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 condition in which the disease or condition is preferably a disease or condition in which overexposure of aldosterone causes a symptom of the disease or condition, comprising a compound which is a compound of (R)-(+)-5-(p-cyanophenyl)-5, 6, 7, 8-tetrahydroimidazo [l, l]-1, 3, 4-triazole-1-yl)-1, 3, 4-triazole-1-yl)-1, 3, 4-triazole-1-yl)-1, 3, 4-triazole-1-yl, 1, 3, 4-triazole-1-yl. The present invention relates to a composition for the preparation of a pharmaceutical composition, preferably (R)-(+)-5-(p-cyanophenyl)-5, 6, 7, 8-tetrahydroimidazolium [l, 5-a] pyridine or a pharmaceutically acceptable salt thereof, said compound preferably being (R)-(+)-5-(p-cyanophenyl)-5, 6, 7, 8-tetrahydroimidazolium [l, 5-a] pyridine dihydric phosphate, said compound in the (R) form having an enantiomeric excess (ee) of 99% or more, said composition being administered once a day to a patient in need thereof for at least eight weeks.

Description

Technical Field

[0001] The present invention relates to a composition for use in treating a disease or condition, wherein the disease or condition is preferably a disease or condition in which symptoms of the disease or condition are caused by excessive exposure to aldosterone, the composition comprises a compound, the compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, the compound is preferably (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine dihydrogen phosphate, the enantiomeric excess (ee) of the (R) form of the compound is greater than 99%, and the composition is administered once daily to a patient in need thereof for at least eight weeks. Diseases of excessive exposure to aldosterone can be diagnosed biochemically, including primary aldosteronism caused by adenoma or nodule of the adrenal gland producing aldosterone or adrenal hyperplasia or apparently normal glands (in decreasing order of severity). Background Art

[0002] Aldosterone excess can be associated with or associated with a variety of deleterious metabolic and cardiovascular structural effects, including sodium and water retention, hypokalemia, hypomagnesemia, hypertension, left ventricular hypertrophy, and cardiac fibrosis. Compared with essential hypertension, primary aldosteronism has serious adverse consequences. Therefore, effective drug therapy that can both lower blood pressure and antagonize 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 diseases in which the production of aldosterone is too high relative to the sodium state, relatively independent of the main secretion regulators (angiotensin II, plasma potassium concentration), and cannot be inhibited by sodium load. Such inappropriate aldosterone production can cause hypertension, cardiovascular damage, sodium retention, plasma renin inhibition, and increased potassium excretion, which may cause hypokalemia in the case of long-term and severe increased potassium excretion. PA is usually caused by benign adrenal adenoma, adrenal nodules, unilateral or bilateral adrenal hyperplasia (BAH), and in rare cases by the genetic condition of adrenal cancer or familial hyperaldosteronism. PA is also called Conn 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's clinical practice guidelines for the management of primary aldosteronism describe in 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 precise method for measuring aldosterone levels involves collecting a 24-hour urine sample and measuring the amount of tetrahydroaldosterone, the main metabolite of aldosterone, in the urine (Funder and Carey, 2022, Hypertens 79:726-735). The authors provide diagnostic cutoff values ​​for abnormal values.

[0005] In addition, the Endocrine Society clinical practice guidelines for the management of primary aldosteronism recommend and describe an invasive approach supported by CT imaging to subtype patients to determine the laterality of the adrenal source of excess aldosterone secretion. Unilateral adrenal adenomas can be surgically removed by adrenalectomy, while bilateral disease requires medical therapy (Funder et al., 2016, J Clin Endocrinol Metab 101:1889-1916).

[0006] The ability of adrenal zona glomerulosa cells to produce aldosterone is primarily controlled by transcriptional regulation of CYP11B2, the gene encoding aldosterone synthase. Inhibition of aldosterone synthase has emerged as an option for the treatment of hypertension, heart failure, and renal disease. The goal is to reduce plasma and tissue aldosterone concentrations, thereby reducing MR-dependent and MR-independent effects in cardiac, vascular, and renal target organs.

[0007] (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine is a small molecule capable of inhibiting aldosterone synthase. WO 2018 / 078049 teaches the preparation of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine and pharmaceutically acceptable salts thereof (e.g., (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate; also known as dexfadrostat phosphate), wherein the enantiomeric excess (ee) of the (R) form is greater than 99%. The high enantiomeric excess values ​​achieved by the method 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 1 clinical trial investigating the use of dexfadrostat phosphate in healthy subjects. Summary of the invention

[0009] In a prospective, double-blind, randomized, Phase 2 efficacy study of patients diagnosed with primary aldosteronism, the inventors unexpectedly discovered that the preferred compounds of the present invention are able to effectively normalize the aldosterone to renin ratio of said patients compared to baseline values ​​by inhibiting aldosterone synthesis (at a dose of 4 mg once daily). This finding is particularly noteworthy because previous clinical Phase 1 studies in healthy subjects with normal aldosterone levels showed limited efficacy of aldosterone inhibition at a dose of 4 mg once daily.

[0010] Furthermore, the inventors have surprisingly shown that the preferred compounds of the present invention are able to normalize plasma aldosterone levels in said patients (once daily doses of 4 mg, 8 mg and 12 mg) regardless of the causative adrenal lesion (e.g., unilateral or bilateral adenoma, unilateral or bilateral nodule, unilateral or bilateral hyperplasia, and normal-appearing adrenal glands). This finding is particularly noteworthy because patients with primary aldosteronism caused by adenoma are characterized by extreme aldosterone and potassium levels and require adrenal surgery.

[0011] In addition, the inventors unexpectedly observed that the preferred compounds of the present invention were able to normalize the patient's plasma aldosterone levels at once daily doses of 4 mg, 8 mg and 12 mg and the response was rapid, i.e., blood pressure and hypokalemia were rapidly normalized within a short treatment period of less than 14 days. This finding is particularly noteworthy because clinical responses to surgery and current drug treatments may take 3 to 12 months to occur.

[0012] In addition, the inventors unexpectedly observed that the preferred compounds of the present invention were able to normalize the patient's plasma aldosterone levels at once-daily doses of 4 mg, 8 mg, and 12 mg, with a rapid response and sustained throughout the treatment period without the need to adjust the dose, resulting in sustained normalization of blood pressure and hypokalemia, indicating long-term cardiovascular protection. This finding is particularly noteworthy because current drug treatments require biweekly dose titration to balance efficacy and tolerability.

[0013] In addition, the inventors unexpectedly observed that the preferred compounds of the present invention were able to normalize the urinary aldosterone secretion of the patients at once daily doses of 4 mg, 8 mg and 12 mg, thereby extending the use of the compounds to diseases characterized by abnormal aldosterone levels in urine, such as essential hypertension, refractory hypertension, and heart and kidney failure. This finding is particularly noteworthy because the disease is further induced by current medical treatments (e.g., mineralocorticoid receptor antagonists) after treatment.

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

[0015] Therefore, on the one hand, the present invention provides a composition for treating a disease or condition, the composition comprising a compound, the compound being (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or dexfadrostat (Formula (I)) or a pharmaceutically acceptable salt thereof, the enantiomeric excess (ee) of the (R) form of the compound being greater than 99%, and the composition being administered to a patient in need thereof once a day at a dose of 1-8 mg.

[0016] On the other hand, the present invention provides a composition for treating a disease or condition, wherein the disease or condition is preferably primary aldosteronism, and further preferably primary aldosteronism of various pathological subtypes (e.g., unilateral or bilateral adenomas, unilateral or bilateral nodules, unilateral or bilateral adrenal hyperplasia, and normal-looking adrenal glands).

[0017] In another aspect, the present invention provides a composition for use in treating a disease or condition, wherein the disease or condition is primary aldosteronism, wherein excessive aldosterone exposure causes debilitating symptoms and events, and the patient requires rapid correction of potential biochemical (hyperaldosteronism, hypokalemia) and clinical (systolic and diastolic blood pressure) health risk hazards.

[0018] In another aspect, the present invention provides a composition for use in treating a disease or condition, wherein the disease or condition is primary aldosteronism, in which excessive aldosterone exposure causes debilitating symptoms and events, and the patient requires continuous and reliable correction of potential biochemical (hyperaldosteronism, hypokalemia) and clinical (systolic and diastolic blood pressure) health risk hazards.

[0019] In another aspect, the present invention provides a composition for use in treating a disease or condition characterized by abnormal or inappropriate levels of aldosterone in urine, such as primary aldosteronism, secondary aldosteronism, heart failure, renal failure, refractory hypertension, essential hypertension, kidney disease, edema, coronary heart disease, hypokalemia and arrhythmia.

[0020] In one aspect, the present invention provides a composition for use in treating a disease or condition, wherein the composition is administered once a day to a subject in need thereof, preferably a human being, and the composition comprises a compound, wherein the compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, and the enantiomeric excess (ee) of the (R) form of the compound is about 99% or more.

[0021] In some embodiments, the composition is administered to a subject in need thereof once daily for at least eight 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 dose of about 1 mg to about 12 mg of the compound. In some embodiments, the compound is administered at a dose of about 4 mg. In some embodiments, the compound is administered at a dose 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 the enantiomeric excess (ee) of the (R) form of the (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate is preferably about 99.5% or more, more preferably about 99.9% or more.

[0025] In some embodiments, the disease or condition is selected from primary aldosteronism, secondary aldosteronism, heart failure, chronic renal failure, hypertension, restenosis, obesity, kidney disease, 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, kidney fibrosis, arrhythmia, kidney disease, edema, hypokalemia-induced muscle weakness, cardiac fibrillation, and decreased myocardial contractility;

[0026] Preferably, the disease or disorder 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 injury, plasma renin suppression, renal fibrosis, arrhythmia, nephropathy and edema.

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

[0028] In some embodiments, the disease or condition is bilateral primary aldosteronism.

[0029] In some embodiments, the disease or disorder is unilateral primary aldosteronism, preferably caused by a unilateral adenoma, a unilateral nodule, or a unilateral hyperplasia.

[0030] In some embodiments, the disease or disorder is essential hypertension and / or resistant hypertension, and the disease or disorder is preferably essential hypertension and / or resistant hypertension with hypokalemia.

[0031] In some embodiments, the disease or condition is hypokalemia.

[0032] In some embodiments, the once daily dose requires no dose adjustment.

[0033] In some embodiments, the subject exhibits a clinical response within about 14 days of treatment, preferably selected from a decrease in plasma aldosterone levels, normalization of plasma aldosterone levels, a decrease in blood pressure, normalization of blood pressure, a decrease in hypokalemia, normalization of potassium concentration, and a decrease in urinary THA.

[0034] It is believed that the excessive increase in aldosterone production in primary aldosteronism is the result of a cluster of cells in the zona glomerulosa of the adrenal glands being derailed from normal physiological control. Therefore, it is further believed that aldosterone synthase inhibitors (if provided at appropriate doses and with appropriate duration of action) have the potential to prevent the sequelae of excess aldosterone synthesis. In a preferred embodiment, the disease or condition treated in the present invention is a condition following aldosterone overexposure, or a condition occurring as a result of aldosterone overexposure. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 Schematic representation of the study design for the Phase II clinical trial described in Example 1.

[0036] Figure 2APlot of aldosterone to renin ratio (ARR) (ng / dL) / (mU / L) recorded for all patients on Day 1 and Day 56. Lognormal value LSM change from baseline -2.54 (95% CI -2.9 to -2.2). *p<0.0001.

[0037] Figure 2B Graph of mean (SEM) 24-hour ambulatory systolic blood pressure (aSBP) (mmHg) recorded for all patients on Days 1 and 56. LSM change from baseline was -10.7 mmHg (95% CI -13.6 to -7.9). *p<0.0001.

[0038] Figure 3A Graph of aldosterone to renin ratio (ARR) (ng / dL) / (mU / L) recorded on days 1, 14, 28, 42, and 56 for patients with unilateral PA.

[0039] Figure 3B Graph of the aldosterone to renin ratio (ARR) (ng / dL) / (mU / L) recorded on days 1, 14, 28, 42, and 56 for patients with bilateral PA or unexplained PA (idiopathic PA).

