical analysis For all efficacy endpoints, changes from baseline were calculated from linear models with 95% confidence intervals and p-values. Log-transformed values ​​were used for change in ARR. The full analysis set (FAS) and safety analysis set were defined as all randomized patients who received at least one dose of study drug.

[0186] Demographic and baseline characteristics One patient discontinued treatment during the placebo run-in period due to COVID-19-related clinical restrictions and was not included in the efficacy or safety analyses. Both the full analysis set (FAS) and safety analysis set included the remaining 35 patients, of whom 74.3% were male and 91.4% were white (Table 1). At baseline (Day 1), the median age (range) was 53.0 years (30-64), the mean (SD) oSBP was 147.7 (11.8) mmHg, and the mean (SD) plasma potassium level was 3.5 (0.4) mmol / L. 31% of patients had hypokalemia. Cardiac disorders, vascular disorders, and renal or urinary disorders were present in 25.7%, 34.3%, and 8.6% of patients, respectively. One patient had previously undergone adrenalectomy (see Table 1).

[0187] [Table 2] [Table 3] [Table 4]

[0188] Primary endpoint The primary endpoint of this study was to evaluate whether 8 weeks of daily dexfadrostat phosphate treatment corrected the biochemical (ARR) and clinical dysregulation (hypertension) caused by primary aldosteronism. Treatment with dexfadrostat phosphate reduced the median plasma ARR from 15.3 to 0.6 (ng / dL) / (mU / L), as shown in Figure 2A and Table 4. Treatment with dexfadrostat phosphate reduced mean 24-hour aSBP by 10.7 mmHg from baseline to day 56, as shown in Figure 2B and Table 5 (p<0.0001 for both reduction in median plasma ARR and reduction in aSBP, all treatment groups combined). [Table 5] [Table 6]

[0189] safety During the 70-day study period, 16 patients reported TEAEs. Seven patients had TEAEs considered related or possibly related to dexfadrostat phosphate, and five had events related or possibly related to antihypertensive treatment received during the study (Table 6). No serious TEAEs, fatal TEAEs, or AEs leading to treatment discontinuation were reported. Adverse events of special interest (AESIs) were hyperkalemia, headache, dizziness, and orthostatic hypotension. AESIs were reported in four patients, all of whom had headaches, and two of which were considered treatment-related or possibly treatment-related. [Table 7]

[0190] Example 2 A double-blind, randomized phase II clinical trial in patients with primary aldosteronism to study the efficacy of dexfadrostat phosphate in correcting biochemical (high plasma ARR) disease parameters caused by another pathology. At the investigator's discretion, the diagnosis of PA was extended according to Endocrine Society clinical practice guidelines by subjecting the patient to a CT scan to image the presence of any adrenal adenomas or nodules, followed by adrenal venous sampling (AVS) to lateralize the aldosterone-producing adrenal gland. Following guideline recommendations, unilateral adenomas or nodules are generally surgically removed by adrenalectomy, as this lesion is considered more severe and medically difficult to manage.

[0191] A per-patient analysis of the results of biochemical correction studies of high plasma ARR levels examined whether patients with defined lesions, such as unilateral adenomas or nodules, responded differently to dexfadrostat phosphate than patients with indeterminate underlying lesions, such as bilateral nodules or hyperplasia or even normal-appearing glands (see Table 7). [Table 8] [Table 9] [Table 10]

[0192] Surprisingly, patients with unilateral disease, e.g., patients 1, 21, 22, and 30 treated with 4 mg dexfadrostat phosphate, patients 6, 16, 24, 27, and 35 treated with 8 mg dexfadrostat phosphate, and patients 3, 4, 9, 13, 15, 19, and 34 treated with 12 mg dexfadrostat phosphate, responded similarly compared with patients with indeterminate or bilateral disease in their respective treatment groups. Combined treatment representations demonstrate that dexfadrostat phosphate normalized the ARR in patients with unilateral disease (Figure 3A) and bilateral or indeterminate disease (Figure 3B).

