R-fadrozole for use in treatment of aldostonerism
An aldosterone and disease-treating technology, which is used in medical preparations containing active ingredients, drug combinations, cardiovascular system diseases, etc., and can solve the problems of unreported clinical development and undisclosed chiral purity of R-enantiomer synthesis.
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[0148] Other preferred aspects and embodiments of the present invention are as follows:
[0149] 1. A composition for treating a disease or condition, wherein the disease or condition is preferably primary aldosteronism or secondary aldosteronism, more preferably primary aldosteronism, wherein the combination The composition is administered to a subject in need thereof once daily, and the composition comprises (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[ A compound of 1,5-a]pyridine, or a pharmaceutically acceptable salt thereof, wherein the enantiomeric excess (ee) of the (R) form of the compound is greater than or equal to 97%.
[0150] 2. A composition for the treatment of a disease or condition, wherein the disease or condition is a disease or condition in which overexposure to aldosterone causes symptoms of the disease or condition, wherein the composition is administered to a subject in need thereof once a day. subject, and the composition comprises (R)-(+)-5-(p...
Embodiment 1
[0229] DP13 administered once daily
[0230] DP13 is an abbreviation herein and refers to the dihydrogen phosphate of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine Salt. Synthesis of the dihydrogen phosphate salt of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine exemplified herein 6 and 7. Further reference is made to the applicant's application PCT / EP2017 / 077511, which is incorporated herein by reference.
[0231]We have found that once-daily administration of DP13 at oral doses of 4, 8 and 16 mg effectively suppressed plasma aldosterone levels in normal men compared to pre-treatment values and placebo-treated control values (Table 1). Responses to oral doses of 4, 8, and 16 mg of DP13 once daily were assessed in 24 normal individuals (8 subjects / dose) and their plasma aldosterone and potassium responses were compared with each other and with 8 placebo-treated individuals for comparison. At all time points where aldosterone ...
Embodiment 2
[0248] Plasma aldosterone levels after ACTH administration
[0249] To demonstrate that once-daily doses of DP13 have the potential to inhibit the elevated autocrine aldosterone levels seen in PA patients, exogenous ACTH administration was performed on the same 32 normal individuals evaluated above. ACTH was administered intravenously (i.v.) on day 7 of DP13 two hours after 08:00h of daily DP13 administration, and blood samples for aldosterone measurements were drawn 1 hour after ACTH and compared with half an hour before ACTH (post DP13 administration). One and a half hours) blood samples were drawn for comparison. This procedure, known as the "ACTH Stress Test", showed that oral doses of 4, 8 or 16 mg DP13 administered once daily were able to prevent the 2- to 3-fold increase in aldosterone caused by ACTH in individuals who received only the daily placebo dose (Table 3). Plasma aldosterone concentrations in the placebo group in response to ACTH ranged from 432 to 825 pmol...
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Abstract
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