[0040] Figure 4A Plot of lognormal LSM changes in aldosterone to renin ratio (ARR) (ng / dL) / (mU / L) recorded on Day 1 and Day 56 in patients (n=10) treated with 4 mg dexafadrostat. Box plots show median, first and third quartiles and range. *p<0.0005.

[0041] Figure 4B Plot of the lognormal LSM changes in aldosterone to renin ratio (ARR) (ng / dL) / (mU / L) recorded on Day 1 and Day 56 for patients (n=12) treated with 8 mg dexafadrostat. Box plots show median, first and third quartiles and range. *p<0.0005.

[0042] Figure 4C Plot of lognormal LSM changes in aldosterone to renin ratio (ARR) (ng / dL) / (mU / L) recorded on Day 1 and Day 56 for patients (n=13) treated with 12 mg dexafadrostat. Box plots show median, first and third quartiles and range. *p<0.0005.

[0043] Figure 4DGraph of LSM changes in 24-hour ambulatory systolic blood pressure (aSBP) (mmHg) recorded on Day 1 and Day 56 in patients (n=10) treated with 4 mg dexafadrostat. *p<0.0005.

[0044] Figure 4E Graph of LSM changes in 24-hour ambulatory systolic blood pressure (aSBP) (mmHg) recorded on Day 1 and Day 56 in patients (n=12) treated with 8 mg dexafadrostat. *p<0.0005.

[0045] Figure 4F Graph of LSM changes in 24-hour ambulatory systolic blood pressure (aSBP) (mmHg) recorded on Day 1 and Day 56 in patients treated with 8 mg dexafadrostat (n=13). *p<0.0005.

[0046] Figure 4G Graph showing LSM changes in urinary tetrahydroaldosterone (THA) (μg / 24h) recorded on Day 1 and Day 56 for patients (n=10) treated with 4 mg dexafadrostat. Box plots show median, first and third quartiles and range. *p<0.0001.

[0047] Figure 4H Graph of LSM changes in urinary tetrahydroaldosterone (THA) (μg / 24h) recorded on Day 1 and Day 56 for patients (n=12) treated with 8 mg dexafadrostat. Box plots show median, first and third quartiles and range. *p<0.0001.

[0048] Fig. 4I Graph of LSM changes in urinary tetrahydroaldosterone (THA) (μg / 24 hours) recorded on Day 1 and Day 56 for patients (n=13) treated with 12 mg dexafadrostat. Box plots show median, first and third quartiles and range. *p<0.0001.

[0049] Figure 5A Figure 2 shows the aldosterone to renin ratio (ARR) (ng / dL) / (mU / L) measured by lognormal LSM change from baseline at Days 14, 28, 42, 56, and 70 for patients treated with 4 mg dexfadrostat (n=10). Box plots show median, first and third quartiles, and range. *p≤0.0008.

[0050] Figure 5BGraph of change from baseline in office systolic blood pressure (oSBP) (mmHg) measured by LSM on Days 14, 28, 42, 56 and 70 for patients treated with 4 mg dexfadrostat (n=10). *p≤0.0008.

[0051] Figure 5C Graph of mean (SEM) plasma potassium concentrations (mmol / L) measured by LSM change from baseline on Days 14, 28, 42, 56 and 70 for patients treated with 4 mg dexfadrostat (n=10). *p≤0.0008.

[0052] Figure 5D Figure 2 is a graph of the aldosterone to renin ratio (ARR) (ng / dL) / (mU / L) measured by lognormal LSM change from baseline at Days 14, 28, 42, 56, and 70 for patients treated with 8 mg dexafadrostat (n=12). Box plots show the median, first and third quartiles, and range. *p<0.0001; **p<0.05.

[0053] Figure 5E Graph of office systolic blood pressure (oSBP) (mmHg) measured by LSM change from baseline on Days 14, 28, 42, 56 and 70 for patients treated with 8 mg dexfadrostat (n=12). *p<0.0001; **p<0.05.

[0054] Fig. 5F Graph of mean (SEM) plasma potassium concentrations (mmol / L) measured by LSM change from baseline on Days 14, 28, 42, 56 and 70 for patients treated with 8 mg dexfadrostat (n=12). *p<0.0001; **p<0.05. DETAILED DESCRIPTION

[0055] Unless defined otherwise, 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.

[0056] Unless otherwise stated, the term "about" when used refers specifically to ± 10%, ± 5% or ± 3% (respectively with reference to a given numerical value). In various embodiments of the present invention, "about" can be deleted. The range of all values ​​disclosed herein shall refer to and include any and all values ​​falling within the range, including the values ​​defining the range. For clarification, for example, a value of 12 to 13 shall refer to a value of 12 or 13 or any and all values ​​falling between 12 and 13, and a daily dose of, for example, 1 mg to 16 mg shall refer to a daily dose of 1 mg or 16 mg or any and all values ​​falling between 1 mg and 16 mg.

[0057] As used herein, the term "adenoma" is a noncancerous or benign tumor that may affect various organs.

[0058] As used herein, the term "adrenal vein sampling" (abbreviated "AVS") refers to a procedure used in conjunction with computed tomography (CT) to subtype primary aldosteronism (PA). Blood circulates from each adrenal gland through the adrenal vein (AV) and ultimately drains into the inferior vena cava (VC; the right AV drains directly into the VC; the left AV drains into the left renal vein, which drains into the IVC). AVS is considered the most reliable method for subtyping PA.

[0059] Intravenous (IV) cannulation is a technique in which a cannula (thin tube) is placed inside a vein to provide venous access. Venous access allows for blood sampling, as well as 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.

[0060] As used herein, the term "aldosterone-producing cell clusters (APCCs)" refers to clusters of cells that strongly express aldosterone synthase (CYP11B2). They are commonly found in the adult adrenal glands and can be found in aldosterone-producing adenomas.

[0061] 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.

[0062] As used herein, the term "chiral purity" is defined as the enantiomeric excess (ee) determined by chiral HPLC (see Examples for details) and calculated according to the following formula:

[0063] ee=(A R –A S ) / (A R +A S )×100%,

[0064] In the formula, A Ris the area of ​​the (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine peak in the HPLC chromatogram of the sample solution, A S It is the area of ​​the (S)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine peak in the HPLC chromatogram of the sample solution.

[0065] The terms "disease" and "disorder" are used interchangeably herein to refer to any disorder, abnormal condition or function or pathological physical or mental state, particularly to abnormal medical conditions (e.g., disease or injury) in which tissues, organs or individuals can no longer function effectively. See Dorland's Illustrated Medical Dictionary (VSIB, Saunders Publishing Company, USA, 27th edition, 1988). Usually, but not necessarily, a disease is associated with or may be accompanied by specific symptoms or signs, indicating the presence of such a disease. Therefore, the presence of such symptoms or signs may indicate that a tissue, organ or individual suffers from a disease. Preferably, the term "disease" or "disorder" also includes the possibility that a tissue, organ or individual at "risk of disease" exhibits the possibility of disease occurrence. Typically, the risk of developing a disease is associated with early or weak signs or symptoms of such a disease.

[0066] As used herein, the expression "a disease or condition in which excessive exposure to aldosterone causes symptoms of the disease or condition" preferably refers to a disease or condition 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 conditions 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, plasma renin inhibition, renal fibrosis, arrhythmia, nephropathy, muscle weakness, cardiac fibrillation and decreased myocardial contractility caused by edema and hypokalemia. Preferably, the 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, plasma renin suppression, renal fibrosis, arrhythmia, nephropathy, edema.

[0067] As used herein, the term "nodule" refers to an abnormal tissue growth that can be found anywhere in the body. Although they are usually benign, some nodules are symptoms of underlying health conditions.

[0068] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is pharmaceutically acceptable and 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 (ed.), Camille G. Wermuth (ed.); 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 hydrochlorides or phosphates, such as salts formed with phosphoric acid, i.e., dihydrogen phosphates.

[0069] The term "phosphate" as used herein refers to a compound comprising a 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-tetrahydroimidazo[1,5-a]pyridinium cation) and further comprising an anion derived from phosphoric acid, wherein the anion is typically and preferably dihydrogen phosphate [H2PO4] - or hydrogen phosphate [HPO4] 2- Preferably, the term "phosphate" as used in the present application refers to the dihydrogen phosphate of formula (I), i.e. the compound of formula (I) is protonated once and the counter ion is [H2PO4] - , so the stoichiometry of monoprotonated (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine to dihydrogen phosphate is 1:1. The latter is referred to herein as (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine dihydrogen phosphate.

[0070] The term "primary aldosteronism" (abbreviated as PA) is defined herein as a group of diseases characterized in that an autonomous excess of aldosterone causes suppression of renin levels. The recommended screening test is the ratio of aldosterone to renin, and the value of PA is pathologically elevated. Therefore, PA also includes diseases in which the production of aldosterone is too high relative to the sodium state, relatively independent of the main secretion regulators (angiotensin II, plasma potassium concentration), and cannot be suppressed by sodium load. The term "primary aldosteronism" also includes aldosterone hyperactivity and diseases and conditions caused by inappropriate aldosterone production, which are usually and preferably selected from hypertension, cardiovascular damage, sodium retention, water retention, plasma renin inhibition, increased potassium excretion and hypokalemia, hypomagnesemia, left ventricular hypertrophy, cardiac fibrosis and renal fibrosis, heart failure, arrhythmia, nephropathy, edema and myasthenia caused by hypokalemia, cardiac fibrillation, weakened myocardial contractility and heart failure (cardiac failure). The term "primary aldosteronism" also includes diseases or conditions that cause PA, which are usually and preferably adrenal adenomas, unilateral and bilateral adrenal hyperplasia (BAH) (e.g., bilateral idiopathic (micronodular) adrenal hyperplasia and primary (unilateral) adrenal hyperplasia), adrenal cancer (e.g., aldosterone-producing adrenocortical carcinoma and ectopic aldosterone-producing adenoma or carcinoma), glucocorticoid-repressible aldosteronism, hereditary conditions of familial aldosteronism, and type II FH. PA is also known as Conn syndrome. The excessive increase in aldosterone production in PA is the result of a cell cluster in the zona glomerulosa of the adrenal glands being out of the normal regulatory control of aldosterone-renin-aldosterone. In some embodiments, hyperaldosteronism is defined as a blood aldosterone concentration of 416 pmol / L (i.e., 15 ng / dL) or more. In some embodiments, hyperaldosteronism is defined as a urine aldosterone concentration of 10 μg / 24 hours or more. In some embodiments, hyperaldosteronism is defined as a blood aldosterone concentration of 416 pmol / L (ie, 15 ng / dL) or more and a urine aldosterone concentration of 10 μg / 24 hours or more. In a preferred embodiment, the hyperaldosteronism is blood pressure-independent hyperaldosteronism.

[0071] 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, which is the cardinal feature of PA. Unilateral disease is usually caused by an aldosterone-producing adenoma (benign tumor) and less often by adrenal cancer or hyperplasia (when the entire gland is overactive). In a preferred embodiment, subtyping is performed using a combination of computed tomography (CT) and adrenal venous sampling (AVS).

[0072] As used herein, the term "bilateral PA" refers to a specific subtype of primary aldosteronism in which both adrenal glands appear to be responsible for the uncontrolled overproduction of aldosterone, which is the main feature of PA. It may be caused by abnormal growth of both adrenal glands, known as bilateral adrenal hyperplasia. In a preferred embodiment, subtyping is performed using a combination of computed tomography (CT) and adrenal venous sampling (AVS).

[0073] As used herein, the term "hyperplastic PA" or "adrenal hyperplasia" refers to another form of primary aldosteronism that is caused by the abnormal or unusual growth of extra cells within the adrenal glands. Hyperplastic PA can present as unilateral or bilateral disease.

[0074] As used herein, the term "idiopathic PA" refers to primary aldosteronism of unknown cause.

[0075] As used herein, the term "hereditary PA" refers to primary aldosteronism due to a genetic cause. Familial aldosteronism is a genetic cause of PA defined as a family history of two or more affected family members that cannot be explained by other genetic mechanisms.

