Aldosterone synthase inhibitor

Abstract

To provide a compound for use in the treatment of diseases and disorders in humans, including women of childbearing potential and pediatric patients, in which aldosterone over-exposure contributes to the deleterious effects of the diseases or disorders.SOLUTION: The present invention provides a compound selected from (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine and a pharmaceutically acceptable salt thereof, the compound having an enantiomeric excess of the (R) form of 97% or higher.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to compounds selected from (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine and pharmaceutically acceptable salts thereof, particularly the phosphate salt of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, both of which preferably have an enantiomeric excess of 97% or greater for the (R) configuration. The present invention also relates to pharmaceutical compositions containing the compounds, their use as medicaments, and in methods for treating diseases and disorders in which excessive aldosterone exposure contributes to the adverse effects of such diseases or disorders, including those in premenopausal women and pediatric patients, as well as in methods for preparing the compounds of the invention. [Background technology]

[0002] Inhibition of aldosterone synthase (CYP11B2), in addition to mineralocorticoid receptor (MR) blockade, has emerged as a new option for the treatment of hypertension, heart failure, and renal disorders. The goal is to reduce aldosterone concentrations in both plasma and tissues, thereby reducing MR-dependent and MR-independent effects in cardiac, vascular, and renal target organs. Aldosterone is produced in the zona glomerulosa of the adrenal gland by the enzymatic action of aldosterone synthase (CYP11B2) on deoxycorticosterone (M. Azizi et al., Nephrol Dial Transplant (2013) 28:36-43).

[0003] Early attempts to inhibit aldosterone synthesis included the use of various nonselective steroidogenesis inhibitors, but these substances had significant safety concerns. The concept of a targeted pharmacological approach to the specific inhibition of aldosterone synthesis began with the discovery that fadrozole hydrochloride (CGS16949A, INN: fadrozole; U.S. Patent Nos. 4,617,307; 4,728,645; and 5,098,911), a known nonsteroidal aromatase inhibitor effective in the treatment of advanced breast cancer, affects aldosterone levels. Subsequent preclinical studies demonstrated that the R-enantiomer (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridine chloride is a potent inhibitor of CYP11B2, while the S-enantiomer is responsible for the potent and highly effective aromatase (CYP19) inhibitory activity of CGS16949A (J. Menard et al., J Hypertens (2006) 24:993; Fiebeler et al., Circulation (2005) 111:3078-94; Furet et al., J Med Chem (1993) 36:1393-1400; US 5,057,521).

[0004] On the other hand, and despite its early discovery, there have been no reports of clinical development of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine chloride in humans, nor has a commercially available synthesis or sufficient chiral purity been disclosed (U.S. Pat. No. 4,889,861). In addition, (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine chloride has been found to be highly hygroscopic (Browne LJ et al., J Med Chem (1991) 34:725-36; Furet et al., J Med Chem (1993) 36:1393-1400; U.S. Pat. No. 4,889,861).

[0005] The chiral purity of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridine chloride is particularly important given the potent and highly effective aromatase inhibitory activity of the corresponding (S) enantiomer, as evaluation of a wide range of aromatase inhibitors in clinical trials has revealed numerous adverse consequences of aromatase inhibition. Accordingly, a systematic review and meta-analysis of seven studies involving 30,023 postmenopausal women with breast cancer treated with aromatase inhibitors demonstrated a significant increase in the incidence of fractures and cardiovascular disease (Amir et al., J Natl Cancer Inst (2011) 103:1299-1309). Furthermore, the longer the duration of aromatase inhibition, the greater the contribution to cardiovascular disease and fractures. Additionally, in premenopausal women, i.e., women of childbearing potential, exposure to aromatase inhibitors can lead to reproductive problems, and in lactating women, newborns can be exposed to aromatase inhibitor compounds through secretion in breast milk. Furthermore, in pediatric patients, aromatase inhibition can lead to developmental problems. Therefore, the need for extremely high purity and avoidance of contaminants and impurities in such drugs is evident. Such drugs are typically administered for long periods of time, or even lifelong.

[0006] Furthermore, and in addition to the required extremely high chiral purity and avoidance of aromatase inhibition as an adverse effect, long-term stability, including solubility in water and enantiomeric stability, to preclude any conversion to aromatase-inhibiting moieties, and ease of processing such drugs into dosage forms suitable for oral administration, such as tablets, are prerequisites for the formulation of such drugs, including all additives. Summary of the Invention

[0007] Surprisingly, the present inventors have now provided (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine of formula (I) having an unprecedented degree of chiral purity, i.e., enantiomeric excess (ee), typically preferably 97% or more of the (R) ee, and more preferably 99% or more or 99.5% or more of the (R) ee. Furthermore, the inventors have surprisingly found that phosphate salts of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, in particular (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, are non-hygroscopic and stable, in particular with respect to purity, water content and enantiomeric purity, over extended periods of time. Furthermore, and importantly, the present inventors have unexpectedly discovered that phosphate salts of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, particularly (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, are a stable crystalline form.In addition, the compounds of the present invention also have reduced, extremely low aromatase activity, and consequently, increased, extremely high aldosterone synthase activity, making the compounds of the present invention highly suitable candidates for clinical development in humans, especially for premenopausal women and pediatric patients.It is believed that extremely low aromatase activity is even a prerequisite for clinical development and even for approved use as a drug for treating diseases and disorders associated with aldosterone overexposure, especially for premenopausal women, therefore, fertile women and pediatric patients. The latter is particularly effective because the amount of aromatase and the percentage of androgen to estrogen conversion are quantitatively smaller in extragonadal tissues, often less than 1% of that in any given tissue, but the impact in terms of hormone action is still significant (Blakemore and Naftolin, Physiology (2016) 31:258-269).Thus, the compounds of the present invention offer the potential for lifelong treatment of disorders adversely affected by aldosterone production by minimizing the adverse and undesirable effects caused by contaminating and more potent aromatase-inhibiting (S) enantiomers.

[0008] Thus, in a first aspect, the present invention provides a compound selected from (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine of formula (I) and pharmaceutically acceptable salts thereof, said compound having an ee of the (R) form of 97% or more, preferably 98% or more, more preferably 99% or more, and also more preferably 99.5% or more, also more preferably 99.8% or more, for example 99.9%. TIFF2025131628000001.tif47160

[0009] In particular, and in a second aspect, the present invention provides (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, which typically has an (R)-form ee of 97% or more, preferably 98% or more, more preferably 99% or more, and also more preferably 99.5% or more, and also more preferably 99.8% or more, for example, 99.9%, which is surprisingly non-hygroscopic and thereby stable over long periods of time, particularly in terms of purity, water content, and chiral purity. This is particularly important because hygroscopicity can adversely affect the stability of active pharmaceutical ingredients. Additionally and importantly, phosphate salts of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, particularly (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, are crystalline in one stable form. Unstable polymorphism typically adversely affects pharmaceutical efficacy properties.

[0010] In a further aspect, the present invention provides (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine and its phosphate salts, preferably having an ee of the (R) form of typically 97% or more, preferably 98% or more, more preferably 99% or more, and also more preferably 99.5% or more, and also more preferably 99.8% or more, for example 99.9%, for use as a medicament for the treatment of a disease or disorder in humans, including women of childbearing potential and pediatric patients, and in methods of treating such diseases or disorders. or (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridine dihydrogen phosphate, wherein excessive exposure to aldosterone contributes to the adverse effects of said disease or disorder, said disease or disorder is typically and preferably selected from primary and secondary hyperaldosteronism, heart failure, chronic renal failure, hypertension, restenosis, obesity, nephropathy, post-myocardial infarction syndrome, renal fibrosis, and coronary heart disease, and more preferably said disease or disorder is selected from primary and secondary hyperaldosteronism. Even more preferably, said method is suitable for use in humans, including particularly women of childbearing age and pediatric patients.

[0011] The chiral resolution and synthesis of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine and (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate achieved in such high chiral purity according to the present invention now enables the preparation of pharmaceutical compositions for the suppression of aldosterone with as little undesirable contaminating aromatase activity as possible, usually and preferably by inhibiting the rate-limiting enzyme in aldosterone synthesis, i.e., aldosterone synthase (CYP11B2). The typical need for lifelong treatment of such diseases and disorders enhances the advantages of the present invention in terms of minimizing contamination from the highly potent aromatase-inhibiting (S)-(−)-enantiomer of the beneficial aldosterone synthase-inhibiting (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, and thereby particularly its phosphate salt, and more preferably (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate. As shown in Tables 10 and 11 of Example 8, the phosphate salts of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine of the present invention, preferably (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, inhibited aldosterone production (aldosterone synthase activity) and estradiol production (aromatase activity) with IC values ​​of 8.1 nM and 5760 nM, respectively, in NCI-H295R adrenal cells. 50The present invention inhibits aldosterone synthase activity by more than 700% and therefore shows a greater inhibition of aromatase activity than aldosterone synthase activity, demonstrating the extremely favorable safety profile of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine and also (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate compared to the phosphate salts of the present invention. Therefore, the present invention is particularly suitable for application in humans, particularly premenopausal women and pediatric patients. It is believed that extremely low aromatase activity is even a prerequisite for clinical development and use as a drug for aldosterone-related diseases and disorders, especially for premenopausal women, therefore, fertile women and pediatric patients.

[0012] The present inventors have discovered that (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, as well as its phosphate salts, particularly (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, prepared by the methods of the present invention, exhibit unprecedentedly low aromatase inhibitory activity. Thus, in a further aspect, the present invention provides compounds having an IC50 of 700 nM or greater against aromatase, as measured by the cell-free human recombinant aromatase enzyme assay described in Example 8. 50

[0010] In Example 8, the phosphate salt of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, preferably (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, has an IC value of 1640 nM. 50 It was found to inhibit aromatase activity.

[0013] Furthermore, the present inventors have found that (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine prepared by the method of the present invention, as well as its phosphate salt, preferably (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, exhibit unprecedentedly high aldosterone synthase inhibitory activity. Thus, in a further aspect, the present invention provides a compound selected from (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine and pharmaceutically acceptable salts thereof, in particular the phosphate salts thereof, more preferably (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, said compound having an IC50 of 100 nM or less in the NCI-H295R adrenal cell assay described in Example 8. 50 It inhibits aldosterone synthase.

[0014] In a further aspect, the present invention provides a process for the preparation of a compound selected from (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine and pharmaceutically acceptable salts thereof, characterized by enantioselective crystallization of the (−)-O,O′-dibenzoyl-L-tartrate salt of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, most preferably said pharmaceutically acceptable salt is the dihydrogen phosphate salt thereof.

