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BR-122022000560-B1 - Aldosterone synthase inhibitor, its use and preparation process, and pharmaceutical composition.

BR122022000560B1BR 122022000560 B1BR122022000560 B1BR 122022000560B1BR-122022000560-B1

Abstract

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

Inventors

  • Christoph Schumacher
  • Walter Fuhrer
  • RONALD EDWARD STEELE

Assignees

  • DAMIAN PHARMA AG

Dates

Publication Date
20260310
Application Date
20171026
Priority Date
20161219

Claims (20)

  1. 1. Compound, characterized in that it is dihydrogen phosphate of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine, wherein it has an enantiomeric excess of the (R) form equal to or greater than 99.5%, wherein said dihydrogen phosphate of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine is a crystalline form I of dihydrogen phosphate of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine, wherein said crystalline form I has an X-ray powder diffraction pattern comprising the following 2θ values measured using radiation of CuKα: 19,504; 21,919 and 24,159, with each peak varying by ± 0.5 degrees, wherein the said dihydrogen phosphate of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine has a melting point equal to or between 184°C and 193°C, as determined by thermogravimetric analysis/differential scanning calorimetry (TGA/DSC).
  2. 2. Compound according to claim 1, characterized in that it has an enantiomeric excess of form (R) equal to or greater than 99.9%.
  3. 3. Compound according to claim 1, characterized in that said crystalline form I exhibits an X-ray powder diffraction pattern comprising the following 2θ values measured using CuKα radiation: 19.504; 21.919; 24.159; 16.003; 26.101; 27.168; 27.542 and 29.029, wherein each peak may vary by ± 0.5 degrees.
  4. 4. Compound according to any one of claims 1 to 3, characterized in that said dihydrogen-phosphate of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine is anhydrous.
  5. 5. Compound according to any one of claims 1 to 4, characterized in that said dihydrogen-phosphate of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine is non-hygroscopic.
  6. 6. Compound according to claim 1, characterized in that said dihydrogen phosphate of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine is a crystalline form I of dihydrogen phosphate of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine, wherein said crystalline form I exhibits an X-ray powder diffraction pattern comprising the following 2θ values measured using CuKα radiation: 19.504; 21,919 and 24,159, with each peak varying by ± 0.2 degrees, wherein the said dihydrogen phosphate of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine has a melting point equal to or between 184°C and 193°C, as determined by thermogravimetric analysis/differential scanning calorimetry (TGA/DSC).
  7. 7. Pharmaceutical composition, characterized in that it comprises a compound, as defined in any one of claims 1 to 6, in a mixture with at least one pharmaceutically acceptable excipient.
  8. 8. Pharmaceutical composition, according to claim 7, characterized in that said pharmaceutical composition is in the form of tablets, pills, dispersible granules, wafers, capsules, powders, lozenges, suppositories or retention enemas.
  9. 9. Pharmaceutical composition, according to claim 7 or 8, characterized in that it is for treating a disease or disorder in a patient wherein overexposure to aldosterone contributes to the harmful effects of said disorder or disease, said disorder or disease being selected from primary and secondary hyperaldosteronism, heart failure, chronic renal failure, hypertension, restenosis, obesity, nephropathy, post-myocardial infarction, renal fibrosis and coronary heart disease.
  10. 10. Pharmaceutical composition, according to claim 9, characterized in that the said disorder or disease is selected from primary and secondary hyperaldosteronism.
  11. 11. Pharmaceutical composition, according to claim 9 or 10, characterized in that the patient is a human being.
  12. 12. Pharmaceutical composition, according to claim 11, characterized in that the patient in question is a premenopausal woman.
  13. 13. Pharmaceutical composition, according to claim 11, characterized in that the patient in question is a pediatric patient.
  14. 14. Process for preparing (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, as defined in any one of claims 1 to 6, characterized in that it comprises the steps of: i. reacting racemic 5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine with (-)-O,O'-dibenzoyl-L-tartaric acid to form the diastereomeric (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine dibenzoyl-L-tartrate salt; and ii. recrystallizing the tartrate salt obtained in step i; and optionally iii. to release the free base of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine by adding a base to a solution of the tartrate salt obtained in step ii; and optionally iv. to form a pharmaceutically acceptable salt by reacting said free base with an acid, wherein said acid is phosphoric acid (H3PO4).
  15. 15. Process according to claim 14, characterized in that the base is Na2CO3.
  16. 16. Use of a compound, as defined in any one of claims 1 to 6, characterized in that it is in the preparation of a medicament to treat a disease or disorder in a patient wherein overexposure to aldosterone contributes to the detrimental effects of said disease or disorder, said disease or disorder being selected from primary and secondary hyperaldosteronism, heart failure, chronic renal failure, hypertension, restenosis, obesity, nephropathy, post-myocardial infarction, renal fibrosis and coronary heart disease.
  17. 17. Use, according to claim 16, characterized in that the said disorder or disease is selected from primary and secondary hyperaldosteronism.
  18. 18. Use according to claim 16 or 17, characterized in that the patient is a human being.
  19. 19. Use according to claim 18, characterized in that the patient in question is a premenopausal woman.
  20. 20. Use according to claim 18, characterized in that the patient in question is a pediatric patient.