[0193] Example 3 A double-blind, randomized phase II clinical trial to investigate the dose-dependent efficacy of dexfadrostat phosphate in correcting biochemical (high plasma ARR) and clinical (hypertension) disease parameters in patients with primary aldosteronism Secondary endpoints of this study evaluated whether dexfadrostat phosphate demonstrated dose-dependent efficacy in correcting biochemical (ARR) and clinical (blood pressure) parameters of primary aldosteronism. Daily doses of 4 mg, 8 mg, and 12 mg of dexfadrostat phosphate were derived from a prior Phase I clinical trial (see PCT / EP2019 / 061283 and WO 2019 / 211394). Analysis of individual dose groups revealed that all three doses mediated a significant reduction in ARR (p<0.0001) from baseline to Day 56 (see Table 8 and Figures 4A, 4B, and 4C). Surprisingly, the 4 mg dose was found to be only slightly less potent than the 8 mg dose. In contrast, the 12 mg dose was less potent than the 8 mg dose, indicating that maximum efficacy was achieved at the 8 mg dose. [Table 11] [Table 12] [Table 13]

[0194] In each dose group, treatment with dexfadrostat phosphate and suppression of the ARR resulted in a significant decrease in 24-hour aSBP (p<0.001) (see Table 9 and Figures 4D, 4E, and 4F). Surprisingly, the 4 mg dose was only slightly less effective than the 8 mg dose. In contrast, the 12 mg dose was less potent than the 8 mg dose, with maximum efficacy achieved at the 8 mg dose. [Table 14] [Table 15] [Table 16]

[0195] Example 4 A double-blind, randomized phase II clinical trial to investigate the dose-dependent efficacy of dexfadrostat phosphate in correcting biochemical (high urinary aldosterone content) disease parameters in patients with primary aldosteronism The exploratory endpoint of this study evaluated whether dexfadrostat phosphate demonstrated dose-dependent efficacy in correcting elevated urinary aldosterone levels, a disease parameter not only in primary aldosteronism but also in other cardiovascular diseases. Daily doses of 4 mg, 8 mg, and 12 mg of dexfadrostat phosphate were derived from a previous phase I clinical trial (see PCT / EP2019 / 061283 and WO 2019 / 211394). Analysis of individual dose groups revealed that all three doses mediated a significant decrease (P<0.0001) in urinary tetrahydroaldosterone (THA), the major metabolite of aldosterone, when 24-hour urine samples collected at the end of active treatment were compared with baseline samples (see Table 10 and Figures 4G, 4H, and 4I). Surprisingly, the 4 mg dose was found to be only slightly less effective than the 8 mg dose. In contrast, the 12 mg dose was less potent than the 8 mg dose, with maximum efficacy achieved at the 8 mg dose. [Table 17] [Table 18] [Table 19]

[0196] Example 5 A double-blind, randomized phase II clinical trial to investigate the time- and withdrawal-dependent efficacy of dexfadrostat phosphate in correcting biochemical (plasma ARR and potassium) and clinical (blood pressure) disease parameters in patients with primary aldosteronism Secondary endpoints of this study evaluated whether dexfadrostat phosphate demonstrated dose- and time-dependent efficacy in correcting biochemical (plasma ARR and potassium) and clinical (blood pressure) parameters of primary aldosteronism. Daily doses of 4 mg, 8 mg, and 12 mg of dexfadrostat phosphate were derived from a prior Phase I clinical trial (see PCT / EP2019 / 061283 and WO 2019 / 211394). Analysis of individual dose groups revealed that all three doses mediated a rapid and significant reduction in ARR (p<0.0001) from baseline to visits on days 14, 28, 42, and 56 (see Table 11 and Figures 5A and 5D). Suppression of ARR remained sustained throughout the active treatment period. At washout, ARR values ​​returned toward baseline values. Surprisingly, the 4 mg dose was found to be only slightly less potent than the 8 mg dose. In contrast, the 12 mg dose was less potent than the 8 mg dose, with maximum efficacy achieved at the 8 mg dose. [Table 20] [Table 21]

[0197] In each dose group, suppression of the ARR resulted in a rapid and significant (p<0.001) increase in plasma potassium levels (see Table 12 and Figures 5C, 5F). The potassium increase remained sustained throughout the active treatment period. Upon drug withdrawal, potassium levels returned toward baseline levels. Surprisingly, the 4 mg dose was as effective as the 8 mg dose. The 12 mg dose did not provide any additional efficacy. [Table 22] [Table 23]

