IP Library › Granted Patent US 12,202,827
Granted Patent B2
US 12,202,827 · App. 17/883,732 · Granted Jan 21, 2025

Aldosterone synthase inhibitor

Inventors: Christoph Schumacher (Walchwil, CH); Walter Fuhrer (Lupsingen, CH); Ronald Edward Steele (Long Valley, NJ)
Assignee: DAMIAN PHARMA AG
C07D471/04A61K31/437A61P9/00A61P9/12A61P13/12
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Quick Facts
Patent No.
US 12,202,827
App. No.
17/883,732
Granted
Jan 21, 2025
Kind
B2
Abstract

The present invention relates to a compound selected from (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine and a pharmaceutically acceptable salt thereof, and in particular to the phosphate salt of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, both having preferably an enantiomeric excess of the (R) form higher than or equal to 97%. Furthermore, the present invention relates to pharmaceutical compositions comprising the same, their use as a medicament and in methods of treatment of diseases and disorders in humans including women of child bearing potential and pediatric patients in which aldosterone over-exposure contributes to the deleterious effects of said diseases or disorders, as well as processes for preparing said inventive compounds.

Claims (28)

1. A compound selected from (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo [1,5-a]pyridine and a pharmaceutically acceptable salt thereof, wherein said compound has an enantiomeric excess of the (R) form higher than or equal to 99%.

2. The compound of claim 1 , wherein said compound inhibits aromatase activity in a cell-free human recombinant aromatase enzyme assay with an IC 50 of 700 nM or more.

3. The compound of claim 1 , wherein said compound inhibits aldosterone synthase in a NCI-H295R adrenal cell assay with an IC 50 of 100 nM or less.

4. The compound of claim 1 , wherein said compound has a selectivity for aldosterone synthase over aromatase of 50 or more, wherein said selectivity is determined by a ratio of the IC50 values for inhibition of aromatase and aldosterone synthase; wherein the IC50 values for inhibition of aldosterone synthase and aromatase are both measured in the NCI-H295R adrenal cell assay.

5. The compound of claim 1 , wherein said compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridine dihydrogen phosphate.

6. The compound of claim 1 , wherein said pharmaceutically acceptable salt is crystalline.

7. The compound of claim 1 , wherein said pharmaceutically acceptable salt is anhydrous.

8. The compound of claim 1 , wherein said pharmaceutically acceptable salt is non-hygroscopic.

9. The compound of claim 5 , wherein said (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridine dihydrogen phosphate has a melting point of equal or between 184° C. to 193° C. as determined by thermogravimetry analysis/differential scanning calorimetry (TGA/DSC).

10. The compound of claim 5 , wherein said (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridine dihydrogen phosphate is a crystalline form I of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridine dihydrogen phosphate, wherein said crystalline form I has an X-ray powder diffraction pattern comprising 2θ values measured using CuKα radiation: 19.504; 21.919 and 24.159, wherein each peak may vary by +0.5 degrees.

11. The compound of claim 1 , wherein said compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo [1,5-a]pyridine.

12. A pharmaceutical composition comprising a compound according to claim 1 in admixture with at least one pharmaceutically acceptable excipient.

13. A method of treating a disease or disorder in a human in need thereof, wherein said disease or disorder is selected from primary and secondary hypoaldosteronism, heart failure, chronic renal failure, hypertension, restenosis, obesity, nephropathy, post-myocardial infarction, renal fibrosis, and coronary heart disease, said method comprising administering an effective amount of the compound of claim 1 to said human.

14. A process for preparing a compound selected from (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo [1,5-a]pyridine and a pharmaceutically acceptable salt thereof according to claim 1 comprising the steps of:

i. reacting racemic 5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo [1,5-a]pyridine with (−)-O,O′-dibenzoyl-L-tartaric acid to form the diastereomeric (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo [1,5-a]pyridine dibenzoyl-L-tartrate salt; and

ii. recrystallizing at least once the tartrate salt obtained in step i; and

iii. liberating the free base (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo [1,5-alpyridine by adding a base to a solution of the tartrate salt obtained in step ii; and optionally

iv. forming a pharmaceutically acceptable salt by reacting said free base with an acid.