[0015] In a further aspect, the present invention provides a compound selected from (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine and pharmaceutically acceptable salts thereof, said compound having a specific rotation [α] of at least +95°, preferably at least +96°, more preferably at least +97°, and even more preferably at least +98°. D 20(CH3CN:H2O 1:1 (vol / vol)), [α] D 20 (ethanol) or [α] D 25 (ethanol), preferably [α] D 20 (CHCN:HO 1:1 (volume / volume)), preferably the compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, and more preferably the compound has an IC50 of 700 nM or greater, preferably 1000 nM or greater, and more preferably 1500 nM or greater in the cell-free human recombinant aromatase enzyme assay described in Example 8. 50 and more preferably, the compound has an IC50 of 100 nM or less, preferably 50 nM or less, and more preferably 10 nM or less in the NCI-H295R adrenal cell assay described in Example 8. 50 In a highly preferred embodiment, the compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, which has a specific rotation [α] of at least +95°, preferably at least +96°, more preferably at least +97°, and even more preferably at least +98°. D 20 (CHCN:H0 1:1 (vol / vol)), and preferably the compound has an IC50 of 700 nM or greater, preferably 1000 nM or greater, and more preferably 1500 nM or greater in the cell-free human recombinant aromatase enzyme assay described in Example 8. 50 and more preferably, the compound has an IC50 of 100 nM or less, preferably 50 nM or less, and more preferably 10 nM or less in the NCI-H295R adrenal cell assay described in Example 8. 50 inhibits aldosterone synthase.

[0016] In a further aspect, the present invention provides a compound selected from (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine and pharmaceutically acceptable salts thereof, said compound having a specific rotation [α] of at least +95°, preferably at least +96°, more preferably at least +97°, and even more preferably at least +98°. D 20 (CH3CN:H2O 1:1 (vol / vol)), [α] D 20 (ethanol) or [α] D 25 (ethanol), preferably [α] D 20 (CHCN:HO 1:1 (volume / volume)), preferably the compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, more preferably the compound has a selectivity for aldosterone synthase over aromatase of 50 or greater, preferably 100 or greater, most preferably 700 or greater, said selectivity being greater than or equal to an IC for aromatase inhibition. 50 values ​​and IC for aldosterone synthase inhibition 50 The IC for aromatase inhibition is determined by the ratio of 50 values ​​and IC for inhibition of aldosterone synthase 50 Both values, preferably simultaneously, are measured in the NCI-H295R adrenal cell assay described in Example 8. In a highly preferred embodiment, the compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine dihydrogen phosphate and has a specific rotation [α] of at least +95°, preferably at least +96°, more preferably at least +97°, and even more preferably at least +98°. D 20(CHCN:H0 1:1 (vol / vol)), and preferably the compound has a selectivity for aldosterone synthase over aromatase of 50 or greater, preferably 100 or greater, most preferably 700 or greater, and said selectivity is determined by an IC for aromatase inhibition. 50 values ​​and IC for aldosterone synthase inhibition 50 The IC for inhibition of aldosterone synthase is determined by the ratio of 50 value and IC for aromatase inhibition 50 Both values ​​are measured, preferably simultaneously, in the NCI-H295R adrenal cell assay described in Example 8.

[0017] In a further aspect, the present invention provides a compound selected from (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine and pharmaceutically acceptable salts thereof, wherein said compound has an IC50 of 700 nM or greater, preferably 1000 nM or greater, and more preferably 1500 nM or greater in the cell-free human recombinant aromatase enzyme assay described in Example 8. 50 Preferably, the compound has an enantiomeric excess of the (R) form of 97% or more, and more preferably, the compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate.

[0018] In a further aspect, the present invention provides a compound selected from (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine and pharmaceutically acceptable salts thereof, wherein said compound has an IC50 of 100 nM or less, preferably 50 nM or less, and more preferably 10 nM or less in the NCI-H295R adrenal cell assay described in Example 8. 50and inhibits aldosterone synthase, preferably the compound has an enantiomeric excess of the (R) form of 97% or more, and more preferably the compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate.

[0019] In a further aspect, the present invention provides a compound selected from (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine and pharmaceutically acceptable salts thereof, said compound having a selectivity for aldosterone synthase over aromatase of 50 or greater, preferably 100 or greater, and most preferably 700 or greater, said selectivity being indicative of an IC for aromatase inhibition. 50 values ​​and IC for aldosterone synthase inhibition 50 The IC for aromatase inhibition is determined by the ratio of 50 values ​​and IC for inhibition of aldosterone synthase 50 Both values, preferably simultaneously, are measured in the NCI-H295R adrenal cell assay described in Example 8, and preferably the compound has an (R) enantiomeric excess of 97% or greater, and more preferably the compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate. [Brief explanation of the drawings]

[0020] [Figure 1] 1 is an X-ray powder diffraction (XRPD) diffractogram of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate. The Y-axis of the diffractogram is recorded intensity in counts per second, and the X-axis is 2θ (degrees). [Figure 2]Figure 1 shows thermogravimetric analysis (TGA) / differential scanning calorimetry (DSC) results for (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate. The top panel shows the TGA thermogram for (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate. The bottom panel shows the DSC thermogram for (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate. The thermogram shows a 1.4% mass loss (top panel) up to a temperature of 225°C, exceeding the melting point of 189°C (bottom panel). The thermogram shows a melting point with an onset at 188°C and a peak at 189°C. [Figure 3] Chiral purity of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate by high-pressure liquid chromatography (HPLC). The chromatogram shows an enantiomeric excess of the R-(+)-enantiomer (retention time: 14.459 min) of greater than 99.9% ee (retention time of the S-(-)-enantiomer: 9.814 min). [Figure 4] Dynamic vapor sorption (DVS) isotherm plots of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate (overlaid with two adsorption / desorption cycles). Each dynamic isotherm plot shows the mass increase up to 1% moisture uptake. [Figure 5] Dynamic vapor sorption (DVS) mass plot of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate (dotted line: relative change in mass; dashed line: target relative humidity (RH)). The mass plot shows reversible water absorption up to 1%. [Figure 6]X-ray powder diffraction (XRPD) diffractograms of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate before (top pattern) and after (bottom pattern) DVS cycling. The overlaid diffractograms show that the reflection patterns of each crystalline form are unaffected by DVS treatment. [Figure 7] The crystal structure and absolute configuration of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate as determined by single crystal X-ray analysis. The single X-ray measurement confirms the R-(+)-configuration at carbon 5. DETAILED DESCRIPTION OF THE INVENTION

[0021] Unless otherwise defined, 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.

[0022] When the term "about" is used, unless otherwise specified, it specifically means ±10%, ±5% or ±3% (relative to the respective given numerical value). In respective embodiments of the present invention, "about" can be omitted.

[0023] As used herein, the term "chiral purity" is defined by the enantiomeric excess (ee) measured by chiral HPLC (see Examples for details) and calculated according to the following formula: ee=(A R -A S ) / (A R +A S )x100%, In the formula, A R is the peak area of ​​the HPLC chromatogram of a sample solution of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, and A Sis the area of ​​the peak in the HPLC chromatogram of a sample solution of (S)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine.

[0024] As used herein, the term " pharmaceutically acceptable salt " refers to the salt that is pharmaceutically acceptable and has the intended pharmacological activity of parent compound.This salt includes the acid addition salt formed with inorganic acid or organic acid known to those skilled in the art (P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor); Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 2nd Revised Edition, March 2011, Wiley-VCH, ISBN: 978-3-90639-051-2).The particularly preferred pharmaceutically acceptable salt in the present invention is the acid addition salt formed with phosphoric acid, that is, dihydrogen phosphate.

[0025] As used in this application, the term "phosphate" refers to a compound containing the 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-tetrahydroimidazolium[1,5-a]pyridine cation, and further containing an anion derived from phosphoric acid, which is typically and preferably dihydrogen phosphate [H2PO4]. - and monohydrogen phosphate [HPO4] 2- Preferably, as used in this application, the term "phosphate" refers to the dihydrogen phosphate of the compound of formula (I), i.e., the compound of formula (I) once protonated and the counter ion is [H2PO4] -(See Figure 7 for single crystal X-ray structure), resulting in a 1:1 stoichiometry of monoprotonated (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine to dihydrogen phosphate. Herein, the latter compound is referred to as (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate.

[0026] The term "aromatase" refers to CYP19, a member of the cytochrome P450 superfamily, which is also known as estrogen synthase.

[0027] The term "aldosterone synthase" refers to the steroid hydroxylase cytochrome P450 enzyme CYP11B2.

[0028] As used herein, the term "amorphous" means a supercooled or viscous liquid that appears solid but does not have a regularly repeating molecular arrangement that is maintained over long ranges, and does not have a melting point, but rather softens or flows above its glass transition temperature.

[0029] The terms "crystalline" and "crystalline purity," used interchangeably herein and in reference to compounds of the invention, refer to a solid having a regularly repeating molecular or surface configuration. When referring to (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, including (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, the terms "crystalline" and "crystalline purity" refer to crystalline Form I, preferably present in at least 60% by weight, preferably at least 70% by weight, more preferably 80% by weight, even more preferably 90% by weight, and even more preferably 95% by weight. The other component may be, for example, amorphous (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridine dihydrogen phosphate. Crystalline purity may be determined by XRPD as described herein. Thus, in a preferred embodiment, the XRPD may be measured using the following equipment, parameters, and measurement conditions: Measurement equipment: Bruker AXS D2 PHASER; irradiation: CuKα (30 kV, 10 mA); scan range: 5–45° (2θ values), sample rotation 5 rpm, 0.5 s / step, 0.010° / step, 3.0 mm detector slit.

[0030] As used herein, the term "crystalline Form I" means (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, which has an X-ray powder diffraction pattern including 2-theta values ​​of 19.504, 21.919, and 24.159, measured using CuKα radiation, and each peak may vary by ±1 degree, or preferably ±0.5 degrees, or more preferably ±0.2 degrees. In a preferred embodiment, as used herein, "crystalline Form I" refers to (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, said (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate having an X-ray powder diffraction pattern including 2θ values ​​of 19.504, 21.919, and 24.159, measured using CuKα radiation, wherein each peak may vary by ±1 degree, or preferably ±0.5 degrees, or more preferably ±0.2 degrees. In a more preferred embodiment, as used herein, "crystalline Form I" refers to (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, said (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate having an X-ray powder diffraction pattern including 2θ values ​​of 19.504, 21.919, and 24.159, measured using CuKα radiation, wherein each peak may vary by ±0.5 degrees, or preferably ±0.2 degrees.In an even more preferred embodiment, the term "crystalline Form I," as used herein, refers to (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, said (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate having an X-ray powder diffraction pattern including 2-theta values ​​of 19.504, 21.919, and 24.159, measured using CuKα radiation, with each peak varying by ±0.2 degrees. In another preferred embodiment, as used herein, "crystalline Form I" means (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, said (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate having an X-ray powder diffraction pattern comprising 19.504; 21.919; 24.159; 16.003; 26.101; 27.168; 27.542 and 29.029 2θ values, measured using CuKα radiation, wherein each peak may vary by ±1 degree, or preferably ±0.5 degrees, or more preferably ±0.2 degrees. In another preferred embodiment, as used herein, "crystalline Form I" means (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, said (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate having an X-ray powder diffraction pattern comprising 19.504; 21.919; 24.159; 16.003; 26.101; 27.168; 27.542 and 29.029 2θ values, measured using CuKα radiation, wherein each peak may vary by ±0.5 degrees, or preferably ±0.2 degrees.