[0198] In each treatment group, suppression of the ARR also resulted in a rapid and significant (p≦0.001) reduction in office blood pressure (see Table 13 and Figures 5B, 5E). The reduction in blood pressure remained sustained throughout the active treatment period. At drug withdrawal, blood pressure values ​​returned toward baseline levels. Surprisingly, the 4 mg dose was nearly as effective as the 8 mg dose. The 12 mg dose did not provide any additional clinical benefit. [Table 24] [Table 25]

[0199] Example 6 A double-blind, randomized phase II clinical trial to study blood potassium levels, blood aldosterone levels, and 24-hour urinary aldosterone content in patients with primary aldosteronism [Table 26-1] [Table 26-2] [Table 27-1]

Table 27-2

Table 28-1

Table 28-2

Claims

1. A composition for use in the treatment of a disease or disorder, comprising the composition is administered once daily to a subject, preferably a human subject, in need thereof; The composition comprises the compound (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof; The compound has an enantiomeric excess (ee) of about 99% or more of the (R) form.

2. 10. The composition for use according to claim 1, wherein the composition is administered once daily to a subject in need thereof for at least 8 weeks.

3. 3. The composition for use according to claim 1 or 2, wherein the disease or disorder is a chronic disease or disorder, preferably a chronic cardiovascular disease or disorder.

4. 3. The composition for use according to claim 1 or 2, wherein the composition is administered to a subject once daily at a dosage of about 1 mg to about 12 mg of the compound.

5. 3. The composition for use according to claim 1 or 2, wherein the compound is administered in a dosage of about 4 mg.

6. The composition for use according to any one of claims 1 to 4, wherein the compound is administered in a dosage of about 8 mg.

7. 3. The composition for use according to claim 1 or 2, wherein the compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, and preferably, the (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate has an enantiomeric excess (ee) of the (R) form of not less than about 99.5%, more preferably not less than about 99.9%.

8. the disease or disorder is selected from the group consisting of primary aldosteronism, secondary aldosteronism, heart failure, chronic renal failure, hypertension, restenosis, obesity, nephropathy, post-myocardial infarction, renal fibrosis, coronary heart disease, sodium retention, water retention, hypokalemia, hypomagnesemia, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular damage, suppression of plasma renin, renal fibrosis, arrhythmia, nephropathy, edema, muscle weakness due to hypokalemia, cardiac fibrillation and weakened myocardial contractility; Preferably, the composition for use according to claim 1 or 2, wherein the disease or disorder is selected from the group consisting of primary aldosteronism, secondary aldosteronism, heart failure, chronic renal failure, hypertension, restenosis, obesity, nephropathy, post-myocardial infarction, renal fibrosis, coronary heart disease, sodium retention, water retention, hypokalemia, hypomagnesemia, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular damage, suppression of plasma renin, renal fibrosis, arrhythmia, nephropathy, and edema.

9. 3. The composition for use according to claim 1 or 2, wherein the disease or disorder is primary aldosteronism.

10. 3. The composition for use according to claim 1 or 2, wherein the disease or disorder is bilateral primary aldosteronism.

11. The composition according to any one of claims 1 to 9, wherein the disease or disorder is unilateral primary aldosteronism, and preferably the unilateral primary aldosteronism is caused by unilateral adenoma, unilateral nodule, or unilateral hyperplasia.

12. 9. The composition for use according to any one of claims 1 to 8, wherein the disease or disorder is essential hypertension and / or resistant hypertension, preferably wherein the disease or disorder is essential hypertension and / or resistant hypertension accompanied by hypokalemia.

13. The composition for use according to any one of claims 1 to 8, wherein the disease or disorder is hypokalemia.

14. 3. The composition for use according to claim 1 or 2, wherein the once-daily dose does not require dose adjustment.

15. 3. The composition for use of claim 1 or 2, wherein the subject exhibits a clinical response within about 14 days of treatment, preferably wherein the clinical response is selected from a decrease in plasma aldosterone levels, a normalization of plasma aldosterone levels, a decrease in blood pressure, a normalization of blood pressure, a reduction in hypokalemia, a normalization of potassium levels, and a decrease in urinary THA.

Images