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US-20260124184-A1 - ONCE DAILY ALDOSTERONE SYNTHASE INHIBITOR (R)-(+)-5-(P-CYANOPHENYL)-5,6,7,8-TETRAHYDROIMIDAZO[L,5-A]PYRIDINE

US20260124184A1US 20260124184 A1US20260124184 A1US 20260124184A1US-20260124184-A1

Abstract

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

Inventors

  • Christoph Schumacher
  • Ronald Edward Steele
  • Teresa GERLOCK

Assignees

  • DAMIAN PHARMA AG

Dates

Publication Date
20260507
Application Date
20231013
Priority Date
20221014

Claims (15)

  1. 1 . A composition for use in the treatment of a disease or disorder, wherein said composition is administered once daily to a subject, preferably a human, in need thereof wherein said composition comprises a compound which is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, wherein said compound has an enantiomeric excess (ee) of the (R) form higher than or equal to about 99%.
  2. 2 . The composition for use of claim 1 , wherein said composition is administered once daily to a subject in need thereof for at least eight weeks.
  3. 3 . The composition for use of any of claim 1 or 2 , wherein said disease or disorder is a chronic disease or disorder, preferably a chronic cardiovascular disease or disorder.
  4. 4 . The composition for use of any of the preceding claims , wherein said composition is administered once daily to said subject at a dosage from about 1 mg to about 12 mg of said compound.
  5. 5 . The composition for use of any of the preceding claims , wherein said compound is administered at a dosage of about 4 mg.
  6. 6 . The composition for use of any of any of claims 1-4 , wherein said compound is administered at a dosage of about 8 mg.
  7. 7 . The composition for use of any of the preceding claims , wherein said compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, preferably wherein said (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate has an enantiomeric excess (ee) of the (R) form higher than or equal to about 99.5%, more preferably higher than or equal to about 99.9%.
  8. 8 . The composition for use of any of the preceding claims , wherein said disease or disorder is selected from the group consisting of primary aldosteronism, secondary aldosteronism, heart failure, chronic renal failure, hypertension, restenosis, obesity, nephropathy, post-myocardial infarction, renal fibrosis, coronary heart disease, sodium retention, water retention, hypokalemia, hypomagnesaemia, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular damage, suppression of plasma renin, kidney fibrosis, arrhythmias, nephropathy, edema, hypokalemia-caused muscle weakness, cardiac fibrillation and weakened cardiac muscle contraction; preferably wherein said disease or disorder is selected from the group consisting of primary aldosteronism, secondary aldosteronism, heart failure, chronic renal failure, hypertension, restenosis, obesity, nephropathy, post-myocardial infarction, renal fibrosis, coronary heart disease, sodium retention, water retention, hypokalemia, hypomagnesaemia, hypertension, left ventricular hypertrophy, cardiac fibrosis, cardiovascular damage, suppression of plasma renin, kidney fibrosis, arrhythmias, nephropathy, and edema.
  9. 9 . The composition for use of any of the preceding claims , said disease or disorder is primary aldosteronism.
  10. 10 . The composition or use of any of the preceding claims , wherein said disease or disorder is bilateral primary aldosteronism.
  11. 11 . The composition of any of claims 1-9 , wherein said disease or disorder is unilateral primary aldosteronism, preferably wherein said unilateral primary aldosteronism is caused by unilateral adenoma, unilateral nodules, or unilateral hyperplasia.
  12. 12 . The composition for use of any of claims 1-8 , wherein said disease or disorder is essential hypertension and/or resistant hypertension, preferably wherein said disease or disorder is essential hypertension and/or resistant hypertension with accompanying hypokalemia.
  13. 13 . The composition for use of any of claims 1-8 , wherein said disease or disorder is hypokalemia.
  14. 14 . The composition for use of any of the above-claims, wherein said once daily dose does not require dose adjustment.
  15. 15 . The composition for use of any of the above-claims, wherein said subject exhibits a clinical response within about 14 days of treatment, preferably wherein said clinical response is selected from reduction in plasma aldosterone levels, normalization of plasma aldosterone levels, reduction of blood pressure, normalization of blood pressure, reduction of hypokalemia, normalization of potassium concentration, and reduction of urinary THA.