[0031] As used herein, the term "anhydrous" means a crystalline form containing less than 3%, preferably less than 2.5%, more preferably less than 2%, more preferably less than 1.5%, and most preferably less than 1% water of hydration.

[0032] The term "non-hygroscopic" refers to the ability of the pharmaceutically acceptable salts of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine of the present invention, particularly the phosphate salts of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, more preferably (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, when present as a powder or granule, to withstand exposure to atmospheric water vapor for periods of 24 hours, weeks, months, or years, as would be expected for commercial use, without exhibiting deleterious phenomena such as aggregation, aggregation, water absorption, or deliquescence. As typically and preferably used herein, when referring to a phosphate salt of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, and preferably when referring to (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, the term "non-hygroscopic" means that upon storage in the open under normal ambient conditions, typically and preferably at 20-25°C and 20% to 80%, preferably 30-60%, relative humidity, the term retains its viscosity as a (preferably free-flowing) powder or granules for at least one day, preferably one week, more preferably one month, and even more preferably at least three months, and even more preferably at least six months, and even more preferably or at least one year or more, particularly so as to meet regulatory ICH standards.More preferably, as used herein, when referring to a phosphate salt of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, and preferably when referring to (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, the term "non-hygroscopic" means that upon storage in the open under normal ambient conditions, usually preferably 20-25°C and 20% to 80%, preferably 30% to 60%, relative humidity, over a 24-hour period, usually preferably as measured in Example 5, the weight gain is less than 5%, preferably less than 3%, more preferably less than 2%, and even more preferably less than 1%. Even more preferably, as used herein, when referring to the phosphate salt of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, and preferably when referring to (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, the term "non-hygroscopic" refers to a material that is hygroscopic under normal ambient conditions, typically preferably at 20-25°C and 20% to 80%, preferably 30%. This means that upon storage in the open at a relative humidity of 10% to 60%, over a period of 24 hours, typically and preferably as measured in Example 5, the phosphate salt, preferably the (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate salt, exhibits a water absorption of less than 5% (wt / wt), preferably less than 3% (wt / wt), more preferably less than 2% (wt / wt), and even more preferably less than 1% (wt / wt).Alternatively and preferably, as used herein, when referring to a phosphate salt of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, and preferably when referring to (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, the term "non-hygroscopic" means that upon storage in the open under normal ambient conditions, usually preferably at 25°C and about 60% relative humidity, over a period of 24 hours, preferably over a period of 1 month, and more preferably at least 3 months, and even more preferably at least 6 months, and even more preferably or at least 1 year, usually preferably has a water content of less than 0.5%, preferably less than 0.4%, and more preferably 0.3% wt / wt or less, as measured in Example 9.

[0033] As used herein, the term "pharmaceutically acceptable excipient" includes any physiologically inert additive routinely used in pharmaceutical dosage forms. The pharmaceutically acceptable excipient is selected from the group including binders, diluents, carriers, lubricants, glidants, coating additives, or combinations thereof.

[0034] As used herein, the term "solubility" means the shorthand descriptive solubility (e.g., in water) in accordance with the US Pharmacopoeia, Chapter "General Notices," § 5.30 "Description and Solubility" (and as defined hereinafter). TIFF2025131628000002.tif54159

[0035] As used herein, the term "female of childbearing potential" means a premenopausal female who is capable of becoming pregnant.

[0036] As used herein, the term "pediatric patient" refers to patients aged 0-18 years, preferably 0-16 years, including preterm and full-term neonates (0-27 days), infants and toddlers (28 days-23 months), children (2-11 years) and adolescents (2-16 / 18 years).

[0037] Thus, in one embodiment there is provided a compound selected from (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine of formula (I) and pharmaceutically acceptable salts thereof, in particular (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, having a solubility in water of greater than 50% volume / volume.

[0038] The expression “I.C. 50 " refers to the half-maximal inhibitory concentration commonly known in the art. IC for aromatase 50 is determined by the cell-free human recombinant aromatase assay described in Example 8. IC for aldosterone synthase 50 is determined by the human NCI-H295R cell assay described in Example 8. When referring to "selectivity for aldosterone synthase over aromatase," the following ratio is intended: Selectivity = (IC for aromatase 50 ) / (IC for aldosterone synthase 50 ) where IC for aldosterone synthase 50 and IC against aromatase 50 are both determined, preferably simultaneously, by the human NCI-H295R cell assay described in Example 8.

[0039] As outlined above, phosphate salts of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, preferably (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, inhibit aldosterone production (aldosterone synthase activity) and estradiol production (aromatase activity) with IC values ​​of 8.1 nM and 5760 nM, respectively, in NCI-H295R adrenal cells. 50 (Example 8, Tables 10 and 11), thus demonstrating selectivity of approximately 700 for aldosterone synthase over aromatase.

[0040] As used herein, the term "disorder" or "disease" means any disturbance or abnormality of function; a morbid physical or mental condition. See Dorland's Illustrated Medical Dictionary (VSIB. Saunders Co. 27th ed. 1988).

[0041] As used herein, the expression "diseases or disorders in which excessive exposure to aldosterone contributes to the adverse effects of the disease or disorder" preferably refers to diseases and disorders caused by abnormal or inappropriate activity / expression of aldosterone synthase and by biological activities or processes associated with abnormal or inappropriate expression of aldosterone synthase. Typical examples of diseases or disorders caused by abnormal or inappropriate activity / expression of aldosterone synthase are primary and secondary hyperaldosteronism, heart failure, chronic renal failure, hypertension, restenosis, obesity, nephropathy, post-myocardial infarction syndrome, renal fibrosis, and coronary heart disease.

[0042] As used herein, the term "abnormal activity of aldosterone synthase" means activity of aldosterone synthase that differs from the activity of the wild-type or native gene or native protein, or that differs from the activity of the gene or protein in a healthy subject. The abnormal activity may be stronger or weaker than the normal activity.

[0043] As used herein, the term "inappropriate activity of aldosterone synthase" means activity of a wild-type or native gene or natural protein, or activity of an aldosterone synthase gene or protein in a healthy subject, which activity is considered appropriate in a healthy subject, but the same said activity is considered inappropriate in a diseased subject, i.e., said activity is considered too strong or too weak for the diseased subject.

[0044] As used herein, the term "treating" or "treatment" of any disease or disorder means ameliorating the disease or disorder (i.e., arresting or reducing the onset of the disease or at least one clinical symptom thereof).

[0045] As used herein, the term "specific rotation" refers to the specific rotation of a solution of the respective compound in a solvent, usually preferably ethanol or CHCN:HO 1:1 (volume / volume), more preferably CHCN:HO 1:1 (volume / volume), and the specific rotation is calculated by the formula: 100 x α / (l x c), where α = observed rotation (degrees); l = cell path length (decimetres); and c = concentration (g / 100 ml); measurements are made at room temperature, usually preferably 20°C or 25°C, at the sodium D line (i.e., 589.3 nm). The term "specific rotation" refers to the [α] D 20 or [α] D 25 It is usually abbreviated as [α] D 20 or [α] D 25 , the sign of the rotation (+ or -) and its actual value are indicated there, or [α] D 20 or [α] D 25 is given the sign of the rotation (+ or -) and its actual value in degrees (°). The full units (degrees dm-1 ·cm 3 ·g -1 ) is usually omitted for clarity.

[0046] In a first aspect, the present invention provides a compound selected from (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine of formula (I) and pharmaceutically acceptable salts thereof, having an enantiomeric excess (ee) of the (R) form of 97% or more, preferably 98% or more, more preferably 99% or more, and also more preferably 99.5% or more, also more preferably 99.8% or more, for example 99.9%.

[0047] In particular, and in a second aspect, the present invention provides (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, typically having an ee of the (R) form of 97% or more, preferably 98% or more, more preferably 99% or more, and also more preferably 99.5% or more, also more preferably 99.8% or more, for example 99.9%, which is surprisingly non-hygroscopic and stable over long periods of time, particularly with respect to purity, water content and chiral purity. Additionally and importantly, phosphate salts of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, particularly (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, are crystalline in one stable form, usually preferably Form I.

[0048] As measured by dynamic water vapor sorption studies, the water absorption of the (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate salt of the present invention was less than 1% at humidity levels above 90% ( FIG. 4 ), and the water absorption was reversible ( FIG. 5 ). Furthermore, the mass loss upon heating to 225°C was only 1.4% ( FIG. 2 ). In conclusion, the phosphate salts of the present invention, preferably (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate salt, are not hygroscopic. As a result, the (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate salt of the present invention can be stored in bulk in conventional pharmaceutical containers at ambient conditions. Furthermore, the (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate of the present invention has been found to be highly crystalline and to have a high level of crystalline purity. Furthermore, surprisingly, the (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate of the present invention, having the described exceptional chiral purity, exists in a single crystalline form, has a consistent X-ray structure, and has the R-(+)-absolute configuration at its chiral center, carbon 5 (Figure 1 and Table 1; Figure 7).

[0049] Multiple crystalline forms, called polymorphism, complicate the manufacturing of pharmaceutical preparations because these forms can be interconverted and require additional measures to prevent such interconversion. Different polymorphisms may behave differently in pharmaceutical formulations, affecting micronization, tablet formation, solubility, and even bioavailability. Because even the smallest compounds may have hundreds of thousands of possible molecular configurations in solid crystals, predicting crystal structures and their properties is a scientific challenge, and it is impossible to know a priori whether polymorphism actually occurs in a given molecule. Therefore, polymorphism is a serious concern when trying to obtain safe and effective forms of drugs. Despite this, the inventors have discovered that crystalline Form I of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate is physically stable, i.e., no polymorphism is observed (Example 6, Table 8; Example 7, Table 9, and Figure 6, Example 9), and can be reliably obtained as expected (Example 3, Step 4). Furthermore, XRPD analysis of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate (Figure 1 and Table 1) showed that the material was essentially free of amorphous material (i.e., no amorphous material was detectable). Unless otherwise specified, XRPD was performed as described in the Examples.

