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EP-4426696-B1 - CRYSTALLINE FORMS OF A MONOACYLGLYCEROL LIPASE INHIBITOR

EP4426696B1EP 4426696 B1EP4426696 B1EP 4426696B1EP-4426696-B1

Inventors

  • ANDREW, Samuel George
  • BUZARD, DANIEL J.
  • ALLAN, AMY
  • GANCEDO, SUSANA DEL RIO
  • CINCOTTI, Antonio
  • PATTERSON, Adam Ross
  • EDWARDS, RICHARD JAMES
  • VETTER, THOMAS
  • JUHL, Martin
  • LOPEZ DE DIEGO, HEIDI
  • GRICE, CHERYL A.
  • WIENER, JOHN J.M.

Dates

Publication Date
20260506
Application Date
20221101

Claims (3)

  1. A crystalline form, wherein the crystalline form is 1-(1-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)-1,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazole-3-carboxylic acid form 1 having a crystal form characterized by an XRPD obtained using CuK α1 radiation (λ=1.5406 Å) showing peaks at the following 2Θ-angles: 8.60°, 10.72°, 11.12°, 14.17°, 15.30°, 19.08°, 22.70°, and 24.30°.
  2. A pharmaceutical composition comprising a crystalline form of 1-(1-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)-1,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazole-3-carboxylic acidaccording to claim 1 and one or more pharmaceutically acceptable carriers or diluents.
  3. The crystalline form of 1-(1-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)-1,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazole-3-carboxylic acid according to claim 1, for use in the treatment of a disease or disorder selected from atopic dermatitis, bladder dysfunction associated with multiple sclerosis, cardiovascular disease, contact dermatitis, cystic fibrosis, dermatomyositis, eczema, endometriosis, enteritis, fibromyalgia, inflammatory bowel disease, interstitial cystitis, irritable bowel syndrome, ischemia, labor, abdominal pain, abdominal pain associated with irritable bowel syndrome, acute pain, back pain, cancer pain, chest pain, functional chest pain, joint pain, menstrual pain, metabolic disorders, musculoskeletal diseases, peripheral neuropathy, migraine, visceral hypersensitivity osteoarthritis, pancreatitis, pharyngitis, post mastectomy pain syndrome, post trigeminal neuralgia, post-operative pain, renal ischemia, rheumatoid arthritis, skeletal muscle contusion, skin diseases, sunburn, systemic lupus erythematosus, toothache, vasoocclusive painful crises in sickle cell disease, and visceral pain.

Description

FIELD OF THE INVENTION The present invention relates to solid forms of 1-(1-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)-1,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazole-3-carboxylic acid, pharmaceutical compositions comprising such solid forms and methods and uses for treating various disorders that would benefit from inhibition of monoacylglycerol lipase (MAGL). BACKGROUND OF THE INVENTION MAGL is a member of the serine hydrolase superfamily. MAGL is expressed throughout the brain, in neurons, microglia, astrocytes, and oligodendrocytes. MAGL is the primary enzyme controlling the degradation of 2-arachidonoylglycerol (2-AG) to arachidonic acid (AA) (Blankman et al. Chem Biol. 2007; Nomura et al. Science. 2011). 2-AG is the most abundant endocannabinoid ligand in the brain where it acts as a retrograde messenger to reduce excessive neurotransmission via the activation of pre-synaptic CB1 receptors (Katona et al., Nat Med. 2008 Sep;14(9):923-30), regulating immune response via the activation of microglial CB2 receptors (Turcotte et al. Cell Mol Life Sci. 2016 Dec;73(23):4449-4470), and promote neuroprotection via e.g., its effects on oligodendrocyte production and survival (Front Neurosci. 2018 Oct 26;12:733). AA is one of the most abundant fatty acids in the brain and the main precursor of eicosanoids such as prostanoids and leukotrienes that are known inflammatory mediators. MAGL is at the crossroads between the endocannabinoid and eicosanoid signaling systems. Inhibiting the action or activation of MAGL is a promising therapeutic approach for the prevention or treatment of brain disorders whose pathological hallmarks include excessive neurotransmission, neuroinflammation or neurodegeneration such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), traumatic brain injury, stroke, epilepsy, pain, migraine, addiction, anxiety, depression and other stress-related disorders (Grabner et al. Pharmacol Ther. 2017 Jul;175:35-46; Mulvihill et al. Life Sci. 2013 Mar 19;92(8-9):492-7; Gil-Ordóñez et al. Biochem Pharmacol. 2018 Nov;157:18-32). WO 2018/217805 discloses 1-(1-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)-1,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazole-3-carboxylic acid as an example of a compound which is a MAGL inhibitor promising for treating disorders, wherein MAGL inhibition may be beneficial. The development of a pharmaceutical compound is highly complex, because it is not possible to predict from previous experience if various solid forms of a compound exist, let alone how to make them. Even after a solid form has been manufactured, the identification and selection of a solid form for further pharmaceutical development are complex, given that a change in a solid form may affect a variety of physical and chemical abilities which are unpredictable and may provide benefits or drawbacks in areas of pharmaceutical development such as processing, formulation, stability, bioavailability, or storage. From this background it is still not possible to predict whether a particular compound or salt of a compound will form polymorphs, whether any such polymorphs will be suitable for commercial use in a therapeutic composition or which polymorphs will display such desirable properties. Hence, there is still an unmet process for making solid forms with desirable properties for further pharmaceutical development. SUMMARY OF THE INVENTION An object of the invention is to provide a solid form of 1-(1-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)-1,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazole-3-carboxylic acid (Compound (I)) suitable for pharmaceutical development. Accordingly in a first aspect of the invention is provided a crystalline form, wherein the crystalline form is 1-(1-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)-1,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazole-3-carboxylic acid form 1 having a crystal form characterized by an XRPD obtained using CuKα1 radiation (λ=1.5406 Å) showing peaks at the following 2Θ-angles: 8.60°, 10.72°, 11.12°, 14.17°, 15.30°, 19.08°, 22.70°, and 24.30°. In a further aspect is provided a pharmaceutical composition comprising a crystalline form of 1-(1-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)-1,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazole-3-carboxylic acid form 1 according to the invention and one or more pharmaceutically acceptable carriers or diluents. In a further aspect is provided a crystalline form of 1-(1-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)-1,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazole-3-carboxylic acid form 1 according to the invention for use in the treatment of a disease or disorder selected from atopic dermatitis, bladder dysfunction associated with multiple sclerosis, cardiovascular disease, contact dermatitis, cystic fibrosis, dermatomyositis, eczema, endometriosis, enteritis, fibromyalgia, inflammatory bowel disease, interstitial cyst