Description

The present invention relates to a composition for use in the treatment of a disease or disorder, wherein said disease or disorder is preferably a disease or disorder in which aldosterone overexposure contributes to the symptoms of said disease or disorder, said composition comprises a compound which is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, wherein preferably said compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, and wherein said compound has an enantiomeric excess (ee) of the (R) form higher than or equal to 99%, and wherein said composition is administered once daily for at least eight weeks to a patient in need thereof. Diseases of aldosterone overexposure can be diagnosed biochemically and include in decreasing severity primary aldosteronism due to adrenal aldosterone-producing adenoma or nodules or due to adrenal hyperplasia or due to apparently normal glands. RELATED ART Aldosterone excess is associated with or can accompany various harmful metabolic and cardiovascular structural effects, including sodium and water retention, hypokalemia, hypomagnesaemia, hypertension, left ventricular hypertrophy and cardiac fibrosis. Primary aldosteronism has a substantially adverse outcome when compared with essential hypertension. Accordingly, effective medical therapy both to lower blood pressure and antagonize the excess activation of the mineralocorticoid receptor are important therapeutic aims (Parthasarathy et al., 2011, J Hypertens 29: 980-990). Primary aldosteronism (PA) is defined as a group of disorders in which aldosterone production is inappropriately high for sodium status, relatively autonomous of the major regulators of secretion (angiotensin II, plasma potassium concentration), and non-suppressible by sodium loading. Such inappropriate production of aldosterone causes hypertension, cardiovascular damage, sodium retention, suppression of plasma renin, and increased potassium excretion that (if prolonged and severe) may lead to hypokalemia. PA is commonly caused by a benign adrenal adenoma, adrenal nodules, unilateral or bilateral adrenal hyperplasia (BAH), or in rare cases adrenal carcinoma or inherited conditions of familial hyperaldosteronism. PA is also known as Conn's syndrome (Funder et al., 2016, J Clin Endocrinol Metab 101: 1889-1916). Aldosterone levels can be measured in the blood and in the urine. The Endocrine Society clinical practice guidelines for the management of primary aldosteronism describe in detail the process and methods to measure 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 cut-off levels for abnormal values. A more accurate method to measure aldosterone levels consist of the collection of a 24-hour urine sample and determination of the content of tetrahydroaldosterone, the main metabolite of aldosterone, in the urine (Funder and Carey, 2022, Hypertens 79: 726-735). The authors provide diagnostic cut-off values for abnormal values. Furthermore, the Endocrine Society clinical practice guidelines for the management of primary aldosteronism recommend and describe an invasive process supported by CT imaging to subtype patients to lateralize the adrenal source of excessive aldosterone secretion. Unilateral adrenal adenoma can be surgically removed by adrenalectomy whereas bilateral disease requires medical treatment (Funder et al., 2016, J Clin Endocrinol Metab 101: 1889-1916). The capacity of adrenal glomerulosa cells to produce aldosterone is controlled largely by the regulated transcription of CYP11B2, the gene encoding aldosterone synthase. Aldosterone synthase inhibition has emerged as an option for the treatment of hypertension, heart failure and renal disorders. The aim is to decrease aldosterone concentrations in both plasma and tissues, thereby decreasing MR-dependent and MR-independent effects in the cardiac, vascular and renal target organs. (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) at an enantiomeric excess (ee) of the (R) form higher than or equal to 99%. The high enantiomeric excess values achieved by the process described in WO 2018/078049 leads to potent (i.e., low nanomolar) and selective aldosterone synthase inhibition by (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine. WO 2019/211394 teaches the results of a phase 1 clinical trial investigating the use of dexfadrostat phosphate in healthy subjects. SUMMARY OF THE INVEN