15. The compound of claim 1 , wherein said compound has a selectivity for aldosterone synthase over aromatase of 100 or more, wherein said selectivity is determined by a ratio of the IC 50 values for inhibition of aromatase and aldosterone synthase and wherein the IC 50 values for inhibition of aldosterone synthase and aromatase are both measured in a NCI-H295R adrenal cell assay.

16. The compound of claim 5 , wherein said (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridine dihydrogen phosphate is a crystalline form I of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridine dihydrogen phosphate, wherein said crystalline form I has an X-ray powder diffraction pattern comprising 2θ values measured using CuKα radiation: 19.504; 21.919 and 24.159, wherein each peak may vary by +0.2 degrees.

17. A pharmaceutical composition comprising the compound of claim 5 in admixture with at least one pharmaceutically acceptable excipient.

18. The pharmaceutical composition according to claim 12 , wherein said pharmaceutical composition is in a tablet, pill, dispersible granule, cachet, capsule, powder, lozenge, suppository or retention enema form.

19. The compound of claim 1 , wherein said compound has an enantiomeric excess of the (R) form higher than or equal to 99.5%.

20. The compound of claim 1 , wherein said compound has an enantiomeric excess of the (R) form higher than or equal to 99.8%.

21. The compound of claim 1 , wherein said compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridine tartrate.

22. The compound of claim 1 , wherein said compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridine dibenzoyl-L-tartrate.

