Pharmacologically acceptable crystalline salts and polymorphs of the glutaminilcyclase inhibitor baloglutamstat.

Abstract

The present invention relates to a crystalline, pharmaceutically acceptable salt of baloglutamstat, a glutaminilcyclase inhibitor. Baloglutamstat is chemically designated as (S)-1-(1H-benzo[d]imidazole-5-yl)-5-(4-propoxyphenyl)imidazolidine-2-one, also known by the code PQ912. The present invention further relates to polymorphs of the hydrochloride salt of (S)-1-(1H-benzo[d]imidazole-5-yl)-5-(4-propoxyphenyl)imidazolidine-2-one, methods for preparing the hydrochloride salt and its polymorphs, pharmaceutical compositions containing the same, therapeutic uses thereof, and therapeutic methods using the same.

Claims

1. 9.5 ± 0.2° and 24.8 ± 0.2° Polymorphs of baroglutamstat hydrochloride characterized by an X-ray powder diffraction peak (2 [theta]) selected from one or more of the following.

2. 9.5±0.2°, 21.3±0.2°, 22.6±0.2°, and 24.8±0.2° A polymorph of baroglutamstat hydrochloride according to claim 1, characterized by an X-ray powder diffraction peak (2 [theta]) selected from one or more of the following.

3. 5.8±0.2°, 9.5±0.2°, 16.9±0.2°, 17.2±0.2°, 18.9±0.2°, 20.7±0.2°, 21.3±0.2°, 21.7±0.2°, 22.6±0.2°, and 24.8±0.2° A polymorph of baroglutamstat hydrochloride according to claim 1 or 2, characterized by an X-ray powder diffraction peak (2 [theta]) selected from one or more of the following.

4. 5.8±0.2°, 9.5±0.2°, 11.3±0.2°, 12.4±0.2°, 15.8±0.2°, 16.9±0.2°, 17.2±0.2°, 18.9±0.2°, 20.2±0.2°, 20.7±0.2°, 21.3±0.2°, 21.7±0.2°, 22.6±0.2°, 23.8±0.2°, 24.8±0.2°, 26.3±0.2°, 27.2±0.2°, 28.3±0.2°, 28.8±0.2°, 29.4±0.2°, 30.1±0.2°, 31.2±0.2°, and 33.8±0.2° A polymorph of baroglutamstat hydrochloride according to any one of claims 1 to 3, characterized by an X-ray powder diffraction peak (2 [theta]) selected from one or more of the following.

5. A polymorph of baroglutamstat hydrochloride according to any one of claims 1 to 4, characterized by the X-ray diffraction spectrum shown in Figure 19.

6. A polymorph of baroglutamstat hydrochloride according to any one of claims 1 to 5, characterized by a differential scanning calorimetry (DSC) thermogram shown in Figure 20.

7. A polymorph of baroglutamstat hydrochloride according to any one of claims 1 to 6, characterized by a DSC endothermic reaction having a starting temperature of 243°C and a peak at 251°C.

8. A polymorph of baroglutamstat hydrochloride according to any one of claims 1 to 7, characterized by the dynamic vapor adsorption (DVS) curve shown in Figure 22.

9. A polymorph of baroglutamstat hydrochloride according to any one of claims 1 to 8, characterized by a thermogravimetric analysis (TGA) thermogram shown in Figure 21.

10. A polymorph of baroglutamstat hydrochloride according to claim 9, characterized by a single mass loss of 3.0% at an initiation / ending temperature of 190 / 215°C prior to the main thermal decomposition of the baroglutamstat hydrochloride.

11. As shown in Figure 23 １ A polymorph of baroglutamstat hydrochloride according to any one of claims 1 to 10, characterized by an H-NMR spectrum.

12. A polymorph of baroglutamstat hydrochloride according to any one of claims 1 to 11, wherein the polymorph substantially does not contain amorphous material.

13. Characterized by an achiral purity of over 95%, preferably over 96% or over 97%, more preferably over 98% or over 99%, most preferably over 99.5% or over 99.8%, and having an achiral property １ A polymorph of baroglutamstat hydrochloride according to any one of claims 1 to 12, determined by 1H-NMR analysis.

14. A hydrochloride salt of baloglutamstat ((S)-1-(1H-benzo[d]imidazole-5-yl)-5-(4-propoxyphenyl)imidazolidine-2-one), comprising or consisting of the polymorph described in any one of claims 1 to 13.

15. The hydrochloride salt of baloglutamstat according to claim 14, wherein the hydrochloride salt of baloglutamstat is nonhygroscopic.

16. The hydrochloride salt of the baroglutamstat according to claim 13 or 14, wherein the hydrochloride salt of the baroglutamstat exhibits a water absorption rate of less than 6.0% at 95% RH.

17. The baroglutamstat hydrochloride salt according to any one of claims 13 to 16, wherein the TGA profile of the baroglutamstat hydrochloride salt exhibits a mass loss of less than 9.20% corresponding to less than two water molecules or any other solvate-related substance per mol.

