IP Library › Granted Patent US 12,378,219
Granted Patent B2
US 12,378,219 · App. 18/311,759 · Granted Aug 5, 2025

Crystalline forms of a MAGL inhibitor

Inventors: Thomas Vetter (Valby, DK); John J. M. Wiener (San Diego, CA); Cheryl A. Grice (Redwood City, CA); Daniel J. Buzard (San Diego, CA); Justin S. Cisar (San Diego, CA); Olivia Delene Weber (San Diego, CA); Amy Allan (San Diego, CA); Nicholas Raffaele (SanDiego, CA); Jeanne V. Moody (San Diego, CA); Michael B. Shaghafi (San Diego, CA)
Assignee: H. LUNDBECK A/S
C07D401/12A61K31/501A61P25/00C07B2200/13
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Quick Facts
Patent No.
US 12,378,219
App. No.
18/311,759
Granted
Aug 5, 2025
Kind
B2
Abstract

Described herein are crystalline forms of the MAGL inhibitor 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate.

Claims (9)

1. A crystalline form of 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate form 3, characterized by having an X-ray powder diffraction obtained using CuKα1 radiation (λ=1.5406 Å) comprising peaks at the following 2θ-angles: 6.61°, 9.16°, 13.09°, and 14.32°.

2. A solid dosage form comprising the crystalline form of claim 1 , and one or more pharmaceutically acceptable carriers or diluents.

3. The solid dosage form of claim 2 , wherein the solid dosage form is selected from capsules, tablets, dragées, pills, lozenges, powders or granules.

4. The solid dosage form of claim 2 , wherein the solid dosage form is a tablet.

5. The solid dosage form of claim 2 , wherein the dosage form contains the crystalline form of 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate form 3 in an amount from 0.1 to 200 mg.

6. The solid dosage form of claim 2 , wherein the dosage form contains the crystalline form of 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate form 3 in an amount from 1 to 40 mg.

7. The solid dosage form of claim 2 , wherein the dosage form contains the crystalline form of 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate form 3 in an amount from 1 to 30 mg.

8. The solid dosage form of claim 2 , wherein the dosage form contains the crystalline form of 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate form 3 in an amount from 1 to 20 mg.

9. A method for treating atopic dermatitis, bladder dysfunction associated with multiple sclerosis, contact dermatitis, dermatomyositis, eczema, enteritis, fibromyalgia, inflammatory bowel disease, interstitial cystitis, irritable bowel syndrome, ischemia, abdominal pain, abdominal pain associated with irritable bowel syndrome, acute pain, back pain, cancer pain, chest pain, functional chest pain, joint pain, menstrual pain, musculoskeletal diseases, peripheral neuropathy, migraine, visceral hypersensitivity osteoarthritis, pharyngitis, post mastectomy pain syndrome, post trigeminal neuralgia, post-operative pain, post-traumatic stress disorder, skeletal muscle contusion, skin diseases, sunburn, systemic lupus erythematosus, toothache, vasoocclusive painful crises in sickle cell disease, or visceral pain in a patient in need thereof; wherein the method comprises administering to the patient a therapeutically effective amount of the crystalline form of 1,1,1,3,3,3-Hexafluoropropan-2-yl(S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate form 3 of claim 3 .