[0050] Thus, in one embodiment, the present invention provides crystalline (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, preferably anhydrous crystalline (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, more preferably anhydrous crystalline (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, having an ee of the (R) form of 97% or more, preferably 98% or more, more preferably 99% or more, and also more preferably 99.5% or more, and also more preferably 99.8% or more, for example, 99.9%.

[0051] Crystals of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate (crystalline form I) are characterized by XRPD (Figure 1) with the following angles, interplanar spacings (d values) and relative line intensities (intensities) of their X-ray powder pattern (Table 1). TIFF2025131628000003.tif251162TIFF2025131628000004.tif111162

[0052] In one embodiment, there is provided crystalline Form I of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, characterized by an X-ray powder diffraction pattern comprising the following 2θ values, measured as described in the Examples section: 19.504; 21.919, and 24.159. In one embodiment, there is provided crystalline Form I of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, characterized by an X-ray powder diffraction pattern comprising the following 2θ values, measured as described in the Examples section: 19.504; 21.919, and 24.159. Each peak may vary by ±1, or preferably ±0.5, or more preferably ±0.2 degrees. 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. Each peak may vary by ±1 or preferably ±0.5, or more preferably ±0.2 degrees.In certain preferred embodiments, there is provided crystalline Form I of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, characterized by an X-ray powder diffraction pattern comprising at least one, and 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;20.433 02;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;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 crystalline Form I of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, characterized by an X-ray powder diffraction pattern including at least one, and more preferably 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or all of the following 2θ values: 6.02312 9;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;20.43 302;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;30.6880 8;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. Each peak may vary by ±1 or preferably ±0.5, or more preferably ±0.2 degrees.In another particularly preferred embodiment, there is provided crystalline Form I of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, characterized by an X-ray powder diffraction pattern including at least one, and more preferably 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or all of the following 2θ values: 6.02312 9;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;20.43 302;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;30.6880 8;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. Each peak may vary by ±0.5, or preferably ±0.2 degrees. In one embodiment, the three largest peaks of crystalline Form I in the XRPD diffractogram have relative intensities of 1:0.85:0.55, particularly 1:0.9:0.6, more particularly 1:0.95:0.65, for example 1:0.97:0.68 (obtained by integration of the respective peaks in the XRPD diagram).In certain embodiments, the largest peak is at a 2-theta (θ) value of about 21.919, the second largest peak is at a 2-theta (θ) value of about 19.504, and the third largest peak is at a 2-theta (θ) value of about 24.159, respectively. In further specific embodiments, the largest peak is at a 2-theta (θ) value of about 21.919±0.5, or preferably ±0.2 degrees, the second largest peak is at a 2-theta (θ) value of about 19.504±0.5, or preferably ±0.2 degrees, and the third largest peak is at a 2-theta (θ) value of about 24.159±0.5, or preferably ±0.2 degrees, respectively. (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate preferably exhibits the XRPD diffractogram shown in FIG. 1.

[0053] Surprisingly, it has been further found that (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate (crystalline Form I) has a single, sharp, high melting point of 189°C as measured by DSC (Figure 2), again indicating high physical stability, which is further beneficial in drug manufacturing, storage and processing into pharmaceutical formulations. Thus, in one embodiment there is provided (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, which typically preferably has a melting point equal to or between 184°C and 193°C using thermogravimetric analysis / differential scanning calorimetry (TGA / DSC), and preferably said (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate has a melting point equal to or between 188°C and 190°C. In a further embodiment, there is provided (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate having a melting point of 184° C., 185° C., 186° C., 187° C., 188° C., 189° C., 190° C., 191° C., 192° C., 193° C., or 194° C., most preferably 189° C. In a further embodiment, there is provided (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate having a melting point of 189±5° C., 189±2° C., 189±1° C., or 189±0.5° C. Unless otherwise specified, melting temperatures herein were obtained by TGA / DSC as described in the Examples section.

[0054] Furthermore, the inventors have found that the solubility of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate (crystalline form I) is low in some non-aqueous solvents (Example 6, Table 7), which are therefore non-solvents for this salt and allow for good precipitation, as well as good yields and purity. On the other hand, crystalline form I is highly soluble in water (Example 6, Table 8), which is advantageous for obtaining oral or parenteral formulations.

[0055] The enantiomerically pure (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate salt described herein, and thus having an ee of greater than 99.9%, prepared from (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine free base, exhibits a specific rotation ([α]) of +98.1° (CHCN:HO 1:1 (vol / vol); Example 3). D 20 ) was found to have

[0056] Thus, in one highly preferred embodiment and aspect of the present invention, the specific rotation [α] of at least +94°, preferably at least +95°, even more preferably at least +96°, more preferably at least +97°, and even more preferably at least +98°. D 20 (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate is provided, having (CHCN:H0 1:1 (volume / volume)).

[0057] In a further embodiment, the present invention provides a specific rotation [α] of at least +120°, preferably at least +121°, more preferably at least +122°, still more preferably at least +123°, still more preferably at least +124°, still more preferably at least +125°, still more preferably at least +126°, still more preferably at least +127°. D 25 (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine having a specific rotation [α] of at least +95°, preferably at least +96°, more preferably at least +97°, more preferably at least +98°, even more preferably at least +99°, even more preferably at least +100°, even more preferably at least +101°, even more preferably at least +102°, and also more preferably at least +103°, even more preferably at least +104°. D 20 (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine chloride with (ethanol).

[0058] In a highly preferred embodiment, the present invention provides (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, preferably crystalline (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, more preferably anhydrous crystalline (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate.

[0059] In also highly preferred embodiments and aspects, the present invention provides (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, preferably crystalline (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, more preferably anhydrous crystalline (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, having an ee of the (R) form of 97% or more, preferably 98% or more, more preferably 99% or more, and also more preferably 99.5% or more, and also more preferably 99.8% or more, for example, 99.9%.

[0060] In also highly preferred embodiments and aspects, the present invention provides crystalline (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, preferably anhydrous crystalline (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, having an ee of the (R) form of 97% or more, preferably 98% or more, more preferably 99% or more, and also more preferably 99.5% or more, and also more preferably 99.8% or more, for example 99.9%. Preferably, the (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate in crystalline Form I, which has an X-ray powder diffraction pattern containing the following 2θ values ​​measured using CuKα radiation: 19.504; 21.919; and 24.159. Each peak may vary by ±0.5, or preferably ±0.2 degrees.

[0061] In also highly preferred embodiments and aspects, the present invention provides crystalline (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, preferably anhydrous crystalline (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, having an ee of the (R) form of 97% or more, preferably 98% or more, more preferably 99% or more, and also more preferably 99.5% or more, and also more preferably 99.8% or more, for example, 99.9%. (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate in crystalline Form I, which has an X-ray powder diffraction (XRPD) pattern containing the following 2θ values ​​measured using CuKα radiation: 19.504; 21.919; and 24.159. Each peak may vary by ±0.5, or preferably ±0.2 degrees. Preferably, the XRPD can be measured using the following equipment, parameters, and measurement conditions: detector: Bruker AXS D2 PHASER; irradiation: CuKα (30 kV, 10 mA); scanning range: 5 to 45° (2θ value), sample rotation 5 rpm, 0.5 sec / step, 0.010° / step, 3.0 mm detector slit.

[0062] In also highly preferred embodiments and aspects, the present invention provides crystalline (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, preferably anhydrous crystalline (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, having an ee of the (R) form of 97% or more, preferably 98% or more, more preferably 99% or more, and also more preferably 99.5% or more, and also more preferably 99.8% or more, for example 99.9%. (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate in crystalline Form I, which has an X-ray powder diffraction pattern measured using CuKα radiation containing the following 2θ values: 19.504; 21.919; and 24.159. Each peak may vary by ±0.5, or preferably ±0.2 degrees. The XRPD can be measured using the following equipment, parameters, and measurement conditions: measurement instrument: Bruker AXS D2 PHASER; irradiation: CuKα (30 kV, 10 mA); scanning range: 5 to 45° (2θ value), sample rotation 5 rpm, 0.5 sec / step, 0.010° / step, 3.0 mm detector slit.

[0063] (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate was further found to be anhydrous (Examples 3 and 5). Thus, in one embodiment, the present invention provides anhydrous (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate. In a particularly preferred embodiment, the present invention provides anhydrous (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate having an ee of the (R) form of 97% or more, preferably 98% or more, more preferably 99% or more, and also more preferably 99.5% or more, and also more preferably 99.8% or more, for example, 99.9%.

[0064] In a more particularly preferred embodiment, the present invention provides anhydrous (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate crystalline Form I.

[0065] In yet further particularly preferred embodiments, the present invention provides anhydrous (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate in crystalline Form I as defined herein, having an ee of the (R) form of 97% or more, preferably 98% or more, more preferably 99% or more, and also more preferably 99.5% or more, and also more preferably 99.8% or more, for example 99.9%.

[0066] As outlined above, the present inventors have surprisingly found that (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine prepared by the method of the present invention (Example 3), as well as its phosphate salts, preferably (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, exhibit unprecedentedly low aromatase inhibitory activity (Example 8), which is crucial for avoiding side effects associated with aromatase inhibition when the compounds of the present invention are used in methods for treating diseases or disorders associated with increased aldosterone synthase activity and / or increased levels of aldosterone, particularly in women of childbearing potential and pediatric patients. Thus, in a further aspect, the present invention provides a compound selected from (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine and pharmaceutically acceptable salts thereof, in particular a phosphate salt thereof, more preferably (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, said compound having a potency of 700 nM or more, preferably 750 nM or more, more preferably 800 nM or more, more preferably 850 nM or more, more preferably 900 nM or more in the cell-free human recombinant aromatase enzyme assay described in Example 8. or above, more preferably 950 nM or more, more preferably 1000 nM or more, more preferably 1050 nM or more, more preferably 1100 nM or more, more preferably 1150 nM or more, more preferably 1200 nM or more, more preferably 1250 nM or more, more preferably 1300 nM or more, more preferably 1350 nM or more, more preferably 1400 nM or more, more preferably 1450 nM or more, more preferably 1500 nM or more, more preferably 1550 nM or more, and most preferably at least 1600 nM, e.g., 1610 nM or 1620 nM or 1630 nM or 1640 nM or at least 1650 nM. 50 It inhibits aromatase activity.