[0076] As used herein, the term "rapid response" refers to an automatic response of the body to a stimulus. In this context, a response "rapid" means that the response occurs faster than would be expected based on the stimulus and the mechanistic pathway of the response.

[0077] As used herein, the term "sustained response" refers to a response that remains stable over time (ie, is maintained over a long period of time without interruption or abation). A sustained response is thus a sustained or prolonged response.

[0078] As used herein, the term "secondary aldosteronism" (SA) (also known as hyperreninism or hyperreninemic hyperaldosteronism) refers to excessive secretion of aldosterone secondary to stimulation from sources other than the adrenal glands. An example of extra-adrenal stimulation is renal hypoperfusion. SA is caused by an overactive renin-angiotensin-aldosterone system. The term "secondary aldosteronism" includes diseases and conditions caused by inappropriate aldosterone and renin production, which are typically and preferably selected from high plasma aldosterone levels, high plasma renin levels, hypertension, hypokalemic alkalosis causing paroxysmal weakness, paresthesias, transient paralysis, tetany, and peripheral edema. The term "secondary aldosteronism" also includes diseases or conditions that cause SA, such as decreased renal blood flow, obstructive renal artery disease (e.g., atherosclerosis, stenosis), renal vasoconstriction, edematous diseases (e.g., heart failure, cirrhosis with ascites, nephrotic syndrome), renin-producing tumors, juxtaglomerular cell tumors, fibromuscular dysplasia, inadequate sodium absorption (e.g., as seen in Bartter and Gitelman syndromes), hypovolemia / hypotension. The term "secondary aldosteronism" also includes secondary hyperaldosteronism.

[0079] The term "subtyping" as used herein in the context of primary aldosteronism refers to the process of determining whether one or both adrenal glands are thought to be responsible for the uncontrolled overproduction of aldosterone. Subtyping involves the use of computed tomography (CT) combined with adrenal venous sampling (AVS) to differentiate between unilateral and bilateral disease. This is currently considered the most accurate diagnostic method.

[0080] As used herein, the ratio of aldosterone to renin (ARR) is understood to mean the plasma aldosterone concentration divided by the renin concentration or renin activity in the blood. Aldosterone is measured as plasma (plasma is the liquid portion of the blood, i.e. minus cells) aldosterone concentration (PAC). Renin is measured as plasma renin activity (PRA) or plasma renin concentration (PRC). In order to determine the ARR, a blood sample is drawn from the patient, and the PAC is divided by 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 for primary aldosteronism (PA).

[0081] As used herein, systolic blood pressure (SBP) is understood to be the pressure exerted by the heart on the arteries during ventricular contraction.

[0082] As used herein, diastolic blood pressure is understood to be the pressure in the arteries between heartbeats. Without wishing to be bound by theory, SBP is more closely associated with cardiovascular events such as stroke and myocardial infarction. Both systolic and diastolic blood pressure are typically determined using a blood pressure cuff placed on the brachial artery (near the elbow). In primary aldosteronism (PA), blood pressure increases due to increased sodium and water retention in the body. Sodium and water are retained due to excessive, uncontrolled production of aldosterone, a steroid hormone primarily responsible for sodium and subsequent water retention in the body. Therefore, hypertension is considered a clinical indicator of PA.

[0083] As used herein, "office systolic blood pressure (oSBP)" is a blood pressure measurement taken in a doctor's office. This blood pressure measurement indicates the patient's blood pressure at a particular moment in the office.

[0084] As used herein, "ambulatory systolic blood pressure (aSBP)" is a collection of blood pressure measurements taken (usually) over a 24-hour period. As used herein, blood pressure measurements are taken 3 times per hour or once every 20 minutes (in the case of the DP13C201 study) over a 24-hour period. The blood pressure monitor is attached to the subject, allowing him / her to maintain normal daily activities. Without wishing to be bound by theory, a 24-hour blood pressure recording is believed to be a more reflective and therefore more accurate method of measuring blood pressure in humans, as it is recorded continuously for 24 hours.

[0085] As used herein, the term "symptom" refers to any indicator of an abnormal state, disease or condition, including deviations from normal function or normal sensation that reflect the presence of an abnormal state, condition or disease, which deviation can be noticed by the subject (preferably the patient) or can be objectively observed (effect or sign).

[0086] As used herein, the term "day" or "every day" refers to a calendar day or a 24-hour period, and the term "day" or "every day" preferably refers to a calendar day.

[0087] As used herein, the term "abnormal activity of aldosterone synthase" refers to an aldosterone synthase activity that is different from the activity of a wild-type or natural gene or protein or different from the activity of a gene or protein of a healthy subject. The abnormal activity may be stronger or weaker than the normal activity.

[0088] As used herein, the term "normal" or the term "normalization" refers to the cutoff value, threshold value or range defined by medical or clinical consensus publications for reference values ​​in the context of clinical parameters (e.g., 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, urine tetrahydroaldosterone content (THA), ambulatory systolic blood pressure (aSBP) and office systolic blood pressure (oSBP)) as a characteristic value for a healthy individual. Therefore, subjects who exhibit "normal" clinical parameters generally do not require additional clinical intervention to treat the parameter. The Endocrine Society Clinical Practice Guidelines recommend the use of the following cutoff values ​​to detect patients with primary aldosteronism (Funder et al., J Clin Endocrinol Metab 2016; 101: 1889-1916) (ARR cutoff values ​​are shown and depend on the detection method and whether PAC, PRA and PRC (DRC) are measured in conventional units or SI units):

[0089]

[0090] a The values ​​shown are based on a PRA (ng / mL / h) to DRC (mU / L) conversion factor of 8.2. DRC assays are still under development; in the recently introduced and commonly used automated DRC assay, the conversion factor is 12 (see text). It should be noted that the correlation between DRC and PRA is poor in the PRA range <1 ng / mL / h, which is the range of primary concern for PA screening (221, 222).

[0091] b The most commonly used cutoff values ​​are 30 for PAC and PRA expressed in conventional units (equivalent to 830 when PAC is expressed in SI units) and 750 for PAC expressed in SI units (equivalent to 27 when expressed in conventional units).

[0092] As used herein, a normal PAC for patients with adenomatous PA is understood to be <15 ng / dL (<410 pmol / L), and a normal PAC for patients with bilateral PA is understood to be <10 ng / dL (<275 pmol / L).

[0093] As used herein, normal PRA for patients with unilateral PA is understood to be >0.5 ng / mL / h, and PRC is understood to be >5 ng / L (using a sensitive assay that can detect PRA as low as 0.2-0.3 ng / mL / h or PRC as low as 2 mU / L). As used herein, normal PRA values ​​for patients with bilateral PA are understood to be >1.0 ng / mL / h, and PRC is understood to be >10 ng / L.

[0094] As used herein, a normal ARR is understood to be less than 3.7 (ng / dL) / (mU / L) (ie, PAC / DRC).

[0095] As used herein, normal urinary aldosterone excretion is understood to be less than 12 μg / 24 hours as measured by tetrahydroaldosterone levels in a 24-hour urine sample.

[0096] As used herein, normal office or clinic blood pressure is understood to be <140 mmHg systolic and <90 mmHg diastolic.

[0097] As used herein, normal ambulatory blood pressure is understood as systolic pressure <135 mmHg and diastolic pressure <85 mmHg; preferably systolic pressure <130 mmHg and diastolic pressure <80 mmHg; normal 24-hour ambulatory blood pressure monitoring is understood as systolic pressure <130 mmHg and diastolic 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.

[0098] As used herein, a normal blood potassium concentration is understood to be a potassium concentration 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 hypokalemic state, while a level above 5.2 mmol / L is understood to define a hyperkalemic state. As used herein, a level (i.e., potassium level) below 3.0 mmol / L is understood to define a severe hypokalemic state.

[0099] As used herein, potassium-resistant hypokalemia refers to a state of hypokalemia, wherein the hypokalemia cannot be treated by administering potassium (e.g., dietary potassium) to a subject suffering from the potassium-resistant hypokalemia. In some embodiments, potassium-resistant hypokalemia is understood to mean that even after potassium (e.g., dietary potassium) is administered to the subject, severe hypokalemia does not change (i.e., the potassium concentration in the blood remains below 3.0mmol / L). In some embodiments, potassium-resistant hypokalemia is understood to mean that even after potassium (e.g., dietary potassium) is administered to the subject, severe hypokalemia is converted to hypokalemia (i.e., the potassium concentration in the blood is higher than 3.0mmol / L but still remains below 3.6mmol / L). In some embodiments, potassium-resistant hypokalemia is understood to mean that even after potassium (e.g., dietary potassium) is administered to the subject, hypokalemia does not change (i.e., the potassium concentration in the blood remains below 3.6mmol / L).

[0100] In some embodiments, the amount of potassium (e.g., dietary potassium) administered to the subject that is insufficient to treat the potassium-resistant hypokalemia is at least 60 mmol / day; preferably, the amount is at least 70 mmol / day, and more preferably, the amount is at least 80 mmol / day.

[0101] As used herein, the term "inappropriate activity of aldosterone synthase" refers to the activity of aldosterone synthase of a wild-type or native gene or protein or the activity of a gene or protein in a healthy subject, which is considered appropriate in a healthy subject, but the same activity is considered inappropriate for a diseased subject, i.e., the activity is too strong or too weak for a diseased subject.

[0102] As used herein, the terms "treatment" and / or "therapy" refer to the management and care of a subject, preferably a patient suffering from a disease or condition, for which the purpose of administering one or more therapeutic compounds or compositions is to combat or alleviate the symptoms and complications of these conditions. Treatment includes administering one or more formulations of the present invention to prevent the occurrence of symptoms or complications, to alleviate symptoms or complications, or to eliminate the disease or condition. As used herein, the term "treatment" (or "therapy", used interchangeably herein) refers to therapeutic therapy and preventive or preventive measures. Preferably, "treatment" or "therapy" refers to therapeutic therapy.

[0103] As used herein, the term "pharmaceutically acceptable excipient" includes any physiologically inert additive commonly used in pharmaceutical dosage forms. Pharmaceutically acceptable excipients are selected from binders, diluents, carriers, lubricants, glidants, coating additives or combinations thereof. Other suitable carriers for active salt preparations of the present invention can be found in "Remington, The Science and Practice of Pharmacy, 2006, Philadelphia, Lippincott Williams & Wilkins".

[0104] As used herein, the term "patient" or "subject" refers to an animal, preferably a mammal, including a human being affected by a "disease" or "disorder". Examples of mammals include humans, dogs, cows, horses, pigs, sheep, goats, cats. In particularly preferred embodiments, the subject is a human being. As used herein, the terms "patient" and "human" are used interchangeably.

[0105] As used herein, the term "administering" refers to the introduction or application of a therapeutic agent into the body of a subject, preferably a patient in need thereof, to treat a disease or condition.

[0106] The term "therapeutically effective amount" refers to a dose of an active agent that is believed to be effective in treating at least one sign or symptom of a disease or condition or providing a specific pharmacological response for which the active agent is administered. The amount of the drug administered may vary depending on the circumstances, such as the disease state of the subject (preferably the patient) being treated, the dosage form, the method of administration, subject factors (preferably patient factors), etc. A therapeutically effective amount of an active agent administered to a particular subject under a particular circumstance is not always effective in treating the conditions described herein, even if the dose is considered by those skilled in the art to be a therapeutically effective amount.

[0107] The term "pharmaceutical composition" refers to a mixture containing at least one therapeutic agent, which is intended for administration to a subject (preferably a patient) to prevent or treat a particular disease or condition affecting the subject (preferably a patient).

[0108] As used herein, the term "use for..." in "composition for use in treating a disease" shall also disclose the corresponding methods of treatment and the corresponding uses of a formulation for preparing a medicament for treating a disease.

[0109] As used herein, the term "chronic cardiovascular disease or disorder" is understood to refer to a heart or blood vessel disease, wherein the disease is chronic. As used herein, the term "chronic" is understood to mean a disease or disorder that lasts for at least 8 weeks, preferably for at least 3 months, more preferably for at least half a year, still more preferably for at least 1 year, still more preferably for at least 2 years, still more preferably for at least 5 years, still more preferably for at least 10 years. In a very preferred embodiment, a chronic disorder is a disorder that lasts for the rest of the patient's life.

