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KR-102961392-B1 - Solid form of N-TERT-butyl-4[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

KR102961392B1KR 102961392 B1KR102961392 B1KR 102961392B1KR-102961392-B1

Abstract

The present invention relates to a novel form of N-tert-butyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 1). In particular, the present invention relates to crystalline polymorphs of forms A and B and amorphous forms.

Inventors

  • 콜링우드, 스테판
  • 멜링, 로베르트

Assignees

  • 티엠이엠16에이 리미티드

Dates

Publication Date
20260508
Application Date
20200724
Priority Date
20190725

Claims (20)

  1. Crystal of a compound (Compound 1) of N-tert-butyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide having the following structural formula, in the form of a crystalline polymorph of type A, characterized by an XRPD diffraction pattern including a main peak at 7.25 (± 0.2 °, 2-theta value) and at least three peaks at positions 14.44, 20.42, 21.68, 24.38, 27.21, 29.01, 30.82, 36.46 and 41.49 (± 0.2 °, 2-theta value): .
  2. A crystal according to claim 1, characterized by an XRPD diffraction pattern comprising a main peak at 7.25 (± 0.2 °, 2-theta value) and at least three peaks at positions 10.20, 14.44, 17.79, 20.42, 20.69, 21.68, 24.22, 24.38, 26.13, 27.21, 29.01, 30.82, 36.46 and 41.49 (± 0.2 °, 2-theta value).
  3. A crystal according to claim 1 or 2, characterized by an XRPD diffraction pattern comprising a main peak at 7.25 (± 0.2 degrees, 2-theta value) and at least three peaks at positions 10.20, 14.44, 16.13, 17.79, 20.42, 20.69, 21.07, 21.68, 24.09, 24.22, 24.38, 26.13, 27.21, 29.01, 29.30, 30.82, 32.50, 36.46 and 41.49 (± 0.2 degrees, 2-theta value).
  4. A determination according to claim 1 or 2, wherein the XRPD diffraction pattern comprises a cluster of peaks at positions 21.68 and 29.01 (± 0.2 degrees, 2-theta value) and peaks at 24.09, 24.22 and 24.3801 (± 0.2 degrees, 2-theta value).
  5. In paragraph 1 or 2, a refined crystal.
  6. A process for manufacturing a crystal according to claim 1 or 2, comprising crystallizing compound 1 from a solvent selected from acetone, butanol, ethanol, ethyl formate, isopropyl acetate, ethyl acetate, methyl acetate, nitromethane, 2-propanol, propionitrile, and acetonitrile.
  7. In paragraph 6, a process comprising the following steps: i. A step of preparing a saturated solution of compound 1 in a solvent at a temperature of 50 to 70°C; ii. A step of cooling the solution to a temperature of 5 to 20°C; iii. A step of leaving the cooled solution to stand until crystals of Compound 1 are formed; and iv. Step of isolating the crystallized product; Here, the solvent is selected from acetone, butanol, ethanol, ethyl formate, isopropyl acetate, ethyl acetate, methyl acetate, nitromethane, 2-propanol, propionitrile, and acetonitrile.
  8. In claim 6, the solvent is selected from acetonitrile, ethanol, ethyl acetate, methyl acetate, butanol, 2-propanol, or isopropyl acetate.
  9. Crystal of a compound (Compound 1) of N-tert-butyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide having the following structural formula, in the form of a solid crystalline polymorph of form B hydrate, characterized by an XRPD diffraction pattern comprising a main peak at position 11.03 (± 0.4 °, 2-theta value) and at least three peaks at positions 5.56, 14.04, 17.28, 18.03, 18.86, 22.08, 23.69, 24.12 and 24.93 (± 0.4 °, 2-theta value): .
  10. A crystal according to claim 9, characterized by an XRPD diffraction pattern comprising a main peak at position 11.03 (± 0.4 degrees, 2-theta value) and at least three peaks at positions 5.56, 14.04, 17.28, 18.03, 18.86, 19.34, 22.08, 23.69, 24.12, 24.93, 25.98, 26.53, 27.28 and 28.79 (± 0.4 degrees, 2-theta value).
  11. A crystal according to claim 9 or 10 having an XRPD diffraction pattern including peaks at positions 5.56 and 22.08 (± 0.4 degrees, 2-theta value).
  12. In paragraph 9 or 10, the refined crystal.
  13. A crystal characterized in that, in claim 9 or 10, the form B polymorph is a form B(I) pseudopolymorph and undergoes unimodal dehydration.
  14. A process for manufacturing a crystal according to claim 9 or 10, comprising crystallizing compound 1 from an aqueous solvent.
  15. In paragraph 14, the process in which the aqueous solvent is water or water mixed with acetonitrile.
  16. In Clause 14, a process comprising the following steps: i. A step of preparing a saturated solution of compound 1 in a solvent at a temperature of 60 to 80°C; ii. A step of cooling the solution to a temperature of 5 to 20°C; iii. A step of leaving the cooled solution to stand until crystals of Compound 1 are formed; and iv. Step of isolating the crystallized product; Here, the solvent is an aqueous solvent.
  17. In paragraph 16, the process in which the aqueous solvent is water or water mixed with acetonitrile.
  18. A process according to claim 17, wherein the aqueous solvent is water mixed with acetonitrile in an acetonitrile/water ratio of 5:1 to 1:5 v/v.
  19. delete
  20. delete

