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US-12617776-B2 - Stable salt and crystal forms of 2-[3-({1-[2-(dimethylamino)ethyl]-2-(2,2-dimethylpropyl)-1H-1,3-benzodiazol-5-yl}sulfonyl)azetidin-1-yl]ethan-1-ol

US12617776B2US 12617776 B2US12617776 B2US 12617776B2US-12617776-B2

Abstract

A salt of 2-[3-({1-[2-(dimethylamino)ethyl]-2-(2,2-dimethylpropyl)-1H-1,3-benzodiazol-5-yl}sulfonyl)azetidin-1-yl]ethan-1-ol with an acid, wherein the acid is selected from the group consisting of hydrochloric acid (HCl), maleic acid, and methanesulfonic acid; a crystalline form of the salt; a pharmaceutical composition comprising the salt; a pharmaceutical composition comprising the crystalline form; a method for preventing or treating a disorder or condition comprising administering the salt; and a process for preparing a pharmaceutically acceptable salt.

Inventors

  • YUKARI INAMI
  • Yoshiyuki Okumura
  • Tracy WALKER

Assignees

  • ASKAT INC.

Dates

Publication Date
20260505
Application Date
20240305

Claims (16)

  1. 1 . A crystalline form of a salt of 2-[3-({1-[2-(dimethylamino)ethyl]-2-(2,2-dimethylpropyl)-1H-1,3-benzodiazol-5-yl}sulfonyl)azetidin-1-yl]ethan-1-ol with an acid, wherein the acid is selected from the group consisting of hydrochloric acid (HCl), maleic acid, and methanesulfonic acid.
  2. 2 . The crystalline form of the salt according to claim 1 , wherein the acid is HCl.
  3. 3 . The crystalline form of the salt according to claim 1 , wherein the salt is a maleic acid salt having a melting endotherm at onset 153° C. in thermogravimetry/differential thermal analysis (TG/DTA).
  4. 4 . The crystalline form of the salt according to claim 1 , wherein the salt is a methanesulfonic acid salt having a melting endotherm at onset 155° C. in thermogravimetry/differential thermal analysis (TG/DTA).
  5. 5 . A crystalline form of an HCl salt of 2-[3-({1-[2-(dimethylamino)ethyl]-2-(2,2-dimethylpropyl)-1H-1,3-benzodiazol-5-yl}sulfonyl)azetidin-1-yl]ethan-1-ol, wherein the crystalline form is characterized by a powder X-ray diffraction (XRPD) pattern comprising peaks in terms of 2-Theta, at 5.6, 6.7, 16.6, 17.1, 18.8, 19.9, 24.0, 25.9, and 26.8 degrees 2-Theta+/−0.2 degrees 2-Theta for each value.
  6. 6 . The crystalline form of the HCl salt of 2-[3-({1-[2-(dimethylamino)ethyl]-2-(2,2-dimethylpropyl)-1H-1,3-benzodiazol-5-yl}sulfonyl)azetidin-1-yl]ethan-1-ol according to claim 5 , wherein the crystalline form is characterized by an XRPD pattern coinciding with the pattern shown by FIG. 7 .
  7. 7 . A crystalline form of an HCl salt of 2-[3-({1-[2-(dimethylamino)ethyl]-2-(2,2-dimethylpropyl)-1H-1,3-benzodiazol-5-yl}sulfonyl)azetidin-1-yl]ethan-1-ol, wherein the crystalline form is characterized by a powder X-ray diffraction (XRPD) pattern comprising peaks in terms of 2-Theta, at 6.2, 7.0, 8.2, 16.6, 18.6, 19.3, 19.8, 20.4, 23.3, 24.4, and 24.7 degrees 2-Theta+/−0.2 degrees 2-Theta for each value.
  8. 8 . The crystalline form of the HCl salt of 2-[3-({1-[2-(dimethylamino)ethyl]-2-(2,2-dimethylpropyl)-1H-1,3-benzodiazol-5-yl}sulfonyl)azetidin-1-yl]ethan-1-ol according to claim 7 , wherein the crystalline form is characterized by an XRPD pattern coinciding with the pattern shown by FIG. 8 .
  9. 9 . A crystalline form of a maleic acid salt of 2-[3-({1-[2-(dimethylamino)ethyl]-2-(2,2-dimethylpropyl)-1H-1,3-benzodiazol-5-yl}sulfonyl)azetidin-1-yl]ethan-1-ol, wherein the crystalline form is characterized by an XRPD pattern coinciding with the pattern shown by FIG. 52 .
  10. 10 . A crystalline form of a methanesulfonic acid salt of 2-[3-({1-[2-(dimethylamino)ethyl]-2-(2,2-dimethylpropyl)-1H-1,3-benzodiazol-5-yl}sulfonyl)azetidin-1-yl]ethan-1-ol, wherein the crystalline form is characterized by an XRPD pattern coinciding with the pattern shown by FIG. 55 .
  11. 11 . A pharmaceutical composition comprising the crystalline form of the salt according to claim 1 .