18. The aforementioned baloglutamstat hydrochloride, Formula I: Crystallinity %=100×A / (A+BC) (Formula I) (In the formula, A is the sum of the net areas of all peaks resulting from the diffraction of the crystal fraction of the sample; B is the area under the diffractogram generated by the sample itself (excluding area A); C is the area of ​​background noise (due to air scattering, fluorescence, equipment, etc.) measured by recording the diffractogram of the (empty) sample holder used to record the diffractogram of the sample being tested. The hydrochloride salt of baloglutamstat according to any one of claims 13 to 17, which exhibits a degree of crystallinity of more than 50% when calculated by [method].

19. The hydrochloride salt of the baroglutamstat according to any one of claims 13 to 18, wherein the crystals of the baroglutamstat hydrochloride salt include needle-shaped crystals as shown in Figure 18.

20. The hydrochloride salt of the baroglutamstat according to any one of claims 13 to 19, wherein the hydrochloride salt of the baroglutamstat has a solubility in water of 0.10 M or more, preferably 0.11 M or more, more preferably 0.12 M or more, and most preferably 0.13 M or more or 0.14 M or more at 20°C.

21. The hydrochloride salt of baroglutamstat according to any one of claims 13 to 20, wherein the crystals of the hydrochloride salt of baroglutamstat substantially do not contain isopropyl chloride.

22. A method for preparing the hydrochloride salt of baloglutamstat, comprising the steps of dissolving baloglutamstat free base in a solvent mixture containing a polar aprotic water-miscible organic solvent and water, adding a solution containing HCl, and recovering baloglutamstat hydrochloride crystals.

23. i. A step of dissolving the free base of baroglutamstat in a polar aprotic water-miscible organic solvent, ii. The step of adding water to the solvent in step i, iii. A step of adding a solution containing an aqueous HCl solution mixed with the organic solvent-water mixture of step ii. iv. A step of optionally adding a seed crystal to the solution of step iii. v. A step of aging the mixture resulting from step iii. and / or step iv. for a time suitable for forming baroglutamstat hydrochloride crystals, vi. A further step of adding a polar aprotic water-miscible organic solvent, vii. A step of cooling the suspension obtained in step vi, viiii. A process for recovering baroglutamstat hydrochloride crystals, The method according to claim 22, including the method described in claim 22.

24. The method according to any one of claims 22 or 23, wherein the polar aprotic water-miscible organic solvent in step i is acetone, and 1.0 equivalent of free baroglutamstat base is dissolved in acetone containing 3 to 7 vol, preferably 4 to 6 vol, most preferably 5 vol, of water.

25. The method according to any one of claims 22 to 24, wherein in step ii, 150 to 300 mg, preferably 200 to 250 mg, most preferably 221 mg of water per 1 mmol of free base is added to the polar aprotic water-miscible organic solvent of step i.

26. The method according to any one of claims 22 to 25, wherein the solution in step i is heated to a temperature in the range of 35 to 55°C, preferably 40°C, and steps ii to v are carried out at a temperature range of 35 to 55°C, preferably 45 ± 5°C.

27. The method according to any one of claims 22 to 26, wherein in step iii, 0.6 to 1.2 equivalents, preferably 0.7 to 1.1 equivalents, more preferably 0.8 to 1.0 equivalents, and most preferably 0.95 equivalents of HCl (32 to 37% w / w aqueous solution), dissolved in the polar aprotic water-miscible organic solvent, preferably dissolved in acetone, is added to the solution of step ii.

28. The method according to any one of claims 22 to 27, wherein the time suitable for forming the baroglutamstat hydrochloride crystals in step v. before cooling is at least 30 minutes, preferably 30 to 60 minutes, more preferably 30, 40, 50 or 60 minutes.

29. The method according to any one of claims 22 to 28, wherein in step vi, a further amount of the polar aprotic water-miscible organic solvent, preferably acetone, is added to the suspension of step v, and then the suspension is stirred at a temperature of 30°C to 55°C, most preferably 45±5°C, for at least 45 minutes, preferably 45 to 90 minutes, more preferably 45 minutes, 60 minutes, 75 minutes, or 90 minutes.

30. The method according to any one of claims 22 to 29, wherein in step vii, the suspension is cooled to a temperature of 15°C to 25°C, preferably 22°C, for a period of at least 45 minutes, preferably 45 to 90 minutes, more preferably 45, 60, 75, or 90 minutes.

31. The method according to any one of claims 22 to 30, wherein the suspension is cooled to 15°C to 25°C, preferably 20±5°C, and then stirred for at least 45 minutes, preferably 45 to 90 minutes, more preferably 45 minutes, 60 minutes, 75 minutes, or 90 minutes.