[0067] In a still further aspect, the present invention provides a compound selected from (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine and pharmaceutically acceptable salts thereof, particularly a phosphate salt thereof, more preferably (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, said compound having an IC50 of 100 nM or less in the NCI-H295R adrenal cell assay described in Example 8. 50 In one embodiment, compounds of the invention have an IC of 90 nM or less, 80 nM or less, 70 nM or less, 60 nM or less, 50 nM or less, 40 nM or less, 35 nM or less, 30 nM or less, 25 nM or less, or 20 nM or less; in particular 15 nM or less, e.g., 15 nM, 14 nM, 13 nM, 12 nM, 11 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM or less in the NCI-H295R adrenal cell assay described in Example 8. 50 In a preferred embodiment, compounds of the invention inhibit aldosterone synthase with an IC of 10 nM or less in the NCI-H295R adrenal cell assay described in Example 8. 50 It inhibits aldosterone synthase.

[0068] In a still further aspect, the present invention provides a compound selected from (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine and pharmaceutically acceptable salts thereof, wherein said compound has a selectivity for aldosterone synthase over aromatase of 30 or greater, preferably 50 or greater, more preferably 100 or greater, more preferably 150 or greater, more preferably 200 or greater, more preferably 250 or greater, more preferably 300 or greater, more preferably 350 or greater, more preferably 400 or greater, more preferably 450 or greater, more preferably 500 or greater, more preferably 550 or greater, more preferably 600 or greater, more preferably 650 or greater, and most preferably 700 or greater, wherein said selectivity is indicative of an IC for aromatase inhibition. 50 values ​​and IC for aldosterone synthase inhibition50 The IC for aromatase inhibition is determined by the ratio of 50 values ​​and IC for inhibition of aldosterone synthase 50 Both values ​​are measured, preferably simultaneously, in the NCI-H295R adrenal cell assay described in Example 8.

[0069] Thus, and in highly preferred embodiments and aspects, the present invention provides crystalline (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, preferably anhydrous crystalline (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, having an ee of the (R) form of 97% or more, preferably 98% or more, more preferably 99% or more, and also more preferably 99.5% or more, and also more preferably 99.8% or more, for example 99.9%. Imidazolium[1,5-a]pyridine dihydrogen phosphate is provided, wherein the (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate in crystalline Form I, which has an X-ray powder diffraction pattern measured using CuKα radiation, including the following 2θ values: 19.504; 21.919; and 24.159. Each peak may vary by ±0.5, or preferably ±0.2 degrees. The XRPD can be measured usually and preferably using the following equipment, parameters and measurement conditions: measurement instrument: Bruker AXS D2 PHASER; irradiation: CuKα (30 kV, 10 mA); scanning range: 5 to 45° (2θ value), sample rotation 5 rpm, 0.5 sec / step, 0.010° / step, 3.0 mm detector slit.Furthermore, the (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridine dihydrogen phosphate has a potency of 700 nM or more, preferably 750 nM or more, more preferably 800 nM or more, more preferably 850 nM or more, more preferably 900 nM or more, more preferably 950 nM or more, more preferably 1000 nM or more, more preferably 1050 nM or more, more preferably 1100 nM or more, in the cell-free human recombinant aromatase enzyme assay described in Example 8. More preferably, an IC50 of at least 1600 nM, for example, 1610 nM or 1620 nM or 1630 nM or 1640 nM or at least 1650 nM. 50 It inhibits aromatase activity.

[0070] In also highly preferred embodiments and aspects, the present invention provides crystalline (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, preferably anhydrous crystalline (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, having an ee of the (R) form of 97% or more, preferably 98% or more, more preferably 99% or more, and also more preferably 99.5% or more, and also more preferably 99.8% or more, for example 99.9%. (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate in crystalline Form I, which has an X-ray powder diffraction pattern measured using CuKα radiation containing the following 2θ values: 19.504; 21.919; and 24.159. Each peak may vary by ±0.5, or preferably ±0.2 degrees. The XRPD can be measured usually and preferably using the following equipment, parameters and measurement conditions: measurement instrument: Bruker AXS D2 PHASER; irradiation: CuKα (30 kV, 10 mA); scanning range: 5 to 45° (2θ value), sample rotation 5 rpm, 0.5 sec / step, 0.010° / step, 3.0 mm detector slit. In addition, the (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate has an IC of 90 nM or less, 80 nM or less, 70 nM or less, 60 nM or less, 50 nM or less, 40 nM or less, 35 nM or less, 30 nM or less, 25 nM or less, or 20 nM or less; particularly 15 nM or less, for example, 15 nM, 14 nM, 13 nM, 12 nM, 11 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM or less, in the NCI-H295R adrenal cell assay described in Example 8. 50 In a preferred embodiment, compounds of the invention inhibit aldosterone synthase with an IC of 10 nM or less in the NCI-H295R adrenal cell assay described in Example 8. 50It inhibits aldosterone synthase.

[0071] In also highly preferred embodiments and aspects, the present invention provides crystalline (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, preferably anhydrous crystalline (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, having an ee of the (R) form of 97% or more, preferably 98% or more, more preferably 99% or more, and also more preferably 99.5% or more, and also more preferably 99.8% or more, for example 99.9%. (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate in crystalline Form I, which has an X-ray powder diffraction pattern measured using CuKα radiation containing the following 2θ values: 19.504; 21.919; and 24.159. Each peak may vary by ±0.5, or preferably ±0.2 degrees. The XRPD can be measured usually and preferably using the following equipment, parameters and measurement conditions: measurement instrument: Bruker AXS D2 PHASER; irradiation: CuKα (30 kV, 10 mA); scanning range: 5 to 45° (2θ value), sample rotation 5 rpm, 0.5 sec / step, 0.010° / step, 3.0 mm detector slit. Furthermore, the (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridine dihydrogen phosphate has a selectivity for aldosterone synthase over aromatase of 30 or more, preferably 50 or more, more preferably 100 or more, more preferably 150 or more, more preferably 200 or more, more preferably 250 or more, more preferably 300 or more, more preferably 350 or more, more preferably 400 or more, more preferably 450 or more, more preferably 500 or more, more preferably 550 or more, more preferably 600 or more, more preferably 650 or more, and most preferably 700 or more, and the selectivity is expressed as an IC 50 values ​​and IC for aldosterone synthase inhibition 50The IC for aromatase inhibition is determined by the ratio of 50 values ​​and IC for inhibition of aldosterone synthase 50 Both values ​​are measured, preferably simultaneously, in the NCI-H295R adrenal cell assay described in Example 8.

[0072] In one aspect, the present invention provides (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine for use as a drug, having an ee of the (R) form of 97% or more, preferably 98% or more, more preferably 99% or more, and also more preferably 99.5% or more, and also more preferably 99.8% or more, for example, 99.9%.

[0073] In a further aspect, the present invention provides (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate for use as a medicament, preferably said dihydrogen phosphate having an ee of the (R) form of 97% or more, preferably 98% or more, more preferably 99% or more, and also more preferably 99.5% or more, also more preferably 99.8% or more, for example 99.9%.

[0074] The present invention relates to (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine and phosphate salts thereof, typically having an ee of 97% or more, preferably 98% or more, more preferably 99% or more, and also more preferably 99.5% or more, and also more preferably 99.8% or more, for example 99.9%, of the (R) form, for use in methods for treating diseases or disorders in humans, including women of childbearing potential and pediatric patients. Preferably, there is further provided (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridine dihydrogen phosphate, wherein excessive exposure to aldosterone contributes to the adverse effects of said disease or disorder, and typically preferably said disease or disorder is selected from primary and secondary hyperaldosteronism, heart failure, chronic renal failure, hypertension, restenosis, obesity, nephropathy, post-myocardial infarction syndrome, renal fibrosis, and coronary heart disease.

[0075] The present invention also provides (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine and its phosphate salts, preferably (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, having an (R)-form ee of typically 97% or more, preferably 98% or more, more preferably 99% or more, and also more preferably 99.5% or more, and even more preferably 99.8% or more, for example, 99.9%, for use in a method for treating a disease or disorder selected from primary and secondary hyperaldosteronism, heart failure, chronic renal failure, hypertension, restenosis, obesity, nephropathy, post-myocardial infarction syndrome, renal fibrosis, and coronary heart disease. More preferably, the method is particularly suitable for use in humans, including women of childbearing age and pediatric patients.

[0076] In further highly preferred embodiments and aspects, the present invention provides crystalline (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, preferably anhydrous crystalline (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, having an ee of the (R) form of 97% or more, preferably 98% or more, more preferably 99% or more, and also more preferably 99.5% or more, even more preferably 99.8% or more, for example 99.9%, for use in a method of treating a disease or disorder in a human being, wherein the disease or disorder is selected from primary and secondary hyperaldosteronism, heart failure, chronic renal failure, hypertension, restenosis, obesity, nephropathy, post-myocardial infarction syndrome, renal fibrosis, and coronary heart disease, and preferably the human being is a female of childbearing potential or a pediatric patient.

[0077] In further highly preferred embodiments and aspects, the present invention provides crystalline (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, preferably crystalline (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, having an ee of the (R) form of 97% or more, preferably 98% or more, more preferably 99% or more, and also more preferably 99.5% or more, and also more preferably 99.8% or more, for example 99.9%, for use in a method for treating a human disease or disorder. provides anhydrous crystalline (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridine dihydrogen phosphate, wherein said disease or disorder is selected from primary and secondary hyperaldosteronism, heart failure, chronic renal failure, hypertension, restenosis, obesity, nephropathy, post-myocardial infarction syndrome, renal fibrosis, and coronary heart disease, preferably said human is a female of childbearing potential or a pediatric patient, and wherein said (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridine dihydrogen phosphate is administered to a subject in need thereof.

[0043] In the cell-free human recombinant aromatase enzyme assay described in Example 8, (1,5-α)-5,6,7,8-tetrahydroimidazolium [1,5-α]pyridine dihydrogen phosphate has a potency of 700 nM or more, preferably 750 nM or more, more preferably 800 nM or more, more preferably 850 nM or more, more preferably 900 nM or more, more preferably 950 nM or more, more preferably 1000 nM or more, more preferably 1050 nM or more, more preferably 1100 nM or more, more preferably An IC of 1150 nM or more, more preferably 1200 nM or more, more preferably 1250 nM or more, more preferably 1300 nM or more, more preferably 1350 nM or more, more preferably 1400 nM or more, more preferably 1450 nM or more, more preferably 1500 nM or more, more preferably 1550 nM or more, most preferably at least 1600 nM, e.g., 1610 nM or 1620 nM or 1630 nM or 1640 nM or at least 1650 nM. 50 It inhibits aromatase activity.