[0110] As used herein, when "associated with" is used to describe two (or more than two) diseases or conditions, it should be understood to refer to a patient suffering from both diseases or conditions. Therefore, in a preferred embodiment, a chronic cardiovascular disease or condition associated with, for example, hypokalemia should be understood to refer to a patient or subject who exhibits both a chronic cardiovascular disease or condition (e.g., primary aldosteronism) and hypokalemia. In some embodiments, the two diseases or conditions that are "associated with" each other can also be related to each other.

[0111] As used herein, the term "associated" is understood to mean related to or having a relationship with something else. In some embodiments where two (or more than two) diseases or conditions are related to each other, one of the diseases or conditions may cause and / or aggravate (i.e., worsen) another disease or condition. Thus, for example, when a subject suffers from a chronic cardiovascular disease associated with hypokalemia, the chronic cardiovascular disease or condition (e.g., primary aldosteronism) is caused or aggravated by hypokalemia. In some embodiments, hypokalemia is caused or aggravated by a chronic cardiovascular disease or condition (e.g., primary aldosteronism).

[0112] Compounds of the present invention

[0113] As used herein, (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine is understood to refer to a compound having the following structure:

[0114]

[0115] The enantiomeric excess (ee) of the (R) form of the (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine is greater than 99%.

[0116] In some embodiments, the compound of 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 of the present invention is selected from (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine hydrochloride, (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[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.

[0117] In a preferred embodiment, the compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate.

[0118] 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, wherein the enantiomeric excess (ee) of the (R) form of the compound is about 99.5% or more. In a preferred embodiment, the compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, wherein the enantiomeric excess (ee) of the (R) form of the compound is about 99.9% or more.

[0119] In some embodiments, the compound is selected from (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine hydrochloride, (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine dihydrogen phosphate and (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine hydrogen phosphate, wherein the enantiomeric excess (ee) of the (R) form of the compound is about 99.5% or more. In a preferred embodiment, the compound is selected from (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine hydrochloride, (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine dihydrogen phosphate and (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine hydrogen phosphate, wherein the enantiomeric excess (ee) of the (R) form of the compound is about 99.9% or more.

[0120] In some embodiments, the compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, wherein the enantiomeric excess (ee) of the (R) form of the compound is about 99.5% or more. In a preferred embodiment, the compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, wherein the enantiomeric excess (ee) of the (R) form of the compound is about 99.9% or more.

[0121] 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.

[0122] In one embodiment, the compound of the present invention is a crystalline form I of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, characterized in that the X-ray powder diffraction pattern comprises the following 2θ values ​​(measured as described in WO 2019 / 211394 (Bruker AXSD2 PHASER; radiation: CuKα (30 kV, 10 mA); scanning range: 5 to 45° (2θ values), sample rotation 5 rpm, 0.5 s / step, 0.010° / step, 3.0 mm detector slit)): 19.504; 21.919 and 24.159. In one embodiment, a crystalline form I of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate for use of the present invention is provided, wherein the crystalline form I is characterized in that the X-ray powder diffraction pattern comprises the following measured 2θ values: 19.504; 21.919 and 24.159, wherein each peak may vary by ±1°, preferably ±0.5°, or further preferably ±0.2°. In a preferred embodiment, the X-ray powder diffraction pattern further comprises the following 2θ values: 16.003, 26.101, 27.168, 27.542 and 29.029. In a preferred embodiment, the X-ray powder diffraction pattern further comprises the following 2θ values: 16.003, 26.101, 27.168, 27.542 and 29.029, wherein each peak may vary by ±1°, preferably ±0.5°, or further preferably ±0.2°.In a particularly preferred embodiment, there is provided a crystalline form I of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate for use according to the present invention, wherein the crystalline form I is characterized in that the X-ray powder diffraction pattern comprises 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 2θ values: 6.023129, 9.969034, 11.2 6224, 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, 20.72 112, 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, 34.35512, 35.02142, 35.06671, 35.68978, 35.93622, 36.50305, 36.56591, 36.92023, 37.14021, 39.60815, 37.89624, and 40.22464.In another particularly preferred embodiment, there is provided a crystalline form I of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate for use according to the present invention, wherein the crystalline form I is characterized in that the X-ray powder diffraction pattern comprises 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 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, 26.58127, 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, 3 37.89624 and 40.22464, wherein each peak may vary by ±1°, preferably ±0.5°, or further preferably ±0.2°.In another particularly preferred embodiment, a crystalline form I of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate is provided, characterized in that the X-ray powder diffraction pattern comprises 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 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, 21.919 06, 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, 32.2700 5, 32.79806, 33.20638, 33.23304, 33.65808, 34.41793, 34.35512, 35.02142, 35.06671, 35.68978, 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°, or preferably ±0.2°. In one embodiment, the relative intensities of the three largest peaks in the XRPD diffraction pattern of the crystalline form I are 1 to 0.85 to 0.55, particularly 1 to 0.9 to 0.6, more particularly 1 to 0.95 to 0.65, for example 1 to 0.97 to 0.68 (which can be obtained by integrating each peak in the XRPD pattern). In a specific embodiment, the largest peak is located at a 2-theta (θ) value of about 21.919, the second largest peak is located at a 2-theta (θ) value of about 19.504, and the third largest peak is located at a 2-theta (θ) value of about 24.159, respectively.In another specific embodiment, the maximum peak is located at a 2-theta (θ) value of about 21.919±0.5° (or preferably ±0.2°), the second largest peak is located at a 2-theta (θ) value of about 19.504±0.5° (or preferably ±0.2°), and the third largest peak is located at a 2-theta (θ) value of about 24.159±0.5° (or preferably ±0.2°), respectively.

[0123] Activity of the compounds of the present invention

[0124] As shown in Examples 1-5 below, the compounds of the present invention successfully correct the biochemical (e.g. ARR) and clinical disorders (e.g. hypertension) caused by primary aldosteronism (i.e., in patients with primary aldosteronism). Figure 2A and Figure 2B As shown, treatment with dexfadrostat phosphate reduced median plasma ARR and mean 24-hour aSBP relative to baseline over a 56-day period at all doses tested (ie, 4 mg, 8 mg, 12 mg).

[0125] From baseline to day 56, the median ARR of patients decreased from 15.3 to 0.6 (ng / dL) / (mU / L). From baseline to day 56, the mean 24-hour aSBP decreased by 10.7 mmHg.

[0126] As shown in Table 7 of Example 2, the 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 results (e.g., ARR) of patients with unilateral PA were similar to those of patients with bilateral PA or unexplained PA (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 often require adrenal surgery for treatment. As shown in Table 7 of Example 2 and Figure 3A and 3B As shown, the tested doses of the compounds of the invention (eg, dexfadrostat phosphate) are effective in treating patients with unilateral PA, and the response of patients with unilateral PA is similar to that of patients with bilateral PA or PA of unknown cause (idiopathic PA).

[0127] As shown in Table 8 of Example 3 and Figure 4A , 4B As shown in Figures 4 and 4C, all three doses tested (i.e., 4 mg, 8 mg, and 12 mg) mediated a significant reduction in ARR from baseline to day 56 (P < 0.0001). The efficacy of the 4 mg dose was only slightly lower than that of the 8 mg dose, while the efficacy of the 12 mg dose was not higher than that of the 8 mg dose.

[0128] As shown in Table 10 of Example 4 and Figure 4G , 4H As shown in Figures 4 and 4I, treatment with dexfadrostat phosphate at all three tested doses (i.e., 4 mg, 8 mg, and 12 mg) mediated a significant decrease in tetrahydroaldosterone levels (the major metabolite of aldosterone) in 24-hour urine samples collected at the end of active treatment compared to baseline samples (P<0.0001). Therefore, in some embodiments, the present invention provides the use of the compounds of the present invention for treating diseases characterized by abnormal aldosterone levels in urine.

[0129] As shown in Tables 11-13 and Figures 5A-5F As shown, from baseline to clinical visits on days 14, 28, 42, and 56, treatment with all three tested doses of dexfadrostat phosphate mediated rapid and significant (p<0.0001) ARR reduction, increased plasma potassium concentration, and reduced blood pressure. ARR inhibition, plasma potassium concentration, and blood pressure reduction remained sustained throughout the active treatment period. Surprisingly, for all three clinical indicators tested, the 4 mg dose was almost as effective as the 8 mg dose, and the 12 mg dose did not provide additional clinical benefits.

[0130] Therefore, in certain aspects, the present invention provides the use of the compounds of the present invention for rapid treatment of a disease or condition (e.g., a disease or condition in which excessive exposure to aldosterone causes symptoms of the disease or condition). Preferably, rapid treatment of the disease includes treatment within 14 days. Without wishing to be bound by theory, clinical responses to current surgical and drug treatments may take 3-12 months to occur.

[0131] In addition, in some aspects, the present invention provides the use of the compounds of the present invention for continued treatment over an extended treatment period (e.g., more than eight weeks) without the need to adjust the dosage (e.g., with a constant daily dosage of 4 mg or 8 mg). Without wishing to be bound by theory, current drug treatments require dosage adjustments every two weeks.

[0132] As shown in the following examples, the compounds of the present invention successfully treat hypokalemia, such as severe and / or potassium-resistant hypokalemia. The compounds of the present invention can treat hypokalemia in patients with chronic cardiovascular diseases or disorders (e.g., primary aldosteronism). Without wishing to be bound by theory, in some embodiments, the compounds of the present invention can also be used to treat hypokalemia, such as severe and / or potassium-resistant hypokalemia, in patients who do not suffer from cardiovascular diseases or disorders (e.g., patients who do not suffer from primary aldosteronism).

[0133] Treatment

[0134] In one aspect, the present invention provides a composition for treating a disease or condition, wherein the composition is administered to a subject in need once a day, the composition comprising a compound, the compound being (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, and the enantiomeric excess (ee) of the (R) form of the compound is about 99% or more.

[0135] In one aspect, the present invention provides a composition for treating a disease or condition, wherein the composition is administered to a subject in need once a day for at least eight weeks, and the composition comprises a compound, wherein the compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, and the enantiomeric excess (ee) of the (R) form of the compound is about 99% or more.

[0136] In a preferred embodiment, the subject in need of the 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 a preferred embodiment, the human is a woman of childbearing potential and a pediatric patient. In some embodiments, the subject is a human.

[0137] In some embodiments, the composition is administered orally, preferably in the form of a tablet or a capsule, more preferably in the form of a capsule.

[0138] In some embodiments, the composition is administered to the subject at a dose of about 1 mg to about 12 mg of the compound once a day. In a preferred embodiment, the composition is administered to the subject at a dose of about 1 mg to about 8 mg of the compound once a day. In a preferred embodiment, the composition is administered to the subject at a dose of 1 mg to 8 mg of the compound once a day. In some embodiments, the composition is administered to the subject at a dose of about 4 mg or about 8 mg of the compound once a day. In some embodiments, the composition is administered to the subject at a dose of 4 mg or 8 mg of the compound once a day.

[0139] In some embodiments, the composition is administered to the subject at a dose of about 1 mg of the compound once a day. In some embodiments, the composition is administered to the subject at a dose of about 2 mg of the compound once a day. In some embodiments, the composition is administered to the subject at a dose of about 3 mg of the compound once a day. In some embodiments, the composition is administered to the subject at a dose of about 4 mg of the compound once a day. In some embodiments, the composition is administered to the subject at a dose of about 5 mg of the compound once a day. In some embodiments, the composition is administered to the subject at a dose of about 6 mg of the compound once a day. In some embodiments, the composition is administered to the subject at a dose of about 7 mg of the compound once a day. In some embodiments, the composition is administered to the subject at a dose of about 8 mg of the compound once a day.

[0140] In a preferred embodiment, the composition is administered to the subject once daily at a dose 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 eight weeks, preferably for at least six months, preferably for at least one year, preferably for at least five years, more preferably for at least ten years; more preferably, wherein the once daily administration never requires dose adjustment.