23. The compound of claim 1 , wherein said compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridine fumarate.

24. The compound of claim 1 , wherein said compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridine chloride.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 9, 2022
From: SCHUMACHER, CHRISTOPH; FUHRER, WALTER; STEELE, RONALD EDWARD
To: DAMIAN PHARMA AG
Reel/Frame 061119/0240 →
Priority Claims (1)
EP 16205019 · Dec 19, 2016 · regional
Continuity (4)
Continuation 16991856 · Aug 12, 2020
Continuation 16345209
Provisional Application 62413635 · Oct 27, 2016
Related Publication 20230047158A1 · Feb 16, 2023
References Cited (57)
US 5057521A · Hausler · 1991 [cited by applicant]
US 5098911A · Ibrahim · 1992 [cited by applicant]
US 5428160A · Browne · 1995 [cited by examiner]
US 10822332B2 · Schumacher · 2020 [cited by examiner]
US 11447491B2 · Schumacher · 2022 [cited by examiner]
US 20090105278A1 · Hartmann et al. · 2009 [cited by applicant]
EP 1886695A1 · 2008 [cited by applicant]
NZ 534086A · 2006 [cited by applicant]
WO 200176574A2 · 2001 [cited by applicant]
WO 2005099695A1 · 2005 [cited by applicant]
WO 2007024945A1 · 2007 [cited by applicant]
WO 2013109514A1 · 2013 [cited by applicant]
WO 2016005880A1 · 2016 [cited by applicant]
WO 2018078049A1 · 2018 [cited by applicant]
Azizi et al., “Aldosterone synthase inhibition in humans,” Nephrology Dialysis Transplantation 28(1):36-43 (2013). [cited by applicant]
International Search Report issued in International Application No. PCT/EP2017/077511, dated Nov. 27, 2017. [cited by applicant]
Fiebeler et al., “Aldosterone Synthase Inhibitor Ameliorates Angiotensin II-Induced Organ Damage,” Circulation 111 :3087-3094 (2005). [cited by applicant]
Furet et al., “Aromatase Inhibitors: Synthesis, Biological Activity, and Binding Mode of Azole-Type Compounds,” J. Med. Chem. 36:1393-1400 (1993). [cited by applicant]
Hojo et al., “Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017a and P450 aromatase localized in neurons,” Proceedings of the National Academy of Sciences 101 (3):865-870 (2004). [cited by applicant]
Kandasamy et al., “Possible Existence of the Hypothalamic-Pituitary-Hippocampal (HPH) Axis: A Reciprocal Relationship Between Hippocampal Specific Neuroestradiol Synthesis and Neuroblastosis in Ageing Brains with Specia… [cited by applicant]
Martin et al., “Discovery of 4-Aryl-5,6,7,8-tetrahydroisoquinolines as Potent, Selective, and Orally Active Adosterone Synthase (CYP11 B2) Inhibitors: In Vivo Evaluation in Rodents and Cynomolgus Monkeys,” Journal of Me… [cited by applicant]
Ménard et al., “Can the dextroenantiomer of the aromatase inhibitor fadrozole be useful for clinical investigation of aldosterone-synthase inhibition?” Journal of Hypertension 24(6):993-7 (2006). [cited by applicant]
Minnaard-Huiban et al., “Fadrozole reverses cardiac fibrosis in spontaneously hypertensive heart failure rats: discordant enantioselectivity versus reduction of plasma aldosterone,” Endocrinology 149(1) :28-31 (2008). [cited by applicant]
Roumen et al., “Construction of 3D Models of the CYP11B Family as a Tool to Predict Ligand Binding Characteristics” J Comput Aided Mol Des 21(8):455-471 (2007). [cited by applicant]
Browne et al., “Fadrozole Hydrochloride: A Potent, Selective, Nonsteroidal Inhibitor of Aromatase for the Treatment of Estrogen-Dependent Disease,” [cited by applicant]
Mulatero et al., “CYP11B2 inhibitor dexfadrostat phosphate suppresses the aldosterone-to-renin ratio, an indicator of sodium retention, in healthy volunteers,” [cited by applicant]
Mulatero et al., Safety and efficacy of once-daily dexfadrostat phosphate in patients with primary aldosteronism: a randomised, parallel group, multicentre, phase 2 trial, [cited by applicant]
Amar et al., “Aldosterone synthase inhibition with LCI699: a proof-of-concept study in patients with primary aldosteronism,” Hypertension 56:831-838 (2010). [cited by applicant]
Briones et al., “Adipocytes produce aldosterone through calcineurin-dependent signaling pathways: implications in diabetes mellitus-associated obesity and vascular dysfunction,” Hypertension 59(5):1069-1078 (2012). [cited by applicant]
Brunssen et al., “Impact of aldosterone synthase inhibitor FAD286 on steroid hormone profile in human adrenocortical cells,” Horm Metab Res 49(9):701-706 (2017). [cited by applicant]
Deliyanti et al., “Neovascularization is attenuated with aldosterone synthase inhibition in rats with retinopathy,” et al., Hypertension 59(3):607-13 (2012). [cited by applicant]
Funder, “Trilostane, FAD286, and the role of aldosterone in the central regulation of blood pressure: focus on Role of central nervous system aldosterone synthase and mineralocorticoid receptors in salt-induced hyperten… [cited by applicant]