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 22, 2023
From: WIENER, JOHN J.M.; GRICE, CHERYL A.; BUZARD, DANIEL J.; CISAR, JUSTIN S.; WEBER, OLIVIA DELENE; ALLAN, AMY; RAFFAELE, NICHOLAS; MOODY, JEANNE V.; SHAGHAFI, MICHAEL B.
To: LUNDBECK LA JOLLA RESEARCH CENTER, INC.
Reel/Frame 064035/0278 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 22, 2023
From: VETTER, THOMAS
To: H. LUNDBECK A/S
Reel/Frame 064035/0330 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 22, 2023
From: LUNDBECK LA JOLLA RESEARCH CENTER, INC.
To: H. LUNDBECK A/S
Reel/Frame 064035/0362 →
Continuity (2)
Provisional Application 63338252 · May 4, 2022
Related Publication 20230357190A1 · Nov 9, 2023
References Cited (81)
US 9133148B2 · Cisar et al. · 2015 [cited by applicant]
US 10030020B2 · Cisar et al. · 2018 [cited by applicant]
US 10781211B2 · Cisar et al. · 2020 [cited by applicant]
US 11059822B2 · Grice et al. · 2021 [cited by applicant]
US 11434222B2 · Wiener et al. · 2022 [cited by applicant]
US 11691975B2 · Grice et al. · 2023 [cited by applicant]
US 20110172230A1 · Ishii et al. · 2011 [cited by applicant]
US 20160137649A1 · Jones et al. · 2016 [cited by applicant]
US 20210230145A1 · Blankman et al. · 2021 [cited by applicant]
US 20240018120A1 · Wiener et al. · 2024 [cited by applicant]
CN 110267962A · 2019 [cited by applicant]
JP 2009514935A · 2009 [cited by applicant]
JP 2014005245A · 2014 [cited by applicant]
WO WO2010089510A2 · 2010 [cited by applicant]
WO WO2010141817A1 · 2010 [cited by applicant]
WO WO2011151808A1 · 2011 [cited by applicant]
WO WO2013103973A1 · 2013 [cited by applicant]
WO WO2014048865A1 · 2014 [cited by applicant]
WO WO2015003002A1 · 2015 [cited by applicant]
WO WO2015154023A1 · 2015 [cited by applicant]
WO WO2016149401A2 · 2016 [cited by applicant]
WO WO2017021805A1 · 2017 [cited by applicant]
WO WO2017171100A1 · 2017 [cited by applicant]
WO WO2017197192A1 · 2017 [cited by applicant]
WO WO2018093946A1 · 2018 [cited by applicant]
WO WO2018093947A1 · 2018 [cited by applicant]
WO WO2018093949A1 · 2018 [cited by applicant]
WO WO2018093950A1 · 2018 [cited by applicant]
WO WO2018093953A1 · 2018 [cited by applicant]
WO WO2018134698A1 · 2018 [cited by applicant]
WO WO2019046318A1 · 2019 [cited by applicant]
WO WO2019046330A1 · 2019 [cited by applicant]
WO WO2022101412A1 · 2022 [cited by applicant]
WO WO2022104079A1 · 2022 [cited by applicant]
Muller-Vahl et al., Pharmacopsychiatry, 55, 148-56 (Year: 2022). [cited by examiner]
Clinical Trial ID NCT05046119; accessed Nov. 26, 2024 from https://clinicaltrials.gov/search?term=MAGL (Year: 2021). [cited by examiner]
Clinical Trial ID NCT04324710; accessed Nov. 26, 2024 from https://clinicaltrials.gov/search?term=MAGL (Year: 2020). [cited by examiner]
Clinical Trial ID NCT03100136; accessed Nov. 26, 2024 from https://clinicaltrials.gov/search?term=MAGL (Year: 2017). [cited by examiner]
Clinical Trial ID NCT05219838; accessed Nov. 26, 2024 from https://clinicaltrials.gov/search?term=MAGL (Year: 2022). [cited by examiner]
Clinical Trial ID NCT04419636; accessed Nov. 26, 2024 from https://clinicaltrials.gov/search?term=MAGL (Year: 2021). [cited by examiner]
Conner, S., Glaxo chief: Our drugs do not work on most patients, The Independent (Year: 2003). [cited by examiner]
Granchi et al., Chapter 20 in Rational Drug Design: Methods and Protocols, Methods in Molecular Biology, Mavromoustakos and Kellici (eds), 335-46, 336 (Year: 2018). [cited by examiner]
Bedse et al. Therapeutic endocannabinoid augmentation for mood and anxiety disorders: comparative profiling of FAAH. Translational Psychiatry 8:92 (2018). [cited by applicant]
Ben-Ari et al. Electrographic, clinical and pathological alterations following systemic administration of kainic acid, bicuculline or pentetrazole: metabolic mapping using the deoxyglucose method with special reference … [cited by applicant]
Berge et al. Pharmaceutical Salts. Journal of Pharmaceutical Sciences 66(1):1-19 (Jan. 1977). [cited by applicant]
Blankman et al. A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chem. Biol. 14:1347-1356 (2007). [cited by applicant]
Collin et al. A double-blind, randomized, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis. Neurol Res 32(5):451-459 (2010). [cited by applicant]
Collin et al. Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. Eur J Neurol 14(3):290-296 (2007). [cited by applicant]
Fiz et al. Cannabis use in patients with fibromyalgia: effect on symptoms relief and health-related quality of life. PLoS One 6(4):e18440 (2011). [cited by applicant]
Fleisher et al. Improved oral drug delivery: solubility limitations overcome by the use of prodrugs. Advanced Drug Delivery Reviews 19:115-130 (1996). [cited by applicant]