[0078] In a further aspect, the present invention provides a method for preparing a compound selected from (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine and pharmaceutically acceptable salts thereof, with a highly preferred pharmaceutically acceptable salt being the phosphate salt thereof, more preferably (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate. The method of the present invention comprises the steps of (i) reacting racemic 5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine with (−)-O,O′-acylated L-tartaric acid, particularly (−)-O,O′-dibenzoyl-L-tartaric acid, to form diastereomeric (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine dibenzoyl-L-tartrate; and (ii) reacting racemic 5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine with (−)-O,O′-acylated L-tartaric acid, particularly (−)-O,O′-dibenzoyl-L-tartaric acid, to form diastereomeric (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine dibenzoyl-L-tartrate in step i. (iii) adding a base to a solution of the tartrate salt obtained in step (ii) to liberate the free base (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, and optionally (iv) reacting the free base with an acid, preferably phosphoric acid (H3PO4), to form a pharmaceutically acceptable salt. In one embodiment, the step (i) of reacting racemic 5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine with (−)-O,O′-dibenzoyl-L-tartaric acid, particularly (−)-O,O′-dibenzoyl-L-tartaric acid, to form diastereomeric (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-L-tartrate is carried out in an alcoholic solution, preferably an ethanolic solution, at a temperature below about 50° C., preferably below about 45° C., and more preferably below 40° C. In one embodiment, the step (ii) of recrystallizing the tartrate salt obtained in step (i) at least once is carried out in a water-alcoholic solution, preferably an aqueous ethanolic solution, preferably in a water:ethanol ratio of about 2.4:about 10.

[0079] In one embodiment, the method for preparing a compound selected from (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine of the present invention and a pharmaceutically acceptable salt thereof does not comprise a step of chiral resolution of 5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (fadrozole) by chiral preparative HPLC, and preferably, the method for preparing a compound selected from (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine of the present invention and a pharmaceutically acceptable salt thereof does not comprise a step of chiral resolution of 5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (fadrozole) by chiral HPLC. Such chiral resolution steps by chiral HPLC typically involve (i) iterative chiral HPLC on a low-capacity column or (ii) preparative HPLC on a high-capacity column.

[0080] In a preferred embodiment, the method of the present invention produces (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine and pharmaceutically acceptable salts thereof, particularly phosphate salts thereof, more preferably (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, having an ee of the (R) form of 97% or more, preferably 98% or more, more preferably 99% or more, and also more preferably 99.5% or more, and also more preferably 99.8% or more, for example, 99.9%.

[0081] In a further preferred embodiment, the method of the present invention produces (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine and pharmaceutically acceptable salts thereof, in particular phosphate salts thereof, more preferably (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, wherein said (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine and pharmaceutically acceptable salts thereof have an affinity for 700 nM or more, preferably 750 nM or more, more preferably 800 nM or more, in the cell-free human recombinant aromatase enzyme assay described in Example 8; More preferably, the IC is 850 nM or more, more preferably 900 nM or more, more preferably 950 nM or more, more preferably 1000 nM or more, more preferably 1050 nM or more, more preferably 1100 nM or more, more preferably 1150 nM or more, more preferably 1200 nM or more, more preferably 1250 nM or more, more preferably 1300 nM or more, more preferably 1350 nM or more, more preferably 1400 nM or more, more preferably 1450 nM or more, more preferably 1500 nM or more, more preferably 1550 nM or more, and most preferably at least 1600 nM, for example, 1610 nM or 1620 nM or 1630 nM or 1640 nM or 1650 nM or more. 50 It inhibits aromatase activity.

[0082] Thus, the method of the present invention utilizes crystallization to obtain (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine and pharmaceutically acceptable salts thereof, and most preferably, phosphate salts thereof, and even more preferably, (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, of exceptionally high chiral purity for commercial pharmaceutical use. On a commercial scale, crystallization offers significant economic advantages over chromatographic resolution by allowing for larger batch preparations, less expensive equipment and facilities, and requiring no specialized expertise.

[0083] In one aspect, there is provided a pharmaceutical composition comprising (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof, particularly a phosphate salt, more preferably (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, in admixture with at least one pharmaceutically acceptable excipient as described herein.

[0084] In one embodiment, the pharmaceutical composition is provided in the form of tablets, pills, dispersible granules, cachets, capsules, powders, troches, suppositories, or retention enemas.

[0085] Example Apparatus, Materials and Methods Specific rotation [α] D Specific rotation [α] D Measurements were carried out in solution using the sodium D line at 589.3 nm on a standard Perkin Elmer polarimeter 343. For the measurements, 1 g of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine dihydrogen phosphate was dissolved in 100 ml of the respective solvent, and the solution was transferred to a 1 decimeter long optical cuvette. Measurements were carried out at temperatures of 20°C or 25°C, respectively. Specific rotation [α] D is calculated by the formula: 100xα / (lxc), where α=observed rotation (degrees); l=cell path length (decimeters); c=concentration (g / 100ml).

[0086] elemental analysis Elemental analysis was carried out on standard equipment (eg, vario EL cube elemental analyzer) to determine carbon, hydrogen and nitrogen values.

[0087] Chiral HPLC Chiral HPLC was carried out using an Agilent 1100 series LC22 measuring instrument with the following column specifications and conditions: Column: Chiralpack AD-H, particle size distribution: 5μm, 250x4.6mm;n° ADH0CE-TF087 Mobile phase: ethanol + 0.1% diethylamine (DEA) Detector wavelength: 230 nm Oven temperature: 25°C Flow rate: 0.5mL / min Injection volume: 5μl; Sample preparation: 0.5 mg / mL in ethanol + 0.1% DEA

[0088] XRPD X-ray powder diffraction studies were performed using a Bruker AXS D2 PHASER in Bragg-Brentano configuration. A Cu cathode was used at 30 kV and 10 mA; the sample stage was rotated normally; and a Kβ filter (0.5% Ni) was used for monochromating. Slits: fixed divergence slit 1.0 mm (=0.61°), primary axis Soller slit 2.5°, secondary axis Soller slit 2.5°. Detector: linear LYNXEYE detector with a 5° detector aperture. The standard sample holder (0.1 mm cavity in a (510) silicon wafer) contributed minimally to the background signal. Measurement conditions: scan range: 5–45° (2θ values), sample rotation 5 rpm, 0.5 s / step, 0.010° / step, 3.0 mm detector slit; all measurement conditions were logged in the instrument control file. For system suitability, a corundum sample A26-826-S (NIST standard) was measured daily.

[0089] The software used for data collection was Diffrac.Commander v2.0.26. Data analysis was performed using Diffrac.Eva v1.4. No background correction or smoothing was applied to the patterns.

[0090] Single crystal X-ray analysis (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridine dihydrogen phosphate single crystals were grown using n-propanol / water mixtures as the solvent. Suitable single crystals were removed from the mother liquor, immediately coated with high-viscosity oil, cut to the required size, mounted on a Mitegen Microloop, and shock-frozen to 150 K. Measurements were performed on a Bruker D8 Quest detector equipped with MoKα radiation using φ-scans and ω-scans. The molecular structure was then solved using direct methods (SHELXT software). All non-hydrogen atoms were refined with anisotropic temperature factors. Bijvoet analysis was performed on the completed model to determine the absolute configuration.

[0091] TGA / DSC Thermogravimetric analysis and differential scanning calorimetry (TGA / DSC) studies were performed using a Mettler Toledo TGA / DSC1 STARe System equipped with a 34-position autosampler. Samples were prepared using A1 crucibles (40 μL; with holes). Typically, 5–10 mg of sample was added to a pre-weighed A1 crucible and held at 30°C for 5 min before heating from 30°C to 350°C at 10°C / min. A 40 ml / min nitrogen purge was maintained above the sample. STARe Software v12.10 build 5937 was used for data collection and evaluation. No corrections were applied to the thermograms.

[0092] DSC DSC studies were performed using a Mettler Toledo DSC1 STARe System. Samples were prepared using an A1 crucible (40 μL; with holes). Typically, 1–8 mg of sample was added to a pre-weighed A1 crucible and held at 30°C for 5 min, then heated from 30°C to 350°C at 10°C / min, and held at 350°C for 1 min. A 40 ml / min nitrogen purge was maintained over the sample. Indium and zinc were used as standards for system suitability checks. STARe Software v12.10 build 5937 was used for data collection and evaluation. No corrections were applied to the thermograms.

[0093] DVS Dynamic water vapor sorption (DVS) studies were performed using a Surface Measurement Systems Ltd. DVS-1 No Video. Typically, 20-30 mg of sample was loaded onto a balance pan and equilibrated at 0% RH. After drying the material, the RH was increased by 10% per step, 1 hour per increment, and terminated at 95% RH. After the sorption cycle was completed, the sample was dried using the same method. The software used for data collection was DVSWin v3.01 No Video. Data analysis was performed using DVS Standard Analysis Suite v6.3.0 (Standard).

[0094] solubility The shake flask method was used to measure solubility; solubility was determined visually at 20° C. To 10 mg of compound, the listed solvents were added stepwise at 15 minute intervals until complete dissolution was achieved or a solubility of 0.05 mg / ml was reached.

[0095] High-throughput experiments High-throughput experiments were performed in a well-plate format using a Freeslate Core Module 2 in crystallization configuration, with a Julabo FPSO for temperature control of the cooling crystallization experiments.

[0096] Solids Dispense System Solids were dosed using a Freeslate Core Module Protege solid dispensing system in the classic SV-hopper configuration equipped with a Sartorius balance. The hoppers used were a 25 ml conventional hopper with an 8 mm valve size and a 4:3 mm funnel size, a 10 ml conventional hopper with an 8 mm valve size and a 4:3 mm funnel size, and an SV hopper with a standard 4 ml glass vial.

[0097] Racemic 5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine The title compound (fadrozole) can be prepared, for example, according to the procedure described by LJ Browne et al. (J. Med. Chem. 1991, 34, 725) or obtained from a commercial source such as Sigma-Aldrich.