[0141] In a preferred embodiment, the composition is administered to the subject once a day at a single daily dose of about 4 mg for at least eight weeks, preferably for at least six months, preferably for at least one year, preferably for at least five years, more preferably for at least ten years; more preferably, wherein the once-daily administration never requires a dose adjustment. In a preferred embodiment, the composition is administered to the subject once a day at a single daily dose of about 8 mg for at least eight weeks, preferably for at least six months, preferably for at least one year, preferably for at least five years, more preferably for at least ten years; more preferably, wherein the once-daily administration never requires a dose adjustment.

[0142] In some embodiments, the subject needs to quickly treat the disease or condition. On the one hand, the present invention includes inducing a clinical response in a subject in need, preferably inducing a clinical response within about 14 days of treatment. In some embodiments, the clinical response is selected from a decrease in plasma aldosterone levels, normalization of plasma aldosterone levels, a decrease in blood pressure, normalization of blood pressure, alleviation of hypokalemia, normalization of potassium concentration, and a decrease in urinary THA. Preferably, the decrease in plasma aldosterone levels includes reaching about <15ng / dL (about <410pmol / L) in patients with unilateral PA and about <10ng / dL (about <275pmol / L) in patients with bilateral PA. Preferably, the normalization of plasma aldosterone levels includes reaching about <15ng / dL (about <410pmol / L) in patients with unilateral PA and about <10ng / dL (about <275pmol / L) in patients with bilateral PA. Preferably, the blood pressure reduction comprises bringing the subject's systolic blood pressure to about <135 mmHg, the diastolic blood pressure to about <85 mmHg, preferably the systolic blood pressure to about <130 mmHg, the diastolic blood pressure to about <80 mmHg. Preferably, the normalization of blood pressure comprises bringing the subject's systolic blood pressure to about <135 mmHg, the diastolic blood pressure to about <85 mmHg, preferably the systolic blood pressure to about <130 mmHg, the diastolic blood pressure to about <80 mmHg. Preferably, the reduction of hypokalemia comprises bringing the plasma potassium concentration to about 3.6 mmol / L to about 5.2 mmol / L. Preferably, the normalization of potassium concentration comprises bringing the plasma potassium concentration to about 3.6 mmol / L to about 5.2 mmol / L. Preferably, the reduction of urinary THA comprises bringing the urinary tetrahydroaldosterone excretion to less than about 12 μg / 24 hours. In one embodiment, the clinical response is a decrease in ARR, preferably the ARR is decreased to less than about 5 (ng / dL) / (mU / L); preferably, the ARR is decreased to less than about 4 (ng / dL) / (mU / L); preferably, the ARR is decreased to less than about 3.7 (ng / dL) / (mU / L); preferably, the ARR is decreased to less than about 3.5 (ng / dL) / (mU / L); preferably, wherein the ARR is decreased to less than about 3 (ng / dL) / (mU / L); preferably, the ARR is decreased to less than about 2 (ng / dL) / (mU / L); preferably, the ARR is decreased to less than about 1 (ng / dL) / (mU / L); preferably, the ARR is decreased to less than about 0.55 (ng / dL) / (mU / L).

[0143] In some embodiments, the subject shows 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 includes reaching about <15 ng / dL (about <410 pmol / L) in unilateral PA patients and about <10 ng / dL (about <275 pmol / L) in bilateral PA patients. In some embodiments, the subject shows a clinical response within 14 days of treatment, wherein the clinical response is normalization of plasma aldosterone levels. Preferably, the normalization of plasma aldosterone levels includes reaching about <15 ng / dL (about <410 pmol / L) in unilateral PA patients and about <10 ng / dL (about <275 pmol / L) in bilateral PA patients. In some embodiments, the subject shows a clinical response within 14 days of treatment, wherein the clinical response is a decrease in blood pressure. Preferably, the blood pressure reduction comprises bringing the subject's systolic blood pressure to about <135 mmHg, the diastolic blood pressure to about <85 mmHg, preferably the systolic blood pressure to about <130 mmHg, the diastolic blood pressure to about <80 mmHg. In some embodiments, the subject shows a clinical response within 14 days of treatment, wherein the clinical response is normalization of blood pressure. Preferably, the normalization of blood pressure comprises bringing the subject's systolic blood pressure to about <135 mmHg, the diastolic blood pressure to about <85 mmHg, preferably the systolic blood pressure to about <130 mmHg, the diastolic blood pressure to about <80 mmHg. In some embodiments, the subject shows a clinical response within 14 days of treatment, wherein the clinical response is a reduction in hypokalemia. Preferably, the reduction in hypokalemia comprises bringing the plasma potassium concentration to about 3.6 mmol / L to about 5.2 mmol / L. In some embodiments, the subject shows a clinical response within 14 days of treatment, wherein the clinical response is a normalization of potassium concentration. Preferably, the normalization of potassium concentration comprises bringing the plasma potassium concentration to about 3.6 mmol / L to about 5.2 mmol / L. In some embodiments, the subject exhibits a clinical response within 14 days of treatment, wherein the clinical response is a decrease in urinary THA. Preferably, the decrease in urinary THA comprises bringing urinary tetrahydroaldosterone excretion to less than about 12 μg / 24 hours.

[0144] In some embodiments, the disease or condition is a disease or condition in which excessive exposure to aldosterone causes symptoms of the disease or condition. In some embodiments, the disease or condition 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 injury, plasma renin inhibition, renal fibrosis, arrhythmia, nephropathy, edema, hypokalemia-induced muscle weakness, cardiac fibrillation, and decreased myocardial contractility;

[0145] Preferably, the disease or disorder 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 injury, plasma renin suppression, renal fibrosis, arrhythmia, nephropathy and edema.

[0146] In a preferred embodiment, the disease or condition is selected from primary aldosteronism and secondary aldosteronism. In a preferred embodiment, the disease or condition is primary aldosteronism. In a preferred embodiment, the disease or condition is secondary aldosteronism.

[0147] In a preferred embodiment, the disease or condition is characterized by abnormal levels of aldosterone and / or tetrahydroaldosterone in urine. Preferably, the disease or condition characterized by abnormal levels of aldosterone and / or tetrahydroaldosterone in urine 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, arrhythmias, nephropathy, edema, hypokalemia-induced muscle weakness, cardiac fibrillation and decreased myocardial contractility.

[0148] Preferably, the disease or condition characterized by abnormal aldosterone and / or tetrahydroaldosterone levels in urine 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 and edema.

[0149] In a preferred embodiment, the disease or condition characterized by abnormal levels of aldosterone and / or tetrahydroaldosterone in the urine is selected from the group consisting of primary aldosteronism, secondary aldosteronism, heart failure, renal failure, refractory hypertension, essential hypertension, kidney disease, edema, coronary heart disease, hypokalemia and cardiac arrhythmia.

[0150] In a preferred embodiment, the disease or condition characterized by abnormal levels of aldosterone and / or tetrahydroaldosterone in urine is selected from the group consisting of heart failure, renal failure, refractory hypertension and essential hypertension.

[0151] In a preferred embodiment, the disease or condition is selected from primary aldosteronism and secondary aldosteronism. In a preferred embodiment, the disease or condition is primary aldosteronism. In a preferred embodiment, the disease or condition is secondary aldosteronism.

[0152] In some embodiments, the primary aldosteronism is unilateral or bilateral primary aldosteronism. In 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-looking adrenal glands.

[0153] In a very preferred embodiment, the disease or condition is unilateral primary aldosteronism. In a preferred embodiment, the disease or condition is unilateral primary aldosteronism caused by an aldosterone-producing adenoma (benign tumor), a unilateral nodule, an adrenal cancer, or a hyperplasia (preferably a unilateral hyperplasia). In a preferred embodiment, the disease or condition is unilateral primary aldosteronism caused by an aldosterone-producing adenoma (benign tumor). In a preferred embodiment, the disease or condition is unilateral primary aldosteronism caused by an adrenal cancer. In a preferred embodiment, the disease or condition is unilateral primary aldosteronism caused by a hyperplasia (preferably a unilateral hyperplasia). In a preferred embodiment, the disease or condition is unilateral primary aldosteronism caused by a unilateral nodule.

[0154] In a preferred embodiment, the primary aldosteronism is unilateral primary aldosteronism, wherein the unilateral primary aldosteronism is undetected or undiagnosed.

[0155] In some embodiments, the primary aldosteronism is bilateral primary aldosteronism, such as bilateral adenomas.

[0156] In a preferred embodiment, the disease or condition is essential hypertension and / or refractory hypertension, preferably, the disease or condition is essential hypertension and / or refractory hypertension with hypokalemia. In a preferred embodiment, the disease or condition is hypokalemia.

[0157] In one aspect, the present invention provides a composition for treating a disease or condition, wherein the composition is administered to a subject in need once a day for at least eight weeks, the composition comprising a compound, the compound being (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, the enantiomeric excess (ee) of the (R) form of the compound being about 99% or more; the disease or condition being unilateral primary aldosteronism; preferably, the unilateral primary aldosteronism is caused by an aldosterone-producing adenoma (benign tumor), unilateral nodule, adrenal cancer or hyperplasia (preferably unilateral hyperplasia).

[0158] In one aspect, the present invention provides a composition for treating a disease or condition characterized by abnormal aldosterone levels in urine, wherein the composition is administered to a subject in need thereof once a day for at least eight weeks, the composition comprising a compound, the compound being (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, and the enantiomeric excess (ee) of the (R) form of the compound being about 99% or more.

[0159] In one aspect, the present invention provides a composition for use in causing a clinical outcome in a subject in need thereof, wherein the composition is administered to the subject once a day for at least eight weeks, the composition comprising a compound, the compound being (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, the enantiomeric excess (ee) of the (R) form of the compound being about 99% or more. In some embodiments, the clinical outcome is selected from a decrease in plasma aldosterone levels, normalization of plasma aldosterone levels, a decrease in blood pressure, normalization of blood pressure, reduction in hypokalemia, normalization of plasma potassium concentration, and a decrease in urinary THA.

[0160] In some embodiments, the present invention provides a composition for reducing the plasma aldosterone level of a subject in need thereof, wherein the composition is administered to the subject once a day for at least eight weeks, the composition comprising a compound, the compound being (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, the enantiomeric excess (ee) of the (R) form of the compound being about 99% or more. Preferably, the plasma aldosterone level is reduced to normal and / or non-pathological levels.

[0161] In some embodiments, the present invention provides a composition for normalizing the plasma aldosterone level of a subject in need thereof, wherein the composition is administered to the subject once a day for at least eight weeks, the composition comprising a compound, the compound being (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, the enantiomeric excess (ee) of the (R) form of the compound being about 99% or more. Preferably, the plasma aldosterone level is reduced to normal and / or non-pathological levels.

[0162] In some embodiments, the present invention provides a composition for lowering the blood pressure of a subject in need thereof, wherein the composition is administered to the subject once a day for at least eight weeks, and the composition comprises a compound, the compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, and the enantiomeric excess (ee) of the (R) form of the compound is about 99% or more. 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.

[0163] In some embodiments, the present invention provides a composition for normalizing the blood pressure of a subject in need thereof, wherein the composition is administered to the subject once a day for at least eight weeks, the composition comprising a compound, the compound being (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, the enantiomeric excess (ee) of the (R) form of the compound being about 99% or more. 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.

[0164] In some embodiments, the present invention provides a composition for alleviating hypokalemia in a subject in need thereof, wherein the composition is administered to the subject once a day for at least eight weeks, the composition comprising a compound, the compound being (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, the enantiomeric excess (ee) of the (R) form of the compound being about 99% or more. Preferably, the hypokalemia is alleviated to normal and / or non-pathological levels.

[0165] In some embodiments, the present invention provides a composition for normalizing the plasma potassium concentration of a subject in need thereof, wherein the composition is administered to the subject once a day for at least eight weeks, the composition comprising a compound, the compound being (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, the enantiomeric excess (ee) of the (R) form of the compound being about 99% or more. Preferably, the plasma potassium concentration is increased to normal and / or non-pathological levels.

[0166] In some embodiments, the present invention provides a composition for reducing the urinary THA level of a subject in need thereof, wherein the composition is administered to the subject once a day for at least eight weeks, the composition comprising a compound, the compound being (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, the enantiomeric excess (ee) of the (R) form of the compound being about 99% or more. Preferably, the urinary THA level is reduced to normal and / or non-pathological levels.