Description

[0001] The present invention relates to a selected compound of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine and a pharmaceutically acceptable salt thereof, and in particular to the phosphate salt of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, both preferably having an enantiomeric excess of the (R) form greater than or equal to 97%. Furthermore, the present invention relates to pharmaceutical compositions comprising the same, their use as a medicament, and methods of treating diseases and disorders in which excessive exposure to aldosterone contributes to the detrimental effects of said diseases or disorders, including in premenopausal women and pediatric patients, as well as processes for preparing said compounds of the invention. RELATED TECHNIQUE [0002] Inhibition of aldosterone synthase (CYP11B2) has emerged as a new option for the treatment of hypertension, heart failure, and renal disorders, in addition to mineralocorticoid receptor (MR) blockade. The goal is to decrease aldosterone concentrations in both plasma and tissues, thereby reducing MR-dependent and MR-independent effects on 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] Initial attempts to inhibit aldosterone synthesis involved the use of various non-selective steroidogenesis inhibitors, but this had a major safety problem. The concept of a pharmacological approach targeting the specific inhibition of aldosterone synthesis was initiated by the finding that fadrozole hydrochloride (CGS16949A, INN: Fadrozole; US 4,617,307; US 4,728,645; US 5,098,911), known as a non-steroidal aromatase inhibitor effective for the treatment of advanced breast cancer, affected aldosterone levels. Subsequent preclinical studies demonstrated that the R-enantiomer chloride, (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine, is a potent inhibitor of CYP11B2, while the S-enantiomer is responsible for the strong and potent aromatase (CYP19) inhibitory activity of CGS16949A (J. Ménard 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, the clinical development of (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine chloride in humans has never been reported, nor has a commercially viable synthesis or satisfactory chiral purity been disclosed (US 4,889,861). Furthermore, (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyridine chloride has been shown 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; US 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 strong and potent aromatase inhibitory activity of the corresponding (S) enantiomer, since exhaustive evaluation of aromatase inhibitors in clinical trials has revealed numerous detrimental consequences of aromatase inhibition. Thus, a systematic review and meta-analysis consisting of seven trials in 30,023 postmenopausal women with breast cancer treated with aromatase inhibitors revealed a significant increase in the occurrence of bone 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 association with cardiovascular disease and bone fractures. Furthermore, in premenopausal women, that is, women still of childbearing age, exposure to aromatase inhibition can lead to reproductive disorders, and in breastfeeding women, newborns can be exposed to aromatase-inhibiting compounds through secretion in breast milk. Additionally, in pediatric patients, aromatase inhibition can lead to developmental disorders. Thus, the need for very high purity and the avoidance of contaminants and impurities in such drugs, which are generally used for a long period of time or even for life, is evident. [0006] In addition, and besides the required very high chiral purity and the prevention of aromatase inhibition as an adverse effect, water solubility and stability including enantiomeric stability over a long period of time in order to exclude any conversion into aromatase-inhibiting molecules, as well as the processability of such a drug, particularly into suitable oral administration forms such as tablets, are also combined prerequisites for a pharmaceutical preparation of such a drug. SUMMARY OF THE INVENTION [0007] The inventors have now surprisingly provided (R)-(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine of formula (I) with an unprecedented degree of chiral purity, i.e., enan