[0098] Example 1 Diastereomeric salt screening using racemic 5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine 100 mg (1.0 equiv.) of the title compound was dissolved in isopropanol, followed by the addition of a solution of the chiral acid (0.5 equiv.) in isopropanol (0.5 mL). The results of the screening are summarized in Table 2. TIFF2025131628000005.tif95162

[0099] Example 2 Salt screening using (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine General procedure: The title compound (free base) was dissolved in ethanol (100 g / L) at 35° C., followed by the addition of acid at the same temperature. The resulting mixture was cooled to 10° C. at a cooling rate of −20° C. / h, and the precipitate (if present) was filtered off, washed with ethanol, and dried under reduced pressure at 50° C. The salt screening results are summarized in Tables 3-5. TIFF2025131628000006.tif97160TIFF2025131628000007.tif97160The phosphate, tartrate and fumarate salts obtained as solids were subjected to solid-state characterization according to Table 5. TIFF2025131628000008.tif50162

[0100] Example 3 Preparation of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridine dihydrogen phosphate (crystalline form I) Step 1: Preparation of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridinedibenzoyl-L-tartrate A 10 L reactor was charged with racemic 5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (328 g, 1.0 equiv.) and ethanol (2.3 L) at 20°C. The mixture was heated to 40°C, and then a solution of (-)-O,O'-dibenzoyl-L-tartaric acid (276.4 g, 0.5 equiv.) in ethanol (1 L) was added. The mixture was held at 40°C for 1 hour, cooled to 20°C over 2 hours, held at this temperature for 1 hour, cooled to 10°C over 0.5 hours, and finally held at 10°C overnight. The precipitate was then filtered off, and the filter cake was washed with cold (0°C) ethanol (1 L) to give the title compound as a white, moist powder (485 g, estimated dry matter based on loss on drying of 413.7 g, 48.4%; ee=87%).

[0101] Step 2: Recrystallization of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridinedibenzoyl-L-tartrate A 10 L reactor was charged at 20 °C with (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridinedibenzoyl-L-tartrate (485 g, ee = 87%, = 413.7 g estimated dry matter, loss on drying = 1.0 equiv.) obtained in Step 1, ethanol (10 L, 24 V), and water (2.4 L, 6 V). The resulting mixture was heated to reflux, forming a solution. The solution was then cooled to 50 °C and held at this temperature for 1 hour. The mixture was then cooled to 10 °C over 2 hours and held at this temperature overnight. The precipitate was filtered off, and the filter cake was washed with cold (0 °C) ethanol (1.2 L). The product was dried under vacuum at 40° C. to give the title compound as a white powder (294.8 g, 71%, single enantiomer). Enantiomeric excess: >99.9% as determined by HPLC.

[0102] Step 3: Preparation of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (free base) A 2 L reactor was charged with (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridinedibenzoyl-L-tartrate (177 g, single enantiomer) from Step 2 and dichloromethane (1.77 L, 10 V). A solution of Na2CO3 (71 g, 2.2 equiv.) in water (875 mL) was then added. After stirring at room temperature for 0.25 h, the mixture was decanted. The resulting liquid phase was clear, and the aqueous phase had a pH of 8–9. The organic phase was washed with water (2 × 875 mL) and then concentrated under vacuum. The residue was dissolved in ethanol and concentrated under vacuum again to give the title compound (70 g, quantitative yield) as an oil that solidified upon standing.

[0103] Step 4. (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate To a 1 L reactor was added (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (94 g, 1.0 equiv.) and ethanol (564 mL), and the mixture was heated to 35 °C. The solution was filtered, and the reactor was rinsed with ethanol (94 mL). A solution of H3PO4 (97 g, 85% w / w in HO) in ethanol (235 mL) was added at the same temperature and rinsed with ethanol (47 mL). After stirring at 35 °C for 1 h, the mixture was cooled to 10 °C (at a rate of -20 °C / h) and held at this temperature for 10 h. The resulting solid was filtered off, and the filter cake was washed with cold (10 °C) ethanol (3 × 94 mL). After drying under reduced pressure at 50 °C, the title compound was obtained as a white, crystalline, free-flowing powder (100 g, 74%). XRPD: See Figure 1 and Table 1. Melting point: 189°C as determined by TGA / DSC (Figure 2). Enantiomeric excess: >99.9% (Figure 3). Chiral HPLC for determination of the enantiomeric excess of the preparation was characterized by a retention time (tr) of 14.459 min for the R-(+) enantiomer and 9.814 min for the R-(-) enantiomer. Absolute configuration: R-(+)- on carbon 5 determined by single crystal X-ray. Specific rotation (CH3CN:H2O 1:1 (vol / vol)): [α] D 20 =+98.1. Hygroscopicity: 1.0% at 90% or higher relative humidity (RH) as measured by DVS. Water absorption is reversible, and the crystal form remains unchanged by DVS treatment (Figures 4-6). Mass loss upon heating to 225°C is 1.4%, as measured by TGA / DSC (Figure 2). The (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridine dihydrogen phosphate crystals were further characterized by elemental analysis and were found to have the molecular formula C 14 H 16 This is consistent with the values ​​calculated from N3O4P (molecular weight: 321.27): C 52.4%, H 5.1%, N 13.03%.

[0104] Example 4 Preparation of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine chloride from (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate via the free base (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate salt (1000 mg, 3.11 mmol) prepared in Example 3 was suspended in EtO (30 mL) and extracted with saturated aqueous NaHCO (30 mL). The aqueous layer was extracted with diethyl ether (2 × 20 mL). The combined organic layers were washed with brine (10 mL) and distilled water (10 mL), dried over NaSO, filtered, and evaporated to give the free base (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine as a white solid, which was dried overnight at 50 °C in vacuo (530 mg). Melting point: 101-102°C; specific rotation (ethanol): [α] D 25 =+127.3; The (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine thus obtained (100 mg, 0.447 mmol, 1 equiv.) was dissolved in methylene chloride (2.2 ml), HCl (2 M in diethyl ether, 0.34 ml, 0.76 mmol, 1.5 equiv.) was added, and the mixture was stirred at room temperature for 30 minutes, then evaporated and dried under vacuum at 80° C. (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine chloride was isolated as a crystalline solid.

[0105] Melting point: 240-243°C; specific rotation (ethanol): [α] D 20 = +104.8; specific rotation (CHCN:H0 1:1 (vol / vol)): [α] D 20 =+124.4.

[0106] Example 5 Hygroscopicity of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydro-imidazolium[1,5-a]pyridine dihydrogen phosphate compared to (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydro-imidazolium[1,5-a]pyridine chloride 100 mg samples of the two crystalline salts were placed in open flasks and stored side-by-side in unconditioned ambient air at room temperature for 24 hours, with weight measurements taken at time 0 and 24 hours (Table 6). (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydro-imidazolium[1,5-a]pyridine dihydrogen phosphate exhibited a weight gain of 0.57% and is considered non-hygroscopic compared to the corresponding (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine chloride, which exhibited a weight gain of 13.1%. TIFF2025131628000009.tif28162

[0107] Example 6 Shake-flask solubility study of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridine dihydrogen phosphate Shake flask solubility studies of the materials were performed according to United States Pharmacopeia (USP) specifications. Shake flask solubility was measured using a set of pharmaceutically acceptable process solvents with different functional groups. The solvent was allowed to evaporate overnight at room temperature at 0-100 mbar. All solids were then analyzed using XRPD. The results of this study can be found in Table 7 below. TIFF2025131628000010.tif77160

[0108] The material is very soluble in water, freely soluble in methanol and acetic acid, slightly soluble in ethanol, and practically insoluble in the other solvents tested. Table 8 shows the XRPD results of measurements performed on the slurry solids or the solution solids after evaporation. TIFF2025131628000011.tif70160 Except for the case of acetic acid (amorphous), no new polymorphic forms were obtained after evaporation of the solvent, confirming the excellent stability of crystalline form I.

[0109] Example 7 Polymorphic investigation for (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridine dihydrogen phosphate The solvent and co-solvent were added in different ratios: 100% solvent and 0% co-solvent, 80% solvent and 20% co-solvent, 60% solvent and 40% co-solvent, 40% solvent and 60% co-solvent, 20% solvent and 80% co-solvent, and 5% solvent and 95% co-solvent. Table 9 shows the configuration of the investigated conditions and the XRPD results for each polymorphic form. TIFF2025131628000012.tif103160

[0110] Starting material (30 mg) was dispensed into a 96-well plate ("master plate") using a Freeslate CM Protege solid dispensing system. After dispensing the solids, the well plate was transferred to the Freeslate Core Module 2 for liquid dispensing (solvent + cosolvent total = 800 μL). The master plate was agitated at 50 °C for 2 h. An aliquot of the master plate sample was transferred to a cooling crystallization plate via a hot filtration plate. The sample in the cooling plate was then cooled from 50 °C to 10 °C over 5 h using a cubic cooling rate. Since none of the wells contained solids, the solvent was evaporated at room temperature between 0 and 100 mbar to simulate evaporative crystallization. All solids formed were analyzed by XRPD. All diffractograms were compared to the reference diffractogram outlined in Figure 1 by overlaying their respective diffractograms (Figure 6). This investigation allowed the identification of only one polymorph of the title compound, crystalline Form I, which possesses the highly beneficial and unexpected properties described. This finding appears to confirm that crystallization is not only a function of salt selection, but also of the crystallization process conditions that result in crystalline Form I of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridine dihydrogen phosphate salt of the present invention (P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor); Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 2nd Revised Edition, March 2011, Wiley-VCH, ISBN: 978-3-90639-051-2).

[0111] Example 8 Evaluation of aromatase and aldosterone synthase inhibition by (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridine dihydrogen phosphate Human NCI-H295R cell assay for aldosterone synthase (CYP11B2) and aromatase (CYP19) activity NCI-H295R cells, a continuous cell line derived from an aggressive primary adrenocortical carcinoma, were obtained from CLS Cell Line Services GmbH (catalog number 300483). Because NCI-H295R cells produce both aldosterone and estradiol, they allow aldosterone synthase activity and aromatase activity to be measured under the same conditions. Prior to use in the assay, cells were maintained in DMEM / Ham's medium containing 15 mM Hepes and 1.2 g NaHCO3, supplemented with 5% steroid-free serum replacement, Panexin BMM (PAN Biotech, Aldenbach, Germany; catalog number PO4-9515A2), 1% penicillin / streptomycin, 1.25% L-glutamine, and 6.25 μg / ml insulin, 6.25 ng / ml selenium, 5.35 μg / ml linoleic acid, and 1.25 mg / ml bovine serum albumin. Cells were maintained at 37°C in an atmosphere of 95% air / 5% CO2. For the assay, cells were plated at 5x10 in 24-well plates. 5 Cells were subcultured at a density of 100 cells / well and grown to 50-60% confluence (48 h). The growth medium was then replaced with 500 μl serum-free DMEM:Ham's F12 containing the test compound dissolved in 1:1 ethanol / water (vol / vol) such that the final concentration in the assay consisted of 0.5% ethanol. Six concentrations were evaluated, and a compound-free control sample was supplemented with 0.5% ethanol. Cells containing the compound were incubated at 37°C under 95% air / 5% CO2 for 6 h. The supernatant was then removed and stored at -20°C until analysis. After removal of the supernatant, cells were assessed for morphological changes under a phase-contrast microscope, optical assessment using a microscope, and viability was ensured by the resazurin assay, which measures the conversion of resazurin to the fluorescent end-product resorufin. Nonviable cells lack the metabolic capacity to carry out this conversion. Conversion was quantified by measuring fluorescence at 544 nm / 590 nm (extinction / emission), respectively, using a Wallac 1420 Multiple Counter Victor Fluorometer / Luminator (Perkin Elmer, Wlatham, Mass.).