  12. 12 . A method for preventing or treating a disorder or condition selected from the group consisting of pain, inflammatory pain, nociceptive pain, neuropathic pain, fibromyalgia, chronic pain, visceral pain, migraine, cluster headache, cancer related pain, complex regional pain syndrome, neuralgias, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, epilepsy, diabetes neuropathy, human immunodeficiency virus (HIV), polyneuropathy, a psychiatric disease, psychosis, autistic spectrum disorder, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, gastroesophageal reflux disease (GERD), constipation, diarrhoea, functional gastrointestinal disorder, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, psoriatic arthritis disease, spondylitides, asthma, allergy, psoriasis, dermatitis, seasonal allergic rhinitis, systemic lupus erythematosus (SLE), acute allograft rejection, gingivitis, encephalitis, cutaneous T cell lymphoma, pancreatic cancer, systemic fibrosis, systemic sclerosis (SSc), vasculitis liver fibrosis, lung fibrosis, kidney fibrosis, keloids, hypertrophic scars, acute respiratory distress syndrome (ARDS), reversible airway obstruction, adult respiratory disease syndrome, chronic obstructive pulmonary disease (COPD), cryptogenic fibrosing alveolitis, bronchitis, glaucoma, age-related macular degeneration (AMD), geographic atrophy, diabetic retinopathy, uveitis, retinal vein occlusion, retinopathy of prematurity, ocular ischemic syndrome, glomerulonephritis, renal ischemia, nephritis, diabetic nephropathy, chronic allograft nephropathy, hepatitis, acute liver failure, liver cirrhosis, non-alcoholic steatohepatitis (NASH), myocardial infarction, cerebral ischemia, ischemia-reperfusion injury, heart failure, stroke, myocardial ischemia, cardiomyopathy, transient ischemic attack, diabetes, osteoporosis, regulation of bone mass, non-alcoholic fatty liver (NAFL), attention-deficit hyperactivity disorder (ADHD), anxiety, depression, insomnia/sleep disorder, obsessive compulsive disorder (OCD), post-traumatic stress disorder (PTSD), Tourette's syndrome, malaria, and pyrexia, the method comprising administering to a subject suffering from the disease or condition an affective amount of the crystalline form of the salt according to claim 1 .
  13. 13 . The method according to claim 12 , wherein the disease or condition is selected from the group consisting of pain, inflammation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) and colitis.
  14. 14 . The method according to claim 12 , wherein the neuralgia is trigeminal neuralgia.
  15. 15 . A process for preparing a crystalline form of a pharmaceutically acceptable HCl, maleic acid or methanesulfonic acid salt of 2-[3-({1-[2-(dimethylamino)ethyl]-2-(2,2-dimethylpropyl)-1H-1,3-benzodiazol-5-yl}sulfonyl)azetidin-1-yl]ethan-1-ol, comprising dissolving 2-[3-({1-[2-(dimethylamino)ethyl]-2-(2,2-dimethylpropyl)-1H-1,3-benzodiazol-5-yl}sulfonyl)azetidin-1-yl]ethan-1-ol in a solvent.
  16. 16 . The process according to claim 15 , wherein the solvent is at least one selected from the group consisting of acetone, acetonitrile, 1-butanol, cyclohexane, dichloromethane, diisopropyl ether, dimethylacetamide, dimethyl sulfoxide, dioxane, ethanol, ethyl acetate, heptane, isopropyl acetate, methyl tert-butyl ether, methyl ethyl ketone, methyl isobutyl ketone, methanol, 2-propanol, toluene, tetrahydrofuran, water, and the mixture of the solvents thereof.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 18/035,195 filed May 3, 2023, which is a national stage entry under 35 U.S.C. § 371 of international application no. PCT/JP2021/041552 filed Nov. 11, 2021, which claims the benefit of U.S. Provisional Application No. 63/112,893 filed Nov. 12, 2020, each of which is incorporated by reference herein in its entirety. TECHNICAL FIELD This invention relates to novel salts and crystal forms of 2-[3-({1-[2-(dimethylamino)ethyl]-2-(2,2-dimethylpropyl)-1H-1,3-benzodiazol-5-yl}sulfonyl)azetidin-1-yl]ethan-1-ol, which is a selective CB2 receptor agonist, wherein the compound may be called Compound A through the present specification. BACKGROUND ART Classical cannabinoids such as the marijuana derived cannabinoid (CB) delta9-tetrahydro-cannabinol, (delta9-THC) produce their pharmacological effects via interaction with specific cannabinoid receptors in the body. The cannabinoid receptors are members of the endocannabinoid system and are involved in a variety of physiological processes including appetite, pain-sensation, mood, and memory ({NPL 1} Goutopoulos A. et al., Pharmacol. Ther. 2002, 95:103-117; {NPL 2} Wright, K. L. et al., Br. J. Pharmacol. 