[0167] In one aspect, the present invention provides a composition for treating a disease or condition, wherein the composition is administered to a subject in need thereof once a day for at least eight weeks, the composition comprising a compound, wherein the compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, wherein the enantiomeric excess (ee) of the (R) form of the compound is about 99% or more; the disease or condition 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 injury, plasma renin inhibition, renal fibrosis, arrhythmia, nephropathy, edema, hypokalemia-induced myasthenia, cardiac fibrillation and decreased myocardial contractility.

[0168] In one aspect, the present invention provides a composition for treating a disease or condition, wherein the composition is administered to a subject in need once a day for at least eight weeks, the composition comprising a compound, the compound being (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, the enantiomeric excess (ee) of the (R) form of the compound being about 99% or more; the disease or condition is selected from primary aldosteronism and secondary aldosteronism.

[0169] In one aspect, the present invention provides a composition for treating a disease or condition, wherein the composition is administered to a subject in need once a day for at least eight weeks, the composition comprising a compound, wherein the compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, and the enantiomeric excess (ee) of the (R) form of the compound is about 99% or more; wherein the disease or condition is primary aldosteronism.

[0170] In one aspect, the present invention provides a composition for treating a disease or condition, wherein the composition is administered to a subject in need once a day for at least eight weeks, the composition comprising a compound, the compound being (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, the enantiomeric excess (ee) of the (R) form of the compound being about 99% or more; and the disease or condition being secondary aldosteronism.

[0171] In one aspect, the present invention provides a composition for treating a disease or condition, wherein the composition is administered to a subject in need once a day for at least eight weeks, the composition comprises compound (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, and the enantiomeric excess (ee) of the (R) form of the compound is about 99.5% or more, preferably about 99.9% or more; the disease or condition is selected from primary aldosteronism and secondary aldosteronism.

[0172] In one aspect, the present invention provides a composition for treating a disease or condition, wherein the composition is administered to a subject in need thereof at a dose of 4 mg once a day for at least eight weeks, the composition comprising compound (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, the enantiomeric excess (ee) of the (R) form of the compound being about 99.5% or more, preferably about 99.9% or more; the disease or condition is selected from primary aldosteronism and secondary aldosteronism; preferably, the dose of 4 mg once a day remains unchanged for at least eight weeks.

[0173] In one aspect, the present invention provides a composition for treating a disease or condition, wherein the composition is administered to a subject in need thereof at a dose of 8 mg once a day for at least eight weeks, the composition comprising compound (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, the enantiomeric excess (ee) of the (R) form of the compound being about 99.5% or more, preferably about 99.9% or more; wherein the disease or condition is selected from primary aldosteronism and secondary aldosteronism; preferably, the dose of 8 mg once a day remains unchanged for at least eight weeks.

[0174] In one aspect, the present invention provides a composition for treating a disease or condition, wherein the composition is administered to a subject in need thereof at a dose of 4 mg once a day for at least eight weeks, the composition comprising compound (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, the enantiomeric excess (ee) of the (R) form of the compound being about 99.5% or more, preferably about 99.9% or more; the disease or condition is primary aldosteronism, preferably unilateral primary aldosteronism, more preferably, the unilateral primary aldosteronism is caused by an aldosterone-producing adenoma (benign tumor), unilateral nodule, adrenal cancer or hyperplasia (preferably unilateral hyperplasia).

[0175] In one aspect, the present invention provides a composition for treating a disease or condition, wherein the composition is administered to a subject in need thereof at a dose of 8 mg once a day for at least eight weeks, the composition comprising compound (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, the enantiomeric excess (ee) of the (R) form of the compound being about 99.5% or more, preferably about 99.9% or more; wherein the disease or condition is primary aldosteronism, preferably unilateral primary aldosteronism, and more preferably, the unilateral primary aldosteronism is caused by an aldosterone-producing adenoma (benign tumor), unilateral nodule, adrenal cancer or hyperplasia (preferably unilateral hyperplasia).

[0176] In one aspect, the present invention provides a composition for use in treating a disease or condition, wherein the composition is administered once a day to a subject in need thereof for at least eight weeks, the composition comprising a compound, the compound being (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, the enantiomeric excess (ee) of the (R) form of the compound being about 99% or more, the disease or condition being unilateral primary aldosteronism, the composition being orally administered once a day to the subject at a dose of about 4 mg or about 8 mg of the compound, wherein the once-a-day dose does not require dose adjustment. In a preferred embodiment, the unilateral primary aldosteronism is caused by an aldosterone-producing adenoma (benign tumor), a unilateral nodule, an adrenal cancer, or a hyperplasia (preferably a unilateral hyperplasia). In a preferred embodiment, the compound is administered at a dose of about 4 mg. In a preferred embodiment, the compound is administered at a dose of about 8 mg. Preferably, the compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate.

[0177] In one aspect, the present invention provides a composition for treating unilateral primary aldosteronism, wherein the composition is orally administered to a subject in need thereof at a dose of about 4 mg once a day for at least eight weeks, the composition comprising compound (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, the enantiomeric excess (ee) of the (R) form of the compound being about 99% or more. In a preferred embodiment, the unilateral primary aldosteronism is caused by an aldosterone-producing adenoma (benign tumor), a unilateral nodule, an adrenal cancer or hyperplasia (preferably unilateral hyperplasia).

[0178] In one aspect, the present invention provides a composition for treating unilateral primary aldosteronism, wherein the composition is orally administered to a subject in need thereof at a dose of about 8 mg once a day for at least eight weeks, the composition comprising compound (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, the enantiomeric excess (ee) of the (R) form of the compound being about 99% or more. In a preferred embodiment, the unilateral primary aldosteronism is caused by an aldosterone-producing adenoma (benign tumor), a unilateral nodule, an adrenal cancer or hyperplasia (preferably unilateral hyperplasia).

[0179] In one aspect, the present invention provides a composition for treating a disease or condition, wherein the disease or condition is a chronic cardiovascular disease or condition accompanied by hypokalemia, and the composition is orally administered to a subject in need thereof once a day, preferably for at least 8 weeks, wherein the composition comprises a compound, wherein the compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, and the enantiomeric excess (ee) of the (R) form of the compound is about 99% or more.

[0180] In one aspect, the present invention provides a composition for treating a disease or condition, wherein the disease or condition is a chronic cardiovascular disease or condition associated with hypokalemia, and the composition is orally administered to a subject in need thereof once a day, preferably for at least 8 weeks, wherein the composition comprises a compound, wherein the compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, and the enantiomeric excess (ee) of the (R) form of the compound is about 99% or more.

[0181] In some embodiments, the chronic cardiovascular disease or condition 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, plasma renin inhibition, arrhythmia, edema, hypokalemia-induced muscle weakness, cardiac fibrillation and decreased myocardial contractility; preferably, the chronic cardiovascular disease or condition associated with hypokalemia is selected from primary aldosteronism, secondary aldosteronism, heart failure, hypertension, restenosis, post-myocardial infarction, coronary heart disease, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular damage, arrhythmia and edema.

[0182] In some embodiments, the chronic cardiovascular disease or condition 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, plasma renin inhibition, arrhythmia, edema, hypokalemia-induced muscle weakness, cardiac fibrillation and decreased myocardial contractility; preferably, the chronic cardiovascular disease or condition associated with hypokalemia is selected from primary aldosteronism, secondary aldosteronism, heart failure, hypertension, restenosis, post-myocardial infarction, coronary heart disease, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular damage, arrhythmia and edema.

[0183] In some embodiments, the chronic cardiovascular disease or disorder with hypokalemia is primary aldosteronism with hypokalemia. In some embodiments, the chronic cardiovascular disease or disorder with hypokalemia is primary aldosteronism associated with hypokalemia.

[0184] In some embodiments, the chronic cardiovascular disease or disorder with hypokalemia is hyperaldosteronism with hypokalemia. In some embodiments, the chronic cardiovascular disease or disorder with hypokalemia is hyperaldosteronism associated with hypokalemia.

[0185] In some embodiments, the chronic cardiovascular disease or disorder with hypokalemia is primary aldosteronism with severe hypokalemia. In some embodiments, the chronic cardiovascular disease or disorder with hypokalemia is primary aldosteronism associated with severe hypokalemia.

[0186] In some embodiments, the chronic cardiovascular disease or disorder with hypokalemia is hyperaldosteronism with severe hypokalemia. In some embodiments, the chronic cardiovascular disease or disorder with hypokalemia is hyperaldosteronism associated with severe hypokalemia.

[0187] In some embodiments, the chronic cardiovascular disease or disorder with hypokalemia is primary aldosteronism with potassium-resistant hypokalemia. In some embodiments, the chronic cardiovascular disease or disorder with hypokalemia is primary aldosteronism associated with potassium-resistant hypokalemia.

[0188] In some embodiments, the chronic cardiovascular disease or disorder with hypokalemia is hyperaldosteronism with potassium-resistant hypokalemia. In some embodiments, the chronic cardiovascular disease or disorder with hypokalemia is hyperaldosteronism associated with potassium-resistant hypokalemia.

[0189] In some embodiments, the composition is administered to the subject at a dose of about 1 mg to about 12 mg of the compound once a day. In some embodiments, the compound is administered to the subject at a dose of about 4 mg. In some embodiments, the compound is administered to the subject at a dose of about 8 mg.

[0190] In one aspect, the present invention provides a composition for treating a disease or condition, wherein the disease or condition is hypokalemia, and the composition is orally administered to a subject in need thereof once a day, preferably for at least 8 weeks, wherein the composition comprises a compound, wherein the compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, and the enantiomeric excess (ee) of the (R) form of the compound is about 99% or more.

[0191] In some embodiments, the hypokalemia is severe hypokalemia. In some embodiments, the hypokalemia is potassium-resistant hypokalemia.

[0192] In some embodiments, hypokalemia is hypokalemia with chronic cardiovascular disease or condition. In a preferred embodiment, the chronic cardiovascular disease or condition is selected from primary aldosteronism, secondary aldosteronism, heart failure, hypertension, restenosis, after myocardial infarction, coronary heart disease, sodium retention, water retention, hypomagnesemia, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular injury, plasma renin inhibition, arrhythmia, edema, myasthenia caused by hypokalemia, cardiac fibrillation and weakened myocardial contractility; preferably, the chronic cardiovascular disease or condition is selected from primary aldosteronism, secondary aldosteronism, heart failure, hypertension, restenosis, after myocardial infarction, coronary heart disease, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular injury, arrhythmia and edema. In a further preferred embodiment, the hypokalemia is hypokalemia with chronic cardiovascular disease or condition, wherein the chronic cardiovascular disease or condition is primary aldosteronism. In some preferred embodiments, the hypokalemia is hypokalemia associated with a chronic cardiovascular disease or disorder, wherein the chronic cardiovascular disease or disorder is hyperaldosteronism.

[0193] In some embodiments, severe hypokalemia is severe hypokalemia with chronic cardiovascular disease or illness. In a preferred embodiment, the chronic cardiovascular disease or illness is selected from primary aldosteronism, secondary aldosteronism, heart failure, hypertension, restenosis, myocardial infarction, coronary heart disease, sodium retention, water retention, hypomagnesemia, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular injury, plasma renin inhibition, arrhythmia, edema, hypokalemia caused by muscle weakness, cardiac fibrillation and myocardial contractility weakening; preferably, the chronic cardiovascular disease or illness is selected from primary aldosteronism, secondary aldosteronism, heart failure, hypertension, restenosis, myocardial infarction, coronary heart disease, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular injury, arrhythmia and edema. In a further preferred embodiment, the severe hypokalemia is severe hypokalemia with chronic cardiovascular disease or illness, wherein the chronic cardiovascular disease or illness is primary aldosteronism. In some preferred embodiments, the severe hypokalemia is severe hypokalemia associated with a chronic cardiovascular disease or disorder, wherein the chronic cardiovascular disease or disorder is hyperaldosteronism.