[0112] Quantification of aldosterone concentration, as a measure of aldosterone synthase activity, was performed by LC-MS as follows. Prior to analysis, sample proteins were precipitated using acetonitrile, and the particle-free supernatant was subjected to LC-MS after centrifugation. The HPLC system consisted of an Accela U-HPLC pump and an Accela Open autosampler (Thermo Fisher Scientific, Waltham, MA). Mass spectrometry was performed using a Q-Exactive MS (Orbitrap) equipped with a thermal electrospray (H-ESI) interface connected to a PC running standard Xcalibur software 2.2 (Thermo Fisher Scientific, Waltham, MA). LC was performed in gradient mode using acetonitrile containing 0.1% formic acid (solvent A) and aqueous 0.1% formic acid (solvent B). The pump flow rate was set to 600 μl / min, and the separation was performed on a Kinetex Phenyl-Hexyl 2.6 μm, 50 x 2.1 mm analytical column (Phenomenex, Germany) equipped with a C6-Phenyl, 4 x 2.0 mm ID precolumn for quantitative analysis. The MS tuning file was a general purpose tuning file, and the lock mass for internal calibration was the [M+H] of diisooctyl phthalate (m / z 391.28492) present in the solvent system. + ions were used. A full MS-SIM analysis (m / z: 250-400) was applied, and the mass resolution of the Orbitrap™ was set to 35,000. The sample injection volume was 20 μl for all samples. Results were expressed as ng / ml, and the inhibition of aldosterone production was expressed as a percentage inhibition relative to the untreated control, i.e., in the absence of any inhibitor (Table 10). IC 50 Values ​​were calculated using linear interpolation using the test compound concentration and the corresponding percentage inhibition just above and below 50% as shown below. I C 50 =(50%-low inh %) / (high inh %-low inh %)x(high conc -low conc )+low conc where "inh" is inhibition and "conc" is concentration. TIFF2025131628000013.tif59162 a high conc = The lowest concentration of test substance that inhibits at least 50% (10 nM) b low conc = The highest concentration of test substance that inhibits less than 50% (1 nM) c high inh = high conc Percent inhibition achieved with test article (60.8%) d low inh = low conc Percent inhibition achieved with test article (8.7%) I C 50 =(50%-8.7%) / (60.8%-8.7%)x(10nM-1nM)+1nM=8.1nM I C 50 = 8.1 nM for inhibition of aldosterone production (aldosterone synthase activity)

[0113] As shown below, much higher concentrations of inhibitors were used to measure IC 50 Aromatase activity was measured by quantifying estradiol concentrations in supernatants from incubations of NCI-H295R cells, as described above for measuring aldosterone synthase activity, except that the IC was obtained using a 17-beta estradiol ELISA kit from IBL-Hamburg (Hamburg, Germany) according to the manufacturer's instructions. A calibration curve was generated by plotting the absorbance of each reference standard (y-axis) against the corresponding logged concentration (x-axis). The absorbance of each sample was used to determine corresponding values ​​by interpolation from the calibration curve using GraphPad Prism 5.04 (GraphPad Software Inc., San Diego, CA). Using the aforementioned equation for the aldosterone synthase data disclosed in Table 11, the IC was calculated. 50 was calculated. TIFF2025131628000014.tif59162 a high conc = The lowest concentration of test substance that inhibits at least 50% (10 μM) b low conc = The highest concentration of test substance that inhibits less than 50% (1 μM) c high inh = high conc Percent inhibition achieved with test article (68.6%) d low inh = low conc Percent inhibition achieved with test article (29.1%) I C 50 = (50%-29.1%) / (68.6%-29.1%) x (10µM-1µM) + 1µM = 5.76µM or 5760nM I C 50 = 5760nM for inhibition of estradiol production (aromatase activity)

[0114] Cell-free human recombinant aromatase assay Aromatase (CYP19) activity was measured using a human CYP19 assay kit (Corning®, Corning, NY; product #456260) according to the manufacturer's instructions. The assay system contains the recombinant human enzyme, the fluorometric substrate MFC (7-methyl-4-trifluoro-methyl-coumarin), and glucose-6-phosphate dehydrogenase, NADP + The NADPH regeneration system, consisting of glucose-6-phosphate and ATP, was used. The enzyme activity was inhibited by 50% (IC 50Eight test concentrations were tested to determine the concentration of test compound that was quantified. Test compounds were dissolved in 1:1 ethanol / water (volume / volume) so that the final ethanol concentration in the assay was 1%. Various concentrations of test compound were added to a 96-well plate along with the NADPH regeneration system. After a 10-minute preincubation, the reaction was initiated by the addition of prewarmed enzyme substrate mix and continued for an additional 30 minutes at 37°C. The reaction was then stopped by the addition of a solution of 80% acetonitrile and 20% 0.5 M Tris base (stop solution). To control for background fluorescence, blank wells (without test sample) were assayed in the same way, except that stop solution was added to these wells before the addition of the enzyme substrate mix. Fluorescent product formation, 7-hydroxy-4-trifluoromethyl-coumarin (HFC), was detected using a Wallac 1420 Multiple Counter Victor Fluorometer / Luminator (Perkin Elmer, Wlatham, MA). The excitation and emission wavelengths were 405 and 535 nm, respectively. Data were compiled using standard software, Wallac 1420 Manager 3.0. In addition to subtracting blank well samples as described above, each test substance was pre-tested for autofluorescence. For this purpose, the NADPH-generating system (cofactor mixture) and enzyme / substrate mixture were replaced by a comparison mixture of control protein, assay buffer, and test compound solvent. These control samples were then pre-incubated and assayed as described above. IC 50 Three independent determinations were made from a best fit plot line of % inhibition versus inhibitor concentration (Table 12). TIFF2025131628000015.tif54162

[0115] Example 9 Evaluation of stability data for (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridine dihydrogen phosphate Important long-term stability data relevant for regulatory considerations were determined, and in this regard, various tests shown in Tables 13-15 below were performed at 25°C and 60% RH (Table 13), 30°C and 65% RH (Table 14), and 40°C and 75% RH (Table 15), and at various time points (initial, 1, 3, and 6 months, or longer).

[0116] (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate was found to be extremely stable over extended periods of time, demonstrating long-term stability, particularly with respect to purity, water content, and therefore hygroscopicity, as well as chiral purity, under the stability conditions and time periods evaluated. Additionally, and importantly, no polymorphic changes were observed under any of the conditions and time periods evaluated. TIFF2025131628000016.tif75162TIFF2025131628000017.tif66160TIFF2025131628000018.tif64162

Claims

1. A compound selected from (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine and pharmaceutically acceptable salts thereof, wherein the enantiomeric excess of the (R) form is 97% or more.

2. IC50 of 700 nM or greater, preferably 1000 nM or greater, and more preferably 1500 nM or greater in a cell-free human recombinant aromatase enzyme assay ５０ 2. The compound of claim 1, which inhibits aromatase activity at

3. IC of 100 nM or less, preferably 50 nM or less, more preferably 10 nM or less in the NCI-H295R adrenal cell assay ５０ 3. A compound according to claim 1 or claim 2 which inhibits aldosterone synthase by

4. The compounds have a selectivity for aldosterone synthase over aromatase of 50 or greater, preferably 100 or greater, and most preferably 700 or greater, such selectivity being indicative of an IC for aromatase inhibition. ５０ values ​​and IC for aldosterone synthase inhibition ５０ The IC for aromatase inhibition was determined by the ratio of the ５０ values ​​and IC for inhibition of aldosterone synthase ５０ The compound of any one of claims 1 to 3, wherein both values ​​are measured in said NCI-H295R adrenal cell assay.

5. The compound according to any one of claims 1 to 4, wherein the compound is (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate.

6. The compound of any one of claims 1 to 5, wherein the pharmaceutically acceptable salt is crystalline.

7. The compound of any one of claims 1 to 6, wherein the pharmaceutically acceptable salt is anhydrous.

8. The compound of any one of claims 1 to 7, wherein the pharmaceutically acceptable salt is non-hygroscopic.

9. 9. The compound of any one of claims 5 to 8, wherein the (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate has a melting point equal to or between 184°C and 193°C, as measured by thermogravimetric analysis / differential scanning calorimetry (TGA / DSC), and preferably the (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate has a melting point equal to or between 188°C and 190°C.

10. 10. The compound of any one of claims 5 to 9, wherein the (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate is crystalline form I of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate, and crystalline form I has an X-ray powder diffraction pattern including 2θ values ​​of 19.504, 21.919, and 24.159, measured using CuKα radiation, with each peak varying by ±0.5, or preferably ±0.2 degrees.

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

12. (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate.

13. 13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate according to claim 12, in admixture with at least one pharmaceutically acceptable excipient, preferably in the form of a tablet, pill, dispersible granule, cachet, capsule, powder, troche, suppository or retention enema.

14. 14. The compound of any one of claims 1 to 11, wherein the disease or disorder is selected from primary and secondary hyperaldosteronism, heart failure, chronic renal failure, hypertension, restenosis, obesity, nephropathy, post-myocardial infarction syndrome, renal fibrosis, and coronary heart disease, more preferably the disease or disorder is selected from primary and secondary hyperaldosteronism; (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine dihydrogen phosphate salt of claim 12, or the pharmaceutical composition of claim 13, for use in a method of treatment, preferably in humans, including premenopausal female and pediatric patients, of a disease or disorder in which excessive exposure to aldosterone contributes to the adverse effects of the disease or disorder, preferably wherein the disease or disorder is selected from primary and secondary hyperaldosteronism, heart failure, chronic renal failure, hypertension, restenosis, obesity, nephropathy, post-myocardial infarction syndrome, renal fibrosis, and coronary heart disease, more preferably wherein the disease or disorder is selected from primary and secondary hyperaldosteronism.

15. A process for preparing a compound selected from (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine and pharmaceutically acceptable salts thereof according to any one of claims 1 to 9, comprising: i. reacting racemic 5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine with (−)-O,O′-dibenzoyl-L-tartaric acid to form diastereomeric (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine dibenzoyl-tartrate; and ii. Recrystallizing the tartrate salt obtained in step i at least once; and iii. adding a base to the solution of the tartrate salt obtained in step ii to liberate the free base (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine; and optionally, iv. Forming a pharmaceutically acceptable salt by reacting the free base with an acid, preferably wherein the acid is phosphoric acid (H ３ P.O. ４ ) A method comprising:

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