Description

Solid form of N-TERT-butyl-4[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide The present invention relates to a novel form comprising a crystalline form of a compound having activity as a positive regulator of TMEM16A, a calcium-activated chloride channel (CaCC). The present invention also relates to a method for preparing a novel form and a pharmaceutical composition containing the same, and to the use of the same in the treatment of diseases and conditions in which TMEM16A plays a role, particularly respiratory diseases and conditions. Humans can inhale up to 12,000 liters of air daily, and there is a possibility that airborne pathogens (such as bacteria, viruses, and fungal spores) could enter the airways. To protect against these airborne pathogens, the lungs have evolved innate defense mechanisms to minimize the potential for infection and colonization in the airways. One such mechanism is the mucus clearance system, in which secreted mucus is propelled out of the airways by the coordinated beating of cilia, accompanied by coughing. This continuous lung 'clearing' continuously removes inhaled particles and microorganisms, thereby reducing the risk of infection. In recent years, it has become evident that the hydration of the mucous gel is crucial for enabling mucus clearance (Boucher 2007; Matsui et al, 1998). In normal, healthy airways, the mucous gel is typically 97% water and 3% w/v solid, and under these conditions, mucus is cleared by mucociliary action. The hydration of the airway mucosa is regulated by the coordinated activity of numerous ion channels and transporters. The balance between the secretion of anions ( Cl⁻ / HCO₃⁻ ), mediated by the Cystic Fibrosis Transmembrane Conductivity Regulator (CFTR) and Calcium-Activated Chloride Conductivity (CaCC; TMEM16A) , and the absorption of Na⁺ via epithelial Na⁺ channels (ENaC) determines the hydration status of the airway mucosa. As ions are transported across the epithelium, water must follow osmotically, resulting in either secretion or absorption of fluid. In respiratory diseases such as chronic bronchitis and cystic fibrosis, the solid percentage of mucus gel increases as hydration and mucus clearance decrease (Boucher, 2007). In cystic fibrosis, if loss-of-function mutations in CFTR impair the airways' ability to secrete fluid, the solid percentage can increase to 15%, which is thought to contribute to small airway obstruction and failure of mucus clearance. Strategies to increase the hydration of airway mucus include stimulating anion secretion to secrete fluid or inhibiting Na + absorption. To this end, stimulating the activity of the TMEM16A channel increases anion secretion, leading to increased fluid accumulation in the airway mucosa, increased mucus hydration, and improved mucus clearance mechanisms. TMEM16A, also referred to as Anoctamin-1 (Ano1), is the molecular identity of a calcium-activated chloride channel (Caputo et al, 2008; Yang et al , 2008). TMEM16A channels open in response to elevated intracellular calcium levels and allow bidirectional flux of chloride, bicarbonate, and other anions across the cell membrane. Functionally, TMEM16A channels have been proposed to regulate transepithelial ion transport, gastrointestinal motility, nociception, and cell migration/proliferation (Pedemonte & Galietta, 2014). TMEM16A channels are expressed by epithelial cells in various organs, including the lungs, liver, kidneys, pancreas, and salivary glands. In airway epithelium, TMEM16A is expressed at high levels in mucus-producing goblet cells, ciliated cells, and submucosal glands. Physiologically, TMEM16A is activated by stimuli that mobilize intracellular calcium, particularly purine agonists (ATP, UTP), and is released by respiratory epithelium in response to periodic shear stress caused by mechanical stimuli such as breathing and coughing. In addition to increased anion secretion that leads to enhanced hydration of the airways, TMEM16A activation plays a significant role in bicarbonate secretion. Bicarbonate secretion is reported to be an important regulator of mucus properties and airway lumen pH, and consequently, the regulation of the activity of natural antimicrobial agents such as defensins (Pezzulo et al ., 2012). Indirect modulation of TMEM16A through the elevation of intracellular calcium has been clinically explored, for example, with denufosol (Kunzelmann & Mall, 2003). While encouraging initial results were observed in small patient cohorts, this approach did not provide clinical benefits in large patient cohorts (Accurso et al 2011; Kellerman et al 2008). This lack of clinical effect was attributed merely to unwanted intracellular calcium elevation effects, such as transient increases in anion secretion resulting from the short half-life of denufosol at the epithelial surface and receptor/pathway desensitization, as well as increased mucus release from goblet cells (Moss, 2013). Compounds acting directly on