[0194] In some embodiments, potassium-resistant hypokalemia is potassium-resistant hypokalemia associated with chronic cardiovascular diseases or conditions. In preferred embodiments, the chronic cardiovascular diseases or conditions are 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, plasma renin inhibition, arrhythmia, edema, hypokalemia-induced muscle weakness, cardiac fibrillation and decreased myocardial contractility; preferably, the chronic cardiovascular diseases or conditions are selected from primary aldosteronism, secondary aldosteronism, heart failure, hypertension, restenosis, post-myocardial infarction, coronary heart disease, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular damage, arrhythmia and edema. In still more preferred embodiments, the potassium-resistant hypokalemia is potassium-resistant hypokalemia associated with a chronic cardiovascular disease or disorder, wherein 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, wherein the chronic cardiovascular disease or disorder is hyperaldosteronism.

[0195] In some embodiments, severe hypokalemia is severe hypokalemia associated with chronic cardiovascular diseases or conditions. In preferred embodiments, the chronic cardiovascular diseases or conditions are 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, plasma renin inhibition, arrhythmia, edema, hypokalemia-induced muscle weakness, cardiac fibrillation and decreased myocardial contractility; preferably, the chronic cardiovascular diseases or conditions are selected from primary aldosteronism, secondary aldosteronism, heart failure, hypertension, restenosis, post-myocardial infarction, coronary heart disease, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular damage, arrhythmia and edema. In still more preferred embodiments, the severe hypokalemia is severe hypokalemia associated with chronic cardiovascular diseases or conditions, wherein the chronic cardiovascular diseases or conditions are primary aldosteronism. In some preferred embodiments, the severe hypokalemia is severe hypokalemia associated with a chronic cardiovascular disease or disorder, wherein the chronic cardiovascular disease or disorder is hyperaldosteronism.

[0196] In some embodiments, potassium-resistant hypokalemia is potassium-resistant hypokalemia associated with a chronic cardiovascular disease or condition. In a preferred embodiment, the chronic cardiovascular disease or condition 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, plasma renin inhibition, arrhythmia, edema, hypokalemia-induced muscle weakness, cardiac fibrillation and decreased myocardial contractility; preferably, the chronic cardiovascular disease or condition is selected from primary aldosteronism, secondary aldosteronism, heart failure, hypertension, restenosis, post-myocardial infarction, coronary heart disease, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular damage, arrhythmia and edema. In still more preferred embodiments, the potassium-resistant hypokalemia is potassium-resistant hypokalemia associated with a chronic cardiovascular disease or disorder, wherein 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, wherein the chronic cardiovascular disease or disorder is hyperaldosteronism.

[0197] 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 some embodiments, the compound is administered at a dose of about 4 mg. In some embodiments, the compound is administered at a dose of about 8 mg.

[0198] On the one hand, the present invention provides a composition for use in treating a disease or condition, wherein the disease or condition is hypokalemia (e.g., severe hypokalemia and / or potassium-resistant hypokalemia), the composition is orally administered to a subject in need once a day, preferably for at least 8 weeks, the composition comprising a compound, the compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, the enantiomeric excess (ee) of the (R) form of the compound is about 99% or more, and the hypokalemia is not associated with other diseases or conditions or is not associated with other diseases or conditions. In some embodiments, the composition is administered to the subject once a day at a dose of about 1 mg to about 12 mg of the compound. In some embodiments, the compound is administered at a dose of about 4 mg. In some embodiments, the compound is administered at a dose of about 8 mg.

[0199] In a preferred embodiment, the composition for use of 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 a solid. More preferably, the oral formulation is selected from tablets, pills, dispersible granules, cachets, capsules, powders, lozenges, suppositories and retention enemas.

[0200] In one embodiment, the pharmaceutical composition is in the form of an oral unit dosage. In another embodiment, the pharmaceutical composition is in the form of an oral solid unit dosage, such as tablets and capsules.

[0201] In a preferred embodiment, the composition for use of the present invention is orally administered once a day. In another preferred embodiment, the composition for use of the present invention is formulated for oral administration (oral preparation). The oral preparation is preferably a solid. More preferably, the oral preparation is selected from tablets, pills, dispersible granules, cachets, capsules, powders, lozenges, suppositories and retention enemas, most preferably capsules.

[0202] In a preferred embodiment, the composition for use of the present invention is continuously applied for a period of n days, wherein n is preferably>1. In a preferred embodiment, the composition for use of the present invention is applied once a day continuously over a period of time. In a very preferred embodiment, the composition for use of the present invention is applied for a long term. In another preferred embodiment, the composition for use of the present invention is applied for at least 1 month, preferably at least 2 months, more preferably at least 3 months, even more preferably at least half a year, even more preferably at least 1 year, even more preferably at least 2 years, even more preferably at least 5 years, even more preferably at least 10 years. In a very preferred embodiment, the composition for use of the present invention is a lifelong treatment.

[0203] Example

[0204] Equipment, Materials, and Methods

[0205] (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate (also known as dexfadrostat phosphate) was prepared according to the teaching of Example 3 of PCT / EP2017 / 077511 (see WO 2018 / 078049) with an ee>99.9%.

[0206] Example 1

[0207] A double-blind, randomized, phase 2 trial in patients with primary aldosteronism to investigate Efficacy of dexfadrostat phosphate in correcting biochemical (high plasma ARR) and clinical (hypertension) disease parameters

[0208] Study Design

[0209] The double-blind, randomized, phase 2 trial (NCT04007406) was conducted at 11 centers in Italy, Switzerland, and the Netherlands between November 2019 and June 2022. After a 14-day single-blind, placebo run-in period, patients were randomized 1:1:1 to receive oral dexfadrostat capsules once daily for 56 days, followed by a 14-day single-blind, placebo-free period ( Figure 1 Patients who required fixed-dose antihypertensive therapy continued treatment throughout the study; steroid therapy, β-adrenergic, and renin-angiotensin-aldosterone system blockers were not permitted. Office blood pressure was recorded every 14 days, and blood samples were collected in a central laboratory for measurement of steroid and peptide hormones and electrolytes. At baseline (day 1) and at the end of active treatment (day 56), 24-hour ambulatory blood pressure was recorded and 24-hour urine samples were collected.

[0210] Blood pressure measurement in the clinic

[0211] At each visit, blood pressure and pulse rate were measured after >15 minutes of sitting rest. Blood pressure and pulse rate were measured using a locally calibrated and validated automated oscillometric device (e.g., Omron Healthcare). An adjusted cuff was placed on the dominant arm. Three repeated measurements were recorded at 10-minute intervals; the average of the 2nd and 3rd measurements was relevant to the study.

[0212] Ambulatory blood pressure measurement

[0213] 24-hour ambulatory blood pressure monitoring (ABPM) included recording of mean daytime and nighttime systolic and diastolic blood pressure (measured every 20 minutes) and heart rate measurement on day -1 before the first dose of dexfadrostat phosphate and on day 55 after the penultimate dose of dexfadrostat phosphate. Centrally calibrated and validated equipment (Spacelab Healthcare) was used; the equipment was installed by qualified medical staff at the hospital outpatient department on days -1 and 55 before the patient took the medication under supervision. The lightweight digital monitor, which comes with a convenient carrying pocket, measures blood pressure readings at fixed intervals for 24 hours by inflating and subsequently deflating a custom cuff placed and wrapped around the non-dominant upper arm, recording approximately 70 readings. The patients followed their daily routine but did not exercise, bathe, or shower. In addition, to ensure correct measurement, the patients were asked to sit down before the reading, keep the cuff at the same level as the heart, and keep the arm stable. The patient was also asked to keep an activity, diet, and sleep diary to record what he / she was doing before the reading. At the end of the 24 hours, the patient can remove the monitor and cuff, shower or bathe, and then return the device to the researcher at the clinic. The machine stores all readings as source data and uploads them to the eCRF.

[0214] Blood sample analysis

[0215] According to GCP regulations, the use of Italian DiaSorin SpA The chemiluminescent immunoassay kit measures plasma aldosterone and plasma renin concentrations centrally. The system uses specific monoclonal antibodies to prevent cross-reactions with other major potential reactants in serum samples. Monoclonal antibodies directed against specific epitopes of the renin molecule allow for precise and sensitive quantification. The assays are performed according to the instructions provided by the manufacturer. The aldosterone assay has a wide measuring range (0.97-100 ng / mL) and is intended to assess aldosterone for diagnosis and evaluation of treatment of PA. The analytical sensitivity is <0.97 ng / mL. The renin assay has a wide measuring range (up to 500 μIU / mL) and is intended to assess renin for diagnosis and evaluation of treatment of PA. The analytical sensitivity is <0.53 μIU / mL.

[0216] Urine sample analysis

[0217] Tetrahydroaldosterone (THA) levels in urine were centrally measured by gas chromatography-mass spectrometry (GC-MS).

[0218] Patient Eligibility

[0219] The main inclusion criteria for patients included in the study were: (i) age between 18 and 65 years; (ii) PA diagnosed within 1 year of enrollment using the Endocrine Society diagnostic criteria; (iii) excessive and autonomous aldosterone production confirmed by pre- and post-suppression ARR; and (iv) office systolic blood pressure (oSBP) greater than 145 mmHg and less than 190 mmHg.

[0220] Specifically, PA diagnosis was defined by plasma aldosterone levels, plasma renin activity (PRA), or plasma renin concentration (PRC) before or after a 4-hour intravenous saline infusion or a 2-hour captopril suppression test, using the following protocol-specific cutoffs:

[0221] ARR ≥40, plasma aldosterone concentration (PAC) ≥15 ng / dL, and plasma renin activity (PRA) <1.0 ng / mL / h. Using plasma renin concentration (PRC) <15 mU / L instead of PRA as the denominator yields a prescreening ARR ≥3.7.

[0222] ●Intravenous saline challenge test (2 L of 0.9% saline infused over 4 hours) with a PAC >7.0 ng / dL after infusion. For patients at risk for volume expansion, a captopril test (50 mg captopril orally) is used instead, with an ARR >30 and a PAC >11 ng / dL (ARR >2.4 using PRC in mU / L instead of PRA as the denominator, respectively).

[0223] The protocol did not require patients to undergo CT adrenal imaging or adrenal vein sampling to further confirm eligibility.

[0224] The main exclusion criteria were: (i) oSBP>190 mmHg; (ii) hyperkalemia; (iii) prolonged QT interval.

[0225] For the Endocrine Society diagnostic criteria, see Funder, JW, et al., J. Clin. Endocrinol. Metab., 2016; 101: 1889-1916.

[0226] end

[0227] The co-primary endpoints were changes from baseline to Day 56 in: (i) median ARR (measured by aldosterone and renin concentrations, combined across all dose groups); and (ii) mean 24-hour ambulatory systolic BP (aSBP) (combined across all dose groups). Secondary and exploratory endpoints included: (i) change in aSBP from baseline to Day 56, stratified by dose; (ii) change in plasma ARR, oSBP, and potassium from baseline to Days 14, 28, 42, 56, and 70, stratified by dose; (iii) change in 24-hour urinary tetrahydroaldosterone excretion from baseline to end of treatment on Day 56; and (iv) treatment-emergent adverse events (TEAEs) and serious adverse events reported between baseline and Day 70.

[0228] Statistical analysis

[0229] For all efficacy endpoints, changes from baseline were calculated by linear models with 95% confidence intervals and p-values. Changes in ARR were log-transformed. The full analysis set (FAS) and safety set were defined as all randomized patients who received at least one dose of study drug.

[0230] Demographics and Baseline Characteristics

[0231] One patient discontinued the trial during the placebo run-in period due to COVID-19 hospital restrictions and was not included in the efficacy or safety analyses. The remaining 35 patients were included in both the full analysis set (FAS) and the safety set, of whom 74.3% were male and 91.4% were white (Table 1). At baseline (day 1), the median age (range) was 53.0 (30-64) years; the mean (standard deviation) oSBP was 147.7 (11.8) mmHg; the mean (standard deviation) plasma potassium concentration was 3.5 (0.4) mmol / L; and 31% of patients had hypokalemia. 25.7%, 34.3%, and 8.6% of patients had cardiac, vascular, and renal or urological conditions, respectively; one patient had previously undergone adrenalectomy (see Table 2).