32. The method according to any one of claims 22 to 31, wherein the recovery step is carried out by filtering and drying the baroglutamstat hydrochloride crystals.

33. The method described above is i. Dissolve 1 equivalent of free baroglutamstat base in 5 volumes of acetone, and heat the solution to 45 ± 5°C. ii. Add 221 mg of water per 1 mmol of the free base from step i, and heat the solution to 45 ± 5°C. iii. A step of adding a solution containing 3 volumes of acetone and 0.95 equivalents of an aqueous HCl solution (32-37% w / w) to the solution in step ii. iv. The step of adding a seed crystal to the solution of step iii. v. A step of incubating the suspension resulting from step iii. and / or step iv. for a time suitable for forming baroglutamstat hydrochloride crystals, vi. A step of further adding 16 volumes of acetone and maintaining the suspension temperature at 45±5°C, vii. A step of cooling the suspension obtained in step vi to 20 ± 5°C, viiii. The step of stirring the suspension of step vii, ix. A step of recovering baroglutamstat hydrochloride crystals by filtration, x. The solid obtained by filtration in step ix is ​​rinsed with a 48:1.6 v / v acetone / water mixture. xi. The process of rinsing the solid from step x twice with pure acetone, xi. The process of drying the baroglutamstat hydrochloride crystals, The method according to any one of claims 22 to 32, including the method described in that claim.

34. A hydrochloride or polymorph of baloglutamstat according to any one of claims 1 to 21, obtained by the method described in any one of claims 22 to 33.

35. A pharmaceutical composition comprising a therapeutically effective amount of baloglutamstat hydrochloride or polymorph according to any one of claims 1 to 21 or 34, together with a pharmaceutically acceptable carrier, diluent, or excipient therefor.

36. The pharmaceutical composition according to claim 35, further comprising at least one compound selected from the group consisting of neuroprotective agents, antiparkinson's disease agents, amyloid protein deposition inhibitors, beta-amyloid synthesis inhibitors, antidepressants, anxiolytics, antipsychotics, antimultiple sclerosis agents, and monoclonal antibodies.

37. PEP inhibitors, LiCl, DP IV or DP IV-like enzyme inhibitors, acetylcholinesterase (ACE) inhibitors, PIMT enhancers, beta-secretase inhibitors, gamma-secretase inhibitors, neutral endopeptidase inhibitors, phosphodiesterase-4 (PDE-4) inhibitors, TNF-alpha inhibitors, muscarinic M1 receptor antagonists, NMDA receptor antagonists, sigma-1 receptor inhibitors, histamine H3 antagonists, immunomodulators, immunosuppressants, or antegrain (natalizumab), Neurelan (fampridine-SR), Campus (aremtuzumab), IR 208, NBI 5788 / MSP 771 (tiprimotide), paclitaxel, Anergix. The pharmaceutical composition according to claim 35 or 36, further comprising at least one compound selected from the group consisting of MS (AG 284), SH636, Differin (CD 271, adapalene), BAY 361677 (interleukin-4), matrix metalloproteinase inhibitors, interferon-tau (trophoblastin), SAIK-MS, and anti-beta-amyloid antibodies.

38. Baloglutamstat hydrochloride or polymorph or pharmaceutical composition according to any one of claims 1 to 21 and 34, for use in the treatment of a disease selected from the group consisting of neurodegenerative diseases, inflammatory diseases, infectious diseases, proliferative diseases and tumors, and kidney diseases.

39. The use of baloglutamstat hydrochloride or polymorph or pharmaceutical composition according to claim 38, wherein the neurodegenerative disease is mild cognitive impairment and / or Alzheimer's disease.

40. The inflammatory disease is psoriasis, rheumatoid arthritis, atherosclerosis, pancreatitis, restenosis, and multiple sclerosis, and the baloglutamstat hydrochloride or polymorph or pharmaceutical composition for use according to claim 38.

41. The use of baloglutamstat hydrochloride or polymorph or pharmaceutical composition according to claim 38, wherein the infectious disease is periodontitis.

42. The use of baloglutamstat hydrochloride or polymorph or pharmaceutical composition according to claim 38, wherein the tumor is a solid tumor and a hematological tumor.

43. The nephropathy is a disease condition selected from the group consisting of acute kidney disease (AKD) or chronic kidney disease (CKD), such as diabetic nephropathy, focal segmental glomerulosclerosis (FSGS), glomerulonephritis, polycystic kidney disease, membranous nephropathy, urinary tract obstruction, vesicoureteral reflux, nephrotic syndrome, recurrent renal infection (pyelonephritis), lupus, and other immune system disorders selected from the group consisting of polyarteritis nodosa, sarcoidosis, Goodpasture syndrome, and Henoch-Schönlein purpura, as described in claim 38.

44. The use of baloglutamstat hydrochloride or polymorph or pharmaceutical composition according to claim 38 or 43, wherein the renal disease is related to impaired glomerular filtration rate (GFR).

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