Aldosterone synthase inhibitor
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.
1. (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate.
2. The compound of claim 1 , wherein said compound has an enantiomeric excess of the (R) form higher than or equal to 97%.
3. 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.
4. 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.
5. 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 IC 50 values for inhibition of aromatase and aldosterone synthase; wherein the IC 50 values for inhibition of aldosterone synthase and aromatase are both measured in the NCI-H295R adrenal cell assay.
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 1 , 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 1 , 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 CuKa radiation: 19.504; 21.919 and 24.159, wherein each peak may vary by ±0.5.
11. A pharmaceutical composition comprising a compound according to claim 1 in admixture with at least one pharmaceutically acceptable excipient.
12. A method of treating a disease or disorder in a human in need thereof including premenopausal female and pediatric patients, in which aldosterone over-exposure contributes to deleterious effects of said disease or disorder comprising administering an effective amount of compound according to claim 1 to said human, wherein said disease or disorder is selected from primary and secondary hyperaldosteronism, heart failure, chronic renal failure, hypertension, restenosis, obesity, nephropathy, post-myocardial infarction, renal fibrosis, and coronary heart disease.
13. 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-a]pyridine by adding a base to a solution of the tartrate salt obtained in step ii; and
iv. forming a pharmaceutically acceptable salt by reacting said free base with an acid,
wherein preferably said acid is phosphoric acid (H 3 PO 4 ).
14. 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.
15. The compound of claim 1 , 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 CuKa radiation: 19.504; 21.919 and 24.159, wherein each peak may vary by ±0.2 degrees.
16. A pharmaceutical composition comprising (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridine dihydrogen phosphate in admixture with at least one pharmaceutically acceptable excipient.
17. The pharmaceutical composition according to claim 16 , wherein said pharmaceutical composition is in a tablet, pill, dispersible granule, cachet, capsule, powder, lozenge, suppository or retention enema form.