Funder et al., “The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline,” J. Clinical Endocrinology & Metabolism 101(5):1889-1916 (2016). [cited by applicant]
Gamliel-Lazarovich et al., “FAD286, an aldosterone synthase inhibitor, reduced atherosclerosis and inflammation in apolipoprotein E-deficient mice,” J Hypertens. 28(9):1900-1907 (2010). [cited by applicant]
Gomez-Sanchez et al., “Aldosterone synthesis in the brain contributes to Dahl salt-sensitive rat hypertension,” Exp Physiol. 95(1):120-130 (2010). [cited by applicant]
Hamlyn et al., “Neuroendocrine humoral and vascular components in the pressor pathway for brain angiotensin II: a new axis in long term blood pressure control,” PLos One 9(10):e108916 (2014). [cited by applicant]
Hofmann et al., “The aldosterone synthase inhibitor FAD286 is suitable for lowering aldosterone levels in ZDF rats but not in db/db mice,” Horm Metab Res 49(6):466-471 (2017). [cited by applicant]
Hofmann et al., “Aldosterone synthase inhibition improves glucose tolerance in Zucker diabetic fatty (ZDF) rats,” Endocrinology 157(10):3844-3855 (2016). [cited by applicant]
Huang et al., “Central infusion of aldosterone synthase inhibitor prevents sympathetic hyperactivity and hypertension by central Na [cited by applicant]
Huang et al., “Central infusion of aldosterone synthase inhibitor attenuates left ventricular dysfunction and remodelling in rats after myocardial infarction,” Cardiovasc Res. 81(3):574-581 (2009). [cited by applicant]
Huang et al., “Role of central nervous system aldosterone synthase and mineralocorticoid receptors in salt-induced hypertension in Dahl salt-sensitive rats,” Am J Physiol Regul Integr Comp Physiol. 296(4):R994-R1000 (20… [cited by applicant]
Huang et al., “Role of brain corticosterone and aldosterone in central angiotensin II-induced hypertension,” Hypertension 62(3):564-571 (2013). [cited by applicant]
Kawarazaki et al. “Mineralocorticoid receptor activation: a major contributor to salt-induced renal injury and hypertension in young rats,” Am J Physiol Renal Physiol. 300(6):F1402-F1409 (2011). [cited by applicant]
Korte et al., “Feedforward activation of endothelial ENaC by high sodium,” FASEB J 28(9):4015-4025 (2014). [cited by applicant]
Lasala et al., “Co-expression of CYP11B2 or CYP11B1 with adrenodoxin and adrenodoxin reductase for assessing the potency and selectivity of aldosterone synthase inhibitors,” Anal Biochem. 394(1):56-61 (2009). [cited by applicant]
Launonen et al., “Adverse effects of an aldosterone synthase (CYP11B2) inhibitor, fadrozole (FAD286), on inflamed rat colon,” Basic Clin Pharmacol Toxicol 133(3):211-225 (2023). [cited by applicant]
Lea et al., “Aldosterone antagonism or synthase inhibition reduces end-organ damage induced by treatment with angiotensin and high salt,” Kidney Int. 75(9):936-44 (2009). [cited by applicant]
Menard et al., “Investigation of aldosterone-synthase inhibition in rats,” Journal of Hypertension, 24(6):1147-1155 (2006). [cited by applicant]
Mulder et al., “Aldosterone synthase inhibition improves cardiovascular function and structure in rats with heart failure: a comparison with spironolactone,” Eur Heart J. 29(17):2171-2179 (2008). [cited by applicant]
Omata et al., “Cellular and Genetic Causes of Idiopathic Hyperaldosteronism,” Hypertension 72(4):874-880 (2018). [cited by applicant]
Oshima et al., “Aldosterone is synthesized in and activates bulbospinal neurons through mineralocorticoid receptors and ENaCs in the RVLM,” Hypertens Res. 36(6):504-512 (2013). [cited by applicant]
Rana et al., “Angiotensin Il and aldosterone activate retinal microglia,” Exp Eye Res 191:107902 (2020). [cited by applicant]
Rigel et al., “Pharmacodynamic and Pharmacokinetic Characterization of the Aldosterone Synthase Inhibitor FAD286 in Two Rodent Models of Hyperaldosteronism: Comparison with the 11ß-Hydroxylase Inhibitor Metyrapone,” J P… [cited by applicant]
Shimoni et al., “Aldosterone and the autocrine modulation of potassium currents and oxidative stress in the diabetic rat heart,” British Journal of Pharmacology 154(3):675-687 (2008). [cited by applicant]
Wang et al., “Role of brain aldosterone and mineralocorticoid receptors in aldosterone-salt hypertension in rats,” Neuroscience 314:90-105 (2016). [cited by applicant]
Weldon et al., “Selectivity of BI 689648, a novel, highly selective aldosterone synthase inhibitor: comparison with FAD286 and LCI699 in nonhuman primates,” Pharmacol Exp Ther. 359(1):142-150 (2016). [cited by applicant]
Yin et al., “3-Pyridyl substituted aliphatic cycles as CYP11B2 inhibitors: aromaticity abolishment of the core significantly increased selectivity over CYP1A2,” PLOS One 7(11):e48048 (2012). [cited by applicant]