2008, 153:263-270; and {NPL 3} Aizpurua-Olaizola, O. et al., Drug Discovery Today 2017, 22:105-110), as well playing an important role in the regulation of inflammatory and immune-responses ({NPL 4} Tanaka M. et al., Front. Neurol. 2020, 11:87). These receptors belong to the rhodopsin family of G protein-coupled receptors (GPCRs). There are currently two known subtypes, termed Cannabinoid Receptor 1 (CB1) and Cannabinoid Receptor 2 (CB2) ({NPL 5} Matsuda, L. A. et al., Nature 1990, 346:561-564; Gerard, C. M. et al., Biochem. J. 1991, 279:129-134). CB1 is expressed most abundantly in the neurons of the central nervous system (CNS), but is also present at lower concentrations in a variety of peripheral tissues and cells ({NPL 5}). In contrast, CB2 is expressed predominantly, although not exclusively, in non-neural tissues, e.g. in hematopoietic cells, endothelial cells, osteoblasts, osteoclasts, the endocrine pancreas, and cancerous cell lines ({NPL 6} Munro, S. et al., Nature 1993, 365:61-65 and {NPL 7} Pacher, P. et al., Pharmacol. Rev. 2006, 58:389-462). CB2 is also widely distributed in the brain where it is found primarily on microglia and not neurons ({NPL 8} Cabral, G. A. et al., Br. J. Pharmacol. 2008, 153:240-51). As such, CB1 is believed to be primarily responsible for mediating the psychotropic effects of cannabinoids on the body, whereas CB2 is unrelated to cannabinoid psychoactivity and believed to be primarily responsible for most of their non-neural effects represented by cannabinoid-induced immune modulation ({NPL 9} Howlett, A. C. et al., Pharmacol. Rev. 2002, 54:161-202; and {NPL 10} Chung, Y. C. et al., Exp. Mol. Med. 2016, 48: e205). There is a considerable interest in the development of selective CB2 receptor agonists since it is believed high selectivity for CB2 may offer avenues for harnessing the beneficial effect of CB receptor agonists while avoiding the central adverse events seen with cannabinoid structures ({NPL 11} Expert Opin. Investig. Drugs 2007, 16:951-965). In general, CB2 receptor agonists could be beneficial for the treatment of a variety of indications in different therapeutic areas including chronic and acute pain (e.g. inflammatory pain, nociceptive pain, neuropathic pain, fibromyalgia, chronic low back pain, visceral pain, complex regional pain syndrome, neuralgias); immunological and inflammatory disorders also with a pain component (e.g. arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, Crohn's disease, ulcerative colitis, asthma, allergy, psoriasis, dermatitis, seasonal allergic rhinitis, systemic lupus erythematosus); gastrointestinal disorders, including irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD), constipation, diarrhea, functional gastrointestinal disorder), oncology (e.g. cutaneous T cell lymphoma, pancreatic cancer); neurodegenerative disorders, such as multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis; fibrotic disorders of heterogeneous aethiology (systemic fibrosis, systemic sclerosis vasculitis liver fibrosis, lung fibrosis, kidney fibrosis); lung disorders (e.g. acute respiratory distress syndrome (ARDS), reversible airway obstruction, adult respiratory disease syndrome, chronic obstructive pulmonary disease or COPD), and many metabolic and multi-aethiology disorders including diabetes, glaucoma, age-related macular degeneration, diabetic retinopathy, uveitis, retinal vein occlusion, retinopathy of prematurity, ocular ischemic syndrome, geographic atrophy, osteoporosis, regulation of bone mass, glomerulonephritis, renal ischemia, nephritis, hepatitis, acute liver failure, chronic allograft nephropathy, diabetic nephropathy, liver cirrhos