[0232] Table 1: Patient demographics and characteristics at baseline

[0233]

[0234]

[0235] Table 2: Patients’ concomitant diseases and previous procedures at baseline

[0236]

[0237] Table 3: Patients’ hypertension control treatment at baseline

[0238]

[0239]

[0240] Primary End Point

[0241] The primary endpoint of this study was to evaluate whether daily dexfadrostat phosphate treatment for 8 weeks could correct the biochemical (ARR) and clinical (hypertension) disturbances caused by primary aldosteronism. Figure 2A As shown in Table 4, dexfadrostat phosphate treatment reduced the median plasma ARR from 15.3 to 0.6 (ng / dL) / (mU / L). Figure 2B As shown in Table 5, dexfadrostat phosphate treatment reduced mean 24-hour aSBP by 10.7 mmHg from baseline to Day 56 (p<0.0001 for median plasma ARR reduction and aSBP reduction; all dose groups combined).

[0242] Table 4: Change in Mean ARR (ng / dL) / (mU / L) from Baseline to Day 56

[0243]

[0244] Table 5: Change in mean aSBP (mmHg) from baseline to day 56

[0245]

[0246] Security

[0247] During the 70-day study period, TEAEs were reported in 16 patients. TEAEs were considered related or possibly related to dexfadrostat phosphate in seven patients, and events were related or possibly related to antihypertensive therapy received during the study in five patients (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. Four patients reported AESIs, all of which were headaches, two of which were considered related or possibly related to treatment.

[0248] Table 6: Treatment-emergent adverse events / treatment-related adverse events

[0249] event N＝35(％) Any TEAE 16(45.7) Serious TEAEs 0(0) TRAE 7(20.0) Subdivision of TRAEs and possible TRAEs Number of events dizziness 1 gastritis 1 nausea 1 Headache 2 amenorrhea 1 Breast pain 1 Frequent menstruation 1 cough 1

[0250] Example 2

[0251] A double-blind, randomized, phase 2 trial in patients with primary aldosteronism to investigate Efficacy of dexfadrostat phosphate in correcting biochemical (high plasma ARR) disease parameters caused by different pathologies

[0252] At the investigators' discretion, the diagnosis of PA was expanded according to the Endocrine Society clinical practice guidelines by: Patients underwent a CT scan to image the presence of an adrenal adenoma or nodule, followed by adrenal venous sampling (AVS) to determine the side of the adrenal gland that produces aldosterone. According to guideline recommendations, unilateral adenomas or nodules are usually surgically removed by adrenalectomy because this pathology is considered more severe and difficult to treat medically.

[0253] A per-patient analysis of the findings for biochemical correction of high plasma ARR levels investigated whether patients with clear pathology (e.g., unilateral adenoma or nodule) responded differently to dexfadrostat phosphate than patients with undetermined underlying pathology (e.g., bilateral nodules or hyperplasia or even normal glands) (see Table 7).

[0254] Table 7: ARR ((ng / dL) / (mU / L)) from 1.5 to 2.5 mg / dL based on the dose of dexfadrostat phosphate and the pathology causing PA. Change from Baseline to Day 56

[0255]

[0256] Surprisingly, patients with unilateral disease (e.g., patients 1, 21, 22, 30 treated with 4 mg dexfadrostat phosphate; patients 6, 16, 24, 27, 35 treated with 8 mg dexfadrostat phosphate and patients 3, 4, 9, 13, 15, 19 and 34 treated with 12 mg dexfadrostat phosphate) showed similar responses compared to patients with unspecified or bilateral disease in the corresponding dose groups. The graphical representation of the dose combinations shows that dexfadrostat phosphate normalized the ARR in patients with unilateral disease ( Figure 3A ), and normalization of the ARR in patients with bilateral or unspecified disease ( Figure 3B ).

[0257] Example 3

[0258] A double-blind, randomized, phase 2 trial of dexfadrostat in patients with primary aldosteronism Dose-dependent efficacy of phosphate in correcting biochemical (high plasma ARR) and clinical (hypertension) disease parameters

[0259] The secondary endpoints of this study evaluated whether dexfadrostat phosphate showed dose-dependent efficacy in correcting biochemical (ARR) and clinical (blood pressure) parameters of primary aldosteronism. The daily doses of 4 mg, 8 mg and 12 mg dexfadrostat phosphate were derived from previous Phase 1 clinical studies (PCT / EP2019 / 061283; see WO2019 / 211394). Analysis of the individual dose arms showed that all three doses mediated a significant reduction in ARR from baseline to Day 56 (p<0.0001) (see Tables 8 and Figure 4A , 4B , 4C). Surprisingly, it was found that the efficacy of the 4 mg dose was only slightly lower than that of the 8 mg dose. In contrast, the 12 mg dose was no more effective than the 8 mg dose, indicating that the 8 mg dose reached the maximum drug efficacy.

[0260] Table 8: ARR ((ng / dL) / (mU / L)) from Baseline to Day 56 Based on Dexfadrostat Phosphate Dose change

[0261]

[0262] Treatment with dexfadrostat phosphate and inhibition of the ARR significantly reduced 24-hour aSBP in each dose arm (p<0.001) (see Table 9 and Figure 4D , 4E , 4F). Surprisingly, the efficacy of the 4 mg dose was only slightly lower than that of the 8 mg dose. In contrast, the efficacy of the 12 mg dose was no more effective than that of the 8 mg dose, indicating that the 8 mg dose reached the maximum drug efficacy.

[0263] Table 9: Mean 24-hour aSBP (mmHg) from Baseline to Day 56 Based on Dexfadrostat Phosphate Dose change

[0264]

[0265] Example 4

[0266] A double-blind, randomized, phase 2 trial in patients with primary aldosteronism to investigate Dose-dependent efficacy of dexfadrostat phosphate in correcting biochemical (high urinary aldosterone) disease parameters

[0267] The exploratory endpoint of this study evaluated whether dexfadrostat phosphate showed dose-dependent efficacy in correcting elevated urinary aldosterone levels, a disease parameter in primary aldosteronism as well as other cardiovascular disease. Daily doses of 4 mg, 8 mg, and 12 mg dexfadrostat phosphate were derived from a previous Phase 1 study (PCT / EP2019 / 061283; see WO 2019 / 211394). Analysis of the individual dose arms showed that all three doses mediated significant reductions (p<0.0001) in tetrahydroaldosterone (THA), the major metabolite of aldosterone in urine, in 24-hour urine samples collected at the end of active treatment compared with baseline samples (see Tables 10 and Figure 4G , 4H , 4I). Surprisingly, the efficacy of the 4 mg dose was only slightly lower than that of the 8 mg dose. In contrast, the 12 mg dose was no more effective than the 8 mg dose, indicating that the 8 mg dose reached the maximum drug efficacy.

[0268] Table 10: Urinary Tetrahydroaldosterone (THA) Levels (24 μg / 24 Hours) Based on Dexfadrostat Phosphate Dosage Change from Baseline to Day 56

[0269]

[0270] Example 5

[0271] A double-blind, randomized, phase 2 trial in patients with primary aldosteronism to investigate Dexfadrostat Phosphate

[0272] Time- and discontinuation-dependent efficacy in correcting biochemical (plasma ARR and potassium) and clinical (blood pressure) disease parameters

[0273] The secondary endpoints of this study evaluated whether dexfadrostat phosphate showed dose- and time-dependent efficacy in correcting biochemical (plasma ARR and potassium) and clinical (blood pressure) parameters of primary aldosteronism. The daily doses of 4 mg, 8 mg, and 12 mg dexfadrostat phosphate were derived from a previous Phase 1 clinical study (PCT / EP2019 / 061283; see WO2019 / 211394). Analysis of the individual dose arms showed that all three doses mediated a rapid and significant reduction in ARR from baseline to outpatient visits on days 14, 28, 42, and 56 (p<0.0001) (see Tables 11 and Figure 5A , 5D). ARR suppression remained sustained throughout the active treatment period. After drug discontinuation, ARR values ​​returned to baseline values. Surprisingly, the efficacy of the 4 mg dose was only slightly lower than that of the 8 mg dose. In contrast, the 12 mg dose was no more effective than the 8 mg dose, suggesting that the 8 mg dose achieved maximum drug efficacy.

[0274] Table 11: ARR (ng / dL) / (mU / L) from Baseline to Day 56 and Discontinuation Based on Dexfadrostat Phosphate Dose Changes on the 70th day after medication

[0275]

[0276] In each dose arm, ARR inhibition rapidly and significantly increased plasma potassium concentrations (p<0.001) (see Tables 12 and Figure 5C , 5F ). The increase in potassium concentrations remained persistent throughout the active treatment period. After discontinuation of the drug, potassium concentrations returned to baseline levels. Surprisingly, the 4 mg dose was as effective as the 8 mg dose. The 12 mg dose provided no additional efficacy.

[0277] Table 12: Plasma Potassium (nmol / L) from Baseline to Day 56 and Discontinuation Based on Dexfadrostat Phosphate Dose Changes after 70 days

[0278]

[0279] In each dose arm, ARR inhibition rapidly and significantly reduced office blood pressure (p≤0.001) (see Tables 13 and Figure 5B , 5E ). The blood pressure reduction remained sustained throughout the active treatment period. After discontinuation of the drug, blood pressure values ​​returned to baseline levels. Surprisingly, the 4 mg dose was almost as effective as the 8 mg dose. The 12 mg dose provided no additional clinical benefit.

[0280] Table 13: Office Blood Pressure (mmHg) from Baseline to Day 56 and Discontinuation Based on Dexfadrostat Phosphate Dose Changes after 70 days

[0281]

[0282] Example 6

[0283] A double-blind, randomized, phase 2 trial in patients with primary aldosteronism to investigate blood potassium levels,

[0284] Blood aldosterone levels and 24-hour urine aldosterone levels

[0285] Table 14. Changes in blood potassium concentrations in patient segments defined by initial blood potassium levels

[0286]

[0287]

[0288]

[0289] Table 15: Changes in Plasma Aldosterone Concentrations in Patient Segments Defined by Initial Plasma Aldosterone Levels

[0290]

[0291]

[0292] Table 16: Changes in urine aldosterone concentrations in patient segments defined by initial urine aldosterone levels

[0293]

[0294]

[0295]

Claims

1. A composition for use in treating a disease or condition, wherein: The composition is administered once a day to a subject in need thereof, preferably a human being, and comprises a compound, which is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, and the enantiomeric excess (ee) of the (R) form of the compound is about 99% or more.

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

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. A composition for use according to any one of the preceding claims, wherein The composition is administered to the subject once daily at a dose of about 1 mg to about 12 mg of the compound.

5. A composition for use according to any one of the preceding claims, wherein The compound was administered at a dose of about 4 mg.

6. The composition for use according to any one of claims 1 to 4, wherein The compound was administered at a dose of about 8 mg.

7. A composition for use according to any one of the preceding claims, wherein The compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate. Preferably, the enantiomeric excess (ee) of the (R) form of the (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate is about 99.5% or more, more preferably about 99.9% or more.

8. A composition for use according to any one of the preceding claims, wherein The disease or condition 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 injury, plasma renin inhibition, renal fibrosis, arrhythmia, nephropathy, edema, hypokalemia-induced muscle weakness, cardiac fibrillation and decreased myocardial contractility; the disease or condition is preferably 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 injury, plasma renin inhibition, renal fibrosis, arrhythmia, nephropathy and edema.

9. A composition for use according to any one of the preceding claims, wherein The disease or condition is primary aldosteronism.

10. The use or composition according to any one of the preceding claims, wherein The disease or condition 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. Preferably, the unilateral primary aldosteronism is caused by unilateral adenoma, unilateral nodule or unilateral hyperplasia.

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

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

14. A composition for use according to any one of the preceding claims, wherein The once daily dose does not require dosage adjustment.

15. A composition for use according to any one of the preceding claims, wherein The subject exhibits a clinical response within about 14 days of treatment, preferably selected from the group consisting of a decrease in plasma aldosterone levels, normalization of plasma aldosterone levels, a decrease in blood pressure, normalization of blood pressure, a decrease in hypokalemia, normalization of potassium concentration, and a decrease in urinary THA.

Images