Gil-Ordonez et al. Monoacylglycerol lipase (MAGL) as a promising therapeutic target. Biochem Pharmacol 157:18-32 (2018). [cited by applicant]
Grabner et al. Monoglyceride lipase as a drug target: At the crossroads of arachidonic acid metabolism and endocannabinoid signaling. Pharmacol Ther 175:35-46 (2017). [cited by applicant]
He et al. Determination of absolute configuration of chiral molecules using vibrational optical activity: a review. Appl. Spectrosc. 65(7):699-723 (2011). [cited by applicant]
Hill et al. Integrating Endocannabinoid Signaling and Cannabinoids into the Biology and Treatment of Posttraumatic Stress Disorder. Neuropsychopharmacology 43(1):80-102 (2018). [cited by applicant]
Hill. Medical Marijuana for Treatment of Chronic Pain and Other Medical and Psychiatric Problems: A Clinical Review. JAMA 313(24):2474-2483 (2015). [cited by applicant]
Ilyasov et al. The endocannabinoid system and oligodendrocytes in health and disease. Front Neurosci 12:733 (2018). [cited by applicant]
Kano et al. Endocannabinoid-mediated control of synaptic transmission. Physiol Rev 8:309-380 (2009). [cited by applicant]
Katona et al. Endocannabinoid signalling as a synaptic circuit breaker in neurological disease. Nat Med. 14(9):923-93 (2008). [cited by applicant]
Keith et al. Heteroarylureas with spirocyclic diamine cores as inhibitors of fatty acid amide hydrolase. Bioorg Med Chem Lett 24(3):737-41 (2014). [cited by applicant]
Langford et al. A double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients … [cited by applicant]
Long et al. Characterization of tunable piperidine and piperazine carbamates as inhibitors of endocannabinoid hydrolases. J Med chem 53(4):1830-1842 (2010). [cited by applicant]
Long et al. Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. Nat Chem Biol. 5(1):37-44 (2009). [cited by applicant]
Mease et al. A randomized, double-blind, placebo-controlled, phase III trial of pregabalin in the treatment of patients with fibromyalgia. J Rheumatol 35(3):502-514 (2008). [cited by applicant]
Mulvihill et al. Therapeutic potential of monoacylglycerol lipase inhibitors. Life Sci 92(8-9):492-497 (2013). [cited by applicant]
Niphakis et al. O-Hydroxyacetamide Carbamates as a Highly Potent and Selective Class of Endocannabinoid Hydrolase Inhibitors. ACS Chem. Neurosci. 3(5):418-426 (2012/Web2011). [cited by applicant]
Nomura et al. Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation. Science 334(6057):809-813 (2011). [cited by applicant]
PCT/EP2021/081522 International Search Report and Written Opinion dated Feb. 7, 2022. [cited by applicant]
Pryce et al. Endocannabinoids in Multiple Sclerosis and Amyotrophic Lateral Sclerosis. Handb Exp Pharmacol 231:213-31 (2015). [cited by applicant]
Pubchem, Substance Database, SID 239803465. Retrieved from Internet: <URL: https://pubchem.ncbi.nlm.nih.gov/substance/239803465> ( 7pgs.) (Available Date Feb. 13, 2015) (retrieved Jun. 27, 2017). [cited by applicant]
Rog et al. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology 65(6):812-819 (2005). [cited by applicant]
Sarchielli et al. Endocannabinoids in chronic migraine: CSF findings suggest a system failure. Neuropsychopharmacology 32(6):1384-1390 (2007). [cited by applicant]
Skrabek et al. Nabilone for the treatment of pain in fibromyalgia. J Pain 9(2):164-173 (2008). [cited by applicant]
Sugaya et al. Crucial Roles of the Endocannabinoid 2-Arachidonoylglycerol in the Suppression of Epileptic Seizures. Cell Rep 16(5):1405-1415 (2016). [cited by applicant]
Turcotte et al. Nabilone as an adjunctive to gabapentin for multiple sclerosis-induced neuropathic pain: a randomized controlled trial. Pain Med 16(1):149-159 (2015). [cited by applicant]
Turcotte et al. The CB2 receptor and its role as a regulator of inflammation. Cell. Mol. Life Sci. 73:4449-4470 (2016). [cited by applicant]
U.S. Appl. No. 17/524,632 Office Action dated Jan. 7, 2022. [cited by applicant]
Ware et al. The effects of nabilone on sleep in fibromyalgia: results of a randomized controlled trial. Anesth Analg 110(2):604-610 (2010). [cited by applicant]
Whiting et al. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA 313(24):2456-2473 (2015). [cited by applicant]
Zajicek et al. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet 362(9395):1517-1526 (2003). [cited by applicant]
Burckhardt et al. The fibromyalgia impact questionnaire: development and validation. J Rheumatol 18(5):728-733 (1991). [cited by applicant]
PCT/EP2023/061626 International Search Report and Written Opinion dated Jul. 6, 2023. [cited by applicant]